Hematologic Disorders

jeffrey R. suchard

haemostatic disorder(7.1)
Michael W. ardagh
lymphomas(7.2)
jeanne M.basior
pancytopenia(7.3); red blood cell disorders(7.4)
anthony J. billittier IV, robert F. reardon,and Douglas R. migden
transfusion (7.5)
thomas nowicki and marc borenstein
white blood cell discorders (7.6)
_________________________________________________________
HEMOSTATIC DISCORDER(7.1)(see 13.4)

Homeostasis involves a complex interactions of psychology process that

result in the arrest of blood flow from or within a blood vessels. A brief of
normal homeostasis is necessary before discussion of the disease states. When a
blood vessels is damage, tissue factor, collagens, and other components of the
sub endothelial matrix are exposed. Platelets then aggregate at the site of injury
by direct adhesion and by the mediation of von Willebrand’s factory (vWF).
Platelets and fibrinogen from a soluble occlusive plug that provides phosholiqid
surfaces for the reaction of the coagulation cascade (Fig.7-1). Tissue factor also
activates the extrinsic cuagulation pathway. Intrinsic pathway protein become
activated by factory VII, thrombin, or by surface contact factory. Both the
intrinsic and extrinsic pathway activate factory X, which converts prothrombin
to thrombin. Thrombin in turn cleaves fibrinogen to fibrin, which from an
insoluble Clot. Fibrin in then cross-linked, and the haemostatic plug gets
anchored into place via clot retraction. Modulating proteins limit extension of
the clot by thrombin inhibition and inactivation of clotting factor. Eventually,
the clot is lysed by plasmin once the vessel is sufficiently healed.
Laboratory tests frequently used to evaluate homeostasis discorders
are the hematocrit, platelets count, prothrombin time (PT), partial
thromboplastin time (PTT), sometime also called the activated partial
thromboplastin time (aPTT), reflects coagulation factor deficiencies of the
intrinsic and common pathways. This test measures the clotting time of citrated
plasma combined with calcium, surface contact activators ( kaolin, celite,
ellagic acid), and phospholipid (the “partial” thromboplastin). The PT is a
measure of the extrinsic and common pathways. This tests adds calcium and
brain tissue thromboplastin to citrated plasma, activating factory VII.
 Uncontrolled bleeding is a common presenting complaint to the emergency
department (ED). Most case are traumatic and treatment is straightforward,
though not necessarily easy. When bleeding is a result of impaired hemostasis
mechanisms, however, specific therapy directed against the pathophysiology is
often needed Most problems are caused by deficiencies or abnormalities in
clotting factors or platelets. Although specific therapy is intellectually
gratifying, no patient should suffer for lack of general supportive measures. All
patients with significant bleeding require immediate stabilization with airway
management ( if necessary), direct pressure,
FIG.7-1. Coagulation and fibrinolytic pathways after tissue injury.PL,
phospholipid;a,activated factory.
(From Rosenthal DS. Hematologic oncologic discorders and heart disease. In:
Braunwaid EB, ed. Heart disease, Philadelphia: Saunders, 1980: 1793).
Venous assess, and infusion of crystalloid solution. Packed red blood cell
(PRBC) transfusion is directed by clinical status, presence and rate of continued
hemorrhage, and the hematocrit
Clotting Factor Discorders (7.1.1)
Hereditary
The hemophilias (7.1.1.1)
Hemophilia A. Classic hemophilia (hemophilia A) is an X- Linked
recessive bleeding discorder occurring in approximately 1 in 10,000 live male
births. Hemophilia A is not single genetic disease, but rather a heterogeneous
set of discorders all leading to abnormal production of factor VIII
(antihemophilic factor),a coenzyme in the intrinsic pathway of the clotting
cascade. One-third of cases are due to spontaneous mutations in the gene
encoding factor VIII, so the absence of a family history does not rule out
Hemophilia.
 Clinically apparent disease only occurs when factor VIII activity is
severely reduced. Mild forms of Hemophilia have 5% to 25% of normal
activity, moderate disease between 1% to 5% , and severe disease with less than
1% of normal. Episodes of spontaneous bleeding are most common in severe
Hemophilia, while mild forms may only be recognized after significant trauma
or surgery.
The hallmarks of Hemophilia are easy bruising, joint and music
hemorrhages, and profuse posttraumatic/ postsurgical bleeding. Minor cuts and
abrasion are not typically associated with excessive bleeding. The platelet count
and PT are normal, but the PTT is prolonged. Specific clotting factor assays
show decreased factor VIII activity, whereas factor IX is affected in the less
common Hemophilia B. Factor VIII circulates in a noncovalent complex with
von Willebrand’s factor, a protein that protects it from proteolysis and
concentrates it at sites of active hemostasis. Von Willebrand’s disease,
therefore, indirectly cause a functional factor VIII deficiency in addition to a
platelet- type bleeding discorder.
About 90% of all bleeding in Hemophilia is joints or muscle.
Hemarthrosis is the most common acute presentation. The knee is affected in
over 50% of cases, but all large extremely joints are at risk. Hemarthrosis is
often heralded by a peculiar tingling sensation and warmth, before painful joint
capsule distention ensues. Some Hemophiliacs develop “target joints” that
undergo a vicious cycle of rebleeding. During resorption of blood, hemosiderin
is deposited leading to inflammation and synovial vascular proliferation, which
in turn increase risk for future hemorrhage. This process ultimately causes a
Hemophiliac arthropathy with erosion of cartilage and bone, and severe
limitation in range of motion Early treatment of hemarthrosis is crucial to
relieve pain and to reduce complications. Factor replacement is indicated for all
joint bleeding, even if objective findings are absent but the patient report typing
symptoms of their bleeding . If treatment is initiated later, ice packs,
compressive elastic dressings, or splinting may be necessary. Hemarthrosis also
requires a hematology consultation to evaluate for admission, since treatment
may take several days. Septic arthritis should also be considered in acutely
painful joints, since Hemophiliacs are at increased risks for joint infection.
Aspiration for diagnostic studies is indicated if the patient is febrile, exhibits
systemic toxicity, or has joint pain that is Unresponsive to factor replacement
therapy.
Intramuscular hemorrhage is the next most common site of spontaneous
bleeding in Hemophilia. The extent of damage and the danger to the patient is
dependent on amount of blood and the site of bleeding. IM bleeding into fascial
compartments puts the patient at risk for neurologic and vascular compromise,
while bleeding in the tougue, pharynx,and neck can obstruct the airway. Most
IM bleeds are easily recognized from the patient’s complaint of pain, localized
tenderness, and swelling. Hemorrhage into the iliopsoas muscles is more
difficult to detect. Typical symptoms include groin pain, flexion of the hip,
passive resistance to extension, and paresthesias from femoral nerve
compression. Diagnosis is confirmed by ultrasound or computed tomography (
CT) scan. Treatment of intramuscular hemorrhage , again, is factor replacement,
splint immobilization , and hematology consultation to evaluate for admission.
Intracranial hemorrhage (ICH) is a dreaded complication of Hemophilia
that uses to be leading cause of death in Hemophiliacs in the pre-AIDS era.
Death occurs in roughly one-third of patients, while half suffer from long-term
neurologic sequelae. In children, ICH is almost always posttraumatic. In adults,
half of cases occur without any know antecedent trauma. Treatment must be
initiated prior to confirmatory head CT in any Hemophiliac with history of head
trauma ( even in the absence of laceration, external contusions, or neurologic
signs) or severe headache lasting longer than 4 hours. Similarly, any acute
headache in a patient with Hemophilia mandates a CT scan. Intraspinal
hemorrhage may also occur and is characterized by backache with or without
immediate neurologic deficits. Treatment is the same: factor replacement to
100% of normal activity, neurosurgical consultation, and confirmatory
radiologic studies if the patient’s condition permits.
Hematuria occurs frequently in Hemophilia and is usually benign.
Once trauma, glomerulonephritis, and renal calculi are rules out, the patient can
be treated conservatively with increased fluide intake. The hematuria should
resolve in a few days. Some authors recommend a short course of oral steroids,
since the proposed mechanism of most episodes of antibody complex
deposition, but the benefits is unproven. If any specific therapy is given, avoid
antifibrinolytics. Permanent renal impairment may result due to impaired clot
lysis.
Oral bleeding from the gingiva or after dental extraction is also
common. Most patients are pretreated with factor replacement and prophylactic
oral antifibrinolytics. E-Aminocaproic acid (EACA) and tranexamic acid (TA)
are lysine analogues that competitive inhibit binding of plasmin to fibrin clots.
Topical antifibrinolytics or microfibrillar collagen may also be effective.
Intraoral lacerations generally need factor replacement and antifibrinolytics.
Subcutaneous hemorrhages and minor cuts rarely need specific therapy.
However, any wound requiring sutures also requires factor replacement, both
acutely and for suture removal. Epistaxis ofter respond to direct pressure.
Packing with porcine fat or microfibrillar collagen can be useful, although
factor replacement is necessary in serious epistaxis. Other presentations in
Hemophiliacs that require factor replacement include fractures, gastrointestinal
bleeding, and severe abdominal pain where bleeding in not, or cannot be, ruled
out.
Patients with mild Hemophilia A and non-life-threat-ending bleeding
can be treated with DDAVP (1-desamino-8-D-arginie vasopression,
desmopression). This antidiuretic hormone analogue releases factor VIII and
von Willebrand’s factor from endothelial and other storage sites, increasing
plasma levels three to five times. Ideal candidates for DDAVP have a baseline
factor VIII activity level of >8%,so a threefold increase reaches a hemostatic
level of about 30% normal. DDAVP is ineffective in moderate or severe
Hemophilia. Dosage is 0.3ug/kg IV in 50 ml NS given over 10 to 15 minutes.
Common side effects are related to a mild, transient vasodilation and include
facial flushing, headache, and minor decreased in blood pressure. Hyponatremia
secondary to antidiuretic effect is more a theoretical concern than a clinical
problem, though oral fluid restriction for 12 to 18 hours after DDAVP is
recommended. Patients requiring serial dosing of DDAVP need admission for
periodic electrolyte monitoring and assessment of clinical effect, since
tachyphylaxis occurs. DDAVP also causes release of tissue-type plasminogen
activator (tPA), prompting some to recommend concurrent antifibrinolytic
therapy; again, this is more of a theoretical than practical concern in most
patients.
Many blood-derived products are available for factor VIII replacement
therapy. Fresh Frozen plasma (FFP) contains all clotting factors, but requires
too much volume to be clinically useful. Cryoprecipitate contains about 100
units future Vlll per bag , but is contaminated with many other unneeded protein
And carries the risk of viral disease transmission. Concentration pooled from
several thousand donors contain about 15 units facture Vlll per milligram of
total protein. Although widely used in the past, these concentrates have fallen
out of favour due to the frighteningly high rate of transmission of hepatitis B
and C, and HIV seroconversion. Pooled plasma concentrates come in
intermediate, high, and ultrahigh purity grades. All are currently heart and
solvent treated to inactivity viruses. The purest produced via monoclonal
antibody immunoaffinity chromatography.
Recombinant factor Vlll produced By genetically engineered hamster
cell lines is now available. These products carry virtually no Rick (except for
hypersensitivity reactions) but may be prohibitively expensive. They are best
reserved for HIV-seronegative patients to maintain their negative status.
 The amount of factor VIII to administer is determined by the severity of
the patient’s bleeding and the risk for complications. Every authority and every
hemophilia treatment center has its own guidelines for calculating dosage; in
general, the more severe the presentation, the higher the dose. Guidelines at our
institution call for increasing the deficient factor’s activity level to 40% for
minor bleeding episodes, and 60% for major episodes. Minor episode include
atraumatic joint/muscle hemorrhage, epistaxis, oral bleeding (greater than
oozing), painless hematuria lasting longer than 2 to 3 days, and minor
procedures such as lumber puncture and thoracentesis. Major episodes include
advanced or traumatic joint/muscle hemorrhage, significant trauma (even
without apparent bleeding), and severe , atraumatic headache without focal
neurologic signs. We further recommend raising the level to 100% of normal in
potentially fatal situations, such as head trauma, hematomas threatening the
airway, and the need for emergent surgery.
Factor VIII is reconstituted from its lyophilized from and administered
intervenously. One unit per kg body weight raises factor VIII activity levels by
2% of normal. Dosing by the above guidelines, therefore, would be 20, 30, or
50 U/kg depending on the indication. The half- life of factor VIII is 8 hours, so
repeated doses are required. Once the patient is initially evaluated, stabilized,
and treated, a hematologist must be contacted, whether to admit the patient, act
as consultant while the patient is hospitalized, or to arrange for timely follow-up
and out-patient therapy.
The majority of bleeding complications in hemophilia are associated with
significant pain. Analgesia should be provided with acetaminophen and PO or
IV narcotics as appo. Intramuscular injections, salicylates, and nonsteroidal
anti-inflammatory drugs (NSAIDs) should all be avoided.
About 15% of patients with severe hemophilia, either A or B, develop
clotting factor inhibitors as a result of repeated exposure to exogenous factor
VII or IX, respectiy. If the titer of these antibodies is relatively low, then simply
replacing the appointment clotting factor may be sufficient to treat bleeding
episodes. Higher titers require hematologic consultation for decisions regarding
treatment with activated prothrombin complex concentrates,
immunosuppression, or plasmaspheresis.
Hemophilia B. Hemophilia B is another X-linked recessive hemorrhage
discorder that is clinically indistinguishable from Hemophilia A. Because it
was first described in the December 25, 1952 issue of the British Medical
Journal, Hemophilia B is also known as Christmas disease, and factor IX is
called the Christmas factor. Factor IX deficiency occurs in 1 in 30,000 to 40,000
live male births.
 Clinical presentation and laboratory tests are identical to hemophilia A,
except for specific clotting factor assays, which are unlikely to be available in a
timely manner in the ED. On the other hand, most patients know their diagnosis,
what treatment are usually effective, and their diagnosis, what treatment are
usually effective, and their hematologist’s name and phone number for
consultation.
Treatment of bleeding episodes is similar to hemophilia A with a few
exceptions. DDAVP is ineffective, since it does not cause release of factor IX.
Also, the dose of factor IX administered to achieve a given level of activity is
twice the amount of factor VIII that is given in hemophilia A. One unit of factor
IX per kilogram body weight raises the activity level by 1% (vs 2% for factor
VIII); the difference is due to more extensive extravascular distribution of factor
IX.
Historical, hemophilia B was treated with FFP and prothrombin-
complex concentrates (PCCs). By definition, plasma contains 1 unit of each
clotting factor per millilitre. Volume constraints limit increase in factor activity
to 10% to 15% of normal. PCCs contain factor IX (1 to 2 U/mg total protein)
and other vitamin K-dependent factors in a lyophilized form that is reconstituted
prior to administration. PCCs allow for large doses of factor IX to be given in a
manageable volume. Both of these treatments carry the risk of viral disease
transmission. Furthermore, PCCs pose the threat of thromboembolic
complications [e.g., myocardial infarction (MI), stroke, deep venous thrombosis
(DVT), pulmonary embolism (PE)] and disseminated intravascular coagulation
(DIC). Adding 5 to 10 units of heparin per millilitre of reconstituted PCC, or
giving prophylactic subcutaneous heparin, reduces the risk of inducing
thrombosis.
Purified factor IX concentrates are currently recommended for hemophilia
B, both in acute and chronic management. There are several preparations
available that are variably treated with heat, solvents, and chromatographic
separation depending on the specific product. The newest products are
monoclonal antibody immunoaffinity purified. Genetically engineered factor IX
products are expected soon, but are not yet commercially available. In general,
the purest and safest ( lowest risk of viral transmission) preparation are the most
highly recommended, but also the most expensive. The half-life of factor IX is
18 to 30 hours, so daily dosing is appropriate.
Other Clotting Factor Discorders. Congenital deficiencies of several
other coagulation factor have been described. Hereditary factor XL (plasma
thromboplastin antecedent) deficiency is an automatically transmitted disorder
characterized by a prolonged PTT and bleeding tendency, similar to hemophilia.
Over half of reported cases are found in Ashkenazi Jews; the heterozygote
frequency in Israel Is estimated at 1 in 8. Treatment is with FFP, or factor XL
concentrate (not currently available in the United States). Hereditary
deficiencies of factors. ll (prothrombin), V (proaccelerin, labile factor), Vll.
(proconvertin), and X (Stuart-power factor) are all rare , autosomal recessive
diseases best treated initially with FFP.
Diagnosis of these conditions will probably never be made in the ED.
If a bleeding patient has no known history of congenital hemostatic disease and
has an abnormal PT and/or PTT, treat with FFP transfusion. Further workup is
deferred to the primary physician or haematologists.
Congenital deficiencies of contact factors [factor Xll (Hageman
factor), prekallikrein , and High molecular weight kininogen] impair initiation
of the intrinsic coagulation pathway and have a striking elevated PTT.
However, there is no associated bleeding diatheis, and emergent treatment is not
needed.
Acquired (7.1.1.2)
Warfarin Therapy and Overdose
Warfarin is a 4- hydroxycoumarin derivative that blocks the regeneration
of vitamin K from its epoxide form. This results is less y-carboxlation of
factors. II, VII, IX, and X, impairing formation of activation complexes in
the coagulation cascade. Warfarin therapy is indicated for anticoagulation
in atrial fibrillation, venous thrombosis, pulmonary embolism, cardiac
value replacement, and sometimes in the immediate postmyocardial
infarction period. Peak plasma concentrations occur within a few hours,
and absorption is essentially complete. Warfarin is roughly 97% protein
bound. The anticoagulant effect is seen within 24 hours, and half-life is
about 60 hours. Warfarin is metabolized in the liver, excreted in the urine.
Most patients requiring anticoagulation are first started on
heparin, and then later switched to oral therapy. Warfarin dosage ranges
from 2 to 10 mg orally per day, with a typical dose of 5 to 7.5 mg. Given
warfarin’s relatively narrow therapeutic window and variability of patient
response, daily monitoring is necessary early in treatment. Once an ideal
dose is established for a given patient,. Monitoring of the coagulation
profile is continued on a regular basis, every few weeks.
The prothrombin time is the first laboratory measurements to
change (due to the short half-life of factor VII), and is the traditional
market of antithrombotic effect. Interlaboratory differences in PT control
values and materials used has lead to the general adoption of monitoring
the International Normalized Ratio(INR) as the test of choice, because it
corrects for these confounding factors. The INR is calculated as
INR=(Patient’sPT/Control PT)IsI
Where ISI is the International sensitivity Index, a measure of the
thrombogenicity of the material used in determining the PT. Low-intensity
anticoagulation, with an INR in the 2 to 3 range , is effective for most
indication. High-intensity anticoagulation (INR = 3-4.5) is sometimes
necessary with mechanical heart values or recurrent thrombosis. “Mini-
intensity” anticoagulation (INR~1.5) may be effective in some patients,
and is an area of active research in the hematology literature.
Patients who, by history, are on what had been a therapeutic
dosing schedule can develop either thrombotic or hemorrhagic
complications through several mechanism. Lack of compliance is always a
potential problem, whether by missing doses or Overdose. Fluctuations in
dietary vitamin K intake may confound warfarin therapy. Green leafy
vegetables are especially rich in vitamin K. Many illnesses, such as acute
viral infections or progression of chronic heart or liver failure, reduce
requirements for therapeutic anticaogulation. Concurrent treatment with
other drugs may affect warfarin metabolism by competition of protein
binding sites (dilantin), inhibition or acceleration of drug clearance
(trimethoprim-sul-famethoxazole, barbiturates), or reduced absorption
(cholestyramine). Aspirin or NSAIDs potentiate any bleeding
complications through their antiplatelet effect.
Some other notable complications that May present to the
emergency physician are warfarin skin necrosis and the purple toe
syndrome. Early warfarin therapy can cause a seemingly paradoxical
thrombosis of the dermal Vasclarature due to decreased production of the
fibrinolytic factors, protein C and protein S. Although uncommon,
warfarin skin necrosis occurs most often in patients without heparin
pretreatment, or with a congenital protein C deficiency. The purple toe
syndrome is caused by warfarin-induced embolization of cholesterol
particles from antheromatous plaques causing microvascular occlusion in
the toes.
Treatment of warfarin-associated bleeding depends on the
severity of hemorrhage. Studies of the annual incidence of hemorrhage in
patients taking warfarin put minor episodes at 9.6%, major episodes at
3%, and fatal bleeding at 0.6%. minor bleeding episodes (e.g., epistaxis
with a therapeutic INR) can often be managed with local measures, brief
discontinuance of warfarin, and close follow-up for coagulation profile
monitoring. Vitamin K is indicated for more serious bleeding, since the
result of overdose is a functional vitamin K deficiency. On the severity
of hemorrhage; 5 to 20 mg of vitamin K (sometimes up to 50 mg) is given
PO, IM, or slow IV push, with the intravenous route preferred in major
bleeding. If rapid reversal of warfarin-induced, coagulopathy is necessary,
FFP transfusion is indicated, starting with at least 4 to 6 units .
Prothrombin-complex concentrate infusion may be used in life-threatening
situations, such as intracranial hemorrhage with deteriorating neurologic
status, but this carries singnificant risk of thrombosis in other sites .
General resuscitative measures, including IV access and PRBC
transfusion as needed, should be performed in all patients with significant
bleeding from warfarin overdose.
Vitamin K Insufficiency
Vitamin k is a fat-soluble vitamin essential for normal hemostasis. In
its reduced from, vitamin K acts as a cofactor in the posttranslational
modification of coagulation factor ll, Vll , lX, and X, as well as
fibrinolytic factors protein C and protein S. Vitamin K-dependent y-car-
boxylation of glutamate residues allows these proteins to bind to
phospholipid membranes and from activation complexes in the
coagulation cascade. Failure of this mechanism leads to the production of
nonfunctional coagulation factors and an impaired clotting mechanism.
Vitamin K insufficiency may arise by malabsorption, malnutrition, or drug
therapy, particularly antibiotics and oral anticoagulants. Because it is a fat-
soluble vitamin and requires bile salts for absorption, biliary obstruction
or fistulae can lead to vitamin K deficiency. Other causes of
malabsorption may also be implicated, including ulcerative colitis,
regional enteritis, extensive bowel resection, celiac disease, and other
malabsorption syndromes. Malnutrition, prolonged pasting, and even
inadequate hyperalimentation may cause vitamin K deficiency. While a
healthy liver contains a 30-day store, deficiency can occur in 7 to 10 days
in acutely I’ll patients. Even with adequate intake, hepatocellular disease
cause a functional vitamin K deficiency. From impaired synthetic ability.
In addition to oral intake, vitamin K also a product by normal colonic
bacteria , so prolonged antibiotics therapy can impair hemostasis by
altering the intestinal flora. Warfarin , cephalosporins with a N-methyl-
thiotetrazole side chains (cefamandole, moxalactam, cefoperazone,
cefazolin, cafezedone), and salicylates inhibit vitamin K epoxide
redustase, the enzyme that regenerates the active from of the cofactor,
disrupting the vitamin K salvage pathway. Maternal anticonvulsant
therapy is associated with increased incidence of Hemorrhagic disease of
the newborn; routine neonatal prophylaxis with perenteral vitamin K is
performed in most hospitals .
With a half-life of only 5 house, factor Vll is the first protein
in the coagulation cascade to decrease in vitamin K insufficiency.
The earliest laboratory abnormality, then, is an increased PT. Later,
the PTT also increases as factors ll, lX, and X because depleted.
Isolated vitamin K deficiency should not cause abnormalities in the
thrombin time, platelet count, or fibrinogen levels.
Nonemergent treatment for vitamin K deficiency ,by PO or
IM replenishment, is both effective and relatively rapid; therefore,
ED treatment is reserved for singnificant hemorrhage. At least 4 to 6
units of FFP, which contains all necessary clotting factors, is given to
adults, and proportionately less to children. Parenteral vitamin K is
also given, either IM or by slow IV infusion. This repletion is
effective even in the presence of warfarin or related long- acting
rodenticides due to an alternate, reduced nicotinamide adenine
dinucleotide phosphate [NAD(P)H] dependent pathway vitamin K
reduction. Dosage is 1 to 5 mg in infants/small children, 5 to 10 mg in
older children, and 10 to 20 mg in adults. Cessation of bleeding and
correction of laboratory abnormality usually occurs within 8 hours.
Liver disease
Bleeding due to liver disease is multifactorial in origin. The
most common site are localized lesions, such as esophageal varices
and peptic ulcers; however, control of bleeding is complicated by
multi-faceted impairment in hemostasis. Defects in the coagulation
cascade, platelet number and functions, consumption of coagulation
factor and systematic fibrinolysis are all associated with liver disease.
Because nearly all components of the clotting cascade are
synthesized in the liver, some of the earliest signs of hepatic
dysfunction are reflected in coagulation abnormalities. Impaired
hemostasis can be even with acute inflammation diseases such as
viral or drug induced hepatitis, with the PT prolonged first and then
PTT. The extent of dysfunction is directed related to the amount of
hepatic damages, following the patient’s clinical course towards
recovery fulminant liver failure. Most patients with a bleeding
tendency from disease have a chronic, progressive hepatitis from
ethanol, persistent viral infection, or primary biliary cirrhosis.
Vitamin k definitely is a frequent confounding factor in these
patients. Clotting factors that are produced, dispite impaired synthetic
ability, do not function properly due to decreased y- carboxylation of
glutamate residues. Non- emergent correction of coagulation defects
in liver disease is by a trial of vitamin k repletion, either by PO or IV
routes. IM injections are avoided due to risk hematoma formation.
Serious bleeding is treated with transfusion of FFP, and possibly
cryoprecipitate if associated with hypofibrinogenemia.
Liver disease also causes abnormalities in platelet number
and function. Thrombocytopenia is due to ethanol-induced inhibition
thrombopoiesis and sequestration of platelets from hypersplenism.
Concomitant folate deficiency also impairs platelet production.
Platelet function defects are due to decreased hepatic clearance of
circulating platelet inhibitors, such as fibrin/fibrinogen degradation
products (FDPs). DDAVP infusion (0.3 μg/kg IV) produces a
significant, if transient, improvement in platelet function in over half
of patients with liver disease. Platelet transfusion are indicated for
active bleeding associated with thrombocytopenia, platelet count
<50,000/μ1.
Chronic, low-grade DIC is found in many patients with advanced
liver disease. Several mechanisms are proposed: release of
procoagulants from damaged hepatocytes, low-grade portal
endotoxemia, impaired clearance of activated clotting factors such as
antithrombin III and protein. Peritoneovenous Shunts commonly
cause DIC, because ascites fluid contains many humoral and cellular
components that promote coagulation. Paracentesis, temporary shunt
occlusion, and sitting the patient up to reduce fluid return may
improve DIC due to this mechanism. DIC in liver disease rarely
requires specific treatment, unless it is the fulminant variety
complicating another illness, such as sepsis, trauma, or malignancy.
Systemic fibrinolysis in liver disease may be due to decrease
in synthesis of 2- antiplasmin, a fibrinolytic modulating protein, and/
or decreased hepatic clearance of activated fibrinolytic proteins. Also,
surgery causes the release of tPA from damaged endothelium, which
may exceed the impaired liver’s ability to compensate, leading to
postoperative bleeding complications. Systemic fibrinolysis is
managed with a trial of FFP transfusion to replete 2-antiplasmin
levels and other Clotting factors, which may be low as a result of
unrecognized DIC. Administration of loading doses of antithrombotic
agents, EACA(100mg/kg IV or PO) or TA (10mg/kg IV), is
considered if FFP fails. Except for rare circumstances, treatment with
EACA or TA will not be initiated in the ED.
Hypofibrinogenemia
Fibrinogen is a glycoprotein essential for normal hemostasis. In
the common coagulation pathway, thrombin converts fibrinogen is
produced by hepatocytes and megakaryocytes. Normal serum levels
range from 200 to 400 mg/d1. Pregnancy and estrogen therapy can
increase levels to 350 to 650 mg/d1, partially accounting for the
increased risk of thrombosis. Fibrinogen is a major acute phase
reactant, and turnover rates can increase 25-fold in times of acute
stress.
Hypofibrinogenemia is caused by a number of uncommon
genetic disease (it also occurs secondary to liver disease, ascites, or
DIC or by drugs such as L- asparaginase, ticlopidine, ethanol, and
pentoxifylline sodium valproate). Isolated hypofibrinogenemia rarely
 requires treatment; when associated with significant hemorrhage,
cryoprecipitate (cryo) transfusion is indicated.
Cryoprecipitate is produced by slow thawing of FFP at 4⁰c and
recovering the cold-insoluble fraction of plasma proteins by centrifugation.
Cryoprecipitate contains 100 to 250 mg fibrinogen in 5 to 30 ml volume. In
addition, cryo contains >80U factor VIII activity per bag ( average 100 U), 40%
to 70% of original vWF, and several other clotting factor. Cryoprecipitate is
stored frozen, and is thawed, pooled, and filtered prior to transfusion. Usual
dosing is one bag per 6kg body weight, which will increase fibrinogen by 75 to
100 mg/d1, the minimal level for hemostasis. Initial doses as high as one bag
per 2kg body weight are recommended for impending or overt shock in patients
with hypofibrinogenemia-associated hemorrhage.
Disseminated Intravascular Coagulation (7.1.2)
Disseminated intravascular coagulation (DIC) is a disease
process characterized by simultaneous unregulated activition of the
coagulation fibrinolytic pathways. DIC is be a called as “consumptive
coagulopathy” in that clotting factor and platelet level fall as
microthormbi or produced, but the most prominent clinical feature is
bleeding. DIC is not a primary disease entity; it is always secondary
to an underlying usually severe, and most often systemic illness.
Pathophysiology
DIC is initiated by the entrance of procoagulant substance Into
the all circulation, either from exogenous sources or injured or
otherwise abnormal tissue. Tissue factor is released from damaged
tissue, activiting the extrinsic coagulation Pathway. Exposure of
subendothelial tissue acticates the intrinsic pathway and indues
platelet aggregation. Plasminogen is convenient to plasmin by tPA
released from damaged endothelial cells and/or by activated intrinsic
pathway factors. Fibrinolysis then produces FDPs that are are
nonclottable, and inhibit fibrin polymerization and platelet
aggregation.
DIC may be initiated by many primary illnesses. The most
common causes are sepsis , malignancy, obstetrical complications,
trauma, and liver disease. Overwhelming infection causes DIC due to
the procoagulant nature of endotoxin, bacterial cell wall components,
and WBC- released factors . Malignant cells can release tissue factor
and other procoagulant; promyelocytice leukemia is especially prone
to inducing DIC. Late pregnancy and childbirth is a particularly DIC-
prone period for both the mother and infant , because amniotic fluid
and the placenta are rich in tissue factor. Retained fetus, amniotic
fluid embolism, placental abruption, and septic or induced abortions
have all been recognized as causes of obstetrical DIC. Burns, crush
injuries, and other trauma are obvious sources of tissue factor.
Chronic liver disease is a common cause of low-grade, compensated
DIV, which rarely needs treatment.
Other causes of DIC that the emergency physician should be
aware of are the presence of prosthetic devices (especially
peritoneovenous Shunts), transfusion reaction, heat stroke, and
envenomations. DIC without identifiable cause should raise suspicion
for hemorrhagic fever viruses, occult malignancy, and unrecognized
pulmonary embolism.
Diagnosis
The diagnosis of DIC is suggested in patients with unexplained
and often widespread bleeding manifestations in the appropriate
clinical setting. The average patient bleeds from three or more
unrelated sites. DIC also causes microvascular thrombosis that is
present even if clinically inapparent. Such microthormbi may present
as end-organ damage to the lung [hypoxemia, adult respiratory
distress syndrome (ARDS)], kidney (oliguria, renal failure),or CNS
(stroke). A thrombotic manifestation of the skin called purapura
fulminans can also occur appearing initially as ecchymotic lesions
that subsequently demarcate and necrosis, or even gangrene of the
extremities.
DIC causes a number of laboratory abnormality. The most useful
diagnostic test is measurement of FDPs. Elevation of FDPs is found
in more than 95% of patients with DIC, representing the effects of
fibrinolytic activation. FDPs impair coagulation and therefore act as
an acquired anticoagulant. The D-dimer assays more specific for
DIC and FDPs, but less sensitive. This test measures the degradation
products of cross-linked fibrin, reflecting concurrent coagulation and
fibrinolysis. PT and PTT are elevated in fulminant DIC, but may
occasionally be normal in early or mild disease. Thrombocytopenia is
prominent, and may be the presenting finding in low-grade,
compensated disease, as found in chronic liver failure.
Hypofibrinogenemia, with level <100 mg/ d1, is expected given the
pathophysiology of the disease. In early DIC, level may be normal,
because fibrinogen is an acute-phase reactant; however, serial
fibrinogen level show a decline. Microangiopathic hemolytic
anemi(decreased hemotocrit, fragmented red cells on peripheral
smear) is persent in over half of cases. Single-tube is a simple but a
often overlooked bedside tests for rapid clinical diagnosis of DIC.
One milliteter of whole blood is collected in a plain glass tube that is
manually titled every 30 second. Normal blood form a clot 4 to 10
minutes, which then undergoes clot retraction. Blood from an
affected patient clot late, if even and fail to retract, leading to an early
presumptive diagnosis of DIC before any quantitative laboratory
value return.
Treatment
The paramount issue in DIC is treatment of the underlying
disease process. Treating the effects of DIC thrombocytopenia,
clotting factor depletion, thrombosis, and hemorrhage) is futile unless
the inciting event is reversed. The vast majority of cases of DIC seen
in the ED are secondary to trauma, sepsis, malignancy. Although
complete resolution of DIC is dependent on subsequent management,
in the operating room, intence care unit, and hospital wards,
emergency physician can impact patient outcome by addressing the
ABCs resuscitative correcting metabolic abnormalities, and rapidly
initiating antibiotic treatment in sepsis.
Specific treatment of DIC remain controversial. Some authorities
insists on heparin as initial therapy. Despite the apparent paradox in
anticoagulating a bleeding patient, there is a sound theoretic basic to
this course of action. First, although bleeding is the most obvious
clinical problem in DIC, the thrombotic components has the greatest
impact on morbidity nad mortality. Second, there is some evidence
that repletion of clotting factor may. “feed the fire,” by providing
substrate for generating more thrombosis and more FDPs, impairing
hemostasis further. Third, the patient is already bleeding, and heparin
is unlikely to make it significantly worse.
The other option for specific DIC therapy is transfusion of
depleted coagulation factor: platelets, clotting, proteins, and
fibrinogen. DIC result in multiple clotting factor deficiencies, all of
which can be correct with FFP. Cryoprecipitate may be given for
severe hypofibrinogenemia. Platelet repletion is also reasonable for
DIC-induced thrombocytopenia. Such transfusion, especially
concomitant correction of the primary disorder, may result in
hemostasis. The effect may be temporary as the transfused factors are
consumed; however, the goal is to have the patient admitted for
definitive therapy by the time repeat laboratory value would return.
We recommend platelet and FFP transfusion over heparin for
the emergency treatment of DIC for the following reasons:
1. Anticoagulation with heparin remains controversial.
2. Serious bleeding complications, such as intracerebral hemorrhage, may
be less likely.
3. Heparin can always be started by the admitting physician and/or
consultant hematologist should transfusion fail.
4. Rapid treatment of the primary disease process reverses DIC is most
cases.
5. Platelets and FFP may improve hemostasis until definitive therapy is
began.
Initiation of heparin in the ED for DIC is reserved for imminent loss
of life or limb from thrombosis.
One unit of random-donor platelets per 10 kg should raise the platlet
count by roughly 50,000μ1. Usual dosing is in multiples of 6 units of
platelet concentrate. Six units is usually adequate to reverse bleeding
 associated with severe thrombocytopenia; more may be needed in DIC due
to continued consumption. Each unit of FFP contains 200 to 280 ml volume
with 0.7 to 1.0 U/ ml of activity of each clotting factor and 1 to 2 mg/ml
fibrinogen. A dose of 10 ml/kg raises clotting factor levels by 15% to 20%
of normal. The initial dose of FFP is at least 4 to 6 units.

Platelet Disorders (7.1.3)

Immune Thrombocytopenic Purpura (7.1.3.1)
Immune thrombocytopenic purpura (ITP) is a bleeding disorder
caused by increased clearance of circulating platelets by the reticuloendothelial
system. ITP was formerly known as idiopathic Thrombocytopenic purpura, until
the 1950s, when autoantibodies against platelets were identified as the etiologic
agent, There are two distinct clinical forms of ITP, acute and chronic. The acute
form is found most often in children and has an excellent prognosis, resolving
quickly and many times spontaneously. Adults are commonly develop chronic
ITP, a lifelong recurrent disease.
The typical clinical picture of acute ITP is the sudden onset of a “ rash”
-----petechiae, purpura, and ecchymoses---- in an otherwise healthy child. The
incidence is equal for males and females, peaks between 2 and 5 years of age,
and has a seasonal predominance in winter and fall. Childhood ITP often
follows an acute viral illness or immunization. Chronic ITP accounts for 75% to
85% of all adult cases. There is a 3:1 male to female predominance, and
frequently an associated family or personal history of autoimmune and
lymphoproliferative disorders. Common manifestations of both acute and
chronic ITP are epistaxis, gingival bleeding, easy bruising, and petechiae on the
lower arms and legs without trauma; 10% to 20% of patients have hematuria,
hematochezia, or menorrhagia. Life-threatening GI or CNS bleeds are rare,
occurring in less than 1% of ITP patients.
Numerous drugs have been associated with the development of
thrombocytopenia. True immune-mediated thrombocytopenia can occur with
heparin, quinidine and quinine, sulfa-containing drugs, penicillins, gold,
valproci acid, diagoxin, and cimetidine. Heparin also causes a dose-related,
nonimmune reduction in platelets, while alcohol and thiazide diuretics directly
inhibit thrombopoiesis. Rapid improvement usually occurs when the offending
agent is discontinued.
Other than bleeding manifestations, the physical examination should be
normal in ITP. Hepatosplenomegaly, adenopathy, history of weight loss, and
fever all suggest alternate diagnosis, such as acute infections with Epstein-Barr
virus (EBV) or cytomegalovirus (CNV), malignancy, collagen vascular disease,
or AIDS. It should be noted, however, that 5% to 10% of children with ITP
have splenomegaly---- the same percentage as for normal children.
Isolated thrombocytopenia should be the most significant laboratory
abnormality in ITP. Anemia may result from hemorrhage or an associated
autoimmune hemolysis (Evan’s syndrome). Pancytopenia suggests bone
marrow failure or infiltration rather than ITP.
Most cases of ITP do not require emergent treatment. Oral Prednisone (1
to 2 mg/kg/ day) or intravenous immune globulin (IVIG, 0.4 to 1.0 mg/kg/day)
are usually effective. The proposed mechanism is by downregulating or binding
of Fc receptors on monocytes and macrophages, thereby decreasing platelet
clearance. Refractory cases are managed by splenectomy, antineoplastics, or
hormone therapy.
Transfused platelets are generally ineffective because of rapid
destruction and removal from circulation. In cases of uncontrollable bleeding,
however, transfusion may provide needed, if transient, hemostasis. Life-
threatening CNS or GI bleeding (or intraocular bleeding) from ITP are clear
indications for emergent treatment. IV methylprednisolone and IVIG are
administered. Plasmaspheresis may also be used, and if so, IVIG is initially
withheld. If splenectomy, craniotomy, or other surgery is necessary, platelet
transfusion is absolutely indicated prior to and during the procedure.
Thrombotic Thrombocytopenic purpura and Hemolytic Uremic
Syndrome (7.1.3.2)
Thrombotic thrombocytopenic purpura (ITP) and hemolytic uremic
syndrome (HUS) are two closely related disorders of microvascular occlusion
by platelet microthormbi. Both disorders tend to occur abruptly in previously
healthy individuals, and have significant risk for morbidity and mortality of not
promptly recognized and treated.
HUS occurs mostly in young children, with greater than 90% of cases
following a prodromal illness, frequently acute bloody diarrhea. Escherichia
coli 0157:H7 is the most commonly associated infectious agent and the one
implicated in recent food-service industry epidemics; however, Shigella
gastroenteritis and many other infections (Mycoplasma, Pneumococcus, viral)
may precede the onset of HUS.
The hemolytic uremic syndrome is heralded by the acute onset of a traid of
symptoms: acute renal failure (oliguria), thrombocytopenia (petechiae, purpura,
and ecchymoses), and microangiopathic hemolytic anemia ( weakness/fatigue).
CNS involvement and fever may be present but are usually, in distinction from
TTP. Anemia, with fragmented red cells on peripheral smear,
thrombocytopenia, leukocytosis, and elevations in BUN, creatinine, and lactate
dehydrogenase (LDH) are expected. Coagulation tests should show a normal
PT/PTT, elevated FDPs, and raised fibrinogen levels; however, DIC may occur
in complicated cases.
Patients diagnosed with, or highly suspicious for HUS require admission
for close supportive care and monitoring for development of complications.
About 75% of cases need dialysis before return of adequate renal function, but
most patients need no other specific therapy. Potential complications include
CNS involvement (hyponatremic seizures, cerebral infarction), pancreatic islet
cell necrosis leading to diabetes mellitus, bowel infarction, arterial thrombosis,
and congestive heart failure (CHF). Heparinisation, plasmaspheresis, or plasma
exchange with FFP may become necessary. Fortunately, the vast majority of
patients survive with mild renal impairment as the only sequels. Recurrence of
HUS is uncommon.
TTP is found most often in young adults with a 2:1 female predominance.
Symptoms are variable, with vagus, nonspecific complaints such as fatigue,
malaise, abdominal pain, and weakness. Onset is usually acute, over hours to
days, without a distinct prodromal illness. The classic pentad of neurologic
signs and symptoms, hemolytic anemia, thrombocytopenia, renal disease, and
fever is seen in 40% to 50% of patients. Kidney failure is significantly less
common than in HUS. Diagnosis of TTP can be difficult, requiring exclusion of
diseases with similar presentations, such as autoimmune hemolytic anemia,
systemic lupus erthematosus (SLE), preeclampsia/ eclampsia, postpartum renal
failure, sepsis/ endocarditis, vasculitis, and drug reactions. Laboratory
abnormalities are similar to those in HUS, but also include hyperbilirubinemia.
Diagnosis or suspicion of TTP mandates admission. Treatment consists of
PO or IV glucocorticoids depending on the severity of illness. Lack of response,
deterioration, and prominent CNS involvement are indications for
plasmaspheresis and plasma exchange with FFP. Splenectomy may help in
refractory cases. Unlike HUS, recurrences of TTP are common. Treatment
reduces mortality from approximately 80% to less than 10% .
Drug Inactivation of Platelets (7.1.3.3)
A variety of vascular diseases are treated with drugs that block platelet
deposition on the surface of disrupted antherisclerotic plaques, preventing
thrombotic and embolic complications. Typical indication for antiplatelet
therapy include myocardial infarction, stable and unstable angina, stroke,
transient ischemic attacks, atrial fibrillation, and chronic lower extremity
ischemia.
Acetylcholine acid (ASA, or aspirin) is the most commonly used
antiplatelet drug due to its low cost, wide availability, relative safety, and
demonstrated efficacy. Aspirin permanently acetylates the prostaglandin-
producing enzyme cyclooxygenase, preventing production of thromboxane
(TXA2). Prolongation of bleeding time and decreased platelet aggregation are
seen within 2 hours after ingestion, and since this inhibition is permanent, the
effect lasts 2 to 4 days. Aspirin simultaneously inhibits endothelial
cyclooxygenase, blocking production of prostacyclin ( PGI 2), a platelet
function inhibitor. However, this latter effect is mitigated by renewal of
endothelial cyclooxygenase in 24 to 48 hours and lower sensitivity of the
endothelial enzyme to ASA. With the generally recommended administration of
aspirin (60 to 325 mg QD or QOD), the net effect is antithrombotic.
Complications of aspirin therapy are well known and potentially
serious. Gastrointestinal symptoms are related to dose and especially common
with>975 mg (three regular tablets) daily. Bruising, GI bleeding, postoperative
hemorrhage, and epistaxis are more common in patients taking aspirin.
 NSAIDs are reversible cyclooxygenase inhibitors. The Antiplatelet
effect of NSAIDs lasts only 6 to 24 hours. Depending on the drug’s half-life.
Sulfinpyrazone and Dipyridamole are being used less commonly since they are
both more expensive and less effective than aspin. B-Lactam antibiotics in
sustained, high doses can impair Platelet function by membrane binding, and
lasting up to 7 to 10 days after withdrawal of therapy.
Discontinuation of the offending agent is the first line Of therapy in
bleeding associated with antiplatelet drugs. Severe hemorrhage is managed with
DDAVP (0.3 μg/kg IV), and platelet transfusions if necessary.
Von Willebrand’s Disease (7.1.4)
In 1924 Erik von Willebrand’s described a bleeding dis-Order he called
“pseudohemophilia” in an extended Finnish family. The disease had varying
penetrance, Equal male and female prevalence, and exhibited pre-Dominantly
mucosal bleeding. As it is now known, Willebrand’s disease (vWD) is a
collection of quantitative and qualitative deficiencies of von Willebrand’s factor
(vWF). vWD is the most common genetic bleeding dis-Order, with a prevalence
of roughly lV. in the general Population, although many cases are mild or
clinically asymptomatic. The majority of identified patients are het-Erozygotes
for these autosomal dominant traits and have mild bleeding manifestations.
Homozygotes or mixed heterozygotes have severe disease.
vWF is a glycoprotein synthesized by endothelial cells and
megakaryocytes, and stored in the endothelium and in platelet granules. vWF
acts as a bridge between platelets and exposed subendothelium, serving as the
basis for formation of a hemostatic plug. In addition, vWF complexes with
andstabilizes factor VIII, protecting it from rapid clearance. vWF is found in
multimers of varying sizes; large multimers are the active form.
vWD is classified according to the type of vWF deficiency. Roughly
80% of patients have type I-vWD, a quantitative deficiency where all multimers
are affected.Type II-vWD occurs in l5o/o to 20Yo of cases and results from a
relative paucity of large multimers. Type IIB-vWD is a subclass char active d
by platelet hyperaggregability. DDAVP is contraindicated in this type due to
risk of inducing thrombocytopenia. Type III-vWD is a severe, Usually
homozygous form of the disease where all multi-Mers are absent or nearly so.
Other genetic variants of vWF exist but are extremely rare. Acquired vWD can
occur with or without autoantibodies, usually in association with myelo- or
lymphoproliferative disorders, gam-myopathies, or tumors.
 Bleeding tendencies from vWD are typical of the kind found in platelet
disorders: cutaneous manifestations (petechiae, purpura, ecchymoses),
postoperative oozing (surgical wounds, dental extraction), and mucosal bleeding
(epistaxis, gastrointestinal, menorrhagia). Routine Coagulation studies are
usually normal; however, the PTT Is variable. Although bleeding time is
prolonged, it does Not distinguish among quantitative and qualitative Platelet
disorders. The platelet count is normal, except in Type IIB-vWD where
significant thrombocytopenia can Occur. Often the most useful diagnostic aid is
a positive family history or the patient’s prior diagnosis of vWF
Theoretically, treatment of bleeding in vWD depends On which type of
the disease the patient has. However, Clinically when a new diagnosis of vWD
is suspected, a Trial of DDAVP (0.3 pg/kg IV in 50 ml NS, over l0 to l5
Minutes) is generally recommended as initial therapy (in The absence of known
contraindications) for the following Reasons: (l) Type I-vWD is most often
encountered and Should respond to this therapy, as well as most type II
Subclasses. (2) Some authorities report that type IIB-vWD is not an absolute
contraindication to DDAVB and that a drop in platelet count represents a
pseudothrombo-cytopenia. (3) DDAVP does not affect type III-vWD, and is
neither indicated nor contraindicated.
 The next line of therapy is replacement of normal vWF through blood
product infusions. Purified factor VIII Concentrates also contain vWF. Of the
commercially available preparations, Hamate-P (Armour) is most recommended
because it has the highest relative concentration of vWF. Dosage is by factor
VIII activity, 50 to 60U/kg given over 5 to 10 minutes. FFP could potentially be
Used, but the volume necessary would be prohibitive. Cryoprecipitate primarily
contains factor VIII/vWF com-Plexes and fibrinogen, but in a much smaller
volume. Dosage is one to two bags per 10 kg body weight depending on
severity of bleeding.
Mild oral mucosal oozing may be treated with a topical antifibrinolytic
mouthwash, tranexamic acid l0 ml of 5% solution QID. With epistaxis,
consideration should be given for using porcine fat (bacon strips, salt pork) as
nasal packing material, whether in vWD or other bleeding tendencies. This
material is an excellent procoagulant (high concentration of tissue factor) and
removal is rela-tively atraumatic due to self-lubrication.
SELECTED READING

Bell WR, ed. Hematologic and oncologic emergencies. New York:

Churchill Livingstone, 1993.
Gilbert JA, Scalzi RP Disseminated intravascular coagulation. Emerg Med Clin
North Am 1993;11(2):465480.
Hathaway WE, Goodnight SH. Disorders of hemostasis and thrombosis: a
clinical guide. New York: McGraw-Hill, 1993.
Hoyer LW. Hemophilia A. N Engl J Med 1994;330(l):3847.
Logan LJ. Treatment of von Willebrand’s disease. Hematol Oncol Clin
North Am 1992;6(5):1079 1094.
Mammen EF. Coagulation defects in liver disease. Med Clin North Am
1994;78(3):545-554.
Pfaff JA, Geninatti M. Hemophilia. Emerg Med CIin North Am 1993;
Il(2):337 363.
Tardio DJ, McFarland JA, Gonzalez MF. Immune thrombocytopenic
Pur-Prra. J Gen Intern Med 1993;8:160-163.
Thorp JA, Gaston L, Caspers DR, Pal ML. Current concepts and contro-Versies
in the use of vitaminK. Drugs 1995;49(3):376-387.
LYMPHOMAS (7.2)
 The lymphomas are a varied group of malignancies with the common
element of tumor infiltration of reticuloendothelial organs. The two major types
are Hodgkin’s disease and non-Hodgkin’s lymphoma. Despite the common
involvement of lymphoid tissues these two varieties have distinct
pathophysiologies and clinical manifestations (Table 7-l).
Lymphadenopathy is the common means of presentation of
lymphomas. In adults a firm lymph node of greater than I cm in size not related
to an identifiable infection that remains enlarged for 6 weeks should be
considered as suspicious for lymphoma. Mediastinal Lymphadenopathy noted
on chest radiograph may be a presentation of lymphoma. The differential
diagnosis list includes infections (infectious mononucleosis, tuberculosis
histoplasmosis), sarcoidosis, and other neoplasms. Weight loss, malaise, fevers,
and sweats may be a manifestation of lymphoma and warrant thorough
evaluation. Anemia and other manifestations of bone marrow infiltration
TABLE 7-1. The lymphomas compounded
 Modified lrom Harrison’s textbook of medicine, 13th ed.
New York: McGraw-Hill 1994;1774, with permission.

Are common with non-Hodgkin’s lymphoma and occur occasionally in

Hodgkin’s lymphoma. Occasionally, lymphoma presents with manifestations of
tumormass such as superior vena caval obstruction, spinal cord compression,
neurologic symptoms, testicular masses, or bone lesions, and gastrointestinal
lymphomas may be complicated by hemorrhage, obstruction, or perforation.
Hodgkin's Disease
Hodgkin’s disease is a malignancy of lymphoid tissue characterized, by
the presence of Reed-Sternberg (RS) cells on microscopic examination of
biopsy tissue. The age distribution of Hodgkin’s disease is bimodal in most of
the Western world with a peak between 15 and 35 years of age and another after
50 years. There is a predominance of male affliction, occurrence in clusters, and
increased prevalence among those with certain human leukocyte antigens
(HLAs), immunodeficiencies, or autoimmune diseases. Furthermore, the EBV
genome has been identified in Reed-Sternberg cells from about 30%of cases
examined. These observations have raised speculation of genetic and
environmental factors, including the possibility of a virus with oncogenic
potential in the etiology of the disease.
Hodgkin’s disease commonly presents as localized involvement of a
group of nodes that are firm, usually nontender, and freely mobile. Spread is to
contiguous Lymphoid structures and ultimately dissemination to non-Lymphoid
tissues. Lymph nodes in the neck and supraclavicular areas are common
presenting sites, and many patients have mediastinal adenopathy at first
presentation.
In approximately 5% of patients the involved tissues become painful after
the ingestion of alcohol; 25% to 30% have some constitutional symptoms such
as fevers, sweats, weight loss, and malaise. Pelepstein fever describes a high,
fluctuating fever associated with drenching night sweats that affects a small
number of patients. For prognostic and therapeutic reasons patients are said to
have “B symptoms” when troubled by unexplained fever of greater than 38%C,
drenching night sweats, or unexplained weight loss of more than l0% of body
weight in the preceding 6 months. Patients without such systemic symptoms are
given the descriptor ‘A”(see Staging, below). Routine blood count often reveals
a moderate normochromic, normocytic anemia and a moderate to marked
leukemoid reaction. The erythrocyte sedimentation rate is commonly raised and
is occasionally used as a nonspecific measure of disease severity. Other
abnormal tests may include elevated lactate dehydrogenase, C-reactive protein,
and other acute phase proteins. Hodgkin’s disease may rarely be the first
manifestation of HIV infection, and HIV serology is warranted. Less
commonly, Hodgkin’s disease presents at a more advanced stage with
symptoms related to dissemination such as cough, shortness of breath, superior
vena cava obstruction, abdominal pain, bone pain, or spinal cord compression.
The diagnosis of Hodgkin’s disease is confirmed by Microscopic
examination of a biopsied lymph node or other involved tissue. Central to the
diagnosis is the presence of the RS cell. RS cells may occasionally be found in
other conditions such as infectious mononucleosis and Non-Hodgkin’s
lymphoma, and therefore an accurate diagnosis of Hodgkin’s disease and
determination of its histologic subtype depends on the morphologic variant of
the RS cell and the cellular and fibrous background in which it lies. The Rye
classification subdivides hodgkin’s disease into four histologic subtypes: (1)
lymphocyte predominant (6%); (2) nodular sclerosis 10%); (3) mixed cellularity
(25%); (4) lymphocyte depleted (5%). Nodular solarising may be further
subdivided into Lymphocyte predominant phase, mixed cellularity and
Lymphocyte-depleted phase. Recent progress in pathology,
immunophenotyping, and cytokine recognition has suggested that some
subtypes, especially nodular lymphocyte predominant, are B-cell, non-
Hodgkin’s lymphomas. Although this histologic classification has therapeutic
and prognostic implications, therapy and prognosis are governed more by the
stage of the disease than its subtype. It is important to note that the opposite
applies with non-Hodgkin’s lymphoma.
Staging
Staging is important for these lymphomas since defining the extent ofthe
disease is essential for the selection Of therapy. This is achieved by the
documentation of systemic symptoms (B symptoms), physical examination,
Laboratory evaluation, chest radiograph, CT scan of chest, abdomen, and pelvis,
and a bone marrow aspirate and biopsy. In certain circumstances, liver biopsy,
lymphangiography, bone scanning, and other tests may be required. Staging
laparotomies are undertaken uncommonly and are considered only if the
findings are likely to alter management. The Ann arbour staging system was
developed in 1965 for Hodgkin’s disease and is still in current use although
with some modification (Table 7-2).The presence of localized extra lymphatic
disease is designated by the suffix E. The presence of important systemic
symptoms is designated by the suffix B and their absence by the suffix A.
Treatment of patients with limited disease such as stage IA, and low
volume IIA, generally involves radio-therapy alone. Stages IB, IIB, bulky stage
II, and stages III and IV disease are usually treated with chemotherapy either
alone or in combination with radiotherapy. High dose chemotherapy with stem
cell rescue is occasionally used for relapsed disease.
TABLE 7-2. The Ann arbour staging system for Hodgkin’s disease
Stage I: Involvement of a single lymph node region or singles extra lymphatic
site
Stage II: Involvement of two or more lymph node regions on the same side of
the diaphragm
Stage III : Involvement of lymph node regions or extra lymphatic sites on both
sides of the diaphragm, and may include the spleen
Stage IV: Disseminated involvement of one or more extra lymphatic organs
with or without lymph node involvement.
Several variables adversely effect the prognosis of hodgkin’s disease. The
number of involved sites and the presence of bulky disease are the most
important variables. Large masses of tissue respond less well to treatment, and
the more disease the greater the likelihood of drug-resistant tumor cells.
Increasing age and systemic B Symptoms are poor prognostic indicators
regardless of the stage. Patients with stages IA and IIA disease treated with
radiation therapy have nearly 80% long term disease-free survival. A disease-
free survival of approximately 50o/o can be achieved with combined therapy of
Disseminated disease.
Non-Hodgkin's Lymphoma
Non-Hodgkin’s lymphomas are among the most common neoplasms of
young adults and their incidence is increasing as a consequence of the acquired
immunodeficiency syndrome.
The etiology of non-Hodgkin’s lymphoma has been determined to be
viral in some cases. A strong association exist between EBV both in endemic
African Burkett’s Lymphoma and in high-grade syrnptoms of immunodeficient
patients, and the human T-cell leukemia virus has been implicated in the
etiology of adult cell lymphoma in endemic areas. A number of diseases of
inherited or acquired immunodeficiency and some autoimmune diseases are
associated with a higher incidence of non-Hodgkin’s lymphoma, probably due
to EBV infection, which may regress if the immunodeficiency is reversed. In
addition, some specific chromosomal abnormalities have been identified in a
number of non-Hodgkin’s lymphomas.
Classification systems, like the Rappaport classification, describe the
appearance of the involved nodes in terms of cell size and follicular or diffirse
patterns of those cells. The Working Formulation has evolved to better reflect
prognosis and natural history. It divides non-Hodgkin’s lymphomas into low-
grade lymphomas (characteized by an indolent clinical course not significantly
altered by therapy) or intermediate- and high-grade lymphomas (which may
have long-term disease-free survival following intensive chemotherapy).
The many classifications used are indicative of the fact that no one
version either predicts the outcome or serves as an adequate guide to treatment.
Furthermore, developments in cytogenetic, immunology, and cytokine
recognition are providing insights into the cellular origin of the Lymphomas and
have lead to the development of the revised European American Lymphoma
(REAL) classification.
More than two-thirds of patients with non-Hodgkin’s. Lymphoma
present with persistent painless peripheral lymphadenopathy. Involvement of
Waldeyer’s ring, epitrochlear or mesenteric nodes, is more suggestive of Non-
Hodgkin’s lymphoma lean Hodgkin’s lymphoma. Approximately 20% of
patients present with mediastinal Lymphadenopathy with cough or discomfort
or as an incidental finding on chest x-ray. Symptoms of an abdominal mass
lesion may complicate massive splenomegaly or a primary gastrointestinal
lymphoma. Involvement of mesenteric, retroperitoneal, and pelvic nodes is
common but usually is asymptomatic. Rarely, bone marrow infiltration results
in anemia. Superior vena cava obstruction, spinal cord compression, and a
variety of isolated extranodal mass lesions may bring the patient to attention.
Primary non-Hodgkin’s lymphoma Of the brain is increasing in incidence as a
consequence Of HIV infection and immunosuppressive therapy following organ
transplantation.
The ann arbour system developed specifically for Hodgkin’s
lymphoma is also used to stage non-Hodgkin’s Syrnptoms; however, it has less
prognostic value since non-Hodgkin’s lymphoma tends to progress by
hematogenous spead rather than contiguous extension. Diagnosis requires
adequate tissue and may necessitate surgical biopsy instead of percutaneous
sampling. Staging evaluation, once biopsy confirmation has been made, is
similar to hodgkin’s lymphoma. Physical examination and documentation of
constitutional symptoms is accompanied by a complete blood count, liver and
renal function tests, lactate dehydrogenase, seem protein electrophoresis, and
Burne-Jones protein (to document the presence of a monoclonal paraprotein).
Chest radiograph, CT scan of abdomen and pelvis, and bone marrow aspirate
and biopsy are required. Due to the association of non-Hodgkin’s lymphoma
with HIV infection, appropriate serology is also warranted. Lymphoid markers
give information regarding cellular origin and more sensitive tests involving
molecular techniques and polymerase chain reactions may further clariffCellular
origin and may identify very small tumour masses. These have particular
application in detecting residual disease after treatment.
The treatment regime chosen depends on the grade, extent, and
volume of the disease and whether treatment is intended to be curative or
palliative. Radiotherapy has some application in the treatment of localized
disease or for palliation of more advanced disease, and chemotherapy is used
for advanced disease. The chemotherapeutic options are dictated by grade and
histologic subtype. Low-grade non-Hodgkin's lymphomas are treated with
alkylating agents, with novel nucleotide therapies undertrial. Intermediate- or
high-grade non-Hodgkin's lymphoma are treated with intensive multiagent
combinations. High-dose therapy with stem cell rescue may bemused in some
patients with high-risk or relapsed disease. Other therapies under trial include
the use of monoclonalantibodies to deliver chemotherapeutic agents,
hematopoietic growth factors to allow more aggressive chemotherapy with less
myelosuppression, and high-dose therapy in low-grade lymphomas to try and
attain a cure.
Non-Hodgkin’s lymphomas are a heterogeneous group of diseases with
considerable variability even within histologic subtypes. Low-grade small
lymphocytic lymphoma patients have a median survival of l0 years, and
treatment is often withheld until symptoms develop. For stage I intermediate
grade lymphoma, greater than 90%Long-term survival may be achieved with
radiation alone or in combination with chemotherapy. Chemotherapy for Other
intermediate-grade and high-grade lymphomas is associated with complete
remission rates of 60% to 70% Or more, and long-term survivals exceeding
30%.
Patients with lymphomas may present to the ED with the complications
of treatment. The acute tumour lysis Syndrome following initial treatment can
produce the Life-threatening metabolic consequences of , renal failure,
hyperkalaemia, hypophosphatemia, and hypocalcaemia, although anticipation,
Allopurinol therapy, and prehydration make this an Uncommon complication.
Acute adverse effects of radiation therapy include dry mouth, pharyngitis,
fatigue, and Weight loss. Radiation pneumonitis and pulmonary fibrosis often
complicate treatment, while myocardial injury is relatively rare. Pelvic
irradiation may be associated with Diarrheal, bladder irritation, and bone
marrow suppression if large fields are irradiated or if the patient was previously
treated. Thermite’s syndrome (paraesthesia in the lower extremities on flexion
of the neck) occurs several months after radiation to the neck and shoulders in
l5% of patients and usually resolves spontaneously.
Chemotherapy causes nausea and vomiting in nearly all patients.
Bone marrow suppression with leukopenia, Thrombocytopenia, and neutropenia
is a common and potentially serious complication. Neutropenia patients are
Susceptible to infection, particularly when their neutrophil count falls below 1.0
x 10⁹ neutrophils per litre (1000 per Cubic millimetre). They commonly present
to the ED with fever or symptoms of infection. They require an evaluation for
possible sites of infection, complete blood count, and early aggressive antibiotic
treatment with consultation. The Emergence of a second malignancy, especially
leukemia or Other lymphoma, is an occasional late complication of radiation or
combined therapy, but is less common than recurrence of the original disease.
SELECTED READING
Carde P Current issues in cancer: Hodgkin’s disease I: Identification and
Classification. Br Med J 1992;305:99 102.
Carde P Current issues in cancer: Hodgkint lymphoma-ll: Treatment and
Delayed morbidily. Br Med J 1992;305:173-176.
Freedman AS, Nadler LM. Malignant lymphomas. In: Harrison s principles Of
internal medicine, l3th ed. New York: McGraw-Hill, 1994;1774-1788.
O’Reilly SE, Connors JM. Current issue in cancer: non-Hodgkin’s lymphoma I:
characterisation and treatment. Br Med J 1992;304:1682-1686.
O’Reilly SE, Connors JM. Current issues in cancer: non-Hodgkin’s lymphoma
II: management problems. Br Med J 1992:305:3942.
PANCYTOPENTA (7.3)
Low blood cell counts may be due to decreased bone marrow
production or increased peripheral destruction. The clinical presentation may be
insidious, often with Nonspecific fatigue due to occult blood loss. Less often
there is obvious hemorrhage or infection. Physical examination may reveal
pallor or petechiae of the skin or mucous membranes. The presence or absence
of lymphadenopathy or splenomegaly assists in narrowing the differential, since
these findings suggest processes other than primary marrow failure.
The prognosis is reflected in the degree of pancytopenia. Severe
complications can be anticipated with leukocyte counts of less than 500/μl,
platelets of less than 20,000/μ1, or anomia with reticulocyte counts of less than
1 More severe disease results in haemorrhagic or infections illnesses.
The etiology can frequently be established on the basis of bone
marrow aspiration and biopsy. Decreased bone Marrow production of
hematopoietic precursors results From a variety of pathologic conditions (see
Table 7-3).
RED BLOOD CELL DTSORDERS (7.4)
Anemia (7.4.1) (See 13.4.1)
The primary function of hemoglobin is the transport of oxygen
and carbon dioxide at the cellular level. Insufficient amounts of
hemoglobin or dysfunctional hemoglobin result in anemia. Anemia may
be due to impaired production of red blood cells, production of abnormal
Erythrocytes, increased peripheral destruction, dilution, or hemorrhage.
Hemolytic (7.4.1.2)
This group of disorders is characterized by an increased destruction of
erythrocy4es. Early RBC
TABLE 7-3. Pathologic conditions associated with pancytopenia
 A. Marrow failure with a hypocellular marrow: aplastic anemia, resulting
from destruction of a common pleuripotential stem Cell
1.Congenital: Fanconi’s anemia, an autosomal recessive disease
2. Toxic
a. Antineoplastic and immunosuppressive drugs
b. and other chronic hydrocarbon exposures
c. Other drugs: chloramphenicol, Suflas, insecticides
3. lonizing radiation
a. accidental exposure
b. therapeutic or occupational exposure
4. lmmunologically mediated mechanisms (such as that associated with
systemic lupus erythematosus)
5. Post infectious aplastic anemia
a. infections, including hepatitis
b. Epstein-Barr viral infections
C. Symptomatically benign upper respiratory infections
6. causes of aplastic anemia (including pregnancy)
7.Idiopathic anaemia’s: most common, causing 50% of cases
B.Marrow failure with normal cellularity: failure of stem cell maturity
1.Myelodysplastic syndromes
a.Usually seen in older individuals
b. May result from chemotherapeutic agents
c. Etiology is often unclear
d. Frequently preleukemicm.
2. Acquired autoimmune deficiency syndrome (AIDS) may cause a primary
marrow failure
C. Marrow failure due to infiltration: myelophthisic anemia; hematopoiesis is
ineffective because marrow is replaced by other cellular elements.
1. Metastatic disease, most commonly from breast, prostate, and lung
carcinoma
2. Primary hematologic malignancies, such as leukemia, lymphoma, or
myeloma
3. Myelofibrosis, osteopetrosis, granulomas, and storage cell disorders
D. lncreased peripheral destruction
1. Hypersplenism-excessive sequestration and destruction of blood cells
within the parenchyma of the spleen
2. nocturnal hemoglobinuria (PNH)-due to a cell membrane defect at the
stem cell level, which results in peripheral hemolysis
a. Increased sensitivity to the hemolytic effects of complement
b. Pancytopenia is usually mild
c. Intermittent gross hemoglobinuria
d. Primarily affects young adults
e. Complicated by both central and peripheral venous thrombosis due
to complement activation
f. Patients may present with abdominal or back pain due to
thrombosis
Destruction occurs most commonly through extravascular Lysis within the
spleen and liver. The reticuloendothelial Systems removes RBCs entrapped
within the microcirculation due to physical abnormalities or to surface
abnormalities such as bound immunoglobulin. Intravascular Hemolysis is the
other mechanism of RBC destruction. Erythrocyte trauma, complement fixation,
or exogenous toxins cause RBC lysis within the circulatory system. Hemolytic
anaemias are a diverse group of disease processes, as illustrated in Table 7-4.
Hemolytic anemia may be either acute or chronic. Acute crises produce
marked anemia, and are the result of intravascular hemolysis. The anemia of
chronic Hemolysis is usually less severe. Physical examination may reveal
icterus, pallor, or bony tenderness. Splenomegaly indicates chronic hemolysis,
which is often complicated by pigment cholelithiasis and signs of Cholecystitis.
Hemolytic anemia is characterized by reticulocytosis in all but the most
acute of presentations, unless there is a concomitant component of marrow
failure. Intravascular hemolysis produces hemoglobinuria and hemoglobinemia.
Unconjugated (or indirect) bilirubin is elevated.
Unconjugated bilirubin is bound to albumin and is not filtered by the kidney;
thus, there is no bilirubin excreted in the urine. In contrast, the
hyperbilirubinemia of primary liver disease results in the presence of bilirubin
in the urine. Haptoglobin is a plasma protein that binds free hemoglobin within
the circulation and is subsequently rapidly removed from the circulation by
phagocytosis. Thus, serum haptoglobin levels are decreased in hemolytic
anemia. Free hemoglobin is bound by albumen to form
methemalbumin;methemalbuminal levels are increased with intravascular
hemolysis.
The peripheral blood smear may demonstrate a number of
abnormalities, depending on the etiology of the hemolytic anemia. Fragmented
RBCs suggest traumatic injury, such as that due to cardiac valvular disease or to
a Microangiopathic process. Spherocytes, sickle cells, spiculated erythrocytes
(acanthocytes), and target cells each suggest specific disease processes.
TABLE 7-4. Types of hemolytic anaemias
Intracorpuscular defects
Red cell membrane defects
Hereditary spherocytosis
Paroxysmal nocturnal hemoglobin
Abnormal erythrocyte metabolism
G6PD deficiency
Defective reducing power
Hemoglobin disorders/hemoglobinopathies
Sickle cell disease
 Thalassemia-u, -B
Unstable haemoglobins
Extracorpuscular defects
Microangiopathic hemolysis
Hemolytic uremic syndrome
Diseased and prosthetic heart valves
Primary pulmonary hypertension
Immune hemolysis (autoimmune hemolytic disease)
Drug -related immune hemolysis
Delayed hemolysis of transfused RBCs
Cold agglutinin disease
Miscellaneous
Hypersplenism
Copper toxicity
Clostridium perfringens toxin
Lead toxicity
 Aplastic (B19 parvovirus)
Snake venoms
Freshwater drowning
Eclampsia
Malaria / babesiosis
From Pollack CV. Emergencies in sickle cell disease. ln: Moore GB Jorden RC,
eds. Emergency medicine clinics of North America: hematologic/oncologic
emergencies. New York: McGraw-Hill, 1 993;365.
The types of congenital hemolytic anemia resulting from
intracorpuscular defects include three membrane Defects: spherocytosis,
elliptocytosis, and stomatocytosis. These defects render the cells more
susceptible to lysis due to osmotic fragility of the cell membrane.
Glucose-6-Phosphate Dehydrogenase Deficiency
Enzymatic defects in erythrocyte ability to metabolize cellular
toxins result in premature RBC death. The most common of these is glucose-6-
phosphate dehydrogenase (G6PD) deficiency, frequently seen in descendants of
populations from central African and eastern Mediterranean areas. Clinically
significant hemolysis develops only when the cellular environment is stressed
beyond capacity. Common precipitating factors include infections, drugs such
as sulfa compounds and antimalarials , and metabolic acidosis. Mediterranean-
type G6PD deficiency may present with a chronic hemolytic anemia due to a
more severe enzymatic deficiency. Some patients may develop acute hemolytic
crisis with exposure to fava beans.
Extracorpuscular defects include a group of disorders that result in
microangiopathic hemolysis. Mechanical trauma may occur when RBCs in the
microcirculation are impacted by physical activities. Prolonged jogging or
Marching may result in hemolysis of normal RBCs. Mechanical trauma from
shear stresses may fragment RBCs as they flow across pressure gradients
created by diseased or prosthetic cardiac valves. This occurs primarily with
nonporcine aortic valve prostheses, paravalvularleaks, or severe calcific aortic
stenosis. Intrinsic vessel disease leading to fibrin deposition and hemolytic
anemia occurs in eclampsia, malignant hypertension, renal graft rejection, and
haemangioma.
Hemolytic Uremic Syndrome
Hemolytic uremic syndrome, a disorder of unclear etiology with a
mortality rate that approaches 20010, occurs in children. It consists of a
constellation of findings including acute hemolysis, thrombocytopenic purpura,
and acute oliguric renal failure. Often there is a viral prodrome. Treatment
consists of transfusion and dialysis. A Similar clinical picture occurs with
thrombotic thrombocytopenic purpura (TTP), which most commonly affects
young women and is of unknown etiology. Acute hemolysis and
thrombocytopenia occur in the face of normal coagulation tests. Fever,
hemorrhage, constitutional symptoms, hepatosplenomegaly, and progressive
renal failure occur. The clinical hallmark of TTP is neurologic involvement
including altered mental status, focal findings, seizure, and coma. Treatment
consists of high-dose corticosteroids and plasmapheresis.
Immune hemolysis occurs when antibodies coat RBCs and induce
lysis. There is a spectrum of clinical presentations, from laboratory
abnormalities with normal hemoglobin levels to fulminant hemolysis. This
process may complicate lymphomas or systemic lupus erythematosus; It may
occur as an idiosyncratic reaction to drugs (crMethyldopa, penicillin,
quinidine); or it may be idiopathic. Treatment consists of steroids, splenectomy,
or immunosuppressive drugs. Complement fixation causes hemolysis in a group
of disorders in which antibodies become reactive in colder ambient
temperatures. So called cold agglutinin disease is associated with infectious
mononucleosis, mycoplasma pneumonia, and lymphoproliferative diseases.
Transfusions may accelerate the hemolytic process and are contraindicated.
Immunosuppressive therapy may be palliative. A similar immunohemolytic
process occurs with transfused RBCs via previously acquired antibodies or
pregnancy.
The Coombs test is diagnostic of immune hemolysis. A direct Coombs
test is positive if specific animal antisera cause agglutination of a patient’s
RBCs. An indirect coombs test distinguishes whether there is an antibody in a
patient’s serum that may react against other human RBCs.

Hypochromic/ Mirocytic ( 7.4.1.3)

This group of anaemias occurs as a result of marrow hypoproliferation.
The most common cause of microcytic anemia is iron deficiency anemia.
Causes of iron deficiency include physiologic changes (pregnancy,
menstruation), bleeding, chronic hemolytic disease, or decrease iron intake
(dietary deficiency, malabsorption). The most common causes of iron
deficiency anemia are menstrual and gastrointestinal blood losses.
Erythrocyte precursors require iron in the synthesis of heme from
porphyrin. Insufficient supplies of iron result in Erythrocytes that are smaller in
size with pigment. This insufficiency is reflected by decreased serum iron levels
and a decrease in transferrin saturation. Transferrin is a protein that binds and
delivers iron to tissues. The total of all binding sites of circulating transferrin
make up the total iron binding capacity (TIBC) of plasma. In the normal State,
20% to 45% of the transfenin binding sites are filled with iron. Thus, in addition
to low circulating levels of iron, the TIBC is high. The reticulocyte count is
normal, Because there is insufficient substrate for erythroid precursors to
proliferate. Serum ferritin levels, reflect iron stores in the body, are depressed in
iron deficiency states.
Patients with suspected iron deficiency anemia should be evaluated
for hemodynamic compromise. Possible Extravascular blood loss should be
sought, and menstrual/pregnancy status verified. Treatment of severe anemia
may require packed red cell transfusion, but more Commonly is accomplished
with iron replacement therapy. Oral ferrous sulfate 300 mg (60 mg elemental
iron) Three times daily for 6 months restores total body stores. Absorption is
highest if taken between meals, but therapy may be better tolerated if taken with
food.
Microcytic iron-deficiency anemia is an important manifestation of
chronic lead toxicity, especially in the Paediatric population. Free erythrocyte
protoporphyrin (FEP) and serum lead assays confirm the diagnosis.
 Sideroblastic anemia involve the inhibition of heme synthesis and
present with microcytic, hypochromic indices. This group of disorders may be
hereditary or acquired. The acquired forms may be associated with
inflammatory or neoplastic processes or due to specific agents including
isoniazid{ alcohol, lead” and chemotherapy agents. Most commonly, acquired
Sideroblastic anemia is idiopathic and occurs in older patients. The common
thread in this group of disorders is the appearance of a morphologically
peculiar cell within the marrow, Termed the ringed Sideroblastic. This is due to
pathologic accumulation of iron around the nuclei of erythroid precursors,
which results from an ineffective utilization of iron. Treatment is supportive and
includes withdrawal of toxins, a trial of pyridoxine, and possible marrow
stimulators, such as erythropoietion.

Megaloblastic (7. 4. 1.4)

Megaloblastic anemia is the result of erlthrocyte hypoproliferation.
DNA synthesis is impaired, yet precursor cell growth continues, resulting in a
macrocytosis and elevated RBC indices. Megaloblastic cells are destroyed
within the marrow, resulting in ineffective erythropoiesis. abnormal cell
morphology is evident on the peripheral smear, including macrocytosis with a
mean corpuscular volume (MCV) over 100, hypersegmented neutrophils, and
giant platelets. The reticulocyte index is characteristically normal.
Folate is necessary in the synthesis of many macromolecules and its
deficiency results in a megaloblastic Anemia. The primary sources of folates are
fruits and vegetables.
Dietary deficiencies, malabsorption disorders, increased physiologic
demands (e.g., pregnancy), and toxins can cause folate deficiencies. Ethanol
depletes hepatic stores of folate. Methotrexate acts as a folate antagonist by
inhibiting dihydrofolate reductase, the enzyme that converts folate to its active
state. Other toxins such as triamterene and trimethoprim act as folate
antagonists. Diagnosis is confirmed by serum folate assay, and treatment
consists of oral folate replacement, 1mg daily, with dietary correction.
Vitamin B12 (cyanocobalamin) is an essential cofactor in
biochemical reactions, including folate metabolism. The primary dietary source
is animal products. Vitamin B12 deficiency results in a megaloblastic anemia.
Dietary deficiency, malabsorption, or competition for vitamin B12 are the
principal causes. A spectrum of neurologic symptoms, including peripheral and
central manifestations, as well organic psychoses, are associated with B12
deficiency. These symptoms are a result of demyelination and may be
irreversible.
Absorption of vitamin B12 depends on a glycoprotein (intrinsic
factor), produced by parietal cells ofthe gastricmucosa. Ingested B12 joins with
intrinsic factoq preventing proteolytic destruction and allowing absorption of
B12 in the terminal ileum. Pernicious anemia is the most common cause of B12
deficiency. This involves an autoimmune destruction of parietal cells with
gastricmucosal atrophy, reducing the production of intrinsic factor. This
condition occurs most frequently in patients over age 60.
Other causes of vitamin B12 deficiency megaloblastic anemia
include partial and total gastrectomy, congenital abnormalities of the gastric
mucosa, and competitive absorption of B12 due to excessive bacterial
colonization of the small intestine within strictures, diverticula, or blind loops.
Fish tapeworm infestation is a competitive Type of B12 deficiency seen rarely
in the United States. Antineoplastic drugs may result in megaloblastic anemia
due to inhibition of DNA synthesis. Macrocytosis may also be cause by
hemolysis, alcoholism, hypothyroidism, and hepatic disease.
The diagnosis of B12 deficiency is confirmed by serumassay. The
Schilling test can define etiology. Oral radiolabeled cobalamin is administered;
a 24-hour urine collection reflects the absorption of cobalamin. In the second
part of the Schilling test, a radiolabeled cboalamin-intrinsic factor complex is
administered, and absorption is again measured. Low absorption in the first
stage, with normalized absorption in the second, suggests pernicious anemia.
Low absorption in both stages suggests bacterial overgrowth.
Treatment consists of intramuscular replacement with vitamin B12.

Normochromic Normoqttic (7.4. 1, 5)

Anemia with normal RBC indices include a wide variely ofdisorders
ofdiverse etiology, but generally fall into two groupings-marrow
hypoproliferation and hemorrhage. Acute extravascular blood loss, whether
apparent Or occult, must be ruled out in any patient presenting with a low
hematocrit and normal indices. Mild iron deficiency anemia presents with a
normal MCV Aplastic anemia is also characterized by normal indices.
Similarly, pura red cell aplasia is manifest by a normochromic, normocytic
anemia with normal leukocyte and platelet counts.
Chronic renal failure results in a deficiency oferythropoietin, a
glycoprotein hematopoietic growth factor synthesized by kidney cells in
response to alterations in tisdue oxygen tension in the renal microcirculation.
Epogen, human recombinant erythropoietin, administered parenterally three
times weekly, is used to treat this condition.
A wide variety of miscellaneous disorders are associated with a chronic
normocytic, normochromic anemia. These include chronic inflammatory
conditions such a rheumatoid arthritis, systemic lupus erythematosus, the
vasculitides, and sarcoidosis. Chronic infectious processes such as tuberculosis,
subacute bacterial endocarditis, osteomyelitis, and lung abscesses demonstrate a
similar type of anemia. The anemia is of mild to moderate severity and the
reticulocyte count is not elevated. A group of hormone deficiency states, such as
hypothyroidism, panhypopituitarism, and Addison’s disease, include anemia as
a manifestation. These are correctable by adequate hormone replacement.
The diagnosis of these disorders is usually one of exclusion after a trial
of iron replacement fails to improve the hematocrit. Treatment is aimed at
correction of underlying pathology. The degree of anemia is seldom severe
enough to warrant transfusion therapy. Hematinic agents such as iron, folate,
and vitamin B12 are ineffective in restoring normal blood counts unless there
are specific deficiencies of these agents associated with the chronic process.

Hemoglobinopathies (7.4. 1.6) (See I 3.4.2)

Sickle Cell Disease/Trait.
Adult hemoglobin (Hg A, a2b2) consists of four globinchains, two
c and two Blinked to a heme moiety. Many hemoglobin variants exist, but the
most clinically significant is due to Hg S. Hg S differs from Hg A by the
substitution of valine for glutamic acid at the sixth position of the p chain. This
biochemical substitution results in an alteration of the physical molecular
structure, providing the basis for the pathophysiology of sickle cell disease
(SCD). When Hg S is deoxygenated the strands elongate. these strands of Hg S
cause the characteristic sickleshaped erythrocytes. Such RBC deformities
obstruct the microcirculation, producing microinfarcts within organs. the
chronic hemolytic anemia associated with SCD is a result of mechanical
fragility.
SCD occurs in populations descended from areas where malaria is
endemic, and is thought to provide a protective mechanism in this disease,
which resulted in genetic selection. In the United States, 8% of the
Africanamerican population carries the Hg S gene. The homozygous state, Hg
SS, occurs in0.l5%o of this population and results in SCD. The heterozygous
population, HgSA, is termed sickle trait. With trait, there is no sickling unless
patients are subject to significant hypoxia, e.g., high altitude. There is an
increased incidence of spontaneous hematuria, splenic infarcts, hyphema, and
leg ulcers in these individuals. Hemoglobin electrophoresis is diagnostic.
Multiple heterozygous variants occur. Hg SC results in a variable
phenotypic expression, from asymptomatic to full disease. Retinopathy,
avascular osteonecrosis, and acute chest syndrome are common. HgSBthal is
prone to symptomatic disease and splenomegaly.
Diagnosis is usually made at 6 to 12 months of age, asfetal
hemoglobin (Hg F) declines. Infants often present with acute dactylitis, a
symmetric painful swelling of the hands and feet due to bony infarcts.
Veno-occlusion and susceptibility to infection account for the
manifestations of SCD. Infections due to encapsulated microorganisms
(Streptococcus pneumoniae, haemophilus influenzae, and Salmonella) are
particularly severe, in part because these patients are functionally asplenic. The
lungs, urinary tract, and bones are frequently affected. Pediatnc patients are
susceptible to meningitis and sepsis; up to 30% of affected children develop
these conditions by age 5. Chronic penicillin prophylaxis may alter the clinical
and culture results. Sickle cell patients younger than 5 years should be admitted
for intravenous therapy when infection is clinically suspected or proven.
 Acute painful crises are the most common emergency presentation in
adult sicklers. The long bones are more frequently affected than the axial
skeleton. There is local tenderness on examination in the absence of a history of
trauma. Repeated episodes result in avascular necrosis, especially in the hip and
digits. There is no objective method to confirm this diagnosis, either clinically
or in the laboratory. Precipitating factors that elicit or worsen sickling should be
sought. These include infection, emotional stress, hypoxia, acidosis,
dehydration, hemorrhage, and exposure to cold ambient temperatures. Other
causes of bony pain must be ruled out, including osteomyelitis and
inflammatory arthritides.
Acute painful crises may also involve the chest, presenting with
severe pain, usually of a pleuritic nature, accompanied by dyspnea and
hyperventilation. This is most frequently seen in the paediatrics population.
Nonproductive cough may occur in the absence of acute infection. This is a
diagnosis of exclusion and other causes of chest pain such as pneumonia,
pulmonary infarcts, and myocardial ischemia must be eliminated.
An acute painful crisis involving the abdomen may occur. The
examination is generally benign. This is also a diagnosis of exclusion, and a
coordinated emergency evaluation, including lab tests, x-rays, ultrasound
examination, and CT scan, is usually required to rule out other causes of
abdominal pain. In particular, intraabdominal processes unique to SCD, such as
splenic and hepatic infarcts and splenic sequestration syndrome, should be
sought during the evaluation.
Moderate leukocytosis of 12,000 to 17,000 cells/mm is common in
uncomplicated sickle cell crisis, and at baseline. Low-grade fever may be
present with pain crises. Lab evaluation should be tailored to the presenting
complaint and findings on physical examination, and specifically focus on
excluding infection. This should include a CBC, and comparison with baseline
values. A reticulocy count should be elevated in acute crises, unless there is an
aplastic crisis. Hematuria may occur independent of urinary tract infections or
nephrolithiasis. Laboratory evaluation should generally be more inclusive in the
pediatric population.
Treatment of painful crisis should focus on hydration, at least two
times maintenance level. With vomiting or altered mental status, intravenous
hydration may be necessary. Although there is tissue hypoxia, supplemental
oxygen has not been demonstrated to be of any benefit in limiting or relieving
painful crises in the absence of other indications for oxygen therapy. Care must
be taken to provide the patient with sufficient analgesia in a timely maanner.
Patients can often guide their own therapy; they may be familiar with analgesics
and doses that have been successful in the past. Patients may be maintained at
home for chronic pain with daily analgesic therapy and an additional agent for
breakthrough pain symptoms.knowledge of the patients’ home medication
regimen may assist in tailoring analgesics for them. Potent oral narcotics are
available (e.g., morphine elixir) with a relatively rapid onset (usually within 30
minutes), and can be titrated with additional doses every 30 minutes. If IV
access is initiated for other indications, titration of intravanous narcotics can be
effective in relieving pain. patients who require admission may benefit from
continuous infusion devices involving patient-controlled analgesia regimens
(PCA pumps). Other parenteral routes of administration, such as intramuscular
and subcutaneous, should be avoided since absorption is erratic, doses are more
difficult to titrate, and areas of repeated injections develop calcific scarring. If
neede4 antiemetic may be provided parenterally or by suppository. Parenteral
NSAIDs such as ketoralac have not been demonstrated to be of much relief.
Infections should be treated with appropriate antibiotic coverage, usually
ceftriaxone, with additional coverage if salmonella osteomyelitis or enteritis is
suspected.
Pain crises usually resolve within 4 to 6 days, and may require
admission if not adequately controlled in the ED.patients who are able to be
discharged from the ED should be provided with adequate oral analgesia and
close follow-up. Recurrent emergency visits within days mandate thorough
reevaluation for precipitating causes.
Patients with SCD are subject to several processes affecting the
cardiopulmonary system in addition to pneumonia. Pulmonary infarcts from
vaso-occlusion may occur and accumulate over time. Chronic tissue hypoxia
may lead to the development of pulmonary hypertension and cor pulmonale.
Cardiomegaly develops as a response to a high-output type of congestive heart
failure and may progress to cardiomyopathy. Adult sicklers may have atypical
chest pain, baseline hypoxia, or a widened arterial to alveolar oxygen gradient.
The typical chest radiqgraph shows bibasilar congestion due to a low-level
congestive heart failure. Patients are also at risk for chronic pulmonary emboli
from peripheral venous thrombosis or fat emboli from marrow.
Hematologic complications of SCD may include symptomatic
anemia due to acute illness, with an elevated reticulocyte count. A pediatric
complication is the aplastic crisis, or acute marrow failure due to infection or
folate deficiency. A reduced reticulocyte count is pathognomonic. This is
usually reversible.
 Acute splenic sequestration of sickle cells may occur spontaneously
and may result in a sudden precarious drop in hemoglobin to levels as low as I
to 2. Presentation may be dramatic, with hypotension, syncope, and painful
splenomegaly. Vigorous fluid resuscitation and transfusion, as well as a search
for underlying infection as a precipitating cause, is indicated. This occurs in
children under age 6 in those with sickle cell anemia; after this age, the spleen
autoinfarcts and is no longer functional. Acute sequestration may occur into
adulthood in patients with SC or Spthal disease in whom splenomegaly persists.
Neurologic complications in SCD include transient ischemic attacks
and stroke, with a high incidence in the pediatric population. Ischemic cerebral
infarction results from RBC sickle occlusion of large vessels. The risk of
recurrent cerebrovascular accident (VA) is also high. Treatment and diagnosis
should parallel that of non-SCD patients, as well as a particular search for
infection. In addition, exchange transfusion is indicated to improve blood flow
to the infarcted area in an effort to salvage the penumbra of tissue at risk.
Chronic transfusion therapy after a CNS infarct has been shown to decrease the
risk of recurrence. Sicklers also have an increased risk of cerebral and
subarachnoid hemorrhage with age. Subarachnoid, subdural, and epidural
hemorrhages afemanaged in the usual fashion.
 Genitourinary complications of SCD may include gross painless
hematuria secondary to renal parenchymal vaso-occlusion. Renal colic with
gross hematuria results from renal papillary necrosis. Management is the same
as that for non-SCD patients, with generous hydration priorto the administration
of hyperosmolar contrast, or the use ofnonionic contrast. Sickle sludging in the
corpora cavernosa of the penis may cause priapism, which may persist for days
if untreated. Management includes hydration, analgesia, and, sedation as
needed. Urgent urologic consultation for needle aspiration of the corpora or an
operative shunting procedure may be indicated.
Other complications of SCD include leg ulcers. Pathogenesis and
treatment is the same as that for the microvasculopathy of diabetes.
Ophthalmologic complications include proliferative retinopathy, retinal
infarctions, and retinal detachment. Avascular necrosis, particularly of the digits
in children and of the femoral head in young adults, is a complication that must
be differentiated from osteomyelitis. The chronic hemolysis associated with
SCD results in accumulation of pigment cholelithiasis; acute inflammatory
cholecystitis must be treated surgically.
The psychosocial aspects of SCD cannot be underestimated. There is
a large proportion of SCD patients who suffer complications less than yearly. A
minority of SCD patients have frequent clinical deteriorations resulting in the
need for hospitalization and ongoing debility. There is another group of
individuals who have a chronic pain syndrome; their reaction depends on their
coping mechanisms. Those with poorer coping mechanisms have organic
depression and dependent-type personality traits. Because there is no objective
evidence for painful sickle crisis, some caregivers may tend to underestimate
the behavior of SCD patients. There are no data that demonstrate an increase in
drug-seeking behavior or drug addiction in this population. Many SCD patients
are from disadvantaged backgrounds and use the ED as a primary source for
acute care. Nonjudgmental compassion and appropriate medical care should
guide the evaluation of each SCD patient.
Thalassemia
The thalassemias are a hereditary group of anemias resulting from a
quantitative defect in the synthesis of globin chains. They are found among
patients descending from the Mediterranean and African countries, the Middle
East, and Southeast Asia. Hemoglobin production is deceased, and the RBCs
are microcytic and hypochromic, more profoundly so than that found in iron
deficiency anemia. Cr-Thalassemia is the deficient production of the A globin.
Cr-Thalassemia trait results in a normal hemoglobin level with microcytosis.
Homozygous G-thalassemia causes a condition known as
hydrops , which results in stillbirth.
Insufficient production of p globin is termed B-tha- lassemia. B-
Thalassemia minor, or B-thalassemia trait, causes a mild microcytic anemia.
The diagnosis is made by hemoglobin electrophoresis. No treatment except
genetic counseling is indicated, and iron therapy is contraindicated. P-
Thalassemia major is the most severe form of congenital hemolytic anemia.
Patients develop a severe anemia in infancy and have retarded growth and
development. As a compensatory mechanism, bony medullary hypertrophy
develops, resulting in skeletal abnormalities. Patients demonstrate signs of
chronic hemolysis, high output cardiac failure, and a typical skin coloring
sometimes characterized as bronze. Patients are transfusion dependent, and may
become iron overloaded. Life expectancy is decreased. Definitive therapy is
bone marrow transplantation. Prenatal diagnosis of B-tha lassemia major is
accomplished by DNA analysis of amniotic fluid cells.

Polycythemia (7.4.2)
 Polycythemia refers to a condition of increased hemoglobin (>18 g/dl)
and hematocrit (>56%).It may be due to an absolute increase in red cell mass, or
to a relative decrease in plasma volume. This relative erythrocytosis may be
caused by any source of dehydration, and treatment is aimed at correction of the
underlying disorder. absolute erythrocytosis may be a physiologic response. any
condition resulting in chronic hypoxia, such as chronic lung disease or high
altitudes, acts as a stimulus for increased erythropoeisis. Tobacco smoking
causes a polycythemia due to the relative tissue hypoxia caused by chronically
elevated carboxyhemoglobin levels. Pathophysiologically, polycythemia causes
increased blood viscosity and sludging in the microcirculation.
Polycythemia rubra vera (p. Vera) is a disease process where there is
absolute erythrocytosis in the absence of hypoxemia and splenomegaly. The
minor associated criteria for this diagnosis are thrombocytosis, leukocytosis,
increased leukocyte alkaline phosphatase, and increased vitamin B12 levels.
The common presentations are ischemic cerebral infarcts and acute Budd-Chiari
syndrome. This is acute thrombosis of the hepatic veins or the infrahepatic vena
cava resulting in the acute onset of massive ascites. Treatment is surgical
thrombectomy. maintenance treatment of p. Vera is chronic phlebotomy.

SELECTED READING
 Babior BH, Bunn HF. Megaloblastic anemias. In: Isselbacher l(J, Braun-
Wald E, Wilson JD,etal. Harrison’s principles of internal medicine, 13th Ed.
New York: McGraw-Hill, 1994;17 26-17 32.
Bayless PA. Selected red cell disorders. In: Moore GP, Jorden RC, eds.
emergency ntedical clinics of North America: hematologic oncologic
emergencies. Philadelphia: Saunders, 1993;481493.
Bridges KR, Bunn HF. Anemias with disturbed iron metabolism. In:
Isselbacher KJ, Braunwald E, Wilson JD, et al. Harrison’s principles of internal
medicine, 13th ed. New York: McGraw-Hill, 1994;1721-1726.
Bum HF. Disorders of hemoglobin. In: Isselbacher KJ, Braunwald E, Wilson
JD, et al. Harrisons principles ofinternal medicine, 13th ed. New york: McGraw-
Hill, 1994;1734 17 43.
Bunn HF. Anemia associated with chronic disorders. In: Isselbacher KJ,
braunwald E, Wilson JD, et al. Hanisonb principles of internal medicine, 13th
ed. NewYork: McGraw-Hill, 1994;1732-1734. pollack CV Emergencies in
sickle cell disease. In: Moore GP, Jorden RC.
Emergency medical clinics of North America: hematologic oncologic
emergencies. Philadelphia: Saunders, 1993;365-31 8.
 Rappeport JM, Bunn HF. Bone marrow failure: aplastic anemia and other
primary bone marrow disorders. In: Isselbacher KJ, Braunwald E, Wil-Son JD,
et aI. Harrisons principles ofinternal medicine, l3th ed. NewYork: McGraw-
Hill, 1994;1754-17 57 .
Rosse W, Bunn HF. Hemolyic anemias. In: Isselbacher KJ, Braunwald E,
wilson JD, et al. Harrison’s principles of internal medicine, 13th ed. New York:
McGraw-Hill, 1994; 17 43-1’7 54.
TRANSFUSTONS (7.s).
Component Therapy (7.5.3)
Techniques for crossmatching, anticoagulation, preservation, and storage of
blood have allowed for the practical use of blood since World War II. Type O
universal donor blood was used successfully during the vietnam War, and in the
1970s, transfusion of blood components, rather than whole blood, became
standard. advances in blood banking and transfusion technology continue to
improve the safety and efficacy of blood component therapy.
Blood Banking and Compatibilily Testing
Each unit of donor blood is typed for ABO and Rh red cell antigens, is
screened for unusual antibodies to other red cell antigens, and is tested for
infectious disease markers. If a unit of donor blood has no evidence of
infectious disease it may be used as whole blood” or may be separated into
components such as packed red blood cells (PRBCs), fresh frozen plasma
(FFP), cryoprecipitate, or leukocytes. To produce these components whole
blood is centrifuged at low speed to separate the red cells from plasma and
platelets. The platelet-rich plasma is then centrifuged at high speed to separate
plasma from the platelet pellet. Albumin can be isolated from plasma by ethanol
fractionation, and cryoprecipitate can be produced by freezing plasma and then
collecting the insoluble proteins that separate out as the plasma is slowly
thawed. Alternatively, greater quantities of platelets, plasma, or leukocytes can
be collected from a single donor by apheresis. This technique involves
collecting and centrifuging donor blood. Unneeded components are then
returned to the donor.
Storage of separate blood components is superior to storage of whole blood
since each component can be stored under different conditions to optimally
preserve its function. PRBCs can be stored up to 42 days when refrigerated
between 1T and 6TC. Red cells can also be frozen and stored up to l0 years.
Platelets are stored at room temperature since their function is impaired by
freezing and refrigeration; and platelets must be used within 5 days of collection
because of the risk of bacterial contamination. FFP is plasma thours of
collection to prevent plasma proteins from egenerating. Cryoprecipitate is also
frozen an4 like FFR can be stored up to one yea can be stored up to one year.
When the potential need for blood arises, a type and screen should be
ordered. It takes 5 to l0 minutes to type a sample of the recipient’s blood for
ABO and Rh antigens. Type specific blood could then be made available to the
patient. The recipie ohemagglutinin antibody, respectively. For example, type A
individuals produce anti-B and type AB nt’s blood is also screened for
preexisting antibodies to other red cell antigens. This screen usually requires at
least 30 minutes to complete; a type andcrossmatch can then be completed
within another 5 to 10 minutes. Units of blood that have been typed and
crossmatched are typically not made available to other patients for 72 hours.
A and B antigens, or agglutinogens, are genetically determined
molecules found on red cell membranes.individuals whose red cells do not
contain A and/or B antigen produce anti-A and/or anti-B immunoglobulin
M(IgM) is individuals produce neither anti-A nor anti-B. Identification ofABO
blood type is important since transfusion ofABO incompatible blood will result
in an intravascular hemolytic reaction (agglutination) that can be life
threatening. Individuals with type O blood (45% of Caucasians and49%o of
African-Americans) are referred to as universal donors since their red cells can
be given to patients with any ABO blood type; and those with type AB blood
(4% of Caucasians and African Americans) are referred to as universal
recipients since they have no anti-A or anti-B antibodies and can receive red
cells of any ABO type. Forly percent of Caucasians and 27o/o of African
americans have type A blood and ll%o and 20o/o have type B blood”
respectively.
The Rh antigen (most commonly the D antigen) is present on the red cell
surface of approximately 85oh of individuals. Unlike the ABO system, those
who are Rh negative have no naturally occurring antibodies to the Rhantigen.
However, they may become sensitized and produce antibodies (usually IgG),
with a 30o/o to 50% incidence following fetal/maternal blood mixing or
transfusion of Rh positive blood. Sensitized individuals are at risk of transfusion
reactions in the future. Rh positive fetuses of sensitized Rh negative mothers are
at risk of erythroblastosis fetalis or isoimmune hemolytic disease of the
newborn. Therefore, when transfusing an Rh negative woman of childbearing
potential, only Rh negative blood products should be used. If Rh negative blood
products are not available, RhoGAM (300 pg intramuscularly) should be given
with the transfusion. It should also be administered whenever fetallmaternal
blood mixing is suspected in a mother who is Rh negative. RhoGAM contains
human anti-Rh IgG andproduces passive immunity. Circulating Rh positive
antigen is thereby neutralized, and the development of active immunity in an Rh
negative patient is suppressed.
Over 350 other potential red cell antigens are known to exist to which
blood recipients may either have naturally occurring antibodies or produce
antibodies following an exposure to these foreign antigens. These latter
alloantibodies may cause clinical sequelae during subsequent transfusions;
however, naturally occurring antibodies rarely cause hemolysis or other
transfusion problems. Rather than complete testing of donor and recipient blood
for all possible red cell antigen/antibody incompatibilities, a screen for the most
common (yetrarely found) alloantibodies (e.g., Duffy, Kell, Kidd, lutheran,
MNS, P) is performed during a type and screen.
Crossmatching, or compatibility testing, refers to mixing recipient and
donor blood and observing for macroscopic or microscopic agglutination
(antigen-antibody reaction). Mixing recipients plasma with donor red cells is
called the major crossmatch. The minor crossmatch is performed by mixing
recipients red cells with donor plasma, but is no longer routinely performed.
The crossmatch contributes little additional safety to a transfusion, but may
reveal an error made during the donor or recipient type and screen.

Administration of Blood Prodacts.

 Transfusion of blood and blood products can be used to correct
hypovolemia, anemia, thrombocytopenia, and coagulopathy. Specific
component therapy should be determined by the clinical needs of the patient.

Red Cells
Transfusion of red cells may be indicated whenever tissue oxygen
delivery is inadequate secondary to an insufficient amount of hemoglobin, and
the delay necessary for correction of the anemia (e.g., iron, vitamin Brz, folic
acid, erythropoietin) cannot be tolerated. Hematocrit and hemoglobin values
may not be reliable, especially in cases of acute blood loss; and the decision to
transfuse should be based on clinical status ratherthan an automatic numerical
threshold (e.g., hemoglobin less than 8 or 10 g/dl). Physiologic compensation
for chronic anemia may allow patients to remain relatively asymptomatic even
with hemoglobins of 7 gldl or less. However, patients with more rapidly
developing anemia (e.g., secondary to acute blood loss) and those with
comorbidity such as pulmonary, peripheral vascular or cardiac disease may not
tolerate low hemoglobin states as well.
Red blood cells undergo significant biochemical changes during
storage. This storage lesion includes a decrease in red cell pliability; diminished
red cell concentrations of 2,3-diphosphoglycerate (2,3-DPG) and adenosine
triphosphate (ATP); a left-shift of the Hemoglobin-oxygen dissociation curve;
hemolysis resulting in elevation of plasma potassium, lactate dehydrogenase
(LDH), and free hemoglobin; and, production of waste products including
ammonia and lactate resulting in a de plasma pH.
A unit of whole blood contains about 450 ml of blood with a
hematocrit between 35oh and 40o/o and 50 ml of anticoagulant/preservative.
Whole blood provides red cells, volume expansion, and some coagulation
factors, and remains the ideal resuscitation fluid for patients with significant
acute blood loss. However, the banking of fresh whole blood is not practical or
efficient, so it is rarely available in the ED setting. Stored whole blood is devoid
of functional platelets and contains decreased amounts of labile clotting factors
(i.e., factors V and VIID.
PRBCs have become the component of choice for correction
ofreduced oxygen carrying capacity. A unit of PRBCs has a hematocrit between
65% and 80% and contains about 300 ml of volume. Unlike whole bloo4 a unit
of PRBCs has only about 50 ml of plasma that may contain ABO alloantibodies.
Therefore, compatible, but not necessarily ABO identical, PRBCs can be given
if necessary since the risk of graft-versus-host reaction is minimal. Type
specific or type O universal donor blood can be given safely to patients
presenting with hemorrhagic shock resistant to crystalloid therapy who cannot
wait the minimum of 45 minutes necessary to complete a type and crossmatch.
PRBCs are also devoid of functioning platelets and clotting factors, and
simultaneous administration of FFP and/or platelets may be necessary.
Each unit of whole blood or PRBCs ideally should be infused within 2
to 4 hours. However, there is no limit to the rate of red cell transfusion or to the
number of units that can be simultaneously infused in the unstable patient. A
diuretic (e.g., furosemide) may be given for patients who are at risk of fluid
overload. Standard blood infusion sets containing an in-line 170-pm filter to
remove large particles allow for rapid infusion of 2 to 3 units before becoming
obstructed. Filters with 40-pm pores may be used for newborns, patients
needing multiple units, or patients with significant pulmonary dysfunction.
Addition of 60 to 100 ml of 0.9o/o sodium chloride to each unit of PRBCs
reduces viscosity and allows for more rapid infusion.
A rise in the hemoglobin of I gldl (hematocrit rise of 3%) can be
expected after transfusion of one unit of whole blood or PRBCs in an adult. In a
chil4 a hematocrit rise of 1% can be expected after transfusion of 1 Ml/kg of
PRBCs.
 Leukocytes can be removed from PRBCs by centrifugation, filtration,
and sedimentation. These more costly alternatives may be necessary for patients
with a history of nonhemolytic febrile transfusion reactions. Washed PRBCs
may also be needed for patients who cannot tolerate leukocytes, plasma, platelet
debris, or the extra potassium normally contained in PRBCs.

Plasma.
A unit of FFP contains between 180 and 300 ml of anticoagulated
plasma, including most of the coagulation factors, albumin, and other proteins
present in a unit of fresh whole blood. FFP contains no cells, platelets, or
cellular debris, but may have red cell antibodies. Therefore, FFP must be ABO
compatible but does not need to be Rhcompatible or crossmatched. FFP should
be ordered as soon as the need is recognized since thawing time is
approximately t hour.
FFP is indicated for correction of coagulopathies of unknown etiology
and coagulopathies caused by deficiencies of multiple coagulation factors
including those vitamin K-dependent factors affected by Coumadin therapy.
FFP may also be given for known factor deficiencies, such as hemophilia A or
B, if specific factor concentrates or cryoprecipitate are not available. FFP is not
indicated for nutritional purposes or for volume expansion since it has no
proven benefit over crystalloid therapy.
The usual initial dose of FFP is one or two units, but larger volumes
may be required depending on the extent ofthe coagulopathy. Each unit of FFP
raises all coagulation factors by 2% to 3% in an average adult. Laboratory
assays of coagulation function (i.e., PT and PTT) along with the patient’s
clinical status should be monitored to evaluate the response to FFP
administration. Infusion of 5 to 10 ml/kg of FFP rapidly corrects most
coagulopathies and bleeding caused by Coumadin.
Each unit of FFP may be given over 15 to 20 minutes to patients with
healthy cardiovascular systems. Patients prone to fluid overload should be given
FFP more slowly, and administration of furosemide should also be considered.
FFP can be infused through a filter with pores as small as 5 pm, but standard
filters are probably adequate.

Platelets
A single unit of platelets contains most of the platelets separated from a
single unit of donor whole blood. These are resuspended in 20 to 70 ml of
plasma. Platelet concentrates may contain red cells, red cell fragments, and
lymphocytes, depending on preparation technique. Therefore, platelets should
be type specific, but do not need to be crossmatched. ABO typing is not an
absolute requirement in an emergency; however, an Rh negative patient can
become sensitized by platelets from an Rh positive donor.
Typically 6 or 10 single units of platelets are pooled and administered as
a six-pack or a ten-pack as quickly as possible. Alternatively, a similarbe
harvested from a single donor by apheresis to mini-mize the risk of infectious
disease and/or provide HLA- matched platelets. Platelet concentrates may be
infused through a standard 170-pm filter; microaggregate filters (20 to 40 pm)
can trap platelets and slow infusion, and their use is controversia their use is
controversial.
Platelet administration is indicated for patients with platelet dysfunction
and/or platelet counts less than 50,000/pl who have either evidence of
microvascular bleeding or a planned invasive procedure (e.g., surgery). patients
with platelet counts less than 10,000 to 20,000/pl whoare at significant risk for
bleeding may be candidates for prophylactic platelet administration.
Ten minutes to I hour after infusion, an increase of 50,000 to 10,000/pl
in the platelet count can be expected for every unit of platelets administered. A
poor response to platelet transfusion may be secondary to a consumptive
process such as disseminated intravascular coagulation (DIC), sequestration
from splenomegaly, or destruction due to fever, sepsis, or idiopathic
thrombocytopenic purpura (ITP). Some patients may be refractory to randorm
donor platelet administration because of antiplatelet alloantibodies that have
developed as a result of prior exposure to foreign platelets. These patients may
benefit from administration of platelets that are HlA-specific, crossmatched, or
donated by family members.
Platelet administration may have a limited and temporary role in patients
with conditions such as ITP and DIC whose underlying pathology also
consumes, sequestrates, destroys, or otherwise inactivates the transfused
platelets. For example, both uremia and recent aspirin ingestion can result in
poorly functioning platelets. An individual with aspirin-induced
thrombocytopathy may benefit from platelet transfusion; however, uremia must
be corrected toimprove platelet function. Platelet administration may actually
aggravate the thrombotic process in patients with thrombotic thrombocytopenic
purpura (TTP) and HELLP syndrome (hemolysis, elevated liver enzymes, and
low platelets).

Complications (7.5.2)
.Infectious.
 Increased awareness of infectious complications resulting from blood
and blood component administration by both the public and medical community
has changed the practice of transfusion therapy more than any other factor in the
last l5 years. Although careful donor screening and testing of donated blood
have made the current blood supply safer than ever, recipients of red cells,
platelets, plasma, and cryoprecipitate are still at risk of transfusion related
infections. Albumin and coagulation factor concentrates currently available are
free from risk of infection because of improved purification and washing
techniques
Blood is not accepted from donors who participate in high-risk
behaviors such as intravenous drug use, homosexual activity, and encounters
with multiple sex partners. Blood that is collected is tested for evidence of
HIVI, HM, hepatitis B, hepatitis C, human T:cell leukemia virus (HTLV-I), and
syphilis infection. Alanine aminotransferase testing (a surrogate marker for
occult hepatitis infection) may also be performed but is no longer routinely
required. Donor blood is discarded if any of these infectious disease markers are
abnormal.
Although transfusion-related hepatitis infection is more prevalent,
greater public awareness and almost certain mortality make HIV the most
feared pathogen. HIVI retrovirus is responsible for 339,000 AIDS cases
reported in the United States. Only about 9,300 (2.7%) are thought to have
resulted from administration of infected blood products, and pooled clotting
factors were responsible for about 3,000 of these cases. Most transfusion-related
HIV transmission occurred between 1982 and 1985 before widespread HIV
antibody screening. A contemporary protein-based enzyme-linked
immunosorbent assay (ELISA) has since resulted in a tremendous improvement
in the safety of the U.S. blood supply.
Despite risk-based donor exclusion, about 3.5 units per 100,000
donations are confirmed seropositive for HIVI and are discarded. HIV infected
units that remain in the blood supply are almost always the result of donation
made during the “window period” when a recently infected donor can transmit
the virus but has not yetdeveloped detectable HIV antibodies. A recent study
estimated that one donation per 360,000 is made during this window period.
Fortunately, window period donations are positive for some other infectious
disease markers and are removed from the blood supply. Currently, it is
estimated that between I in 450,000 and 1 in 660,000 units available for
transfusion are HIV contaminated. This risk may be higher where HIV infection
is more prevalent. Some collection agencies have also begun to screen for the
HIV antigen through p24 antigen testing and assays using polymerase chain
reaction. This should further reduce the incidence of HIV contaminated blood
produts.
Transmission of hepatitis B by transfusion of blood products has
become vanishingly rare, and the frequency isnot distinguishable from the
background rate of the general population. However, documented cases of
transfusion related hepatitis B infections still occur. It is estimated that the risk
of hepatitis B transmission is I case per 200,000 units transfused.
Hepatitis C is now recognized as the agent in most cases of non-A,
non-B hepatitis. Risk of hepatitis C transmission prior to the initiation of donor
unit testing was I per 200 units transfused. In 1990, an ELISA test for hepatitis
C protein became available, and in l992Ihe risk of hepatitis C transmission was
estimated to be I per 3,300 units transfused. It is estimated that and introduction
of a second generation multiantigen ELISA test has since decreased the
transmission rate to I case per 6,000 units transfused
A small percentage of transfusion-related hepatitis cannot be
accounted for by currently available viral serologic testing. It is likely that an
unidentified hepatitis virus is responsible.
Human T:cell leukemia (HTLV) viruses have been causally associated
with adult T:cell leukemia, spastic paraparesis, and progressive myelopathy.
HTLV-I and HTLV-II have been identified, and screening of all blood products
in the United States for anti-HTLV-I antibody began in 1989. This assay also
has some cross-reactivity so trant some HTLV-II antibodies are also detected.
Risk of transfusion-related infection with HTLV-I or -II is estimated at I per
70,000 units transfused.
Neonates and immunodeficient patients are at risk of transfusion-
related cytomegalovirus (CMV) infection. Risk for CMV infection is estimated
to be less than I case per I million units transfused. Blood products can be tested
for anti-CMV antibody, or leukocyte-depleted blood can be used in these
patients.
Parvovirus Bl9 can cause serious fetal disease following maternal
infection and may rarely induce aplastic crises in immunocompromised patients.
Risk of transfusion-related infection is estimated at I per 10,000 units
transfused.
Serious bacterial infection, including septic shocks may result from
transfusion of contaminated blood products. Platelets stored at room
temperature must be used within 5 days to decrease the risk of bacteria
contamination. Some cold-growing bacteria, especially
Yersinia enterocoliticq, infect PRBSs stored between 1Y and 6TC. The risk of
transfusion-related serious bacterial infection is estimated to be 1 per 1 million
units transfused. Patients developing high fever and hypotension during a
transfusion should be cultured and started on broad-spectrum antibiotics. The
nontransfused portion of the offending blood product should also be sent for
Gramstain and culture.
Transmission of syphilis, Lyme disease, malaria, Chagas disease,
leishmaniasis, toxoplasmosis, babesiosis, and filariasis are rare in the United
States.

Noninfectious
Acute intravascular hemolytic transfusion reactions secondary to
complement-mediated lysis of transfused red cells result from ABO
incompatibility and occur within minutes of the start of transfusion.
Complement fixing antigen/antibody systems can cause mast cell degranulation.
Pulmonary dysfunction may result from granulocyte migration to the pulmonary
capillary beds. Antibody-coated red cells may induce renal vasoconstriction and
result in renal tubular acidosis and renal failure. DIC may also result from
activation of the coagulation system. The most common cause of incompatible
transfusion is clerical or laboratory error; however, reactions can also be the
result of preexisting alloantibodies missed on antibody screening of the
recipient’s blood.
Patients with acute hemolytic reactions may develop fever, chills,
headache, dizziness, flushing, nausea, vomiting, joint or low back pain,
bronchospasm, shortness of breath, chest pain, tachycardia, hypotension, shock,
and sense of impending doom. Abnormal bleeding may be seen if DIC occurs.
Hemoglobinuria and hemoglobinemia also acutely develop and are suggested
by red urine or pink plasma. A decrease in the haptoglobin level and an
elevation of the bilirubin and LDH levels may be seen within hours.
Treatment of a suspected hemolytic transfusion reaction should be
initiated immediately since a mil4 treatable reaction may become life
threatening. Transfusion should be stopped immediately, and any remaining
blood product should be returned to the blood bank for testing. Copious
intravenous fluids should be administered to maintain urine output of at least
100 ml per hour for 24 hours. Diuretics may be helpful, but the use of mannitol
has become controversial. Pressors and bronchodilators may also be required.
Administration of FFP and/or heparin may be indicated if DIC occurs. Close
monitoring of urine output, renal function, electrolytes, and coagulation status is
prudent. Hemodialysis may become necessary.
 A delayed intravascular hemolytic transfusion reaction results from
gradual development of red cell antibodies following a transfusion. This
condition usually does not present as an emergency, but rather is manifested as
a slowly decreasing hemoglobin 4 to 14 days post transfusion. Gradual
generation of C3a and C5a result in mild sustained hemoglobinuria and
hemoglobinemia. These reactions are often secondary to Rh incompatibility and
the acute development of Rh sensitivity. Delayed hemolytic reactions are not
likely to require acute intervention, and patients are usually asymptomatic.
Acute extravascular hemolytic transfusion reactions develop secondary
to ABO incompatibility when complement activation, but not fixation, of C3a
and C5a occurs. Red cells with IgG antibodies on their surfaces are cleared by
the liver and the spleen. These reactions result in a low-grade fever and mildly
decreasing hemoglobin. They rarely cause hemoglobinuria and hemoglobinemia
but do produce a positive antibody test.
A febrile nonhemolytic transfusion reaction should be suspected if the
recipient’s temperature rises more than ITC during or after transfusion and no
other etiology can be found. Fever and shaking chills, without hemoglobinuria
and hemoglobinemia, are the hallmark of febrile transfusion reactions. These
reactions are caused by agglutinating antibodies in the patient’s plasma against
antigens present on leukocytes or platelets in transfused products. The
mediators of febrile transfusion reactions are interleukins, cytokines, and
tumour necrosis factor.Symptoms usually begin shortly after the start of the
transfusion but may occur hours later. Symptoms worsen as the rate and volume
of transfusion increase and may include true rigors, nausea, and vomiting. These
reactions are self-limiting with effervescence occurring within 8 hours after
transfusion, although elderly and compromised patients may experience
respiratory failure or shock. Treatment consists of acetaminophen and patient
reassurance. The transfusion should be interrupted temporarily while a sample
of the donor blood is rechecked to assure that ABO incompatibility has not
occurred. Patients with a history of febrile transfusion reactions should be
premedicated and/or receive leukocyte products. The mediators of febrile
transfusion reactions are interleukins, cytokines, and tumour necrosis
factor.Symptoms usually begin shortly after the start of the transfusion but may
occur hours later. Symptoms worsen as the rate and volume of transfusion
increase and may include true rigors, nausea, and vomiting. These reactions are
self-limiting with effervescence occurring within 8 hours after transfusion,
although elderly and compromised patients may experience respiratory failure
or shock. Treatment consists of acetaminophen and patient reassurance. The
transfusion should be interrupted temporarily while a sample of the donor blood
is rechecked to assure that ABO incompatibility has not occurred. Patients with
a history of febrile transfusion reactions should be premedicated and/or receive
leukocyte depleted blood products.
Allergic reactions to transfused products are characterized by the
attachment of preformed antibodies to foreign plasma proteins (as opposed to
cellular elements) leading to mast cell degranulation and histamine release. The
majority of life{heartening anaphylactic reactions occur in recipients who have
an IgA deficiency and therefore make antibodies to IgA. The incidence is higher
in patients who have a history of prior blood transfusion. Any type of blood
product may contain sufficient IgA to initiate an anaphylactic reaction.
Symptoms of allergic reaction may include flushing of the skin, hives,
increased respiratory tract secretions, increased vascular permeability smooth
muscle interaction causing bronchospasm, a sense of impending doom, and
shock. Fever is not part of the symptomatology. Most allergic reactions occur
within the first hour after the start of the transfusion, and the severe
anaphylactoid-type reactions tend to begin immediately after the transfusion is
begun. Treatment of a mild, urticarial reaction consists of temporarily stopping
the transfusion and administering antihistamines until symptoms improve. If
more significant sequelae do not develop, the transfusion may be slowly
restarted. Therapy for anaphylactic-type reactions include halting the
transfusion; administering parenteral epinephrine, antihistamines, and steroids;
and providing supportive care.
Massive Blood Transfusion (7. 5.2. 5)
Transfusion of 10 or more units of PRBCs acutely is considered a
massive transfusion. Complications of massive transfusion may be
overshadowed by the danger of persistent shock and continued tissue hypoxia.
In fact, many of the metabolic derangements often ascribed to massive
transfusion such as acidosis, coagulopathy, and pulmonary injury may actually
be due to persistent shock. Hypothermia may be caused by the infusion of cold
blood products and other fluids. Complications of this condition include
decreased metabolism of lactate and citrate, increased hemoglobin-oxygen
affinity, platelet dysfunction, coagulopathy, and cardiac arrhythmias. Devices
may be used to warm blood to 40o C, but these may not be readily available.
Infusion of warm crystalloid with red cells may be a practical alternative.
Red cell solutions contain significant amounts of citrate and lactate.
Citrate is the anticoagulant used to keep blood products from clotting and
lactate is produced by stored red cells. Metabolism of citrate and lactate in the
liver usually occurs shortly after transfusion. However, if the transfusion rate
exceeds one unit per 5 minutes or if liver function is impaired secondary to
hypothermia, shock, or chronic disease, citrate and lactate will not be cleared
adequately. The excess citrate and lactate may cause metabolic acidosis.
Citrate also binds to ionized calcium in the circulation and may
produce hypercalcemia. Severe hypocalcemia can cause decreased myocardial
function and hypotension. Routine calcium replacement is not recommended in
such patients and should only be given if persistent hypotension or known
hypocalcemia are present. Also, Calcium administration through the same
intravenous line used for transfusion may cause clotting in that line.
Hyperkalemia may result from massive transfusion and can cause
cardiac arrhythmias, especially when hyperkalemia and hypocalcemia coexist.
Potassium move out of red cells during storage, resulting in high concentrations
in the storage medium. Excess potassius is usually drawn into cells or excreted
shortly after transfusion. However, a transient hyperkalemia may develop if
transfusion occurs rapidly. Treatment for hyperkalemia is usually not indicated,
but all patients receiving large-volume transfusion should be on a cardiac
monitor. Patients with renal compromise are also at increased risk of significant
hyperkalemia.
 A coagulopathy may be associated with massive transfusion.
Thrombocytopenia and coagulation factor deficiencies may result from the
delusional effects of blood products not containing platelets or adequate
amounts of coagulation factors. Platelet counts, however, are usually not as low
as would be predicted based on simple dilution. This is probably due to the
release of platelets from the spleen and bone marrow. Further, even low
concentrations of coagulation factors are usually adequate to prevent
microvascular bleeding. Therefore, significant bleeding due to clotting
dysfunction does not usually occur until 15 to 20 units of PRBCs have been
transfused. Shock, DIC, and platelet dysfunction can also contribute
significantly to abnormal bleeding. Platelet dysfunction can be caused by
hypothermia. DIC may occur in up to 30%of massively transfused patients,
probably secondary to diffuses hypoxic tissue damage from shocks.
Correction of coagulopathy should be a clinical decision since platelet
counts and clotting times are not immediately available and may not correlate
well to a patient’s actual coagulation status. Platelets and coagulation
Factors should not be administered prophylactically but should be based on the
presence of shock and the degree of microvascular bleeding. Transfusion of
platelet concentrates may be the preferred first line of therapy since 6 units of
platelets includes about 300 ml of plasma containing significant amounts of
active coagulation factors. If bleeding continues, large volumes of FFP may be
required. Cryoprecipitate may be helpful in patients with DIC since it contains
significant amounts of fibrinogen.
Adults respiratory distress syndrome (ARDS) may result from
sequestration of microaggregate in the lungs of patients receiving massive
transfusions. Microaggregate are composed of fibrin, platelets, and white cells
that accumulate in stored blood. It is difficult, however, to separate the effects
of microaggregate from the effects of shock on the lung. The use of specialized
filters to eliminate microaggregate from transfused blood remains controversial.
Again, it is difficult to delineate complications of massive transfusion
from those caused by the underlying condition that necessitated the massive
transfusion. Aggressive and adequate treatment of hemorrhagic shock should be
the first priority in these patients.
Alternatives to Transfusion of Blood Products
Salvage of lost blood for the purpose of auto transfusion is done
routinely in operating rooms via a cell saver apparatus. Blood from a sterile
operating field is collected by suction and then separated, washed” and stored
by the cell saver. This blood can then be rein fused, Decreasing the need for
homologous blood products. The use of a cell saver in the ED may not be as
practical since expensive equipment and setup time for collection of
noncontaminated blood are necessary. Blood from a hemothorax is probably the
only sterile blood that can be practically salvaged in the ED. Special chest tube
suction reservoirs are now available that can be attached to a standard chest tube
collection system. The reservoirs can then be hung for immediate reinfusion of
chest tube output.
The discovery of an oxygen-carrying blood substitute would be a
significant breakthrough in resuscitation medicine. A practical substitute for red
cell transfusion should effectively deliver oxygen to tissues, remove carbon
dioxide from tissues, and maintain acid-base balance in the circulation. A
product should be sought that has a reasonable storage profile and a long half-
life in the circulation, and that is nontoxic and nonimmunogenic. Hemoglobin is
the ultimate oxygen transport molecule, and a useful blood substitute will most
likely be a derivative of the hemoglobin molecule. The infusion of cell-free
hemoglobin is not an option since this has been shown to increase pulmonary
vascular resistance and decrease cardiac output. Also, free hemoglobin is
unstable, raises onncotic pressure, and is excreted by the kidneys. To
circumvent these shortcomings, free hemoglobin collected from outdated blood
may be attached to large molecules or polymers. Phase I trials of a number of
such compounds are now in progress.
The development of perfluorocarbons is a different approach to a
practical blood substitute. Perfluorocarbon emulsions are halogenated liquids in
which oxygen is extremely soluble. However, perfluorocarbons (including
fluosol-DA) are not currently available. The development of a practical blood
substitute may eliminate some complications of blood transfusion and allow for
safer and more timely resuscitation.
Jehovah's Witnesses and Blood Transfusion. jehovah’s Witnesses are
members of a Christian denomination that forbids the acceptance of blood
transfusions. Whole blood, packed red blood cells, white blood cells, platelets,
fresh frozen plasma, and autologous stored blood are clearly prohibited. Other
blood components and related therapy are accepted by some but not all
witnesses. Many Witnesses accept hemodialysis and heart-lung bypass as long
as the necessary equipment is used as an essentially uninterrupted extension
ofthe circulatory system and blood is not used as a primer. The same principle is
applicable to chest-tube reservoir autotransfusion systems. Albumin,
hemophiliac factor preparations, serum-based immunizations, organ transplants,
and epidqral blood patches are also accepted by many but not all Witnesses. If
the Witness believes the particular blood component therapy is not given to feed
the body but rather to fight against disease, it is more likely to be allowed.
Although Witnesses have frequently survived sever anemia and
hemorrhage when physicians predicted otherwise, the mortality due to anemia
when blood is with held in Witness patients with Hb <5 gldl appears to be at
least 36Yo. Furthermore, applying a specific hemoglobin value to the ED
setting is often inappropriate since rapid blood loss presents as hemorrhagic
shock not necessarily accompanied by a decrease in hemoglobin concentration.
When treating an adult Witness who is conscious and has decision-
making capacity and who emergently needs blood component therapy, the
emergency physician should do the following:Discuss the need for transfusion
with the patient when no family members, friends, or religious advisors are
present. Inform the patient of the risks of refusing and of accepting the
recommended blood component therapy. Specifically address whether the risk
of HIV and hepatitis infection is a significant concern and put such risks in
perspective. Alternatives to blood should also be discussed ifthey are reasonable
options. Tell the patient that any decision he or she makes in regard to refusing
or accepting blood products will be respected and, if desired, will remain
absolutely confidential. If the patient accepts blood products, reducing the risk
of death as a result of anemia or a coagulopathy, the appropriate blood product
should be administered. However, transfusing with strict confidentiality in the
ED setting is potentially difficult. Extra staff and resources should be devoted to
this task, and resuscitation in the privacy of the operating room should be
considered for trauma patients. If the patient refuses bloo4 make appropriate
modifications in monitoring and treatment (e.g., admit to the ICU instead of a
regular ward, surgery instead of observation for splenic trauma).Consider
asking the patient whether blood will be allowed if it is ordered by a court.
Some Witnesses have accepted a transfusion as long as they did not personally
consent to it. A judge might order a transfusion under these circumstances.
A Witness who presents to the ED unconscious and indeed of blood with
a signed “No Blood” advance medical directive creates a dilemma
encompasslng potentially conflicting medical, ethical, and legal concepts. There
are no rigid standards for blood to be withheld or given in such circumstances.
Courts have both supported and ruled against physicians who have transfused
unconscious patients in the presence of a “No Blood” advance directive. Ifan
advance directive does not exists or is not available in a timely manner and the
patient needs blood emergently, begin transfusion-even if family or friends
object. If an advance directive does exist, assess its authenticity. However, the
presence of a “No Blood” advance directive, particularly a wallet card” does not
necessarily ensure that informed refusal requirements are satisfied. Withhold
blood if you believe that a “No blood” advance directive satisfies informed
refusal requirements, but transfuse if you do not believe informed refusal
requirements are satisfied.
Contact the hospital administrator and attorney as soon as possible if an
unconscious Witness in need of blood presents to the ED. However do not
assume they will have answers. Consult a second physician as well. Whether
you withhold blood or transfuse, do your best to provide otherwise perfect care,
as these cases are likely to be scrutinized extensively.
If time permits, an emergency court order can be obtained authorizing
transfusion for a minor who needs blood emergently and whose Jehovah’s
Witness parent refuses to consent. However, blood should be given immediately
if a legal proceeding will result in an unacceptable delay in treatment. A
hospital policy should delineate the procedure for obtaining a court order to
transfuse minors.
SELECTED READING
Beutler E, et al., eds. Llilliams’ hematology, 5th ed. New york, McGraw-hill,
1995.
Dale DC, Federman DD, et al., eds. Scientific American medicine. New York:
Scientific American, 1 995.
Dodd RY. Transfusion transmitted hepatitis virus infection. Hematol Oncolclin
North Am I995;l: 137.
Dodd RY. Viral contamination of blood components and approaches for
reduction of infectivity. Immunol Invest 199 5 ;24(1,2):25.
Donaldson MDJ, Seaman MJ, Park GR. Massive blood transfusion. Br -r
anaesth 1992;69:621.
Draker RA. The development and use ofoxygen-carrying blood substitutes.
Immuno Invest 199 5 ;24(1,2) 403.
Fakhry SM, Sheldon GF. Blood administration, risks, and substitutes. Advsurg
1995;28:71.
Jeter EK, Spivey MA. Noninfectious complications of blood transfusion.
Hematol Oncol Clin North Am 1995;1:187.
Kleimann I. Written advance directives refusing blood transfusion: ethical
and legal considerations. Am J Med 1994;96:563-567.
Labadie LL. Transfusion therapy in the emergency department. Emerg MedcIin
North An 1993;2:379.
Lackritz EM, et al. Estimated risk of transmission of the human
immunodeficiency virus by screened blood in the United States. N Engl J Med
1995:333:1721.
Lo B. Resolting ethical dilemmas: a guide for clinicians. Baltimore: williams &
Wilkins, 1995.
Nachta. The use ofblood products in shock. Crit Care Clin 1992;2:255. roberts
JR, Hedges JR, eds Clinical prccedures in emergenq, medicine, 2nd ed.
Philadelphia: Saunder l99l.
Rosen P, Barkin RM, et al., eds. Entergenct ntedicine concepts and clinical
practice. St. Louis: Mosby-Year Book, 1992.
Viele MK, Weiskopf RB. Wlat can we learn about the need for transfusion
from patients who refuse blood? The experience with Jehovahb Witnesses.
Tiznfrstion 1994;3 4:396401.
WHITE BLOOD CELL DTSORDERS (7.6)
Leukemia (7.6.1)
 The leukemias are a group of neoplastic disorders thought to be derived
from a single hematopoietic progenitor cell located in the bone marrow.
Leukemias may proliferate rapidly and infiltrate the bone marroq leading to
suppression of the normal elements. Over time these malignant cells spread to
the peripheral blood” spleen, lymph nodes, and other tissues, ultimately causing
death inttle untreated patient. Leukemias have been extensively studied since
Virchow characterized them in 1849 as a pathologic situation in which there is a
blockage of the normal differentiation of young blood cells into specific types.
This observation stills holds true today as we continue to define the defective
progression of leukemic cells into mature forms.
Although difficult, classification of the leukemias is of major importance
in determining both prognosis and treatment. In this regard it has been useful to
determine whether the cell line of origin is lymphoid or myeloid and whether
the patient’s clinical presentation is acute or chronic. Although the etiology of
leukemia is largely unknown, there have been associations made to both
environmental and genetic factors. As our understanding of the leukemias
progresses, improved diagnosis, prevention, and treatment becomes possible.
Classffication
 The leukemias are mainly classified by their cell of origin and rapidity
of clinical course. The lymphoid and myeloid cell line of origin can be
combined with the rate of the leukemic clinical course to create a classification
of the leukemias into the following categories: acute lymphocytic leukemia
(ALL), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL), and
chronic myeloid leukemia (CML). The acute leukemias demonstrate younger
and less differentiated cells than those seen in the chronic leukemias. In
addition, they are characterized by a rapid progression of illness. Modern
biological, antigenic, and molecular techniques have allowed for greater detail
in classifuing and subdividing the leukemias; however, these general categories
remain useful and continue to facilitate our understanding ofthe disease.
During the early stages of leukemia there may be no morphologically
distinguishable cells in the peripheral blood. More invasive testing such as bone
marrow biopsy may be required to achieve a correct diagnosis and
classification. Despite advances in this fiel4 it is not always possible to verify
the diagnosis of leukemia or accurately classify the disease. For example,
lymphomas that originate in the lymph nodes and spread to the bone marrow
can be quite difficult to distinguish from leukemia because both diseases have
phenotypically identical cells.
 Incidence and Epidemiology
The overall incidence of leukemia in the United States regardless of
class is approximately l3 cases per 100,000 people each year. The overall
incidence of both acute and chronic leukemia is higher in men than in women.
There are age differences in the incidence of leukemia according to specific
class.
ALL is a disease primarily occurring in children and young adults with
a peak incidence at 2 to 4 years of age. ALL is the most common form of
pediatric cancer with approximately 4,200 new cases reported each year. The
incidence of CLL increases with age. There are 12,500 new cases each year,
accounting for nearly l0% of all cancers in Caucasians but only l%0 of all
cancer in african-Americans.
AML is primarily a disease of older adults. The median age at diagnosis
is 60 to 65 years. The incidence of AML is 2 to 3 cases per 100,000 individuals,
making it the most common form of leukemia. Several risk factors have been
associated with the development of AML, including exposure to chemicals and
cigarette smoking. The incidence of CML peaks in the fifth and sixth decades of
life with male predominance. There are over 6,000 new cases of CML reported
each year, representing l5Vo to 25o/o of a1l new patients diagnosed with
leukemia.
Several chemicals including chloramphenicol, chemotherapeutic agents,
benzene, and other aromatic molecules and have been associated with the
development of leukemia. Some viruses such as the HTLV have also been
investigated as possible contributing factors.
Clinical M anifestations, Diagnosis, and Treatment.
Chronic Myelogenous Leukemia.
The initial clinical presentation of leukemia can be quite varied, and
diagnosis requires a high index of suspicion along with a basic knowledge of
the disease. Leukemias commonly present with signs and symptoms related to
the infiltration of leukemic cells into the bone marrow or other blood forming
organs. Symptoms consistent with anemia such as fatigue, weight loss, and
lethargy are typical in patients with leukemia. Left upper quadrant (LUQ) pain
is common in patients with CML due to the infiltration of leukemic cells into
the spleen, and splenomegaly is the most consistent physical finding in CML
observed in greater than90o/o of cases. Increased abdominal girth secondary to
hepatosplenomegaly is also observed in many patients.
 CML is characteized by a marked increase in myelopoiesis and the
presence of the Philadelphia chromosome (t9,22). The diagnosis is made when
these two findings are associated with splenomegaly. Bone marrow
aspirate/biopsy demonstrating granulocytic hyperplasia with loss of the normal
fat spaces is confirmatory. The white blood cell count $fBq is ffpically in the
range of 100,000 to 300,000/mm3 at the time of diagnosis and can reach levels
of 800,000/mm3 or more. A normochromic normocytic anemia is common as
the bone marrow becomes infiltrated with white blood cells. Anemia is rarely
observed until the peripheral white blood cell count has exceeded
100,000/mm3. Often there is an associated thrombocytosis in the range of
300,000 to 600,000/mm3 with a majority of patients having a level of greater
than 450,000/mm3. Hyperuricemia is quite common due to high cell turnover.
Many other laboratory investigations have demonstrated usefulness in veri$zing
the disease in difficult cases. Deficiency of leukocyte alkaline phosphatase
(LAP) and lack of the Philadelphia chromosome have been reach levels of
800,000/mm3 or more. A normochromic normocytic anemia is common as the
bone marrow becomes infiltrated with white blood cells. Anemia is resarely
observed until the peripheral white blood cell count has exceeded
100,000/mm3. Often there is an associated thrombocytosis in the range of
300,000 to 600,000/mm3 with a majority of patients having a level of greater
than 450,000/mm3. Hyperuricemia is quite common due to high cell turnover.
Many other laboratory investigations have demonstrated usefulness in veri$zing
the disease in difficult cases. Deficiency of leukocyte alkaline phosphatase
(LAP) and lack of the Philadelphia chromosome have been useful in
distinguishing CML from a leukemoid reactio useful in distinguishing CML
from a leukemoid reaction.
CML has classically been separated into three phases: chronic phase,
accelerated phase, and blast phase. The most common course of disease is a
stepwise progression from chronic phase to accelerated phase to blast phase.
Thee majority of patients are first diagnosed while in chronic phase. Chronic
phase is designated when blast cells make up no more than l5%o of cells on
bone marrow biopsy or peripheral smear. Surprisingly, 10%o to 30% of patients
diagnosed in this stage are discovered on routine blood work revealing a WBC
over 50,000/mm3 with left shift and increased number of granulocytes. The
chronic phase is characterizedby mild symptomatology including left upper
quadrant discomfort dr.re to splenomegaly and complaints from an anemic state.
Bone pain and splenic infarction are rare this early in the disease. Visual
disturbances are usually due to retinal hemorrhage but occur infrequently. The
duration of this phase can be quite variable with a median time of 3 to 4 years.
The risk of direct transformation from chronic phase to blast phase is
approximately 25% per year. Usual survival is 4 to 5 years from the time of
diagnosis.
The accelerated phase is defined by the presence of >15% blast cells in
the peripheral blood or by >30% of blast cells in the bone marrow. In this phase
there is worsening of symptoms such as LUQ discomfort resulting from
hepatosplenomegaly, anorexia, and weight loss. A chronic low-grade fever is
associated with this phase and may require a careful evaluation to rule out an
underlying infection or sepsis. White blood cell counts increase during this
phase and can be associated with either severe thrombocytosis or
thrombocytopenia. Bone marrow biopsy begins to reveal myelofibrotic changes
in addition to marrow infiltration with leukemic blast cells. During the
accelerated phase there is also a characteristic resistance to treatment.
Progression to the blast phase is the most ominous stage of this disease
and is characterizedby >30% ofthe peripheral blood cells consisting of blast
forms. Patients in this phase become more acutely ill. They develop diffuse
lymphadenopathy and begin to experience bone pain. As bone marrow
involvement becomes extensive, bone pain can be excruciating and include the
extremities. During the blast phase central nervous system (CNS) involvement
may produce a variety of neurologic manifestations. Survival in this phase is
measured in weeks to months with a median of 2 to 4 months. Death from
infection, hemorrhage, or thrombosis occurs rapidly in 85% of patients once the
blast phase has begun.
Currently the only possible curative treatment for CML is bone marrow
transplant (BMT). Long-term disease free survival is achievable in 50%o to
70o/o of chronic phase patients after receiving an allogenic BMT from an HlA-
matched sibling. BMT is much less successful in the accelerated phase or blast
phase with 30o/o and l0o/0 long-term survival, respectively.
Several chemotherapeutic drugs have been used in the treatment of CML
including busulfan, hydroxyurea, and Alkylating agents such as
cyclophosphamide. Interferoncr has been used with increasing frequency and is
associated with significant side effects including liver toxicity, neurologic
toxicity, and leukopenia/thrombocytopenia. Hydroxyrrea is commonly used to
control the blood cell counts in those patients who are not BMT candidates.
Treatment of the blast crisis is usually determined by the cell type that
predominates in the crisis. Myelogenous blast crisis follows the same treatment
recommendations for AML induction therapy. Lymphogenous blast crisis
follows the same treatment pathway recommended for all. Emergency treatment
of CML is usually not required unless the patient presents with acute symptoms
that are most commonly produced by blast infiltration or Hyperuricemia.
Acute Myelogenous Leukemia
AML by definition must have >30% of the bone marrow or peripheral
blood occupied by myeloblasts. Auerrods can be observed in approximately
50%o of patients with AML and are confirmatory for the myeloblastic or
monoblastic form of disease. The differential diagnosis of AML includes
rheumatic fever, infectious mononucleosis, upper respiratory tract infection,
leukemoid reaction, aplastic anemia, and tuberculosis. Diagnosis of AML as
with other leukemias requires a bone marrow aspirate or biopsy.
Initial symptoms usually are present for less than 3 months and most
commonly consist of anemia, pallor, fatigue, and dyspnea on exertion.
Petechiae, easy bruising, and gingival hemorrhage secondary to
thrombocytopenia is a common presentation. Thrombocytopenia below
20,000/mm3 may be associated with more serious bleeding. DIC secondary to
procoagulant activity has been described. Infections of the pha4mx, lung,
perirectal area, blood, skin, and gingiva often cause the patient to seek initial
medical evaluation. Both gram-positive and -negative organisms are common
pathogens at the time of initial presentation. Fungal infections fypically occur
later in the course of disease. Liver function tests are usually normal.
Survival in these patients is inversely proportional to age. Long-term
survival in those over 60 years old is less than 20% despite intensive
chemotherapy. Remission induction therapy along with symptomatic treatment
is the primary goal in AML. Remission is often achieved after treatment with a
combination of medications such as cytarabine and an anthracycline such as
daunorubicin. Many treatment protocols add 6-thioguanine to this combination.
Once remission has been achieved, cytarabine is usually continued at a lower
dosage for maintenance therapy. BMT has been most successful in patients
younger than 40 to 45 years during their first remission.
Symptomatic treatment often includes platelet transfusions for bleeding
secondary to thrombocytopenia. Filtered platelets to reduce the number of white
blood cells transferred to these patients are preferred. Fever is of major concern
in these patients especially when the absolute neutrophil count is less than
500/mm3. It is recommended that treatment with broad-spectrum antibiotics be
maintained until bone marrow function returns, even if the fever resolves and
cultures are negative. Electrolyte abnormalities are also common. Hypokalemia
can be present secondary to renal tubular damage. Tirmor lysis syndrome can
produce hypocalcemia, hyperphos phatemia, hyperkalemia, and hyperuricemia.
The latter can lead to nephropathy and often requires treatment with hydration,
allopurinol to block conversion of xanthine to uric acid, and urine alkalinization
to maintain the more soluble uprate form.
Several special considerations arise in AML during advanced disease
including leukostasis and extramedullary leukemia. When the myeloblast count
increases to levels over 100,000/mm3, the patient is placed at increased risk for
microinfarction and hemorrhage in small blood vessels as a result of sludging
and thrombus formation. The pulmonary vasculature is frequently affected,
resulting in radiologic infiltrates and hypoxemia. Involvement of the CNS
vasculature leads changes in mental status, cerebral infarction, and death.
Treatment is aimed at vigorous hydration and reducing the WBC count with
hydroxyurea. Leukapheresis and whole-brain irradiation may be essential in
more extreme cases. It is interesting that these symptoms do not appear to occur
in ALL.
As the number of myeloblasts increases, deposition of cells into
extramedullary tissue occurs. Common sites of involvement are the skin, lungs,
CNS, gingiva, and buccal mucosa. Dentists often diagnose this disease when the
findings of painful gums with gingival hyperplasia are discovered. Chest films
may prove useful to demonstrate pleural effirsion or infection in these
situations. Chemotherapeutic agents achieve poor levels in the CNS and
therefore the addition of intrathecal methotrexate is often necessary to treat
extramedullary leukemia involving the CNS. Headache, nausea, and cranial
nerve palsies are the most common presentations of CNS involvement.
Acute LymphogenoLts Leukemia.
ALL is the proliferation of immature lymphoid cells in the bone
marrow. The incidence of this disease is bimodal, peaking in the teenage years
and again rising in individuals over the age of 45 years old. ALL has an
interesting association with Down syndrome, occurring 20 times more
commonly in these patients. Strong clinical suspicion and detailed history and
physical examination are required to make the early diagnosis of ALL because
patient presentations are often vague or nonspecific. Typical symptoms and
signs of illness are manifestations of anemia, thrombocytopenia, and
neutropenia. fatigue, pallor, weakness, tachycardia, and chest pain may result
from anemia. Patients may have an underlying neutropenia with fever and chills
secondary to infection. Eacchymosis, petechia, and mucosal bleeding are
characteristic manifestations of thrombocytopenia. CNS involvement, often
without clinically apparent neurologic changes, may occur in2o/o to l0% of
patients. As in other forms of leukemia, lymphadenopathy and
hepatosplenomegaly are common findings on physical examination. T cell
variants of this disease may present as an incidental mediastinal mass on chest
film.
Staging of CLL involves the degree of lymphocytosis and the presence
or absence of various physical findings and symptoms. Secondary malignancy,
particularly lungcancer and melanoma, occurs with increased frequency patients
with CLL. A small proportion of CLL patients can progress to a more
aggressive disease. Richter syndrome is the most common form of advanced
and aggressive CLL, characterizedby worsening adenopathy, fevers, abdominal
pain, and anemia. There is a rapid rise in peripheral lymphocyte count and a
decreased response to treatment. Median survival once CLL has progressed to
this stage is 4 to 5 months. Several other transformations are possible from the
chronic course of CLL, including the development of ALL, multiple myeloma
(MM), and even Hodgkin’s lymphoma.
Treatment is noncurative and is associated with significant toxicity,
including a predisposition to secondary tumors. It is usually initiated only after
disease-related symptoms have become well established. Alkylating agents such
as chlorambucil and nucleoside analogues such as fludarabine are among the
most common agents chosen to treat this disease. Very few complete remissions
defined by the absence of clinical symptoms are achieved. Several multidrug
therapies have been studied and show no advantage over single-drug therapy.
BMT and radiotherapy are not recommended in the treatment of CLL. An
increased frequency of opportunistic infections is seen during advanced stages
of disease due to diminished opsonization and the adverse effects of
chemotherapy.
Leukemoid Reaction (7.6.2)
A leukemoid reaction is typically defined as a persistent neutrophilia of
30,000 to 50,000/mm3 or greater. However, a leukemoid reaction can be a
difficult entity to diagnose in patients with a hematologic picture of leukemia
who do not have a clinical course consistent with leukemia. Anemia, young
WBC forms, thrombocytopenia, splenomegaly, and fever can be present in both
leukemia and leukemoid reaction, making the clinical presentations nearly
indistinguishable. Even at the time of autopsy, some cases have remained
indeterminate. There are many causes of a leukemoid reaction, including
infection, intoxication, and rnalignancy. Adding to the complexity of this entity
is the fact that there are numerous grades of leukemoid reaction ranging from
simple leukocytosis without immature forms to a complex picture
indistinguishable from AML. Table 7-5 demonstrates a portion of the known
causes of leukemoid reaction.
Dffirentiation from Leukemia.
Leukemoid reactions can occur as a result of multiple causative factors
and can mimic any class of leukemia. The differentiation between leukemia and
a leukemoid reaction may require thorough testing of the bone marrow And/or
lymph node biopsy, including cultures and specialized stains. Reactions that
mimic myeloid leukemias can be the result of various infections, malignancies,
and intoxications. A CML-type picture can result from pneumonia, meningitis,
chicken pox, infectious mononucleosis, tuberculosis, eclampsia, burns, and
various malignancies. In difficult cases, presence of the Philadelphia
chromosome, and elevations of the leukocyte alkaline phosphatase and serum
vitamin Brz levels can be very useful in distinguishing true leukemia from a
leukemoid reaction.
Table 7-5 Causes of leukemoid reaction.
Infection
as myelocytic reaction
PneumAureus(S. Aureus)
 Meningitis (H. Influenzae, N. Meningitidis)
Tuberculosis
Bubonic plague.
Presenting as a lymphocytic reaction
Chicken pox
Whooping cough
Lnfectious mononucleosis
Tuberculosis
Lntoxications
Eclampsia
Burns
Mercury poisoning
Malignancies
Multiple mmyeloma.
Hodgkin’s disease
Myelofibrosis
 Gastric/breast CA
Other
Hemorrhage/hemolysis
Rheumatoid arthritis
A logical approach to the patient with suspected infection and an
otherwise unknown source of leukocytosis is to obtain cultures and treat with
broad-spectrum antibiotics. Antileukemic therapy should only be instituted once
it is clear that the patient is presenting with a true leukemia and not simply a
leukemoid reaction.
Leukopenia (7.6.3).
The term leukopenia describes a decreased number of white blood cells of
any type. Neutropenia is a specific form of leukopenia in which there is a
decreased number of neutrophils. The normal neutrophil count ranges from
1500 to 8000 cells/mm3 in peripheral blood samples. Where the neutrophil
count falls below 1000 cells/mm3, there is a definite increase in the risk of
infection. Individuals with <500 neutrophils/mm3 are considered to be at high
risk for bacterial and fungal infections alike. The inflammatory response sharply
disappears at neutrophil counts below 200 cells/mm3. The most common cause
of neutropenia is iatrogenic, resulting from immunosuppressive therapy.
Conditions As sociatedlltith Neutropenia.
Clinical Signs and Symptoms.
The most worrisome presentation of neutropenia is when it is associated
with a fever (generally accepted as a temperature -100.5”F), as this combination
represents a true medical emergency. Neutropenia often masks what would
otherwise be an obvious infection (Table 7-6). The lack of neutrophils results in
a diminished or absent
TABLE 7-6. Conditions associated with neutropenia
Lnfection
Human immunodeficiency virus
Epstein-Barr virus
Measles/chickenpox/rubel la
Tuberculosis
Colorado tick fever/yellow fever
Drugs
 Lmmunosuppressive agents
Antithyroid medications
Antibiotics (chloramphenicol, AZT, bactrim)
Anticonvulsants
Phenothiazines
Lbuprofen
Antihistamines
Other
Malnourishment and debilitated states (alcoholism)
Splenomegaly
Anaphylaxis
Congenital causes
Modified from Lee GR, BithellTC, Foerster J, et al.Wintrobe’s clinical
hematology, 9th ed. Philadelphia: Lea & Febiger, 1993;1590.
Inflammatory response, thereby damplning the usual signs and symptoms
associated with infection. The production of purulent material is minimal, as are
redness and swelling at the site of infection. Fever, however, is usually
preserved in the neutropenic patient as a result ofendogenous pyrogens released
from fixed macrophages in the liver, spleen, and Lungs, and should be taken
seriously when present.
Management
It is extremely important to search carefully for infections in neutropenic
patients with fever. These infections can lead to life-threatening or fatal sepsis
in hours. Therefore, it is vital that empiric antibiotic treatment be initiated
rapidly. The majority of infections are caused by endogenous flora particularly
from the skin and gastrointestinal tract. Bacteria from the surrounding
environment are also common sources of infection. Gram-negative bacteria
have previously accounted for up to 50% of infections. However, there has been
a recent rise in gram-positive bacteria due to the increasing use of indwelling
catheters and invasive critical care.
Meticulous physical examination with particular attention to the skin
and mucosal surfaces often demonstrates the source of fever. Cultures of blood
and other potential sites are indicated when the source of fever is less obvious.
Cultures should be obtained rapidly and antibiotics administered promptly.
Standard antibiotic regimens include broad coverage of synergistic and
bactericidal combinations such as an aminoglycoside and extended-spectrum
penicillin or third-generation cephalosporin. Vancomycin is the agent of choice
when an infection with methicillin resistant S. Aureus is suspected.
Indwelling catheters warrant special consideration. Patients often
require them for essential vascular access and hemodynamic monitoring.
Although catheters may often be retained when an exit-site infection or
uncomplicated bacteraemia is present, catheter removal is indicated in the
presence of tunnel infections, endocarditis, systemic fungal infections,
infections that fail antibiotic treatment, or bacteraemia with diphtheroids.
Multiple Myeloma (7.6.4)
Multiple myeloma (MM) is a disorder in which there is a malignant
proliferation of plasma cells stemming from a single clone. In MM the
maturation of B lymphocytes into antibody-secreting plasma cells is no longer
controlled. The normal situation in which conversion into mature plasma cells
requires exposure to a particular antigen is lost in these cells.
About 95%of patients with MM possess an increased concentration
of hyper secreted immunoglobulin referred to as the monoclonal or “M-
component.” The most common immunoglobulin found in these patients is IgG;
however, IgA is observed in up to 25% of patients. The finding of an M-
component is useful as a tumor marker
but serves as a poor screening test due to its low specificity. M-component can
also be found in patients with CLL, lymphomas, breast cancer, cirrhosis, and
several other conditions.
Immunoglobulins are constructed of both heavy and light chains.
Approximately 20% of patients have only the light chain detectable. When
observed this light chain is referred to as the Bence Jones protein.

Incidence and Epidemiology

MM accounts for 10% to l5% of hematologic neoplasms in Caucasians
and up to one-third of hematologic neoplasms in African-Americans. The
incidence is approximately 4 cases per 100,000/ year and is currently rising. The
median age at onset is 68 years with >90% of patients being over the age of 50.
This disease is very rare in individuals younger than 40. Males have a slight
preponderance.

Diagnosis and Clinical Manifestations

Bone marrow plasmacytosis, lytic bone lesions, and the finding of an M-
component make up the classic triad of MM. This triad should be sought if the
diagnosis of MM is being considered. The most common present which is often
worse at night and while resting. Lytic bone lesions can lead to pathologic
fractures. Spinal cord compression syndromes may occur. A high index of
suspicion should be utilized when encountering prolonged or unexplained back
pain in the older individual bone lesions can lead to pathologic fractures. Spinal
cord compression syndromes may occur. A high index of suspicion should be
utilized when encountering prolonged or unexplained back pain in the older
individual.
The finding of a normochromic, normocytic anemia in an older individual
is another common presentation of MM. This is caused by bone marrow
myelophthisis, resulting in decreased erythropoiesis in addition to increased
destruction of red blood cells. Platelet dysfunction as a result of the M-
component predisposes to bleeding, which contributes to the anemic state.
Anemia complicates up to 80% of myeloma patients
Approximately 25% of patients present with recurrent bacterial infection.
Pneumonia and pyelonephritis are common, and frequent pathogens include
Staphylococcus, Streptococcus, and gram-negative organisms. These infections
are due to hypogammaglobinaemia and diminished neutrophil migration.
Hypogammaglobinaemia results from increased destruction of both monoclonal
and normal antibodies. Regulatory mechanisms lead to decreased production of
normal antibodies due to the high concentration of total immunoglobulin.
Several other abnormalities are often encountered in MM. Renal failure
eventually complicates approximately one-fourth of myeloma patients and
results from Bence jones proteinuria and hypercalcemia. Neurologic symptoms
occur in the setting of hyper viscosity and hypercalcemia. Hypercalcemia
results from the osteoplastic activating factors released by the increased number
of plasma cells. Symptoms of hypercalcemia include weakness, anorexia,
abdominal cramping, constipation, and mental status changes. Hyper viscosity
commonly leads to blurred vision, headache, fatigue, and mental status changes.
Laboratory investigation is useful in the definitive diagnosis of MM.
Bone marrow aspirate and biopsy help to measure the degree of marrow
plasmacytosis. By definition this is greater than l5o/o in patients with myeloma.
Serum and urine electrophoresis assist in determining the levels of M-
component and Bence Jones proteins, if present. CBC can demonstrate the
anemia commonly associated with myeloma. Rolex formation is another useful
finding on CBC that is seen as the M-component concentration increases. The
anion gap can be calculated in these patients and is characteristically decreased
due to the high concentration of cationic M-component that leads to chloride
retention. Pseudo hyponatremia may be observed also, due to the high
concentration of M-component. Alkaline phosphatase is usually normal despite
bone involvement because of the lack of osteoplastic activity. Urine dipstick
an.:lysis does not reveal Bence jones proteins. X-ray investigation of the skull,
pelvis, lumbar, and any tender areas is often useful in locating lytic lesions.
Bone scan is typically no diagnostic due to the lack osteopath
Treatment and disposition
Symptomatic treatment is usually the first priority in MM and should be
directed by the individual presentation. Treatment of pain, dehydration, and
hypercalcemia should be handled initially. Severe bone pain requiring adequate
opiate analgesia can be experienced by these patients. Vigorous hydration is
important and sometimes the critical component of therapy to reverse
dehydration that can compound hypercalcemia, which is often concurrently
present. Dehydration can also worsen renal failure and intensify symptoms due
to hyper viscosity. Severe hypercalcemia may require high dose steroid
treatment or dialysis when hydration and diuresis are not sufficient
Chemotherapeutic treatment of MM provides only modest
prolongation of survival. Due to the toxic nature of treatment it is generally
delayed until the patient is sufficiently symptomatic to warrant such
medications. Occasionally treatment is initiated to control severe
hypercalcemia. The most common medications are alkylating agents such as
Melpalan combined with oral steroids. Treatment leads to a mild neutropenia
and a gradual decline in the concentration of M-component. Complete
remission is only achieved in approximately 10% to 15% of patients as defined
by disappearance of the M-component. Approximately 50% of myeloma
patients achieve control of their disease once treatment is initiated. The
asymptomatic patient should be followed continuously with laboratory testing
every 3 to 6 months and periodic x-ray evaluation. Median survival is around 3
years from the time of presentation.
SELECTED READING
AbeloffMD, Armitage JO, LichterAS, Niederhuber JE. Clinical oncologt.New
York: Churchill Livingstone, I 995.
Dameshek W. Wlliam Dameshek and Frederick Gunz s Leukemia, 5th ed.
Philadelphia: Saunders, 1 990
Henderson ES, ListerTA. Leukemia Philadelphia: Saunders, 1990.
Isbister JP, Pittiglio DH. Clinical hematology: a problem-oriented
approach. Baltimore: Williams & Wilkins, 1988.
Lee GR, Bithell TC, Foerster J, et al. Wintrobeh clinical hematology, 9th ed.
Philadelphia: Lea & Febiger, i993.
Nealon TF. Management of the patient with cancer, 3rd ed. Philadelphia:
Saunders, 1986.

Immune System Disorders

Michael S. Beeson
Immune System Disorders (8.0); Humoral Immunity (8.1); Cellular Immunity
(8.2);
Chemical Mediators (8.3); Complement (8.4)
Paul T. Preisz
Autoimmune Diseases (8.5)
Dietrich V. K. Jehle
Immune Deficiency Syndromes (8.6)
Susan P. Graham
Transplant-Related Problems (8. 7)
Richard S. Krause
Hypersensitivity (8.8)

TMMUNE SYSTEM DTSORDERS (8.0)

The science of immunology has progressed dramatically over the last 20
years. Today, it is recognized that the immune system is composed of complex
interactions between humoral and cellular immunity components. These
complex interactions result in an interdependent response to antigenic
challenge. The result is a coordinated and efficient response to antigens
introduced into the human body. However, in its quest for efficiency, the
immune system may develop hypersensitivity responses to antigenic challenge.
These hypersensitivity reactions are not purely humoral or cellular in terms of
immune response. Rather, they are complex interactions involving both humoral
immunity (marrow-derived B lymphocytes) and thymus-derived T lymphocytes.
HUMORAL TMMUNTTY (8.1)
The humoral immune response begins with B lymphocytes that
produce immunoglobulins. This immunity is antigenically quite specific. There
are literally millions of different antibody molecules with differing antigen
specificities. The immunoglobulins are secreted into the plasma where they may
form specific antigen-antibody complexes. Additionally, some
immunoglobulins are membrane bound on antigen-specific memory B
lymphocytes, allowing for a secondary humoral response.
Before B lymphocytes can become antigen specific, they must first be
activated. This activation occurs with the assistance of helper T lymphocytes.
There are numerous chemical mediators secreted by the T helper cells as well as
the B lymphocytes that facilitate B lymphocytic activation. Once activate4 the B
lymphocytes differentiate into plasma cells that produce large amounts of
soluble plasma-bound immunoglobulin, and memory B cells that have
membrane-bound immunoglobulin present. Memory B lymphocytes have
pivotal roles in the secondary immune response, e.g., when an immunized
individual is challenged again with the same or nearly identical antigen.
There are three recognized types of hypersensitivity. type I
hypersensitivity reactions result in anaphylaxis. These reactions involve the
combining of a specific antigen to mast cell membrane-bound immunoglobulin
E (IgE) and to basophils. Membrane-bound IgG can also cause the same
reaction, although IgE antibody is much more predominant. The antigen-
antibody complex that forms on the membranes of the mast cells and basophils
causes the release of chemical mediators. These mediators are very potent
vasoactive and inflammatory mediators including histamine, heparin, serotonin,
eosinophil chemotactic factor (ECF-A), neutrophil chemotactic factor (NCF-A),
a variety of proteases, and other mediators that are synthesized at the time of
mast cell or basophil stimulation. These additional mediators include platelet
activating factor (PAF), slow reaction substance of anaphylaxis (SRS-A), and
several prostaglandins and throm boxanes. These mediators may cause the
classic signs and symptoms of anaphylaxis including smooth muscle
contraction, increased capillary permeability, chemotaxis of eosinophils and
neutrophils, platelet aggregation, and bronchoconstriction. The overall
physiologic effects of these mediators are bronchospasm and profound vasodi-
(IgE) and to basophils. Membrane-bound IgG can also cause the same reaction,
although IgE antibody is much more predominant. The antigen-antibody
complex that forms on the membranes of the mast cells and basophils causes the
release of chemical mediators. These mediators are very potent vasoactive and
inflammatory mediators including histamine, heparin, serotonin, eosinophil
chemotactic factor (ECF-A), neutrophil chemotactic factor (NCF-A), a variety
of proteases, and other mediators that are synthesized at the time of mast cell or
basophil stimulation. These additional mediators include platelet activating
factor (PAF), slow reaction substance of anaphylaxis (SRS-A), and several
prostaglandins and throm boxanes. These mediators may cause the classic signs
and symptoms of anaphylaxis including smooth muscle contraction, increased
capillary permeability, chemotaxis of eosinophils and neutrophils, platelet
aggregation, and bronchoconstriction. The overall physiologic effects of these
mediators are bronchospasm and profound vasodilatation, resulting in severe
hypotensilatation, resulting in severe hypotension.
The prototypical type I hypersensitivity reaction is termed atopy.
Atopy refers to the production of increased amounts of IgE to common
substances that are inhaled or ingested. These common allergies include
ragweed, pollen, and others that cause allergic rhinitis. Type II hypersensitivity
reactions occur when circulating antibody combines with cellular antigenic
components. This reaction usually results in complement activation and in
phagocytosis or cytolysis of the cell with the antigenic component. Examples of
type II hypersensitivity reaction include hemolytic anemias resulting in
incompatible transfusions, pemphigus, and Good pasture’s syndrome.
Type III hypersensitivity reactions occur when antigen antibody
complexes (i.e., immune complexes) are formed and deposited in blood vessels
or tissues. Components of this reaction include the activation of complement.
Certain components of complement are formed increasing vascular endothelial
permeability as well as causing neutrophilic chemotaxis. Clinical features of
type III hypersensitivity reactions include the Arthus reaction. This type of
reaction is typified with the localized angry cellulitis reaction to repeated
antigenic challenge by immunization. Other clinical entities associated with
type III hypersensitivity reactions include serum sickness, post streptococcal
glomerulonephritis, autoimmune disease, and hypersensitivity pneumonitision.
CELLULAR TMMUNTTY (8.2)
As noted previously, it is difficult to separate immunity on the basis
of function. Cellular immunity refers to the immune response by T
lymphocytes. It is now recognized however that cellular immunity function is
integral to humoral immunity as well. When an antigen is initially encountered,
it is processed by an antigen-processing cell (APC). Macrophages are the
prototypical antigen processing cells. The macrophage ingests the antigen, and
processes it in such a way that it can be presented on its cell membrane to a T
lymphocyte helper cell. The helper T lymphocyte cells become activated, and
cause the secretion of chemical mediators that in turn activate cytotoxic T
lymphocytes and antibody-secreting plasma cells. activation of the cytotoxic T
lymphocytes causes the secretion of additional chemical mediators that lead to
the death ofthe infected target cell.
 The prototypic hypersensitivity reaction involving cellular immunity
is type IV This hypersensitivity reaction involves T lymphocytes, and does not
rely on antibodies or complement. This reaction is a delayed hypersensitivity
reaction. This reaction is delayed because ofthe need for T cell lymphocytes to
become sensitized after contact with the specific antigen. This in turn causes
chemical mediators to be expressed that attract more T cell lymphocyes to
migrate to the area of antigen challenge. examples of type IV hypersensitivity
reactions include skin testing for tuberculosis, contact dermatitis,
hypersensitivity pneumonitis, allograft rejection, and hypersensitivity reactions
to drugs. Manifestations of delayed hypersensitivity to drugs usually occur 24 to
48 hours after exposure. However, exposure may not occur until the patient has
nearly finished a course of treatment with the offending drug. Clinical
manifestations include urticaria, fever, eosinophilic pulmonary infiltrates, and,
rurely, vasculitides. Treatment includes removing the offending agent,
symptomatic relief of urticaria, and, in patients demonstrating multisystem
involvement, the administration of corticosteroids.
CHEMTCAL MEDTATORS (8.3)
Central to the functioning of both the cellular and humoral
immune systems is the communication between cells. This communication is in
the form of chemical mediators (Table 8-1) that are secreted by cells in response
to antigen exposure or exposure to activated immune cells. These chemical
mediators serve multiple functions including stimulation of the immune and
inflammatory responses. These chemical mediators are important in that they
cause the further production of other mediators that further stimulate B and T
cell proliferation, immunoglobulin production, and effects on other
inflammatory cells such as macrophages. Collectively, the soluble chemical
mediators are called cytokines. They are produced primarily by lymphocytes
and macrophages. Their effects are primarily local. There are only a few
cy4okines that are detectable in quantities sufficient to produce a generalized
effect. Cytokines are secreted in response to specific stimuli and produce effects
locally on target cells. These effects are an absolute requirement in the overall
functioning of the
TABLE 8-1. Chemical mediators of inflammation.
Histamine
Platelet-activating factor (PAF)
Prostaglandins
Leukotrienes (includes SRS-A, or slow-reacting substance Of inflammation)
Cytokines [interleukins = 1, 2, 3,4, 5, 6, 7, 8, 9,and 10;
Tumor necrosis factor (TNF); eosinophil chemotactic
Factor (ECF-A); neutrophil chemotactic factor (NCF-A)l
Complement components
Heparin
Serotonin
Lnterferons
Immune system as they perform a required function of co-stimulation of T and
B lymphocytes. Cytokines are either peptides or glycoproteins in nature and
number in the hundreds that have been identified thus far. These include the
interleukins, tumor necrosis factor (TNF), the interferons, and colony-
stimulating factors.
Chemical mediators as a whole are secreted in response to contact
with specific antigens, contact with specific activated T:cell helper lymphocytes
and by stimulation by other cytokines. The effect of the chemical mediators is to
co-stimulate the various responses within the immune system.
COMPLEMENT (8.4)
 Complement is a term that refers to over 25 proteins present in the
plasma and cell membranes of immunologic cells. These proteins cascade in a
sequence of events, activating each subsequent component of the complement
pathway. The ultimate function of complement is to lyse infected cells, bacteria,
and viruses. Complement also serves in the process called opsonization in
which complement protein fragments coat bacteria, viruses, or other infected
cells, allowing them to be recognized by macrophage cells. Complement plays
an inexact role in the regulation of immune and inflammatory responses.
TABLE 8-2. Complement activation
Classic pathway (Ag/Ab complex) Alternative pathway. Common
components of both pathways
________________________________________________________________
________________
Way. There is an alternative pathway to complement activation that bypasses
the need for antigen-antibody complexes. However, both pathways converge
early in the cascade sequence, ultimately resulting in a membrane attack
complex that ultimately results in the lysis of the offending cell.
One of the by-products of complement activation is a protein
fragment termed C3b. This protein coats either bacteria or antigen-antibody
complexes. Numerous cell types have surface receptors for C3b, including
neutrophiles, eosinophiles, macrophages, B cells, and basophiles. When
attached to bacteria or antigen-antiboddy complexes, cells with C3b receptors
ultimately ingest the particles. Genetic lack of the C3 protein fragment results in
an inability to opsonize with the subsequent recurrent pyogenic infections.
Finally, activation of the complement pathway results in numerous
small protein fragments, each of which has important biological functions such
as immunoregulatory effects, opsonization, release of histamine and other
chemical mediators, and the release of polymorphonucleocytes sites from bone
marrow.
SELECTED READING
 Frank MM. Complement and kinin. In: Stites DP, Terr AI, Parslow TG, eds.
basic and clinical immunology,8th ed Norwalk, CT: Appleton &
Lange,1994:124-136.
Goodman JW. The immune response. In: Stites DP, Terr AI, Parslow TG, eds.
Basic and clinical inmunology, 8th ed. Norwalk, CT: Appleton & lange,
1994;4049.
Haynes BF, Fauci AS. Cellular and molecular basis of immunity. In:
Isselbacher KJ, Braunwald E, Wilson JD, et al., eds. Harrison s principles of
inlernal medicine, l3th ed. NewYork: McGraw-Hill, 1994;1543-1559.
Nossal GJV Current concepts: immunology: the basic components of the
immune system. N Engl J Med 1987;316:1320.
AUTOTMMUNE DISEASES (8.s).
Immunology and Autoimmune Diseases
Immune responses are characterized by specificity, including the
ability to differentiate between what is normal self and what is not, and by
memory, the ability to recognize a previously encountered foreign antigen and
to mount a rapid and intense response upon reexposure. the mechanisms by
which immune tolerance to self develops are incompleteinvolve such processes
as central deletion (e.g., deletion of self-recognizing T cells during development
in the thymus), sequestration of some antigens so they are not exposed to the
immune system (e.g., in the cornea),anergy, peripheral deletion, and
suppression. Memory is achieved by the formation, during an initial immune
response, of specific long-lived memory cells capable of recognizing a
particular antige recognizing a particular antigen.
Lymphocytes arise from progenitor cells that have migrated to the
primary lymphoid organs and have under-gone a process of development and
maturation. In the thymus these progenitor cells develop into T lymphocytes,
and in the fetal liver and in bone marrow they develop into B lymphocytes.
After release lymphocytes aggregale in secondary lymphoid organs such as the
spleen and lymph nodes from which they may circulate throughout the body. B
lymphocytes produce antibodies that recognize free antigens made of protein,
polysaccha ride, or nucleic acid. With help from activated T helper cells the B
lymphocytes will proliferate and secrete antibody that can specifically recognize
and bind to the antigen that initiated the process.
Antibody binding to antigen can lead to opsonization, netfiralization
of free antigen, and further stimulation of immunocytes, platelets, and other
cells (such as mast cells), in addition to stimulation of vascular smooth muscle
and increased vascular permeability. In a number of settings these effects are
mediated through plasma enzymes known collectively as the complement
system. when complement is activated by interaction with antigen-antibody
complexes, this is known as activation by the classical pathway. Complement
can also be activatedvia an alternative pathway by interaction with some
microorganism polysaccharides and endotoxins. immunoglobulin antibodies
consist of a number of basic units. Each antibody unit has two light and two
heavy chains. These are arranged such that the molecule has two variable F(Ab)
binding sites for antigen and two fixed or constant F(c) binding sites for binding
to immunocytes and to complement.
Great variability exists in the F(Ab) binding sites so that a large
number of foreign antigens can be recognized by different antibody molecules.
The five classes of immunoglobulin have different structure and functions and
are referred to as IgG, IgA, IgM, IgD, and IgE.
T cells carry glycoprotein antigens on their surface. some of these
antigens such as CD3 occur on all T cells, others occur on T cells, B cells,
macrophages, and other cells. The CD4 glycoprotein is found on T which
interact with B cells by releasing cytokines during antibody-mediated immune
responses. These cytokines are small polypeptides that bind specific receptors
on target cells to exert their effects. Important examples of cytokines include the
interleukins, tumor necrosis factor, and interfero and interferon.
T cells recognize foreign antigens that have been fragmented and
transported to the surface of cells where they are bound to class I or class II
major histocompatibility complex (MHC) antigens. These MHC antigens are
encoded by genes on chromosome 6, with MHC class I proteins encoded at
HLA-A, HLA-B, and HLA-C loci, and MHC class II proteins encoded at the
HLA-DB HLA-DQ, and HLA-DR loci.
It is not known why a number of diseases are associated with particular
HLA epitypes (e.g., HLA-827 and ankylosing spondylitis, HLA-DR3 and
Graves’ disease).
Cytotoxic T cells carry the CD8 surface glycoprotein. they recognize
antigens displayed on the surface of cells associated with class I HLA and
attack these cells by releasing protein molecules to disrupt the cell membrane
and by releasing cytokines. Natural killer cells are large granular lymphocytes
that are not categorized as T or B in type. They play an important role as
antiviral and antitumor agents as well as being involved in graft rejection. many
other cells, including mast cells, dendritic cells, and macrophages, play vital
roles in normal immune homeostasis.
 Inappropriate reactivity of components of the immune system with
aberrant responses to self antigens are features of those diseases that are
described as autoimmune. The mechanisms by which these processes occur are
incompletely understood but include cross-reactivity of epitopes (e.g., hepatitis
B and polyarteritis nodosa), loss of active suppression, release of hidden
antigens (e.g., dresser’s syndrome), generation of modified self antigens, T cell
bypass, and superantigen stimulation ofT cell populations (e.9., by streptococcal
antigens in rheumatic fever).
Acute Rheumatic Fever (8.5.1)
Rheumatic fever is most often a disease of children between the ages
of 5 and 15 years. The disease has a degree of familial predominance, and
affected individuals are prone to recurrent attacks .
While the exact pathophysiologic mechanisms remain unproven,
rheumatic fever is thought to be due to an uncommon dysfunctional immune
response following pharyngeal infection with some strains of group A
phemolytic streptococcus resulting in inflammatory changes in the heart, skin,
joints, and other tissues. While the history of antecedent pharyngitis is often
lacking, patients with acute rheumatic fever usually have increased titers of
antibodies to streptococcal antigens, indicating infection within the preceding
month.
Focal inflammation around small blood vessels with fibrinoid
degeneration of the surrounding collagen is usually seen. In the myocardium
small granulomas (Aschoff bodies) are classically described. In joints an
exudative arthritis that resolves without sequelae is typical. The subcutaneous
nodules are fibrinoid granulomas. no typical neurologic lesion has been
identified and the cerebrospinal fluid is often normal.
The clinical presentation is most commonly as an acute febrile illness
with fever greater than 38’C and migratory polyarthritis of the larger limb
joints. Cardiac symptoms and signs are less common, although the murmurs of
mitral, or less often aortic, incompetence usually appear ifcarditis is present.
Marked tachycardia, pericarditis, and in severe cases, cardiac
enlargement and failure may occur. First- or second-degree heart block may
also be seen.
Sydenham’s chorea, when present, occurs late in the Illness and may
develop insidiously. It is characteizedby sudden erratic jerking movements that
are most marked on effort, anxiety, or excitement, and that are not present
during sleep. Muscle weakness may be quite severe and emotional lability may
also be present.
Erythema marginatum is an evanescent, macular, pink rash that is
nonpruritic and has irregular borders with central clearing. It occurs most often
on the trunk and proximal limbs. Subcutaneous nodules tend to be peasized,
painless, and positioned over prominences of bone.
Rheumatic fever is a clinical diagnosis using the revised Jones criteria.
The major criteria are carditis, polyarthritis, chorea, erythema marginatum, and
subcutaneous nodules. The minor criteria are fever, arthralgia (in the absence of
arthritis), previous rheumatic fever or rheumatic heart disease, acute phase
reaction such as leukocytosis, elevated erythrocyte sedimentation rate (ESR) or
abnormal C-reactive protein (CRP), and ECG changes such as prolonged PR
interval. Evidence of recent streptococcal throat infection (e.g., positive throat
swab culture or raised antistreptolysin antibodies) and either two major or one
majcr and two minor criteria are required to make the diagnosis. Other
symptoms that may accur include fatigue, weight loss, and abdominal pain.
History physical examination, ECG, and chest x-ray are all of
importance in establishing the diagnosis. Laboratory tests may determine the
presence of recent group a streptococcal pharyngeal infection by throat swab
culture or by serologic testing and may demonstrate nonspecific markers of
inflammation such as raised ESR, CRP, leukocytosis, and anemia. Further
investigations such as echocardiography should be undertaken in conjunction
with specialist consultation.
Having established the diagnosis, bed rest and supportive therapy are
instituted as clinically indicated. Parenteral penicillin or an acceptable
alternative antibiotic should be administered. The nature and duration of long-
term antibiotic prophylaxis to prevent rheumatic fever recurrence must be
determined on an individual basis. Patients with subsequent rheumatic heart
disease require prophylaxis to prevent bacterial endocarditis.
Salicylates are usually adequate to relieve the syrnptoms of arthritis.
Corticosteroids are prescribed for several weeks in patients with carditis who
have not responded to salicylate therapy. Sedatives, tranquilizers, reassurance,
and appropriate nursing care are indicated in the management of chorea.
Rheumatic fever typically is self-limiting and can be expected to last for several
months. The ESR and CRP are useful laboratory markers of disease activity.
Prevention ofrecurrent attacks and subsequent cumulative cardiac
damage is important. In some patients emergency management of significant
cardiac failure, arrhythmias, or other complications may be urgently required.
 Collagen Vascular Diseases (8.5.2)
Collagen vascular diseases are a group of disorders characterized by
abnormalities of the immune system, vasculitis, and varying multisystem
involvement. They may be difficult to diagnose and may themselves mimic
infections, malignancies, thromboses, or a number of other diseases. Some
connective tissue disorders such as thyroiditis are relatively organ specific,
others such as systemic lupus erythematosis are less so. The types and sites of
vessels involved also vary and this largely determines the clinical
manifestations. As the clinical presentations of this group of disorders are
legion, they must be considered as a part of the differential diagnosis in a wide
variety of clinical settings.
Despite a number of attempts to standardize classification, the
incomplete understanding of the underlying processes has meant that all
systems have their limitations and that many patients will not fit easily into one
category. Such patients may display features of several diseases and may
continue to evolve for quite some time before conforming to a recognizable
pattern.
D ermatomyositis (8. 5. 2. 1) and Po lymyositis (8. 5. 2. 2)
 Polymyositis is an uncommon inflammatory disease of muscle
characterized by lymphocytic infiltration without suppuration; when it is
associated with skin involvement, it is called dermatomyositis. A significant
proportion of patients also have connective tissue disease such as rheumatoid
arthritis or systemic lupus erythematosus, and up to l0o/o are ultimately found
to have an underlying malignancy, most commonly in patients over 60 years of
Age. There is some familial predominance, and the disease is more common in
patients with some particular HLA epitypes. The role of viral infection in
pathogenesis is as yet unclear. Polymyositis can occur in patients with AIDS
and less commonly as a side effect of zidovudine therapy.
The clinical symptoms usually appear gradually. Proximal muscle
weakness sometimes with pain and tenderness may precede or be preceded by a
rash. The rash may appear lilac colored (heliotrope) and present in a butterfly
facial distribution, or it may present in a variefy of ways including erythema or
even as an itchy dermatitis. rarely the onset may be as dramatic weakness,
some-times with rhabdomyolysis.
Reflexes may be normal or brisk. Involvement of striated esophageal
muscle leads to dysphagia, and cardiac involvement may manifest as
arrhythmias or as heart failure. Typically ESR and creatine kinase (CK)
elevation can be expected.
The electromyogram often demonstrates muscle irritability as well as
changes typical of myopathy. Muscle biopsy provides confirmation; however, it
should be borne in mind that muscle involvement is patchy, and obtaining a
representative sample may be difficult. Evidence of associated connective tissue
disorder should be sought as well as a search for malignancy in older patients.
Treatment with glucocorticoids should be instituted
Once the diagnosis has been established. Prednisone 1 to 2 mglkg is
usually adequate. The dose may be reduced as clinical improvement occurs,
although the duration of initial therapy is often several weeks and alternate day
dosing should be considered. Monitoring is by clinical assessment, as serial CK
measurements are initially unreliable.
Severe, refractory, or relapsing disease may require treatment with
cytotoxic drugs such as azathioprine or cyclophosphamide, either alone or in
combination with lower dose steroid therapy.
Older patients, those with severe, chronic, widespread or resistant
disease, and those with associated malignancy or connective tissue disease have
a worse prognosison.
 Reiter’s Syndrome (8. 5. 2.3)
Reiter’s syndrome is a relatively coflrmon form of reactive athritis
triggered by urogenital chlamydial infection. It is most common inHLA-827-
positive young men and is part of the spectrum of reactive arthritis that also
includes arthritis following gastrointestinal infection with salmonella, shigella,
or other enterobes.
Reiter’s syndrome is characterized by arthritis, urethritis,
conjunctivitis, and mucocutaneous lesions. The initial symptoms are typically of
intermittent, sometimes painless, urethral discharge, followed by constitutional
symptoms such as fever, fatigue, and malaise. Prostatitis may also be present.
The arthritis is acute, painful, and asymmetrical, involving few joints at first,
with others being affected over days to weeks. The lower limbs, feet, and low
back are common sites, although upper limb joints including fingers (dactylitis)
may also be involved. Fasciitsiand tendonitis are also common. Mild
conjunctivitis and less frequently uveitis is seen. Superficial, relatively painless
oral and penile ulcers may be present. Typical skin lesions (keratoderma
blenorrhagica) consist of vesicles on the palms, soles, and elsewhere, which
later become hyperkeratotic and encrusted.
 Initial laboratory investigations demonstrate nonspecific markers of
acute inflammation. Rheumatoid factor and antinuclear antibody (ANA) are
usually negative and most patients are HLA-B27 positive. At the time of first
presentation x-rays may be normal, and, while joint fluid is often nondiagnostic,
it may still be required to exclude septic arthritis or gout. In some cases it is
possible to culture chlamydia from the urogenital tract.
Treatment with tetracyclines should be initiated when chlamydial
infection is present. Nonsteroidal antiinfl ammatory drugs (NSAIDs) are
effective in treating arthritis. in some situations local steroid injection may be
helpful.
If uveitis is present, topical and oral glucocorticoids should be given.
Rarely, aggressive or refractory disease may require treatment with cytotoxics.
Some patients suffer recurrent illness and a small number have permanent
residual disability.
Rheumatoid Arthritis (8, 5. 2. 4).
Rheumatoid arthritis is a relatively common disease that can be seen in
all age groups but is most common in women between the ages of 35 and 50
years. Its pathogenesis is incompletely understood but it is highly likely that an
element of genetic predisposition is present; in particular there seems to be a
high incidence in patients with specific types of a beta chain found on HLA-
DR4 in a number of population groups and HLA-DRI in others. the role of
infectious agents and other environmental factors remains unclear.
The predominant pathologic changes initially seen in joints consist of
synovial hyperplasia, T cell infiltration, and microvascular injury, resulting in
damage to cartilage and bone. There is an increase in the secretion ofsynovial
fluid with evidence of active inflammation, including a predominance of
polymorphs in the fluid. Rheumatoid nodules are thought to be a result of
vasculitis in periarticular structures, and consist of an area of central necrosis
surrounded by macrophages and an outer zone of granulation tissue. Vasculitis
may also involve skin, nerves, or other organs, although renal disease is rare.
Low-grade fever and constitutional symptoms such as fatigue and
lethargy are in part due to cytokine release. joint disease often begins as the
slow onset of a symmetrical, peripheral polyarthritis, with morning stiffness.
The wrists, metacarpophalangeal and proximal interphalangeal joints, elbows,
knees, and feet ainvolved. Spinal disease usually involves the upper cervical
region. The hallmarks of inflammation are usually present, although atypical
presentations do occur. Long-standing disease leads to deformities, especially in
the wrists, fingers, and feet. Synovial inflammation spreading beyond the knee
into the popliteal space is a cause of Baker's cyst.
Extraarticular manifestations are relatively common and tend to occur
mostly when titers to rheumatoid factor are high. Rheumatoid nodules occur
around joints and occasionally on serous membranes such as pleura. Pulmonary
nodules may cause respiratory impairment and may some-times cavitate.
Vasculitis may present as necrotic areas of skin, digital ischemia, or following
infarction of gut or other organs. Neurologic manifestations may be related to
compression entrapment or vasculitis. Dry eyes (Sjogren’syndrome) are
relatively common; however, other ophthalmic complications such as scleritis
are much rarer’ A number of syndromes such as Caplan’s syndrome (pulmonary
rheumatoid nodules in patients with pneumoconiosis and pulmonary fibrosis)
and Felty’s syndrome (rheumatoid arthritis, splenomegay, neutropenia, and
thrombocy’topenia) have been descrdescribe
Vasculitis (8.5.5)
The term vasculitis is used to describe pathologic inflammation of
blood vessels of varying sizes and at varying sites. Vessel lumen occlusion
leads to ischemia of affected organs and increased vascular permeability, which
may lead to edema. Vasculitis may be localized or widespread destructive or
benign, and may be precipitated by infection, hypersensitivity, connective tissue
disorders, malignancy, or unknown causes.
The manifestations of vasculitis vary widely. For many patients the
diagnosis requires the assessment of clinical symptoms and signs, laboratory
investigations including serology, and imaging with biopsy of an involved
organ.
Having made a diagnosis of vasculitis the following steps should be
underlaken to provide confirmation. The markers of active inflammation should
be sought. Elevated ESR, leukocytosis, the presence of C-reactive protein, and
other acute-phase reactants as well as anemia may be present. Assessment of
liver and renal function as well as tests specific to other organ systems
potentially involved should be done. It should be noted that the finding of
vasculitis at one site does not always mean that other areas are involved” and
other potential causes of organ dysfunction should be sought and excluded.
A search for precipitants and associated conditions should be made,
including screening for infection (e.g.,syphilis, gonorrhea, hepatitis B),
malignancy, allergy, and connective tissue diseases. Specific testing of serum
immunoglobulins, ANA, rheumatoid factor, and complement levels as well as
antineutrophil cytoplasmic autoan- tibodies (ANCA) should be performed.
Imaging of involved organs should be done, particularly if ischemia is
suspected.
Treatment depends on identifying the clinical syndrome and any
associated diseases or precipitants and then instituting appropriate therapy. In
general, therapy can be subdivided into management of organ failure,
supportive therapy, treatment for allergy or infection, treatment of associated
diseases, and the use of immunosuppression. It is often necessary to follow
patients over a considerable period as evolution into a more serious syndrome
may occur later.
IMMUNE DEFICIENCY SYNDROMES (8.6)
Immunodeficiency syndromes are charactetized by a remarkable
susceptibility to infections, autoimmune disease, and lymphoreticular
malignancies. The unusual types of infections often provide the initial clue to
the presence of the immune defect. These disorders may be spontaneously
acquired, congenital, or iatrogenic. The most common of the acquired disorders
is the acquired immunodeficiency syndrome (AIDS), which occurs as a result of
infection with the human immunodeficiency virus (HIV). Other causes of
spontaneously acquired immunodeficiency include malnutrition, protein-losing
enteropathy, and catabolic states such as myotonic dystrophy and
lymphoreticular malignancy. Congenital immunodeficiencies are categorized
according to pattern of inheritance and involvement of T lymphocytes, B
lymphocytes, or both. The iatrogenic immune disorders occur secondary to
treatment with cytotoxic drugs, antilymphocyte serum, or radiation.
HIV Disease/AIDS (8.6.1)
AIDS was initially recognized in the summer of 1981 when five
cases of Pnettmocystis carinii pneumonia and 26 cases of Kaposi’s sarcoma
were reported in otherwise healthy homosexual men. HIV was isolated and
demonstrated as the etiologic agent of AIDS in 1984 and serologic testing for
the virus soon followed. The earliest retrospective diagnosis of AIDS has been
made reviewing records from the late 1950s. The numbers of cases of AIDS has
grown in epidemic proportions over the last one and one-half decades. Among
adults ages 25 to 44, AIDS disease is the number one cause of death for men
and the number four cause of death for women.
HIV disease is fundamentally an infection of the immune system
that results in progressive premature drestruction of the Thelper (CD4)
lymphocytes. There is a broad spectrum of HIV disease starting with a brief
symptomatic or asymptomatic primary infection followesymptomatic phase that
follows (AIDS) is characterized by an increased frequency of infections that are
normally kept in check by an ordinary immune system. In addition, involvement
of the nervous system or hemopoietic tissues May be seen during this
progressive late stag.
Definition
The current definition of AIDS includes all patients with HIV
infection and a CD4 count less than 200luI, CD4/CD8 ratio <0.14, and/or an
AlDS-indicator (opportunistic) condition such as unusual secondary infections,
specific neoplasms, or neurologic disease (Table 8-3).
Etiologlt
There are two types of HIV viruses that have been identified as
causingAIDS in humans: HIV-1 and HIV-2. The most common cause in AIDS
HIV-l virus. The HIV-2 has been most frequently identified in West Africa and
parts of Asia; however, this virus is extremely rare in the United States,
accounting for only 0.01% of HIV infections (almost all traceable to Western
Africa). The HIV-2 virus may be less virulent than HIV-I and resembles some
members of the group of simian immunodeficiency viruses. The transmission
and clinical features of the HIV-l and HIV-2 viruses are similar. Routine
screening of blood donors in the United States for HIV-2 using a combined
enzyme immunoassay for both HIV-1 and -2 was initiated in 1992.
Epidemiology
Incidence and Prevalence
It is estimated that there are more than 19 million people worldwide infected
with the HIV virus. Projections.
TABLE 8-3. Al DS-defining disorders.
Candidiasis, pulmonary or esophageal
Cervical cancer
Occidioidomycosis
Cryptococcosis, extrapulmonary
Cryptosporidiosis
Cytomegalovirus, chronic (more than 1 month) or esophageal
Histoplasmosis
Kaposi’s sarcoma
Lymphoma
Mycobacterium avium
Mycobacterium kansasii
Mycobacterium tubercuiosis
Pneumocystis
Pneumonia, recurrent
Progressive multifocal leukoencephalopathy
For the year 2000 are for this number to grow to 30 to 40 million HIV
infections. The largest number of infections (highest prevalence) are in sub-
Saharan Africa; however,asia is expected to surpass Africa as the region with
the largest number of new cases (highest incidence) by the year 2000. In the
United States it is estimated that 750,000 to 1.4 million individuals are infected
with the HIV virus. There have been at least 501,000 AIDS cases diagnosed in
the United States from l98l through October 1995; of these, 620/have died.
Roughly 40,000 new cases are diagnosed each year in the United States and an
equivalent number of patients die annually of this disease.
The initial epidemiologic data from AIDS patients in the United
States found that among men with the disease, 670/o were homosexual, lJoh
were IV drug users, 80% were both homosexual and IV drug users, 3% received
blood products prior to 1985, 2%had heterosexual contact with an HIV infected
female, and 3Yo were without identified risk factors. Women with AIDS had
the following risk factors: 53oh were IV drug users, 30%o had a heterosexual
contact with an HlV-infected male, l0o/o received blood products prior to 1985,
and, joh had no identified risk factors. In 1988, when HIV screening of job
Corps applicants in the United States was initiated, men were found to be twice
as likely as women to have HIV infection. However, more recent
seroprevalence studies of Job Corps applicants have now demonstrated a higher
rate of HIV infection among women than men, similar to the ratios seen in
Africa and Asia for some time. Behaviors or events that are associated with
greater risk of acquiring HIV infection include male homosexuality, IV drug
abuse, prostitution, tattooing, acupuncture, heterosexual exposure to a partner at
risk, having a large number of sexual partners, receiving blood products prior to
1985, and being born to a HlV-infected mother.
The prevalence of HIV infection varies greatly in different popul
ations-7 5o/o in factor Vlll-deficient hemophiliacs to 0.02% in voluntary blood
donors (Table 8-4). There is also significant geographic variability in
seropositivity in emergency department (ED) populations; 4.2% to ll.3% in
large urban inner cities versus <l% in suburban settings. A large percentage of
these patients are unaware of their HIV infection. Nonwhite populations and
victims of penetrating trauma are at significantly higher risk of being
seropositive when screened in the ED.
 Transmission
HIV infection is most frequently transmitted via sexual intercourse,
parenteral route, perinatal maternal-fetal inoculation, or breast milk. The HIV
virus is concentrated in cells; therefore, cellular fluids are significantly more
infectious than a cellular secretions. Blood and its compaction.
TABLE 8-4. Prevalence of HIV infection in selected populations
in the United States
Nents are probably the most infectious. Other documented sources of HIV
transmission include semen, cervical and vlaginal secretions, breast milk,
cerebrospinal flui4 and pleural and peritoneal fluids. Infectivity correlates with
degree of viremia; thus. The risk of HIV transmission is greatest during initial
seroconversion and with advanced disease when viremia is at its highest levels.
There is no evidence to date that HIV infection can be spread by routine casual
contact.
Sexual transmission of HIV has been reported with unprotected
vaginal intercourse, oral intercourse with ejaculation, and anal intercourse.
Sexual behaviors that are associated with the highest rates of transmission are
anal intercourse and sex during menses. Worldwide, heterosexual transmission
is the most common mode of transmission, although this is responsible for a
minority of all HIV cases in the United States. However, the number of cases
that were transmitted heterosexually in the United States has increased from 3%
between l98l and 1987 to l0% from 1993 to 1995. The percent of cases among
women in the United States also rose from 8o/o to lSoh during this time period.
The risk of sexual transmission correlates with the absence of mucosal integrity.
The greater prevalence of untreated chancroid, syphilis, and genital herpes
simplex (open ulcerated genital lesions) in Western Africa and parts of Asia
may partially explain the higher rate of heterosexual transmission in these
populations.
Parenteral transmission of HIV occurs most frequently secondary to
sharing of needles and syringes among IV drug users. In addition, donation of
blood products by HlV-infected individuals results in HIV infection in
approximately 90% of recipients. Testing blood donors for antibodies to HIV
(initiated in 1985) significantly reduces the risk of transmission via transfusions;
however, there is still a I in 40,000 to 250,000 risk of acquiring infection from a
donor that has just recently been infected and has not yet developed detectable
antibodies. Transfer of the virus by HlV-contaminated needle-stick to a health
care worker carries a risk of 0.3% to 0.4% per exposure. The risk of transfer of
HIV from a physician to a patient is extremely small.
Maternal-fetal transmission occurs in l3% or 39% of infants born to
HlV-infected mothers. Breast-feeding should be convincingly discouraged
among HlV-infected mothers as there is additional risk of HIV transmission
from infected milk.
 Testing.
The interval between HIV infection and antibody response is from I
to 3 months. Antibodies to HIV usually appear within 2 weeks of onset of the
acute retroviral syndrome (when present) and are almost always present within
8 weeks. Enzyme-linked immunosorbent assay (ELISA) for HIV antibody is the
best of the currently available screening tests with sensitivities and specificities
of over 99 .5% and 99%, respectively. In low-risk populations (e.g., blood
donors), a majority of positive tests represent false positives. The Western blot
assay is utilized most frequently as a confirmatory test for positive ELISA tests
results. This test has sensitivities and specificities that approach 100%;however,
it is labor intensive and costly. Indeterminate test results should be repeated
inlto3months.
The p24 antigen assay is an ELISA test that has a sensitivity of
approxim ately 30% in detecting HIV infection. This sensitivity can be
increased to 50% using acid dissociation of immune complexes. This test is
helpful in diagnosing acute retroviral infection prior to the development of HIV
antibodies. The polymerase chain reaction test (quantitative viral load assay) is
extremely sensitive and is now available outside of the university/research
setting. Direct culture of HIV from blood has excellent sensitivity and
specificity; however, limited availability and time to grow (it requires at least 28
days) restricts its usefulness in the clinical arena.
Measurement of the T-helper lymphocyte (CD4) level and viral load
are currently the most accurate ways to assess the degree of immune
suppression. Abrupt shifts in CD4 counts should be cautiously evaluated as
there may be diurnal variation of 50 to 150/μl in normal patients. However the
daily variation in counts is significantly less in patients with low CD4 counts.
Certain opportunistic infections in AIDS patients are only seen with CD4 counts
below specific levels. In general, patients with CD4 counts above 500/μl have a
basically normal immune response, while those below 200/pl are aI risk for
AlDS-related secondary infections (Table 8-5). There is a rare syndrome,
idiopathic CD4 T lymphocy’topenia (ICL), which is characteized by low CD4
counts without evidence of HIV infection or explained under$ing defect in
cellular immu.
TABLE 8-5. Relationship between CD4 cell counts and infections
CNS, central nervous system; Gl, gastrointestinal; MAC, Mycobacterium avium
complex; TB, tuberculosis. Adapted from Gallant JE. Lnfectious complications
of HIV disease. Emerg Med Clin North Am 1995;13(1):73-104.
Nity; it was first noted in l992.There is no evidence of sexual transmission
and the clinical course is more benign. Opportunistic infections do occur in
association with this disorder and should be treated appropriately.
Natural History
Acute Retroviral Infection
 The primary infection is estimated to be symptomatic (acute
retroviral syndrome) in 30Yo to 70oh of cases and this generally follows 3 to 6
weeks after the primary exposure to HIV The acute retroviral syndrome usually
presents as a mononucleosis-type illness with fever, pharyngitis,
lymphadenopathy, headache, nausea, myalgias, arthralgias, and malaise. An
erythematous maculopapular rash, hepatosplenomegaly, meningismus, and an
encephalitic picture have been described. Symptoms are generally self-limiting
and usually resolve in 7 to 10 days. The severity of the acute retroviral
syndrome is usually relatively mild; however, 30% of patients seek medical care
for these complaints.
Clinical Staging
There is a long asymptomatic period (median: 9 to 10 years for
homosexual men, shorter for IV drug users) following the primary infection.
Staging of HIV disease subsequent to the primary infection is currently based
on CD4 counts: early disease >500/μl, intermediate disease 200 to 500/μl, late
symptDmatic disease 50 to 200/μl, and advanced disease <50/μl. During the
early disease phase, patients may have lymphadenopathy, but usually have no
other symptoms secondary to the HIV infection. In the intermediate disease
group, patients may have candidiasis, oral hairy leukoplakia, herpes simplex
virus (HSV) disease, herpes zoster, seborrheic dermatitis, TB, HIV-related
malignancies, or bacterial infections. Constitutional symptoms such as
headache, fever, night sweats, weight loss, diarrhea, and fatigue are common.
Unusual opportunistic infections are relatively infrequent in the intermediate
stage. The late symptomatic disease stage that follows is characterized by
opportunistic infections and generalized disease progression. Patients with
advanced disease have a high probability of developing multiple opportunistic
infections. Disseminated, Mycobacterium avium infections and
cytomegalovirus infect-patients may have lymphadenopathy, but usually have
no other symptoms secondary to the HIV infection. In the intermediate disease
group, patients may have candidiasis, oral hairy leukoplakia, herpes simplex
virus (HSV) disease, herpes zoster, seborrheic dermatitis, TB, HIV-related
malignancies, or bacterial infections. Constitutional symptoms such as
headache, fever, night sweats, weight loss, diarrhea, and fatigue are common.
Unusual opportunistic infections are relatively infrequent in the intermediate
stage. The late symptomatic disease stage that follows is characterized by
opportunistic infections and generalized disease progression. Patients with
advanced disease have a high probability of developing multiple opportunistic
infections. Disseminated, Mycobacterium avium infections and
cytomegalovirus infections are characteristically seen only in this stage.
 Clinical Manifestations and Management of Associated Disease.
The symptomatic phase of HIV infection is characterizedby a wide
variety of infections secondary to bacteria, viruses, parasites, and fungi. Some
of these infections occur with only mild immune suppression, while others
develop only in the presence of advanced disease. Treat-ment and prophylaxis
of some of the common HIV- related opportunistic infections are summarized in
Table 8-6. In addition, there are alarge group of noninfectious complications of
HIV disease that involve almost every organ system. With the exception of the
HlV-related neoplasms, these will be approached from atarget organ
perspective.
Patients with HIV disease are at greater risk of developing
malignancies, as is the case with other immune deficiencies. The cancers that
are identified with HIV disease include Kaposi’s sarcoma, non-Hodgkin’s
lymphoma, and anogenital malignancies. All of these tumors have distinctive
epidemiologic profiles among patients with HIV disease. There are additional
malignancies that occur with equivalent frequencies in the HIV and non-HlV-
infected patient; however, it is not unusual to see a more fulminant course in
those with AIDS.
 Kaposi’s sarcoma (KS) is the most cornmon cancer associated with
HIV disease; however, most of the reported cases (96%) have occurred in
homosexual or bisexual men. This has raised the possibility that the presence of
Kaposi’s sarcoma may be related to a distinct infectious agent or cofactor
(possibly a herpes type virus). Kaposi’s sarcoma may present at any stage of
HIV infection. The lesions may involve skin, mucous membranes, lymph nodes,
gastrointestinal tract, or lungs. Typically, these sarcomas appear as raised,
reddish to purple macules (may be papules or nodules) measuring from a few
millimeters to several centimeters. KS can involve any cutaneous location but is
most commonly found on the face, genitalia, and feet. The diagnosis of KS is
established by the pathologic appearance of tissue on biopsy.
The natural history of this disease varies from an indolent to an
aggressive course. However, in light of the fact that less than 10% of AIDS
patients with KS die directly of this sarcoma, most authors support a cautious
treatment regimen that avoids further immune suppression. Treatment with
interferon-o, decreases tumor bulk and improves survival in patients with
greater than 200/μl CD4 cells. Combination chemotherapy with low-dose
doxorubicin, bleomycin, and vinblastine plus radiation therapy is indicated for
patients with life-threatening disease.
 Non-Hodgkin’s lymphoma (NHL) is generally a late manifestation
(CD4 <200/μl) of AIDS. Approximately 3% of all AIDS patients develop a
lymphoma as a complication of their disease, with the highest prevalence in
hemophiliacs and lowest in African groups with heterosexual transmission. The
great majority of the HIV-Related lymphomas are high grade B-cell tumors.
The most common types include immunoblastic lymphoma, Burritt’s
lymphoma, and primary CNS lymphoma. Occasionally, Epstein-Barr virus
(EBV) appears to play an etiologic role, and EBV genetic material is found in
half of all HlV-related lymphomas.
The clinical progression of systemic NHL in the AIDS patient is
much more aggressive than that seen in the normal host. Characteristically,
patients note a rapidly growing mass or nonspecific symptoms (fever, night
sweats, or weight loss). Extranodal disease is found on presentation In98%”
ofAIDS patients, while this is only seen in 40% of HlV-negative patients.
Standard intensive chemotherapeutic regimens have been rejected due to poor
response rates and complicating opportunistic infections.
The patients with HlV-related primary CNS lymphoma can present
with focal neurologic findings, headache, changes in mental status, or seizures.
On computed tomography (CT) scanning (with contrast), lymphoma may be
confused with CNS toxoplasmosis, since both diseases may demonstrate ring-
enhancing lesions. Usually patients with lymphoma have single lesions
measuring greater than 3 cm at presentation, while CNS toxoplasmosis has
multiple smaller lesions. Magnetic resonance imaging (MRI) and nuclear
medicine studies have been utilized to assist in differentiating these diseases. In
addition, a tridl ofantibiotic therapy directed against toxoplasmosis is frequently
utilized to help make a tentative diagnosis. Only patients who fail this regimen
should undergo brain biopsy. Treatment of primary CNS lymphoma is almost
always futile; however, radiation therapy and steroids have been palliative in
soofantibiotic
Anogenital malignancies (cervical and anal squamous cell
carcinomas) are seen slightly more often in the patient with HIV disease as a
result of coincidental infection with the human papilloma virus (HPV). Periodic
rectal and pelvic examinations with Papanicolaou smears supplemented by
colposcopy should be performed in the HlV-infected patient to identify early
stages of disease (dysplasia or intraepithelial neoplasia).
Pulmonary Involvement
Respiratory tract infections are seen in practically all patients with
AIDS. In the patient with early or intermediate disease there is an increased
incidence of bacterial pneumonia and tuberculosis. As the HIV disease
progresses to the late stages (CD4 count < 200), a variety of opportunistic
pulmonary infections are encountered. The most common of these, and one of
the AlDs-defining infections, is Pneumocystis carinii pneumonia. Treatment
and prophylaxis for common HlV-related opportunistic respiratory infections is
outlined in Table 8-6.
Bacterial pneumonia and sinusitis are found in all stages of HIV
infection. There may be a slightly increased incidence of disease with
encapsulated bacteria in AIDS, and infections with Streptococcus pneumoniae,
haemophilus influenzae, and other classical encapsulated bacterial pathogens
predominate. Bacterial pneumonia usually presents with a relatively sudden
onset of symptoms of fever, sputum production, and pleuritic chest pain over a
period of 3 to 5 days. Radiographically, bacterial pneumonia tends to display
focal consolidation or cavitary disease; however, diffirse bilateral infiltrates are
occasionally reported. When the suspected respiratory pathogens include both
common bacteria and pneumocystis, treatment with high-dose trimethoprim-
sthis gives adequate coverage for both groups. Sinusitin generally involves the
maxillary sinuses, but may involve the other sinuses as well. Treatment of
sinusitis should include broad-spectrum antibiotics and decongdiffirse
 Pneumocystis carinii pneumonia (PCP) was seen in 80% ofAIDS
patients during the mid-I980s. This dropped to 40% in the early 1990s, as a
result of the successful aggressive use of prophylaxis against PCP in patients
with CD4 counts less than 200l1tl or patients with higher CD4 counts with
prominent constitutional symptoms. P carinii was originally classified as a
protozoa; however, there is some evidence to suggest that it actually represents
a fungus. Patients with PCP often describe prodromal symptoms of fever,
fatigue, and weight loss for several weeks prior to onset of pulmonary
manifestations of dyspnea and nonproductive cough. The chest radiograph most
often demonstrates bilateral interstitial or alveolar infiltrates, yet focal
infiltrates, cavitary lesions, pleural effirsions, nodular densities, and
pneumothorax have been encountered. Upper lobe disease cavitary disease may
be seen in patients receiving aerosolized pentamidine prophylaxis. When the
diagnosis is unclear, sputum should be induced with nebulized saline.
Fluorescein staining has improved the sensitivity of sputum examination for P.
Carinii in comparison to the traditional silver stain technique. If this is
unsuccessful, bronchoscopy with bronchoalveolar lavage/biopsy increases the
sensitiviry to the 100% range. The arleial blood gas generally demonstrates
hlpoxemia or at least desaturation with exercise. Several trials have
demonstrated that corticosteroids (prednisone 40 mg BID x 5 days, 40 mg QD x
5 days followed by 20 mg QD for 10 days) prevent the alveolar inflammation
and hypoxia associated with the antibiotic treatment of pneumocystis. This
reduces the risk of intubation and death from respiratory failure by
approximately 50oh. Adjuvant steroids demonstrate their benefit primarily in
patients with a PaOz <70 Mm Hg or alveolar-arterial gradient >35 mm Hg on
room air.
Fungal disease of the lung in the AIDS patient may also be secondary
to Cryptococcus, Coccidiomycosis, Histoplasmosis, or Aspergillus.
Cryptococcus neoformans is the second (to PCP) most common cause of fungal
pneumonia in HIV disease and is discussed further in conjunction with
cryptococcal meningitis. Although Aspergillus is an important cause of
pneumonia in immunocompromised hosts, it is an infrequent pathogen in the
AIDS patient.
Coccidioides immitis is found primarily in the deserts of the
Southwest. Pneumonitis in the AIDS patient is usually the result of reactivation
of the fungus. Patients present with slowly progressive constitutional and
respiratory symptoms. Radiographic findings are more extensive in HIV disease
and diffirse nodular or interstitial infiltrates are frequently detected.
 Histoplasma capsulatum is endemic to parts of the Mississippi and
Ohio river valleys and exists in soil contaminated by bird or bat excrement.
Histoplasmosis characteristically presents with fever and pneumonia in the
AIDS patient. Adenopathy, bone marrow involvement, and mucocutaneous
disease may occur. The disease is diagnosed by culture or histopathologic
appearance of the organism from blood, bone marrow, or infected tissue.
The incidence of tuberculosis (TB) has increased significantly as a
result of the spread of HIV disease. The risk of reactivation and primary
infection with Mycobacterium tuberculosis is striking higher in the patient with
HIV disease. M. Tuberculosls is one of the most virulent opportunistic
infections seen in HIV disease. As a result, reactivation tuberculosis frequently
occurs with only mild to moderate decreases in the CD4 counts. The radiologic
appearance of pulmonary tuberculosis in these patient is fairly typical with
apical and cavitary infiltrates. When tuberculosis occurs in patients with
advanced HIV disease (CD4 < 50/pl), the x-ray finding may be more atypical
(lower lobe or miliary patterns also seen).
A positive purified protein derivative (PPD) may support the diagnosis
of TB; however, a negative test is less useful since anergy is common in
patients with HIV disease. The diagnosis of TB is made by examination of the
sputum for acid-fast bacilli (AFB) with confirmatory culture. Standard
treatment of active TB in the HlV-seropositive and HlV-seronegative patient is
equally efficacious. Because of the high risk of development of TB in early HIV
disease, any HlV-positive patient with a PPD >5 mm induration, a history of a
positive PPD, or a significant exposure should receive 12 months of isoniazid.
Multiple drug resistant TB (MDR-TB) has emerged as a problem
particularly among HlV-infected patients in institutional settings. Unfortunately,
there is only marginally effective treatment for MDR-TB in the HlV-infected
patient. Most authorities recommend the standard four drug regimen for TB plus
two additional drugs based on local MDR-TB strain susceptibility.
Nonimmunocompromised patients with MDR-TB have only a 50% probability
of sterilizing their sputum cultures and the outcome is significantly worse in
those with HIV disease.
Mycobacterium kansasii produces a disease that is clinically analogous
to tuberculosis in patients with advanced HIV disease. The organism is usually
found in pulmonary secretions. It is relatively easy to treat, responding well to
12 to 18 months of isoniazid, revamping, and ethambutol.
Neuro logic Manifes tations
 Central nervous system disorders associated with HIV disease include
primary and secondary CNS infections, peripheral neuropathies, myopathies,
vascular complications, and neoplasms. Neurologic involvement occurs in 75%
to 90% of patients with AIDS and is the first manifestation of AIDS in l0% to
20% of patients.
Toxoplasma gondii, the etiologic agent of toxoplasmosis, is a protozoa
that typically infects humans through the ingestion of substances contaminated
by cat faces or the consumption of undercooked meat. The primary infection is
relatively asymptomatic, often occurring early in life. Toxoplasmosis in patients
with AIDS usually occurs as the result of reactivation of T. gondii cysts and
generally presents as an encephalitis; however, it may present as transverse
myelitis, retinochoroiditis, pulmonary disease, peritonitis, or orchitis. It is the
most frequently encountered secondary CNS infection in HIV disease and the
leading cause of intracranial mass lesions in patients with AIDS. Toxoplasmic
encephalitis is usually seen in patients with CD4 counts less than 100/μl.
Patients with CNS toxoplasmosis typically present with altered mental
status, focal neurologic deficits, or seizures. Fever and headache are commonly
present. Individuals with lggtoxoplasma seropositivity are at higher risk for
CNS toxoplasmosis, yet this test is not particularly helpful in making or ruling
out this diagnosis. Lumbar puncture may show a mild pleocytosis and an
elevated protein level, However, this is contraindicated in patients with
significant mass lesions. CT scanning with contrast or MRI scanning (more
sensitive) are the preferred techniques to confirm the presence of toxoplasmosis.
Thallium scanning may also help distinguish CNS toxoplasmosis from CNS
lymphoma (positive with malignancy, negative with toxoplasmosis). The
definitive diagnosis of CNS toxoplasmosis can only be made with a brain
biopsy; however, in light of the morbidity associated with this invasive
procedure, this is usually reserved for patients who clinically appear to have
toxoplasmosis yet do not respond to2to 4 weeks of appropriate therapy.
Chemoprophylaxis to prevent toxoplasmosis reactivation is indicated in toxo-
seropositive patients with CD4 counts less than 200/μl.
Cryptococcus neoformans is the most common cause of meningitis in
individuals with HIV disease occurring in 60% to l2% of all AIDS patients.
This ubiquitous encapsulated yeast is of low virulence, causing disease only in
AIDS patients with CD4 counts less than 100/pl. The clinical presentation of
cryptococcal meningitis may be subtle and subacute. Headache (76%), fever
(65%), meningismus (22%), and photophobia (18%) are the most commonly
reported symptoms. Pulmonary disease is present in 40% of patients with
cryptococcal infections, 900% of whom also have CNS involvement.
Cerebrospinal fluid (CSF) may demonstrate leukocyte counts between 0 and
700/μl(most 0 to 20l1tl), protein elevation (55%), and a low glucose (24%).
The India ink stains (75%) and CSF cryptococcal antigen (95%) are more
helpful than other CSF studies; however, neither test is as sensitive as the serum
cryptococcal antigen (98%). The definitive diagnosis is based on culturing C.
Neoformans from the CSF.
AIDS dementia complex (also called HIV encephalopathy and HIV
dementia) is characterized by impairments in cognitive, motor, and behavioural
function. This is usually occurs late in the course of HIV disease. Deficits in
attention, forgetfulness, and decreased cognitive function are initial symptoms.
Apathy, withdrawal, ataxia, and deterioration of fine motor skills follow as the
disease advances. In rare cases, an agitated or manic state may develop. During
the later stages of this disorder, patients may develop severe motor dysfunction
and with incontinence of bowel and bladder. Neuroimaging (CT/MRI) typically
shows cerebral atrophy, ventricular enlargement, subcortical gray matter lesion,
and parenchymal changes in the white matter. The CSF may demonstrate mild
pleocytosis (25%) and elevation of the protein level (65%). There is no clearly
effective treatment of AIDS dementia complex; however, there are anecdotal
reports of improvement with antiretroviral therapy.
 Peripheral neuropathies are common manifestations of HIV disease. An
inflammatory demyelinating neuropathy similar to Guillain-Barr6 has been
described in patients with early HIV disease. In advanced disease, painful
sensory neuropathies are frequently noted. However, painless sensory, pure
motor, mixed” and autonomic neuropathies are also described. In addition,
several of the reverse transcriptase inhibitors (ddl, ddc, and d4T) can cause
peripheral neuropathies.
The myopathy associated with HIV disease is characteized by slowly
progressive proximal muscle weakness, wasting of upper and lower extremities,
elevated creatinine phosphokinase, and a myopathic picture on
electromyography. Prolonged treatment with azido thymidine (AZT) may also
result in a myopathy that presents with prolonged muscle weakness, wasting of
the buttocks and lower extremities, and elevated creatinine phosphokinase. This
diagnosis can be confirmed on muscle biopsy. The AZT should be discontinued
and a short course of prednisone may accelerate recovery of motor function.
The Jakob-Creutzfeldt (JC) virus is the etiologic agent of progressive
multifocal leukoencephalopathy (PML). This demyelinating disorder involves
the cerebral hemispheres, cerebellum, and brain stem, and is generally only seen
in advanced AIDS. Patients may develop multiple focal neurologic deficits or
have an encephalitic presentation. The diagnosis is typically made with MRI
scanning, which demonstrates multiple white matter lesions. There is no known
effective treatment, and patients generally die 3 to 9 months after onset of
symptoms.
GI Complications
The most common gastrointestinal disturbance in AIDS is diarrheal
disease. HIV enteropathy, Kaposi’s sarcoma, Cryptosporidium, Mycobacterium
avium complex (MAC), and Microsporidia can all result in chronic diarrhea that
is difficult to treat. In addition, patients with HIV disease are at risk for treatable
causes of diarrhea that include Isospora, Giardiq, Endamoebas
histolytica,Campylobacte4 Salmonella, and, Shi gella. Crypto sporidium
parvum is the most frequent cause of diarrheal illness in AIDS. It is
characteized by copious watery diarrhea and crampy abdominal pain.
Examination of the stool reveals no red or white blood cells. In addition,
Cryptosporidium may involve the biliary tract, resulting in cholestatic jaundice
and acalculous cholecystitis; cytomegalovirus (CMV) may also involve the
biliary tract. The diagnosis is made by acid-fast staining of oocysts in stool or
biopsy specimens. Therapy is symptomatic with antimotility agents and
nutritional supplements. Strict enteric precautions are indicated since this
parasite can be transmitted to otherwise healthy hosts, resulting in an acute self-
limiting diarrheal illness.
Esophagitis occurs in 40%to 50%of AIDS cases. Candida is the most
common pathogen (50% to 70%), with Herpes simplex and CMV implicated for
most of the remaining cases. Most patients with esophageal candidiasis present
with dysphagia, oral thrush, and a CD4 count less than 100/μl. Treatment of
presumed esophageal candidiasis without fuither diagnostic testing in the setting
of oral thrush is appropriate since it is easily treatable with 14 to 2l days of
fluconazole or ketoconazole. Patients who present with odynophagia or
dysphagia of questionable etiology or those patients that do not respond after
several days of therapy for candida esophagitis should undergo barium swallow
or endoscopy (endoscopy is more sensitive and specific).
Cutaneous Manifes tations
Dermatologic conditions are described in over 90% of AIDS patients.
The cutaneous manifestations of HIV disease may be secondary to the acute
retroviral syndrome, infections, malignancies, drug therapies, nutritional
disorders, or autoimmune phenomenon. In addition, there a variety of common
dermatologic conditions (e.g., seborrhoea and psoriasis) that have an
exaggerated presentation in the AIDS patient. Many of these are discussed in
other sections of this chapter; this section focuses predominantly on the
infectious dermatosis seen in the patient with HIV disease.
Oral and vaginal candidiasis is common in all stages of HIV disease.
Oropharyngeal candidiasis most often presents as "pseudomembranous"
candidiasis that is characteized. by an easily removable white plaque. An
erythematous form, with red patches on the mucous membranes and angular
cheilitis, is also frequently reported. Less commonly, patients present with
candidal leukoplakia, with white patches that cannot be removed. Treatment
with topical or oral antifungal agents is usually effective for both oral and
vaginal candidiasis. Candida albicans is the etiologic agent in most cases;
however, the prolonged use of systemic antifungal agents has now led to the
development of an occasional resistant yeast infections. Caused by Candida
krusei, Torulopsis glabrata, or resistant strains of C. Albicans. These resistant
infections may respond to higher dose “azoles” or may require treatment with
amphotericin B.
Oral hairy leukoplakia is an Epstein-Barr virus associated condition
that presents with painless thick white lesions on the lateral surface of the
tongue (buccal mucosa may also be involved). In contrast to typical thrush,
these lesions cannot be removed when scraped. Oral hairy leukoplakia is
typically an early manifestation of HIV disease, predating other opportunistic
infections. No specific treatment is generally required; however, the lesions may
respond to oral acyclovir, AZT, and topical tretinoin.
Rochalimaea henselae, the etiologic agent of bacillary angiomatosis, is
a rickettsial organism that causes a proliferative vascular disorder seen most
commonly in patients with HIV disease. Patients present with angiomatous
papules, skin nodules, or cellulitic plaques. Patients may have constitutional
symptoms (fever, weight loss, and malaise) and visceral involvement of the
liver, spleen, lymph nodes, bone marrow, CNS, and lungs. The diagnosis is
confirmed by the histologic appearance of the biopsy and the identification
ofthe organism on the warthin-starry silver stain. Patients have been
successfully treated with 4 weeks of either erythromycin or doxycycline.
Recurrent herpes simplex virus (HSV) infections are frequently seen in
HIV disease. In early HIV disease, the course of HSV infection is similar to that
in a Nonimmunocompromised host. With HIV disease progression (CD4 counts
<200/μl), HSV disease presents in a more aggressive manner. The diagnosis of
HSV infection is usually made clinically, yet patients with extensive disease or
atypical presentations should have the diagnosis confirmed with viral cultures.
Acyclovir is the treatment of choice for these patients, although patients who
have received prolonged treatment with acyclovir may develop resistant strains
(may also occur with herpes zoster) that are responsive to foscarnet.
Herpes zoster, representing reactivation of latent varicella-zoster virus
(VZV), develops more commonly in the HlV-infected patient. Young, otherwise
healthy patients who present with VZV infection should be tested for HIV
disease, as this may be the initial clinical manifestation of worsening immune
suppression. As the degree of immune suppression progresses, individuals are
more likely to develop disseminated disease. Dermatomal YZY can be treated
with oral agents, while disseminated, ophthalmic, or visceral disease should be
treated with intravenous antivirals.
Treponema pallidum, the etiologic agent of syphilis, is a spirochete
that enters the body through mucous membranes or broken skin. The course of
primary and secondary syphilis in the patient with HIV disease is basically
unaltered; however, treatment failure after standard penicillin therapy may
occur more frequently in AIDS, and some authorities routinely recommend
three weekly doses (rather than one dose) of penicillin in this setting. There are
several unusual manifestations of late syphilis that develop in the AIDS patient,
including lues maligna (necrotizing vasculitis) and atypical early neurosyphilisl
(presenting with meningitis, stroke, blindness, or deafness). The diagnosis of
neurosyphilis may be more difficult to confirm in the AIDS patient, because of
the coexistent CSF abnormalities and the insensitivity of the CSF VDRL.
Ophthalmoiogic Manifestations.
CMV retinitis is the leading ocular complication of HIV disease. This
generally occurs as a manifestation of afvanced HIV disease (CD4 <50/pl).
There is a strong predilection of CMV to the retina. Approximately 90o/o of
patients with invasive disease develop eye involvement. patients generally
describe floaters, decreased visual acuity, or field deficits. The diagnosis is
based on retinal findings (hemorrhage, exudates, dense opaque lesions, and
vasculitis) on indirect ophthalmoscopy. Serologic testing is nonspecific and
does not help confirm the diagnosis. If untreated, CMV retinitis is rapidly
destructive, leading to blindness. With appropriate antiviral therapy, the
progression of the disease is slowed significantly. CMV infection may also
involve the esophagus, stomach, colon liver, adrenals, and CNS. The role of
oral ganciclovir for CMV prophylaxis of patients with CD4 counts less than
50/pl appears promising and is undergoing further evaluation. Other less
frequent causes of retinitis in the AIDS patient include herpes zoster,
Pneumocystis carinii, Tbxoplasma gondii, and ischemic retinitis.
Renal Manifestations.
 HIV nephropathy is characteized by striking proteinuria,
hypoalbuminemia, anasarca, and rapidly progressive azotemia. This condition
occurs more frequently in young black males (male/female ratio l0:l). The
course of HIV nephropathy is rapidly progressive with the development of end-
stage renal disease within 4 months. The kidneys are frequently enlarged and
the diagnosis can be confirmed with renal biopsy. Unfortunately, there is no
effective therapy for HIV nephropathy.
Systemic Disease
Mycobacterium avium complex causes disseminated infections in
patients with advanced HIV disease. Infection occurs as a result of ingesting
contaminated soil or water. These patients typically present with fever, sweats,
abdominal pain, and diarrhea. Anemia and elevated alkaline phosphatase levels
are frequently reported, reflbone marrow involvement. MAC is simple to
diagnose, with sensitivities of two blood cultures approaching 100%. MAC is
often isolated from sputum in patients with and without disseminated infection,
yet it infrequently causes pulmonary disease. MAC infection cannot be
completely eradicated; however, antibiotic therapy reduces bacteremia and
alleviates clinical symptoms. Chemoprophylaxis to prevent disseminated MAC
is recommended for patients with CD4 counts less than 50 to100/úl.
 Treatment
There is currently no treatment that cures AIDS. However, there
are several antiretroviral drugs that delay the progression of HIV disease and
may improve survival. most of the available drugs that have some efficacy in
HIV disease are nucleoside analogues that act as reverse transcriptase inhibitors
or protease inhibitors. Of these agents, the greatest amount of experience has
been with zidorudine (AZT or more recently ZDY), a nucleoside analogue
reverse transcriptase inhibitor. Nonnucleoside reverse transcriptase inhibitors
may have some utility in treating HIV disease and should be available in the
near fature. Bone marrow transplantation, lymphocyte transfusions, interleukin-
2, and interferon have been utilized with limited success.
Most patients with HIV produce a strong humoral and cellular
response to the virus. Despite this vigorous response, the immune system is
ultimately incapable of blocking the progression ofthe disease. Unfortunately,
no effective vaccine against the HIV virus has been produced to date. The
extremely high mutation rate of the HIV virus has mediated against the success
of several attempted HIV vaccines. There has been some interest in developing
a live attenuated HIV vaccine; however, there are concerns that a HIV clone
could change back to a virulent form over time.
Zidovudine (AZT/ZDV)
Zidovudine therapy (500 to 600 mg/day in divided doses) is
recommended for patients with CD4 counts less than 500/pl. Some authors
recommend delaying onset of therapy in asymptomatic patients with counts
between 200 and 500/μl. Treatment of patients with CD4 counts greater than
500/μl is not recommended. Headache, nausea, vomiting, myalgias, malaise,
dyspepsia, and insomnia have been described after initiation of therapy. The
most significant toxicities associated with AZT therapy are anemia leukopenia
and neutropenia. These resolve promptly after withdrawal of AZT.If the
neutropenia or anemia reoccurs with reinitiation of therapy, AZT should be
switched to a different antiretroviral. Prolonged administration of AZT in
patients with late disease is associated with the development of drug resistance
and diminished effectiveness (assessed by viral load testing).
Other Reverse Transcriptase Inhibitors.
Didanosine (ddl) in doses of 200 to 440 mglday increases CD4
counts and decreases p24 antigenemia in the short term. Didanosine is effective
in patients who have become resistant to AZT therapy. Peripheral neuropathy,
pancreatitis, hyperamylasemia, hyperuricemia, dry mouth, nausea, vomiting,
diarrhea, liver toxicity, electrolyte disturbances, and cardiac arrhythmias have
been reported with ddl.
Zalcitabine (ddC) therapy in divided doses totaling 1.125 to 2.25 mg
day improves survival in patients intolerant to AZT and has been advocated
together with AZT as combination therapy in patients with late disease who
have yet to receive antiretroviral treatment. Side effects of ddC include fevers,
cutaneous eruptions, mucosal ulcers, and painful peripheral neuropathy.
Stavudine (d4T) in doses 30 to 80 mg/day increases CD4 counts and
decreases p24 antigenemia. Stavudine has been shown to be more effective than
continued AZT in patients who had been previously treated with AZT.
headache, nausea, vomiting, confusion, elevations of hepatocellular enzymes,
pancreatitis, and painful peripreral neuropathy have been described with
Stavudine.
Lamirudine (3TC) in doses of 150 mg BID when used withAZT
results in synergistic inhibition of HIV disease. when used alone, resistance to
the drug develops rapidly. Concurrent use of 3TC raises the serum levels of
AZT. adverse effects of lamivudine include gastrointestinal distress,
pancreatitis, and neutropenia.
Protease Inhibitors.
 Protease inhibitors are a new class of antiretroviral drugs that prevent
cleavage of protein precursors essential for HIV infection. Recommended
dosages of three protease inhibitors currently available are Saquinavir 600 mg
TID, Ritonavir 600 mg BID, and Indinavir 800 mg TID. Saquinavir appears to
be the least effective and ritonavir the poorest tolerated, and they are all
relatively expensive in comparison to the reverse transcriptase inhibitors. These
drugs have generally been used in combination therapy with the reverse
transcriptase inhibitors. Saquinavir and Ritonavir have gastrointestinal side
effects and interfere with the cytochrome P-450 enzyme system. Indinavir may
cause mild elevations of indirect bilirubin and urolithiasis, but is usually well
tolerated. These drugs have shown some efficacy in patients with advanced
disease (for at least 6 months); however, how long these effects persist and
whether these drugs are effective in early disease remain to be determined.
Prevention.
Prevention of sexual transmission of HIV includes avoidance
ofbehaviors associated with an increased like-lihood of transmission (e.g., anal
intercourse and sex during menses) and most importantly limiting the number of
sexual partners coupled with the use of latex condoms. awareness of HIV
seropositivity of potential partners can certainly decrease the risk of becoming
HIV infected.
High-Risk Groups.
Patients with HIV infection need to understand how to prevent further
transmission of the virus. These patients should be persuaded to abstain from
sexual relationships if their partner is not infected. Although condoms are very
effective barriers to viral passage in the lab, they are not effective clinically
unless used compulsively. Individuals with an intravenous drug habit should
enter a substance abuse program at time of diagnosis.
Antiretroviral therapy significantly reduces the incidence of maternal-
fetal HIV transmission (decreased by approximately two thirds). The HlV-
positive mother should receive AZT during the second and third trimester of
pregnancy followed by a 6-week course of treatment for the newborns. Prenatal
testing of fetal blood is not indicated, as this is thought to increase the risk of
HIV infection in the baby.
Health Care Workers.
Precautions in handling potentially infectious fluids are paramount in
preventing occupational transmission. Compliance with universal precautions is
the most effective preventive measure for health care workers. AZT has been
frequently used prophylactically for health care workers who have been exposed
to HIV contaminated material. There is limited data (one retrospective
casecontrol study) supporting the use of AZT in this setting, and it has
significant side effects. There have been at least 14 clearly documented cases of
HIV infection despite early administration of AZT. In light of the limited
options, many authorities currently recommend tripledrug therapy for
significant exposures.
SELECTED READING.
Bartlett JG, ed. The Johns Hopkins Hospital guide to medical care of patients
with HIV infection, 4th ed. Baltimore: Williams & Wilkins,1994;52-61.
Beral ! Peterman TA, Berkelman RI, et al. Kaposi’s sarcoma among persons
with AIDS: a sexually transmitted infection? Lancet 1990;335: 123-t28
CDC. First 500,000 AIDS cases-United States, 1995. MMWR 1995;44: 849-
8s3.
CDC. Case-control sfudy of HIV seroconversion in health-care workers after
percutaneous exposue to HlV-infected blood-France, United Kingdom, and
United States, January 1988-August 1994. MMWR 1995;44:929-933.
Clark SJ, Saag MS, Decker WD, et al. High titers of cytopathic virus in plasma
of patients with symptomatic primary HIV-I infection. N Engl J med
1991;324:954-960.
Clifford DB, Campbell JW. Management of neurologic opportunities disorders
in human immunodeficiency virus infection. ,Semin Nettrol 1992;12:28-33.
Fahey JL, Taylor JM, Detels R, et al. The prognostic value of cellular and
serologic markers in infection with human immunodeficiency virus type l. N
Engl J Med 1990;322:166-172
Fischl MA, Daikos GL, Uttamchandani RB, et al. Clinical presentation and
outcome of patients with HIV infection and tuberculosis caused by multiple-
drug-resistant bacilli. Ann Intern Med 19921.117 :184-190.
Galetto G, Morrow CT Noninfectious manifestations of human immunod-
eficiency virus infection. Emerg Med Clin North Am 1995;13(l):105-132.
Gallant JE. Infectious complications of HIV disease. Emerg Med Clin north Am
I 995; 1 3(l):73-104.
Hardy WD, Feinberg J, Finklestein DM, et al. A controlled trial of
trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary pro-
phylaxis of Pneumocystis carinii pneumonia in patients with the acquired
immunodeficiency sl.ndrome. AIDS Clinical Trials Group Protocol 021. N Engl
J Med 1992;327:1842-1848.
Phair J, Munoz A, Detels R, et al. The risk of Pneumocystis carinii pneumonia
among men infected with human immunodeficiency virus type l. Multicenter
AIDS Cohort Study Group. N Engl J Med 1990;322:161-l 65.
Porter SB, Sande MA. Toxoplasmosis of the central newous system in the
acquired immunodeficiency syndrome. N Engl J Med 1992;327:R643-1648.
Powderly WG, Saag MS, Cloud GA, et al. A controlled trial of fluconazole or
amphotericin B to prevent relapse of cryptococcal meningitis in patients with
acquired immunodeficiency syndrome. The Mycoses Study group. NEngl “/
Med 1992;326:793-798.
Robertson KR, Hall CD. Human immunodeficiency virus-related cognitive
impairment and the acquired immunodeficiency syndrome dementia complex.
Semin Neurol 1992;12:18-27.
Saag MS, Powderly WG, Cloud GA, et al. Comparison of amphotericin B with
fluconazole in the treatment of acute AlDS-associated cryptococcal meningitis.
The NIAID Mycoses Study Group. N Engl J Med 1992;326:83-89.
Sloand EM, Pitt E, Chiarello RL HIV testing. State of the art. JAMA
L99l;266:2861-2866.
Smith PD Quinn TC, Strober W et al. NIH Conference. Gastrointestinal
infections in AIDS. Lnz Intern Med 1992;116:63-77.
Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic
human immunodeficiency virus infection. A controlled trial in persons with
fewer than 500 CD4-positive cells pre cubic millimeter. The AIDS clinical
Trials Group ofthe National Institute ofAllergy and Infectious diseases. N Engl
J Med 1990;322:941-949.
TRANSPLANT:RELATED PROBLEMS (8.7)
Tiansplant Rejection (8.7.1)
Rejection of a transplanted organ is a consequence of acute or chronic
immunologic attack on the foreign tissue. Hyperacute rejection, immediately
after implantation, almost never occurs due to preoperative donor recipient
matching. Acute rejection is most common in the first weeks and months after
transplantation, although it can occur any time if the immunosuppressive
medications are reduced or stopped. Chronic rejection is a more insidious
process leading to destruction of the organ months to years following
transplantation.
The designations “acute” and “chronic” rejection have been
supplemented by specific terms describing the pathologic processes as observed
in a diagnostic biopsy (Table 8-7). Acute rejection is characterizedby an active
lymphocytic infiltrate and cellular necrosis. Chronic rejection may occur early
or late after transplantation but produces a different type ofdamage: progressive
destruction and fibrosis of the organ and its supporting elements. Ductopenic
rejection (liver), obliterative bronchiolitis (lung), and cardiac allograph
vasculopathy (heart) describe the irreversible process, which ultimately
culminates in organ (graft) failure. In the long run, the majority of patients who
survive the first 6 months of transplantation die of chronic rejection, infection,
or concurrent medical problems.
The reason why some individuals are more susceptible to rejection
than others is not clearly understood. Research has identified HLA antigens,
gender, and genetic background as being important factors in organ survival,
but the process is multifactorial and no simple answer can explain the patient-
to-patient variability. By the end of the first year following transplantation,
some patients have experienced no episodes of acute rejection but most have
had at least one to three episodes.
TABLE 8-7. Terms used for rejection.
Heart
Acute
Cellular
Humoral
Vascular
Chronic
Cardiac allograph vasculopathy
Transplant coronary disease
Lungs
Acute
Chronic
Boncholitis obliterans
Obliterative broncholitis
 chronic vascular rejection
Kidney
Acute
Cellular
humoral
Chronic
Liver
Acute
Chronic
Ductopenic
Portal/periportal hepatitis, cholangitis, and/or endothelitis.
Acute rejection is diagnosed by routine surveillance biopsy or by tests
confirming organ dysfunction. The signs and symptoms of chronic rejection are
usually subtle. Patients usually present with nonspecific complaints of malaise,
saying, “Something isn’t right.” It should be assumed that patients with a
transplanted organ who present to the ED have a serious illness and should be
fully evaluated even if they do not look particularly ill at the time.
 Coming to a correct diagnosis in a transplant patient is a major challenge.
Immunosuppressive drugs alter the usual clues for diagnosis. Rejection,
infection, and drug toxicity are the three principal diagnoses until proven
otherwise. Infections may be viral, fungal ,protozoal, or bacterial, with the signs
and symptoms of infection modified by concurrent medications.
The most important sources of information are the patient and a member of
the transplant team. The patients may know more about themselves, their
medical and surgical history, recent laboratory values, medications, and side
effects than do nontransplant physicians. Prompt communication with the
transplant center is of key importance to help interpret the data and arrive at an
acceptable treatment plan.
Kidney
Rejection of a transplanted kidney may cause decreased urine output.
However, the patient may present with systemic complaints of malaise, low-
grade fever, abdominal pain, nausea, myalgias, artbralgias, and other
nonlocalizing symptoms. Since the advent of cyclosporine, the transplanted
kidney, which may be palpable in the abdomen, does not become swollen or
edematous as it did in the precyclosporine era. Since patients are often
discharged early after renal transplantation, a postoperative surgical problem as
well as rejection or infection, should be considered in the differential diagnosis.
A serum creatinine and cyclosporine levels and an abdominal
ultrasound are the most valuable diagnostic tests to evaluate for kidney
rejection. The patient may know their baseline serum creatinine level. The
immunosuppressive drugs, cyclosporine and tacrolimus, raise the creatinine
level (Table 8-8). Thus, a single creatinine level is not sufficient information to
lead to a diagnosis of rejection. Proteinuria is not helpful since it is a
nonspecific finding and may reflect spillage from the native kidney. An
abdominal ultrasound identifies fluid around the kidney (lympocele) and flow in
the renal artery and vein, and visualizes any other abnormalities in the
abdominal cavity.
Chronic rejection is seen as worsening renal insufficiency over time, with
the signs and symptoms of renal failure predominating. The late occurrence of
renal artery stenosis with renovascular hypertension may also occur.
TABLE 8-8. Common laboratory changes due to Immunosuppressive
medications.
WBC
 Reduction
Azathioprine
Ganciclovir
Acyclovir
Trimethoprim sulfamethoxazole
OKT3
ALG
Elevation
Prednisone
Creatinine
Elevation
Cyclosporine
Tacrolimus
Ganciclovir
Acyclovir
Amylase
 Elevation
Pancreatitis f rom azathioprine
Trimethoprim/sulfamethoxazole
ECG
Heart transplants usually have right bundle branch block liver function tests.
Azathioprine, ganciclovir, acyclovir, cyclosporine glucose elevation
Prednisone
Megaloblastic RBC indices (MCV)
Azathioprine, thimethoprim/sulfamethoxazole

Viral infections, especially with CMV are common, and the patient may present
with nonspecific malaise or a severe systemic illness including pneumonitis
encephalitis. Milder symptoms are more common and the diagnosis of CMV
may be difficult due to overlap with symptoms of rejection and of high serum
levels of cyclosporine or tacrolimus.
Kidney-Pancreas
 Kidney-pancreas transplantation is becoming more frequent as a
definitive treatment for diabetic nephropathy. Other than the serum glucose
level, there is no easy diagnostic test to measure pancreas function.
Immunosuppressive levels are kept high and the function of the kidney is
followed for signs of rejection. High doses of steroids used as
immunosuppressive agents may increase serum glucose levels (Table 8-8). Loss
of pancreas function with preservation of kidney function may occur, although
kidney failure with retention of pancreas function is rare.
An abdominal ultrasound is the best diagnostic test to search for an
abscess in the pancreas bed or abdomen. The presence ofa fluid collection
should raise the possibility of a serious problem that may need prompt attention.
Lung
The diagnosis of lung transplant rejection should be highly suspected but
may be difficult to prove without invasive testing by bronchoalveolar lavage
(BAL). The patient may complain of malaise, low-grade fever, increasing
dyspnea, or cough. These symptoms may occur with rejection or infection, and
both possibilities should be entertained.
A good-quality chest x-ray compared with previous studies and
spirometry are the two most useful noninvasive tests in the diagnosis of lung
rejection. Some patients follow their own spirometry values and a drop of 10 to
L5% would support the diagnosis of rejection. Interpretation of the chest x-ray,
the physical examination, and the arterial blood gas may be confusing,
depending on whether the patient has undergone a single- or double lung
transplantation. An infiltrate on chest x-ray may be from rejection or infection.
The sputum Gram stain is helpful to look for acute bacterial pathogens, but viral
infections and rejection cannot be diagnosed by this technique. Additionally,
contamination from the native lung in a single-lung transplant patient, may
negate the usefulness of a sputum sample.
Heart
The diagnosis of acute cardiac rejection is made by endomyocardial
biopsy. However, a patient presenting with increasing dyspnea, enlarging
cardiac silhouette, or evidence of cardiac failure would be assumed to have
rejection until proven otherwise. Arrhyhmias (both atrial and ventricular) may
be a harbinger of rejection. Brady-cardia may be a sign of impending death or
asystole. patients with heart rates below 70 bpm should be evaluated promptly
until further information is obtained. Isoproterenol may be necessary to treat a
patient with bradycardia and hypotension. The vast majority of cardiac
transplant patients have a right bundle branch block pattern on their
electrocardiograms (ECG) from the time of transplantation (Table 8-8). The
denervated heart often has a resting sinus tachycardia that clouds the
interpretation of heart rate as a sign of rejection, heart failure, or infection. Sinus
tachycardia is a physiologic rhythm and should never be directly treated since it
maintains cardiac output and is a response to concomitant illness.
Dyspnea may be the only symptom of rejection, infection, or
myocardial ischemia since patients usually do not experience chest pain.
Patients with a transplanted heart can have an acute myocardial infarction, but
the destructive process of cardiac vasculopathy primarily targets the small
perforating arterioles of the heart. Thus, significant myocardial ischemia may
occur without the classic findings of infarction. In a minority of patients, nerve
regrowth may occur with restoration of neural pathways and the potential for
angina.
Heart-Lang
In patients with heart and lung transplantation, the management and
diagnosis of rejection are usually based on findings in the lung since cardiac
rejection is rare without simultaneous lung rejection.
Liver
 Patients undergoing liver transplantation usually remain in the hospital
long enough to deal with the immediate postoperative surgical complications.
Liver rejection may present subtly with symptoms of malaise. Laboratory
testing may or may not be useful in the acute phase of rejection. Drug
interactions and sepsis can affect liver function tests and should be high on the
list of diagnostic possibilities (Table 8-8).
In severe rejection, there are abnormalities of the liver function tests. In
ductopenic rejection, a more chronic process affecting the biliary tree, elevation
of the serum bilirubin and alkaline phosphatase are useful parameters to
measure.
Diagnostic Testing
Measurement of serum chemistries, a complete blood count, and
cyclosporine level (ifavailable) should be performed on all patients, realizing
that the immunosuppressive medications influence laboratory values (Table 8-
8). for patients on azathioprine, a normal white blood count (WBC) may be
3000 to 4000; a WBC of 7000 may reflect an infectious process. With renal and
pancreas transplants, an abdominal ultrasound is useful. In lung and heart
patients, a good-quality chest x-ray (PA and lateral), should be obtained and an
electrocardiogram is important in heart and heart/lung transplant recipients.
 After thorough evaluation, including a history physical examination,
and review of laboratory and diagnostic studies, it is essential to discuss the
patient’s case with the transplant center. Signs and symptoms of rejection and
infection as well as other illnesses are easily misinterpreted. Patients tend to
look healthier than they are and their appearance may hide a serious impending
illness. In all immunosuppressed patients, infections can progress with alarming
rapidity.
Transfer and Transport of Rejection Cases
Communication with the transplant center can determine the
necessity of transfer of patients with an acute problem. Stabilization in the ED
and initiation of treatment may be required. For acutely ill patients, the current
or recent use of prednisone should be ascertained to decide if stress doses of
steroids are required. The treatment of acute rejection is augmentation of
immunosuppressive agents, either as an inpatient or as an outpatient, depending
on patient stabiliry history, and organ function.
Special Precautions
Patients with transplanted organs may present with local or systemic
infections. Due to the possibility of cytomegalovirus, pregnant workers should
not be exposed to patients if this infection is suspected. Health care workers
with upper respiratory infections should not be given direct patient
responsibility due to the patients vulnerability to viral infections. Hand washing
before and after examining the patient is essential.
Institutional water may be contaminated with Legionella, so transplant
recipients should be given sterile water to drink. It is important to maintain the
patient’s schedule of immunosuppressive drugs and administer medicines on
time, even while they await the completion of their evaluation in the ED.
Appropriate cultures for bacterial, viral, protozoal, and fungal pathogens should
be obtained before instituting therapy.
SELECTED READING
Paul LC. Chronic rejection of organ allograft: magnitude of the problem.
Trans pros 1993 :25 :2022-2023.
Trulock EP. Management of lung transplant rejection. Chest
1993;103:1 566-1 576.
Wiesne RH. Advances in diagnosis, prevention, and management of hepatic
allograft rejections. CIin Chem 19941’401 1 1(9):217 4-2185.
HYPERSENSTTIVITY (8.8)
Anaphylactic/Anaphylactoid Reactions (8.8.1)
The term anaphylaxis was first used in 1902 to describe a
paradoxical reaction to an immunization protocol in which dogs repeatedly
injected with an allergen developed increased sensitivity rather than immunity.
Later, it became clear that the phenomenon required an initial exposure to an
allergen followed by a delay of days to weeks before the reaction could be
elicited by reexposure. Subsequently it has been demonstrated that the clinical
features of anaphylaxis are mediated by activation of antigen-specific IgE
attached to mast cells and basophils’ when reposed to the allergen, IgE causes
the release of mediators from mast cells and basophils. These mediators are
responsible for the observed clinical manifestations. The classic anaphylactic
reaction is thus an immunediated phenomenon. A nearly identical clinical
syndrome known as an anaphylactoid reaction does not require previous
exposure. It immediately follows an exposure to an inciting substance.
Anaphylactoid reactions involve the same mediators implicated in anaphylaxis
but is not IgE mediated. In the clinical setting, the term anaphylaxis is often
used to describe both types of phenomenon. In this chapter anaphylaxis will be
used to represent both conditions unless otherwise specified.
 A variety of substances including foreign proteins and drugs can
elicit anaphylaxis. In the classic mechanism exposure to a foreign substance,
either in isolation or bound as a happen to a carrier protein, elicits the
generation of an IgE antibody. The antibody binds to receptors on mast cells
and basophils. The receptors are activated on reexposure and mediators are
released causing the clinical manifestations of anaphylaxis. Certain other
agents, such as radiocontrast, can directly trigger mediator release. A third
mechanism that may produce anaphylaxis involves complement activation after
exposure, with subsequent generation of mediators known as anaphylaxis. For
some substances, exposure leads to anaphylaxis with no clearly identified
mechanism (NSAIDs are one example). In addition, in the entity known as
idiopathic anaphylaxis, no inciting agent can be identified.
The most commonly implicated medical agents that cause anaphylaxis
are antibiotics. Penicillins and cephalosporins are the most often cited.
Reactions are much more common after parenteral administration and are more
severe than those that follow oral exposures. Approximately I in 5000 exposures
leads to anaphylaxis. More than 100 deaths per year are reported.
Approximately l0% of patients sensitive to penicillin may have cross-sensitivity
to cephalosporins, even with no history of previous cephalosporin exposure.
Aspirin and NSAIDs are common causes of medication-induced anaphylaxis.
Radiocontrast media administered intravenously may cause an anaphylactoid
reaction that is clinically very
Similar to true anaphylaxis, although it is not IgE mediated and does not require
previous exposure. One to two percent of patients experience reactions, but
fatalities are rare. The use of low molecular weight contrast media or
pretreatment with antihistamines and steroids leads to lower rates of
anaphylaxis. Gastrointestinal administration of contrast is an unlikely cause of
anaphylaxis
Hymenoptera stings are the most common environmental cause of
anaphylaxis. The rate of reactions is not well established. The fatality rate is
low, with less than 100 deaths occurring per year in spite of the large numbers
of exposures. Less serious allergic reactions (e.g. Urticaria, local reactions) are
also very common with stings. Foods are another common cause anaphylaxis.
Most cases are mild, but fatal anaphylaxis due to foods has been reported. Nuts
and seeds, legumes, shellfish, and chocolate are common offending agents.
The major physiologic events in anaphylaxis include increased mucous
secretion, bronchospasm, decreased vascular smooth muscle tone, and increased
capillary permeability. Mucous secretion and bronchospasm are responsible for
the signs and symptoms of shortness of breath, chest tightness, tachypnea,
wheezing, and hypoxia. Airway mucosal edema also contributes to respiratory
difficulty. Decreased vascular smooth muscle tone and increased capillary
permeability can cause cardiovascular collapse. Many of the clinical and
physiologic manifestations of anaphylaxis can be explained by the actions of
histamine released from mast cells. Elevated plasma histamine has been
measured in patients experiencing anaphylaxis. Additional mediators have also
been implicated and include leukotriene C4, prostaglandin D2, and tryptase.
The degree of sensitivity and the dose, route, and rate of administration
of the offending agent determine the timing of onset of an anaphylactic reaction.
Large, intravenous doses are most likely to produce immediate, severe
reactions. Most reactions occur within minutes to hours, but symptoms may be
delayed up to 3 days after an oral exposure. It is a generally accepted clinical
maxim that the more rapidly the symptoms develop, the more severe the
reaction is likely to be. A biphasic reaction in which recurrent symptoms
develop hours after initial improvement has been described. The incidence is
not precisely known, but has been reported in up to 20% of cases of severe
anaphylaxis. Biphasic reactions are associated with a delayed onset of
symptoms after initial exposure.
SELECTED READING
Atkinson TP, Kaliner MA Anaphylaxis. Med Clin North Am 1992;76(4): 841.
Austen KL Diseases of immediate type hypersensitiviry In: Wilson JD, et al.
Harrisonb principles of internal medicine, 12th ed. New york: McGraw-Hill,
1991.
Bohner BS. Anaphylaxis N Engt J Med 1991;324(25):1755.
Cochrance CB, Koffler D. Immune complex disease in experimental animals
And man. Adv imnumol 1963;16:185.
Greenberger PA. Contrast media reactions. J Allergy CIin Immunol 1984:
74:600.
Lawley TJ, Frank MM. Immune-complex diseases. In: Wilson JD, et al.
Harrison’s principles of internal medicine, l2th ed. Newyork: McGraw- hill,
1991.
Stark BJ, Sullivan TJ. Biphasic and protracted anaphylaxis. J altergy Ctin
immtmol 1986;78:76.

Systemic Infectious Disorders.

Gregory A. Volturo
Systemic Infectious Disorders (9.0); Meningococcemia (9.1.5); Plague (9.1.6);
Spirochetes (9.1.9); Rocky Mountain Spotted Fever (9.4.1); Ehrlichiosis (9.4.2)
Thomas Germano
Botulism (9.1.1); Gonococcal Disease (9.1.2); Sepsis (9.1.3); Mycobacterial
Diseases (9.1.a); spirochetes (9.1.9) ; Slphilis (9.1.9.2)
Valerie Schevon Nicoletti
Chlamydia (9.1.10);Human ImmunodeficiencyVirus (9.5.1);Herpes
SimplexVirus (9.5.10)
Ajeet J. Singh
Tetanus (9.1.7);Toxic Shock Syndrome (9.1.8); Infectious Mononucleosis
(9.5.2);Influenza (9.5.3); Mumps (9.5.4); Poliomyelitis (9.5.5); Rabies (9.5.6).
Laura Peterson
Malaria (9.3.1);Toxoplasmosis (9.3.2);American Trypanosomiasis (Chagas’
Disease);African trypanosomiasis; Rubella (9.5.7); Roseola (9.5.8);Varicella-
Zoster (9.5.9)
SYSTEMIC TNFECTTOUS DTSORDERS
(9.0)
While not as dramatic as trauma or cardiac care, the
management of infectious diseases is vitally important to the practice of
emergency medicine. Illness resulting from infection precipitates a large
number of emergency department (ED) visits. Community acquired infections
in both pediatric and adult patients are primarily evaluated in the ED. Illness
may range from benign self-limiting conditions to more severe life-threatening
infections. Some infections may be routine and common, while others are rare,
elusive, or completely foreign to a specific geographic area. Knowledge about
all these diseases, however, is required by all emergency care providers.
Infectious disease management issues facing emergency physicians
are often different from those issues confronted by physicians in other practice
settings. The ability to differentiate between serious and minor illness based on
data immediately available determines initial management as well as subsequent
patient outcome. Decisions such as whether to admit a patient to the hospital or
arrange outpatient therapy are often made in the ED. Culture and sensitivity
results are usually not available, and as a result diagnoses are presumptively
based on clinical presentation. treatment with antibiotics frequently is empiric.
Many ED patients do not have continuing care physicians, and they tend to be
noncompliant with treatment and fail to return for follow-up, thereby affecting
decisions about antibiotic selection, dosage, and route of delivery.
Emergency care providers have a relatively high exposure to
communicable disease and must have a solid knowledge regarding both
treatment and prevention of disease. Human immunodeficiency virus (HlV)-
related infections and the increasing incidence of tuberculosis have further
burdened the ED, requiring emergency physicians to have much more
knowledge regarding infectious diseases.
Lastly, with continued growth of managed care and emphasis on cost
reduction in medical care, the ED will be key in developing and
implementmanage more severe infections as an outpatient. While
Many infectious diseases are discussed throughout the text, this chapter
discusses systemic infectious diseases not covered elsewhere not covered
elsewhere.

BACTERTAL (9.1)
Botulism (9.1.1)
Botulism is a disease mediated through a protein exotoxin that is
produced by the bacteria Clostridium botulinum. Humans who contract the
disease do so as a result of the oral ingestion of preformed toxin or by the
colonization of the gut or wounds by the causative organism. The result is a
syndrome characterized by autonomic dysfunction and muscular weakness,
which may progress to ventilatory failure and death. The disease is rare, the
initial manifestations of the disease may be nonspecific, and symptoms may
present with varying severity and rapidity, so proper diagnosis is frequently
delayed resulting in increased patient morbidity and mortality. In hopes of
avoiding such delays, the emergency physician should be knowledgeable about
the pathophysrology of botulism and the clinical situations where the disease
should be considered.
Etiology and Epidemiology
 Clostridium botulinum is a gram-positive rod that is obligately
anaerobic and spore forming. The organism is ubiquitous in soil and has
worldwide distribution. The spores are resistant to heat, desiccation, and
radiation. Sources of the bacteria and spores that have been implicated in human
disease have included contamination of open wounds by soil or other organic
material, and ingestion of fruits, vegetables, fish, meats, and honey. the disease
has several forms including infantile botulism (the most common form), food-
borne botulism, and wound botulism. All human disease is mediated through an
exotoxin produced by the bacteria, which acts to prevent the release of the
neurotransmitter acetylcholine
Infantile botulism has been recognized since 1976. It may affect
children from several days to over a year of age. While the disease has proven
elusive for many years, several things have been made clear. The disease is
more common in breast-fed infants but for unknown reasons it seems to have a
somewhat attenuated course when it occurs in bottle-fed infants. This may have
to do with the varying Gl chemistry and bacteriology found in bottle-fed versus
breast-fed infants. In one study, while the ingestion of honey was statistically
significantly associated with the development of botulism, only 16% of infants
with botulism had ingested honey. IJp to 25%o of honey has been shown to
contain spores. Other food associations are possible but have yet to be
confirmed. another possible risk factor is living in a rural or farm community.
Food-borne botulism has been associated with several sources. As
opposed to the infantile form, most cases of the food-borne variety occur as a
result of preformed toxin. There is a well-known association of botulism and
inadequately processed canned foods. This has primarily involved home-canned
foods but several outbreaks ofthe disease involving commercially canned foods
are known to have occurred. While commercially and restaurant prepared foods
have been responsible for only a small percentage of outbreaks, they may
represent a disproportionate percentage of cases, since there is potential for any
one episode to involve multiple patients. Baked potatoes that have been
wrapped in foil have also been associated with the disease as this may
potentially create an anaerobic environment suitable for the growth of the
causative organism. More unusual sources of botulism have included saut6ed
onions, frozenpot pies, stew, and turkey loaf. The risk of botulism is increased
in foods that are not heated immediately prior to eating, as the toxin is heat
labile.
Wound botulism has been typically associated with large, open
contaminated wounds, especially if associated with devitalized tissue or
compound fracture. There is also an association recognized with IV drug use.
Additionally, it is an extremely rare complication of surgery. This has been the
rarest form of the disease with only about 40 cases being reported in the
English-language literature prior to 1994. Colonization of the wound is believed
to occur with the subsequent production of exotoxin.
In a subset of patients no source of the toxin can be identified. It is
thought that an underlying gastrointestinal abnormality predisposed some
patients to GI colonization by the organism similar to that in the infantile form
of the disease. It is believed that the normal intestinal flora of the adult gut is
protective and thus the infantile form of the disease generally does not occur in
adults. Alteration in the normal flora may predispose the patients to colonization
by clostridia with subsequent production of toxin.
Pathophysiology and Diagnosis.
Regardless of how the toxin is produced, the mechanism for its
action is the same. The exotoxin is a protein that irreversibly binds the
presynaptic membrane at the cholinergic neural junction. This has effects at the
neuromuscular junction as well as at the ganglionic level of the sympathetic
nervous system and at the pre- and postganglionic level of the parasympathetic
nervous system. thus the typical symptoms of the disease ensue: motor
weakness and aufood-borne botulism the toxin is usually ingested, whereas in
wound and infantile botulism the toxin is formed within the body of the host as
a result of colonization with the causative organisnization with the causative
organism.
In cases of food-borne botulism the onset of clinical illness is
usually within hours to a couple of days of ingestion of the toxin. An antecedent
prodrome of nausea and vomiting may occur. This is followed by bulbar
symptoms of blurred vision, diploplia, ptosis, dysarthria, and dysphagia. These
symptoms are followed by a descending paralysis that first involves the upper
extremities then the lower extremities. This descending type of paralysis occurs
in all forms of the disease and helps to distinguish botulism from other forms of
weakness. Autonomic symptoms include dryness of the mouth,pupillary
abnormalities, urinary retention, and constipation. Milder forms of the disease
may occur with only bulbar symptoms noted. In addition to the findings above,
the physician may find diminished deep tendon reflexes. Situations where
multiple patients are affected; especially if they are known to have eaten
together, should cause the physician to consider the diagnosis more seriously. A
history of having eaten home-canned goods is particularly suggestive.
 In wound botulism the onset of the symptoms may be delayed up to
3 weeks, although the average length of incubation is about I week. The onset of
symptoms may be as soon as several days. Diplopia is a frequent first symptom.
A history of an antecedent wound, especially if associated with a compound
fracture or devitalized tissue, should be sought. In this form of the disease the
organism may be cultured from the wound.
The diagnosis of infantile botulism is particularly challenging. The
early manifestations of this form of the disease are frequently nonspecific and
include constipation, poor tone, and poor suck. Constipation is present in the
majority of cases and may precede the other manifestations of the disease by
weeks. It is likely that the toxin itself slows GI motility. While sepsis is
frequently considered in the differential diagnosis, the infants are usually
afebrile. The disease may be the cause of death in some cases of sudden infant
death syndrome (SIDS). Eventually in the course of the illness there appears the
typical descending paralysis with potential respiratory compromise. A history of
honey ingestion should be sought
The differential diagnosis of botulism is complex and is summarized
in Table 9-1. Laboratory testing may assist in the confirmation of suspected
cases of the disease; however, this frequently will not occur soon enough to be
helpful for patient management. The toxin may be detected in blood or stool,
the latter being helpful in cases of infantile botulism. Electromyogram (EMG)
may also suggest the diagnosis, but a normal EMG does not rule it out. Findings
on EMG that ate consistent with the diagnosis include potentiation of the
TABLE 9-1. Differential diagnosis of botulism.
Acute alcohol intoxication
Hypermagnesemia
Hypocalcemia
Carbon monoxide poisoning
Basilar artery thrombosis
Sepsis
Meningitis/encephalitis
Guillain-Barr6 syndrome
Eaton-Lambert syndrome
Tick paralysis
Myasthenia gravis
Muscular dystrophy
Poliomyelitis
Congenital myopathies
Heavy metal poisoning
Organophosphate poisoning
Saxitoxin/tetrodotoxi n
Hypothyroidism

Action potential during repetitive stimulation and a diminished response to a

single stimulus. The edrophonium challenge test may cause partial improvement
in the patient with botulism and is therefore not helpful in distinguishing
botulism from myasthenia gravis. hyponatremia may occur as a result of the
associated syndrome of inappropriate secretion of antidiuretic hormone
(SIADH).
Treatment, Disposition, and Prevention.
The most formidable risk to the patient with botulism is that of
airway or ventilatory compromise. Thus patients with suspected botulism
should be admitted to an ICU setting to be closely monitored. Early intubation
with active ventilation prevents unnecessary morbidity and mortality. While the
causative agent is known to be sensitive to penicillin, antibiotic therapy has not
been shown to alter the course of the disease. It should be remembered that in
cases of food-borne botulism the toxin is ingested and not formed in vivo. Thus
in this form of botulism there is not even a hypothetical argument for the
administration of antibiotics. The use of antitoxin, which is available from the
Centers for Disease Control (CDC), is controversial. It does appear that there is
some benefit from its use in wound botulism. Since the antitoxin only binds free
toxin and has no effect on already bound toxin, it can only slow the progression
of the disease.
Recovery is the general rule for the patient with botulism assuming
the patient experiences no formidable complications during the illness. Clinical
improvement occurs as a result of the synthesis of new receptors that are free of
toxin. Prevention of this disease may be enhanced by adequate food preparation,
especially among home canners, and proper wound care. In addition it has been
recommended that infants under 12 months of age not be given honey.
SELECTED READING
 Burningham M, Walter F, Mecham C, et al. Wound botulism. Ann Emerg
Med 1994;24:1184-1 1 87.
Cherington M. Botulism. Semin Neurol 1990;10:(1);27-31.
Ferrari N, Weisse M. Botulism. Adv Pediatr Infect Dis 1995;10:81-91.
Jagoda A, Renner G. Infant botulism: case report and clinical update. Am J
Emerg Med 1990;8:318-320.
MacDonald K, Cohen M, Blake P The changing epidemiology of adult borulism
in the United States. Am J Epidemiol 1986;124:794-799.
Schmidt R, Schmidt T. Infant botulism: a case series and review of the literalxe.
. J Emerg Med 1992;10:713-718.
Schreiner M, Field E, Ruddy R. Infant botulism: a review of 12 yeart experience
at the Childrent Hospital of philadelphia. Pediahics l99l;g7:1 59-l 65.
Spika J, Shaffer N, Hargrett-Bean N, et al. Risk factors for infant botulism in
the United States. AJDC 1989:143:828-832.

Gonococcal Disease (9.1.2)

 Gonococcal infections occur as a result of mucosal colonization
by sexually transmitted Neisseria gonorrhoeqe. Nearly a million gonococcal
infections occur in the United States each year. While many of these are
localized to the site of entry, both locally invasive and widespread disease may
occur, leading to disastrous complications. The clinical presentation of these
patients in the ED may range from classic urethritis in a sexually active male to
frank sepsis of uncertain etiology. The disease may also be asymptomatic in
some patients and therefore only be discovered as a result ofscreening studies
done on an at-risk individual. While the treatment of gonococcal disease was
once straightforward, in recent years pjactamase-producing strains resulting in
drug resistance have caused an increased number of treatment failures. Since
ED physicians are likely to encounter gonorrhea with a continued high
frequency, a strong database with regard to the clinical presentation, diagnosis,
and treatment is crucial.
Epidemiology
While gonorrheal disease may affect individuals of any age, it
is most prevalent in young, sexually active individuals, having a peak incidence
in males at ages 20 to 24; the peak incidence in females occurs one to several
years earlier. Risk factors for the disease include being single, living in an urban
area, being a homosexual male, indigence, and prostitution. Sexual intercourse
without barrier contraception is also a risk factor for acquiring gonorrhea.
Transmission of the disease between individuals may occur without the
knowledge of either party since the male or female with gonorrhea may transmit
the disease prior to the onset of symptoms and since in both sexes the disease
may well remain asymptomatic. The disease appears to be more easily
transmitted from male to female during vaginal intercourse rather than vice
versa.
Pathophysiologt
Neisseria gonoruhoeae are gram-negative cocci that are round
or oval in shape, characteristically growing in pairs but sometimes singly. They
are fastidiously aerobic,with optimal growth occurring in an environment of
2% to 5% CO2.. The organism is frequently covered by fimbrae, which assist
the organism in adhering to mucosal epithelial cells of the host. Several protein
mediators of host inflammation are present in the bacterial cell wall. These
proteins vary and play a pivotal role in the avoidance of the Neisseria to host
immune defenses. An immunoglobulin A (IgA) protease secreted by the
organism appears to be important in overcoming secreted human
immunoglobulin. There are a number of clinical syndromes that are caused by
the organism that will be considered here
In the heterosexual male the usual manifestation of the disease is
acute urethritis. The typical period of incubation is 2 to 5 days. Complications
of this initialurethral infection include epididymitis, orchitis, and prostatitis. The
degree of symptomatology that an individual experiences in likely related to the
particular gonococcal auxotype causing the infection as well as host factors.
In women the clinical manifestations of gonococcal illness usually occur
as a result of an initial infection of the cervix. It is estimated that about l5%o of
patients with mucopurulent cervicitis will develop ascending genitaltract disease
involving the uterus, fallopian tubes, ovaries, or peritoneum. The clinical
syndrome that encompasses these infections is termed pelvic inflammatory
disease (PID). Infection that involves the fallopian tubes, in addition to placing
the patient at risk for peritoneal infection, also is responsible for the serious
sequelae of PID, specifically pelvic adhesions and chronic pain, infertiliry and
ectopic pregnancy. The risk of sterility has been estimated to be as high as 25%
Yo for each episode ofgonococcal salpingitis with a concomitant sixfold
increase in the risk for ectopic pregnancy. It should be remembered that PID
may be caused by organisms other than the Neisseriq species, such as
Chlamydia, and as such a diagnosis of PID does not immediately implicate the
gonococcus as the etiologic agent.
Other acute complications of PID include Fitz-Hugh-curtis
syndrome (perihepatitis) and the formation of tubo-ovarian abscess. In addition
to the ascending genital infection, localized infection may occur in the female
urethra, Skene’s glands, or Bartholin’s glands manifesting as dysuria, labial
edema, or abscess. Obstetrical complications of gonorrhea include septic
abortion, premature rupture of the membranes, preterm delivery, and
intrauterine growth retardation.
In either males or females other sites of mucosal infection may
occur as a result of oral or anal sex. Rectal infection with resultant proctitis is
frequently associated with a purulent discharge. Pharyngitis is frequently
asymptomatic but appears to be associated with a higher risk of dissemination.
The natural history in most patients with pharyngeal infection involves
spontaneous resolution by 3 months. Neisseria gonorrhoeae, which may be
blinding, is an infrequent but important cause of conjunctivitis in both adults
and neonates. When responsible for conjunctivitis in the neonatal perio( the
illness is usually acquired at birth from the mother’s genital tract and presents
within a week following birth. It usually presents as a bilateral conjunctivitis
with edema of the cornea and an exudate.
Disseminated gonococcal disease occurs as a result of the
hematogenous spread of the organism from its original. site of mucosal
infection, resulting in distant infection. While this may theoretically involve any
site, it most typically presents as a migratory polyarthritis, tenosynovitis, or a
rash. Patients may present with all or only one of these entities. Rare but
devastating sites of dissemination include the heart, with resultant endocarditis,
and the meninges. Perihepatitis may occur unassociated with clinical PID as a
result of dissemination.
The typical pattern of joint involvement is that of anoligo- or
polyarthralgia that is migratory or less commonly additive and may be
associated with constitutional symptoms such as fever and chills. While any
joint is a potential site of involvement, the knees, elbows, wrists, hands, and
ankle are the more frequently affected sites. Of these, the knee is the most
common. Less than half of the patients with arthralgia have a proven septic
arthritis. Only approximately one-third develop a synovial effrrsion. Permanent
joint destruction may occur. An associated tenosynovitis frequently occurs and
usually involves the dorsum of the hands and wrists, fingers, ankles, or toes.
 Skin lesions usually are relatively few in number (less than 20) and
generally occur on the extremities. These lesions are usually pustules on an
erythematous base that frequently become hemorrhagic, necrotic, or ulcerative.
In general the rash is painful and may infrequently be macular or petechial.

Diagnosis
When gonococcal disease is considered in the differential
diagnosis, the patient should be queried regardi 4g sexual practices. However,
the physician should bear in mind that patients frequently are evasive regarding
this history, and thus even without a suggestive history the possibility should
not be ruled out. While most emergency physicians will consider the possibility
in the patient with genital tract complaints, the diagnosis of gonococcal illness
might not be appropriately considered in the more atypical presentation such as
rash or arthralgia.
The symptoms of the male with urethritis include dysuria and
urethral discharge. The discharge is usually purulent but may also be described
as white, mucoid, or cloudy. While the disease may cause intense dysuria, and
discharge, perhaps 50%or more of males with culture proven infection are
asymptomatic or have minimal symptoms for which they don’t seek medical
attention.
 The female patient with genital tract disease may have several
complaints including vaginal discharge or bleeding, pelvic or abdominal pain,
dyspareunia, labial pain, or dysuria depending on the site of infection. Physical
examination may reveal cervical injection and friability, a mucopurulent
cervical or vaginal discharge, labial swelling or mass, or findings suggestive of
PID. Low abdominal tenderness, cervical motion tenderness, and adnexal
tenderness are required for the diagnosis of PID. Additional findings include
fever >38”C, an elevated WBC count or sedimentation rate, a purulent cervical
discharge, a positive Gram stain for gram-negative intracellular diplococci, and
the presence of an inflammatory mass on examination or ultrasound.
Pelvic inflammatory disease may present with a wide range of
clinical acuities from the patient who appears well to the toxic-appearing patient
with severe abdominal pain and fever. The differential diagnosis of the female
in the reproductive years with abdominal pain is complex. Other acute
abdominal conditions, particularly appendicitis, may be frequently difficult to
distinguish from PID. Other gynecologic emergencies such as ruptured ovarian
cyst and ectopic pregnancy may also be mistaken for PID. While PID can and
does occur in the pregnant patient, a new diagnosis of PID should be made with
caution, especially in the gravid patient of greater than about 12 weeks’
gestation. By this time in the pregnancy, the attachment of the chorion to the
uterine decidua has obliterated the endometrial cavity, making ascending genital
tract disease less likely. If previous documentation that the pregnancy is
intrauterine has not been established, a confirmatory ultrasound would seem
prudent prior to a diagnosis of PID.
While PID enters into the differential diagnosis of all the
aforementioned circumstances, a careful history and meticulous physical
examination should lead the physician to the correct diagnosis in most cases.
Ancillary studies including qualitative and quantitative human chorionic
gonadotropin (hCG), CBC, sedimentation rate, liver profile, urinalysis, and
plain abdominal x-rays should be considered where appropriate. In addition,
abdominal and vaginal probe ultrasound can be valuable in the detection
ofsalpingitis, tubo-ovarian abscess, ovarian cystic disease, or appendicitis and to
confirm the presence or absence ofan intrauterine pregnancy. Rarely the true
nature of a patient's problem will be diagnosed only at laparoscopy or surgical
exploration.
The diagnosis of disseminated gonococcal illness is particularly
challenging. The differential diagnosis is complex and includes Reiter’s
syndrome, septic arthritis, gout and pseudogout, rheumatic fever, secondary
sysphilis, hepatitis, Lyme disease, meningococcemia, and bacterial endocarditis.
Since at the time of dissemination the initial mucosal infection may be
asymptomatic, the diagnosis may easily be missed. Women have higher
incidences of asymptomatic infection and thus are at higher risk for
dissemination than their male counterparts. Dissemination is more likely to
occur during the beginning of the menstrual cycle. While a toxic appearance,
elevated WBC count, and fever may be present, these findings may be
notoriously absent in the patient with disseminated disease. It is estimated that
the prevalence of dissemination is 0.5% to 3.0%of all cases of gonococcal
infection.
The diagnosis of disseminated disease is confirmed by the isolation
ofthe diplococci from the blood or synovial fluid or from its recovery from a
mucosal surface such as the urethra, cervix, rectum, or oropharynx. It must be
remembered, however, that the sensitivity of cultures is limited and the initial
site of infection may be asymptomatic. Blood cultures in the patient with
disseminated disease are positive in less than 30Yo of cases. They are more
likely to be positive in patients with the syndromes oftenosynovitis and rash, as
these patients are frequently bacteremic.
inteffirsion is present, thoracenteses should be performed and the fluid
analyzed for white blood cell count, glucose, crystal analysis, and Gram stain.
WBC count will usually be greater than 50,000 with a predominance of
polymorphonuclear cells. A low glucose will also be frequently observed. Gram
stain has a sensitivity of about 30% and, culture of the fluid may confirm the
diagnosis in approximately one-half of cases. In one study the sensitivity of
culture was only 17%.
Probably the best methods to confirm the diagnosis of gonorrhea is
either by Gram stain or culture of the initial site of infection. Cultures of the
mucosal site of involvment may have a sensitivity of 60%to 80%,with cultures
of the cervix and urethra having the highest yields. To improve the sensitivity of
culture the following points should be kept in mind. First, in the female the
culture must be taken from the endocervix as the cocci are found there with
greater concentration. When culturing sites with other expected flora, a selective
test such as Thayermartin media s Neisseriahould be used. The cultures should
be plated as soon as possible in an environment containing 3%to 5%CO2.
A Gram stain should not be overlooked, especially in a male with a
symptomatic urethral discharge, as it has sensitivity of close to l00o/o in some
reports. The sensitivity for a cervical Gram stain is considerably less, possibly
in the 600/o range. The sensitivity is also poor for men with asymptomatic
urethral infection as well as those with rectal disease. The specificity of a Gram
stain that shows gram-negative intracellular diplococci is about 95% if taken
from the urethra, cervix, rectum, or joint fluid but is less reliable from the
mouth due to native flora. Non-culture methods for the detection of Neisseria
gonorrhoeae include DNA probe and enzyme-linked immunosorbent assay
(ELISA) technologies. These have the benefit of rapid turnaround time but have
the disadvantages ofhigher costs.
If the possibility of gonorrhea is considered in a child there must be a
prompt evaluation for the possibility of sexual abuse. The recovery of Neisseria
gonorrhoeae from any pediatric patient beyond the neonatal period is highly
predictive of a sexual contact. The most frequent clinical manifestation of
gonorrhea in girls is vulvovaginitis with clinical PID being uncommon. For the
purposes of medicolegal considerations the presence of the organism must be
documented by culture.
Treatment and Disposition
There are currently multiple regimens available for the treatment of
uncomplicated gonococcal disease. The four regimens currently recommended
by the CDC are listed in Table 9-2. While some controversy exists regarding the
treatment of gonococcal illness some principles are generally agreed upon:
 l. Since infection with Chlamydia trachomatrs is so prevalent in patients with
gonorrhea and since the sequelae of this infection are similar to those of
infection with the gonococcus it should be assumed to be present and treated as
such, especially in the ED population in whom follow-up cannot be guaranteed.
2. For reasons yet to be explained, pharyngeal infection responds less well to
treatment and carries a higher risk of dissemination.
3. Patients with disseminated disease and females with a toxic appearance,
peritoneal signs, or possible tubo-ovarian abscess cannot be treated with a one-
time dose regimen.
4. Since it is unknown what the true prevalence of incubating syphilis is in these
patients nor what impact treatment has on this disease where there is the
possibilify of concomitant syphilis, surveillance studies should be arranged for
or initiated in the ED and follow-up arranged.
5. Quinolone antibiotics, while being highly effective, are contraindicated in
pregnancy, lactating females, and children under 12 due to associated
arthropathy. Quinolones and spectinomycin are believed to have minimal if any
effect on incubating syphilis.
TABLE 9-2. Treatment of gonococcal infections
Uncomplicated infections
Male urogenital tract
Female urogenital tract-outpatient ttreatmenta.
Pharyngeal infectionb
Rectal infection
Medication
1. Ceftriaxone 125 mg lM or 250 mg lM: The lower dose has been shown to
have nearly the same efficacy for gonorrhea as the higher dose and at reduced
costs. Lt was previously recommended to use the 250-mg dose based in part on
the consideration that this dose could eradicate incubating syphilis. Currently, it
is not understood whether the possibility of incubating syphilis is a significant
or theoretical concern in most patients. Where it is deemed that the risk of
incubating syphilis is high the higher dose would seem prudent.
2. Ciprofloxacin 500 mg po
3.Ofloxacin 400 mg po
4. Cefixime 400 mg po
5. Alternative-spectinomycin 2 g lM may be useful for those who are not
candidates for either cephalosporin or quinolone therapy.
In addition, a regimen to treat coexistent chlamydial disease such as
doxycycline 100 mg bid x 7 days. Complicated infections.
Disseminated gonococcal disease.
Medication
1. Ceftriaxone 1 g lV q8h
2. Cefotaxime 1 g lV q8h
3. Alternative-spectinomycin 2 g lM q12h
lV antibiotics should be continued for 48 hours after improvement is first
noted. Treatment should
be continued with celixime 400 mg po bid or ciprofloxacin 500 mg po
bid for least a full week of
treatment.
In addition, a regimen to treat coexistent chlamydial disease such as
doxycycline 100 mg lV q12h.
female u rogenital tract-inpatient treatment.
 Medication
1. Cefoxitin 2 g lV q6h
2. Cefotetan 2 g lV q12h
3. Clindamycin 900 mg lV q8h + gentamicin (2 mg/kg load then 1.5 mg/kg
q8h)
In addition, a regimen to treat coexistent chlamydial disease such as
doxycycline 100 mg lV q12h.
Gonococcal meningitis or endocarditis
Medication
Ceftriaxone 1-2 g lV q12h. For meningitis treatment should be
continued for 10-14 days; for endocarditis treatment should be continued
for 4 weeks.
In addition, a regimen to treat coexistent chlamydial disease such as
doxycycline 100 mg lV q12h.
Ophthalmic disease.
Ophthalmia neonatorum
medication
 Ceftriaxone 25-50 mg/kg (not to exceed 125 mg) lV or lM single
dose
Adult gonococcal conjunctivitis
Medication
Ceftriaxone 1 g lM single dose; lavage eye with saline
Usee Table 9-3 for guidelines for the treatment of PID inpatient vs. Outpatient.
Only regimens of ceftriaxone and ciprofloxacin should be used to treat
pharyngeal infection.
Adapted from Centers for Disease Control and Prevention. 1993 sexually
transmitted disease treatment guidelines. MMWR 1992;42(RR-14):1-1O2; and
Moran J, Levine W. Drugs of choice for the treatment of uncomplicated
gonococcal infections. Clin lnfect Dis 1995;2O(suppl 1):s47-s65.

6. The sex partners of individuals treated for these and other sexually
transmitted diseases should be referred for evaluation and empiric treatment.
Since females are frequently asymptomatic, the screening of high-
risk female patients is important to containing the spread of the disease.
Limitation of the number of sexual partners as well as barrier contraception is
an effective means of controlling the transmission of the disease and should be
reinforced by physicians whenever possible. patients with disseminated disease,
locally invasive disease such as complicated PID, and those unable to comply
with outpatient treatment or follow-up should be hospitalized in most
circumstances (Table 9-3).
TABLE 9-3. Pelvic inflammatory disease_admission
criteria
Diagnosis uncertain-possible acute abdominal or
gynecologic/obstetric emergency
Not ruled out
Possible abscess
Pregnancy
Adolescent age-due to high probability of noncompliance
Lmmunocompromised host
Clinical toxicity
Significant nausea and vomiting making oral therapy difficult
Social circumstances-unable to comply with treatment or
Follow-up within 72 hours
Failure to improve on adequate outpatient treatment.
Adapted from Moran J, Levine W. Drugs of choice for the treatment of
uncomplicated gonococcal infections. Ctin lnfect Dis 1 995;2O(suppt 1 ):s47-
s65.

SELECTED READY
Central for Disease Control and prevention. 1993 sexually transmitted disease
treatment guidelines MMWR 1992;42 (RR-14):1—102.
Judson F. Gonorrhea, Med clin North Am 1990;74(64):1356—1336.
Kerle k, mascola j, Miller T. Disseminated gonococcal infection. Am Fam
physician 1992;45(1):209—214
McNaby WK,WG Barnes. Urethral and endocervical culturing: gonorrhea and
chlamydia. Ann Emerg Med 1986;15:333—336.
McNeely G. Gonococcal infections in women. Obstet Gynecol CIin North Am
1989;16(3):467—447.
Moran J, Levine w. Drugs of choice for the treatment of uncomplicated
gonococcal infections. Clin infect Dis. 1995;20(suppl 1):s47-s65.
Peterson H, Galaid E, Cates W. Pelvic inflammatory disease. Med CIin North
Am 1990;74(6):1603—1613.
Scapolite’s E, Martinez-Osuna p. Gonococcal arthritis. Rheum Dis Clin North
Am 19(2):363—177.
Suleiman A, Grimes E, Jonas H. Disseminated gonococcal infections. Obstet
Gynecol 1983;61 :48-51.
Sepsis (9.1.3)
Sepsis is a clinical syndrome manifested by systemic inflammation in
the setting of infection. While sepsis is associated with infection it is probably
just one ficet of the systemic inflammatory response syrdrome (SIRS). This
syndrome may be precipitated by trauma, pancreatitis, or other noninfectious
etiologies but the end result is the same-a systemic inflammatory response that
is manifested by multiple organ dysfunction and eventual vascular collapse. A
patient may experience minimal or life-threatening
Complications as a result of SIRS. Sepsis should not be confused with
bacteraemia-the presence of bacteria which is probably present in a sepsis-
septic shock-is the global hypoperfusion inflammatory responses to infection.
The patient with manifestations of sepsis represents a special challenge to
emergency physicians from both a diagnosis and therapeutic standpoint. While
many patients persent with fever and an obvious source, in many others,
praticalarly the elderly , very young, and immunocompromised, the true nature
of the persent symptoms may be far more difficult to elucidate. Supportive care,
the initiation of a diagnosis plan , and the responsibility of the emergency
physician.

Epidemiology
There are more than 200,000 deaths due to sepsis and septic shock each
year. It is the 13th leading cause of death in the nation for pertains odern than 1
year and the ninth leading cause for children ages 1 to 4. There is no service
within the hospital that can be considered exempted from caring for the
potentially seplic patient. Those who appear to be at greater risk for sepsis
include immunosuppressive patient , those with significant comorbid condition,
infant under. 1 year and the elderly , particularly those Older than 74 year.
Additionally, patient with indwelling Foley catheters or indwelling intravanous
lines are at greater risk for the developmen process has advanced to shock the
associated mortality may be 50o/o or more. In one study predictors of an
increased likelihood of death included J chest x-ray with bilateral interstitial
infiltrates, an elevated serum creatinine, and abnormal coagulation profile. In
addition, bacteremic patients who are not febrile appeared to have a higher
overall mortality as well.

Pathophysiologt
The initial event in the downhill spiral from health to death in the patient
with sepsis is an initial infectious focus. Common initial sources include the
urinary tract, the lung, and the skin. Additionally, intraabdominai infection and
sinusitis are examples of more occult sources of sepsis. In fact, in one study
only 17% of patients with sepsis and 69% of patients with septic shock had
positive blood Cultures.
Thus it appears that sepsis as may result from the direct invesion of the blood
by bacteria or via the liberation of chemical mediators of inflammation. While
some aspects of the inflammatory response have been well elucidated, it is safe
to conclude that much more remains elusive.
One well-recognized trigger of the septic process is exposure of the
immune system to certain chemical moieties produced by various strains of
bacteria or other microbes. Bacterial exotoxins are inflammatory mediators that
are secreted by viable organisms. Such substances may be liberated by either
gram-positive or gramnagative orproteins secreted by certain strains of
Staphylococcus and streptococcus responsible for toxic shock syndromes
observed in patients with these infections. These exotoxins are potent mediators
of both the humeral and cellular components of the inflammatory response.
Similar to the response characteized by exotoxins is that which is caused
by bacterial endotoxin. Endotoxin is different from exotoxin in that it is not
secreted but rather is intrinsic to the bacterial cell wall. It has been identified as
the lipopolysaccharide (LPS) found in gram-negative cell walls. Numerous
humeral mediators of the inflammatory response have been described and it is
likely that many more have yet to be recognized. Of these mediatoral several
have been well characterized. Tumor necrosis factor (TNF) is a protein
produced by macrophages, monocytes, and other cells in response to exposure
to endotoxin. TNF is currently recognized as one of the earliest and most potent
mediators of the inflammatory cascade. TNF is believed to cause an amplified
response of the inflammatory cascade with subsequent increased production of
various mediators of inflammation such as interleukins, platelet activators,
prostaglandins, and leukotrienes. Subsequent activation of the complement
cascade as well as degranulation of macrophages results in vascular endothelial
damage allowing fluid leakage from capillary beds. This, along with an
increased level of circulating vasodilatory substances such as serotonin,
bradykinin, and histamine, results in systemic vasodilation, causing relative
hypovolemia. This peripheral vasodilation combined with a decreased
responsiveness of arteriolar smooth muscle to catecholamines and the third
spacing described above results in a decrease in systemic vascular resistance
and a decrease in venous return to the heart, with subsequent loss of cardiac
output and blood pressure. This is poorly tolerated by the septic patient,
especially iffebrile, since these patients appear to have an increased overall
cellular oxygen demand. The situation is made worse by myocardial
suppression, which results directly from TNF and other inflammatory
substances. Shock resistant to IV fluids and pharmacologic therapy may ensue
as a preterminal event.
The net results of the aforementioned circulatory dysfunction are
widespread and can be severe. Third spacing of fluid in the lung may lead to the
adult respiratory distress syndrome (ARDS) with resultant hypoxemia and
ventilatory failure. Activation of the coagulation cascade by endotoxin, TNR or
other mediators of inflammation may result in disseminated intravascular
coagulation (DIC) with its own concomitant complications. Cerebral
involvement may result in encephalopathic symptoms that range from mild
alteration of mental status to frank coma. Hepatic dysfunction may result in
elevation of liver transaminases. Elsewhere in the GI tract loss of mucosal
integrity may occur with resultant leakage of intestinal bacteria as well as other
toxic substances into systemic circulation. Some of these toxins are thought to
further contribute to myocardial dysfunction. Pancreatitis or gastrointestinal
bleeding may complicate the course of the patient with sepsis. Diminished urine
output and elevation of BUN and serum creatinine may occur as a result of
acute renal failure. Adrenal failure (Waterhouse-Friderichsen syndrome) may
result from septic shock. Patients with underlying vascular disease may
experience complications of hypoperfusion including limb ischemia, mesenteric
insufficiency, cerebral vascular accident, or myocardial infarction.

Diagnosis
Sepsis in any given patient may be clinically obvious or notoriously
occult. Emergency physicians must iden-Tiff at-risk individuals and institute
appropriate therapy early on since once the process becomes advanced the
likelihood of a “good” outcome is considerably reduced. Historical clues to a
probable difficult course in the setting of an infectious disease include patients
at the extremes of age, patients with comorbid conditions such as heart disease
or diabetes, those who are immunocompromised such as asplenic patients, HlV-
infected individuals, patients undergoing chemotherapy for malignancy, and
patients maintained on steroid therapy for a variety of maladies. As noted
above, patients with indwelling catheters, whether urinary or intravenous, have
additional risks from these sources. Where valvular heart disease or intravenous
drug use is suspected, endocarditis is a concern. Finally, physicians should
approach patients who have failed appropriate antibiotic therapy with some
trepidation as these patients also tend to have increased morbidity and mortality.
Additionally, in this latter group the possibility of abscess, drug resistance,
incorrect diagnosis, infectious complication, or foreign body should be
considered. Failure to respond to treatment should never be immediately
dismissed as patient noncompliance.finally, although infrequent, persons with
no previous underlying medical history may develop sepsis and succumb to an
infectious illness despite adequate care. Again, the physician should be reluctant
to discharge patients who still appear ill even if there is a lack of risk factors for
a poor outcome.
The presentation of the potentially septic patient varies widely from
the straightforward (flank pain, dysuria, fever, and tachycardia in a young,
previously healthy female) to the nonspecific (subtle alteration in mental status
in an elderly patient with underlying dementia). In addition, the presentations of
individuals who are either very young or old as well as those who are
immunosuppressed are frequently nonspecific or bizarre. Examples include the
patient maintained on steroids with appendicitis who displays minimal
symptoms, or poor feeding and irritability in a newborn. At times, particularly
in elderly patients, the chief complaint may not even seem to be related at all to
infection. In one study of elderly patients with bacteremia, it was noted that
about half presented with alteration of mental status and one-third had
experienced falls, including several who were found on the floor at home.
Historical data are of critical importance and should never be slighted as they
will assist in the choice of ancillary studies, consultations, choice of antibiotics,
and disposition of these patients.
A fundamental rule of emergency practice is to ..know the vital
signs.” With respect to the evaluation and diagnosis of the potentially septic
patient this is of critical importance. A rectal temperature is still the most
important modality to find a fever. Most patients who are seseptic or bacteremic
are febrile, but normothermia and hypothermia may occur, particularly in
neonates, the immunosuppressed, and the elderly. Physicians should be wary of
normothermic patients given antipyretics prior to ED presentation as well as
infants whose parents report either documented or subjective fever. Tachypnea
may result from acidosis, agitation, or pulmonary pathology such as pneumonia
or ARDS. Tachycardia may result from fever alone, dehydration, or third space
losses as a result of sepsis. Hypotension in the setting of an acute infectious
process is a late and ominous sign and should be aggressively treated. Patients
with septic shock are frequently warm and dry in the initial phases of their
illness, unlike patients with hypovolemic or cardiogenic shock who are
vasoconstricted.
Alterations of mental status may be subtle and difficult to recognize
especially in patients with a history of dementia. Often, information regarding
the patients previous level of functioning is obtained by speaking with family
members, nursing home staff, home health aides, or others who have frequent
contact with the patient. A thorough neurologic examination helps to distinguish
sepsis from intracranial pathology. Patients should be completely undressed
unless the source of their problem is obvious. Skin findings of importance
include areas of cellulitis, petechiae, pu{pura, or rash. Inspecting the feet is
important especially in diabetic patients and in those with vascular disease or at
risk for neuropathy, such as the alcoholic. The back should be examined for
perirectal or pilonidal abscess as well as decubitis ulcer. Costovertebral angle
percussion tenderness should be sought; when present, it suggests
pyelonephritis. Since pneumonia and intraabdominal sources of sepsis are
common, careful examination of the chest and abdomen is mandatory. Nuchal
rigidity mandates lumbar puncture, although nuchal rigidity may be absent in
the elderly or those under 24 months of age, even with meningitis. More occult
sources of infection would include the sinuses or orthopedic foci in
noncommunicative patients.
Ancillary studies in the infected patient may provideclues to the
source and severity of the initial focus of infection. A complete blood count
should be obtained with an understanding that most but not all patients with a
significant source of infection have an elevated WBC count. In adults and in
pediatric patients there may be a crude association between the magnitude of the
white count and the seriousness of its underlying cause. Patients with WBC
counts lower than normal should be approached with extra caution. In the
absence of DIC, sepsis should not cause anemia or thrombocytopenia. When the
suspense for DIC exists, laboratory confirmsion should be carried out.
Chemistry values of specific importance include BUN and creatinine, which
may suggest renal failure, serum glucose to rule out either hypo- or
hyperglycemia, which may suggest diabetic ketoacidosis (DKA) or
hyperosmolar coma, as well as serum sodium and chloride, which when taken
together with the renal functions may reveal dehydration. Additionally, serum
bicarbonate may become depressed in the septic patient, which may be the
result of systemic hypoperfusion, ischemia to an extremity or the bowel, or
other metabolic derangements. Abnormalities may occur in the liver functions
with elevation of transaminases. Abnormal coagulation parameters should be
considered DIC until proven otherwise. Elevations of pancreatic amylase and
lipase may also occur. Arterial blood gases may reveal hyperventilation as the
result of agitation or sepsis or a high alveolar-arterial oxygen gradient in the
setting of pneumonia or ARDS. Hypoxemia unresponsive to supplemental
oxygen may result from ARDS. ECG and cardiac enzymes may identify
patients with underlying heart disease or concomi- BUN and creatinine, which
may suggest renal failure, serum glucose to rule out either hypo- or
hyperglycemia, which may suggest diabetic ketoacidosis (DKA) or
hyperosmolar coma, as well as serum sodium and chloride, which when taken
together with the renal functions may reveal dehydration. Additionally, serum
bicarbonate may become depressed in the septic patient, which may be the
result of systemic hypoperfusion, ischemia to an extremity or the bowel, or
other metabolic derangements. Abnormalities may occur in the liver functions
with elevation of transaminases. Abnormal coagulation parameters should be
considered DIC until proven otherwise. Elevations of pancreatic amylase and
lipase may also occur. Arterial blood gases may reveal hyperventilation as the
result of agitation or sepsis or a high alveolar-arterial oxygen gradient in the
setting of pneumonia or ARDS. Hypoxemia unresponsive to supplemental
oxygen may result from ARDS. ECG and cardiac enzymes may identify
patients with underlying heart disease or concomitant myocardial ischemitant
myocardial ischemia.
Blood cultures should be obtained from at least two peripheral
sites. In the immunocompromised, viral and fungal cultures should be obtained.
Direct antigen detection modalities may also prove to be valuable and may be
done on blood or urine. Gram stain and culture done on potential sources of
infection such as sputum may also be of value. Urinalysis and culture should be
performed on any patient where the urinary tract may be the source of infection.
A chest x-ray is warranted unless the patient has a known source and is free of
any pulmonary symptoms. Other radiologic studies such as abdominal plain
films or computed tomography (CT), ultrasound, or head CT should be
employed under the correct clinical paradigms. A CT is not a prerequisite for
lumbar puncture in the patient with a nonfocal neurologic examination and
without signs of increased intracranial pressure but should be performed in
cases where the patient has a risk for an intracranial mass, such as those with a
history of malignancy or immunosuppression.

Treatment and Disposition

 As with all ED patients, securing the fundamental ABCs is the
physician’s first priority. In the patient with an advanced septic process this
process requiring airway intervention, volume expansion, and vasopressor
therapy. In addition, the resuscitation of any potentially septic patient should not
be considered complete until parenteral antibiotics have been given. As in the
majority of emergency practice the choice of antibiotics in the septic patient is
empiric (not based on culture) most of the time.
Patients who have minimal pulmonary reserve due to underlying lung
disease, congestive heart failure, or pneumonia may require intubation and
mechanical ventilation. Patients who have significant degrees ofhypoperfusion
should also be considered for active airway management since maximizing
oxygen delivery in these patients is of critical importance. Similarly, those with
obtundation require airway protection to minimize the risk of aspiration.
Intravenous fluids may be all that is required to restore normal perfusion in
these patients. Since few Eds have the resources for invasive monitoring,
clinical parameters of perfusion such as normalization of blood pressure and
capillary refill, resolution of tachycardia, and improvement in mental status
should be followed. A urinary catheter also helps guide resuscitation, and a
reasonable goal is a minimum hourly urine output of 0.5 to 1.0 cclkg.
 There has been controversy in the past with respect to the choice of IV
fluids to use in the resuscitation of the patient with sepsis or septic shock.
Choices have included saline or Ringer’s solutions or colloids such as dextran,
hetastarch, albumin, or blood. Proponents of colloids cite the fact that colloids
remain in the intravascular space longer and thus less volume is required to
attain hemodynamic stability. Balanced crystalloidstend to leak into the
intravascular space rapidly and thus a greater total volume is required. They are
cheaper to use and in general more rapidly infused. The additional third spacing
ofcrystalloids appears to have no clinical significance. If crystalloids are used
then an isotonic solution should be used. Significantly anemic patients should
receive bloo4 since the primary goal in the treatment of the septic patient is to
optimize tissue oxygen delivery. For frankly toxic-appearing patients or those
with hypotension, volume resuscitation should proceed rapidly with close
monitoring of the patient’s respiratory status. For pediatric patients an initial
bolus of 20 cclkg is indicated and may be repeated. Patients who fail to respond
to volume expansion or do so only transiently require pressor agent support.
The first-line agents employed are usually dopamine and norepinephrine. In one
study norepinephrine was found to be the more efficacious agent.
For the emergency physician the early administration of antibiotics is
of critical importance. In patients who are possibly septic, only intravenous
therapy will suffice. Empiric monodrug therapy is usually adequate, but in
several circumstances additional coverage is warranted. Regardless of the
specific regimen chosen, the administration of antibiotics should not be
significantly delayed to await ancillary tests or consultations from other
services. A particular antibiotic choice may always be modified later. One such
situation is that of suspected nosocomial pneumonia where double pseudomonal
coverage is necessary. Another situation is that of the febrile patient who is
immunocompromised, such as the febrile neutropenic cancer patient. In addition
to the double drug regimen, some authors include vancomycin, particularly in
the presence of an indwelling IV line.
Since the cascade ofevents that lead from infection to shock and death
are mediated by the host’s immune system, it seems reasonable that attempts to
mitigate the inflammatory response may be clinically useful. Such attempts
have been made with steroid therapy as well as with the use of several
mediators of the inflammatory cascade. With respect to the use of steroids,
some early work in animals suggested improvement in outcome when steroids
were administered prior to the onset of sepsis; however, clinical work has not
thus far demonstrated any benefit. At this time the administration of steroids
cannot be recommended. The administration of antiendotoxin monoclonal
antibodies has also been evaluated in an effort to moderate the host immune
response and thus improve outcome in septic patients. While clinical trials using
monoclonal antibodies HA-1A and E5 have been promising, neither agent is
currently considered more than experimental at this time.
Patients who are believed to have any significant degree of sepsis
should be hospitalized for intravenous antibiotics. Concerns of patient
noncompliance or a poor social situation may also warrant admission. Patients
who have persistently abnormal physiologic parameters should be strongly
considered for admission to an intensive care unit. Infrequently the etiology of
shock may remain elusive in the ED and in these casesswan-Ganz
catheterization may provide valuable information. Apart from basic
resuscitation, the most significant impact the emergency physician makes is the
early administration of appropriate empiric antimicrobial therapy.
SELECTED READING
Aube H, Milan C, Bleftery B. Risk factors for septic shock in the management
of bacteremia. Am J Med 1992;93:283-288.
Bone R. Sepsis syndrome. New insights into its pathogenesis and treatment.
Infect Dis Clin North Am 1991;5(4):793-805.
Cunha BA. The antibiotic treatment of sepsis. Med Clin North Am
1995;79(3):55 1-558.
Esposito A, Gleckman R, Cramm S, et al. Community acquired bacteremia in
the elderly: analysis of one hundred consecutive episodes. J Am Geriatr Soc
1980;28(7):315 319.
Giamarellou H. Empiric therapy for the infections in the neutropenic
compromisedhost. Med Clin North Am 1995;3:559 581.
Giroir B. Mediators of septic shock: new approaches for interrupting the
endogenous inflammatory cascade. Crit Care Med 1993;21:780-789.
Glauser MP, Heupotential strategies for the prevention and treatment of septic
shock: an update. Clin Infectdis 1994;18(suppl 2):s205-s21 update.
Haglund U. Systemic mediators released from the gut in critical illness. Care
Med 1993;2 1 (suppl 2):s1 5-sl 8.
Harris R, Musher D, Bloom K, et al. Manifestations of sepsis. Arch Intern med
1987 ;147 :1895-1 906.
Jafari H, McCracken G. Sepsis and septic shock: a review for clinicians. Preiatr
Infect Dis 1992;l l(9):7 39-7 48.
Lefering R, Neugebauer E. Steroid controversy in sepsis and septic shock: a
meta-analysis. Crit care Med 1995;23:1294-1303.
Martin M. Epidemiology and clinical impact of gram negative sepsis. Infect dis
Clin North Am 1991;5(4):739-752.
Martin C, Papazian L, Perrin G, et al. Norepinephrine or dopamine for the
treatment of hyperdynamic septic shock. Chest 1993;103:1 826-1831.
Parrillo J. Pathogenetic mechanisms of septic shock. N Engl J Med 1993;
328(20):147 1-1477 .
Rangel-Frausto M, Pittet D, Costigan M, et al, The natural history of the
systemic inflammatory response (SIRS). A prospective sfidy. JAMA
1995;273:117-123.
Richardson J. Bacteremia in the elderly. J Gen Intern Med 1993;8:89-9
Sheagran J. Corticosteroids for the treatment of septic shock. Infect Dis clin
North Am I 99 I ;5(4):875-882.
Shires Gl Barber A, Illner H. Current status of resuscitation: solutions including
hypertonic saline. Adv Surg 1995;28:133-163.
Alan D. Recent developments in our understanding of sepsis: evaluation of anti-
endotoxin antibodies and biological response modifierc. An Emerg med 1993
:22:187 l- 1890.
Thijs LG, de Boer JP, de Groot MCM, Hack CE. Coagulation disorders in
septic shock. Intensive Care Med 1993;19:s8-s15.
Vicent JL. Cardiovascular management of septic shock. Infect Dis Clin north
Am 1993;5(4):807-816.

Mycobacterial Diseases (9.1.4)

Mycobacterium is a genus that consists ofthree classes of
organisms that are known to cause clinical disease in humans. These are the
tubercle bacillus, which is responsible for tuberculosis in humans, the human
leprosy bacillus, which is the causative agent of leprosy (Hansen’s disease), and
a group of organisms known as the afypical mycobacteria, which are
responsible for disease affecting primarily immunocompromised hosts. While
Hansen’s disease is relatively infrequent in the united States, the recent
epidemic caused by the human immunodeficiency virus (HIV) has resulted in
increased numbers of patients afflicted with tuberculosis and disease caused by
the opportunistic atypical mycobacteria presenting to emergency rooms. The
former especially has recently become a formidable public health concern
again. Thus emergency physicians must have a good understanding ofthese
entities from both a clinical and an epidemiologic perspective.

Hsnsen’s Disease (Leprosy)

Although there are over seven million known world-wide cases of
Hansen’s disease, the disease is rare in the united States. Thus many physicians,
including emerjilc), piiysicians, failtc, cver consider the diagnosis even in the
applopriate setting. Delay in diagnosis contributes to an increased morbidity
experienced by these patients, which potentially includes loss of limb.

Etiology and Epidemiology

Leprosy occurs in much of the world including
subshharan Africa, India, South America, Southeast Asia,
china, the Caribbean, southern Europe, and parts of the pacific.
In the United States the disease is usually encountered in
foreign-born individuals who have immigrated to this country.
It is indigenous to parts of the southeastern United States,
California, Hawaii, and puerto Rico. U.S. cities with large
numbers of immigrants tend to have a higher prevalence of
leprosy. The disease usually is first diagnosed in adolescents
and young adults, although it may present atany age. Because
of the prolonged incubation period ofthe disease and the fact
that documenting the exact time of exposure to the etiologic
organism is nearly impossible, much information regarding the
epidemiology of Hansen’s disease has ramained elusive.
Hansen’s disease is caused by Mycobacterium leprae,
a slow-growing, acid fast bacillus. It is believed that once a
person is exposed, the average length of incubation is from 2
to 5 years, although in some individuals clinical disease may
not manifest for decades. Why some individuals infected with
the bacilli develop disease and others do not is poorly
understood, but probably has to do with genetic and
environmental factors. In addition, there are several forms of
the disease that occur and these may correlate with a patient’s
relative immunity to the bacilli or lack thereof. Unlike the
tubercle bacilli, the pathogenicity of the organism is low and it
is believed that most patients with Hansen’s disease acquired
the disease as a result of substantial exposure to the bacilli. It
is believed that the disease is transmitted by airborne droplets.
Skin to skin contact, transmission from the bites of insects,
breast milk, and vertical transmission are less common routes
of infection. Humans are the only important reservoir for the
infection.

Pathophysiology and Diagnosis

Following infection the thermolabile bacilli disseminate, preferentially
to the cooler peripheral areas of the body. Leprosy is predominantly a disease of
skin and peripheral nerves, although involvement of the eyes and upper
respiratory tract also occurs. The disease is characterized in two broad
categories-tuberculoid and lepromatous. It is unclear why certain patients
exhibit one or the other form, although cellular immunity probably plays an
important role.
Lepromatous leprosy occurs in patients who are anergic, and thus the
lesions that occur in these patients harbour large numbers of bacilli and few
granulomas. Patients with this form of leprosy may carry huge numbers of
organisms. Numerous symmetric, ill-defined skin lesions are the rule. These
lesions may be maculopapular or nodular and may ulcerate. A symmetric
peripheral neuropathy occurs, resulting in sensory loss, which may display a
"stocking and glove" distribution. The sensory neuropathy leads to abnormal
pressure points and repeated trauma. The result is ulceration and secondary
infection. Autonomic nerve dysfunction results in anhydrosis, which leads to
dry skin creating a portal for secondary infection. Neuronal dysfunction may
occur as well as direct infection of muscles by the bacilli, causing weakness and
paralysis. The end result is limbs that are deformed as a result of pathologic
fracture, trauma, and infections such as osteomyelitis. The disease preferentially
affects the cooler tissues of the body, including the anterior chamber of the eye,
the upper airway, or the testes in men. The skin involvement may be so
extensive as to involve nearly the entire surface of the body. Involvement of the
head leads to loss of the eyebrows, earlobe hypertrophy, and waxy nodular
facial deposits, resulting in the characteristic leonine facies. The nose may be
affected with resultant septal collapse. Oral involvement may lead to loss of
dentition. Involvement of the eyes may be the result of direct involvement,
corneal drying, trauma, and infection as a result of inadequate lid closure
stemming from facial nerve involvement.
Tuberculoid leprosy occurs in patients who have relatively intact cell-
mediated immunity. Thus lesions in this form of the disease exhibit well-formed
granulomas and a much less intense tissue burden of mycobacterium.
Tuberculoid leprosy more often presents as a solitary or small number of skin
lesions. The center of the lesion may be hypoesthetic. Central healing may
occur. A characteristic finding in this form of leprosy is the involvement of only
a few peripheral nerves. The affected nerve may be enlarged and palpable near
the skin surface. This important diagnostic finding should be sought in relation
to the nerves of the face as well as the ulnar, peroneal, and posterior tibial
nerves. Nerve involvement with enlargement may lead to a permanent
neuropathy.
Many patients with leprosy have a form of the disease that falls
between the so-called borderline or dimorphous forms of leprosy. The course of
Hansen's disease may be punctuated by two types of "Lepra" reactions. These
occur as a response to the development of hypersensitivity to certain leprosy
antigens. They occur generally in patients who are being treated. The reactions
may be manifested by fever and general malaise as well as by an apparent
acceleration in the dermatologic and neurologic involvement of the disease as a
result of acute inflammation or immune complex deposition.
The diagnosis of leprosy should be suspected if any of the following
are discovered during the course of a patient assessment:
1. Skin lesion or lesions that may be maculopapular and vary with respect to
pigmentation; the possibility of hansen's disease is increased if the center
of the lesion is found to be hypoesthetic when tested by light touch;
2. . The presence of palpable thickening of a peripheral nerve;
3. . Sensory loss;
4. A risk factor for the disease such as intimate contact with an untreated
individual or being an immigrant from a part of the world where the
disease is prevalent.
Hansen’s disease should be considered in the differential diagnosis
of any complaint of a chronic nature that involves the skin, peripheral nerves, or
other cooler areas of the body. When suspected, appropriate consultation should
be arranged. The disease may be confirmed be skin biopsy.
Treatment and Disposition
Individuals treated for leprosy become noninfectious in a matter of
weeks. Treatment is generally with a multidrug regimen that usually includes
dispone, rifampin, and clofazimine. Steroids have been used to control acute
lepra reactions. Given the limited experience that most ED physicians have with
this entity, consultation is urged. Assistance with diagnosis and referral to a
practitioner experienced in the long-term care of these patients may be obtained
from the National Hansen’s Disease Center at Carville, Louisiana, telephone
504-642-7771, ext. 406.

Tuberculosis (9. 1.4. 1)

Tuberculosis (TB) is a disease that is associated with chronic cell-
mediated inflammation most often affecting the lungs, although multiple
extrapulmonary sites may be involved. In the United States during much of the
20th Century the incidence of TB has declined. However, since the mid-1980s
there has been a resurgence of the disease owing to several factors including the
HIV epidemic, the rise in the number of individuals living in public shelters or
other institutionalized settings, as well as the laxity of public health efforts to
control the disease after decades of success. In addition, in recent years, the
prevalence of TB infection stemming from strains of the causative agent
Mycobacterium tuberculosis, which have been resistant to standard
antituberculous agents, has risen at an alarming rate. Since the transmission of
TB has been established to occur within municipal buildings, especially
hospitals, the emergency physician has a unique responsibility as “gatekeeper”
to the hospital to identify potentially infectious individuals. Air borne
transmission with extremely high virulence, the risks to other patients and staff
are formidable. With
the public presenting to the ED now more than ever for both emergent as well
as nonemergent health care needs, the ED assumes a significant role in the
control of TB in this modern epidemic the risks to other patients and staff are
formidable. With the public presenting to the ED now more than ever for both
emergent as well as nonemergent health care needs, the ED assumes a
significant role in the control of TB in this modern epidemic
Epidemiology
Worldwide it is estimated that there are eight to ten million new
cases and three million deaths annually as a result of TB. In the United States
during the latter part of the 20th century reports of TB declined annually by
approximately 6% resulting from improved standards of living and the
development of the antituberculous drugs. Since 1985, however, there has been
an increase in the number of new TB cases. The current HIV epidemic appears
to be the single most important contributor to this resurgence of TB. Other
factors have included non-compliance with drug therapy, the increasing
prevalence of infection with multiple-drug-resistant strains of Mycobacterium
tuberculosis, and an increase in the number of homeless living in municipal
facilities. It is estimated that active TB is between 150 and 300 times more
prevalent in the homeless. Urban areas have reported a disproportionately high
incidence of TB, paralleling their increased incidence of HIV disease. The
incidence of active TB is perhaps elevated 500-fold in patients with acquired
immune deficiency syndrome (AIDS). Black and Hispanic individuals have
represented a disproportionate increase in TB when compared to other segments
of the population. In addition, there has been a recent increase in immigration to
the United states from nations where the prevalence of TB is high such as
Vietnam, the Philippines, and Mexico. For decades TB was considered mainly a
disease of the elderly, and active pulmonary disease was thought to result from
reactivation of dormant TB; however, in this Era of TB resurgence, primary
infection is taking on a more significant role than ever before. With alarming
frequency, primary TB infection is the active cause, Affecting pediatric and
middle-aged patients. Children and the immunosuppressed are at increased
danger of active pulmonary and disseminated TB.
Tuberculosis is spread from individuals by the airborne route by
droplet nuclei, which may remain suspended in room air for hours. Since the
bacilli are highly sensitive to the UV light found in sunlight, transmission
occurs almost exclusively indoors. Crowding in municipal buildings, including
hospitals, is therefore known to contribute greatly to the spread of TB. The
organism may be spread within buildings via ventilation and air conditioning
ducts. In addition, several cases of TB acquired during air travel have also been
reported. Transmission is dependent on several factors including the number of
bacilli aerosolized by an individual with active pulmonary TB, The length of
exposure of a previously uninfected individual, proximity to the source, and
internal air sanitation measures within buildings.

Pathophysiology
Tuberculosis is a disease of cell-mediated hypersensitivity and
granuloma formation within host tissues. The causative agent Mycobacterium
tuberculosis is a curved aerophilic bacillus whose cell membrane contains
alarge amount of surface lipids, rendering them difficult to decolorize with
alcohol or to dilute with mineral acid rendering them “acid-fast.” They are
usually stained with carbolfuchsin stain. They are nontitle, obligatory aerobic
organisms whose cell walls contain lipid and nonlipid moieties, which render
them highly immunoreactive. The disease is spread by true airborne
transmission. Minute droplet nuclei, which may contain one or several
organisms and measure less than l0 pm, account for the majority of TB
transmission. Large droplet transmission is not an important mode of the spread
of the disease. Once aerosolized, these particles may remain suspended for
hours to days in calm room air. They are resistant to drying and remain
infectious for days even if floating as dry dust in the air. The organisms are
highly virulent, with a single inhaled bacillus capable of producing clinical
disease regardless of an individual’s immune status. Rare cases of transmission
via the alimentary or genitourinary route have occurred. In years past, infection
from Mycobacterium bovid octree as a result ofthe use ofunsanItized
contaminated milk.
Bacilli contained in larger droplets usually impact the mucosa of the
upper airways and are generally eliminated by the mucociliary system. It is the
small droplet nuclei and free-floating bacilli that are responsible for the vast
majority of transmission, as these particles settle in the alveoli. With primary
infection, the lower lung segments are most often involved, owing to gravity
and the increased ventilation of these areas. Within the alveolus the bacilli are
ingested by macrophages. The bacilli are resistant to killing by these
macrophages. Organisms at this primary site of infection multiply both intra-
and extracellularly and may be transported to mediastinal lymph nodes.
Additionally, the organisms may disseminate elsewhere in the body via the
lymphatics or bloodstream. While the bacilli are not killed by the initial cellular
immune response in the majority of patients, the spread of the infection is
usually contained by the formation of tubercles for which the disease is named.
Tubercles represent foci of chronic granulomatous inflammation mediated by
macrophages and T lymphocytes, which surround and contain organisms in the
lung or elsewhere. These tubercles may follow one of several courses including
caseation and central necrosis, coalescence with other granulomas, or
calcification. Viable bacilli may remain
within the tubercles for decades. It is reactivation of previously dormant TB,
rather than new primary infection, that accounts for the majority of active TB
today, although the latter is recently taking on a more role. Primary infection
does not imply active diseasemose social at this stage most patients are
asymptomatic. Individuals with primary infection may be identified only on the
basis of development of delayed type hypersensitivity to purified protein
derivative (PPD) manifested by con-version to a positive skin test. In about
90o/o of healthy individuals the disease never becomes symptomatic and
remains dormant for the duration of the individual's life.
In addition to the initial site of infection, granulomas may form in the
corresponding mediastinal lymph nodes as a result of lymphatic spread of the
organism. The finding of a calcified pulmonary granuloma and a calcified
mediastinal lymph node on chest x-ray is known as the ghon complex and is
highly suggestive of TB exposure. Wth active pulmonary disease, tubercles
continue to grow and may coalesce with adjoining granulomas to from large
masses distorting normal pulmonary anatomy. Caseation may occur with efflux
of highly infectious liquefied material leaving behind the empty tubercle
cavirvence the typical appearance of cavitary TB on chest x-ray. Bacilli may be
spread throughout the airways, resulting in pneumonitis, endobronchial disease,
or tuberculous laryngitis. Patients with the latter two forms of TB are highly
contagious. The pleura and pericardium may also become involved as a result of
direct extension of the disease or as a result of hematogenous spread. The
disease may lead to constrictive pericarditis. Mediastinal disease may also
involve the great vessels, which carries a particularly poor prognosis. The
inflammatory process may also cause erosion into lymphatics or blood vessels,
with the latter resulting in hemoptysis and hematogenous spread.
 Tuberculosis, even with the primary infection, may be progressive if
the bacilli fail to become contained. Progressive disease may appear clinically
as atypical pnemonia, pleuritis with effirsion, upper lobe involvement, or as
progression to extrapulmonary TB. Occasionally, the course of pulmonary
disease may be fulminant. Progressive disease occurs in approximately 5oh of
individuals and is more common in the immunosuppressed as well as in the
pediatric patient. Active disease often develops within a year of exposure in
these patients. Extrapulmonary dissemination may occur concomitant with
progressive pulmonary disease. Most patients with extrapulmonary TB have
clinically silent lung disease, and in about l5% of cases the initial presentation
of TB is extrapulmonary. One-half of patients presenting with extra pulmonary
disease have a normal chest x-ray.
Patients with extrapulmonary disease may manifest disease in nearly
any organ system. The kidneys are the granulomas, or calcification. Viable
bacilli may remain within the tubercles for decades. It is reactivation of
previously dormant TB, rather than new primary infection, that accounts for the
majority of active TB today, although the latter is recently taking on a more
significant role. Primary infection does not imply active disease since at this
stage most patients are asymptomatic. Individuals with primary infection may
be identified only on the basis of development of delayed type hypersensitivity
to purified protein derivative (PPD) manifested by conversion to a positive skin
test. In about 90%of healthy individuals the disease never becomes
symptomatic and remains dormant for the duration of the individual’s life. In
addition to the initial site of infection, granulomas may form in the
corresponding mediastinal lymph nodes as a result of lymphatic spread of the
organism. The finding of a calcified pulmonary granuloma and a calcified
mediastinal lymph node on chest x-ray is known as the ghon complex and is
highly suggestive of TB exposure. With active pulmonary disease, tubercles
continue to grow and may coalesce with adjoining granulomas to form large
masses distorting normal pulmonary anatomy. Caseation may occur with efflux
of highly infectious liquefied material leaving behind the empty tubercle caviry.
Hence the typical appearance of cavitary TB on chest x-Ray. Bacilli may be
spread throughout the airways, resulting in pneumonitis, endobronchial disease,
or tuberculosis laryngitis. Patients with the latter two forms of TB are highly
contagious. The pleura and pericardium may also become involved as a result of
direct extension of the disease or as a result of hematogenous spread. The
disease may lead to constrictive pericarditis. Mediastinal disease may also
involve the great vessels, which carries a particularly poor prognosis. The
inflammatory process may also cause erosion into lymphatics or blood vessels,
With the latter resulting in hemoptysis and hematogenous spread.
 Tuberculosis, even with the primary infection, may be progressive if
the bacilli fail to become contained. Progressive disease may appear clinically
as atypical pneumonia, pleuritic with effirsion, upper lobe involvement, or as
progression to extrapulmonary TB. Occasionally, the course of pulmonary
disease may be fulminant. Progressive disease occurs in approximately 5oh of
individuals and is more common in the immunosuppressed as well as in the
pediatric patient. Active disease often develops within a year of exposure in
these patients. Extrapulmonary dissemination may occur concomitant with
progressive pulmonary disease. Most patients with extrapulmonary TB have
clinically silent lung disease, and in about l5% of cases the initial presentation
of TB is extrapulmonary. One-half of patients presenting with extrapulmonary
disease have a normal chest x-ray. Patients with extrapulmonary disease may
manifest disease in nearly any organ system. The kidneys are the most
commonly involved extra thoracic organs. Repost commonly involved extra
thoracic organs. Renal failure may result if the process is bilateral. Likewise,
theadrenal glands may be affected with resultant addisoniancrisis. In men, TB
may cause mass lesions of the testes,epididymis, or prostate, and be easily
confused with malignancy. In women, TB may cause pelvic masses, infertility,
or tuberculous salpingitis, with resultant tuberculous peritonitis developing in
some patients. The alimentary canal may become involved, causing a clinical
presentation consistent with inflammatory bowel disease or malignancy. When
TB involves the serosal surfaces of the abdomen mass, adhesions or ascities
may result. Musculoskeletal TB frequently involves the axial skeleton.Vertebral
body involvement, known as Pott's disease, may result in neurologic
compromise. Tuberculous lymphadenitis most frequently involves the
mediastinum,although any lymphoid tissue may be involved. Involvement of
the central nervous system is frequently rapidly progressive. Tuberculous
meningitis may result in compression ofneural structures, infarction, or
obstruction of cerebrospinal fluid (CSF) flow with hydocephalus. Less
commonly, TB may present as an intracranial mass or failure may result if the
process is bilateral. Likewise, the adrenal glands may be affected with resultant
addisoniancrisis. In men, TB may cause mass lesions of the testes, epididymis,
or prostate, and be easily confused with malignancy. In women, TB may cause
pelvic masses,infertility, or tuberculous salpingitis, with resultant tuberculous
peritonitis developing in some patients. The alimentary canal may become
involved, causing a clinical presentation consistent with inflammatory bowel
disease or malignancy. When TB involves the serosal surfaces of the abdomen
mass, adhesions or ascities may result. Musculoskeletal TB frequently involves
the axial skeleton.Vertebral body involvement, known as Pott's disease, may
result in neurologic compromise. Tuberculous lymphadenitis most frequently
involves the mediastinum, although any lymphoid tissue may be involved.
Involvement of the central nervous system is frequently rapidly progressive.
Tuberculous meningitis may result in compression ofneural structures,
infarction, or obstruction of cerebrospinal fluid (CSF) flow with hydocephalus.
Less commonly, TB may present as an intracranial mass or with spinal cord
involvement.
Tuberculosis may undergo widespread dissemination with a high
degree of bacillemia and involvement of multiple pulmonary and
extrapulmonary sites simultaneously known as miliary TB named for its millet-
seed appearance on chest x-ray. The progressive form of TB with a prominence
of constitutional symptoms is fatal without treatment. It occurs more frequently
in pediatric patients, the anergic, and those with comorbidity, especially HIV
infection.
In the patient with HIV the likelihood of the occurrence of
progressive forms of TB is inversely related to the CD4* count. The finding of
extrapulmonary TB in an individual with HIV is considered an AIDS defining
condition. The immunosuppressed patient is at higher risk for the development
of progressive pulmonary TB, disseminated or extrapulmonary TB, as well as
reactivation of dormant disease. Because of the high virulence of TB, it is more
likely to cause active disease during the earlier stages of HIV and may be the
first manifestation of rmmunosuppresslon.

Diagnosis.
Signs and Symptoms. The majority of patients remain asymptomatic
during the initial stages of the disease. Others may develop only nonspecific
symptoms, including fever, malaise, or erythema nodosum. Initial intrathoracic
disease may present with symptoms referable to marked hilar adenopathy,
including bronchial compression or obstruction, hoarseness due to recurrent
laryngeal nerve compression, odynophagia, and emesis as a result of esophageal
compression or symptoms referable to the obstruction of blood or lymphatic
flow to the upper extremity. Cough is not a likely feature of primary infection in
most individuals and is usually nonproductive if present. Obstructive symptoms
are more common in children.progressive pulmonary disease may cause patients
to experience cough , which may be productive or non-productive , dyspnea , or
hemoptysis is rare. Chest pain may herald involvement of the pleura or
pericardium. Patients may also experience symptoms consistent with
pneumothorax.
In case pulmonary TB is progressive, individuals are likely to appear
quite ill with the above-mentioned constitutional symptoms in addition to
weight loss. The disease may present similarly to acute pneumonia. Pleuritic
chest pain as well as dyspnea may occur as a result of tuberculous effusion or
pneumothorax.
Disseminated disease may present with any number of symptoms.
Abdominal TB may present as abdominal or pelvic pain or increasing
abdominal girth, or with symptoms consistent with bowel obstruction. Urologic
symptoms may include hematuria, dysuria, and flank pain. In women
tuberculous salpingitis may occur and present as pain or vaginal bleeding.
Males may present with testicular pain, swelling, or mass. Skeletal involvement
may present as pain or mass. Involvement of the vertebral column may cause
vertebral collapse with or without neurologic deficit. TB of the central nervous
system may present as focal deficits, headache, alteration of mental status, or
seizure.

Physical Examination
The examination of patients without active disease is likely to be
normal. Chest findings when present include unequal breath sounds as a result
or consolidation, effusion, bronchial compression, or pneumothorax; wheezes as
a result of endobronchial disease or airway compression; rales over areas of
caseation; or effusion or egophony associated with cavitary disease. Abdominal
examination may reveal mass, clinical ascites, or sigs of GI obstruction.
Females may exhibit signs on pelvic examination consistent with adnexal mass
or PID. Examination of the lymph system may reveal adenopathy patient with
tuberculous meningitis or cerebral investment may present with signs of
increased intracranial pressure, meningismus, or focal deficit.
Ancillary Studies.
The tuberculin skin test screens patients of the development of
delayed-type hypersensitivity to antigens in the mycobacterial cell wall,
implying exposure to TB. Clinicans must bear in mind several important facts
when evaluating patients with these test. Frist up to 20% of normal individuals
and a much greater percentage of immunosuppressed patients and those with
chronic diseases are attitgi.. Anergy may be checked for by placing a positive
conirol on the patient at the tim-e of the TB test' Because the Mantoux test using
PPD allows for better control of the amount of antigen use4 it is superior to the
multiple puncture tests and is replacing those in most clinical ,.tting.. PPD is
injected intradermally and th9 patient evaluai'ed at 48 to 72 hours' The CDC has
applied variable criteria to the interpretation of the Mantoux test*ith..gurd to the
diameter of induration in individuals at Jiff..itti risks for infection with TB
(Table 9-4)' While pevisuer immunization with BCG may produce a positive
'N4antoux test, a large percentage of individuals either fail to convert to positive
FPD ttutot after such immunization or revert back to negative PPD status' Thus
a history of frerriorrs immunizat6n with BCG should be disregarded when
interpreting the TB skin test, and a positive test should stilfimply infection with
the bacilli' Immunization with BCGIs never a contraindication to skin testing' in
individuals previously sensitized to tuberculin either from BCG vaccination or
from continued exposure to the Lacillus, repeat skin testing may result in an
enlarging zone of induration known is the "booster phenomenon'" skin testing’
by itself does not cause the development of delayedtfe irypersensitivity. The
Physician should be awaie tnaf the positive predictive value of the Mantoux test
is questiottibl" in low-risk individuals' A chest x-ray is warranted in any patient
with a newly reactive skin test as well as to follow the course of pulmonary
disease in puti"*. with clinical disease and to gauge the effect of antituberculous
therapy' Those with symptoms consistent with infection or abnormal chest x-
rays should be referred for sputum examrnation and culture in an effort to
obtain microbiologic confirmation and sensitivity.immunosuppressed patients
and those with chronic diseases are attitgi.. Anergy may be checked for by
placing a positive conirol on the patient at the time of the TB test' Because the
Mantoux test using PPD allows for better control of the amount of antigen use4
it is superior to the multiple puncture tests and is replacing those in most clinical
,.tting.. PPD is injected intradermally and th9 patient evaluai'ed at 48 to 72
hours' The CDC has applied variable criteria to the interpretation of the
Mantoux test *ith..gurd to the diameter of induration in individuals at Jiff..itti
risks for infection with TB (Table 9-4)' While previous immunization with BCG
may produce a positive 'N4antoux test, a large percentage of individuals either
fail to convert to positive FPD ttutot after such immunization or revert back to
negative PPD status' Thus a history of frerriorrs immunizat6n with BCG should
be disregarded when interpreting the TB skin test, and a positive test should
stilfimply infection with the bacilli' Immunization with BCGIs never a
contraindication to skin testing' in individuals previously sensitized to
tuberculin either from BCG vaccination or from continued exposure to the
Lacillus, repeat skin testing may result in an enlarging zone of induration
known is the "booster phenomenon' skin testing’ by itself does not cause the
development of delayed-tfe irypersensitivity. The Physician should be awaie
tnaf the positive predictive value of the Mantoux test is questiottibl" in low-risk
individuals' A chest x-ray is warranted in any patient with a newly reactive skin
test as well as to follow the course of pulmonary disease in puti"*. with clinical
disease and to gauge the effect of antituberculous therapy' Those with
symptoms consistent with infection or abnormal chest x-rays should be referred
for sputum examrnation and culture in an effort to obtain microbiologic
confirmation and sensitising analysis of the bacilli involve.
With the findings of TB on chest x-ray may be entirely nonspecific
(especially in the immunocompromised), certain patterns should raise the
physician’s level of susplcion for TB. These include patchy or nodular
infiltrates in the superior segments of the lower lobes or in the apical or
posterior subapical areas of the upper lobes. Additionally, cavitation, especially
if associated with air fluid levels, is highly suggestive of the diagnosis.
TABLE 9-4. Criteria for positive skin test
Test positive-induration equal to or greater than 5 mm
HIV positive
Susoicious chest x-ray
Close contacts of infected individuals
Test positive-induration equal to or greater than 10 mm
Children under 4 Years
Other high risk for TB individuals including health care workers
Low-risk individual younger than 35 years
Test positive--induration equal to or greater than 15 mm
Low-risk individual 35 years of age or older

Apical lordotic views are helpful in evaluating the upper lung segments. Any
pneumonic process, if associated with hilar adenopathy, should suggest the
possibility of TB. Primary infection with containment may manifest as a
calcified granuloma possibly associated with a calcified enlarged hilar lymph
node (Ghon complex).
Laboratory findings are nonspecific and include a mild leukocytosis,
which may exhibit a predominant monocytosis, and anemia of chronic disease.
Elevation of the erythrocyte sedimentation rate (ESR) may occur. Hyponatremia
may occur with SIADH or tuberculous disease of the adrenal glands. Mild
hypercalcemia has also been described. An increase in liver transaminases may
be seen with hepatic involvement. Pyuria or hematuria may result from urinary
system involvement. With tuberculosis meningitis CSF findings include
hypoglycaemia, elevated protein levels, and a moderate pleocytosis (100-1000
Cells/mm3) with a usual predominance of lymphocytes.
Treatment
 Classically five drugs-isoniazid, rifampin, ethambutol, streptomycin, and
pyrazinamide-have been used to treat TB. The treatment of TB in the recent
epidemic has become more complicated owing to an increase in the occurrence
of multiply resistant strains of TB. Multiple-drug-resistant TB (MDR-TB) has
been defined by most authors as drug resistance to at least isoniazid and
rifampin, the two most effective drugs used to treat TB. Drug resistance may be
acquired in patients with a history of previous treatment with clinical failure, or
be the result of primary infection with a multiply resistant strain. Patients are at
high risk for being infected with a multiply resistant organism if they have a
previous history of inadequately treated TB for any reason or they are from an
endemic area for MDR-TB. With increasing frequency these areas include
urban areas of the United
TABLE 9-5. Guidelines for the prophylaxis of tuberculosis
For patients with new positive TB skin test, for high risk for TB individuals
with demonstrated anergy, and for childhood close contacts of infectious
individuals (even if skin test negative):
INH (isoniazid) 300 mg/d adults
10-15 mg/kg/d not >300 mg children
 Duration-6 mo-normal host
Duration-9 mo-pediatric patients
Duration-12 mo-immunocompetent patients
Note: Prophylaxis is indicated for patients, regardless of age, who are
known to be HIV positive, at risk for HIV with unknown serologic status,
immunosuppressed, intravenous drug users, have comorbid conditions, or are
malnourished.
Patients at higher risk for TB other than those above should be given
prophylaxis if they are younger than 35 years of age. This category includes
health care workers. A Treatment may be discontinued if repeat skin testing at
12 weeks after the last contact is negative.
TABLE 9-6. lnitial treatment of active TB
Option I
INH + RIF + PYR daily for 8 weeks followed by INH + RIF 2-3 times/week for
16 weeks (DOT) Lf local resistance to INH is possible, ETH or STP
should be added initially until bacteriologic confirmation of INH sensitivity has
been documented
Option 2
INH + RIF + PYR + STP or ETH daily for 2 weeks followed by same drugs 2
times/week for two weeks (DOT)followed by INH + RIF 2 times/week
(DOT)for 16 weeks
Option 3
INH + RIF + PYR + ETH or STP 3 times/week (DOT) for 6 months
Note: ln all the scenarios above, patients should symptomatically improve and
sputum cultures revert to negative within 3 months. Treatment of
extrapulmonary disease is the same as for confined pulmonary disease.
DOT, direct observation of therapy (see text). lNH, isoniazid 300 mg/d
adult, 10-15 mg/kg/d pediatric (maximum 300 mg/d), major side effects-
hepatitis, peripheral neuropathy. RlF, rifampin 600 mg/d adult, 10-20 mg/kg/d
pediatric (maximum 600 mg/d), side effects-Gl upset, rash, thrombocytopenia,
jaundice, orange colour to urine, tears.
ETH, ethambutol 25 mg/kg initial dose then 15 mg/kg (maximum 2.5 g),
major side effect-ototoxicity, nephrotoxicity; decrease dose or avoid in elderly
patients. Major side effect-retro bulbar neuritis. Not recommended for children.
STP, streptomycin 15 mg/kg lM (maximum 1 g), 20-30 mg/kg lM q12hr
pediatric.
States. The treatment of TB varies depending on the age and immune status of
the patient. Additionally, asymptomatic patients who develop delayed-type
hypersensitivity as manifested by a reactive Mantoux or Tine skin test should be
strongly considered for prophylaxis, even if the chest roentgenogram is
negative, as about 5% of these patients develop active disease within I year of
exposure
(Table 9-5).
Current guidelines for the treatment of TB appear in Table 9-6. As TB
frequently affects populations of patients at high risk for noncompliance with
therapy, and since noncompliance has been implicated as a cause for the surge
in the number of cases of MDR-TB, many authors have advocated direct
observation of therapy (DOT) as the only modality used to treat patients with
TB. In some reports noncompliance has been estimated at 50%.
Emergency physicians can play a pivotal role in the referral of patients
with TB to treatment Centers as well as identifying patients who are
noncompliant.
Prevention, Control, and Disposition
As mentioned above, the emergency physician’s greatest potential
impact on the control of TB is to suspect the diagnosis and to institute proper
isolation procedures of potentially infectious individuals. Especially in patients
whose presenting complaint is pulmonary in nature, the physician should
maintain a high index of suspicion for TB and query the patient regarding risk
factors for the disease. It is again stressed that TB may mimic pneumonia both
symptomatically and radiographically, especially in the immunosuppressed.
When in doubt and where follow-up is believed to be possible, as well as for
admitted patients, the Mantoux skin test with anergy panel should be
considered. If time or resources do not permit this in the ED, provisions should
be made for it soon after patient disposition. Admitted patients at high
risk for TB, especially if experiencing significant respiratory symptoms, should
be placed in isolation. It is
important that this be started in the ED since once a patient is "labeled" with
another diagnosis TB may go
unsuspected or be discovered only by sputum examination or culture, which
may take days, and all the while the patient aerosolizes bacilli within the
hospital. In hospitals so equipped, adequate isolation may be accomplished by
placing the patient in negative pressure isolation rooms that vent air to the
outside. Additionally, UV lighting within hospitals has recently been instituted
to cut the rate of nosocomially acquired disease. While it is believed that UV
lights kill airborne mycobacteria, no clinical trials have proven their efficacy in
preventing nosocomial disease.
Where possible, TB should be treated in the outpatient setting to lessen the
possibility of nosocomial transmission. Individuals with comorbidity or
extenuating social circumstances, or who are likely to require more rigorous
diagnostic or therapeutic intervention, may require hospitalization.

Atypical Mycobacteria (9. 1. 4. 2)

The atypical or environmental mycobacteria are a group of
nontuberculous mycobacteria that are ubiquitous in nature that in general have
low virulence in healthy individuals. In recent years, however, physicians have
cared for growing numbers of immunocompromised patients with clinical
disease stemming from these organisms. While there are several species of these
organisms, the groups that accounts for the greatest percentage of illness are
Mycobacterium avium and Mycobacterium intracellulare, collectively known as
the Mycobacterium avium-intracellulare complex (MAC). Infection with MAC
is the most widely encountered bacterial opportunistic infection in patients with
AIDS. Other species that have been reported to cause clinical disease include M.
kansasiL M. Fortuitum, M. Xenopi, M. Simiae, M. Haemophilum, and others.
For the emergency physician, these may all be considered in a similar way-each
heralds a high degree of immunosuppression. Unlike M. Tuberculosis, these
organisms do not cause clinical disease in immunocompetent hosts. As such
they are less a public health concern than the tubercle bacilli.
Epidemiology
It is estimated that perhaps one-half of AIDS patients will acquire disease
with MAC at some point in their disease course. The nontuberculous
mycobacteria are found widely throughout nature and have been isolated from
water, soil, and certain foods. In humans the portals of entry and the sites of
initial colonization are the respiratory and gastrointestinal tracts. In normal
hosts this is generally of no consequence; however, in the immunosuppressed
patient these sites serve as foci of blood borne dissemination. Previous
opportunistic infection should alert the physician to advanced HIV and the
possibility of disseminated MAC. With the use of antiretroviral drugs as well as
improved care for the complications of HIY these patients are now living
longer, and thus physicians can expect to encounter greater numbers of AIDS
patients with disseminated MAC.

Pathophysiology
 Following colonization, blood-borne dissemination may occur with
widespread distribution of MAC organisms to virtually any site in the body. It is
possible that colonization may not produce clinical disease particularly in
healthy individuals. The original site of colonization may be transient and
further dissemination may occur as a result of new sites of infection with
ongoing bacterial replication. Regardless of mechanism, wide-spread
dissemination with high tissue burdens of MAC organisms is the rule in the
immunosuppressed. Unlike disease caused by the tubercle bacillus, granuloma
formation is not a prominent feature of infection with
MAC. Contained localized disease is much less common but may occur and be
the cause of any number of clinical syndromes. These include pulmonary
disease with nodules, pneumonic infiltrates, and even cavitary disease,
endobronchial disease, pericardial disease, musculoskeletal disease, skin
lesions, lymphadenitis, GI tract lesions with resultant malabsorption and chronic
diarrhea, intraabdominal MAC including abscess formation, As well as CNS
disease. Any of these may be associated with dissemination. When MAC affects
the lung, its clinical presentation may be identical to lhat of M. Tuberculosis.
It has been difficult to elucidate exactly the impact MAC has by itself on
morbidity and mortality in AIDS patients since it is so frequently associated
with advanced HIV and the concomitant existence of other opportunistic
infections such as toxoplasmosis, cytomegalovirus (CMV), and Pneumocystis
carinii. By itself MAC is believed to have low pathogenicity, although in some
individuals it has produced significant disease. Exactly which patients develop
clinically significant infection with MAC and why they develop it has not been
well understood. It is generally believed that disease caused by MAC does
accelerate the downward spiral of the AIDS patient to death as co-infection with
MAC has been observed to significantly shorten life expectancy.

Diagnosis
The manifestations of infection with MAC are protean. Furthermore, co-
infection with other pathogens is the rule in patients who have disseminated
MAC. Thus, Attributing specific signs and symptoms to MAC infection has
proven difficult. Constitutional symptoms such as fever, night sweats, anorexia,
generalized malaise, and weight loss are frequent. Diarrhea, abdominal pain,
nausea, and vomiting have also been associated with disseminated MAC.
Pulmonary disease may present syndrome consistent with bronchitis,
pneumonia, or mass with obstruction. While MAC does not involve the CNS
with high frequency, CNS involvement may present as headache, alteration in
mental status, or seizure. Historical factors that are valuable in the medical
history include risk factors for HIV. The recent use of immunosuppressive
drugs, or other comorbid conditions such as malignancy. In patients with HIV
infection, asking the patient or local doctor, or reviewing the medical record for
the date and level of the last CD4* count will prove helpful. Any previous
opportunistic infection such as with Pneumocystis carinii should be considered
a definite risk for the presence of disseminated MAC illness.
Physical examination may reveal a multitude of pulmonary findings
consistent with the above-named syndromes, abdominal tenderness or mass,
hepatosplenomegaly, or lymphadenopathy. CNS findings consistent with the
diagnosis include nuchal rigidity and abnormalities in mental status.
Unfortunately, none of these examination findings is specific, and each may
have several etiologies in the patient with immunosuppressive disease.
The use of radiologic and laboratory data helps in the diagnosis of
infection with MAC as well as in evaluating the possibility of other more
serious opportunistic infections in a given patient. There is no chest x-ray
finding that is specific for the diagnosis of MAC infection nor distinguishing
disease caused by MAC from tuberculous infection. Laboratory findings
supporting the diagnosis of MAC include a profound anemia as well as an
elevated alkaline phosphatase. Lumbar puncture in cases of CNS disease reveals
a CSF leukocytosis. Smears taken from affected tissues display acid-fast bacilli.
Blood culture confirms the presence of disseminated MAC in many instances.

Treatment and Disposition

Rifabutin is an oral medication similar to rifampin that has been
approved for the prophylaxis of disseminated MAC in the AIDS patient. It is
indicated in HlV-positive patients with CD4* counts less than 100/mm3. Prior
to the administration of this agent, at least one blood culture for MAC should be
obtained since a positive culture would mandate more aggressive therapy. The
proper adult dose is 450 to 600 mg per day. Side effects include neutropenia,
thrombocytopenia, elevated liver function, as well as GI symptomatology.
Patients with proven disseminated MAC (positive blood culture) should
be started on at least a two-drug regimen. One of these drugs should be either
clarithromycin or azithromycin. Ethambutol is frequently used as the second
drug. Third- and fourth line agents include clofazimine, rifabutin, rifampin,
ciprofloxacin, and amikacin. Once institute4 prophylaxis and/or treatment
should continue for the duration of the patient’s life. Clinical improvement from
the constitutional symptoms of disseminated MAC with prolongation of life are
the goals of therapy. The emergency physician must realize that all patients with
known disseminated MAC or at risk for it are severely immunocompromised
and therefore careful evaluation for the other complications of
immunosuppression is warranted. Admission to the hospital is clearly mandated
for some patients due to the presence of more significant opportunistic
infections, poor social circumstance, or clinical deterioration.

SELECTED READING
Hansen's Disease
Pust R, Campos-Outcalt D. Leprosy in the United States. Risks, recognition,
regimens, resources. Postgrad Med 1 985 ;77(5):151-l 59.
Style A. Early diagnosis and treatment of leprosy in the United States. Am Fam
Physician 1995;52(l):172—178.
Simon H. Infections due to mycobacterium. Sci Am Med 1995;18(9):1-26.
Trautman J. Epidemiological aspects of Hansen’s disease. Bull NY Acad Med 1
984 ;60(7 ):7 22-7 3 l.

Tuberculosis
Barclay D, Richardson J, Friedman L. Tuberculosis in the homeless. Arch Fam
Med 1995;4:541-546.
 Barnes P, Le Hanh Quoc, Davidson P. Tuberculosis in patients with HIV
infection. Med CIin North Am 1993;6:1369-1390.
Bausch L, Bass I The treatment of tuberculosis. Med Clin North Am 1993;77
(6):1277 -1288.
Centers for Disease Control. Treatment of tuberculosis and tuberculosis
infection in adults and children. Am J Respir Crit Care Med 19941,149:13s9-
t374.
Centers for Disease Control. Exposure of passengers and flight crew to
mycobacterium tuberculosis on commercial aircraft, 1992-1995.MMWR 199 5
;44(8): 137—140.
Huebner R, Castro K. The changing face of tuberculosis. Annu Rev Med
1995;46:47-55.
Kent J. The epidemiology of multidrug-resistant tuberculosis in the United
States. Med Clin North Am 1993;77(6):1391-1407.
McSherry G, Connor E. Current epidemiology of tuberculosis. Pediatr Ann
1993;22:600—404.
Nardell E. Environmental control of tuberculosis. Med Clin North Am 1993;77
(6)13ts-t334.
Pozsik C. Compliance with tuberculous therapy. Med Clin North Ann 1991 ;77
(6):1289—1302.
Simon H. Infections due to mycobacterium. Sci Am Med 1995;18(9):1-26.
Starke J. The tuberculin skin test. Pediatr Ann 1993;22(10):612-620.
Telzak E, Sepkowitz K, Alpert P, et al. Multi-drug resistant tuberculosis in
patients without HIV infection. N Engl J Med 1995;333:907-911.
Waagner D. The clinical presentation of tuberculosis disease in children.pediatr
Ann1993 ;22(1 0) :622—628.
Yamaguchi E, Reichman L. Pulmonary tuberculosis in the HIV positive
patients. Infect Dis CIin North Am 199l;5(3):623-633.

Atypical Mycobacterium
Meningococcemia is meningococcal bacteremia, which usually
results from seeding from the nasopharynx. Neisseria meningitidis, a gram-
negative coccus, colonizes the nasal mucosa of 5% to 15% of humans in the
general population; however, it must invade the mucosa to cause disease. Most
cases occur in children and adolescents, with the highest incidence in the first
year of life, although any age group may be affected. Military recruits are also
particularly susceptible to meningococcal disease, although outbreaks among
this population have decreased over the past 10 years with the routine use of
vaccine. The disease may present as acute meningococcal septicemia, which
may be fulminant (Waterhouse-friderichsen syndrome), meningococcal
meningitis, or chronic meningococcemia. From 30% to 50% of the patients with
meningococcal disease have meningococcemia without meningitis.
Meningococcemia may be an acute process, presenting either as a mild systemic
infection or one that is rapidly lethal, or may be a chronic relapsing illness that
may last for several months. From 2% to 15% of the patients may be chronic
carriers of meningococci. Early recognition of meningococcal disease is
essential for successful treatment. The illness is characterized by fever, systemic
toxicify with or without hypotension, petechial or purpuric rash, and high
morbidity and mortality. The mortality of meningococcemia, ranging from 10%
to 30% is higher than that of meningococcal meningitis alone.
Meningococcemia has its highest incidence in children aged 6 months
to 1 year and has its lowest incidence in persons over 20 years of age.
Transmission from person to person is principally through inhalation of droplets
of infected nasopharyngeal secretions, and close person-to-person contact. The
disease has occurred worldwide, as the asymptomatic carrier state (the most
common form), sporadic cases, limited outbreaks, and widespread epidemics.
The peak incidence of occurrence is during midwinter and early spring. Patients
with complement deficiency, either congenital or due to underlying disease,
seem to be at increased risk for invasive infection as do asplenic patients and
alcoholics. This may be an important risk factor in the development of the first
episodes of Nonepidemic meningococcal disease. The incubation period from
the initiation of nasopharyngeal infection to systemic bacteremia appears to be
less than l0 days. Once the organism has entered the bloodstream, over 90% of
the patients present with either meningitis or meningococcemia.

Clinical Presentation
Meningococcemia usually follows an upper respiratory infection.
Initially, patients may be minimally symptomatic with flu-like symptoms of
headache, cough, sore throat, myalgias, nausea, and vomiting. More severe
illness develops with spiking fevers, chills, and arthralgias when
nasopharyngeal infection has progressed to bacteremia. Some 75% of the
patients develop a petechial rash that is characteristic. Lesions are usually sparse
and involve the axillae, flanks, wrists, and ankles. In severe cases purpuric spots
or ecchymosis develops. Absence of a rash does not necessarily indicate a more
mild illness. The disease can range from an indolent, slowly progressing
infection to sudden onset of fulminant disease that may progress to death in a
day or less. Meningococcemia may manifest primarily as bacteremia, or as a
localized infection. Acute meningococcemia and acute meningitis are the most
common forms of meningococcal disease.
Mild acute meningococcemia, the most common form of
meningococcemia, is characterized by the rapid development of malaise, chills,
fever, arthralgias, and myalgias following cultures growing N. meningitidis. In
other cases, the initial symptoms are followedin24 to 48 hours by the recurrence
of chills and the development of classic erythematous skin lesions that may be
petechial, macular, or maculopapular with pale gray vesicular centers. The rash
is most evident on the extremities.
Fulminant meningococcemia occurs in approximately 10% to 20%
of the patients with meningococcemia. Fulminant meningococcemia
characteristically has a very abrupt onset and is rapidly progressive. The illness
presents with rigor, high fever, dizziness, headache, and profound malaise. All
symptoms tend to develop over a few hours. Petechiae, purpura, and
hypotension develop rapidly along with peripheral vasoconstriction and shock.
Extensive purpura, circumoral cyanosis, hemorrhagic bullae, and peripheral
gangrene are key features of fulminant meningococcemia. Disseminated
intravascular coagulation is frequently present with enlarging hemorrhagic and
necrotic areas on the skin. Mucosal, respiratory tract, and gastrointestinal
bleeding may occasionally develop. As the illness progresses, patients may
become hypothermic. Patients who recover may have extensive sloughing of
skin lesions due to gangrene, which may require extensive skin grafting.
Chronic meningococcemia, a rare form of meningococcal infection, is
characterizedby periodic fevers lasting 1 to 6 days, presenting with chills,
headache, myalgias, and migratory arthralgias. Each episode of fever is
associated with the development of an erythematous macular and popular rash
with rare petechiae and purpura. The total number of lesions is small. Up to
20% of he patients may have splenomegaly. Up to two-thirds of the patients
may present with joint involvement. Patients are only minimally toxic in
appearance, fever is intermittent, and infection may last for weeks or months.
Diagnosis is made by blood culture drawn during the febrile period. Failure to
treat chronic meningococcemia may result in the development of meningitis in
20% of the patients. Endocarditis and epididymitis are rarer complications.
Meningitis is a common form of meningococcal disease. Most cases of
meningococcal meningitis occur in children and adolescents. Commonly
patients present with symptoms of both meningitis and meningococcemia. From
20% to 40% of patients may have meningitis without evidence of
meningococcemia. The onset of symptoms (fever, chills, stiff neck, headache,
vomiting, malaise, confusion, or lethargy) may be very rapid, progressing in
less than 24 hours. It may be preceded by a mild upper respiratory infection.
Unlike other pathogens causing meningitis, meningococcal meningitis is not
associated with predisposing otitis media or pneumonia. In patients presenting
with delirium, N. Meningitidis is more commonly the etiologic agent. When
meningitis occurs in association with a petechial or purpuric rash, a presumptive
diagnosis of meningococcal disease is warranted. Occasionally during
convalescence a nonseptic arthritis-pericarditis syndrome may develop;
otherwise the features and complications of meningococcal meningitis are
similar to other meningitides.
Meningococcal pneumonia is more commonly of primary origin
rather than a result of hematogenous spread. The clinical presentation is similar
to that of community-acquired pneumonia. The lower lobes are usually
involved. Bacteremia occurs in about l5% of the cases. Meningococcal
pneumonia occasionally develops during the course of meningococcemia or
meningococcal meningitis. The clinical picture, however, is dominated by the
extrapulmonary symptoms.
Arthritis complicates from 2% to 16% of the cases of acute
meningococcal disease. The arthritis may present in several forms:
monoarticular acute suppurative meningococcal arthritis (rare), polyarthritis
(early onset), and Mono- or oligo arthritis (late onset). With acute suppurative
arthritis the joint aspirate has the appearance of a septic arthritis. Early-onset
arthritis usually occurs during the first 1 to 3 days of meningococcal disease.
This is the most common form of meningococcal-associated arthritis. It is
polyarticular, and joints are acutely inflamed without effrrsion or a very
minimal effusion.
Pericarditis also may complicate meningococcal disease in 2% to 20% of
the patients. Like arthritic, it may present early, in the course of the illness, or
late, during recovery. Early pericarditis is usually purulent and due to the
invasion of the pericardium by N. Meningitidis. Late pericarditis is usually
sterile. Isolated purulent pericarditis due to N. Meningitidis without signs of
meningococcal disease is very rare. Ocular and genitourinary involvement
complicate less than 1% of the cases.

Diagnosis
The diagnosis of meningococcemia should be entertained in anyone who
presents with fever, malaise, and a petechial or maculopapular rash, with or
without signs and symptoms suggestive of meningeal infection. Aside from
bacteriologic data, other laboratory studies are of little value in establishing a
diagnosis of meningococcal disease. The diagnosis is confirmed by finding
organisms on stained smears from infected areas when appropriate, by isolation
of N. Meningitidis from blood or infected body fluids, and by detection of N.
Meningitidis polysaccharide antigen in blood or cerebrospinal fluid (CSF) by
latex agglutination or counterimmunoelectrophoresis. Blood cultures are
positive for N. Meningitidis in 50% to 75% of the patients with
meningococcemia, and in approximately one-third of the patients with
meningitis. In patients with meningitis, polysaccharide antigen in demonstrated
in CSF approximately 70% of the time.
The differential diagnosis should include other bacteremias.
Occasionally meningitis caused by Haemophilus influenzae and Streptococcus
pneumoniae may present with a petechial skin rash. Acute bacterial endocarditis
caused by Staphylococcus aureus may also present with petechial lesions,
presenting a clinical picture that is almost indistinguishable from
meningococcemia. In addition, gonococcemia, vasculitis, viral exanthems, and
Rocky Mountain spotted fever should also be considered.

Treatment
Because of the rapidity with which this disease progresses, as soon as
the diagnosis of meningococcemia or meningococcal meningitis is suspected,
antibiotic therapy should be instituted. Patients should by placed in respiratory
isolation to minimize spread of infection. Antibiotics that have been shown to
be effective include penicillin G (2 million units every 2 hours), ampicillin (2 g
every 6 Hours), chloramphenicol (4 g/days), and ceftriaxone (up to 4 g/days;
100 mg/kg in children). Treatment should be continued for a minimum of 7
days or for at least 4 to 5 days after the patient becomes afebrile. Treatment of
severe meningococcemia requires aggressive supportive care to manage shock,
DIC, and other complications. This may include monitoring in an intensive care
setting, supplemental oxygen to maintain oxygenation, volume expansion and
the utilization of vasoactive agents to maintain blood pressure, and the
administration of bicarbonate to correct acidosis. Most deaths occur within 24 to
48 hours of admission to the hospital.

Prevention
Chemoprophylaxis should be administered to all close contacts of
patient with meningococcal disease. This should include all same-household
members, day-care center members, and medical personnel who have had
intimate contact with the patient, such as administering mouth-to-mouth
resuscitation. Since secondary cases usually occur within the first week after
initial contact, prophylaxis should begin as soon as the initial case is identified.
Rifampin is the drug of choice for chemoprophylaxis, and is 80% to 90%
effective in eliminating meningococci from the nasopharynx of asymptomatic
carriers. Rifampin is administered for 2 days at the following dosages: adults
(600 mg twice a day), children younger than I month of age (5 mg/kg
administered twice a day), children older than 1 month but younger than 12
years (10 mg/kg administered twice a day with a maximum dose of 1200 mg per
day). Commercially available meningococcal vaccine is not recommended for
routine vaccination due to the low incidence of the disease in the absence of
outbreaks. Vaccination should be considered for individuals who are traveling
to countries in which there is an epidemic of meningococcal disease. Current
vaccine, however is not effective in preventing disease from all groups of
meningococci, nor is it effective in younger children who are at most risk for
infections.

SELECTED READING
Achtman M. Epidemic spread and antigenic variability of Neisseria
meningitidis Trends Microbial 1995;3(5): 1 86—192.
Figueroa J, Andreoni J, Densen P. Complement deficiency states and
meningococcal disease. Immuno Res 1993 ;12:295—311.
Hart CA, Rodgers TRF. Meningococcal disease. J Med Microbiol 1993;39:3—
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Herrera R, Hobar PC, Ginsburg CM. Surgical intervention for the complications
of meningococcal induced purpura fulminans. Pediatr Infect Dis J
1994;13(8):734—737.
Jarvis GA. Recognition and control ofneisserial infection by antibody and
complement. Trend s Mic robio 1995;3(5):198—201.
Klein NJ, Heyderman RS, Levin M. Management of meningococcal infections.
Br J Hosp Med 1993;50(l):42—49.
Marhoum el Filali K. Noun M, Chakib A, et al. Ceftriaxone versus penicillin G
in the short term treatment of meningococcal meningitis in adrits. Eur J Clin
Mioobiol Infect Dis 1993;12(10):766—789.
Paulson E, ed. Guidelines for control of meningococcal disease. Canada
Communicable Disease Report 1994;20:17—17.
Riedo FX, Plikaytis BD, Broome CV Epidemiology and prevention of
meningococcal disease. Pediatr lttfect Dis J 1995;14(8):643—456.

Plague (9.1.6)
 Plague is a bacterial infection of humans and animals, caused by the
aerobic, gram-negative, nonmotile, coccobacillus Yersinia pestis. The disease
may vary from a local reaction at the regional lymph nodes proximal to the site
of inoculation-acute regional lymphadenitis called bubonic plague, to a
fulminant disseminated infection without adenopathy-septicemic plague.
Pneumonic plague, the most serious epidemic form of plague, may be
transmitted from person to person via aerosols. Meningeal plague is less
common. Plague may be rapidly fatal if left untreated. Plague is usually
transmitted to humans by the bites of fleas that parasitize wild rodents. Plague
borne by rat fleas devastated Europe during the Middle ages, and has been
recognized in North America since the early part of this century. Since 1925 all
known cases of plague reported in the United States have been associated with
exposures to wild rodents and their fleas in the western half of the country.
Significant foci of plague also exist in Africa and Asia.
Plague in the United States appears to be geographically restricted to the
western part of the country, and it is most common in New Mexico, Aizona,
California, and colorado. American Indians are disproportionately represented
among plague cases in the United States, possibly because many reside in rural
areas in the western part of the country. Plague in the United States is most
frequently transmitted to humans from flea bites from infested rock squirrels,
California ground squirrels, prairie dogs, chipmunks, and woodrats. Occasional
cases of human plague have been reported in hunters exposed to the incidentally
infected carcasses of deer, antelope, gray fox, badger, bobcat, and coyote. These
animals rarely develop overt illness and are not thought to be part of the usual
endemic transmission cycle. Only rarely, during epidemics of human
pneumonic plague, is the infection passed directly from person to person
The occurrence of human plague is always linked to the transmission of
plague among the natural animal reservoirs, and the incidence of human plague
is a function of both the frequency of infection in the local rodent population
and the rate of exposure to the infected rodents and their fleas. Typically plague
occurs in very focal areas, involving one town or a city street, with adjacent
areas being plague free. This has been attributed to the parochial behavior of
rats, which tend to stay near one food supply for extended periods of time.
Rapid suburbanization of endemic states has increased the number of persons
living in or near active plague foci. Plague predominantly occurs in warm
tropical climates, and outbreaks tend to occur during humid warm seasons. In
the United States, the majority of cases tend to occur during the months of May
through September, with the peak incidence during the month of July. Due to
the mild winter months in some of the south-western states, however, cases can
occur during any month ofthe year.
 The most common clinical form of human plague is bubonic plague.
Bubonic plague usually presents as a febrile illness beginning 2 to 7 days
following a bite from an infected flea. During the incubation period, bacteria
proliferate in the regional lymph nodes. Patients typically present with the
sudden onset of fever, chills, weakness, and headache, followed by painful
lymphadenopathy (buboes) proximal to the infected bite, usually at the same
time or within 12 to 24 hours. Pain and tenderness often precede palpable and
visible adenitis. The most common sites are the groin and the axillae, resulting
from the inoculation of the extremities by flea bites. Pain may be so intense so
as to restrict any movement of the affected areas. Buboes are oval swellings that
may vary from 1 to 10 cm in length. The overlying skin may be elevated, or
appear stretched or erythematous. The buboes may appear smooth and egg
shaped or may feel like an irregular cluster, with surrounding edema, which
may be pitting or gelatinous in nature. Palpation typically elicits tenderness and
warmth.
In uncomplicated bubonic plague, patients are usually prostrate and
lethargic. They often exhibit restlessness and agitation; seizures are common in
children. The temperature is usually in the 38.5 to 40.0’C range. Pulse is
elevated and the blood pressure is usually in the range of 100/60 mm Hg due to
vasodilatation. The liver and spleen may be palpable and tender. There is no
characteristic skin rash; however, pustules may develop at the sites of flea bites.
With fulminant systemic disease, patients may develop purpura that may
become necrotic resulting in gangrene-the probable basis for the term black
death. A fulminant clinic days of the onset of symptoms. Nearly all fatal cases
of plague in the United States are a result of delays in seeking treatment or in
making the diagnosing treatment or in making the diagnosis.
In patients with septicemic plague, hematogenous spread of bacteria
from the bubo to the lung may result in pneumonia. Plague pneumonia is
characterized by fever, Lymphadenopathy with cough productive of purulent
sputum, chest pain, and often hemoptysis. Chest radiography may reveal a
patchy bronchopneumonia or consolidation. When septicemic plague results in
pneumonia, it is classified as secondary plague pneumonia. Primary pneumonic
plague is caused by the inhalation ofan infectious respiratory droplet, which
may have originated from another human pneumonic plague case. While this
distinction is of little therapeutic importance, the public health implications are
significant. Plague pneumonia is highly contagious by airborne transmission, it
has a short incubation period, and it can spread rapidly in close person-to-
person contact. While primary pneumonic plague is now rare, it is a potential
threat to any person who is exposed to a patient with plague who has a cough. It
may be so rapidly fatal that individuals have been reported to have been
exposed, become ill, and died in the same day. Pneumonic plague is invariably
fatal if antibiotic therapy is delayed more than 20 hours after the onset of
symptoms. Gram-negative septicemia and endotoxic shock account for many of
the early deaths from pneumonic plague.
Primary pneumonic plague has also been reported to have been
transmitted to humans by animals-most often domestic cats, in whom plague
produces a severe, often fatal infection. These animals probably develop
secondary pneumonic plague after ingesting infected wild rodents, and may
transmit the infection via infectious aerosols from the animal’s cough to their
owners or veterinary professionals caring for them.
Plague meningitis, a rare complication of bubonic plague, occurs
usually as a result of inadequately treated plague. It is characterizedby fever,
headache, meningismus, and CSF pleocytosis. As in secondary pneumonic
plague, it is a result of hematogenous spread of bacteria from a bubo. When
compared to uncomplicated bubonic plague, the mortality rate is very high.
There may be an association between buboes located in the axilla and the
development of meningitis. Occasionally, plague meningitis may appear as a
primary infection, without any antecedent lymphadenitis.
 Plague pharyngitis, a rare clinical form of plague, is thought to result
from the inhalation or ingestion of the plague bacilli. It may resemble acute
tonsillitis with inflamed anterior cervical lymph nodes. Y. Pestis may be
recovered by throat culture.

Diagnosis
The diagnosis of plague should be suspected in febrile patients who
have been exposed to rodents or other mammals in known endemic areas of the
world. Eliciting a history of recent travel in plague endemic areas of the United
States, South America, Africa, or Southeast Asia is of obvious value. Because
of the similarities between plague and the recently discovered Hantavirus
pulmonary syndrome, the diagnosis of plague may be further complicated. A
bacteriologic diagnosis may be made in many patients by smear and culture of
bubo aspirate. This may be obtained by inserting a 20-gauge needle on a 10-
ccsyringe containing 1 ml of sterile saline solution into a bubo. The solution is
then injected and aspirated several times until it is blood tinged. Drops of the
aspirate should then be placed onto slides and air dried for both Gram and
Wayson's or Giemsa stain. These will readily demonstrate the bipolar ("safety-
pin") morphology that is characteristic, but not diagnostic, of Y pestis. Pus from
a fluctuant bubo or sputum also may be smeared and treated in the same
fashion. Rapid presumptive identification of the organism can also be made
using a fluorescent antibody test. Aspirate as well as blood should be sent for
culture, which will confirm the diagnosis.

Treatment
Untreated plague may evolve into a fulminant illness complicated by
septic shock, with an estimated mortality of greater than 50%. Hospitalization,
fluid hydration, and early treatment with effective antibiotics can be lifesaving.
Streptomycin is the drug of choice for the treatment of plague. It can reduce the
case fatality rate to less than 5%. No other drug has been demonstrated to be
more efficacious or less toxic. Streptomycin should be administered
intramuscularly, in two divided doses daily, totaling 30 mg per kilogram of
body weight per day for l0 days. Most patients improve rapidly, and they
defervesce in approximately 3 days. A 10-day course of therapy is
recommended because viable bacteria have been isolated from buboes of
patients with plague during convalescence. During a 1O-day course of
streptomycin, the risk of vestibular damage and hearing loss is minimal. The
antibiotic, however, should be used cautiously during pregnancy, in the elderly,
and in patients with previously impaired hearing. In such patients, the course of
therapy may be shortened to 3 days after the patient becomes a febrile. Renal
failure with this regimen is rare; however, the serum creatinine should be
monitored, and the dose of streptomycin reduced if the creatinine concentration
rises significantly. In patients who present with renal impairment, the dosage of
streptomycin should be adjusted accordingly. Other aminoglycosides known to
be effective for treatment of plague are gentamicin and kanamycin.
Tetracycline is an alternative therapy for plague in patients who are
allergic to streptomycin or who prefer oral treatment. Tetracycline is
administered orally in a dose of 2 to 4 g per day in four divided doses for 10
days. Tetracycline is contraindicated in children and in pregnant women to
avoid staining developing teeth. It is also contraindicated in patients with renal
failure.
Intravenous chloramphenicol is the drug of choice for patients who
may have profound hypotension resulting in poor absorption of an
intramuscular injection, and in patients who have meningitis and require a drug
with good cerebrospinal fluid penetration. Chloramphenicol should be
administered intravenously with a loading dose of 25 mg per kilogram of body
weight followed by 60 mg per kilogram per day in four divided doses. After
clinical improvement, oral chloramphenicol should be continued to complete a
total course of l0 days. The dosage may be reduced to 30 mg per kilogram per
day to reduce the magnitude of bone marrow suppression.
Other antibiotics that have been used for the treatment of plague include
ampicillin, sulfonamides, and trimethoprim-sulfamethoxazole. These have not
been shown to be as effective as streptomycin. Fluoroquinolones and p-lactam
antibiotics also appear to be effective in vitro against Y pestis; however, further
investigation is still needed. Antibiotic resistance has not been seen with plague;
therefore, there is no indication for the use of multiple antibiotics in the
treatment of plague. Buboes usually resolve spontaneously. Occasionally they
may become fluctuant and require incision and drainage. Despite the
development of disseminated intravascular coagulation and purpura in severely
ill patients, neither heparin norsteroids have had any proven benefit in the
treatment of plague. Many patients who present with plague are dehydrated due
to fever, nausea, and vomiting, or they may be hypotensive. In either case they
may require vigorous fluid resuscitation with a balanced saline solution.

Prevention
As soon as a diagnosis of plague is suspected public health officials
should be notified. Patients with uncomplicated infections who are promptly
treated are not a health hazard to other persons. If pulmonary symptoms were
prominent from the beginning of the illness, a human or animal source and other
contacts of that source must be rapidly identified. Those patients with cough or
other signs of pneumonic plague must be placed in respiratory isolation for at
least a period of48 hours after the start of antibiotic therapy, or until sputum
cultures are negative. The close (within 2 m) contacts of an index case of plague
must be identified and evaluated for prophylaxis. Reliable contacts can be
instructed to take their temperatures and to seek medical attention immediately
should they develop a fever or any respiratory symptoms, including a sore
throat. Antibiotic prophylaxis may be given to heavy contacts. Tetracycline is
an excellent drug for the prophylaxis of plague in patients for whom it is not
contraindicated.
An inactivated plague vaccine is available for travelers to endemic
areas and for individuals who must live or work in close contact with wild
rodents. It is recommended for laboratory workers performing research with Y
pestis or with frequent exposures to clinical or field- collected materials
possibly infected with plague. Persons in wilderness locations with limited
access to medical care, such as park and forest rangers, and fish and wildlife
workers, may be candidates for vaccine. Similarly, Peace Corps volunteers,
journalists, photographers, disaster workers, and others who may have long-
term potential exposures in endemic areas with limited access to health care
should be considered candidates for plague vaccine. The vaccine is initially
administered as a primary series of two doses with a recommended 1- to 2
month interval between doses. Booster injections are given every 6 months as
long as the exposure continues.
The control of plague by local health departments requires the
knowledge of the epidemiology of the infected animals, the vectors of
transmission, and the potential sources of human contact. Control measures
usually involve the use of insecticides to control fleas, trapping of animals, and
the education of people to avoid contact with certain animals. Persons living in
endemic areas should provide themselves with personal protection such as
living in rat-proof houses, wearing shoes and garments that cover the legs, and
applying insecticides. Sick animals, especially cats, should not be handled.
Dead animals should not be skinned by hunters with ungloved hands.
SELECTED READING
Bonacorsi SP, Scavizzi MR, Guiyoule A, et al. Assessment of a
fluoroquinolone, three beta lactams, two aminoglycosides and a cycline in the
treatment of murine Yersinia pestis infection. Antimicrob Agents chemother 1
994;38(3):48 l-486.
Butler T. Yersinia irfections: centennial of the discovery of the plague bacillus.
CIin Infect Dis 1994’19:655-663.
Craven RB, Barnes AM. Plague and tularemia. Infect Dis CIin North Am 1991
;5( I ): 165-l 75.
Craven RB, Maupin GO, Beard ML, et al. Reported cases of human plague in
the United States, 1970-1991. J Med entomol 1993;30(4):7 58-7 61. Doll J, Fink
TM, et al. Plague. MMHR 1992;41,(42):787-790.
Morris JT, McAllister CK. Bubonic plaglue. South Med J 1992;85(3): 326-327.
Opulski A, MacNeil E, et al. Pneumonic plague-Arizona, 1992. MMWR
1992;41(40):731-739.
Weinberg AN. Respiratory infections transmitted by animals. Infect Dis clin
North Am 1991 ;5(3):651-661.
Werner SB, Murry R, et al. Human plaglue. MMIIR 1994;43(13):242-246.

Tetanus (9.1.7)
Tetanus is a toxin-mediated disease first described by the ancient
Egyptians with subsequent graphic illustrations over the following centuries. In
the early l9th century, the use of curare, coupled with artificial ventilation, was
postulated as a treatment for tetanus. Howein the 1950s, with the development
of handheld manual ventilators for polio, did this mode of therapy become
available.
There are fewer than 100 cases of tetanus yearly in the united States,
the majority in the elderly. Worldwide, over a million cases per year are
recorded; 50% of these occur in neonates, a reflection of inadequate maternal
immunization and unsterile obstetrical practices, with an estimated mortality
rate of 90%.
When introduced into a wound under appropriate anaerobic
conditions, Clostridium tetani, a ubiquitous, gram-positive, anaerobic bacillus,
forms a highly stable spore. The spores germinate and elaborate two toxins: (l)
tetanolysin, of unclear significance; and (2) Tetanospamin, the prime etiologic
agent of tetanus.
Tetanospasmin is a 151-kd polypeptide that requires cleavage for
activation. The heavy chain facilitates attachment and neurocellular
internalization, whereas the light chain inhibits neurotransmitter release.
Initially, alpha motor neurons are involved. The toxin is then transferred to the
neurons and the extracellular space of the central nervous system via retrograde
transport and diffirsion. Once in the CNS, the toxin affects presynaptic T-
aminobutyric acid (GABA)ergic and postsynaptic glycinergic neurons,
preventing the release of their inhibitory neurotransmitters. The resulting
disinhibition permits uncontrolled agonist and antagonist muscular contraction
and spasm characteristic of generalized tetanus. In addition to its local
neuromuscular actions and CNS disturbance, tetanospasmin also involves the
autonomic nervous system, clinically manifested as a labile, sympathetic
overflow, not unlike a pheochromocytoma. An important consideration during
management is that once internalized in a neuron, the toxin is no longer
accessible to antitoxin, resulting in prolonged recovery until new presynaptic
receptors are formed.
The diagnosis of tetanus is clinical; cultures are of minimal value.
Up to 2lo/o of patients have no obvious demonstrable wound. There are
essentially four variants oftetanus, a reflection ofthe groups ofneurons involved:
(1)Generalize4 (2) cephalic, (3) neonatal, and (4) local tetanus. The shorter the
incubation period and period of onset, the worse the prognosis. The portal of
entry is also an important prognostic indicator; burns, umbilical stumps, surgical
procedures, open fractures, IM injections, and septic abortions all potentiate the
likelihood of severe disease
 Trismus, “lock jaw,” is the most common presenting symptom of
generalized tetanus. Also common is risussardonicus, or “sneering grin.” The
most dramatic presentation, however, is generalized muscular contractions with
opisthotonos and maintenance of consciousness. The diffirse spasms result in
severe pain. Diaphragmatic and vocal cord involvement may result in
respiratory compromise. Progression of the disease for up to 2 weeks followed
by a prolonged recovery period may occur.
Cephalic tetanus usually involves the lower cranial nerves. A Bell’s
palsy is often the first presenting complaint. Cephalic tetanus has been linked to
otitismedia/externa and has occurred in fully immunized individuals.
Neonatal tetanus generally results from an infected umbilical stump.
Nonimmunized mothers cannot confer passive immunity to their neonates.
Newborns present I to 2 weeks after birth with a weak sucking reflex rapidly
progressing to generalized spasms. A high mortality is associated with severe
autonomic dysfunction.
Localized tetanus is characterized by rigidity within the vicinity of
the initial wound. Additionally, there is muscular weakness and often enhanced
deep tendon reflexes (DTRs). Symptoms usually resolve with appropriate
treatment, but progression to generalized tetanus may occur.
 Strychnine poisoning involves postsynaptic glycinergic neurons and
is the only close mimicker of generalized tetanus. Dystonic reactions,
meningitis, peritonsillar and retropharyngeal abscesses, seizures, hypocalcemia
and “stiff-man syndrome,” a consequence of antibodies to ward GABAergic
neurons, should be considered in the differential diagnosis.
Therapy begins with early and appropriate airway maintenance.
Patients may require orotracheal intubation or tracheostomy in the event of
vocal cord and/or diaphragmatic spasms. Unregulated muscular contractions
should be controlled with benzodiazepines as well asparalytics, if needed. The
liberal administration of pain medication is warranted. Human tetanus
immunoglobulin (HTIG) (500 U IM) and either tetanus-diphtheria toxoid (Td),
diphtheria-pertussis-tetanus (DPT), or tetanus toxoid (TT) at a separate site
(deltoid muscle), should be given. The use of antibiotics is controversial but
may serve to reduce the overall toxic burden by eradicating clostridium tetani.
Control of autonomic dysfunction is essential; the use of labetolol, clonidine,
morphine, MgSO4,or epidural blockade has been suggested.
Complications associated with tetanus include hypoxic organ
injury, pneumonias, autonomic lability, rhabdomyolysis, spine and long bone
fractures, gastrointestinal stress ulcerations, deep venous thrombosis (DVT) and
pulmonary emboli, and decubitus ulcers.
There is no natural immunity to tetanus and infection does not
confer immunity.
Adsorbed toxoid should be given during infancy; three initial doses
of DPT I to 2 months apart followed by a booster at age I and just prior to
entering grammar school. Children younger than 7 receive DPT unless allergic
to the pertussis component.
Following initial immunization, Td should be administered every 10
years. The elderly with unclear immunization history should receive a Td and
two subsequent boosters, the first I to 2 months and the second 6 to 12 months
following the primary Td.
Individuals with complete immunization history should be
reimmunized if the wound is tetanus prone (penetration wounds, those with dirt
or saliva, burns, frostbite injuries, wounds with devitalized tissue) and the last
booster was greater than 5 years.
Individuals with a history of incomplete immunization or those with
no recall should receive a Td and HTIG (250u IM) for a tetanus-prone wound
followed by complete immunization. For a clean wound, passive immunization
is not required.
In general, reactions to tetanus immunization are mild and include
localized swelling, erythema, and pain. Rarely, a hypersensitivity reaction may
occur.
Along with appropriate immunization, proper wound management is
necessary to reduce the risk of tetanus and includes thorough wound irrigation
and the debridement of devitalized tissue.

SELECTED READING
Bleck TP Tetanus: pathophysiology, management, and prophylaxis. Dumon
1991 ;37 (9) :547 403.
Giangrasso I Smith RK. Misuse of tetanus immunoprophylaxis in woundcarc.
Ann Emerg Med 1985;14(6):573-579.
Kefer MP. Tetanus. Am J Emerg Med 1992;10(5):445448
La Force M, et al. Tetanus in the United States: epidemiologic and clinical
features N emerg J Med 1969;280(11):569-574.
Peebles TC, Levine L, Eldred MC, Edsall G. Tetanus-toxoid emergency bosters.
N Engl J Med 1969;280(11):575-581.
Sutton DN, Tremlett MR, Woodcock TE, Nielsen MS. Management of
autonomic dysfunction in severe tetanus: the use ofmagnesium sulphate and
clonodine. Intensive Care Med 1990;16(2):75-80.

Toxic Shock Syndrome (9.1.8)

In the late 1970s Todd et al. First described toxic shock syndrome
(TSS) as a distinct clinical entity characteized by profound hypotension, fever,
multiorgan involvement, and a diffuse erythroderma that subsequently
desquamates. TSS gained public notoriety in the early 1980s due to an
unsettling number of cases noted in menstruating women, epidemiologically
related to the use of highly absorbent tampons. With the withdrawal from the
market of these tampons and heightened awareness of the occurrence of TSS,
and most likely other concomitant factors, the number of catamenial-related
cases of TSS has been greatly reduced, with non-menses-related cases now
constituting the greater fraction.
 The development of TSS requires colonization or infection by a
toxigenic strain of Staphylococcus aureus (approximately 20%) elaborating the
exotoxin toxic shock syndrome toxin-l (TSST-l), a22-to 24-kd protein. Greater
than 90% of the S. Aureus isolates from patients with menstrual related TSS
produce TSSTI, whereas approximately 60% of isolates from non-menstrual
derived cases elaborateTSSTl. The effects ofTSSTl are protean and it is likely
that the manifestation of TSS is related both to thinduction of other mediators
such as interleukin-l and tumor necrosis factor. In addition, host susceptibility is
related to a deficiency in protective antibodies directed toward TSST-1. An
anaerobic, neutral pH, magnesium-deficient microenvironment is the ideal
condition for the elaboration of TSST1 by toxigenic S. qureus.
Toxic shock syndrome is characterized by hyperphrexia, a fine,
diffuse, erythroderma that spreads centrifugally and desquamates in I to 2 weeks
(especially palms and soles), nausea, vomiting, diarrhea, cephalgia, pharyngitis,
painful myalgias. And profound hypotension.it is a specific clinical diagnosis
that must meet the CDC’s strict case definition criteria (Table 9-7). Renal
involvement is common and may be secondary to prerenal failure, acute tubular
necrosis, or rhabdomyolysis, resulting in elevated BUN, creatinine, metabolic
acidosis, and diminished urine output. Diarrhea, preceded by vomiting, is often
seen as is elevation in hepatic transaminases, most often the y-glutamyl
transpeptidase (GGTP). Adult respiratory distress syndrome (ARDS) may
occur, and pleural effirsions are commonly present in severe clases. Muscle
breakdown may result in gross elevation of creatine kinase with resultant
myoglobinuria.
Central nervous system encephalopathy may range from a mild
headache to severe disorientation and seizures. Dermatologically, the classical
rash associated with TSS is a scarlatiniform exanthem that is nonpruritic,
blanching, and generally begins on the lower torso, eventually spreading and
involving the extremities. Conjunctival and tympanic membrane hyperemia is
often noted along with erythematous mucous membranes and a “strawberry
tongue.” Mild anemia may be present along with other hematologic
abnormalities including microangiopathic hemolysis, leukocytosis, eosinophilia,
thrombocytopenia, and disseminated intravascular coagulation. A pelvic
examination is essential in any woman with TSS for the removal of a tampon or
other foreign object. The vaginal walls are usually erythematous and a
"strawberry cervix" may be appreciated. Menstrual blood and a malodorous
discharge may be present, with gram stain of the discharge revealing gram
positivecocci in clusters.
 The differential diagnosis of TSS includes staphylococcal-scalded
skin syndrome, Kawasaki disease, scarlet fever, Rocky Mountain spotted fever,
leptospirosis, erythema multiforme major, typhus, Lyme disease,
menigococcemia, staphylococcal food poisoning, gram-negative urosepsis, and
toxic streptococcal syndrome. Toxic streptococcal syndrome warrants special
mention as it is a toxin-related condition that closely mimics staphylococcal
TSS. Streptococcal pyrogenic exotoxin A, synthesized by Streptococcus
pyogenes, a group A streptococcus, is thought to be the etiologic agent
responsible for the hypotension, multisystem failure, hypocalcemia, and
thrombocytopenia observed in toxic streptococcal syndrome, similar to
staphylococcal TSS. Skin and soft tissue portals of entry as well as respiratory
and genitourinary sources have been identified as potential sites of infection by
toxigenic strains of S. Pyogenes.
Therapy begins with aggressive management of the shock state
with the infusion of intravenous crystalloid solution (normal saline or lactated
Ringer's). In the presence of refractory hypotension, peripheral pressors are
employed. A concerted effort to identifl, and remove the source of the infection
(e.g., tampon, surgical wound infection, soft tissue abscess) is essential. The use
of antistaphylococcal antibiotics is controversial since this is primarily a toxin-
mediated condition..
 However, antimicrobial agents may serve to eradicate toxin-
producing staphylococci, thereby lowering the overall toxic burden. The use of
corticosteroids is also controversial and not well established. Estrogens may
improve catamenial-related TSS by the cessation of menses. Patients with TSS
have a low anti-TSSTI anti

TABLE 9-7. Centers for Disease Control case definition of toxic shock
syndrome
 BUN, serum urea nitrogen; WBC, white blood cells; hpf, high-power
field.
Body titer and therefore may benefit from the passive immunization rendered
by the administration of immunoglobulins.

SELECTED READING
Brady WJ, DeBehnke D, Crosby DL. Dermatological emergencies.
Am J emerg Med 1994;1 2(2) :217 -237 .
Freedman JD, Beer DJ. Expanding perspectives on the toxic shock
syndrome. Adv Intern Med 1991;36:363-397.
Reingold AL. Toxic shock syndrome: an update. Am J Obstet
Gynecol 1991 ;r 65 (4): 123 6-1239.
Resnick SD. Staphylococcal toxic-mediated syndromes in children.
Senindermatol 1992;1 1(1): I 1-18.
Strausbaugh LJ. Toxic shock syndrome: Are you recognizing its
changing presentations? Postgrad Med 1993 ;94(6): 107-118.
Spirochetes (9.1.9)
Lyme Disease (9.1.9.1)
Lyme disease was first observed in 1975 (as Lyme arthritis) due
to an unusual epidemic of arthritis occurring in a group of children in the town
of Lyme, Connecticut. The arthritis was often preceded by a distinctive skin
rash, erythema chronicum migrans (ECM). The correlation between the bite of a
tick and ECM was already known in Europe. The multisystem nature of the
illness was soon assesse4 and it was more correctly rename lyme disease. Lyme
disease, the entity as we know it today, is a complex immune-mediated
multisystem disorder that may affect patients of any age or sex. The disease is
caused by a spirochelte Borrelia burgdorferi, which is transmitted to humans via
a tick bite most commonly from the species lxodes (the deer tick). Lyme disease
is generally a benign disorder that is frequently overdiagnosed and overtreated.
The disease has attracted great media attention, and although it may be serious,
inappropriate public anxiety has developed.
Epidemiology.
Lyme disease is particularly prevalent in North America and
Europe, and has also been reported in South america, Asia, and Africa. In the
United States, B. Burgdorferi infection has been reported in 46 states, and now
ranks first among the arthropod-transmitted zoonoses. Lyme borreliosis is
secondary to infection with a gram-negative microaerophilic bacterium
belonging to the order Spirochetales. Ixodidae ticks may infest domestic
mammals,large, medium-sized, and small wild mammals, reptiles, and birds.
They are smaller than common dog and wood ticks. The peak incidence of
Lyme disease appears to be at the end of spring and early summer; however late
manifestations may occur throughout the year. this coincides with the peak
activity of ticks. Humans may be exposed when frequenLyme disease is
endemic. Typically, Lyme disease occurs in areas where deer populations are
increasing. This usually parallels suburban expansion into areas that were
previously farmland.

Clinical Findings
Lyme disease can be divided into three groups: (l) early localized
infection, (2) early disseminated infection, and (3) late Lyme disease. Early
disease may begin within several hours of infection, or up to several weeks or
months later. Early localized infection is characterized by erythema chronicum
migrans (ECM) without any other manifestations. Erythema chronicum migrans
occurs in about half of the cases of Lyme disease. It is an expanding
erythematous rash usually with a well-demarcated border. The primary lesion
occurs at the site of the tick bite, with erythema expanding outward. ECM is
often raised, is usually not painful, and may become indurated, warm, and itchy.
It is usually larger than 5 cm in size, and may expand within hours. ECM may
develop within hours or up to 30 days after a tick bite, but rarely beyond this
time. ECM may appear only occasionally during the day, most frequently in the
morning. As ECM only causes moderate discomfort, it may go unnoticed by the
patient. If left untreated the rash resolves, without scarring, several days to
several weeks after onset.
Early disseminated disease is characterized by ECM-associated
general systemic manifestations similar to other infective diseases. Some
patients may have minor constitutional symptoms such as headache, low-grade
fever, and myalgias in addition to ECM. Other patients may appear quite toxic
with high fever, chills, severe headache, stiff neck, malaise, arthralgias, and
nonproductive cough. Patients may also present with hematuria and edema of
the testes. Secondary skin lesions may cover the entire body. Signs of hepatitis
may be seen in 15% of the patients with early disseminated disease. Mild to
moderate elevation of the transaminases resolves over several weeks.
Lyme carditis occurs in l0% to l5% of patients with early
disseminated Lyme disease in the United States. In europe, the prevalence of
Lyme carditis is much lower. Similarly, while chronic cardiomyopathy
secondary to lyme carditis has been reported in Europe, there have been no such
cases reported in the United States. The different clinical manifestations in
Europe and the United states are thought to be due to strain heterogenicity of
B.burgdorferi. Lyme carditis is characterized by a mild myocarditis usually
associated with variable degrees of atrioventricular node conduction
abnormalities. Approximately 50% of the affected patients develop complete
heart block, which is always reversible. Lyme carditis has not been shown to
affect heart valves or cause distal conduction system disease .
Neurologic manifestations can occur during any phase of Lyme
disease and frequently present the most significant diagnostic problem. In early
disseminated Lyme disease, patients can develop disease of the peripheral
nervous system, meningitis, or encephalitis. Symptoms are usually of acute
onset. Cranial neuropathies are common. Most common are Bell’s palsies and
ophthalmoplegia with diplopia. The symptoms may be bilateral or unilateral,
may wax and wane, and present alone or associated with other manifestations of
Lyme disease. Headache, fever, and stiffneck are common complaints in early
disseminated Lyme disease. A significant percentage of these patients are found
to have Lyme meningitis. Some patients may present with signs and symptoms
more suggestive of a meningoencephalitis, with acute cognitive difficulties and
emotional lability. If not treated, the neurologic manifestations of Lyme disease
may last for months, but they usually will resolve even without antibiotic
therapy.
Lyme arthritis is usually a late manifestation of Lyme disease, but
many patients develop arthralgias early in the illness. Some patients may
develop frank arthritis within days of the onset of the illness. Lyme arthritis may
also present as migratory musculoskeletal pain similar to that in patients with
fibromyalgia. Articular manifestations are more common in the United States,
where 60% of the cases develop arthritis. Lyme arthritis is an asymmetric,
oligoarticular arthritis, fypically involving large joints. Involved joints are
painful, warm, erythematous, edematous, and are functionally impaired. The
arthritis tends to occur in intermittent attacks that may last from several days to
several weeks. Approximately l0% of the cases develop a chronic arthritis that
may last 2 to 3 years after a period of intermittence. The knees are the most
common affected site for chronic arthritis. Large joint effrrsions are common in
the knees. The arthritis is usually less painful than that of rheumatoid arthritis,
and typically morning rigidity is absent. Lyme arthritis frequently resolves
without treatment and with little or no joint dysfunction. A small group of
patients may develop chronic unremitting erosive arthritis that often fails to
respond to antibiotic therapy. Although antibiotic therapy clearly affects the
natural history of Lyme arthritis, not all patients immediately respond and it
may take several months for the symptoms to resolve even after successful
antibiotic treatment.
Late Lyme disease can occasionally affect the central nervous
system. Patients may have symptoms of low-grade encephalopathy such as
forgetfulness, irritability, change in personality, drowsiness, fatigue syndromes,
and in some cases upper motor neuron disease. These patients almost always
have earlier manifestations of the disease such as ECM, cranial nerve palsies, or
oligoarthritis.
Eye involvement in Lyme disease is rare, but can occur at any stage
ofthe illness. The spirochethe eye early and remains dormant, accounting for
both early and late findings. Approximately l0% of the patients with early Lyme
disease develop conjunctivitis. Several months later this may be followed by a
keratitis, iridocyclitis vasculitis ofthe retina, choroiditis, and opticneurosis.
Long-term inflammation can lead to loss of eyesight. Management includes the
use of intravenous antibiotics.

Diagnosis
The diagnosis of Lyme disease relies on clinical and epidemiologic
criteria, with the support of serologic and histologic investigations. There is no
single highly sensitive and highly specific marker for Lyme disease, but under
the appropriate clinical conditions, standard immunologic assays are very
reliable. Anti-B. Burgdorferi antibodies of the immunoglobulin M (igM) class
are detectable as early as 2 weeks after the onset of ECM, but may take as long
as up to 2 months. They peak at 4 to 6 weeks and are usually no longer
detectable after 8 weeks. Both immunofluorescent assays (IFA) and enzyme-
linked immunosorbent assays (ELISA) are available. ELISA tests are more
sensitive and specific, with a sensitivity in early Lyme disease of 40% to 60%
that increases to 95% in late Lyme disease.
While serologic testing is extremely useful in diagnosing Lyme
disease, it is subject to inherent limitations. Testing should not be used as a
screening tool, and should only be performed when there is significant
likelihood that the disease is present. Both false-negative and more commonly
false-positive results occur. Therefore, laboratory testing must be interpreted
within context of the patient’s clinical picture. In early Lyme disease
serodiagnosis may have low sensitivity, and clinical diagnosis based on
symptoms, history of exposure, and associated ECM or rising convalescent
titers 4 to 6 weeks later is more helpful. The assay may be reactive to antibodies
of other spirochetes, resulting in a false-positive Lyme assay. In addition, there
may be a background seropositivity rate, ranging from5%to25%, in populations
resid-B. burgdorferi.. In late Lyme disease it is important to determine whether
signs and symptoms fit the clinical syndrome. In such individuals, serologic
testing can be used to establish or exclude the diagnosis. Serologic testing is
much more reliable in late Lyme disease than in the early stages of disease.
 In patients with Lyme meningitis, the CSF is almost universally
abnormal. CSF abnormalities usually appear 3 to 4 weeks after inoculation and
may persist for months. The CSF pleocytosis seen in Lyme meningitis is
dominated by lymphocytes and monocytes. Because of this, lyme meningitis is
often confused with viral meningitis. An elevated CSF protein is common in
patients with Lyme meningitis. Antibodies to B. burgdorferi can be found in the
CSF of infected individuals.
Treatment
Therapy of Lyme disease is tailored to the individual patient (Table 9-
8). In general, most patients with early lyrne disease are treated with oral
antibiotics. Patients with carditis, meningitis, and necrologic manifestations are
usually treated with intravenous antibiotics. Lyme arthritis and late or chronic
Lyme disease can be treated either orally or with intravenous antibiotics;
however, oral therapy may not be sufficient to sterilize a possible occult central
nervous system focus. Patients who fail oral therapy should be offered a course
of parenteral antibiotics, but only after a period of observation of 2 to 4 months,
as lyme arthritis may resolve gradually. The severity of Lyme disease at its
outset to some extent predicts the likelihood of the development of late
manifestations. Treatment recommendations offer arange of therapy duration,
anticipating that the initially sicker individuals will require longer periods of
treatment. There are no studies that validate giving several months of therapy in
Lyme disease.
The treatment of Lyme disease in pregnancy is an area of special
concern. Transplacental transmission of B. Burgdorferi has been reported in the
first trimester. There have been several documented cases ofneonatal death as a
result of untreated or inadequately treated Lyme disease during pregnancy.
Pregnant women with early Lyme disease should be treated with oral
antibiotics, and those
With late disease should be treated with intravenous anntibiotics. Tetracycline
products should be avoided in pregnancy.
Antibiotic prophylaxis following asymptomatic tick bites in endemic
areas is generally not recommended. Individuals with asymptomatic deer-tick
bites are at low risk for developing infection. In pregnancy, however,
prophylactic treatment with a l0- to 14-day course of oral antibiotics is probably
warranted based on the potential adverse effects on the fetus.
In most instances Lyme disease can easily be managed in the outpatient
setting. Coordination with primary care providers and home nursing providers
can even allow for the administration of intravenous antibiotics without
admission to the hospital. Patients with Lyme carditis and meningitis should be
admitted to the hospital and monitored.
Prevention
Avoidance of the tick habitat would be the best prevention of Lyme
disease. With the continued expansion of suburbs into rural woodlands,
however, the likelihood of exposure to a deer tick is increased. Pets such as dog
and cats can bring the tick into the home. Wooded patches of landscape that can
support deer increase the risk, and increased use of woodlands for recreation
increase the exposure.
In high-risk areas for Lyme disease, individuals should take measures to
protect themselves from tick bites.
TABLE 9-8. Therapy of Lyme disease
aErythromycin is less effective than the other drugs listed, and should be
reserved for children under 9 years of age with documented penicillin allergy.
These measures include wearing light-colored clothing to make crawling ticks
visible, tucking pant cuffs into socks to prevent ticks from gaining access to
exposed skin, and using repellents. Permethrin repellents can be applied to the
clothes, which will enhance their protection, and repellents containing DEET
(1{N-diethyl-m-tolumide) can be applied to exposed skin areas. Daily
inspections for attached ticks should be routine in endemic areas. Attached ticks
should be removed immediately with a fine forceps. The transmission of B.
Burgdorferi increases with time. The maximum efficiency of transmission by
the infected tick does not occur until after being attached for 48 hours.
SELECTED READING
Couch P, Johnson CE. Prevention of Lyme disease. Am J Hosp Pharm
1992;49:1164-1173.
Fish D. Environmental risk and prevention of Lyme disease. Am J Med
1995;98(suppl 4.A):s2-s9.
Ilowite NT. Muscle, reticuloendothelial, and late skin manifestations of lyme
disease. Am J Med 1995;98(suppl 4A):s63-s69.
Jantausch BA. Lyme disease, Rocky Mountain spotted fever, ehrlichiosis:
emerging and established challenges for the clinician. Ann Allerg’ 1994’.73:4-
11
Lastavica CC, Wilson ML, Bernardi VP, et al. Rapid emergence of a focal
epidemic of Lyme disease in coastal Massachusetts. N Ergl Med
1989;320(3):133-137.
Lesser RL. Ocular manifestations of Lyme disease. Am J Med 1995; 98(suppl
4,A’):s60-s62.
Meyers SA, Sexton DJ. Dermatologic manifestations of artkopod-borne
diseases. Infect Dis Clin NorthAm 1994;8(3):689-712.
Olsen LJ, Emmanuel OC, Clements IP. Cardiac involvement in Lyme disease:
manifestations and management. Mayo Clin Proc 1986:61:745-749.
PachnerAR. Early disseminated Lyme disease: Lyme meningitis . Am J Med
1995;98(suppl 4,A.):s30-s42.
Scarpa C, Trevisan G, Stinco G. Lyme borreliosis. Dermatol CIin 1994
12(4):669-68s.
Schoen RT. Identification of Lyme disease. Rheum Dis Clin North Am
1994;20(2):361-369.
Sigal LH. Lyme disease: testing and treatment. Rheum Dis Clin North Am
1993;19(1):79-93.
Sigal LH. Management of Lyme disease refractory to antibiotic therapy. Rheum
Dis Clin North Am 1995;21 (l):217-230.
Spach DH, Liles WC, et al. Tick borne diseases in the United States. N Engl J
Med 1993 ;329 (1 3):936-947.
Zemel LS. L),rne disease-a pediatric perspective. J Rheumatol 1992;19(suppl
34):sl-s13.

Leptospirosis
Leptospirosis is a disease caused by a tightly coiled spirochette
Leptospira interrogans, with reservoirs of infection in rodents, skunks, foxes,
domestic livestock, and dogs. It is transmitted to humans when they come in
contact with infected tissues, fluids such as urine, or contaminated waters.
Transmission may occur through cuts, mucous membranes, and abraded skin.
Leptospirosis is an occupationalhazzard of sanitation workers and farmers.
Leptospirohouse workers and fresh water fishing workers, and recently
nonvocational cases have been reported in those engaged in recreational
activities involving contact with inland natural waterways. This is probably due
to farmlands draining into these bodies of water.
In the United States leptospirosis is uncommon, with approximately 1
50 cases reported annually. Leptospirosis is more common in tropical and
subtropical climates. The peak number of cases occurs in the summer months,
especially during periods of high rainfall. Leptospires are extremely infectious.
The mechanism by which leptospirosis causes illness in unclear. It may be a
combination ofboth toxic factor produced by the organism as well as damage
secondary to an immunologic mechanism. Many animals who carry the illness
may exhibit prolonged urinary shedding of the organism without any clinical
illness.
Clinical Findings
The diagnosis of leptospirosis should be suspected in patients who
presents with fever, headache, severe myalgias, nausea, vomiting, and
conjunctival suffirsion. Very commonly patients with leptospirosis are
misdiagnosed with aseptic meningitis, which may occur in up to l8% of the
patients with leptospirosis. After exposure, the incubation period ranges from 2
to 20 days, with most infections occurring in the 7 – to 14-day range. One-half
of the patients present with abrupt onset of symptoms over a 1- to 2-hour perio4
which persist for 4 to 9 days. Some 60% of the patients have accompanying
nausea and vomiting. Fever is usually greater than 102oF. Headache is usually
severe and retrobulbar or occipital in nature. Patients may also may complain of
sore throat, lymphadenopathy, and rash,leading to the misdiagnosis of a viral
illness. Rarely patients may present with jaundice and gastrointestinal
hemorrhage. On physical examination, up to 25% of the patients have
hepatomegaly. Splenomegaly is a less common finding. Muscle pain and
tenderness are classic features of leptospirosis. The illness may mimic
pancreatitis and cholecystitis as acute dilatation of the gallbladder may occur
with leptospirosis. Pulmonary involvement in leptospiral infection is common
and usually mild, presenting with cough. Rarely, however, it may be a
predominant symptom and the etiology for respiratory failure. Occasionally,
patients may present with a change in mental status, encephalitis, and cranial
nerve palsies. Presenting symptoms may range from a mild flu-like illness to
Weil’s syndrome, characterized by profound jaundice, mental status changes,
hemorrhage, purpura or petechiae, renal failure, and cardiovascular collapse.
The first sign of Weil’s syndrome is usually jaundice, occurring between the
fifth and the ninth day. Often renal insufficiency accompanies the jaundice.
Petechiae and purpura initially appear on mucosal surfaces. Most individuals
rapidly recover; however there is a l5% mortality with severe leptospirosis.
 Leptospirosis usually lasts from 4 to 9 days, and ifleftuntreated, most
cases are nonfatal and self-limited. In about 15% of the patients, the disease
persists and may last up to 7 weeks. Overall mortality from leptospirosis varies
from 5% to l0%; however, it is age dependent, with30% mortality over age 60.
Jaundiced patients have a l5% mortality

Diagnosis
The key to making a diagnosis of leptospirosis is to have a high index
of suspicion in patients who present with symptoms of fever, headache, and
myalgias, and who have a history of potential exposure to animals, sewage, or
natural bodies of fresh water. An early symptom in 80% of leptospirosis
patients is an abnormal urinalysis. Most commonly, microscopic hematuria,
piyuria, and proteinuria are also found. Leukocyte counts are generally less than
15,000 per cubic millimeter, but have been reported as high as 50,000 per cubic
millimeter, with a neutrophilic predominance. Anemia is uncommon.
Thrombocytopenia and elevated prothrombin time have been seen in some cases
of leptospirosis, but this is not responsible for the hemorrhagic diathesis seen in
patients with Weil’s syndrome.
Liver function tests are frequently abnormal, with elevations of up to
20 times normal being reported in some patients. The direct bilirubin may rise
in severe leptospirosis; however, it is usually below 20 mg perdeciliter. Up to
25% of the patients may experience a rise in blood urea nitrogen. The creatinine
kinase is frequently elevated in leptospirosis.
Cerebrospinal fluid examination may be abnormal in up to 90% of
the patients. The total cell count is usually below 500 per cubic millimeter with
a neutrophilic predominance. The glucose concentration is usually normal and
protein usually ranges between 50 and 110 mg perdeciliter. The chest x-ray may
appear abnormal in up to 25% of the patients, with the most common
abnormality being a patchy bronchopneumonia, predominantly in the lower
lobes. ECG may reveal low voltage and bradycardia or nonspecific ST changes
in up to 40% of the patients.
The diagnosis can be confirmed by blood culture during the first
week of the illness, and by urine culture thereafter. Leprospires may be excreted
in the urine for a prolonged time even after clinical illness has resolved. An
ELISA is available to detect IgM antibodies to leptospirosis in human serum
and saliva, which is more rapid than culture.

Treatment
The administration of tetracycline or doxycycline is effective in
shorteningin the first 2 to 4 days of the illness. If given later, their effectiveness
is unknown. The effect of antibiotic treat-ment on mortality is also unknown.
Doxycycline prevents the urinary shedding of bacteria. The mainstay of
treatment, however, is the close management of the renal, hepatic, hematologic,
pulmonary, and central nervous system complications of leptospirosis.
Young, otherwise healthy, non-toxic-appearing patients can be
managed with outpatient therapy. Elderly patients or patients with other
underlying illness need close observation because of the sharp increase in
mortality in these groups.

Prevention
While effective vaccines for leptospirosis exist for animals, there is
no such vaccine for humans. In high-risk groups, doxycycline, 100 mg once a
week, prevents leptospirosis for periods up to 3 weeks. The efficacy for longer
periods is unknown.

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Alani FS, Mahoney LP, Ormerod Lp, et al. Leptospirosis presenting as atypical
pneumonia, respiratory failure and pyogenic mentngitis. J Infect 1993:27:281-
283.
Da_Silva MD, Dias Carmargo E,yaz AJ, Batista L. Immunodiagnostics of
human leptospirosis using salla. Trans R Soc Trop Ued med hyg 1992;86:560-
561.
Farr RW. Leptospirosis. Clin Infect Dis 1995;21(1):l-6.
Friedlander JS, Warrell DA. The Jarisch-Herxheimer reaction in leptospirosis:
possible pathogenesis and review. Rev lnfect dis 207-210.
Health SE Johnson R. Leptospirosis. J Am Vet Med assoc 1994;205(11): L 5l8-
1523.
O’Neil KM, Rickman LS, Lazarus AA. Pulmonary manifestations of
leptospirosis. Rev Infect Dis 1991;13:705-709.
Overstreet DS, Bowen MG, Hawkins SC, Roy TM. The respiratory
complications of leptospirosis. Kentuclq med assoc J 1991;99:270_213.
Shaked Y, Shpilberg O, Samra D, Samra y Leptospirosis in pregnancy and its
effect on the fetus: case report and review. Clin Infect dis 1993;17:241:243.
Teglia OF, Battagliotti C, Villavicencio RL, Cunha BA. Leptospiral pneumonia.
Chest 1995; 108(3):874-875.
Torre D, Giola M, Martegani R, et al Aseptic meningitis causedby Leptospiru
australis. Eur J Clin Microbiol Infect Dis 1994;13(6):496497
Syphilis (9.1.9.2)
Syphilis, a disease caused by the organism Treponema
pallidum, is characterized,by episodes of active and clinically latent disease.
The disease is almost always contracted sexually; however, it can also be
contracted congenitally by transplacental inoculation. There have been
occasional reports of unsuspecting health care workers contracting the illness
after examining a lesion. Congenital syphilis is the oldest recognized congenital
infection. Syphilis may have alarge variety of presentations and at one time was
termed the “great imitator.” If untreated” it may progress through primary,
secondary, and tertiary stages. These episodes may overlap and exhibit a
variable course. Initial lesions may spontaneously heal, and the disease may
remain clinically latent for a long period of time. In approximately 30% of the
untreated patients, disease ofthe heart, central nervous system, or other organs
eventually develops. While syphilis is less cofirmon now than it had been in the
prepenicillin era, over the past 10 years the disease has been on the rise.
Epidemioiogy / Pathophysioiogy
Both the natural history and pathogenesis of syphilis are complicated
and incompletely understood. T. Pallidum, a thin helical spirochete, was first
discovered to be the causative agent in syphilis in 1905. The organism is too
thin to be visualizedby Gram stain, but can be visualizedby dark-field
microscopy, silver stains, or fluorescent antibody methods. It has not been
possible to culture T pallidum in vitro.
Syphilis is most prevalent in larger cities, and in young, sexually active
individuals. The peak incidence for both men and women occurs between the
ages of 20 and 24. There is an increased incidence with increased numbers of
different sexual partners. By the mid 1950s, the efficacy of penicillin in treating
syphilis had been establishe4 and the incidence ofthe disease fell to a historical
low in the early 1980s. Over the past 10 years, however, the incidence of
syphilis has been on the rise. This presumably has been due to changes in sexual
behavior.
T. pallidum may enter the body through minor abrasions in the epithelial
surface or it may penetrate directly through normal mucosa. The first lesions
appear at the site of inoculation, presumably due to the high numbers of
treponemes at this site. Syphilis, however, is a systemic illness from its onset.

Clinical Findings
The typical lesion of primary syphilis is the chancre, which usually
presents as a papule at the site of T. Pallidum inoculation. The papule then
ulcerates and its borders become indurated” firm, and raised. Typically the
chancre is a painless, clean-based ulcer; however, on occasion secondary
infection may change the appearance of the ulcer and it may become painful.
The inoculation period from the time of initial exposure to the development of a
primary lesion ranges from l0 to 90 days but is generally 14 to 2l days. Most
chancres are solitary, ranging in size from several millimeters to 2 cm in
diameter, but multiple lesions are not uncommon. Most chancres are found on
the genitals and heal spontaneously in 4 to 6 weeks, often leaving a thin
atrophic scar. They are usually associated with painless regional
lymphadenopathy, either unichancre by about 7 days. In women, the chancre
may occur on the cervix and may be overlooked by the patient.
While traditionally 90% of the chancres have occurred in the genital
region, extra genital chancres are occurring in higher proportion, especially in
homosexual males, in whom rectal, perirectal, and oral chancres are commonly
seen. Rectal chancres may have an atypical appearance and mimic rectal
fissures. Chancres may also appear on the lips, fingers, nipples, and other body
areas.
In general, the suspicion of syphilis should be raised with any ulcer
occurring in the genital and rectal areas. Several other conditions should also be
included in the differential diagnosis. While herpes simplex or chancroid
(Haemophilus dacrya) may appear as a chancre, they are typically painful.
Chancroid usually presents with multiple ulcers that are exudative and
nonindurated. Lymph granuloma venereum may present as a small papule with
regional lymphadenopathy. Other conditions that also must be considered
include granuloma inguinale, drug eruptions, trauma, carcinoma, fungal
infections, and lichen planus.
Secondary syphilis usually develops 4 to 6 weeks after the chancre has
healed, although it may occur when the primary infection is still healing. This
stage is characterizedby low-grade fever, headache, malaise, sore throat, and
other systemic symptoms in 70% of the patients. Most patients have generalized
lymphadenopathy including epitochlear nodes, which is believed to be unique to
syphilis. Approximately 90% of the patients have a mucocutaneous rash that
classically is characterizedby macular and papular lesions on the palms and
soles. The rash usually begins on the trunk and spreads to the extremities,
eventually involving the entire body. The face, however, is usually spared
except around the mouth. The rash is usually minimally symptomatic,
nonpruritic, and variant in its appearance. The rash may be maculopapular,
follicular, or pustular in appearance, and is almost never vesicular. The rash is
usually widespread and symmetrical in distribution. Lesions ate typically
polymorphic, Indurated (except in the earliest stages), and rounded, with a
superficial scale. They range from pink and dusky red to a coppery colour.
Upon healing, lesions may leave areas of pigmentation or depigmentation.
Ulceration of the lesions may occur.
Lesions that occur around the hair follicles may result in a patchy
alopecia. In warm moist intertiginous areas, large, flat-topped popular lesions
may coalesce to form Gray-white to erythematous plaques known as
condylomara lata, which are highly infectious. Lesion of the mucous
membranes are very common. Superficial erosions called mucous patches may
appear on the lips, oral mucosa, tongue, and genitalia. Mucous patches occur in
approximately 35% of the patients, and are alsorgan system involvement.
Hepatitis has been reported in up to 10% of the patients with secondary syphilis.
Proctitis, glomerulonephritis, iritis, and meningitis have also been report up to
10% of the patients with secondary syphilis. periostitis, glomerulonephritis,
iritis, and meningitis have also been reported.
The differential diagnosis for secondary syphilis is extensive. The rash is
often confused with pityriasis rosea, drug eruptions, viral exanthems, psoriasis,
lichen planus, and scabies. The mucous patch may resemble oral candidiasis.
Syphilis is also frequently confused with hepatitis and infectious
mononucleosis.
In the untreated patient, lesions of secondary syphilis heal
spontaneously within 2 to 6 weeks, and the disease enters a latent stage that has
no clinical manifestations. Latent syphilis is divided into two phases, early and
late. The CDC currently defines early latent syphilis as the first year of
infection. Late latent syphilis is after the first year of infection. Most relapses
and infectious spread of syphilis occur during the first year of the infection. Late
latent syphilis ordinarily is not infectious except in the case of pregnancy, where
transmission of the disease to the fetus may occur.
Approximately 25% of the patients with early latent syphilis may
develop relapsing lesions of secondary syphilis. This stage may last for a
lifetime, and only be picked up with a positive screening test for treponemal
antibody. Up to 35o/o of the patients with untreated latent syphilis will go on to
develop tertiary or late syphilis.
Late or tertiary syphilis is a slowly progressive inflammatory disease
that can affect any organ system. Late syphilis is not infectious. Among
untreated patients who progress to tertiary disease, l0% develop cardiovascular
syphilis, l0% develop neurosyphilis, and 15% develop gummatous or late
benign syphilis.
Gumma or late benign syphilis was at one time the most common
complication of tertiary syphilis. Since the advent of penicillin, however,
gummas arerare. Gummas are benign, granulomatous lesions that typically
develop 3 to 7 years after the initial infection and may occur any-where in the
body. Gummas may be solitary or multiple, are usually asymmetrical, and are
often grouped. Although they may be very destructive, they respond rapidly to
treatment with penicillin. Gummas commonly involve the skin, but also may
involve deep visceral organs. The respiratory tract, gastrointestinal tract, and
bones are the most common deep visceral sites. Skeletal gummas
characteristically present with nocturnal pain, usually involving the long bones,
skull, and clavicles. X-ray studies may reveal either lytic or sclerotic destructive
osteitis.
Cardiovascular syphilis is characterized by aortitis, which usually involves
the thoracic aorta. Syphilitic aneurysms are typically more saccular than
aneurysms secondary to atherosclerosis, and generally do not lead to aortic
dissection. Less commonly other large arteries may be involved. Pathologically,
this is a result of medial necrosis with destruction of elastic tissue in the
vesselwall. Dilatation of the ascending aortamay result in aortic insufficiency
and aneurysms of the aorta. Rarely involvement of the coronary ostia results in
coronary insufficiency.
Cardiovascular syphilis usually begins within 5 to 10 years after the
primary infection, however, it may not become clinically apparent until l0 to 40
years after primary infection. Cardiovascular syphilis appears to be more
common in men and does not occur after congenital infection. Treatment with
antibiotics has little effect on cardiovascular syphilis, although it prevents other
complications of tertiary syphilis. Treatment should focus on the medical
management of aortic insufficiency and surgical intervention when necessary.
Neurosyphilis may coexist in l0% to 25% of the patients with cardiovascular
syphilis; therefore, lumbar puncture should be performed in all patients with
cardiovascular syphilis.
Neurosyphilis may be categorized as either asymptomatic, meningeal,
meningovascular, tabes dorsalis, or general paresis. The divisions are not
absolute, and there is considerable overlap between the various syndromes.
Between 8o/o and 40o/o of untreated patients with neurosyphilis are
asymptomatic. Diagnosis is made when there is a positive Venereal Disease
Research Laboratory test (VDRL) in the cerebrospinal fluid (CSF) without signs
or symptoms of neurologic disease. The CSF usually reveals an increased total
protein and a lymphocytic pleocytosis, but may be normal. A negative VDRL
does not rule out neurosyphilis. Early treatment with penicillin has been shown
to prevent progression to more severe disease.
Meningeal syphilis is characterized by an acute to subacute aseptic
meningitis that may occur at any time after the primary infection, but usually
occurs within the first year. Ten percent of the cases coincide with the skin
lesions of secondary syphilis, and may be associated with unilateral or bilateral
cranial nerve palsies. The CSF usually reveals an elevated total protein,
lymphocytic pleocytosis, and a normal glucose concentration.
The onset oftabes dorsalis is often 20 to 30 years after the primary
infection. It is a slowly progressive degenerative disease involving the posterior
columns and posterior roots of the spinal cord. Patients present with
“lightening” type pains (sudden and severe painful crisis of uncertain cause),
progressive loss of peripheral reflexes, impairment of position and vibration
sense, and progressive ataxia. Incontinence of the bladder and impotence are
common. In advanced cases, patients may present with chronic destructive
changes ofaffected extremities (Charcot's joints). Optic atrophy is seen in 20o/o
of the patients and Argyll Robertson pupils (bilaterally small pupils that do not
constrict to light but respond normally to accommodation) are seen in up to
90% of the cases of tabes dorsalis. The cause of tabes dorsalis is unclear and
treatment with penicillin does not reverse symptoms.
General paresis is a chronic meningoencephalitis that occurs 10 to 20
years after the primary infection and results in a progressive loss of cortical
function. Early on, general paresis presents with increased irritabiliry fatigue,
headaches, forgetfulness, and personality changes. As the disease progresses,
memory and judgment become impaired, and there is a lack of insight into the
illness, and often depression or marked elation. As the disease continues to
progress, delusions and seizures may develop, as well as aphasia, altered mental
status, and paralysis. Notably, Argyll Robertson pupils, optic atrophy, and
cranial nerve palsies are rare. Reflexes are usually increased, and CSF is almost
always abnormal. General paresis responds well to antibiotic therapy if treated
early; however, up to a third of the patients may develop progressive neurologic
decline in later years.
In general paresis, the VDRL is almost always positive in both the CSF
and serum. The VDRL, however, may be negative in late neurosyphilis. The
fluorescent treponemal antibody absorption (FTA-ABS) test must be performed
before syphilis can be excluded as a cause of an undiagnosed neurologic illness
.
Congenital syphilis results from transplacental transmission of syphilis
from the mother to the fetus. Syphilis during pregnancy, even if subclinical in
the mother, invariably infects the fetus. The risk of fetal infection is greatest in
the early stages of untreated maternal syphilis and declines thereafter. The
mother may infect her fetus for at least the first 5 years of her infection.
Adequate treatment of the mother prior to the l6th week of gestation, before
fetal immunologic maturation, usually prevents clinical illness in the neonate.
Only fulminant cases of syphilis are evident at birth, secondary to mothers who
contracted syphilis during the third trimester of their pregnancy and were not
treated; 50% ofthese infantsdiein utero or soon after birth.
The more common presentation of early congenital syphilis is that of a
child who appears healthy at birth, but who becomes ill several weeks to months
later. Clinical presentation may include rhinitis, mucocutaneous rash (similar to
the rash seen in adults with secondary syphilis), generalized lymphadenopathy,
and hematologic and central nervous system abnormalities. Early congenital
syphilis must be differentiated from rubella, toxoplasmosis, bacterial sepsis, and
cytomegalovirus infection.
 Children who present with syphilis after age 2 are considered to have late
congenital syphilis. Neurologic manifestations are common. Other clinical
features include interstitial keratitis, eighth nerve deafnedeformiry bilateral knee
arthritis with effrrsions (Clut-ton's joints), notched and tapered central incisors
(Hutchinson's teeth), and anterior bowing of the shins ("sabor shins").

Diagnosis
The diagnosis of syphilis is made on clinical findings that arc
generally confirmed by serologic testing. Routine culture of T pallidum is not
available as a diagnostic tool.
Dark-field microscopy is almost always positive in priosyphilis and
in the moist mucosal lesions of secondary syphilis. It also may occasionally, be
positive in lymph node aspirates during secondary syphilis. This technique
involves first cleaning the suspected lesion with sterile saline solution and a
galuze, without inducing any bleeding, followed by obtaining a sample of the
exudative or serous material from the lesion on a glass slide. The specimen is
then viewed using a microscope with a dark-field condenser. Light is
transmitted through the condenser aI an angle allowing the spirochete to be
visualized. A single negative test is insufficient to exclude primary syphilis. A
false-negative result can occur if the patient applies soaps or other toxic
compounds to the lesion, and considerable skill is needed to perform this
technique. If an initial examination is negative, the patient should be instructed
to avoid washing the lesion and to return for two consecutive examinations to
assure that the test results are accurate.
In many areas dark-field microscopy may be difficult to obtain
secondary to lack of appropriate equipment or personnel skilled in the
technique. T pallidum may also be demonstrated in biopsies or pathologic
specimens by fluorescent antibody or sliver stains.
Serologic tests for syphilis are grouped into two categories,
treponemal and nontreponemal. Nontreponemal tests detect antibodies to lipids
found on the membranes of T. Pallidum. Their specificity is not as great as that
of the treponemal test, and they are primarily used as screening tests.
Nontreponemal tests become positive 2 to 6 weeks after inoculation, and their
test titers are highest during secondary and latent syphilis. A negative test does
not exclude primary syphilis. In untreated patients the sensitivity for
nontreponemal tests is about 75%for primary syphilis, 95% to 100% for
secondary and latent syphilis, andT}oh for late latent and tertiary syphilis. The
two most commonly used nontreponemal tests are the VDRL and the rapid
plasma reagin (RPR) tests. Both tests are equally sensitive, and can be
performed as both qualitative and quantitative examinations, thus allowing the
tests to be used for both screening and monitoring of response to treatment. In
adequately treated patients, non-treponemal test should become negative within
I to 2 years of treatment. In late latent and tertiary syphilis, the titers do not
change with treatment.
Treponemal test detect specific antibody to T. Pallidum antigen. The
FTA-ABS test and the microhemagglutination T. Pallidum assay (MHA-TP) are
the most widely utilized tests. Other available treponemal tests include
fluorescent treponemal antibody absorption double-staining (FTA-ABS DS),
hemagglutination treponemal test for syphilis (HATTS), and the T pallidum
immobilization (TPI). Treponemal tests become positive at about 3 to 4 weeks
after inoculation, are nonquantitative, and are erported only as reactive or
nonreactive. Treponemal tests are indicated to confirm a positive VDRL or
RPR, and to confirm the diagnosis of syphilis based on clinical presentation.
The FTA-ABS is positive in 95% of patients with tertiary syphilis and therefore
may be the only positive test in patients with this stage of the disease, and may
remain positive for life. Treponemal test may also be positive with other
treponemal diseases such as yaws, pinta, and bejel.
 False-positive test results may occur in a variety of diseases other than
syphilis. The incidence of false-positive results for the nontreponemal tests
ranges from 5% to 20%. An “acute” false-positive VDRL or RPR is the term
applied to false-positive test results that persist for 6 months or less. This
occasionally occurs with atypical pneumonia, malaria, and other bacterial or
viral infections, and after vaccinations. Chronic false-positive results are those
that remain positive for 6 months or more. These are relatively common in
autoimmune disorders such as systemic lupus erythematosus or other con-
nective tissue disorders. Chronic false-positive results may also be seen in drug
addicts, malignancies, and those patients over 70 years of age. If a false-positive
nontreponemal test is suspecte4 it must be confirmed with a negative
treponemal test. False-positive treponemal tests rarely occur, but may be seen
with certain connective tissue disorders. False-negative results occur in l0% or
less of the patients with syphilis. False-negative results, how-ever, are becoming
more common, especially in patients with HIV infection. This is presumed to be
secondary to a reduced or absent antibody response.

Treatment
T. pallidum is highly susceptible to penicillin, which is the drug of
choice for treating all stages of the disease. In addition, there have been no
reported cases of T pallidum resistance to penicillin. Penicillin acts only on
dividing cells, and since treponemes divide slowly it is necessary to assure
appropriate levels of antibiotics for many days. asthe length of infection
increases so does the required duration of antibiotic therapy.
Early syphilis (less than I year) may be treated with an intramuscular
injection of 2.4 million units of benzathine penicillin, which provides effective
serum levels for over 2 weeks. Alternative treatments include ceftriaxone 250
mg intramuscularly daily for l0 days, or oral tetracycline or erythromycin2 gper
day for 15 days. Empiric therapy for primary syphilis is frequently started,
based on clinical history and physical examination, prior to definitive diagnosis.
Therapy failures occur in approximately 5% of the patients treated with
penicillin, and more frequently with other regimens. Careful follow-up is
particularly needed for patients who have been treated with oral antibiotics, as
they may not be fully compliant with these prolonged, multiple daily dosing
regimens. All patients should receive follow-up VDRL or RPR testing. The
patient's nontreponemal antibody titer should decrease fourfold by 3 months if
therapy has be adequate. Lumbar puncture and CSF examination is not
necessary for mg intramuscularly daily for l0 days, or oral tetracycline or
erythromycin 2g per day for 15 days. Empiric therapy for primary syphilis is
frequently started, based on clinical history and physical examination, prior to
definitive diagnosis. Therapy failures occur in approximately 5%of the patients
treated with penicillin, and more frequently with other regimens. Careful
follow-up is particularly needed for patients who have been treated with oral
antibiotics, as they may not be fully compliant with these prolonged, multiple
daily dosing regimens. All patients should receive follow-up VDRL or RPR
testing. The patient's nontreponemal antibody titer should decrease fourfold by
3 months if therapy has be adequate. Lumbar puncture and CSF examination is
not necessary for patients who have had syphilis for I year or less.
Patients who have had syphilis for more than I year require larger doses
of penicillin for a longer period of time. In addition, a majority of these patients
should undergo lumbar puncture for CSF examination to rule out neurosyphilis.
Patients should receive a total of three intramuscular injections of 2.4 million
units of benzathine penicillin each, administered 7 days apart. Patients who are
allergic to penicillin can be treated effectively with oral tetracycline or
erythromycin , 2 g per day for 30 days.
Benzathine penicillin does not provide adequate levels of penicillin in the
spinal fluid. While in asymptomatic patients with neurosyphilis benzathine
penicillin is curative, in cases of symptomatic neurosyphilis patients should be
admitted to the hospital and treated with penicillin G (20 million units per day
in divided doses) for a period of at least l0 days. Patients with suspected
penicillin allergy should undergo testing, and if positive, they should undergo
subsequent desensitization in order to receive therapy with penicillin. Patients
treated for neurosyphilis should have follow-up lumbar punctures with CSF
examination every 6 months for at least 3 years.
Currently it is recommended that all pregnant women undergo VDRL or
RPR testing at the time of their first prenatal visit and at the time of delivery.
Women at high risk for syphilis should also undergo nontreponemal antibody
testing in their third trimester of pregnancy. If subsequent treponemal antibody
testing is confirmatory, the patient should be treated with penicillin, according
to herstage of disease, as soon as possible. Drugs other than penicillin have not
been shown to be effective in protecting the fetus, or are known to be toxic to
the fetus. There fore, patients who are allergic to penicillin, should undergo skin
testing and desensitization procedures followed by treatment with penicillin.
Proper treatment of the mother usually prevents active neonatal syphilis.
Most cases of congenital syphilis today are a result of unrecognized maternal
infection. Infected infants may be clinically normal at birth and seronegative if
the mother’s infection was acquired late in her pregnancy. The infant should be
treated at birth if the mother has received no treatment or treatment with a
regimen other than penicillin. Treatment should not be withheld because
ofinadequate proofofdiagnosis, ifthought to be clinically indicated. All children
with suspected congenital syphilis should undergo lumbar puncture and CSF
examination. The current recommended treatment for congenital syphilis is
procaine penicillin, 50,000 units per kilogram body weight intramuscularly for
10 to 14 days.
The resurgence of syphilis has paralleled the AIDS epidemic, which has
led some researchers to speculate that in patients who have concurrent infection
with both HIV and. T pallidum, the course of each infection may be affected by
the presence of the other. The natural course of syphilis may be drastically
altered by HIV infection, and our present understanding of the disease process
appears to be incomplete.
There is a high prevalence of HlV-seropositivity among patients with
syphilis, and the presence of one disease should prompt the clinician to search
for the other. The presence of lesions of primary syphilis may serve as a port of
entry and proliferation of the HIV virus. Routine serology testing may not be
diagnostic in patients with HIV Any cutaneous lesions that are suspected of
being caused by syphilis should be biopsied prior to treatment.in patients who
have HIV infection, there appears to be a dysregulation of the antibody response
to luetic infection, resulting in rapid progression of syphilis into its tertiary
stages. All patients with syphilis at risk for HIV infection should undergo
lumbar puncture to rule out central nervous system involvement. CSF may not
be diagnostic of neurosyphilis in patients with HIV Based on clinical flindings,
it may be necessary to empirically treat if infection is suspected. While
benzathine penicillin has been the drug of choice to cure syphilis for many
years, many treatment failures have occurred in immunocompromised patients.
Benzathine penicillin does not reach bactericidal levels in the central nervous
system, and immunocompromised patients may be at more risk for reactivation
of syphilis with a more fulminant course. More aggressive therapy is required in
these patients. Alternative therapies include aqueous penicillin G (2.4 million
units IV every 4 hours for l0 days), or procaine penicillin G (2.4 million units
IM every day for 10 days) plus probenecid (500 mg orally four times a day for
10 days). Both regimens should be followed by benzathine penicillin (2.4
million units IM weekly for 3 weeks). Ceftriaxone (250-500 mg IM daily for l0
days) is also an acceptable treatment.
Reactivated secondary syphilis has been reported to follow influenza
vaccination in patients with HIV infection. All unnecessary vaccinations should
be avoided in this group. Close monitoring and frequent follow-up are the key
to managing syphilis in the HIV patient.
 The Jarisch-Herxheimer reaction, a transient febrile reaction, may occur
after therapy for syphilis. The reaction has been seen in up to 50% of the
patients with primary sy20% of the patients with latent syphilis. The reaction
usually begins within the first few hours after therapy, peaks within 6 to 8
hours, and may last 12 to 24 hours. It is characterized by fever, chills, myalgias,
and headache. There may be associated mild vasodilatation with flushing and
mild hypotension. The reaction is usually of no clinical significance and may be
managed with salicylates. The etiology is believed to be the result of the release
ofa heat stable pyrogen by the spirochete.

Prevention
The present control of syphilis depends entirely on the clinical
awareness on the part of the physician, patient education regarding “safe sex,”
reporting to public health officials, and preventative treatment of sexual
contacts. Currently there is no prospect for a vaccine in the immediate future.

SELECTED READING
Goens JL, Janninger CK, DeWolf K. Dermatologic and systemic manifestations
of syphilis. Am Fam Physician 1994;50(5):1013-1020.
Gregory N. Clinical problems of syphilis in the presence of HlY. CIin Dermatol
l99l;9:71-74.
Johnson RA, White M. Syphilis in the 1990s: cutaneous and neurologic
manifestations. Semin Neurol 1992;12(4):287-298.
Kirchner JT. Syphilis-an STD on the increase. Am Fam Physician
l99l;44(3):843-854.
Larsen SA, Steiner BM, Rudolph AH. Laboratory diagnosis and interpretation
of tests for syphilis. Clin Miuobiol Rev 1995;8(1):1-21.
Starling SP Syphilis in infants and young children. Pediatr Ann 1994;23(7):334-
340.
Stoll BJ. Congenital syphilis: evaluation and management ofneonates born to
mothers with reactive serologic tests for syphilis. Pediat Infect Dis J 1994;
13(10):84s-8s2.
Wendel PJ, Wendel GD. Sexually transmitted diseases rnpregnancy. Semin
perinatoi 1993 ;17 (6):44345 l.
Young H. Syphilis: new diagnostic directions. Int J STD AIDS 1992;3:391-413

Chlamydia (9.1.10)
 The genus Chlamydia contains different species such as
B.Psittaci, C. Trachomatis, and C. Pneumoniae [Taiwan acute respiratory agent
(TWAR)] C. Psittaci can produce genital, conjunctival, intestinal, and
respiratory infections. C.Pneumoniae is a frequent cause of pneumonia mainly
in children and young adults. TWAR outbreaks have been known to occur
among young adults. C. Trachomatis is known to cause genital infections and
perinatal infections including conjunctivitis and pneumonia. Trachoma is a
chronic conjunctivitis associated with infectionby C. Trachomatis serotypes A,
B, and C. It has produced an estimated 20 million cases of blindness throughout
the world and remains an important preventable cause of blindness. Of the 15
serotypes of C. Trachomatis, serotyp€s L1, L2, and L: are knovrm to cause the
less common condition lymphogranuloma venereum.

Epidemiologlt
The incidence of chlamydial genital infections has increased in
recent years. “Genital infections caused by B.Trachomqlls are the most common
sexually transmitted disease in the United States” (Stamm, 1991).
Asymptomatic genital infection is common among both men and women.
Although lymphogranuloma venereum is rare in the United States, it is endemic
inAsia, Africa, and South america. The prevalence exceeds 5%o among
pregnant women, regardless of race/ethnicity or socioeconomic status. “In
addition, one third to one half of infants exposed during birth acquire the
organism. These infants are at risk of developing pneumonitis” (Fleisher, 1993).
Infection with T. Psittaci seems to be more prevalent in england,
where birds are popular household pets.

Pathophysiology/Etiiogy
Chlamydia are obligate intracellular bacteria that have a growth cycle
that alternates between two morphologic forms. C. Trachomalis infection in
men can cause urethritis, epididymitis, and proctitis. In women, urethritis,
cervicitis, and pelvic inflammatory disease are common. The incubation period
ranges from 1 to 3 weeks. There is a high co-infection rate with gonococcal
infection; therefore, presumptive treatment for all patients being treated for
gonorrhea is recommended
C.Trachomalis infection of neonates results from perinatal exposure to
the mother's infected cervix, causing a conjunctivitis or a subacute, afebrile
pneumonia with onset from 1 to 3 months of age.
Psittacosis, a severe pneumonia caused by C. Psittaci, is quite rare.
These infections occur in patients who have had contact with infected birds
harbouring these organisms. The organism is transmitted to humans by the
respiratory tract.
C.Pneumonia produces epidemics of pneumonia and respiratory illness
followed by periods of infrequent infection. Transmission is presumed to be
from person to person

Clinical Findings.
Clinical symptoms of chlamydial caused no gonococcal urethritis
include dysuria, urethral pruritis, and a urethral discharge. Signs may include
meatal erythema and tenderness. Approximately one-third of men infected with
chlamydia have no demonstrable signs or symptoms. Pelvic inflammatory
disease occurs via ascending spread of C. Trachomatis from the lower genital
tract. Complications of PID include infertility, ectopic pregnancy, and
perihepatitis (Fitz-Hugh-Curtis syndrome).
Clinical findings in lymphogranuloma venereum include painless skin
lesions in the genital areas that may form shallow ulcerations, popular or
vesicular. This is usually followed by tender inguinal adenopathy that is
unilateral in two-thirds of the cases. Extensive enlargement of inguinal chain
nodes produces the linear “groove sign.” Proctocolitis may be seen in females
or homosexually active men from lymphatic inflammation causing fistula and
stricture formation. Systemic signs of fever, chills, headache, and malaise may
be present. Other uncommon sites of involvement include the joints and
meninges. Late complications include fistula formation, chronic ulcerative
lesions, sinus tract formation in inguinal areas, and lymphatic obstruction that
can produce elephantiasis.
Neonatal C. Trachomqtis can involve the mucous membranes of the
eye, oropharynx, urogenital tract, and rectum. C. Trachomatis conjunctivitis,
also known as neonatal-inclusion conjunctivitis, appears as early as 5 to 7 days
after birth and is usually the first recognizable sign of infection with C.
Trachomatis. It is usually associated with preauricular adenopathy that is not
present in gonococcal infection. A chlamydial etiology should be considered for
all infants younger than 30 days of ages with conjunctivitis.
After an incubation period of 7 to 14 days, the clinical manifestations
of psittacosis begin consisting of a fever, chills, headache, dry cough, myalgias,
and gastrointestinal symptoms. Diffuse patchy infiltrates on chest x-ray are
seen.
The clinical spectrum of C. Pneumonlae (TWAR) infection includes
upper respiratory symptoms, fever, nonproductive cough, and small segmental
infiltrates on chest x-ray. In elderly patients, illness from C. Pneumoniae can be
more severe, necessitating hospitalization.

Diagnosis
Culturing chlamydia is expensive, technically demanding, and usually
results in a low yield. For most chlamydia cerotypes, confirmatory tests usually
involve indirect methods using direct immunofluorescence, ELISA, and DNA
probes that are now available. “Newer assays that can be performed on urine are
also available” (Morris, 1996).
While the specific chlamydia serotypes in lymphogranuloma venereum
(LGV) usually grow well on culture media, serologic tests are also used in
LGV.
Tissue cultures from the nasopharynx should be tested to diagnose
chlamydia pneumonia for C. Trachomatis. Indirect methods using
immunofluorescence are useful but not widely available. Since there is a delay
in obtaining test results for chlamydia, empirical therapy should be started based
on clinical and radiologic findings.
The diagnosis of C. Psittaci and C. Pneumoniae can be confirmed by
isolation of the microorganism or by serologic tests. The demonstration of a
rising titer of complement-fixing antibody in serum is another diagnostic
approach.
Treatment- Disposition
Doxycycline 100 mg twice a day for 7 days has been the standard therapy
for treating C. Trachomalis genital infections. A newer regimen of azithromycin
I g orally in a single dose has been shown to be effective. Erythromycin 500 mg
orally four times a day for 7 days and tetracycline 500 mg four titnes a day for 7
days is an alternate therapy. Erythromycin base may be used in pregnant
patients (do not use the estolate form in pregnancy).
Doxycycline 100 mg orally fwice a day for 21 days is the usual regimen
for lymphogranuloma venereum. Treatment for chlamydial conjunctivitis (C.
Trachomatis) is erythromycin 50 mg/kg per day orally for 14 days. Chlamydial
pneumonia (C. Trachomafrs) response rate to erythromycin 50 mglkglday orally
for 10 to 14 days is approximately 80Yo, and a second course of therapy may be
needed.
Tetracycline or erythromycrn 2 g daily for at least 7 days is consistently
effective against C.Psittaci or C.Pneumoniae atypical pneumonias.
Prevention
 One should advise treatment of sexual partners and abstinence until
treatment regimen is finished and the patient is symptom free. Patients need to
be counseled regarding the different methods of 5 sexually transmitted diseases.
It is recommended once a patient is diagnosed with a STD that there be a
serologic test for syphilis, and counseling for HIV testing. “STD/HIV and
acquired immunodeficiency syndrome (AIDS) cases should be reported in
accordance with local statutory requirements to local health authorities in a
timely manner” (CDC, 1993).
Neonatal ocular prophylaxis with silver nitrate solution or antibiotic
ointments is ineffective in preventing perinatal transmission of chlamydial
infection from mother to infant. Yet ocular prophylaxis should be continued
since it has been shown to prevent transmission of gonococcal ophthalmia.
Prenatal screening of pregnant women can prevent chlamydial infection among
neonates.
SELECTED READING
Adimora AA. Sexually transmitted diseases-companion handbook. Newyork:
McGraw-Hill, 1994.
Centers for Disease Control and Prevention. 1993 sexually transmitted
diseases treatment guidelines. MMWR 1993;42(RR- 14):7,50 59.
Fleisher GR. Infectious disease emergencies. In: Fleisher GR, et al., ed textbook
of pediatric emergency medicine, 3rded. Baltimore: Williams & Wilkins,
1993;625.
Handsfield HH, et al. Criteria for selective screening for Chlamydia trachomatis
infection in women aftending family planning clinics. JAMA 1986;255:1730.
Morris D. Infectious diseases and allergy in emergency medicine: a
comprehensive study guide, 4thed. New York: McGraw-Hill, 1996;695
Morris D. Sexually transmitted diseases. In: Tintinalli JE, et al., eds. Emergency
medicine: a comprehensive study guide, 4th ed. New York: McGraw-Hill,
1996;69 5-697 .
Scientific American Medicine SAM-CD. Sexually transmitted diseases. New
York: Scientific American, I 993.
Stamm WE. Chlamydial infections. In: Hatisonb principles in internal
medicine, 12th ed. New York: McGraw-Hill, l99l;764-766.
PROTOZOAN-PARASTTES (9.3)
Malaria (9.3.1)
Named in the 17th cenlury by the Italians (“mal aria” meaning
“bad air”), malaria remains one of the most prevalent of infectious diseases
worldwide. There are about 300 million cases reported annually, with over I
million deaths every year in Africa alone.
Since malaria is rapidly becoming resistant to chloroquine, long a
mainstay of treatment and prophylaxis, and since the alternative
chemoprophylaxes currently available are of limited efficacy andlor produce
toxic side effects, there is an increase in the numbers of American travelers
becoming infected with malaria. Many of these patients present to the ED. Since
symptoms associated with malarial infection can range from relatively benign to
life threatening, and since clinical deterioration and organ failure can occur in a
matter of hours, it behooves the emergency physician to be familiar with the
disease and its myriad presentations.
Epidemiologlt
Malaria is found in tropical areas, where it is a leading cause of
morbidity especially among women and children. It used to be endemic in the
United States (the anopheles mosquito vector is prevalent in the south and
west), but there has been no sustained native transmission of malaria in the
United States since eradication of the disease here in the 1940s. Transfusion-
related transmission of malaria is possible but rare, occurring at a rate of I for
every 4 million units of packed red cells transfused. Most malaria cases in the
United States now are found in travelers. The risk of malaria for travelers to
tropical areas depends on their destination. It is highest in sub-Saharan africa,
and lowest (by a factor of 100) in Asia and Latin america.
The death rate for malaria in the United States is l% to 4%.The cause of
death can almost always be related to delay in diagnosis and/or treatment, older
age, or failure to take chemoprophylaxis prior to travel.
Pathophysiologt
Malaria is transmitted by the bite of an Anopheles mosquito
infected with a Plasmodium parasite. Sporozoites in the salivary glands
of the mosquito are transferred to the blood of a human, where they
migrate to the liver. There the exoerythrocytic reproductive cycle begins
in infected liver cells, which in turn rupture and release merozoites to the
blood. These are taken up by erythrocytes, where fuither reproduction
and maturation takes place in the trapezoidal and schizont stage.
Subsequent cycles of erythrocyte rupture and merozoite release may be
related to the cyclic chills and fever characteristic of malaria infection.
There are four species of Plasmodia that can cause malaria in
humans: P falciparum, P vivax, P ovale, and P malariae (Table 9-9).
Each is endemic to different geographical areas (although they overlap),
has different duration of reproductive cycles in the host, and has
preference for different aged red blood cells. By far the most potentially
lethal is infection with P. Falciparum. Its rapid, and proliferative
reproductive cycle (7 to l0 days) and its ability to infect any age red
blood cell leads to high levels of circulating parasite. Red cells infected
with P falciiparum become adherent to vessels in the brain, heart, lung,
and kidneys, leading to further complications (see below). In addition, P
falciparum is the most resistant to conventional antimalarial therapy.
Because of the variation in reproductive cycle of the parasite,
there is a difference in the susceptibility of various groups to infection.
For instance, p.vivax occurs rarely in Africa because most blacks are
resistant to it, presumably because they lack the specific erythrocyte
receptors required for parasite uptake. In addition, hemoglobins
associated with sickle cell anemia have been shown to incur innate
resistance to infection with
p.falciparum.
Of note, although they are more easily treated when in the
circulation, P.ovale and. P. Vivqx can enter a dormant stage in the liver,
allowing for a span of months to years before peripheral proliferation and
subsequent clinical relapse.
Clinical Findings
The hallmark of malarial infection is the “malarial paroxysm”: cyclic
fever, chills, and rigors. Typically, there is a “cold stage” rigor that lasts 20 to
60 minutes, followed by a “hot stage” of 3 to 8 hours of fever, followed by the
“wet stage” of defervescence, diaphoresis, and exhaustion. The cycles need not
be regular, and fever is the only consistent initial finding. Often as high as 4l’C
(105”F), it may be much less striking, especially in infants. There is generally a
prodrome of nonspecific malaise one to several days to the paroxysm.
TABLE 9-9. Chemotherapy of malaria according to
infecting species
aRecommended dosages are given in Table 9-10.
bNo established standard for treatment of chloroquine failures. Options include
a single dose of mefloquine (exquisite sensitivity allows lower dose therapy,
500 mg lor an adult), or quinine over a 7-day course. plrimethamine/sulfidoxine
should not be used because of reduced susceptibility in P vivax.
From Redd SC, Campbell C. Malaria. Ln: Hoeprich PD, Jordan MC, Ronald
AR, eds. Infectious diseases, sth ed. Phitadetphia: lippincott, 1994;1341 -1342.

The “benign” malarias (P vivax, P. Ovale, P. Malariae, and some P

folciparum infections) are limited in their clinical courses to fever, mild anemia,
and hypersplenism. Acute mortality rates from these infections are very low.
The most pronounced clinical findings, and those responsible for the most
morbidity, are those indicating specific organ involvement due to severe P
falciparum infection. Sequestration of parasitized erythrocytes in vascular
endothelium leads to stagnant anoxia of vital end organs. For example,
splanchnic vessel involvement leads to hepatic necrosis and renal tubular
acidosis. Indeed one-third of all P falciparum patients have some degree of
renal insufficiency, usually reversible. In addition, coronary vessel obstruction
can occur. Pulmonary edema may develop, and is actually more likely to be due
to overzealous fluid resuscitation than to vessel occlusion. Perhaps the most
striking result of vessel damage is referred to as cerebral malaria, which occurs
when intracerebral small vessel obstruction leads to CNS tissue necrosis and
hemorrhage. This is the most common of the severe malaria complications, and
it occurs only with P. Falciparum infection. Cerebral malaria can present as a
general decline in level of consciousness, seizure, or coma, and it has a very
high mortality rate (10 to 50%).
Diagnosis
Due to the nonspecific clinical findings associated with malaria, the
diagnosis should be considered in any patient at risk who presents with a febrile
illness. ‘At risk” is generally defined as having a history of travel to amalaria-
prone region within the past year. Knowledge of the region where exposure
likely occurred helps narrow the search for type of infection.
Diagnosis is confirmed by the presence of parasites on giemsa-stained
peripheral blood smears. These need to be obtained at the time the diagnosis is
considere4 and repeated every 6 to 12 hours thereafter. If no parasite is seen on
smears collected over 48 to 72 hours, the diagnosis of malaria can be considered
unlikely.
Malaria blood smears must be prepared as both thick and thin smears,
thick to ensure adequate concentrations of parasite for detection, and thin to
ensure adequate isolation ofa parasite for species identification.
 Secondary tests do not help confirm or exclude the diagnosis of malaria.
However, once the diagnosis has been made, they can help determine the
presence and severity of complications. Tests to be considered include CBC,
serum electrolytes, glucose, coagulation studies, urinalysis, chest x-ray, ECG,
and blood cultures.
Serologic testing for malaria, most commonly indirect fluorescent
antibody screening, is available. It is not useful in the detection of acute
infection, because the antibodies are not reliably present until 2 weeks after
infection and they may persist for several years. Such testing is used in
epidemiologic surveys and to identify infected donors in cases of transfusion-
acquired malaria.
Therapy
The purpose of drug therapy for malaria is twofold: to halt multiplication
of the parasites, and to remove existing parasites from the blood. There are
several factors to consider when planning therapy and anticipating the prognosis
for the malaria patient:
Density of infection-a parasite load of over 5% of peripheral erythrocytes is
considered severe.
Infecting species-M. Falciparum is the most serious.
Hematocrit-a presenting hematocrit of less than 20%carries a poor prognosis.
Patient characteristics-those at the extremes of age, pregnant patients, and those
with no immunity to malaria require more intensive treatment.
Other organ involvement.
There are multiple treatment choices for the patient presenting with
malaria (Table 9-10). If the infecting species in unknown, therapy for
falciparum should always be initiated. If the presentation is uncomplicated, this
can be oral therapy. If the patient presents with any complications or with a
severe infection, intravenous therapy must be initiated. Drugs currently
recommended for malaria include:
Chloroquine-Previously the mainstay of malaria therapy, it remains
effective against all ovale and malariae species infections, although resistance
by falciparum and now vivax is spreading. Chloroquine is given orally over a3-
day course.
Pyrimethamine- sulfadoxine (Fansiday)-This is used for low-density
falciparum infections from areas known to have resistance to chloroquine. It is
given as a single, oral dose.
Mefloquine-This can be used in the same way as Fansidar, but at curative
doses it has many side effects (vertigo, GI problems, seizures, and psychosis),
so mefloquine is now more likely to be used as prophylaxis.
 Quinine-There are several forms of quinine now being used in the
treatment of malaria. In its oral form, quinine can be used to treat moderate
infections of chloroquine-resistant falciparum. Because of the high likelihood of
cinchonism (dizziness, tinnitus, visual disturbances, and headache), even at
therapeutic levels, quinine should be continued only until no parasites are seen
in peripheral smears (3-7 days). Only oral primaquine can eradicate intrahepatic
dormant forms of vivax and ovale.
Intravenous quinine is used in severe falciparum infections. Quinine
hydrochloride is no longer available in the United States; quinidine sulfate is an
enan
TABLE *1O. Dosages of antimalarial drugs used in
chemotherapy.
 aConsider higher dose (22.5 mg/day) for 14 days or a 3-week course of 15
mg/day for exposure in lndonesia or Papua New guinea, where resistance has
been documented. Alternatively, 45 mg every week for 8 weeks can be used to
prevent relapses of resistant strains.
From Redd SC, Campbell C. Malaria. Ln: Hoeprich PD, Jordan MC, Ronald
AR, eds. Lnfectious diseases,5thed. Philadelphia:lippincott, 1994;1341 -1342.
Tiomer of quinine and is the current recommended therapy for these cases. It
appears to be as effective but is far more cardiotoxic; therefore, its
administration requires close monitoring
Ktracycline-Jhis is sometimes used as an adjunct to quinine. Effective
combination therapy should bring about clinical improvement and reduction in
visible parasitemia in 24 to 48 hours.
Supportive care is critical in severe malaria cases. Patients can die of
pulmonary or renal complications even after the elimination of the parasite.
Such care can include exchange transfusions to rapidly lower the parasiite load
and correct severe anemia; airway management; diuresis; treatment of
coagulopathies, and pressor support. Corticosteroids and/or osmotic diuresis has
not been shown to be of benefit in the treatment of CNS involvement. There is a
highly significant relationship between delay in treatment and mortality in
cerebral edema.
Prevention
The World Health Organization (WHO) had a world-wide malaria
eradication program in place from 1955 to 1976, when it was declared a failure
due to vector resistance to DDT and parasite resistance to chloroquine. Current
prevention efforts are therefore based more on the individual, as well as vaccine
development. Individual protection is twofold. First, there is chemoprophylaxis,
which varies depending on the species of parasite and resistance levels in the
area visited. Travelers to the evershrinking areas that have not yet seen
chloroquine resistance should be instructed to take 500 mg of chloroquine once
a week starting 2 weeks before travel and continuing for 6 weeks after return.
The chemoprophylaxis for travel into areas with chloroquine-resistant
malaria remains more controversial, due to the potential side effects of the drugs
available. Because ofthe rapidly changing areas of resistance, and frequent
changes in recommendations, clinicians should refer to the CDC’s annual
publication of recommendations entitled “Health Information for International
Travel” IDHHS publication no.(CDC)88-8280]. Alternatively, updated
information is available around the clock from the CDC at (404) 639-1610. In
addition, regardless of the traveler’s destination, personal protection to
minimize exposure is recommended, including insect repellents, protective
clothing, and the use of screens and netting.
SELECTED READING
Bia FJ. Trends and controversies in the prophylaxis and treatment
of malaria. Infect Agents D is 1992; 1 (2): 108-113.
Heck JE. Malaria. Prim Care 1991;18(l):195-211.
Jofte RS, Scott J. Malaria: review of features pertinent to the emergency
physician. J Emerg Med 1993;11:729-736.
Redd SC, Campbell C. Malaria. In: Hoeprich PD, Jordan MC, Ronald AR, eds.
Infectious diseases, 5th ed. Philadelphia: Lippincott, 19941’1335-1344.
Wyler DJ. Malaria chemoprophylaxis in the traveller. N Engl J Med
1993;329(l):31-37.
Wyler DJ. Plasmodium species (malaria). In: Mandell GL, Douglas RG Jr,
berurett JE, eds. Principles and practice of infectiotts disease, 3rd ed. New York:
Churchill Livingstone, 1990;2056-2066.
Toxoplasmosis (9.3.2)
Caused by the obligate intracellular protozoan Tbxoplasma gondii,
toxoplasmosis is one of the most common latent parasitic infections in the
world. In humans it can be congenital or acquired” and infection can be
subclinical or it can lead to any of a cluster of symptoms known as
toxoplasmosis. Such infections are nost threatening in the immunocompromised
host or the infant in utero. Severe infections are most common in the
immunocompromised population, i.e., patients with HIV infection, lymphomas,
and cardiac or bone marrow transplants. In these cases sequelae can be long-
term and devastating, with costs, in addition to human suffering, of millions of
dollars per year in treatment and therapy.
Epidemiology
Tbxoplasma gondii is ubiquitous in nature, infecting all mammals,
some birds, and some reptiles. Cats appear to be the definitive host, because
they support the only form of the parasite that can survive for any length of time
out-side a host (the oocyte shed in cat feces). Humans are usually infected by
ingestion of the cystic form, found in meat (25% of pork and l0%of lamb and
beef in the united States). Congenital transmission can also occur, as can
transmission via blood transfusion and organ transplant.
Pathophysiology
Human infection with Tbxoplasrua usually occurs after ingestion of the
cystic form (in undercooked meat) or the Oocystic form (in cat feces). Once
absorbed through the digestive tract, the trophozoite form invades all types of
mammalian cells via an unknown mechanism, and proliferates. This leads to
cell rupture and subsequent necrotic tissue foci surrounded by an intense
inflammatory response. In the immunocompetent host, this area is walled off
and becomes a localized tissue cyst, provoking little or no further inflammatory
response and persisting in a latent, viable form for the life of the host. If host
immuniry particularly cell-mediated, is impaire4 cell invasion can lead to
persistent lesions like necrotizing encephalitis, pneumonitis, or myocarditis.
Congenital transmission of Tbxoplasmo occurs via the placenta in an
infected mother. The severity of the effect on the fetus depends on its age at the
time of transmission. In the untreated, infected mother, transmission to the fetus
occurs 25oh of the time in first trimester pregnancies (with severe impairment
of the fetus), while the transmission rate is 540% and 650%, respectively, in the
second and third trimesters, with milder results. Congenital transmission
appears to occur only when the mother is acutely infected during the pregnancy.
Clinical Findings
Toxoplasmosis is divided into four forms: congenital, acquired, ocular,
and immunocompromised. It cannot be diagnosed based on clinical findings
alone, because it is so variable in presentation and mimics so many other
diseases.
 Congenital toxoplasmosis, if clinically apparent at birth, can present in a
wide range of findings from fever or rash to seizures or psychomotor
retardation. Any clinical signs in the neonate indicate a high likelihood of
severe sequelae; 75% of infected infants are asymptomatic at birth. However,
the overall incidence of sequelae exceeds 850%, usually by age 8. Most later
effects include sensorineural hearing loss, retinochoroiditis, hydrocephalus, and
delayed psychomotor development. Markedly elevated CSF protein is the
hallmark of congenital toxoplasmosis, and differentiates it from the other
diseases included in the TORCH syndrome (rubella, cytomegalovirus, herpes
simplex) as well as congenital syphilis and sepsis.
Acquired toxoplasmosis in the immunocompetent host can range from
mild lymphadenopathy to acute fulminating and fatal illness, with the former
fortunately being the most common. The lymphadenopathy can be localized or
diffuse; it has been mistaken for breast cancer (when the parapectoral nodes are
involved) and for lymphoma. Its presentation can mimic mononucleosis or
CMV infection, and it can be the ultimate cause of “ievers of unknown origin.”
Such adenopathy in benign and selflimited, usually resolving within months and
rarely lasting beyond 12 months. The major differential diagnoses include
Hodgkin’s disease and other lymphomas; definitive diagnosis requires biopsy
and serologic testing. Toxoplasmosis is thought to account for 30% to 70% of
all clinically significant lymphadenopathies. The rare severe illnesses in the
immunocompetent host are associated with signs and symptoms referable to the
organ involved, as described below with disease in the immunodeficient host.
Ocular toxoplasmosis account for 35o/o of all cases of retinochoroiditis.
The characteristic retinal lesion is caused by focal necrosis. Initially appearing
as a yellow-white “cotton patch,” it becomes an atrophic white-gray plaque with
black pigment and distinct borders. Most cases are congenital, but ocular
toxoplasmosis occurs in lo/o of all cases of acquired disease. Usually, it is
unilateral when acquired, and bilateral when congenital. Most cases occur in the
second and third decades of life; it is rare after age 40. Multiple recurrences can
lead to glaucoma. Presenting symptoms include blurred vision, scotomae, pain,
photophobia, and epiphoria. The differential diagnosis includes the posterior
uveites of syphilis, leprosy, and TB.
In the immunodeficient host, toxoplasmosis can be either acquired or
reactivated from a latent infection acquired when the host was healthy; the latter
is more common. In patients with AIDS, toxoplasmosis usually occurs when the
CD4 count drops below 100. Signs and symptoms may be like those found in
the immunocompetent; however, most present with involvement of the heart,
lungs, or CNS, as necrotizing myocarditis, pneumonitis, or encephalitis. More
than50% of patients have findings referable to the CNS, and toxoplasmosis is
the most common cause of intracerebral mass lesions in patients with AIDS (in
the United States, the rate is currently 5% to l0%). It usually presents with
symptoms compatible with a mass lesion; hemiparesis, focal seizures. R,isual
disturbances, confusion, and lethargy are the most common. A CT scan usually
reveals multipls lesions, 90% of which u’ill be ring-enhancing. This is a
nonspecific finding also associated with bacterial, fungal, or TB lesions.
Routine anaiysis of the CSF may be normal, or it may reveal low WBCs, low to
normal glucose, or high-normal protein. Serologic testing rarely confirms the
diagnosis, but a negative serum IgG diminishes the likelihood of the diadiagnosi
Diagnosis
As previously mentioned, the diagnosis of toxoplasmosis cannot be
made on clinical findings alone. However, especially with AIDS patients, the
diagnosis is frequently inferred based on the response to empiric therapy. The
usefulness of a diagnostic method varies with the category of infection; right
diagnostic test must be performed and interpreted based on the individual
patient’s clinical situation. Isolation of T. Gondii in tissue sections, smears, or
body fluids, characteristic lymph node histology, or serology may prove only
the presence of latent cysts, not active infection. Currently, the most useful
serologic test for T. Gondii is IgM-ELISA. It can also be performed on CSF and
aqueous humor. Any immunocompromised patient with CNS findings should
have CT with contrast or magnetic resonance imaging (MRI) to look for
possible toxoplasmosis lesions.
Women planning pregnancy should be tested serologically for evidence
of previous toxoplasmosis infection. If they test positive for antibodies, they
have little or no risk of transmitting the disease to a fetus. If they test negative,
they should be followed for possible seroconversion durmg pregnancy.
Treatment
Most acquired toxoplasmosis infections in the immunocompromised
host do not require treatment. Acutely infected pregnant women are treated with
sulfadiazine or trisulfolrimidines in the first trimester. In the second and third
trimester, and in treatment of the neonate, pyrimethamine is added to the
regimen. Clindamycin is standard chemoprophylactic treatment in the neonate
for the prevention of retinochoroiditis; treatment is continued until a decrease is
observed in serologic titers.
Ocular toxoplasmosis is treated with pyrimethamine and sulfa or
clindamycin for I month, with repeat courses as clinically indicated. Systemic
corticosteroids are required for lesions involving the macula, optic nerve head,
or papillomacular bundle.
Combination therapy with pyrimethamine and sulfadiazine or
clindamycin has traditionally been the treatment ochoice for
immunocompromised patients with toxoplasmosis. Trimethoprim-
sulfamethoxazole has also been used as chemoprophylaxis. Because treatment is
only effective against trophozoites and not the cysts, therapy must be continued
until the host cell-mediated response can prevent recrudescence. In some
patients 6 to 8 weeks may suffice; in AIDS patients the treatment is frequently
lifelong. All patients treated with pyrimethamine combination therapy must be
followed for the development of blood dyscrasias.
Currently, clarithromycin and azithromycin are being tested as treatment
for toxoplasmosis, as they have been shown to be effective against the cystic
form of the organlsm.

Prevention
Acquired toxoplasmosis can be prevented through the adequate
cooking of meat (to 60’C) or freezing meat to less than -20’C for 24 hours (U.S.
freezers frequently do not reach this temperature). People should be instructed
to wash their hands after any contact with raw meat, and to wash fruits and
vegetables. Pregnant women in particular should avoid areas likely to be
contaminated with cat feces.
 Research is being conducted into the feasibility of a vaccine for
nonimmune women of childbearing age, and/or for the prevention of oocysts in
household cats.
SELECTED READING
Decker CF, Tuazon CU. Toxoplasmosis: an update on clinical and therapeutic
aspects. Prog CIin Parasitol 1993;3:2141.
Luft BJ, Remington JS. Toxoplasmosis. In: Hoeprich PD, Jordan MC, ronald
AR, eds. Infectious diseases, 5thed. Philadelphia: Lippincott, 1994;1201-1213.
McCabe RE, Remington IS. Toxoplasma gondii. In: Mandell GL, Douglas RG
Jr, Bennett JE, eds. Principles and practice of infectious disease, 3rded. New
York: Churchill Livingstone, 1990;2090-2101.
New LC, Holliman RE. Toxoplasmosis and human immunodeficiency vurus
(HIV) disease. J Antimicrob Chemother 1994;33(6): 1079-1082.
St. Georgiev V Management of toxoplasmosis. Drugs 1994;48(2):179-188.
wong Sl Remington JS. Toxoplasmosis in pregnancy. Clin infect Dis 1994;
18(6):853-86 l.
American Trypanosomiasis (Chagas’ Disease)
Described in 1909 by the Brazllian physician Carlos chagas,
American trypanosomiasis is caused by the flagellated protozoan Trypanosoma
cruzi. It is initially an acute systemic illness, and it can, after a long latent
period, lead to a chronic and often fatal disease of the heart and gastrointestinal
tract. It is a leading cause of death in South America, particularly among young
and middle-aged adults.
Epidemiology
Trypanosoma cruzi is a zoonosis. Humans are participants in its life
cycle, but are unnecessary to its continuation. The protozoans are transmitted by
the blood-sucking reduviid (kissing or assassin bug), which lives in the cracked
walls or palm-thatched roofs of impoverished rural areas and urban slums. It is
found in the Western hemisphere from the southern half of the United States
south to Argentina, and is most prevalent in Brazll, argentina, Chile, Bolivia,
and Venezuela. There are only three reported autochthonous cases in the United
States; this is attributed to the relatively high housing standards in the United
States and the tradition of separating farm animals from humans, thus
discouraging a domestic cycle of transmission. However, 16 to l8 million
people worldwide are infected with T.cruzi, and more than 50,000 immigrants
to the United States are estimated to carry the chronic infection. The disease can
also be spread by transfusion, and it is estimated that one in eight transfusions
from asymptomatic seropositive donors results in an acute infection in the
recipient. Reliable serologic screening of donor blood is not yet uniformly
available, and at present blood is not routinely screened for T. Cruzi in the
United States. Three cases of transfusion-acquired trypanosomiasis have been
reported in the united States.
Pathophysiology
The T. cruzi protozoan is transmitted via the reduviid bug’s feces,
left on the host during a blood meal. They enter the host cells via breaks in the
skin and mucus membranes. Parasitized host cells rupture, leading to an
inflammatory response most prevalent in cardiac, striated, and smooth muscle,
and glial cells. This can cause an acute myocarditis, destruction of autonomic
ganglia in the heart and digestive tract, and occasionally CNS damage. The
acute inflammation gradually subsides as the immune response leads to a
decrease in the number of prolozoa in the blood and tissue.
However, low numbers of protozoa persist for the life of the host,
which can lead to the chronic complications known as Chagas’ disease.
Progressive cardiac or gastrointestinal disease occurs in20% to 30%of all
patients, as cardiac muscle and,/or autonomic ganglia are replaced with
inflammatory cells and fibrous tissue. The factors that determine the outcome of
chronic sequelae-or why only a few develop them-is not understood.
Interestingly, there is a regional variation to the development of these sequelae,
with gastrointestinal problems being most prevalent in Chile, cardiac in
Venezuela, Columbia, and panama, and both (often in the same person) in
Brazil.
Clinical Findings
Fewer than l)oh of patients infected with T. Cruzi develop any acute
symptoms of infection. The insect bite itself is painless and occurs at night. The
most common symptoms, occurring I to 2 weeks after exposure, are those of a
mild flu-like illness lasting I to 2 months and resolving spontaneously.
Occasionally there is a “chagoma”-an ery.thematous cutaneous nodule several
centimeters in diameter at the site of the insect bite. Meningoencephalitis occurs
rarely in the very young; when it does, it is usually fatal.
Following the acute infection there is a variable (usually lifelong) latent
period during which there is no evidence of disease. However, parasitemias
remain at low levels and serologic tests for antibodies to T. Cruzi remain
positive.
Chronic sequelae can take decades to develop from the acute infection.
The first cardiac finding is usually a right bundle branch block pattern on ECG;
this can occur years before exercise tolerance is impaired. Eventually the patient
will manifest symptoms of congestive heart failure, usually dyspnea on exertion
and right ventricular failure with low cardiac output. The patient may present
with chest pain; however, the coronary arteries are usually not affected. About
one-third of patients with Chagas’ myocardiopathy die from ventricular
fibrillation, atrioventricular block, or pulmonary embolism from mural
thrombus.
Megacolon or megaesophagus also takes decades to develop. With the
latter, patients present with dysphagia, odynophagia, and regurgitation caused
by incomplete relaxation of the esophageal sphincter and decreased peristalsis.
This can lead to recurrent aspiration pneumonias, malnutrition, and carcinomas.
Patients with megacolon present with obstipation, obstruction, or volvulus.

Diagnosis
A history suggestion of possible exposure should make one suspicious
of the diagnosis, especially in an other wise healthy young person who suddenly
develops congestive heart failure, arrhythmias, heart block, or disorders of
swallowing or defecation. Laboratory testing is required for confirmation of the
diagnosis. In the acute stage, this can be done with observation of
trypomastigotes on a blood smear. Antibody testing is positive at any stage of
the disease, beginning about I month after the acute infection. There is a high
incidence of false positives on serologic testing due to cross-reactivity with
diseases such as syphilis or leischmaniasis; therefore, it is recommended that
three different conventional serologic wise healthy young person who suddenly
develops congestive heart failure, arrhythmias, heart block, or disorders of
swallowing or defecation. Laboratory testing is required for confirmation of the
diagnosis. In the acute stage, this can be done with observation of
trypomastigotes on a blood smear. Antibody testing is positive at any stage of
the disease, beginning about I month after the acute infection. There is a high
incidence of false positives on serologic testing due to cross-reactivity with
diseases such as syphilis or leischmaniasis; therefore, it is recommended that
three different conventional serologic tests be performed on each specimen.
Treatment
There is at present no specific and effective treatment for Chagas’
disease. Two antiprotozoal agents, nifurtomox and benznidazol, have been
shown to rapidly decrease the parasite concentration, decrease symptoms, and
improve survival when given during the acute infection. However, neither
completely eradicates the parasite and both are associated with significant side
effects. The effectiveness in preventing the chronic sequelae by treating the
acute stage remains to be determined. Neither drug is available in the United
States, but nifurtomox may be obtained from the CDC.
Treatment during the chronic stage seems to have little effect on its
course. Supporlive treatment is all that can be offered to patients with cardiac
symptoms, with two-thirds of such patients dying within 2 years of their first
episode of congestive heart failure. Cardiac transplantation can be effective, but
must be carried out at a center equipped to manage acute reactivation of
infection. Surgery is eventually required for patients with gastrointestinal
complications, and it can significantly relieve symptoms.
Prevention
Because treatment is so ineffective, current strategies for dealing with
American try/panosomiasis are aimed at prevention. This involves the use of
insecticides and improved housing conditions, as well as public health
education. Such programs have already reduced the numbers of new cases
reported annually in some countries, and the Pan American Health Organization
is investigating the feasibility of eliminating all new human cases by the year
2000.
SELECT READING
Kirchhoff L. Trypanosoma species (American trypanosomiasis, Chagas’
disease): biology of trypanosomes. In: Mandell GL, Douglas RG Jr, Bennett JE,
eds. Principles and practice of infectious disease,3rd ed. New York: Churchill
Livingstone, 1990;2077 -2084.
Maguire JH, Hoff R. American trypanosomiasis. In: Hoeprich PD, Jordan MC,
Ronald AR, eds. Infectious diseases,5th ed. Philadelphia: Lippincott, 1994:1201-
1213.
Villanueva MS. Trymanosomiasis of the central nervous system. Semin Neurol
1993 ;13(2) :209—21 8.
African Trypanosomiasis (Sleeping Sickness)
A protozoal disease caused by Trypanosoma brucei, african sleeping
sickness is transmitted to humans by the bite of the tsetse fly. It is found only in
Africa, where it is divided into the West African (gambiense) chronic form and
the East African (rhodesiense) acute form. The latter is more likely to be
encountered in an American ED, in a tourist recently returned from a game park
safari. In the past 20 years, 15 such cases have been reported to the CDC.
Epidemiology
Sleeping sickness is endemic in 36 sub-Saharan african countries,
where 20,000 cases are reported per year. The East African and West African
diseases are epidemiologically distinct, although the causative agents are
indistinguishable. Trypanosomes are transmitted to humans by the bite of the
blood-sucking tsetse fly. Congenital transmission or transmission by transfusion
are extremely rare.
Pathophysiology
T.brucei is able to evade the human host immune system by the
development of a glycoprotein coat made up of antigens that can be varied over
a dozen ways. The host sequentially mounts humoral responses to the
predominant antigens. Grossly, this leads to findings of vasculitis, intracerebral
ring hemorrhages, pancarditis, and inflammatory infiltrates and local necrosis in
other organs.
Clinical Findings
In the first stage of the disease, a cutaneous chancre develops at
the site of inoculation and persists for 3 weeks. Other symptoms of early disease
are nonspecific, resembling malaria, including intermittent fever and myalgias.
There may be transient edema of the extremities. Lymphadenopathy is
common; Winterbottom’s sign refers to posterior cervical nodes.
Stage two of the disease includes neurologic manifestations that
accompany progressive changes in the makeup of the central nervous system. In
Western try-panosomiasis these may take years to develop; in the eastern
version they occur within weeks, without a clear delineation between the first
and second stage. In either form, these manifestations are described as a
“progressive indifference,” with somnolence and sometimes extrapyramidal
signs progressing to coma and death.
Diagnosis
Clinical diagnosis of sleeping sickness requires a high index of
suspicion on those who have been in endemic areas. It is confirmed by
identification of the trypomastigotes in the blood, lymph nodes, CSE, or
aspiration of the chancre. Any CSF abnormality in patients with trypanosomes
isolated elsewhere must be viewed as indicative of CNS involvement. Serologic
testing for antibodies is nonspecific and thus far not reliable.
Treatment
Untreated, African trypanosomiasis is always fatal. Identification and
treatment in the early stages of the disease is almost always curative. Once the
disease spreads to the CNS the treatment itself can be lethal, and there is a l0%
mortality despite treatment at this stage.
Chemotherapy relies on three drugs, and the same regimen has been
used successfully for about 40 years. Pentamidine is used for prophylaxis and
treatment of the western form. Suramin is used for treatment of the early stage
of either Western or Eastern forms. Melarsoprol is used for late-stage, CNS
trypanosomiasis, because the other drugs do not cross the blood-brain barrier.
An arsenic derivative, it is highly toxic, and requires inpatient administration for
several 3-day series with 7-day rests between administrations. It can itself cause
a fatal toxic encephalopathy, and a reactive encephalopathy due to the rapid
destruction of trypanosomes (the Jarisch-Herxheimer reaction) may occur in up
to l0% of patients treated.
Prevention.
The old method of epidemic control, widespread destruction of
entire ecosystems, is successful but no loger tolerated in an environmentally
conscious world. Widespread application of insecticides has met with some
success. Personal protection with clothing, repellents, and avoidance of infested
areas is the most effective preventative method available for travelers.
Prophylactic drugs are toxic and are not appropriate for the tourist. There is no
vaccine available.
SELECTED READING
Bales JD J1 Harrison S. African trypanosomiasis. In: Hoeprich PD, Jordan MC,
Ronald AR, eds. Infectious diseases,5th ed. Philadelphia: Lippincott, 1994;1214-
1218.
Cattand P, deReedt P. Laboratory diagnosis of trypanosomiasis. Clin Lab Med
1991 ;11 (4): 899-908.
Kirchhoff LV Agents of African trypanosomiasis (sleeping sickness). In:
Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and practice of
infections disease, 3rd ed. New York: Churchill Livingstone, 1990;2085—2089.

RTCKETTSTAL (9.4)
Rocky Mountain Spotted Fever (9.4.1)
Rocky Mountain spotted fever (RMSF) is the most frequently reported,
and most virulent rickettsial disease in the United States. First identified in
Idaho and Montana in the late 1800s, RMSF is known to occur widely outside
of the Rocky Mountain region. It is endemic in the south-eastern United States,
and has been reported from every region of the continental United States.
Rickettsia rickettsii,the etiologic agent of RMSR was first identified in the early
part of the 20th century. The organisms are small, obligate, intracellular
coccobacilli that are poorly visualized by Gram stain. The may be demonstrated
by smears of infected tissue stained by the gimenez method or by
immunofluorescence. RMSF is transmitted by the bite of an infected tick, and
should be included in the differential diagnosis of anyone who presents with a
febrile illness after possible exposure to ticks. RMSF is usually clinically severe
and may be fatal unless recognized early and treated appropriately. Prior to the
advent of effective antibiotic treatment, fatality from RMSF in some areas may
have been as high as 80%. Permanent morbidiry although uncommon, has been
almost entirely attributed to delays in diagnosis.
Epidemiology /pathophysiology
Rocky Mountain spotted fever is transmitted by the wood tick
Dermacentor undersoil in the Rocky Mountain states, and the dog tick
Dermacentor variables in the Easter and southern states. It is uncertain whether
the lone Star tick Amblyomma americium serves as a vector for RMSF. RMSF
is a seasonal disease. Adult ticks feed on humans and infection occurs when the
organism is inoculated into the skin from the infected tick saliva. Infection
usually occurs between late spring and summer, with 95% of the cases reported
between April 1 and September 30. Sporadic cases have been reported
throughout the year, especially if the winter months are warm. Before
transmission can occur to humans, two conditions must be met: first, R.
Rickettsia must undergo reactivation from an a virulent state to a pathogenic
state. This occurs while the tick ingests a blood meal, and takes approximately 6
to 48 hours. Second, a period of time is required to release the organism from
the salivary glands ofthe tick. Prompt removal of the tick can prevent the
occurrence of infection.
While the incidence has decreased in the Rocky Mountain region, the
southeastern states have seen a dramatic rise in the incidence if RMSF. The
disease is endemic in every state except Maine, Alaska, and Hawaii. RMSF has
been reported from rural, suburban, and urban environments.
The highest incidence of infection occurs in persons aged 5 to 9
years. Other factors that are associated with increased incidence of infection
include contact with dogs, living in wooded areas, and male gender.
Once R. Rickettsii enter the body, they travel via lymphatics and
blood, proliferate in endothelial cells, and eventually invade the walls of blood
vessels, resulting in increased vascular permeability and vasculitis. The
mechanism by which the organism damages cells, however, is not clearly
understood.
Clinical Findings
Rocky Mountain spotted fever is a multisystem disease. Most patients
experience a moderate to severe illness that is characterizedby fever, rash, and
headache. frequently initial symptoms are nonspecific, including malaise,
myalgias, nausea, vomiting, anorexia, abdominal pain, and photophobia. A
history oftick exposure is found in60%to 70o/o ofthe cases. The usual
incubation period is 2 to 14 days, with the average being 7 days.
The rash typically appears between the third and the fifth day of the
illness; however, it may be delayed in up to 50%of the cases (almost spotless
fever) and approximately 10% of the cases may never develop a rash (spotless
fever). The rash usually begins on the extremities around the wrists and ankles,
spreads inward to the trunk and axilla, and may include the soles and palms.
The face is usually spared. The lesions initially begin as a pink maculopapular
rash that progresses to petechiae and purpura. The rash generally is nonpruritic
but rarely may be urticarial and pruritic. Progression to skin necrosis and
gangrene has been reported in2%to 4% ofthe cases.
Gastrointestinal signs and symptoms are common in RMSR especially
early in the course of the illness. Seven percent of the patients present with a
chief complaint of gastrointestinal problems. Abdominal pain, nausea, vomiting,
and diarrhea may occur, prompting a diagnosis of gastroenteritis and in some
cases has led to surgical exploration of the abdomen. As R. Rickettsii invade the
pancreas, liver symptoms of mild pancreatitis, hepatitis, or acute cholecystitis
may occur. Hepatomegaly, splenomegaly, and jaundice may be seen in 8% to
20% of the cases.
Pulmonary vasculature is a major target for infection by R. Rickettsli.
Pneumonitis results from vascular damage. Respiratory involvement in RMSF
occurs in 2%to 7% of the patients, and may result in a potentially life-
threatening pneumonitis. Patients may present with cough, dyspnea, pulmonary
edema, and hypoxemia. Infiltrates may be visible on chest x-ray.
 Rickettsial infection of the blood vessels of the brain may result in
rickettsial encephalitis. Patients may present with confusion, stupor,
deliriutransient hearing loss, and sensory neuropathy. Inappropriate secretion of
antidiuretic hormone and tardive dyskinesia have also been reported. On
physical examination patients may have papilledema and meningismus.
Neurologic dysfunction has been seen in 23% to 38% of patients with RMSF.
Most patients regain normal neurologic function; however, in patients whose
diagnosis has been delayed, resulting in severe illness, significant residual
deficits may persist.
Approximately l0% to l1oh, of patients may develop mild elevations in
the blood urea nitrogen. Development of acute renal failure is suggestive of a
poor prognosis. While electrocardiographic abnormalities are common in
RMSF, the heart is only mildly affected. Myocarditis has been reported in 5%
of patients. Conjunctivitis has been noted in l5%to 60% of patients.
Diagnosis
The clinical diagnosis of RMSF is frequently very difficult, despite
careful history and physical examination. Laboratory findings and early clinical
manifestations of RMSF are nonspecific, there may not be a history of tick
exposure, and the classical rash may be delayed or absent. In cases that are
ultimately fatal, the rash may be absent on initial presentation in up to 80% of
the patients. RMSF is relatively uncommon as compared with other viral
illnesses that occur during the same time of year, and it may mimic numerous
infectious and noninfectious disorders such as respiratory infections and
abdominal pathology. early definitive diagnosis of RMSF can be made with
skin biopsy of the rash and demonstration of R. Rickettsii by fluorescent-
antibody methods. Serologic testing, including the indirect hemagglutination
assay (IHA), indirect immunofluorescent assay (IFA), and latex agglutination
test, can be used for confirmation of the diagnosis. Since treatment must be
initiated before antibody is usually detectable (serologic studies usually do not
become positive for 6 to 10 days), the diagnosis of RMSF must be made on the
bases of clinical findings and history of potential exposure.
The leukocyte count in RMSF is usually normal; however, there is a
tendency to have more immature forms. Up to 80% of the patients have an
elevated white blood cell count greater than 15,000 cells/mm and l0% of the
patients have up to 50Yo band forms. Anemia has been noted in up to 30% of
the patients with RMSF. While 30% to 50% of the patients develop a mild
thrombocytopenia, severe thrombocytopenia is seen in less than 10% ofthe
cases.
 Elevated liver transaminases and total bilirubin are frequently seen in
RMSR but overt liver failure has not been reported. Hyponatremia has been
reported in 20% of the patients, and creatinine phosphokinase (CPK) has also
been noted to be elevated in many patients.
In general cerebrospinal spinal fluid (CSF) is normal. In patients with
moderately severe illness and potential brain involvement, the CSF shows
elevated protein and pleocytosis. Eight percent of the patients who undergo
lumbar puncture also have a glucose concentration in the CSF that is less than
50 mg/dl. The differential cell count in the CSF with RMSF typically has a
lymphocytic or polymorphonuclear cell predominance.
Treatment
Mortality for RMSF ranges from 4% to 8% and is higher in patients in
whom the diagnosis is delayed. Early treatment with rickettsial static antibiotics
such as doxycycline, tetracycline, chloramphenicol, and rifampin can be
lifesaving. Ciprofloxacin has also been shown to have antirickettsial activity.
Adults should receive doxycycline 100 mg orally two times a day; or
tetracycline hydrochloride 500 mg orally four times a day; or chloramphenicol
50 to 75 mg per kg per day intravenously in four divided doses. Children (under
45 kg) should receive chloramphenicol intravenously 100 mg per kg per day up
to a total dose of 3 g in four divided doses, followed by chloramphenicol 50 mg
per day orally. For children who are over 9 years of age doxycyline 4.4 mg per
kg is given orally in two divided doses on day 1, followed by 2.2 mg per kg per
day in a single dose; or tetracycline hydrochloride 30 to 40 mg per kg per day in
four divided doses. Doxycycline has been considered the drug of choice and
chloramphenicol has been reserved for children under 9 years of age and during
pregnancy. Due to the potential toxicities of chloramphenicol and short courses
of doxycycline in children only having clinically unapparent staining of teeth,
some authorities are recommending doxycycline for the treatment of RMSF
even in children under the age of 9 years. Physicians should consult with their
patients and discuss the risks for children with RMSF. Treatment should be
administered for at least 2 to 3 days after the patient is afebrile and has
clinically improved; usually this is for a total of 6 to 10 days. Antibiotics should
be administered intravenously in any patient who has nausea and vomiting.
Signs and symptoms that are associated with a poor prognosis and mortality are
hepatomegaly, jaundice, stupor, marked neurologic dysfunction, renal
dysfunction, age greater than 60 years, and inappropriate antibiotic therapy.
Management should also include close monitoring of fluid and
electrolyte balance, secondary to the fluid losses associated with increased
vascular permeability. Most patients with RMSF should be considered for
hospitalization. In very mild cases, patients who are tolerating oral antibiotics
and in whom compliance and close follow-up can be assured are appropriate for
outpatient treatment.
Prevention
Individuals who are outdoors in endemic areas should take
measures to protect themselves from tick bites. These measures include wearing
light-colored clothing to make crawling ticks visible, tucking pant cuffs into
socks to prevent ticks from gaining access to exposed skin, and using repellents.
Permethrin repellents can be applied to the clothes, which enhances their
protection, and repellents containing DEET (N N-diethyl-m-tolumide) can be
applied to exposed skin areas. Daily inspections for attached ticks should be
routine in endemic areas. Attached ticks should be removed immediately with a
fine forceps. The use of antibiotics during the incubation period delays the onset
ofthe illness but does not prevent the eventual development of the disease.
SELECTED READING
Archibald LK, Sexton DJ. Long term sequelae of Rocky Mountain spotted
fever. Clin Infect Dis 1994;20:1122 1125.
Dumler JS, Walker DH. Diagnostic tests for Rocky Mountain spotted fever and
other rickettsial diseases. Dermatol Clirn 1994;19(l):25-36
Jantausch BA. Lyme disease, Rocky Mountain spotted fever, ehrlichiosis:
emerging and established challenges for the clinician. Ann Allergy 1994;’73:4-
ll.
Kamper C. Treatment of Rocky Mountain spotted fever J Pediatr Health care
1994 ;5 (4):216-222.
Kirkland KB, Wilkinson WE, Sexton DJ. Therapeutic delay and mortality in
cases of Rocky Mountain spotted fever. Clin Infect Dis 1995;20:11 l81-121
Meyers SA, Sexton DJ. Dermatologic manifestations of arthropod-borne
diseases. Infect Dis Clin North Am 1994;8(3):689-712.
Sexton DJ, Corey GR. Rocky Mountain spotless and almost spotless fever: a
wolf in sheep’s clothing . Clin Infect Dis 1992;15:439448.
Shaked Y Rickettsial infection of the central nervous system. Q J Med 1991
;79(288):301-306.
Spach DH, Liles WC, Campbell GL, et al. Tick bome diseases in the United
states. N Engl J Med 1993;329(13):936-947.
Walker DH. Rocky Mountain spotted fever: a seasonal alert. Clin Infect Dis
1995;20:1111-1117.
Weber DJ, Walker DH. Rocky Mountain spotted fever. Infect Dis Clin north
Am l99l :5(l):19 35.
Ehrlichiosis (9.4.2)
Human ehrlichiosis was first recognized in the United states in
1986. The diagnosis of human ehrlichiosis has been difficult because its
nonspecific initial clinical presentation is easily confused with less significant
viral illnesses, and other tick-borne zoonoses such as Lyme disease and Rocky
Mountain spotted fever. Most cases of human ehrlichiosis have occurred in the
south central and southeastern part of the United States; however, some cases
have also been reported in the northeastern and the northwestern part of the
country. Ehrlichia chaffeensis, a small obligate intracellular bacteria, is believed
to be the causative agent of human monocytic ehrlichiosis (HME), and a
phylogenetically distinct organism of the genusehrlichia, which has yet to be
fully identified, is believed to be responsible for human granulocytic
ehrlichiosis (HGE). Studies suggest that ehrlichiosis is transmitted to humans by
the bite of Amblyomma americanum, a tick common in the south central and
southeastern United states. It also appears that other tick species such as deer
ticks and dog ticks may be capable of transmitting E.chaffeensis or other
antigenically related ehrlichiae.
Epidemiology/Pathophysiology
 Ehrlichiosis and Rocky Mountain spotted fever have similar
clinical presentations and epidemiologic features. Both diseases are more
common in the spring and early summer, which parallels the feeding activity of
ticks. Both diseases are also more common in males, most cases occur in the
southeastern and south central parts of the United States, and two-thirds of the
patients have a rural residence. Clinical and serologic evidence of E.
Chaffeensis infection, however, has also been reported from Europe and Africa.
The prevalences of human ehrlichioses are unknown; however, data suggests a
prevalence similar to that of Rocky Mountain spotted fever. Unlike Rocky
Mountain spotted fever, ehrlichiosis is not an endothelial infection, and
vasculitis is rare. The exact pathogenic mechanism of tissue injury is unknown.
All the natural animal reservoirs of E. Chaffeensis are unknown;
however, deer have been shown to have serologic evidence of E. Chaffeensis
infection. It would not be surprising if deer, horses, sheep, goats, cattle, or dogs
were all epidemiologically important hosts.
Clinical Presentation
Despite the different microbial etiologies of HGE and HME, their
clinical and laboratory manifestations are similar. Typically, the incubation
period ranges from 1 to 2l days, with a median of 11to 12 days. Patients usually
present with fever, headache, and myalgias. Often there are associated
gastrointestinal symptoms. A maculopapular rash occurs in less than 50oh of the
adult patients; as a result, ehrlichiosis has been termed spotless Rocky mountain
spotted fever. A rash, however, is apparent in most of the pediatric patients.
Petechial lesions are rarely seen.
Characteristic laboratory abnormalities that suggest the diagnosis
include the progressive development of leukopenia (often with a left shift),
thrombocytopenia, and anemia. Mild to moderate elevations in the serum
hepatic transaminase concentration are also typically present. Occasionally
patients present with signs and symptoms that are suggestive of a single organ
system predominance, resulting in initial diagnoses such as septic shock, viral
hepatitis, cholangitis, and hematologic malignancy. Specific findings may
include a cough with infiltrates on chest x-ray, gastroenteritis. Acute abdominal
pain, and meningitis.
The mean duration of the illness from date of onset until recovery
exceeds 3 weeks. While more than 60 %of the patients who are diagnosed with
ehrlichiosis are admitted to the hospital, this probably just reflects our bias
toward diagnosing more severe infections. Asymptomatic infections probably
occur about three times as often. Almost 16%o of the patients who are
diagnosed with ehrlichiosis develop severe complications, including renal
failure, disseminated intravascular coagulation, seizures, and coma. This
underscores the severe potential of these infections.
The fatality rate is not known, but it is estimated to be 2% to 5%for
HME and 7%to l0% for HGE. Mortality is increased in the elderly and in
patients in whom treatment has been delayed. Death due to secondary
nosocomial infections or opportunistic infections seems to be a common
finding.
Diagnosis
The diagnosis of ehrlichiosis depends mainly on clinical findings.
Early clinical diagnosis based on a high degree of suspicion and early
administration of antibiotics is necessary to assure a good clinical outcome.
diagnosis can be confirmed in retrospect by acute and convalescent serology at
least 2 to 4 weeks apart that reveals a fourfold rise in titer. Or diagnosis may be
made by a single high antibody titer for a patient with a compatible clinical
history. It must be emphasized that HME and HGE are caused by two different
organisms, and assays that confirm one do not identiff the other.
Ehrlichial infections may be recognized by the presence of morulae in
circulating peripheral blood leukocytes. This method, however, is insensitive in
diagnosing HME and its sensitivity in diagnosing HGE is unknown. Culture of
E. Chaffeensis has taken longer than 30 days, and thus is of little use in the
diagnosis of HME. The organism causing HGE has not been isolated. Currently,
more sensitive tools are being developed to allow for the early specific
diagnosis of human ehrlichiosis.
Treatment
Because of the similarities between Rocky Mountain spotted fever
and human ehrlichiosis, human ehrlichiosis was initially treated with
doxycycline, tetracycline, and chloramphenicol, with reported success. The in
vitro sensitivity of E. Chaffeensrs has since revealed that the organism is only
sensitive to doxycycline. Chloramphenicol does not appear to be effective in
vitro. Human ehrlichiosis may be severe or fatal in both children and adults;
therefore, doxycycline therapy should be administered as soon as possible to
both children and adults with suspected ehrlichiosis.
The recommended therapy for adults is doxycycline, oral or
intravenous, 100 mg twice a day, and forofdoxycycle doxycycline 3 mg per
kilogram per day in two divided doses. In children the total dose ofdoxycycline
should be minimized to avoid staining of the teeth. Most patients defervesce
within the first 24 to 48 hours after initiation of therapy. Doxycycline should be
continued for at least 3 days after defervescence. Current in vitro data suggest
that rifampin may be useful as alternate therapy in tetracycline-allergic patients.
Elderly patients, patients with underlying illness, and patients in whom therapy
has been delayed should all be admitted to the hospital for intravenous therapy,
as morbidity and mortality is high in these groups. Studies thus far appear to be
biased toward diagnosing and treating patients who are very ill with human
ehrlichiosis, and while we know that there is probably a significant number of
patients with asymptomatic infection, we currently do not know the full
spectrum of this illness. Patients who receive intravenous antibiotics seem to
defervesce faster than those with oral antibiotics; thus it would be prudent to
admit most patients with the diagnosis of ehrlichiosis, reserving outpatient
management for those patients with minor illness and close follow-up
Chronic ehrlichiosis and relapsing infection in humans has thus far
been reported only once. This is a problem, however, in a closely related species
reported in the veterinary literature. Close follow-up should be established for
recrudescence.
Prevention
Prevention of ehrlichiosis is the same as for Rocky mountain spotted
fever. Individuals who are outdoors in endemic areas should take measures to
protect themselves from tick bites. These measures include wearing light-
colored clothing to make crawling ticks visible, tucking pant cuffs into socks to
prevent ticks from gaining access to exposed skin, and using repellents.
Permethrin repellents can be applied to the clothes, which will enhance their
protection, and repellents containing DEET (N,N-diethyl-m-tolumide) can be
applied to exposed skin areas. Daily inspections for attached ticks should be
routine in endemic areas. Attached ticks should be removed immediately with a
fine forceps. The use of antibiotics during the incubation period delays the onset
of the illness but does not prevent the eventual development ofthe disease.
SELECTED READING
Bakken JS, Krueth J, Wilson-Nordskog C, et al. Clinical and laboratory
characteristics of human granulocytic ehrlichiosis. JAMA 199 6;27 5(3): 199-
205.
Dumler JS, Bakken JS. Ehrlichial disease of humans: emerging tick borne
infections. Clin Infect Dis 1995 ;20: I 112-1110.
Dumler JS, Dawson JE, Walker DH. Hematopathology and immunohistologic
detection of Ehrlichia chaffeensis. Hum Pathol 1993;24(4):39l-396.
Dumler JS, Sutker WL, Walker DH. Persistent infection with Ehrlichia
chaffeensis. Clin Infect Dis 1993 :17 :903-905.
Dumler JS, Walker DH. Diagnostic tests For Rocky Mountain spotted fever and
other rickettsial diseases. Dermatol Clin 1994;12(1):25-36
Everett ED, Evans KA, Henry B, McDonald G. Human ehrlichiosis in adults
after tick exposure. Ann Intern Med 1994;120(9):730-735.
Fishbein DB, Dawson JE, Robinson LE. Human ehrlichiosis in the United
states, 1985 to 1990. Ann Intern Med 1994;120(9):736-743.
Goodman JL, Nelson C, Vitale B, et al. Direct cultivation of the causative agent
of human granulocyic ehrlichiosis. N Engl J Med 1996;334(4):209 215.
Jantausch BA. Lyme disease, Rocky Mountain spotted fever, ehrlichiosis:
emerging and established challenges for the clinician. Ann Allergy 1994;73:4-
11.
Meyers SA, Sexton DJ. Dermatologic manifestations of arthropod-borne
diseases.infect Dis Clin NorthAm 1994;8(3):689-712.
Pancholi P, Kolbert CB Mitchell PD, et al. Ixodes dammini as a potential vector
of human granulocytic ehrlichiosis. J Infect Dis 1995;172: 1007-1012.
Silberg SL, Bisonni R, Parker DE, et al. Human ehrlichiosis-an overview. J
Okla State Med Assoc 1993;86:124-127.
Spach DH, Liles WC, Campbell GL, et al. Tick borne diseases in the United
states. N Engl J Med 1993;329(13):936-947.
Standaert SM, Dawson JE, Schaffner W, et al. Ehrlichiosis in a _qolforiented
retirement community. N Engl J Med 1995;333(7):420425.
Wormser G, McKenna P, Aguero-Rosenfield M. Et al. Human granulocyic
ehrlichiosis-New York 1995. MMIIR 1995;44(32):593-595.
VIRAL(9.5)
Human Immunodeficiency Virus (9.5.1)
Acquired immunodeficiency virus infection (AIDS) has been
recognized since 1981. The rate ofincrease in new cases has continued to rise,
but at a slower rate in the last 3 years. The CDC initially defined AIDS in 1982
and listed approximately 20 conditions signifying deficiency of cell-mediated
immunity related to the disease. The CDC has since made revisions of the
diagnostic criteria of AIDS, and in 1987 was the first to make reference to HIV
infection. The AIDS surveillance case definition was modified again in 1993 to
include additional clinical illnesses associated with the HIV infection, changes
in the clinical management of HIV-infected persons, and. A CD4 cell count less
than 200 cells/mm3 as one of the defining criteria ofAIDS (Table 9-l l). HIV
seroprevalence is unknown, but estimates in the United States have been
reported ranging from 0.5 million to 3.0 million cases. The incidence of newly
diagnosed AIDS in the United States is 50,000 cases/year.
Emergency physicians should be alert as to the possibility of HIV
infection when any patient presents with a history of having risk factors for HIV
and has clinical presentations consistent with opportunistic infections and those
diseases associated with AIDS. HIV testing is rarely indicated in the ED;
however, if suspicious of diagnosis, proper referral for counseling cannot be
stressed enough.
TABLE 9-11. Conditions included in the 1993 AIDS Surveillance
Case Definition
Bacterial infections, multiple or recurrent à
Candidiasis of bronchi, trachea, or lungs
Candidiasis, esophageal
Cervical cancer, invasive b
Coccidioidomycosis, disseminated or extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis, chronic intestinal (>1 month duration)
Cytomegalovirus disease (other than liver, spleen, or Nodes)
Cytomegalovirus retinitis (with loss of vision)
Encephalopathy, HIV-related
Herpes simplex, chronic ulcer(s) (>1 month duration); or
Bronchitis, pneumonitis, or esophagitis
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal (>1 month duration)
Kaposi’s sarcoma
Lymphoid interstitial pneumonia and/or pulmonary lymphoid
Hyperplasia
Lymphoma, Burkitt’s (or equivalent term)
Lymphoma, immunoblastic (or equivalent term)
Lymphoma, primary, of brain
Mycobacterium avium-intracellulare complex or M. Kansasii, disseminated or
extrapulmonary
Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary)
Mycobacterium, other species or unidentified species, disseminated or
extrapulmonary
Pneumocystis carinii pneumonia
Pneumonia, recurrent
progressive multifocal leukoencephalopathy
salmonella septicemia, recurrent
toxoplasmosis of brain
wasting syndrome due to HIV
‘Children younger than 13 years old.
Added in the 1993 expansion of the AIDS surveillance case definition for
adolescents and adults.
Pathophysiology
HIV was first described in 1983. This virus is a cytopathic retrovirus
that carries its genetic material in the form of RNA an4 with the enzyme reverse
transcriptase, can convert the viral RNA to DNA. This DNA is then
incorporated into the host cell’s genetic material. HIV is composed of an outer
envelope and a dense core containing RNA, reverse transcriptase, and p24
protein. The envelope contains gp4l, which is detected by ELISA and western
blot, and also a Wl20 protein. At least two types of this virus have been
identified HIV-I and HIV-2 in humans, HIV attacks monocytes, macrophages,
and particularly T helper cells, causing dysregulation of immunity, which
results in a defect in cellular immunity. Once viral exposure occurs,
seropositivity develops in as little as 4 weeks to as long as 6 to 8 months. The
mean tine between exposure and diagnosis of AIDS is 8.23 years for adults and
1.97 years for children under 5 years of age. The virus has been isolated in
bloo4 semen, vaginal secretions, urine, CSF, tears, breast milk, synovial fluid,
and saliva. However, only a few proven modes of transmission have been
identified, including sexual contact with both homosexual and heterosexual
exposure, intravenous drug abuse (IVDA), blood transfusion (especially prior to
1985), and maternal-neonatal transmission.
Diagnosis
A presumptive diagnosis of AIDS can be made by the clinical criteria
outlined by the CDC in 1993. The definitive diagnosis is most often attained by
HIV-I antibody tests. HIV-2 prevalence in the United States is extremely low at
this time and is not routinely tested. Screening assay includes the ELISA test
and results are confirmed by Western blot. HIV antibody is present in greater
than 95% of patients after 6 months of infection. Polymerase chain reaction
(PCR) detection of the p24 HIV-I antigen can be employed to determine the
presence of HIV Both of these tests are useful in detecting virus in individuals
Who have been recently infected but have not yet mounted an antibody
response, such as in newborns or following needle stick injury. Early
identification of HIV infection is important for several reasons. First, treatments
are available to slow the decline of immune system function. Second, patients
with HIV who have altered immune systems are at risk for other opportunistic
infections such as TB, Pneumocystis carinii pneumonia (PCP), and bacterial
pneumonias for which preventative regimens are available. Finally, HIV affects
the diagnosis, evaluation, and treatment of many diseases. HIV counseling is
recommended, and informed consent is required prior to testing.
 The CD4 Lymphocyte count is the best laboratory test indicating
severity of clinical progression. Patients with counts >500 cells/pl usually do
not show manifestations of clinical immunosuppression. Patients with CD4
counts <200 cells/pl are at a high risk for developing complicated AIDS
presentations.

Clinical Presentation
Systemic Symptoms
Within the first 2 weeks after infection with HIV a acute viral illness
may develop consisting of lymphadenopathy, fever, weight loss, and fatigue.
This occurs in approximately 20% of patients with HIV infection. Certain
individuals with HIV infection may present with generalized lymphadenopathy
that persists for more than 3 months. The axillary and posterior cervical nodes
are most commonly affected. The nodes are firm, mobile, and nontender.
Mucous Membrane and Cutaneous Manifestations
Kerosis and Pruritis. Kerosis and pruritis are common among HlV-
infected patients. It is usually manifested prior to opportunistic infections.
Treatment with emollients or topical steroids are the mainstay. Bacterial
infections are commonly seen in these patients. Staphylococcus aureus infection
may present as folliculitis, etyma, or bullous impetigo. HlV-infected patients are
also more susceptible to chronic ulcerations with Pseudomonas aeruginosa.
Kaposi’s Sarcoma. Kaposi’s sarcoma (KS) is the second most common
manifestation of AIDS. “It is characterized histopathologically by proliferation
of a mixed cell population including endothelial cells” (Fauci, I991). Its
etiology remains unclear. “KS occurs most often among homosexual AIDS
patient populations and with only a small occurrence of KS in a number of HIV-
negative homosexual men, it is suggested that KS is due to a transmissible
infectious agent present in the male homosexual population” (Ray and Gately,
1994).
KS initially presents as small erythematous papules resembling insect
bites. The disease can progress, especially among AIDS patients, to a fulminant
course with skin and extensive visceral involvement. Lymph nodes, the
gastrointestinal tract, and the lungs are affected the most, although any organ
can be involved. In advanced disease, large plum-colored plaques develop with
angulated edges that spread to squamous epithelial and mucous membranes.
Therapy is usually recommended if morbidity with large tumor masses,
extensive edema, or ulceration are present. There is no curative treatment for
KS, and drug-induced toxicity is the limiting factor for prolonged use of the
current approaches. The use of chemotherapeutic agents such as vinblastine and
doxorubicin has resulted in transient improvement in advanced disease. Local
radiation (10 rads) for l0 treatments to the affected area, and cryotherapy have
also been used. A new liposomal drug, daunoXome, has been recently approved
to treat KS
Varicella Zoster. Varicella Zoster eruptions are common. With advanced
HIV disease, lesions can involve one or several dermatomes or may become
widely disseminated or ulcerative. The possibility of systemic involvement
should be considered. Herpes ophthalmicus, involvement of the trigeminal
nerve branch V¹, can lead to ocular complications if treatment is not initiated
early. Treatment consists of oral acyclovir and pain management if there are
only local symptoms of varicella zoster. Admission and IV acyclovir (5 to l0
mg/kg IV every 8Hours) is recommended until clinical resolution if debilitating
disseminated cutaneous lesions or systemic infection is present. Varicella zoster
immune globulin (VZIG) is recommended for HIV patients with primary
varicella zoster infection and for those with visceral involvement.
Herpes Simplex Infections (HSV-I and HSV-2). There may be local or
systemic involvement. “Most persons infected with HIV are co-infected with
one or both HSVtypes” (Safrin et al., 1991). These lesions may become chronic
and ulcerative, with the most common location in HIV patients being the
perianal area. The severity of illness depends on whether HSV infection is
primary or recurrent, on the site of infection, and on the degree of HIV-induced
immunosuppression.
HSV gingivostomatitis in HlV-infected patients, which is usually
secondary to HSV-I, may be more protracted than in the normal host with
extensive tissue destruction, poor healing of ulcerative lesions, and occasional
virus dissemination. Primary genital herpes, usually caused by HSV-2,
generally results in a more severe local infection, prolonged course, and more
severe systemic symptoms including fever, headache, and myalgias. Genital
herpes in HlV-infected patients, especially those with <50 to 100 CD4 cell
counts, have very frequent and exceptionally severe recurrences. Ulcerative
lesions may become secondarily infected. Other HSV infections include herpes
proctitis, herpes esophagitis, and HSV encephalitis.
Direct-virus culture from suspected lesions is the diagnostic
procedure of choice. Tzanck smear showing inclusions or multinucleated giant
cells, direct staining by infected cells for virus antigen, and antibody detection
methods are also used. HSV serology is rarely useful and does not change the
management. Acyclovir is the drug of choice for treating HlV-related HSV
infection. In non-imunocompromised patients with local infection, oral
acyclovir 200 mg five times daily for 10 days can be used. IV acyclovir at 5 to
l0 mg/kg every 8 hours is used for immunocompromised patients or patients
with severe, disseminated cases. These patients need to be hospitalized. Patients
with acyclovir-resistant HSV can be prescribed foscarnet at a dose of 40 mglkg
intravenously every 8 hours until clinical resolution. Although acyclovir is
important to the therapy of severe HSV infections, the safety of systemic
acyclovir has not been established. Oral acyclovir can be used as
chemosuppression for patients with frequently recurring (six or more episodes
per year) HSV infections.
Molluscum Contagiosum. Molluscum contagiosum is a superficial
cutaneous viral infection occurring in up to 20% of HlY-infected patients. The
lesions appear as multiple, small, flesh-colored umbilicated papules with a
whitish core in the center of each papule. They occur most frequently on the
head, neck, and intertriginous areas. The lesions can be sexually transmitted
with papules forming in the pubic area. Once the CD4 count falls below 200,
lesions tend to proliferate. Because the lesions rarely cause medical
complications, treatment is primarily for cosmetic reasons. Cryosurgery or
topical agents are used, yet lesions often recur.
Intertriginous Infections. Intertriginous infections are common
acaused by fungi such as Candida or Tricophyton. Diagnosis is made by
examining microscopic potassium hydroxide (KOH) slides of lesion scrapings.
Topical antifungal creams are the mainstay of treatm ant-fungal creams are the
mainstay of treatment
Human Papillomavirus Infection. Human papillomavirus (HPV)
infection, which causes genital warts, occurs in HIV patients with increased
frequency and severity. The lesions may be extensive and resistant to therapy.
The genital and perianal areas are usually involved
Treatment consists of cryotherapy, topical therapy containing
salicylic and lactic acids, and in extreme cases laser surgery. Cervical dysplasia
and carcinoma are clearly associated with HPV infection. Careful evaluation
and close follow-up are necessary once premalignant lesions have been
diagnosed.
Other Cutaneous Manifestations. Other cutaneous manifestations of
disease that occur with increased frequency and severity in HIV patients include
Epstein-Barrvirus, scabies, seborrheic dermatitis, and Reiter’s syndrome.
Neoplasms
There is a higher incidence of certain malignancies among HIV
patients including Kaposi’s sarcoma (as discussed above); lymphoma;
squamous cell carcinoma of the cervix, anus, and mouth; and basal cell
carcinoma. Pediatric HIV patients have a higher incidence of embryonic
carcinomas.
 ‘Approximately one-fourth of the lymphomas occurring in the United
States are HlV-related” (Rhame, 1994). These lymphoma tumors are mostly B
cell type. The course of illness is usually more progressive, with a median
survival of 4 months. Bone marrow biopsy is the diagnostic procedure of
choice. Extralymphatic disease is common with cutaneous nodules, oral
ulceration, and gastrointestinal involvement, with abdominal pain occasionally
being the initial presenting complaint. Response to treatment is poor.
Cervical dysplasia, a precursor lesion that may progress to cervical
cance! Is common among HIV-infected women and increases in severity as
immunosuppression worsens. The addition of invasive cervical cancer to the
1993 CDC diagnostic criteria for AIDS emphasizes the importance of
gynecologic care for HIV-infected women.
Neurologic Complications
AIDS Dementia. AIDS dementia, also referred to as HIV
encephalopathy, is caused by direct HIV infection of central nervous system
endothelial cells, astrocytes, and microglial cells. It is a progressive dementia
that consists of impairment of recent memory, inawith activities of daily living.
This syndrome occurs in over one-third of HIV patients and is progressive,
leading to severe mental deterioration. CT or MRI scans show cerebral atrophy
and widening of the sulci. Zidovudine (AZT) is used in therapy.
 Progressive Multifocal Leukoencephalopathy (PML). Progressive
multifocal leukoencephalopathy is caused by the Jakob-Creutzfeldt (JC) virus, a
polyoma virus that affects approximately 4o/o of patients with advanced HIV
disease. This subacute or chronic progressive illness is characterized by focal
neurologic findings such as hemiparesis, gait disturbances, visual field defects,
and personality changes. With severe disease one can see dementia,
encephalopathy, and coma. CT or MRI scans show focal or diffuse lesions in
the white matter. Most cases of PML progress to death within 4 to 5 months.
Experimental therapy with AZT or intrathecal cytosine arabinoside (araC) has
shown some stabilization of symptoms in a small group of patients.
Tbxoplasmosis. Toxoplasma gondii is an obligate intracellular
protozoan and is the most common cause of focal encephalitis in patients with
AIDS. The majority of patients present with a severe, incapacitating headache
and fever. Patients may also have focal neurologicdeficits, altered mental stafus,
and seizures. Frankeningismus is uncommon. Involvement of other organs,
including the lung, heart, muscles, gastrointestinal tract, and eyes, are common.
Diagnosis with contrast-enhanced CT scan showing ring-enhancing
lesions identifies CNS toxoplasmosis. MRI or delayed CT scanning may be
needed to make the diagnosis. Lumbar puncture results are nonspecific, but can
rule out other opportunistic infections. A PCR assay to detect toxoplasmosis is
being developed. Serologic tests are useful in diagnosis.
Treatment consists of oral sulfadiazine 100 mglkg/day in two divided
doses for 2 days as a loading dose followed by 75 to 100 mg/day with
pyrimethamine 75 mgikg loading dose followed by 75 to 100 mg/day. Folinic
acid therapy should be given since these medications block folic acid
metabolism. Chronic suppressive therapy is needed after the initial episode is
treated.
Cryptococcal Infection. Cryptococcus neoformans is by far the most
common life-threatening fungal pathogen in patients with HIV infection. The
most common source is soil contaminated by bird droppings. Altered host
immune defenses allow local proliferation of fungus and dissemination. The
two most common sites of involvement include the central nervous system
(CNS) and pulmonary system. Cryptococcal CNS infection is seen in
approximately l0% of AIDS patients, causing meningitis, encephalitis, and a
focal granulomatous disease. Patients with CNS involvement present with fever,
headache, malaise, mental status changes, and cranial nerve palsies. These
symptoms may be subtle. Seizures are rare. Respiratory involvement leads to
symptoms such as cough and fever. Chest radiograph may reveal multiple
subpleural nodules or infiltrates. Both the CNS and respiratory involvement can
lead to disseminated infection with painless skin lesions (macules, pustules, or
ulcers) and can involve other organs such as the heart, kidneys, adrenal, bone,
lymph nodes, and eyes.
Diagnosis of cryptococcal infection is by india ink preparation,
culture, or by detection of cryptococcal antigen in the CSF via a latex
agglutination test. The latter is positive in >90% of HlV-infected patients with
cultureproven cryptococcal meningitis. The CSF findings in non-HIV patients
include an elevated opening pressure and protein, low glucose, and a
lymphopleocytosis. These CSF findings may by absent in HlV-
immunocompromised patients.
Cryptococcal meningoencephalitis may be treated with either IV
amphotericin B (0.4 to 0.6 mglkg/day) or in combination with flucytosine for 6
weeks. Sixty percent of patients respond to therapy. Patients with extraneural
cryptococcosis most often require similar treatment with amphotericin with or
without flucytosine. Chronic suppressive therapy is also needed.
Herpes Simplex Virus (HSV) Encephalitis. HSV encephalitis usually
occurs in the setting of reactivated HSV infection. The majority of cases are
secondary to HSV-1. Symptoms include headache, seizures, altered mental
status, and coma.
 Diagnosis of HSV encephalitis in HIV patients with advanced disease
by clinical presentation alone is difficult. Some patients present with subtle
abnormalities, while others present with frank mental status changes, seizures,
and coma. In general, with the presence of headache, fever, and seizure in the
absence ofother clear etiologies in an HIV patient, empirical treatment for HSV
encephalitis should be started. CT scan may reveal enhanced cortical uptake in
the temporal area. Lumbar puncture findings in HSV encephalitis are
nonspecific with elevated protein, normal glucose, and a lymphocytic
pleocytosis. Viral cultures of CSF are usually negative. Newer diagnostic
procedures such as detection of HSV DNA from CSF by PCR are still
investigational. EEG may show diffuse slowing or periodic laLeralized
epileptiform discharges. Definitive diagnosis is by biopsy only.
Intravenous acyclovir 1.5 mglkglday is the treatment of choice for 7
days or until clinical resolution. Patients with acyclovir resistant HSV can be
prescribed foscarnet at a dose of 40 mgkg intravenously every 8 hours. These
patients require hospitalization.
HIV Neuropathy. HIY neuropathy usually presents with a painful
peripheral neuropathy. Toxic neuropathies associated with didanosine (ddl) or
calcitabine (ddC) always present initially with symptoms in the feet or the
hands. Neuropathy may respond to zidovudine. Some patients receive
symptomatic relief from amitriptyline.
Pulmonary Complications
Pneumocystis carinii pneumonia (PCP) is the most contmon life-
threatening opportunistic infection in patients infected with HIV P carinii, once
considered to be a protozoan, has recently been shown through studies of RNA
to show a similarity with fungi. P carinii is ubiquitous in nature and commonly
exists in a latent phase in many asymptomatic individuals. The mode of
transmission is unknown but is presumed to be by the airborne route. The
opportunistic pathogen can cause severe disease when the host’s immune
system becomes depressed. This infection is most likely to occur when the CDa
count is less than 200 cells/mm3.
Symptoms usually have an insidious onset including fever, chills,
sweats, cough, and dyspnea on exertion. Physical findings include tachypnea,
tachycardia, and cyanosis, but lung auscultation usually reveals minimal
abnormality. In patients with HIV disease, extrapulmonary infection is common
and can include the eyes, skin, thyroid, pituitary bone marrow, kidneys, heart,
liver, and lymph nodes.
 The white blood cell count variability is usually secondary to drug
effects or other disease manifestations rather than as a result of PCP
involvement. Serum lactate dehydrogenase (LDH) is frequently elevated. ‘A
recent study showed that only 7%o of those patients with documented PCP had
normal LDH levels” (Simon, 1994). Arterial blood gas measurements usually
show an increased P(A-a)Oz gradient and a low PaOz. A P(A-a)Oz gradient
greater than29 mm Hg and aPaOz less than 70 Mm Hg are associated with a
poor outcome. Diffirseinterstitial infiltrates with peripheral sparing is the most
common chest radiograph finding. Other findings include abscesses, cavitations,
lobar consolidation, nodular lesions, pneumothoraces, and normal chest
radiographs. Pleural effirsions are rare.
Sputum stains are not very sensitive. Fluorescent antibody stain has
been shown to be as high as 90% sensitive. Sputum induction with hypertonic
saline solution has a sensitivity of approximately 75%,and if negative the
diagnosis should be confirmed with the combination of bronchoalveolar lavage
(BAL), bronchial brushings, and washings with a transbronchial biopsy, which
has become the gold standard with a diagnostic yield of near 100%. BAL alone
has a sensitivity of approximately 80% to 90%. Serologic testing for PCP is not
helpful. Gallium scanning of the lung is very sensitive for PCP but specificity is
low at 21%
 Treatment of PCP is with trimethoprim (TMP) (20 mglkgl day)-
sulfamethoxazole (SMX) (l 00 mglkgl day). Adverse reactions include rash,
increased liver function tests, vomiting, and neutropenia. In patients who have
adverse reactions or fail to respond to the above regimen, pentamidine at 4
mgkgl day intravenously can be given. About 50o/o of patients on pentamidine
develop adverse reactions, including hypotension, renal toxicity, hypoglycemia,
neutropenia, thrombocytopenia, rash, elevated liver enzymes, and pancreatitis.
The usual length of treatment is 14 to 2l days. Oral dapsone/TMP in
combination has been used for outpatient treatment of PCP. Dapsone is
contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency
and pretreatment screening is recommended. Other drug regimens used to treat
PCP are clindamycin and primaquine.
Prophylaxis with oral TMP (5 mglkglday) and SMX (25 mglkglday),
or oral dapsone (50 to 100 mg/day) has been shown to be effective. Aerosolized
pentamidine (300 mgl4 weeks) is also used for pulmonary prophylaxis but is not
effective for systemic prophylaxis secondary to poor systemic absorption.
Steroids have been shown to be beneficial for patients with POz less than 70
mm Hg or P(A-a)Oz gradient greater than 35. It should be started within 72
hours of antimicrobial treatment. In patients with HIV disease, the mortality rate
for the first episode is now 10% to 15%, which is reduced from earlier rates of
60%to 70% This is thought to be secondary to better drug regimens and earlier
diagnoses. Since HIV patients with PCP can decompensate quickly, they should
be admitted for initial treatment of pneumocystis infection.

Tuberculosis
Tuberculosis is a frequent and treatable cause of moribidity and
mortality in HlV-infected patients. The majority of these cases are due to the
reactivation of dormant infection secondary to immunodeficiency. Racial and
ethnic minorities, immigrants, and residents of overcrowded institutions such as
shelters and prisons account for the majority of cases. “There is now evidence
that the reported increase in tuberculosis cases is related to the emergence of
AIDS” (Mehta et al., 1992). M. Tuberculosis is an obligate aerobic organism
that is spread mainly by the respiratory route. The clinical presentation of
tuberculosis in HlV-infected patients maybe atypical and diagnosis may be
more difficult, requiring more invasive diagnostic procedures. Pulmonary
involvement of tuberculosis is the major manifestation in immunocompetent
patients as well as in HlV-infected patients with a CD4 count greater than 300
cells/mm3. Patients usually present with fever, weight loss, malaise, cough, and
night sweats. These patients usually have focal pulmonic infiltrates and
cavitations. In HlV-infected patients with CD4 counts less than 200 cells/mm3,
the presentation is more atypical with a much greater frequency of
extrapumonary involvement and diffirse pulmonary disease with-out
cavitations. These patients more often have miliary tuberculosis and
involvement of lymph nodes, central nervous system, soft tissues, bone marrow,
and liver.
Physical examination findings include tachypnea due to
lunginvolvement,hepatosplenomegaly, and lymphadenopathy. Bacteremia
caused by M. tubercalosrs has been recently described. Chest radiographs show
diffuse interstitial lower lobe infiltrates with hilar enlargement as opposed to
typical radiograph findings of upper lobe infiltrates seen in immunocompetent
patients
Diagnosis is difficult in patients with HIV disease. Approximately
30% to 40% of these patients react to the tuberculin skin test. Sputum should be
sent for acid-fast bacillus smear and culture. Diagnosis may require smear and
culture of tissue specimens from involved sites or by bronchoscopy with biopsy.
“Most alarming is the emergence and transmission of multidrug
resistant Mycobacterium tuberculosis (MDRTB) defined as strains resistant to
two or more first-line drugs most commonly isoniazid and rifampin” (Uttley et
al., 1993). Treatment regimens involving five or six drugs are necessary. Other
choices of therapy include ciprofloxacin, amikacin, and imipenem. Initial drugs
should be chosen depending on drug susceptibilities from tuberculosis
organisms in the patient’s geographic location followed by susceptibility testing
of the organism isolated from the patient. Recommended treatment duration is
l8 to 24 months.
All patients with HIV and tuberculin skin test reaction gteater than
or equal to 5 mm who don’t have active TB should receive isoniazid
prophylaxis (300 mg/day for 12 months). HIV patients with possible TB
exposure should be evaluated with an anergy panel including control antigens
such as mumps, Candida, or tetanus toxoid. Even if the PPD skin response is
negative, those patients with anergic panels should receive isoniazid
prophylaxis for 1 year.

Psychiatric Disorders
The most common psychiatric disease presentations seen in patients
with HIV infection include delirium, dementia, depression, and psychosis.
Depression is common among AIDS patients and is exacerbated especially in
those with a history of depression before their HIV illness. Treatment consists
of hospitalization and psychosocial intervention. Antidepressants may be used
in those patients with symptoms of depression that last longer than 6 weeks.
 Delirium and dementia may be a manifestation of a primary
physiologic disease that should be thoroughly investigated since treatment can
be offered.
Psychosis in AIDS patients can present with a variety of symptoms
including hallucinations, abnormal behavior, and delusions. The etiology is
unclear. Treatment is similar to other psychosis. A full workup is recommended
for the initial presentation.

Ophthalmologic Manifestations
Cotton wool spots are the most common finding on fundoscopic
examination of patients with HIV infection. The etiology is uncertain and
patients are usually asymptomatic. The lesions may regress spontaneously and
patients usually have an excellent prognosis. No specific treatment is necessary.
Follow-up examinations are recommended.
Cytomegalovirus retinitis infection occurs in l0% to 15% of patients
with HIV infection. The virus can be spread by sexual contact, blood
transfusion, organ transplantation, or breast milk. In immunocompromised
patients the virus may reactivate, causing colitis, pneumonia, esophagitis, and
neurologic complications. The most common involvement in HIV patients is
ocular disease. Symptoms include painless loss of vision, visual field defects,
and a complaint of floaters. Fundoscopicexamination reveals large, yellow-
white granular areas with perivascular exudate and hemorrhage. Treatment is
with ganciclovir 5 mg/kg intravenously every 12 hours for 10 to 14 days.
Foscarnet 60 mg/kg intravenously every 8 hours can also be used. Maintenance
treatment is necessary.

Gastrointestinal Complications
Oral and Esophageal Candidiasis
Candida species are the most common fungal pathogens in HlV-infected
patients. Clinical presentations include mucocutaneous infections and rarely
systemic involvement. The majority of cases are caused by B.Albicans. Oral
involvement demonstrates curdlikepatches on the tongue and buccal mucosa.
The underlying mucous membranes are usually inflamed. Esophageal
involvement includes symptoms of odynophagia, dysphagia, and retrosternal
pain. Esophageal candidiasis is now included as one of the AlDS-defining
criteria. Rare extensive involvement with pseudomembrane formation has been
known to cause partial obstruction. “In patients with advanced HIV disease with
candidal esophagitis, oral thrush is almost always present” (Tauber et al.,1994).
Other mucocutaneous findings include balanitis, folliculitis, intertrigo, and
onychomycosis. Systemic candida is rare in HlV-infected patients yet should be
considered in patients with severe neutropenia, indwelling catheters, or
prolonged broad-spectrum antibiotics. Dissemination of Candida to sites such as
the lung, central nervous system, heart, and kidney has been documented.
The diagnosis of oral thrush is made by microscopic evaluation of oral
scrapings treated with 10% potassium hydroxide solution indenturing yeast and
pseudo hyphae. Cultures of oral lesions are not useful. The differential
diagnosis includes oral hairy leukoplakia, usually seen on the lateral borders of
the tongue. Unlike candidal thrush, the lesions cannot be scraped off.
Diagnosis of esophageal involvement by barium swallow is not as
sensitive as esophagoscopy with biopsy for definitive diagnosis. A presumptive
diagnosis of candidal esophagitis in a patient with esophageal complaints and
oral candidiasis should be made and the patient should be started on empiric
therapy with an antifungal agent for 2 weeks. Ifno oral thrush is evident,
esophagoscopy should attempted to rule out other causes of esophagitis such as
CMV or HSV In systemic involvement, blood cultures are often negative.
Diagnosis is usually made postmortem.
 Standard treatment of oral candiasis involves clotrimazole troche (10
mg) three to five times/day for 7 to 14 days. Also, nystatin suspension
mouthwash can be used. Oral ketoconazole (200 to 400 mglday) is also
effective if other regimens fail. For esophageal candidiasis, oral ketoconazole or
fluconazole for 2 weeks or for I week after symptoms resolve is the preferred
treatment. For those patients with esophageal involvement who fail oral
treatment, low-dose intravenous amphotericin B (10 to 20 Mglday) may be
used. Systemic infection requires intravenous amphotericin B (0.6 to 0.8
mg/kg/day) for 6 to 8 weeks.

Herpes Esophagitis
Herpes esophagitis affecting patients with HIV disease presents with
similar complaints as esophageal candidiasis with dysphagia and retrosternal
discomfort, yet visible oral lesions are often not present. The diagnosis of HSV
esophagitis often requires endoscopic evaluation with tzanck smear and biopsy
obtained for viral culture. Treatment is with acyclovir 200 to 400 mg orally five
times/day for mild or moderate HSV infection. Intravenous acyclovir at 5 mg/kg
every 8 hours is used to treat more severe HSV esophagitis. Treatment is
usually for 10 days or until all external lesions have crusted.

Herpes Proctitis
 Herpes proctitis is a frequent cause ofnongonococcal proctitis in
sexually active homosexual men. Symptoms include anorectal pain, perianal
ulceration, difficulty with urination, obstipation, and sacral neurologic findings.
Sacral paresthesias occur more frequently with HSV proctitis than with other
causes of proctitis. Diagnosis is by direct inspection of rectal mucosa and
virologic testing such as direct antigen detection or viral culture.

Hepatomegaly
Tender hepatomegaly and splenomegaly occur frequently with acute
HIV infection. Acute hepatitis has also occurred with hepatic enzyrnes,
returning to normal within 6 weeks. Hepatomegaly occurs in more than 50% of
patients with advanced HIV disease. “Mycobacterium avium-intracellulare
(MAC) is the most frequent hepatic pathogen in advanced HIV disease
occurring in l9% to 70% of patients” (Orenstein et al., 1985). CMV is also
noted to be a frequent infectious pathogen of the liver in patients with HIV M.
Tuberculosis, KS, cryptococcus, P carinii, and non-Hodgkin’s lymphoma are
also cited. Drug-induced hepatitis, mainly with sulfonamides, has been
implicated. Hepatitis B and C are common among HIV patients with a history
of intravenous drug use.
 Diagnosis is by history or liver biopsy findings. Treatment depends on
underlying cause and includes antimicrobial agents for specific infection or
chemotherapy for neoplasms such as KS.
Mycobacterium Avium-Intracellulare (MAC)
Other mycobacterium pathogens seen in HlV-infected patients include
the nonchromogenic Mycobacterium Avittm-intracellulare complex. M. Avium-
intracellulare is found in soil, dust, and water. The exact mode of transmission
is unknown. Clinically, these patients may present with fever, anorexia, malaise,
and weight loss, with diarrhea and abdominal pain secondary to involvement of
the gastrointestinal tract. Pulmonary symptoms are less cornmon. Compared to
M. Tuberculosis, MAC infections seem to occur later in course of HIV
infection, most often when the CD4 cell count is less than 50/mm3.
Diagnosis is made by attaining positive blood cultures, since bacteremia
is common with disseminated disease. Soft tissue biopsy and culture ofinvolved
sites also aids in diagnosis. Rapid diagnosis by acid-fast bacilli smear is helpful
for initiating empiric therapy for M. Tuberculosis until the culture results
become available. Unbke M.tuberculosis, MAC infection in AIDS is not
effectively treated with current chemotherapy regimens. A combination of drugs
including amikacin, ethambutol, clorazimine, and rifabutin is one possible
treatment for MAC, with a quinolone added as needed.
Diarrhea
Diarrhea is the most common gastrointestinal complaint and occurs in
50% to 90% of patients with advanced HIV disease. There are a wide vaiety of
protozoal,viral, and bacterial pathogens known to cause diarrhea in HIV
patients. Protozoan organisms include isospora belli, Giardia, microsporidium,
and cryptosporidium. The bacterial pathogens, primarily Salmonella, Shigella,
and Campylobacter, have higher rates of bacteremia and antibiotic resistance in
HIV patients.Infections are also more frequent and more severe. Viruses such as
CMV and HSV as well as fungi including Candida. histoplasmosis, and
coccidioidomycosis have also been known to cause diarrhea in these patients.
Malignancy with KS or lymphoma are other diagnostic possibilities. MAC
should always be ruled out in immunocompromised HIV patients who present
with gastrointestinal symptoms.
An idiopathic AIDS enteropathy has been proposed to account for the
diarrhea in HlV-infected patients who lack an identifiable pathogen. The
pathogenesis is unknown. It is thought that enteric HIV infection leads to
mucosal atrophy causing diarrhea and weight loss.
 Diagnostic measures include microscopic evaluation of stool for
leukocytes, ova and parasites, acid-fast organisms, and occult blood. Cultures
also should be done. Treatment involves hydration and correcting electrolyte
disturbances. Some bacterial dysenteries may require antibiotics.
Cardiovascular Complications
Cardiac involvement in HIV disease is uncommon. The most common
cardiac disturbances include pericarditis, pericardial effirsion, and dilation of
the right ventricle secondary to pulmonary hypertension. Focal myocarditis with
wall motion abnormalities may be seen. It is not known whether these
echocardiographic abnormalities seen in patients with advanced disease is due
to the HIV infection itself, to superinfection with other organisms, or is
secondary to unrelated factors. Cardiomyopathy is rare.
Renal Complications
Acute renal failure most commonly includes acute tubular necrosis, acute
interstitial nephritis secondary to drug toxicity, tubular obstruction secondary to
tumorlysis syndrome, and hemolytic uremic syndrome or thrombotic thrombocytopenic
purpura. Parenchymal renal disease may be from opportunistic infections such as CMV
Cryptococcus, Candida, Mycobacterium, aspergillus, and tumors such as KS and
lymphoma that invade renal parenchyma. HIV nephropathy occurs in 50% to l0% of
patients with HIV infection. This usually progresses to end-stage renal disease requiring
dialysis. The clinical presentation includes heavy proteinuria. Azotemia, normal blood
pressure, and enlarged kidneys on ultrasound.
Othermiscellaneouss Conditions
Idiopathic thrombocytopenia (ITP) in the HlV-infected patient presents with
complications associated with low platelets. Normal numbers of megakaryocytes are
seen in the bone marrow. Patients respond to treatment with zidor,.udine, prednisone,
immune globulin, and as a last resort, splenectomy. Relapses are common if steroids are
tapered.
HIV myopathy in the HlV-infected patient presents with proximal muscle
wasting and an elevated CPK from breakdown of affected muscles. The first step in
treatment is a holiday from zidovudine. Trials with nonsteroidal antiinflammatory
agents are used for treatment, and in severe cases steroids are used with some success.
Antiviral Drugs in Clinical Practice
Antiviral therapy in HI! Although of limited success as yet, is still the
best treatment course available to slow the progression of AIDS. The antiviral
drugs being used at present are targeted to inhibit HIV replication steps
including the HIV reverse transcriptase and protease enzyme pathways. There
are now six Food and Drug administration (FDA)-approved drugs to treat HIV:
 1. Zidol.udine (AZT, Retrovir)-reverse transcriptase inhibitor
indications: Asymptomatic individuals with CD4 Lymphocye counts less
than 500
Dose: (100 mg tab)-5 tab qd also given 2 tab t.i.d.
toxicities: Anemia, neutropenia, myopathy, headache, nausea
2. Didanosine (ddl, Videx)-reverse transcriptase inhibitor
Indications: Patients who cannot tolerate AZT or are failing onAZT
Dose: (100 mg tab) two tab b.i.d.
Toxicities: Pancreatitis, peripheral neuropathy, diarrhea, nausea
3. Calcitabine (ddC, Hivid)-reverse transcriptase inhibitor
Indications: Patients who cannot tolerate AZT or are failing onAZT
Dose: 0.75 mg t.i.d.
Toxicities: Peripheral neuropathy, mucositis, pancretitis, arthralgias
4. Stavudine (d4T, Zerit)-reverse transcriptase inhibitor
Indications: Patients who cannot tolerate AZT or arc failing on AZT
Dose: 40 mg b.i.d.
Toxicities: Peripheral neuropathy, liver function abnormalities
5. Lamirudine (3TC, Epivir)-reverse transcriptase inhibitor
Indications: To be used in combination with AZT
Dose: 150 mg b.i.d.
Toxicities: GI upset, but generally very well tolerated
6. Saquinavir-protease inhibitor
Indications: To be used in combination therapy
Dose: 600 mg t.i.d.
Toxicities: Diarrhea, GI upset
Studies have shown that AZT increases survival in patients with advanced HIV
disease. Resistance has been documented and usually develops after I year of
use. Combination therapy with AZT and ddl or AZT and ddC have been found
to be more efficacious than AZT treatment alone. “These protease inhibitors
may act synergistically against HIV when used with other drugs acting at a
different stage ofthe virus life cycle” (Johnson et al., 1992). This combination
therapy is now being used to reduce toxicity and to reduce the rate of resistance
development.
Prevention
There has been a great deal ofprogress in the prevention of transmission
of AIDS today. Blood products are now much safer due to screening and heat
treatment. Hospitals need to continue encouraging medical personnel to follow
universal precautions when dealing with blood products. Prevention of sexual
transmission has been a challenge. The use of condoms has markedly reduced
transmission in major segments of the population but continued education is
still needed. Therapeutic vaccines are being evaluated against HIV yet no large-
scaletrials have been attempted at this time.
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Hermans P, Clumeck M. Kaposi’s sarcoma in patients infected with human
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18th ed. Norwalk, CT: Appleton & Lange,1989.
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Layton MC, Cantwell MF, Dorsinville GJ, et al. Tuberculosis screening among
homeless persons with AIDS living in single-room-occupancy hotels. Am J
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Acad Med Singapore 1995;24:442—446.
Loachim HL. Kaposi’s sarcoma and KSHV Lancet 1995;346(8686):1360.
Martinez AJ, Sell M, Mitrovics T, et al. The neuropathology and epidemiology
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tuberculoma—a comparative study in patients with and without HIV infection.
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Pauza CD, Streblow DN. Therapeutic approaches of HIV infection based on
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8(7):1184-1192.
Infectious Mononucleosis (9.5.2)
Infectious mononucleosis (IM) is a virally mediated generally benign,
lymphoproliferative disease characterized by tonsillitis, pharyngitis,
lymphadenopathy, hepatosplenomegaly, fever, fatigue, and malaise. Usually
children and young adults are affected with the vast majority of the population
exposed and immune to reinfection by age 25. In countries with poorer hygiene,
IM is a disease of early childhood and is rarely encountered in adults.
In 1967, the Epstein-Barr Virus (EBV), a double stranded DNA, herpes
virus, strongly trophic toward B Lymphocytes and epithelial cells of the
oropharynx and cervix, was identified as the etiologic agent of IM. Infection of
B lymphocytes by EBV permits unrestricted, indefinite, cellular proliferation in
the absence of adequate immune control, as witnessed in immunodeficiency
syndromes and transplant recipients. The oncogenetic potential of EBV-infected
cells is demonstrated through the association of EBV with such malignancies as
Burkitt’s lymphoma, nasopharyngeal carcinoma, T:cell Lymphoma, Hodgkin
and CNS lymphomas, and some thymomas. Additionally, oral hairy
leukoplakia, an overgrowth of epithelial cells on the tongue and buccal mucosa,
often noted in AIDS patients, is caused by EBV unlike other herpes viruses,
however, reactivation of EBV disease rarely occurs in immune-competent hosts.
Following exposure from respiratory droplets or oropharyngeal
secretions, and an incubation period of 3 to 7 weeks, patients with IM most
commonly present with the triad of pharyngitis, fever, and adenopathy. Blood
analysis reveals a predominant lymphocytosis with greater than l0% atypical
lymphocytes and frequently a mild thrombocytosis. The presence of heterophile
antibodies capable of agglutinating sheep erythrocytes with a titer of l:56 or
greater, as measured by the Paul-Bunnelldavidsohn assay, along with the above
clinical and hematologic parameters, is generally adequate for the diagnosis of
IM. The Paul-Bunnell-Davidsohn assay has subsequently been refined into the
rapid latex agglutination test, the Monospot. It is essential to note that up to
20% of addts and an even greater percentage of children
Under 4 years of age fail to produce heterophile antibodies resulting in a false-
negative Monospot. Additionally, anywhere from 5% to l5% of patients
demonstrate a false-positive Monospot in response to heterophile antibodies
produced to other infections such as cytomegalovirus, adenovirus, and
toxoplasmosis. In the few instances where it is imperative to definitively
identify the presence of EBY specific assays are available to detect various
EBV components.
The vast majority of patients with IM require only supportive care.
However, up to 50% of patients with IM develop an enlarged and congested
spleen susceptible to rupture from seemingly even minor trauma. Additionally,
spontaneous splenic rupture, though rare, is also known to occur. Splenic
rupture is the most common cause of death due to IM. It seems wise, therefore,
to advise patients to refrain from contact sports for 3 to 6 months following
illness or until splenomegaly has resolved, as determined by ultrasound. The
exudative pharyngitis, common in IM, should be cultured for concomitant group
A B-hemolytic strep infection and appropriately treated if present. Ampicillin or
amoxicillin should not be used due to the frequent rash they precipitate in
patients with IM. Special attention should be paid to the patency of the airway
with the use of corticosteroids to reduce tonsillar and pharyngeal edema and
obviate airway obstruction. Additionally, steroids may be beneficial for the
treatment of other complications of
IM such as severe hemolytic anemia, thrombocytopenia, or neurologic
manifestations such as Guillain-Barr6 syndrome, encephalitis, meningitis,
transverse myelitis, neuropathies, optic neuritis, cranial nerve palsies, and
cerebellar ataxic.
The differential diagnosis for patients presenting with symptoms
compatible with IM includes streptococcal pharyngitis, Cyanobacterium
diphtheria, CMY, rubella, HIV adenovirus, hepatitis A and B, Tbxoplasma
gondii, and other lymphoproliferative disorders.

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Anderson JP. Clinical aspects on Epstein-Barr virus infection. Scand J Infect
Dis Suppl 199l;78:94-104.
Bailey RE. Diagnosis and treatment of infectious mononucleosis. Am Fam
Physician 1994;49(4):87 9-885.
Connelly KP, DeWitt LD. Neurological complications of infectious
mononucleosis. Pediatr Neurol 1994;10(3):181-184.
MacGowan JR, Mahendra P, Ager S, Marcus RE. Case report:
thrombocytopenia and spontaneous rupture ofthe spleen associated with
infectious mononucleosis CIin Lab Haematol 1995;(l7):93-94.
Straus SE, Cohen JI, Tosato G, Meier J. Epstein-Barr virus infections: biology,
pathogenesis, and management. Ann Intern Med 1993;118(1):45-58.
Influenza (9.5.3)
Influenza is a virally mediated disease characterized by frequent epidemics
and episodic global pandemics. It has a seasonal predilection and occurs in the
winter months in the northern hemisphere and summer months in the southern
hemisphere and year round in the tropics. Thousands of deaths are attributed
yearly either directly to influenza or to its related complications. Additionally,
the four pandemics this century have resulted in millions of lost lives. The
pandemic of l9l8-1919 alone resulted in 20 million deaths, more than those due
to the first world war. Further, absenteeism from work and school due to
influenza has significant economic consequences.
The influenza viruses are single-stranded RNA viruses belonging to the
orthomyxovirus family. Influenza types A, B, and C are distinguished by their
nuclear material. Types A and B are clinically relevant to human disease.
Influenza virus (type A) has two glycoprotein surface antigens, hemagglutinin
and neuraminidase, that allow for the formation of unique subtypes through
antigenic shift. There is minimal to no immune cross-reactivity of the new
subtype relative to prior strains, this exposing large masses of the global
population to disease and subsequent worldwide pandemics. Antigenic drift
permits minor alterations of the surface antigens of both influenza A and B and
accounts for the observed yearly variations in viral strains. Vaccines for
influenza A and B are generated based on predicting which strains will be
prevalent during the infectious season.
A24-to 48-hour incubation period follows exposure to the virus via
aerosolized or droplet transmission. The viral syndrome begins with the abrupt
onset of fever and progresses rapidly, causing myalgias, headache,
nonproductive cough, rhinorrhoea, sore throat, and malaise. Photophobia is also
often present. Generally, systemic symptoms abate within 5 days with
symptomatic treatment alone, although fatigue may persist for several weeks.
The diagnosis of influenza is most often clinical and based on the presence of
known influenza in the community and the above symptomatology. Laboratory
conformation through viral culture or serologic markers is not adequately rapid
to be clinically relevant, but it is useful for epidemiologic considerations. The
differential diagnosis of influenza includes mycoplasma, early measles, Q fever,
and other viral upper respiratory tract infections.
 Infection rates during epidemics is highest among young children and
adolescents; however, complications due to influenza most commonly occur in
the very young, The elderly with superimposed medical conditions, or immune-
compromised individuals. Influenza pneumonitis is a rare but aggressive and
potentially devastating complication of influenza that most often affects patients
with underlying cardiopulmonary disease. Secondary bacterial pneumonias due
to Staphylococcus aureus, streptococcus pnettmonia, or Haemophilus
influenzae may occur 1 to 2 weeks following the initial viral disease. Other
complications include encephalitis, pericarditis, myocarditis, and myositis.
Reye’s syndrome has been associated with the use of salicylates in young
children with Influenza B and varicella zoster.
Prevention of influenza through effective immunization of the high-risk
population remains the cornerstone of influenza control. The elderly and those
with preexisting cardiac or pulmonary disease or immune compromise
are primary targets for vaccination. Additionally, those living in close quarters
who desire to limit exposure and reduce out of work J school time should
receive vaccine prophylaxis. Pregnant women who are at moderate risk of
influenza complications should be vaccinated during the second or third
trimester; however, vaccination should not be withheld at any time should the
patient be at high risk for complications. At present, an inactivated,trivalent
(antigens of influenza B strain and two strains of influenza A), vaccine is
available in the United States. The effectiveness of the vaccine is in part related
to the antigenic proximity of the vaccine to the actual influenza
Strains ofthe season in addition to host response factors. The vaccine is most
efficacious when given intramuscularly within 2 to 4 months but at least 2
weeks prior to exposure. Children less than 9 years of age should receive
Two doses of 4 vaccine weeks apart to ensure an adequate immune response.
Children less than 12 years of age should receive the “split-virus” (disrupted
virus) vaccine since this is less react genic. Those older than 12 years of age
receive the “whole-virus” vaccine. The vaccine is produced in fertilized hens’
eggs; consequently, hypersensitivity to egg proteins is a contraindication to the
administration of the vaccine. Reactions to the vaccine include localized
erythema and discomfort, fever, chills, and myalgias. Anaphylaxis is rare and
most likely related to egg protein, neomycin, or polymyxin allergy. Children
under 6 months should not receive the vaccine due to the frequent occurrence of
febrile reactions. Immunization should be postponed in any person acutely
febrile until the fever has subsided.
 Chemotherapy utilizing amantadine and rimantadine, oral antiviral
agents, provides effective influenza prophylaxis as well as attenuates the
severity of the disease if given within 48 hours of the onset of symptoms. These
drugs have minimal if any activity against influenza B and C. Amantadine is
administered at a dose of 200 mg daily, 100 mg daily in the elderly and those
with renal impairment. These drugs have few serious side effects. Intolerance to
amantadine is manifested by central nervous system symptoms of insomnia,
headache, light-headedness, vertigo, and difficulty concentrating. These effects
are less pronounced with the use of rimantadine.

SELECTED READING
Cesario TC, Yousefi S. Viral infections. Clin Geriatr Med 1992;8(4):735-737.
LaForce FM, et al. Influenza: virology, epidemiology, disease, and prevenrton.
Immunization in Medical Education (supplement issues to Am J prev med)
1994;10:3140.
Wiselka M. Influenza: diagnosis, management, and prophylaxis. Br Med J
1994;308:1341-l 345.

Mumps (9.5.4)
 Mumps is generally a benign and self-limited disease caused by a
paramyxovirus. It predominantly afflicts young children and peaks during the
late winter and early spring months. Despite a radical reduction in the number
of yearly cases since the introduction of the mumps vaccine in 1967, the case-
fatality ratio remains relatively unchanged at approximately 1.8 deaths/10,000
cases.
The transmission of the mumps virus is via respiratory secretions.
Following replication in the respiratory epithelium and local lymph nodes, a
blood-borne viremia leads to seeding of other organs. Unilateral or bilateral
Parotitis is nearly always present and occurs within 3 weeks of exposure.
Additionally, fever and malaise are often noted. Meningoencephalitis associated
with mumps occurs at a rute of about 2.6/1000 cases with a fatality
rate of 1.4%.In one study orchitis occurred in nearly 10% males over 12 years
of age. Of significance is the rare case of sterility due to mumps orchitis. Other
complications of mumps include arthritis, pancreatitis, thyroiditis, myocarditis,
nephritis, cerebellar dysfunction, and hearing loss. The vast majority of these
complications are self-limited.
Vaccination is the primary mode of mumps control. A live, attenuated
virus vaccine was approved for use in 1967 and is currently administered in
association with measles and rubella vaccine as the MMR. Seroconversion to
the mumps vaccine is on the order of 95%. Adverse reactions to mumps
vaccination are infrequent but include Parotitis, fever, rash, pruritis, purpura,
and rare cases of CNS dysfunction.

SELECTED READING
Hayden GF, Preblud SR, Orenstein WA, Conrad JL. Current status of mumps
and mumps vaccine in the United States. Pediatrics 1978;62(6):965-969.
Nussinovitch M, Volovitz B, Varsano I. Complications of mumps requiring
hospitalization in children. Eur J Pediatr 1995;154:732-734
Quion N, Dewitt TG. Diagnosis: mumps parotitis (case 3). Pediatr Ret
1995;16(9):351.
Sullivan KM, Halpin TJ. Kim-Farley R. Varks JS. Mumps disease and its health
impact: an outbreak-based report. Pediatrics 1985;76(4):533-536.
Volk WA Essentials of microbiology, 2nd ed. Philadelphia: Lippincott,
1982:661-662

Poliomyelitis (9.5.5)
 Acute poliomyelitis reached epidemic proportions during the first half
of the 20th century. Outbreaks were sporadic and unpredictable but with a
predilection for late summer and fall months. The polio virus, with its
propensity for afflicting children, left a significant youthful population
paralyzed and debilitated or dependent on artificial ventilation. Images of
children with respiratory muscle involvement interned in the now famous, yet
Obsolete, “iron lungs” graphically demonstrate the physical devastation
rendered by the disease. Prior to the introduction of the Salk inactivated
poliovirus vaccine (IPV) in 1955 and the Sabin live, attenuated, oral poliovirus
vaccine (OPV) in the early 1960s, an estimated 25,000 to 50,000 cases of
poliomyelitis occurred annually. With the advent of effective immunization, a
radical reduction of the incidence of acute poliomyelitis occurred within a short
span of a few years.
The poliovirus is an RNA-based enterovirus from the family
Picornaviridae. Transmission is via the oral-fecal route and replication occurs
primarily in the oral and insestinal mucosa. Following infection, a viremia
occurs with subsequent viral involvement of the CNS in nonimmunized
individuals. Neurologic sequelae may include headache and meningismus (signs
of aseptic meningitis), and may progress to paralysis of respiratory, swallowing,
and extremity motor functions due to necrosis of anterior. Horn nerve cells.
Interestingly, susceptibility to acute poliomyelitis appears to increase with
pregnancy, trauma, and tonsillectomy. Also, despite being primarily a disease of
childhood rarely are infants less than 6 months of age infected, most likely a
result of passive transference of maternal immunity.
There appear to be three primary expressions of acute poliomyelitis: a
mild, self-limited form characterized by headache, fever, malaise, and upper
respiratory tract and gastrointestinal symptomatology that resolves without
residual deficit; a more severe variant with enhanced CNS features suggestive
of significant CNS and meningeal irritation, coupled with other attendant
aspects of the milder disease and again, self-limited; and an acute paralytic
poliomyelitis with extensive CNS involvement and anterior horn cell
destruction leading to varying degrees of paralysis and, at times, death. An
estimated 1/100 Patients developed the most fulminant form of acute
poliomyelitis during the epidemic period.
After an initial viral incubation period of 7 to 14 days, patients infected
by the polio virus generally present with nonspecific complaints similar to other
viral prodromes: fever, malaise, headache, sore throat, nausea, vomiting, and
diarrhea. Patients who eventually develop paralysis show increasing evidence of
CNS involvement and are noted to be irritable with varying degrees of CNS
depression. Meningeal irritation is marked, and patients complain of severe
headache and neck stiffness. Between 2 and 5 days after onset of CNS
symptoms, paralysis is displayed. Rather than weakness, most patients note
severe myalgias and spasm initially; often the back and neck are primarily
involved. Muscles are very sensitive to touch. Soon, an irregular pattern of
flaccid paralysis develops, usually involving the lower extremities first.
Infrequently, upper extremity or trunk paralysis occurs. Bulbar involvement
leads to the inability to handle secretions and occasional facial and extra ocular
muscle paralysis. Respiratory muscle compromise requires ventilatory support
to sustain life. On examination, nucheal rigidity is easily elicited. Hyperreflexia
and a positive Babinski sign reveal upper moto neuron dysfunction, and a
patchy muscle weakness is noted. During the polio epidemics, CSF analysis was
required for viral isolation and accurate diagnosis. A predominant
lymphocytosis (10 to 1000/hpf), elevated protein, normal glucose, and bacterial
culture negative are the usual findings. Currently, Poliovirus can also be
obtained and identified from CSF fluid, nasopharyngeal swabs, as well as fecal
material. Following the acute illness, recovery is slow and a significant subset
of patients are left with residual paralysis requiring prolonged rehabilitation.
 Treatment for acute poliomyelitis is largely supportive. Until the
introduction of artificial ventilation in the 1930s (the iron lung), many patients
with respiratory muscle paralysis died. Thus, despite its cumbersome
appearance, the iron lung greatly reduced the mortality associated with polio.
Rehabilitation was a primary focus of treatment. Initially, paralyzed limbs were
casted and immobilized. However, muscle wasting and further diminution of
function showed the ineffectuality of this approach anciled to aggressive
mobilization-based therapy. Extremities with continued need for support were
braced.
It is the success of worldwide immunization (particularly the Western
world) that has truly reduced the occurrence of polio.
Of import is the recent recognition of the post polio syndrome (PPS)
characterized by new neuromuscular symptoms 15 to 30 years following
recovery from acute paralytic poliomyelitis. PPS can be described as a slow
diminution of function of previously involved muscles following a period of
relative stability past the remote acute viral illness. Symptoms are most likely
related to decompensation of an already depleted pool of motor neurons. PPS is
a diagnosis of exclusion and generally only requires physician understanding
and patient reassurance owing to its slow and stuttering course.
SELECTED READING
Dalakas MC. The post-polio syndrome as an evolved clinical entiry Ann NY
Acad Sci 1995;753:68-80
Johnson RT. Pathogenesis of poliovirus infections. Ann NY Acad Sci
1995;753:361,-365 .
Mulder DW. Clinical observations on acute poliomyelitis. Ann NY Acad Sci
I 995;753: 1- 10.
Pascuzzi RM Poliomyelitis and the postpolio syndrome. Sentin Neurol
1992;12(3):193-199.
Volk WA. Essentials of medical microbiology,2nd ed. Philadelphia: Lippincott,
1982;636-639.

Rabies (9.5.6)
Annually, thousands of people die from rabies throughout the world. The
majority of these cases occur in developing nations, a reflection of widespread
disease in the animal population and inadequate rabies immunization.
 Over half a million people are bitten by animals in the united States
yearly. Between 20,000 and 30,000 receive postexposure rabies prophylaxis
(PEP). Although most cases of rabies in the United States have been secondary
to wild animal bites, the administration of PEP has been overwhelmingly
skewed toward dog and cat bites. The overall economic burden, inclusive of
animal vaccination, is estimated at approximately $300 million yearly.
In the 1940s, dogs and cats were the primary reservoir for rabies. Now
the vast majority of rabid animals in the united States are wild. Aggressive
rabies vaccination of domesticated animals has resulted in a radical reduction of
human rabies occurrences.
The skunk is the most commonly reported rabid animal followed by
raccoons, foxes, and bats. Bats are the most ubiquitous source of rabies.
Rodents are very rare carriers of rabies. Only about 15% of all rabid animals
isolated and domestic. Since their introduction to the hunting clubs of West
Virginia in the late 1970s, raccoons have established themselves as a major
source of rabies in the mid-Atlantic states.
Rabies virus is from the viral family rhabdoviridae. When introduced
into a wound, the virus remains at the site of inoculation from I to 4 days, then
presumably migrates into the CNS via nerve pathways. Involvement of the
salivary glands is most likely secondary to hematologic spread. Once symptoms
begin, the disease is nearly always fatal, with death occurring within 3 to l0
days.
The presence of Negri bodies, cytoplasmic inclusion particles in neurons,
is diagnostic of rabies, although a newer method, immunofluorescent labeling,
is often the test ofchoice.
Various modes of rabies transmission exist, the most common being a
bite wound with the introduction of virally contaminated saliva. Bite wounds
cause almost all cases of rabies, with bites to the face considered most serious
due to rapid involvement of cranial nerves. Non-bite exposures rarely result in
rabies infection. Corneal transplants have resulted in the only human-to-
liumantransmission. A few isolated cases of rabies via viral inhalation have also
been documented (i.e., in bat caves and laboratory exposure).
Symptoms of rabies infection are often nonspecific: fever, malaise,
headache, upper respiratory infection (URI), GI symptomatology, and, at times,
subtle alteration in mentation. Sialorrhea, agitation, weakness, or paralysis may
also be present. The incubation period is variable and often long
The most characteristic symptoms are hydrophobia due to dysphagia, a
result ofbulbar palsy, and paresthesias around the wound site. There is,
however, no single finding diagnostic ofrabies. Once established, the diseasr
nearly always progresses to a fatal encephalitis. Antiviral agents apper oflittle
value in altering the course ofthe infection.
Rabies is the only disease where postexposure immunotherapy results in
a cure. Ideally, treatment should be initiated within 24 hours of exposure but
should not be with help whenever the risk of rabies is suspected, owing to the
virus’s often extended incubation period
There are three cornerstones to successful treatment that must be
followed scrupulously: (l) wound cleaning (soap and water), (2) human rabies
immunoglobulin (HRIG) (passive immunization), and (3) human diploid cell
vaccine (HDCV) (active immunization). HRIG is given (20 IU/kg), with 50%
infiltrated around the wound site and 50% IM in the gluteal region. HRIG
suppresses the body’s response to HDCV so no more than the recommended
dose should be given. HRIG may be administered up to 8 days after HDCV
HDCV is given IM in the deltoid (1 ml on days 0, 3, 7, 14, and 28) for maximal
immune response. HRIG and HDCV should never be injected adjacently since
HRIG will inactivate HDCV Preexposure prophylaxis with HDCV should be
considered for individuals with a higher likelihood of encountering rabid
animals. The recommended vaccination sequence is HDCV I ml IM in the
deltoid on days 0, 7, and2l. A booster of HDCV I ml IM in the deltoid is given
on days 0 and 3 following exposure. HRIG is not administered.
Potential rabies exposure is reportable to public health departments.
Animals should be evaluated then appropriately observed, quarantined, or
sacrificed for pathology inspection, depending on the the circumstances of the
attack as well as their immunization and health status.

SELECTED READING
Anderson LJ, Nicholson KG, Tauxe RY Winkler WG. Human rabies in the
united States, 1960 to 1979: epidemiology. Diagnosis, and prerention. Ann
Intern Med 1984l-100:728-135
Fishbein DB, Baer GM. Animal rabies: implications for diagnosis and human
treatment .Ann Inrern Med 1988:109:935-937.
Fishbein DB. Robinson LE. Rabies. N Engl J Med 19931’329(22):1632-1638
Hatnvick MAW, Rubin RH, Music S, et al. Postexposure rabies prophylaxis
with human rabies immune globulin. JAMA 1974;227(4):407410.
Hatnvick MA, Hochberg FH, Landrigan PJ, Gregg MB. Skunk-associated
human rabies. JAMA 197 2;222(I):4447
Helmick CG. The epidemiology of human rabies postexposure prophylaxis,
1980-1981. JAMA 1983;250(1 5): 1 990-1996.
Houff SA, Burton RC, Wilson RW, et al. Human-to-human transmission of
rabies virus by corneal transplant. N Engl J Med 1979;300(ll):603-604. MCEP
News. 1993; l5(4):5-9.
Tintinalli JE, et al., eds. Emergency medicine: a comprehensive study guide, 2nd
ed. New York: McGraw-Hill, 1988 ;758-759.
Volk WA. Essentials of microbiology, 2nd ed. Philadelphia: Lippincott,
1982;668-67 1.

Rubella (9.5.7) (See 13.12.4.4)

Rubella, also known as German measles, is a moderately
contagious and typically mild illness, usually of children and young adults. It is
of importance because when acquired early in pregnancy it can cause multiple
fetal abnormalities collectively known as the congenital rubella syndrome

Epidemiologly
Humans are the only known natural host of rubella. The virus is
spread through inhalation of droplet nucleiemanating from the respiratory tract
of an infected carrier. Close and prolonged contact with the carrier seems to be
required for transmission; a single brief encounter does not appear to lead to
infectionest communicability appears to be from 5 days before to 5 days after
the appearance ofthe typical viral exanthem on the infected person. Infection
confers lifelong immunity in most people.
Since in the United States there is now a vaccine for rubella given in
childhood, most recent outbreaks have been among nonimmunized young adults
in prisons, colleges, and the military. While it is endemic throughout the year, in
the Northern Hemisphere most such outbreaks occur in the spring.
The widespread use of the vaccine in the United States has drastically
reduced the overall incidence of rubella, and virtually eliminated congenital
rubella syndrome (CRS). However 6% to 25% of women of childbearing age in
the United States are still susceptible to rubella. The risk of development of
CRS in infants approaches 100% when the mother contracts rubella in the first 2
Months of gestation; it decreases to virtually nil by 20 Weeks, gestation. In
addition, infants born with CRS are contagious for the virus for many months
after birth.

Pathophysiology
 The incubation period for rubella is 14 to 21 days, with viremia present
7 days before the presence of the exanthem. Within 24 to 48 hours of the
development of the rash, antibodies are detectable and circulating virus
disappears, leading to speculation that the rash represents an inflammatory
effect of an antibody-virus complex. Virus can be recovered during the viremic
phase of infection from all bodily fluids. After it disappears from the blood, it
continues to be shed from the nasal passages for up to 2 weeks.
When a woman in early pregnancy contracts rubella, the maternal
viremia causes placental infection from which the virus enters the fetal
circulation. There are four mechanisms that are ultimately responsible for the
development of congenital rubella syndrome: persistent infections causes
inhibition of cellular multiplication and retardation of organ growth;
vasculopathies interfere with blood supply to developing organs; direct tissue
necrosis occurs; and there is increased incidence of chromosomal damage. All
of this results in fetal malformation and/or death. The severity of the outcome
seems to be related mostly but not entirely to the time of infection.

Clinical Findings
A few days before the appearance ofthe classic rubella rash there is
usually a mild prodrome, especially in young adults. This consists of
conjunctivitis, headache, low-grade fever, malaise, and tender
lymphadenopathy, especially posterior cervical. The adenopathy peaks during
the rash a persists for weeks to occasionally months after-ward.
The classic rubella exanthem is a discrete pink maculopapular
eruption starting on the face and spreading rapidly downward, and fading in the
same order in which it appeared. It lasts 3 days in total. In adults, the rash can
be very pruritic, which can lead to a misdiagnosis of contact dermatitis if the
associated adenopathy is missed.
The prodrome, lymphadenopathy, and rash are all part of classic
rubella, but any one or all of these manifestations may not be apparent in every
case. The frequency of “inapparent rubella” ranges from 1 in 9 in the general
population to 6 in 7 in military recruits. In general, it is considered that 30% of
rubella cases are subclinical and therefore not detected.
There are rare complications of acquired rubella. Encephalitis is rare
(1 in 6000 cases), and more likely to occur in children. Mortality is high, but
there is a low incidence of permanent sequelae in those that do survive. Arthritis
occurs in 33% of women with rubella and is rare in children and adult males. It
can range from a mild arthralgia to overt arthritis, usually involving the fingers,
wrists, and knees. It is generally self-limited and clears without residua in 2 lo
30 days. In addition, skin and mucous membrane hemorrhage, myocarditis,
pericarditis, hepatitis, hemolyic-uremic syndrome, and testicular pain have all
been rarely described as associated with rubella.
Congenital rubella syndrome involves every fetal organ system; the
“expanded list” of manifestations associated with CRS includes 59 findings.
Major diagnostic categories include cataracts, retinopathy, and glaucoma;
congenital heart disease; hearing loss; microcephaly; mental retardation; and
meningoencephalitis.

Diagnosis
Acquired rubella can be clinically diagnosed with assurance only in the
presence of all the classic findings, or in an epidemic. Sporadic cases are almost
impossible to diagnose clinically. Specific diagnosis is usually made by
serologic testing, and several tests are available for detection of the rubella
antibody. A fourfold or greater rise in titers in samples obtained I to 2 weeks
apart indicates a recent infection. The presence of antibody is a reliable
indicator of past infection and therefore a presumptive indicator of immunity.
The diagnosis of congenital rubella syndrome is made by identification of
a series of malformations, with serologic testing confirming rubella (in the
neonate, this is usually both active IgM and passive maternal IgG).
Treatment
The treatment of acquired rubella is symptomatic in the vast
majority of cases, where the prognosis is excellent for full recovery. Supportive
therapy is indicated in the event of complications. Bacterial complications are
rare and there is no evidence that antimicrobials alter the course of
uncomplicated disease.
There is as yet no treatment for congenital rubella syndrome. Some
manifestations, such as glaucoma and hearing loss, require early detection and
intervention to ensure optimal future development.

Prevention
The United States Public Health Advisory Committee on
Immunization Practices recommends that the current live attenuated rubella
vaccine be given (usually in combination with measles and mumps vaccines) to
all children between the age of 12 months and puberty, adolescent and adult
males, and adolescent and adult females who are not pregnant, will not get
pregnant within 3 months, and are shown to be seronegative.
Vaccination during early pregnancy carries a small (0 to 1%) risk of
serious fetal malformation. The vaccine is also contraindicated in patients with
acute febrile illnesses or the immunocompromised. Complications of the
vaccine are related to the transient viremia it may cause, are more common in
adults, and are mild and self-limited.
Human immune serum globulin has been used prophylactically to prevent
rubella infection in seronegative women exposed to the virus early in
pregnancy. Its efficacy has not been established. It should not be given routinely
in these situations, but it may be considered in cases where a therapeutic
abortion would not be an acceptable alternative. If serologic testing confirms the
presence of rubella during the first trimester of pregnancy, therapeutic abortion
should be considered due to the high risk to the fetus. During the period of
communicability, patients with suspected rubella should be advised to avoid
contact with women of childbearing age.

SELECTED READING
Caserta Ml Hall CB. Human herpesvirus-6. Annu Rev Med 1993;44:377-383.
Chou S. Roseola infantum and other infections caused by human herpesvirus-6.
In: Hoeprich PD, Jordan MC, RonaldAR, eds. Infectiotts diseases, 5th ed.
Philadelphia: Lippincott, 1994;915-918.
Eischenfield LF, Honig PJ. New developments in pediatric dermatology. Curr
Probl Pediatr 199l;21(10):421427 .
Krueger GR, Kluepelberg U, HoftnanA, Ablashi DV Clinical correlates of
infection with human herpesvirus-6. In Vivo 1994;8(4):45’7485.

Varicella-Zoster (9.5.9) (See 13.12.4.5)

Varicella-zoster virus (VZV) is a herpesvirus. The primary infection
of VZV is chicken pox, the reactivation infection is zoster or shingles.
Childhood VZV remains endemic worldwide, and the severity of acute and
recrudescent infection in immunocompromised patients has been a major
impetus in the development of preventive and treatment measures.

Epidemiology
Varicella-zoster virus has been recognized as a highly communicable
disease for centuries. It occurs worldwide, and it is most prevalent in large
urban centers and in temperate climates where it is most frequent in late winter
and ear$ spring. Humans are the only known species naturally infected. In the
United States it is now the most commonly occurring exanthem of childhood
with an estimated 3 million cases annually. Most are in children ages 5 to 9.
Infants under the age of I and adults over the age of 19 (the populations with the
highest risk of complications) account for less than3% of all cases. However,
the disease remains an important entity in this country, where there are
approximately 100 deaths from it annually.
The virus is spread through close contact with an infecis shed in
respiratory secretions. The virus is also shed in the vesicle exudate, although not
in the vesicle scab. Therefore, patients are generally considered to be contagious
for a period extending from 4 days before the appearance ofthe rash to 4 to 5
days after, or until all the vesicles are crusted. The virus can be transmitted by
contact with a person with varicella or with zoster, although the rate of
transmission is much higher with varicella.
Reactivation of YZY, which is presumed to establish latency in the
dorsal root ganglia, leads to shingles or zoster. Zoster occurs at a rate of
300,000 cases per year and is said to account for 1.5 million physician visits per
year. The incidence increases steadily with age. It is estimated that half the
people who live to age 85 will have at least one episode of zoster. There is no
increased risk of cancer in patients with zoster.

Clinical Findings
Varicella
 In the normal chil4 varicella is usually a benign entity. The
incubation period for the virus is 10 to 2l days, usually 2 weeks, and there is a
mild prodromal stage of fever and malaise 24 hours before the onset of the rash.
The fever may persist for several days but rarely exceeds 39”C. The patients do
not appear acutely ill, although they may be uncomfortable due to pruritis. The
classic rash consists ofa superficial vesicle surrounded by a halo of erythema,
referred to as a “dewdrop on a rose petal.” there are lesions in varying stages of
maturation (papule tovesicle to crusted scabs) in the same area of the body.
The most common complications of childhood varicella are due to
secondary bacterial infections and CNS involvement. It is estimated that l\oh of
patients requiring hospitalization for such complications will die. Bacterial
infections range from relatively benign impetigo to varicella gangrenosa, caused
by group A strep and toxogenic S. Aureus. One must search carefully for
bacterial infection in any child who presents with worsening fever, increasing
rash, or any respiratory symptoms.
The most common complications of childhood varicella are due to
secondary bacterial infections and CNS involvement. It is estimated that l\oh of
patients requiring hospitalization for such complications will die. Bacterial
infections range from relatively benign impetigo to varicella gangrenosa, caused
by group A strep and toxogenic S. Aureus. One must search carefully for
bacterial infection in any child who presents with worsening fever, increasing
rash, or any respiratory symptoms.
Central nervous system complications occur in I in 5000 children,
and can range from benign self-limited cerebellar ataxia to encephalitis. The
former presents with vomiting, ataxia, slurred speech, and tremor; the later, with
a severe headache and progressive obtundation. Ataxia can occur as late as 2 I
days after the rash, but usually occurs within the first week. In both cases, the
CSF usually reveals lymphocytic pleocytosis and an elevated protein. EEGs in
encephalopathic children are usually diffirsely abnormal.
Varicella is also associated with l0% to 20% of the cases of Reye’s
syndrome in the United States, generally when there is concomitant use of
salycilates. This may present occurs later in the course ofthe illness, and is
associated with elevated serum glucose and ammonia levels.
Varicella is associated with more complications in adults. The initial
presentation is frequently more severe, with more pronounced malaise and a
prolonged fever. In addition, adults are more likely to develop pneumonia, with
I in 400 requiring hospitalization for it. Varicella pneumonia occurs in the
vesicular stage of the disease, and chest x-ray findings of nodular opacifications
and peribionchial infiltrates are usually more impressive than the clinical
findings. In one study only 25% of those with radiographically findings had
associated symptoms of pneumonitis. Varicella pneumonia must be
differentiated from a secondary bacterial pneumonia, which occurs later in the
course ofthe infection and is generally caused by staph.
Varicella in the immunocompromised host has a high incidence if
serious complications. The acute illness is more severe, with higher fevers, a
longer period of vesicle formation (10 to 14 days), and larger vesicles that often
coalesce into bullae. There is a high incidence of visceral dissemination,
approaching 35%. One-fifth of these patients will die if they are not treated
early with antiviral drugs. Life-threatening complications include pneumonia
(varicella and bacterial), pancreatitis, bowel hemorrhage, perforation or
obstruction, encephalopathy, and SIADH.

Zoster
Reactivation ofYZY manifests as zoster. This is rarely life threatening,
but its long-term sequelae are the source of tremendous morbidity. It begins as a
unilateral sharp, burning, and well-localizedpain, followed by the eruption of
vesicles in a clearly defined dermatomal distribution. Thoracic dermatomes are
the most often affected. About l0% of patients have involvement of the
ophthalmic branch of the fifth cranial nerve; one-fifth of these have ocular
involvement. These patients can be readily identified due to the involvement of
the nasocilliary branch of the trigeminal nerve, leading to lesions on the side
and tip of the nose.
zoster lesions heal over a period of 2 to 3 weeks, during which time
the patient may experience, in addition to pain, low-grade fevers, nausea, and
severe fatigue. After healing, l% of patients are left with postherpetic neuralgia,
which can be extremely disabling. It is more common in the elderly.
Complications of zoster include bacterial superinfection and,
rarely, dissemination. When there is ocular involvement, keratopathy can lead
to corneal scarring and loss of vision. From 1% 5% of patients experience
pralysis in the region effected by zoster, due to involvement of anterior horn
cells.
Zoster can be severe, prolonged, and even fatal in the
immunocompromised patient. Pain remains the usual presenting symptom,
although the dermatomal rash may be confluent bullae. Dissemination occurs in
one-third of these patients. It is in itself not life threatening, but it may herald
the development of visceral zoster, which occurin in l0% of patients with
dissemination.
Diagnosis
A diagnosis of varicella can usually be made based on clinica finding,
coupled with the typical history of exposure. The differential diagnosis includes
measles (which may have vesicles), insect bites, and scabies. Secondary
impetigo can also make the diagnosis difficult. The variety of lesions in
different stages of development, how-ever, is usually pathognomonic.
Definitive diagnosis can be achieved by isolation of the VZV virus. The most
rapid test available is the Tzanck smear, which is done by examining scrapings
from the base of a vesicular lesion stained with Giemsa, Papanicolaou, or
hematoxylin-eosin stain and identifying multinucleated giant cells and inclusion
bodies. The Tzanck smear will be positive for any herpes infection; when done
in conjunction with the clinical examination it can help confirm the suspected
diagnosis of VZV

Treatment
Varicella
Since the disease in the normal child is usually a benign 5- to l0-day
course, treatment has been mainly symptomatic, with local treatment for pruritis
(drying agents and occasionally antihistamine s) and acetaminophen for fever.
Aspirin should be avoided due to its association with reye’s syndrome.
Complications such as varicella gangrenosa and bullous varicella require
hospitalization. The use of acyclovir to treat varicella in the normal child
remains controversial. There has been shown to be a reduction in the duration of
fever, lesion formation, and total number of lesions; however, the clinical
significance and public health implications of this are unclear. Routine
treatment with acyclovir is probably not warranted in the child under 6.
Secondary child cases within one family may benefit more from antiviral
treatment than the primary case; there may be reason to treat them.
Primary VZV infections in adolescents, adults, and the
immunocompromised should be promptly treated with antivirals, ideally within
24 hours of the appearance of the rash.
The immunocompromised patient with primary YZY infection requires
intravenous antiviral therapy. Any evidence of visceral dissemination in any
patient should also be aggressively treated. Antiviral therapy is probably not
useful in the treatment of neurologbecause these do not appear to be the result
ofviral replication in the CNS.
 Treatment with acyclovir does not appear to prevent development of
varicella in those who have been exposed to the virus, and there is no evidence
that any antiviral treatment prevents the subsequent development of zoster.

Zoster
Treatment of zoster in the normal host consists mainly ofpain reduction
and the prevention ofpostherpetic neuralgia. Adequate hydration is important
and may be difficult, especially in the debilitated elderly patient. High-dose oral
acyclovir has been shown to shorten the course of the acute zoster if started
early enough (within 2 to 3 days ofthe onset ofthe rash), and it decreases the rate
of complications of trigeminal zoster. Topical acyclovir is not recommended for
the treatment of zoster. Recently, famcyclovir has been introduced as an
effective alternative treatment. Any clinical advantage over acyclovir has yet to
be determined, but it does have some pharmacologic advantage, requiring three
doses per day instead of five at a similar cost. There is no demonstrated benefit
from the use of steroids in the treatment of zoster, and there is a theoretic risk of
the promotion of dissemination through resultant immunologic
compromise.
In the immunocompromised host, the goal of zoster treatment is to
reduce complications, especially dissemination and subsequent mortality. Since
there is no way to identifu who is at risk for dissemination, and since the
occurrence rate ranges from 10% to 50%, all immunocompromised patients
with zoster require at least high-dose oral acyclovir and close follow-up, and
many will benefit from intravenous acyclovir. The efficacy of oral acyclovir in
these cases remains unproven. The cost of therapy as opposed to the risk of
serious complications is also an important consideration.

Prevention
An attenuated varicella vaccine is under investigation for use in
normal and immunocompromised children and adults. Complications of the
vaccine have included mild to moderately severe cases of varicella, as well as
reactivation of the vaccine as zoster. However, the incidence of zoster after the
vaccine appears to be less than that after natural infection. A vaccine has been
used successfully in japan, and clinical trials remain under way in the United
states.
Passive immunization via varicella-zoster immuneglobulin (VZIG)
confers fairly reliable immunity to YZY for up to 42 days. It should be given to
high-risk patients (those with acquired or congenital immunodeficiencies,
malignant disease, and immunosuppressive therapy) within 96 hours of
exposure to the virus.
SELECTED READING
Balfour HH Jr. Current management of varicella zoster virus infections. Med
Virol 1993;(suppl l):s74-s81.
Englund JA, Balfour HH Jr Varicella and zoster infections. In: Hoeprich PD,
Jordan MC, Ronald AR, eds. Infectious diseases,5th ed. Philadelphia: Lippincott,
1994;9 52-9 62.
Gershon AA, LaRussa ! Hardy I, et al. Varicella vaccine: the American
experience. J Infect Dis 1992;166(suppl 1):s63-s68.
Nikkels AF, Pierard GE. Recognition and treatment of shingles. Drurgs
1994;48(4):528-548.
Tyring SK. Natural history of varicella zoster virus. Semin Dermatol
1992;t1(3):2ll-217.
Whitley RJ Therapeutic approaches to varicella zoster infections. J Infect dis
1992;166(suppl l):s51-s57.
Whitley RJ. Varicella-zoster virus. In: Mandell GL, Douglas RG Jr, Bennett JE,
eds. Principles and practice of infectiolts disease, 3rd ed New York: churchill
Livingstone, 1990;1 153-l 159
Herpes Simplex Virus (9.5.10)
Herpes simplex virus (HSV) infections, which are common, cause a
variety of other infections involving mucocutaneous surfaces, the central
nervous system, and occasionally visceral organs. Herpes infections are caused
by a DNA virus specific to human beings. Our understanding of the HSV
clinical spectrum has expanded since the development of viral isolation
techniques and serologic markers. Two serotypes of HSV have been identified,
HSV-1 and HSV-2.

Epidemiologly
Herpes simplex virus has a worldwide distribution. Hunans are the only
natural reservoir. HSV-I is transmitted primarily by contact with oral secretions,
while HSV-2 is spread by sexual contact. Genital herpes is the most common
cause of genital ulcers in industrialized countries. ‘Approximately 30 million
persons in the united States may have genital herpes” (U.S. Department of
Health and Human Services, 1993). Rates of HSV-2 infections are higher in
blacks, individuals of lower socioeconomic status, and those with a history of
sexually transmitted disease. The risk of spread of HSV-I infection to other skin
areas is increased in certain occupations such as dentists and respiratory
therapists.

Pathophysiology
In primary HSV infection the virus replicates locally, resulting in
lysis of infected cells and a local inflammatory response. Multinucleated cells
are formed. Local lymphadenopathy is common. Further virus replication may
result in viremia and visceral dissemination depending on the immune
competence of the infected organism. After primary infection, HSV may
become latent within sensory nerve ganglion sites. Infection tends to recur
frequently with both HSV types, secondary toof the virus. Precipitating factors
for recurrences of HSV-I lesions include sunlight, fever, local trauma,
menstruation, and emotional stress. Recurrent HSV keratitis is less common.
The frequency of genital recurrences depends on gender, HSV type, and the titer
of neutralizing antibody. Many persons have asymptomatic disease with viral
shedding, which may contribute to continued transmission of HSV

Clinical Findings
Although primary infection areas are usually perioral, ocular, or
genital, any skin site may be involved. Primary HSV-l may present as
gingivostomatitis and pharyngitis. Incubation periods range from 2to 12 days.
Fever is usually present followed by the onset of small vesicles on the
pharyngeal and oral mucosa that can spread to the soft palate, tongue, buccal
mucosa, lips, and cheeks. Cervical adenopathy is present. In older adolescent
patients, infection more often resembles a posterior pharyngitis. The duration of
primary infection is usually 10 to 14 days and usually involves systemic
symptoms such as fever, malaise, and headache. Autoinoculation of fingers in
young children is not uncommon and is referred to as a herpetic whitlow.
Recurrent herpes labialis, which tends not to be as severe as the primary
episode, is usually heralded by a prodrome of pain, burning, or itching lasting 6
to 48 hours. The vesicles that appear are usually on the vermilion border of the
lips. Healing is complete in 8 to 10 days. Systemic symptoms usually are not
present durang recurrences.
HSV-l dendritic keratitis presents as unilateral follicar
conjunctivitis, photophobia, and edema of the eyelids. Dendritic epithelial
opacities may be seen on the cornea. The duration of illness is usually 2 to 3
weeks. Spontaneous healing of the cornea and conjunctiva is usually complete
with treatment. Ocular infection may recur as keratitis, blepharitis, or
keratoconjunctivitis. Ulcers that stain with fluorescein are diagnostic. Steroids
should be avoided. Recurrent infections may lead to deep stromal involvement
and uveitis, dense scars, and neovascularization. Permanent visual loss may
result.
Primary genital infection is caused by HSV-2 in 70% to 95% of the
cases. The incubation period is 2 to 7 days. Painful genital lesions initially
appear as clusters of fluidfilled vesicles on an erythematous base that
subsequently denude to form ulcers. The initial infection is usually more severe
and lasts longer than subsequent recurrences. Along with the local lesions
described” the initial infection can be accompanied by systemic symptoms such
as headache, fever, arthralgia, and regional adenopathy. “Hepatitis, aseptic
meningitis and autonomic nervous system dysfunction can occur” (Morris,
1996). Autonomic nerve involvement can manifest as bladder and bowel
incontinence and loss of sensation in the sacral nerve distribution. In the male
patient the most common site of occurrence is the glans and prepuce, while in
the female patient the cervix and rulva are most frequently infected.
Certain complications of HSV infection may arise. Herpers
encephalitis is usually caused by HSV-I beyond the neonatal period. This rare
complication is believed to be caused by viral spread via neural routes directly
to the brain. The temporal lobes are the principal area involved. The clinical
course includes headache, fever, behavioral disorder, and focal seizures.
Examination of the cerebrospinal fluid aids in the diagnosis. EEG and MRI
scanning may provide the earliest evidence of localization. The mortality in
untreated cases is approximately 60% to 80%.
Neonatal HSV infection can range from mild localization infection
to a fatal disseminated case. The incidence is estimated to be 1 in 5000 live
births. The retrograde spread of HSV-2 is secondary to maternal genital
infection or passage of the infant through an infected maternal genital tract.
Congenital infection may present at birth with skin vesicles, microcephaly,
jaundice, seizures, or chorioretinitis. Neonatal infection appears several days to
weeks after birth and presents as conjunctivitis, skin vesicles, seizures, cranial
nerve palsies, lethargy, and coma. Disseminated infection may occur and has a
very high mortality.
Severe HSV infections are seen in immunocompromised individuals
including transplant recipients, malnourished patients, and patients with AIDS.
The infection can present as esophagitis, pneumonia, encephalitis, hepatitis, and
viral dissemination. “In addition, genital herpes may be a risk factor for the
acquisition of HIV infection among heterosexuals” (Hook et al., 1993).

Diagnosis
 The diagnosis of genital herpes is supported by the clinical
presentation and confirmed by culture of the virus. It is recommended that the
culture swab attain the inoculate from the vesicle fluid and at the base of the
ulcer to attain culture sensitivity of 85% to 95%. One can see multinucleated
giant cells on a Tzanck smear with wright or Giemsa stain in 50% of cases.
Direct immunofluorescent testing can also be used. Other sexually transmitted
diseases need to be ruled out among these patients.

Treatment/Disposition
Oral-labial HSV infection is often best treated palliatively with topical
anesthetic agents such as viscous xylocaine and with the application of warm
saline rinses. The use oforal acyclovir in herpes labialis has not been
extensively studied, although Zovirax (acyclovir) 200 mg given five times a day
can be used for primary attacks in adults. Patients with severely painful oral
lesions may develop dehydration secondary to decreased oral intake and may
require hospitalization. Recurrent herpes labialis responds very rarely to oral
acyclovir and if it is used it should be started early during the prodrome stage.
Oral acyclovir is suggested for treating local HSV infections in those patients
who are immunocompromised. Frequent recurrences can be suppressed with
daily oral acyclovir. Antibiotics should be prescribed for those lesions that are
secondarily infected.
Treatment of herpes simplex keratoconjunctivitis consists of topical
0.3% trifluridine (Viroptic) nine times per day for 2 to 3 weeks. Oral acyclovir
(800 mg five times a day for l0 days) decreases the incidence of ocular
complications in ophthalmic zoster but must be initiated within 72 hours of
onset. Reactivation can occur with iritis and stromal keratitis and may last
months to years after the initial dermatomal outbreak. Referral to an
ophthalmologist is of paramount importance.
Acyclovir 200 mg given five times a day for 7 to 10 days is
recommended for primary genital herpes, and a 5- day regimen is recommended
for recurrent cases. This regimen is useful in ameliorating the symptoms and
signs of HSV infection but it does not affect the frequency or severity of
recurrences. Daily prophylactic therapy has been shown to decrease the
frequency of HSV recurrences by approximately 75Vo among patients with
frequent recurrences (six or more per year). After I year of prophylaxis,
acyclovir should be discontinued to assess the patient’s rate ofrecurrent
episodes.
 Immunocompromised patients, those with severe cases of
pneumonitis or hepatis, disseminated cases, or those involving the central
nervous system, such as encephalitis, should be hospitalized. In the setting
oflife-threatening HSV infection, intravenous acyclovir is indicated.
Intravenous acyclovir should be started at 5 to l0 mg/kg every 8 hours for 7
days or until clinical resolution. Patients with acyclovir-resistant HSV can be
prescribed foscarnet at a dose of 40 mg/kg intravenously every 8 hours until
clinical resolution. The safety of systemic acyclovir has not been established.
Vidarabine has been shown to be efficacious in both HSV encephalitis and
neonatal herpes infections.
Topical treatment with acyclovir is less effective than the oral route
and its use is discouraged.

Prevention
The patient should be advised to abstain from sexual activity when
lesions are present. It is necessary to explain to tcan occur without evidence of
lesions, which can cause transmission of disease. Pregnant patients who have
genital herpes should be referred to an obstetrician for management to prevent
neonatal transmission. Experimental vaccines are undergoing trials at this time.
SELECTED READING
Adimora AA. Sexually transmitted diseases----companion handbook.
Newyork: McGraw-H 1ll, 1994.
Buddingh GJ, et al. Studies on the natural history ofherpes simplex infections.
Pediatrics 1953;11:595.
Corey L, Nahmias AJ, Guinan ME, et al. A trial of topicat acyclovir in genital
HSV infection. N Engl J Med 1982;306:1313-1319.
Erlich KS, Mills J, Chatis P, et al. Acyclovir-resistant herpes simplex virus
infections in patients with the acquired immunodeficiency syndrome. N Engl J
Med 1989;320:293-296.
Francis DP, Herrmann KL, MacMahon JR, et al. Nosocomial and maternally
acquired herpesvirus hominis infection. Am J Dis Child 1975;129:889-893
Hook EW III, Cannon RO, Nahmias Al et al. Herpes simplex virus infection as
a risk factor for HIV infection in heterosexuals. J Infect Dis 1993;165:251-255.
Johnson JR, Egaas S, Gleaves CA, et al. Hepatitis due to HSV in
marrowtransplant recipients. Clin Infect Dis 1992;14:3845.
Kaplowitz LG, Baker D, Gelb L, et al. Prolonged continuous acyclovir
treatrnent of normal adults with frequently recurring genital herpes simplex
virus infection. JAMA 1991;265:747
Lazzer RB. Neuralgia in recurrent herpes simplex . Arch Neurol 1974:31:233 .
Mandell GL, Douglas RG Jr, Bennett JE, eds. Pnnciples and pmctice of
mfectious diseases, 4th ed. NewYork: Churchill Livingstone, 1995;1172-1194.
Morris DL. Vulvovaginitis. In: Tintinalli JE, et al., eds. Emergency medicine: a
comprehensive study guide, 4th ed. New york: McGraw-Hill, 1996:562-563.
Nilsen AE, Aasen I Halsos AM, et al. Efficacy of oral acyclovir in treatment of
initial and recurrent genital herpes. Lancet 1982;2:57 l.
Rosato FE, Rosato EF, Plotkin SA. Herpetic paronychia: an occupational hazard
of medical personnel. N Engl J Med 1970;283:804
Straus SE, Rooney JF, Sever JL, et al. Herpes simplex virus infection: biology,
treatment, andprevention. Ann Intern Med 1985;103:404.
U.S. Department of Health and Human Services. 1993 sexually transmitted
diseases treatment guidelines. MMWR 1993;42:l-102.
Whitley RI, Gnann AJ Jr. Acyclovir: a decade later. N Engt J Med
1992;327:782.
Whitley RI, Nahmias AJ, Soong SJ, et al. Vidarabine treatment of neonatal
HSV infection. Pediatics 1980;66:495.

Musculoskeletal Disorders (Nontraumatic)

Rania Habal
Bony Abnormalities (10.1 )
Carl M. Ferraro
Joint Abnormalities (10.2)
James D. Kocjancic
Disorders of the Spine (10.3)
Lauren Pipas
Overuse Syndromes (10.4) ; Muscle Abnormalities (10.5)
Christopher J. Markus
Soft Tissue Infections (10.6)
MUSCULOSKELETAL DISORDERS
(NONTRAUMATTC) (10.0)

BONY ABNORMALTTTES (10.1)

Diseases of the musculoskeletal system are frequently encountered in
the emergency department (ED). Symptoms include pain, weakness, deformiry
and loss of function and may have devastating effects on the quality of life.
Nontraumatic bony abnormalities result from a number of different conditions,
including infectious, inflammatory, degenerative, endocrine, neoplastic, and
genetic causes. Although they rarely result in an immediately life-threatening
condition, acute problems such as osteomyelitis, hypercalcemia, pathologic
fractures, and their complications require emergency treatment
Bone’s main constituents are type I collagen and mineral salts. Its
structure is maintained by three types of cells: osteoblasts, osteocytes (both of
which derive from the mesenchymal cell line), and osteoclasts (which originate
from the hematopoietic cell line). Osteoblasts synthesize collagen and organize
it into an intricate matrix called osteoid. When this matrix calcifies, osteoblasts
become embedded into the matrix and are then called osteocytes. The
mechanisms by which calcium salts are incorporated into bone continue to
elude scientists, despite intensive research in this area. They are, however,
believed to be under the control of a number of different local as well as
systemic factors. Osteoclasts, on the other hand, ensure phagocytosis, lysis, and
resorption of bone. Functionally, bone may be classified into two types. The
metabolically active trabecular bone forms the inner layers and constitutes 25%
of total bone mass; the compact outer layer of bone constitutes 75% of total
bone mass and is less metabolically active. As the life of bone depends on the
interplay among resorption, mineralization, and growth, failure in any aspect of
bone remodeling leads to devastating and disabling disease

Aseptic Necrosis of the Hip (10.1.1)

Unlike most bones, the femoral head, the humeral head, and the
navicular bone of the wrist have limited collateral blood supply. Necrosis of
bone may occur in the setting of complete disruption of its vascular supply (as
occurs in fractures) or as a result of external pressure on vessel walls (mass,
infection, or edema). When infarction of bone is due to embolic phenomena,
hypercoagulable states, hyperlipidemia, vasculitis, and hemoglobinopathies, the
bones most susceptible to necrosis are those with the least developped collateral
circulation. Because of its anatomical blood supply and the stress of weight
bearing, the femoral head is, by far, the most commonly affected region. Other
notable risk factors for the development of aseptic necrosis of the hip include
chronic alcohol consumption and the use of glucocorticoids (where 5% to 20%
of patients are thought to be affected). The condition often involves both
femoral heads. The underlying mechanism for bone necrosis remains unclear,
but is probably multifactorial and may involve fat microemboli and
microfractures with abnormal healing.
The clinical picture and the urgency of treatment depend on the
underlying insult, which may manifest itsself either acutely or in a chronic
manner. Infarction of small areas of bone are usually asymptomatic; however,
in the setting of sickle cell disease, dysbaric air embolus, or other large embolic
phenomena, acute infarction of a large area of bone occurs. Patients present
with sudden onset of severe pain and are unable to bear weight or use the
affected extremity. The physical examination reveals decreased use and motion
of the extremity, and although laboratory tests are nonspecific, they may be
helpful in diagnosing the underlying cause. As the initial radiographs are
normal, further studies such as a bone scan or magnetic resonance imaging
(MRI) must be obtained. Treatment should be aggressive and directed at the
underlying cause of the infarction. In the chronic form of the disease, patients
present with worsening hip pain. Initially, the pain is vague, occurs on
ambulation and weight bearing, and is relieved by rest. In the advanced stages,
however, pain may be constant and disabling. The physical examination may
reveal a decrease in the range of motion of the hip. Laboratory tests are not
helpful, but radiographs may be useful in classifuing the extent of the disease.
These may show mottling of bone, bone cysts with sclerotic margins, increased
density of the femoral head crescent-shapedradiolucencies, or collapse of the
joint. As the disease is now established, the most important factor affecting the
outcome of these patients is to limit the progression of the disease by
withdrawing the inciting factor, encouraging non-weight bearing and referral to
the orthopedic service.

Osteogenesis Imperfecta (10.1.2)

Osteogenesis imperfecta (OI) refers to a number of genetic
diseases characterized by various abnormalities in the synthesis of type I
collagen and resulting in defective bone matrix. The disease is thought to affect
1 out of 20,000 live births and is characteized by fragile bones. Associated
findings include blue sclerae, hearing loss, and abnormalities in dentogenesis.
Rarely, the disease may be associated with hydrocephalus, carotid cavernous
fistulas, and pulmonary hypoplasia. OI is classified into four types depending
on the clinical manifestations and its mode of inheritance. The most common
type, Sillence type I, which accounts for 70% to 80% of all cases of OI, is
characterized by mild to moderately severe disease and is inherited in an
autosomal dominant manner with occasional sporadic mutations. Affected
individuals appear normal at birth and during childhood, but have an increased
incidence of fractures and mildly stunted growth. Once the growth period is
completed, The risk of fractures decreases, only to rebound in the later years.
The characteristic blue sclerae are prominent and are thought to be due to
thinning of scleral collagen, Thus allowing the choroid to be more apparent.
Otosclerosis leading to sensorineural deafness occurs in most affected
individuals and begins after adolescence. Sillence type II, also called lethal OI,
accounts for l0% of 01 cases and is characterized by absent ossification in the
fetus, multiple intrauterine fractures, and severe fetal deformities that are
incompatible with life. Death occurs in utero or soon after birth. Sillence type
III is a progressively deforming disease characterized by severe osteopenia
leading to multiple fractures that occur spontaneously or with minimal trauma.
Abnormal healing of these fractures results in striking skeletal deformities,
growth retardation, and severe kyphoscoliosis. Sillence type IV is also rare and
is inherited as an autosomal dominant trait with variable manifestations.
Although manifestations are similar to those in type I of OI they are more
severe. Marked osteopenia is usually present, but sclerae are usually white and
dentogenesis is variably affected.
Prenatal diagnosis of severe forms of OI has been facilitated by the
use of sonography, which may note in utero fractures and skeletal deformities.
The mild form of OI, on the other hand" may go unrecognized for many years.
Children with this form of the disease are at risk for multiple fractures in the
absence of a clear mechanism for the injuries. These patients present a special
challenge to the ED physician as the differential diagnosis rightfully includes
inflicted nonaccidental trauma. Other conditions, such as glucocorticoid excess,
malabsortion syndromes, and nutritional deficiencies have also been associated
with an increased fragility of bone and should therefore be considered in the
differential diagnosis. The presence of a family history of OI, blue sclerae, or
abnormal dentogenesis, however, should guide the physician towards the
diagnosis of OL The ED management of OI rests in the diagnosis and treatment
of immediately life-threatening complications, and in the appropriate splinting
of fractures and referral/admission to the appropriate service. When the
diagnosis is unclear, a multidisciplinary consultation, including social services,
should be considered.

Osteomyelitis (10.1.3)
 Osteomyelitis refers to the suppurative infection of bone that may
lead to extensive bone necrosis and significant morbidity and mortality.
Risk factors for the development of osteomyelitis include
malnutrition, intravenous drug use, and conditions associated with suppression
of the immune system such as diabetes mellitus, corticosteroid use, chronic
alcohol consumption, sickle cell disease, and the immunodeficiencies.
Invasion of bone by bacteria may occur in two different ways:
hematogenous, where seeding of bone occurs during a bacteremic episode; and
contiguous spread, where infection is spread through extension from an adjacent
site or through direct inoculation (as occurs in open fractures, puncture wounds,
or during septic surgical procedures).
Contiguous osteomyelitis may be further categorized based on whether
peripheral vascular disease is present or not. Whatever the mechanism, all may
progress to the chronic form of the disease with its devastating complications,
including chronic pain and loss of function, draining sinuses, and bone necrosis.
Early detection and treatment are, therefore, necessary in order to minimize
these sequelae.

Microbiology
 Hematogeneous osteomyelitis occurs most commonly in children
(85%), intravenous drug users, hemodialysis patients, and the elderly. In
children, the metaphyses of long bones are preferentially infected presumably
because of the rich blood supply to that region coupled with the sluggish blood
flow through the venous sinusoids. As bones mature, the metaphysis loses its
collateral circulation, while the vertebrae maintain a rich blood supply. This,
coupled with a valueless venous system, accounts for the preferential infection
of vertebrae in adults. In the majority of cases of acute hematogeneous
osteomyelitis, a single organism is isolated as the infecting pathogen, with
Staphylococcus aureus accounting for most cases. In the elderly, however, the
genitourinary system is frequently the source of bacteremia, and gram-negative
coliform bacteria are commonly isolated as pathogens in bone infections.
Patients with sickle cell disease are at risk for salmonella osteomyelitis, and
neonates have a high incidence of group B streptococci. Pseudomonas
aeruginosa is an important pathogen in intravenous drug users. Furthermore,
with the resurgence of mycobacterial disease, tuberculosis of the spine is
becoming an increasingly common presentation in the ED
In contrast to hematogeneous bone infections, osteomyelitis resulting
from contiguous spread or from direct inoculation is usually polychromies
involving aerobic as well as anaerobic organisms. Although Staphylococcus
qureus remains a commonly isolated organism, Pseudomonas aeruginosa
becomes an important pathogen in burn victims and in patients with puncture
wounds to the feet.

Clinical Syndromes
Acute hematogeneous osteomyelitis in children usually presents
acutely with fever chills, and pain in the involved bone. This results in a limp
and the child’s refusal to bear weight or use the involved extremity. Other
symptoms such as abdominal pain, anorexia, and general malaise may be
persent. Physical examination may reveal an acutely ill child with fever and
point tenderness of the involved area of bone. There may be accompanying
erythema and edema of the soft tissues overlying the area. The erythrocyte
sedimentation rate (ESR) and whole blood cell count (WBC) are generally
elevated.
Vertebral osteomyelitis, on the other hand, mainly affects adults with a
mean age of 60 to 70 years, and in those patients, the source of infection is
frequently traced to the genitourinary system. The disease may be acute or
subacute, and most commonly affects the lumbar spine, followed by thoracic
and cervical spines. In the acute presentation of the disease, patients complain
of fever, back pain, and back stiffness. The physical examination reveals
tenderness to palpation and percussion of the involved area. There may be
paraspinal muscle spasm, with splinting and kyphosis. Back motion is limited.
The ESR is generally elevated. The WBC is not consistently elevated.
Occasionally, the infection may spread rapidly to involve adjacent vertebral
bodies or inwards to involve the spinal canal. When the latter occurs, patients
present with neurologic deficits or signs of spinal cord compression. In about
half of the cases, vertebral osteomyelitis is subacute. Patients may present with
vague, dull pain over weeks to months. In these instances, fever is typically
absent or low grade, and the WBC count is typically within normal limits, but
the ESR is generally

Diagnosis and Treatment

The diagnosis of osteomyelitis can often be made on the basis of
history and physical examination, and laboratory and radiographic evaluation.
The ESR, which is a nonspecific test, has been found to be elevated in a great
majority of patients with osteomyelitis. The WBC count is a less reliable test.
Blood cultures may identify the causative organism in acute hematogeneous
osteomyelitis in children and occasionally in the adult. Routine radiographs
should be obtained as they may be helpful in staging the disease. The earliest
radiographic findings of acute osteomyelitis, however, may lag l0 to 14 days
behind the clinical syndrome, and may only show periosteal elevation and focal
osteopenia. In advanced stages and chronic osteomyelitis, radiographs may
demonstrate a characteristic periosteal reaction, as well as
Evidence of bone necrosis and sclerosis. When the diagnosis is suspected, but
laboratory and radiographic evidence are sparse, a triple phase technetium 99
bone scan is often recommended as it is a highly sensitive test that may be
diagnostic early in the infection. False-positive bone scans occur in healing
fractures, heterotopic ossification, and bone tumors, and false-negative results
occur in areas where the edema causes decreased vascular flow and ischemia of
the affected area. Other radioisotope scans (gallium and indium) have also been
used with good results. CT scan may be useful in the early diagnosis of
osteomyelitis as it may demonstrate increased density of the bone marrow and
intramedullary gas, and may identifu areas of necrotic bone. MRI, which
permits a three-dimensional visualization of infected soft tissue and the
delineation of the boundaries of the infection, May also be considered.
Admission to the hospital and prompt anribiotic administration are
advisable at least initially, until culture and sensitivity results are obtained.
Failure to diagnose and treat acuie osteomyelitis may lead to devastating
complications such as extensive bone necrosis, chronic osteomyelitis, and death.
Indications for surgery in acute hematogeneous osteomyelitis include the
presence of subperiosteal and subcutaneous abcesses, as extensive bone necrosis
may occur. The choice of antibiotics must be guided by the patient's risk factors
and based on etiologic considerations. Because Staphylococcus aureus is the
most commonly isolated pathogen, antibiotic treatment must include coverage
for this organism. An antistaphylococcal penicillin such as nafcillin or a first
generation cephalosporin such as cefazolin would be reasonable choices.
Vancomycin would be the alternative in the individual allergic to penicillin and
cephalosporin as well as in the treatment of osteomyelitis caused by methicillin-
resistant Staphyloccocus qureus (MRSA).treatment of immunosuppressed
patients, those with hemoglobinopathies, chronic alcohol consumers, diabetics,
and the elderly should also include coverage for gram-negative organisms. A
third generation cephalosporin such as ceftazidime or an aminoglycoside are
recommended in such instances. An antipseudomonal penicillin and/or an
aminoglycoside should be considered in burn victims, in intravenous drug users,
and in those with puncture wounds to the feet. In contrast to
acutchematogeneous osteomyelitis, antibiotics alone are ineffective in treating
chronic and contiguous osteomyelitis. In those instances, surgery is often
necessary in order to remove devitalized bone and to restore its structure and
vascularity.
 Tumors (10.1.4)
Bone tumors may be primary or metastatic. Except for
multiple myeloma, primary bone tumors predominantly occur in
children and adolescents, during maximal growth rates. They may
be benign or malignant, and may arise from the hematopoietic,
stromal, vascular, and neural cell lines. In adults, metastatic bone
lesions from breast, lung, kidney, prostate, and thyroid tumors
predominate. A detailed description of all tumors affecting bone is
beyond the scope of this chapter; only the most common neoplasms
are discussed.
Benign Bone Tumors
Most benign bone tumors do not cause pain, unless a fracture or
compression of other structures have occurred. Patients present with a history
several weeks or months in duration, of a slowly growing mass or deformity of
bone. Radiographically, benign tumors may be well circumscribed or expansile,
septated or not, radiolucent or mixed with sclerotic lesions. Benign bone
tumormay originate from cartilage (chondromas, chondroblastomas), bone
(osteoma, osteoid osteoma, osteblastoma), mixed bone and cartilage
(osteochondroma), or giant cells.
Osteochondroma is the most common benign tumor of bone.
Usually nonpainful, it is an exostosis of well-differentiated bone covered by
cartilage. It affects children and adolescents most commonly, and is generally a
solitary lesion. When multiple lesions are found, the condition may be familial
and may have a higher incidence of malignant degeneration
Chondromas are relatively common benign lesions of cartilagenous
origin. They are usually solitary; however, they may be multiple in the familial
Ollier’s disease. Chondromas most commonly affect the diaphysis of small
bones of the hands and feet. Malignant degeneration into chondrosarcoma may
occur in Ollier’s disease.
Chondroblastoma is an uncommon benign neoplasm with a
predilection for the epiphysis. It occurs most commonly in males younger
than20 years of age.
Osteoid osteoma, a benign tumor that is closely related to
osteoblastoma, commonly presents during the second decade of life,
predominantly in males. The most frequent sites are the femur and tibia.
Patients typically present with progressively worsening pain of the involved
bone, which is worse at night. It is generally relieved by salicylates. The
physical examination may only disclose tenderness of the involved area, or it
may disclose ominous signs such as edema, erythema, induration, and
tenderness, especially seen in the tibia. Radiographically, this hrmor is a well-
circumscribed radioluscent area surrounded by a sclerotic margin. Referral for
excision is indicated.
Osteomas are well-circumscribed benign collections of sclerotic bone
that occur almost exclusively in the face and skull. They are rare, commonly
affect young adults, and are very similar to osteoid osteoma, but are typically
larger and lack the sclerotic margin on radiographic evaluation. These may be
associated with the familial Gardners syndrome.

Malignant Bone Tumors

In children and young adults, malignant bone tumors are highly
aggressive, rapidly growing tumors that have a high prpensity for metastatic
spread. It is not uncommon for patients to have metastases at the time of
presentation. The neoplasms may originate from bone (osteogenic sarcoma),
cartilage (chondrosarcoma), neuroectodermal elements (Ewing’s sarcoma), or
lymphoid tissue (multiple myeloma, leukemia, etc.). Osteogenic sarcoma and
Ewing’s sarcoma occur primarily in children and young adults, whereas
chondrosarcoma occurs primarily in middle age and multiple myeloma in the
elderly. For a complete description of tumors originating from lymphoid tissue,
refer to the second entitled White Blood Cell Disorders (7.6).
Osteogenic sarcome is the most common malignant bone tumor in
children and young adults, where it is thought to have a genetic predisposition,
whereas in older patients it may occur as a complication of Paget’s disease or
after exposure to radiation. It is highly aggressive, with a propensity for rapid
hematogeneous spread to the lungs. The neoplasm most commonly affects the
metaphysis of the distal femur and may exhibit skip areas histologically.
Patients present with pain of a few weeks’ duration, associated with a limp or
limited motion of the extremity. The physical examination may reveal a painful,
tender mass associated with edema, increased warmth, and erythema.
Radiographic evaluation may disclose a typical “sunburst” appearance, with a
radioluscent intramedullary area surrounded by sclerosis and periosteal new
bone formation with extension of the calcification into the surrounding soft
tissue. Recent advances in chemotherapy have greatly improved prognosis of
this neoplasm.
Ewings sarcoma is the second most common malignant bone
neoplasm in children and has recently been reclassified as a tumor of
neuroectodermal origin. It is highly aggressive and, like osteogenic sarcoma,
metastasizes rapidly through the bloodstream to the lungs.
Patients present with pain, which may be chronic, and tenderness of
the involved extremity. This may be accompanied by fever and leukocytosis.
Radiographically, ewing’s sarcoma is described as a radioluscent intramedullary
area surrounded by eroded cortical bone and reactive new bone formation,
which gives it the appearance of “onion layers.” Metastases are common at
presentation, and, although aggressive chemotherapy and surgery have
improved survival, prognosis remains poor.
Chondrosarcomas occur most commonly in adults Can be primary or
may arise from malignant degeneration of a preexisting benign bone neoplasm.
They most commonly affect the pelvis, ribs, and shoulders, but any bone may
be affected. Patients present with a painful mass in bone, which is expansile and
may become extensive, resulting in pathologic fractures. They metastasize
slowly through the bloodstream to involve other bones and the lungs.
Chondrosarcomas are both radioresistent and chemotherapy resistent, making
surgical excision the principal mode of treatment. Prognosis depends on the
histologic grade ofthe disease, and ranges from excellent for grade I to poor for
grade III.
 ED management of bone tumors consists of obtaining A detailed
history and physical examination and rapidly assessing patients for potentially
immediately life-threatening or disastrous complications. These include
pathologic fractures, impingement on vital structures such as the central nervous
system, and metabolic abnormalities. Once stabilized, the ED workup of bone
tumors consists of x-rays ofthe involved bones and a chest x-ray searching for
metastases. CT scanning is also an important tool as it is able to delineate the
borders and the extent ofthe lesion; furthermore. It is more sensitive than the
radiograph in detecting metastatic lesions of the lungs. Immediate referral to
orthopedic and oncology services are indicated” since definitive diagnosis
requires a biopsy.

Bone Cysts (10.1.5)

Bone cysts are uncommon lesions of bone, which grow slowly and
are thought to be secondary to developmental defects. They tend to present
insidiously with a slowly growing mass, chronic pain, and often with a
pathologic fracture. They may be classified into two categories.
Solitary or unicameral bone cysts occur most commonly in children
and young adults and frequently affect the metaphysis of long bones. The cyst,
which may vary in size, is of unknown etiology, and may contain hemosiderin
and cholesterol deposits. Cysts commonly present as a pathologic fracture.
Occasionally, patients may give a history of chronic pain or a slowly growing
mass. Treatment is mainly supportive and preventative, unless the cyst is large,
in which case, patients may require surgical evacuation and, occasionally, bone
grafting.
Aneurysmal bone cysts occur most commonly in the second decade of
life and most frequently affect flat bones, although the metaphysis of any long
bone may also be affected. These lesions are often multicystic, destructive, and
expansile. They contain hemorragic fluid and cause pain and swelling in the
involved bone. Radiographically, aneurysmal bone cysts appear as lytic bone
lesions that are well-circumscribed and delimited by periosteum and that expand
into the surrounding soft tissue. These lesions respond to radiation therapy;
however,unless the lesion is inaccessible, surgical excision is the treatment of
choice.

Osteoporosis (10.1.6)
Osteoporosis is a term used to describe a decrease in bone mass. Both
the collagenous matrix (osteoid) and bone mineralization are affected. The most
important risk factors are gonadal senescence and advanced age. Other factors,
such as diabetes and the use of glucocorticoids, chronic alcohol and nicotine
consumption, prolonged immobilization, and malabsorption syndromes, may
also predispose to the development of osteoporosis.
Occasionally, it may be idiopathic. Osteoporosis is generally clinically
silent until fractures occur. In the absence of fractures, chronic back pain is the
most common presenting complaint.
When osteoporosis is associated with loss of gonadal function, both
bone resorption and formation are increased but resorption occurs at a higher
rate. This is characterized by an increase in osteoclastic activity and so most
visible in areas where cancellous bone is prominent, such as the vertebrae, the
ribs, and the pelvis. When fractures occur, they do so after seemingly trivial
trauma. Rib fractures, for example, may result from coughing and sneezing.
Patients present with pain and splinting of their respirations. Physical
examination may reveal tenderness and crepitation over the fractured rib, or
they may present with complications of rib fractures such as atelectasis,
hypoxia, and pneumonia. Vertebral compression fractures may result from such
mundane activities as bending or jumping. Patients present with back pain that
begins suddenly and may radiate to the abdomen. It may be exacerbated by
standing and valsalva maneuvers. The physical examination reveals tenderness
over the spinous process, and radiographic evaluation will show anterior
vertebral body collapse and wedging with decreased mineral bone density.
In contrast to postmenopausal events, osteoporosis of aging is associated
with a decline in osteoblastic activity, especially noted in cortical areas of long
bones. This form of osteoporosis most commonly affects patients older than 70
years. Patients may develop fractures of the femoral and humeral heads after
minor mechanisms of trauma such as falls from a bed or tripping over a carpet.
Pain and decreased range of motion of the involved extremity are common
findings. As radiographic evaluation may yield negative results, a high index of
suspicion should be kept in the elderly with falls, and further diagnostic workup
with bone scans or CT scans should be pursued.
Treatment should focus on the stabilization of patients and immobilization
of the injured bone. For compression fractures of the vertebrae, treatment is
symptomatic with bed rest and adequate pain relief, and instructions should
focus on the elimination of additional trauma. As these fractures may be
complicated by paralytic ileus, patients must be given instructions to return for
symptoms of bowel obstruction. Cautious mobilization should begin as pain
resolves. Femoral head fractures require hospitalization and surgical fixation.
They are associated with a high complication rate, including thromboembolic
phenomena and death.
When decreased bone mass is an incidental radiographic finding, patients
must be referred for workup. A number of therapeutic modalities have been
suggested;however, none have proven to be beneficial when the disease is
already established. These include calcium supplements, vitamin D, and
estrogens, among others. ED instructions’ must focus on preventative measures
such as the avoidance of sudden movements and cautious back exercrses.

.Osteomalacia (10.1.7)
Osteomalacia is a metabolic bone defect in the adult in which the
mineralization of bone is defective. As mineralization of bone depends on an
adequate supply of calcium, which in turn depends on vitamin D, any process
that interferes with the function or quantity of vitamin D may result in
osteomalacia (in adults) and rickets (in children). These include decreased
vitamin D intake, decreased sunlight exposure, malabsorption syndromes, renal
failure, and drug interactions. In the presence of normal vitamin D function,
osteomalacia may also be caused by low levels ofphosphate or by a decreased
ability of bone to rapidly accumulate calcium (as occurs in aluminium toxicity).
The clinical manifestations of osteomalacia include generalized bone pain and
tenderness, which may be severe enough to restrict activity of the patient.
Proximal muscle weakness may be a prominent finding. When the pelvic or hip
girdle is affecte4 patients may present with an abnormal gait. Bone fractures
may occur with minimal trauma. Radiographically, bone may be normal even in
advanced disease or show a generalized decrease in mineralization.
Occasionally, pseudofractures or looter’s zones may be noted: these are
bilateral, symmetrical linear radiolucencies that are perpendicular to the axis of
bone and that involve only one cortex. They are not tender and are not
associated with any evidence of bone healing. They are thought to be secondary
to the mechanical stress imposed by the nourishing arteries. A careful clinical
history and physical examination will guide the physician towards the
diagnosis. Often, the underlying disease may dominate the clinical picture, and
treatment of these conditions, when they do present to the ED, may supercede
the diagnosis of osteomalacia. The treatment of osteomalacia is therefore
deferred until the underlying condition is stabilized and the exact mechanism of
the disease established.

Bone Spurs (10.1.8)

Bone spurs (osteophytes) are bony protrusions frequently noted in
the middle aged and older patient and are thought to result from chronic stress
on the involved bone. The exact mechanism of spur formation remains unclear.
They may be incidental radiographic findings or may present with pain.
Bone spurs are common in the cervical and lumbar spines, and are
usually associated with chronic degenerative disk disease of the spine. When
symptoms occur, pain, paresthesias, and sensory or motor deficits secondary to
nerve root compression are common complaints. Treatment is supportive, with
soft collars, salicylates, or other nonsteroidal antiinflammatory drugs
(NSAIDS).
Another frequent site for spur formation is at the plantar aspect of the
calcaneum. Although these spurs are frequently asymptomatic and found
incidentally, many patients with calcaneal spurs complain of heel pain, which is
worse in the morning, improves during the early part ofthe day, but intensifies
at the end ofthe day. ED treatment consists of heel padding, NSAIDs, and
referral for orthotic considerations.

Paget’s Disease (10.1.9)

Paget’s disease is a disease of unknown etiology that may affect up to
3% of the population older than 40 years. It is characterized by an increased
resorption of bone, with a rapid but disorganized deposition of new bone. The
disease is usually localized to one area ofthe skeleton but occasionally may be
widespread. Characteristically, patients are asymptomatic. The diagnosis is
suspected based on the mosaic appearance of bone on the radiographs. When
symptoms do occur, pain in the involved bone is the initial complaint, or the
patient may present with a complication of the disease, such as pathologic
fractures, nerve root compression, and hypercalcemia. Rarely, the disease is
complicated by the occurrence of osteogenic sarcoma. Owing to increased
blood flow to affected bone, patients may also present with high-output cardiac
failure. The ED diagnosis is made based on the radiographic appearance and the
presence of elevated levels of alkaline phosphatase. Treatment is usually
symptomatic. When pain occurs, mild analgesics are effective. Complications
are treated accordingly, fractures need to be immobilized and referred to the
orthopedic surgeon, adequate hydration must be ensured, and symptomatic
hypercalcemia must be treated with intravenous fluids, furosemide, and
corticosteroids. Corticosteroids have also been found to alleviate the high
cardiac outputs associated with Paget’s disease. The use of agents that reduce
excessive bone resorption such as calcitonin and etidronate are indicated when
patients present with spinal or cranial nerve involvement and should only be
given after consultation with the appropriate services.

SELECTED READING
Babbitt AM. Osteoporosis. Orthopedics 1994;10:935.
Bassett GS. Idiopathic and heritable disorders. In: Weinstein SL, Buckwalter
JA, eds. Tureks orthopaedics. Principles and their application, 5th Ed.
Philadelphia: Lippincoft, 1994;251-255.
Crenshaw AH. Campbell s operative orthopedics, VoL I, 8th ed. St Louis:
mosby, 1992.
Esterhai JL Jr. Orthopedi c infection Orthop Clin North Am 1991 ;22:363 -5 49.
Lane NE Osteoporosis. Rheumatol Clin NorthAm 1994;20:535-803.
Levine SE, Esterhai JL Jr, Heppenstall RB, et al. Diagnosis and
staging:osteomyelitis and prosthetic joint infections. Clin Orthop 1993;293:77-
86.
Lewis MM. Bone tumors: evaluation and treatment. Orthop Clin North Am
1989;20:273—416.
Mankin HJ. Nontraumatic necrosis of bone. N Engl J Med 1992;326:1473.
Manolagas SC, Jilka RL. Bone marrow cytokines and bone remodelling:
Emerging insights into the pathophysiology of osteoporosis. N Engl J Med
1995:332:30
McGuire MH. The pathogenesis of adult osteomyelitis. Orthop Res 1989;
18:564
Ono K. Recent advances in avascular necrosis of the femoral head. Clin Orthop
1992;277:l—30.
Rowe DW, Shapiro JR. Heritable disorders of structural proteins. In: Kelley
WN, Harris ED, Ruddy S, et al., eds. Textbook of rheumatology, 4th ed.
Philadelphia: Saunders, 1993:1567—1592.

JOINT ABNORMALTTIES (10.2)

Arthritis (10.2.1)
Patients with joint abnormalities can present to the ED in a
variety of ways, from acute pain to chronic disability. The majority of joint
abnormalities fall under the broad classification of arthritis. A less frequent
condition, Osteochondritis dissecans, may also present with a complaint
referable to a joint. By recognizing the typical presentations and using
appropriate ancillary tests, the ED Physician can rapidly and accurately
diagnose and expediently manage the patient with a joint abnormality.
 Arthritis is any condition that results in inflammation of a joint,
specifically affecting the synovial cavity. Arthralgia is pain in a joint without
signs of joint disease. Over 2 million persons in the United States suffer from
some sort of arthritis, with an estimated 5% to 10% of all ED visits annually
being attributed to joint complaints. Septic arthritis is an inflammation of a joint
due to an infectious agent, most commonly bacterial, but it may also be due to
viral and fungal agents.
Crystal-induced arthritis is arthritis due to deposition of crystal within
the joint; two common forms are gout due to urate crystals and pseudogout due
to calcium Pyrophosphate dehydrate (and others) crystals. Traumatic arthritis is
inflammation of a joint after injury, either from a reactive synovitis or from
bleeding into the joint.
Hemarthrosis is blood in the joint causing inflammation and can be due
to inborn or drug-induced coagulopathy, or may occur spontaneously.
Rheumatoid arthritis includes a number of diseases affecting joints
usually in typical patterns and often with serologic markers.
Degenerative joint disease is also called osteoarthritis due to chronic
wearing down of the normal joint architecture.
 Osteochondritis dissecans is a degenerative disorder that affects joints
characteized by a portion of bone near a joint becoming loose.

Pathophysiology of Joint Abnormalities

Joint Anatomy
Synovial joints are characteized by their being bounded by articular
surfaces of bones typically covered with cartilage and by the synovium itself.
The synovium is a thin layer of tissue that surrounds the joint producing the
fluid called joint fluid or synovial fluid which acts as lubrication and provides
some cushioning. This fluid is an ultra filtrate of serum and normally has the
appearance and consistency of motor oil. When a joint becomes inflamed the
composition and sometimes amount of the joint fluid is altere4 resulting in
irritation of the synovial lining. This irritation may be due to inflammatory cells
within the joint, direct irritation from blood or stretching or pressure on the
synovium. It is this irritation that leads
to the pain that patients often complain of in the ED.

Etiologies
The specific entities that result in arthritis occur by various
mechanisms. The bacteria that cause septic arthritis are usually blood borne and
then seed the joint. Less commonly, a nearby infection may directly spread into
a joint, and similarly there may be direct inoculation of bacteria by an invasive
procedure such as arthrocentesis or arthroscopy, or by traumatic violation of the
joint. Septic arthritis can cause permanent changes in a joint in as little as I
week and may lead to chronic disability. The destructive nature of joint
infections should lead all ED personnel to be highly suspicious for the presence
of an infected joint, and all efforts to recognize and treat early in its course
should be undertaken. Crystal deposition in a joint is mostly influenced by
increased concentration of a substance in the serum, but local factors such as
temperature and pressure can also affect crystal formation. The inflammatory
response to trauma may take several days to fully develop and is characterized
by white blood cell migration into the synovial cavity. If there is a non
traumatic bloody effrrsion, the bleeding is typically from coagulation disorders
such as hemophilia or as a result of therapeutic anticaogulation such as a patient
on coumarin. Rarely, a spontaneous hemarthrosis may occur in a patient without
trauma and with normal coagulation studies. Rheumatoid arthritis classically
affects the small joint in an asymmetric pattern over time, whereas the closely
related spondyloarthopathies mainly affect the spine and axial skeleton.
Although the underlying pathogenesis of osteoarthritis is unknown, it seems to
be a result of aging, with an increasing incidence with advanced age.
Emergency Department Evaluation
Presentation
Patients with joint abnormalities frequently complain of pain in or
about the affected joint(s). The pain may be referred to nearby structures. There
may be loss of range of motion or loss of function at a joint or of an extremity.
In children, unwillingness or inability to use a limb or, in the case of a lower
extremity problem, a limp may be the initial presentation. There may have been
preceding trauma, or there may be constitutional symptoms such as fever.

History
Patients with joint complaints should be asked about the onset,
duration, and progression of symptoms, characteristics of pain, and
exacerbating/alleviating factors. Besides taking a history concerning the joint
itself, a general history looking for clues to the etiology of the joint problem
should be elicited. Previous episodes of similar problems and systemic
symptoms, as well as antecedent trauma, current medication, drug use, and
sexual practices should be assessed.

Physical Exam
 Similar to the history-taking, two examinations must be performed.
First, a thorough examination of the affected joint must be carried out. One
should look for Effrrsion, edema, tenderness, loss of range of motion, joint
instability, and crepitus. Second, a complete examination looking for other signs
that may indicate the cause ofthe joint pathology should be done to include
searching for gouty tophi, seeking clues to underlying metabolic or endocrine
disorders, and looking for fever and Rash.

Dffirentiation of Intraarticular from Periarticular

Problems
Within the first several days of the development of a joint problem,
there are distinguishing features that can help differentiate an intraarticular
process (something that is in the joint-arthritis in one of its many forms). From
a periarticular process (something that is near a joint) such as bursitis or
tendonitis. Diseases that involve the synovial cavity cause tenderness and
swelling about the entire joint, whereas with diseases near joints, the tenderness
and swelling are localized to a small area. Active and passive range of motion is
painful in all directions in intraarticular processes, whereas in periarticular
diseases there may be little pain with passive motion and only in limited planes.
Ancillary Tests
Blood Tests
Blood tests are only supportive of any specific diagnosis and
are considered optional in the evaluation of an acute joint problem. An elevated
WBC and ESR are non-specific indicators of inflammation. Uric acid levels are
of little help in the acute setting.
Radiographs
Standard views of the affected joints should be obtained. The
most common finding in the setting of an acute monoarticular process is a
normal film except for soft tissue swelling. In chronic diseases, you may see
characteristic changes such as chondrocalcinosis of Pseudogout (stippling of the
articular cartilages), loss of joint space in degenerative arthritis, or chronic
deformities common in rheumatoid arthritis. Osteochondritis dissecans will
appear as a lucency surrounding a small portion of periarticular bone.

Arthrocentesis
Indications. For diagnostic purposes, joint fluid should be
obtained in the setting of nontraumatic joint disease or for suspected
ligamentous or bony injury where the diagnosis is not readily evident.
Therapeutic indications include reducing pain by instillation of medications or
by relieving a tense effusion.
Contraindications. Overlying infection is an absolute
contraindication, whereas a prosthetic joint and bleeding diatheses are relative
contraindications.
Synovial Fluid Analyses. This analysis is composed of the
following four elements:
1. Gross appearance: Synovial fluid will appear as one of four types: (a)
normal (clear, pale, yellow to straw colored); (b) inflammatory (cloudy
but otherwise like normal); (c) purulent (appears like pus); or
(d)hemorrhagic (grossly bloody).
2. Gram stain and culture: This is to help identify the presence of and type
of organism in the setting of Septic arthritis.
3. Crystal analysis: The presence of appropriate crystals is diagnostic of
gout or pseudogout; however, their presence does not rule out other
etiologies that may be concurrent.
 4. Cell count: This is to help guide classification of the synovial fluid. (This
is a nonspecific test as there is great overlap between the different disease
entities.)

Emergency Department Intervention/Dispositions

The type of joint abnormality identified by the evaluation in the ED
will determine which intervention should be carried out acutely and which
patients require admission. All patients who have an arthrocentesis performed
should have the affected joint adequately immobilized. Pain medication as
indicated should be administered. If the patient is found to have a septic joint or
there is a high index of suspicion for an infectious process, antibiotics must be
administered early and arrangements for admission made. The choice of
antibiotics is ideally guided by gram stain results; however, empiric therapy
based on age and a common pathogens can direct initial antibiotic selection. In
children, coverage for Staph, Strep, and Hemophilia influenza indicated. In
healthy adults, gonococcus as well as Staph and Strep should be covered. In the
elderly or immunocompromised additional coverage for the gram-negatives
should be added. The patient with crystal-induced arthritis acutely requires pain
control. This is commonly achieved by using NSAIDs; however, Narcotics may
be necessary for severe pain. In the remainder of etiologies of joint pain,
analgesia is the mainstay of acute therapy with appropriate referral. Patients
with infectious arthritis should be admitted where as all other joint
abnormalities should be admitted based on clinical grounds such as intractable
pain or inability to ambulate.

SELECTED READING
Freed JF, Nies KM, Boyer RS, Louie JS. Acute monoarticular arthritis: a
diagnostic approach. JAMA 1980 ;243 :2314—2316.
Goldenberg DL, Reed JI. Bacterial arthritis. N Engl J Med 1985:312: 764—771.
McCarty DJ, Koopman WJ, eds. Arthritis and allied conditions: a textbook of
rhettmatology. 12th ed. Malvern, PA: Lea & Febiger, 1993.
Preslar AJ, Heckman JD. Emergency department evaluation of the swollen
joint. Emerg Med Clin North Am 1984;2:425—441.
Smith JW Infectious arthritis. Infect Dis Clin North Am 1990;4:523—538.

DTSORDERS OF THE SPINE (10.3)

The human vertebral column consists of 33 bony vertebrae
that support the skull, the thoracic cage, and, indirectly, the pelvic girdle, which
is fixed to the sacral portion of the column. The cervical spine consists of the
first seven vertebrae, followed by 12 thoracic vertebrae that bear ribs, five
lumbar vertebrae, five sacral vertebrae Fused into one unit, and four coccygeal
vertebrae, also fused into one unit. The movements at each level of vertebrae
are quite limited, but the sum of the movements leads to a very mobile and
functional support unit. This is largely in part due to the very complex network
of ligaments, paraspinal musculature, and flexible, shock-supporting
intervertebral disks that separate the vertebrae yet join the column.
Vertically, the vertebral column is visualized as two columns: an
anterior column and a posterior column. The anterior column consists of the
bony vertebrae and the intervertebral disks, and is mainly supported by the
anterior and posterior longitudinal ligaments. The posterior column consists of
the transverse processes. Spinous processes, pedicles, laminae, and articulating
facets. The existing space between these structures is the spinal canal. The
support of the posterior column is a complex network of ligaments: the nuchal
ligament, the supra-, Infra-, and interspinous ligaments, the capsular ligament,
and the ligamentum flavum.
The movements of the vertebral column can produce variable
motions: flexion, extension, side bending (lateral flexion), and rotation about a
vertical axis. These movements vary in degrees at each level of the column.
Depending on the orientation of the joints between the vertebral arches, the size
of the bony processes, and the specific ligamenture and musculature associated
with that level.
The purpose of this section is to review the most common of
these disorders that affect the spine.