Albendazole Versus Thiabendazole as Therapy for ...

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Albendazole Versus Thiabendazole as Therapy for Trichinosis: A Retrospective Study Andre Cabie, Olivier Bouchaud, Sandrine Houze, Marie-Aude Khuong, Catherine Ruggeri, Thierry Ancelle, Sophie Matheron, and Jean-Pierre Coulaud

From Service des Maladies Infectieuses et Tropicales and Service de Parasitologie, Hopital Bichat Claude Bernard; and Service de Parasitologie, Hopital Cochin, Paris, France

An outbreak of trichinosis caused by ingestion of horse meat occurred in December 1993 in France; more than SOO people were affected. We compared the immediate and midterm efficacy and tolerability of thiabendazole and albendazole as therapy for the 46 patients seen in our department. Forty-four patients (96%) were treated. The first 26 patients received thiabendazole therapy; the next 18 received albendazole therapy. All the patients were treated with prednisone. Eight relapses occurred (seven in the thiabendazole group and one in the albendazole group [not significant]). Side effects of treatment were reported by seven patients, all of whom were treated with thiabendazole (P = .01). Six months after treatment, 16 of the 31 patients who responded to a questionnaire still had symptoms, the most frequent of which were myalgias (81%) and fatigue (69%). No significant difference was observed between the two treatment groups. The immediate efficacy of thiabendazole and albendazole as therapy for trichinosis was comparable, but albendazole was better tolerated.

Received 11 September 1995; revised 16 January 1996. Reprints or correspondence: Dr. Andre Cabie, Service des Maladies Infectieuses et Tropicales (Pr Coulaud), Hopital Bichat Claude Bernard, 46, rue Henri Huchard, 75018, Paris, France. Clinical Infectious Diseases

1996;22:1033-5

© 1996 by The University of Chicago. All rights reserved. 1058--4838/96/2206-0019$02.00

Patients and Methods This retrospective study was carried out in the Tropical Diseases Unit of Bichat-Claude Bernard Hospital, Paris, between January and September 1994. First, we compared the immediate efficacy and tolerability of thiabendazole and albendazole. We then assessed the midterm efficacy by means of a questionnaire sent to the patients in June 1994. All patients who presented during the outbreak with at least three of the following characteristics were included in the study: fever (temperature, > 38°C), myalgias, facial edema, eosinophilia (> 500 cells/mm3), and consumption of horse meat during the months preceding the onset of illness. The following data were analyzed at the time of the onset of illness: the patient's demographic characteristics and eating habits, the date of onset of the clinical course, clinical and laboratory findings, the response to treatment and tolerability of treatment, and serological findings. Six months after the onset of illness, we studied the duration and nature of clinical manifestations and the recurrence of characteristic signs. Serological tests for trichinosis were done at the Parasitology Laboratory of Bichat-Claude Bernard Hospital by means of indirect immunofluorescence (cutoff value for positive results, 1:200). No muscle biopsies were performed. The initial response to treatment was assessed in clinical terms on the basis of fever and myalgias. Relapse was defined as the recurrence of clinical manifestations after the end of treatment.

Statistical Analysis We used StatView 4.02 software (Abacus Concepts, Berkeley, CA). Numerical data were expressed as means ± SD. Rates were compared by means of Fisher's exact test. Means

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Trichinosis is a parasitic infection due to Trichinella species that occurs worldwide. The adult worm infests the small intestine, while larvae live in the host's striated muscle cells [1]. It is the larvae that cause clinical manifestations. Transmission to humans occurs through the ingestion of larva-infested meat (classically pork). However, since 1976, most cases oftrichinosis in France have been due to consumption of horse meat, which has caused four epidemics (125 cases in 1976, 431 cases in August 1985, 642 cases in September 1985, and 21 cases in 1991) [2, 3]. The treatment of trichinosis has not yet been standardized. Available anthelminthic drugs are poorly active against Trichinella larvae, and to our knowledge, no controlled studies have proven the efficacy of antiparasitic treatments. However, several investigators recommend the therapeutic use of benzimidazoles, such as thiabendazole and albendazole [4, 5]. An outbreak of trichinosis due to ingestion of horse meat infested with Trichinella spiralis affected >500 people in three regions of France [3]. Forty-six of the 173 individuals with trichinosis in northern Paris were seen in our department from 2 December 1993 to 1 February 1994. We compared the immediate and midterm efficacy and tolerability of thiabendazole and albendazole by treating the first patients with thiabendazole and the subsequent patients with albendazole.

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were compared with use of the Mann-Whitney test. P values of ~.05 were considered significant.

Table 2. Comparison of patients with trichinosis who were treated with thiabendazole or albendazole. Feature

Results

Table 1. Clinical manifestations of trichinosis, at diagnosis, at relapse, and 6 months after treatment.

Thiabendazole

Albendazole

Pvalue

26 15 (58) 38.9 ± 17.8

18 8 (44) 53.3 ± 16.5

.5 .01

7.2 ± 4.7

15.1 ± 15.3

.15

23 (88) 25 (96) 23 (88)

15 (83) 14 (78) 14 (78)

.6 .1 .4

26

2

18 2

NS NS

26 8 7 7

18 8 0 1

NS NS .01 .27

No. of patients No. (%) of females Mean age (y) ± SD Mean time (d) from onset to treatment No. (%) with manifestation at presentation Fever Facial swelling Myalgias Initial improvement No. of patients Median time (d) Symptom relief No. of patients Median time (d) No. with side effects No. with relapse NOTE.

NS = not significant.

.27). The mean time until relapses occurred after completion of treatment was 9.7 ± 2.6 days (range, 7-14 days). Threefourths of the patients who relapsed had the same clinical manifestations as they did initially. The frequencies of the different clinical manifestations are given in table 1. Side effects were observed in seven patients treated with thiabendazole and in none of those treated with albendazole (P = .01); the mean time after the start of treatment until these effects occurred was 6.1 ± 2.9 days (range, 2-10 days). The side effects included skin reactions (urticarial rash, 2 cases; generalized maculopapular rash, 3 cases) in 5 cases, neurosensory disorders (dizzy spells, headache, tinnitus, and photopia) in 3 cases, and gastrointestinal disturbances (epigastric pain, nausea, and vomiting) in 3 cases. The skin reactions occurred 1 or 2 days after steroid therapy was stopped, and one patient had to be admitted to the hospital because of a generalized rash and altered mental status. Side effects (dizzy spells and photopia) necessitated discontinuation of treatment in two cases.

No. (%) of patients with indicated clinical manifestation

Outcome at 6 Months Clinical manifestation Fatigue Facial swelling Fever Myalgias Diarrhea Abdominal pain

At diagnosis (n = 46) 37 39 38 38 13 8

(80) (85) (83) (83) (28) (17)

At relapse (n = 8) 4 3 3 6 I I

(50) (37) (37) (75) (12) (12)

6 mo after treatment (n = 16) II (69) 4 (25) I (6) 13 (81)

o 8 (50)

Thirty-one patients (67%) answered a questionnaire 6 months after treatment. Fifteen (48%) of these patients reported that their symptoms disappeared before June 1994. The mean time to full clinical recovery after the start of treatment was 7.2 ± 5.7 weeks (median, 8 weeks; range, 1-20 weeks), and no significant difference was observed between the two treatment groups (P = .15). Of the 16 patients who still had symptoms in June 1994, four (25%) never fully recovered, and the other


Forty-six patients met the inclusion criteria. There were 25 females and 21 males; the mean age of the patients was 44.1 ± 18 years (range, 5-82 years). By definition, all the patients had eaten horse meat during the previous months, and 80% ate it regularly (raw, 58%; rare, 40%; and well cooked, 2%). The mean period between the onset of symptoms and diagnosis was 10.3 ± 10.9 days (median, 7 days; range, 1-60 days). The clinical manifestations at diagnosis, at relapse, and 6 months after treatment are indicated in table 1. The cardinal signs of trichinosis (fever, myalgias, and facial swelling) were present in >80% of cases. Eosinophilia (>500 cells/mm3) was observed in every case (median, 2,000 cells/mm3 ; range, 510-11,020 cells/mm3). Elevated levels of creatine kinase (200 U/L) and lactate dehydrogenase (450 U/L) were observed in 63% and 72% ofcases, respectively. Serological tests for trichinosis were positive in 17 cases (37%). Levels of specific antibody were low; 41 % and 71 % of the patients had titers that were less than 1:400 and 1:600, respectively. Thirty-one patients (67%) required admission to the hospital. Two patients were not treated because they were free of symptoms at the time of diagnosis. Thus, the analysis of the efficacy and tolerability oftreatment involved 44 patients (table 2). The first 26 patients received treatment with thiabendazole (45 ± 7.3 mg/kg daily) for 6.1 ± 1.7 days. The subsequent 18 patients received treatment with albendazole (13 ± 2.6 mg/kg daily) for8 days. All the patients were treated with prednisone (0.75 mg/kg daily) for 8.3 ± 1.7 days. The median duration of treatment until all the patients' conditions improved was 2 days. The mean time required for clinical manifestations to resolve was 10.7 ± 9.3 days (median, 7.5 days; range, 1-30 days), and no significant difference was noted between the two treatment groups. Seven patients treated with thiabendazole relapsed, compared with only one receiving albendazole treatment (P =

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Treatment of Trichinosis

12 (75%) had intermittent symptoms. Four patients (25%) used treatments for their symptoms.

Discussion

therapy for the classical forms of trichinosis. Albendazole appears to be preferable to thiabendazole because of its markedly better tolerability. This outbreak shows once more that the diagnosis of trichinosis is based on the classical triad of clinical manifestations and hypereosinophilia; creatine kinase assays and serological tests lack sensitivity. Serological tests were only positive in 37% of our cases, possibly because the diagnosis was made before the emergence of specific antibodies. We were unable to confirm this hypothesis by testing patients who were initially seronegative with serial serologies. A large number of patients still had clinical manifestations 6 months after the acute phase of trichinosis: 16 (52%) of those who answered the questionnaire and 35% of the overall patient population. However, myalgias and fatigue are relatively common months and even years after the acute infection. In a prospective study, Harms et al. [9] observed persistent symptoms in 98% ofpatients 2 years after the acute phase of trichinosis and in 25% of patients after 10 years. These symptoms may be due to the presence of larvae in muscle tissue, but to our knowledge, this circumstance has never been demonstrated. In our study, the number of patients with symptoms 6 months after treatment may have been overestimated because of a selection bias (i.e., asymptomatic patients are less likely to answer a questionnaire). Acknowledgments The authors thank Adrien Gerard Saimot for critically reading the manuscript and David Young for revising the English syntax. References

1. Grove DI. Tissue nematodes (trichinosis, dracunculiasis, filariasis). In: Man-

2.

3.

4.

5. 6.

7.

8. 9.

dell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett's principles and practice of infectious diseases. 4th ed. New York: Churchill Livingstone, 1995:2531-7. Ancelle T, Dupouy-Camet J, Bougnoux M, et al. Two outbreaks oftrichinosis caused by horse meat in France in 1985. Am J Epidemioll988; 127: 1302-11. Ancelle T, Dupouy-Camet J, Desenclos J, et al. Epidemie de trichinellose (France, 1993). Bilan des investigations. Bulletin Epidemiologique Hebdomadaire 1994;29:127-9. Fourestie V, Bougnoux M, Ancelle T, et al. Randomized trial ofalbendazole versus thiabendazole plus flubendazole during an outbreak of human trichinellosis. Parasitol Res 1988;75:36-41. Campbell WC, Denham DA. Chemotherapy. In: Campbell WC, ed. Trichinella and trichinosis. New York: Plenum Press, 1983:335-66. Jernigan JA, Pearson RD. Antiparasitic agents. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett's principles and practice of infectious diseases. New York: Churchill Livingstone, 1995:458-92. Dupouy-Camet J, Fourestie V, Soule C, Touratier L, Ancelle T. Trichines et trichinellose. In: Encyclopedie Medico-Chirugicale. Paris: Editions techniques, 1992 (Maladies Infectieuses: 8-517-A-lO). Grove DI, Mahmoud AAF, Warren KS. Eosinophils and resistance to Trichinella spiralis. J Exp Med 1977; 145:755-9. Harms G, Binz P, Feldmeier H, et al. Trichinosis: a prospective controlled study of patients ten years after acute infection. Clin Infect Dis 1993; 17: 637-43.


The aim of this retrospective study was to compare the immediate and midterm efficacy and tolerability of thiabendazole and albendazole as therapy for trichinosis. Randomization was not performed owing to the problems inherent in setting up a controlled study during an outbreak; this lack of randomization meant that the two groups were not strictly identical. In particular, the patients treated with albendazole were older than those treated with thiabendazole and were treated later in the outbreak. These patients may have eaten the infested meat later in the epidemic than did the other patients or may have been exposed to a smaller inoculum than were the other patients. As a result, the patients treated with albendazole may have been less severely ill. Nonetheless, this study suggests that the initial efficacy of the two drugs is comparable. The rapid, sometimes remarkable, improvements in the patients' conditions after the start of treatment were probably due more to steroid therapy than to the antiparasitic drugs. In contrast, the safety of albendazole was undeniably better than that of thiabendazole, as has been previously reported [4, 6]. The influence of the two antiparasitic drugs on the persistence of clinical manifestations 6 months after treatment was comparable. The large proportion of patients who still had symptoms 6 months after treatment suggests that neither drug was particularly effective; indeed, this rate would have probably varied slightly in the absence of antiparasitic treatment. Treatment of trichinosis is controversial. To our knowledge, the curative efficacy of antiparasitic drugs has never been convincingly demonstrated; certain investigators [1] recommend therapy with aspirin and bed rest for simple symptoms, reserving steroids for the more serious cases, while others [7] prefer to use antiparasitic drugs routinely with the aim of limiting larval production by adult worms. Systemic steroid therapy has a remarkable impact on symptoms, which can be highly unpleasant, especially for the elderly. Thus, it is tempting to prescribe steroid therapy for all patients with clinical manifestations. Clinical manifestations during the acute phase of trichinosis are mainly due to the systemic inflammatory reaction, which is largely mediated by eosinophils and is provoked by larval forms. Therefore, it seems logical to control these manifestations by systemic steroid therapy, as in cases ofhypereosinophilic syndrome [8]. In our study, a short course of systemic steroid therapy rapidly (within 48 hours) decreased symptoms to an acceptable level (apyrexia and moderate myalgias and fatigue) without side effects in every case. Thus, the combination of a well-tolerated antiparasitic drug and systemic steroids, both for 8 to 15 days, seems best as

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