Am. J. Trop. Med. Hyg., 73(1), 2005, pp. 122–124 Copyright 2005 by The American Society of Tropical Medicine and Hygiene SUBCUTANEOUS IVERMECTIN AS A SAFE SALVAGE THERAPY IN STRONGYLOIDES STERCORALIS HYPERINFECTION SYNDROME: JEROME PACANOWSKI, MARIE DOS SANTOS, ANTOINE ROUX, CHRISTINE LE MAIGNAN, JACQUES GUILLOT, Départements de Microbiologie, Soins Intensifs de Pneumologie, et d’Oncologie Médicale, Hôpital Européen Georges Pompidou, Assistance Publique des Hôpitaux de Paris, Pairs, France; Université Paris V, Paris, France; Département de Parasitologie-Mycologie, Ecole Nationale Vétérinaire d’Alfort, Maisons-Alfort, France Strongyloides stercoralis hyperinfection syndrome due to the acceleration of the autoinfective cycle of the nematode is a life-threatening form of the infection occurring in immunocompromised hosts. Intestinal ileus, which is commonly encountered in this form, may reduce the bioavailability and thus the efficacy of oral anthelminthic drugs used in the treatment of the S. stercoralis hyperinfection syndrome. We report the efficacy and safety of subcutaneous administration of ivermectin in a patient infected with human T cell lymphotropic virus type I with S. stercoralis hyperinfection syndrome who was unresponsive to an oral combination of ivermectin and albendazole.
small bowel and compressive retroperitoneal lymphadenopa-thies were observed. A diagnosis of relapse was considered.
Strongyloidiasis is an intestinal parasitic disease caused by Gastro-duodenal aspiration was started and a steroid bolus the nematode Strongyloides stercoralis1 and is common in (methylprednisolone, 120 mg/day) was given for seven days.
tropical countries. In immunocompetent hosts, the infection commonly leads to minor symptoms such as transient diar- At day 7, his condition worsened and he was admitted to the rhea and abdominal pain, and may be asymptomatic and la- Oncology Department of the Hôpital Européen Georges tent for decades due to the ability of the parasite to sustain Pompidou. Physical examination showed fever, intestinal il- itself by autoinfection. In immunocompromised hosts, the eus, headache, confusion, and dyspnea. The white blood cell overwhelming accelerated autoinfective cycle can potentially count was 11.3 × 109/L with 10.5 × 109/L neutrophils and lead to a life-threatening illness with multi-organ failure due 0.5 × 109/L eosinophils. The C-reactive protein level was 66 to a massive larval invasion known as hyperinfection syn- mg/L. Microbiologic findings showed Klebsiella pneumoniae drome.2 The reported mortality of this hyperinfection syn- in a peripheral blood culture and Escherichia coli meningitis.
drome is high (up to 87%), highlighting the importance of He was then treated with intravenous cefotaxime (2 grams prophylactic anthelminthic treatment in immunocompro- every 4 hours for 48 hours, then 2 grams every 6 hours for 8 mised patients.3 The intestinal ileus associated with the hy- or more days) ciprofloxacine (200 mg twice a day for 10 days).
perinfection syndrome can reduce the bioavailability and the Demonstration of numerous S. stercoralis rhabditiform and efficacy of an oral formulation of antiparasitic drugs. We re- filariform larvae in the gastric fluid confirmed Strongyloides port a case of a S. stercoralis hyperinfection syndrome that hyperinfection syndrome. Oral ivermectin (12 mg/day) plus was refractory to a combination of two oral drugs and was oral albendazole (400 mg/day) were given in a nasogastric successfully treated with subcutaneous ivermectin.
catheter. Steroids were decreased rapidly during four daysand then discontinued. Two days after initiation of the anthel- minthic therapy, the patient showed acute respiratory failuredue to interstitial pneumonitis. He was referred to the inten- A 28-year-old African man born in Côte d’Ivoire who lived in France since he was seven years old was diagnosed with a Bronchoalveolar lavage fluid, gastric fluid, and stool speci- human T cell lymphotropic virus type 1 (HTLV-1)–associated mens showed persistent numerous S. stercoralis rhabditiform T cell leukemia lymphoma. He was treated with two cycles of and filariform larvae. The eosinophil count increased to doxorubicine, dacarbazine, vinblastine, bleomycine, and 1.79 × 109/L. Due to the persistence of the intestinal ileus, the methylprednisolone (120 mg on days 1 and 15) alternating absorption and efficacy of the oral treatment were uncertain.
with two cycles of vepeside, ifosfamide, cisplatine, and meth- As a life-saving therapy, after informed consent of the pa- ylprednisolone (120 mg/day on days 1–5). He had diarrhea tient’s family and agreement of the French drug administra- and a weight loss of 10 kg. He showed complete remission at tion (Agence Française de Sécurité Sanitaires des Produits de the end of the induction treatment. However, soon after the Santé) were obtained, a veterinary formulation of parenteral fourth cycle, he complained of asthenia, fever, abdominal ivermectin (Ivomec௡; Merial, Lyon, France) was given (6 mg pain, and incoercible vomiting. A painful tender abdomen twice a day) by subcutaneous injections in the thighs or ab- and palpable cervical lymphadenopathies were noted. Com- domen wall. Treatment with oral albendazole was continued.
puted tomography of the abdomen demonstrated distension The patient’s condition improved rapidly and the amount of of the stomach and dilatation of both the duodenum and the living larva in the stools decreased dramatically 48 hours after proximal jejunum. Diffuse wall edema in the stomach and the the initiation of parenteral ivermectin. Four days later, no larva could be demonstrated in the stool, gastric fluid, or sputum. Parenteral ivermectin was administered for six days * Address correspondence to Muriel Cornet, Laboratoire de Micro- biologe, Hoˆtel-Dieu, 1, Place du Parvis Notre-Dame, 75181, Paris (6 mg twice a day) and was then replaced by the oral route (12 Cedex 04, France. E-mail: mg/day) for six additional days. The tolerance of the injec- SALVAGE THERAPY FOR STRONGYLOIDES HYPERINFECTION tions was good, except for transient pain at the injection site in cattle because these formulations are much more conve- in the abdomen. The eosinophil count remained high (1.0 × nient to use than oral formulations and the dosage is not 109/L) for two weeks after the beginning of oral treatment variable. The present case confirms the efficacy and safety for and then decreased to a stable count of 0.2 × 109/L. The the salvage therapy of humans of a parenteral administration patient did not have any relapse of the S. stercoralis infection of veterinary ivermectin that is not currently licensed for hu- after discontinuation of treatment, but he died five weeks man use. However, oral albendazole was concurrently given later of progressive lymphoma, despite a new regimen of in- to our patient and could have provided a partial and late An association between HTLV-I infection and S. stercoralis increased prevalence, treatment failure, recurrent strongy- Strongyloides stercoralis hyperinfection syndrome has been loidiasis, and hyperinfection syndrome has been reported.2 described in immunocompromised patients. The most com- However, this association remains controversial.13 Con- mon predisposing factors are the use of steroids and HTLV-I versely, it has been suggested that S. stercoralis might be a infection.2,4,5 Other underlying diseases leading to immuno- cofactor in the pathogenesis of HTLV-I-induced T cell lym- deficiency such as lymphomas, leukemias, or infection with phomas.2,14 As observed in our patient before treatment, the human immunodeficiency virus have been reported to facili- lack of eosinophilia is typical in patients infected with tate Strongyloides hyperinfection.6 As in our patient, initial HTLV-1 infection; this retrovirus enhances the production of features of S. stercoralis hyperinfection may be bacteremias, interferon-␥, and decreases the production of interleukin-5 pneumonias, or meningitis due to enteric bacteria that can be and the IgE response.15 In our patient, corticosteroid therapy carried by the larvae.2 Patients with such bacterial infections could have contributed to the lack of eosinophilia.
without an obvious cause should be investigated for the car- This report confirms that the subcutaneous use of a veteri- riage of S. stercoralis. Bacterial infections associated with nary ivermectin preparation is a safe salvage therapy in pa- strongyloidiasis are very severe and mortality may be as high tients with S. stercoralis hyperinfection syndrome unrespon- as 87%.3 The use of an early effective anthelminthic treat- sive to oral therapy. Further studies assessing on a larger scale ment in association with appropriate antibacterial therapy is the pharmacokinetics parameters and tolerance of parenteral crucial for improving the prognosis.
Currently available regimens for treatment of strongyloidi- asis in humans include only oral agents. Ivermectin is now Received September 28, 2004. Accepted for publication January 19, recognized as the drug of choice because it showed compa- rable and better rates of larval clearance than thiabendazole Authors’ addresses: Jerome Pacanowski, Service de Maladies Infec- and albendazole, respectively, and fewer and comparable side tieuses, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, effects than thiabendazole and albendazole, respectively.7,8 75012 Paris, France. Marie Dos Santos and Veronique Lavarde, Laboratoire de Microbiologie, Hôpital Européen Georges Pompi- Albendazole has been used successfully in treating S. hyper- dou, 20 Rue Leblanc, 75015 Paris, France. Antoine Roux, Service de infection syndrome.9 However, since the clinical features of S. Pneumologie, Hôpital Européen Georges Pompidou, 20 Rue Leb- stercoralis hyperinfection include intestinal ileus, oral absorp- lanc, 75015 Paris, France. Christine Le Maignan, Service d’Oncologie tion of the drugs may be impaired. Only a few reports of Médicale, Hôpital Européen Georges Pompidou, 20 Rue Leblanc, non-oral therapy for hyperinfection syndrome have been pub- 75015 Paris, France. Jacques Guillot, Département de Parasitologie- Mycologie, Ecole Vétérinaire d’Alfort, 7 Avenue du Général de lished. One patient with bowel obstruction was successfully Gaulle, 94700 Maisons-Alfort, France. Muriel Cornet, Laboratoire de treated by rectal administration of thiabendazole.10 Tarr and Microbiologie, Hôtel-Dieu, 1, Place du Parvis Notre-Dame, 75181, others reported the use of rectal ivermectin enemas concur- Paris Cedex 04, France, Telephone: 33-1-42-34-82-73, Fax: 33-1-42- rently to oral albendazole and ivermectin in a patient with ileus but without diarrhea.11 Only two previous reports de- scribed the successful subcutaneous administration of iver- mectin to human patients with S. stercoralis hyperinfection 1. Mahmoud AA, 1996. Strongyloidiasis. Clin Infect Dis 23: 949– syndrome12 (Turner SA and others, unpublished data). In two of the three patients, as in our patient, the hyperinfection 2. Keiser PB, Nutman TB, 2004. Stongyloides stercoralis in the im- munocompromised population. Clin Microbiol Rev 17: 208– syndrome was associated with an HTLV-I infection. Since these studies reported a daily dose of 200 ␮g/kg/day, up to 14 3. Link K, Orenstein R, 1999. Bacterial complications of strongy- consecutive days in the patient described by Turner and oth- loidiasis: Streptococcus bovis meningitis. South Med J 92: 728– ers (unpublished data), we chose the same daily regimen.12 No significant accumulation of ivermectin was seen in the 4. Cruz T, Reboucas G, Rocha H, 1966. Fatal strongyloidiasis in patients receiving corticosteroids. N Engl J Med 275: 1093– patient described by Turner and others (unpublished data). In our patient, the subcutaneous treatment was replaced by the 5. Civantos F, Robinson MJ, 1969. Fatal strongyloidiasis following oral route after six days because no larva could be detected in corticosteroid therapy. Am J Dig Dis 14: 643–645.
the specimen collected and the condition of the patient im- 6. Celedon JC, Mathur-Wagh U, Fox J, Garcia R, Wiest PM, 1994.
Systemic strongyloidiasis in patients infected with the human immunodeficiency virus. A report of 3 cases and review of the Several veterinary avermectins (including ivermectin) are literature. Medicine (Baltimore) 73: 256–263.
now available. These drugs are frequently used for the treat- 7. Gann PH, Neva FA, Gam AA, 1994. A randomized trial of ment and prophylaxis of gastrointestinal strongyloidiases in single- and two-dose ivermectin versus thiabendazole for treat- cattle at a dosage of 200 ␮g/kg. However, the approval pro- ment of strongyloidiasis. J Infect Dis 169: 1076–1079.
8. Marti H, Haji HJ, Savioloi L, Chwaya HM, Mgeni AF, Ameir JS, cess for drugs for veterinary use is different from those for Hatz C, 1996. A comparative trial of a single-dose ivermectin human use. Many parenteral formulations are licensed for use versus three days of albendazole for treatment of Strongyloides stercoralis and other soil-transmitted helminth infections in 2000. Parenteral ivermectin in Strongyloides hyperinfection.
children. Am J Trop Med Hyg 55: 477–481.
9. Nandy A, Addy M, Patra P, Bandyopashayay AK, 1995. Fulmi- 13. Courouble G, Rouet F, Hermann-Storck C, Nicolas M, Candolfi nating strongyloidiasis complicating Indian kala-azar. Trop E, Strobel M, Carme B, 2000. Human T-cell lymphotropic vi- rus type I association with Strongyloides stercoralis: a case con- 10. Boken DJ, Leoni PA, Preheim LC, 1993. Treatment of Strongy- trol study among Caribbean blood donors from Guadeloupe loides stercoralis hyperinfection syndrome with thiabendazole (French West Indies). J Clin Microbiol 38: 3903–3904.
administered per rectum. Clin Infect Dis 16: 123–126.
14. Yamaguchi K, Matutes E, Catovsky D, Galton DA, Nakada K, Takatsuki K, 1987. Strongyloides stercoralis as candidate co- 11. Tarr PE, Miele PS, Peregoy KS, Smith MA, Neva FA, Lucey DR, factor for HTLV-I-induced leukaemogenesis. Lancet 2: 94–95.
2003. Rectal administration of ivermectin to a patient with 15. Porto AF, Neva FA, Bittencourt H, Lisboa W, Thompson R, Strongyloides hyperinfection syndrome. Am J Trop Med Hyg Alcantara L, Carvalho EM, 2001. HTLV-1 decreases Th2 type of immune response in patients with strongyloidiasis. Parasite 12. Chiodini PL, Reid AJC, Wiselka MJ, Firmin R, Foweraker J,



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