Toxic Appearance and Fever
Patients with a toxic appearance with fever often present difficult diagnostic dilemmas. As has
already been discussed, malaria must be ruled out. Other potential diagnoses already
discussed such as typhoid fever, early shigellosis, leptospirosis, and anicteric hepatitis remain
in the differential diagnosis. This group of conditions can be further subdivided into the
presence or absence of a rash. The presence of a hemorrhagic rash is somewhat helpful in
narrowing the differential to arboviral, rickettsial, and meningococcal etiologies but even this
is not completely reliable. Maculopapular rashes can be either the common exanthem of that
illness (i.e., measles) or an earlier stage in an evolving exanthem (i.e., rickettsial or
meningococcal disease). Rickettsial diseases are usually in the differential for critically ill
patients with fever and rash. There has been increasing recognition of rickettsial infections as
etiologies of serious travel-associated infections (144,145). The majority of imported rickettsial
disease in travelers is due toR. africae,the spotted fever group agent of African tick bite fever,
and less commonly,R. conorii,the spotted fever group agent of boutonneuse fever, both of
which typically present as mild and self-limited illnesses (144,146–149). Scrub typhus has
reported case fatality rates in indigenous populations of 15% and rarely has caused life-
threatening disease in returning travelers (150). These reports highlight the importance of
including rickettsial agents in the differential diagnosis and consideration of empiric therapy
with doxycycline. Rapid responses to doxycycline therapy within 24 hours support the
diagnosis and the lack of response should prompt alternative diagnoses. Sexually transmitted
diseases such as secondary syphilis, disseminated gonococcal infection, or acute retroviral
syndrome may rarely present in this manner and need consideration. Measles has significant
morbidity with the most common complication, pneumonitis, resulting in mortality rates of 2%
to 15% in children and <1% in adults (151,152). A study of hospitalized adults with
complications of typical measles revealed pneumonitis rates of approximately 50% with
respiratory failure and mechanical ventilation in 18% (153).
Dengue fever is, by far, the most common arboviral etiology of nonspecific febrile illness
in returning travelers (126,154,155). Global estimates of 150 million cases of classic dengue
fever and 250,000 cases of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS),
continued regional spread in the western hemisphere, and the urban peridomestic transmis-
sion from infectedAedes aegypti(alsoA. albopictus) mosquito vectors make dengue fever a
prominent consideration in returning travelers with fever (156). As with other arboviral
etiologic agents of viral hemorrhagic fever (VHF), illness onset with an elapsed time exceeding
three weeks (two weeks with dengue) from the potential exposure effectively rules out these
agents (157). Dengue fever may be caused by any one of the four serotypes with the relative
risk of severe disease (DHF/DSS) 100-fold higher during the second dengue infection then
with the first (156). Dengue fever rarely presents with life-threatening infection in US travelers
probably due to the lack of prior dengue infections. In West Africa, Lassa fever is endemic,
causing 100,000–300,000 human infections and approximately 5000 deaths each year (158).
Other than in regions where it is endemic, Lassa fever is encountered rarely. To date,
approximately 20 cases of imported Lassa fever have been reported worldwide with one death
in the United States in 2004 after travel to West Africa (158). Etiologies of VHF that have been
known to cause person-to-person transmission [Lassa virus, Ebola virus, Marburg virus, and
Crimean-Congo hemorrhagic fever (CCHF) virus] are particularly important since specific
recommendations are available for patient management and proper containment of these
potentially deadly viruses (157,159,160). VHF is characterized by fever, nonspecific symptoms
(i.e., pharyngitis, myalgias, respiratory symptoms, headache, and malaise), and in severe cases,
shock and hemorrhagic manifestations (157,159–162). These viruses have distinct geographic
distributions, variable case fatality rates, and potential therapeutic options as detailed on Table 3.
Nosocomial transmission has been documented for each of these agents and is primarily
transmitted through direct contact or aerosolization of blood or body fluids from often terminally
ill infected patients (157,162). Table 4 summarizes the general concepts from the CDC in properly
managing a suspected VHF patient. Recent interim CDC guidance provides updates on VHF
transmission and infection control precautions with specific focus on patient care practices,
environmental procedures, reporting, specimen handling, human remains handling, and
postexposure management (163) (Table 5). Consideration should also be given to postexposure
332 Wood-Morris et al.