949 STATE-OF-THE-ART CLINICAL ARTICLE Strongyloidiasis Adel A. F. Mahmoud Human infection with the intestinal nematode Strongyloides stercoralis is prevalent in tropical and subtropical regions of the world. S. stercoralis infection also is endemic in some parts of Europe, the southeastern United States, and Puerto Rico. Clinically, strongyloidiasis is significant because infection persists for many years in the human host, usually as an undetected, asymptomatic condition. In areas of endemicity and nonendemicity (because of travel, etc.), this prolonged course of infection results in a significant but unsuspected worm load in the infected population. Under specific circumstances (e.g., immunosuppression), this undetected worm load produces extensive tissue invasion by parasite larvae, the so-called hyperinfection syndrome. This syndrome is a serious medical condition that necessitates a high index of suspicion and aggressive, early therapeutic intervention. Biologically, S. stercoralis is unique among human helminths, which, as a rule, do not multiply within the definitive host. This worm is capable of reproducing within the human host. The normal autoinfection cycle involves the release of parasite larvae by adult worms in the gastrointestinal tract, and instead of passing to the outside environment in feces, they change into infective larvae and penetrate the gut wall or penanal skin of the same individual. Acceleration of this autoinfection cycle results in the hyperinfection syndrome with extensive tissue invasion by larvae. The life cycle of S. stercoralis is further complicated by its ability to pursue either parasitic or free-living patterns of existence. These biological characteristics play a significant role in shaping the outcome of the hostparasite interaction. S. stercoralis larvae were first described in 1876 in stools of French troops with severe diarrhea who were returning from Indochina. The larvae were subsequently identified as those of the intestinal nematode S. stercoralis. Etiology Strongyloidiasis is caused by infection of humans with the small (length, 2.2 mm; diameter, 50 sum) adult female worms. From the Department of Medicine, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio The body of the worm contains an esophagus occupying approximately one-third of the anterior portion, while the posterior part contains ovaries, oviducts, and uteri (which open through a vaginal orifice). Adult female worms live in tunnels between the enterocytes in the small bowel of humans. These intestinal nematodes reside, therefore, in the host's tissues, thus explaining the close association between strongyloidiasis and peripheral blood eosinophilia. One of the biological features of strongyloidiasis relates to the absence of parasitic male adult worms. Only adult females exist in infected individuals; they reproduce by parthenogenesis. Eggs containing mature larvae are released by adult females in the intestinal lumen. These ova hatch immediately, releasing rhabditiform larvae that are passed to the environment and can be seen during stool examination. In the environment, these organisms may change into the infective stage, filariform larvae, or they may differentiate into free-living adult male and female worms. Thereafter, the free-living adults release eggs that hatch and differentiate into the infective filariform larvae (figure 1). Humans acquire S. stercoralis infection by penetration of skin or mucous membranes by the infective filariform larvae; this infection is usually a result of contact with contaminated soil. Autoinfection also occurs, whereas the rhabditiform larvae change into the infective filariform organisms while they are within the gut lumen. They then penetrate the intestinal wall or perianal region and maintain low levels of infection in the same host. In circumstances associated with suppression of the host's immune response (particularly T cell function), this cycle accelerates, thus leading to an overwhelming parasite load [1]. The migration of infective larvae from the subcutaneous or submucosal sites has traditionally been described to proceed via venous circulation to the lungs, where they break into the alveolar spaces; they ascend via the bronchi and trachea and are subsequently swallowed, reaching their final habitat in the small intestine. This traditional migratory pathway is now being perceived to be combined with an equally significant direct migration from the skin to the duodenum. Received 3 June 1996. Reprints or correspondence: Dr. Adel A. F. Mahmoud, Department of Medicine, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, Ohio 44106. Clinical Infectious Diseases 1996; 23:949-53 1996 by The University of Chicago. All rights reserved. 1058-4838/96/2305 0001 $02.00 Epidemiology The global prevalence of strongyloidiasis is estimated to be 100 million cases. This is a general assessment, and the prevalence of this infection varies considerably in different areas. In the United States, the highest prevalence rates (4%) are found in
950 Mahmoud CID 1996; 23 (November) Filariform larvae (soil or small intestine) infective stage Adult parasitic female Ova production by parthenogenesis Rhabditiform larvae Free-living male and female worms Ova Filariform larvae infective stage Figure 1. Schematic representation of the parasitic and free-living life cycles of Strongyloides stercoralis. eastern Kentucky and rural Tennessee. The prevalence rates in the areas of the world with high endemicity may vary from 15%-82% in Brazil to 1.1%-16.5% in Costa Rica, 26% in Zaire, and 48% in the Central African Republic [2]. There are three groups of individuals for whom strongyloidiasis represents a significant problem: residents of mental institutions (among whom prevalence rates of 1.7%-40% have been described), veterans who were prisoners of war in areas of endemicity during World War II (retrospective surveys have demonstrated prevalence rates of 0.5%-37% among these veterans), and refugees and immigrants to the United States and Europe (more recent surveys have demonstrated prevalence rates of 0.6%-38% among these individuals) [2]. These data on the prevalence of strongyloidiasis need to be considered carefully. Most of these studies were not based on random selection of study participants from populations in areas of endemicity. Furthermore, most of these surveys employed stool examination for parasite identification. Besides its difficulty, this procedure has low sensitivity. More recent surveys employed examination for serum antibodies. In general, these studies demonstrated high prevalence rates in several areas of endemicity. Information on the epidemiology of the hyperinfection syndrome of strongyloidiasis is less precise. Certain patient groups appear to be more susceptible to this syndrome, including those with malignancies (especially hematologic), autoimmune diseases, and malnutrition. The syndrome also is frequently seen in patients receiving immunosuppressive therapy, including corticosteroids. The association of immunosuppression due to HIV or human T lymphotropic virus infection and hyperinfection with S. stercoralis has been observed in only a few circumstances. Of particular note is the lack of correlation in areas where both HIV infection and S. stercoralis infection exist, such as sub-saharan Africa and Brazil. Pathogenesis and Clinical Presentation Primary infection with S. stercoralis is initiated through skin penetration by the infective filariform larvae. This acute infection with the early stage of the pathogen in the human host is usually asymptomatic. Larva currens is a more frequent cutaneous manifestation that occurs in association with autoinfection. It is an allergic reaction to filariform larvae that migrate in the skin at a relatively fast rate and leave itchy urticarial tortuous tracks. The condition is usually detected over the lower abdominal wall, buttocks, or thighs. Larva currens may last for a few days but usually recurs over prolonged periods. Symptomatic pulmonary strongyloidiasis due to migrating larvae is seen rarely. Clinically, it resembles LOffler's syndrome with cough, shortness of breath, wheezing, and transient pulmonary infiltrates. Peripheral blood eosinophilia is usually detected in individuals with this type of strongyloidiasis. By the time that the adult female worms reach maturity in the gastrointestinal tract, abdominal symptoms and signs may be observed [3]. In a recent controlled study, the following complaints were significantly more prevalent in infected individuals: indigestion, crampy abdominal pain, diarrhea with malabsorption, and weight loss [3]. Radiographic findings associated with gastrointestinal strongyloidiasis include duodenal edema with irregular mucosal folds, ulcerations, and strictures. Eosinophilia is a common finding, as is elevation of levels of nonspecific and specific IgE. The most significant clinical presentation of strongyloidiasis occurs in patients with the hyperinfection syndrome [4]. Because of the massive tissue invasion with S. stercoralis larvae, symptoms and signs manifest as an exaggeration of the clinical features of established infection in immunocompetent patients. Furthermore, invasion of multiple organs leads to manifestations related to these organs. Finally, the introduction of bowel organisms results in bacteremia and septicemia. Patients with the hyperinfection syndrome may manifest cutaneous lesions in the form of petechial and purpuric rashes. Pulmonary involvement results in cough, wheezing, or hemoptysis. Because signs and symptoms may mimic bronchitis or bronchospasm, the diagnosis may be delayed. Peripheral blood eosinophilia, although not a constant feature, may help in pointing to the correct diagnostic workup. Pulmonary imaging studies reveal that migratory larvae are the cause of this clinical feature of the hyperinfection syndrome
CID 1996;23 (November) Strongyloidiasis 951 [5]. Fine miliary nodules or diffuse reticular intestinal opacities may be demonstrated on chest radiographs or CTs. In severe cases, bronchopneumonia (either segmental or lobar opacities) may be seen. In such cases, clinical progression to adult respiratory distress syndrome is frequently encountered. Pleural effusion may be a complication of any of the above-mentioned pulmonary clinical features. Furthermore, lung cavitation and formation of abscesses may develop in association with secondary bacterial infections. The spectrum of gastrointestinal features includes abdominal pain, anorexia, nausea and vomiting, and diarrhea. These features are related to thickening and congestion of the mucosal lining of the small and large intestine in addition to frequent mucosal ulceration. Steatorrhea, malabsorption, protein-losing enteropathy, and paralytic ileus are the common physiological abnormalities seen in patients with gastrointestinal strongyloidiasis. Involvement of other organs, such as the CNS, is commonly seen in patients with the hyperinfection syndrome [6]. Symptoms include headache, change in mental status, focal seizures, and, in extreme cases, coma. Bacterial meningitis is usually a common feature of the pathological changes seen. The third and perhaps equally important feature of the hyperinfection syndrome is bacterial infection. Gut flora invade host tissues either through penetration of infective larvae from the bowel lumen or through damaged intestinal epithelium. The most common pathogens are Escherichia coli and Klebsiella. The resulting bacteremia may be recurrent and is probably responsible for most mortalities. Eosinophilia is a prominent and clinically significant feature of S. stercoralis infection in humans. All through their life cycles in humans, the organisms (larvae and adult female worms) are actually localized in host tissues. Clinically, the association of skin lesions, pulmonary infiltrates, or abdominal pain and diarrhea with peripheral blood eosinophilia suggests very strongly the possibility of strongyloidiasis [7]. In spite of this association, the hyperinfection syndrome occurs mainly in immunosuppressed individuals with little or no ability to mount an eosinophilic response. Therefore, patients with the hyperinfection syndrome may not have an elevated eosinophil count. Management The first and most important step in diagnosing S. stercoralis infection is to consider it in the differential diagnosis of recurrent skin lesions, multiple pulmonary infiltrates, and abdominal presentation with pain, diarrhea, or malabsorption. Furthermore, it should be considered in the differential diagnosis of immunocompromised patients presenting with fever, bacteremia, and pneumonia. Finally, the presence of peripheral blood eosinophilia in individuals with a suggestive geographic history necessitates examinations for S. stercoralis infection. The definitive diagnosis may be made by examination of body fluids that contain parasite larvae. The different diagnostic modalities for S. stercoralis infection and their sensitivities are summarized in table 1. The basic technique for parasite identification is based on examination of a preserved stool sample; this technique yields positive findings in few instances. Repeated stool examinations enhance the sensitivity of this technique [8]. A more sensitive approach is the Baermann test, but the availability of this test in most Table 1. Comparison of available diagnostic procedures for Strongyloides stercoralis infection in immunocompetent hosts and immunocompromised hosts (those with the hyperinfection syndrome). Percent of hosts for whom procedures provide diagnosis Immunocompetent Immunocompromised Diagnostic procedures hosts hosts Nonspecific tests Elevation of total IgE level..^-, 5% eosinophils in blood Examinations for parasites Direct stool Single specimen Three or more specimens Concentrated stool Duodenal sample via string test or endoscopic aspirate Sputum and other body fluids Serological tests ELISA (IgE to S. stercoralis antigen) Indirect immunofluorescence 50% 40%-80% 20%-30% 60%-70% Variable, up to 80% 40%-90%... t Variable <20% >30% >80% * * Moderate to high 80%-90% Unknown, may be low Variable, up to 90% Unknown NOTE. Data adapted from [4]. * Test usually not necessary. t Larvae are rarely found in sputum.
952 Mahmoud CID 1996;23 (November) clinical settings is variable. Direct microscopic examination of other body fluids, such as sputum or duodenal contents (obtained by aspiration or the string test), may be useful. In general, parasite identification is easier in cases of the hyperinfection syndrome. On the other hand, serological tests provide a distinct advantage. ELISA is both sensitive and specific [9]. Until recently, chemotherapy for strongyloidiasis has been limited to one drug, thiabendazole; 25 mg of thiabendazole/kg of body weight is administered orally for 2 or 3 days. For patients with the hyperinfection syndrome, thiabendazole therapy should be given for 7-10 days. Other measures such as reducing the dose of immunosuppressive therapy and treating secondary bacterial infection are essential elements in the management of these patients. The efficacy of thiabendazole is considerable; rates of parasite eradication are in the 90% range. However, this therapy may not be sufficient for infection due to worms capable of maintaining low levels in the host, which may result in the hyperinfection syndrome if the host's immune status changes. Therefore, close follow-up of treated individuals is required to assure complete elimination of the worms. The other considerable problem with thiabendazole therapy is frequent side effects (e.g., nausea, headache, hypotension, and hypersensitivity reactions). These side effects may occur in 30% of treated individuals. Rare and severe neuropsychiatric reactions as well as rare mortalities have been reported. The search for alternative chemotherapeutic agents has resulted in experimenting with albendazole and ivermectin. Human trials with both compounds have demonstrated rates of parasite eradication ranging from 60% to 90% [10]. A recent comparative study [10] showed that ivermectin appears to be equally effective as thiabendazole for treating uncomplicated chronic strongyloidiasis and is associated with far fewer side effects. Both albendazole and ivermectin are not yet approved for use in cases of strongyloidiasis. of the hyperinfection syndrome. Exposure to S. stercoralis larvae in areas of endemicity, whether tropical or temperate, is a result of skin contact with larva-infected soil. The main preventive strategy is wearing shoes. Transmission in institutional settings may be reduced by decreasing fecal contamination of the environment, such as bedding. Prevention of the hyperinfection syndrome depends mainly on considering the infection in the preparatory workup for organ transplantation or when immunosuppressive therapy is initiated. References 1. King CH. Strongyloidiasis. In: Mahmoud AAF, ed. Tropical and geographical medicine companion handbook. 2nd ed. New York: McGraw-Hill, 1993:87-91. 2. Genta RM. Global prevalence of strongyloidiasis: critical review with epidemiologic insights into the prevention of disseminated disease. Rev Infect Dis 1989; 11:755-67. 3. Grove DI. Strongyloidiasis: a conundrum for gastroenterologists. Gut 1994;35:437-40. 4. Liu LX, Weller PF. Strongyloidiasis and other intestinal nematode infections. Infect Dis Clin North Am 1993; 7:655-82. 5. Woodring JH, Halfhill H 2nd, Reed JC. Pulmonary strongyloidiasis: clinical and imaging features. AJR Am J Roentgenol 1994; 162:537-42. 6. Cappello M, Hotez PJ. Disseminated strongyloidiasis. Semin Neurol 1993; 13:169-74. 7. Mahmoud AAF. Eosinophilia. In: Warren KS, Mahmoud AAF, eds. Tropical and geographical medicine. 2nd ed. New York: McGraw Hill, 1990: 65 70. 8. Sato Y, Kobayashi J, Toma H, Shiroma Y. Efficacy of stool examination for detection of Strongyloides infection. Am J Trop Med Hyg 1995; 53: 248-50. 9. Lindo JF, Conway DJ, Atkins NS, Bianco AE, Robinson RD, Bundy DA. Prospective evaluation of enzyme-linked immunosorbent assay and immunoblot methods for the diagnosis of endemic Strongyloides stercoralis infection. Am J Trop Med Hyg 1994;51:175-9. 10. Gann PH, Neva FA, Gam AA. A randomized trial of single- and twodose ivermectin versus thiabendazole for treatment of strongyloidiasis. J Infect Dis 1994; 169:1076-9. Prevention The most significant preventive strategies for strongyloidiasis are based on avoiding infection and reducing the incidence Suggested Reading Neva FA. Biology and immunology of human strongyloidiasis. J Infect Dis 1986; 153:397-406.
953 OFFICE OF CONTINUING MEDICAL EDUCATION UCLA SCHOOL OF MEDICINE This test affords you the opportunity to assess your knowledge and understanding of the material presented in the preceding clinical article, "Strongyloidiasis," by Adel A. F. Mahmoud, and to earn continuing medical education (CME) credit. The Office of Continuing Medical Education, UCLA School of Medicine, is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians. The Office of Continuing Medical Education, UCLA School of Medicine, designates this educational activity for up to 1 hour in category I credit towards the Physician's Recognition Award of the American Medical Association. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. To earn credit, read the State-of-the-Art Clinical Article carefully and answer the following questions. Mark your answers by circling the correct responses on the answer card (usually found toward the front of the issue), and mail the card after affixing first-class postage. To earn credit, a minimum score of 80% must be obtained. Certificates of CME credit will be awarded on a per-volume (biannual) basis. Each answer card must be submitted within 3 months of the date of the issue. This program is made possible by an educational grant from Roche Laboratories. 1. The life cycle of Strongyloides stercoralis is unique because the helminth is capable of A. Autoinfection B. Producing hyperinfection C. Differentiating into free-living forms 2. S. stercoralis infection in humans is acquired by A. Mosquito bites B. Swimming in fresh water C. Walking barefooted D. Blood transfusion 3. Larva currens is caused by A. Superficial fungal infection B. Schistosomiasis C. S. stercoralis infection D. Hookworm disease 4. Hyperinfection with S. stercoralis occurs in association with A. Steroid therapy B. Immunosuppressive medication C. Severe malnutrition 5. Eosinophilia is a common feature of strongyloidiasis because A. Parasite larvae migrate in tissues B. Adult worms are embedded in the intestinal wall C. Worms induce IL-5 production 6. The current drug of choice for treating strongyloidiasis is A. Chloroquine B. Thiabendazole C. Mebendazole D. Praziquantel 7. The diagnosis of strongyloidiasis may be accomplished by A. Repeated stool examinations B. ELISA C. Detection of specific IgE 8. Mortality due to the hyperinfection syndrome of strongyloidiasis is caused by A. Severe tissue damage B. Extremely high larva load C. Bacterial infection 9. Individuals with strongyloidiasis harbor chronic infection for decades because of A. Repeated exposure B. Autoinfection C. The long life-span of worms D. The long life-span of larvae 10. Eosinophilia in patients with the hyperinfection syndrome may not be a component of the clinical presentation because of A. Consumption of eosinophils during the host's response to helminths B. Destruction of the host's eosinophils C. The associated immunosuppression D. The shortened life-span of eosinophils