Critical Care Medicine

Infections in Travelers (Malaria, Strongyloides)

Infections in returning travelers from developing countries

Diseases associated with a short incubation period include: malaria, typhoid fever, dengue and other hemorrhagic fevers, chikungunya, influenza, and acute HIV. Though hepatitis A might also be included, all travelers should have been immunized. Diseases associated with a longer incubation period include: malaria, tuberculosis and strongyloides.

1. Description of the problem

What every clinician needs to know

A clinically useful way to organize this topic is to consider separately infections with a short incubation period (patients present within a few weeks of return) and a long incubation period (patients who present beyond one month of returning from their trip).Though there are many unusual diseases that can occur in travelers to developing parts of the world, the vast majority of diagnosed conditions are limited to a small number of infections.

In addition, it is also always important not to get "tunnel vision" about the travel. The patient's problem may have nothing to do with the trip so one has to keep these considerations in the differential diagnosis.

This review with focus on patients with a relatively non-specific clinical presentation. Patients who present with fever and a focal problem (e.g. pneumonia or diarrhea) need a workup focused on the focal problem.

Clinical features

Short Incubation period

A. Malaria:malaria has a "flu-like" presentation of fevers, rigors, headache and myalgias. About 25% also have some gastrointestinal symptoms. Most patients do not manifest a) the classical cyclical fevers; b) splenomegaly; or c) clinically significant anemia.

B. Typhoid fever: this has a more sub-acute onset than malaria with a step-wise increase in fever over several days to a week. It is not characterized by diarrhea; that is salmonella gastroenteritis a different salmonella syndrome.

C. Dengue and other hemorrhagic fever viruses:dengue has a world-wide distribution. It is primarily transmitted by the aedes mosquito. Dengue also has a "flu-like" presentation with particularly prominent myalgias. A rash can be seen up to 50% of the time. The other hemorrhagic fever viruses such as ebola, marburg and lassa are much less common but have implications for contagiousness and should be suspected if there are hemorrhagic manifestations.

D. Chikungunya:this deserves a brief mention because of the large epidemic involving millions of people that started in the Indian Ocean islands and spread east to India and west across Africa. A number of cases have also been reported from Southern Europe. It is similar to dengue in that it is transmitted by the bite of the aedes mosquito and is characterized by the acute onset of a "flu-like" illness. Characteristic features include severe arthralgias and arthritis and a non-specific rash.

E. Influenza: influenza is distributed throughout the world. It is primarily seen in the cooler months in temperate areas, but is present throughout the year in tropical areas. Travelers should be immunized

F. Acute HIV: several studies have noted the markedly increased risk of casual unprotected sex in international travels. The prevalence of HIV is generally higher that in the United States in much of the developing world. This diagnosis needs to be considered in any febrile returning traveler.

Long incubation period

A. Malaria: as above, malaria can present as early as 10 days after exposure, but in 5% of cases presents a year or more after returning from an endemic area.

B. Tuberculosis: the risk of acquiring tuberculosis is generally much greater in the developing world than in the United states. It typically presents as a sub-acute to chronic pulmonary disease but can occasionally have extra-pulmonary manifestations.

C. Strongyloides: strongyloides is a nematode that unlike other worms can autoinfect an individual. The result of this is that one can carry this organism for many years before it becomes clinically manifested. The adult worms live in the small intestine. Most infected persons are asymptomatic, but under certain circumstances, such as depressed cell mediated immunity related to steroid treatment, the tissue migrating larvae can increase in numbers, producing fever, pulmonary infiltrates, encephalitis and SIRS. The migrating larvae can also facilitate bowel wall translocation of bacteria, resulting in recurrent Gram negative bacillary bacteremias.

Key management steps

Malaria: There are three critical steps in the proper management of malaria. There are no characteristic history, physical examination or initial laboratory findings.

  1. Think of it. It should be considered in every febrile person who has been traveling to a malaria area within the past 1-2 years. Once considered the proper diagnostic testing can be done.

  2. Rule out P. falciparum.Of the five malaria species that can infect humans this is the only one that is a medical emergency and the only one with a significant mortality.

  3. If it is P. falciparum determine if the patient acquired it in an area of the world where there is the potential for chloroquine resistant organisms. The only remaining areas of the world where P. falciparum continues to be chloroquine sensitive are Hispaniola, Argentina and the Middle East.

Typhoid fever: again, the critical feature is to consider the diagnosis. If the diagnosis is considered the proper laboratory testing can be obtained to confirm it.

Dengue: this arbovirus is transmitted by day-biting mosquitoes (rather than night-biting transmitters of malaria). Though the features are often non-specific, patients with dengue characteristically complain of severe myalgias and often have a rash.

Chikungunya: the "clue" to considering this diagnosis is the joint complaints in a person with an acute febrile illness who has recently traveled to endemic parts of the world.

Influenza: influenza has a relatively sudden onset of fevers, rigors, myalgias and headache. As mentioned above, in temperate regions influenza occurs in the cooler months, but in equatorial countries it can be seen throughout the year.

Acute HIV: the onset tends to be more subacute than the other diagnoses in this category. Typical features include diffuse adenopathy, pharyngitis and a non-specific rash. Other than the rash the presentation is very reminiscent of mononucleosis.

Tuberculosis: Extra-pulmonary tuberculosis can be very protean in its manifestations. It can cause focal disease in many organs or it can present as a disseminated disease with non-focal fevers (miliary).

Strongyloides: consider strongyloides in immunosuppressed patients with culture negative SIRS, diffuse pulmonary infiltrates or recurrent Gram negative sepsis. Many patients do not have an eosinophilia.

2. Emergency Management

Emergency management typically requires a diagnosis, since the treatable diseases have different therapies and some do not have specific treatment. The most urgent diagnoses to consider are malaria, particularly P. falciparum, the hemorrhagic fever viruses because of public health implications, and hyperinfection strongyloidiasis. All of these have significant risks of death. Clearly typhoid fever should be diagnosed quickly and once malaria has been ruled out this becomes the next most likely and urgently treatable diagnosis.

Management points not to be missed

Malaria: The proper management of malaria requires speciation of the protozoan. The only species which is a true emergency is P. falciparum. The nuances of treatment of malaria is beyond the scope of this article; however, if the patient acquired malaria in the few remaining parts of the world where there is no chloroquine resistance, this is the drug of choice. Emergency treatment of P. falciparum acquired in areas where there is the potential for drug resistance should include either artemether/lumefantrine by mouth or artesunate plus a second agent by vein.

Artesunate can be obtained emergently from the Centers for Disease Control on a 24 hour basis [contact CDC for information (770) 488-7788 Monday-Friday 8 am to 4:30 pm EST, (770) 488-7100 after hours, weekends and holidays]. Infections with P. malariae and P. knowlesi can be treated with chloroquine. Infections with P. vivax and P. ovale can be treated with chloroquine to control the patient's symptoms and then a course of primaquine (check G6PD status first) to eradicate the latent liver phase from which these species can relapse.

Dengue and the other hemorrhagic fever viruses: most have no specific anti-viral treatment (Lassa fever should be treated with ribavirin). Patients with these infections will often need intensive care unit support. Patient with suspected ebola, Lassa fever or Marburg virus infection should be put in strick isolation and the public health authorities notified.

Influenza: initiation of neuraminidase inhibitors oseltamivir or zanamivir within the first 48 hours will shorten the course by several days.

Strongyloidiasis: ivermectin should be given as soon as the diagnosis is established. Albendazole is a less effective option.

3. Diagnosis

Diagnostic criteria and tests

Malariais diagnosed and speciated by looking a peripheral blood smears. In mild infections it may take up to six smears to find the parasite. There are several licensed rapid diagnostic tests for malaria. They are very sensitive and specific and can be used as a screening test. Blood smears should still be obtained to confirm speciation and to estimate parasite burden (percent parasitemia).

Typhoid fever: culture of blood, urine and feces will generally yield the organism. Culture of bone marrow is another high yield source.

Dengueis diagnosed serologically. If any of the other hemorrhagic fever viruses are being considered, the Centers for Disease Control should be immediately notified. They can advise on isolation, treatment, and can organize diagnostic testing.

Chikungunya is diagnosed serologically.

Acute HIV: serology is often negative during acute HIV infection. The diagnosis can be confirmed by getting a serology during convalescence or by obtaining an HIV viral load which is typically at a very high titer during acute infection.

Tuberculosis: (extra-pulmonary) can be difficult to diagnose. Isolator bloood culture, biopsies of bone marrow, enlarged lymph nodes and/or liver should be considered. The material must be sent for both smear and culture.

Strongyloidiasis is diagnosed by finding larva in stool (may take multiple specimens), sputum, and/or duodenal aspirate (most sensitive). Serology FYI: Serology can also be very helpful, but generally takes too long to get the results in the management of extremely ill patients.

Establishing the diagnosis

Malaria: a peripheral blood smear can be used both to diagnose and to speciate malaria. As mentioned above, the critical issue (after making the dagnosis) is to determine if the species is P falciparum or not. The distinguishing features of P falciparum include:

  1. Potential for high grade parasitemia; all of the other species are limited to a few percent; any infection with more than 5% of the RBCs involved should be consider P. falciparum.

  2. Only ring forms; the other species will be characterized by trophozoites and schizonts.

  3. Banana shaped gametocyte.

  4. Infected cells are of all sizes (ages).

  5. Multiple parasites per cell infected cells.

Malaria, and all of the other infections discussed in this chapter other than strongyloidiasis, can be associated with relative leucopenia rather than leucocytosis. All can manifest mildly elevated transaminases. Though eosinophilia is typically associated with strongyloides infections, it is often not present with the hyperinfection syndrome.

Confirming the diagnosis

For the short incubation period diseases, presentations and initial laboratory testing can be quite similar, so specific diagnostic testing is required. A rash would be atypical for malaria, tuberculosis or typhoid (rose spots look different), but can be seen with acute HIV, dengue and chikungunya. Strongyloidiasis may be associated with several different cutaneous manifestations. Though uncommon, a pruritic, erythemaous, serpiginous eruption called larva currans is diagnostic.

4. Specific Treatment

Malaria:As mentioned the treatment depends upon the species.

A. If P. falciparum:

  • (1) If from areas of the world where chloroquine resistance has not been reported, chloroquine is the treatment of choice.

  • (2) If from areas of the world where chloroquine resistance has been reported:

    • (a) If not severely ill - arthemether/lumefantrine or malarone.

    • (b) If severely ill - intravenous atesunate (obtained from the Centers for Disease Control) plus doxycycline.

B. If P. vivax or p. ovale:

  • (1) Chloroquine.

  • (2) Check G6PD status and if normal, add primaquine.

C. If P. malariae or P. knowlesi - chloroquine.

Typhoid: azithromycin, a fluoroquinolone or ceftriaxone.

Dengue, Chickungunya, acute HIV: there is no specific treatment for these viral infections.

TUBERCULOSIS: isoniazid, rifampin, ethambutol and pyrazinamide.

Drugs and dosages

Malaria

Oral regimens

Chloroquine PO: 1000mg stat then 500mg at 6, 24 and 48 hours.

Artemether/Lumefantrine (Coartem) PO: 4 tabs stat then 4 tabs in 8 hours then 4 tabs twice a day x 2 days.

Atavoquone/proguanil (Malarone) PO: 4 tabs daily x 3 days.

Quinine sulfate: 648 mg po tid x 3 or 7 days.

Doxycycline: 100 mg po bid x 7 days.

Clindamycin: 20 mg /kg/day po divided tid x 7 days.

Primaquine phosphate: 52.6 mg po qd x 14 days.

Parenteral regimens

Artesunate IV: 2.4 mg/kg stat then 2.4 mg/kg 12 and 24 hours later, then 2.4 mg/kg daily x 5 days.

Quinidine gluconate: 10 mg /kg loading dose IV over 1-2 hrs, then 0.02 mg /kg/min continuous infusion for at least 24 hours.

Typhoid

Azithromycin 1 gm daily x 5-7days.

Ciprofloxacin 500 mg twice a day x 7-10 days.

Ceftriaxone 2 gm IV daily x 7-14 days.

Influenza

Oseltamivir 75 mg PO twice a day x 5-7 days.

Zanamivir 10 mg (two inhalations) twice daily x 5-7 days.

Strongyloidiasis

Ivermectin 200 mcg/kg daily x 2 days.

Albendazole 400 mg twice daily x 3-7 days (not as effective as ivermectin).

Refractory cases

Malaria: consideration should be given to exchange transfusion in patients with evidence of end organ damage such as cerebral malaria, ARDS or acute renal failure, or in persons with parasitemias over 10%.

Dengue: in patients who develop dengue shock syndrome and/or dengue hemorrhagic fever support in an intensive care unit setting is necessary.

Tuberculosis: sensitivity testing should always be obtained because of the spread of multiple drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis.

5. Disease monitoring, follow-up and disposition

Malaria:It is important to follow peripheral smears to document that the percent parasitemia is decreasing.

Typhoid:response is typically slow, often taking several days.

Acute HIVdoes not have emergent treatment, but clearly if this is the diagnosis followup is critical because most persons will eventually need treatment.

Pathophysiology

NA

Epidemiology

NA

Prognosis

All the diseases listed have the potential to cause significant morbidity and mortality. This is particularly true if in those diseases which have specific antimicrobial treatment, the treatment is delayed.

Special considerations for nursing and allied health professionals.

NA

What's the evidence?

Freedman, DO, Weld, LH, Kozarsky, PE, Fisk, T. "For the GeoSentinel Surveillance Network. Spectrum of disease and relation to place of exposure among ill returned travelers". N Engl J Med. vol. 354. 2006. pp. 119.

(Thirty GeoSentinel sites, which are specialized travel or tropical-medicine clinics on six continents, contributed clinician-based sentinel surveillance data for 17,353 ill returned travelers and compared the frequency of occurrence of each diagnosis among travelers returning from six developing regions of the world.)

Wilson, ME, Weld, LH, Boggild, A. "For the GeoSentinel Surveillance Network. Fever in returned travelers: results from the GeoSentinel Surveillance Network". Clin Infect Dis. vol. 44. 2007. pp. 1560.

(Fever is a marker of potentially serious illness in returned travelers. An approach organized by geographic area and traveler characteristics can facilitate timely appropriate treatment and preventive measures. Using a large, multicenter database, the authors defined the causes of fever by place of exposure and traveler characteristics. Of 24,920 returned travelers seen at a GeoSentinel clinic from March 1997 through March 2006, 6,957 (28%) cited fever as a chief reason for seeking care. 35% had a febrile systemic illness, 15% had a febrile diarrheal disease and 14% had fever and a respiratory illness. Malaria was the most common specific etiologic diagnosis, found in 21% of ill returned travelers with fever. More than 17% of travelers with fever had a vaccine-preventable infection or falciparum malaria, which is preventable with chemoprophylaxis. Malaria accounted for 33% of the 12 deaths among febrile travelers.)

Bottieau, E, Clerinx, J, Schrooten, W. "Etiology and outcome of fever after a stay in the tropics". J. Arch Intern Med. vol. 166. 2006. pp. 1642.

(A total of 1,842 fever episodes were included. Diagnosis often remained unknown [24%]. The pattern of tropical diseases was mainly influenced by the travel destination, with malaria [35%, mainly Plasmodium falciparum] and rickettsial infection [4%] as the leading diagnoses after a stay in Africa; dengue [12%], malaria [9%], and enteric fever [4%] after travel to Asia; and dengue [8%] and malaria [4%] on return from Latin America.)

Hochedez, P, Canestri, A, Buihot, A. "Management of travelers with fever and exanthema, notably dengue and chikungunya infections". Am J. Trop. Med. Hyp. vol. 78. 2008. pp. 710.

(Review of febrile exanthema in travelers with discussion of dengue and chickungunya: clinical presentation and diagnostic testing.)

Nuesch, R, Zimmerli, L, Stockli, R. "Imported strongyloidosis: a longitudinal analysis of 31 cases". J Travel Med. vol. 12. 2005. pp. 80.

(Review of the clinical features and of proper diagnosis and treatment is presented based on 31 patients with imported strongyloidiasis.)

"WHO guidelines for the treatment of malaria". 2006.

(Comprehensive)

"Preventing malaria in International Travelers". Jour of Travel Medicine. vol. 8. 2001.

(The entire issue is devoted to related topics and is still timely though written 10 years ago.)

Lynch, MF, Blanton, EM, Bulens, S. "Typhoid fever in the United States, 1999-2006". JAMA. vol. 302. 2009. pp. 898.

(Review of the epidemiology and antimicrobial resistance of S. Typhi in the USA.)
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