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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, 178,000237,000 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.
some (previously termed moderate in the WHO criteria for the classification of dehydration). Mouth Skin and Thirst Decision Pinch Tongue Moist Drinks Goes Patient has no signs of normally. including at least 1 * slowly slowly sign. The skin pinch may be less useful in patients with marasmus (severe wasting). floppy Condition Well. Assessment of the Patient With Diarrhea for Dehydration Open table in new window [ CLOSE WINDOW ] Table Mouth and Thirst Tongue Normal Prese Moist Drinks nt normally. not thirsty Sunken Abse Dry *Thirsty. some dehydration is present. Tears are relevant signs only for infants and young children. *Goes If the patient has 2 or drinks back more signs.Dehydration can develop with remarkable rapidity. Table 1. including at least 1 * sign. Very dry *Goes *Goes If the patient has 2 or more back very back very signs. floppy Very Abse sunken nt and dry If the patient has 2 or more signs. other signs for severe dehydration include absent radial pulse and low blood pressure. Very dry *Goes *Goes If the patient has 2 or more back very back very signs. not quickly thirsty Dry *Thirsty. In adults and children older than 5 years. within hours after the onset of symptoms. including at least 1 eagerly slowly * sign. severe dehydration is present. . or obesity. and wrinkled ("washer woman") hands. This contrasts with disease produced by infection from any other enteropathogen. nt drinks eagerly Eyes Tear s Very Abse sunken nt and dry Tear s Skin Pinch Goes back quickly *Goes back slowly Condition Well. 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. severe dehydration is present. water loss is proportional between 3 body compartments. and none (previously termed mild by the WHO). kwashiorkor (severe malnutrition with edema). some dehydration is present. *Restless. Table 1 shows the clinical findings associated with the classification. Intracellular and intravascular dehydration is manifested in decreases skin turgor. irritable *Lethargic or unconscious. alert Decision Patient has no signs of dehydration. alert Eyes Normal Prese nt *Restless. irritable Sunken Abse nt *Lethargic or unconscious. and interstitial. including at least 1 * slowly slowly sign. Because the dehydration is isotonic. intravascular. Physical Dehydration Dehydration has been classified into the following 3 categories to facilitate patient treatment: severe. sunken eyes. back dehydration.
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. man and water. exhaustion of glycogen stores. hypoglycemia is the most common lethal complication of cholera in children.Decreased intravascular volume is manifested by tachycardia. accumulation of lactate because of diminished perfusion of peripheral tissues. 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. and hyperphosphatemia. Hypoglycemia is a result of diminished food intake during the acute illness. Children have decreased skin turgor. Hypokalemia is most severe in children with preexisting malnutrition who have diminished body stores of potassium and may be manifested as paralytic ileus. and spontaneous titanic contractions can occur. Hypokalemia develops only after the acidosis is corrected and intracellular hydrogen ion is exchanged for extracellular potassium. epidemic. Such secondary spread commonly occurs in households but can also occur in clinics or hospitals where patients with cholera are treated. Rehydration therapy with bicarbonate-containing fluids can also produce hypocalcemia by decreasing the proportion of serum calcium that is ionized. Secondary transmission occurs through fecal-oral spread of the organism through person-toperson contact or through contaminated water and food. and changes in interstitial and intracellular volume are the primary manifestations of illness. Acidemia occurs when respiratory compensation is unable to sustain a normal blood pH. cardiac output and vascular resistance are normal. despite severe total body potassium depletion. Hypokalemia results from potassium loss in the stool. In these patients. with a mean potassium concentration of approximately 30 mmol/L. Risk of primary infection is facilitated by seasonal increases in the number of organisms. Because of the existing acidosis. Certain environmental and host factors appear to play a role in the spread of V cholerae. Primary infection in humans is incidentally acquired. V cholerae is rarely isolated from animals. as manifested by prolonged skin tenting in response to a skin pinch (the most reliable sign of isotonic dehydration). possibly associated with changes in water temperature and algal blooms. Acidosis in cholera is a result of bicarbonate loss in stools. Chvostek and Trousseau signs are often present. Infection rates predictably are highest in communities in which water is not potable and personal and community hygiene standards are low. Metabolic and systemic manifestations After dehydration. and animals do not play a role in transmission of disease. Children with some (moderate) dehydration have lost approximately 7-10% of body water (approximately 5% of body weight). and defective gluconeogenesis secondary to insufficient stores of gluconeogenic substrates in fat and muscle. Children without clinically significant dehydration (<5% loss of body weight) may have increased thirst without other signs of dehydration. Host susceptibility factors that may affect the course of infection with V cholerae O1 . and hypotension. Environmental factors V cholerae is a saltwater organism. and its primary habitat is the marine ecosystem where it lives in association with plankton. and a normal pulse. however. absent or barely palpable peripheral pulses. or a pandemic disease. Causes Cholera can be an endemic. children often have normal serum potassium concentrations when first observed. Cholera has 2 main reservoirs.
Co-chair. For the same reason. MD. Principal Investigator. crowding. Chest Clinic. also known as enteric fever.2 Transmission S typhi has no nonhuman vectors. the patient's level of consciousness is truly clouded.000 organisms causes infection in more than 50% of healthy volunteers. Roberto Corales. 2010 Introduction Background Typhoid fever. vagotomy. intestinal hemorrhage. Attending Physician. Survivors may be left with long-term or permanent neuropsychiatric complications. diffuse abdominal pain. Chief. AIDS Community Health Center. In the advanced stages of typhoid fever. Asymptomatic carriers: This may have a role in transfer of disease in areas where the disease is not endemic. Rates are lower in areas where infection is endemic and if there are preexisting vibriocidal antibodies from previous encounters with the organism. Department of Medicine. The Cleveland Clinic Foundation Contributor Information and Disclosures Updated: Apr 8. 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. DO. gastric surgery. an ethereal smoke or cloud that was believed to cause disease and madness. Lawrence Memorial Hospital. O blood group: The role played by O blood group is less certain. thriving in conditions of poor sanitation. The following are modes of transmission: • • • Oral transmission via food or beverages handled by an individual who chronically sheds the bacteria through stool or. Cambridge Health Alliance Coauthor(s): Thomas Garvey. 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. JD. but incidence of infection appears to be twice as high in this population. is a potentially fatal multisystemic illness caused primarily by Salmonella typhi. MD.4 . Co-director of Infectious Disease Fellowship Program. The classic presentation includes fever. and social chaos. The cause is unknown. Medical Director.1 The name S typhi is derived from the ancient Greek typhos. obtundation. it remains endemic in developing countries. Although carriage usually is short-lived. and second infections rarely occur or are mild. adults are symptomatic less frequently than children. Untreated. It may have responsible for the Great Plague of Athens at the end of the Pelopennesian War.The following may affect the course: • • • • • Malnutrition Hydrochlorhydria or achlorhydria of any cause (including Helicobacter pylori infection. less commonly. Assistant Professor of Medicine. Previous exposure and acquired immunity: Infection rates of household contacts of cholera patients range from 20-50%. and death within one month of onset. Although antibiotics have markedly reduced the frequency of typhoid fever in the developed world. Steven K Schmitt. typhoid fever is a grueling illness that may progress to delirium. a few individuals may excrete the organisms for a prolonged period. Department of Medicine and Infectious Disease Service. Lemuel Shattuck Hospital. S typhi has been a major human pathogen for thousands of years. The protean manifestations of typhoid fever make this disease a true diagnostic challenge. MD. FACP. Department of Infectious Disease. and constipation. Medical Affiliated Services. malaise. Consulting Staff. Medical Advisory Committee for the Elimination of Tuberculosis. especially in adults. bowel perforation. Harvard Medical School. Typhoid Fever Author: John L Brusch.
The result is that the organism re-enters the gastrointestinal tract in the bile and reinfects Peyer patches.2 Risk factors S typhi are able to survive a stomach pH as low as 1. gastrectomy. it is probably minor. PARK2 and PACGR code for a protein aggregate that is essential for breaking down the bacterial signaling molecules that dampen the macrophage response. Macrophages and intestinal epithelial cells then attract T cells and neutrophils with interleukin 8 (IL-8). Antacids. 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. Afterward. The fimbriae of S typhi bind in vitro to cystic fibrosis transmembrane conductance receptor (CFTR). 35.6 In contrast to the nontyphoidal salmonellae. just as malaria maintains sickle cell disease in Africa. which then pass them through the mucosa and present them to the macrophages in the lamina propria.Pathophysiology All pathogenic Salmonella species are engulfed by phagocytic cells. and lymph nodes. Nontyphoidal salmonellae are phagocytized throughout the distal ilium and colon. With toll-like receptor (TLR)–5 and TLR-4/MD2/CD-14 complex. Frequency United States Since 1900. In 2006.994 cases of typhoid fever were reported. improved sanitation and successful antibiotic treatment have steadily decreased the incidence of typhoid fever in the United States. If an association exists.13.5 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. as members of this cohort often come to the United States for higher degrees.9. sharing food from the same plate. proton pump inhibitors.10.16 American clinicians should keep this in mind.6 HIV/AIDS is clearly associated with an increased risk of nontyphoidal Salmonella infection. The homozygous F508del mutation in CFTR is associated with cystic fibrosis. Bacteria that do not reinfect the host are typically shed in the stool and are then available to infect other hosts. however. the main relay point for macrophages traveling from the gut into the lymphatic system. the bacteria induce macrophage apoptosis. living in the same household with someone who has new case of typhoid fever. S typhi enters the host's system primarily through the distal ilium. S typhi has a Vi capsular antigen that masks PAMPs. typhoid fever may contribute to evolutionary pressure that maintains a steady occurrence of cystic fibrosis.6. which is expressed on the gut membrane. Two to 5% of white persons are heterozygous for the CFTR mutation F508del. there were 314.12 As the middle class in south Asia grows. causing inflammation and suppressing the infection. . Polymorphisms in their shared regulatory region are found disproportionately in persons infected with Mycobacterium leprae and S typhi.5.6 The gallbladder is then infected via either bacteremia or direct extension of S typhi –infected bile. In 1920. drinking unpurified water. washing the hands inadequately.5. These risk factors often also predispose to other intracellular pathogens. the data and opinions in the literature as to whether this is true for S typhi infection are conflicting. For instance.12 On the other hand. Thus. S typhi has specialized fimbriae that adhere to the epithelium over clusters of lymphoid tissue in the ilium (Peyer patches). Once there. bone marrow. protective host mutations also exist. avoiding neutrophil-based inflammation. histamine-2 receptor antagonists (H2 blockers). macrophages recognize pathogen-associated molecular patterns (PAMPs) such as flagella and lipopolysaccharides.15. which is associated with a decreased susceptibility to typhoid fever. breaking out into the bloodstream to invade the rest of the body. The bacteria then induce their host macrophages to attract more macrophages. and achlorhydria decrease stomach acidity and facilitate S typhi infection.8. spleen. and living in a household that does not have a toilet. the S typhi bacteria pause and continue to multiply until some critical density is reached.11 Other risk factors for clinical S typhi infection include various genetic polymorphisms.14 Environmental and behavioral risk factors that are independently associated with typhoid fever include eating food from street vendors. as well as to cholera and tuberculosis.
10. it has few long-term sequelae and a 0. most cases of typhoid fever arise in international travelers. and Oceania. The presentations in these age groups may be atypical.2 Mortality/Morbidity With prompt and appropriate antibiotic therapy.6 per 1.17 Age Most documented typhoid fever cases involve school-aged children and young adults.2. the notorious gastrointestinal manifestations of the disease develop. Laos.18 Within those countries. Monocytic infiltration inflames Peyer patches and .7. The case fatality rate in the United States in the pre-antibiotic era was 9%-13%.16.17 International Typhoid fever occurs worldwide. China. Indonesia.1. but 80% of cases come from Bangladesh.17 Untreated typhoid fever is a life-threatening illness of several weeks' duration with long-term morbidity often involving the central nervous system. Classic typhoid fever syndrome Typhoid fever begins 7-14 days after ingestion of S typhi. only 17% of cases acquired domestically were traced to a carrier. Remarkably.6 million people (incidence of 3. The peaks and troughs rise progressively over time. 79% of typhoid fever cases occurred in patients who had been outside of the country within the preceding 30 days. Sex Fifty-four percent of typhoid fever cases in the United States reported between 1999 and 2006 involved males.2% risk of mortality. and the S typhi infection may go unrecognized. Pakistan.3 Africa . typhoid fever is typically a short-term febrile illness requiring a median of 6 days of hospitalization. the true incidence among very young children and infants is thought to be higher.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).000 population) and kills an estimated 200. or Vietnam.20 Race Typhoid fever has no racial predilection. The fever pattern is stepwise. Two thirds of these individuals had just journeyed from the Indian subcontinent.0 Western Hemisphere outside Canada/United States . Treated.5 India . in some cases. fierce colicky right upper quadrant pain. typhoid fever is most common in underdeveloped areas. Typhoid fever is endemic in Asia. ranging from a mild febrile illness to severe convulsions. These include diffuse abdominal pain and tenderness and. 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. Nepal.Between 1999 and 2006. Typhoid fever infects roughly 21. However. Over the course of the first week of illness. India. the Caribbean.000 people every year.89 (122 in 2006) Total (for all countries except Canada/United States) .19 In the United States. characterized by a rising temperature over the course of each day that drops by the subsequent morning.6 Asia . Africa. 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. primarily in developing nations whose sanitary conditions are poor. The average yearly incidence of typhoid fever per million travelers from 1999-2006 by county or region of departure was as follows:17 • • • • • • Canada . Latin America.
maculopapules usually 1-4 cm wide and fewer than 5 in number. Weight loss and debilitating weakness last months. Atypical manifestations of typhoid fever include isolated severe headaches that may mimic meningitis. delirium. Abdominal distension is severe. If the individual survives to the fourth week. Intestinal and neurologic complications may still occur in surviving untreated individuals. severe jaundice. In addition. these generally resolve within 2-5 days.2 At approximately the end of the first week of illness. the fever. and one third of immunocompetent adults who develop typhoid fever develop diarrhea rather than constipation. mental state.25 meningitis. gallbladder cancer (RR=167. typhoid fever is generally more apt to cause diarrhea than constipation. Some patients experience foul. osteomyelitis. the fever has a steady insidious onset. long-term neurologic sequelae (extremely rare). dull frontal headache. Other unusual complications include pancreatitis. especially in India and Africa. which is characterized by apathy. The individual may descend into the typhoid state. The abdomen becomes distended. Necrotic Peyer patches may cause bowel perforation and peritonitis.narrows the bowel lumen. 3%-4% chronic carriers. In most contemporary presentations of typhoid fever.29. which are salmon-colored. Relative bradycardia and dicrotic pulse (double beat. in some localities. and the infecting bacterial strain.24. in extremely rare cases. and soft splenomegaly is common.2 Table 1. Some survivors become asymptomatic S typhi carriers and have the potential to transmit the bacteria indefinitely. and abdominal distension slowly improve over a few days. This complication is often unheralded and may be masked by corticosteroids. The timing of the symptoms and host response may vary based on geographic region.23. carriers) Very Very common commona Very rareb Almost allc Uncommon Almost all Very common Almost all Almost Typhoid . the second beat weaker than the first) may develop. myocarditis. truncal.28. the still febrile individual grows more toxic and anorexic with significant weight loss.22 During the second week of illness. Young children. and an increasingly stuporous malaise. and abscesses anywhere on the body. liquid diarrhea (pea soup diarrhea). green-yellow. At this point. The individual then develops a dry cough. causing constipation that lasts the duration of the illness. blanching. and the patient is tachypneic with a thready pulse and crackles over the lung bases. overwhelming toxemia.2. or fever alone.16. or intestinal hemorrhage may cause death. acute lobar pneumonia. the signs and symptoms listed above progress. urinary symptoms. The stepladder fever pattern that was once the hallmark of typhoid fever now occurs in as few as 12% of cases.30 Open table in new window [ CLOSE WINDOW ] Table Incubat Week 1 ion Systemic Stepladder fever pattern or insidious onset fever Acute high fever Chills Rigors Anorexia Diaphoresis Neurologic Malaise Week 2 Week 3 Week 4 Recovery phase or death (15% of untreated cases) Post 10%-20% relapse.2 These are bacterial emboli to the dermis and occasionally develop in persons with shigellosis or nontyphoidal salmonellosis. present primarily with neurologic manifestations such as delirium or.26. the fever plateaus at 103-104°F (3940°C). individuals with AIDS.27. confusion. isolated arthralgias. orchitis. parkinsonian symptoms or Guillain-Barré syndrome. Incidence and Timing of Various Manifestations of Untreated Typhoid Fever2. In the third week.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. Some patients. race factors. The patient develops rose spots. and even psychosis. The conjunctivae are infected.
Insomnia Confusion/delirium Psychosis Catatonia Frontal headache (usually mild) Meningeal signs Parkinsonism Ear. 3%-4% of untreated chronic carriers. nose. Very common usually trace Rare Common Common Very rare Common Common (pea soup) intestinal perforation Hepatosplenomegaly Jaundice Gallbladder pain 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 rare Incubat Week 1 ion Systemic Stepladder fever Very pattern or insidious commona Extreme Extremely ly rare rare Week 2 Week 3 Week 4 Post Very common Recovery phase 10%-20% or death (15% relapse. and throat Coated tongue Sore throatf Pulmonary Mild cough Bronchitic cough Rales Pneumonia Cardiovascular Dicrotic pulse Myocarditis Pericarditis Thrombophlebitis Gastrointestinal Constipation Diarrhea Bloating with tympany Diffuse mild abdominal pain Sharp right lower quadrant pain Gastrointestinal hemorrhage all state (common) Very commo n Commond Very commo n Very rare Commo n Very rare Very common Raree Rare Very rare Very common Common Common Common Rare Rare (lobar) Rare Common Rare Extremely rareg Common (basal) Very rare Very common Rare Very common (84%) 30 Very common Rare Very rare. .
and throat Coated tongue Sore throatf Pulmonary Mild cough Bronchitic cough Rales Pneumonia Cardiovascular Dicrotic pulse Myocarditis Pericarditis Thrombophlebitis Gastrointestinal Constipation Diarrhea Bloating with tympany Diffuse mild abdominal pain Sharp right lower quadrant pain Gastrointestinal hemorrhage Common Common Common Rare Rare (lobar) Rare Common Rare Extremely rareg Common (basal) Very rare Very common Rare Very common (84%) 30 Very common Rare Very rare. carriers) Confusion/delirium Psychosis Catatonia Frontal headache (usually mild) Meningeal signs Parkinsonism Ear.onset fever Acute high fever Chills Rigors Anorexia Diaphoresis Neurologic Malaise Insomnia cases) Very rareb Almost allc Uncommon Almost all Very common Almost all Almost Typhoid all state (common) Very commo n Commond Very commo n Very rare Commo n Very rare Very common Raree Rare Very rare Very common long-term neurologic sequelae (extremely rare). Very common usually trace Rare Common Common Very rare Common Common (pea soup) intestinal perforation Hepatosplenomegaly Jaundice Gallbladder pain 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 . nose. gallbladder cancer (RR=167.
cardiac. Department of Internal Medicine. MD. e Rare: Symptoms occur in 5%-35% of cases. or water or on the contaminated hands of food handlers. resulting in trophozoites (invasive form).Miscellaneous Abscess (anywhere) Extremely Extreme Extremely rare ly rare rare a Very common: Symptoms occur in well over half of cases (approximately 65%-95%). genitourinary. Amebic liver abscess is the most common manifestation of invasive amebiasis. Consulting Staff. In 1913. amebiasis primarily affects migrants from and travelers to endemic regions. d Common: Symptoms occur in 35%-65% of cases. Petersburg. Fecal-oral transmission can also occur in the setting of anal sexual practices or direct rectal inoculation through colonic irrigation devices. MD. c Almost all: Symptoms occur in almost all cases. g Extremely rare: Symptoms have been described in occasional case reports. Professor. Upon colonization of the colonic mucosa. secretory bloody diarrhea. MSc. Walker and Sellards documented the cyst as the infective form of E histolytica. Very rare: Symptoms occur in less than 5% of cases. Any delay in treatment increases the likelihood of complications and recovery time. the trophozoites can spread hematogenously via the portal circulation to the liver or even to more distant organs. men who have sex with men. leading to tissue destruction. Excystation then occurs in the terminal ileum or colon. In addition. cysts can be found in fecally contaminated soil. Although most cases of amebiasis are asymptomatic. including pleuropulmonary. 2009 Introduction Background Amebiasis is caused by Entamoeba histolytica. and cutaneous sites. and immunosuppressed or institutionalized individuals. in the Philippines. dysentery and invasive extraintestinal disease can occur. Department of Medicine. a protozoan found worldwide. but other organs can also be involved. Division of Infectious Diseases. Sir William Osler reported the first North American case of amebiasis. Fellow in Infectious Diseases. cerebral. MD. Division of Infectious Diseases. Amebic infection was first described by Fedor Losch in 1875 in St. renal. Russia. Methodist Healthcare of Memphis. University of Tennessee College of Medicine. the disease begins to remit after about 2 days. Viable in the environment for weeks to months. University of Tennessee at Memphis Coauthor(s): Kerry O Cleveland. J Robert Cantey. Humans and perhaps nonhuman primates are the only natural hosts. Medical University of South Carolina Contributor Information and Disclosures Updated: Feb 9. b Treated typhoid fever If appropriate treatment is initiated within the first few days of full-blown illness. The life cycle was then established by Dobell in 1925. The species name E histolytica was first coined by Fritz Schaudin in 1903. In 1890. In developed countries. when he observed amebae in stool and abscess fluid from a physician who previously resided in Panama. Amebiasis Author: Alexandre Lacasse. and the patient's condition markedly improves within 4-5 days. and colitis resembling inflammatory bowel disease. The highest prevalence of amebiasis is in developing countries where barriers between human feces and food and water supplies are inadequate. nonflagellated protozoal parasite that causes proteolysis and tissue lysis (hence its name) and can induce host-cell apoptosis. f Blank cells: No mention of the symptom at that phase was found in the literature. fertilizer. the trophozoite may encyst and is then excreted in the feces or may invade the intestinal mucosal barrier and gain access to the blood . Associate Professor of Medicine. E histolytica is transmitted via ingestion of the cystic form (infective stage) of the protozoa. Pathophysiology E histolytica is a pseudopod-forming. Ingestion of E histolytica cysts from the environment is followed by excystation in the terminal ileum or colon to form highly motile trophozoites. The trophozoites can penetrate and invade the colonic mucosal barrier.
1.11 Frequency United States The overall prevalence of amebiasis is approximately 4%. Cytolysis can be undertaken by amoebapores. Entamoeba dispar. Egypt).stream and disseminate to the liver. 10% of individuals returning with diarrhea were found to have amebiasis. certain groups are predisposed to amebic colitis.1.2 A mucosal immunoglobulin A (IgA) response against this lectin can result in fewer recurrent infections. a membrane inhibitor of the C5b-9 attack complex in human red blood cells. and other sites. trophozoites induced apoptosis via a non-Fas and non–tumor necrosis factor-α1 receptor pathway.1 The genus Entamoeba contains many species. Africa.8. 3 mo). approximately 20%-30% of men who have sex with men are colonized with E dispar. can also induce apoptosis. including IL-1B.11 However. asymptomatic E dispar and E histolytica infections are equally prevalent. 33% of cases were reported in Hispanic immigrants and 17% in immigrants from Asia or the Pacific Islands. some of which (ie. a family of peptides capable of forming pores in lipid bilayers. In Egypt.7 Epithelial cells also produce various inflammatory mediators. the only Entamoeba species definitely associated with disease. leading to the attraction of neutrophils and macrophages.12 Asymptomatic E histolytica infections seem to be regiondependent. Entamoeba coli. but the processes of encystation and excystation are poorly understood. but recent molecular techniques established them as two different species. and Asia.11 Mortality/Morbidity . 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. Entamoeba polecki.9 Corticosteroid therapy is known to worsen the clinical outcome. E histolytica is. Since the introduction of molecular techniques.1 Amebic liver abscess has been reported in travel exposures as short as 4 days (median. Entamoeba hartmanni) can reside in the human interstitial lumen. 38% of individuals presenting with acute diarrhea to an outpatient clinic were found to have amebic colitis. suggesting that E histolytica are able to kill hepatocytes without direct contact. suggested by the finding that a region of the GAL/GalNAc–specific lectin showed antigenic crossreactivity with CD59. However. whereas amebic colitis is uncommon in short-term travelers. cleaving IL-1 precursor to its active form. Entamoeba moshkovskii. which appears to be 10 times more common than E histolytica. in animal models of liver abscess. thus far.3 Both lytic and apoptotic pathways have been described. The prevalence of Entamoeba infection is as high as 50% in areas of Central and South America.4 The amoebapores. International Entamoeba species infect approximately 10% of the world's population. Travelers to endemic areas are at risk for infection.5 The cysteine proteinases can also cleave and inactivate the anaphylatoxins C3a and C5a. could be inhibited directly by the trophozoites. and malnourished individuals. including very young patients. with E dispar being commensal (including in patients with HIV infection) and E histolytica pathogenic. it is estimated that 500 million individuals with Entamoeba infection are colonized by E dispar.6. Disease may be caused by only a small number of cysts. at sublytic concentrations. as well as IgA and immunoglobulin G (IgG). The adherence of trophozoites to colonic epithelial cells seems to be mediated by a galactose/N -acetylgalactosamine (GAL/GalNAc)–specific lectin. including the complement system. and cyclooxygenase-2. as high as 11% in Brazil.1 In 1993. Additional host defenses. Brazil. in certain regions (eg. lung.1 Furthermore.1 E histolytica seroprevalence studies in Mexico revealed that more than 8% of the population were positive. the others are considered nonpathogenic.1 In Western countries. IL-8. a total of 2970 cases of amebiasis were reported to the Centers for Disease Control and Prevention (CDC). pregnant women. recipients of corticosteroids.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.11 More recent studies have recovered E dispar and E moshkovskii from patients with gastrointestinal symptoms. it is now estimated that many individuals with Entamoeba infections are colonized with E dispar. Excreted cysts reach the environment to complete the cycle. E histolytica. possibly because of its blunting effect on this innate immune response.11 E dispar and E histolytica cannot be differentiated by direct examination.11 In fact. but a causal relationship is undetermined.
Cerebral amebiasis o Occurring in 0. with a predominance among men aged 18-50 years. and respiratory distress may be clues to rupture through the diaphragm. o Only approximately 10-30% of patients with amebic colitis develop fever. Amebic colitis evolves to fulminant necrotizing colitis or rupture in approximately 0. only 4%-10% of individuals with asymptomatic amebiasis who were monitored for one year eventually developed colitis or extraintestinal disease. Jaundice is unusual.000-100. The combined prevalence of amebic colitis and amebic liver abscess is estimated at 40-50 million cases annually worldwide. with concomitant weight loss and anorexia. Amebic liver abscess o The most typical presentation of amebic liver abscess is fever. pregnancy. pleuritic chest pain. leading to a higher mortality rate. in such cases. especially in children. abdominal pain. o Rectal bleeding without diarrhea can occur. and very young age.000 deaths. and mental status change should prompt rapid investigation for CNS involvement. o Fulminant or necrotizing colitis usually manifests as severe bloody diarrhea and widespread abdominal pain with evidence of peritonitis and fever. o A more subacute presentation can be seen. Alcohol may also been an important risk factor. corticosteroid use.1 Amebic liver abscess is 7-12 times more common in men than in women. o Weight loss and anorexia may occur. as the prevalence of amebic liver abscess is also increased among postmenopausal women. The reason for this sexual disparity is unknown. • • Amebic colitis affects both sexes equally. . resulting in 40.1. o Sixty to 70% of patients with amebic liver abscess do not have concomitant colitis. the mortality rate jumps to greater than 40%. HIV seropositivity is a risk factor for invasive extraintestinal amebiasis.11. vomiting. abrupt onset of nausea.1 Race • Sex In Japan and Taiwan. headache. However. Nevertheless. o Cough can occur. o A history of alcohol abuse is common.13 Asymptomatic intestinal amebiasis occurs in 90% of infected individuals. o Predisposing factors for fulminant colitis include poor nutrition. and tenderness of less than 10 days’ duration. a rare but serious complication of amebic liver abscess.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. although a history of dysentery within the previous year may be obtained. o Unlike amebic colitis. right upper quadrant pain. but a clear causal relationship is unclear.9%-9. and tenderness spanning several weeks’ duration. The sexual distribution is equal in children.6% of amebic liver abscess cases. amebic liver abscess is complicated by sudden intraperitoneal rupture in 2-7% of patients.1%.• • • • Amebiasis is second only to malaria in terms of protozoa-associated mortality.5% of cases. o Acute abdominal symptoms and signs should prompt rapid investigation for intraperitoneal rupture. Pleuropulmonary amebiasis: Cough. although hormonal effects may be implicated.11 Case fatality rates associated with amebic colitis range from 1. o Amebic liver abscess may manifest years after travel to or residency in an endemic area.15 This has not been observed elsewhere. amebic liver abscess is associated with fever in 85-90% of cases.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.
Department of Emergency Medicine. which can cause colitis and other extraintestinal manifestations. DTM&H. Infective cysts can be found in fecally contaminated food and water supplies and contaminated hands of food handlers. 2009 Introduction Background Dengue. William H Shoff. • • 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. and herd immunity contribute to the control of these epidemics. This syndrome is termed dengue hemorrhagic fever (DHF). which may cause death. MD.2 Some patients with dengue hemorrhagic fever develop shock (dengue shock syndrome [DSS]). 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. Dengue is transmitted by mosquitoes of the genus Aedes. although dengue vasculopathy has been proposed as a better term. Associate Residency Director. Department of Emergency Medicine. Transmission appears to begin in urban centers .1 may result in a nonspecific febrile illness. family Flaviviridae. especially in the setting of oral-anal practices.o Physical Progression can be very rapid. a greater fatality risk than bleeding per se. changes in weather. Department of Emergency Medicine. which are widely distributed in subtropical and tropical areas of the world. Dengue Fever Author: Suzanne Moore Shepherd. PENN Travel Medicine Coauthor(s): Patrick B Hinfey. Initial dengue infection may be asymptomatic (50%-90%). Sexual transmission is possible. Newark Beth Israel Medical Center. explosive transmission can occur. DTM&H. including liver abscess (most common) and pleuropulmonary. Director of Education and Research. 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. or may produce the symptom complex of classic dengue fever (DF). MD. with an infection incidence of 25%-50%. E histolytica is transmitted primarily through the fecal-oral route. is caused by infection with 1 of the 4 serotypes of dengue virus. cardiac. genus Flavivirus (single-stranded nonsegmented RNA viruses). MS. Mosquito-control efforts. Director. and is classified as a major global health threat by the World Health Organization (WHO). Epidemic dengue transmission occurs when dengue virus is introduced into a region as an isolated event that involves a single viral strain. Hospital of the University of Pennsylvania. FACEP. the most common arboviral illness transmitted worldwide. FAAEM. If the number of vectors and susceptible pediatric and adult hosts is sufficient. Dengue virus transmission follows two general patterns—epidemic dengue and hyperendemic dengue. including gastrointestinal bleeding. as fluid loss into tissue spaces can lead to prolonged shock and complications. Hospital of the University of Pennsylvania Contributor Information and Disclosures Updated: Oct 23. distension. and cerebral dissemination. PENN Travel Medicine. Associate Professor. Associate Professor. MD.
000 cases of dengue shock syndrome. A pattern developed in which dengue fever epidemics occurred with increasing frequency and were associated with occasional dengue hemorrhagic fever cases. and 158 reported deaths. Dengue transmission spread from Southeast Asia into surrounding subtropical and tropical Asian countries. The epidemiology of dengue fever in Africa is more poorly characterized. Nepal has not reported dengue transmission. and the Cook Islands. areas of Asia where the virus has reemerged. Travelers to these areas are more likely to be infected than are travelers to areas that experience only epidemic transmission. A aegypti mosquitoes repopulated most of the countries in which they had been eliminated. Currently. Probable outbreaks of dengue fever occurred sporadically every 10-30 years until after World War II. 9 countries reported dengue outbreaks. and the Philippines. more than 50% of deaths have occurred in individuals older than 15 years. This may be explained by a genetic factor in these populations. and all deaths occurred in patients older than 5 years. Malaysia.000 cases of dengue hemorrhagic fever. After that. northeastern Australia. with major outbreaks occurring approximately every 3 years. This pattern has repeated itself as dengue fever has spread to new regions. India. Although initial epidemics were located in urban areas. Dengue continues to extend its range. antibody prevalence increases with age and most adults are immune. Serotype 1 dengue (DENV-1) was introduced into a largely susceptible population in Cuba in 1977. Palau. In the Americas. In these populations. Pakistan. outbreaks of dengue fever became more common. Outbreaks of febrile illnesses compatible with dengue fever have been recorded throughout history. Systematic spraying was halted in the early 1970s because of environmental concerns. Since 1982 in Singapore.and then spreads to the rest of a country. with hundreds of thousands of cases of dengue in both children and adults. an estimated 60. Several of these countries had not previously reported dengue. despite the fact that all 4 dengue serotypes circulate in the continent. Benjamin Rush. young adults in Jakarta and provincial areas make up a larger percentage of infected patients. Thailand. Eventually. and many had not reported dengue in 20 years. The socioeconomic disruptions caused by World War II resulted in increased worldwide spread of dengue viruses. Aedes aegypti is present in a large portion of the Middle East and sub-Saharan Africa. the Indian subcontinent and Sri Lanka. with Indonesia reporting the majority of dengue hemorrhagic fever cases. published an account of a probable dengue fever epidemic that had occurred in Philadelphia in 1780. MD. Rush coined the term breakbone fever to describe the intense symptoms reported by one of his patients. In 1789. By the 1990s. with only mild disease reported.3 This is the current pattern of transmission in parts of Africa and South America. Tonga. 10. Hyperendemic transmission appears to be a major risk for dengue hemorrhagic fever. Of interest and significance in prevention and control.000 persons were infected with dengue. In the 1950s. 24. Dengue fever is present in 19 countries on the African continent. New Guinea. During the 2000 epidemic in Bangladesh. and several Pacific islands. 3 surveillance studies in Asia report an increasing age among infected patients and increasing mortality rate. dengue epidemics were rare postwar because Aedes mosquitoes had been eradicated from most of the region through coordinated vector-control efforts. Dengue fever–like illnesses were described in Chinese medical writings dating back to 265 AD. The first dengue hemorrhagic fever epidemic in the Americas occurred in Cuba in 1981 and involved serotype 2 dengue (DENV-2). Of note. the Philippines. The only continents that do not experience dengue transmission include Europe and Antarctica. and down the island nations of Malaysia. increased dengue spread has involved suburban and rural locales in Asia and Latin America. dengue hemorrhagic fever is one of the leading causes of hospitalization and death in children in many Southeast Asian countries. including Tahiti. Subsequently. . dengue hemorrhagic fever epidemics occurred yearly. no major dengue hemorrhagic fever epidemics have occurred in Africa. In Indonesia. and small island nations. The first epidemic of dengue hemorrhagic fever was described in Manila in 1953. In a 1993 epidemic in the Comoros. the geographic distribution includes more than 100 countries worldwide. with the first epidemic described in 1635 in the West Indies. Serosurveys indicated that more than 44% of the population was infected. Hyperendemic transmission is reported in Vietnam. This is the predominant pattern of global transmission. up to 82% of hospitalized patients were adults. Indonesia. 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. southern China and southern Taiwan. today. Travelers to these areas are at increased risk of acquiring dengue during these periods of epidemic transmission. dengue hemorrhagic fever epidemics occurred every few years.
A aegypti has also been reported sporadically in portions of North Carolina.6. Bhutan. and dengue shock syndrome and dengue hemorrhagic fever were seen only in adults who had previously been infected with DENV-1 in 1977. Factors believed to be responsible for the spread of dengue include explosive population growth. In 2001-2002. Colombia. reports of dengue infections in long-term expatriates.5 Over the past decade. the Galapagos. viral serotypes: dengue virus 1 (DENV-1). A aegypti is abundant year-round in most countries in the Caribbean basin. Hong Kong. Guadeloupe. and mid to south Florida. dengue does occur in several overseas territories of European Union members. and Hawaii. Unplanned urbanization is believed to have had the largest impact on disease amplification in individual countries. and the Cayman Islands. Easter Island.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 . As such. Two competent vectors. poor standing water and vector control. and increased international recreational. aid workers. A aegypti is present in all countries in South America except Chile. Curacao. However. is now found in limited areas of Brazil. Asian genotype DENV-2 was reintroduced. The outbreak involved 2 variants of DENV-1 that were transmitted by A albopictus. dengue fever and dengue hemorrhagic fever cases have progressively increased. Since 2000. Arkansas. Cuba. Carriers of the virus were believed to have crossed the border from Mexico. including Nepal. unplanned urban overpopulation with inadequate public health systems. the US Virgin Islands. A aegypti and A albopictus.5 Pathophysiology Dengue infection is caused by 1 of 4 related. More recent studies have not supported an earlier suggestion that climate change is also directly responsible for increased transmission. Colombia.In 1997. South Carolina.495) in the Americas since 1985. Georgia.1. and Martinique. and Venezuela report the most cases of dengue and dengue hemorrhagic fever. Maryland. Alabama. the local vector population was then infected. Louisiana. Since then. whereas travel is believed to have had the largest impact on global spread. In recent decades.3.4. Cuba. The range of A albopictus extends almost as far north as the Great Lakes. Hyperendemic circulation of all 4 dengue serotypes is present in the northern countries of South America.7. the Dominican Republic. Arizona. with low-level transmission occurring year-round but with most occurring during periods of epidemic transmission. viral evolution. the Dominican Republic. Hawaii experienced its first outbreak of dengue since World War II ended. Tennessee.000 cases in 2002). at least 8 areas previously without dengue have reported outbreaks. Such sentinel travel surveillance can augment global and national public health surveillance. but antigenically distinct. The Pan American Health Organization (PAHO) reported that 2007 saw the highest number of dengue fever and dengue hemorrhagic fever cases (918. Brazil (700. Macau. Significant outbreaks of dengue have been reported in 2005 and 2006 in Puerto Rico. 122 cases of dengue fever spread slowly on Maui. Honduras. Bolivia.5 Since then. El Salvador. In 1986. seasonal autochthonous infection has been reported in both Texas and Hawaii. immigrants. New Mexico. 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. All of these factors must be addressed to control the spread of dengue and other mosquito-borne infections. dengue virus 2 (DENV-2). military personnel. originally from Asia. Predominantly affecting young adults and adults. Mexico. Since many cases of dengue in US citizens are due to endemic transmission in some US territories. including Texas. business. and dengue virus 4 (DENV-4). the Centers for Disease Control and Prevention (CDC) currently conducts laboratory-based surveillance in Puerto Rico. are currently seasonally abundant in some areas of the southwestern and southeastern United States. Oahu. dengue virus 3 (DENV-3). the disease is not statutorily notifiable in most member states. which was then experiencing a severe outbreak of the infection. the first clearly identified local transmission of dengue in the United States occurred in Texas. and Kauai. Guatemala. and New Jersey. Data from other countries supports the finding that the severity of secondary dengue infections appears to intensify with longer intervals between infections. 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. Mississippi. The epidemic was traced to viremic visitors from Tahiti. Madagascar. and military travel to endemic areas. and travelers returning from the tropics and subtropics have been increasing. Barbados. 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. Aedes albopictus.6.
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. dengue has an incubation period of 3-14 days (average 47 d) while viral replication takes place in target dendritic cells. have been proposed to result in increased viral entry and replication and increased cytokine production and complement activation. and damage to the liver. certain nonhuman primates in Africa and Asia also serve as hosts but do not develop dengue hemorrhagic fever. interleukin [IL]–2). when bound by macrophage and monocyte Fc receptors. in part because more epidemics of dengue hemorrhagic fever have been associated with DENV-2 than with the other serotypes. Humans serve as the primary reservoir for dengue.14. often breeding around dwellings in small amounts of stagnant water found in old tires or other small containers discarded by humans. The mosquito can transmit dengue if it immediately bites another host.10. have been proposed to be more virulent. a 5. Entire families who develop infection within a 24. Infection with one dengue serotype confers lifelong homotypic immunity and a very brief period of partial heterotypic immunity. In addition. low albumin levels. but each individual can eventually be infected by all 4 serotypes.9 The eggs of Aedes mosquitoes withstand long periods of desiccation.21 In persons with fatal dengue hepatitis.20 Most patients who develop dengue hemorrhagic fever or dengue shock syndrome have had prior infection with one or more dengue serotypes. This is similar to that seen with fatal yellow fever and Ebola infections. but are killed by temperatures of less than 10°C. hepatocytes. Recovery is usually complete by 7-10 days. soluble CD220.127.116.11. ranging from petechial skin hemorrhages to life-threatening gastrointestinal bleeding.20. infection was demonstrated in more than 90% of hepatocytes and Kupffer cells with minimal cytokine response (tumor necrosis factor [TNF]– alpha.to 36-hour period. In individuals with low levels of neutralizing antibodies.1.19 Following incubation. including TNF-alpha.to 65-day lifespan. particularly those of DENV-2. and deranged coagulationparameters(PT. Each serotype is known to have several different genotypes. Some researchers suggest T-cell immunopathology may play a role. Bleeding is caused by capillary fragility and thrombocytopenia and may manifest in various forms. Dengue viruses are transmitted by the bite of an infected Aedes (subgenus Stegomyia) mosquito. however. Once inoculated into a human host. Infection of target cells. Female Aedes mosquitoes are daytime feeders. resulting in severe fluid losses and bleeding. Mosquitoes acquire the virus when they feed on a carrier of the virus. Globally. are not unusual. Increased concentrations of interferon have been recorded 1-2 days following fever onset during symptomatic secondary dengue infections.Africa. Vertical transmission of dengue virus in mosquitoes has been documented.to 7-day acute febrile illness ensues. They inflict an innocuous bite and are easily disturbed during a blood meal. approximately at the time of defervescence.16.17.18. type.8 Albert Sabin speciated these viruses in 1944.22 The activation of cytokines. Aedes mosquito species have adapted well to human habitation. but A albopictus and other Aedes species can also transmit dengue with varying degrees of efficiency. TNF receptors.13 result in the production of immune mediators that serve to shape the quantity. certain dengue strains. primarily those of the reticuloendothelial system. such as dendritic cells.PTT). . and soluble IL-2 receptors. Liver damage manifests as increases in levels of alanine aminotransferase and aspartate aminotransferase. and duration of cellular and humoral immune response to both the initial and subsequent virus infections. Several serotypes can be in circulation during an epidemic. reportedly as long as 1 year. This phenomenon is called antibody-dependent enhancement.17 In addition. A aegypti is the predominant highly efficient mosquito vector for dengue infection. The mosquito remains infected for the remainder of its 15. transmission occurs after 8-12 days of viral replication in the mosquito's salivary glands (extrinsic incubation period). The major pathophysiological abnormalities caused by dengue hemorrhagic fever and dengue shock syndrome include the rapid onset of plasma leakage. making them efficient vectors. nonneutralizing antibodies to one dengue serotype. has been correlated with disease severity.11. as well as pleural effusion and ascites. Plasma leakage is caused by increased capillary permeability and may manifest as hemoconcentration. causing them to move on to finish a meal on another individual. presumably from the bites of a single infected vector. with increased T-cell activation and apoptosis. Dengue hemorrhagic fever or dengue shock syndrome usually develops around the third to seventh day of illness. and endothelial cells. altered hemostasis.
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. Tamaulipas. however. ethnicity. where dengue is hyperendemic. Texas. The mortality rate associated with dengue fever is less than 1%.9 cases of dengue infection went unrecognized because of absent or minimal symptoms.000 individuals develop dengue hemorrhagic fever. A 5-year prospective study in Thai children examined the relative economic burden of dengue infection in children on the local population. Even patients who meet strict criteria for dengue hemorrhagic fever or dengue shock syndrome usually recover without sequelae. and the manifestations are often nonspecific. Factors that affect disease severity include patient age. Laredo-area health care providers identified 161 suspected dengue fever cases and serologically confirmed 18 cases. dengue hemorrhagic fever usually affects children younger than 15 years. The Texas Department of Health reviewed 494 patient records from 5 outpatient sites and was able to confirm 11 cases of dengue fever.24 Mortality/Morbidity • • • • Recovery from dengue infection is usually complete. the sequence of infection with different dengue serotypes. and health care providers were notified of the dengue fever cases. However. In the latter half of 1999. 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. in . many US physicians are not aware of dengue or its manifestations.5-3 billion people in approximately 110 tropical and subtropical countries worldwide are at risk for dengue infection. 90 confirmed or probable cases of dengue fever were imported into the United States. In 1999. resulting in one fatality.000 individuals are hospitalized with the infection. Yearly. and the quality and extent of available medical care. Data from the 1997 Cuban epidemic suggests that. for every clinically apparent case of dengue fever. In a 1997 Cuban epidemic. This merits further study. the fatality rate in patients who met criteria for dengue hemorrhagic fever or dengue shock syndrome was approximately 6%. more than 300 cases of dengue fever were reported from Nuevo Laredo. The fatality rate associated with dengue shock syndrome varies by country. with DENV-2 and DENV-3 responsible for 30% and 29%.23 Nuevo Laredo lies directly across the Rio Grande River from Laredo. from 12%44%.Frequency United States In 1998. International An estimated 2. Mosquito abatement measures were instituted in Laredo. • Dengue affects people of all ages. 13. Aedes mosquitoes are present in both cities. virus genotype. The mean cost of illness from dengue was significantly higher than that from other febrile illnesses. and 24. respectively.000 deaths are attributed to dengue worldwide. nutritional status. Annually. approximately 500. and 250. approximately 50-100 million people are infected with dengue. the true number of dengue fever cases is believed to be higher because reporting is voluntary. Some African and Haitian data demonstrate a relative dearth of dengue hemorrhagic fever and dengue shock syndrome during dengue fever epidemics. Mexico. Sex • Age Dengue viruses affect both sexes. Race • Dengue affects all races. At that time. The current estimate is 100 cases per year. suggesting that these populations may share a genetic advantage to the virus. 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. In Southeast Asia. no dengue cases had been reported in Laredo in more than 12 years.
sore throat. Patients report fatigue and malaise. Conjunctival injection develops in approximately one third of patients with dengue hemorrhagic fever. Physical • • • • • • • • • Fever is present. 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. o Results from a tourniquet test are often positive. Patients typically describe a maculopapular or macular confluent rash over the face.25 Pharyngeal injection develops in almost 97% of patients with dengue hemorrhagic fever. Patients may report conjunctival injection. a pattern that has been called saddleback fever. the fever abates for a day and then returns. Occasionally. The results are considered positive if more than 20 petechiae per square inch are observed on the skin of the arm. or hematemesis. abdominal pain in conjunction with restlessness. hypothermia. and flexor surfaces. Hemorrhagic manifestations include the following o Petechiae and bleeding at venipuncture sites are most common. and menorrhagia. Hepatomegaly is present more often in dengue shock syndrome than in milder cases. and hepatic injury. and cough. Clinical History • • • • • • • • • • Fever in persons with symptomatic dengue fever may be as high as 41°C. 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 . abating with the cessation of viremia. thorax. 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. with tachycardia during the febrile period and bradycardia and conduction defect. Patients are at risk for development of dengue hemorrhagic fever or dengue shock syndrome at approximately the time of defervescence. and more commonly in children. Myocarditis and congestive heart failure are rare. anoxia. with islands of skin sparing. and a drop in the platelet count presages the development of dengue hemorrhagic fever. Cardiomyopathy is reported. hyponatremia. Abdominal pain is reported. Hepatic transaminase levels may be mildly elevated. Rash is described as follows: o Up to half of patients with dengue fever develop a characteristic rash. The rash typically begins on day 3 and persists 2-3 days. intracranial hemorrhage. change in mental status. Headache is usually generalized. especially of the knees and shoulders. Retroorbital pain is common and is often described as severe. menorrhagia. melena. often. dengue hemorrhagic fever shows no age predilection. Optic neuropathy has been reported and occasionally results in permanent and significant visual impairment.the Americas. Generalized lymphadenopathy is observed. Patients may report nausea and vomiting. Dengue fever presents in a nonspecific manner and may not be distinguishable from other viral or bacterial illness. o Petechiae and purpura may develop as hemorrhagic manifestations. The fever typically begins on the third day and lasts 5-7 days. arms. erythematous mottling of the skin. hematemesis. Fever is often preceded by chills. Hemorrhagic manifestations may range from small amounts of bleeding from the nose or gums to melena. o The rash is variable and may be maculopapular or macular. o Other hemorrhagic manifestations include nasal or gingival bleeding. particularly of the lower back. and facial flushing (a sensitive and specific indicator of dengue fever). Encephalopathy is a rare complication that may result from a combination of cerebral edema. where dengue is becoming progressively hyperendemic. and arthralgias. In travelers. Patients may have severe myalgias. and legs.
hypoproteinemia) o Dengue shock syndrome is diagnosed in cases meeting all of the above criteria plus evidence of circulatory failure. which added the above early predictors of compensated shock and considered models using varying combinations of evidence of hemorrhagic tendencies. 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. leukocytes. 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. indicated by raised diastolic pressure and increased PVR in an alert patient. injection sites. DENV-1. ecchymoses. DENV4) and is transmitted to humans by the bite of an infected mosquito. Rabies . the main predictors of dengue infection included skin rash.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. clammy skin Altered mental status. or purpura Bleeding from the mucosa. thrombocytopenia. comparable IgG EIA titers. ascites. such as the following: Rapid.• • 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. or other sites Hematemesis or melena and thrombocytopenia (<100. and leukopenia. 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. gastrointestinal tract. 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. After malaria was ruled out. although the patient may initially remain alert o The onset of shock may be subtle. serum. DENV-3. plasma. 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. DENV-2. thrombocytopenia.14 The clinical reliability of the WHO criteria was compared with those of several modified systems.26 Causes Dengue infection is caused by 1 of the 4 dengue viruses (ie. A Belgian study examined predictors of diagnosis in 1962 febrile travelers and expatriates returning from the tropics. with increased peripheral vascular resistance (PVR) and elevated diastolic pressure Hypotension Cool. pleural effusion. 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. 76-94) for the detection of dengue shock syndrome. The WHO classification system was recently studied in Indonesian children and was found to have a sensitivity of 86% (95% CI. or signs of plasma leakage (eg. greater than 20% drop in hematocrit level following volume replacement compared to baseline. weak pulse Narrow pulse pressure (<20 mm Hg).
Opossums are rarely infected and are not considered a likely risk for exposure. The virus is transmitted in saliva or in aerosolized secretions from infected animals. Pathophysiology Rabies is a highly neurotropic virus that evades immune surveillance by its sequestration in the nervous system. 2008 Introduction Background Rabies is a viral disease that affects the CNS. Rabies is recognized as a zoonosis worldwide. University of South Florida College of Medicine. Division of Infectious Diseases and International Medicine. the source of exposures cannot be identified. transmission via organ transplantation has also been documented in other countries.2 The rabies virus is a bullet-shaped virion with a single-stranded RNA nucleocapsid core and lipoprotein envelope. For centuries.Author: Sandra G Gompf. skunks. Mokola virus. University of South Florida College of Medicine. unvaccinated dogs serve as the main reservoir worldwide. Albert L Vincent. Associate Professor. A prolonged incubation follows. At this point. MD. Its multiplication in the ganglion is heralded by the onset of pain or paresthesia at . rabies serogroup. Rochambeau virus. wolves. Other very rare sources of exposure have included neurally derived tissues (eg. Division of Infectious Diseases and International Health. the focus of this article. Through such programs. 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. Associate Professor of Infectious Diseases and International Medicine. Director. James A Haley Veterans Hospital Coauthor(s): Charurut Somboonwit. prophylactic therapy becomes futile. Recently. These reservoirs allow rabies to remain an indefinite public health concern. Raccoons. followed by cats and cattle. Animal-control and vaccination strategies currently supersede postexposure prophylaxis in preventing the spread of rabies. Its nucleocapsid material comprises the Negri bodies observed in the cytoplasm of infected neurons. The fatal madness of rabies has been described throughout recorded history. and insect-eating bats remain the prime vectors in the United States. Undomesticated canines. MD. jackals. and rabies can be expected to follow its fatal course.1. transplanted corneas) and laboratory aerosols. however. and ether. Obodhiang virus. includes the classic rabies virus. The genus Lyssavirus contains more than 80 viruses. Upon inoculation. Assistant Professor of Medicine. ultraviolet rays. Duvenhage virus. and Australian bat Lyssavirus. Increasingly in the United States. Polk County Health Department. University of South Florida College of Medicine. unfortunately. detergents. The virus is not hardy and is quickly inactivated by drying. Infectious Diseases Section. the length of which depends on the size of the inoculum and its proximity to the CNS. Hillsborough County Health Department Contributor Information and Disclosures Updated: Oct 3. with predictable results. and its association with rabid canines is well known. Tri M Pham. The rabies virus travels along these axons at a rate of 12-24 mm/d to enter the spinal ganglion. MD. Human rabies reflects the prevalence of animal infection and the extent of contact this population has with humans. rabies has been eliminated in several nations and some areas in the US territories. the first US instance of human rabies transmission via solid organ transplantation was documented in 3 recipients of a donor unsuspected of having rabies. Kotonkan virus. Amplification occurs until bare nucleocapsids spill into the myoneural junction and enter motor and sensory axons. but the risk of death from rabies is exceedingly low. Occupational Health and Infection Control Programs. Classic rabies. Less than 5% of cases in developed nations occur in domesticated dogs. most of which only rarely cause human disease. In the 19th century. dog bites were treated prophylactically with cautery. PhD. University of South Florida College of Medicine. Chief. FIDSA. Department of Internal Medicine. In 1997. trypsin. an unusual bat Lyssavirus caused a brief outbreak of a rabieslike illness in Australia. Senior Physician. with fewer than 5 cases documented per year. x-rays. and ongoing public health measures are critical to its control. with a mortality rate of 100%. European bat Lyssavirus types 1 and 2. typically via a bite. The genus Lyssavirus. such as coyotes. Scientific and Research Advisor to the Division of Epidemiology. FACP. it enters the peripheral nerves. is the prototypical human Lyssavirus pathogen. Fellow. are most prone to rabies and serve as reservoirs. and foxes. Ten viruses are in the rabies serogroup. Division of Infectious Disease and International Medicine.
Bat rabies virus variants were implicated in the rabies cases in Texas and Indiana. some of which may have been unnecessary. Since 1940.3 Approximately 16. An estimated 10 million people receive postexposure prophylaxis each year after being exposed to animals with suspected rabies. she received an investigational regimen of ribavirin. Clinical . death is imminent. Sex Rabies has no known sexual predilection. Thereafter. whereas exposure to a dog in the Philippines was responsible for the case in California. Most were related to rabid-dog exposure. In addition. 15 cases of human rabies were reported in the United States. approximately 30% of health care worker contacts exposed to known cases of rabies have been treated with postexposure prophylaxis in the United States. Mortality/Morbidity If rabies treatment is not initiated before the onset of symptoms.000-39. 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.000 deaths annually worldwide and that gross underreporting is likely.000-50. or neurologic tissue. 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. The case. International Rabies is more prevalent in the developing world than in the developed world. assessing whether this therapy was genuinely efficacious. 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. In 2006. 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. the rabies virus spreads quickly. amantadine. which is the first clinical symptom and a hallmark finding. and Texas. however. the virus spreads to the periphery and salivary glands. Five cases of survival of human rabies have been documented in individuals who had been previously vaccinated or received postexposure prophylaxis. Despite the lack of proven occupational transmission. 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. 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. at a rate of 200-400 mm/d. underscores the potentially long incubation period (in this case. when canine rabies vaccination programs began. From here.4 Notably. into the CNS. 3 cases of human rabies were reported in California.000 people receive rabies postexposure prophylaxis each year. the average number of documented cases declined to 2 per year. with an average of 50 documented cases per year. tears.the site of the inoculum. or whether these results are in fact reproducible is difficult. From 2001-2005. wherein the victim did not seek medical attention after handling a bat and being bitten. Age Rabies has no known age predilection. cerebrospinal fluid (CSF). and a ketamine-midazolam– induced coma. and spread is marked by rapidly progressive encephalitis. Indiana. The World Health Organization (WHO) estimates that rabies is responsible for 35. Some concern exists regarding occupational transmission of rabies from patients to health care workers. whether other factors may have been involved.
o The rabies virus is segregated from the immune system during this period. 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. Seizures may occur. psychosis. salivation. This may be related to a violent response of the airway irritant mechanisms. facial palsy. Recovery o This is unlikely. nausea. headaches. hyperventilation. Prodromal period: The virus enters the CNS. incubation lasts as long as 19 years. o Paralysis occurs from the outset. agitation. confusion. Hydrophobia and aerophobia are pathognomonic for rabies and occur in 50% of patients. insomnia. Patients develop agitation. Furious episodes last less than 5 minutes. anisocoria. auditory. o The average duration of incubation is 20-90 days. o Patients may not recall exposure because of the prolonged incubation period. or hallucinations. After several hours to days. the duration varies. A few reports indicate that persons who survived had preexposure or postexposure prophylaxis. restlessness. and death occur shortly after coma. and aphasia. deep wounds. thrashing. agitation. chills. mydriasis. diarrhea. hypertension. In more than 90% of cases. Coma o This begins within 10 days of onset. o Paresthesia or pain at the inoculation site is pathognomonic for rabies and occurs in 50% of cases during this phase. lacrimation.History • • • • • Incubation period o The rabies virus transfers from peripheral areas to the CNS. emesis. this becomes episodic and interspersed with calm. despite intensive supportive care. Physical • • • Incubation period: The virus transfers from peripheral areas to the CNS. Even the suggestion of drinking may induce hydrophobic spasm. tachycardia. 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. lucid periods. hyperactivity. this may be the individual’s only presenting sign. o Most US cases result in death within 14 days because of complications. o Twenty percent of patients do not develop the furious form. pharyngitis. 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. incubation is less than 1 year. o Furious rabies may develop in this period. arrest. Episodes may be triggered by visual. drooling. biting. Prodromal period o The virus enters the CNS. This phase may end in cardiorespiratory arrest or may progress to paralysis. Attempting to drink or having air blown in the face produces severe laryngeal or diaphragmatic spasms and a sensation of choking. cooperative. Physical findings are not present. restlessness. or tactile stimuli or may be spontaneous. Acute neurologic period o This period is associated with objective signs of developing CNS disease. o The duration is 2-7 days. o Nonspecific symptoms and signs develop. o The duration of this period is 2-10 days. . o Fever and headache are prominent. muscular fasciculations. Autonomic instability is observed. anorexia. including fever. fever. Neurologic period o Furious rabies Patients present with episodic delirium. or large wounds. seizures. emesis. anxiety. o Without intensive supportive care. and postural hypotension. Other neurologic signs include cranial nerve involvement with diplopia. Signs include fever. perspiration. Rarely. thrashing. o Symptoms may include malaise. o The infected individual remain asymptomatic. respiratory depression. or diarrhea. and depression. and optic neuritis. and no antibody response is observed.
Several family members and friends who possibly had contact with the patient's saliva received postexposure prophylaxis. o Causes • • • • High-risk exposures consist of contact with saliva or infected CNS tissue. dead bats also were discovered inside the home. presence of clinical features of rabies. Bradycardia and cardiac arrest occur. o Raccoons: Raccoons have been recognized a reservoir for rabies in the southeastern United States since the 1950s. stupor. Coma: Respiratory failure occurs within one week of neurologic symptoms. Vermont. o Corneal transplants: Currently. These areas include the north-central United States. West Virginia. Transplant patients: The innate state of immunosuppression in this population often provides a favorable environment for viral replication. The sensory system is usually spared. and most have no known exposure to a rabid animal. o Foxes o Dogs and cats along the Mexican border: Because of limited resources and minimal public health infrastructure in the bordering communities. o Organ donation: Clinical screening of potential organ donors should include a history of animal bites. family members recalled that bats were commonly seen outside the home. silver-haired bats. if a bat is found in a room where a child has been sleeping. Paralysis is symmetric and may be either generalized or ascending and may be mistaken for Guillain-Barré syndrome. the south-central United States. a previously healthy 10-year-old boy in Mississippi died from encephalitis later attributed to rabies. eastern pipistrelles). the risk of raccoon transmission exists in all of the eastern coastal states and Alabama.7 Currently. donated corneas are not accepted if the donor died from an encephalitis that may be consistent with rabies. Acute respiratory distress syndrome is common. The recipients developed clinical rabies within 30 days. bat bites can go completely unrecognized by the patient. At least 30 of the more than 39 species of bats in the United States have been reported as rabid at some time. the bat should be captured and submitted for examination to the county or state health authorities. Preexposure rabies immunization of potential organ recipients is being evaluated as an alternative approach to prevent transmission associated with organ transplantation. o Skunks: Three areas are associated with skunk-borne rabies. Calm clarity gradually progresses to delirium. o Kidney and liver transplants: In 2004. 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. approximately 150 rabid cattle are been reported to the CDC.) In September 2005. see the eMedicine article Rabies in the Pediatrics: General Medicine volume. On two occasions. cardiac arrhythmias. and then coma. In 60% of cases.• Paralytic rabies Fever and nuchal rigidity may occur. and Ohio. organs were inadvertently transplanted from a donor from Texas with rabies that had gone undiagnosed. One third of rabies cases occur in children. are generally thought to be trivial injuries because of the small size of most temperate-zone species (eg. 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 1990.8 . Hypoventilation and metabolic acidosis predominate. appropriate postexposure prophylaxis is not administered. and hypothermia ensue. and a travel history (within a period of months) to areas where rabies is endemic. Upon further questioning after the patient's death.5 High-risk animal species in the United States include the following: o Bats Bat bites. Pennsylvania. and California. resulting in 100% mortality. consequently. testing of the bat can avoid the need for rabies immunization. including corneal transplants. Because children may not be able to recall contact with a bat. if noticed by the patient. efforts to maintain animal control through dog-vaccination programs are hindered. Wide variations in blood pressure.6 (For additional information on pediatric rabies. In addition.
pregnant women. Richard L Oehler. Her history findings revealed that she was bitten when she took a vaccinia-rabies virus vaccine out of her dog's mouth. FACP.net/Big_Virology/BVDNAadeno. patients with an exfoliative skin condition). implying prior infection. adenovirus is recognized as the etiologic agent of various diverse syndromes. cats. Director. in The Big Picture Book of Viruses.9 This oral animal vaccine may cause adverse effects. These primary cell cultures were often noted to spontaneously degenerate over time. Assistant Epidemiologist. and ferrets in areas not near a border. Only one case has been documented of a pregnant woman developing a skin infection and needing surgery after she was bitten by her dog. particularly in hosts with altered immunocompetence and in persons in whom smallpox vaccination is contraindicated (eg. most infections are asymptomatic. Univ of South Florida College of Medicine. 2010 Introduction Background Adenovirus. Infectious Diseases Section. Associate Professor of Infectious Diseases and International Medicine. Adenovirus is known to be oncogenic in rodents but not in humans. University of South Florida College of Medicine. a DNA virus. survives long periods outside a host. Department of Infectious Diseases and International Medicine. Assistant Professor.virology. FACP. Fellow.html. and most adults have measurable titers of anti-adenovirus antibodies.• • Lower-risk animal species in the United States include dogs. a fecal-oral route. MD. FIDSA. The vaccinia-rabies glycoprotein virus used to bait wild animals is a self-replicating agent. MD. Division of Infectious Diseases and Tropical Medicine. Adenoviruses Author: Sandra G Gompf. and adenoviruses are now known to be a common cause of asymptomatic respiratory tract infection that produces in vitro cytolysis in these tissues. Chief. was first isolated in the 1950s in adenoid tissue–derived cell cultures. A virus image from the International Committee on Taxonomy of Viruses. Possessing 52 serotypes. Division of Infectious Diseases. or ferret held in quarantine for 10 days. Occupational Health and Infection Control Programs. . adenovirus is ubiquitous in human and animal populations. Adenovirus is often cultured from the pharynx and stool of asymptomatic children. and is endemic throughout the year. hence the name. cat. James A Haley Veterans Hospital Coauthor(s): Dhanashree Kelkar. however. or exposure to infected tissue or blood. Tampa VA Medical Center Contributor Information and Disclosures Updated: Feb 12. University of South Florida College of Medicine. MD. Department of Internal Medicine. No person in the United States has ever contracted rabies from a dog. It is transmitted via direct inoculation to the conjunctiva. An extremely hardy virus. The virus is capable of infecting multiple organ systems. aerosolized droplets. available at http://www.
with regard to infections among military recruits. co-infection with non-vaccine strains (B1 and E) have developed following vaccination. Thereafter. Prolonged pharyngeal shedding and communal quarters contribute to outbreaks. However. Pathophysiology Adenovirus is a double-stranded DNA virus that measures 70-90 nm and that has an icosahedral capsid. The CDC's Morbidity and Mortality Weekly Review published an article entitled " Acute Respiratory Disease Associated with Adenovirus Serotype 14—Four States. enzymatic." Mortality/Morbidity . while gastrointestinal tract involvement results from fecal-oral transmission. is the immune response to the viral vector itself. The reservoirs exist within the training environment itself. The second is chronic or latent infection. Lost productivity and interrupted military training have prompted reinvestigation of vaccine production. which results in cytolysis. Ad4 seropositivity of new recruits has been demonstrated to rise from 30% to almost 100%. Lastly.2. Additionally. 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 virus itself can be engineered to remove its replicative capacity by removing essential genes. the exact mechanism of which is unknown. Notably. the replication cycle is truncated.4 and surveillance for emerging non-vaccine strains is still needed.3 Adenoviruses can infect various cells. and Ad4 has been detected on lockers. The first is lytic infection. In 2007. the greatest challenge in viral gene therapy. and adenoviral DNA is then integrated into the host cell’s DNA. Frequency United States Adenovirus is isolated most commonly in infants and children. 2006-2007. respiratory tract infection infections result from droplet inhalation. as might be expected. Suicide gene systems that convert nontoxic systemically delivered prodrugs to active chemotherapeutic agents have been delivered via adenoviral vectors directly into cancer cells. which occurs when an adenovirus enters human epithelial cells and continues through an entire replication cycle. The site of entry generally determines the site of infection. and bedding.Adenovirus has been associated with both sporadic and epidemic disease and. A clear role for adenovirus in human oncogenesis has not been established. and thus hold the promise of targeting many different tissues and diseased cell lines. both proliferating and quiescent. cytokine production. During oncogenesis. and induction of host inflammatory response. adenovirus produces potent E1A proteins that immortalize primary rodent cells by altering cellular transcription. with illness most commonly arising in weeks 3 to 5. rifles. media attention following adenovirus outbreaks in the United States focused on serotype 14. Of most recent interest is the role of adenoviruses as vectors in vaccination and in gene therapy. specific genes can be inserted into the virus that then can repair defective metabolic. is a significant cause of economic cost and morbidity because of the cessation of vaccine production in 1996. one of three different interactions with the cells may occur. with Ad4 predominating in 98% of cases. which frequently involves asymptomatic infection of lymphoid tissue. ultimately leading to deregulation of apoptosis and malignant transformation. Upon infection with adenovirus. The economy-driven cessation of vaccine production by its sole producer in 1996 resulted in re-emergence of outbreaks. 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.1. or synthetic pathways in the host. oncogenic transformation has been observed in rats. 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.
ARD is more common in spring and winter months. while some other studies have reported no such findings.7 Race • Sex No racial predilection has been described. o The contagiousness of adenovirus is facilitated by very high levels of viral particles (100. The prevalence of other syndromes does not appear to be affected by the sex of the individual. The major syndromes covered in this article include (1) acute respiratory disease (ARD). adults who lack antibody may be infected by the inhalation of as few as 5 virions in droplet nuclei. • Adenovirus infection typically affects children from infancy to school age.6. and rapid advances in molecular methods of detection. usually lasting 3-5 days. including tracheobronchitis. o Lower respiratory tract infections. may mimic respiratory syncytial virus infection or influenza. • Age Adenovirus urinary tract infections are more common in males. and 6. 14. Additionally. such as transplant patients and those with inherited and acquired immunodeficiency states. conjunctivitis in the presence of bronchitis suggests adenoviral infection. 5. are typical symptoms of adenoviral ARD. cough. however. with resulting concern that this virus caused various cancers. and pneumonia.000. the major syndromes are discussed separately. live adenovirus vaccines in the 1950s became contaminated with simian virus 40 (SV40). and 30. hepatitis. The reader is encouraged to review the literature for more detail regarding infection in specific settings. Given the range of manifestations.5 Morbidity and deaths due to pronounced host inflammatory responses have occurred in past gene vector trials. bronchiolitis. Young adults in any setting of close quarters and stress may be affected. as with military trainees. 21. 2.000/mL) in the sputum or oral secretions of infected adults. (4) acute hemorrhagic cystitis. After subsequent long-term follow-up. some studies have found a moderate association between SV40 and human cancers as a transforming virus. Severe adenovirus infections have been reported in immunocompromised patients. A live enteric-coated oral vaccine against these . (3) epidemic keratoconjunctivitis. o Fever. 7.• • • • Severe morbidity and mortality associated with adenovirus infections are rare in immunocompetent hosts. and (5) adenoviral infections in immunocompromised hosts. Adenovirus serotypes 4 and 7 were primarily involved. o Fatal pneumonia is uncommon but is more likely in neonates and has been associated with serotypes 3. Notably. As with polio vaccines. including neonates. a comprehensive review of adenovirus infection in the immunosuppressed host is beyond the scope of this article. occasionally. (5) gastroenteritis. Approximately half of adenovirus respiratory infections do not cause symptoms.8 o Encephalitis. adenoviruses accounted for significant acute disease in 70% of military recruits. the author plans to report the most salient features and general updates here. but children of any age may be affected. (2) pharyngoconjunctival fever. the varying levels and effects of immunosuppressive therapies. o From the 1950s to 1971 (prevaccine era). and sore throat. • Acute respiratory disease (predominantly adenovirus types 1. Clinical History Because the manifestations of adenovirus infections are protean. and myocarditis are uncommon. Uncommon complications that increase the risk of mortality include meningoencephalitis and pneumonitis. 3 and 7) o As with many other viral syndromes.000-1. Mortality rates associated with adenovirus infections among pediatric and adult transplant recipients have varied from 6%-70%. rhinorrhea. Adenoviruses account for 10% of all childhood lower respiratory tract infections.
however. o Malaise and headache are reported. Interestingly. o After an 8-day incubation period. a large epidemic of more than 500 cases associated with serotypes 3 and 7 occurred in US Navy recruits. Upper respiratory tract symptoms may precede ocular findings or may be absent.15 Gastroenteritis (most commonly associated with serotypes 40 and 41. spreading to involve both eyes. AIDS). o Uncommonly. referred to as the "super cold" in the media. In 1997. airborne particles). The cases in Texas involved military trainees at Lackland Air Force Base. and subsequent cases were reported at Lackland. Epidemic keratoconjunctivitis (predominantly serotypes 8. o Many serotypes are fastidious in culture. o Inflammation may persist for weeks. water sample cultures are often not confirmatory. contaminated ophthalmic solutions. and residual scarring and visual impairment may occur. shipyard eye]. an exanthem or diarrhea may occur. Oregon. and the hands of health care workers. Spread occurs via the respiratory route and contact with ocular secretions during the acute illness. and 7) o This syndrome most often affects school-aged children. o Nephritis has occurred in recipients of hematopoietic stem cell transplants and is associated with fever. Boys are affected more often than girls. but mild pain or discomfort. and 37) o This is highly contagious.• • • • serotypes was introduced in 1971 and reduced adenovirus-related respiratory illness by more than 95% in recruits and thus attenuated outbreaks. and red eyes. It can also affect adults. Vaccine production ceased in 1996 for economic reasons. Patients have photophobia. especially summer camps in the setting of an inadequately chlorinated water source such as a pool or lake. although both eyes may be affected simultaneously. and morning crusting are common. and Washington. with the exception of Ad14. Symptoms may be more prolonged in hematopoietic stem cell recipients. from kidney or bone marrow transplantation. pruritus. Almost 40% of affected persons were hospitalized. their presence in the setting of a diarrheal syndrome may be incidental. sore throat. an insidious onset of unilateral red eye occurs. o The classic presentation is characterized by fever. 4.9. with a 5% overall mortality rate. Encephalitis may occur but is rare. a nosocomial outbreak in a hematology unit has been reported. o Dysuria. almost half in intensive care. in some settings. Hematuria is selflimited to 3 days. hematuria.16 Adenoviruses replicate readily in the human intestine and may be cultured from asymptomatic individuals. Texas. frequency. and grossly bloody urine are reported.13 Corneal trauma facilitates infection. but others may be involved) o Enteric adenovirus infection is a common cause of infantile diarrhea in the daycare setting. Severe pain is atypical. has caused rare outbreaks of ARD since 1955. Most recent analyses suggest that serotype 4 has caused most military outbreaks since 1999. three other Texas military bases. and pain (indicating corneal involvement). 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. less common than infection with astroviruses. Contagious in nature.11. thus. 141 cases of Ad14 infection were reported in clusters in New York. tearing. whether adenovirus is an etiologic cause of the syndrome remains unclear. Serotypes 40 and 41 had been termed "noncultivatable. with approximately 10% transmission in household contacts via hands and fomites.12 Pharyngoconjunctival fever (predominantly serotypes 3. Transmission has also been associated with instrumentation. o Conjunctivitis usually begins in one eye and then spreads to the other. sporadic outbreaks of adenovirus infection occur in small groups. and other symptoms resolve later. Adenovirus may be isolated from children with whooping cough syndrome in the presence or absence of Bordetella pertussis infection. industrial trauma (shipyard workers [ie." However. in addition. they have been cultured in the setting of . Between May 2006 and June 2007.14. and flank pain.10 o Adenovirus serotype 14 Ad14. o It usually is self-limited to 5 days (incubation period is 5 d). and one eye culture in a civilian unassociated with the military. welders. Children may have fever and lymphadenopathy. but less common than rotavirus infection and. tearing. o Acute conjunctivitis may occur with or without pharyngitis or a respiratory syndrome. 19. and vaccination administration was limited to high-risk periods until supplies ran out in 1999. coryza.
However. enzyme-linked immunosorbent assay. nephritis was associated with acute renal failure in more than 90% of patients. which may be dramatic. young age. The role of adenovirus in this setting is unclear.17 Adenoviral infection following pediatric lung transplantation has been reported. follicles in bulbar. and liver failure have been reported. General considerations o Pulmonary infiltrates are often diffuse and reticulonodular. particularly in infants and children infected with HIV. o Abnormal transaminase levels. . 2. Monoclonal antibody assays. A high level of suspicion for adenovirus is warranted in these cases. 5. o Diarrhea may indicate adenoviral gastroenteritis.17. T-cell immunodeficiency related to HIV infection has been associated with adenoviral infections. Prolonged neutropenia or immunosuppression also enhances the risk of adenoviral infections. Both allograft loss and recovery have been reported. In fact. 40. Manifestations may vary but include hemorrhagic cystitis/nephritis. coryza. note that a prior history of adenoviral infection in a patient with recovered immunocompetence may herald recurrence when the patient again becomes immunosuppressed. however. T-cell depletion and nonmyeloablative conditioning regimens such as high-dose alemtuzumab (Campath) antibody therapy. In one series. o Pulmonary rhonchi and rales may be found on auscultation. intussusception may be related to multiple etiologies. hematuria. severe hepatitis. However. but they may be lobar. Adenovirus should be considered in patients with a fever. its presence in the setting of a viral conjunctivitis is very suggestive of adenovirus infection. Physical • • • Acute respiratory disease o Exudative pharyngitis and conjunctivitis may be seen. particularly during the acute posttransplantation period prior to engraftment. thus. flank pain. Pharyngoconjunctival fever o Fever. as has diffuse adenoviral infection of the allograft itself. or histopathologic viral inclusion findings). and worsening renal function. o Preauricular lymphadenopathy (ie. Parinaud syndrome). o Fever and watery diarrhea are usually limited to 1-2 weeks. and/or palpebral conjunctivae (typically mild granular appearance) may be observed. 6). 41). 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. serology. and most have no evidence of infection with enteric strains (ie. pharyngitis (may be exudative). o Preauricular lymphadenopathy is not common but is a pathognomonic finding with adenovirus infection. Pneumonitis and hemorrhagic cystitis are cited most often. o Cervical lymphadenopathy may be seen. Epidemic keratoconjunctivitis o Severe follicular keratoconjunctivitis has been reported (conjunctiva may be granular). o Palpebral edema is a finding. o Visual haziness or impairment resulting from keratitis or corneal involvement may develop and may persist for months to years. Cholecystitis. most patients with intussusception have no evidence of adenoviral infection (based on culture. with small lymph nodes palpable just anterior to the ear is not common.18 o Immunosuppression in recipients of solid organ transplants has also been associated with the above syndromes. and electron microscopy support the association of these strains with enteric disease.5 o Uncommonly. 3. lymphopenia.• • diarrheal syndromes using newer cell lines. may indicate adenoviral hepatitis. various serotypes of adenovirus have been associated with infectious diarrheal syndromes in recipients of hematopoietic stem cell transplants. o Mesenteric adenitis and intussusception have been associated with nonenteric adenovirus serotypes (ie. and graft versus host disease. pneumonitis. one cannot assume that enteric disease is limited to these strains. and gastroenteritis. Approximately 40% of infants with intussusception have positive findings from cultures of stool or mesenteric lymph nodes for nonenteric serotypes.19 o Importantly. Hemorrhagic conjunctivitis develops in some cases. types 1. hepatitis/liver failure. Risk factors for adenovirus disease include allogeneic stem cell transplantation. o Hematuria may occur in the setting of nephritis or hemorrhagic cystitis. Mesenteric lymphadenitis or hyperirritable small bowel associated with nonenteric adenoviral infection has been postulated to lead to intussusception.
and diarrhea . pulmonary rhonchi and rales.• • • Acute hemorrhagic cystitis/nephritis o No significant features are described in the setting of hemorrhagic cystitis. other than evidence of blood in the urine. o Flank pain and fever are seen in nephritis. dry cough. grossly bloody urine. Adenoviral infections in immunocompromised hosts: Features include dyspnea. Fever is generally absent. Gastroenteritis: Patients with severe gastroenteritis may have signs of dehydration.
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