key: cord-0040612-aj4ljb9h authors: Boggild, Andrea K.; Liles, W. Conrad title: Travel-Acquired Illnesses Associated with Fever date: 2016-09-23 journal: The Travel and Tropical Medicine Manual DOI: 10.1016/b978-0-323-37506-1.00020-9 sha: ba346e01e2b15fc382d2b4aafbcde1372942e2db doc_id: 40612 cord_uid: aj4ljb9h nan Herpes simplex Rubella Gnathostomiasis Malaria (without prophylaxis) Lassa fever of returned ill travelers; with increasing numbers of outbreaks of dengue in regions popular with tourists over the past 5 years, such as the Caribbean, dengue is becoming increasingly recognized as a specific cause of fever in the returned traveler. Enteric fever and acute hepatitis, both vaccine preventable, were less common, diagnosed in only 2% and 1%, respectively, of febrile returning travelers. Rickettsioses were also rare as a cause of fever, occurring in only 2% of cases. Rates of hospitalization due to post-travel fever range from 20 to 30%, with Plasmodium falciparum malaria being the most likely specific cause of hospitalization in this setting. In general, high-risk areas for the acquisition of febrile illnesses include sub-Saharan Africa, Southeast Asia, and Latin America. Sub-Saharan Africa and Oceania are "hot spots" for malaria acquisition, whereas South Central Asia contributes many cases of travel-acquired enteric fever (i.e., typhoid fever and paratyphoid fever due to Salmonella enterica serotypes Typhi and Paratyphi, respectively). Travelers returning with rickettsial infections have traveled almost exclusively to sub-Saharan Africa, while dengue infections are most commonly acquired in Southeast Asia, Latin America, and, increasingly, the Caribbean. With the emergence of chikungunya in the Americas in late 2013, and Zika in late 2015, these viral infections remain on the differential diagnosis of fever in travelers returning from all parts of the Caribbean, and Central and South America, as well as areas of prior endemicity, such as the Indian Ocean islands. The medical history, including pre-travel preparation and the details of activities and exposures during travel, is essential in identifying the differential diagnosis of fever in travelers. First, always establish the patient's vaccination status. No vaccination is 100% effective; efficacy ranges from the near-perfect, 10-year protection provided by yellow fever vaccine to the approximately 65% efficacy of both the injectable and oral typhoid vaccines. The efficacy of the current hepatitis A and hepatitis B vaccine series is >90%. When a dose of oral polio vaccine is repeated in adult life, as recommended for risk of exposure, vaccine efficacy approaches 90-100%. Thus, a documented history of recent vaccination administered appropriately renders the diagnosis of yellow fever, hepatitis A, hepatitis B, or polio unlikely, while illnesses with poorer vaccine efficacy, such as typhoid fever and influenza, remain more probable. Similarly, administration of immune globulin within 3 months of exposure makes hepatitis A highly unlikely. A history of compliance with prophylaxis for malaria or traveler's diarrhea is helpful, although one should bear in mind that prophylaxis for malaria is not 100% effective (see Chapters 6 and 21). It is also important to inquire as to previous diagnostic tests and treatment, some of which may have occurred while traveling. It is important to learn the details of itinerary, duration, and style of travel, as well as the particular characteristics of a given trip, to ascertain the risk of serious disease presenting as fever. The travel itinerary is important because many diseases are limited in their geographic distribution (see Tables 20.6, 20.8, 20.10, 20.11, and 20.12). In addition to geographic exposure, there may be a significant association between length of travel and serious illness, and infections vary significantly between short-term travelers and immigrants exposed to similar conditions in the same geographic area. For example, schistosomiasis may present as Katayama fever (acute schistosomiasis) among travelers, but this syndrome is rarely observed in individuals born and raised in endemic areas, who may present as immigrants with symptoms of chronic schistosomiasis, such as abdominal discomfort, ascites, and splenomegaly (Chapter 48). Age at time of exposure, underlying health, genetic factors, and intensity and duration of parasite exposure probably contribute to these differences. Travel style can be associated with an increased risk of serious illness, especially if an individual resided with locals or participated in an "adventure tour" as opposed to staying in urban, first-class hotels. Travel on cruise ships is a notorious risk factor for norovirus infection and invasive bacterial gastroenteritis. Younger age and being a student also increase the risk of becoming ill while traveling. Exposures are clues that can narrow the differential diagnosis (Table 20 .4). It is important to inquire specifically about arthropod bites, animal contact, sexual behavior, blood-and body-fluid exposures from injections or transfusions of blood products, caring for ill individuals (see Table 20 .3), and ingestion of unpurified water, unpeeled raw fruits, raw vegetables, raw or undercooked meat/seafood, or unpasteurized dairy products. One should inquire about bathing or swimming in fresh water in areas where schistosomiasis or leptospirosis are prevalent. Barefoot exposure to sand or soil establishes risk for geohelminth infections such as strongyloidiasis and hookworm infection. Travelers may be reluctant to volunteer information regarding sexual contact abroad, but a complete sexual history is always warranted. Patients such as volunteers, missionaries, long-term expatriates, and military personnel may present with diseases seen in both travelers and immigrants, presumably reflecting more intense and prolonged exposures. It is important to establish the onset of fever in relation to exposures, because the incubation period of illness can narrow the diagnostic possibilities. Some infections may present long after exposure, such as amebic liver abscess, malaria (especially if due to Plasmodium vivax, P. ovale, or P. malariae), human immunodeficiency virus (HIV), brucellosis, hepatitis B, tuberculosis, visceral leishmaniasis, and human African trypanosomiasis. It is also helpful to note whether the course of illness has been acute or chronic. Table 20 .5 is helpful as a guide, but many of the chronic illnesses listed, such as American and African trypanosomiasis, may also present as acute febrile syndromes during primary infection. Interval to presentation can serve as a proxy for incubation period. Falciparum malaria is most likely to present in the 7-to 14-day post-travel window, whereas malaria due to P. vivax may present beyond 42 days post-travel. Dengue seldom presents beyond 10 days post-travel, and chikungunya and rickettsioses rarely beyond 12 days. Similarly, fever due to common agents of traveler's diarrhea or influenza rarely present beyond 1 week post-travel. Fever patterns, although potentially helpful, may not be as characteristic of certain diseases in short-term travelers as they are in immigrants. Fevers of primary malaria rarely exhibit the intermittent pattern of tertian or quartan fevers (every 2 or 3 days, respectively) characteristically experienced by partially immune individuals. "Saddle-back fever," which refers to the phenomenon in which fever lysis is followed within several days by the resumption of high fevers, is found in 60% of cases of dengue fever but can also be seen in relapsing fever resulting from Borrelia species or with P. malariae (quartan malaria) infection, leptospirosis, and many arboviral infections other than dengue. Continuous fever with temperature/pulse dissociation (relative bradycardia) is often present in enteric (typhoid or paratyphoid) fever, tick typhus, and arboviral infections. Remittent fevers, in which the body temperature fluctuates more than 2° C (3.6° F) but does not completely return to normal, can occur in pulmonary tuberculosis but may also be seen with bacterial sepsis and bacterial abscesses. Specific symptoms may help establish a diagnosis. Severe myalgia and arthralgia, although characteristic of many febrile illnesses, are extremely severe in arboviral infections such as chikungunya and dengue. Chills are especially prominent in malaria, bacterial infections or sepsis, and dengue. Spontaneous bleeding suggests the possibility of infection with one of the hemorrhagic viruses (e.g., Lassa fever, yellow fever, dengue hemorrhagic fever) but is also reported with various bacterial and rickettsial diseases (Table 20.6). Bleeding may range from easy bruising typical of mild dengue to severe epistaxis, gastrointestinal bleeding, and possible spontaneous central nervous system hemorrhage seen with severe hemorrhagic viral diseases. Diarrhea associated with fever is typically caused by common bacterial agents of traveler's diarrhea such as Campylobacter species, enterohemorrhagic, enteroaggregative, and enteroinvasive Escherichia coli strains, Salmonella species, Shigella species, Entamoeba histolytica, and intestinal viruses. Occasionally, febrile diarrhea may present due to other gastrointestinal pathogens such as hookworm, coccidia such as Cyclospora cayetanensis or Cryptosporidium, and rarely with Giardia lamblia. However, many systemic illnesses can present with diarrhea, including malaria. Respiratory symptoms that suggest viral upper respiratory infections may be manifestations of tuberculosis, bacterial pneumonia, Q fever, melioidosis, or the pulmonary migration phase of helminths such as Ascaris lumbricoides and Strongyloides stercoralis. Fever with localized respiratory signs and symptoms in a traveler to South Central or Southeast Asia should raise the specter of highly pathogenic avian influenza or severe acute respiratory syndrome (SARS) . Middle East respiratory syndrome coronavirus should be considered when evaluating fever, respiratory symptoms, and recent travel to the Middle East or Korea. Hepatosplenomegaly along with fever suggests malaria, mononucleosis, hepatic amebiasis, acute schistosomiasis (Katayama fever), visceral leishmaniasis, or enteric fever, among other infectious diseases. Lymphadenopathy evokes mononucleosis, HIV, acute schistosomiasis, plague, typhoid fever, tularemia, and trypanosomiasis, among others (Table 20.7). Of course, neoplastic and collagen vascular diseases may also induce lymphadenopathy and fever. Meningismus, confusion, and other signs of central nervous system dysfunction may be caused by a variety of viral, parasitic, and bacterial agents (Table 20.8). Many of these pathogens are restricted to certain ecologic niches, so the patient's geographic itinerary, season of travel, and exposure history are essential. For example, Japanese encephalitis virus is limited to the Far East, is a disease of summer in temperate climates, and is transmitted by mosquitoes. Spinal cord disease associated with fever can result from West Nile virus, schistosomiasis, human T-cell lymphotrophic virus type 1 (HTLV-1) infection, or polio virus infection. Cutaneous manifestations of disease are common but seldom specific (Table 20 .9). The erythema chronicum migrans of Lyme disease and rose spots in typhoid fever are examples of unique, specific rashes. Nonetheless, rash can refine a differential diagnosis considerably. For example, an eschar at the site of inoculation is typical of tick typhus, boutonneuse (Mediterranean spotted) fever, and anthrax. Cutaneous ulcers are seen in leishmaniasis, tropical phagedenic ulcer, Buruli ulcer (Mycobacterium ulcerans), cutaneous amebiasis, arthropod bites, syphilis, yaws, tuberculosis, and leprosy. When evaluating a patient who has received previous treatment, it is important to recall that rash and fever can be caused by reactions to drugs, such as sulfa drugs, antimalarials, and other antibiotics. Rickettsial diseases are frequently associated with rash, but the absence of rash may be misleading and does not exclude the possibility of rickettsial disease (see Table 20 .13). Genital ulcers, such as those seen with syphilis, chancroid, and lymphogranuloma venereum, should be construed as markers of exposure to other sexually transmitted diseases that should be excluded in affected travelers, as well. +/− + + + + Amebiasis (hepatic) + + +/− − − Babesiosis + + + + +/− +/− Fascioliasis + + +/− − − Filariasis − − + + + Malaria + + + − − A thorough but directed evaluation, bearing in mind that most fevers are self-limited, is warranted for the traveler presenting with fever. A careful history covering pre-travel prophylaxis, itinerary, travel style and exposures, apparent incubation period, fever pattern, symptoms, previous treatment, and diagnostic studies is essential. Laboratory tests to consider in the diagnostic evaluation include blood smears for malaria (and Borrelia, trypanosomes, Babesia, etc.), complete blood count and white cell differential, absolute eosinophil count, serum electrolytes, blood urea nitrogen and creatinine, glucose, bilirubin, hepatic transaminases, urinalysis, chest radiograph, tuberculin skin test, hepatitis serologies, and bacterial cultures of blood, urine, and stool. In many instances, it is prudent to obtain and save an acute serum sample for future comparative serologic studies. Suspected cases of viral hemorrhagic fevers, severe malaria, and enteric fever should be immediately hospitalized. Travel in a rural African environment is a significant risk factor for exposure to viral hemorrhagic fevers, although other hemorrhagic viruses, including those causing dengue fever, Hantaan, yellow fever, and Crimean-Congo hemorrhagic fever, have a more cosmopolitan distribution in widely scattered parts of the world (Table 20.6). All cases of suspected viral hemorrhagic fevers should be reported immediately to both the local health department and the Centers for Disease Control and Prevention (CDC). The clinically stable patient with travel-related fever in whom the initial history, physical examination, and screening laboratory studies, including at least two blood films for malaria Travel-Acquired Illnesses Associated with Fever separated by >6 but not more than 24 hours, are unremarkable may be observed. The patient should be instructed to keep a temperature record and return in 2-3 days if fever fails to resolve, or sooner if symptoms worsen. Empiric treatment for enteric fever (and/or rickettsioses) may be considered in patients who continue to have fever >48 hours after all diagnostic work-up has been initiated but in whom specific tests have been noncontributory (see Public Health Agency of Canada, Fever in the Returning Traveller 2011). Because the majority of travel-related febrile illnesses are self-limited viral syndromes, most fevers will resolve spontaneously. If fever persists, however, repeat malarial smears and blood cultures are warranted. Directed serologic studies to detect diseases compatible with the patient's history and physical examination should be considered. Imaging studies (e.g., abdominal computed tomography or ultrasound) and biopsies (e.g., bone marrow, liver, lymph nodes) may be indicated. Hospitalization may be justified to expedite the work-up in certain circumstances. During the evaluation of perplexing cases of apparent travel-related illness, the clinician should bear in mind that non-infectious disorders, such as pulmonary embolism, occult malignancies, systemic lupus erythematosus, and temporal arteritis, may present with fever. Presumptive empiric therapy directed against a likely pathogen may be justified, especially when adequate diagnostic studies are not readily available or a patient is clinically deteriorating. Examples include intravenous artesunate for suspected severe infection with P. falciparum, quinolones or third-generation cephalosporins for suspected enteric fever, doxycycline for suspected rickettsioses, and ribavirin for suspected Lassa fever (Table 20 .2). Early initiation of appropriate therapy may significantly reduce morbidity and potential mortality from these serious febrile illnesses of travelers. Selected infectious diseases that should be considered in the traveler with fever are discussed in this section, with the goal of providing an overview. References to other chapters in this book are given as appropriate; however, the reader is encouraged to consult, when possible, standard textbooks on infectious diseases and tropical medicine and to contact the CDC for current and detailed information on the diagnosis and treatment of exotic diseases. The experts at the CDC can provide 24-hour emergency medical consultation by telephone to healthcare providers dealing with a very ill patient. Fever in a traveler from a malarious area should be evaluated carefully, with multiple blood smears for malaria. Although malaria is discussed in greater detail in Chapter 21, key points are worth repeating here. P. falciparum infection can be life-threatening when associated with high parasitemia, blackwater fever, cerebral malaria, or acute respiratory distress syndrome. Chemoprophylaxis is often effective, but only when taken as directed. Of the 231 cases of severe malaria in travelers reported to the CDC in 2012, 75% were due to P. falciparum, and 79% of these infections were acquired in sub-Saharan Africa; only 7 of 200 patients in whom information on prophylaxis was known were adherent to their drug regimen. However, drug-resistant P. falciparum is now widespread, and even perfect compliance with prophylaxis does not provide absolute protection from malaria infection. The case-fatality rate for P. falciparum in US travelers was approximately 0.4% in 2012 (6 deaths among 1687 total cases). Clinical manifestations of P. vivax and P. ovale infections can develop up to 5 years after exposure. The diagnosis of malaria in immune individuals or individuals who have received prophylaxis or partial treatment may be complicated by low parasitemia. Multiple blood smears in combination with highly sensitive rapid diagnostic tests or, occasionally, nucleic acid amplification tests such as polymerase chain reaction may be helpful in difficult cases (see also Chapters 6 and 21). Enteric fever is caused by Salmonella enterica serovar Typhi (S. typhi) or Salmonella paratyphi. Persistently rising fever, relative bradycardia, rose spots, and normal leukocyte counts with mild to moderate elevation of hepatic transaminases are all clues to the diagnosis; however, these characteristics are often absent. The organism can be cultured from the blood in >80% of patients during the first week of illness and from bone marrow aspirated from the iliac crest in more than 90% of documented cases, if no antibiotics are administered before obtaining the culture. The organism can be cultured from stool during the incubation period occasionally, and in one-third to two-thirds of patients during the second through fourth weeks of illness. Neither the oral nor the parenteral vaccine provides complete immunity (Chapter 5). In immunized populations, however, a higher percentage of individuals with enteric fever will have disease caused by S. paratyphi, although disease caused by S. typhi still occurs. Of the approximate 5700 cases of typhoid fever that occur annually in the United States, up to 75% are travel acquired. Of the 1902 laboratory-confirmed cases of typhoid fever reported by Lynch and colleagues (2009 Lynch and colleagues ( ) between 1999 Lynch and colleagues ( and 2006 in the United States where epidemiologic information was available, foreign travel in the preceding 30 days was reported by 79%, yet only 5% had received typhoid vaccine prior to travel. Seventy-three percent of cases were hospitalized, and 0.2% died. Resistance to antimicrobials has been reported for S. typhi isolates in many countries, although fluoroquinolones are usually effective against typhoid fever acquired outside the Indian sub-continent and Southeast Asia (Chapter 31). Arboviral diseases are caused by arthropod-borne viruses; most are zoonoses (shared between humans and other vertebrate hosts). More than 400 arboviruses, classified into many families and genera, have been described (Table 20 .10). Arboviral diseases are present throughout the tropics; however, some arboviruses, such as o'nyong-nyong, Mayaro, Ross River, Oropouche, and Rift Valley fever viruses, are limited in geographic distribution. Diagnosis usually depends on clinical suspicion and serologic confirmation, the latter generally requiring acute and convalescent serum samples. The arboviral diseases can be divided into four syndromes based on clinical presentation: (1) undifferentiated fever, (2) dengue fever, (3) hemorrhagic fever, and (4) encephalitis. The syndrome of undifferentiated fever (e.g., Oropouche, Mayaro, and sand fly fever) is generally characterized by one or more of the following: fever, headache, myalgia, pharyngitis, coryza, nausea, vomiting, and diarrhea. The dengue fever syndrome (dengue, chikungunya, o'nyong-nyong, Sindbis, West Nile, Ross River viruses) is characterized by fever, rash, arthralgia, and leukopenia. The syndrome of hemorrhagic fevers (Lassa fever, Ebola, Marburg, Crimean-Congo, Argentine, Bolivian, dengue, yellow fever viruses) ranges from mild petechiae to severe purpura and bleeding diathesis. The 2014 West African outbreak of Ebola virus disease (EVD) underscores that prior estimates of the frequency of hemorrhagic manifestations in EVD are likely inflated. In this outbreak of EVD, which has led to >27,000 cases and >11,000 deaths, bleeding and hemorrhagic manifestations have been noted to occur in 5-15% of patients (Chertow et al. 2014; Qin et al. 2015) . Dengue is the most widespread arbovirus, distributed throughout the tropics, and frequently encountered in travelers returning from the tropics. Dengue virus is a single-stranded RNA flavivirus transmitted by the day-biting urban mosquito Aedes aegypti or the jungle mosquito Aedes albopictus. Four serotypes are recognized. Infection with one serotype results in immunity to that particular serotype; however, after a short period of cross-protection, individuals are susceptible to infection with another serotype. Clinical infection ranges from a mild febrile syndrome to a severe dengue syndrome. Individuals with dengue who recover fully following defervescence are considered to have uncomplicated dengue, while those who deteriorate clinically are classified as having "warning signs," which include any of the following manifestations: abdominal pain, persistent vomiting, fluid accumulation, mucosal bleeding, lethargy, hepatic enlargement, and worsening thrombocytopenia in the setting of hemoconcentration. A minority of patients with warning signs will continue to deteriorate despite fluid resuscitation, and those are The incubation period of dengue is 5-8 days. A viral prodrome of nausea and vomiting is common, followed by high fever for a mean of 5 days; the fever often lyses abruptly. Myalgia and arthralgia are particularly prominent, giving rise to the common name of "breakbone fever." Headache (especially retro-orbital), lymphadenopathy (frequently cervical), and/or rash (scarlatiniform, maculopapular, or petechial; characteristic "islands of white macules on a sea of red") frequently develop. The rash may occur late during the course of illness, and fever may reappear after several days. (Note: this "saddleback" fever pattern is present in about 60% of cases.) Previous infection with one serotype of virus may predispose an individual to more severe disease on infection with another serotype. This immune enhancement of viral pathogenesis is thought to result from immunoglobulin-mediated dengue virus uptake into macrophages, where growth is favored. Thus the hemorrhagic fever/shock syndrome, which is most common in indigenous children, is unlikely to occur in a traveler who has not been previously infected with dengue. Prolonged convalescent periods, characterized by extreme fatigue often persisting for months, have been noted by many travelers who have acquired dengue fever. Dengue vaccine trials in endemic areas show some benefit in children. Chikungunya virus infection has been historically noted among travelers from Southeast Asia and Africa. However, in late 2013, the virus emerged for the first time in the Americas, leading to a widespread and ongoing outbreak in the Caribbean and Central and South America affecting at least 44 individual countries, with cases numbering into the hundreds of thousands. This has resulted in high numbers of cases among North American and European travelers to the Caribbean and Central America, in particular. This disease presents in a fashion similar to dengue fever, although incubation and duration of symptoms are typically more prolonged. Myalgia and arthralgia are particularly severe with chikungunya, with function-limiting arthropathy persisting for years in a minority of patients. Zika virus was discovered in Uganda in 1947, and human infectinos were extraordinarily rare until 2015, when an epidemic began to sweep across South and Central America. Most adult patients have a clinical illness very similar to Dengue and Chikungunya, although neurological injury such as Guillan-Barre has been described. Of greatest concern is its association with microcephaly if the patient is pregnant during infection. Women who return from endemic areas with fever should be assessed for this infection, and if infected and pregnant, counseled on strategies for aggressive fetal monitoring or termination options. In the Americas, yellow fever is transmitted by Haemagogus mosquitoes in the jungle environment and A. aegypti in urban settings. In Africa, transmission to humans occurs via Aedes spp. Historically, in both urban and rural environments, only 50-200 cases of yellow fever per year have been reported from the tropical Americas. However, yellow fever is an emerging problem in the Amazon and other jungle regions of Brazil, Colombia, Venezuela, and Peru, with resurgence of the disease in the early 2000s leading to mass vaccination initiatives. Sporadic urban transmission still occurs in large outbreaks in Africa. Although A. aegypti is ubiquitous in the Far East, yellow fever virus transmission has never been reported from this region. The reason is unclear, but either the lack of virus importation into the region or possible immune cross-resistance induced by endemic dengue immunity may be responsible. The spectrum of clinical disease ranges from a dengue fever-like illness to a severe hemorrhagic illness associated with hepatic and renal failure. The disease is almost 100% preventable by vaccination with live attenuated 17D-strain vaccine (Chapter 5). Among unvaccinated travelers from the United States and Europe, nine cases of yellow fever occurred between 1970 and 2011, five of which were acquired in sub-Saharan Africa, and four in South America. Eight of these cases were fatal. Viruses causing hemorrhagic syndromes, such as Lassa fever virus, Ebola virus, Marburg virus, and Machupo virus, have been associated with life-threatening infections that can be spread nosocomially. Patients who are suspected of having one of these viruses should be placed in airborne and contact isolation. Laboratory work should be kept to a necessary minimum and the laboratory alerted to the possibility of contagious virus in patient specimens. The CDC and state health department should be contacted immediately. An arthropod vector has not been identified for many of these viruses, such as Lassa fever, which is transmitted via contact with rodent reservoirs in rural West Africa or with infected humans. Early symptoms include fever, malaise, weakness, and myalgia. A few days later, cough, pharyngitis, and chest and epigastric pain develop. Vomiting and diarrhea occur by about day 5, associated with fever of 39-40° C. By the sixth day, respiratory distress, cardiac instability, hepatic and renal failure, and hemorrhagic phenomena begin to appear. Lassa fever can be diagnosed by either the isolation of virus or the demonstration of a fourfold increase in antibody titer. Early treatment with ribavirin may improve outcome with Lassa fever virus, Hantaan virus, and other hemorrhagic viruses with the exception of Ebola, yellow fever, and dengue viruses. Other viruses of importance are listed in Table 20 .11. (See also Chapter 28.) Rickettsial diseases are acute, usually self-limited febrile illnesses caused by obligate intracellular Gram-negative bacteria of the order Rickettsiales. Rickettsiae can be divided into the spotted fever group and the typhus fever group. All are transmitted by ticks, fleas, lice, or mites. Rickettsiae are widely distributed throughout the world (Table 20.12) . The spectrum of illness ranges widely and includes subclinical infection. Incubation periods for the various diseases vary widely, on the order of 2-30 days (Table 20. Clinical illness is generally characterized by an abrupt onset of fever, chills, and sweats, frequently associated with rash, headache, conjunctivitis, pharyngitis, epistaxis, myalgias, arthralgias, and hepatosplenomegaly. An eschar often develops at the site of the bite of the mite or tick in scrub typhus, due to Orientia tsutsugamushi, and the spotted fever group rickettsioses. Vasculitis underlies the typical pathologic manifestations of rickettsial disease. Complications are rare but include encephalitis, renal failure, and shock. Most rickettsial disease reported in the United States is acquired domestically (e.g., Rocky Mountain spotted fever). Spotted fever group rickettsioses, including Mediterranean spotted fever/boutonneuse fever and African tick bite fever, appear to be the most common (Jensenius et al. 2009 ). Typhus fever group rickettsioses are endemic to areas in southern Europe, Africa, and the Middle East, although most cases are also reported in travelers to Africa. Diagnosis requires clinical suspicion (often mandating empiric antibiotic therapy) and specific serologies. Therapy consists of doxycycline (200 mg/day in divided doses) generally for 3-4 days after defervescence and a minimum of 1 week total therapy. Recent evidence suggests that short courses of macrolide antibiotics, such as azithromycin or clarithromycin, may be acceptable alternatives for the therapy of rickettsioses other than Rocky Mountain spotted fever. Schistosomiasis is caused by a fluke and transmitted by freshwater exposure in endemic regions. Katayama fever, or acute schistosomiasis, develops 2-10 weeks after exposure. This serum sickness-like illness is believed to represent a reaction against antigen-antibody complexes formed as a result of egg deposition. This syndrome is most severe in Schistosoma japonicum infections, in which egg production is greatest. Characteristic clinical manifestations include fevers, chills, sweating, headache, cough, lymphadenopathy, hepatosplenomegaly, and eosinophilia. Although death has been reported in S. japonicum infections, most patients with Katayama fever experience a self-limited illness that is commonly undiagnosed. Travelers appear to be more likely to develop this syndrome than those raised in endemic areas. Serologic studies are helpful in the diagnosis. Recommended treatment involves administration of praziquantel and corticosteroids (see Chapter 48). Mounting evidence suggests that asymptomatic travelers returning from high-risk areas should be screened (serologically and/ or with stool/urine ova and parasites, the latter >6 weeks after exposure) and treated. The filariasis syndromes associated with fever include onchocerciasis (river blindness), lymphatic filariasis (lymphangitis, often complicated by bacterial superinfection), loiasis, and nocturnal fever with or without pulmonary symptoms resulting from circulating microfilariae. Of these entities, loiasis is most commonly seen in travelers and short-term residents of risk areas (rainforest regions of Central Africa). Eosinophilia is common in patients with filariasis. The diagnosis is usually established by the demonstration of microfilariae in skin snips (onchocerciasis) or in blood. (Note: in lymphatic filariasis, the microfilariae circulate nocturnally, while microfilaremia of Loa loa peaks in the late afternoon.) Serologic study may be helpful when the disease is suspected (see Chapter 47). Strongyloidiasis, usually acquired when larvae in contaminated soil penetrate the skin, rarely causes a febrile illness in travelers. However, a Löffler syndrome, characterized by pulmonary infiltrates with eosinophilia, may occur during the obligate lung migration phase of larvae and may be accompanied by fever. Immunocompromised hosts, particularly due to HTLV-1 or corticosteroids, can develop a life-threatening hyperinfection syndrome, which is frequently complicated by significant disseminated strongyloidiasis outside the gastrointestinal tract (see Chapter 45). Trichinosis, usually associated with high-grade eosinophilia, muscle pain, and fever, can be acquired by travelers who ingest undercooked meat (see Chapter 49). Paragonimiasis is an illness caused by a lung fluke that induces a febrile response either during its migration to the lungs or by its obstruction or destruction of lung parenchyma. Hemoptysis can occur, mimicking pulmonary tuberculosis. The disease is usually acquired by ingestion of raw freshwater crustaceans in Asia, South America, and Africa, though case series are reported in the United States from imported freshwater crab or local crawfish ingestion. Diagnosis can be established by examination of the sputum and stool for ova. Serologic studies are available (see Chapter 48). The ingestion of food or water contaminated by echinococcal eggs from canid feces can cause hydatid cyst disease involving the lungs or liver. Fever is usually absent unless the cyst or cysts become secondarily infected or rupture (see Chapter 46). Amebiasis E. histolytica is usually acquired by ingesting cysts in water or food contaminated by human feces but may be transmitted sexually. Both amebic dysentery and amebic liver abscess may cause fever. Amebic liver abscess is associated with right upper quadrant discomfort, hepatomegaly, an elevated right hemidiaphragm, and high serologic reactivity to E. histolytica antigens. Often, E. histolytica cannot be identified in the stool at the time of presentation of amebic abscess. Treatment is with metronidazole plus another agent to clear luminal cysts, such as iodoquinol (see Chapter 32). Chagas disease (American trypanosomiasis), caused by infection with Trypanosoma cruzi, is typically acquired by dwelling in mud or thatched-roof housing, via the feces of the reduviid bug, which defecates on the patient during a silent blood meal. In addition, transmission in Latin America is often congenital or via blood transfusion in endemic countries and occasionally in the United States. It is increasingly recognized as a food-borne illness when cane-sweetened juices are contaminated by crushed reduviid bugs. In typical transmission, after an incubation period of 1-2 weeks, T. cruzi causes a febrile illness during the acute stage of infection that persists for 2-4 weeks. The illness is accompanied by local swelling at the site of inoculation of trypanosomes (Romaña sign), lymphadenopathy, hepatosplenomegaly, and influenza-like symptoms. Trypanosomes may be seen during the acute stage of infection in peripheral blood by blood smear or in biopsy specimens obtained from the site of inoculation. Serology studies may be helpful. Treatment during the acute stage of infection with benznidazole or nifurtimox is beneficial in attenuating the progression to chronic Chagas disease. This disease is rare among travelers but is increasingly recognized in nonendemic countries among Latin American immigrants (see Chapter 26). African trypanosomiasis (infection with Trypanosoma brucei gambiense or T. brucei rhodesiense) cause febrile syndromes due to circulating trypanosomes. West African disease often presents in a subacute or chronic fashion, whereas East African disease is less well adapted to humans and thus has a more fulminant course. Both diseases are transmitted by the bite of the tsetse fly in Africa. Occasionally, a chancre can be seen at the site of inoculation during acute infection. Lymphadenopathy is common, particularly in the posterior cervical chain. Later, the trypanosomes invade the central nervous system, and lumbar puncture must be performed to determine which treatment regimen should be administered. If disease has progressed to the central nervous system, treatment with arsenicals, such as melarsoprol, or difluoromethylornithine is recommended for East and West African trypanosomiasis, respectively. African trypanosomiasis is uncommon among travelers, although clusters have been reported, mainly in travelers returning from East Africa. Both East and West African disease are ultimately fatal without treatment, so recognition and rapid action is essential (see Chapter 27). Visceral leishmaniasis, or kala-azar, is characterized by hepatosplenomegaly, severe wasting, and fevers, a syndrome evocative of lymphoma. Leishmania spp. are transmitted by the bite of the sand fly. The kala-azar syndrome is usually caused by Leishmania donovani. Visceral leishmaniasis is extremely uncommon among travelers. Treatment is with amphotericin B in lipid formulations, pentavalent antimonials, or miltefosine (see Chapter 39). Toxoplasmosis, which can cause an acute febrile syndrome, may be acquired by travelers via the consumption of undercooked meat. Transmission may occur in unexpected places, such as France, where infection with Toxoplasma gondii is much more common because of the popular ingestion of uncooked meat. Tuberculosis is an uncommon disease among short-term travelers (Table 20.1). Travelers at increased risk are those going abroad to perform medical service and those residing abroad for prolonged lengths of time. Occasionally, tuberculosis transmission has been reported among air travelers as the result of relatively poor air turnover on airlines and the presence of a passenger with active pulmonary tuberculosis. In a study of American healthcare workers returning from Botswana, tuberculin skin test conversion occurred in 4.2%, corresponding to a rate of 6.87 per 1000 person-weeks of travel (Szep et al. 2014) . Healthcare workers, missionaries, teachers, and others who anticipate close daily contact with resident populations in countries where the incidence of tuberculosis is high should receive the tuberculin skin test before travel to establish a baseline status, and 8-12 weeks following travel (see Chapter 25). Meningococcal infection occurs sporadically in travelers to endemic areas (sub-Saharan Africa and Nepal) and in epidemics during times of crowding. An example of the latter is the reported high incidence of meningococcal disease and carriage after pilgrimage to Mecca. Purpuric lesions and signs of meningismus are helpful diagnostic clues, but individuals may present with only fever and respiratory symptoms. Diagnosis is established by culture of blood and cerebrospinal fluid, and treatment with parenteral ceftriaxone is usually effective. Close contacts of documented cases should receive prophylaxis with rifampin or ciprofloxacin. Travelers going to areas of known meningococcal transmission should undergo meningococcal vaccination before departure (see Chapter 5). Leptospirosis is acquired by contact with water contaminated by animal urine containing spirochetes. It is common in the tropics and subtropics (Chapter 23). This disease may be contracted by abattoir workers, swimmers, and campers. Large outbreaks have occurred among triathletes in Illinois (98 cases) and competitive swimmers in Borneo (70 cases). Clinical illness ranges from relatively mild disease to fulminant hepatic failure with icterohemorrhagic fever (Weil's disease). Definitive diagnosis is based on either serologic studies or the demonstration of leptospires in specimens of clinical fluids. As with rickettsioses, empiric treatment is often considered. Brucellosis is usually transmitted by unpasteurized dairy products but may be encountered in abattoirs. Illness ranges from an indolent febrile syndrome to fulminant endocarditis. Brucellosis is occasionally encountered in the post-travel setting, although laboratory acquisition is well documented and remains a risk for medical and laboratory workers who volunteer or work overseas. In their study of >42,000 ill returned travelers entered into the GeoSentinel database between 2007 and 2011, Leder and colleagues (2013) reported 33 cases of acute brucellosis, most of which were acquired in India, the Sudan, and Iraq. Plague is reported to be epidemic in humans in certain regions of Vietnam and is endemic in rodent populations in the southwestern United States and other areas of the world. Larger outbreaks can occur, as in India in 1994. Plague causes a clinical syndrome of painful regional lymphadenitis associated with necrotizing pneumonia and septicemia. Prophylactic doxycycline may be given to travelers at risk, since the plague vaccine is not widely available (see Chapter 5). Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, produces a tuberculosis-like illness or septicemia. The disease is particularly prevalent in Southeast Asia, where it is especially common in rice-paddy workers. Many Vietnam veterans have serologic evidence of past infection with B. pseudomallei. Like tuberculosis, the bacteria may remain dormant for many years before reactivating and causing illness. Relapsing fever (caused by Borrelia species) is a worldwide tick-borne endemic disease, but louse-borne human-human transmission still occurs in highlands of Ethiopia, Sudan, Somalia, Chad, Bolivia, and Peru. Diagnosis depends on the demonstration of extracellular spirochetes by blood smear and Giemsa staining. Bartonellosis, caused by Bartonella bacilliformis, is transmitted by sand flies only in Andean river valleys with elevations between 2000 and 8000 ft in Peru, Ecuador, and Colombia. This infection can lead to acute hemolysis (i.e., Oroya fever), in which intraerythrocytic organisms may be detected on pathologic stains (e.g., Giemsa) or in chronic, angioproliferative skin lesions (i.e., verruga peruana, lesions that may be sessile, miliary, nodular, pedunculated, or confluent and may be as large as 1-2 cm). A newly described species, Bartonella rochalimae, was reported to cause an Oroya fever-like illness, characterized by anemia, fever, and splenomegaly, in an American traveler to Peru (Eremeeva et al. 2007 ). The patient had been traveling in an area endemic for B. bacilliformis, but to date, no clear vector has been identified. This case highlights the sustained possibility of discovering novel pathogens as international travel becomes increasingly attractive and affordable. Cutaneous anthrax generally has been associated with exposure to infected animals, contaminated animal hides, and wool. Because Bacillus anthracis spores can survive for prolonged periods, contaminated hides or wool remain infectious and may rarely be responsible for disease transmission. Anthrax is sometimes associated with a local eschar, where bacteria proliferate and invade the bloodstream. Travelers purchasing souvenirs or articles of clothing made with contaminated animal hides or wool are a group at theoretical risk for the acquisition of anthrax; hunters are another potential group at risk. In contrast, inhalational anthrax is usually thought to be associated with bioterrorism. Gonorrhea, syphilis, chlamydia, lymphogranuloma venereum, herpes simplex virus, HIV, granuloma inguinale, and chancroid are all sexually transmitted diseases that may give rise to fevers (see Chapters 41-44). Common respiratory and enteric viruses are the most common causes of fever in travelers, accounting for over 50% of cases of febrile illness in travelers in most case series. Hepatitis viruses are a relatively common cause of fever in travelers (100-200/100,000 travelers); prodromal symptoms associated with fever may precede icterus. Hepatitis A occurs most frequently, but >90% of cases could be prevented by pre-travel immunization with hepatitis A vaccine. Adults over the age of 40 years who acquire hepatitis A are at much greater risk of having a complicated course or dying of their disease than are those who are younger. Hepatitis B and C may occur in healthcare workers, individuals with a history of sexual contact abroad, and patients who receive blood transfusions, although the hepatitis B immunization is also highly effective (see Chapter 22). Hepatitis E has been serologically confirmed in many returned travelers; it undoubtedly occurs more often. In long-term travelers to the developing world, the seroconversion rate for hepatitis E is ~5%. Acute HIV infection, resulting from sexual activity, blood transfusion, and intravenous drug use, has been reported among returned travelers (see Chapter 41). In their analysis of GeoSentinel data, Leder and colleagues (2013) reported 84 cases of acute HIV among >42,000 ill returned travelers, making HIV the seventh most common specific cause of fever in this group. Rash and lymphadenopathy combined with appropriate history can be clues to suspect primary infection. Plasma RNA levels are more sensitive than serodiagnostic tests, which may be negative in the early period of infection. Acute infection with Epstein-Barr virus (EBV) may occur in susceptible travelers, especially in the 15-to 30-year-old age group. Hepatosplenomegaly, lymphadenopathy, mucopurulent pharyngitis, heterophile antibodies, and the presence of atypical lymphocytes on the blood smear are helpful clues. Specific EBV serologies are useful to establish the diagnosis of acute infection. Cytomegalovirus (CMV) infections may cause an infectious mononucleosis-like illness with elevated hepatic transaminases in travelers and may be diagnosed by CMV serologies. Rubeola (measles) remains an important cause of morbidity and mortality in developing countries and poses a substantial risk to travelers who have not received adequate immunization. Furthermore, the syndrome of atypical measles may result from exposure to wild virus in individuals who may have received killed virus vaccine (used in the United States before 1963). A large outbreak involving a US theme park in 2014 underscored the risk of measles to unvaccinated individuals and the risk of exported disease via commercial air travel. Complications of measles include progressive pneumonitis (especially in pregnant or immunocompromised patients), pulmonary bacterial superinfection, and encephalitis. Endemic mycoses such as histoplasmosis and coccidioidomycosis are becoming increasingly recognized among international travelers and can present as undifferentiated fever. Among 13 cases of acute pulmonary histoplasmosis in a group of US travelers to Martinique, trekking through a mountain tunnel full of bats emerged as the common epidemiologic risk factor. Participation in construction projects at an orphanage in Tecate, Mexico was similarly associated with a cluster of cases of coccidioidomycosis among US travelers. Penicilliosis can also be acquired by travelers. Endemic mycoses can present as a systemic febrile or flu-like illness, with or without accompanying respiratory, cutaneous, or articular manifestations, and should therefore be considered in the differential diagnosis of post-travel fever. 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