Failure of Repeated Treatment With Praziquantel and Arthemeter in Four Patients With Acute Schistosomiasis

Authors


Corresponding Author: Liliana Praticò, MD, Infectious Diseases Department, San Matteo Hospital, University of Pavia, Viale Taramelli 5/7, Pavia I-27100, Italy. E-mail: liliana_pratico@libero.it

Abstract

Schistosomiasis is on the rise but still difficult to treat in international travelers; it should be suspected in patients returning from endemic areas. Praziquantel (PZQ) is not effective and may aggravate symptoms. More recently, combination treatment with artemisinin derivatives have shown promising results. We report four cases of acute schistosomiasis (AS) in which several courses of combined therapy had been necessary to obtain negative serology.

Schistosomiasis should be suspected in ill, nonimmune returning travelers presenting with suggestive clinical findings and/or eosinophilia with a history of freshwater exposure in endemic areas.[1, 2] Currently diagnosis of acute schistosomiasis (AS) is difficult as microscopic examination of stools and urine as well as the serological tests are negative at the early stage of AS.[1, 3] As antibodies can be detected for years after therapy, assessing treatment outcome is difficult.[1] Praziquantel (PZQ) efficacy has mainly been tested in endemic areas in patients with chronic schistosomiasis, while in nonendemic settings limited data suggest a high rate of treatment failure in AS.[4] Given that drug resistance to PZQ is unlikely to be involved because widespread drug resistance has not been documented,[5] this impaired response is due to the known poor efficacy of PZQ during the early phase of the Schistosoma life cycle (juvenile forms)[2, 4] and to the absence of a specific immune response. Therefore, some authors recommend waiting for at least 3 months after exposure before initiating PZQ treatment,[3] while others suggest additional courses of PZQ or combined regimens in patients affected by AS who are nonimmune for schistosomal infection.[6] Furthermore in AS sometimes PZQ can worsen symptoms, inducing a paradoxical reaction due to parasitic destruction.[4] Therefore, some authors suggest the use of corticosteroids to reduce potentially life-threatening symptoms[4] even if the use of corticosteroids decreases plasma level of PZQ by 50%.[7] More recently, artemisinin derivatives have been added to the antischistosomal armamentarium. These drugs act by inducing a worm burden reduction, a hepatic shift of schistosomes post-treatment, a decreased worm body size, and diffuse tegumental alterations of reproductive organs, particularly in the schistosomule.[8, 9] Arthemeter (ART) at the dosage of 6 mg/kg/day in combination with PZQ appears to be more effective than single drug PZQ therapy, particularly in patients with repeated exposure.[10] Mefloquine plus artesunate showed high rates of cure.[11] Two small investigational studies in Senegal and Sudan, run on young children infected with both Plasmodium falciparum and schistosomes[12, 13] obtained high cure rates (87%–100%) by employing different artemisinin combined therapies (ie, artesunate–sulfadoxine/pyrimethamine, artesunate with sulfamethoxypyrazine plus pyrimethamine, artesunate–amodiaquine, and artemether–lumefantrine).

Case Report

In the winter of 2007, nine subjects traveled to Uganda for vacation; six of them were on malaria prophylaxis with mefloquine. On December 20th, six of them bathed in Lake Victoria. Soon after bathing, four of them developed an itchy rash with red papules. On their way back to Italy after 20 days, one of the four (patient A, a 12-year-old female) developed fever (maximum 37.5°C), sore throat and fatigue. She was treated with paracetamol with some benefit. Ten days later, she was febrile again (maximum 39°C), her chest X-ray was negative and a course of amoxicillin plus clavulanate was prescribed. As there was no improvement, the patient was admitted to our Infectious Disease ward. Blood tests showed marked eosinophilia [4.900/uL (normal value 100–500), 64.5%] and a positive schistosoma serology (IHA, Siemens Healthcare, Marburg, Germany) [1/32,768 (normal value < 1/32)]. Both urine and stools were positive for Schistosoma mansoni eggs. On February 26th, she was treated with PZQ 40 mg/kg in a single dose. At the same time, two more subjects (patient B, a 11-year-old female and patient C, a 7-year-old male) among the six who had bathed in the lake, developed fever, skin eruptions, abdominal pain, and diarrhea; patient C had facial edema too. Both patients B and C were treated with steroids and antibiotics by their general practitioner with slight improvement, but were eventually referred to our clinic. Schistosoma serology was positive (both 1/32,768) as was stool examination (presence of S. mansoni eggs). After recognizing the common epidemiological source, all the other subjects who had bathed in Lake Victoria were tested for schistosomiasis. One of these, patient D, a 41-year-old female was positive (1/16,384) with eosinophilia (2.800/uL, 52%). Stool and urine samples tested positive. All three patients, B, C, and D, received PZQ 40 mg/kg in a single dose. In the following weeks a strict clinical follow-up was scheduled (see Table 1). Because gastrointestinal symptoms and eosinophilia persisted, a second course of PZQ was prescribed to all four patients (patients A, B, C, and D). ART (6 mg/kg/day) was also added every 10 days for two to five courses and in August 2008 a third course of PZQ was administered. Patient D showed a good clinical response with rapid normalization of eosinophils and a dramatic decrease in serotiter. Patient B kept complaining about abdominal pain and eosinophilia persisted. In January 2009 a further course of PZQ was given and finally symptoms disappeared. After a rapid decline in serotiter, in January 2009 patient A showed a threefold increase in serotiter. A fourth course of PZQ was prescribed and a fourfold drop of serotiter was observed. One year later the titer rose again (two dilutions) and the patient was treated once more (PZQ). Finally in July 2012 schistosoma serology became negative. A similar clinical course occurred with patient C who, after August 2008, developed two episodes of significant increase in antibodies (May 2011 and May 2012) and needed three more courses of PZQ to normalize antibody titer (see Figure 1).

Table 1. Clinical, laboratory, and treatment data at the enrollment and during follow-upThumbnail image of
Figure 1.

Trend of serotiter and eosinophils.

Discussion

This case report allows clinicians to consider different aspects regarding AS. Firstly, the poor efficacy of PZQ in the early phase of infection.[2] In AS, development of schistosomules is not synchronous and different stages of the parasitic lifecycle may overlap. As a consequence, adult worms start egg excretion when circulating schistosomules are still around. As PZQ is much less effective on immature forms of the parasite, different rates of response to treatment can be expected according to the period of treatment.[3] Furthermore, PZQ requires an adequate immune response to be effective so that in international travelers, treatment failure can also be explained by the absence of parasite-specific immune response.[14] As the activity of ART against the immature forms is maximal,[8] combination treatment such as PZQ plus ART might be more effective in AS. At the time of diagnosis, we decided to treat our patients with PZQ alone because we had extensive experience on the use of this drug. In these patients, we decided not to use corticosteroids because they presented only with a mild form of the disease. Subsequently, as symptoms persisted for 3 months, we added ART to enhance clinical response. At 6 and 9 months after the first course of treatment, as symptoms were still present and a clear fall in antibodies titer was not seen, we repeated PZQ alone. In patient C, even in the absence of clear clinical symptoms, after assessing a rise in antibodies titer, we prescribed two more courses of PZQ at 24 and 48 months even though we were not sure of the persistence of live helminths. The second problem clinicians have to face when dealing with schistosomiasis is the absence of reliable laboratory tests to assess if the infection is cured. Schistosomal infections are highly immunogenic and serological assays usually become positive as early as 4 weeks after the infection. These tests are sensitive but may cross-react with other helminths and remain positive long after the active infection is cured. Antibodies react mainly to glycan epitopes, which larvae and adult worms share.[15] The test used in our laboratory is manufactured exclusively with adult worm antigens, hence the rise of antibody titer assessed during follow-up in our patients, cannot be explained as a recurrence of egg shedding. We can only speculate that detected antibodies cross reacted with miracidia antigens.[15] As after every course of treatment we obtained a dramatic drop in antischistosomal serotiter, our data suggest a correlation between parasite viability and antibody titration.[3] DNA detection in serum by real-time polymerase chain reaction (PCR) assay might be a promising and more sensitive diagnostic test to confirm schistosomiasis infection at an early stage.[16] Schistosomiasis should be suspected in any international traveler returning from endemic areas. Several courses of combined treatment can be necessary to attain complete cure. Finally, we recommend prolonged serological, microbiological, and differential white blood cell count follow-up of at least 2 years after the first administration of treatment.

Declaration of Interests

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

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