Malaria is caused by four human Plasmodium species: falciparum, vivax, ovale, and malariae. P. falciparum is the most common infecting species and causes a potentially lethal form of the disease. More than 1000 cases of malaria occur in the United States every year, almost all are imported cases.2 Malaria parasites are transmitted to the human by the bite of Anopheles mosquitoes. After injection into the blood stream by the mosquito, the parasites immediately enter the liver and replicated there. In falciparum malaria, the parasites exit the liver after 1–2 weeks and begin the blood stage of infection, which causes disease. As the parasites replicate in red blood cells, rupture and infect new cells, the typical signs and symptoms of fever, chills and anemia develop. Respiratory and gastrointestinal complaints may also be associated with malaria. The time from initial infection to clinical illness may be prolonged in patients who received antimalarial prophylaxis, treatment with antibiotics with antimalarial properties or preexisting immunity. P. vivax and P. ovale have the unique ability to persist for long periods of time in the liver as hypnozoites. Blood stage infection that causes malaria illness can develop months to years after exposure. In the absence of treatment of the liver stage of the disease (typically with primaquine), disease can recur even after effective treatment of the blood-stage parasites. The diagnosis and management of malaria is discussed in Chapter 66.
Dengue virus is the most important arboviral infection among travelers.3 It is transmitted by the Aedes aegypti mosquito and typically presents as a nonspecific, self-limited febrile illness, but secondary infection (infection with a new serotype) can cause the severe manifestations of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS).
Dengue is responsible for 11–33% of fevers among children in Southeast Asia.4,5 Although the incidence of dengue in Latin America is similar to Southeast Asia, the disease is more evenly distributed among the adults and children in both the Americas. Dengue is the leading cause of systemic febrile illness among travelers returning from Southeast Asia, the Caribbean, and Central America.6 Dengue occurs in most other regions of the world but is extremely rare in travelers to Africa.
Symptomatic dengue infection is classified into three syndromes: dengue fever, DHF, and DSS. The typical presentation of dengue fever includes fever, severe headache, myalgias, and arthralgias. The pain is so severe that it is often referred to as “break-bone fever.” Rash may appear after the onset of fever. A typical finding that occurs in approximately 50% of patients with dengue fever is a positive tourniquet test. The test is performed by inflating a blood pressure cuff halfway between the systolic and diastolic blood pressures for approximately 5 minutes. After release, the number of petechiae in a 2.5 × 2.5 cm patch is counted. Greater than 20 petechiae indicates a positive test. The fever may have a “saddleback pattern” in which a second episode of fever and symptoms develop after an initial resolution. Mild mucosal bleeding may occur, but rarely is the amount life threatening. Fatigue may linger for up to 6 months after dengue infection.
DHF and DSS occur almost exclusively in individuals who have previous infection with a heterologous strain of one of the four dengue serotypes. DHF and DSS are clinical syndromes with World Health Organization-defined case definitions that have been called into question recently and may undergo revision.7 In general, the criteria for DHF are: fever for 2–7 days, hemorrhage, thrombocytopenia (<100,000 platelets/mm3) and hemoconcentration (>20% rise in hematocrit over baseline), or evidence of increased capillary permeability (pleural effusion, ascites, low serum protein). The tourniquet test is almost always positive. The severe presentation of DSS usually occurs after the thrombocytopenia and plasma leakage. It is characterized by a rapid, weak pulse with narrowed pulse pressure or hypotension with cool extremities and restlessness.8
The diagnosis of dengue is most frequently made by comparing paired serological titers. A specimen should be obtained within the first 5 days of symptoms. This acute-phase sample can be used for virus isolation and detection of IgG and IgM. In dengue, IgM frequently rises later in the course of illness so early diagnosis is often difficult. A convalescent phase specimen should be obtained at least 1 week after the onset of symptoms. The testing is done by the CDC and the specimens can be sent directly or through the state laboratory. In dengue-endemic countries, rapid tests are often used, but none are available in the United States.
The treatment of dengue is symptomatic with an emphasis on fluid resuscitation. In patients with dengue fever, a rising hematocrit is often the first sign of impending DHF/DSS and increased fluid administration may avert severe disease. In patients who develop shock, a fluid bolus of 25 cc/kg over 2 hours followed by maintenance plus replacement fluids is associated with excellent survival. Colloid and crystalloid are equally effective in most patients but colloid is preferred in the most severe cases.9,10 Antipyretics that interfere with coagulation, such as aspirin and nonsteroidal anti-inflammatory drugs, should be avoided in cases of dengue because of the increased risk of hemorrhage.
Rickettsial infections present with an influenza-like febrile illness often associated with rash and an eschar at the site of inoculation. Because these infections are difficult to diagnose, rickettsial illnesses are under-recognized.11 Clinical suspicion and obtaining appropriate specimens for diagnosis are therefore essential.
Rickettsial infections are usually transmitted by arthropod vectors such as ticks, lice, fleas, and mites. Most travelers with rickettsial infections do not recall an arthropod bite.12 Outdoor activities during travel including camping, hiking and safari excursions in areas of known transmission increase the risk of exposure to these infections.
The most common rickettsial infection in travelers is African tick bite fever. The disease occurs as a result of the infection with Rickettsia africae carried by ticks in sub-Saharan Africa. The ticks that carry the infection usually feed on cattle but also on large animals found in game parks. Other rickettsial infections occasionally found in travelers include Mediterranean spotted fever, murine typhus and scrub typhus, caused by R. conorii, R. typhi, and Orientia tsutsugamushi, respectively.13
The incubation period is around 1–2 weeks. Common symptoms include fever, myalgia, headache, and rash. An eschar at the site of the original insect bite with regional lymphadenophathy is a characteristic finding. Infections often cause leukopenia, thrombocytopenia, and elevated liver enzymes. The ticks that carry African tick bite fever attack aggressively, and it is common for infected individuals to have several eschars representing multiple bites after exposure. There are no life-threatening complications of African tick bite fever and no fatalities have been reported.14 Complications have rarely been reported with Mediterranean spotted fever and murine typhus, but untreated scrub typhus can lead to multiorgan failure and death.
The mainstay of diagnosis is serological testing. Indirect immunofluorescence assay and enzyme immunoassay are the recommended and commercially available techniques with the highest sensitivity and specificity for rickettsial infection. Low or moderate levels of antibodies during the initial phase of the illness may represent previous exposure to rickettsial infection, and cross-reactivity of antibodies between different rickettsial species may occur. Definitive diagnosis can only be made with the detection of a fourfold rise in IgG titers between acute and convalescent specimens over a 2–3-week period. High IgM titers may aid in the confirmation of acute or recent infection. These serological assays often cannot distinguish the specific species causing infection. Further testing at reference laboratories may be required, if speciation is needed. Polymerase chain reaction (PCR) assays of whole blood or tissue yield rapid results, but are currently only available in reference and research laboratories. Diagnosis can also be made through immunohistologic detection by indirect immunofluorescence assay staining of tissue samples. Shell vial culture of the organisms for species diagnosis is potentially hazardous and should only be done by specialized laboratories.
Treatment must be initiated based on clinical suspicion because of the delay in obtaining confirmatory laboratory results. It is most effective if initiated within the first week of illness. Doxycycline 2 mg/kg (100 mg maximum) administered twice a day is given orally or intravenously. The duration of therapy is usually 5–14 days depending on the severity of illness and the response to therapy. Treatment should continue for 3 days after defervescence.15 Even though doxycycline may cause dental staining in children younger than 8 years, the risk of a short course of therapy is justified in the face of this potentially life-threatening disease. Chloramphenicol is effective in treating most forms of rickettsiosis. Although this medication is rarely used in the United States, it is frequently administered for a variety of illnesses in developing countries. Third-generation cephalosporins are active against scrub typhus and ciprofloxacin is an effective alternative to treat Mediterranean spotted fever.
Almost all rickettsial infections respond rapidly to doxycycline. If treatment is initiated based on clinical suspicion and there is no response after 48 hours, the diagnosis of rickettsial infection should be reconsidered.
Leptospirosis is a disease caused by the pathogenic spirochete Leptospira species found in urine and feces of wild and domestic animals. It is endemic in tropical and subtropical climates where outbreaks may be seasonally related to increased rainfall and warmer weather. Exposure can occur through direct contact with animals or their excretions, contact with infected freshwater or after flooding in urban or rural areas where infected animals live. Transmission occurs when mucous membranes or compromised skin contact contaminated water, soil, or vegetation. After hematogenous dissemination, the pathogen can invade a wide variety of tissues. Disease is caused by both direct infection and the host immune response.
Most cases of leptospirosis are subclinical and do not come to medical attention. Recognized cases of systemic leptospirosis classically present with biphasic illness, although this might not be appreciated by the patient. The initial, acute presentation is characterized by a febrile illness with headache, myalgia, and prostration. Conjunctival suffusion and muscle tenderness are characteristic findings during this stage. The acute, septicemic phase is followed by the immune phase where antibody is produced and organisms are excreted in urine. During this stage of the illness, most patients recover and develop immunity to further infection, but a minority may progress to severe leptospirosis. In cases of severe disease, aseptic meningitis and anterior uveitis can develop. Spontaneous pulmonary hemorrhage syndrome associated with leptospirosis is increasing in frequency and is associated with a 50% mortality rate.16 The classical form of severe disease is icteric leptospirosis, known as Weil's disease, with jaundice, renal failure, and hemorrhage. The characteristic laboratory finding is elevated bilirubin out of proportion to liver transaminases. As a result of a similar clinical presentation and geographic distribution, leptospirosis is often confused with dengue fever.17
Microscopic agglutination test (MAT) is most commonly employed to make a diagnosis. Rapid tests are available from the CDC, but should always be confirmed by either a culture of blood or other body fluids, a positive PCR of blood or serum, or demonstration of seroconversion based on the MAT performed on samples obtained 2 weeks apart.18 Blood culture specimens should be obtained early in the course of illness as leptospiremia begins before symptom onset and ends 1 week after illness onset. After the second week of illness, the organisms are excreted in urine, so a urine culture may be diagnostic. Urinary excretion may persist for several weeks. Special medium for blood and body fluid cultures is available commercially, but growth may take up to 13 weeks.19
The treatment of leptospirosis requires early antibiotic therapy, monitoring and supportive care. Penicillin, doxycycline, cefotaxime, ceftriaxone, and azithromycin are effective therapies. Although penicillin has been considered the treatment of choice for severe disease, trials in Thailand found that cephalosporins and doxycycline are as effective as penicillin in the treatment of severe disease and have the advantage of also treating rickettsial infections that may either be clinically indistinguishable at first or occur concurrently.20,21 Ceftriaxone allows for once-daily dosing and does not require adjustment in renal failure. Jarisch-Herxheimer reaction can occur with the initiation of beta-lactam therapy.
Typhoid fever, also known as enteric fever, is most commonly caused by infection with S. typhi and less often, but with increasing frequency, S. paratyphi. The vast majority of cases in the United States are travel related. S. typhi and S. paratyhpi only infect humans and are transmitted through the fecal–oral route with an infectious dose of 103 to 106 organisms.22 Common sources for infection are water and food contaminated by infected individuals. Chronic carriers are asymptomatic and the carrier state can be prolonged. The highest incidence of disease is found in South Asia, followed by Southeast Asia and travel-associated infection occurs in a similar distribution.6
When S. typhi is ingested, the low gastric pH serves as a key barrier in preventing further passage. Surviving organisms then enter the small intestine to adhere to and penetrate mucosal cells. After invasion, the bacteria travel through intestinal lymph nodes and can invade bone marrow, liver, and spleen. Salmonella organisms multiply in mononuclear cells and then cause clinically apparent disease when large numbers of organisms enter the general circulation.
The incubation period for typhoid fever is approximately 7–14 days. The onset of generalized nonspecific symptoms, such as fever, malaise, and headache usually correlates with the release of the organism into the bloodstream. Fever rises in a “stepladder” pattern to 39–40°C by the second week of illness, when patients often start to appear toxic and have sustained fever. Diarrhea is more common in children, while constipation occurs more frequently in adults. Other common symptoms are nausea, vomiting, and abdominal cramping. Because of the widespread use of suboptimal selection or dose of antibiotics, presentation and course of illness may be atypical.
Frequent physical examination findings are hepatomegaly, splenomegaly and abdominal tenderness. The pathognomonic rose spots, blanching erythematous macular lesions approximately 2–4 mm in diameter, are seen in about a third of cases. Relative bradycardia in relation to the amount of fever is considered a characteristic sign of typhoid fever, but only occurs in about a quarter of cases. Hematologic evaluation may show early leukocytosis or leukopenia, anemia, thrombocytopenia, and clotting abnormalities. Commonly, liver enzymes are moderately elevated. Pyuria, proteinuria, and casts may be seen on urine analysis. EKG may show nonspecific ST-wave and T-wave abnormalities.
Complicated disease occurs in approximately 10% of cases in endemic areas. The most common complications are intestinal perforation and hemorrhage. Encephalopathy with altered mental status and intermittent confusion, delirium, or coma is associated with a high case fatality rate. Extraintestinal infections are rare but the organism can cause meningitis, pneumonia, myocarditis, hepatitis and splenic and liver abscesses.23 The incidence of complicated disease and case fatality for typhoid fever is very low in the United States where adequate access to diagnosis and therapy is available. In the developing world, poorly or untreated cases of complicated disease carry a fatality rate of 30–50%.24,25
Following illness, 45% of children younger than 5 years excrete Salmonella for 12 weeks or more, compared to 5% of older children and adults.26 Approximately 1–5% of patients become chronic carriers harboring Salmonella in the gallbladder or rarely in the genitourinary system for more than 1 year.27
Cultures of blood or bone marrow positive for S. typhi or S. paratyphi are diagnostic. Stool cultures are useful in identifying excretion and chronic carriage, but are not diagnostic for enteric fever. The sensitivity of blood cultures ranges from 30% to 90%. The highest yield results from large volume blood cultures obtained early in the course of illness. Bone marrow cultures have much higher sensitivity (85–90%) and remain positive after antibiotic treatment is initiated.28 Although bone marrow aspirate is an invasive procedure, it should be considered in patients in whom there is a high suspicion for typhoid fever and blood cultures are negative. Isolation of an organism for susceptibility testing is especially important in patients returning from South and Southeast Asia where highly resistant S. typhi strains circulate.
The classic serologic test for S. typhi, the Widal test, has low sensitivity and specificity. Newer serologic rapid test kits and nucleic acid identification are being developed but are not yet commercially avaible.29
Treatment is complicated by widespread plasmid-mediated multidrug resistance to traditional first choice antibiotics such as chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole. Fluoroquinolones are preferred because they achieve high intracellular concentration and are excreted in the biliary system, where Salmonellae often cause chronic infection that leads to the persistent carrier state. The risk of administering a relatively short course of fluoroquinolones to young children is generally outweighed by the excellent efficacy of the drug and the ability to administer the medication orally. Ofloxacin or ciprofloxacin (15 mg/kg) is recommended for 5–7 days for uncomplicated disease and 10–14 days for complicated disease. Intravenous third-generation cephalosporins are also effective and there is increasing evidence that azithromycin may be an effective oral alternative.27,30
In some areas of South and Southeast Asia, chromosomally acquired resistance to fluoroquinolones—the current first choice treatment—has become prevalent over the last decade.31 Assessment of fluoroquinolone clinical susceptibility should be based on both fluoroquinolone (such as ciprofloxacin or ofloxacin) and quinolone (nalidixic acid) disk testing. Nalidixic acid-resistance based on in vitro testing, even when the fluoroquinolone MIC falls within the susceptible range, is a predictor of poor clinical response to fluoroquinolones.32 Therefore, infections should be treated as if they are fluoroquinolone resistant if they are resistant to nalixidic acid.
First line therapy for fluoroquinolone-resistant typhoid fever is a third-generation cephalosporin such as ceftriaxone (75 mg/kg for 10–14 days) or cefotaxime (80 mg for 10–14 days). Azithromycin (10 mg/kg for 7 days) is another option.27,33 Hospitalization for parenteral antibiotic therapy is recommended for infants, patients who cannot tolerate oral medication, or anyone suspected of having complicated disease such as intestinal perforation or hemorrhage, shock, or encephalopathy. Hospitalization for intravenous antibiotics should be considered for all patients until the susceptibility pattern of the infecting organism is identified. Dexamethasone should be considered in patients with altered mental status or shock.
Traveler's diarrhea is the leading cause of illness among returned travelers. The most common causes are: Escherichia coli, Campylobacter jejuni, Shigella spp., and Salmonella spp. Typical traveler's diarrhea may present with low-grade fever but fever is rarely a prominent complaint. This should be distinguished from dysentery which is a febrile illness with blood and mucus in the stool. Dysentery is typically caused by Shigella and E. coli. Other causes of inflammatory enteritis associated with fever that can occur after travel include Campylobacter, amebic dysentery, schistosomiasis, trichinosis, cholera, and typhoid fever. Most parasitic infections such as Cryptosporidium, Cyclospora, and microsporidium cause persistent diarrhea without systemic symptoms.
Prior to travel, patients are advised to carry a course of antibiotics to treat traveler's diarrhea while abroad. In cases of diarrhea in returned travelers, a bacterial stool culture may demonstrate the infecting organism. It is therefore appropriate to obtain a microbiological specimen and then begin an empiric course of antibiotics. The standard treatment for traveler's diarrhea is cirpofloxacin for 1–3 days. In children, azithromycin is another option. In cases of persistent diarrhea, stool can be examined for ova and parasites as described in Table 65–5.
With the recent introduction of hepatitis A into the pediatric vaccination schedule and widespread practice of pretravel immunization, this infection is found infrequently in travelers. Evaluation of hepatitis should therefore include febrile syndromes that present with hepatitis, such as typhoid fever, rickettsial infections, leptospirosis, malaria, and schistosomiasis. For the minority of patients who have not been vaccinated for hepatitis A or B, serologic testing should be obtained. Acute infection with hepatitis C is unlikely in the absence of significant exposures such as blood transfusion, injection drug use, body piercing, and unprotected intercourse. Travelers to South Asia and North Africa may be at risk for infection with hepatitis E, but infections usually occur in outbreaks and infection in children is rare.