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Strongyloides hyperinfection syndrome: an emerging global infectious disease
Transactions of the Royal Society of Tropical Medicine and Hygiene (2008) 102, 314—318
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/trst
REVIEW
Strongyloides hyperinfection syndrome: an emerging global infectious disease Luis A. Marcos a,b,∗, Angelica Terashima b, Herbert L. DuPont a,c,d,e, Eduardo Gotuzzo b a
Internal Medicine Department, University of Texas Health Science, 6431 Fannin Street, Suite 1.150, Houston, TX 77030, USA Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru c University of Texas, School of Public Health, Houston, TX, USA d St. Luke’s Episcopal Hospital, Houson, TX, USA e Baylor College of Medicine, Houston, TX, USA b
Received 13 August 2007; received in revised form 24 January 2008; accepted 25 January 2008
KEYWORDS Strongyloidiasis; Strongyloides stercoralis; Hyperinfection; Emerging diseases; Review
Summary The hyperinfection syndrome (HS) caused by Strongyloides stercoralis has a high mortality rate (15% to 87%). A variety of risk factors and predisposing conditions have been described, including new immunosuppressive therapies; HTLV-1 infection; cadaveric transplantation; immune reconstitution syndrome; haematological malignancies (especially lymphoma); tuberculosis; malnutrition secondary to chronic Strongyloides diarrhoea; international travel and immigration. Inhibition of Th2 cell-mediated, humoral or mucosal immunity is associated with HS. HS is more frequently seen in HTLV-1 than HIV patients. In AIDS, there is an increase in Th2 cytokines, while in HTLV-1 infection there is a decrease in the Th2 response, leading to an increased risk of autoinfection. Corticosteroid use remains the most frequent risk factor for HS. A number of ELISAs are useful for diagnosis and post-treatment evaluation. Once diagnosed, the disease may be managed effectively with anthelminthic drugs, including ivermectin. HS causes diverse symptoms and signs, with unusual manifestations leading to misdiagnosis and medical errors related to healthcare providers’ lack of familiarity with the condition. HS is an example of an emerging tropical infection migrating to developed countries and requiring greater clinician awareness. © 2008 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.
Introduction
∗
Corresponding author. Tel.: +1 713 500 6500; fax: +1 713 500 6497. E-mail address: [email protected] (L.A. Marcos)
The soil-transmitted helminth, Strongyloides stercoralis, causes strongyloidiasis affecting an estimated of 3—100 million people in the world, mostly in tropical and subtropical countries but also in the United States, Europe and
0035-9203/$ — see front matter © 2008 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.trstmh.2008.01.020
Strongyloides hyperinfection syndrome
Figure 1
315
Clinical syndromes of Strongyloides stercoralis infection.
Asia. Due to its low incidence in industrialized countries, misdiagnoses and medical errors may occur (Boulware et al., 2007). Strongyloidiasis associated with persistent and unexplained diarrhoea has also been described in international travellers (Nuesch et al., 2005). Strongyloides stercoralis infection encompasses five clinical syndromes: i) acute infection with Loeffler’s syndrome; ii) chronic intestinal infection; iii) asymptomatic autoinfection; iv) symptomatic autoinfection; and v) hyperinfection syndrome (HS) with dissemination (DS) (Figure 1). In HS and DS, eosinophilia is often absent (Genta, 1989). Presentation and outcome of infection are determined by interaction between the host and parasite. Disruption in Th2 cell-mediated, humoral or mucosal immunity may trigger parasite transformation from rhabditiform larvae into filariform larvae, followed by replication and migration from the small intestine to the pulmonary or gastrointestinal tracts (HS), or to other organs (DS) (Concha et al., 2005). The mortality of HS is 15%, increasing to 87% when there is dissemination (Vadlamudi et al., 2006). This article highlights recent progress in the recognition of populations at high risk for HS and the implications for diagnosis and treatment. It also emphasizes gaps in our knowledge that merit attention in the clinical setting.
Risk factors for acquiring Strongyloides stercoralis infection The largest risk factor for acquiring S. stercoralis infection is visiting an endemic area. Here, bathing in rivers and consuming non-potable water are associated with strongyloidiasis (P < 0.05) (Herrera et al., 2006). Other risk factors are employment in agriculture and gardening as
well as visiting contaminated beaches (Terashima, personal communication). All clinicians likely to see patients with strongyloidiasis should be familiar with the risk factors, clinical features and diagnostic approaches so that early treatment can be initiated.
High-risk populations for developing hyperinfection syndrome Many physicians recognize the most common presentation of HS, which is seen after the initiation of immunosuppressive therapy (e.g. pulses of corticosteroids or anti-TNF␣ therapy, etc), in HTLV-1 carriers (Verdonck et al., 2007), alcoholics (Oude Lashof et al., 2007) and diabetics, in patients with hypochlorhydria, hematologic malignancies (especially lymphoma) (Genta et al., 1989), in kidney transplant recipients, in patients with impaired gut motility, tuberculosis or protein-caloric malnutrition secondary to chronic Strongyloides diarrhoea (Terashima, personal communication). These patients develop systemic illness and larvae of S. stercoralis are found in the stools and/or sputum. The link between corticosteroid therapy and strongyloidiasis has been reported widely and has recently been reviewed by Fardet et al. (2006). Corticosteroid use is the most frequent risk factor for development of HS in developed countries. While corticosteroid therapy is associated with a two- to three-fold increase in the risk of being infected by S. stercoralis (Davidson et al., 1984; Nucci et al., 1995), in patients with asymptomatic latent S. stercoralis infection, immunosuppression induced by corticosteroids can trigger severe forms of the disease (Siddiqui and Berk, 2001). Corticosteroids reduce the levels of
316 circulating eosinophils by inhibiting their proliferation and increasing apoptosis (Corrigan, 1999). Furthermore, corticosteroids can induce cell death in immature lymphocytes. Loss of the jejunal mast cell response to Strongyloides antigenic stimulation following steroid treatment has been seen in nonhuman primates with subsequently fatal strongyloidiasis (Barrett et al., 1988). Corticosteroids may also directly affect the female worms, increasing the output of infective larvae, thus increasing the risk of developing HS (Neva, 1986). An association between strongyloidiasis and organ transplantation has been reported. The most frequent association has been with renal transplantation. In 1986, Morgan et al. (1986) showed that HS developed in 0.7% of 1068 renal transplant patients. No cases have been published of Strongyloides hyperinfection complicating heart, liver, lung or pancreas transplantation (Palau and Pankey, 1997). Cadaveric transplants may be the source of infection; in Kuwait, HS occurred so frequently in cadaveric transplantation that routine screening for strongyloidiasis is now performed for all donors (Said et al., 2007). Lymphoma is the most common malignancy associated with the occurrence of strongyloidiasis (Genta et al., 1989). In a retrospective study including 253 patients with haematological malignancies (73 Hodgkin’s lymphoma, 97 non-Hodgkin’s lymphoma and 83 acute leukaemia), 21% had strongyloidiasis and only one fatal disseminated strongyloidiasis (1.9%) (Nucci et al., 1995). In a review of 16 cases of disseminated strongyloidiasis associated with lymphoma, 11 had dissemination following chemotherapy, nine of which patients’ therapy included corticosteroids (Genta et al., 1989). In these patients the immunosuppressive therapy played a major role in the development of HS. In HIV infection the immune reconstitution syndrome seen after starting highly active antiretroviral therapy may trigger the development of HS (Brown et al., 2006), although HS is seen more frequently in HTLV-1 infection. Only 14 cases of systemic strongyloidiasis had been reported in HIV patients by 1994 (Celedon et al., 1994). The few reported cases of S. stercoralis hyperinfection seemed to have been incidental rather than to have represented HIV-associated opportunistic infections. In Brazil, the prevalence of strongyloidiasis in HIV patients was found to be 4.5% compared with a rate of 1.4% for the general population (Cimerman et al., 1999). Because of the low number of cases of Strongyloides HS in AIDS patients, the U.S. Centers for Disease Control and Prevention in 1987 excluded HS as a criterion of AIDS [Centers for Disease Control (CDC), 1987]. AIDS is characterized by a variety of disturbances in the regulation of cytokine expression, including a possible increase in Th2 cytokines and a decrease in the expression of Th1 cytokines (Tanaka et al., 1999). This Th2 response can predispose to accelerated replication of HIV-1 (Barker et al., 1995; Valdez and Lederman, 1997). The dominant Th2 cytokine pattern present in HIV infection is associated with cryptosporidiosis, because a Th1 response may be required for elimination of cryptosporidial infection (Culshaw et al., 1997) but is not associated with Strongyloides hyperinfection. Therefore, in AIDS patients, the dominant Th2 pattern seems to favour coccidian rather than helminthic infestation (Petithory and Derouin, 1987).
L.A. Marcos et al. By contrast with patients infected with S. stercoralis alone, those with HTLV-1 and strongyloidiasis have a stronger Th1 response (high levels of IFN-␥) and a weaker Th2 response (low levels of IL-4, IL-5, IL-13, IgE, and eosinophilia). The decreases in IL-4 and IgE reduce mast cell degranulation and the low level of IL-5 impairs eosinophil recruitment and parasite killing activity (Satoh et al., 2002). There is now epidemiological evidence that HTLV-1 is not only associated with S. stercoralis hyperinfection but also with strongyloidiasis in general and with relapse after treatment with ivermectin, thiabendazole and albendazole (Carvalho and Da Fonseca, 2004; Hirata et al., 2006; Terashima et al., 2002). On the basis of a Japanese cohort, it is estimated that the risk of developing strongyloidiasis is twice as high among HTLV-1infected people as among healthy controls (Hirata et al., 2006).
Screening in high-risk populations and diagnosis It is recommended that before using high doses of corticosteroids for asthma or systemic illness (e.g. systemic lupus erythematosus, vasculitis or pemphigus), Strongyloides infection should be ruled out through examination for specific serum antibodies or by searching for the organism in stool samples. ELISAs for the detection of anti-Strongyloides stercoralis antibodies in serum showed sensitivities of 83—93% and specificities of 95—97.7% for diagnosing strongyloidiasis (Van Doorn et al., 2007). There is a significant association between positive serostatus measured by ELISA and the presence of active strongyloidiasis (Page et al., 2006). The study highlighted the value of serologic follow up for strongyloidiasis in treated persons, indicating that reversion to negative serostatus after ivermectin therapy is common and occurs at higher rates than seen following albendazole therapy. Another ELISA method using the S. ratti antigen allowed the detection of specific IgE, IgG1 and IgG4 antibody subclasses rather than total IgG antibodies to Strongyloides, which may improve the serodiagnosis of human strongyloidiasis (Rodrigues et al., 2007). A serologic test may be positive because of a resolved or unresolved previous Strongyloides infection. Thus, examination of faecal samples should follow a positive serologic test. A modified Baermann’s technique is the preferred test for detection of Strongyloides larvae in stools and sputum, and for follow up after treatment (Marcos et al., 2005). In developing countries, a modified Baermann’s technique developed by Dr Hugo Lumbreras in 1963 in Peru is currently applied routinely for diagnosis because of high sensitivity and low cost (Herrera et al., 2006; Marcos et al., 2005; Terashima et al., 2002).
Clinical management Limited guidelines exist for the prevention and management of S. stercoralis infection in immunocompromised patients. Ivermectin is considered the drug of choice for most patients with strongyloidiasis, with thiabendazole and albendazole being alternatives. Thiabendazole is an option in endemic
Strongyloides hyperinfection syndrome rural areas, where an efficacy of 90% has been reported (Marcos et al., 2005). In HS, rapid initiation of therapy with broad-spectrum antibiotics and anthelminthic drugs is the first step in management. The bacteria most commonly cultured from blood and/or spinal fluid of patients with HS are: Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Bacteroides fragilis, Pseudomonas aeruginosa and Alcaligenes faecalis (DeVault et al., 1990; Link and Orenstein, 1999). In a review of 38 cases of serious bacterial infections associated with strongyloidiasis, 55% had meningitis and 73% had bacteraemia, of which 8% were polymicrobial (Link and Orenstein, 1999). The antibiotics employed in complicated HS should be targeted against these organisms. A recent clinical trial in Peru demonstrated that ivermectin 200 g/kg for two days, every two weeks, repeated three times, with a follow up at day 15 and 30 produced a cure rate of >90% in patients with HS co-infected with HTLV-1 (Terashima et al., unpublished data). In DS, the most serious form of the Strongyloides infection, oral anthelminthic drugs are of doubtful value since coexistent intestinal paralytic ileus may reduce the bioavailability and efficacy of the drugs. While parenteral ivermectin appears to be useful in these cases (Marty et al., 2005; Pacanowski et al., 2005), limited trials have been carried out in DS.
Hyperinfection syndrome in developed countries Recent epidemiological studies have identified endemic rates of Strongyloides infection in developed countries, including the United States. Delays in making a diagnosis, errors in empiric treatment and facilitating the development of HS by initiating steroids for asthma occur all too frequently where healthcare providers are not familiar with immigrant/travel medicine (Boulware et al., 2007).
Conclusions The following conclusions summarize the current situation with Strongyloides infection: 1. Strongyloides stercoralis infection is underestimated in many areas of the developing world. 2. Clinicians likely to see these patients need to appreciate the risk factors for this parasitic infection and to have an index of suspicion for the disease. 3. Strongyloidiasis is an emerging global infection that has migrated from developing regions to industrialized areas, with immigrants being at particular risk for developing Strongyloides HS. Funding: None. Conflicts of interest: None declared. Ethical approval: Not required.
317
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318 Link, K., Orenstein, R., 1999. Bacterial complications of strongyloidiasis: Streptococcus bovis meningitis. South. Med. J. 92, 728—731. Marcos, L.A., Terashima, A., Samalvides, F., Alvarez, H., Lindo, F., Tello, R., Canales, M., Demarini, J., Gotuzzo, E., 2005. Thiabendazole for the control of Strongyloides stercoralis infection in a hyperendemic area in Peru. Rev. Gastroenterol. Peru 25, 341—348. Marty, F.M., Lowry, C.M., Rodriguez, M., Milner, D.A., Pieciak, W.S., Sinha, A., Fleckenstein, L., Baden, L.R., 2005. Treatment of human disseminated strongyloidiasis with a parenteral veterinary formulation of ivermectin. Clin. Infect. Dis. 41, 5—8. Morgan, J.S., Schaffner, W., Stone, W.J., 1986. Opportunistic strongyloidiasis in renal transplant recipients. Transplantation 42, 518—524. Neva, F.A., 1986. Biology and immunology of human strongyloidiasis. J. Infect. Dis. 153, 397—406. Nuesch, R., Zimmerli, L., Stockli, R., Gyr, N., Christoph, F.R., 2005. Imported strongyloidosis: a longitudinal analysis of 31 cases. J. Travel Med. 12, 80—84. Nucci, M., Portugal, R., Pulcheri, W., Spector, N., Ferreira, S.B., De Castro, M.B., Noe, R., De Oliveira, H.P., 1995. Strongyloidiasis in patients with hematologic malignancies. Clin. Infect. Dis. 21, 675—677. Oude Lashof, A., Lesterhuis, W.J., Wanten, G., Beckers, P., Keuter, M., 2007. Colitis in an alcohol-dependent woman. Lancet 369, 2050. Pacanowski, J., Santos, M.D., Roux, A., Maignan, C., Guillot, J., Lavarde, V., Cornet, M., 2005. Subcutaneous ivermectin as a safe salvage therapy in Strongyloides stercoralis hyperinfection syndrome: a case report. Am. J. Trop. Med. Hyg. 73, 122—124. Page, W.A., Dempsey, K., McCarthy, J.S., 2006. Utility of serological follow-up of chronic strongyloidiasis after anthelminthic chemotherapy. Trans. R. Soc. Trop. Med. Hyg. 100, 1056—1062. Palau, L.A., Pankey, G.A., 1997. Strongyloides hyperinfection in a renal transplant recipient receiving cyclosporine: possible Strongyloides stercoralis transmission by kidney transplant. Am. J. Trop. Med. Hyg. 57, 413—415. Petithory, J.C., Derouin, F., 1987. AIDS and strongyloidiasis in Africa. Lancet 1, 921.
L.A. Marcos et al. Rodrigues, R.M., De Oliveira, M.C., Sopelete, M.C., Silva, D.A., Campos, D.M., Taketomi, E.A., Costa-Cruz, J.M., 2007. IgG1, IgG4, and IgE antibody responses in human strongyloidiasis by ELISA using Strongyloides ratti saline extract as heterologous antigen. Parasitol. Res. 101, 1209—1214. Said, T., Nampoory, M.R., Nair, M.P., Halim, M.A., Shetty, S.A., Kumar, A.V., Mokadas, E., Elsayed, A., Johny, K.V., Samhan, M., Al-Mousawi, M., 2007. Hyperinfection strongyloidiasis: an anticipated outbreak in kidney transplant recipients in Kuwait. Transplant. Proc. 39, 1014—1015. Satoh, M., Toma, H., Sato, Y., Takara, M., Shiroma, Y., Kiyuna, S., Hirayama, K., 2002. Reduced efficacy of treatment of strongyloidiasis in HTLV-I carriers related to enhanced expression of IFN-gamma and TGF-beta1. Clin. Exp. Immunol. 127, 354—359. Siddiqui, A.A., Berk, S.L., 2001. Diagnosis of Strongyloides stercoralis infection. Clin. Infect. Dis. 33, 1040—1047. Tanaka, M., Hirabayashi, Y., Gatanaga, H., Aizawa, S., Hachiya, A., Takahashi, Y., Tashiro, E., Kohsaka, T., Oyamada, M., Ida, S., Oka, S., 1999. Reduction in interleukin-2-producing cells but not Th1 to Th2 shift in moderate and advanced stages of human immunodeficiency virus type-1-infection: direct analysis of intracellular cytokine concentrations in CD4+ CD8- T cells. Scand. J. Immunol. 50, 550—554. Terashima, A., Alvarez, H., Tello, R., Infante, R., Freedman, D.O., Gotuzzo, E., 2002. Treatment failure in intestinal strongyloidiasis: an indicator of HTLV-I infection. Int. J. Infect. Dis. 6, 28—30. Vadlamudi, R.S., Chi, D.S., Krishnaswamy, G., 2006. Intestinal strongyloidiasis and hyperinfection syndrome. Clin. Mol. Allergy 30, 4—8. Valdez, H., Lederman, M.M., 1997. Cytokines and cytokine therapies in HIV infection. AIDS Clin. Rev. 98, 187—228. Van Doorn, H.R., Koelewijn, R., Hofwegen, H., Gilis, H., Wetsteyn, J.C., Wismans, P.J., Sarfati, C., Vervoort, T., Van Gool, T., 2007. Use of enzyme-linked immunosorbent assay and dipstick assay for detection of Strongyloides stercoralis infection in humans. J. Clin. Microbiol. 45, 438—442. Verdonck, K., Gonz´ alez, E., Van Dooren, S., Vandamme, A.M., Vanham, G., Gotuzzo, E., 2007. Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect. Dis. 7, 266—281.
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/trst
REVIEW
Strongyloides hyperinfection syndrome: an emerging global infectious disease Luis A. Marcos a,b,∗, Angelica Terashima b, Herbert L. DuPont a,c,d,e, Eduardo Gotuzzo b a
Internal Medicine Department, University of Texas Health Science, 6431 Fannin Street, Suite 1.150, Houston, TX 77030, USA Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru c University of Texas, School of Public Health, Houston, TX, USA d St. Luke’s Episcopal Hospital, Houson, TX, USA e Baylor College of Medicine, Houston, TX, USA b
Received 13 August 2007; received in revised form 24 January 2008; accepted 25 January 2008
KEYWORDS Strongyloidiasis; Strongyloides stercoralis; Hyperinfection; Emerging diseases; Review
Summary The hyperinfection syndrome (HS) caused by Strongyloides stercoralis has a high mortality rate (15% to 87%). A variety of risk factors and predisposing conditions have been described, including new immunosuppressive therapies; HTLV-1 infection; cadaveric transplantation; immune reconstitution syndrome; haematological malignancies (especially lymphoma); tuberculosis; malnutrition secondary to chronic Strongyloides diarrhoea; international travel and immigration. Inhibition of Th2 cell-mediated, humoral or mucosal immunity is associated with HS. HS is more frequently seen in HTLV-1 than HIV patients. In AIDS, there is an increase in Th2 cytokines, while in HTLV-1 infection there is a decrease in the Th2 response, leading to an increased risk of autoinfection. Corticosteroid use remains the most frequent risk factor for HS. A number of ELISAs are useful for diagnosis and post-treatment evaluation. Once diagnosed, the disease may be managed effectively with anthelminthic drugs, including ivermectin. HS causes diverse symptoms and signs, with unusual manifestations leading to misdiagnosis and medical errors related to healthcare providers’ lack of familiarity with the condition. HS is an example of an emerging tropical infection migrating to developed countries and requiring greater clinician awareness. © 2008 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.
Introduction
∗
Corresponding author. Tel.: +1 713 500 6500; fax: +1 713 500 6497. E-mail address: [email protected] (L.A. Marcos)
The soil-transmitted helminth, Strongyloides stercoralis, causes strongyloidiasis affecting an estimated of 3—100 million people in the world, mostly in tropical and subtropical countries but also in the United States, Europe and
0035-9203/$ — see front matter © 2008 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.trstmh.2008.01.020
Strongyloides hyperinfection syndrome
Figure 1
315
Clinical syndromes of Strongyloides stercoralis infection.
Asia. Due to its low incidence in industrialized countries, misdiagnoses and medical errors may occur (Boulware et al., 2007). Strongyloidiasis associated with persistent and unexplained diarrhoea has also been described in international travellers (Nuesch et al., 2005). Strongyloides stercoralis infection encompasses five clinical syndromes: i) acute infection with Loeffler’s syndrome; ii) chronic intestinal infection; iii) asymptomatic autoinfection; iv) symptomatic autoinfection; and v) hyperinfection syndrome (HS) with dissemination (DS) (Figure 1). In HS and DS, eosinophilia is often absent (Genta, 1989). Presentation and outcome of infection are determined by interaction between the host and parasite. Disruption in Th2 cell-mediated, humoral or mucosal immunity may trigger parasite transformation from rhabditiform larvae into filariform larvae, followed by replication and migration from the small intestine to the pulmonary or gastrointestinal tracts (HS), or to other organs (DS) (Concha et al., 2005). The mortality of HS is 15%, increasing to 87% when there is dissemination (Vadlamudi et al., 2006). This article highlights recent progress in the recognition of populations at high risk for HS and the implications for diagnosis and treatment. It also emphasizes gaps in our knowledge that merit attention in the clinical setting.
Risk factors for acquiring Strongyloides stercoralis infection The largest risk factor for acquiring S. stercoralis infection is visiting an endemic area. Here, bathing in rivers and consuming non-potable water are associated with strongyloidiasis (P < 0.05) (Herrera et al., 2006). Other risk factors are employment in agriculture and gardening as
well as visiting contaminated beaches (Terashima, personal communication). All clinicians likely to see patients with strongyloidiasis should be familiar with the risk factors, clinical features and diagnostic approaches so that early treatment can be initiated.
High-risk populations for developing hyperinfection syndrome Many physicians recognize the most common presentation of HS, which is seen after the initiation of immunosuppressive therapy (e.g. pulses of corticosteroids or anti-TNF␣ therapy, etc), in HTLV-1 carriers (Verdonck et al., 2007), alcoholics (Oude Lashof et al., 2007) and diabetics, in patients with hypochlorhydria, hematologic malignancies (especially lymphoma) (Genta et al., 1989), in kidney transplant recipients, in patients with impaired gut motility, tuberculosis or protein-caloric malnutrition secondary to chronic Strongyloides diarrhoea (Terashima, personal communication). These patients develop systemic illness and larvae of S. stercoralis are found in the stools and/or sputum. The link between corticosteroid therapy and strongyloidiasis has been reported widely and has recently been reviewed by Fardet et al. (2006). Corticosteroid use is the most frequent risk factor for development of HS in developed countries. While corticosteroid therapy is associated with a two- to three-fold increase in the risk of being infected by S. stercoralis (Davidson et al., 1984; Nucci et al., 1995), in patients with asymptomatic latent S. stercoralis infection, immunosuppression induced by corticosteroids can trigger severe forms of the disease (Siddiqui and Berk, 2001). Corticosteroids reduce the levels of
316 circulating eosinophils by inhibiting their proliferation and increasing apoptosis (Corrigan, 1999). Furthermore, corticosteroids can induce cell death in immature lymphocytes. Loss of the jejunal mast cell response to Strongyloides antigenic stimulation following steroid treatment has been seen in nonhuman primates with subsequently fatal strongyloidiasis (Barrett et al., 1988). Corticosteroids may also directly affect the female worms, increasing the output of infective larvae, thus increasing the risk of developing HS (Neva, 1986). An association between strongyloidiasis and organ transplantation has been reported. The most frequent association has been with renal transplantation. In 1986, Morgan et al. (1986) showed that HS developed in 0.7% of 1068 renal transplant patients. No cases have been published of Strongyloides hyperinfection complicating heart, liver, lung or pancreas transplantation (Palau and Pankey, 1997). Cadaveric transplants may be the source of infection; in Kuwait, HS occurred so frequently in cadaveric transplantation that routine screening for strongyloidiasis is now performed for all donors (Said et al., 2007). Lymphoma is the most common malignancy associated with the occurrence of strongyloidiasis (Genta et al., 1989). In a retrospective study including 253 patients with haematological malignancies (73 Hodgkin’s lymphoma, 97 non-Hodgkin’s lymphoma and 83 acute leukaemia), 21% had strongyloidiasis and only one fatal disseminated strongyloidiasis (1.9%) (Nucci et al., 1995). In a review of 16 cases of disseminated strongyloidiasis associated with lymphoma, 11 had dissemination following chemotherapy, nine of which patients’ therapy included corticosteroids (Genta et al., 1989). In these patients the immunosuppressive therapy played a major role in the development of HS. In HIV infection the immune reconstitution syndrome seen after starting highly active antiretroviral therapy may trigger the development of HS (Brown et al., 2006), although HS is seen more frequently in HTLV-1 infection. Only 14 cases of systemic strongyloidiasis had been reported in HIV patients by 1994 (Celedon et al., 1994). The few reported cases of S. stercoralis hyperinfection seemed to have been incidental rather than to have represented HIV-associated opportunistic infections. In Brazil, the prevalence of strongyloidiasis in HIV patients was found to be 4.5% compared with a rate of 1.4% for the general population (Cimerman et al., 1999). Because of the low number of cases of Strongyloides HS in AIDS patients, the U.S. Centers for Disease Control and Prevention in 1987 excluded HS as a criterion of AIDS [Centers for Disease Control (CDC), 1987]. AIDS is characterized by a variety of disturbances in the regulation of cytokine expression, including a possible increase in Th2 cytokines and a decrease in the expression of Th1 cytokines (Tanaka et al., 1999). This Th2 response can predispose to accelerated replication of HIV-1 (Barker et al., 1995; Valdez and Lederman, 1997). The dominant Th2 cytokine pattern present in HIV infection is associated with cryptosporidiosis, because a Th1 response may be required for elimination of cryptosporidial infection (Culshaw et al., 1997) but is not associated with Strongyloides hyperinfection. Therefore, in AIDS patients, the dominant Th2 pattern seems to favour coccidian rather than helminthic infestation (Petithory and Derouin, 1987).
L.A. Marcos et al. By contrast with patients infected with S. stercoralis alone, those with HTLV-1 and strongyloidiasis have a stronger Th1 response (high levels of IFN-␥) and a weaker Th2 response (low levels of IL-4, IL-5, IL-13, IgE, and eosinophilia). The decreases in IL-4 and IgE reduce mast cell degranulation and the low level of IL-5 impairs eosinophil recruitment and parasite killing activity (Satoh et al., 2002). There is now epidemiological evidence that HTLV-1 is not only associated with S. stercoralis hyperinfection but also with strongyloidiasis in general and with relapse after treatment with ivermectin, thiabendazole and albendazole (Carvalho and Da Fonseca, 2004; Hirata et al., 2006; Terashima et al., 2002). On the basis of a Japanese cohort, it is estimated that the risk of developing strongyloidiasis is twice as high among HTLV-1infected people as among healthy controls (Hirata et al., 2006).
Screening in high-risk populations and diagnosis It is recommended that before using high doses of corticosteroids for asthma or systemic illness (e.g. systemic lupus erythematosus, vasculitis or pemphigus), Strongyloides infection should be ruled out through examination for specific serum antibodies or by searching for the organism in stool samples. ELISAs for the detection of anti-Strongyloides stercoralis antibodies in serum showed sensitivities of 83—93% and specificities of 95—97.7% for diagnosing strongyloidiasis (Van Doorn et al., 2007). There is a significant association between positive serostatus measured by ELISA and the presence of active strongyloidiasis (Page et al., 2006). The study highlighted the value of serologic follow up for strongyloidiasis in treated persons, indicating that reversion to negative serostatus after ivermectin therapy is common and occurs at higher rates than seen following albendazole therapy. Another ELISA method using the S. ratti antigen allowed the detection of specific IgE, IgG1 and IgG4 antibody subclasses rather than total IgG antibodies to Strongyloides, which may improve the serodiagnosis of human strongyloidiasis (Rodrigues et al., 2007). A serologic test may be positive because of a resolved or unresolved previous Strongyloides infection. Thus, examination of faecal samples should follow a positive serologic test. A modified Baermann’s technique is the preferred test for detection of Strongyloides larvae in stools and sputum, and for follow up after treatment (Marcos et al., 2005). In developing countries, a modified Baermann’s technique developed by Dr Hugo Lumbreras in 1963 in Peru is currently applied routinely for diagnosis because of high sensitivity and low cost (Herrera et al., 2006; Marcos et al., 2005; Terashima et al., 2002).
Clinical management Limited guidelines exist for the prevention and management of S. stercoralis infection in immunocompromised patients. Ivermectin is considered the drug of choice for most patients with strongyloidiasis, with thiabendazole and albendazole being alternatives. Thiabendazole is an option in endemic
Strongyloides hyperinfection syndrome rural areas, where an efficacy of 90% has been reported (Marcos et al., 2005). In HS, rapid initiation of therapy with broad-spectrum antibiotics and anthelminthic drugs is the first step in management. The bacteria most commonly cultured from blood and/or spinal fluid of patients with HS are: Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Bacteroides fragilis, Pseudomonas aeruginosa and Alcaligenes faecalis (DeVault et al., 1990; Link and Orenstein, 1999). In a review of 38 cases of serious bacterial infections associated with strongyloidiasis, 55% had meningitis and 73% had bacteraemia, of which 8% were polymicrobial (Link and Orenstein, 1999). The antibiotics employed in complicated HS should be targeted against these organisms. A recent clinical trial in Peru demonstrated that ivermectin 200 g/kg for two days, every two weeks, repeated three times, with a follow up at day 15 and 30 produced a cure rate of >90% in patients with HS co-infected with HTLV-1 (Terashima et al., unpublished data). In DS, the most serious form of the Strongyloides infection, oral anthelminthic drugs are of doubtful value since coexistent intestinal paralytic ileus may reduce the bioavailability and efficacy of the drugs. While parenteral ivermectin appears to be useful in these cases (Marty et al., 2005; Pacanowski et al., 2005), limited trials have been carried out in DS.
Hyperinfection syndrome in developed countries Recent epidemiological studies have identified endemic rates of Strongyloides infection in developed countries, including the United States. Delays in making a diagnosis, errors in empiric treatment and facilitating the development of HS by initiating steroids for asthma occur all too frequently where healthcare providers are not familiar with immigrant/travel medicine (Boulware et al., 2007).
Conclusions The following conclusions summarize the current situation with Strongyloides infection: 1. Strongyloides stercoralis infection is underestimated in many areas of the developing world. 2. Clinicians likely to see these patients need to appreciate the risk factors for this parasitic infection and to have an index of suspicion for the disease. 3. Strongyloidiasis is an emerging global infection that has migrated from developing regions to industrialized areas, with immigrants being at particular risk for developing Strongyloides HS. Funding: None. Conflicts of interest: None declared. Ethical approval: Not required.
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