Acute Febrile Respiratory Reaction After Praziquantel Treatment During Asymptomatic Late Form of Acute Schistosomiasis
Corresponding Author: Andreas L.C. Neumayr, MD, DTM&H, MCTM, Swiss Tropical and Public Health Institute, Socinstr. 57, P.O. Box, Basel CH-4002, Switzerland. E-mail: firstname.lastname@example.org
Paradoxical reactions (Jarish Herxheimer-like reactions) have been described in patients treated with praziquantel (PZQ) during acute schistosomiasis (infected ≤ 3 mo), while PZQ treatment of chronic schistosomiasis is generally considered to be safe. We report an acute febrile reaction with respiratory decompensation following PZQ treatment in a 17-year-old male patient who had no potential (re)exposure to infection for at least 5 months and was therefore considered to have reached the chronic stage of disease. We speculate that the clinical manifestations in our patient constitute a very late paradoxical reaction in an unusually long acute phase of infection.
A family of six immigrated from Yemen to Switzerland on March 5, 2011. Presenting with painless macrohematuria and a blood eosinophilia of 16% (0.6 × 109/L), the 15-year-old son of the family was diagnosed with a Schistosoma haematobium–Schistosoma mansoni mixed infection by detection of parasite eggs in stool and urine. A serology screen of the five remaining asymptomatic family members indicated four had schistosomal infections (13-year-old son: eosinophils 1.1 × 109/L, adult-antigen enzyme-linked immunosorbent assay (ELISA) 1.85 OD, egg-antigen ELISA 1.45 OD, IFAT 640; 17-year-old son: eosinophils 2.9 × 109/L, adult-antigen ELISA 1.47, egg-antigen ELISA 1.51, IFAT 640; father: eosinophils 0.3 × 109/L, adult-antigen ELISA 1.22 OD, egg-antigen ELISA 0.79 OD, IFAT 320; mother: eosinophils 0.074 × 109/L, adult-antigen ELISA 0.69 OD, egg-antigen ELISA 0.31 OD, IFAT 160 [references: adult-antigen ELISA <0.15; egg-antigen ELISA <0.3; IFAT <80]). However, no eggs were found in subsequent urine and stool examinations. The last contact with potentially contaminated freshwater was late February 2011 in a lake close to Aden, Yemen. The patients were diagnosed by the end of July 2011. Praziquantel (PZQ; 60 mg/kg body weight) was administrated orally on August 10, 2011 to the parasitological-confirmed index patient and the four sero-positive family members. PZQ was well tolerated, except by the 17-year-old son about whom we report here (see above and Table 1 for baseline laboratory parameters). Within 24 hours of PZQ administration, the patient developed fatigue, fever, cough, and increasing dyspnoea. A physical examination revealed an impaired general condition including fever [38.7°C (tympanal)] with stable circulatory parameters (pulse rate 99/min, blood pressure 127/87 mmHg) but also marked broncho-pulmonary obstruction (wheeze) on auscultation and progressive signs of respiratory decompensation [respiratory rate 33/min, oxygen saturation 84% (by pulse oxymetry)]. The laboratory investigation showed a leukocytosis of 16.6 × 109/μL with an eosinophil fraction of 51% and an elevated C-reactive protein (Table 1). The chest X-ray was normal. Due to compromised respiratory function, the patient was admitted to the hospital for symptomatic treatment (oxygen supplementation and inhaled bronchodilators) and monitoring. Within 2 days the patient's respiratory function stabilized, and the patient was discharged. A follow-up examination 3 days later (August 16) at our outpatient department showed that the patient's general condition continued to improve (no fever, no dyspnoea). On the other hand, wheeze was still prominent on auscultation, and the pulmonary function test showed a persisting airflow obstruction [forced expiratory volume/1 s (FEV1) 54%; forced vital capacity (FVC) 48%]. Simultaneous blood investigation revealed a leukocytosis of 28.0 × 109/μL with an eosinophil fraction of 70.5% (Table 1). Additional laboratory investigation showed mildly elevated liver function tests [aspartate transaminase (AST) 47.5 U/L (<40), alanine transaminase (ALT) 58.4 U/L (<41), gamma-glutamyltransferase (γGT) 81.9 U/L (11–50), and alkaline phosphatase (AP) 237 U/L (<270)]. Under the tentative diagnosis of an acute systemic allergic reaction, we initiated symptomatic treatment with oral prednisolone (1.5 mg/kg body weight OD) and inhaled budesonide/formoterol (200/6 µg BID). Under this treatment the respiratory symptoms improved, the laboratory parameters normalized, and it was possible to taper down and finally discontinue oral prednisolone on August 29. Inhaled budesonide/formoterol was stopped on September 12 when the patient indicated complete resolution of all symptoms. A follow-up spirometry on October 11 was normal.
Table 1. Laboratory parameters
|Clinical symptoms||Last exposure to potentially infected fresh water||None||None||Acute fever and progressive broncho-pulmonary obstruction||Respiratory decompensation (SpO2 88%)||Respiratory recompensation||Slowly regressive pulmonary obstruction||Marked improvement of pulmonary symptoms||Complete resolution of symptoms|
|Medical treatment|| ||—||Administration|
|—||Hospital admission: oxygen supplementation and inhaled bronchodilators||OPD: start of oral prednisolone and inhaled budesonide/formoterol|| || || ||Stop of oral prednisolone||Stop of inhaled budesonide/formoterol|
|WBC (×109/L) [4–10]|| ||6.9||—||—||16.6||28.0||25.9||17.2||9.7|
|Eosinophils (×109/L) [0.0004–0.4]|| ||2.9||—||—||8.5||19.6||9.1||4.0||1.4||6.3||—|
|Eosinophils (%) [0.01–4]|| ||42||—||—||51||70.5||35||23.5||14.0||0.5||—|
|CRP (mg/L) [<8]|| ||—||—||—||102||44||35||—||<8||8.5||—|
Since the advent of PZQ in the late 1970s, the drug has become the treatment of choice against all species of Schistosoma. As the drug is largely ineffective on young (7- to 28-d-old) stages of the parasite (schistosomula), delivery of treatment will only be effective upon maturation of the parasite and once the chronic stage of the infection has been reached. In addition, the administration of PZQ during the acute phase may be associated (in 40–50% of cases) with paradoxical reactions (Jarish Herxheimer-like reactions) due to the drug's partial effect on juvenile parasite stages.[3, 4] Hence it is generally advised to wait at least 3 months after exposure (marked by presence of eggs in stool or urine) before initiating PZQ treatment.[4, 5] On the other hand, delaying treatment increases the risk of severe ectopic manifestations (eg, neuroschistosomiasis). To reduce the immunological reactions, and to avoid or attenuate paradoxical reactions in patients with acute schistosomiasis (AS), co-administration of corticosteroids with PZQ is occasionally considered. This approach, however, has the drawback that co-administration with corticosteroids decreases the plasma level of PZQ by approximately 50%.
Symptomatic AS (as a treatment-independent phenomenon during the early natural course of infection) and treatment-induced paradoxical reactions can manifest with identical symptoms: namely, fever, fatigue, and pulmonary symptoms (dry cough, shortness of breath, wheezing) as well as neurological signs.[3, 7, 8] Both are considered to constitute allergic reactions after exposure of a naive host to a high level of parasite antigens. These are evoked either by larval maturation and early oviposition in symptomatic AS or by parasite destruction in treatment-induced paradoxical reactions. In both cases eosinophil-mediated toxicity leading to vasculitis is considered to be the most likely pathophysiological correlate of the clinical manifestations (eg, pulmonary, cardiac, cerebral).[8, 9] The pulmonary symptoms in AS (S haematobium and S mansoni) have frequently been reported to persist for weeks (or even months) and may present without radiological findings.[3, 8, 9]
Our patient left the endemic region more than 5 months prior to diagnosis and initiation of PZQ treatment and had no re-exposure risk. The negative stool- and urine-microscopy did not allow species identification, but as S haematobium and S mansoni are the only two species endemic in Yemen, it can be assumed that our patient had either a mono-infection with either species or a mixed species infection. Neither the reported patient, nor any other infected family member, had had signs or symptoms of AS which generally manifests 14 to 84 days after infection. Theoretically, the reported patient had a chronic infection; thus, the window has passed for clinical manifestations of AS and paradoxical reactions due to administration of PZQ are no longer expected. Therefore the observed acute febrile inflammatory reaction and pulmonary decompensation was puzzling.
The differential diagnosis included (1) clinical presentation unrelated to the Schistosoma infection (ie, febrile infection with concomitant bronchial hyperreagibility); (2) allergic reaction to PZQ (without involvement of underlying schistosomiasis); (3) treatment-independent, symptomatic AS with delayed presentation; (4) treatment-induced paradoxic reaction (Jarish Herxheimer-like reaction) in a prolonged acute phase of infection/asymptomatic AS; and (5) chronic schistosomiasis complicated by a treatment-induced paradoxic reaction (Jarish Herxheimer-like reaction). We considered (1) to be unlikely in the absence of bronchial hyperreagibility/asthma, (2) unlikely as the very short elimination half-life of PZQ (1–1.5 h) does not explain the prolonged pulmonary symptoms, (3) unlikely as the reaction was clearly associated with administration of PZQ, and (5) unlikely as the high eosinophil count (the patient had the highest eosinophil count of all infected family members) in the absence of detectable eggs suggests acute rather than chronic infection.
We conclude that the patient's clinical manifestations constitute a delayed treatment-induced paradoxical reaction in an atypically protracted acute phase of infection or asymptomatic AS. Therefore the patient most likely acquired the infection just before migrating to Switzerland, and the chronic stage of infection was—despite a time span of more than 5 months—not yet reached. The patient did not take any medications which would possibly cause retardation of parasite development and could explain a prolonged acute phase of infection. Whether the other family members acquired the infection simultaneously or were previously infected (and had already reached the chronic stage of infection) remains unclear. We were unable to obtain detailed individual exposure histories. The index patient was the only family member exhibiting signs of a chronic infection; namely, Schistosoma eggs in stool and urine. The assumption of an acute phase infection is supported by the patient's prolonged pulmonary symptoms (see above). In addition, we can speculate that the high baseline eosinophil count of our patient reflected a pre-existing hypersensitive immunological state predisposing the patient to develop severe paradoxical reactions.
Our case report highlights that, in the absence of detectable eggs, the differentiation of acute and chronic schistosomiasis—which are rather the two endpoints of the parasite's evolution within the host, than clearly distinct phases—should not be based solely on the elapsed time since infection. In some patients the acute phase might be much longer than generally assumed and potentially severe treatment-induced paradoxical reactions can occur very late after infection. We suggest that a high eosinophil count in the absence of detectable eggs should raise the suspicion for AS and the risk for treatment-induced paradoxical reactions.
Declaration of Interests
The authors state that they have no conflicts of interest.