HEMOSTATIC DISORDERS (7.1) (See 13.

4)

Hemostasis involves a complex interaction of physiologic process that result in the arrest of blood flow from or within a blood
vessel. A brief description of normal hemostasis is necessary before discussion of the disease states. When a blood vessel is
damaged, tissue factor, collagen, and other components of the subendothelial matrix are exposed. Platelets then aggregate at the site
of injury by direct adhesion and by the mediation of von Willebrand’s factor (vWF). Platelets and fibrinogen form a soluble
occlusive plug that provides phospholipid surfaces for the reaction of the coagulation cascade (Fig. 7-1). Tissue factor also activates
the extrinsic coagulation pathway. Intrinsic pathway proteins become activated by factor Ⅶ, thrombin, or by surface contact factors.
Both the intrinsic and extrinsic pathways factor Ⅹ, which converts prothrombin to thrombin. Thrombin in turns cleaves fibrinogen
to fibrin, which forms an insoluble clot. Fibrin is then crosslinked, and the hemostatic plug gets anchored into place via clot
retraction. Modulating proteins limit extension of the clot by thrombin inhabitation and inactivation of clotting factors. Eventually,
the clot lysed by plasmin once the vessel is sufficiently healed. Laboratory tests frequently used to evaluate hemostatic disorders are
the hematocrit, platelet count, prothrombin time (PT), and partial thromboplastin time (PTT). The PTT, sometimes 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 contacts activators (kaolincelite, ellagic acid), and
phospholipid (the “partial” thromboplastin). The PT is a measure of the extrinsic and common pathways. This test adds calcium
and brain tissue thromboplastin to citrated plasma, activating factor Ⅶ. Uncontrolled bledding is a common presenting complaint to
the emergency department (ED). Most cases are traumatic and treatment is straightforward, though not necessarily easy. Whne
bleeding is a result of impaired hemostatic 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 factor . (From Rosenthal DS .
Hematologic oncologic disorders and heart disease . In: Braunwald EB , ed. Heart disease, Philadelphia: Saunders, 1980: 1793.)

Venous access, and infusion of crystalloid solution . Packed red blood cell (PRBC)t transfusion is directed by clinical status , presence and
rate of continued hemorrhage , and the hematocrit.

Clotting Factor Disorders (7.1.1)

Hereditary

The HEMOPHILIAS (7.1.1.1)

Hemophilia A. Classic hemophilia (hemophilia A) is an X-linked recessive bleeding disorder occurring in approximately 1 in 10,000 live
male births. Hemophilia A is not a single genetic disease , but rather a heterogeneous set of disorders 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. Clinical 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 muscle hemorrhages, and profuse posttraumatic/ postsurgical bleeding . Minor cuts and abrasions 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 hemostatis. Von Willebrand’s disease,
therefore, indirectly causes a functional factor Ⅷ deficiency in addition to a platelet-type bleeding disorder. About 90% of all bleeding in
hemophilia is into joints or muscle. Hemarthrosis is the most common acute presentation. The knee is affected in over 50% of cases, but all
large extremity 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 point” that undergo a vicious cycle of rebleeding. During resorption of hemosiderin is
deposited, leading into inflammation and synovial vascular proliferation, which in turn increases risk for future hemorrhage. The 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 reports typical 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 risk forjoint 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
tongue, 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 used to be
the 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 known antecedent
trauma. Treatment must be initiated prior to confirmatory head CT in any hemophiliac with history of head trauma (even in the absence of
lacerations, 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 characteized by backache with or without
immediate neurologic deficits. Treatment is the same: factor replacement to 100% of normal activiry 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 ruled out, the patient can be treated conservatively with increased fluid intake. The
hematuria should resolve in a few days. Some authors recommend a short course oforal steroids, since the proposed mechanism of most
episodes is antibody complex deposition, but the benefit 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 competitively 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 often responds 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 is not, or cannot be, ruled out. Patients with mild hemophilia A and
non-life-threatening bleeding can be treated with DDAVP (1-desamino8-D-arginine vasopressin, desmopressin). 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 >80/o, so a threefold increase reaches a hemostatic level of
about 30% normal. DDAVP is ineffective in moderate or severe hemophilia. Dosage is 0.3 pglkg IV in 50 ml NS given over l0 to 15
minutes. Common side effects are related to a mil4 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 patlents. 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 factor VIII per bag, but is
contaminated with many other unneeded proteins and carries the risk of viral disease transmission. Concentrates pooled from several
thousand donors contain about 15 units factor VIII per milligram of total protein. Although widely used in the past, these concentrates have
fallen out offavor 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 heat and solvent treated to inactivate viruses. The
purest products are produced via monoclonal antibody immunoaffinity chromatography. Recombinant factorVIII produced by genetically
engineered hamster cell lines is now available. These products carry virhrally no risk (except for hypersensitivity reactions) but may be
prohibitively expensive. They are best reserved for HlV-seronegative patients to maintain their negatlve 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 40o/o for minor bleeding episodes, and 60Yo for major episodes.
Minor episodes 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 lumbar 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 form and administered intravenously. One
unit per kg body weight raises factor VIII activity levels by 2Vo 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, stabilize( 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 outpatient 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 appropriate. Intramuscular injections,
salicylates, and nonsteroidal antiinflammatory drugs (NSAIDs) should all be avoided. About l5o/o of patients with severe haemophilia ,
either A or B, develop clotting factor inhibitors as a result of repeated exposure to exogenous factor VII or IX, respectively. If the titer of
these antibodies is relatively low, then simply replacing the appropriate 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 plasmapheresis. Hemophilia B. Hemophilia B is another X-linked recessive hemorrhagic disorder that is clinically
indistinguishable from hemophilia A. Because it was first described in the December 25, 1952 issue of the British Medical Jotu'nal,
hemophilia B is also known as Christmas disease, and factor IX is called the Christmas factor. Factor IX deficiency occurs in I 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 treatments 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. 2Yo for factor V[I); the difference is due to more extensive extravascular distribution of factor IX.
Historically, hemophilia B was treated with FFP and prothrombin-complex conceptrates (PCCs). By definition, plasma contains I unit of
each clotting factor per milliliter. Volume constraints limit increases in factor activity to 10% to l5o/o of normal. PCCs contain factor IX (1
to 2 Ulmg 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 ffansmission.
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 I 0 units of heparin per milliliter 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) preparations are the most highly recommended, but also the most expensive.
The half-life of factor IX is l8 to 30 hours, so daily dosing is appropriate. Other Clotting Factor Disorders . Congenital deficiencies of
several other coagulation factors have been described. Hereditary factor XI (plasma thromboplastin antecedent) deficiency is an autosomally
transmitted disorder characterizedby 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 I in 8. Treatment is with FFP or factor XI concentrates (not currently
available in the United States). Hereditary deficiencies of factors II (prothrombin), V (proaccelerin, labile factor), VII (proconvertin), and X
(Stuart-Prower 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 PTI
treat with FFP transfusion. Further workup is deferred to the primary physician or hematologist. Congenital deficiencies of contact factors
[factor XII (Hageman factor), prekallikrein, and high molecular weight kininogenl impair initiation of the intrinsic coagulation pathway and
have a strikingly elevated PTT. However, there is no associated bleeding diathesis, 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 in less y-
carboxylation 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 valve 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 97o/o protein bound. The anticoagulant effect is seen within 24 hours, and half-life is about 60 hours. Warfarin is
metabolized in the liver, excreted into the bile, reabsorbe4 and ultimately 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 measurement to change (due to the short half-life of factor VII), and is the
traditional marker 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 factor s.
The INR is calculated as INR = (Patient’s PT / 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 indications. High-intensity anticoagulation (INR : 34.5) is sometimes necessary with mechanical heart valves 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 mechanisms. 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 leaff 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 anticoagulation. Concurrent
treatment with other drugs may affect warfarin metabolism by competition for protein binding sites (dilantin), inhibition or acceleration of
drug clearance (trimethoprim-sulfamethoxazole, 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
vasculature 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 atheromatous 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 at9.6%, major episodes at3%, 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. Dosage and
route of administration is variable, depending 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 significant risk of thrombosis inother 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 form, vitamin K acts as a cofactor in the posttranslational
modification of coagulation factors II, VII, IX, and X, as well as fibrinolytic factors protein C and protein S. Vitamin K-dependenty-
carboxylation of glutamate residues allows these proteins to bind to phospholipid membranes and form 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 fasting, and even inadequate hyperalimentation may cause
vitamin K deficiency. While a healthy liver contains a 30-day store, deficiency can occur in 7 to l0 days in acutely ill patients. Even with
adequate intake, hepatocellular disease causes a functional vitamin K deficiency from impaired synthetic ability. In addition to oral intake,
vitamin K is also produced by normal colonic bacteria, so prolonged antibiotic therapy can impair hemostasis by altering the intestinal flora.
Warfarin, cephalosporins with a N-methyl-thiotetrazole side chains (cefamandole, moxalactam, cefoperazone) cefazolin, cefazedone), and
salicylates inhibit vitamin K epoxide reductase, the enzyme that regenerates the active form 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 parenteral vitamin K is performed in most hospitals. With a half-life of only 5 hours, factor VII 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 II, IX, and X become 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 significant 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)HI -dependent pathway for vitamin K reduction. Dosage is I to 5 mg in infants/small children, 5 to
l0 mg in older children, and 10 to 20 mg in adults. Cessation of bleeding and correction of laboratory abnormalities usually occurs within 8
hours.

Liver Disease

Bleeding due to liver disease is multifactorial in origin. The most common sites are localized lesions, such as esophageal varices and peptic
ulcers; however, control of bleeding is complicated by multifaceted impairments in hemostasis. Defects in the coagulation cascade, platelet
number and function, consumption of coagulation factors, and systemic fibrinolysis are all associated with liver disease. Because nearly all
components of the clotting cascade are synthesized in the liver, some of the earliest sigls of hepatic dysfunction are reflected in coagulation
abnormalities. Impaired hemostasis can be seen even with acute inflammatory diseases, such as viral or druginduced hepatitis, with the PT
prolonging first and then the PTT. The extent of dysfunction is directly related to the amount of hepatic damage, following the patient's
clinical course toward recovery or fulminant liver failure. Most patients with a bleeding tendency from liver disease have a chronic,
progressive hepatitis from ethanol, persistent viral infection, or primary biliary cirrhosis. Vitamin K deficiency is a frequent confounding
factor in these patients. Clotting factors that are produced, despite impaired synthetic ability, do not function properly due to decreased y-
carboxylation of glutamate residues. Nonemergent 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 of hematoma formation. Serious bleeding is treated with transfusions of FFB
and possibly cryoprecipitate if associated with hypofibrinogenemia. Liver disease also causes abnormalities in platelet number and function.
Thrombocytopenia is due to ethanol-induced inhibition of 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 pglkg IV) produces a significant, if transient,
improvement in platelet function in over half of patients with liver disease. Platelet transfusions 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, and decreased levels of profibrinolytic factors such as antithrombin III and protein C. 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 decreases in synthesis of cr2-antiplasmin, a fibrinolytic modulating protein, and/or
decreased hepatic clearance of activated fibrinolytic proteins. Also, surgery causes the release of PA 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 crz-antiplasmin levels and other clotting factors, which may be low as a result of unrecognized DIC.
Administration of loading doses of antifibrinolytic agents, EACA (100 mg/kg IV or PO) or TA (10 mglkg 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 to fibrin,
which forms a soluble clot. Factor XIII then stabilizes the clot by fibrin polymerization. Fibrinogen is produced by hepatocytes and
megakaryocytes. Normal serum levels range from 200 to 400 mgidl. Pregnancy and estrogen therapy can increase levels to 350 to 650
mg/dl, 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 diseases (it also occurs secondary to liver
disease, ascites, or DIC or by drugs such as L-asparaginase, ticlopidine, ethanol, and pentoxifflline 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 4oC 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 >80 U factor VIII activity per bag
(average 100 U), 40% to70% of original vWF, and several other clotting factors. Cryoprecipitate is stored frozen, and is thawed, pooled"
and filtered prior to transfusion. Usual dosing is one bag per 6 kg body weight, which will increase fibrinogen by 75 to 100 mg/dl, the
minimal level for hemostasis. Initial doses as high as one bag per 2 kg body weight are recommended for impending or overt shock in
patients with hypofibrinogenemia-associated haemorrhage.

Disseminated Intravascular Coagulation (7.1.2)

Disseminated intravascular coagulation (DIC) is a disease process characterized by simultaneous unregulated activation of the coagulation
and fibrinolytic pathways. DIC has been called a "consumptive coagulopathy," in that clotting factor and platelet levels fall as microthrombi
are 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 substances into the circulation, either from exogenous sources or injured or otherwise
abnormal tissue. Tissue factor is released from damaged tissue, activating the extrinsic coagulation pathway. Exposure of subendothelial
tissue activates the intrinsic pathway and induces platelet aggregation. Plasminogen is converted to plasmin by tPA released from damaged
endothelial cells and/or by activated intrinsic pathway factors. Fibrinolysis then produces FDPs that 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 WBCreleased factors. Malignant cells can release tissue factor and other procoagulants; promyelocytic
leukemia is especially prone to inducing DIC. Late pregnancy and childbirth is a particularly DlC-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 oftissue factor. Chronic liver disease is a common cause of low-grade, compensated DIC, 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 reactions, heat stroke, and envenomations. The underlying cause of DIC is usually obvious. 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 microthrombi may present as end-organ damage to the lung fhypoxemia, adult respiratory distress syndrome
(ARDS), kidney (oliguria, renal failure), or CNS (stroke). A thrombotic manifestation of the skin called purpura fulminans can also occur,
appearing initially as ecchymotic lesions that subsequently demarcate and necrose. Large vessel thrombosis can cause acral cyanosis,
necrosis, or even gangrene of the extremities. DIC causes a number of laboratory abnormalities. The most useful diagnostic test is
measurement of FDPs. Elevation of FDPs is found in more than95% of patients with DIC, representing the effects of fibrinolytic activation.
FDPs impair coagulation and therefore act as an acquired anticoagulant. The D-dimer assay is more specific for DIC than FDPs, but less
sensitive. This test measures the degradation product 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 levels <100 mg/dl,
expected given the pathophysiology of the disease. In early DIC, levels may be normal, because fibrinogen is an acute-phase reactant;
however, serial fibrinogen levels show a decline. Microangiopathic hemolytic anemia (decreased hematocrit, fragmented red cells on
peripheral smear) is present in over halfofcases. Single-tube clotting time is a simple but often overlooked bedside test for rapid clinical
diagnosis of DIC. One milliliter of whole blood is collected in a plain glass tube that is manually tilted every 30 seconds. Normal blood
forms a clot in 4 to l0 minutes, which then undergoes clot retraction. Blood from an affected patient clots late, if ever, and fails to retract ,
leading to an early presumptive diagnosis of DIC before any quantitative laboratory values 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, and malignancy. Although complete resolution of DIC is dependent on subsequent management, in the
operating room, intensive care unit, and hospital wards, emergency physicians can impact patient outcome by addressing the ABCs of
resuscitation, correcting metabolic abnormalities, and rapidly initiating antibiotic treatment in sepsis. Specific treatment of DIC remains
controversial. Some authorities insist on heparin as initial therapy. Despite the apparent paradox in anticoagulating a bleeding patient, there
is a sound theoretic basis to this course of action. First, although bleeding is the most obvious clinical problem in DIC, the thrombotic
component has the greatest impact on morbidity and mortality. Second, there is some evidence that repletion of clotting factors 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 factors: platelets, clotting proteins, and fibrinogen. DIC results in multiple clotting factor deficiencies, all of which can be
corrected with FFP. Cryoprecipitate may be given for severe hypofibrinogenemia. Platelet repletion is also reasonable for DlC-induced
thrombocytopenia. Such transfu sions, especially with 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 values would return. We recommend platelet and FFP transfusions over heparin for the emergent 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
coagulation factor transfusion fail. 4. Rapid treatment of the primary disease process reverses DIC in most cases. 5. Platelets and FFP may
improve hemostasis until definitive therapy is begun. 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 platelet count by roughly 50,000/pl. 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 I to 2 mg/ml fibrinogen. A dose of 10 ml/kg raises clotting factor levels by l5% 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 more commonly develop chronic
ITP, a lifelong recurrent disease. The typical clinical picture of acute ITP is the sudden onset of s '(1ssfu"-petechiae, pulpura, and
ecchym6sss-in an otherwise healthy child. The incidence is equal for males and females, peaks between2 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
75Yo to 85% of all adult cases. There is a 3:l 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; l0o/o to 20Yo of patients have hematuria, hematochezia, or menorrhagia.
Life-threatening GI or CNS bleeds are rare, occurring in less than l%o 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, valproic acid, digoxin, 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 ofweight loss, and fever all suggest alternate diagnoses, such as acute infections with Epstein-Barr virus (EBV) or cytomegalovirus
(CMV), malignancy, collagen vascular disease, orAIDS. It should be note4 however, that 5% to l0% 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 (l 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. Plasmapheresis 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 (TTP) and hemolytic uremic syndrome (HUS) are two closely related disorders of microvascular
occlusion by platelet microthrombi. Both disorders tend to occur abruptly in previously healthy individuals, and have significant risk for
morbidity and mortality if not promptly recognized and treated. HUS occurs mostly in young children, with greater Ihan 90oh 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 infeclions (Mycoplasma,
Pneumococcus, viral) may precede the onset of HUS. The hemolytic uremic syndrome is heralded by the acute onset of a triad 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 unusual, in distinction from TTP' Anemia, with fragmented red cells
on peripheral smear, thrombocytopenia, leukocytosis, and elevations in BIIN, 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). Heparinization, plasmapheresis, or plasma
exchange with FFP may become necessary. Fortunately, the vast majority of patients survive with mild renal impairment as the only
sequela. Recurrence of HUS is uncommon. TTP is found most often in young adults with a 2:1 female predominance. Symptoms are
variable, with vague, 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 erythematosus
(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 plasmapheresis 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 l0%.

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 atherosclerotic plaques,
preventing thrombotic and embolic complications. Typical indications for antiplatelet therapy include myocardial infarction, stable and
unstable angina, stroke, transient ischemic attacks, atrial fibrillation, and chronic lower extremity ischemia. Acetylsalicylic 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 (TXAz).
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
(PGI2), 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 aspinn. 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 described a bleeding disorder he called "pseudohemophilia" in an extended Finnish family. The disease had
varying penetrance, equal male and female prevalence, and exhibited predominantly mucosal bleeding. As it is now known, von
Willebrand's disease (vWD) is a collection of quantitative and qualitative deficiencies of von Willebrand factor (vWF). VWD is the most
common genetic bleeding disorder, with a prevalence of roughly 1% in the general population, although many cases are mild or clinically
asymptomatic. The majority of identified patients are heterozygotes 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 and stabilizes 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 l5% to 20 % cases and results from a relative paucity of large multimers. Type IIB-vWD i s a subclass char
acteize 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 multimers 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, gammopathies, 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 vWD. 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 IIBvWD is not an
absolute contraindication to DDAVB and that a drop in platelet count represents a pseudothrombocytopenia. (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, Humate-P (Armour) is most
recommended because it has the highest relative concentration of vWF. Dosage is by factor VIII activity, 50 to 60 U/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
complexes and fibrinogen, but in a much smaller volume. Dosage is one to two bags per 10 kg body weight depending on severity
ofbleeding. 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 relatively
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 L W. 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 purpura . J Gen Intern Med 1993;8:160-163. Thorp JA, Gaston L,
Caspers DR, Pal ML. Current concepts and controversies in the use of vitamin K. 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

{ TABLE 7-1 . The lymphomas compared.}

infiltration are common with non-Hodgkin's lymphoma and occur occasionally in Hodgkin's lymphoma. Occasionally, lymphoma presents
with manifestations of tumor mass such as superior vena caval obstruction, spinal cord compression, neurologic symptoms, testicular
masses, or bone lesions, and gastrointestinal lymphomas may be complicated by haemorrhage , obstruction, or perforation.

Hodgkin’s Disease

Hodgkin's disease is a malignancy of lymphoid tissue characlerized, 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 nonlymphoid tissues. Lymph nodes in the neck and supraclavicular areas are common
presenting sites, and many patients have mediastinal adenopathy at first presentatron. 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. Pel-Epstein 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%,
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 compresslon. 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 ); (3) mixed cellularity (25%); (4) lymphocyte depleted (5%). Nodular
sclerosing may be further subdivided into lymphocyte predominant phase, mixed cellulariry 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 ofchest,
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 Arbor 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 extralymphatic 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 radiotherapy 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. Highdose chemotherapy with stem cell rescue is occasionally used for
relapsed disease.

TABLE 7-2. The Ann Arbor staging system for Hodgkin’s disease

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+erm disease-free survival. A disease-free survival of approximately
50% 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 exists between EBV both in endemic African Burkitt's lymphoma and in high-grade lyrnphoma of immunodeficient
patients, and the human T-cell leukemia virus has been implicated in the etiology of adultTcell lymphoma in endemic areas. A number of
diseases of inherited or acquired immunodeficiency and some autoimmune diseases are associated with a higher incidence of nonHodgkin'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 Rappoport classification,
describe the appearance of the involved nodes in terms of cell size and follicular or diffi.rse patterns of those cells. The Working
Formulation has evolved to better reflect prognosis and natural history. It divides nonHodgkin'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 cytogenetics, 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 lhan Hodgkin's lymphoma. Approximat ely 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 Arbor system
developed specifically for Hodgkin's lymphoma is also used to stage non-Hodgkin's lyrnphoma; however, it has less prognostic value since
nonHodgkin's lymphoma tends to progress by hematogenous spread 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, semm protein electrophoresis, and BenceJones 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
firrther clariff cellular origin and may identify very small tumor 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 under trial. Intermediate- or high-grade non-
Hodgkin's lymphoma are treated with intensive multiagent combinations. High-dose therapy with stem cell rescue may be used in some
patients with high-risk or relapsed disease. Other therapies under trial include the use of monoclonal antibodies 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 tumor lysis syndrome following initial treatment can produce the life-threatening
metabolic consequences of hyperuricemia, renal failure, hyperkalemia, hyperphosphatemia, and hypocalcemia, 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 diarrhea, bladder irritation, and bone marrow suppression if large fields are
irradiated or if the patient was previously treated. Lhermitte's syndrome (paresthesia 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. Neutropenic patients are susceptible to infection, particularly when their neutrophil count falls below 1.0 x
lOe neutrophils per liter (1000 per cubic millimeter). 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.

PANCYTOPENIA (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 ofpancytopenia. Severe complications can be anticipated with leukocyte counts of less than 500/µl, platelets of less
than 20,00011t"1, or anemia with reticulocyte counts of less than 1 More severe disease results in hemorrhagic or infectious 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 ofpathologic conditions (see Table 7-3)

RED BLOOD CELL DISORDERS (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 characteized by an increased destruction of erythrocy4es. Early RBC

TABLE 7-3 Pathologic condition associated with pancytopenia

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 anemias are a diverse group of disease processes, as illustrated in Table 7-4. Hemoll'tic
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; methemalbumin 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 haemolytic anemias

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, paravalvular leaks, or severe calcific aortic stenosis. Intrinsic vessel
disease leading to fibrin deposition and hemolyic anemia occurs in eclampsia, malignant hypertension, renal graft rejection, and
hemangiomas.

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 ofclinical 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. Socalled cold agglutinin disease is associated with infectious mononucleosis,
mycoplasma pneumonia, and lymphoproliferative diseases. Transfusions may accelerate the hemolytic prooess 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/Microcytic (7.4.1.3)

This group of anemias 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 decreased 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, 20o/o to
45o/o 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,
which reflect iron stores in the body, are depressed in iron deficiency states. Hnueror-oclc DISoRDERS / 377 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 pediatric
population. Free erythrocyte protoporphyrin (FEP) and serum lead assays confirm the diagnosis. Sideroblastic anemias involve the
inhibition of heme synthesis and present with microcytic, hlpochromic 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
isoniazi{ 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 sideroblast. 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 erythropoietin.

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, 1 mg 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 Brz 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 gastric mucosa. 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 gastric mucosal 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 Brz 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
Brz deficiency is confirmed by serum assay. 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 cobalamin-
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 over growth. Treatment
consists of intramuscular replacement with vitamin B12.

Normochromic Normocytic (7.4.1.5)

Anemia with normal RBC indices include a wide variety of disorders 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, pure 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 tissue oxygen tension in the renal
microcirculation. Epogen, human recombinant erythropoietin, administered parenterally three times weekly, is used to treat this
conditron. 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 13.4.2)

Sickle cell disease / Trait

Adult hemoglobin (Hg A, o2B2) consists of four globin chains, two c and two p, linked 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, as fetal 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 infl ammatory 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 pediatric 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 Hnruerolocrc
DTsoRDERS / 379 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 reticulocyte 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 manner. 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 intravenous 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 need antiemetics 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 a fewdays 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 radiograph 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 afe managed 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 prior to 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. B-Thalassemia is the deficient production of the a globin. B-Thalassemia trait results in a normal hemoglobin level with
microcytosis. Homozygous G-thalassemia causes a condition known as hydrops fetalis, which results in stillbirth. Insufficient
production of p globin is termed B-thalassemia. 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. B-Thalassemia major is the most severeform 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 p-thalassemia major is accomplished by DNA
analysis of amniotic fluid cells.

SELECTED READING

Babior BH, Bunn HF. Megaloblastic anemias. In: Isselbacher l(J, Braunwald 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. HnMerolocrc DTsoRDERS / 381 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, Wilson JD, et aI. Harrisons principles ofinternal medicine, l3th
ed. New York: McGraw-Hlll, 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.

TRANSFUSIONS (7.5)

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 Compatibility 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), platelets, albumin,
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 that has been frozen within 8hours of collection to prevent plasma
proteins from degenerating. Cryoprecipitate is also frozen an4 like FFR 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 recipient'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 and crossmatch 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 B antigen produce anti-A and/or anti-B immunoglobulin M (IgM)
isohemagglutinin antibody, respectively. For example, type A individuals produce anti-B and type AB 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% 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 27% of
AfricanAmericans have type A blood and ll% and 20% have type B blood" respectively. The Rh antigen (most commonly the D
antigen) is present on the red cell surface of approximately 85% of individuals. Unlike the ABO system, those who are Rh negative
have no naturally occurring antibodies to the Rh antigen. However, they may become sensitized and produce antibodies (usually
IgG), with a 30% 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 (yet rarely 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 Products

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 rather than 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 hemo-
globin-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 decreased 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 65oh 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 andlor 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 0.9% sodium chloride to each unit of PRBCs reduces viscosity
and allows for more rapid infusion. A rise in the hemoglobin of I gmldl (hematocrit rise of 3oh) can be expected after transfusion of
one unit of whole blood or PRBCs in an adult. In a chil4 a hematocrit rise of 1o/o 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 Rh compatible 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 ofFFP 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 µm, 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 similar quantity of platelets may be harvested from a single donor by apheresis to minimize the risk of infectious
disease and/or provide HLAmatched platelets. Platelet concentrates may be infused through a standard 170-µm filter;
microaggregate filters (20 to 40 µm) can trap platelets and slow infusion, and their use is controversial. Platelet administration is
indicated for patients with platelet dysfunction and/or platelet counts less than 50,000/µl 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/µl who are at
significant risk for bleeding may be candidates for prophylactic platelet administration. Ten minutes to I hour after infusion, an
increase of 5,000 to 10,000/µl 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 random 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 to improve 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 transfusionrelated infections. Albumin and coagulation factor concentrates currently
available are free from risk ofinfection 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 yet developed
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
products. Transmission of hepatitis B by transfusion of blood products has become vanishingly rare, and the frequency is not
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 introduc- tion 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 that 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 shock, may result from transfusion of
contaminated blood products. Platelets stored at room temperature must be used within 5 days to decrease the risk of bacterial
contamination. Some cold-growing bacteria, especially Yersinia enterocoliticq, may 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 Gram stain 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. Complementfixing 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 posttransfusion. 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 tumor 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 selflimiting with defervescence 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 leukocytedepleted blood products. Allergic reactions to transfused products are characterizedby 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{hreatening 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 anaphylactoid reaction. Symptoms of allergic reaction may include flushing
of the skin, hives, increased respiratory tract secretions, increased vascular permeabiliry smooth muscle contraction 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
hypocalcemia. 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 arrhyhmias, especially when hyperkalemia and hypocalcemia coexist. Potassium moves
out of red cells during storage, resulting in high concentrations in the storage medium. Excess potassium 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 30o/o of massively transfused patients, probably secondary to diffi.rse hypoxic tissue damage from shock. 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 coagula- tion 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. Adult respiratory distress syndrome (ARDS) may result from sequestration
of microaggregates in the lungs of patients receiving massive transfusions. Microaggregates are composed of fibrin, platelets, and
white cells that accumulate in stored blood. It is difficult, however, to separate the effects of microaggregates from the effects of
shock on the lung. The use of specialized filters to eliminate microaggregates 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 autotransfusion 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
reinfused, 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,
raisesoncotic 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 severe anemia and hemorrhage when
physicians predicted otherwise, the mortality due to anemia when blood is withheld in Witness patients with Hb < 5 g /dl appears to
be at least 36%. Furthermore, applying a specific haemoglobin value to the ED setting is often inappropriate since rapid blood loss
present 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 if they 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 in need 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, McGrawHill, 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
Oncol CIin 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 I I nv es t I 99 5 ;24(1,2):403. Fakhry SM,
Sheldon GF. Blood administration, risks, and substitutes. ldv Surg 1995;28:71 Jeter EK, Spivey MA. Noninfectious complications
of blood transfusion. Hematol Oncol Clin NorthAm 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 Med CIin 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 Mect 1995:333:1721 Lo B. Resolt'ing 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: Saunders, 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. Tiznf rs i o n 1994;3 4:396401.

WHITE BLOOD CELL DISORDERS (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 in ttle
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.

Classification

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 ofboth 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 ofCLL each year, accounting for nearly l0% ofall cancers in
Caucasians but only l%o ofall 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.
Etiology

Although no single factor has been determined to be solely causative in the development of leukemia, both environmental and
genetic elements have been demonstrated to increase the incidence ofthis disease. Ionizing radiation produced by the atomic bomb
attacks on Japan resulted in significantly higher rates of leukemias, including AML and CML. The incidence of CML was observed
to peak 5 ro 12 years after this radiation exposure and was found to be dose related. Other sources of ionizing radiation have been
implicated in the development of leukemia, such as radiation used in the treatment of cancer and ankylosing spondylitis or excessive
exposure to diagnostic x-rays secondary to inadequate shieldlng. 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. The presence of a genetic marker, the Philadelphia
chromosome, has been noted in over 90% of patients diagnosed with CML. Several of the leukemias have shown increased
concordance in identical twins. Preexisting chromosomal abnormalities also increase the risk of developing leukemia as evidenced
by individuals with Down syndrome and Fanconi's anemia.

Clinical Manifestations, 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 $fBq is ffpically in the range of 100,000 to 300,000/mm3 at the time
of diagnosis and canreach levels of 800,000/mm3 or more. A normochromic normocytic anemia is common as the bone marrow
becomes infiltrated with white blood cells. Anemia is rarely observed until the peripheral white blood cell count has exceeded
100,000/mm3. Often there is an associated thrombocytosis in the range of 300,000 to 600,000/mm3 with a majority of patients
having a level of greater than 450,000/mm3. Hyperuricemia is quite common due to high cell turnover. Many other laboratory
investigations have demonstrated usefulness in veri$zing the disease in difficult cases. Deficiency of leukocyte alkaline phosphatase
(LAP) and lack of the Philadelphia chromosome have been 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. The 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 ofgranulocytes. 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 ofthis 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% ofpatients once the
blast phase has begun. Currently the only possible curative treatment for CML is bone marrow transplant (BMT). Long-term
diseasefree 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/o 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. Auer rods 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 20o/o 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 ifthe 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,
hyperphosphatemia, hyperkalemia, and hyperuricemia. The latter can lead to nephropathy and often requires treatment with
hydration, allopurinol to block conversion ofxanthine to uric acid, and urine alkalinization to maintain the more soluble urate 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 Lymphogenous 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.
Ecchymosis, petechia, and mucosal bleeding are characteristic manifestations of thrombocytopenia. CNS involvement, often
without clinically apparent neurologic changes, may occur in2% 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.

Chronic Lymphogenous Leukemia

This is the most common form of adult leukemia in western countries. CLL is more prevalent in males than females and has no
known risk factors. It should be suspected when a sustained increase in small matureappearing lymphocytes is encountered on a
peripheral smear. Criteria for diagnosing CLL requires that >30oh of the bone marrow be infiltrated with lymphocytes. Although
many lymphocytes may appear morphologically mature, extensive immune dysfunction is associated with CLL. The B cells
produce decreased amounts of immunoglobulin in response to antigenic presentation. The number and function of T cells and
natural killer cells are also decreased. However, T cell CLL is considered to be a distinct and separate classification of leukemia.
Staging of CLL involves the degree of lymphocytosis and the presence or absence ofvarious physical findings and symptoms.
Secondary malignancy, particularly lung cancer 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.

Differentiation 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

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. When the neutrophil count falls below 1000 cells/mm3, there is a definite increase in the risk of infection.
Individuals with <500 neutrophils/mm3 are consider 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 Associated With 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

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 grampositive bacteia 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 methicillinresistant 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 bacteremia is present, catheter removal is indicated in the presence of
tunnel infections, endocarditis, systemic fungal infections, infections that fail antibiotic treatment, or bacteremia 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 95o/o of patients with MM
possess an increased concentration of hypersecreted 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 25oh 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%o 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 l5o/o of hematologic neoplasms in Caucasians and up to one-third of hematologic neoplasms in African-
Americans. The incidence is approximately 4 cases per 100,000lyear 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 presentation of MM is that of bone pain affecting
nearly 70oh of patients. Commonly this manifests as unexplained back pain. The bone pain of MM is worsened by movement. This
is in contrast to the bone pain of metastatic cancer, 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. 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 hypogammaglobinemia and
diminished neutrophil migration. Hypogammaglobinemia 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 hyperviscosity and hypercalcemia. Hypercalcemia results from the osteoclastic activating factors released by the increased
number of plasma cells. Symptoms of hypercalcemia include weakness, anorexia, abdominal cramping, constipation, and mental
status changes. Hyperviscosity 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. Rouleaux 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. Pseudohyponatremia 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 osteoblastic 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 nondiagnostic due to the lack ofosteoblastic activity.

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 hyperviscosity. Severe hypercalcemia may require highdose 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
nafure 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 l}oh to 15% of patients as defined by disappearance of the M-component.
Approximately 50o/o 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 ^1. Wintrobeh clinical hematology, gth ed. Philadelphia: Lea & Febiger, i993.
Nealon TF. Management of the patient with cancer, 3rd ed. Philadelphia: Saunders, 1986.
CHAPTER 8

Immune System Disorders

IMMUNE SYSTEM DISORDERS (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 IMMUNITY (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 lymphocyte
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 thromboxanes. 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 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 Goodpasture's syndrome. Type III hypersensitivity reactions occur when
antigenantibody 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, poststreptococcal
glomerulonephritis, autoimmune disease, and hypersensitivity pneumonitis.

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 altract 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

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. There are two pathways to complement
activation (Table 8-2). The first pathway is initiated by the interaction of antigen-antibody complexes. This is followed by a cascade
of complement protein components that enzymatically catalyze the sequential activation of the pathIrr,rvruNr, Svsrnu DIsorutns /
397 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-antibody 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.

AUTOIMMUNE DISEASES (8.5)

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 incompletely understood but are thought to

TABLE 8-2 Complement activation

involve 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 antigen. Immune responses occur constantly in normal individuals and are a part of normal homeostasis.
They involve multiple interactions eventually resulting in a response characterized by a particular type ofcellular activity and
requiring assistance from other cells and systems for the response to be effective. This is particularly true of the interactions
between B and T lymphocytes. Lymphocytes arise from progenitor cells that have migrated to the primary lymphoid organs and
have undergone 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, polysaccharide, 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 activated via 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 helper cells, 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 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 ofcells 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., Dressler'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 occur 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 longterm antibiotic prophylaxis to prevent rheumatic fever InruuNe Svsrnu DrsoRltRs /
399 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 ofdisease 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 ofvessels 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.

Dermatomyositis (8. 5. 2. 1) and Polymyositis (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, sometimes 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 prognosis.

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. Fasciitis and 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 are commonly involved. Spinal disease usually involves the upper cervical region. The hallmarks of
inflammation are usually present, although atypical presentations do occur. Longstanding 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 sometimes 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's
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, splenomegaly, neutropenia, and thrombocy'topenia) have been described.

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 autoantibodies (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 destruction of the Thelper (CD4)
lymphocytes. There is a broad spectrum of HIV disease starting with a brief symptomatic or asymptomatic primary infection
followed by a relatively long asymptomatic phase. The symptomatic 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 stage.

Definition

The current definition of AIDS includes all patients with HIV infection and a CD4 count less than 200/µl, CD4/CD8 ratio <0.14,
and / or an AIDS- INDICATOR (opportunistic) condition such as unusual secondary infections, specific neoplasms, or neurologic
disease ( Table 8-3) .

Etiology

There are two types of HIV viruses that have been identified as causing AIDS in humans: HIV-1 and HIV-2. The most common
cause of AIDS is the 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. AIDS-defining disorders

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/ohave 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%o in voluntary blood donors (Table 8-4). There is also significant geographic variability in seropositivity in emergency
department (ED) populations; 4.2Yo to ll.3%o in large urban inner cities versus <1% in suburban settings. A large percentage of
these patients are unaware of their HIV infection. Nonwhite populations and victims of penetrating trauma are at
significantlyhigher 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 acellular secretions.
Blood and its components <TABLE 8-4.> Prevalence of HIV infection in selected populations in the United States

are probably the most infectious. Other documented sources of HIV transmission include semen, cervical and vaginal 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 ofAsia 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 IvnruNn Sysrnlr DrsononRs / 403 infected and has not y"t developed detectable antibodies. Transfer of the
virus by HlV-contaminated needle-stick to a health care worker carries a risk of 0.3% to 0.4Yo per exposure. The risk of transfer of
HIV from a physician to a patient is extremely small. Maternal-fetal transmission occurs in l3o/o to 39o/o 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 99oh, 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 30o/o in detecting
HIV infection. This sensitivity can be increased to 50oh 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/pl in normal patients. Howeveq the daily variation in counts is significantly less in patients with
low CD4 counts. Certain opporlunistic infections in AIDS patients are only seen with CD4 counts below specific levels. In general,
patients with CD4 counts above 500/pl 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
characterized by low CD4 counts without evidence of HIV infection or explained underlying defect in cellular immunity; 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.

TABLE 8-5 . Relationship between CD4 cell counts and infections

NATURAL HISTORY

Acute Retroviral Infection

The primary infection is estimated to be symptomatic (acute retroviral syndrome) in 30% to 70% 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/pl,
intermediate disease 200 to 500/pl, late symptomatic 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, HIVrelated 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
ofadvanced disease. Treatment and prophylaxis of some of the common HIVrelated 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.
HIV – Related Malignancies

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 oftissue on biopsy. The natural history ofthis disease varies from an indolent to an
aggressive course. However, in light of the fact that less thanl}Yo ofAIDS patients with KS die directly of this sarcoma, most
authors support a cautious treatment regimen that avoids fuither immune suppression. Treatment with interferon-o, decreases tumor
bulk and improves survival in patients with greater than 200l1tl CD4 cells. Combination chemotherapy with low-dose doxorubicin,
bleomycin, and vinblastine plus radiation therapy is indicated for patients with lifethreatening disease. Non-Hodgkin's lymphoma
(NHL) is generally a late manifestation (CD4of 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 HIVrelated lymphomas are high grade B-cell tumors. The most common types include
immunoblastic lymphoma, Burkitt'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 noe 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 some patients. 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 ofbacterial 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-sulfamethoxazole (TMP/SMX) should be contemplated asthis gives adequate coverage for both
groups. Sinusitis generally involves the maxillary sinuses, but may involve the other sinuses as well. Treatment of sinusitis should
include broad-spectrum antibiotics and decongestants. Pneumocystis carinii pneumonia (PCP) was seen in 80% ofAIDS patients
during the mid-I980s. This dropped to 40o/o 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 ofintubation and death from respiratory failure by approximately 50%. Adjuvant
steroids demonstrate their benefit primarily in patients with a PaOz 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/µl), 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 fourdrug 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,
rifampin, and ethambutol.

Neurologic Manifestations

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. Tbxoplasma gondii, the etiologic agent of toxoplasmosis, is
a protozoa that typically infects humans through the ingestion of substances contaminated by cat feces or the consumption of
undercooked meat. The primary infection is relatively asymptomatic, often occurring early in life. Toxoplasmosis in patients
withAIDS usually occurs as the result ofreactivation of Z 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 20011t1. Cryptococcus neoformans
is the most common cause of meningitis in individuals with HIV disease occurring in 60/o 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/µl. 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 40o/o of patients with
cryptococcal infections, 900% of whom also have CNS involvement. Cerebrospinal fluid (CSF) may demonstrate leukocyte counts
between 0 and 700/pl (most 0 to 20l1tl), protein elevation (55%), and a low glucose (24oh). 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 behavioral function. This usually
occurs late in the course of HIV disease. Deficits in attention, forgetfulness, and decreased cognitive func, tion 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
azidothymidine (AZT) may also result in a myopathy that presents with proximal 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 ofprednisone 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, Entamoeba histolytica,
Campylobacte4 Salmonella, and, Shi gella. Crypto sp oridium 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 selfJimiting 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 Manifestations

Dermatologic conditions are described in over 90o/o 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., seborrhea 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 infectionscaused by Candida lvusei, 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 , HSVinfection 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
neurosyphilis (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.

Ophthalmologic Manifestations

CMV retinitis is the leading ocular complication of HIV disease. This generally occurs as a manifestation of advanced HIV disease
(CD4 <50/µl). There is a strong predilection of CMV to the retina. Approximately 90% 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/µl
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, reflecting bone 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 to 100/pl.

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 future. 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/pl. Treatment of patients
with CD4 counts greater than 500/pl 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 peripheral 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 ofprotein 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 likelihood 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 twothirds). 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 newborn. 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 triple drug therapy for significant exposures.

TRANSPLANT-RELEATED PROBLEMS (8.7)

Transplant 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 donorrecipient 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

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 8-8Common laboratory change due to immunosuppressive medications

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 ofrejection. 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 doublelung 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. Bradycardia 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-Lung

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.

HYPERSENSITIVITY (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 reexposed 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 immunemediated 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 anaphylqxis 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 hapten 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
anaphylatoxins. 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 ofpatients 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
ofcontrast is an unlikely cause ofanaphylaxis. 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 of 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 Cq, 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 20o/o of cases of severe anaphylaxis. Biphasic reactions are
associated with a delayed onset of symptoms after initial exposure. Airway obstruction from upper airway edema is the most
cornmon cause of death in anaphylaxis. Bronchospasm with wheezing, shortness of breath, and chest tightness are lower airway
manifestations of anaphylaxis. Respiratory failure can occur. Cardiovascular abnormalities are responsible for the remaining major
clinical manifestations of anaphylaxis. Hypotension is common and thought to result from increased vascular permeability with
intravascular volume depletion and vasodilation. Frank cardiovascular collapse may occur with profound hypotension leading to
confusion, syncope, or seizures. While ECG changes of ischemia may be seen, there is no evidence that mediators have direct
cardiotoxicity. The cardiac effects are probably secondary to ischemia, resulting from volume depletion, loss of vascular tone,
hypotension, and decreased oxygen delivery. The clinical picture of anaphylaxis almost always involves the skin. One or more
manifestations of pruritis, erythema, urticaria, or angioedema are noted in more than 900/o of patients. Mucosal edema and
erythema of the nose, eyes, or mouth may also be seen with resultant tearing, itching, nasal congestion, and sneezing. The GI tract is
also effected. Symptoms of abdominal pain, nausea, vomiting, and diarrhea are often observed. Visceral congestion is a common
finding at autopsy. The diagnosis of anaphylaxis is clinical and based on the observation of the typical features. When these are
associated with a history of exposure to a foreign substance, the diagnosis is virtually certain. Cutaneous reactions, airway
obstruction, bronchospasm, cardiovascular effects, or GI symptoms may occur singly or in any combination. Diagnostic confusion
may occur when cutaneous manifestations are lacking. Anaphylaxis should be considered when a patient presents in shock or
syncope without an obvious cause. The differential diagnosis of acute airway obstruction includes infections of the upper airway
and foreign body aspiration. The history and physical examination usually allow these to be differentiated. Angiotensin-converting
enzpe (ACE) inhibitors nray cause angioedema of the upper airway, and this diagnosis should be considered in patients taking these
medications who develop facial or airway swelling. Treatment for this condition is similar to that for anaphylaxis. Status
asthmaticus may mimic the lower airway manifestations of anaphylaxis, but a history of asthma is almost always present and a
history of exposure less likely. Myocardial infarction can cause hypotension, pulmonary congestion, and changes in mental statuS,
but is usually accompanied by typical chest discomfort and ECG changes. Pulmonary embolism can cause respiratory distress and
shock, but symptoms are usually limited to the respiratory system and the lungs are usually clear. Chest pain is often present and
there are often risk factors for deep venous thrombosis. Hereditary angioedema is due to a deficiency of the enzyme C1 esterase
inhibitor. It can cause airway obstruction, angioedema, and GI symptoms. The GI symptoms are often prominent and there may be a
family history. Urticaria does not occur and cardiovascular effects are not noted. The symptoms of scombroid fish poisoning are
very similar to those of anaphylaxis. They occur when spoiled fish with a high histadine content are ingested. The histidine is
broken down to histamine and this is responsible for the symptoms. Exposure to monosodium glutamate (MSG) can cause flushing,
chest discomfort, and nausea in individuals susceptible to the "Chinese restaurant" syndrome. Headache is common and urticaria
does not occur. Patients may present with respiratory distress, stridor, and inability to swallow due to globus hystericus. In this
condition there is no identified pathology on indirect or fiber optic laryngoscopy. Globus hystericus is a diagnosis of exclusion and
may be a form of Munchausen's syndrome. Prehospital assessment and stabilization of patients with signs and symptoms of
anaphylaxis begin with standard interventions provided to all patients with potentially serious conditions. After airway patency is
assured, high-flow oxygen and cardiac monitoring should be applied. Intubation, if needed, may be difficult due to airway edema.
Bag/mask ventilation may be effective as atemporizing measure while drugs are administered. Surgical airway intervention may be
needed in rare cases. A large bore intravenous line with isotonic crystalloid solution is advisable, even for a normotensive patient.
Hypotensive patients should receive vigorous fluid resuscitation. An initial bolus of I L for adults or 20 mg/kg for children is often
appropriate. In patients with known or suspected cardiac or renal disease, fluid resuscitation should be cautious. A systolic blood
pressure of 80 to 100 mm Hg is acceptable in adults. The mainstay of management is pharmacologic. Epinephrine is the primary
agent and should be available on all advanced life support ambulances. Many patients with a history of Hymenoptera sting or food-
induced anaphylaxis have an epinephrine autoinjector. If epinephrine is not available on the ambulance, the patient's autoinjector
should be sought and used. Epinephrine increases intracellular production of adenosine 3',5'-cyclic monophosphate (cAMP) in mast
cells and basophils with resultant inhibition of mediator release. In addition, epinephrine is a physiologic antagonist to the
vasodilatory, bronchoconstricting, and cutaneous effects of histamine and other mediators. It therefore counteracts bronchospasm,
hypotension, urticaria, and angioedema. Subcutaneous administration is recommended except for patients in profound shock, in
which case epinephrine may be given intravenously. Sublingual injection is an alternative for patients in severe distress who lack IV
access. The adverse effects of epinephrine IulruNr Sysrrru Drsonnr,ns / 419 are predominantly cardiovascular. Hypertension and
dysrhythmias occur, predominantly when the intravenous route is used in patients with preexisting cardiac disease or hypertension.
Malignant dysrhythmias, myocardial infarction, and death have been reported, especially after intravenous use in patients older than
50 years. Dosages for epinephrine and other drugs are noted in Table 8-9. Patients taking p-receptor blocking agents may be
resistant to the pressor effects of epinephrine. Glucagon may be effective as a treatment of refractory hypotension in these patients,
due to positive inotropic and chronotropic effects that are not mediated by p- receptors. Inhaled pagonists are useful as secondary
therapy for bronchospasm. Upper airway edema may respond to nebulized racemic epinephrine. Antihistamines and corticosteroids
are not primary agents in serious anaphylactic or anaphylactoid reactions. While some authors have theorized that corticosteroids
decrease the incidence or severity ofbiphasic or protracted reactions, this has not been verified. Antihistamines seem to affect
predominantly the cutaneous manifestations of anaphylaxis, although in theory histamine-induced vasodilatation should also
respond. While both the Hr and H2 effects of histamine may play a role in anaphylaxis, H1 blocking agents have a more logical role
and should be used first. Some authors have suggested a role for Hz blockers in prevention of biphasic or protracted reactions, but
this has not been verified. Corticosteroids are useful in treatment of bronchospasm and urticaria. The slow onset of

TABLE 8-9, Pharmacologic treatment of anaphylaxis

action of corticosteroids and their lack of effect on the cardiovascular manifestations of anaphylaxis make them second-line agents.
Pretreatment with antihistamines and corticosteroids prevents or ameliorates reactions to intravenous contrast agents. Prior to
administration of contrast to patients at high risk of an anaphylactoid reaction, pharmacologic prophylaxis should be administered
with antihistamines and corticosteroids. There are also short-term desensitization regimens effective in preventing reactions to
penicillin antibiotics. These should be considered when a patient with a history of a serious anaphylactic reaction requires penicillin
as a first-line agent for a life-threatening infection. Most patients treated in the ED for anaphylaxis respond rapidly to treatment, but
patients with persistent manifestations involving the cardiovascular or respiratory systems require admission for further treatment
and observation. Published materials regarding the majority of patients who respond to treatment also recommend a period of
observation up to 24 hours. These recommendations are based on the occurrence ofa second phase of the anaphylactic response
occurring 4 to 8 hours after the initial stimulus. Anaphylaxis with a delayed second phase is known as biphasic anaphylaxis and is
reported in up to 20%o of cases. Prevention of biphasic anaphylaxis with corticosteroids is theoretically attractive, but the true
incidence ofbiphasic anaphylaxis and the efficacy ofcorticosteroids is not well established. Given the lack of definitive data, hospital
admission for patients with airway compromise or hypotension represents the most conservative approach and is therefore advised.
Other patients may be considered for discharge after a period of observation.

Angioedema and Urticaria (8.8.2)

Urticaria is a common cutaneous condition also known as hives. Three major mechanisms of pathogenesis have been described.
Most commonly, urticaria is a manifestation of acute IgE-mediated hypersensitivity. As with the classic anaphylaxis, IgE-mediated
urticaria occurs when a sensitized host is reexposed to an antigen. Preformed mediators are then released from mast cells and
basophils. Histamine is the primary mediator. As with anaphylaxis, urticaria also may be caused by complement-mediated reactions
or specific drug reactions, or may be idiopathic. Physical agents such as cold, sun exposure, and pressure also cause urticaria.
Urticaria is characteized by superficial dermal edema and vascular dilation with capillary leakage of plasma. Angioedema can be
regarded as a more severe form of urticaria. It is characterized by vasodilation and exudation of plasma into the deeper layers of the
dermis and may also occur on the mucosal surfaces of the respiratory or gastrointestinal tract. Causes of angioedema include those
listed for urticaria. In addition, there is an inherited form of angioedema known as hereditary angioneurotic edema (HAE). HAE is
inherited as an autosomal dominant but may also occur sporadically. It is caused by a deficiency of the enzyme Cl esterase inhibitor.
This deficiency results in an inappropriate activation of the complement pathway with the resultant clinical manifestations of
angioedema. Urticarial lesions are also known as hives. The lesions are red and raised and vary in size from very small (papular
urticaria) up to many centimeters (giant urticaria). There may be only a few, small lesions or they may be numerous and become
large and confluent. Urticarial lesions are pruritic. The individual lesions are evanescent and tend to first enlarge and then resolve
over several hours with new lesions occurring at other locations. When lesions are fixed in one location and persist for more than 24
hours, the diagnosis of vasculitis should be considered. Urticarial lesions may occur on any part of the body. The deeper lesions of
angioedema are nonpitting and are often nonpruritic. Angioedema may involve the face, oral cavity, palms, soles, and genitalia.
Airway compromise can result from edema of the tongue or pharynx. In HAE, symptoms of abdominal pain, nausea, and vomiting
are common and result from localized edema of the gastrointestinal mucosa. The diagnosis of urticaria is based on the history and
observation ofthe characteristic skin lesions. Angioedema is diagnosed by observing the typical pattern of asymmetric, nonpitting
edema. Patients with HAE and abdominal pain usually carry the previous diagnosis of HAE. Other causes of abdominal pain must
be ruled out. Most cases of urticaria are idiopathic. Specific causes include many drugs and foods. Commonly implicated drugs
include the penicillins and sulfonamide antibiotics, salicylates, other NSAIDs, insulin, codeine, and other narcotics. Food substances
associated with urticaria include shellfish, chocolate, aged cheeses, peanuts, and many others. Viral infections including hepatitis,
varicella, and infectious mononucleosis are frequently associated with urticaria. Occult infections such as sinusitis and prostatitis
may also precipitate urticaria. Physical urticaria may also occur due to a variety of physical stimuli including cold, heat, pressure, or
sun exposure. Urticaria may occur as a local allergic phenomenon at the site of exposure to an allergen. Acquired (e.g.,
nonhereditary) angioedema is most often idiopathic. The ACE inhibitors used for treatment of hypertension and congestive heart
failure may cause angioedema by an unknown mechanism. After the diagnosis is established, the ED evaluation of urticaria or
angioedema is aimed at differentiating among common possible causes by the history and physical examination. Laboratory testing
is not usually part of this evaluation unless the history or physical points to an underlying systemic illness. Important historical
factors include exposure to commonly implicated agents and other inciting factors. Patients should be questioned about the signs
and symptoms of either systemic or local infections. The past history should include questions about previous episodes and any
previous evaluation. A family history of similar episodes suggests HAE. The physical should seek signs suggesting that the urticaria
is a manifestation of a more severe episode of systemic anaphylaxis. Airway patency should be assured and hlpotension or
tachycardia regarded as possible indications of anaphylaxis. The symptoms of faintness, dizziness, or syncope are also indications
of a possible anaphylactic reactlon. The treatment of urticaria and angioedema is empiric and symptomatic. If potential inciting
agents are identifie4 further exposure should be avoided. Mild cases of urticaria or angioedema may be treated with an oral
antihistamine alone. Parenteral routes may be utilized for a more rapid effect. Typical regimens are either diphenhydramine
(Benadryl), 25 to 50 mg, or hydroxyzine (Vistaril, Atarax) 25 mgevery 6 hours until the symptoms are resolved. Severe cases of
urticaria with generalized hives and severe itching or angioedema involving the upper airway should be treated with both
subcutaneous epinephrine and a parenteral antihistamine. Epinephrine often produces dramatic relief. Doses are outlined in Table 8-
9. Corticosteroids are often used in the treatment of acute urticaria and angioedema but should be considered second-line agents. Hz
blockers have also been used but their efficacy is unproven. Insect stings may cause reactions that are purely local (swelling and
itching adjacent to the sting) or progress to generalized urticaria or anaphylaxis. Urticaria and anaphylaxis are treated in the usual
manner. Local reactions may be treated with ice and antihistamines. Most patients with urticaria or angioedema may be discharged
for outpatient follow-up. Patients with airway involvement or possible anaphylaxis should be considered for observation. When a
patient experiences generalized urticaria or anaphylaxis as a result of an envenomation, they are at risk of anaphylaxis on
subsequent exposure. They should be instructed to avoid situations likely to lead to an exposure, and consideration should be given
to prescribing an epinephrine autoinjector. When angioedema is associated with ACE inhibitor use, the drug should be discontinued
and an agent from another class of antihypertensives selected.

Allergic Rhinitis (8.8.3)

Allergic rhinitis is an antibody-mediated reaction localized to the nasal mucous membranes. It is very common in adolescents with
a reported prevalence of up to 25%. The clinical manifestations include nasal congestion, drainage, and sneezing. Conjunctivitis is a
commonly associated symptom. The pathophysiology involves sensitization and reexposure of mucosal mast cells to an
environmental allergen. Allergic rhinitis may occur in a seasonal or perennial pattern. In the seasonal form pollen is the inciting
allergen and the condition tends to reoccur at the same time each year. In perennial allergic rhinitis, dust, dander, or chemical
exposure may elicit symptoms at any time. The diagnosis of allergic rhinitis is based on the history and the presence of
characteristic symptoms. Typical findings on physical examination include swollen, pale, boggy nasal mucosa. There may be
associated conjunctivitis, but systemic signs and symptoms are lacking. The main differential diagnosis is upper respiratory tract
infection, which is not seasonal and is unrelated to environmental factors. Upper respiratory infections are usually associated with
systemic symptoms of fever, malaise, and myalgias. Symptomatic treatment of allergic rhinitis consists mainly of antihistamines.
The newer nonsedating agents are effective, but are more expensive than older Hr blockers. Nasal corticosteroids are also expensive
but are effective and have few adverse effects. Topical nasal decongestants are effective, but tachyphylaxis and rebound nasal
congestion limit their utility. Perennial rhinitis also responds to antihistamines but is best treated by avoiding inciting agents. If
allergens cannot be avoide4 immunotherapy may be effective. Drug and Food Allergies (8.8.4) Allergic reactions to foods and food
additives are common. Nuts, eggs, legumes, chocolate, peanuts, and dairy products are often implicated. Most reactions are
mediated by IgE-coated mast cells, which line the mucosa of the GI tract. After prior sensitization, ingestion of the allergen causes
release of histamine and other mediators. Non-IgE-mediated reactions may also occur. The diagnosis offood allergies depends on
the history' Prior reactions are usual. Many patients give a history of multiple allergic symptoms. The most common symptoms of
food allergy are limited to the GI tract. Crampy abdominal pain, nausea with or without vomiting, and local swelling of the lips,
tongue, and pharynx are observed. Occasionally, generalized urticaria or anaphylaxis are seen. Treatment is symptomatic, with
antihistamines used for mild symptoms and epinephrine for severe urticaria or anaphylaxis. Ifthe offending agent can be identified"
avoidance should be advised as a preventative measure. Drugs are commonly implicated in allergic reactions. Most drugs are not
true allergens but function as haptens. When the drug molecules are bound to plasma proteins, they may become immunogenic.
Many adverse allergiceffects are not immunologically mediated but mimic true allergic reactions. ACE inhibitor associated
angioedema and reactions to IV contrast are prominent examples. Penicillin is the most commonly implicated drug in severe allergic
reactions, but allergy to almost any drug can occur. The clinical manifestations and treatment of acute drug allergy does not differ
from other acute allergic reactions. Topical reactions may be treated by avoidance and topical corticosteroids or oral antihistamines.
Generalized urticaria or angioedema is treated using antihistamines with epinephrine added in more severe cases. When an allergic
reaction occurs in the setting of exposure to a likely offending agent, patients should be counseled regarding avoidance.

Serum Sickness (8.8.5)

Serum sickness provides the classic model of an immune-complex disease and is most often caused by drug hypersensitivity. When
an allergen is introduced into a sensitized individual, it binds to specific antibody and immune complexes are formed. Usually, these
immune complexes are cleared by the reticuloendothelial system without complications. When the immune complexes exceed a
certain size and are present in large amounts they may be deposited in tissues with resultant inflammation and tissue damage. The
kidney, joints, skin, and blood vessels walls are the tissues usually affected. In drug-induced serum sickness, drug molecules act as
haptens with resulting sensitization and formation of specific antibody. On reexposure, immune complexes form and serum sickness
may result. Implicated agents include sulfonamides, penicillins, diphenylhydantoin, and thiazides. Blood products may also cause
serum sickness. Serum sickness and late-onset anaphylaxis has also been reported to occur after insect stings. Clinical
manifestations of serum sickness typically begin I to 3 weeks after the initial exposure to an agent and may occur much sooner (12
to 36 hours) ifthere has been prior sensitization. Typical signs and symptoms include fever, malaise, arthralgias, and cutaneous
rashes. Gastrointestinal symptoms, lymphadenopathy, and proteinuria also occur but are less common. The skin eruption may be
morbiliform or urticarial and is often confined to the trunk, though it may be generalized. Less often, frank arthritis or vasculitis
may occur. Vasculitis may affect the kidney, central nervous system, and the coronary arteries. The diagnosis ofdrug-induced serum
sickness is based on the clinical presentation and a history ofexposure to a likely offending agent. Laboratory tests to detect
circulating immune complexes are available but are not helpful during the initial patient encounter in the ED. Druginduced serum
sickness typically resolves within days of withdrawal of the offending drug, so no specific treatment is usually needed.
Antihistamines may provide relief from the cutaneous manifestations. Corticosteroids are recommended for severe cutaneous
manifestations or if there is significant vasculitis. Acetaminophen may be used for arthralgias and fever.

CHAPTER 9

SYSTEMIC INFECTIOUS DISORDERS

SYSTEMIC INFECTIOUS DISORDERS (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
implementing new strategies to manage more severe infections as an outpatient. While many infectious diseases are discussed
throughout the text, this chapter discusses systemic infectious diseases not covered elsewhere.

BACTERIAL (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 bottlefed 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 autonomic dysfunction. In the case of food-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 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 theaction 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).

TABLE9-1. Differential diagnosis of botulism

Treatmen , 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 ofbotulism 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 addi-tion, it has been recommended that infants under 12 months of age not be given honey.

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 2o/o to 5oh COz. 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 initial urethral 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 genital tract 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 25Yo 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-HughCurtis 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 compli- cations 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 an oligo- 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 regardi4g sexual practices.
However, the physician should bear in mind that patients frequently are evasive regarding thishistory, 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 50o/o 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 ofPID. 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, ovar-ian 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 syphilis, 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.\oh 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. When joint effirsion is present, arthrocentesis 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 30o/o 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 involvement may have a sensitivity of 60ohto 80oh, 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 should be used. The cultures should be
plated as soon as possible in an environment containing 3o/o to 5oh COz. 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. Nonculture
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 onetime
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.

TABLE9-2. Treatment of gonococcal infections\

<6>. The sex partners ofindividuals 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. Plevic inflammatory diseaseadmission criteria

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, pancreati_ tis, 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 should not be confused with bacteremia – the presence of bacteria within the blood
stream , which is probably present in a significant percentage of sepsis cases. The end stage of sepsis- septic shock – is the global
hypoperfusion (cardiovascular collapse) of the body as a result of the inflammatory response to infection . The patient with
manifestations of sepsis challenge to emergency physicians from both a diagnostic and therapeutic standpoint .while many patients
present with fever and an obvious sourse , in many others , particularly the elderly , very young , and immunocompromised , the
true nature of the patients symptoms may be far more difficult to elucidate . supportive care , the initation of a diagnodtic plan , and
the choice of empiric antibiotic therapy are specifically the responsibility of the emergency physician.

Epidemiology

There are more than 200,000 deaths due to sepis and sepis shock each year. It is the 13 th leading cause of death in the nation for
patients older than 1 year and the ninth leading cause for children ages 1 to 4. There is no service within the hospital that can be
consideredexempted from caring for the potentially septic patient. Those who appear to be a greater risk for sepisis include
immunosuppressed patients , those with significant comorbid conditions , infants under 1 year , and the elderly , particularly
thoseolder than 75 years. Additionally, patients with indwellingFoley catheters or indwelling intravenous lines are at greater risk for
the development of sepsis as a result of these sources. Once the septic 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 pstients who are not febrile
appeared to have a higher overall mortality as well.

Pathophysiology

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 infec_ tion and sinusitis are examples of more
occult sources of sepsis. As noted above , bacteremia is not a prerequisite for 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 may result from the direct
invasion 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 gramnegative organisms. Examples of exotoxins are theproteins secreted by certain strains of
Staphylococcus and Streptococcu.s 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 mediators 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
tofurther 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 identiff 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 septic 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 patient,s 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
provide clues 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 suspicion for DIC exists , laboratory confirmation 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 concomitant 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 may be a labor-intensive 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 crystalloids tend 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 cases Swan-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.

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 worldwide cases of Hansen's disease, the disease is rare in the United States. Thus
many physicians, including emer- -,Jilc), piiysicians, fail tc, 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 subSaharan 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 ofthe 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 remained 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.

Pathophys iology 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 harbor large numbers of bacilli and few granulomas. Patients with this form of
leprosy may carry huge numbers of organisms. Nnodular 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. Tirberculoid 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 ofleprosy should be suspected ifany 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 by 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 dapsone, 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 and institute appropriate isolation procedures. This may prove difficult in many instances as TB may present
with a myriad of symptoms and findings especially in the immunosuppressed. As TB can infect healthy, nonimmunocompromised
individualsvia airborne 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.

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 noncompliance with drug therapy, the increasing prevalence of infection with multiple-drug-
resistant strains of Mycobacterium tubercttlosis, 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 ofTB 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 nonmotile, 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 bovis occttrred 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 othergranulomas, 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 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. 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 xray. 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 pneumonia, 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 l5o/o 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 extrathoracic organs. Renalfailure may result if the process is bilateral. Likewise, the adrenal glands may be
affected with resultant addisonian crisis. 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 non-productive if present . Obstructive symptoms are more common in children . Progressive pulmonary disease may
be productive or non productive , dyspnea , or hemoptysis. While hemoptysis is common , massive hemoptysis is rare. Chest pain
may herald involvement of the pleura or pericardium . Patients may also experience symptoms consistent with pneumothorax. In
cases where pulmonary TB is progressive ,individual also are likely to apper 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 occurnas a result of tuberculous effusion or pneumothorax. In cases where 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 similary
to acute pneumonia . Pleuritic chest pain as well as dyspnea may occur as a result of tuberculous effusion or pneumothorax. In cases
where 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 similary to actute 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 .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. Involment
of the 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 consistent with adnexal mass or PID , Examination of the lymph system may reveal adenopathy. Patients with
tuberculous meningitis or cerevral involvement may present with tuberculous meningitis or cerebral involvement may present with
sign of increased intracranial pressure , meningismums , or focal deflect.

Ancillary Studies

The tuberculin skin test screens patients for the development of delayed – type hypersensitivity to antigens in the mycobacterial cell
wall , implying exposure to TB. Clinicians must bear in mind several important facts when evaluating patients with these tests.
First, up to 20% of normal individuals and a much grater percentage 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 pr""i*i 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 stilf imply
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'" ili" at,i"g 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 sensitivity analysis of the bacilli involved' Wttit" the findings of TB on chest x-ray may be entirely nonspecific
(especially in the immunocompromisedj, certain patterns should raise the physician's level of susplcion tor fg. 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'. 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 hypoglycemia, elevated protein levels, and a moderate pleocytosis
(100-1000 cells/mm3) with a usual predominance of lymphocytes.

Tretment

Classically five drugs-isoniazid, rifampin, ethambutol, streptomycin, and pyrizinamide-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. Multipledrug-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 ofinadequately 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

TABLE 9-6 . Initial treatment of active TB

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 ifthe 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 ofpotentially 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 ofillness are Mycobacterium avium and Mycobacterium
intracellulsre, 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 bloodborne 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, widespread 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 syndromes 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 HI! 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 Dispostion

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
fourthline agents include clofazimine, rifabutin, rifampin, ciprofloxacin, and amikacin. Once institute4 prophylaxis andJor
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

Hunsen’s Disease

Pust R, Campos-Outcalt D. Leprosy in the United States. Risks, recognition, regimens, resources. Postgrad Med 1 985 ;77(5): I 5 1-
l 59. Style A. Early diagnosis and treatment of leprosy in the United St^tes. Am Fam Physician 1995;52(l):17 2-17 8. Simon H.
Infections due to mycobacteitm. Sci Am Med 1995;18(9):1-26. Trautman J. Epidemiological aspects of Hansen's disease. Buil NY
Acad Me d 1 984 ;60(7 ):7 22-7 3 l.

Tuberculosis

Barclay D, Richardson J, Fredman L. Tuberculosis in the homeless. lrcft 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. Brausch 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): 1
37-1 40. Ciesielski S. BCG vaccination and the PPD: what the clinician needs to know. J Fam Pract 1995;40:.76-80. Huebner R,
Castro K. The changing face oftuberculosis. Annu Rev Med 1995;46:47-55. Kent J. The epidemiology ofmultidrug-resistant
tuberculosis in the United States. Med Clin North Am 1993;77(6):1391-1407. McSherry G, Connor E. Current epidemiology
oftuberculosis. Pediatr Ann 1993;22:600404. Nardell E. Environmental control of tuberculosis. Med Clin North Am 1993;77
(6)13ts-t334. Pozsik C. Compliance with tuberculous therapy. Med Clin North Anr 1991 ;7 7 (6) : 1289-130 l. Simon H. Infections
due to mycobacteilm. 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.
Waagler D. The clinical presentation of tuberculosis disease in children. Pe di atr A n n 1993 ;22(1 0) :622-628. Yamaguchi E,
Reichman L. Pulmonary tuberculosis in the HIV positive patients. Infect Dis CIin NorthAm 199l;5(3):623-633.

Atypical Mycobacterium

Beck K. Mycobacterial disease associated with HIV infection. J Gen Intern M e d 199 1 ;6(stppl) : s I 9-s23. Beson C. Disease due
to the Mycobacterium avium complex in patients with AIDS epidemiology and clinical syndrome. Clin Infect Dis 1994; I
8(suppl):s2 I 8-s222. Jacobson MP, Hopewell D, Yajko WK. Natural history of disseminated Mycobacterium avium complex
infection in AIDS. J htfect Dis 1991; 164:994-998. Gyure K, Prayson R, Estes M, Hall G. Symptomatic Ml,cobacteriunt aviunt
complex infection of the central nervous system. A case report and review ofthe literature. Arch Pathol Lab Med 1995;119:836-839.
Masur H, and the Public Health Service Task Force on Prophylaxis and Therapy for Mycobacterium avium Complex.
Recommendations on prophylaxis and therapy for disseminated Mycobacterium avium complex disease in patients infected with the
human immunodeficiency virus N Engl J Med 1993;329(12):898-903. Rigsby M, Curtis A. Pulmonary disease from nontuberculous
mycobacteria in patients with human immunodeficiency virus. Chest 19941'106: 913-919.

Meningococcemia (9.1.5)

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 (WaterhouseFriderichsen syndrome), meningococcal meningitis, or chronic
meningococcemia. From 30% to 50%o 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 2o/o 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 30Yo, 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 ofdroplets of infected nasopharyngeal secretions, and close person-toperson
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 90Yo 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 an upper respiratory infection.
Occasionally, diarrhea has been reported as a symptom that has been associated with early meningococcemia. In its mildest form,
symptoms may spontaneously resolve within a few days, and diagnosis is only made in retrospect by blood 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 IDoh to 200/o 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 I 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 papular rash with rare petechiae and purpura. The total number of lesions is small. Up to 20Vo of the 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 20o/o of the patients. Endocarditis
and epididymitis are rarer complicatrons. 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%o to 40o/o 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 warted . 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
communityacquired 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%o to 16Yo 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 oligoarthritis (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 eftrsion or a
very minimal effirsion. Pericarditis also may complicate meningococcal disease in 2c/o to 20% of the patients. Like arthritib, 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 withott
signs of meningococcal disease is very rare. Ocular and genitourinary involvement complicate less thanl%o 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 75oh 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 glday), and ceftriaxone (up to 4 glday; 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 mglkg 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 infection.

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 ofboth the frequency ofinfection 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 ofrats, 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 southwestern 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
begindng 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 I to 10 cm in length. The overlying skin may be elevated, or appear sfretched or erythematous. The buboe 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 clinical course can produce death within 2 to 4days 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 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 mam-mals 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 2}-gauge needle on a 10-cc syringe containing I 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 ("saftey-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 50oh.
Hospitalization, fluid hydration, and early treatment with effective antibiotics can be lifesaving. Streptomycin is the drug of choice
for the treatment ofplague. 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 afebrile. 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 pfague in patients who are allergic to streptomycin or who prefer oral treatment. Tetracycline is administered orally in a dose of2
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 nor steroids 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 fieldcollected
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.

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.
However, onlyin 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%o. 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) Tetanospasmin, 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 Taminobutyric 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
risus sardonicus, 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 otitis media/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 toward 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 as paralytics, 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 tetqni. Control of autonomic dysfunction is essential; the
use of labetolol, clonidine, morphine, MgSOa, 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.

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%o of the ^S. aureus isolates from patients with menstrual related TSS produce TSSTI,
whereas approximately 60% of isolates from non-menstrualderived cases elaborateTSSTl. The effects ofTSSTl are protean and it is
likely that the manifestation of TSS is related both to the direct activity of the toxin as well asinduction 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, magnesiumdeficient microenvironment is the ideal condition for the elaboration of
TSST1 by toxigenic S. qureus. Toxic shock syndrome is characterized by hyperpyrexia, 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 cases. 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 foreignobject. 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 positive
cocci 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 ofantistaphylococcal 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 antibody titer and therefore may benefit from the passive immunization rendered
by the administration of immunoglobulins.

TABLE 9-7. Centers for disease control case definition of toxic shock syndrome

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 renamed 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; howeveq late manifestations may occur throughout the year. This coincides with the peak activity of ticks.
Humans may be exposed when frequenting woodlands where Lyme 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 ECMassociated
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 l0o/o to
l5Yo 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 .8. burgdorferi. Lyme carditis is characterized by a mild myocarditis usually associated with variable
degrees of atrioventricular node conduction abnormalities. Approximately 50o/o 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 lowgrade 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
spirochete invadesthe 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 optic neurosis. 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 60oh that
increases to 95%o 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%oto25o/o, in populations residing in Lyme endemic areas
due to subclinical exposure to 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 withLyme 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, anticipat ing 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 antibiotics. 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. 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 Bburgdorferi increases with time. The maximum efficiency of transmission by the infected tick does not occur until
after being attached for 48 hours.

TABLE 9-8. Therapy of Lyme disease

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. Leptospirosis has also been reported in slaughterhouse 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 25o/o 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; howeveq there is a l5o/o mortality with severe leptospirosis.
Leptospirosis usually lasts from 4 to 9 days, and ifleft untreated, 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 5o/o to l0%; however, it is
age dependent, with30Yo mortality over age 60. Jaundiced patients have a l5Yo 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 hematuri a, 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 per deciliter. Up to 25Yo 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 90o/o ofthe 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 per
deciliter. The chest x-ray may appear abnormal in up to 25o/o 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 40Yo ofthe 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 shortening the course of leptospirosis if given in the first 2 to 4 days of
the illness. If given later, their effectiveness is unknown. The effect of antibiotic treatment 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.

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.

Epidemiology / Pathophysiology
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 unilateral or bilateral, which follow the appearance of
thechancre 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, extragenital 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 ducreyi) may appear as a
chancre, they are typically painful. Chancroid usually presents with multiple ulcers that are exudative and nonindurated.
Lymphogranuloma 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 70Yo 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 varied 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 color. 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 papular 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 also very infectious. Secondary syphilis is associated with ongoing spirochetemia, which
accounts for the potential for multiple organ system involvement. Hepatitis has been reported in 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 ofinfection. 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 anywhere 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. Xray 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 vessel wall. 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 25o/o 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. Meningovascular syphilis most commonly occurs between 4 and 7 years after initial infection and is more cofiImon
in males. Meningeal involvement is less prominent, but underlying endarteritis and perivascular inflammation result in
cerebrovascular thrombosis and infarction. Signs and symptoms are typical of cerebrovascular thrombosis of any cause. 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 refl exes, 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 of large joints in affected 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 infants die in 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 deafness, saddle nosedeformiry bilateral knee arthritis with effrrsions (Clutton'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 primary syphilis 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. Z 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 75o/o for primary syphilis, 95oh 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, nontreponemal 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 reported 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 95o/o 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 connective 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, however, 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. As the 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 5oh 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 her stage 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.
Therefore, 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
findings, 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 syphilis,T5o/o of those with secondary syphilis, and20%o 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.

Chlamydia (9.1.10)

The genus Chlamydia contains different species such as C. 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.

Epidemiology

The incidence of chlamydial genital infections has increased in recent years. "Genital infections caused by C. 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 C. psittaci seems to be more prevalent in England, where birds are popular household pets.

Pathophysiology / Etiology

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 I 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. trachomatls
infection of neonates results from perinatal exposure to the mother's infected cervix, causing a conjunctivitis or a subacute, afebrile
pneumonia with onset from I 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 harboring these organisms. The organism is transmitted to
humans by the respratory 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 nongonococcal 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 mayform shallow ulcerations, papular 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 ofage with conjunctivitis.
Characteristic signs of chlamydial pneumonia secondary to C. trachomatis among infants include a repetitive staccato cough,
tachypnea, hyperinflation, and diffuse infiltrates on chest roentgenogram. Infants are usually afebrile. 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. Diffi.rse 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 serotypes,
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 Diagnosis of C.
trachomatis conjlnctivitis is usually made by finding intracytoplasmic inclusion bodies in conjunctival scrapings or less often by
culture. Tissue cultures from the nasopharynx should be tested to diagnose chlamydia pneumonia for C. tra- chomatis. 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 – Diposition

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. pn eu m oniae 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 preventing 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.

PROTOZOAN-PARASITES (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.

Epidemiology

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 4Yo.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.

Pathophysiology

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 tropozoite 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 ofreproductive 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 falciparum 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
falcipqrum. 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
prior to the paroxysm. 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%).

TABLE 9-9. Chemotherapy of malaria according to infecting species

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 oftravel to a malaria-prone region within the past
year. Knowledge of the region where exposure likely occurred helps narrow the search for type ofinfection. 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 ofparasite 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%o of peripheral erythrocytes is considered severe. Infecting species-M. falciparum is the most
serious. Hematocrit-a presenting hematocrit of less than 20o/o 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 (Fans iday'-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 enantiomer 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 this 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 parasite 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

TABLE9-10. .-Dosages of antimalarial drugs used in chemotherapy

Prevention

The World Health Organization (WHO) had a worldwide 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
ofresistance, 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.

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 outside a host (the oocyte shed in cat
feces). Humans are usually infected by ingestion of the cystic form, found in meat (25Yo of pork and l0o/o 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 Tbxopla.srua 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 54%o 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; 75o/o 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 3o/o to 7%o 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 35% of all cases of retinochoroiditis. The characteristic
retinal lesion is caused by focal necrosis. Initially appearing as a yellowwhite "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%o 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 multiple 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 diagnosis.