We describe a case of an imported schistosomiasis with difficulties in making diagnosis because of a very late seroconversion, presumably due to previous treatment with artemisinin during the acute infection.
We describe a Schistosoma haematobium infection with asymptomatic eosinophilia, persistently negative urine microscopy, and late seroconversion (7.5 months) in a traveler returning from Mali. After initial negative parasitological tests, travel history led to diagnostic cystoscopy, allowing final diagnosis with urine microscopy after the bladder biopsy. The patient was successfully treated with praziquantel. Difficulties in making the diagnosis of schistosomiasis in asymptomatic returning travelers are discussed; we propose a trial treatment in these cases.
A healthy 26-year-old Caucasian male was admitted to our clinic with asymptomatic eosinophilia. The patient reported returning from a 6-week trip to Mali, Senegal, and Gambia, 4 months previously. He had been hiking through the Dogon Country (Mali). He received the Centers for Disease Control and Prevention (CDC) recommended vaccination for travelers to the region and used atovaquone-proguanil (250/100 mg daily) as malaria prophylaxis. While in Mali he experienced an episode of fever with chills that lasted for 3 days. Empirical treatment with artesunate was given (4 mg/kg on day 1 and 2 mg/kg for 3 days) and he remained asymptomatic for the rest of the trip. Although the first contact with water took place approximately 6 weeks before returning, the patient repeatedly denied having fresh water swims until he was diagnosed. The febrile episode occurred 3 weeks after water exposure.
The week after returning, his parasitological tests in both stool and urine showed negative results. Three months after his return (4.5 months after exposure), he experienced acute sharp pain in the right flank with a transiently positive urine strip test for hemoglobin. A presumptive diagnosis of urolithiasis was made, the patient was given nonsteroidal anti-inflammatory drugs and was discharged asymptomatic. No parasitological tests were performed at this time.
One month later (5.5 months after exposure) the patient came to our center for a urology consultation. Physical examination was normal; haematuria and proteinuria were absent. Liver and kidney function tests were normal, and abdominal computed tomography was unremarkable. Of note, an elevation of eosinophil count was seen [absolute eosinophil count (AEC) 5.240/μL, 40%], resulting in referral to the Infectious Disease Department.
Serological tests for schistosomiasis [S mansoni, S japonicum, and S haematobium/ova antigen/passive hemagglutination (IHA)], hydatidosis, toxoplasmosis, trichinosis, fascioliasis, human immunodeficiency virus (HIV), leishmaniasis, filariasis, and larva migrans visceral were performed but all results were negative. Urine and stool microscopic examinations were normal. No empiric antiparasitic treatment was administered at this time owing to the absence of parasitological diagnosis and the patient's denial of fresh water swims as an epidemiological factor.
At a follow-up visit 2 months later (7.5 months after exposure), the patient continued to be asymptomatic with a high eosinophil count (AEC 3.200/μL, 29%). After negative urine and stool microscopy for the third time, a second series of serological tests were requested [S mansoni, S japonicum, and S haematobium/ova antigen/enzyme-linked immunosorbent assay (ELISA)]. Also, bone marrow aspirate and phenotype confirmed non-clonal reactive eosinophilia.
At a third visit (8 months after exposure), a concentrated 24-hour urine parasitological test was performed, the result of which was also negative. At this moment, the patient continued to deny fresh water contact, therefore, a cystoscopy was performed revealing multiple nodular lesions compromising the bladder mucosa (Figure 1A). Biopsy of a nodule showed eosinophilic cystitis with giant multinucleated cells (Figure 1B) without parasites. Microscopic examination of the urine carried out after the biopsy revealed Schistosoma haematobium ova (Figure 1C). The results of the ELISA serology were available 1 month after diagnosis, with a positive result (index 3.1; normal below 1.1). Three doses of praziquantel 1200 mg were given in 24 hours (45 mg/kg) with complete resolution of eosinophilia. At a follow-up visit 6 months after treatment, the patient had a normal eosinophil count (AEC 320/μL, 4.1%), persistently positive serology (S mansoni, S japonicum, and S haematobium ova antigen/ELISA) and negative urine microscopic examination.
The epidemiological probability of schistosomiasis in this case was high. First, schistosomiasis is associated with eosinophilia in approximately 60% of cases; in fact, eosinophilia in a returning traveler from a Schistosoma-endemic region should be sufficient to suspect infection. Second, Dogon Country has a high prevalence of schistosomiasis, as a result, 44% of cases reported by TropNetEurop since 1999 (412 cases) have come from Dogon Country in Mali and Lake Tanganyika in Malawi. Third, the febrile episode experienced by the patient during the final part of the trip was likely an acute schistosomiasis.
Artemisinin has been reported to be partially effective against Schistosoma and schistosomules. Eradication has been achieved in 25% of chronic infections, together with >95% reduction in ova production. Artemisinin is not active in adult schistosomes older than 6 weeks (given 3 weeks after exposure in our case); however, it may have some activity against immature worms. Thus, artemisinin exposure may have reduced the adult worm burden in our patient resulting in late seroconversion and absence of parasites in the urine microscopies.
Serology is more sensitive in returning travelers than urine or stool microscopy. Indeed, series describe up to 88% of imported cases of schistosomiasis as being diagnosed with serology, of whom only 44% had parasites in stool or urine. Seroconversion typically occurs from 6 weeks onwards, although late seroconversions (6 months after exposure) have been reported. In this case, the negative IHA serology 5.5 months after exposure together with persistently negative urine microscopy and denial of the epidemiological factor made us question a parasitic etiology, and led us to perform a diagnostic cystoscopy while waiting for the second serology result. Although not a first line diagnostic tool, invasive techniques such as cystoscopy or rectal snips can be helpful in diagnosis of difficult cases; these tests are highly sensitive and typically demonstrate ova invading the mucosa with the characteristic submucosal granulomatous reaction. In this case, cystoscopy was decisive to reach the final diagnosis, as ova were only released into the urine after the biopsy, resulting in a pathogen-directed treatment. Despite reasonable doubts about parasitic infection, we are aware that cystoscopy could have been avoided by waiting for the second serology or simply by administering empirical treatment, especially if eosinophilia after returning from an endemic region was assumed to be schistosomiasis, despite the patient's denial of water exposure.
Different techniques were used for the first and second serological determination (IHA and ELISA, respectively). The sensitivity of the techniques varies according to the type of antigen and the stage of the infection. IHA is generally more widely available and recommended as first line assessment, although it is less sensitive than ELISA. On the other hand, ELISA ova-directed diagnostic tests may result in false negatives in early infections. A near 100% specificity has been reported with the combination of both techniques. Although we cannot rule out the possibility of the IHA result being a false negative, we believe that artemisinin treatment delayed our patient's seroconversion to 7.5 months, reflecting an absence of active ova-directed immune response at 5.5 months and likely a low level of ova production at this time. To our knowledge, seroconversion after 6 months has not been previously reported, and thus, it may be reasonable to consider longer seroconversion windows for returning travelers exposed to other active antiparasitic medications.
In conclusion, returning travelers with Schistosoma infection can be asymptomatic and late seroconversion (>6 months) may occur, as was the case in our patient. In these circumstances, a negative serology should not exclude the diagnosis. Epidemiological history of fresh water contact as well as previous antiparasitic treatment is highly relevant. Invasive techniques for diagnosis should not be routinely considered, especially in asymptomatic patients. Final diagnosis can be difficult, and thus if suspicion is strong, an empirical therapeutic test should be considered.
We thank Dr Carlos Chaccour for his input on the development of this manuscript. We also thank Prof Paul Miller for help with the language editing of the manuscript.
Declaration of Interests
The authors state they have no conflicts of interest to declare.