Hyperinfection by Strongyloides stercoralis probably associated with Rituximab in a patient with mantle cell lymphoma and hyper eosinophilia

Hiperinfección por Strongyloides stercoralis probablemente asociada con Rituximab en una paciente con linfoma e hipereosinofilia

CASE REPORT

Hyperinfection by Strongyloides stercoralis probably associated with Rituximab in a patient with mantle cell lymphoma and hyper eosinophilia

Hiperinfección por Strongyloides stercoralis probablemente asociada con Rituximab en una paciente con linfoma e hipereosinofilia

Renzo Nino Incani^I; Marcos Hernández^II; María Elena González^III

^IDepartamento de Parasitología

^IIDepartamento de Medicina, Facultad de Ciencias de la Salud, Universidad de Carabobo, Valencia 2001, Venezuela

^IIICentro de Especialidades Quirúrgicas, Guacara, Venezuela

^{Correspondence to}

SUMMARY

The first report to our knowledge, of hyperinfection by Strongyloides stercoralis (HS) and hypereosinophilia, associated to immune suppression by Rituximab (the only drug received for the last one year and 10 months), in a patient with mantle-cell lymphoma (MCL), is presented. The patient has a 3-year history of MCL, and developed two accesses of HS during 2008, including meningitis, pneumonia and presence of larvae of S. stercoralis in the lungs. We had a unique chance to look at cytotoxicity of filariform larvae in the expectoration after Ivermectin treatment, showing immobilization and death of larvae, associated with eosinophils attached to the cuticle of the parasite.

Keywords:Strongyloides stercoralis; Hyperinfection; Rituximab; Eosinophilia; Lung dissemination; Lymphoma; Mantle-cell lymphoma.

RESUMEN

Se presenta el primer reporte, hasta donde tengamos información, de hiperinfección por Strongyloides stercoralis (HS) e hipereosinofilia asociados a inmunosupresión por Rituximab (el único medicamento recibido durante 1 año y 10 meses), en un paciente con linfoma de células del manto (LCM). La paciente tuvo una historia de 3 años con LCM, y desarrolló 2 accesos de HS durante el 2008, incluyendo meningitis, neumonía y presencia de larvas de S. stercoralis en los pulmones. Se tuvo la oportunidad única de observar la citotoxicidad contra las larvas filariformes en la expectoración, luego del tratamiento con Ivermectina, mostrando la inmovilización y muerte de las larvas, asociada a la presencia de eosinófilos adheridos a la cutícula del parásito.

INTRODUCTION

Hyperinfection by Strongyloides stercoralis (HS) is a well known clinical and parasitological event, in which the parasitic infection, usually limited to the intestinal wall of the upper small intestine, causing few or no symptoms, can spread to other areas of the gastro intestinal tract and to other organs; the latter is sometimes referred to as disseminated strongyloidiasis (DS)^14,15,16. This situation is triggered by immune deficiency. Relevant causes of immune deficiencies associated with hyperinfection by S. stercoralis are malignancies such as lymphoma^7,16, leukaemia¹⁴, immunosuppression with drugs, among which steroids are of major importance^14,15,16, organ and tissue transplants^5,19. In a high percentage of all these situations, treatment with immunosuppressive drugs, particularly steroids, seems to be important⁶. Steroids are known to suppress eosinophilia and lymphocyte activation^4,14. Other important causes include coinfection with the human T cell lymphotropic virus type-1 (HTLV-1)^9,26, hypogammaglobulinemia and malnutrition¹⁴. Coinfection with HIV has also been implicated, although the views are somewhat conflicting and the accepted view is that there are no solid criteria to establish a relationship between HIV infection and HS^14,16. The death rate from HS, particularly in the DS form, can be as high as 60-86% ^7,13. Although Ivermectin at one or two doses per day is the drug of choice for S. stercoralis infection, the dosing for HS or DS does not appear to have been worked out yet, as it has not for Thiabendazole, an effective drug, but with side effects, or Albendazole, a much less effective drug¹⁴.

In this paper we report a case of hyperinfection by S. stercoralis with hyper-eosinophilia and respiratory distress, in a patient with non-Hodgkin's mantle cell lymphoma (MCL) receiving only Rituximab (anti-CD20 monoclonal antibody) as maintenance treatment, not associated to HTLV-1 infection, clinically cured with Ivermectin, and in which eosinophil cytotoxicity against larval stages in the lung could be documented.

CASE DESCRIPTION

The patient was a 59-year-old Venezuelan-born female, with a 3-year history of MCL in clinical remission, after receiving Rituximab-Hyper-CVAD, high dose Methotrexate and ARA-C for five cycles (October 2005-April 2006), and maintenance with Rituximab alone for one year and 10 months before admission. She was admitted to hospital on the 6^th of February 2008 with a diagnosis of meningitis caused by a coagulase-negative Staphylococcus (apparently S. warneri), which was resolved with intravenous Vancomycin. However, fever and mild respiratory symptoms persisted. Three weeks later she was readmitted because of abdominal pain, diarrhea, persistent productive cough, fever and periodical symptoms of intestinal pseudo-obstruction. Fecal examination showed abundant larvae of S. stercoralis. Examination of expectoration samples revealed abundant filariform larvae of S. stercoralis (about 40 larvae/50µL sputum). Klebsiella pneumoniae and Candida albicans were isolated from expectoration. Deterioration of health prompted admission to the Intensive Care Unit. Treatment included Cefotaxime 14 days, Fluconazole seven days, and Ivermectin (200 µg/kg/day for two days), with improvement of the symptoms. New examination of the patient at day 7 after Ivermectin treatment showed diffuse abdominal pain and no visceromegalies, edema in both legs, dry, desquamate and itchy skin, fever and cough still persistent with white expectoration, the feces were solid. A second 2-day course of Ivermectin was repeated, with improvement of respiratory symptoms. Direct and agar culture of expectoration and fecal examination samples using the concentration method of Baermann, carried out at 30 and 52 days after 2^nd Ivermectin treatment, did not show larvae of S. stercoralis. Four months after first admission (25 June 2008), she again had pneumonia due to K. pneumoniae and was treated with Ceftazidine with clinical improvement, but high blood cell count (32,500/mm³) and eosinophilia (22,425/mm³) prompted examination of feces and expectoration, showing rabditiform larvae of S. stercoralis in both samples. She was previously medicated by others with Albendazole 400 mg/day for five days with no success, and later by us with Ivermectin 200 µg/kg/day for five days. Examination of feces (Direct, Baermann and agar plate²³) and expectoration (Direct and agar plate) 12 days and two months after completion of treatment did not evidence the presence of larvae of S. stercoralis.

Background history: Lymphoma was diagnosed in April 2005 by biopsy of cervical lymph node. Chemotherapy-immunotherapy treatment Hyper-CVAD included three monthly cycles of Cyclophosphamide, Doxorubicin, Vincristine and dexamethasone, alternated with three monthly cycles of Methotrexate and Cytarabine, with Rituximab before each cycle²². Cycles of chemotherapy lasted until April 2006, after which only Rituximab bi-monthly was administered: in 2007 she received five doses, and in 2008 (up to August) four doses. She had frequent cough, diagnosed as bronchitis and findings of the chest tomography and x-ray were reported as interstitial bilateral infiltrates. Abdominal pain and diarrhea were reported since the beginning of chemotherapy for lymphoma, three years before admission. S. stercoralis infection was diagnosed in feces first time after last cycle of chemotherapy, and thereafter treated several times including a course of 1200 mg/day for three days with one day's rest for four cycles, without complete success. Six months before admission, she was treated at our Clinic of Parasitology with a single 200 µg/kg dose of Ivermectin because of a diagnosis of strongyloidiasis infection. Gastrointestinal bleeding and hematuria associated to pancytopenia post chemotherapy was observed in February 2006. Upper endoscopy in March 2006 showed chronic gastritis and granular duodenitis. The patient has been a permanent city dweller for the last 34 years, with no rural contacts. The expected time of infection by S. stercoralis, according to prolonged rural contacts with limited sanitation, appears to be 49-58 and/or 34-43 years previously.

Laboratory

Relevant laboratory tests available since August 2007: Haemoglobin between 10 and 14 gr/dL, white blood cell counts between 9,000 and 34,700/mm³, eosinophils between 1,344 and 22,425/mm³. Total proteins, albumin, globulins (range of normal values in mg/dL) around the time of first pneumonia: 5.3 (6.3-8.5), 3.4 (3.5-5.1), 1.9 (2.5-3.0) and two months after pneumonia: 5.7 (6.4-8.9), 4.4 (3.1-5.0), 0.1 (0.9-1.8) respectively. Immunoglobulins: IgG 212 (700-1600 mg/mL), IgM 16 (40-230 mg/dL), IgE 7.5 (< 48 IU/mL) and IgA 46.3 (70-400 mg/dL). Cerebral-spinal fluid examination at the time of meningitis showed signs of bacterial infection, and the culture showed gram positive Staphylococcus. Cultures of expectoration at the time of first and second pneumonia infections showed Klebsiella pneumoniae and Candida albicans. Anti-core HBV was positive. S. stercoralis larvae in feces first time in April 2006, and thereafter several times diagnosed and incompletely treated until apparently successfully treated with Ivermectin (August 2007) six months before meningitis; again diagnosed at the time of first and second pneumonia infections. S. stercoralis larvae were observed in expectoration at time of first and second pneumonia infections. Culture of left external otitis secretion (May 2008) showed abundant growth of coagulase-negative Staphylococcus sp. HIV and HTLV I-II tests (carried out twice) were negative.

Cytotoxicity of Strongyloides stercoralis larvae: Expectoration samples provided a unique chance to look at filariform larval destruction. At day of diagnosis, larvae were all alive and moved vigorously. Two days after first 2-day doses of Ivermectin about 2/3 of the larvae were immobilized or with difficult movements, and surrounded by a cloud of cells (Fig. 1a). Most of the free cells and cells attached to the larval cuticle were eosinophils and some eosinophilic material could be detected at the parasite surface (Fig. 1b). By day 5 post Ivermectin, most larvae were dead or with little movements and surrounded by eosinophils.

White blood cell counts, Rituximab and Strongyloides stercoralis hyperinfection accesses: Figure 2 shows the total and differential white blood cells (WBC) counts that could be recovered from December 2007 to July 2008. WBC counts were usually above normal throughout this period. Three peaks of eosinophilia were detected: the 1^st coinciding with diagnosis of meningitis, the 2^nd at the time of the first HS, and the 3^rd coincided with a 2^nd diagnosis of HS. Treatment of HS with Ivermectin and antibiotics resulted in clinical cure and a reduction in WBC counts. Lymphocyte counts were unremarkably constant throughout the period of observation. Rituximab applications did not appear to be associated to detectable changes in WBC counts.

DISCUSSION

Strongyloidiasis HS has a long lasting history of association with lymphoma, although it appears that it is more a consequence of the immunosuppressive treatment of this malignancy, particularly the use of steroids. The first diagnosis of strongyloidiasis in our patient was made after the last cycle of chemotherapy-immunotherapy of mantle cell lymphoma. Thereafter, she was diagnosed of strongyloidiasis several times before admission and treated with Albendazole, without eradication of the parasite. The cycles of chemotherapy-immunotherapy with Rituximab-Hyper-CVAD included the corticosteroid dexamethasone, known to be associated with HS, and could explain the first exacerbations of the parasite infection. However, the actual relapses of HS do not appear to be related to steroid treatment since the cycles of chemotherapy-immunotherapy were concluded one year and 10 months before admission. Since the only immunosuppressive drug she has been receiving thereafter (and is still receiving) is Rituximab, a relationship between HS and this drug could be postulated.

Rituximab is a chimeric murine/human monoclonal antibody anti-CD20, an antigen present in B lymphocytes and in most B cells of non-Hodgkin's lymphoma. In vitro evidence shows that Rituximab works with the human immune system to induce B-cell lysis through an antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and stimulates apoptosis². It can also induce neutropenia¹⁸. There are reports in which Rituximab alone or its addition to standard chemotherapy schedules for lymphoma has increased the risk of life-threatening infections, either opportunistic or not, such as bacterial, fungal, protozoan, viral and viral reactivations³. However, it appears that infections are more frequent in HIV-associated B-cell lymphoma. To our knowledge, ours appears to be the first report of a helminth opportunistic infection that could be related to a B-cell immunosuppressant agent. Rituximab also induces a reduction in immunoglobulin levels particularly IgG¹² and IgM⁸. It has been shown that B-cells and IgM are relevant in immunity against S. stercoralis, and probably prevent the parasite spreading^1,10.

Eosinopenia, or at least absence of eosinophilia, is associated with most conditions in which immunodeficiency leads to S. stercoralis hyperinfection and consequently to high lethality^6,13. On the other hand, patients with strongyloidiasis and hyper eosinophilia appear to survive longer^6,20 and may have few symptoms in spite of immune suppression²⁵. Our case is unusual in the fact that hyper-eosinophilia has been constant throughout eight months of observation. Eosinophilia has been considered a good prognosis factor in cases of HS ^14,25, a contention which is reinforced by the survival of this patient to meningitis and pneumonia, both highly lethal complications in HS. This may lead to think that hyper-eosinophilia and larval destruction by an antibody-dependent eosinophil-mediated cytotoxicity, after Ivermectin initial damage to the parasite, may have been a major cause for survival and quick health recovery of this patient. This in spite of low serum levels of total immunoglobulins subclasses detected in this patient. However, some specific IgE response against parasite antigens could be detected in her serum (not shown in this paper).

Eosinophils are major effector cells of cytotoxicity against larval stages of parasitic helminths¹¹. If eosinophils are not available in sufficient quantities, cytotoxicity may not be efficient, once treatment has been administered. It appears that in this immunosuppressed patient, there may be a potentiation between the drug and the eosinophil damage to the parasite, as it has been observed experimentally in filarial infections with Ivermectin²¹ or Diethylcarbamazine¹⁷.

Failure of Ivermectin treatment is another point to consider. The patient had been unsuccessfully treated with frequent and prolonged doses of Albendazole. Eventually, as Ivermectin became available to this patient, she received several schemes with therapeutic failures, until a continuous five dose per day scheme was administered, with successful disappearance of larvae in feces and sputum. The only condition we have found in the literature related to drug failure in strongyloidiasis treated with Albendazole, Thiabendazole or Ivermectin, is coinfection with the HTLV-1 virus²⁶. Our patient does not appear to be coinfected with HTLV-1 and other explanations like immune suppression by Rituximab or insufficient Ivermectin doses should be sought.

ACKNOWLEDGEMENTS

We wish to acknowledge the following members of the Universidad de Carabobo, Valencia, Venezuela, for their invaluable help: Dr. Emilia Barrios (for the preliminary results of Western blots), Lic. María Alejandra De Almeida (for figures processing), and Lic. Marlen García (for photography processing), all from the Faculty of Health Sciences, and Lic. Ruben Toro, from the Faculty of Dentistry, for providing stained slides of expectoration. Thanks also to Dr. Eduardo Gotuzzo, Instituto de Medicina Tropical, Universidad Peruana Cayetano Heredia, Lima, Perú, for critical revision of the manuscript. Informed consent was obtained from the patient for publication of her case. The authors do not have any conflict of interest to disclose

Received: 22 September 2009

Accepted: 22 April 2010

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Publication Dates

• Publication in this collection
  25 Aug 2010
• Date of issue
  Aug 2010

History

• Received
  22 Sept 2009
• Accepted
  22 Apr 2010