Travelers and Eosinophilia
Abstract & Commentary
By Maria D. Mileno, MD
Dr. Mileno is Director, Travel Medicine, The Miriam Hospital, Associate Professor of Medicine, Brown University, Providence, RI.
Dr. Mileno reports no financial relationships relevant to this field of study.
Synopsis: Travelers returning from tropical countries may have significant exposures to helminths, yet there is no established clinical approach to identify and treat those who are both infected and presenting with eosinophilia. An approach to cases of eosinophilia in which schistosomiasis in returning travelers had been excluded is outlined in this recent publication.
Source: Meltzer E, Percik R, Shatzkes J, et al. Eosinophilia among returning travelers: A practical approach. Am J Trop Med Hyg 2008;78(5):702-709.
There is a broad differential diagnosis for eosinophilia, defined as an absolute eosinophil count of > 500 cells/µl, yet cases due to helminthic disease probably occur more often in routine travelers than in the general population. There is a high index of suspicion concerning potential eosinophilia in immigrants and refugees. Schistosomiasis is an important cause of eosinophilia, followed by filariasis, primarily in persons residing in Africa, and is not rare in travelers returning from endemic areas.
This retrospective case series from Israel looked at travelers (excluding expatriates and immigrants) who returned from developing countries between January 1994 and June 2006. Eosinophilia was defined as total eosinophil count > 500/µl or > 6% on differential counts. All patients had a CBC, chemistry panel including liver function tests, and one or more stool samples for ova/parasites. Travelers to schistosomiasis-endemic areas were also tested for Schistosoma ova in urine and received a serologic test for schistosomiasis.
Other travelers underwent serologic tests for additional helminth infections such as strongyloidiasis and Toxocara infections performed at the Laboratory for Parasitic Diseases at the Centers for Disease Control (CDC), Atlanta, GA. Testing such as imaging or biopsies were performed according to clinical judgment. Patients diagnosed with schistosomiasis were treated with praziquantel 60 mg/kg for one day divided into two doses. Diagnosed cases of acute schistosomiasis received repeated dosing within three months. Other cases with eosinophilia were treated with albendazole 400 mg twice each day for 3 to 5 days. Symptoms and eosinophil count were evaluated.
Of 995 post-travel patients evaluated, 82 (8.6%) had eosinophilia, 44 (53.7%) of these had schistosomiasis-associated eosinophilia (SAE) and 38 (46.3%) had post-travel non-schistosomal eosinophilia (NSE).
Age, travel duration, and male/female ratio were not significantly different between NSE and SAE cases. Geographically, SAE were almost exclusively acquired through travel to Africa (95%). Most NSE cases had traveled to Asia (65.7%), with Southeast Asia and India being primary areas of transmission. Acute schistosomiasis occurred in 21 of 44 SAE cases and particularly presented with fever, rash, and respiratory symptoms. Sixteen of 44 (36.6%) were asymptomatic fellow travelers of a diagnosed index case and were identified through screening. Only 7 (16.9%) presented with chronic schistosomiasis, usually genitourinary.
At presentation, 94.7% of persons with NSE were symptomatic, with abdominal pain and protracted diarrhea as leading symptoms followed by dermatologic findings (rash or pruritis) and respiratory symptoms, mainly dry cough. Symptoms occurred in isolation or in combination. Two patients presented with only symptoms of fatigue. Symptoms began in most cases during travel and were already present for several weeks on presentation to the clinic. Median time to presentation was six weeks (range from 1 day to > 1 year).
NSE had a median initial eosinophil count of 1700 cells/µl compared to SAE cases who had 1400 cells/µl (P=0.067). Mildly abnormal liver function tests occurred in 5.3% of NSE cases and 13.0% of SAE cases—not a statistically significantly difference. Serologic testing was positive in all 44 SAE cases. Diagnosis by observation of ova was made in 22.7% of cases. Only a smattering of NSE cases had diagnostic findings. Two cases had hookworm alone documented, and one case had hookworm and Ascaris. Blastocystis hominis and Entamoeba histolytica/dispar were found alone or with helminths in four cases. One patient had hookworms noted in a sputum sample. Five tests for strongyloidiasis were positive. No tests for toxocariasis, filariasis, or trichinosis were positive. In fact, definitive parasitologic diagnosis was achieved in only 9 NSE cases (23.7%). Two patients had non-infectious causes of eosinophilia, one with drug allergy; another with positive Strongyloides serology had increasing lymphadenopathy and, ultimately, B-cell lymphoma was diagnosed.
In terms of treatment, all persons with SAE tolerated praziquantel with no documented treatment failure. Thirty-seven NSE patients were offered empiric therapy with albendazole. One declined and four others were lost to follow up. Of 30 treated patients available for evaluation of clinical response, 90% (27/30) showed a favorable response to treatment; 76.7% had complete remission of symptoms; 13.3% had significant improvement; 3 cases (10%) had no response. One had lymphoma, one had eosinophilic gastroenteritis, and one remained without a specific diagnosis but responded to corticosteroid treatment as did the patient with eosinophilic gastroenteritis.
This study showed that NSE is certainly not rare and represented 4% of all referrals to this post-travel clinic. Some forms of travel pose even higher risks; the incidence of NSE reported in military personnel actively screened after deployment to a developing country has been 50%. What lessons can we learn from this study, and from what we know about refugees and immigrants? Although diagnostic yields were low, responses to treatment were high. Screening for eosinophilia in travelers returning from Africa may have an important impact for the immediate and future health of these individuals. Knowing about significant levels of eosinophilia would provide an important clue to the potential diagnosis and treatment of strongyloidiasis and schistosomiasis.
Young healthy travelers to developing countries who develop eosinophilia should be evaluated first and foremost for helminth infections. Strongyloidiasis and schistosomiasis have the strongest associations with eosinophilia. Other infectious diseases may be associated with eosinophilia, including cocoidioidomycosis, aspergillosis, isosporiasis, Dientamoeba fragilis, Mycobacterium leprae, and chronic Mycobacterium tuberculosis infections, although the diagnostic yields are quite low when based solely upon the finding of eosinophilia.
Schistosomiasis is an important and frequent cause of eosinophilia, and this diagnosis should be pursued using serology and attempted ova detection. Identified cases, and arguably individuals with known exposure or fellow travelers of index cases, should be treated with praziquantel.
Hookworm and strongyloides are the most prevalent helminthic infections. In some groups, strongyloides seroprevalence reached 77%. Canine hookworms have recently been shown to occasionally cause NSE and eosinophilic gastroenteritis. A case can be made that empiric therapy is most sensible, rather than an extensive diagnostic workup in travelers returning from regions of such high endemicity. Universal treatment with albendazole, a broad spectrum antihelminthic, is highly effective in populations with high incidence of helminthic infection, such as refugees and immigrants, and has an excellent safety record.
One algorithm for travelers returning from Africa with eosinophilia might include empiric treatment for schistosomiasis with praziquantel followed by albendazole. Travelers with NSE might have an evaluation that includes a thorough history and physical examination, stool samples for ova and parasites, and a therapeutic trial of albendazole. If a strongyloides serology is positive, treatment with ivermectin would be administered. Further testing should be reserved for individuals who remain symptomatic.
In summary, eosinophilia that is associated with schistosomiasis is uncommon but not rare. NSE is more a more common scenario. Travelers with NSE are often symptomatic, and eosinophilia is most probably associated with helminthic infection(s). A better methodology is still needed to evaluate persons with eosinophilia for potential parasitic infection. Empiric albendazole results in resolution of symptoms and eosinophilia in most cases, with further treatment reserved for the few cases that do not respond to initial empiric treatment. Lastly, consideration of the noninfectious causes of eosinophilia including allergic disorders, medications, toxins, autoimmune diseases, and endocrine disorders such as Addison's disease may yield the diagnosis.