Long-Term Follow-Up of Schistosomiasis Serology Post-Treatment in Australian Travelers and Immigrants

Authors

  • Michelle K. Yong FRACP,

    Corresponding author
    1. Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, Victoria, Australia
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  • Carolyn L. Beckett FRACP,

    1. Infectious Diseases Department, Box Hill Hospital, Melbourne, Victoria, Australia
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  • Karin Leder FRACP, PhD,

    1. Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, Victoria, Australia
    2. Department of Clinical Epidemiology, Monash University, Melbourne, Victoria, Australia
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  • Beverley A. Biggs FRACP, PhD,

    1. Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, Victoria, Australia
    2. Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
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  • Joseph Torresi FRACP, PhD,

    1. Department of Infectious Diseases, Austin Hospital, Heidelberg, Victoria, Australia
    2. Department of Medicine, Austin Hospital, University of Melbourne, Melbourne, Victoria, Australia
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  • Daniel P. O’Brien FRACP

    1. Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, Victoria, Australia
    2. Infectious Diseases Department, Geelong Hospital, Geelong, Victoria, Australia
    3. Médecins Sans Frontières, Amsterdam, The Netherlands
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Michelle K. Yong, FRACP, Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, VIC 3050, Australia. E-mail: michyong@yahoo.com

Abstract

Background. We undertook an observational follow-up study of schistosomiasis serology in both travelers and immigrants in a nonendemic country to determine the natural history of schistosomiasis antibody titer post-adequate treatment in those who have not been reexposed.

Methods. Longitudinal study of all adult travelers and immigrants presenting to the Royal Melbourne Hospital, Australia with positive schistosomiasis serology (titer >1: 64) between July 1995 and December 2005. All patients were treated with praziquantel and followed up clinically and serologically for a period up to 30 months.

Results. A total of 58 patients were included in the study including 26 travelers and 32 immigrants. Antibody titers often increased in the first 6 to 12 months post-treatment, especially in immigrants. After 30 months of post-treatment, 68% of travelers and 35% of immigrants (p < 0.01) achieved a fourfold antibody decline.

Conclusions. Schistosomiasis antibody titers varied after adequate treatment. Therefore an increase in titer in the first 6 to 12 months or a failure to reduce after 3 years should not automatically justify re-treatment.

Schistosomiasis is estimated to affect more than 200 million people globally.1 The majority of infections occur in persons living in endemic regions of sub-Saharan Africa, the Middle East, Asia, South America, and the Caribbean. Travelers visiting endemic countries for even brief periods are susceptible to infection. In one report, 18% of asymptomatic travelers who return after exposure to freshwater in Africa were found to have schistosomiais.2 In nonendemic Australia, returned travelers and new immigrants are often diagnosed with schistosomiasis by serological methods after having presented with symptoms or as part of asymptomatic screening.3,4

Infection with schistosomiasis is acquired via contact with freshwater containing infectious, freeliving cerciariae which penetrate the skin or mucosa, commonly through activities such as bathing and swimming in freshwater, scuba diving, water skiing, and rafting. There are four major Schistosoma species affecting humans (haematobium, mansoni, japonicum, and intercalatum) causing a range of symptoms from “swimmer's itch,” Katayama fever, hematuria, hematospermia, dysmenorrhia, and menorrhagia to bloody diarrhea. Acute schistosomiasis (Katayama fever) presents as a hypersensitivity reaction with fever, myalgias, malaise, dry cough, eosinophilia, and pulmonary infiltrates on chest X-ray. It is more frequently seen in travelers rather than chronically exposed populations. Chronic infection can result in gastrointestinal disturbance, hepatic fibrosis with portal hypertension, bladder cancer, and serious neurological complications such as transverse myelitis and localized cerebral neuroschistosomiasis. The neurological complications have been reported after minimal exposure and infection with a low worm burden.5 The need to prevent these and other chronic complications highlights the importance of treating schistosomiasis in those infected, regardless of whether they are symptomatic.6,7

Schistosomiasis is diagnosed by identification of parasite eggs in urine or feces and serological assays for the detection of specific antibodies or circulating parasite antigens.1,6 Anti-schistosomal antibody tests are useful in infected individuals who have a low worm burden and low egg excretion, but cannot distinguish between chronic and recent infection.6 The sensitivity and specificity of current commercially available indirect hemagglutination test (IHA) tests are reported to be 94% and 94.7%, respectively.8 Praziquantel is the drug of choice for the treatment of all schistosome species1 resulting in cure rates of up to 97%.9

Where eggs have been found in urine or feces, or where there is an elevated eosinophil count at presentation, these markers are often checked post-treatment to determine the adequacy of drug therapy. However, for patients diagnosed on serology alone, follow-up serology may be performed after completion of treatment, but to date there is little data from nonendemic areas to guide its use in those not at risk of reexposure.2,10 This creates a problem for the treating physician if relying on serological evidence of cure. A persistently elevated antibody titer following treatment may be interpreted as evidence of unresolved infection and consequently result in multiple treatment courses which may be unnecessary and associated with side-effects and additional cost.

We undertook a longitudinal prospective study of schistosomiasis serology in both travelers and immigrants in a nonendemic country to determine the natural history of schistosomiasis antibody titer post-recommended treatment in those who have not been reexposed.

Patients and Methods

All adult patients presenting to the Victorian Infectious Diseases Service (VIDS) at the Royal Melbourne Hospital, Australia between July 1995 and December 2005 identified with a positive serological test for schistosomiasis (defined as titer greater than 1:64), and had received treatment for schistosomiasis without possible reexposure were considered for this study.

Schistosomiasis serology was performed at baseline and at subsequent visits and grouped according to those performed within 3, 6, 12, 18, 24, and 30 months of treatment. Serology was identified as being greater than or equal to fourfold increase or decrease, twofold increase or decrease, conversion to negative or unchanged from baseline prior to treatment. All serological testing for schistosomiasis was performed by the Victorian Infectious Diseases Reference Laboratory (VIDRL) in Victoria, Australia using an IHA assay (Cellognost*-Schistosomiasis H, Behring, Germany). This test specifically detects total circulating antibodies to antigens of adult Schistosoma mansoni worms; however, due to the similarity of antigens, antibodies to Schistosoma haematobium and Schistosoma japonicum can also be detected. Although prepared with adult S mansoni worms, IHA has a 92% sensitivity and 94% specificity for detecting S haematobium.8 Cross-reactivity with other helminths has been reported due to shared antigenic determinants.11 These other helminthic infections were excluded where epidemiologically appropriate through relevant serology and fecal testing. Parallel testing of paired sera of individual patients was performed in > 90% of cases.

The recommended treatment given to all patients in this study was praziquantel at a dose of 20 mg/kg twice daily for 3 days.12,13 At review, patients were assessed for adherence, evidence of persisting infection (symptoms, parasite detection on microscopy, or eosinophilia), and history of reexposure to endemic areas. Patients were excluded from the longitudinal study if serological testing was performed at an outside laboratory, if there was evidence of persisting infection, if there was a history of reexposure or if treatment was incomplete. There were seven patients who were re-treated and therefore excluded from our study. Ethics approval was obtained for this study from the Human Research Ethics Committee of the Royal Melbourne Hospital.

Analysis

Statistical analyses were conducted to determine differences between immigrant and returned traveler populations. Fisher's exact probability test was used for categorical values while the Mann–Whitney U test was used for median values.

Results

Sixty-four patients were included in the study of whom 28 (43.8%) were travelers and 36 (56.2%) were immigrants (Table 1). The predominant region of acquisition of schistosomiasis infection was Africa (93.8%) with 55% of returned travelers identifying Malawi and 44% of immigrants identifying Ethiopia as the country of exposure. The majority of immigrants were diagnosed by asymptomatic screening (63.9%). Travelers were more likely to report one or more symptom (54%) such as diarrhea (5 patients), hematuria (4), fever (4), abdominal pain (3), itch/rash (3), headache (2), and testicular pain (1). No travelers were diagnosed with neurological involvement. The median baseline schistosomiasis antibody titer was greater in travelers (1:512) compared with immigrants (1:128) (p = 0.057). There was no correlation between antibody titer levels and presence of eosinophilia.

Table 1.  Demographic and clinical characteristics of 64 patients with schistosomiasis
CharacteristicAll patients (n = 64)Travelers (n = 28)Immigrants (n = 36)p Value
 Sex, male40 (62.5%)14 (50%)26 (72.2%)0.07
 Age, median, range (years)32 (16–69)28.5 (21–69)34 (16–59)0.16
 Symptomatic at presentation28 (43.8%)15 (53.6%)13 (36.1%)0.16
 Asymptomatic screening36 (56.2%)13 (46.4%)23 (63.9%)0.16
 Africa60 (93.8%)26 (92.9%)34 (94.4%)1.0
 Middle East2 (3.1%)02 (5.6%)0.50
 Asia2 (3.1%)2 (7.1%)00.19
Median baseline antibody titer2565121280.057
Number with high eosinophil count (≥ 0.5 × 109/L)22 (34.4%)10 (35.7%)12 (33%)0.84
Number with microbiological confirmation (feces or urine)5 (7.8%)2 (7.1%)3 (8.3%)1.0
Number of patients with follow-up serology58 (90.6%)25 (89.3%)33 (91.7%) 
Mean number of follow-up serology2.282.252.28 
Median follow-up, range (days)510 (120–1560)495 (150–1560)495 (120–1440) 

The longitudinal observational follow-up schistosomiasis serology results demonstrate that returned travelers are significantly more likely to achieve a greater than equal to fourfold decline in serology compared to immigrants at 12 months (45% vs 10%; p < 0.003), 18 months (55% vs 19%; p < 0.008), 24 months (64% vs 29%; p < 0.01), and 30 months (68% vs 35%; p < 0.01) post-treatment (Figure 1). Six patients who had baseline serology only were excluded from this longitudinal follow-up study. The duration of follow-up serology for patients ranged from 4 months to 48 months. We chose 30 months as our cutoff as there were only five patients with serology results beyond 30 months. Thirty-six of the 58 patients participating in the longitudinal study had serology results performed beyond 12 months.

Figure 1.

The percentage of observed immigrants and travelers who achieve a fourfold decline in schistosomiasis serology after treatment.

Within the immigrant group, 10 patients recorded a follow-up serology which had increased by fourfold or greater, 80% occurring within 6 months of treatment. This compares to the travelers group where no increase by fourfold or greater was observed (p < 0.001). Four travelers (18%) were observed to have an increase in titer of twofold magnitude occurring between 6 months and 12 months.

Discussion

Our study is one of the first to compare the natural history of schistosomiasis serology in populations of travelers and immigrants in a nonendemic country with a follow-up beyond 1 year post-treatment with praziquantel.2,10 It demonstrates that follow-up schistosomiasis serology differs between immigrants and returned travelers, with travelers having higher mean baseline levels and more likely to achieve a greater than or equal to fourfold decrease in antibody titer. It was also observed that within the first 6 to 12 months post-treatment, serology results can be varied with increases by two- to fourfold often seen in the immigrant group. No traveler was found to have had a greater than or equal to fourfold increase in serology post-treatment.

It is postulated that travelers are more likely to demonstrate a fourfold decrease in serology due to a shorter duration of infection and a lower parasite burden which results in a lower antigen load and therefore a more rapid serological decline. The possible explanations for why this change was not seen in immigrants include failed treatment, reexposure, or serology performed too early to demonstrate a decline. Nevertheless, in our study it is believed that all patients received effective schistosomiasis treatment with praziquantel and eradicated their infection based on the known effectiveness of the drug, our relatively high dosing regime, and no documented cases with evidence of persisting infection (symptoms, parasite detection on microscopy, or eosinophilia). Furthermore, investigators also enquired into reexposure risk and patients who were possibly reinfected were excluded from the study.

The results of this study are comparable to a previous study by Whitty et al.2 which observed variable ELISA antibody titer response within the first 3 to 5 months after treatment, with an increase in 22%, decrease in 46%, and unchanged in 32%. However, this was not a prospective long-term follow-up study and did not differentiate between travelers and immigrants. Using the immunofluorescence antibody test (IFAT), Tarp et al. also observed variable serological change within the first 10 months post-treatment.10 The finding of increasing antibody titers performed in the early months post-treatment supports our findings, and it appears that the different serological methods used do not affect this trend. In three reported returned travelers to Italy where longer term follow-up serology was performed, two patients achieved a fourfold decrease in serology 6 to 18 months post-treatment.14

A limitation of our study was that a proportion of the patients only had a single documented post-treatment serology and those with multiple follow-up serologies often had these performed at variable times. This likely reflects the itinerant characteristics of returned travelers and immigrants who have often presented through asymptomatic screening. It may also be a result of selection bias, whereby those with abnormal results are more likely to return for follow-up.

In conclusion, we have described the natural history of schistosomiasis serology in travelers and immigrants who have been adequately treated with praziquantel, showing that titers can increase in the first 6 to 12 months post-treatment, especially in immigrants. For most travelers, the titers will fall significantly with time; however, even up to 3 years' post-treatment only two thirds achieve a fourfold decrease. In the majority of immigrants, titers do not fall significantly even after 3 years. Therefore, after recommended treatment in those not reexposed, an increase in antibody titer in the first 6 to 12 months or a failure to reduce after 3 years, should not automatically justify re-treatment. Instead this should be based on symptoms, parasite identification, or eosinophilia.

Acknowledgment

We would like to acknowledge Elizabeth Matchett for her assistance in collecting the clinical data for this study.

Declaration of Interests

The authors state they have no conflicts of interest to declare.

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