Strongyloides stercoralis is a human intestinal parasitic nematode which is transmitted through the soil and causes strongyloidiasis. This disease affects an estimated 3-100 million people in the world, mostly in the tropical and subtropical countries, and at a lower prevalence, the Appalachian region of southern United States, Europe and  Japan.[1] In industrialised nations, strongyloidiasis is most commonly found among international travellers, immigrants, and refugees from endemic areas. Strongyloides stercoralis (S.stercoralis) is among the few helminths that has the unique ability to multiply both outside the body, sexually, and within the human intestine (autoinfective cycle) asexually; thus the infection can propagate itself indefinitely. Patients may present with infection decades after

the original exposure. Symptomatic infections in World War II veterans have been described more than 50 years after the subjects had been released from prisoner-of-war (POW) camps in Southeast Asia.[2]

The risk factors for infection are low socio-economic status, alcoholism, male gender and contact with contaminated soil. In recent times, the incidence of strongyloidiasis has increased dramatically, mainly in patients of altered immune status, accompanied by malnutrition, malignancies and transplant recipients. The most common risk factors for these complications are immunosuppression caused by corticosteroids and infection with human T lymphotropic virus type 1 (HTLV 1). In immunosuppressed patients, a hyperinfection syndrome or disseminated disease may occur. The greatest single risk factor for acquiring S. stercoralis infection is visiting an endemic area. In these areas bathing in rivers and consuming non-potable water are associated with strongyloidiasis.[3]

Clinical significance of Strongyloides stercoralis in our environment

S.stercoralis is the most common human parasitic nematode. The majority of patients (over 50%) with strongyloidiasis have asymptomatic infection or mild disease unless the worm burden is high and/or long-term damage from chronic infection has led to pathological changes sufficient to cause illness. Acute infection may cause local inflammation at the area of larval penetration (larva currens) and may cause respiratory symptoms as the worm

travels through the lungs. In chronic infection the worm maintains a low level of reproduction. When autoinfection occurs, a high number of infecting larvae can gain access to the bloodstream by penetrating the colonic mucosa leading to a severe hyperinfection syndrome (HS) and the development of disseminated strongyloidiasis (DS). Several studies have shown that the dormant or carrier state of Strongyloides may persist for a very long time without the onset of clinical disease.[4]

The development of clinical manifestations, in many cases, is attributed to a decline in host resistance. 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. 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 (hyperinfection), or to the other organs (dissemination).[5] HS and DS are alarming clinical situations. The term hyperinfection describes the syndrome of accelerated autoinfection, which is a quantitative distinction and not clearly defined. The diagnosis implies the presence of systemic manifestations attributable to increased larval migration, including an exacerbation of gastrointestinal and pulmonary symptoms. Dissemination of larvae to organs not normally participating in the pulmonary autoinfective cycle is an additional outcome of hyperinfection.[4] However these two forms are clinically difficult to distinguish. The majority of cases of S.stercoralis hyperinfection are associated with long-term corticosteroid therapy and with predisposing immunosuppressive conditions, such as hematological malignancies, HTLV 1 infection, and organ transplantation. Chronic malnutrition, diabetes mellitus, chronic obstructive pulmonary disease (COPD), alcoholism, and chronic renal failure are also recognised predisposing conditions.[6] Clinically, the hyperinfection syndrome is characterised by enteritis, pneumonitis (often hemorrhagic), gram-negative bacteremia (meningitis or peritonitis), and hemorrhagic purpura of the anterior abdominal wall. Eosinophilia is often absent, and stool examination results are almost always positive. The hyperinfection syndrome caused by Strongyloides stercoralis as a high mortality rate (15% to 87%).

Diseases associated with stronglyoidiasis

(i)    Strongyloides stercoralis colitis is a severe, but easily curable form of strongyloidiasis that carries a high mortality   rate if untreated. The misdiagnosis and resultant mortality rates can be quite high. A low index of suspicion and morphologic resemblance to ulcerative colitis can possibly be the main sources of diagnostic error. Features of Strongyloides colitis that contrast with those of ulcerative colitis include (1) skip pattern of the inflammation, (2) distal attenuation of the disease, (3) eosinophil-rich infiltrates, (4) relatively intact crypt architecture, and (5) frequent involvement of the submucosa. It has been noted that a history of steroid therapy, chronic colitis refractory to conventional immune-modifying management, and endoscopic finding of distal attenuation of the colitis are helpful clues.[7]

(ii)  Association with gastrointestinal (GI) cancers: The frequency of positive S.stercoralis diagnosed by parasitological and/or serological methods in gastrointestinal cancer was 24.2% (8/33) compared to 4.5% (2/44) of non-gastrointestinal cancer in a recent study carried out in Brazil.[8] The odd ratio for gastrointestinal cancer was 6.7 (CI 1.32-34.20, p<0.05), meaning thereby that patients with gastrointestinal cancer had a 6-7 fold greater chance of testing positive for Strongyloides infection. The findings observed in this small number of patients analysed, highlight the importance of diagnosing S. stercoralis in patients with gastrointestinal cancer living in endemic areas as they have a higher risk of becoming infected with S. stercoralis than patients with other types of cancer. Similarly, 52% patients with cancer, who had strongyloidiasis, were diagnosed with an underlying malignancy in the United States of America.[9] It is possible that the habitat of this nematode in the intestinal mucosa and the substances secreted and excreted by this parasite at the infection site can lead to an augmented predisposition to developing gastrointestinal neoplasia. This hypothesis is based on in vitro study, which showed that substances secreted and excreted by different nematode species are able to induce the proliferation of tumour cell lines.[10]

(iii)  Corticosteroid therapy and strongyloidiasis: The link between corticosteroid therapy and strongyloidiasis has been reported widely. Corticosteroid therapy is associated with a two to three fold increase in the risk of being infected by S.stercoralis.[11] In patients with asymptomatic latent S.stercoralis infection, immunosuppression induced by corticosteroids can trigger severe forms of the disease. Corticosteroids reduce the levels of circulating eosinophils by inhibiting their proliferation as well as by increasing apoptosis. Corticosteroids can also induce cell death in immature lymphocytes and cause loss of the jejunal mast cell response to Strongyloides antigenic stimulation following steroid treatment. This has been seen in nonhuman primates with subsequent fatal strongyloidiasis.[12]

(iv) Strongyloidiasis and organ transplantation: An association between strongyloidiasis and organ transplantation has been reported. The most frequent association has been with renal transplantation. Strongyloidiasis has also been reported in patients with bone marrow, heart and liver transplantation.[13]

(v)   Association with viral agents: The human T cell lymphotropic virus type 1 (HTLV-1) predominantly infects T cells and induces spontaneous lymphocyte proliferation and secretion of high levels of type 1 cytokines. Strongyloides stercoralis patients with HTLV-1 coinfection have a modified immunological response against parasite antigens. Patients with HTLV-1 have a stronger Th1 response (high levels of IFN-gamma) and a weaker Th2 response (low levels of IL-4, IL-5, IL-13, IgE, and eosinophilia). The decrease in IL-4 and IgE reduce mast cell degranulation and the low level of IL-5 impairs eosinophil recruitment and parasite killing activity.[14] On the basis of a Japanese cohort, it is estimated that the risk of developing strongyloidiasis is twice as high among HTLV-  1 infected people as among healthy controls.[15] Moreover, there is a decline in the efficacy of treatment of S.stercoralis in patients coinfected with HTLV-1. Alterations in the immune response against helminths and a decrease in the efficacy of anti-parasitic drugs are responsible for the increased prevalence of Strongyloides stercoralis in HTLV- 1 infected subjects. This makes HTLV-1 infection the most important risk factor for disseminated strongyloidiasis. Both S.stercoralis and HTLV-1 are endemic to Central Australia.[16]

Although it may seem counterintuitive, it is unclear whether the association of severe strongyloidiasis in Acquired Immunodeficiency Syndrome (AIDS) is a true nonoccurrence or an under-recognised and under-reported phenomenon. Patients with AIDS rarely develop severe infection. This is probably due to the fact that in AIDS patients the dominant Th2 pattern seems to favour coccidian rather than helminthic infestation. The pathogenesis of the hyperinfection syndrome and disseminated strongyloidiasis in AIDS may be related to the following factors: (i) AIDS may have a negative effect on the immune response to strongyloidiasis, (ii) AIDS enteropathy may result in mucosal damage that could interfere with local intestinal immunity and (iii) AIDS gastropathy may lead to achlorhydria and hypochlorhydria, potentially promoting a permissive effect on parasite reproduction in the upper gastrointestinal tract.[17]

In Human Immunodeficiency Virus (HIV) infection the immune reconstitution syndrome seen after starting highly active antiretroviral therapy (HAART) may trigger the development of HS.[18] Available limited reports are considered incidental rather than truly representative of HIV-associated opportunistic infections.

(vi)  Bacterial superinfections: The bacteria most commonly cultured from blood, cerebrospinal fluid in patients with strongyloidiasis especially with HS are Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Pseudomonas aeruginosa, Alcaligenes faecalis, and Bacteroides fragilis. The postulated mechanism of sepsis in these cases is transmission of enteric bacteria through the bowel wall in association with invading filariform larvae.[19]

Screening of high-risk population and diagnosis

In patients with chronic non-disseminated infection, presence of rhabditiform larvae in stools is the rule, whereas filariform larvae are rarely seen. A single stool examination will yield positive results in only 30%-50% of cases.[12] Repeated stool examinations alone may not be worthwhile and aspiration of duodenal fluid provide [8] a greater yield of organisms. A modified Baerrman’s technique is the preferred test for detection of larvae in clinical samples.[20] Stool culture on a blood agar plate is much more sensitive and uses larvae to diagnose infection, because the tracks of larvae across a plate seeded with stool bacteria are readily detected. The sensitivity of this stool test has been estimated to be as high as 96%.[20] The blood agar plate test is a practical and highly sensitive test for stool parasites. Recently, significant association between seropositive status measured by ELISA and the presence of active  strongyloidiasis has been noted. This association also has the value of serologic follow up for strongyloidiasis in treated persons, indicating reversion to negative sero-status after therapy. ELISA for detection of anti-Strongyloides stercoralis antibodies in the serum revealed a sensitivity of 83%-93% and specificity of 95%-98% for diagnosing strongyloidiasis.[21] Specific S.stercoralis IgA and IgG antibodies in milk samples have also been detected. Thus, in endemic areas, infants may acquire antibodies to S.stercoralis from breast milk, possibly contributing to the enhancement of specific mucosal immunity against this parasite. Another ELISA method using the Strongyloides ratti antigen allowed the detection of specific IgE, IgG1 and IgG4 antibody subclasses rather than total IgG antibodies to Strongyloides, which may further improve the serodiagnosis of human strongyloidiasis.[22]
 

Treatment options

Treatment options include ivermectin, thiabendazole, and albendazole. All patients with strongyloidiasis, regardless of

whether they are asymptomatic, must be treated to prevent possible late-onset complications. For complicated infection, thiabendazole at a dose of 25 mg/kg orally twice a day for three days has been the regimen of choice. Thiabendazole is  an option in endemic areas where an efficacy of 90% hasbeen reported.[4] Albendazole is an alternative to thiabendazole but with lower efficacy (38%-45%). Recently, ivermectin at a dose of 200 mg/kg body weight given once or twice daily per oral has been considered the drug of choice for most patients, with thiabendazole and albendazole being alternatives. Ivermectin treats strongyloidosis by killing the worms in the intestines.[23]

Management of disseminated infection is often challenging, because patients are usually severely ill and unable to ingest oral medication. In the hyperinfection syndrome and disseminated strongyloidiasis, a prolonged course of ivermectin up to one week is recommended and the patient should be observed for two weeks thereafter. Multiple stool samples shoud be examined, as the internal cycle of parasite development takes nearly two weeks.[24]

In patients with disseminated strongyloidiasis, oral anthelminthic drugs are of doubtful value since co-existent intestinal paralytic ileus may reduce the bioavailability and efficacy of these drugs. Parenteral ivermectin therapy at a dose  of 200 mg/kg body weight given subcutaneously every 48 hours until oral therapy can be administered has been recommended. To prevent a recurrence of disseminated  infection when immunosuppression persists or in persons with HTLV-1 infection, a regimen of 2 doses (200 mg/kg body weight) of ivermectin every 2 weeks has been used to keep larvae suppressed. A recent clinical trial in Peru demonstrated that ivermectin 200 mg/kg body weight for two days, every two weeks, repeated three times, with follow up at days 15 and 30 produced a cure rate of >90% in patients with HS co-infected with HTLV-1 (Terashima et al, unpublished data). While parenteral ivermectin appears to be useful in these cases, limited trials have been carried out in DS.

Conclusion

Strongyloidiasis is a preventable life-threatening disease but due to its relatively low worldwide incidence, misdiagnoses do occur. A high index of suspicion and careful application of diagnostic methods are essential for accurate diagnosis. The varied clinical spectrum of strongyloidiasis further emphasizes the need to consider these pathogens when patients present with unexplained diarrhoeal illnesses associated with upper abdominal symptoms and eosinophilia. These findings in patients with compromised immune system or in candidates for immunosuppressive therapy should prompt a thorough investigation to rule out this parasite, since disseminated strongyloidiasis is often fatal. Current therapy with thiabendazole or ivermectin is very effective at a cure rate greater than 98%. Misdiagnosis and mortality rates of this curable, but sometimes deadly, infectious disease are alarming and warrant efforts to increase awareness.

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