VARICELLA ZOSTER VIRUS is one of eight herpes viruses known to shingles in adults, until the vaccination was given
he vaccination was given to the entire population—
infect humans (and other vertebrates). It commonly causes chicken-pox in
children and both shingles and post herpetic neuralgia in adults.
• Nomenclature
Varicella zoster virus is known by many names, including: chickenpox virus,
Varicella virus, zoster virus, and human herpes virus type 3 (HHV-3).
• Human disease
Primary VZV infection results in chickenpox (Varicella), which may rarely
result in complications including encephalitis or pneumonia. Even when
clinical symptoms of chickenpox have resolved, VZV remains dormant in the
nervous system of the infected person (REDIRECT virus latency), in the
trigeminal and dorsal root ganglia. In about 10-20% of cases, VZV
reactivates later in life producing a disease known as herpes zoster or
shingles. Serious complications of shingles include post herpetic neuralgia,
zoster multiplex, myelitis, herpes ophthalmicus, or zoster sine herpete.
• Morphology
VZV is closely related to the herpes simplex viruses (HSV), sharing much
genome homology. The known envelope glycoprotein (gB, gC, gE, gH, gI,
gK, gL) correspond with those in HSV, however there is no equivalent of
HSV gD. VZV also fails to produce the LAT (latency-associated transcripts)
that play an important role in establishing HSV latency (REDIRECT herpes
simplex virus). VZV virions are spherical and 150-200 nm in diameter. Their
lipid envelope encloses the nucleocapsid of 162 capsomeres arranged in an
icosahedral form. Its DNA is a single, linear, double-stranded molecule;
125,000 nt long. The capsid is surrounded by a number of loosely associated
proteins known collectively as the tegument; many of these proteins play
critical roles in initiating the process of virus reproduction in the infected cell.
The tegument is in turn covered by a lipid envelope studded with
glycoproteins that are displayed on the exterior of the virion.
The virus is very susceptible to disinfectants, notably sodium hypochlorite.
Within the human body it can be treated by a number of drugs and
therapeutic agents including acyclovir, zoster-immune globulin (ZIG), and
vidarabine.
• Vaccine
A live attenuated VZV Oka/Merck strain vaccine is available and is marketed
in the United States under the trade name Varivax. It was developed by
Merck, Sharp & Dohme in the 1980s from the Oka strain virus isolated and
attenuated by Michiaki Takahashi and colleagues in the 1970s. It was
submitted to the U.S. Food and Drug Administration for approval in 1990 and
was approved in 1995. Since then, it has been added to the recommended
vaccination schedules for children in Australia, the United States, and many
other countries. Varicella vaccination has raised concerns in some that the
immunity induced by the vaccine may not be lifelong, possibly leaving adults
vulnerable to more severe disease as the immunity from their childhood
immunization wanes. Vaccine coverage in the United States in the
population recommended for vaccination is approaching 90%, with
concomitant reductions in the incidence of Varicella cases, and
hospitalizations and deaths due to VZV. So far, clinical data has proved that
the vaccine is effective for over 10 years in preventing Varicella infection in
healthy individuals and when breakthrough infections do occur, illness is
typically mild. In 2007, the ACIP recommended a second dose of vaccine
before school entry to ensure the maintenance of high levels of Varicella
immunity.
In 2006, the FDA approved Zostavax for the prevention of shingles. Zostavax
is a more concentrated formulation of the Varivax vaccine, designed to elicit
an immune response in older adults whose immunity to VZV wanes with
advancing age.
Some countries require the Varicella vaccination or an exemption before
entering elementary school. Protection is not permanent and further
vaccination is necessary five years after the initial immunization.
In the United Kingdom, Varicella antibodies are measured in women with no
history of the disease as part of routine of prenatal care. By 2005 all National
Health Service personnel had determined their immunity and been
immunized if they were non-immune and have direct patient contact.
Population-based immunization against Varicella is not otherwise practiced
in the UK. It is feared that there would be a greater number of cases of
because adults who have had chickenpox as a child are less likely to have
shingles in later life if they have been exposed occasionally to the
chickenpox virus (for example by their children). This is because the
exposure acts as a booster vaccine.
• Chickenpox
Chickenpox is a highly contagious illness caused by primary infection with
Varicella zoster virus (VZV). It generally begins with conjunctival and
catarrhal symptoms and then characteristic spots appearing in two or three
waves, mainly on the body and head rather than the hands and becoming
itchy raw pockmarks, small open sores which heal mostly without scarring.
Chickenpox has a 10-21 day incubation period and is spread easily through
aerosolized droplets from the nasopharynx of ill individuals or through direct
contact with secretions from the rash. Following primary infection there is
usually lifelong protective immunity from further episodes of chickenpox.
Chickenpox is rarely fatal, although it is generally more severe in adults than
in children. Pregnant women and those with a suppressed immune system
are at highest risk of serious complications. The most common late
complication of chicken pox is shingles, caused by reactivation of the
Varicella zoster virus decades after the initial episode of chickenpox.
• Signs and symptoms
Chickenpox is a highly contagious disease that spreads from person to
person by direct contact or through the air from an infected person's
coughing or sneezing. Touching the fluid from a chickenpox blister can also
spread the disease. A person with chickenpox is contagious from one to five
days before the rash appears until all blisters have formed scabs. This may
take 5-10 days. It takes from 10-20 days after contact with an infected
person for someone to develop chickenpox.
The chicken pox lesions (blisters) start as a two to four millimeter red papule
which develops an irregular outline (a rose petal). A thin-walled, clear vesicle
(dew drop) develops on top of the area of redness. This "dew drop on a rose
petal" lesion is very characteristic for chickenpox. After about 8 to 12 hours
the fluid in the vesicle gets cloudy and the vesicle breaks leaving a crust.
The fluid is highly contagious, but once the lesion crusts over, it is not
considered contagious. The crust usually falls off after seven days
sometimes leaving a crater-like scar. Although one lesion goes through this
complete cycle in about seven days, another hallmark of chickenpox is the
fact that new lesions crop up every day for several days. Therefore it may be
a week before new lesions stop appearing and existing lesions crust over.
Children are not to be sent back to school until all lesions have crusted over.
Zoster, also known as shingles, is a reactivation of chickenpox and may also
be a source of the virus for susceptible children and adults. It is not
necessary to have physical contact with the infected person for the disease
to spread. Those infected can spread chickenpox before they know they
have the disease - even before any rash develops. People with chickenpox,
in fact, can infect others from about two days before the rash develops until
all the sores have crusted over, usually four or five days after the rash starts.
• Infection in Pregnancy and Neonates
Varicella infection in pregnant women can lead to viral transmission
via the placenta and infection of the fetus. If infection occurs during the first
28 weeks of gestation, this can lead to fetal Varicella syndrome (also known
as congenital Varicella syndrome). Effects on the fetus can range in severity
from underdeveloped toes and fingers to severe anal and bladder
malformation. Possible problems include:
a. Damage to BRAIN: encephalitis, microcephaly, hydrocephaly, aplasia
of brain
b. Damage to the EYE (optic stalk, optic cap, and lens vesicles):
microphthalmia, cataracts, chorioretinitis, optic atrophy
c. Other NEUROLOGICAL disorder: damage to cervical and lumbosacral
spinal cord, motor/sensory deficits, absent deep tendon reflexes,
anisocoria/Horner's syndrome
d. Damage to BODY: hypoplasia of upper/lower extremities, anal and
bladder sphincter dysfunction
e. SKIN disorders: (cicatricial) skin lesions, hypopigmentation
Infection late in gestation or immediately post-partum is referred to as
neonatal Varicella. Maternal infection is associated with premature delivery.
The risk of the baby developing the disease is greatest following exposure to
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infection in the period 7 days prior to delivery and up to 7 days post-partum.
The neonate may also be exposed to the virus via infectious siblings or other
contacts, but this is of less concern if the mother is immune. Newborns that
develop symptoms are at a high risk of pneumonia and other serious
complications of the disease.
• Pathophysiology
Chickenpox is usually acquired by the inhalation of airborne respiratory
droplets from an infected host. The highly contagious nature of VZV explains
the epidemics of chickenpox that spread through schools as one child who is
infected quickly spreads the virus to many classmates. High viral titers are
found in the characteristic vesicles of chickenpox; thus, viral transmission
may also occur through direct contact with these vesicles, although the risk
is lower.
After initial inhalation of contaminated respiratory droplets, the virus infects
the conjunctivae or the mucosa of the upper respiratory tract. Viral
proliferation occurs in regional lymph nodes of the upper respiratory tract 2-4
days after initial infection and is followed by primary viremia on postinfection
days 4-6. A second round of viral replication occurs in the body's internal
organs, most notably the liver and the spleen, followed by a secondary
viremia 14-16 days postinfection. This secondary viremia is characterized by
diffuse viral invasion of capillary endothelial cells and the epidermis. VZV
infection of cells of the Malpighian layer produces both intercellular and
intracellular edema, resulting in the characteristic vesicle.
Exposure to VZV in a healthy child initiates the production of host
immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A
(IgA) antibodies; IgG antibodies persist for life and confer immunity. Cell-
mediated immune responses are also important in limiting the scope and the
duration of primary Varicella infection. After primary infection, VZV is
hypothesized to spread from mucosal and epidermal lesions to local sensory
nerves. VZV then remains latent in the dorsal ganglion cells of the sensory
nerves. Reactivation of VZV results in the clinically distinct syndrome of
herpes zoster (shingles).
• Diagnosis
The diagnosis of Varicella is primarily clinical. In a non-immunized individual
with typical prodromal symptoms associated with the appropriate appearing
rash occurring in "crops", no further investigation would normally be
undertaken.
If further investigation is undertaken, confirmation of the diagnosis can be
sought through either examination of the fluid within the vesicles, or by
testing blood for evidence of an acute immunologic response. Vesicle fluid
can be examined with a Tsanck smear, or better with examination for direct
fluorescent antibody. The fluid can also be "cultured", whereby attempts are
made to grow the virus from a fluid sample. Blood tests can be used to
identify a response to acute infection (IgM) or previous infection and
subsequent immunity (IgE).
Prenatal diagnosis of fetal Varicella infection can be performed using
ultrasound, though a delay of 5 weeks following primary maternal infection is
advised. A PCR (DNA) test of the mother's amniotic fluid can also be
performed, though the risk of spontaneous abortion due to the amniocentesis
procedure is higher than the risk of the baby developing fetal Varicella
syndrome.
• Treatment
There is no evidence to support the effectiveness of topical application of
calamine lotion, a topical barrier preparation containing zinc oxide in spite of
its wide usage and excellent safety profile. [9] It is important to maintain good
hygiene and daily cleaning of skin with warm water to avoid secondary
bacterial infection.
If exposure to Varicella in certain 'at risk' populations is confirmed
(immunosuppressed individuals, pregnant seronegative women, neonates),
anti-Varicella zoster immunoglobulin may be given prior to onset of disease
symptoms.
Infection in otherwise healthy adults tends to be more severe and active;
treatment with antiviral drugs (e.g. acyclovir) is generally advised. Patients of
any age with depressed immune systems or extensive eczema are at risk of
more severe disease and should also be treated with antiviral medication. In
the U.S., 55 percent of chickenpox deaths are in the over-20 age group,
even though they are a tiny fraction of the cases.
• Prognosis
Chickenpox infection is milder in young children, and symptomatic treatment,
with a sodium bicarbonate baths or antihistamine medication may ease
itching. Paracetamol (acetaminophen) is widely used to reduce fever.
Aspirin, or products containing aspirin, must not be given to children with
chickenpox (or any fever-causing illness suspected of being of viral origin),
as this risks causing the serious and potentially fatal Reye's Syndrome.
In adults, the disease can be more severe, though the incidence is much
less common. Infection in adults is associated with greater morbidity and
mortality due to pneumonia, hepatitis and encephalitis. In particular, up to
10% of pregnant women with chickenpox develop pneumonia, the severity of
which increases with onset later in gestation. In England and Wales, 75% of
deaths due to chickenpox are in adults. [4] Inflammation of the brain, or
encephalitis, can occur in immunocompromised individuals, although the risk
is higher with herpes zoster. Necrotizing fasciitis is also a rare complication.
Secondary bacterial infection of skin lesions, manifesting as impetigo,
cellulitis, and erysipelas, is the most common complication in healthy
children. Disseminated primary Varicella infection, usually seen in the
immunocompromised or adult populations, may have high morbidity. Ninety
percent of cases of Varicella pneumonia occur in the adult population. Rarer
complications of disseminated chickenpox also include myocarditis, hepatitis,
and glomerulonephritis.
Hemorrhagic complications are more common in the immunocompromised
or immunosuppressed populations, although healthy children and adults
have been affected. Five major clinical syndromes have been described:
febrile purpura, malignant chickenpox with purpura, postinfectious purpura,
purpura fulminans, and anaphylactoid purpura. These syndromes have
variable courses, with febrile purpura being the most benign of the
syndromes and having an uncomplicated outcome. In contrast, malignant
chickenpox with purpura is a grave clinical condition that has a mortality rate
of greater than 70%. The etiology of these hemorrhagic chickenpox
syndromes is not known.
• Epidemiology
Primary Varicella is an endemic disease. Cases of Varicella are seen
throughout the year but more commonly in winter and early spring. This is
unlike enteroviruses and lends some support to the view that, like measles
and rubella, Varicella is spread mainly by the respiratory route. In contrast,
herpes zoster occurs sporadically and evenly throughout the year. Varicella
is one of the classic diseases of childhood, with the highest prevalence in the
4 - 10 years age group. Like rubella, it is uncommon in preschool children.
Varicella is highly communicable, with an infection rate of 90% in close
contacts. Most people become infected before adulthood but 10% of young
adults remain susceptible. However, this pattern of infection is not universal,
e.g. in rural India, Varicella is predominantly a disease of adults, with the
mean age of infection 23.4 years. It has been suggested that this could be
due to interference by other respiratory viruses that children are exposed to.
Historically, Varicella has been a disease predominantly affecting preschool
and school-aged children. In adults the pock marks are darker and the scars
more prominent than in children.
• History
One history of medicine book credits Giovanni Filippo (1510–1580) of
Palermo with the first description of Varicella (chickenpox). Subsequently in
the 1600s, an English physician named Richard Morton described what he
thought a mild form of smallpox as "chicken pox." Later, in 1767, a physician
named William Heberden, also from England, was the first physician to
clearly demonstrate that chickenpox was different from smallpox. However, it
is believed the name chickenpox was commonly used in earlier centuries
before doctors identified the disease.
There are many explanations offered for the origin of the name chickenpox:
Samuel Johnson suggested that the disease was "less dangerous", thus a
"chicken" version of the pox; the specks that appear looked as though the
skin was pecked by chickens; the disease was named after chick peas, from
a supposed similarity in size of the seed to the lesions; the term reflects a
corruption of the Old English word giccin, which meant itching.
As "pox" also means curse, in medieval times some believed it was a plague
brought on to curse children by the use of black magic.
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From ancient times, neem has been used by Indians to alleviate the external
symptoms of itching and to minimize scarring. Neem baths (neem leaves and
a dash of turmeric powder in water) are commonly given for the duration.
Neem branches are hung at the entrance of households to announce that
illness to visitors. Neem branches are kept handy by the affected person to
gently brush the skin, to soothe the itching sensation.
During the medieval era, oatmeal was discovered to soothe the sores, and
oatmeal baths are today still commonly given to relieve itching.
MENINGITIS is the inflammation of the protective membranes covering
the brain and spinal cord, known collectively as the meninges. Meningitis
may develop in response to a number of causes, usually bacteria, viruses
and other pathogens, but also physical injury, cancer or certain drugs. While
some forms of meningitis are mild and resolve on their own, meningitis is a
potentially life-threatening condition due to the proximity of the inflammation
to the brain and spinal cord. The potential for serious neurological damage or
even death necessitates prompt medical attention and evaluation. Infectious
meningitis, the most common form, is typically treated with antibiotics and
requires close observation. Some forms of meningitis (such as those
associated with meningococcus, mumps virus or pneumococcus infections)
may be prevented with immunization.
• Signs and symptoms
Severe headache is the most common symptom of meningitis (87 percent)
followed by nuchal rigidity ("neck stiffness", found in 83%). The classic triad
of diagnostic signs consists of nuchal rigidity (being unable to flex the neck
forward), sudden high fever and altered mental status. All three features are
present in only 44% of all cases of infectious meningitis. Other signs
commonly associated with meningitis are photophobia (inability to tolerate
bright light), phonophobia (inability to tolerate loud noises), irritability and
delirium (in small children) and seizures (in 20-40% of cases). In infants (0-6
months), swelling of the fontanel (soft spot) may be present.
Nuchal rigidity is typically assessed with the patient lying supine, and both
hips and knees flexed. If pain is elicited when the knees are passively
extended (Kernig's sign), this indicates nuchal rigidity and meningitis. In
infants, forward flexion of the neck may cause involuntary knee and hip
flexion (Brudzinski's sign). Although commonly tested, the sensitivity and
specificity of Kernig's and Brudzinski's tests are uncertain.
In "meningococcal" meningitis (i.e. meningitis caused by the bacteria
Neisseria meningitidis), a rapidly-spreading petechial rash is typical, and
may precede other symptoms. The rash consists of numerous small,
irregular purple or red spots on the trunk, lower extremities, mucous
membranes, conjunctiva, and occasionally on the palms of hands and soles
of feet. Other clues to the nature of the cause may be the skin signs of hand,
foot and mouth disease and genital herpes, both of which may be associated
with viral meningitis.
Meningitis can be diagnosed after death has occurred. The findings from a
post mortem are usually a diffuse (widespread) inflammation of the pia-
arachnoid area. Neutrophil leucocytes tend to have migrated to the
cerebrospinal fluid and the base of the brain, along with cranial nerves and
the spinal cord, may be surrounded with pus—as may the meningeal
vessels.
• Diagnosis/Investigations
Investigations include blood tests (electrolytes, liver and kidney function,
inflammatory markers and a complete blood count) and usually X-ray
examination of the chest. The most important test in identifying or ruling out
meningitis is analysis of the cerebrospinal fluid (fluid that envelops the brain
and the spinal cord) through lumbar puncture (LP). However, if the patient is
at risk for a cerebral mass lesion or elevated intracranial pressure (recent
head injury, a known immune system problem, localizing neurological signs,
or evidence on examination of a raised ICP), a lumbar puncture may be
contraindicated because of the possibility of fatal brain herniation. In such
cases a CT or MRI scan is generally performed prior to the lumbar puncture
to exclude this possibility. Otherwise, the CT or MRI should be performed
after the LP, with MRI preferred over CT due to its superiority in
demonstrating areas of cerebral edema, ischemia, and meningeal
inflammation.
During the lumbar puncture procedure, the opening pressure is measured. A
pressure of over 180 mm H2O is indicative of bacterial meningitis.
The cerebrospinal fluid (CSF) sample is examined for white blood cells (and
which subtypes), red blood cells, protein content and glucose level. Gram
staining of the sample may demonstrate bacteria in bacterial meningitis, but
absence of bacteria does not exclude bacterial meningitis; microbiological
culture of the sample may still yield a causative organism. The type of white
blood cell predominantly present predicts whether meningitis is due to
bacterial or viral infection. Other tests performed on the CSF sample include
latex agglutination test, limulus lysates, or polymerase chain reaction (PCR)
for bacterial or viral DNA. If the patient is immunocompromised, testing the
CSF for toxoplasmosis, Epstein-Barr virus, cytomegalovirus, JC virus and
fungal infection may be performed.
Cultures are often negative if CSF is taken after the administration of
antibiotics. In these patients, PCR can be helpful in arriving at a diagnosis. It
has been suggested that CSF cortisol measurement may be helpful.
Aseptic meningitis refers to non-bacterial causes of meningitis and includes
infective etiologies such as viruses and fungi, neoplastic etiologies such as
carcinomatous and lymphomatous meningitis, inflammatory causes such as
sarcoidosis (neurosarcoidosis)) and chemical causes such as meningitis
secondary to the intrathecal introduction of contrast media.
Although the term "viral meningitis" is often used in any patient with a mild
meningeal illness with appropriate CSF findings, certain patients will present
with clinical and CSF features of viral meningitis, yet ultimately is diagnosed
with one of the other conditions categorized as "aseptic meningitis". This
may be prevented by performing polymerase chain reaction or serology on
CSF or blood for common viral causes of meningitis (enterovirus, herpes
simplex virus 2 and mumps in those not vaccinated for this).
A related diagnostic and therapeutic conundrum is the "partially treated
meningitis", i.e. meningitis symptoms in patients who have already been
receiving antibiotics (such as for presumptive sinusitis). In these patients,
CSF findings may resemble those of viral meningitis, but antibiotic treatment
may need to be continued until there is definitive positive evidence of a viral
cause (e.g. a positive enterovirus PCR).
• Prediction rules
The Bacterial Meningitis Score predicts reliably whether a child (older than
two months) may have infectious meningitis. In children with at least 1 risk
factor (positive CSF Gram stain, CSF absolute Neutrophil count ≥ 1000
cell/µL, CSF protein ≥ 80 mg/dL, peripheral blood absolute Neutrophil count
≥ 10,000 cell/µL, history of seizure before or at presentation time) it had a
sensitivity of 100%, specificity of 63.5%, and negative predictive value of
100%.
• Causes
Most cases of meningitis are caused by microorganisms, such as viruses,
bacteria, fungi, or parasites, that spread into the blood and into the
cerebrospinal fluid (CSF).[9] Non-infectious causes include cancers, systemic
lupus erythematosus and certain drugs. The most common cause of
meningitis is viral, and often runs its course within a few days. Bacterial
meningitis is the second most frequent type and can be serious and life-
threatening. Numerous microorganisms may cause bacterial meningitis, but
Neisseria meningitidis ("meningococcus") and Streptococcus pneumoniae
("pneumococcus") are the most common pathogens in patients without
immune deficiency, with meningococcal disease being more common in
children. Staphylococcus aureus may complicate neurosurgical operations,
and Listeria monocytogenes is associated with poor nutritional state and
alcoholism. Haemophilus influenzae (type B) incidence has been much
reduced by immunization in many countries. Mycobacterium tuberculosis
(the causative agent of tuberculosis) rarely causes meningitis in Western
countries but is common and feared in countries where tuberculosis is
endemic.
• Treatment
a. Initial treatment
Meningitis is a life-threatening condition and treatment should not be delayed
for confirmation if suspected. If a physician is present on scene then
treatment should begin immediately with benzylpenicillin. High-flow oxygen
should be administered as soon as possible, along with an intravenous fluids
if hypotensive or in shock.
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 b. Bacterial meningitis
Bacterial meningitis is a medical emergency and has a high mortality rate if
untreated. All suspected cases, however mild, need emergency medical
attention. Empiric antibiotics must be started immediately, even before the
results of the lumbar puncture and CSF analysis are known. Antibiotics
started within 4 hours of lumbar puncture will not significantly affect lab
results. Adjuvant treatment with corticosteroids reduces rates of mortality,
severe hearing loss and neurological sequelae in adults, specifically when
the causative agent is Pneumococcus.
Age group Causes
Group B Streptococci, Escherichia coli, Listeria
Neonates
monocytogenes
Neisseria meningitidis, Haemophilus influenzae, Streptococcus
Infants
pneumoniae
Children N. meningitidis, S. pneumoniae
Adults S. pneumoniae, N. meningitidis, Mycobacteria, Cryptococci
The choice of antibiotic depends on local advice. In most of the developed
world, the most common organisms involved are Streptococcus pneumoniae
and Neisseria meningitidis: first line treatment in the UK is a third-generation
cephalosporin (such as ceftriaxone or cefotaxime). In those under 3 years of
age, over 50 years of age, or immunocompromised, ampicillin should be
added to cover Listeria monocytogenes. In the U.S. and other countries with
high levels of penicillin resistance, the first line choice of antibiotics is
vancomycin and a carbapenem (such as meropenem). In sub-Saharan
Africa, oily chloramphenicol or ceftriaxone are often used because only a
single dose is needed in most cases.
Staphylococci and gram-negative bacilli are common infective agents in
patients who have just had a neurosurgical procedure. Again, the choice of
antibiotic depends on local patterns of infection: cefotaxime and ceftriaxone
remain good choices in many situations, but ceftazidime is used when
Pseudomonas aeruginosa is a problem, and intraventricular vancomycin is
used for those patients with intraventricular shunts because of high rates of
staphylococcal infection. In patients with intracerebral prosthetic material
(metal plates, electrodes or implants, etc.) then sometimes chloramphenicol
is the only antibiotic that will adequately cover infection by Staphylococcus
aureus (cephalosporins and carbapenems are inadequate under these
circumstances).
Once the results of the CSF analysis are known along with the Gram-stain
and culture, empiric therapy may be switched to therapy targeted to the
specific causative organism and its sensitivities.
Neisseria meningitidis (Meningococcus) can usually be treated with a 7-day
course of IV antibiotics:
- Penicillin-sensitive -- PENICILLIN G or AMPICILLIN
- Penicillin-resistant -- CEFTRIAXONE or CEFOTAXIME
- Prophylaxis for close contacts (contact with oral secretions) -- RIFAMPIN
600 mg bid for 2 days (adults) or 10 mg/kg bid (children). Rifampin is not
recommended in pregnancy and as such, these patients should be
treated with single doses of CIPROFLOXACIN, AZITHROMYCIN or
CEFTRIAXONE
Streptococcus pneumoniae (Pneumococcus) can usually be treated with a 2-
week course of IV antibiotics:
- Penicillin-sensitive -- PENICILLIN G
- Penicillin-intermediate -- CEFTRIAXONE OR CEFOTAXIME
- Penicillin-resistant -- CEFTRIAXONE or CEFOTAXIME + VANCOMYCIN
Listeria monocytogenes is treated with a 3-week course of IV AMPICILLIN +
GENTAMICIN.
Gram negative bacilli -- CEFTRIAXONE or CEFOTAXIME
Pseudomonas aeruginosa -- CEFTAZIDIME
Staphylococcus aureus
- Methicillin-sensitive -- NAFCILLIN
- Methicillin-resistant -- VANCOMYCIN
Streptococcus agalactiae -- PENICILLIN G or AMPICILLIN
Haemophilus influenzae -- CEFTRIAXONE or CEFOTAXIME
c. Viral meningitis
Patients diagnosed with mild viral meningitis may improve quickly enough to
not require admission to a hospital, while others may be hospitalized for
many more days for observation and supportive care. Overall, the illness is
usually much less severe than bacterial meningitis.
Unlike bacteria, viruses cannot be killed by antibiotics. Drugs such as
acyclovir may be employed if herpes virus infection is either suspected or
demonstrated.
d. Fungal meningitis
This form of meningitis is rare in otherwise healthy people but is a higher risk
in those who have AIDS, other forms of immunodeficiency (an immune
system that does not respond adequately to infections) and
immunosuppression (immune system malfunction as a result of medical
treatment). In AIDS, Cryptococcus neoformans is the most common cause of
fungal meningitis; it requires Indian ink staining of the CSF sample for
identification of this capsulated yeast. Fungal meningitis is treated with long
courses of highly dosed antifungal.
• Complications
In children there are several potential disabilities which result from damage
to the nervous system. These include sensorineural hearing loss, epilepsy,
diffuse brain swelling, hydrocephalus, cerebral vein thrombosis, intra
cerebral bleeding and cerebral palsy. Acute neurological complications may
lead to adverse consequences. In childhood acute bacterial meningitis
deafness is the most common serious complication. Sensorineural hearing
loss often develops during first few days of the illness as a result of inner ear
dysfunction, but permanent deafness is rare and can be prevented by
prompt treatment of meningitis.
Those that contract the disease during the neonatal period and those
infected by S. pneumoniae and gram negative bacilli are at greater risk of
developing neurological, auditory, or intellectual impairments or functionally
important behavior or learning disorders which can manifest as poor school
performance.
In adults central nervous system complications include brain infarction, brain
swelling, hydrocephalus, intracerebral bleeding; systemic complications are
dominated by septic shock, adult respiratory distress syndrome and
disseminated intravascular coagulation. Those who have underlying
predisposing conditions e.g. head injury may develop recurrent meningitis. [18]
Case-fatality ratio is highest for gram-negative etiology and lowest for
meningitis caused by H. influenzae (also a gram negative bacillus). Fatal
outcome in patients over 60 years of age is more likely to be from systemic
complications e.g. pneumonia, sepsis, cardio-respiratory failure; however in
younger individuals it is usually associated with neurological complications.
Age more than 60, low Glasgow coma scale at presentation and seizure
within 24 hours increase the risk of death among community acquired
meningitis.
• Prevention
a. Immunization
Vaccinations against Haemophilus influenzae (Hib) have decreased early
childhood meningitis significantly.
Vaccines against type A and C Neisseria meningitidis, the kind that causes
most disease in preschool children and teenagers in the United States, have
also been around for a while. Type A is also prevalent in sub-Sahara Africa
and W135 outbreaks have affected those on the Hajj pilgrimage to Mecca.
Immunization with the ACW135Y vaccine against four strains is now a visa
requirement for taking part in the Hajj.
Vaccines against type B Neisseria meningitidis are much harder to produce,
as its capsule is very weakly immunogenic masking its antigenic proteins.
There is also a risk of autoimmune response, and the porA and porB
proteins on Type B resemble neuronal molecules. A vaccine called MeNZB
for a specific strain of type B Neisseria meningitidis prevalent in New
Zealand has completed trials and is being given to many people in the
country under the age of 20 free of charge. There is also a vaccine,
MenBVac, for the specific strain of type B meningococcal disease prevalent
in Norway, and another specific vaccine for the strain prevalent in Cuba.[citation
needed]
According to reports released in May 2008, Novartis is in the advanced
stages of testing a general meningococcus type B vaccine.
Pneumococcal polysaccharide vaccine against Streptococcus pneumoniae is
recommended for all people 65 years of age or older. Pneumococcal
conjugate vaccine is recommended for all newborns starting at 6 weeks - 2
months, American Academy of Pediatrics (AAP) recommendations.
Mumps vaccination has led to a sharp decline in mumps virus associated
meningitis, which prior to vaccination occurred in 15% of all cases of mumps.
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 b. Prophylaxis
In cases of meningococcal meningitis, prophylactic treatment of close
relatives with antibiotics (e.g. rifampicin, ciprofloxacin or ceftriaxone) may
reduce the risk of further cases.
• Epidemiology
Meningitis can affect anyone in any age group, from the newborn to the
elderly.
The "Meningitis Belt" is an area in sub-Saharan Africa which stretches from
Senegal in the west to Ethiopia in the east in which large epidemics of
meningococcal meningitis occur (this largely coincides with the Sahel
region). It contains an estimated total population of 300 million people. The
largest epidemic outbreak was in 1996, when over 250,000 cases occurred
and 25,000 people died as a consequence of the disease.
• History
Meningitis was first described in the 1020s in Avicenna's The Canon of
Medicine, and again more accurately by Avenzoar of al-Andalus in the 12th
century. Symptoms of the disease were also noted in 1805 by the Swiss
Gabinetto Vieusseux (a scientific-literary association) during an outbreak in
Geneva, Switzerland. In 1887, Dr. Anton Weichselbaum (1845-1920) of
Vienna became the first to isolate the specific germ, meningococcus.
In the 19th century, meningitis was a scourge of the Japanese imperial
family, playing the largest role in the horrendous pre-maturity mortality rate
the family endured. In the mid-1800s, only the Emperor Kōmei and two of his
siblings reached maturity out of fifteen total children surviving birth. Kōmei's
son, the Emperor Meiji, was one of two survivors out of Kōmei's six children,
including an elder brother of Meiji who would have taken the throne had he
lived to maturity. Five of Meiji's 15 children survived, including only his third
son, Emperor Taishō, who was feeble-minded, perhaps as a result of having
contracted meningitis himself. By Emperor Hirohito's generation the family
was receiving modern medical attention. As the focal point of tradition in
Japan, during the Tokugawa Shogunate the family was denied modern
"Dutch" medical treatment then in use among the upper caste; despite
extensive modernization during the Meiji Restoration the Emperor insisted on
traditional medical care for his children.
TUBERCULOUS MENINGITIS is also known as TB meningitis or
tubercular meningitis. Tuberculous meningitis is a Mycobacterium
tuberculosis infection of the meninges. It is the most common form of CNS
tuberculosis.
• Clinical features
Fever and headache are the cardinal features. Confusion is a late feature
and coma bears a poor prognosis. Meningism is absent in a fifth of patients
with TB meningitis. Patients may also have focal neurological deficits.
• Pathology
Mycobacterium tuberculosis of the meninges is the cardinal feature and the
inflammation is concentrated towards the base of the brain. Infection begins
in the lungs and may spread to the meninges by a variety of routes.
Blood-borne spread certainly occurs and 25% of patients with miliary TB
have TB meningitis, presumably by crossing the blood-brain barrier; but a
proportion of patients may get TB meningitis from rupture of a cortical focus
in the brain (a so-called Rich focus); an even smaller proportion get it from
rupture of a bony focus in the spine. It is rare and unusual for TB of the spine
to cause TB of the central nervous system, but isolated cases have been
described.
• Diagnosis
Diagnosis of TB meningitis is made by analyzing CSF collected by lumbar
puncture. When collecting CSF for suspected TB meningitis, a minimum of
1ml of fluid should be taken (preferably 5 to 10ml).
The CSF usually has a high protein, low glucose and a raised number of
lymphocytes. Acid-fast bacilli are sometimes seen on a CSF smear, but more
commonly, M. tuberculosis is grown in culture. A spiderweb clot in the
collected CSF is characteristic of TB meningitis, but is a rare finding.
More than half of cases of TB meningitis cannot be confirmed
microbiologically, and these patients are treated on the basis of clinical
suspicion only. The culture of TB from CSF takes a minimum of two weeks,
and therefore the majority of patients with TB meningitis are started on
treatment before the diagnosis is confirmed.
a. Nucleic acid amplification tests (NAAT)
This is a heterogeneous group of tests that use polymerase chain reaction
(PCR) to detect mycobacterial nucleic acid. These tests vary in which nucleic
acid sequence they detect and vary in their accuracy. The two most common
commercially available tests are the amplified mycobacterium tuberculosis
direct test (MTD, Gen-Probe) and Amplicor. In 2007, a systematic review of
NAAT by the NHS Health Technology Assessment Program concluded that
for diagnosing tuberculous meningitis "Individually, the AMTD test appears to
perform the best (sensitivity 74% and specificity 98%)”. In the NHS meta-
analysis, they found the pooled prevalence of TB meningitis to be 29%;
however there was much heterogeneity in the reported sensitivities. Using a
clinical calculator, these numbers yield a positive predictive value of 94%
and a negative predictive value of 90%; however the 30% prevalence may
be high due to referral bias. Alternate estimates of disease prevalence can
be entered into the clinical calculator to refine the predictive values.
b. Imaging
Imaging studies such as CT or MRI may show features strongly suggestive
of TB meningitis, but cannot diagnose it.
• Treatment
The treatment of TB meningitis is isoniazid, rifampicin, pyrazinamide and
ethambutol for two months, followed by isoniazid and rifampicin alone for a
further ten months. Steroids are always used in the first six weeks of
treatment (and sometimes for longer). A few patients may require
immunomodulatory agents such as thalidomide.
Treatment must be started as soon as there is a reasonable suspicion of the
diagnosis. Treatment must not be delayed while waiting for confirmation of
the diagnosis.
Hydrocephalus occurs as a complication in about a third of patients with TB
meningitis and will require a ventricular shunt.
DENGUE FEVER and DENGUE HEMORRHAGIC FEVER
(DHF) are acute febrile diseases, found in the tropics and Africa, and
caused by four closely related virus serotypes of the genus Flavivirus, family
Flaviviridae. The geographical spread is similar to malaria, but unlike
malaria, dengue is often found in urban areas of tropical nations, including
Puerto Rico, Singapore, Malaysia, Taiwan, Indonesia, Philippines, India and
Brazil. Each serotype is sufficiently different that there is no cross-protection
and epidemics caused by multiple serotypes (hyperendemicity) can occur.
Dengue is transmitted to humans by the Aedes aegypti (rarely Aedes
albopictus) mosquito, which feeds during the day.
• Signs and symptoms
This infectious disease is manifested by a sudden onset of fever, with severe
headache, muscle and joint pains (myalgias and arthralgias—severe pain
gives it the name break-bone fever or bonecrusher disease) and rashes. The
dengue rash is characteristically bright red petechiae and usually appears
first on the lower limbs and the chest; in some patients, it spreads to cover
most of the body. There may also be gastritis with some combination of
associated abdominal pain, nausea, vomiting or diarrhea. Other symptoms
include:
- fever
- bladder problems
- constant headaches
- severe dizziness
- loss of appetite
- uncontrollable laughing
- extreme constipation
Some cases develop much milder symptoms which can, when no rash is
present, be misdiagnosed as influenza or other viral infection. Thus travelers
from tropical areas may inadvertently pass on dengue in their home
countries, having not been properly diagnosed at the height of their illness.
Patients with dengue can pass on the infection only through mosquitoes or
blood products and only while they are still febrile.
The classic dengue fever lasts about six to seven days, with a smaller peak
of fever at the trailing end of the disease (the so-called "biphasic pattern").
Clinically, the platelet count will drop until the patient's temperature is normal.
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Cases of DHF also show higher fever, hemorrhagic phenomena,
thrombocytopenia, and hemoconcentration. A small proportion of cases lead
to dengue shock syndrome (DSS) which has a high mortality rate.
Dengue should be suspected when you have sudden onset of high fever, 39-
40°C, accompanied with severe headache, pain behind the eyes, body
aches, rashes on the skin and nausea or vomiting. The fever lasts for 5-7
days. In some patients, fever comes down on the third or fourth day but it
recurs.
• Diagnosis
The diagnosis of dengue is usually made clinically. The classic picture is
high fever with no localizing source of infection, a petechial rash with
thrombocytopenia and relative leukopenia.
The WHO definition of dengue hemorrhagic fever has been in use since
1975; all four criteria must be fulfilled:
- Fever
- bladder problem
- constant headaches
- severe dizziness and loss of appetite
a. HEMORRHAGIC TENDENCY (positive TOURNIQUET TEST,
spontaneous bruising, bleeding from mucosa, gingival, injection sites,
etc.; vomiting blood, or bloody diarrhea)
b. THROMBOCYTOPENIA (<100,000 platelets per mm³ or estimated
as less than 3 platelets per high power field)
c. EVIDENCE OF PLASMA LEAKAGE (hematocrit more than 20%
higher than expected, or drop in hematocrit of 20% or more from
baseline following IV fluid, pleural effusion, ascites, hypoproteinemia)
DENGUE SHOCK SYNDROME is defined as Dengue Hemorrhagic
Fever plus:
- Weak rapid pulse,
- Narrow pulse pressure (less than 20 mm Hg) or,
- Cold, clammy skin and restlessness
- Serology and polymerase chain reaction (PCR) studies are available
to confirm the diagnosis of dengue if clinically indicated
• Treatment
The mainstay of treatment is supportive therapy. Increased oral fluid intake is
recommended to prevent dehydration. Supplementation with intravenous
fluids may be necessary to prevent dehydration and significant concentration
of the blood if the patient is unable to maintain oral intake. A platelet
transfusion is indicated in rare cases if the platelet level drops significantly
(below 20,000) or if there are significant bleeding.
The presence of melena may indicate internal gastrointestinal bleeding
requiring platelet and/or red blood cell transfusion.
Like most viral diseases there is no specific cure for dengue fever. Antibiotics
do not help. ASPIRIN and NON-STEROIDAL ANTI-INFLAMMATORY
DRUGS should be avoided as these drugs may worsen the bleeding
tendency associated with some of these infections. Patients may receive
paracetamol preparations to deal with these symptoms if dengue is
suspected.
Most patients with dengue fever can be treated at home. They should take
rest, drink plenty of fluids and eat nutritious food. Whenever available, Oral
Rehydration Salt (commonly used in treating diarrhea) should be used.
Sufficient fluid intake is very important. Generally the progression towards
dengue hemorrhagic fever or dengue shock syndrome occurs after 3-5 days
of fever. At this time, fever has often come down. This may mislead many of
us to believe that the patient is heading towards recovery. This is the most
dangerous period that requires high vigilance. It is best to consult a
physician. Indications for hospitalization are persistent vomiting, inability to
take oral fluids, persistent abdominal pain, restlessness, or bleeding from
any site (nose, gums, passage of black stools).
a. Emerging treatments
Emerging evidence suggests that mycophenolic acid and ribavirin inhibit
dengue replication. Initial experiments showed a fivefold increase in
defective viral RNA production by cells treated with each drug. In vivo
studies, however, have not yet been done.
• Epidemiology
The first epidemics occurred almost simultaneously in Asia, Africa, and North
America in the 1780s. The disease was identified and named in 1779. A
global pandemic began in Southeast Asia in the 1950s and by 1975 DHF
had become a leading cause of death among children in many countries in
that region. Epidemic dengue has become more common since the 1980s.
By the late 1990s, dengue was the most important mosquito-borne disease
affecting humans after malaria, there being around 40 million cases of
dengue fever and several hundred thousand cases of dengue hemorrhagic
fever each year. There was a serious outbreak in Rio de Janeiro in February
2002 affecting around one million people and killing sixteen.
On March 20, 2008, the secretary of health of the state of Rio de Janeiro,
Sérgio Côrtes, announced that 23,555 cases of dengue, including 30 deaths,
had been recorded in the state in less than three months. Côrtes said, "I am
treating this as an epidemic because the number of cases is extremely high."
Federal Minister of Health José Gomes Temporão also announced that he
was forming a panel to respond to the situation. Cesar Maia, mayor of the
city of Rio de Janeiro, denied that there was serious cause for concern,
saying that the incidence of cases was in fact declining from a peak at the
beginning of February. By April 3, 2008, the number of cases reported rose
to 55,000
Significant outbreaks of dengue fever tend to occur every five or six months.
The cyclicity in numbers of dengue cases is thought to be the result of
seasonal cycles interacting with a short-lived cross-immunity for all four
strains, in people who have had dengue (Wearing and Rohani 2006). When
the cross-immunity wears off, the population is then more susceptible to
transmission whenever the next seasonal peak occurs. Thus in the longer
term of several years, there tend to remain large numbers of susceptible
people in the population despite previous outbreaks because there are four
different strains of the dengue virus and because of new susceptible
individuals entering the target population, either through childbirth or
immigration.
There is significant evidence, originally suggested by S.B. Halstead in the
1970s that dengue hemorrhagic fever is more likely to occur in patients who
have secondary infections by serotypes different from the primary infection.
One model to explain this process is known as antibody-dependent
enhancement (ADE), which allows for increased uptake and virion replication
during a secondary infection with a different strain. Through an
immunological phenomenon, known as original antigenic sin, the immune
system is not able to adequately respond to the stronger infection, and the
secondary infection becomes far more serious. This process is also known
as superinfection (Nowak and May 1994; Levin and Pimentel 1981).
In Singapore, there are about 4,000–5,000 reported cases of dengue fever
or dengue hemorrhagic fever every year. In the year 2003, there were six
deaths from dengue shock syndrome. It is believed that the reported cases
of dengue are an underrepresentation of all the cases of dengue as it would
ignore subclinical cases and cases where the patient did not present for
medical treatment. With proper medical treatment, the mortality rate for
dengue can therefore be brought down to less than 1 in 1000.
• Prevention
a. Vaccine development
There is no commercially available vaccine for the dengue Flavivirus.
However, one of the many ongoing vaccine development programs is the
Pediatric Dengue Vaccine Initiative which was set up in 2003 with the aim of
accelerating the development and introduction of dengue vaccine(s) that are
affordable and accessible to poor children in endemic countries. Thai
researchers are testing a dengue fever vaccine on 3,000–5,000 human
volunteers after having successfully conducted tests on animals and a small
group of human volunteers. A number of other vaccine candidates are
entering phase I or II testing.
b. Mosquito control
Primary prevention of dengue mainly resides in mosquito control. There are
two primary methods: LARVAL CONTROL and ADULT MOSQUITO
CONTROL. In urban areas, Aedes mosquitoes breed on water collections in
artificial containers such as plastic cups, used tires, broken bottles, flower
pots, etc. Continued and sustained artificial container reduction or periodic
draining of artificial containers is the most effective way of reducing the larva
and thereby the Aedes mosquito load in the community. Larvicide treatment
is another effective way of control the vector larvae but the Larvicide chosen
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should be long lasting and preferably have World Health Organization
clearance for use in drinking water. There are some very effective insect
growth regulators (IGR`s) available which are both safe and long lasting e.g.
pyriproxyfen. For reducing the adult mosquito load, fogging with insecticide is
somewhat effective.
c. Prevention of mosquito bites
Prevention of mosquito bites is another way of preventing disease. This can
be achieved either by personal protection or by using mosquito nets. In
1998, scientists from the Queensland Institute of Research in Australia and
Vietnam's Ministry of Health introduced a scheme that encouraged children
to place a water bug, the crustacean Mesocyclops, in water tanks and
discarded containers where the Aedes aegypti mosquito was known to
thrive. This method is viewed as being more cost-effective and more
environmentally friendly than pesticides, though not as effective, and
requires the ongoing participation of the community.
d. Personal protection
Personal prevention consists of the use of mosquito nets, repellents
containing NNDB or DEET, covering exposed skin, use of DEET-
impregnated bednets, and avoiding endemic areas.
e. Potential antiviral approaches
In cell culture experiments and mice Morpholino antisense oligos have
shown specific activity against Dengue virus.
The yellow fever vaccine (YF-17D) is a related Flavivirus, thus the chimeric
replacement of yellow fever vaccine with dengue has been often suggested
but no full scale studies have been conducted to date.
In 2006, a group of Argentine scientists discovered the molecular replication
mechanism of the virus, which could be attacked by disruption of the
polymerase's work.
• History
The origins of the word dengue are not clear, but one theory is that it is
derived from the Swahili phrase "Ka-dinga pepo", which describes the
disease as being caused by an evil spirit. The Swahili word "dinga" may
possibly have its origin in the Spanish word "dengue" (fastidious or careful);
describing the gait of a person suffering dengue fever or, alternatively, the
Spanish word may derive from the Swahili. It may also be attributed to the
phrase meaning "Break bone fever", referencing the fact that pain in the
bones is a common symptom.
Outbreaks resembling dengue fever have been reported throughout history.
The first definitive case report dates from 1789 and is attributed to Benjamin
Rush, who coined the term "breakbone fever" (because of the symptoms of
myalgia and arthralgia). The viral etiology and the transmission by
mosquitoes were deciphered only in the 20th century. Population
movements during World War II spread the disease globally.
In 2007 replication mechanism of the virus was interrupted by interception of
the viral protease, and currently a project to identify new protease
interception mechanisms of the whole family of the virus has been launched
(Dengue virus belong to the family Flaviviridae, which includes among others
HCV, West Nile and Yellow fever viruses).

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