Travel-Acquired Illnesses Associated with Fever

Incubation Period

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

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

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.

Dengue Fever

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 considered to have severe dengue, characterized by severe plasma leakage, severe bleeding, or organ failure ( ).

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

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

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.