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Authors: Megan Donohue, MD MPH; Phil Magidson, MD MPH; Erica Bates, MD; Adeolu Ogunbodede, MD; Mark Sutherland, MD; Akilesh Honasoge, MD
Editors: Michael C. Bond, MD FAAEM and Kelly Maurelus, MD FAAEM
Originally Published: Common Sense November/December 2016
With increasing frequency of international travel, EMPs often find themselves caring for travelers who return ill. According to the International Society of Travel Medicine global surveillance network, fever was the chief complaint in approximately one third of ill travelers. The care of these patients may be challenging given the broad differential diagnosis that must be considered, including many illnesses that are uncommon in the US. This article provides a review of the literature on the epidemiology of febrile illness in the returning traveler and offers an approach to the initial evaluation, management, and diagnosis.
Wilson ME, Weld LH, Boggild A, et al. Fever in Returned Travelers: Results from the GeoSentinel Surveillance Network for the GeoSentinel Surveillance Network. Clin Infect Dis. 2007;44:1560-1568.
Wilson et al., utilized a GeoSentinel database to examine the presentation, etiology, and outcome of febrile returned travelers. Data from 31 travel or tropical medicine clinics on six continents was collected from 1997-2006. Of 24,920 patients reviewed, 6,957 presented with fever as the chief complaint. Most travelers with fever presented within 1 month of their return. Fever was more common among those travelers who visited friends, family, or relatives as business and tourism travelers were more likely to have visited a doctor and received prophylactic treatment or vaccines prior to travel.
Travel-related illness may affect many different organ systems and be caused by diverse pathogens. The most common systems affected were: systemic illnesses (35%), diarrheal illnesses (15%), respiratory (14%), genitourinary (4%), dermatologic (4%), and hepatitides (1%) with 22% unspecified. Malaria accounted for the bulk of systemic illness and 21% of all febrile patients. Uncommon illnesses observed included leptospirosis, amebic liver abscess, and viral meningitis.
Hospitalization was required in 26% of the cohort and 12 patients (0.2%) died. The leading causes of death was malaria (n=4). Other causes of note were acute respiratory distress syndrome (n=2), pulmonary embolism (n=1), acute HIV (n=1), angiostrongyliasis (n=1), and Epstein Barr Virus (n=1). The incidence of death attributed to malaria is particularly concerning given some studies show malaria diagnosis is missed on initial presentation 59% of the time.
Geographic variation of disease is noteworthy. For example, malaria is the most common cause of severe febrile illnesses after travel to sub-Saharan Africa while malaria and dengue are equally common causes after travel to Central or South America. The CDC Yellow Book provides a simple set of maps, tables, and graphical summaries of this data. Given this vast array of tropical illnesses and range of severity, an organized approach to evaluation and workup is needed.
Pigott D. Emergency department evaluation of the febrile traveler. Journal of Infection 2007; 54, 1-5.
A screening tool for febrile travelers including travel history, exposure history, fever pattern, and physical exam findings may be useful in developing a differential diagnosis and determine appropriate diagnostic testing. Key points of information are: region of travel including layovers, duration of any prophylaxis, contact with bodies of water, exposure to animals or insects, a food diary, and a sexual history. Many emergent disease processes involve the neurologic and dermatologic systems so complete review of systems with emphasis on these areas may help identify the need for hospitalization.
The skin should be thoroughly examined for any rashes, petechiae, or ecchymoses. Mucous membrane bleeding is often indicative of viral hemorrhagic fevers such as Ebola, Marburg, or Lassa, all of which require special precautions.
Schwartz D. Fever in the Returning Traveler, Part Two: A Methodological Approach to Initial Management. Wilderness and Environmental Medicine 2003; 14, 120-130.
Schwartz recommends a thorough laboratory evaluation for the febrile traveler including a CBC with differential, Wright stain, thick and thin peripheral blood smears, chemistries, liver function tests, blood culture, urinalysis, and chest radiograph. The presence of gastrointestinal symptoms should prompt testing of stool for ova and parasites, culture, and fecal leukocytes. While these diagnostic tests often do not establish a definitive diagnosis, they may identify patients who require additional testing or hospitalization. Such additional testing may include lumbar puncture, STD testing, or imaging including possible CT or MRI to examine for parasites. Disease-specific serologies are available for some pathogens but the results are often delayed. Treatment should be initiated pending the results if there is a high clinical suspicion.
Kotlyar S, Rice B. Fever in the Returning Traveler. Emerg Med Clin N Am 31 (2013) 927-944.
A definitive diagnosis is never made in up to 30% of travelers who return with fever. For those with a definitive cause, the most common are malaria, dengue, typhoid fever, or a rickettsial disease.
Dengue hemorrhagic fever, meningococcemia, and severe rickettsial infection are the most serious disease processes that should be considered in a returning traveler with fever and rash. As these are potentially deadline diseases, patients clinically suspected of having these should be admitted to the hospital on respiratory and droplet isolation. Treatment should be initiated in conjunction with a thorough workup and not delayed until a definitive diagnosis is made.
Malaria commonly presents with cyclical fever which peaks every 3-4 days, chills, rigors, body aches, nausea, gastrointestinal complaints, and malaise. Of the four main species of Plasmodium, patients with P. falcifarium may present severely ill with fever, DIC, dehydration, and altered mental status due to cerebral edema. Although malaria is classically diagnosed by blood film analysis, EMPs should be aware that rapid antigen testing exists and may be available in many laboratories. Treatment depends on the severity of illness as well as the region of exposure as resistance patterns vary. An important resource is the CDC 24-hour malaria hotline (855-856-4713) with expert consultation available for specific treatment recommendations.
Dengue fever is a common cause of fever worldwide and an increasing cause of fever in returning travelers, especially in those returning from Southeast Asia. Common signs and symptoms are retro-orbital pain, a lateral gaze, myalgias, and arthralgias. This is classically referred to as “break-bone fever.” Rash is often, but not always present. Seen mostly in patients with a history or previous dengue infection, dengue hemorrhagic fever is often deadly. Signs and symptoms suggestive of dengue hemorrhagic fever are thrombocytopenia, easy bleeding or bruising, edema, and effusions. Patients should be admitted to an ICU as even with treatment the mortality is nearly 40%. Other viral hemorrhagic fevers, such as Ebola, are treated similarly with intense supportive care and strict isolation.
Yellow fever is another mosquito-borne cause of fever. Symptoms include fatigue, myalgias, vomiting, abdominal pain, and hepatomegaly. LFTs may be markedly elevated. PCR and serologic tests are available for diagnosis and care is supportive.
Typhoid fever is transmitted fecal-orally by Salmonella typhi and should be considered in patients who traveled in regions with low sanitary standards. Although significant variation exists, the average incubation period is 3 weeks which is often longer than malaria or dengue fever. Symptoms are non-specific and along with fever may include a variety of gastrointestinal complaints including constipation or diarrhea. Two findings that are more suggestive of typhoid fever include “rose spots” which are small pink macules appearing early in the disease process, and the Faget sign or sphygmothermic dissociation which is relative bradycardia during periods of high fever. Typhoid is diagnosed by blood and stool cultures and results are not immediate. Treatment with a quinolone or third generation cephalosporin should be started pending the results if there is a high clinical suspicion.
Rickettsial infection is also a common cause of fever in returning travelers and, among others, includes Rocky Mountain spotted fever, Mediterranean spotted fever, African tick bite fever, typhus, and Q fever. In addition to fever, common signs and symptoms include malaise, myalgias and arthralgias, diarrhea, rash, and lymphadenopathy. The classic triad of rash, lymphadenitis, and inoculation eschar is seen in less than half of all patients. PCR testing is accurate and generally available. While confirmatory tests are pending, treatment with a tetracycline such as doxycycline should be initiated.
Schwartz D. Fever in the Returning Traveler, Part One: A Methodological Approach to Initial Evaluation. Wilderness Medicine 2003; 14, 24-32.
In this article, Schwartz summarizes less common causes of fever in the returning traveler including those caused by bacteria, parasites, and protozoa. Bacterial causes of febrile illness include leptospirosis, bubonic plague, and brucellosis. Parasitic and protozoal causes of febrile illness include African sleeping sickness, schistosomiasis, and leishmaniasis.
Leptospirosis is caused by a spirochete found in the urine and feces of domestic animals and associated contaminated water. An initial flu-like febrile phase occurs 10-21 days after exposure, followed by a second immune-mediated phase which may involve vasculitis, aseptic meningitis, glomerulonephritis, uveitis, and rarely liver failure with DIC. Early treatment with tetracycline during the initial phase prevents later complications.
Bubonic plague is surprisingly still found in the US and abroad. Presentation is characterized by fever, myalgias, and lymphadenopathy which may evolve into an abscess. Treatments include streptomycin or chloramphenicol.
Brucellosis is caused by a gram-negative organism found in unpasteurized dairy and meat. It causes fever, vomiting, diarrhea, lymphadenopathy, and can cause chronic infection if not treated. Trimethoprim/sulfamethoxazole, doxycycline, streptomycin, or rifampin are recommended therapies.
African sleeping sickness is transmitted via the bite of the tsetse fly, and causes fevers, chills, muscle aches, nausea, vomiting, and headache. A well-circumscribed, 2cm-5cm indurated red chancre commonly occurs during the acute illness. Laboratory findings include anemia, leukopenia, thrombocytopenia, and transaminitis. If the parasite burden is high, the diagnosis can be made through stained peripheral smear. If the parasite burden is low, it can be detected by examination of the buffy coat. Over a period of weeks to months, CNS involvement can manifest as personality changes, movement derangements, dementia, coma, and may result in death. Lumbar puncture must be done to evaluate for CNS involvement, and CSF should be examined for the parasite. Pentamadine is the treatment of choice.
Schistosomiasis is caused by a parasite transmitted by freshwater snails in Southeast Asia and Africa. Snails release larvae into water which then breach intact skin leading to infestation. The presentation may vary but typically includes fever, myalgia, headache, and hepatomegaly. Ectopic egg deposition in any organ such as brain, spine, or kidneys leads to a local immune complex-mediated inflammation. CNS sequelae include headache and symptoms of space-occupying lesions, such as visual field deficits, seizure, and incontinence. Focal neurological deficits should be further examined by emergent MRI and appropriate surgical consultation. Diagnosis of schistosomiasis is made by examination of urine and stool for eggs, serology, or western blot. The CDC can aid in providing these testing modalities. Treatment is praziquantel.
Leishmaniasis is a protozoan infection transmitted via the bite of the sandfly, which is found in the Middle East, Southern Europe, Africa, and South America. Cutaneous manifestations of the infection may take weeks to months to develop and include a non-healing ulcer with heaped-up margins. Visceral Leishmaniasis, which may be fatal, can take months or years to develop and is characterized by fever, poor appetite, and splenomegaly. Diagnosis is confirmed by biopsy, and treatment varies based on disease severity.
Conclusion
A methodological approach to the evaluation of the febrile traveler is key to making the correct diagnosis and providing proper treatment. While a definitive diagnosis is often not made in the ED, we must maintain a high level of suspicion for potential deadly causes of fever and treat them accordingly. EPs should know the identifiable attributes of each disease process and be aware of available resources at the local and federal level including infectious disease colleagues, institutional disaster management protocols, the CDC Yellow Book, and the CDC 24-hour phone line.
References:
1. Doherty JF, Grant AD, Bryceson AD. Fever as the presenting complaint of travellers returning from the tropics. QJM. 1995;88(4):277-81.
2. Freedman DO, Weld LH, Kozarsky PE, et al. Spectrum of disease and relation to place of exposure among ill returned travelers. N Engl J Med. 2006;354(2):119-30.
3. Jensenius M, Fournier P-E, Vene S, et al. African Tick Bite Fever in Travelers to Rural Sub-Equatorial Africa. Clin Infect Dis. 2003;36(11):1411-1417. doi:10.1086/375083.
4. Kotlyar S, Rice B. Fever in the Returning Traveler. Emerg Med Clin N Am 31 (2013) 927-944.
5. Pigott. Emergency department evaluation of the febrile traveler. Journal of Infection 2007; 54, 1-5.
6. Schwartz D. Fever in the Returning Traveler, Part One: A Methodological Approach to Initial Evaluation. Wilderness Medicine 2003; 14, 24-32.
7. Schwartz D. Fever in the Returning Traveler, Part Two: A Methodological Approach to Initial Management. Wilderness and Environmental Medicine 2003; 14, 120-130.
8. Wilson ME, Weld LH, Boggild A, et al. Fever in Returned Travelers: Results from the GeoSentinel Surveillance Network for the GeoSentinel Surveillance Network. Clin Infect Dis. 2007;44:1560-1568. doi:10.1086/518173.
9. Wilson ML. Ecology and infectious disease, in Ecosystem Change and Public Health: A Global Perspective, J.L. Aron and J.A. Patz, Editors. 2001, Johns Hopkins University Press: Baltimore. p. 283-324.
10. Wilson ML. Post Travel Evaluation. CDC Yellow Book, Chapter 5. 2016. Available at: http://wwwnc.cdc.gov/travel/yellowbook/2016/post-travel-evaluation/fever-in-returned-travelers.