Virology and Pathophysiology

Yellow fever is a single-stranded RNA flavivirus. Strain differences are of little clinical relevance, although they may be of use in epidemiologic studies. The pathophysiologic mechanisms operating in viral hemorrhagic fevers are not well defined. In general, viral replication occurs at the site of inoculation. After the virus spreads to lymph nodes and monocyte-rich organs, further reproduction results in massive viremia.

The liver is the principal target organ. Pathologic studies show coagulative necrosis of hepatocytes and appearance of various markers of cell involvement (Councilman and Torres bodies). However, the degree of physiologic derangement is usually much more severe than expected for the extent of hepatic damage seen on pathologic examination. Perivascular edema and occasional focal bleeding occur in the kidneys, heart, and brain, but these changes are less severe than expected for the degree of clinical disease.

Ecology and Epidemiology

In the Americas, primates in the forest canopy serve as hosts for the yellow fever virus. Mosquitoes of the genus Haemagogus transmit infection. Because this vector does not travel far from the forest, jungle yellow fever occurs when humans enter jungle areas or the forest border zones. Urban yellow fever involves a different vector, A. aegypti. This mosquito is highly anthropophilic, lives in and around human habitations, and prefers domestic water storage containers for breeding. The presence of a large population of A. aegypti breeding sites in an urban area is a significant risk for epidemic spread of yellow fever once the virus is introduced from a nearby forest area. In Africa the presence of larger numbers of mosquito species that can serve as vectors has hindered complete understanding of the ecology of the disease.

Currently, both the Americas and Africa have a constant low level of jungle yellow fever because of inability to control either the monkey reservoir or the mosquito vector. Overall there are about 200,000 cases per year, resulting in approximately 30,000 deaths, occurring primarily in sub-Saharan Africa.⁷⁹ Some suggest that these rates are underestimated by at least 10-fold. Persons at risk include workers or travelers in or near the tropical rainforest canopy. Urban yellow fever had been reduced in the western hemisphere through massive campaigns to control breeding and spread of the Aedes vector. However, the benefits of these campaigns have declined, and there is currently an increased threat of further outbreaks of disease. Introduction of Aedes albopictus, an aggressive anthropophilic dengue vector from Southeast Asia, and reemergence of A. aegypti into the Americas raise the specter of increased yellow fever transmission in the western hemisphere.⁶⁵ Less-intense vector control measures and a more complex ecology have made elimination of urban yellow fever in Africa even more difficult.

Clinical Presentation

Although yellow fever may appear as an undifferentiated viral syndrome, classic disease is characterized by a triphasic pattern. The infection phase begins with sudden onset of headache, fever, and malaise, often accompanied by bradycardia and conjunctival suffusion. After approximately 3 to 4 days, victims often experience brief remission. Within 24 hours, however, the intoxication phase develops, characterized by jaundice, recrudescent fever, prostration, and, in severe cases, hypotension, shock, oliguria, and obtundation. Hemorrhage is usually manifest as hematemesis; however, bleeding from multiple sites may occur. Signs of a poor prognosis include early onset of the intoxication phase, hypotension, severe hemorrhage with disseminated intravascular coagulation (DIC), renal failure, shock, and coma. Death occurs in one-quarter to one-half of all cases. Diagnosis in the infection phase is difficult. With development of the classic syndrome, the differential diagnosis narrows somewhat, but still includes malaria, leptospirosis, typhoid fever, typhus, Q fever, viral hepatitis, and other viral hemorrhagic fevers. The standard means of diagnosis is evaluation for neutralizing antibodies in acute and convalescent sera (available through the Centers for Disease Control and Prevention [CDC] and state health departments in the United States). Several new systems for early detection of immunoglobulin M (IgM) or viral antigen are now being evaluated for more rapid diagnosis. A specimen of whole blood (at −70° C [−94° F] on dry ice) should be sent to the state health laboratory for isolation. Growth of the virus is possible in a number of systems, including Vero cells and infant mice. The virus is most easily isolated during the first 4 days of fever.

Management

Appropriate management of viral hemorrhagic fevers requires awareness of the geographic distribution of the disease and travel history of the victim. In the first several days of infection, differentiation of a viral hemorrhagic fever from other infectious diseases is nearly impossible. However, occurrence of an undifferentiated febrile syndrome in a traveler from a yellow fever–endemic area warrants a careful physical examination, thick and thin blood smears to rule out malaria, and blood cultures for bacterial pathogens (e.g., Salmonella typhi). In recently returned travelers, dengue serologic tests should be considered. Progression to the intoxication phase or any sign of volume disturbance, renal failure, or hemorrhage mandates immediate admission to an intensive care unit. There is no effective antiviral therapy for yellow fever. Intensive supportive care and management of end-organ failure is paramount. Although efficacy of intensive care treatment has not been studied for victims of yellow fever, clinical experience with DSS suggests that similar benefits might be obtained.

Prevention

Avoidance of this potentially fatal infection is possible through use of yellow fever vaccine. The vaccine strain 17D is an attenuated live virus grown in chicken embryos. Greater than 95% of persons vaccinated achieve significant antibody 1evels. Repeat vaccinations are recommended every 10 years, although persistent antibody titers have been detected as long as 30 to 40 years after vaccination. Yellow fever vaccine is generally well tolerated, with headache or malaise occurring in less than 10% of those vaccinated. Rare allergic side effects occur primarily in persons with hypersensitivity to eggs. Other serious adverse events, including death, have been reported, with the greater risk being associated with age older than 60 years.^5,49,66,81 Vaccination is not recommended in the first 6 months of life or in other situations where live virus vaccines are contraindicated. Although pregnant women have received the vaccine without adverse effect to themselves or their infants, it is not recommended for use in this group because of possible teratogenic effects. Other means of reducing the risk for yellow fever (and any mosquito-borne infectious disease) include liberal use of mosquito repellent and netting in endemic areas. Outbreak control in endemic countries is primarily through focused vaccination campaigns.

Treatment of severe yellow fever is difficult and often unsuccessful, with a mortality rate of approximately 50%. Avoidance through mosquito protection measures and administration of the highly effective vaccine before entry into endemic areas are of utmost importance.

Virology and Pathophysiology

The etiologic agent is a single-stranded RNA flavivirus, which may be one of four serotypes, denoted DEN-1 through DEN-4. As with yellow fever, local viral replication is followed by dissemination to lymphocyte- and macrophage-rich areas, where most of the reproductive activity occurs. Infection with one virus serotype provides long-lasting immune protection against that type only. After infection with one serotype, a subsequent infection with a heterologous serotype may result in a more severe clinical course. Non-neutralizing antibodies produced in response to infection to the primary infection are thought to facilitate entrance of the heterologous virus into host macrophages. Although cases of DHF and DSS may result from this “immune enhancement,” severe DHF and DSS also occur with other serotypes in the absence of previous infection with a heterologous dengue virus serotype.^60,61 Pathologic studies of DHF and DSS show hemorrhage, congestion, and perivascular edema of multiple organs. The liver may show areas of focal necrosis. As with yellow fever, the extent of pathologic findings does not correspond to severity of the clinical course.

Ecology and Epidemiology

A. aegypti is the principal vector for dengue viruses worldwide. In the Americas and Asia, viral transmission is maintained through a mosquito–human cycle without a major animal reservoir. Monkey carriers have been identified in Africa and Asia, but their importance in transmission is unclear. A. albopictus, an anthropophilic dengue vector from Southeast Asia, has also been recognized recently in the western hemisphere. Both of these mosquitoes are capable of large-scale transmission to humans in endemic areas. Currently, dengue is endemic in tropical and subtropical Asia, Africa, South America, and the Caribbean basin. In the early 1920s, large epidemics occurred in Texas, where dengue infections were reported in 500,000 inhabitants. In the last 30 years, endemic transmission on the mainland United States has been documented only in Texas. Travelers to Southeast Asia have highest risk for dengue, especially when travel takes place during periods of high transmission and epidemic dengue.⁹⁸

Clinical Presentation

Most dengue infections appear after an incubation period of 2 to 14 days, either as an undifferentiated viral syndrome with fever and mild respiratory or gastrointestinal symptoms or as dengue (“break-bone”) fever with bone pain, generalized myalgia, severe headache, and retroorbital pain. Febrile illnesses that appear more than 2 weeks after putative exposure to dengue virus are unlikely to be due to this virus. After 1 to 3 days, a quiescent period may ensue. There may be a subsequent second episode of fever accompanied by a patchy maculopapular or morbilliform rash that spreads outward from the chest and that ultimately desquamates. Lymphadenopathy and leukopenia occur during this phase of the illness. The distinct severe forms of dengue disease referred to as either DHF or DSS may occur around the usual time of recovery. These are due to the development of capillary leak syndrome with associated hemorrhagic manifestations (Figure 85-1). The advanced forms have the unique feature that the platelet count decreases to less than 100,000 per mm³ and hematocrit increases by more than 20%. The severity is classified as grade I to IV, according to World Health Organization guidelines. In cases of grade I DHF, the only hemorrhagic manifestation is a positive tourniquet test, in which inflation of a tourniquet to midway between systolic and diastolic blood pressure for 5 minutes leads to development of 20 or more petechiae per square inch distal to the tourniquet. A complete blood cell count classically shows decreased platelet and leukocyte counts and increase in hematocrit value. Grade II DHF is defined as the above with hemorrhage from any site (e.g., gingiva, nares, conjunctivae). Grade III DSS includes clammy skin, hypotension, or a narrow pulse pressure (<20 mm Hg) in a patient with DHF. An undetectable blood pressure defines grade IV DHF and DSS. Most studies have noted DHF and DSS primarily in infants and young children, usually with a history or serologic evidence of previous heterologous dengue infection, but there is an increasing trend of cases in adults.

FIGURE 85-1 Hemorrhagic manifestations of dengue hemorrhagic fever or dengue shock syndrome.

(From Ryan ET, Wilson ME, Kain KC: Illness after international travel, N Engl J Med 347:505, 2002.)

Prevention and Management

There is currently no vaccine to protect against dengue infection or disease, although several encouraging candidates are in development with one in clinical trials.^24,92

Awareness of the local epidemiology of DHF and DSS, especially the occurrence of other cases, is important in establishing the diagnosis. The diagnosis may be confirmed by a fourfold change in antibody titer between acute and convalescent sera or by presence of antidengue IgM antibodies. In the United States, isolation of the virus from serum can be arranged through state health departments. Management is symptomatic and directed in severe cases to fluid management. In the dengue fever syndrome, acetaminophen may be given for fever and myalgia. Salicylates should not be used. Hydration should be vigorously maintained.

Select victims of grade I or II DHF may be managed as outpatients. However, outpatient care requires careful monitoring of hematocrit value, platelets, and electrolytes. If significant bleeding develops, hospitalization is appropriate for rapid and continuous assessment. Progression to DSS (grade III or IV) is a medical emergency and requires immediate hospitalization. There is no specific antiviral chemotherapy. Supportive measures with careful monitoring are appropriate.

Epidemiology

The principal animal host for this virus is a rat, Mastomys natalensis, which prefers living in and around human dwellings. The rodents become chronically infected, secreting viral particles for long periods. Natural infection in humans occurs after rodent contamination of food and drink, inhalation of aerosolized rodent secretions, or contact with rodent material through skin abrasions. Lassa fever has been reported in several areas of sub-Saharan West Africa, and large outbreaks have been noted in Nigeria, Sierra Leone, Guinea, and Liberia.^21,62 It affects up to 500,000 people with 5000 deaths annually.⁵⁴ Complete seroprevalence data are lacking, making definition of an endemic area impossible at this time. Secondary human infection has been reported and may occur after contact with infected secretions.

Virology and Pathophysiology

Lassa virus is a single-stranded RNA arenavirus. Proliferation and dissemination presumably occur after initial replication at the inoculation site. As with the flaviviral diseases, the extent of end-organ involvement noted at autopsy does not account for the rapid death of infected patients. Recent work in an animal model provides evidence for platelet dysfunction and an endothelial cell defect in shock caused by Lassa fever virus.³¹ DIC, believed to be a major cause of bleeding and death in patients with other viral hemorrhagic fevers, appears to play a relatively minor role in arenavirus infections. The liver is most consistently the organ in which pathologic changes are observed at autopsy.

Clinical Presentation

Most seroconversions to Lassa virus are not accompanied by obvious symptoms.^63,64,69 Only 5% to 14% of seroconverters experienced a febrile illness. The incubation period is between 3 and 21 days. Patients hospitalized with Lassa fever show a distinct clinical syndrome. Fever, malaise, and purulent pharyngitis often develop after the insidious onset of headache. Retrosternal chest pain, possibly a result of pharyngitis and esophagitis, suggests the diagnosis. The combined presence of retrosternal chest pain, fever, pharyngitis, and proteinuria is the best predictor of Lassa fever.⁶² Hemorrhagic complications (hematemesis, vaginal bleeding, hematuria, lower gastrointestinal bleeding, and epistaxis) were seen in fewer than 25% of patients with Lassa fever. Nonfatal disease usually begins to resolve in 8 to 10 days. The combined presence of fever, sore throat, and vomiting was associated with a poor prognosis (relative risk for death = 5.5). Terminal stages of fatal disease were accompanied by hypotension, encephalopathy, and respiratory distress caused by stridor (presumably secondary to laryngeal edema). The most common complication after recovery from Lassa fever is sensorineural hearing loss, presumably due to host immune response reactions against elements of the inner ear.

Diagnosis

Establishing an accurate diagnosis is extremely difficult during the early phase of the infection. As the classic clinical syndrome develops, differentiation from other viral hemorrhagic fevers depends on serologic confirmation. Serologic diagnosis is made by indirect fluorescent antibody analysis of acute and convalescent sera or detection of Lassa-specific IgM antibody. Clotted whole blood may be sent to the CDC for viral culture if handled appropriately. If the diagnosis is suspected, the CDC should be contacted immediately for assistance in diagnosis, isolation, and management.

Management

Ribavirin has been used with success in patients with Lassa fever. It is most effective if started early in the course of the illness. For adults, a 2-g loading dose, followed by 1 g every 6 hours for 4 days, then 0.5 g every 8 hours for 6 days is recommended. Additional supportive care with maintenance of appropriate fluid and electrolytes, ventilation and blood pressure support, and treatment with broad-spectrum antibiotics for concomitant bacterial superinfections are often necessary.

Lassa fever has been associated with outbreaks of fatal person-to-person spread. Secondary infection occurs through direct contact with infected persons or their secretions. The role of aerosols in person-to-person spread is unclear. Blood and body fluids should be considered infectious. In light of the potentially fatal outcome of Lassa fever and the relative ease of transmission, the CDC has published specific recommendations for management of possible or confirmed cases. If a person has (1) a compatible clinical syndrome (especially pharyngitis, vomiting, conjunctivitis, diarrhea, and hemorrhage or shock); (2) a relevant travel history, including time spent in an endemic area; and (3) prior contact within 3 weeks of presentation with a person or animal from an endemic area suspected of having a viral hemorrhagic fever, he or she should be isolated and local, state, and federal health officials contacted. Ideally, an isolation unit with negative air pressure vented outside the hospital should be used. However, lack of a negative-pressure room alone is not a reason for transfer to another medical care facility.

The probability of transmission of Lassa fever virus to medical and nursing staff can be reduced by routine blood and body fluid precautions as well as strict barrier nursing. Barrier nursing includes wearing gloves, gown, mask, shoe covers, and, if there is risk for splashing fluids, goggles whenever entering the patient’s room. Decontamination of solid articles and rooms may be accomplished with 0.5% sodium hypochlorite solution. Recommendations for the management of patients with viral hemorrhagic fever have been published.^17,11

There is no vaccine available. Prevention is through avoidance of contact with rodents, especially in geographic areas where outbreaks occur.

Pathophysiology and Clinical Presentation

Marburg and Ebola viruses are presumed to act through similar pathophysiologic mechanisms that involve initial infection of monocytes, macrophages, and dendritic cells that are then distributed through the circulation to many organs and cell types. The viruses suppress both innate and adaptive host immune responses, leading to overwhelming infection and wide release of proinflammatory cytokines and chemokines causing fever, vascular instability, hypotension, and shock followed by multiorgan failure and death.^7,22,41,57

Patients present after an incubation period of 4 to 10 days with fever, headache, and myalgias. Diarrhea and abdominal pain occur commonly. In many victims, rash, conjunctivitis, sore throat, and chest pain appear early in the disease. As in other hemorrhagic fevers, hemorrhage, hypotension, shock, and electrolyte abnormalities mark fatal courses. The high mortality reported in various outbreaks and transmission to health care workers taking care of patients emphasizes the importance of intensive supportive care and precautions that limit contact with body secretions of infected individuals.⁷²

Diagnosis and Treatment

If these diseases are suspected, strict isolation procedures should be instituted and the local health authorities and the CDC notified immediately. Diagnosis may be made on a serologic basis or by polymerase chain reaction (PCR). There appears to be no serologic cross reactivity between the two viruses. Although anecdotal reports suggest the efficacy of immune sera in therapy, this has not been consistently observed in experimental studies. There are currently no specific antiviral therapies for Marburg or Ebola virus infection. Care is supportive. Vaccines are in development with one in Phase I testing.^7,47,60,85

Virology and Epidemiology

The etiologic agent of Crimean-Congo hemorrhagic fever (CCHF) is a bunyavirus. Ixodid ticks serve as both reservoirs and vectors of the virus. Infection in humans results from tick bites or direct contact with infected secretions from crushed ticks, animals, or humans. Most cases occur in individuals with occupations or living conditions that bring them in contact with domestic goats, sheep, or cattle on which ticks feed. The disease has been observed in southeastern Europe, south central Asia, the Middle East, and much of Africa.⁹⁵ Nosocomial transmission through contact with infected body fluids has been well documented.^32,89,90,91

Pathophysiology and Clinical Presentation

Pathophysiologic mechanisms are presumably similar to those of other hemorrhagic fevers.²⁸ One in five infections results in clinical disease with a case fatality rate ranging from 10% to 50%. The incubation period is approximately 1 week with initial symptoms of fever, severe headache, myalgias, vomiting, and diarrhea. Various forms of hemorrhage, including petechiae, large ecchymoses, melena, and hematemesis, are more pronounced in CCHF than in other hemorrhagic viral diseases. Severe cases progress rapidly to DIC, shock, and death.

Diagnosis

The diagnosis can be confirmed with acute and convalescent serologic evaluation for a fourfold rise in IgG antibody titers. The virus can be detected by PCR or cultured from whole blood if it is drawn during the first week of symptoms and kept on dry ice (or at −70° C [−94° F]) during shipment to the CDC.

Management

Initial management is similar to those for Lassa, Marburg, and Ebola virus infections, with strict patient isolation and notification of health authorities. Supportive therapy with attention to fluid balance and electrolytes in addition to oxygenation and hemodynamic support is the primary treatment. Although not confirmed in clinical trials, ribavirin has good activity in vitro against CCHF virus. The CDC recommends that patients believed to have CCHF receive intravenous (IV) ribavirin in the doses suggested for treatment of Lassa fever.²⁷ Persons in contact with CCHF patients should receive prophylactic ribavirin as suggested for Lassa fever contacts. To date, almost all therapy has used the oral form of ribavirin.

Epidemiology

Hantaviruses cause chronic, nondebilitating infections of various rodent species. Human infection is initiated by contact with rodent secretions or inhalation of aerosolized rodent material. The disease occurs most commonly in rural areas, although occasional urban outbreaks occur, presumably with the common house rat as vector. Cases have been described most often from Asia, including China, Korea, Japan, and the Soviet Union, but the disease also occurs in Eastern Europe. A recent epidemiologic study from China found the highest rates of infection in men who engaged in heavy farm work and slept on the ground (rather than on raised wooden beds).⁹⁹ The Sin Nombre virus appears to cause chronic infection of the deer mouse, Peromyscus maniculatus, which is the main reservoir of the virus in the United States. Since the initial outbreak, additional cases have been described across the United States and South America. The risk for infection is likely to be related to rodent exposure, but transmission is infrequent.

Virology and Pathophysiology

Members of the genus Hantavirus (family Bunyaviridae) are single-stranded RNA enveloped viruses that form one of the largest viral families, with over 300 species. The most common virus associated with HFRS in Asia is the Hantaan virus. The most common European hantavirus is Puumala virus, which causes a mild form of HFRS termed nephropathia epidemica. Severe HFRS cases in Europe have been caused by the hantavirus Dobrava-Belgrade virus. Sin Nombre virus is one cause of HPS in the United States. Hantaviruses enter host endothelial cells and spread rapidly.

Clinical Presentation

Hantaviruses cause a vascular leak syndrome. As with most viral hemorrhagic fevers, infection may be asymptomatic or accompanied by mild nonspecific illness. In the classic severe form, an initial febrile phase is associated with petechiae, proteinuria, and abdominal pain. After 3 to 5 days, a hypotensive phase occurs, with decreased platelet count and more severe hemorrhagic phenomena. An oliguric phase follows with concomitant electrolyte abnormalities. A diuretic phase usually commences 10 days after the onset of illness. Death occurs from hemorrhage, hypotension, and pulmonary edema, presumably secondary to fluid overload and renal failure. With modern management, the case fatality rate of classic HFRS is about 5%. The more benign nephropathia epidemica syndrome has a case fatality rate of less than 1%. In this disease, hypotension, shock, and hemorrhagic manifestations are rare. With HPS, there is usually a prodromal illness with fever and mild respiratory or gastrointestinal symptoms, followed by shock and pulmonary edema. The tempo of the disease at this stage may be rapid and require respiratory and circulatory support in an intensive care unit. HPS has a case mortality rate of 50%.

Diagnosis

The diagnosis of HFRS, nephropathia epidemica, and HPS is confirmed by indirect fluorescent or enzyme-linked immunosorbent assay (ELISA) for antibodies in acute and convalescent sera. IgM antibody determination may also be helpful. Virus isolation is difficult, but PCR and immunohistochemical staining may be useful in affected tissues.

Management

Care of patients with HFRS is supportive. With HFRS, renal dysfunction occurs early and may require institution of dialysis soon after diagnosis to prevent fluid overload and to correct electrolyte disturbances. Patients’ secretions should be handled with care, and enteric precautions (but not strict isolation) are prudent. It is not clear whether person-to-person transmission of the virus through direct inoculation occurs. For the hantaviruses, viremia recedes and antibody levels rise as the clinical phase appears. Accordingly, nosocomial transmission or hematogenous transmission with hantavirus infections has not been frequently documented, although presumed nosocomial transmission has been reported.⁹⁹ No vaccine is available.

Epidemiology

JE is the most common cause of encephalitis in Asia. Of the estimated 35,000 to 50,000 cases annually, 20% to 30% of infected individuals die and of those that recover, 30% to 50% have neurologic sequelae.^30,46 Transmission correlates with monsoon rains in the tropics and in the summer and fall seasons in temperate regions. Rice field–breeding and other culicine mosquitoes serve as the vectors. In addition to humans, birds and pigs can be infected. Pigs play an important role as amplifying hosts because they develop high-grade viremia from which large numbers of mosquitoes may be infected. Most infections in endemic areas occur in children, whereas all age-groups of previously unexposed populations are at risk. Transmission of JE currently occurs in India, Southeast Asia, China, Korea, Indonesia, and the Western Pacific region.³⁰ Routine use of JE vaccine in Japan has been eliminated because of low risk in this country. Recent outbreaks and case reports of JE in islands of the Torres Strait, which runs between Northern Australia and Papua New Guinea, indicate that the virus spread southward from Asia, presumably by migratory ardeid birds.³⁹

Virology and Pathophysiology

JE is caused by a neurotropic flavivirus that is phylogenetically related to West Nile and dengue viruses. It is transmitted by mosquitoes. After initial replication near the mosquito bite, viremia occurs, which if prolonged may seed infection to the brain. The cytopathologic effect of the flavivirus is believed to cause nerve cell destruction and necrosis.

Clinical Presentation

Incubation period is typically 2 to 15 days. Most infections do not cause clinical illness. Many patients recall a mild undifferentiated febrile illness, which probably coincides with the viremic phase of infection. Patients with encephalitis often report a similar prodrome. The encephalitis syndrome is not easily distinguished from other arboviral encephalitides. The patient usually complains of headache, lethargy, fever, and confusion and may display tremors or seizures. One clinical series suggested that the presence on admission of (1) unresponsiveness to pain, (2) low levels of anti–Japanese B encephalitis virus IgG or IgM antibodies (in serum or cerebrospinal fluid [CSF]), or (3) virus in CSF culture was associated with death. Of the 16 patients with fatal disease, all died within 7 days of hospitalization.¹⁵

Diagnosis

Acute and convalescent sera for antibody determination (virus neutralization or hemagglutination inhibition assays) provide the only reliable method of diagnosis. Paired sera should be sent for these assays through state health departments. Sensitive assays for determinations of IgG and IgM antibodies in serum and CSF have been developed but are not yet widely available. Because most patients seek treatment long after the viremic phase, blood cultures are rarely positive for the virus and CSF cultures are often positive only in patients with a poor prognosis.

Management

There is no specific therapy. The main interventions are prophylactic: vaccination and reduced arthropod exposure. Supportive care may require an intensive care unit. Because the virus is present in body fluids, especially CSF, blood and body fluid precautions should be considered. JE is only one of several arthropod-borne viruses that may cause encephalitis in different areas of the world. Others include Murray Valley encephalitis in Australia, tick-borne encephalitis in Europe (for which a vaccine exists), and La Crosse, West Nile, and St Louis encephalitis in the United States.

Epidemiology

Hepatitis A virus is transmitted primarily by the fecal–oral route by either person-to-person contact or ingestion of contaminated food or water. Food items commonly associated with outbreaks are raw or undercooked clams and shellfish. Risk factors include contact with a hepatitis A–infected person, international travel, household or personal contact with a child who attends a child care center, foodborne outbreaks, male homosexual activity, and use of illegal drugs.^3,59 Occasional cases are associated with exposure to nonhuman primates. Transmission by blood transfusion has been reported, but this is an uncommon source of infection. Hepatitis A is endemic worldwide, but underdeveloped nations have a higher prevalence than those in North America. Most persons in these areas show serologic evidence of past infection with hepatitis A virus. Hepatitis A is a common viral infection occurring in travelers, but rates are declining with increased use of hepatitis A vaccine

Virology and Pathophysiology

Hepatitis A virus is a picornavirus with a single-stranded RNA genome. Although the pathophysiologic mechanism has not been delineated, most infections begin with introduction of viral particles into the proximal gastrointestinal tract. Brief viremia precedes seeding of hepatocytes, where viral replication has been documented. With replication, hepatocellular necrosis is accompanied by lymphocytic infiltration. In the vast majority of cases, hepatic regeneration occurs after acute disease and no significant sequelae are observed. Chronic infection does not occur with hepatitis A.

Clinical Manifestations

The incubation period ranges from 2 to 7 weeks. The infection may be asymptomatic or mild, especially in children, but also in a minority of adults. The classic syndrome includes initially anorexia, followed by nausea, vomiting, fever, and abdominal pain. These symptoms may be accompanied by hepatosplenomegaly. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels rise within a few days of the onset of symptoms. In children, AST and ALT return to normal levels in 2 to 3 weeks, whereas in adults, resolution of elevated serum aminotransferase levels may take several months. Bilirubin level rises shortly after AST and ALT elevations. Jaundice usually follows gastrointestinal symptoms by several days to a few weeks. Resolution of jaundice may take another 3 to 4 weeks. The syndrome is occasionally preceded by arthralgias and rash, but these prodromal symptoms are uncommon. Resolution of acute disease is permanent in most instances, but rare cases of relapse have been noted. Pregnant women have a higher risk for severe illness than does the general adult population. Anti–hepatitis A antibody (primarily IgG) is detectable in the blood for many years after infection. The presence of the antibody confers immunity. Accordingly, reinfection with hepatitis A virus is not believed to occur.

Diagnosis

The clinical presentation of hepatitis A is usually milder than other types of viral hepatitis. Consequently, the symptoms are not distinctive enough to allow a firm diagnosis, which requires detection of hepatitis A antigen in the stool or serologic evaluation for hepatitis A–specific IgM or total anti–hepatitis A virus antibody. Stool hepatitis A antigen is maximal before the onset of symptoms but may be detected as long as 2 weeks after the onset of disease. A more practical test is measurement of hepatitis A–specific IgM antibody, which is usually present by the time symptoms are recognized and generally absent 6 months later. Measurement of anti–hepatitis A antibodies may be helpful in evaluating possible causes of past icteric episodes or for seroepidemiologic studies, but their presence does not differentiate recent from past infection.

Management

No specific therapy exists for hepatitis A. Affected persons are usually managed as outpatients and should be instructed on enteric precautions to avoid transmission to others. Although infectivity drops sharply soon after the onset of jaundice, it is prudent to maintain enteric and blood-drawing precautions for about 2 weeks after jaundice appears. Nosocomial transmission has also been documented, but most spread probably occurs before jaundice and diagnosis.

Prevention

Active immunization with hepatitis A vaccine is recommended for most travelers to at-risk areas.¹ In addition, hepatitis A vaccine is now recommended as part of routine U.S. infant/child immunization programs and for postexposure prophylaxis.^1,4,75

Epidemiology

With the widespread use of serologic markers for hepatitis B disease, it became apparent that spread occurs through exchange of blood, semen, or, rarely, saliva of infected people. Although spread is possible from persons with acute disease, the primary sources of viral particles are chronic carriers. Persons are defined as carriers if blood samples obtained 6 months apart both contain hepatitis B surface antigen particles (HBsAg). The carrier state follows acute infection in up to 90% of infected infants and 10% of adults. Risk factors for acquisition of hepatitis B infection in the United States include IV drug use, homosexual activity, and working in health care. In the United States, most victims are adults, and the carrier rate in the general population is less than 0.5%. In many areas of the developing world, most infections occur in infancy or childhood, and chronic carriers may constitute as much as 10% to 20% of the total population; thus travelers are more likely to be exposed to carriers than is the nontraveling population. The risk is higher in persons regularly exposed to body fluids, including medical personnel and persons with many sexual partners.¹⁰⁰

Virology and Pathophysiology

Hepatitis B virus is a deoxyribonucleic acid (DNA) virus unrelated to the agent responsible for hepatitis A. Infection occurs naturally in humans and can be induced easily in some nonhuman primates. Most hepatitis B infections are subclinical. In those resulting in clinical disease, entry of the virus into the liver is followed by viral replication and hepatocyte necrosis. HBsAg, a viral particle, appears in the bloodstream within 3 months of infection. In most cases, IgM antibody to the hepatitis B core antigen (HBcAg) appears first, followed by anti-HBsAg (surface) antibody. Antibody to a third hepatitis antigen, the e antigen (HBeAg), is present for variable periods. The course of the disease varies widely, depending on a number of factors that are not well defined. In brief, most cases are self-limited and resolve in 4 to 6 months. In these patients, anti-HBsAg or anti-HBcAg IgG antibodies can be detected for years after the episode of hepatitis. Chronic carriers do not develop anti-HBsAg antibody, but rather maintain measurable levels of HBsAg. Similarly, carriers with persistent HBeAg detectable in blood samples appear to be more infectious than are carriers without circulating HBeAg. The intricate network of antibody-antigen relationships in hepatitis B is believed to play a role not only in development of acute and chronic hepatitis but also in the many extrahepatic syndromes associated with hepatitis B. Immune complex formation has been suggested as etiologic in hepatitis B–associated arthritis, rash, arteritis, and renal disease.⁵⁵

Clinical Presentation

The incubation period for hepatitis B ranges from 7 to 22 weeks; however, the patient may be antigenemic for a large portion of that time. Manifestations of hepatitis B infection are similar to those of hepatitis A and include fever, anorexia, nausea, vomiting, and abdominal pain. In addition, a prodrome of rash, arthralgia or arthritis, and fever is seen in up to 20% of hepatitis B patients, compared with its rarity in hepatitis A. Glomerulonephritis is occasionally seen. Jaundice usually appears a short time after the onset of gastrointestinal symptoms. In the self-limited form of disease, recovery is complete by 6 months. Some infections follow a fulminant course; case fatality rates are 2% or less in most series. In addition to complete resolution or death, three other sequelae are possible with acute hepatitis B. A person may become an asymptomatic chronic carrier and remain HBsAg positive but have no detectable active hepatitis. Another sequela is chronic persistent hepatitis, a term used to describe persistent but not progressive, hepatic inflammation (usually monitored by serum transaminase levels), often with HBsAg in the serum. Persons with chronic active hepatitis may be HBsAg positive and have progressive hepatitis, which may result in cirrhosis and death directly related to liver disease. Any of these three conditions results in the presence of hepatitis B viral particles in the blood.⁵⁵

Diagnosis

A variety of antigen and antibody tests have been developed for diagnosis and monitoring of hepatitis B disease. The most practical and widely available test for diagnosis of acute disease is the assay for HBsAg. Antigen is usually present before the onset of symptoms and persists during symptomatic disease. Occasionally HBsAg may be undetectable in patients with clinical disease caused by hepatitis B. In these cases, antibody to HBcAg is often present. Later, antibody to HBsAg will appear, but this is often long after the episode of clinical hepatitis.

Management

Management is similar to that of hepatitis A. Prolonged viremia makes blood and body fluid precautions necessary until the absence of HBsAg antigen and presence of antibody to HBsAg are established. For patients with chronic infection, therapy with interferon-α and lamivudine is recommended.^55,71 Even in individuals with good prognostic indicators, the response rate in terms of long-term clearance of virus and seroconversion only approaches 30%.

Prevention

Universal immunization of U.S. infants beginning at birth and catch-up immunization of children and adolescents are the current recommendations. Vaccination for at-risk adults is also advised. Travelers to highly endemic areas who stay for 6 or more months or have close contact with inhabitants should be vaccinated. Available vaccines are discussed in Chapter 84.

Epidemiology

Delta virus infection is found only in patients concomitantly or previously infected with hepatitis B. Transmission follows a pattern similar to hepatitis B. In the United States, affected populations are IV drug abusers and multiply transfused hemophiliacs. Serologic evidence of delta virus disease has been documented in the Mediterranean basin, West Africa, and parts of South America.⁹³

Virology and Pathophysiology

The delta agent has been termed a defective virus because it requires hepatitis B virus activity for its own replication.⁷⁸ The agent is a single-strand of RNA enclosed in a protein coat of HBsAg. The delta agent infects cells at approximately the same time as does hepatitis B virus (coinfection), or it may be introduced later in the course of persistent hepatitis B infection (superinfection). In coinfected patients, the clinical picture may not differ from hepatitis B, but a higher percentage of such patients develop severe disease than do those with hepatitis B alone. Patients superinfected with the delta agent develop flare-ups of hepatitis, which may become fulminant. After the acute infection, the delta agent can cause progressive disease in previously stable hepatitis B patients. In general, infection with the delta agent worsens the prognosis of hepatitis B disease. The diagnosis can be made by detection of antibody to the delta antigen in the serum.⁷⁸ All hepatitis B–infected individuals should be tested for anti–hepatitis D virus (HDV) IgG antibodies at least once.

Management and Prevention

Management of acute hepatitis consists of supportive care. Only interferon-α has proved antiviral activity against HDV and is associated with clearance in approximately 25% of infected patients.^29,93 Precautions against transmission are the same as for hepatitis B. There is no specific vaccine or Ig for the delta agent. The best preventive measure is to be vaccinated for hepatitis B because delta agent infection cannot occur in the absence of the former virus.

Epidemiology

Risk factors for hepatitis C include IV drug use and, before routine testing, transfusion of blood products. Nonparenteral routes of infection are less important for hepatitis C than for hepatitis B. Hepatitis C is a global problem. Approximately 80% of exposed individuals develop chronic infection, which may lead to cirrhosis in 20% of subjects and hepatocellular carcinoma in up to 5% of this subset of infected persons. Rates of infection vary from 1% to 5% in most Western countries to 20% in parts of the Middle East, such as Egypt.

Virology and Clinical Manifestations

Hepatitis C is a single-stranded RNA virus of the Flaviviridae family. Acute disease is indistinguishable from hepatitis A or hepatitis B virus infections. Most infections are asymptomatic with jaundice occurring in fewer than 20% of infected individuals. Transition to chronic hepatitis after an insidious asymptomatic infection is the usual pattern. Chronic hepatitis may be asymptomatic or associated with nonspecific symptoms, such as lethargy, nausea, and abdominal discomfort. The patterns of cirrhosis and hepatocellular carcinoma, when they occur, do not differ significantly from those of other conditions. Extrahepatic syndromes associated with hepatitis C infection include porphyria cutanea tarda, membranous glomerulonephritis, and mixed cryoglobulinemia.

Diagnosis

Two types of tests are available for diagnosis, including Ig enzyme immunoassays and RNA detection tests. Enzyme immunoassays detect only IgG antibodies, and assays for IgM or early/acute infection are not available. False negative results may occur early in the course of acute infection. Within 15 weeks of exposure, the majority of hepatitis C–infected patients will seroconvert. Viral RNA can be detected in blood 1 to 2 weeks after exposure and before IgG detection. Assays for detection of hepatitis C RNA are used to detect infection in infants born to hepatitis C–infected mothers, for monitoring patients on antiviral therapy, and to identify seropositive patients who have persistent hepatitis C infection.⁴⁵ RNA tests can give false-positive and false-negative results. Viral RNA can also be shed intermittently, making a single negative assay inconclusive.

Management and Prevention

Prevention of hepatitis C largely depends on risk reduction, especially with respect to IV drug use. Pooled immunoglobulin has been used after exposure, but this should be procured from donors screened for hepatitis C. It is, however, not generally recommended. Unlike hepatitis B, protective antibody responses have not been demonstrated. Treatment of acute hepatitis C is supportive.⁵⁸ People with chronic hepatitis C infection are at risk for developing cirrhosis and primary hepatocellular carcinoma. Treatments are expensive and have significant side effects. They are effective in only 50% of infected individuals. Interferon-α is the drug of choice and may be used in combination with ribavirin. Response depends on the hepatitis C infecting genotype and patient comorbidities.^13,44,45

Epidemiology

Typhoid fever occurs worldwide, but its prevalence and attack rates are much higher in underdeveloped countries. Humans are the only host for S. typhi, the most common cause of the typhoid fever syndrome. Nearly all cases are contracted through ingestion of contaminated food or water. Transmission occurs through a variety of mechanisms, the most common of which are contact with a chronic carrier of the organism, especially food handlers, and ingestion of untreated waste material or sewage. Improved sewage and tracking of chronic carriers have markedly reduced the incidence in developed countries, although several hundred cases a year are reported to the CDC. Typhoid fever is estimated to cause 26 million illnesses and 200,000 deaths per year.²⁰ This may be underestimated because diagnosis can be difficult (especially in children) and because typhoid fever is not a reportable disease in most countries. Travel to Asia and especially India is associated with the highest risk for contracting typhoid fever.²⁶

Bacteriology and Pathophysiology

Salmonella species are gram-negative enteric bacilli. S. typhi is the prime cause of typhoid fever, but other species, including many of the Salmonella enteritidis serotypes and some non-Salmonella enteric organisms such as Yersinia or Campylobacter, may cause a typhoid fever–like syndrome. Salmonella species are easily grown on routine bacterial culture plates, but if multiple organisms are present, media with selective growth inhibitors may be needed for optimal sensitivity. After ingestion of food or water containing the pathogen, organisms are subjected to the acid stomach environment, which results in significant bacterial killing. If the organisms pass through the small intestine, several processes may occur. The bacteria may simply pass through, causing few clinical symptoms. If the bacteria multiply and invade the mucosa, a gastroenteritis-like syndrome will result. Typhoid fever requires penetration of the intestinal mucosa and intestinal lymphatics, where intracellular replication of S. typhi occurs. Soon thereafter bacteria seed the bloodstream and are transported to reticuloendothelial cells throughout the body, where further intracellular replication can take place. After the acute episode of infection is over, Salmonella species may remain and asymptomatically reproduce in scarred or chronically inflamed tissues. Persons may shed organisms from such foci for years and serve as a source of outbreaks while they themselves are asymptomatic. The most common site for such colonization is the chronically diseased gallbladder.

Clinical Presentation

After exposure to the pathogen, 10 to 14 days usually pass before the onset of clinical illness. Some patients may experience gastroenteritis early in the course of disease, and abdominal pain or diarrhea may be present at the time the classic typhoid fever picture develops. Fever is usually the first sign of disease. Fever increases slowly over several days and may remain constant for 2 to 3 weeks, after which time defervescence begins. With antibiotic therapy, fever resolves more rapidly, often within 3 to 4 days. Relative bradycardia may accompany fever. Most victims also report headache, malaise, and anorexia. Rose spots (2- to 4-mm [0.08- to 0.16-inch] maculopapular blanching lesions) are classically described on the trunk, although they are not seen in the majority of patients. Hepatomegaly and splenomegaly have been reported in a large number of patients.⁴³ Laboratory investigations early in the course may show a high white blood cell (WBC) count, anemia, and mild elevations of serum hepatic enzyme levels, including AST, lactate dehydrogenase, and alkaline phosphatase. Later in the course of the disease, leukopenia (WBC <3500/mm³) develops. Uncomplicated and untreated typhoid fever resolves in 3 to 4 weeks. Several complications may herald or contribute to death. Intestinal perforation, presumably secondary to necrosis of lymphoid areas of the bowel wall, may lead to peritonitis and death. Significant gastrointestinal hemorrhage may occur but rarely is fatal. Secondary pneumonia is common. A subgroup of patients has more severe disease, which may include myocardial involvement, mental status changes, hyperpyrexia, and multisystem failure. The overall case fatality rate has ranged from 12% to 32% in the developing world but is less than 2% in industrialized nations.²⁵

Diagnosis

Culture of a bacterial species associated with the syndrome (most likely S. typhi) from a normally sterile fluid is the gold standard; however, it is expensive and requires expertise that many developing countries cannot afford. Multiple studies have evaluated the usefulness of various diagnostic tests. In general, bone marrow culture is the most sensitive method, detecting up to 90% of cases, whereas blood cultures are less sensitive. Both methods are most useful in the first week of disease. Stool cultures (and string test cultures) may be positive later in the course of disease but provide only circumstantial evidence of the causative agent. Other serodiagnostic methods are in development but have not yet proved useful.⁴

Management

Chloramphenicol had been the mainstay of treatment for typhoid fever since the late 1940s. Ampicillin and trimethoprim-sulfamethoxazole were the traditional alternatives. In the last decade, multiple drug resistance has increased, so ciprofloxacin is now the first-line antibiotic. Unfortunately, increasing resistance to quinolones has been observed, especially from the Indian subcontinent. In cases of quinolone resistance, either laboratory or clinical, ceftriaxone or other third-generation cephalosporins are indicated.⁶ Other treatment modalities include fluid support and adequate nutrition. Corticosteroids have been used empirically for many years. A single randomized double-blind study showed that administration of high-dose dexamethasone (3 mg/kg for the first dose, followed by 1 mg/kg every 6 hours for eight more doses) with chloramphenicol resulted in significantly lower mortality in patients with severe typhoid fever than in those treated with chloramphenicol alone.⁴² Severe typhoid fever was defined in this study by the presence of obtundation, delirium, stupor, coma, or shock (systolic blood pressure <90 mm Hg for those 12 years or older and <80 mm Hg in younger children). High-dose steroids are not recommended for those with less severe disease and should be used cautiously in those with severe disease.¹⁹

Prevention

Two vaccines exist for prophylactic use. An oral vaccine was licensed for use in the United States in 1989. The vaccine contains the Ty21 strain of S. typhi, and is associated with minimal side effects. The Ty21a vaccine is given as a four-dose series, with 1 day between each dose. Immunosuppression, antibiotic use, and gastroenteritis are contraindications to the use of this vaccine. The parenteral vaccine contains the Vi (virulence) polysaccharide of S. typhi purified from formalin-killed bacteria. It is administered as a single intramuscular injection and is therefore most useful when vaccination is required on short notice. A booster is required every 2 years.⁹⁴ Even when the vaccine is given before travel, it is important to observe routine precautions for ingestion of food and water to prevent typhoid fever and acquisition of other pathogens by the fecal–oral route.

Epidemiology

Cases of meningococcal disease occur sporadically worldwide, with epidemic disease generally limited to developing nations. The five predominant strains of meningococcal infections are A, B, C, Y, and W-135. Serogroup A (and less so serogroup C) is most frequently associated with epidemics in sub-Saharan Africa. Increasingly, serogroup W-135 has emerged in Saudi Arabia (associated with the Hajj pilgrimage) and West Africa.⁹⁷ Epidemic situations clearly pose the greater health problem to both travelers and resident populations. The “meningitis belt” in sub-Saharan Africa (a region that extends from Ethiopia in the east to Senegal in the west) experiences 100 to 800 cases/100,000/yr. In contrast, the U.S. population experiences approximately 1 case/100,000/yr, and the U.K. population experiences 2 to 3 cases/100,000/yr.⁷⁶ Particularly in sub-Saharan Africa and China, the disease demonstrates yearly incidence peaks and periodic massive outbreaks, the exact determinants of which are unknown. Transmission of the organism occurs by exchange of respiratory secretions; contact is believed to be important in the spread of the disease. Asymptomatic transient nasopharyngeal carriage of the meningococcus, occurring with a baseline prevalence of 5% to 10%, may increase during epidemic periods and in close contacts of cases. The secondary attack rate among household contacts of patients with sporadic disease is 2 : 1000 to 4 : 1000, whereas that in epidemics ranges from 11 : 1000 to 45 : 1000 household contacts.

Bacteriology and Pathogenesis

Neisseria meningitidis is a gram-negative diplococcus that grows easily on several common media, including chocolate and blood agar. The organism is characterized further on the basis of serologic analysis of capsular antigens. The most common serogroups are A, B, C, Y, and W-135. In the United States, serogroups B, C, and Y account for 30% of reported cases. In U.S. infants, 50% of cases are caused by serogroup B, for which there is no vaccine. Asymptomatic persons may carry various serotypes of N. meningitidis in the nasopharynx for short periods of time. An antibody response is often generated to these strains during asymptomatic carriage. The conditions that cause one person to become clinically ill with invasive disease, while another carrier remains healthy are not well understood. The route of entrance of the organism to the bloodstream and central nervous system (CNS) is presumably through the nasopharynx or respiratory tract.

Clinical Presentation

Meningococcal disease may appear in a variety of forms, including, but not limited to, bacteremia with septic shock; meningitis, often accompanied by bacteremia; and pneumonia. Sustained meningococcemia may lead to severe toxemia with hypotension, fever, and DIC. In the fulminant presentation, adrenal hemorrhage may lead to Waterhouse-Friderichsen syndrome, and death may follow intractable shock. In the United States, the case fatality rate for sustained meningococcemia is generally higher than for meningococcal meningitis. There is also a clinical syndrome of chronic meningococcemia with a much more insidious onset.

Meningitis caused by N. meningitidis classically begins with fever, headache, and a stiff neck. It may also be accompanied by bacteremia and any of several skin manifestations, including petechiae, pustules, or maculopapular rash. In either meningitis or bacteremia, progression of petechiae to broad ecchymoses is a poor prognostic sign. As with septic meningococcemia, severe meningitis may progress with mental status deterioration, hypotension, congestive heart failure, DIC, and death. The case fatality rate of meningococcal meningitis with or without bacteremia is now estimated to be about 10%.⁵¹ In classic cases of meningitis or bacteremia with sepsis, the peripheral WBC count is elevated, with polymorphonuclear cell predominance. CSF typically is purulent, usually with more than 500 polymorphonuclear cells/mm³. There may be a more heterogeneous cell population and fewer cells if CSF is obtained early in the course or if the patient has been treated with antibiotics. The CSF glucose level is usually low and protein high, as in other bacterial meningitides. Gram stain of CSF may show the gram-negative diplococci. Meningococcal pneumonia is a well-known but less common clinical entity described in military recruit populations involving serogroup Y organisms.

Diagnosis

The presumptive diagnosis in an epidemic can be made on the basis of clinical presentation and purulent spinal fluid. The presence of characteristic bacterial forms on Gram stain is also suggestive. A definitive diagnosis requires culture of the organism from CSF or a normally sterile fluid (usually peripheral blood). This may be impossible in the case of a patient who was previously treated with antibiotics before CSF culture. Several commercial kits for measuring meningococcal antigen are now available for use on CSF or blood samples; they have variable sensitivity and specificity.

Management

Treatment of meningococcal meningitis or sepsis is a medical emergency. Fortunately, the organism remains sensitive to a large number of antibiotics. Treatment of choice is penicillin G, 300,000 units/kg/day (up to 24 million units/day), given intravenously in divided doses every 2 hours. Between 7 and 10 days of therapy for serious disease is appropriate. Ceftriaxone is an alternative antimicrobial agent. If the patient is allergic to penicillin, chloramphenicol (100 mg/kg/day) may be given, although the emergence of chloramphenicol-resistant strains of N. meningitidis is of great concern.³³ Antibiotic treatment before culture or hospital referral is recommended in clinically suspected cases. Supportive care should include close monitoring for hypotension and cardiac failure. Fluids and vasoactive and cardioselective agents may be important. This type of support necessitates invasive monitors and intensive care unit technology. Development of DIC is an ominous sign. Although focal bleeding and adrenal necrosis may lead to acute adrenal insufficiency, the role of replacement steroids in the treatment of Waterhouse-Friderichsen syndrome is unclear. Because the infectious agent has been found in household contacts and in those with exposure to oral secretions, contacts should receive prophylaxis to eradicate the organism. Rifampin, 600 mg by mouth every 12 hours for four doses, is standard adult prophylaxis. Children should receive 10 mg/kg of rifampin every 12 hours for four doses if they are older than 1 month and 5 mg/kg every 12 hours for four doses if they are younger than 1 month. More recently, alternate regimens using ceftriaxone and ciprofloxacin have also been proved to be efficacious, although rifampin remains the standard.

Prevention

Effective meningococcal vaccines are available that target serogroups A, C, Y, and W-135. MPSV4 is a tetravalent meningococcal polysaccharide vaccine containing serogroups A, C, Y and W-135 licensed for use in children greater than 2 years and adults. It can be given as one subcutaneous injection of 0.5 mL. Clinical efficacy of more than 65% is maintained for at least 3 years in persons immunized at 4 years of age or older, although protection wanes more rapidly in children vaccinated at younger than 4 years of age. The tetravalent meningococcal conjugate vaccine (MCV4) also contains serogroups A, C, Y and W-135 and is licensed for use in children older than 2 years and adults. With increased meningococcal disease rates in college dormitories and military barracks, it is recommended that all adolescents 11 to 18 years of age be immunized with a single dose of MCV4. In addition, asplenic individuals, those with specific complement deficiencies, and travelers to meningitis belt countries during the dry season or to regions with ongoing epidemics are advised to be vaccinated. Vaccination is a Hajj visa requirement for Hajj/Umrah pilgrims traveling to Saudi Arabia.⁹⁶ Because the areas in which epidemic meningococcal disease occur change over time, it is prudent to check with appropriate authorities to determine current recommendations for meningococcal vaccination before travel.

Epidemiology

Pertussis is found throughout the world. The incidence is currently highest in undeveloped countries, where immunization rates are low and socioeconomic conditions predispose to many communicable diseases. Pertussis is highly infectious, with attack rates of greater than 90% in unvaccinated household contacts. Untreated individuals remain infectious for greater than 6 weeks. In the United States, the most severe disease occurs in children under 5 years old and particularly in young infants. Transmission is by airborne particles from respiratory secretions of infected persons.

Bacteriology and Pathophysiology

Bordetella pertussis is a gram-negative coccobacillus. The organism produces several toxins when present in the respiratory tract. Pertussigen stimulates lymphocytosis and hemagglutination. Dermonecrotic toxin and tracheal cytotoxins damage respiratory epithelium. In addition, endotoxin is produced. During the course of the somewhat protracted disease, complications can occur that may cause death. The most serious of these are secondary pneumonia or encephalopathy. In addition, fits of coughing often result in pneumothorax, hemorrhage (facial, conjunctival, and CNS), and aspiration.

Clinical Presentation

Classic pertussis develops after an incubation period of 7 to 10 days. The disease appears in three stages: catarrhal, paroxysmal, and convalescent. The catarrhal stage lasts 1 to 2 weeks and resembles an undifferentiated upper respiratory tract infection with cough and mild fever. Progression of the cough to yield the classic whoop (which results when the patient gasps for breath after a prolonged coughing episode) marks the paroxysmal stage, which again can last as long as 2 weeks. During this stage, the WBC count may show marked lymphocytosis. Finally, cough resolves during the convalescent stage. Death may occur from pertussis alone or from complications such as aspiration pneumonia. Recent case fatality rates for Americans were 0.4% for all persons and 1% for patients younger than 1 year. The disease in adults is often milder, although it may show a severe classic pattern. Some investigators believe mild or atypical disease in adults may serve as a reservoir for infection of susceptible children.

Diagnosis

Culture of the organism from a nasopharyngeal swab is the most efficient way to diagnose pertussis; however, the culture is positive most frequently early in the illness, and late cultures (after the second week of illness) are rarely helpful. For optimal recovery, Bordet-Gengou media should be used, with methicillin added to reduce overgrowth by other bacteria present in the nasopharyngeal flora. Direct fluorescent antibody techniques may also be used to evaluate nasopharyngeal swabs or sputum samples for the presence of organisms. PCR is increasingly being used for detection.

Management

Treatment with antibiotics, unless begun in the incubation or catarrhal period, has little effect on the course of the disease. Antibiotics can reduce subsequent transmission to contacts, however, and should be instituted as soon as the diagnosis is made. Macrolides are the drugs of choice with azithromycin, erythromycin, or clarithromycin all appropriate choices for first-line treatment and prophylaxis. Treatment should be given for at least 2 weeks. Other useful agents include doxycycline, trimethoprim-sulfamethoxazole, and chloramphenicol. In patients with severe disease, corticosteroids may provide some improvement. Perhaps more important than specific antibiotics is supportive care, including hydration, nutrition, care to maintain adequate ventilation, and supplemental oxygen. In addition, external stimuli, which seem to exacerbate symptoms, should be kept to a minimum.

Prevention

Universal immunization of children younger than 7 years, as well as boosters for adolescents (age 11 to 18 years) and adults, is recommended. In the United States, acellular pertussis vaccines are currently used. The pertussis vaccine is combined with diphtheria and tetanus toxoids (pediatric DTaP formulation and adolescent/adult Tdap formulations). The Tdap replaces Td to boost waning pertussis immunity in the adult population where the majority of pertussis infections are perpetuated. In cases of pertussis exposure, immunization of unimmunized or underimmunized individuals should be initiated. In addition, chemoprophylaxis (with azithromycin, erythromycin, or clarithromycin) should be started for all household contacts and other close contacts regardless of age and immunization status. If 21 days has elapsed since exposure, chemoprophylaxis is of limited value.²

Epidemiology

Humans are the natural host for Corynebacterium diphtheriae. Person-to-person spread occurs through contact with respiratory secretions or diphtheritic skin lesions. A carrier state exists in which people who have either been immunized or previously infected can harbor the organism and asymptomatically transmit it to others. Evidence suggests that diphtheria can be transmitted through food or water, but this is not a major route of transmission.

Bacteriology and Pathogenesis

C. diphtheriae is a gram-positive, club-shaped bacillus. On Gram stain, the clustered bacteria have the characteristic “Chinese letter” configuration. The organisms grow on standard media, but to avoid overgrowth of other oral flora, selective media (Loffler’s culture medium or cysteine-tellurite agar) are suggested. The presence of a lysogenic bacteriophage in some C. diphtheriae organisms induces production of diphtheria toxin. The toxin is produced as a single molecule with two subunits, fragments A and B. Fragment B facilitates attachment to the cell membrane of host cells, and after attachment, fragment A enters the cell. Cell death results from large-scale disruption of protein synthetic capabilities.

Clinical Presentation

The most important manifestation of diphtheria is respiratory tract infection. Illness begins after an incubation period of about a week with nonspecific symptoms of malaise, fatigue, mild sore throat, and slight fever. The classic lesion is exudative pharyngitis progressing to a greenish-gray membrane that is difficult to dislodge. This membrane may spread over the posterior pharynx, tonsils, and uvula and down the respiratory tree to involve the larynx and trachea. Any one of these areas may be involved selectively, and the severity of illness is to some extent related to the area grossly involved. In severe disease, swollen tissues may result in a bull-neck appearance. Major complications include obstruction of the respiratory tract, which may result from direct parapharyngeal swelling or laryngeal involvement in young children, and sloughing of the tracheobronchial membrane in older patients. In addition to respiratory tract damage, toxin directly injures myocardial and neural tissue. Endocarditis occurs in some patients. Early signs in the first week of disease include ST-T wave depression and atrioventricular conduction abnormalities on the electrocardiogram. Congestive heart failure and cardiac enlargement may develop. Neurologic deficits usually begin with pharyngeal and cranial nerve paralysis. Cranial nerve paralysis may progress to bilateral motor paralysis, which generally resolves over a period of 3 to 6 months. In the tropics, cutaneous diphtheria is seen frequently. The skin lesions are not consistent in appearance and range from very superficial impetigo-like lesions to deep ulcers. In most cases of cutaneous disease, absorption of toxin is not great enough to cause the multisystem involvement seen in respiratory tract disease. The prevalence of skin lesions increases the overall likelihood of coming in contact with toxigenic C. diphtheriae.

Diagnosis

Reliable isolation of the organism requires a selective medium and several days of culture. Treatment should be started as soon as the patient is evaluated and is guided by clinical manifestations.

Management

Because the toxin and not the organism per se mediates life-threatening clinical manifestations of diphtheria, neutralization of absorbed toxin is crucial. A horse-derived antitoxin is available and should be administered as soon as the diagnosis is seriously considered. A 0.1-mL test dose of intradermal antitoxin diluted to a 1 : 1000 concentration (with a saline control) is observed for 20 minutes. If no reaction occurs, full doses can be given intravenously. Antitoxin should be diluted to 1 : 20 in saline and given no faster than 1 mL/min. For mild cases, 20,000 units may be adequate, 40,000 units for moderate cases, and as much as 80,000 to 120,000 units for severely ill patients.¹⁷ Erythromycin or penicillin G may be given to eradicate the carrier state, although their use has no effect on the clinical course of disease. Close observation is crucial to evaluate the need for respiratory support, especially in young children. Serial electrocardiograms and neurologic evaluation establish the onset of complications. If significant conduction abnormalities are present, continuous heart monitoring should be undertaken. Strict bed rest is recommended for all patients for 2 to 3 weeks. Immunization should be given during convalescence because disease survival does not necessarily confer immunity.

Prevention

Close contacts of patients with respiratory diphtheria should receive diphtheria vaccine if they have not received at least three doses previously or if 5 or more years have elapsed since the last dose. In addition, unimmunized or partially immunized contacts should receive either intramuscular benzathine penicillin (600,000 units if younger than 6 years, 1.2 million units if older than 6 years) or 7 to 10 days of erythromycin (40 mg/kg/day for children or 1 g/day for adults, in four divided doses). Antitoxin is not recommended for contacts. The most important way to prevent diphtheria in adults, however, is to ensure that all adults receive a booster dose of Tdap every 10 years.

Epidemiology

The bacterium and its spores are ubiquitous. Approximately 10% of people in the general population carry Clostridium tetani in fecal flora. Person-to-person spread is not an important cause of this disease. Disease occurs when the organism is introduced into an environment suitable for its growth, specifically wound sites with an anaerobic environment. In the developing world, the vast majority of cases are in neonates as a result of umbilical stump infections.

Bacteriology and Pathophysiology

C. tetani is a gram-positive, anaerobic, spore-forming rod. The spores are hardy and can occasionally survive boiling for short periods. After proliferating in an appropriate anaerobic environment, C. tetani releases the toxin tetanospasmin, which, in generalized disease, reaches the spinal column and CNS by hematogenous spread. The toxin is taken up by inhibitory neurons, where it interferes with release of inhibitory neurotransmitters, resulting in disinhibition of motor groups. Disinhibition of the sympathetic nervous system neurons occurs through a similar mechanism. The result is muscular spasm of varying severity and signs of sympathetic nervous system hyperactivity, including tachycardia, sweating, arrhythmias, and high blood pressure.

Clinical Presentation

A tetanus-prone wound precedes most adult disease, which may not be evident at the time of presentation. Localized tetanus, with spasm of a focal set of muscle groups, may occur and remain localized for weeks, then slowly resolve. This form of tetanus is much less common than is the generalized form, which often begins with trismus, or spasm of the masticator muscle group (Figure 85-2). Gradual onset of spasm of other muscle groups usually involves the trunk and extremities. Because the posterior muscles are stronger during spasms, the victim exhibits lumbar lordosis, with the neck and legs extended and arms flexed at the elbows (opisthotonos). Spasms seem to be exacerbated by external stimuli, such as sudden sound or light. The primary danger is loss of ability to breathe, especially during prolonged spasms. Respiratory failure is the main cause of death. The clinical picture in neonatal tetanus is similar but begins with restlessness and failure to nurse, with progression to tetany and sympathetic overactivity. There is no definitive laboratory test to confirm the diagnosis of tetanus, but the clinical picture is adequate in the majority of cases.

FIGURE 85-2 Patient with tetanus following a leg wound suffered during the 2010 earthquake in Haiti. Note difficulty with handling of oral secretions.

(Courtesy S. Paul Auerbach, MD.)

Management

Emergency medical treatment of tetanus patients should include (1) excision of the wound, (2) administration of human tetanus immunoglobulin (TIG; 3000 to 6000 units in a single dose), and (3) administration of an antibiotic effective against C. tetani, such as penicillin or metronidazole for 10 to 14 days.⁸³ Depending on the severity of disease, different levels of supportive care and sedation may be appropriate. Diazepam may be given to mildly affected patients for sedation. Patients should be evaluated carefully for dysphagia. If dysphagia is present or other respiratory difficulties arise, endotracheal intubation or a tracheostomy should be performed. With prolonged spasms, hypoxia and cyanosis may occur; mechanical ventilation with pharmacologic paralysis is appropriate. At the same time, attention must be given to fluid balance and nutrition. Enteral feeding by a nasogastric tube is the least invasive way to supply both. β-Blockers have been suggested to relieve symptoms of autonomic overactivity, such as tachycardia and hypertension, but there is no proved benefit to their prophylactic use. Sources of sensory stimulation should be reduced when the spasms are uncontrolled.

Prevention

Although rare cases of tetanus have occurred in previously immunized persons, immunization is considered at least 99.9% effective. Several vaccine formulations are now available in the United States. Children younger than 7 years may receive either DTaP or DT (diphtheria and tetanus toxoid only) vaccine. A third vaccine, Tdap, is manufactured for use in persons at least 7 years old and consists of tetanus toxoid and a smaller amount of diphtheria toxoid and pertussis than is present in the pediatric vaccines. A reduced amount of diphtheria toxoid is used in the adult preparation, because both the amount of toxoid and increasing age are associated with more severe reactions to vaccination. Adults who are unimmunized should be given a series of three doses (0.5 mL intramuscularly) of Tdap, with the second dose 4 to 8 weeks after the first and the third dose 6 to 12 months after the second. A booster should be given every 10 years thereafter. All travelers should know when they were last immunized and stay up to date with booster doses. From the standpoint of tetanus prevention, care of wounds is crucial. The tetanus-prone wound, contaminated with dirt or feces or caused by puncture, crush, avulsion, or frostbite, should be cleaned and debrided appropriately. Persons with tetanus-prone wounds should receive 250 units of TIG IM (for all ages) if their immunization history is unknown or their immunization series is incomplete. These persons should also receive a dose of Tdap and complete an immunization series. Persons fully immunized and given an appropriate booster before a tetanus-prone wound should not receive TIG. If they have not received a booster within 5 years, however, they should get a dose of Tdap.

Clinical Manifestations

The initial sign of infection is a nodule at the site of the tsetse fly bite. This lesion becomes erythematous and painful over a period of 1 week and usually recedes after several days. Dissemination of the trypanosome throughout the body causes clinical symptoms, notably fever, headache, and severe malaise. On physical examination, enlarged supraclavicular and posterior cervical lymph nodes are noted. This phase of illness lasts several days and is followed by an asymptomatic period of several weeks. The acute phase may then recur. In the case of T. brucei gambiense infection, symptoms are less severe and evolve into a syndrome characterized by behavioral changes and chronic somnolence. T. brucei rhodesiense infections cause severe anemia, frequent episodes of fever, and eventual heart failure and severe CNS involvement. Both forms have high fatality rates. Without treatment, infected patients die within weeks to months after T. brucei rhodesiense disease, and within a few years from T. brucei gambiense disease.

Diagnosis

Definitive diagnosis depends on identification of parasites in blood, lymphatics, or CSF. Thick blood smears and buffy coat preparations should be prepared with Giemsa stain and examined for the presence of trypanosomes. The CSF should be subjected to centrifugation and the sediment examined for parasites. Associated laboratory abnormalities include anemia, monocytosis, and elevated serum and CSF IgM levels.

Management

Suramin (available from the CDC) should be used for treatment of early T. brucei rhodesiense infection, although the drug may cause proteinuria. A test dose of 100 mg IV is first given to detect possible idiosyncratic reactions. If tolerated, 1 g should be given on the initial day of treatment and 3, 7, 14, and 21 days later. If CNS involvement is diagnosed or strongly suspected (CSF lymphocytosis and elevated IgM), melarsoprol (available from the CDC) should be administered. This drug should be given at 2 to 3.6 mg/kg/d IV for 3 days. After a week with no drug given, additional injections of 3.6 mg/kg/d IV for 3 days are given. Repeat again after one week with no drug given. This arsenical compound is toxic, causing encephalopathy and exfoliative dermatitis, and should be used only in a controlled hospital setting. For early T. brucei gambiense infection, pentamidine (4 mg/kg body weight intramuscularly, up to 300 mg/kg given over 7 days) is the treatment of choice. Eflornithine, 100 mg/kg every 6 hours for 14 days, should be used for more advanced cases of this infection.

Clinical Manifestations

Affected individuals generally do not recall initial contact with the insects, during which time triatomid feces containing the protozoan organisms are deposited on broken skin or mucous membranes and then multiply within local macrophages. The macrophages rupture and elicit an inflammatory reaction that appears as a nodule with slightly painful satellite nodules or draining lymph nodes. A symptomatic phase, characterized by fever and diffuse lymph node enlargement, develops. Hepatosplenomegaly may also occur. In severe cases, acute myocarditis, pericarditis, or endocarditis is seen. After several months, the acute phase resolves, and chronic disease appears, characterized by cardiomyopathy, megaesophagus, or megacolon.⁷⁷ It is rare for the traveler to develop these signs or symptoms.

Diagnosis

Diagnosis during the acute phase may be made by demonstration of parasites in leukocytes in Giemsa-stained blood smears. Amastigotes of T. cruzi may also be present in biopsy specimens of lymph nodes or muscle. Elevated IgM antibody titers to T. cruzi (performed by the CDC) also support the diagnosis. In the chronic phases of Chagas’ disease, the clinical findings of cardiomyopathy, megaesophagus, or megacolon, in concert with isolation of T. cruzi from blood, support the diagnosis. To detect trypanosomes in blood, uninfected triatomids are permitted to feed on the patient’s forearm for 30 minutes. The insects are then kept for 30 days, and the intestinal contents of the insect inspected for T. cruzi. If negative, the examination may be repeated 60 days later. This test is positive in about 50% of cases. Serologic tests, including complement fixation anti-T. cruzi antibodies, are useful but may also be positive in long-term residents of endemic areas.

Management

Acute Chagas’ disease is treated with nifurtimox, 8 to 10 mg/kg body weight orally per day in four divided doses for 120 days. The drug is available from the CDC. Chronic disease manifestations are treated with supportive/palliative therapies, including heart transplantation for severe cardiomyopathies.

Clinical Manifestations

Signs and symptoms of infection vary among the three schistosome species. The initial presentation of acute S. mansoni infection may include fever, anorexia, weight loss, and abdominal pain. This unusual symptom complex, which occurs in individuals with heavy infection, has been referred to as Katayama fever and appears 18 to 60 days after exposure.⁸⁰ Travelers with light or moderate exposure, however, usually have no specific signs or only mild local dermatitis (swimmer’s itch) associated with contact with cercariae, the infective stage of the parasite released by snails (Figure 85-4). In persons with established infections, the prevalence of clinical manifestations is low. Most individuals have no signs specifically attributable to S. mansoni infection. Hepatomegaly or splenomegaly, attributable to portal hypertension after granulomatous reactions to eggs deposited in the liver, occurs in 15% of subjects. Eggs may also embolize to the lungs and induce granulomatous lesions and cor pulmonale. Those at greatest risk are persons who have the heaviest intensity of infection as judged by fecal egg counts. These complications may ultimately result in esophageal and gastrointestinal varices, which cause acute blood loss. The manifestations of S. japonicum infections are similar to S. mansoni infections, except that Katayama fever appears to be more frequent in the former case. In addition, there is a unique manifestation of S. japonicum infection attributable to embolization of eggs to the brain. Generalized or jacksonian seizures are the major signs of cerebral schistosomiasis. Because S. haematobium adult worms inhabit the venous system of the genitourinary tract, the signs and symptoms of this helminth infection are primarily secondary to granulomatous reactions to eggs present in the ureters and bladder wall. Dysuria and hematuria have been reported in many individuals who reside in endemic areas. Treatment for all species is a one-time dose of praziquantel. Intense reactions may benefit from a course of oral corticosteroids.

FIGURE 85-4 Mild local dermatitis associated with contact with cercariae, the infective stage of Schistosoma spp. released by snails.

(From Ryan ET, Wilson ME, Kain KC: Illness after international travel, N Engl J Med 347:505, 2002.)

The major risk to travelers is encountered when exposure to large numbers of cercariae occurs by bathing in fresh water that contains infective snails. Cases of transverse myelitis have been reported in these circumstances. Appropriate preventive measures include counseling to avoid bathing or swimming in fresh water in endemic areas.