Cholera

Author: Vidhu V Thaker, MBBCh, MD, Attending Pediatrician, Haverstraw Pediatrics

Contributor Information and Disclosures

Updated: Sep 2, 2010

Introduction

Background

The appellation for cholera probably derives from the Greek word for the gutter of a roof,
comparing the deluge of water following a rainstorm to that of the anus of an infected person.
Cholera is an ancient disease caused by Vibrio cholerae O1 or, more recently, by V cholerae
O139 (see the image below).

Electron microscopic image of Vibrio cholerae

The hallmark for the disease is profuse secretory diarrhea. Cholera can be spread as an
endemic, epidemic, or pandemic disease. Despite all the major advances in research, the
condition still remains a challenge to the modern medical world.

Throughout history, populations all over the world have sporadically been affected by
devastating outbreaks of cholera. Records from Hippocrates (460-377 BC) and Galen (129-216
AD) describe an illness that might well have been cholera, and numerous hints indicate that a
choleralike malady was also known in the plains of the Ganges River since antiquity.

The seventh pandemic of cholera, caused by V cholerae O1, biotype El Tor, began in 1961 and
continues today. Reports also document endemics caused by biotype O139.

Cholera has been rare in industrialized nations for the last 100 years; however, the disease is
still common in other parts of the world, including the Indian subcontinent and sub-Saharan
Africa. It is transmitted by the fecal-oral route. Epidemics occur after war, civil unrest, or
natural disasters when water and food supplies become contaminated with V cholera in areas
with crowded living conditions and poor sanitation. In the United States, because of advanced
water and sanitation systems, cholera is not a major threat; however, everyone, especially
travelers, should be aware of how the disease is transmitted and what can be done to prevent
it.

Pathophysiology

The species V cholerae has been classified according to the carbohydrate determinants of its
somatic O antigens. Approximately 200 serotypes have been defined and are classified broadly
as those that agglutinate in antisera to the O1 group antigen (V cholerae O1) or those that do
not agglutinate in antisera to the O1 group antigen (non-O1 V cholerae).

Pathogenic V cholerae has 2 biotypes, classic and El Tor, which are defined on the basis of
their biochemical and other laboratory parameters. Each biotype has been divided further into
2 serotypes, Inaba and Ogawa. V cholerae O1 was the cause of most pandemics until a new
strain, termed V cholerae O139 (non-O1 type), was recognized as a cause of epidemic in
southern India and parts of Bangladesh in 1992.

Cholera is a toxin-mediated disease. The clinical features and epidemiologic manifestations of

disease caused by cholera O139 are indistinguishable from those caused by O1 strains.
Cholera toxin (CTX) is a potent protein enterotoxin elaborated by the organism in the small
intestine. To reach the small intestine, however, the organism has to negotiate the normal
defense mechanisms of the GI tract. Because the organism is not acid-resistant, it depends on
its large inoculum size to bypass gastric acidity. Using its own properties, such as motility,
chemotaxis, and elaboration of hemagglutinin/protease, the organism transcends the mucous
layer of the small intestine.

Once established, the organisms produce CTX that consists of subunits A and B. The B subunit
is the binding subunit, and the A subunit is the enzymatic subunit. These 2 working in
harmony, transfer adenosine diphosphate (ADP) and activate it to cyclic adenosine
monophosphate (cAMP), which inhibits the absorptive sodium transport and activates the
excretory chloride transport in the intestinal crypt cells, eventually leading to an accumulation
of sodium chloride in the intestinal lumen.1,2

The high osmolality in the intestinal lumen is balanced by water secretion that eventually
overwhelms the lumen absorptive capacity and leads to diarrhea. Unless the wasted fluid and
electrolytes are replaced adequately, shock (caused by profound dehydration) and acidosis
(caused by loss of bicarbonate) follow.

The O139 Bengal strain of V cholerae has a very similar pathogenic mechanism except that it
produces a novel O139 lipopolysaccharide (LPS) and an immunologically related O-antigen
capsule. These 2 features enhance its virulence and increase its resistance to human serum in
vitro and occasional development of O139 bacteremia.

Frequency

United States

In the United States, cholera has virtually been eliminated because of improved hygiene and
sanitation systems.

A unique strain of V cholerae O1 that is related closely to, but distinguishable from, the strain
of the seventh pandemic was recognized in Louisiana and along the Gulf of Mexico in 1973.
Since then, this strain has become indigenous to the Gulf coast, although its environmental
reservoirs and ecology remain unclear. With the current level of sanitation, epidemic spread of
this organism is not expected.

The incidence of Vibrio infection in the United States continues to be low, with highest number
documented in the age group older than 50 years old which has been around 0.50 cases per
100,000 population from 2003-2008. The frequency of cholera among international travelers
returning to the United States has averaged 1 case per 500,000 population, with a range of
0.05-3.7 cases per 100,000 population, depending on the countries visited.

International

Periodic global or pandemic spread of cholera from its endemic reservoir in the Indian
subcontinent was recognized as characteristic of cholera as early as 1831, when the second
pandemic reached England.

Of the 6 pandemics that occurred in the 19th century, 5 affected Europe and 4 reached the
United States, causing more than 150,000 deaths in 1832 and 50,000 deaths in 1866. The
seventh pandemic of cholera, and the first in the 20th century, began in 1961; by 1991, it had
affected 5 continents. This was the first pandemic recognized to be caused by the El Tor
biotype of V cholerae O1. After its spread in Asia in the 1960s, V cholerae O1 El Tor entered
Africa in the early 1970s, causing epidemic cholera and establishing itself as a significant
endemic infection. Cholera epidemics now occur regularly in Africa.

The number of patients with cholera worldwide is uncertain because most cases go
unreported. The likely contributory factors are that (1) most cases occur in remote areas of
developing countries where definitive diagnosis is not possible, (2) reporting systems often are
nonexistent in such areas, (3) the stigma of reporting cholera has direct consequences on
commercial trade and tourism, and (4) many countries with endemic cholera do not report at
all.

In 1990, fewer than 30,000 cases were reported to the WHO. Reported cases increased more
than 10-fold with the beginning of the Latin American epidemic in 1991. In 1994, the number
of cases (384,403) and countries (94) reporting cholera was the largest ever registered at the
WHO. Even Europe experienced a 30-fold increase in cholera from 1993-1994, with reported
cases increasing from 73 to 2,339 and deaths increasing from 2 cases to 47.

According to the WHO, the number of cases surged again in 2005. In the last 3 years, 178,000-
237,000 cases and 4000-6300 deaths have been reported annually worldwide.3 However, the
actual global burden is estimated to be 3-5 million cases and 100,000-130,000 deaths per
year. The 2008 outbreak in Zimbabwe lasted longer than a year with more than 98,000 cases
and more than 4000 deaths.4

Mortality/Morbidity

In 1950, during the sixth pandemic, case fatality rates were very high, and as many as 50-70%
of patients died. With the replacement of classic cholera with El Tor, a less virulent strain, case
fatality rates reduced dramatically during the 1960s. Fatality rates have declined further
because of better treatment and, in particular, increasingly available oral rehydration therapy,
which was introduced during the early 1970s but became widely available in many parts of the
world in the 1980s.

For most patients, treatment with oral rehydration is sufficient; however, when safe water or
oral rehydration salts are not available, case fatality rates can be very high. A case fatality rate
of 25-50% was estimated among untreated patients in refugee camps in Goma. Where good
treatment is readily accessible, the case fatality rate is less than 1%. In Africa, a marked
decline in case fatality rates has occurred since 1970; however, Africa continues to have the
highest reported case fatality rates (approximately 5% in 1998 and 4% in 1999) compared to
the rest of the world.

Average case fatality rates for Europe and the Americas continue to hover around 1%. Because
the fatality rates vary in different parts of the world, the global case fatality rates only partly
reflect the trends in each region because the global rates also are affected by the global
distribution of cases.

Age

In nonendemic areas, incidence of infection is similar in all age groups, although adults are
less likely to become asymptomatic than children. The exception is breastfed children, who are
protected against severe disease because of less exposure and because of the antibodies to
cholera they obtain in breast milk.

Clinical

History

Diarrhea

Profuse watery diarrhea is a hallmark of cholera. Cholera should be suspected when a patient
older than 5 years develops severe dehydration from acute, severe, watery diarrhea (usually
without vomiting) or in any patient older than 2 years who has acute watery diarrhea in an
area where an outbreak of cholera has occurred.

Stool volume during cholera is more than that of any other infectious diarrhea. Patients with
severe disease may have a stool volume of more than 250 mL/kg body weight in a 24-hour
period.

The stool may contain fecal material early in the course of clinical illness. The characteristic
cholera stool is an opaque white liquid that is not malodorous and often is described as having
a rice water appearance (ie, in color and consistency, it resembles water that has been used to
wash or cook rice).

V cholerae does not elicit an inflammatory response, and cholera stool contains few leukocytes
and no erythrocytes.

Because of the large volume of diarrhea, patients with cholera have frequent and often
uncontrolled bowel movements.

Patients experience abdominal cramps, probably caused by distention of loops of small bowel
as a result of the large volume of intestinal secretions.

Vomiting

Vomiting, although a prominent manifestation, may not always be present. It occurs early in
the course of the disease when the vomiting is caused by decreased gastric and intestinal
motility and later in the course of the disease when acidemia is more likely.

If untreated, the diarrhea and vomiting lead to isotonic dehydration and, in patients with
severe disease, vascular collapse, shock, and death.
Dehydration can develop with remarkable rapidity, within hours after the onset of symptoms.
This contrasts with disease produced by infection from any other enteropathogen.

Because the dehydration is isotonic, water loss is proportional between 3 body compartments,
intracellular, intravascular, and interstitial.

Physical

Dehydration

Dehydration has been classified into the following 3 categories to facilitate patient treatment:
severe, some (previously termed moderate in the WHO criteria for the classification of
dehydration), and none (previously termed mild by the WHO). Table 1 shows the clinical
findings associated with the classification.

Table 1. Assessment of the Patient With Diarrhea for Dehydration

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Table

Mouth
Tear Skin
Condition Eyes and Thirst Decision
s Pinch
Tongue
Well, alert Normal Prese Moist Drinks Goes Patient has no signs of
nt normally, back dehydration.
not quickly
thirsty
*Restless, Sunken Abse Dry *Thirsty, *Goes If the patient has 2 or
irritable nt drinks back more signs, including at least 1
eagerly slowly * sign, some dehydration is
present.
*Lethargic or Very Abse Very dry *Goes *Goes If the patient has 2 or more
unconscious, sunken nt back very back very signs, including at least 1 *
floppy and dry slowly slowly sign, severe dehydration is
present.
Mouth
Tear Skin
Condition Eyes and Thirst Decision
s Pinch
Tongue
Well, alert Normal Prese Moist Drinks Goes Patient has no signs of
nt normally, back dehydration.
not quickly
thirsty
*Restless, Sunken Abse Dry *Thirsty, *Goes If the patient has 2 or
irritable nt drinks back more signs, including at least 1
eagerly slowly * sign, some dehydration is
present.
*Lethargic or Very Abse Very dry *Goes *Goes If the patient has 2 or more
unconscious, sunken nt back very back very signs, including at least 1 *
floppy and dry slowly slowly sign, severe dehydration is
present.

In adults and children older than 5 years, other signs for severe dehydration include absent
radial pulse and low blood pressure.

The skin pinch may be less useful in patients with marasmus (severe wasting), kwashiorkor
(severe malnutrition with edema), or obesity.

Tears are relevant signs only for infants and young children.

Patients with severe dehydration have a characteristic clinical appearance that is attributable
to the loss of approximately 15% of total body water (approximately 10% of total body weight).

Intracellular and intravascular dehydration is manifested in decreases skin turgor, sunken

eyes, and wrinkled ("washer woman") hands.
Decreased intravascular volume is manifested by tachycardia, absent or barely palpable
peripheral pulses, and hypotension.

Tachypnea and hypercapnia also are part of the clinical picture and are attributable to the
metabolic acidosis that invariably is present in patients with cholera who are dehydrated.

Children with some (moderate) dehydration have lost approximately 7-10% of body water
(approximately 5% of body weight). In these patients, cardiac output and vascular resistance
are normal, and changes in interstitial and intracellular volume are the primary manifestations
of illness. Children have decreased skin turgor, as manifested by prolonged skin tenting in
response to a skin pinch (the most reliable sign of isotonic dehydration), and a normal pulse.

Children without clinically significant dehydration (<5% loss of body weight) may have
increased thirst without other signs of dehydration.

Metabolic and systemic manifestations

After dehydration, hypoglycemia is the most common lethal complication of cholera in

children. Hypoglycemia is a result of diminished food intake during the acute illness,
exhaustion of glycogen stores, and defective gluconeogenesis secondary to insufficient stores
of gluconeogenic substrates in fat and muscle.

Acidosis in cholera is a result of bicarbonate loss in stools, accumulation of lactate because of

diminished perfusion of peripheral tissues, and hyperphosphatemia.

Acidemia occurs when respiratory compensation is unable to sustain a normal blood pH.

Hypokalemia results from potassium loss in the stool, with a mean potassium concentration of
approximately 30 mmol/L. Because of the existing acidosis, however, children often have
normal serum potassium concentrations when first observed, despite severe total body
potassium depletion. Hypokalemia develops only after the acidosis is corrected and
intracellular hydrogen ion is exchanged for extracellular potassium. Hypokalemia is most
severe in children with preexisting malnutrition who have diminished body stores of potassium
and may be manifested as paralytic ileus.

Rehydration therapy with bicarbonate-containing fluids can also produce hypocalcemia by

decreasing the proportion of serum calcium that is ionized.

Chvostek and Trousseau signs are often present, and spontaneous titanic contractions can
occur.

Causes

Cholera can be an endemic, epidemic, or a pandemic disease. Initiation and maintenance of

epidemic and pandemic disease by V cholerae require human infection and poor sanitation
with assistance from human migration and seasonal warming of coastal waters. Certain
environmental and host factors appear to play a role in the spread of V cholerae.

Environmental factors

V cholerae is a saltwater organism, and its primary habitat is the marine ecosystem where it
lives in association with plankton.

Cholera has 2 main reservoirs, man and water. V cholerae is rarely isolated from animals, and
animals do not play a role in transmission of disease.

Primary infection in humans is incidentally acquired. Risk of primary infection is facilitated by

seasonal increases in the number of organisms, possibly associated with changes in water
temperature and algal blooms.

Secondary transmission occurs through fecal-oral spread of the organism through person-to-
person contact or through contaminated water and food. Such secondary spread commonly
occurs in households but can also occur in clinics or hospitals where patients with cholera are
treated.

Infection rates predictably are highest in communities in which water is not potable and
personal and community hygiene standards are low.

Host susceptibility factors that may affect the course of infection with V cholerae
O1
The following may affect the course:

• Malnutrition
• Hydrochlorhydria or achlorhydria of any cause (including Helicobacter pylori infection,
gastric surgery, vagotomy, use of H2 blockers for ulcer disease): The reason it is easily
discernible is that gastric acid can quickly render an inoculum of V cholerae
noninfectious before it reaches the site of colonization in the small bowel.
• O blood group: The role played by O blood group is less certain. The cause is unknown,
but incidence of infection appears to be twice as high in this population.
• Previous exposure and acquired immunity: Infection rates of household contacts of
cholera patients range from 20-50%. Rates are lower in areas where infection is
endemic and if there are preexisting vibriocidal antibodies from previous encounters
with the organism, especially in adults. For the same reason, adults are symptomatic
less frequently than children, and second infections rarely occur or are mild.
• Asymptomatic carriers: This may have a role in transfer of disease in areas where the
disease is not endemic. Although carriage usually is short-lived, a few individuals may
excrete the organisms for a prolonged period.

Typhoid Fever

Author: John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School;
Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health
Alliance
Coauthor(s): Thomas Garvey, MD, JD, Chief, Medical Affiliated Services, Department of
Medicine, Lemuel Shattuck Hospital; Attending Physician, Chest Clinic, Lawrence Memorial
Hospital; Co-chair, Medical Advisory Committee for the Elimination of Tuberculosis; Roberto
Corales, DO, Medical Director, Principal Investigator, AIDS Community Health Center; Steven
K Schmitt, MD, Co-director of Infectious Disease Fellowship Program, Department of
Infectious Disease, The Cleveland Clinic Foundation
Contributor Information and Disclosures

Updated: Apr 8, 2010

Introduction

Background

Typhoid fever, also known as enteric fever, is a potentially fatal multisystemic illness caused
primarily by Salmonella typhi. The protean manifestations of typhoid fever make this disease a
true diagnostic challenge. The classic presentation includes fever, malaise, diffuse abdominal
pain, and constipation. Untreated, typhoid fever is a grueling illness that may progress to
delirium, obtundation, intestinal hemorrhage, bowel perforation, and death within one month
of onset. Survivors may be left with long-term or permanent neuropsychiatric complications.

S typhi has been a major human pathogen for thousands of years, thriving in conditions of
poor sanitation, crowding, and social chaos. It may have responsible for the Great Plague of
Athens at the end of the Pelopennesian War.1 The name S typhi is derived from the ancient
Greek typhos, an ethereal smoke or cloud that was believed to cause disease and madness. In
the advanced stages of typhoid fever, the patient's level of consciousness is truly clouded.
Although antibiotics have markedly reduced the frequency of typhoid fever in the developed
world, it remains endemic in developing countries.2

Transmission

S typhi has no nonhuman vectors. The following are modes of transmission:

• Oral transmission via food or beverages handled by an individual who chronically

sheds the bacteria through stool or, less commonly, urine
• Hand-to-mouth transmission after using a contaminated toilet and neglecting hand
hygiene
• Oral transmission via sewage-contaminated water or shellfish (especially in the
developing world)3

An inoculum as small as 100,000 organisms causes infection in more than 50% of healthy
volunteers.4
Pathophysiology

All pathogenic Salmonella species are engulfed by phagocytic cells, which then pass them
through the mucosa and present them to the macrophages in the lamina propria. Nontyphoidal
salmonellae are phagocytized throughout the distal ilium and colon. With toll-like receptor
(TLR)–5 and TLR-4/MD2/CD-14 complex, macrophages recognize pathogen-associated
molecular patterns (PAMPs) such as flagella and lipopolysaccharides. Macrophages and
intestinal epithelial cells then attract T cells and neutrophils with interleukin 8 (IL-8), causing
inflammation and suppressing the infection.5,6

In contrast to the nontyphoidal salmonellae, S typhi enters the host's system primarily through
the distal ilium. S typhi has specialized fimbriae that adhere to the epithelium over clusters of
lymphoid tissue in the ilium (Peyer patches), the main relay point for macrophages traveling
from the gut into the lymphatic system. S typhi has a Vi capsular antigen that masks PAMPs,
avoiding neutrophil-based inflammation. The bacteria then induce their host macrophages to
attract more macrophages.5

It co-opts the macrophages' cellular machinery for their own reproduction 7 as it is carried
through the mesenteric lymph nodes to the thoracic duct and the lymphatics and then through
to the reticuloendothelial tissues of the liver, spleen, bone marrow, and lymph nodes. Once
there, the S typhi bacteria pause and continue to multiply until some critical density is
reached. Afterward, the bacteria induce macrophage apoptosis, breaking out into the
bloodstream to invade the rest of the body.6

The gallbladder is then infected via either bacteremia or direct extension of S typhi –infected
bile. The result is that the organism re-enters the gastrointestinal tract in the bile and reinfects
Peyer patches. Bacteria that do not reinfect the host are typically shed in the stool and are
then available to infect other hosts.6,2

Risk factors

S typhi are able to survive a stomach pH as low as 1.5. Antacids, histamine-2 receptor
antagonists (H2 blockers), proton pump inhibitors, gastrectomy, and achlorhydria decrease
stomach acidity and facilitate S typhi infection.6

HIV/AIDS is clearly associated with an increased risk of nontyphoidal Salmonella infection;

however, the data and opinions in the literature as to whether this is true for S typhi infection
are conflicting. If an association exists, it is probably minor.8,9,10,11

Other risk factors for clinical S typhi infection include various genetic polymorphisms. These
risk factors often also predispose to other intracellular pathogens. For instance, PARK2 and
PACGR code for a protein aggregate that is essential for breaking down the bacterial signaling
molecules that dampen the macrophage response. Polymorphisms in their shared regulatory
region are found disproportionately in persons infected with Mycobacterium leprae and S
typhi.12

On the other hand, protective host mutations also exist. The fimbriae of S typhi bind in vitro to
cystic fibrosis transmembrane conductance receptor (CFTR), which is expressed on the gut
membrane. Two to 5% of white persons are heterozygous for the CFTR mutation F508del,
which is associated with a decreased susceptibility to typhoid fever, as well as to cholera and
tuberculosis. The homozygous F508del mutation in CFTR is associated with cystic fibrosis.
Thus, typhoid fever may contribute to evolutionary pressure that maintains a steady
occurrence of cystic fibrosis, just as malaria maintains sickle cell disease in Africa.13,14

Environmental and behavioral risk factors that are independently associated with typhoid fever
include eating food from street vendors, living in the same household with someone who has
new case of typhoid fever, washing the hands inadequately, sharing food from the same plate,
drinking unpurified water, and living in a household that does not have a toilet.15,12 As the
middle class in south Asia grows, some hospitals there are seeing a large number of typhoid
fever cases among relatively well-off university students who live in group households with
poor hygeine.16 American clinicians should keep this in mind, as members of this cohort often
come to the United States for higher degrees.

Frequency

United States

Since 1900, improved sanitation and successful antibiotic treatment have steadily decreased
the incidence of typhoid fever in the United States. In 1920, 35,994 cases of typhoid fever
were reported. In 2006, there were 314.
Between 1999 and 2006, 79% of typhoid fever cases occurred in patients who had been
outside of the country within the preceding 30 days. Two thirds of these individuals had just
journeyed from the Indian subcontinent. The 3 known outbreaks of typhoid fever within the
United States were traced to imported food or to a food handler from an endemic region.
Remarkably, only 17% of cases acquired domestically were traced to a carrier.17

International

Typhoid fever occurs worldwide, primarily in developing nations whose sanitary conditions are
poor. Typhoid fever is endemic in Asia, Africa, Latin America, the Caribbean, and Oceania, but
80% of cases come from Bangladesh, China, India, Indonesia, Laos, Nepal, Pakistan, or
Vietnam.18 Within those countries, typhoid fever is most common in underdeveloped areas.
Typhoid fever infects roughly 21.6 million people (incidence of 3.6 per 1,000 population) and
kills an estimated 200,000 people every year.19

In the United States, most cases of typhoid fever arise in international travelers. The average
yearly incidence of typhoid fever per million travelers from 1999-2006 by county or region of
departure was as follows:17

• Canada - 0
• Western Hemisphere outside Canada/United States - 1.3
• Africa - 7.6
• Asia - 10.5
• India - 89 (122 in 2006)
• Total (for all countries except Canada/United States) - 2.2

Mortality/Morbidity

With prompt and appropriate antibiotic therapy, typhoid fever is typically a short-term febrile
illness requiring a median of 6 days of hospitalization. Treated, it has few long-term sequelae
and a 0.2% risk of mortality.17 Untreated typhoid fever is a life-threatening illness of several
weeks' duration with long-term morbidity often involving the central nervous system. The case
fatality rate in the United States in the pre-antibiotic era was 9%-13%.20

Race

Typhoid fever has no racial predilection.

Sex

Fifty-four percent of typhoid fever cases in the United States reported between 1999 and 2006
involved males.17

Age

Most documented typhoid fever cases involve school-aged children and young adults.
However, the true incidence among very young children and infants is thought to be higher.
The presentations in these age groups may be atypical, ranging from a mild febrile illness to
severe convulsions, and the S typhi infection may go unrecognized. This may account for
conflicting reports in the literature that this group has either a very high or a very low rate of
morbidity and mortality.16,21

Clinical

History

A severe nonspecific febrile illness in a patient who has been exposed to S typhi should always
raise the diagnostic possibility of typhoid fever (enteric fever).

Classic typhoid fever syndrome

Typhoid fever begins 7-14 days after ingestion of S typhi. The fever pattern is stepwise,
characterized by a rising temperature over the course of each day that drops by the
subsequent morning. The peaks and troughs rise progressively over time.

Over the course of the first week of illness, the notorious gastrointestinal manifestations of the
disease develop. These include diffuse abdominal pain and tenderness and, in some cases,
fierce colicky right upper quadrant pain. Monocytic infiltration inflames Peyer patches and
narrows the bowel lumen, causing constipation that lasts the duration of the illness. The
individual then develops a dry cough, dull frontal headache, delirium, and an increasingly
stuporous malaise.2

At approximately the end of the first week of illness, the fever plateaus at 103-104°F (39-
40°C). The patient develops rose spots, which are salmon-colored, blanching, truncal,
maculopapules usually 1-4 cm wide and fewer than 5 in number; these generally resolve within
2-5 days.2 These are bacterial emboli to the dermis and occasionally develop in persons with
shigellosis or nontyphoidal salmonellosis.22

During the second week of illness, the signs and symptoms listed above progress. The
abdomen becomes distended, and soft splenomegaly is common. Relative bradycardia and
dicrotic pulse (double beat, the second beat weaker than the first) may develop.

In the third week, the still febrile individual grows more toxic and anorexic with significant
weight loss. The conjunctivae are infected, and the patient is tachypneic with a thready pulse
and crackles over the lung bases. Abdominal distension is severe. Some patients experience
foul, green-yellow, liquid diarrhea (pea soup diarrhea). The individual may descend into the
typhoid state, which is characterized by apathy, confusion, and even psychosis. Necrotic Peyer
patches may cause bowel perforation and peritonitis. This complication is often unheralded
and may be masked by corticosteroids. At this point, overwhelming toxemia, myocarditis, or
intestinal hemorrhage may cause death.

If the individual survives to the fourth week, the fever, mental state, and abdominal distension
slowly improve over a few days. Intestinal and neurologic complications may still occur in
surviving untreated individuals. Weight loss and debilitating weakness last months. Some
survivors become asymptomatic S typhi carriers and have the potential to transmit the
bacteria indefinitely.16,23,24,2,6

Various presentations of typhoid fever

The clinical course of a given individual with typhoid fever may deviate from the above
description of classic disease. The timing of the symptoms and host response may vary based
on geographic region, race factors, and the infecting bacterial strain. The stepladder fever
pattern that was once the hallmark of typhoid fever now occurs in as few as 12% of cases. In
most contemporary presentations of typhoid fever, the fever has a steady insidious onset.

Young children, individuals with AIDS, and one third of immunocompetent adults who develop
typhoid fever develop diarrhea rather than constipation. In addition, in some localities, typhoid
fever is generally more apt to cause diarrhea than constipation.

Atypical manifestations of typhoid fever include isolated severe headaches that may mimic
meningitis, acute lobar pneumonia, isolated arthralgias, urinary symptoms, severe jaundice, or
fever alone. Some patients, especially in India and Africa, present primarily with neurologic
manifestations such as delirium or, in extremely rare cases, parkinsonian symptoms or
Guillain-Barré syndrome. Other unusual complications include pancreatitis,25 meningitis,
orchitis, osteomyelitis, and abscesses anywhere on the body.2

Table 1. Incidence and Timing of Various Manifestations of Untreated Typhoid Fever2,26,27,28,29,30

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Table

Incubat Week 1 Week 2 Week 3 Week 4 Post

ion
Systemic Recovery phase 10%-20%
Stepladder fever Very Very common or death (15% relapse; 3%-4%
pattern or insidious commona of untreated chronic carriers;
onset fever cases) long-term
Acute high fever Very rareb neurologic
sequelae
Chills Almost allc
(extremely
Rigors Uncommon rare);
Anorexia Almost all gallbladder
Diaphoresis Very common cancer
Neurologic (RR=167;
Malaise Almost all Almost Typhoid carriers)
 all state
Insomnia Very (common)
commo
n
Confusion/delirium Commond Very
commo
n
Psychosis Very rare Commo
n
Catatonia Very rare
Frontal headache Very
(usually mild) common
Meningeal signs Raree Rare
Parkinsonism Very rare
Ear, nose, and throat
Coated tongue Very
common
Sore throatf
Pulmonary
Mild cough Common
Bronchitic cough Common
Rales Common
Pneumonia Rare Rare Common
(lobar) (basal)
Cardiovascular
Dicrotic pulse Rare Common
Myocarditis Rare
Pericarditis Extremely
rareg
Thrombophlebitis Very rare
Gastrointestinal
Constipation Very Common
common
Diarrhea Rare Common (pea
soup)
Bloating with Very
tympany common
(84%) 30
Diffuse mild Very
abdominal pain common
Sharp right lower Rare
quadrant pain
Gastrointestinal Very rare; Very common
hemorrhage usually
trace
intestinal perforation Rare
Hepatosplenomegaly Common
Jaundice Common
Gallbladder pain Very rare
Urogenital
Urinary retention Common
Hematuria Rare
Renal pain Rare
Musculoskeletal
Myalgias Very rare
Arthralgias Very rare
Rheumatologic
Arthritis (large joint) Extremely rare
Dermatologic
Rose spots Rare
Miscellaneous
Abscess (anywhere) Extremely Extreme Extremely
rare ly rare rare
Incubat Week 1 Week 2 Week 3 Week 4 Post
ion
Systemic Recovery phase 10%-20%
Stepladder fever Very Very common or death (15% relapse; 3%-4%
pattern or insidious commona of untreated chronic carriers;
onset fever cases) long-term
Acute high fever Very rareb neurologic
Chills Almost allc sequelae
(extremely
Rigors Uncommon
rare);
Anorexia Almost all gallbladder
Diaphoresis Very common cancer
Neurologic (RR=167;
Malaise Almost all Almost Typhoid carriers)
all state
Insomnia Very (common)
commo
n
Confusion/delirium Commond Very
commo
n
Psychosis Very rare Commo
n
Catatonia Very rare
Frontal headache Very
(usually mild) common
Meningeal signs Raree Rare
Parkinsonism Very rare
Ear, nose, and throat
Coated tongue Very
common
Sore throatf
Pulmonary
Mild cough Common
Bronchitic cough Common
Rales Common
Pneumonia Rare Rare Common
(lobar) (basal)
Cardiovascular
Dicrotic pulse Rare Common
Myocarditis Rare
Pericarditis Extremely
rareg
Thrombophlebitis Very rare
Gastrointestinal
Constipation Very Common
common
Diarrhea Rare Common (pea
soup)
Bloating with Very
tympany common
(84%) 30
Diffuse mild Very
abdominal pain common
Sharp right lower Rare
quadrant pain
Gastrointestinal Very rare; Very common
hemorrhage usually
trace
intestinal perforation Rare
Hepatosplenomegaly Common
Jaundice Common
Gallbladder pain Very rare
Urogenital
Urinary retention Common
Hematuria Rare
Renal pain Rare
Musculoskeletal
Myalgias Very rare
Arthralgias Very rare
Rheumatologic
Arthritis (large joint) Extremely rare
Dermatologic
Rose spots Rare
Miscellaneous
Abscess (anywhere) Extremely Extreme Extremely
rare ly rare rare

a
Very common: Symptoms occur in well over half of cases (approximately 65%-95%).
b
Very rare: Symptoms occur in less than 5% of cases.
c
Almost all: Symptoms occur in almost all cases.
d
Common: Symptoms occur in 35%-65% of cases.
e
Rare: Symptoms occur in 5%-35% of cases.
f
Blank cells: No mention of the symptom at that phase was found in the literature.
g
Extremely rare: Symptoms have been described in occasional case reports.

Treated typhoid fever

If appropriate treatment is initiated within the first few days of full-blown illness, the disease
begins to remit after about 2 days, and the patient's condition markedly improves within 4-5
days. Any delay in treatment increases the likelihood of complications and recovery time.

Amebiasis

Author: Alexandre Lacasse, MD, MSc, Fellow in Infectious Diseases, University of

Tennessee at Memphis
Coauthor(s): Kerry O Cleveland, MD, Associate Professor of Medicine, University of
Tennessee College of Medicine; Consulting Staff, Department of Internal Medicine, Division of
Infectious Diseases, Methodist Healthcare of Memphis; J Robert Cantey, MD, Professor,
Department of Medicine, Division of Infectious Diseases, Medical University of South Carolina
Contributor Information and Disclosures

Updated: Feb 9, 2009

Introduction

Background

Amebiasis is caused by Entamoeba histolytica, a protozoan found worldwide. The highest

prevalence of amebiasis is in developing countries where barriers between human feces and
food and water supplies are inadequate.

Although most cases of amebiasis are asymptomatic, dysentery and invasive extraintestinal
disease can occur. Amebic liver abscess is the most common manifestation of invasive
amebiasis, but other organs can also be involved, including pleuropulmonary, cardiac,
cerebral, renal, genitourinary, and cutaneous sites. In developed countries, amebiasis primarily
affects migrants from and travelers to endemic regions, men who have sex with men, and
immunosuppressed or institutionalized individuals.

E histolytica is transmitted via ingestion of the cystic form (infective stage) of the protozoa.
Viable in the environment for weeks to months, cysts can be found in fecally contaminated
soil, fertilizer, or water or on the contaminated hands of food handlers. Fecal-oral transmission
can also occur in the setting of anal sexual practices or direct rectal inoculation through
colonic irrigation devices. Excystation then occurs in the terminal ileum or colon, resulting in
trophozoites (invasive form). The trophozoites can penetrate and invade the colonic mucosal
barrier, leading to tissue destruction, secretory bloody diarrhea, and colitis resembling
inflammatory bowel disease. In addition, the trophozoites can spread hematogenously via the
portal circulation to the liver or even to more distant organs.

Amebic infection was first described by Fedor Losch in 1875 in St. Petersburg, Russia. In 1890,
Sir William Osler reported the first North American case of amebiasis, when he observed
amebae in stool and abscess fluid from a physician who previously resided in Panama. The
species name E histolytica was first coined by Fritz Schaudin in 1903. In 1913, in the
Philippines, Walker and Sellards documented the cyst as the infective form of E histolytica. The
life cycle was then established by Dobell in 1925.

Pathophysiology

E histolytica is a pseudopod-forming, nonflagellated protozoal parasite that causes proteolysis

and tissue lysis (hence its name) and can induce host-cell apoptosis. Humans and perhaps
nonhuman primates are the only natural hosts. Ingestion of E histolytica cysts from the
environment is followed by excystation in the terminal ileum or colon to form highly motile
trophozoites. Upon colonization of the colonic mucosa, the trophozoite may encyst and is then
excreted in the feces or may invade the intestinal mucosal barrier and gain access to the blood
stream and disseminate to the liver, lung, and other sites. Excreted cysts reach the
environment to complete the cycle.

Disease may be caused by only a small number of cysts, but the processes of encystation and
excystation are poorly understood. The adherence of trophozoites to colonic epithelial cells
seems to be mediated by a galactose/N -acetylgalactosamine (GAL/GalNAc)–specific lectin.1,2 A
mucosal immunoglobulin A (IgA) response against this lectin can result in fewer recurrent
infections.3 Both lytic and apoptotic pathways have been described. Cytolysis can be
undertaken by amoebapores, a family of peptides capable of forming pores in lipid bilayers.1
Furthermore, in animal models of liver abscess, trophozoites induced apoptosis via a non-Fas
and non–tumor necrosis factor-α1 receptor pathway.4 The amoebapores, at sublytic
concentrations, can also induce apoptosis.

Cysteine proteinases have been directly implicated in invasion and inflammation of the gut
and may amplify interleukin (IL)–1–mediated inflammation by mimicking the action of human
IL-1–converting enzyme, cleaving IL-1 precursor to its active form.1,5 The cysteine proteinases
can also cleave and inactivate the anaphylatoxins C3a and C5a, as well as IgA and
immunoglobulin G (IgG).6,7

Epithelial cells also produce various inflammatory mediators, including IL-1B, IL-8, and
cyclooxygenase-2, leading to the attraction of neutrophils and macrophages.8,9 Corticosteroid
therapy is known to worsen the clinical outcome, possibly because of its blunting effect on this
innate immune response. Additional host defenses, including the complement system, could
be inhibited directly by the trophozoites, suggested by the finding that a region of the
GAL/GalNAc–specific lectin showed antigenic crossreactivity with CD59, a membrane inhibitor
of the C5b-9 attack complex in human red blood cells.10 Trophozoites that reach the liver
create unique abscesses with well-circumscribed regions of dead hepatocytes surrounded by
few inflammatory cells and trophozoites and unaffected hepatocytes, suggesting that E
histolytica are able to kill hepatocytes without direct contact.1

The genus Entamoeba contains many species, some of which (ie, E histolytica, Entamoeba
dispar, Entamoeba moshkovskii, Entamoeba polecki, Entamoeba coli, Entamoeba hartmanni)
can reside in the human interstitial lumen. E histolytica is, thus far, the only Entamoeba
species definitely associated with disease; the others are considered nonpathogenic.11 More
recent studies have recovered E dispar and E moshkovskii from patients with gastrointestinal
symptoms, but a causal relationship is undetermined.11

E dispar and E histolytica cannot be differentiated by direct examination, but recent molecular
techniques established them as two different species, with E dispar being commensal
(including in patients with HIV infection) and E histolytica pathogenic.11 In fact, it is now
estimated that many individuals with Entamoeba infections are colonized with E dispar, which
appears to be 10 times more common than E histolytica.11 However, in certain regions (eg,
Brazil, Egypt), asymptomatic E dispar and E histolytica infections are equally prevalent.1 In
Western countries, approximately 20%-30% of men who have sex with men are colonized with
E dispar.11

Frequency

United States

The overall prevalence of amebiasis is approximately 4%. However, certain groups are
predisposed to amebic colitis, including very young patients, pregnant women, recipients of
corticosteroids, and malnourished individuals.1 In 1993, a total of 2970 cases of amebiasis were
reported to the Centers for Disease Control and Prevention (CDC); 33% of cases were reported
in Hispanic immigrants and 17% in immigrants from Asia or the Pacific Islands. Travelers to
endemic areas are at risk for infection; 10% of individuals returning with diarrhea were found
to have amebiasis.1 Amebic liver abscess has been reported in travel exposures as short as 4
days (median, 3 mo), whereas amebic colitis is uncommon in short-term travelers.

International

Entamoeba species infect approximately 10% of the world's population. The prevalence of
Entamoeba infection is as high as 50% in areas of Central and South America, Africa, and Asia.
In Egypt, 38% of individuals presenting with acute diarrhea to an outpatient clinic were found
to have amebic colitis.1 E histolytica seroprevalence studies in Mexico revealed that more than
8% of the population were positive.12 Asymptomatic E histolytica infections seem to be region-
dependent, as high as 11% in Brazil. Since the introduction of molecular techniques, it is
estimated that 500 million individuals with Entamoeba infection are colonized by E dispar.11

Mortality/Morbidity
 • Amebiasis is second only to malaria in terms of protozoa-associated mortality. The
combined prevalence of amebic colitis and amebic liver abscess is estimated at 40-50
million cases annually worldwide, resulting in 40,000-100,000 deaths.11,1,13
• Asymptomatic intestinal amebiasis occurs in 90% of infected individuals. However,
only 4%-10% of individuals with asymptomatic amebiasis who were monitored for one
year eventually developed colitis or extraintestinal disease.11
• Case fatality rates associated with amebic colitis range from 1.9%-9.1%. Amebic colitis
evolves to fulminant necrotizing colitis or rupture in approximately 0.5% of cases; in
such cases, the mortality rate jumps to greater than 40%.14
• The mortality rate due to amebic liver abscess has fallen to 1-3% in the last century
following the introduction of effective medical treatment. Nevertheless, amebic liver
abscess is complicated by sudden intraperitoneal rupture in 2-7% of patients, leading
to a higher mortality rate.1

Race

• In Japan and Taiwan, HIV seropositivity is a risk factor for invasive extraintestinal
amebiasis.15 This has not been observed elsewhere.

Sex

• Amebic colitis affects both sexes equally.1

• Amebic liver abscess is 7-12 times more common in men than in women, with a
predominance among men aged 18-50 years. The reason for this sexual disparity is
unknown, although hormonal effects may be implicated, as the prevalence of amebic
liver abscess is also increased among postmenopausal women. Alcohol may also been
an important risk factor. The sexual distribution is equal in children.1

Age

Very young children seem to be predisposed to fulminant colitis.

Clinical

History

• Amebic colitis
o The most common presentation of amebic colitis is gradual onset of bloody
diarrhea, abdominal pain, and tenderness spanning several weeks’ duration.
o Rectal bleeding without diarrhea can occur, especially in children.
o Only approximately 10-30% of patients with amebic colitis develop fever.
o Weight loss and anorexia may occur.
o Fulminant or necrotizing colitis usually manifests as severe bloody diarrhea
and widespread abdominal pain with evidence of peritonitis and fever.
o Predisposing factors for fulminant colitis include poor nutrition, pregnancy,
corticosteroid use, and very young age.
• Amebic liver abscess
o The most typical presentation of amebic liver abscess is fever, right upper
quadrant pain, and tenderness of less than 10 days’ duration.
o Unlike amebic colitis, amebic liver abscess is associated with fever in 85-90%
of cases.
o A more subacute presentation can be seen, with concomitant weight loss and
anorexia.
o Cough can occur. Jaundice is unusual.
o Acute abdominal symptoms and signs should prompt rapid investigation for
intraperitoneal rupture.
o Sixty to 70% of patients with amebic liver abscess do not have concomitant
colitis, although a history of dysentery within the previous year may be
obtained.
o Amebic liver abscess may manifest years after travel to or residency in an
endemic area.
o A history of alcohol abuse is common, but a clear causal relationship is unclear.
• Pleuropulmonary amebiasis: Cough, pleuritic chest pain, and respiratory distress may
be clues to rupture through the diaphragm, a rare but serious complication of amebic
liver abscess.
• Cerebral amebiasis
o Occurring in 0.6% of amebic liver abscess cases, abrupt onset of nausea,
vomiting, headache, and mental status change should prompt rapid
investigation for CNS involvement.
 o Progression can be very rapid.

Physical

• Amebic colitis
o Fever (10-30%)
o Weight loss (40%)
o Diffuse abdominal tenderness (12-85%)
o Heme-positive stools (70-100%)
o Abdominal pain, distension, and rebound tenderness likely in fulminant colitis
• Amebic liver abscess
o Fever (85-90%)
o Right upper quadrant abdominal tenderness (84-90%)
o Weight loss (33-50%)
o Hepatomegaly (30-50%)
o Jaundice (6-10%)

Causes

• Amebiasis is an infection caused by the protozoal organism E histolytica, which can

cause colitis and other extraintestinal manifestations, including liver abscess (most
common) and pleuropulmonary, cardiac, and cerebral dissemination.
• E histolytica is transmitted primarily through the fecal-oral route. Infective cysts can be
found in fecally contaminated food and water supplies and contaminated hands of food
handlers. Sexual transmission is possible, especially in the setting of oral-anal
practices.

Dengue Fever

Author: Suzanne Moore Shepherd, MD, MS, DTM&H, FACEP, FAAEM, Associate
Professor, Department of Emergency Medicine, Hospital of the University of Pennsylvania;
Director of Education and Research, PENN Travel Medicine
Coauthor(s): Patrick B Hinfey, MD, Associate Residency Director, Department of
Emergency Medicine, Newark Beth Israel Medical Center; William H Shoff, MD, DTM&H,
Director, PENN Travel Medicine, Associate Professor, Department of Emergency Medicine,
Hospital of the University of Pennsylvania
Contributor Information and Disclosures

Updated: Oct 23, 2009

Introduction

Background

Dengue, the most common arboviral illness transmitted worldwide, is caused by infection with
1 of the 4 serotypes of dengue virus, family Flaviviridae, genus Flavivirus (single-stranded
nonsegmented RNA viruses). Dengue is transmitted by mosquitoes of the genus Aedes, which
are widely distributed in subtropical and tropical areas of the world, and is classified as a major
global health threat by the World Health Organization (WHO).

Initial dengue infection may be asymptomatic (50%-90%),1 may result in a nonspecific febrile
illness, or may produce the symptom complex of classic dengue fever (DF). A small percentage
of persons who have previously been infected by one dengue serotype develop bleeding and
endothelial leak upon infection with another dengue serotype. This syndrome is termed
dengue hemorrhagic fever (DHF), although dengue vasculopathy has been proposed as a
better term, as fluid loss into tissue spaces can lead to prolonged shock and complications,
including gastrointestinal bleeding, a greater fatality risk than bleeding per se.2 Some patients
with dengue hemorrhagic fever develop shock (dengue shock syndrome [DSS]), which may
cause death.

Dengue virus transmission follows two general patterns—epidemic dengue and hyperendemic
dengue. Epidemic dengue transmission occurs when dengue virus is introduced into a region
as an isolated event that involves a single viral strain. If the number of vectors and susceptible
pediatric and adult hosts is sufficient, explosive transmission can occur, with an infection
incidence of 25%-50%. Mosquito-control efforts, changes in weather, and herd immunity
contribute to the control of these epidemics. Transmission appears to begin in urban centers
and then spreads to the rest of a country.3 This is the current pattern of transmission in parts of
Africa and South America, areas of Asia where the virus has reemerged, and small island
nations. Travelers to these areas are at increased risk of acquiring dengue during these
periods of epidemic transmission.

Hyperendemic dengue transmission is characterized by the continuous circulation of multiple

viral serotypes in an area where a large pool of susceptible hosts and a competent vector (with
or without seasonal variation) are constantly present. This is the predominant pattern of global
transmission. In these populations, antibody prevalence increases with age and most adults
are immune. Hyperendemic transmission appears to be a major risk for dengue hemorrhagic
fever. Travelers to these areas are more likely to be infected than are travelers to areas that
experience only epidemic transmission.

Dengue fever–like illnesses were described in Chinese medical writings dating back to 265 AD.
Outbreaks of febrile illnesses compatible with dengue fever have been recorded throughout
history, with the first epidemic described in 1635 in the West Indies. In 1789, Benjamin Rush,
MD, published an account of a probable dengue fever epidemic that had occurred in
Philadelphia in 1780. Rush coined the term breakbone fever to describe the intense symptoms
reported by one of his patients. Probable outbreaks of dengue fever occurred sporadically
every 10-30 years until after World War II. The socioeconomic disruptions caused by World War
II resulted in increased worldwide spread of dengue viruses.

The first epidemic of dengue hemorrhagic fever was described in Manila in 1953. After that,
outbreaks of dengue fever became more common. A pattern developed in which dengue fever
epidemics occurred with increasing frequency and were associated with occasional dengue
hemorrhagic fever cases. Subsequently, dengue hemorrhagic fever epidemics occurred every
few years. Eventually, dengue hemorrhagic fever epidemics occurred yearly, with major
outbreaks occurring approximately every 3 years. This pattern has repeated itself as dengue
fever has spread to new regions.

Although initial epidemics were located in urban areas, increased dengue spread has involved
suburban and rural locales in Asia and Latin America. The only continents that do not
experience dengue transmission include Europe and Antarctica. In the 1950s, 9 countries
reported dengue outbreaks; today, the geographic distribution includes more than 100
countries worldwide. Several of these countries had not previously reported dengue, and many
had not reported dengue in 20 years.

Dengue transmission spread from Southeast Asia into surrounding subtropical and tropical
Asian countries, southern China and southern Taiwan, the Indian subcontinent and Sri Lanka,
and down the island nations of Malaysia, the Philippines, New Guinea, northeastern Australia,
and several Pacific islands, including Tahiti, Palau, Tonga, and the Cook Islands. Nepal has not
reported dengue transmission. Hyperendemic transmission is reported in Vietnam, Thailand,
Indonesia, Pakistan, India, Malaysia, and the Philippines. Dengue continues to extend its range.

Currently, dengue hemorrhagic fever is one of the leading causes of hospitalization and death
in children in many Southeast Asian countries, with Indonesia reporting the majority of dengue
hemorrhagic fever cases. Of interest and significance in prevention and control, 3 surveillance
studies in Asia report an increasing age among infected patients and increasing mortality rate.
Since 1982 in Singapore, more than 50% of deaths have occurred in individuals older than 15
years. In Indonesia, young adults in Jakarta and provincial areas make up a larger percentage
of infected patients. During the 2000 epidemic in Bangladesh, up to 82% of hospitalized
patients were adults, and all deaths occurred in patients older than 5 years.

The epidemiology of dengue fever in Africa is more poorly characterized. Aedes aegypti is
present in a large portion of the Middle East and sub-Saharan Africa. Dengue fever is present
in 19 countries on the African continent. In a 1993 epidemic in the Comoros, an estimated
60,000 persons were infected with dengue. Of note, no major dengue hemorrhagic fever
epidemics have occurred in Africa, despite the fact that all 4 dengue serotypes circulate in the
continent. This may be explained by a genetic factor in these populations.

In the Americas, dengue epidemics were rare postwar because Aedes mosquitoes had been
eradicated from most of the region through coordinated vector-control efforts. Systematic
spraying was halted in the early 1970s because of environmental concerns. By the 1990s, A
aegypti mosquitoes repopulated most of the countries in which they had been eliminated.

Serotype 1 dengue (DENV-1) was introduced into a largely susceptible population in Cuba in
1977. Serosurveys indicated that more than 44% of the population was infected, with only mild
disease reported. The first dengue hemorrhagic fever epidemic in the Americas occurred in
Cuba in 1981 and involved serotype 2 dengue (DENV-2), with hundreds of thousands of cases
of dengue in both children and adults, 24,000 cases of dengue hemorrhagic fever, 10,000
cases of dengue shock syndrome, and 158 reported deaths.
In 1997, Asian genotype DENV-2 was reintroduced, and dengue shock syndrome and dengue
hemorrhagic fever were seen only in adults who had previously been infected with DENV-1 in
1977. Disease and case fatality rates were higher in those who had been infected with DENV-2
twenty years after their initial DENV-1 infection than those who were infected 4 years apart.
Data from other countries supports the finding that the severity of secondary dengue
infections appears to intensify with longer intervals between infections.4,5 Since then, dengue
fever and dengue hemorrhagic fever cases have progressively increased.

A aegypti is abundant year-round in most countries in the Caribbean basin. Significant

outbreaks of dengue have been reported in 2005 and 2006 in Puerto Rico, the US Virgin
Islands, the Dominican Republic, Barbados, Curacao, Cuba, Guadeloupe, and Martinique.

Aedes albopictus, originally from Asia, is now found in limited areas of Brazil, Bolivia, Colombia,
the Dominican Republic, El Salvador, Guatemala, Honduras, Mexico, Cuba, and the Cayman
Islands. A aegypti is present in all countries in South America except Chile. Hyperendemic
circulation of all 4 dengue serotypes is present in the northern countries of South America.
Brazil (700,000 cases in 2002), Colombia, and Venezuela report the most cases of dengue and
dengue hemorrhagic fever, with low-level transmission occurring year-round but with most
occurring during periods of epidemic transmission.

In 1986, the first clearly identified local transmission of dengue in the United States occurred in
Texas. Carriers of the virus were believed to have crossed the border from Mexico; the local
vector population was then infected. Since then, seasonal autochthonous infection has been
reported in both Texas and Hawaii. In 2001-2002, Hawaii experienced its first outbreak of
dengue since World War II ended. The outbreak involved 2 variants of DENV-1 that were
transmitted by A albopictus. Predominantly affecting young adults and adults, 122 cases of
dengue fever spread slowly on Maui, Oahu, and Kauai. The epidemic was traced to viremic
visitors from Tahiti, which was then experiencing a severe outbreak of the infection.

Two competent vectors, A aegypti and A albopictus, are currently seasonally abundant in some
areas of the southwestern and southeastern United States, including Texas, Arizona, New
Mexico, Louisiana, Mississippi, Alabama, Georgia, and mid to south Florida. A aegypti has also
been reported sporadically in portions of North Carolina, South Carolina, Tennessee, Arkansas,
Maryland, and New Jersey. The range of A albopictus extends almost as far north as the Great
Lakes. Since many cases of dengue in US citizens are due to endemic transmission in some US
territories, the Centers for Disease Control and Prevention (CDC) currently conducts
laboratory-based surveillance in Puerto Rico.

Dengue fever does not naturally occur in the European Union and in continental Europe
because these areas do not have an appropriate vector population to allow further spread of
dengue from viremic patients returning from other countries. As such, the disease is not
statutorily notifiable in most member states. However, dengue does occur in several overseas
territories of European Union members. In recent decades, reports of dengue infections in
long-term expatriates, aid workers, military personnel, immigrants, and travelers returning
from the tropics and subtropics have been increasing.

Since 2000, at least 8 areas previously without dengue have reported outbreaks, including
Nepal, Bhutan, Macau, Hong Kong, Madagascar, the Galapagos, Easter Island, and Hawaii. The
Pan American Health Organization (PAHO) reported that 2007 saw the highest number of
dengue fever and dengue hemorrhagic fever cases (918,495) in the Americas since 1985.

Factors believed to be responsible for the spread of dengue include explosive population
growth, unplanned urban overpopulation with inadequate public health systems, poor standing
water and vector control, viral evolution, and increased international recreational, business,
and military travel to endemic areas. All of these factors must be addressed to control the
spread of dengue and other mosquito-borne infections. Unplanned urbanization is believed to
have had the largest impact on disease amplification in individual countries, whereas travel is
believed to have had the largest impact on global spread.3,6,7,1,5

Over the past decade, the GeoSentinel Network of Travel Medicine providers has demonstrated
that dengue has become more frequently diagnosed than malaria in travelers returning from
tropical areas other than Africa. Such sentinel travel surveillance can augment global and
national public health surveillance. More recent studies have not supported an earlier
suggestion that climate change is also directly responsible for increased transmission.6,4,5

Pathophysiology

Dengue infection is caused by 1 of 4 related, but antigenically distinct, viral serotypes: dengue
virus 1 (DENV-1), dengue virus 2 (DENV-2), dengue virus 3 (DENV-3), and dengue virus 4
(DENV-4). Genetic studies of sylvatic strains suggest that the 4 viruses evolved from a
common ancestor in primate populations approximately 1000 years ago and that all 4 viruses
separately emerged into a human urban transmission cycle 500 years ago in either Asia or
Africa.1,8 Albert Sabin speciated these viruses in 1944. Each serotype is known to have several
different genotypes.

Infection with one dengue serotype confers lifelong homotypic immunity and a very brief
period of partial heterotypic immunity, but each individual can eventually be infected by all 4
serotypes. Several serotypes can be in circulation during an epidemic.

Dengue viruses are transmitted by the bite of an infected Aedes (subgenus Stegomyia)
mosquito. Globally, A aegypti is the predominant highly efficient mosquito vector for dengue
infection, but A albopictus and other Aedes species can also transmit dengue with varying
degrees of efficiency.

Aedes mosquito species have adapted well to human habitation, often breeding around
dwellings in small amounts of stagnant water found in old tires or other small containers
discarded by humans. Female Aedes mosquitoes are daytime feeders. They inflict an
innocuous bite and are easily disturbed during a blood meal, causing them to move on to finish
a meal on another individual, making them efficient vectors. Entire families who develop
infection within a 24- to 36-hour period, presumably from the bites of a single infected vector,
are not unusual.

Humans serve as the primary reservoir for dengue; however, certain nonhuman primates in
Africa and Asia also serve as hosts but do not develop dengue hemorrhagic fever. Mosquitoes
acquire the virus when they feed on a carrier of the virus. The mosquito can transmit dengue if
it immediately bites another host. In addition, transmission occurs after 8-12 days of viral
replication in the mosquito's salivary glands (extrinsic incubation period). The mosquito
remains infected for the remainder of its 15- to 65-day lifespan. Vertical transmission of
dengue virus in mosquitoes has been documented.9 The eggs of Aedes mosquitoes withstand
long periods of desiccation, reportedly as long as 1 year, but are killed by temperatures of less
than 10°C.

Once inoculated into a human host, dengue has an incubation period of 3-14 days (average 4-
7 d) while viral replication takes place in target dendritic cells. Infection of target cells,
primarily those of the reticuloendothelial system, such as dendritic cells, hepatocytes, and
endothelial cells,10,11,12,13 result in the production of immune mediators that serve to shape the
quantity, type, and duration of cellular and humoral immune response to both the initial and
subsequent virus infections.14,15,10,16,17,18,19 Following incubation, a 5- to 7-day acute febrile illness
ensues. Recovery is usually complete by 7-10 days.

Dengue hemorrhagic fever or dengue shock syndrome usually develops around the third to
seventh day of illness, approximately at the time of defervescence. The major
pathophysiological abnormalities caused by dengue hemorrhagic fever and dengue shock
syndrome include the rapid onset of plasma leakage, altered hemostasis, and damage to the
liver, resulting in severe fluid losses and bleeding. Plasma leakage is caused by increased
capillary permeability and may manifest as hemoconcentration, as well as pleural effusion and
ascites. Bleeding is caused by capillary fragility and thrombocytopenia and may manifest in
various forms, ranging from petechial skin hemorrhages to life-threatening gastrointestinal
bleeding. Liver damage manifests as increases in levels of alanine aminotransferase and
aspartate aminotransferase, low albumin levels, and deranged
coagulationparameters(PT,PTT).20,21

In persons with fatal dengue hepatitis, infection was demonstrated in more than 90% of
hepatocytes and Kupffer cells with minimal cytokine response (tumor necrosis factor [TNF]–
alpha, interleukin [IL]–2). This is similar to that seen with fatal yellow fever and Ebola
infections.20

Most patients who develop dengue hemorrhagic fever or dengue shock syndrome have had
prior infection with one or more dengue serotypes. In individuals with low levels of neutralizing
antibodies, nonneutralizing antibodies to one dengue serotype, when bound by macrophage
and monocyte Fc receptors, have been proposed to result in increased viral entry and
replication and increased cytokine production and complement activation. This phenomenon is
called antibody-dependent enhancement.

Some researchers suggest T-cell immunopathology may play a role, with increased T-cell
activation and apoptosis. Increased concentrations of interferon have been recorded 1-2 days
following fever onset during symptomatic secondary dengue infections.22 The activation of
cytokines, including TNF-alpha, TNF receptors, soluble CD8, and soluble IL-2 receptors, has
been correlated with disease severity.10 Cuban studies have shown that stored serum sample
analysis demonstrated progressive loss of cross-reactive neutralizing antibodies to DENV-2 as
the interval since DENV-1 infection increased.17 In addition, certain dengue strains, particularly
those of DENV-2, have been proposed to be more virulent, in part because more epidemics of
dengue hemorrhagic fever have been associated with DENV-2 than with the other serotypes.
Frequency

United States

In 1998, 90 confirmed or probable cases of dengue fever were imported into the United States,
resulting in one fatality. The current estimate is 100 cases per year; however, the true number
of dengue fever cases is believed to be higher because reporting is voluntary, many US
physicians are not aware of dengue or its manifestations, and the manifestations are often
nonspecific.

In 1999, more than 300 cases of dengue fever were reported from Nuevo Laredo, Tamaulipas,
Mexico.23 Nuevo Laredo lies directly across the Rio Grande River from Laredo, Texas. At that
time, no dengue cases had been reported in Laredo in more than 12 years. Aedes mosquitoes
are present in both cities. The Texas Department of Health reviewed 494 patient records from
5 outpatient sites and was able to confirm 11 cases of dengue fever. Mosquito abatement
measures were instituted in Laredo, and health care providers were notified of the dengue
fever cases. In the latter half of 1999, Laredo-area health care providers identified 161
suspected dengue fever cases and serologically confirmed 18 cases. This report underscores
the need for health care providers to be aware of dengue fever and its manifestations and to
test for the infection in appropriate cases.

International

An estimated 2.5-3 billion people in approximately 110 tropical and subtropical countries
worldwide are at risk for dengue infection. Yearly, approximately 50-100 million people are
infected with dengue, and 250,000 individuals develop dengue hemorrhagic fever. Annually,
approximately 500,000 individuals are hospitalized with the infection, and 24,000 deaths are
attributed to dengue worldwide. The Pan American Health Organization (PAHO) member states
reported twice as many cases of dengue fever and dengue hemorrhagic fever in 1998 as they
did in 1997.

A 5-year prospective study in Thai children examined the relative economic burden of dengue
infection in children on the local population. Most disability-adjusted life years (DALYs) lost to
dengue resulted from long-duration illness in children who had not been hospitalized. The
infecting serotype appeared to be a determining factor of DALYs lost, with DENV-2 and DENV-3
responsible for 30% and 29%, respectively. The mean cost of illness from dengue was
significantly higher than that from other febrile illnesses.24

Mortality/Morbidity

• Recovery from dengue infection is usually complete. Even patients who meet strict
criteria for dengue hemorrhagic fever or dengue shock syndrome usually recover
without sequelae.
• The fatality rate associated with dengue shock syndrome varies by country, from 12%-
44%. In a 1997 Cuban epidemic, the fatality rate in patients who met criteria for
dengue hemorrhagic fever or dengue shock syndrome was approximately 6%. The
mortality rate associated with dengue fever is less than 1%.
• Data from the 1997 Cuban epidemic suggests that, for every clinically apparent case
of dengue fever, 13.9 cases of dengue infection went unrecognized because of absent
or minimal symptoms.
• Factors that affect disease severity include patient age, nutritional status, ethnicity,
the sequence of infection with different dengue serotypes, virus genotype, and the
quality and extent of available medical care.

Race

• Dengue affects all races. Some African and Haitian data demonstrate a relative dearth
of dengue hemorrhagic fever and dengue shock syndrome during dengue fever
epidemics, suggesting that these populations may share a genetic advantage to the
virus. This merits further study.

Sex

• Dengue viruses affect both sexes.

Age

• Dengue affects people of all ages. In Southeast Asia, where dengue is hyperendemic,
dengue hemorrhagic fever usually affects children younger than 15 years. However, in
 the Americas, where dengue is becoming progressively hyperendemic, dengue
hemorrhagic fever shows no age predilection.

Clinical

History

• Fever in persons with symptomatic dengue fever may be as high as 41°C. The fever
typically begins on the third day and lasts 5-7 days, abating with the cessation of
viremia. Fever is often preceded by chills, erythematous mottling of the skin, and facial
flushing (a sensitive and specific indicator of dengue fever). Occasionally, and more
commonly in children, the fever abates for a day and then returns, a pattern that has
been called saddleback fever. Patients are at risk for development of dengue
hemorrhagic fever or dengue shock syndrome at approximately the time of
defervescence. In travelers, symptoms that begin more than 2 weeks after they depart
from an endemic area and fever that lasts longer than 10 days are probably not due to
dengue.
• Headache is usually generalized. Retroorbital pain is common and is often described as
severe.
• Patients may report nausea and vomiting.
• Patients typically describe a maculopapular or macular confluent rash over the face,
thorax, and flexor surfaces, with islands of skin sparing. The rash typically begins on
day 3 and persists 2-3 days.
• Patients may have severe myalgias, particularly of the lower back, arms, and legs, and
arthralgias, especially of the knees and shoulders.
• Hemorrhagic manifestations may range from small amounts of bleeding from the nose
or gums to melena, menorrhagia, or hematemesis.
• Abdominal pain is reported; often, abdominal pain in conjunction with restlessness,
change in mental status, hypothermia, and a drop in the platelet count presages the
development of dengue hemorrhagic fever.
• Patients report fatigue and malaise.
• Patients may report conjunctival injection, sore throat, and cough.
• Cardiomyopathy is reported, with tachycardia during the febrile period and
bradycardia and conduction defect. Myocarditis and congestive heart failure are rare.

Physical

• Fever is present.
• Rash is described as follows:
o Up to half of patients with dengue fever develop a characteristic rash.
o The rash is variable and may be maculopapular or macular.
o Petechiae and purpura may develop as hemorrhagic manifestations.
• Conjunctival injection develops in approximately one third of patients with dengue
hemorrhagic fever. Optic neuropathy has been reported and occasionally results in
permanent and significant visual impairment.25
• Pharyngeal injection develops in almost 97% of patients with dengue hemorrhagic
fever.
• Generalized lymphadenopathy is observed.
• Hepatomegaly is present more often in dengue shock syndrome than in milder cases.
Hepatic transaminase levels may be mildly elevated.
• Hemorrhagic manifestations include the following
o Petechiae and bleeding at venipuncture sites are most common.
o Results from a tourniquet test are often positive. This test is performed by
inflating a blood pressure cuff on the upper arm to midway between diastolic
and systolic blood pressures for 5 minutes. The results are considered positive
if more than 20 petechiae per square inch are observed on the skin of the arm.
o Other hemorrhagic manifestations include nasal or gingival bleeding, melena,
hematemesis, and menorrhagia.
• Encephalopathy is a rare complication that may result from a combination of cerebral
edema, intracranial hemorrhage, anoxia, hyponatremia, and hepatic injury.
• Dengue fever presents in a nonspecific manner and may not be distinguishable from
other viral or bacterial illness. The PAHO has developed the following case definitions
for the diagnosis of dengue fever and dengue hemorrhagic fever or dengue shock
syndrome:
o The clinical description of dengue fever is an acute febrile illness of 2-7 days
duration associated with 2 or more of the following:
 Severe headache
 Retroorbital pain
 Severe myalgias
  Arthralgia
 Characteristic rash
 Hemorrhagic manifestations
 Leukopenia
o Laboratory criteria for diagnosis include one or more of the following:
 Isolation of the dengue virus from serum, plasma, leukocytes, or
autopsy samples
 Demonstration of a 4-fold or greater change in reciprocal
immunoglobulin G (IgG) or immunoglobulin M (IgM) antibody titers to
one or more dengue virus antigens in paired serum samples
 Demonstration of dengue virus antigen in autopsy tissue via
immunohistochemistry or immunofluorescence or in serum samples via
enzyme immunoassay (EIA)
 Detection of viral genomic sequences in autopsy tissue, serum, or
cerebral spinal fluid (CSF) samples via polymerase chain reaction (PCR)
o Cases are classified as suspected if they are compatible with the clinical
description.
o Cases are classified as probable if they are compatible with the clinical
definition and satisfy one or more of the following criteria:
 Supportive serology (reciprocal hemagglutination-inhibition antibody
titer greater than 1280, comparable IgG EIA titers, or positive IgM
antibody test in late acute or convalescent-phase serum specimen)
 Occurrence at the same location and time as other confirmed cases of
dengue fever
o A confirmed case is one that is compatible with the clinical definition and is
confirmed by the laboratory.
o Criteria for the diagnosis of dengue hemorrhagic fever include a probable or
confirmed case of dengue infection and hemorrhagic tendencies as evidenced
by one or more of the following:
 A positive result from the tourniquet test
 Petechiae, ecchymoses, or purpura
 Bleeding from the mucosa, gastrointestinal tract, injection sites, or
other sites
 Hematemesis or melena and thrombocytopenia (<100,000 cells/μL)
and evidence of plasma leakage due to increased vascular
permeability that manifests as one or more of the following: greater
than 20% rise in average hematocrit level for age and sex, greater
than 20% drop in hematocrit level following volume replacement
compared to baseline, or signs of plasma leakage (eg, pleural effusion,
ascites, hypoproteinemia)
o Dengue shock syndrome is diagnosed in cases meeting all of the above criteria
plus evidence of circulatory failure, such as the following:
 Rapid, weak pulse
 Narrow pulse pressure (<20 mm Hg), with increased peripheral
vascular resistance (PVR) and elevated diastolic pressure
 Hypotension
 Cool, clammy skin
 Altered mental status, although the patient may initially remain alert
o The onset of shock may be subtle, indicated by raised diastolic pressure and
increased PVR in an alert patient.
• The WHO classification system was recently studied in Indonesian children and was
found to have a sensitivity of 86% (95% CI, 76-94) for the detection of dengue shock
syndrome.14 The clinical reliability of the WHO criteria was compared with those of
several modified systems, which added the above early predictors of compensated
shock and considered models using varying combinations of evidence of hemorrhagic
tendencies, thrombocytopenia, and hemoconcentration. These modified systems were
found to yield higher sensitivities (88%-99%) for dengue diagnosis than the WHO
classification system and were more in line with clinical determinations made by local
expert physicians.
• A Belgian study examined predictors of diagnosis in 1962 febrile travelers and
expatriates returning from the tropics. After malaria was ruled out, the main predictors
of dengue infection included skin rash, thrombocytopenia, and leukopenia.26

Causes

Dengue infection is caused by 1 of the 4 dengue viruses (ie, DENV-1, DENV-2, DENV-3, DENV-
4) and is transmitted to humans by the bite of an infected mosquito.

Rabies
Author: Sandra G Gompf, MD, FACP, FIDSA, Associate Professor of Infectious Diseases
and International Medicine, University of South Florida College of Medicine; Chief, Infectious
Diseases Section, Director, Occupational Health and Infection Control Programs, James A Haley
Veterans Hospital
Coauthor(s): Charurut Somboonwit, MD, Assistant Professor of Medicine, Division of
Infectious Disease and International Medicine, University of South Florida College of Medicine;
Senior Physician, Polk County Health Department; Tri M Pham, MD, Fellow, Division of
Infectious Diseases and International Medicine, University of South Florida College of Medicine;
Albert L Vincent, PhD, Associate Professor, Division of Infectious Diseases and International
Health, Department of Internal Medicine, University of South Florida College of Medicine;
Scientific and Research Advisor to the Division of Epidemiology, Hillsborough County Health
Department
Contributor Information and Disclosures

Updated: Oct 3, 2008

Introduction

Background

Rabies is a viral disease that affects the CNS. The genus Lyssavirus contains more than 80
viruses. Classic rabies, the focus of this article, is the prototypical human Lyssavirus pathogen.
Ten viruses are in the rabies serogroup, most of which only rarely cause human disease. The
genus Lyssavirus, rabies serogroup, includes the classic rabies virus, Mokola virus, Duvenhage
virus, Obodhiang virus, Kotonkan virus, Rochambeau virus, European bat Lyssavirus types 1
and 2, and Australian bat Lyssavirus. In 1997, an unusual bat Lyssavirus caused a brief
outbreak of a rabieslike illness in Australia.

The fatal madness of rabies has been described throughout recorded history, and its
association with rabid canines is well known. For centuries, dog bites were treated
prophylactically with cautery, unfortunately, with predictable results. In the 19th century,
Pasteur developed a vaccine that successfully prevented rabies after inoculation and launched
a new era of hope in the management of this uniformly fatal disease. Rabies is recognized as a
zoonosis worldwide. Animal-control and vaccination strategies currently supersede
postexposure prophylaxis in preventing the spread of rabies. Through such programs, rabies
has been eliminated in several nations and some areas in the US territories.

Human rabies reflects the prevalence of animal infection and the extent of contact this
population has with humans. Less than 5% of cases in developed nations occur in
domesticated dogs; however, unvaccinated dogs serve as the main reservoir worldwide.
Undomesticated canines, such as coyotes, wolves, jackals, and foxes, are most prone to rabies
and serve as reservoirs. These reservoirs allow rabies to remain an indefinite public health
concern, and ongoing public health measures are critical to its control. Raccoons, skunks, and
insect-eating bats remain the prime vectors in the United States, followed by cats and cattle.
Increasingly in the United States, the source of exposures cannot be identified, but the risk of
death from rabies is exceedingly low, with fewer than 5 cases documented per year. Opossums
are rarely infected and are not considered a likely risk for exposure.

Other very rare sources of exposure have included neurally derived tissues (eg, transplanted
corneas) and laboratory aerosols. Recently, the first US instance of human rabies transmission
via solid organ transplantation was documented in 3 recipients of a donor unsuspected of
having rabies; transmission via organ transplantation has also been documented in other
countries.1,2

The rabies virus is a bullet-shaped virion with a single-stranded RNA nucleocapsid core and
lipoprotein envelope. Its nucleocapsid material comprises the Negri bodies observed in the
cytoplasm of infected neurons. The virus is transmitted in saliva or in aerosolized secretions
from infected animals, typically via a bite. The virus is not hardy and is quickly inactivated by
drying, ultraviolet rays, x-rays, trypsin, detergents, and ether.

Pathophysiology

Rabies is a highly neurotropic virus that evades immune surveillance by its sequestration in
the nervous system. Upon inoculation, it enters the peripheral nerves. A prolonged incubation
follows, the length of which depends on the size of the inoculum and its proximity to the CNS.
Amplification occurs until bare nucleocapsids spill into the myoneural junction and enter motor
and sensory axons. At this point, prophylactic therapy becomes futile, and rabies can be
expected to follow its fatal course, with a mortality rate of 100%.

The rabies virus travels along these axons at a rate of 12-24 mm/d to enter the spinal
ganglion. Its multiplication in the ganglion is heralded by the onset of pain or paresthesia at
the site of the inoculum, which is the first clinical symptom and a hallmark finding. From here,
the rabies virus spreads quickly, at a rate of 200-400 mm/d, into the CNS, and spread is
marked by rapidly progressive encephalitis. Thereafter, the virus spreads to the periphery and
salivary glands.

Frequency

United States

The prevalence of rabies varies by location depending on animal-control effectiveness and

immunization programs. The largest number of human deaths annually was recorded during
the first half of the 20th century, with an average of 50 documented cases per year. Most were
related to rabid-dog exposure. Since 1940, when canine rabies vaccination programs began,
the average number of documented cases declined to 2 per year. From 2001-2005, 15 cases of
human rabies were reported in the United States. In 2006, 3 cases of human rabies were
reported in California, Indiana, and Texas. Bat rabies virus variants were implicated in the
rabies cases in Texas and Indiana, whereas exposure to a dog in the Philippines was
responsible for the case in California.3 Approximately 16,000-39,000 people receive rabies
postexposure prophylaxis each year.

Some concern exists regarding occupational transmission of rabies from patients to health
care workers. Despite the lack of proven occupational transmission, approximately 30% of
health care worker contacts exposed to known cases of rabies have been treated with
postexposure prophylaxis in the United States, some of which may have been unnecessary.
The delivery of health care to a patient with rabies is not an indication for postexposure
prophylaxis unless mucous membranes or open wounds are contaminated by saliva, tears,
cerebrospinal fluid (CSF), or neurologic tissue. Adherence to standard infection-control
precautions recommended by the US Centers for Disease Control and Prevention (CDC) is
expected to minimize the risk for exposure to rabies in caregivers.

International

Rabies is more prevalent in the developing world than in the developed world. The World
Health Organization (WHO) estimates that rabies is responsible for 35,000-50,000 deaths
annually worldwide and that gross underreporting is likely. An estimated 10 million people
receive postexposure prophylaxis each year after being exposed to animals with suspected
rabies.

Mortality/Morbidity

If rabies treatment is not initiated before the onset of symptoms, death is imminent. Five cases
of survival of human rabies have been documented in individuals who had been previously
vaccinated or received postexposure prophylaxis. The survival of a teenaged girl from
Wisconsin received substantial attention in October 2004 as the first case of human survival of
rabies in the absence of preceding vaccination or postexposure prophylaxis.4 Notably, she
received an investigational regimen of ribavirin, amantadine, and a ketamine-midazolam–
induced coma; however, assessing whether this therapy was genuinely efficacious, whether
other factors may have been involved, or whether these results are in fact reproducible is
difficult.

In addition, bat rabies virus (isolated from the Wisconsin survivor) may be less neurovirulent
than canine or other variants that are responsible for most human cases of rabies. The case,
wherein the victim did not seek medical attention after handling a bat and being bitten,
underscores the potentially long incubation period (in this case, 1 mo) and the need for
ongoing public awareness of the risk of contracting this almost uniformly fatal infection.

Race

Rabies has no known racial predilection.

Sex

Rabies has no known sexual predilection.

Age

Rabies has no known age predilection.

Clinical
History

• Incubation period
o The rabies virus transfers from peripheral areas to the CNS.
o The infected individual remain asymptomatic.
o The average duration of incubation is 20-90 days. Rarely, incubation lasts as
long as 19 years. In more than 90% of cases, incubation is less than 1 year.
o The incubation period is less than 50 days if the patient is bitten on the head
or neck or if a heavy inoculum is transferred through multiple bites, deep
wounds, or large wounds. A person with a scratch on the hand may take longer
to develop symptoms of rabies than a person who receives a bite to the head.
o The rabies virus is segregated from the immune system during this period, and
no antibody response is observed.
o Patients may not recall exposure because of the prolonged incubation period.
• Prodromal period
o The virus enters the CNS.
o The duration of this period is 2-10 days.
o Nonspecific symptoms and signs develop.
o Paresthesia or pain at the inoculation site is pathognomonic for rabies and
occurs in 50% of cases during this phase; this may be the individual’s only
presenting sign.
o Symptoms may include malaise, anorexia, headaches, fever, chills,
pharyngitis, nausea, emesis, diarrhea, anxiety, agitation, insomnia, and
depression.
• Acute neurologic period
o This period is associated with objective signs of developing CNS disease.
o The duration is 2-7 days.
o Furious rabies may develop in this period. Patients develop agitation,
hyperactivity, restlessness, thrashing, biting, confusion, or hallucinations. After
several hours to days, this becomes episodic and interspersed with calm,
cooperative, lucid periods. Furious episodes last less than 5 minutes. Episodes
may be triggered by visual, auditory, or tactile stimuli or may be spontaneous.
Seizures may occur. This phase may end in cardiorespiratory arrest or may
progress to paralysis.
o Paralytic rabies is also known as dumb rabies or apathetic rabies because the
patient is relatively quiet compared with a person with the furious form.
o Twenty percent of patients do not develop the furious form.
o Paralysis occurs from the outset.
o Fever and headache are prominent.
• Coma
o This begins within 10 days of onset; the duration varies.
o Without intensive supportive care, respiratory depression, arrest, and death
occur shortly after coma.
• Recovery
o This is unlikely. A few reports indicate that persons who survived had
preexposure or postexposure prophylaxis.
o Most US cases result in death within 14 days because of complications, despite
intensive supportive care.

Physical

• Incubation period: The virus transfers from peripheral areas to the CNS. Physical
findings are not present.
• Prodromal period: The virus enters the CNS. Signs include fever, agitation, emesis, or
diarrhea.
• Neurologic period
o Furious rabies
 Patients present with episodic delirium, psychosis, restlessness,
thrashing, muscular fasciculations, seizures, and aphasia.
 Hydrophobia and aerophobia are pathognomonic for rabies and occur
in 50% of patients. Attempting to drink or having air blown in the face
produces severe laryngeal or diaphragmatic spasms and a sensation of
choking. This may be related to a violent response of the airway
irritant mechanisms. Even the suggestion of drinking may induce
hydrophobic spasm.
 Autonomic instability is observed, including fever, tachycardia,
hypertension, hyperventilation, drooling, anisocoria, mydriasis,
lacrimation, salivation, perspiration, and postural hypotension.
 Other neurologic signs include cranial nerve involvement with diplopia,
facial palsy, and optic neuritis.
 o Paralytic rabies
 Fever and nuchal rigidity may occur.
 Paralysis is symmetric and may be either generalized or ascending and
may be mistaken for Guillain-Barré syndrome. The sensory system is
usually spared.
 Calm clarity gradually progresses to delirium, stupor, and then coma.
• Coma: Respiratory failure occurs within one week of neurologic symptoms.
Hypoventilation and metabolic acidosis predominate. Acute respiratory distress
syndrome is common. Wide variations in blood pressure, cardiac arrhythmias, and
hypothermia ensue. Bradycardia and cardiac arrest occur.

Causes

• High-risk exposures consist of contact with saliva or infected CNS tissue, including
corneal transplants, via the following:
o The bite of an rabid animal
o Contact with broken skin
o Contact with mucous membranes
o Exposure to aerosolized secretions from an rabid animal
• Contact with unpasteurized milk from dairies: Each year since 1990, approximately
150 rabid cattle are been reported to the CDC.
• Transplant patients: The innate state of immunosuppression in this population often
provides a favorable environment for viral replication.
o Corneal transplants: Currently, donated corneas are not accepted if the donor
died from an encephalitis that may be consistent with rabies.
o Kidney and liver transplants: In 2004, organs were inadvertently transplanted
from a donor from Texas with rabies that had gone undiagnosed. The
recipients developed clinical rabies within 30 days, resulting in 100% mortality.
o Organ donation: Clinical screening of potential organ donors should include a
history of animal bites, presence of clinical features of rabies, and a travel
history (within a period of months) to areas where rabies is endemic. Pre-
exposure rabies immunization of potential organ recipients is being evaluated
as an alternative approach to prevent transmission associated with organ
transplantation.5
• High-risk animal species in the United States include the following:
o Bats
 Bat bites, if noticed by the patient, are generally thought to be trivial
injuries because of the small size of most temperate-zone species (eg,
silver-haired bats, eastern pipistrelles). In addition, bat bites can go
completely unrecognized by the patient; consequently, appropriate
postexposure prophylaxis is not administered.
 One third of rabies cases occur in children, and most have no known
exposure to a rabid animal. Because children may not be able to recall
contact with a bat, if a bat is found in a room where a child has been
sleeping, the bat should be captured and submitted for examination to
the county or state health authorities. In 60% of cases, testing of the
bat can avoid the need for rabies immunization.6 (For additional
information on pediatric rabies, see the eMedicine article Rabies in the
Pediatrics: General Medicine volume.)
 In September 2005, a previously healthy 10-year-old boy in Mississippi
died from encephalitis later attributed to rabies. Upon further
questioning after the patient's death, family members recalled that
bats were commonly seen outside the home. On two occasions, dead
bats also were discovered inside the home. Several family members
and friends who possibly had contact with the patient's saliva received
postexposure prophylaxis.
 At least 30 of the more than 39 species of bats in the United States
have been reported as rabid at some time.
o Raccoons: Raccoons have been recognized a reservoir for rabies in the
southeastern United States since the 1950s.7 Currently, the risk of raccoon
transmission exists in all of the eastern coastal states and Alabama,
Pennsylvania, Vermont, West Virginia, and Ohio.
o Skunks: Three areas are associated with skunk-borne rabies. These areas
include the north-central United States, the south-central United States, and
California.
o Foxes
o Dogs and cats along the Mexican border: Because of limited resources and
minimal public health infrastructure in the bordering communities, efforts to
maintain animal control through dog-vaccination programs are hindered. Viral
studies of human cases reported from US border states implicate an urban
canine rabies strain and a link to coyote rabies in southern Texas.8
 • Lower-risk animal species in the United States include dogs, cats, and ferrets in areas
not near a border. No person in the United States has ever contracted rabies from a
dog, cat, or ferret held in quarantine for 10 days.
• The vaccinia-rabies glycoprotein virus used to bait wild animals is a self-replicating
agent. Only one case has been documented of a pregnant woman developing a skin
infection and needing surgery after she was bitten by her dog. Her history findings
revealed that she was bitten when she took a vaccinia-rabies virus vaccine out of her
dog's mouth.9 This oral animal vaccine may cause adverse effects, particularly in hosts
with altered immunocompetence and in persons in whom smallpox vaccination is
contraindicated (eg, pregnant women, patients with an exfoliative skin condition).

Adenoviruses

Author: Sandra G Gompf, MD, FACP, FIDSA, Associate Professor of Infectious Diseases
and International Medicine, University of South Florida College of Medicine; Chief, Infectious
Diseases Section, Director, Occupational Health and Infection Control Programs, James A Haley
Veterans Hospital
Coauthor(s): Dhanashree Kelkar, MD, Fellow, Department of Infectious Diseases and
International Medicine, University of South Florida College of Medicine; Richard L Oehler,
MD, FACP, Assistant Professor, Department of Internal Medicine, Division of Infectious
Diseases and Tropical Medicine, Univ of South Florida College of Medicine; Assistant
Epidemiologist, Division of Infectious Diseases, Tampa VA Medical Center
Contributor Information and Disclosures

Updated: Feb 12, 2010

Introduction

Background

Adenovirus, a DNA virus, was first isolated in the 1950s in adenoid tissue–derived cell cultures,
hence the name. These primary cell cultures were often noted to spontaneously degenerate
over time, and adenoviruses are now known to be a common cause of asymptomatic
respiratory tract infection that produces in vitro cytolysis in these tissues.

A virus image from the International Committee on Taxonomy of Viruses, in The Big
Picture Book of Viruses, available at
http://www.virology.net/Big_Virology/BVDNAadeno.html.

An extremely hardy virus, adenovirus is ubiquitous in human and animal populations, survives
long periods outside a host, and is endemic throughout the year. Possessing 52 serotypes,
adenovirus is recognized as the etiologic agent of various diverse syndromes. It is transmitted
via direct inoculation to the conjunctiva, a fecal-oral route, aerosolized droplets, or exposure to
infected tissue or blood.

The virus is capable of infecting multiple organ systems; however, most infections are
asymptomatic. Adenovirus is often cultured from the pharynx and stool of asymptomatic
children, and most adults have measurable titers of anti-adenovirus antibodies, implying prior
infection. Adenovirus is known to be oncogenic in rodents but not in humans.
Adenovirus has been associated with both sporadic and epidemic disease and, with regard to
infections among military recruits, is a significant cause of economic cost and morbidity
because of the cessation of vaccine production in 1996.

Of most recent interest is the role of adenoviruses as vectors in vaccination and in gene
therapy.1,2,3 Adenoviruses can infect various cells, both proliferating and quiescent, and thus
hold the promise of targeting many different tissues and diseased cell lines.

The genome of adenovirus is well known and can be modified with relative ease to induce lysis
or cytotoxicity of a specified cell line without affecting others.

The virus itself can be engineered to remove its replicative capacity by removing essential
genes. Additionally, specific genes can be inserted into the virus that then can repair defective
metabolic, enzymatic, or synthetic pathways in the host. Suicide gene systems that convert
nontoxic systemically delivered prodrugs to active chemotherapeutic agents have been
delivered via adenoviral vectors directly into cancer cells. However, the greatest challenge in
viral gene therapy, as might be expected, is the immune response to the viral vector itself.

The complex mechanisms by which viral vectors may be incorporated into gene therapy and
the rapid growth in this field put further discussion beyond the scope of this text.

Pathophysiology

Adenovirus is a double-stranded DNA virus that measures 70-90 nm and that has an
icosahedral capsid.

The site of entry generally determines the site of infection; respiratory tract infection infections
result from droplet inhalation, while gastrointestinal tract involvement results from fecal-oral
transmission. Upon infection with adenovirus, one of three different interactions with the cells
may occur.

The first is lytic infection, which occurs when an adenovirus enters human epithelial cells and
continues through an entire replication cycle, which results in cytolysis, cytokine production,
and induction of host inflammatory response.

The second is chronic or latent infection, the exact mechanism of which is unknown, which
frequently involves asymptomatic infection of lymphoid tissue.

Lastly, oncogenic transformation has been observed in rats. During oncogenesis, the
replication cycle is truncated, and adenoviral DNA is then integrated into the host cell’s DNA.
Thereafter, adenovirus produces potent E1A proteins that immortalize primary rodent cells by
altering cellular transcription, ultimately leading to deregulation of apoptosis and malignant
transformation. A clear role for adenovirus in human oncogenesis has not been established.

Frequency

United States

Adenovirus is isolated most commonly in infants and children. An increased incidence of

infection was found in military recruits until the introduction of an effective vaccine against
serotype 4 (Ad4) and serotype 7 (Ad7) in 1971. The economy-driven cessation of vaccine
production by its sole producer in 1996 resulted in re-emergence of outbreaks, with Ad4
predominating in 98% of cases. The reservoirs exist within the training environment itself, and
Ad4 has been detected on lockers, rifles, and bedding. Ad4 seropositivity of new recruits has
been demonstrated to rise from 30% to almost 100%. Prolonged pharyngeal shedding and
communal quarters contribute to outbreaks, with illness most commonly arising in weeks 3 to
5.

Lost productivity and interrupted military training have prompted reinvestigation of vaccine
production. Notably, co-infection with non-vaccine strains (B1 and E) have developed following
vaccination,4 and surveillance for emerging non-vaccine strains is still needed.

In 2007, media attention following adenovirus outbreaks in the United States focused on
serotype 14. The CDC's Morbidity and Mortality Weekly Review published an article entitled "
Acute Respiratory Disease Associated with Adenovirus Serotype 14—Four States, 2006-2007."

Mortality/Morbidity
 • Severe morbidity and mortality associated with adenovirus infections are rare in
immunocompetent hosts. Uncommon complications that increase the risk of mortality
include meningoencephalitis and pneumonitis.
• Severe adenovirus infections have been reported in immunocompromised patients,
such as transplant patients and those with inherited and acquired immunodeficiency
states. Mortality rates associated with adenovirus infections among pediatric and adult
transplant recipients have varied from 6%-70%.5
• Morbidity and deaths due to pronounced host inflammatory responses have occurred
in past gene vector trials.
• As with polio vaccines, live adenovirus vaccines in the 1950s became contaminated
with simian virus 40 (SV40), with resulting concern that this virus caused various
cancers. After subsequent long-term follow-up, some studies have found a moderate
association between SV40 and human cancers as a transforming virus, while some
other studies have reported no such findings.6,7

Race

• No racial predilection has been described.

Sex

• Adenovirus urinary tract infections are more common in males. The prevalence of
other syndromes does not appear to be affected by the sex of the individual.

Age

• Adenovirus infection typically affects children from infancy to school age, but children
of any age may be affected, including neonates. Young adults in any setting of close
quarters and stress may be affected, as with military trainees.

Clinical

History

Because the manifestations of adenovirus infections are protean, the major syndromes are
discussed separately. The major syndromes covered in this article include (1) acute respiratory
disease (ARD), (2) pharyngoconjunctival fever, (3) epidemic keratoconjunctivitis, (4) acute
hemorrhagic cystitis, (5) gastroenteritis, and (5) adenoviral infections in immunocompromised
hosts.

Given the range of manifestations, the varying levels and effects of immunosuppressive
therapies, and rapid advances in molecular methods of detection, a comprehensive review of
adenovirus infection in the immunosuppressed host is beyond the scope of this article;
however, the author plans to report the most salient features and general updates here. The
reader is encouraged to review the literature for more detail regarding infection in specific
settings.

• Acute respiratory disease (predominantly adenovirus types 1, 2, 5, and 6; occasionally,

3 and 7)
o As with many other viral syndromes, ARD is more common in spring and winter
months. Approximately half of adenovirus respiratory infections do not cause
symptoms. Adenoviruses account for 10% of all childhood lower respiratory
tract infections.
o The contagiousness of adenovirus is facilitated by very high levels of viral
particles (100,000-1,000,000/mL) in the sputum or oral secretions of infected
adults. Additionally, adults who lack antibody may be infected by the inhalation
of as few as 5 virions in droplet nuclei.
o Fever, rhinorrhea, cough, and sore throat, usually lasting 3-5 days, are typical
symptoms of adenoviral ARD.
o Lower respiratory tract infections, including tracheobronchitis, bronchiolitis,
and pneumonia, may mimic respiratory syncytial virus infection or influenza.
Notably, conjunctivitis in the presence of bronchitis suggests adenoviral
infection.
o Fatal pneumonia is uncommon but is more likely in neonates and has been
associated with serotypes 3, 7, 14, 21, and 30.8
o Encephalitis, hepatitis, and myocarditis are uncommon.
o From the 1950s to 1971 (prevaccine era), adenoviruses accounted for
significant acute disease in 70% of military recruits. Adenovirus serotypes 4
and 7 were primarily involved. A live enteric-coated oral vaccine against these
 serotypes was introduced in 1971 and reduced adenovirus-related respiratory
illness by more than 95% in recruits and thus attenuated outbreaks. Vaccine
production ceased in 1996 for economic reasons, and vaccination
administration was limited to high-risk periods until supplies ran out in 1999. In
1997, a large epidemic of more than 500 cases associated with serotypes 3
and 7 occurred in US Navy recruits. Most recent analyses suggest that
serotype 4 has caused most military outbreaks since 1999, with the exception
of Ad14.9,10
o Adenovirus serotype 14
 Ad14, referred to as the "super cold" in the media, has caused rare
outbreaks of ARD since 1955.
 Between May 2006 and June 2007, 141 cases of Ad14 infection were
reported in clusters in New York, Oregon, Texas, and Washington.
Almost 40% of affected persons were hospitalized, almost half in
intensive care, with a 5% overall mortality rate. The cases in Texas
involved military trainees at Lackland Air Force Base, and subsequent
cases were reported at Lackland, three other Texas military bases, and
one eye culture in a civilian unassociated with the military. Adenovirus
may be isolated from children with whooping cough syndrome in the
presence or absence of Bordetella pertussis infection; however,
whether adenovirus is an etiologic cause of the syndrome remains
unclear.11,12
• Pharyngoconjunctival fever (predominantly serotypes 3, 4, and 7)
o This syndrome most often affects school-aged children. Contagious in nature,
sporadic outbreaks of adenovirus infection occur in small groups, especially
summer camps in the setting of an inadequately chlorinated water source such
as a pool or lake. Interestingly, water sample cultures are often not
confirmatory. Spread occurs via the respiratory route and contact with ocular
secretions during the acute illness.
o The classic presentation is characterized by fever, sore throat, coryza, and red
eyes. Upper respiratory tract symptoms may precede ocular findings or may
be absent.
o Acute conjunctivitis may occur with or without pharyngitis or a respiratory
syndrome. Encephalitis may occur but is rare.
o Conjunctivitis usually begins in one eye and then spreads to the other,
although both eyes may be affected simultaneously. Severe pain is atypical,
but mild pain or discomfort, tearing, pruritus, and morning crusting are
common.
o It usually is self-limited to 5 days (incubation period is 5 d).
o Uncommonly, an exanthem or diarrhea may occur.
• Epidemic keratoconjunctivitis (predominantly serotypes 8, 19, and 37)
o This is highly contagious, with approximately 10% transmission in household
contacts via hands and fomites. Transmission has also been associated with
instrumentation, industrial trauma (shipyard workers [ie, shipyard eye],
welders, airborne particles), contaminated ophthalmic solutions, and the hands
of health care workers.13 Corneal trauma facilitates infection.
o After an 8-day incubation period, an insidious onset of unilateral red eye
occurs, spreading to involve both eyes. Patients have photophobia, tearing,
and pain (indicating corneal involvement). Children may have fever and
lymphadenopathy.
o Malaise and headache are reported.
o Inflammation may persist for weeks, and residual scarring and visual
impairment may occur.
• Acute hemorrhagic cystitis (serotypes 11 and 21)/nephritis
o Acute hemorrhagic cystitis usually affects children aged 5-15 years but may
also affect immunosuppressed adults (eg, from kidney or bone marrow
transplantation, AIDS). Boys are affected more often than girls.
o Dysuria, frequency, and grossly bloody urine are reported. Hematuria is self-
limited to 3 days, and other symptoms resolve later. Symptoms may be more
prolonged in hematopoietic stem cell recipients.
o Nephritis has occurred in recipients of hematopoietic stem cell transplants and
is associated with fever, hematuria, and flank pain.14,15
• Gastroenteritis (most commonly associated with serotypes 40 and 41, but others may
be involved)
o Enteric adenovirus infection is a common cause of infantile diarrhea in the
daycare setting, but less common than rotavirus infection and, in some
settings, less common than infection with astroviruses. It can also affect
adults; in addition, a nosocomial outbreak in a hematology unit has been
reported.16 Adenoviruses replicate readily in the human intestine and may be
cultured from asymptomatic individuals; thus, their presence in the setting of a
diarrheal syndrome may be incidental.
o Many serotypes are fastidious in culture. Serotypes 40 and 41 had been
termed "noncultivatable." However, they have been cultured in the setting of
 diarrheal syndromes using newer cell lines. Monoclonal antibody assays,
enzyme-linked immunosorbent assay, and electron microscopy support the
association of these strains with enteric disease. However, one cannot assume
that enteric disease is limited to these strains. In fact, various serotypes of
adenovirus have been associated with infectious diarrheal syndromes in
recipients of hematopoietic stem cell transplants.
o Fever and watery diarrhea are usually limited to 1-2 weeks.
o Mesenteric adenitis and intussusception have been associated with nonenteric
adenovirus serotypes (ie, types 1, 2, 3, 5, 6). Approximately 40% of infants
with intussusception have positive findings from cultures of stool or mesenteric
lymph nodes for nonenteric serotypes, and most have no evidence of infection
with enteric strains (ie, 40, 41). The role of adenovirus in this setting is unclear.
Mesenteric lymphadenitis or hyperirritable small bowel associated with
nonenteric adenoviral infection has been postulated to lead to intussusception.
However, most patients with intussusception have no evidence of adenoviral
infection (based on culture, serology, or histopathologic viral inclusion
findings); thus, intussusception may be related to multiple etiologies.
• Adenoviral infections in immunocompromised hosts (multiple serotypes)
o Adenovirus is increasingly known to cause disease during the
posttransplantation period in patients who have received hematopoietic stem
cell transplants. Risk factors for adenovirus disease include allogeneic stem
cell transplantation, T-cell depletion and nonmyeloablative conditioning
regimens such as high-dose alemtuzumab (Campath) antibody therapy,
lymphopenia, young age, and graft versus host disease. Prolonged neutropenia
or immunosuppression also enhances the risk of adenoviral infections.
Manifestations may vary but include hemorrhagic cystitis/nephritis,
pneumonitis, hepatitis/liver failure, and gastroenteritis, particularly during the
acute posttransplantation period prior to engraftment. In one series, nephritis
was associated with acute renal failure in more than 90% of patients.
Adenovirus should be considered in patients with a fever, hematuria, flank
pain, and worsening renal function.17,5
o Uncommonly, T-cell immunodeficiency related to HIV infection has been
associated with adenoviral infections, particularly in infants and children
infected with HIV. Pneumonitis and hemorrhagic cystitis are cited most often.
Cholecystitis, severe hepatitis, and liver failure have been reported.18
o Immunosuppression in recipients of solid organ transplants has also been
associated with the above syndromes, as has diffuse adenoviral infection of
the allograft itself. Both allograft loss and recovery have been reported.17
Adenoviral infection following pediatric lung transplantation has been
reported.19
o Importantly, note that a prior history of adenoviral infection in a patient with
recovered immunocompetence may herald recurrence when the patient again
becomes immunosuppressed. A high level of suspicion for adenovirus is
warranted in these cases.
• General considerations
o Pulmonary infiltrates are often diffuse and reticulonodular, but they may be
lobar.
o Hematuria may occur in the setting of nephritis or hemorrhagic cystitis.
o Abnormal transaminase levels, which may be dramatic, may indicate
adenoviral hepatitis.
o Diarrhea may indicate adenoviral gastroenteritis.

Physical

• Acute respiratory disease

o Exudative pharyngitis and conjunctivitis may be seen.
o Pulmonary rhonchi and rales may be found on auscultation.
• Pharyngoconjunctival fever
o Fever, coryza, pharyngitis (may be exudative), follicles in bulbar, and/or
palpebral conjunctivae (typically mild granular appearance) may be observed.
o Cervical lymphadenopathy may be seen.
o Preauricular lymphadenopathy (ie, Parinaud syndrome), with small lymph
nodes palpable just anterior to the ear is not common; however, its presence in
the setting of a viral conjunctivitis is very suggestive of adenovirus infection.
• Epidemic keratoconjunctivitis
o Severe follicular keratoconjunctivitis has been reported (conjunctiva may be
granular). Hemorrhagic conjunctivitis develops in some cases.
o Palpebral edema is a finding.
o Preauricular lymphadenopathy is not common but is a pathognomonic finding
with adenovirus infection.
o Visual haziness or impairment resulting from keratitis or corneal involvement
may develop and may persist for months to years.
• Acute hemorrhagic cystitis/nephritis
o No significant features are described in the setting of hemorrhagic cystitis,
other than evidence of blood in the urine. Fever is generally absent.
o Flank pain and fever are seen in nephritis.
• Gastroenteritis: Patients with severe gastroenteritis may have signs of dehydration.
• Adenoviral infections in immunocompromised hosts: Features include dyspnea, dry
cough, pulmonary rhonchi and rales, grossly bloody urine, and diarrhea