INTRODUCTION
Strongyloidiasis, the disease caused by the infection with Strongyloides stercoralis, and to a lesser extent by Strongyloides fuelleborni fuelleborni and S. fuelleborni kelleyi, is a soil-transmitted helminthiasis with an estimated 30–100 million people infected worldwide (Genta, Reference Genta1989; Schar et al. Reference Schar, Trostdorf, Giardina, Khieu, Muth, Marti, Vounatsou and Odermatt2013). Although the burden of the disease has been felt to be underestimated (Viney and Lok, Reference Viney and Lok2007; Olsen et al. Reference Olsen, van Lieshout, Marti, Polderman, Polman, Steinmann, Stothard, Thybo, Verweij and Magnussen2009; Schar et al. Reference Schar, Giardina, Khieu, Muth, Vounatsou, Marti and Odermatt2015, Reference Schar, Inpankaew, Traub, Khieu, Dalsgaard, Chimnoi, Chhoun, Sok, Marti, Muth and Odermatt2014), S. stercoralis infections in humans range from asymptomatic light infections to chronic symptomatic strongyloidiasis. However, uncontrolled multiplication of the parasite (hyperinfection) and potentially life-threatening dissemination of larvae in immunocompromised patients result in mortality rates of up to 85% (Keiser and Nutman, Reference Keiser and Nutman2004; Mejia and Nutman, Reference Mejia and Nutman2012).
The parasite, occurring naturally in dogs, primates and humans, is endemic to the tropics and subtropics; foci of infection occur in temperate regions as well (Genta, Reference Genta1989; Schar et al. Reference Schar, Trostdorf, Giardina, Khieu, Muth, Marti, Vounatsou and Odermatt2013) where poor sanitation or other factors facilitate the transmission through fecal contamination. In parts of Africa and in Papua New Guinea, human infections caused by S. fuelleborni fuelleborni and S. fuelleborni kelleyi respectively have been reported (Pampiglione and Ricciardi, Reference Pampiglione and Ricciardi1971; Hira and Patel, Reference Hira and Patel1977; Vince et al. Reference Vince, Ashford, Gratten and Bana-Koiri1979; Crouch and Shield, Reference Crouch and Shield1982; Evans et al. Reference Evans, Markus, Joubert and Gunders1991; Freedman, Reference Freedman1991; Ashford et al. Reference Ashford, Barnish and Viney1992). In Africa, S. fuelleborni fuelleborni is primarily a parasite of primates, but in Papua New Guinea no animal host has been demonstrated for S. fuelleborni kelleyi (Ashford et al. Reference Ashford, Barnish and Viney1992; Viney and Lok, Reference Viney and Lok2007).
Strongyloides stercoralis is unique among nematodes infectious for humans in that larvae passing in the feces can give rise to a free-living generation of worms which, in turn, give rise to infective larvae. This so-called heterogonic development process serves as an amplification mechanism that allows for increased numbers of infective larvae in the external environment. The infective larvae are active skin penetrators; infection per os, while possible, is probably of limited importance. Because the parasitic female's eggs hatch often within the gastrointestinal tract, the potential for autoinfection exists when precociously developing larvae attain infectivity while still in the host. When the rate of autoinfection escapes control by the host, massive re-penetration and larval migration may result.
LIFE CYCLE
The S. stercoralis (and S. fuelleborni spp.) life cycle encompasses both free-living and parasitic stages. Adult female worms parasitizing the human small intestine lay eggs in the intestinal mucosa that hatch into rhabditiform larvae, which are shed in the stool. In the environment, under warm moist conditions that often characterize the tropical and subtropical endemic areas, rhabditiform larvae can either moult into infective filariform larvae or develop through succeeding rhabditiform stages into free-living adults. Sexual reproduction occurs exclusively in the free-living stage.
Humans are generally infected transcutaneously, although infection has also been experimentally induced by oral administration of water contaminated with filariform larvae (Grove, Reference Grove1996). After dermal penetration, the filariform larvae, through undefined mechanisms, migrate to the small intestine. The most clinically relevant, though perhaps not the predominant (Mansfield et al. Reference Mansfield, Niamatali, Bhopale, Volk, Smith, Lok, Genta and Schad1996), migration is the classic pulmonary route, in which organisms enter the bloodstream and are carried to the lungs, ascending the tracheobronchial tree to enter the gastrointestinal tract. Only female adults are detectable in humans and subsequent reproduction occurs asexually through parthenogenesis (Neva, Reference Neva1986).
Some rhabditiform larvae transform into invasive filariform larvae before being excreted. As such, they are capable of re-infecting the host by invading the intestinal wall or the perianal skin (Grove, Reference Grove1996). This autoinfective cycle can occur at a low level throughout infection and allows subsequent generations to persist in the host indefinitely (Neva, Reference Neva1986).
In the immunocompetent host, it is felt that cellular immune effector mechanisms and intrinsic parasite biology both serve to regulate the population density of adult worms in the intestine. With an alteration in host immune responsiveness, even one adult female can multiply rapidly by parthenogenesis, leading to accelerated autoinfection and/or dissemination.
EPIDEMIOLOGY
While endemic to the tropics and subtropics, foci of infection occur in temperate regions such as Japan, Italy, Australia and the USA (Genta, Reference Genta1989; Al-Hasan et al. Reference Al-Hasan, McCormick and Ribes2007; Schar et al. Reference Schar, Trostdorf, Giardina, Khieu, Muth, Marti, Vounatsou and Odermatt2013). Immigrants and refugees comprise a significant population at risk for strongyloidiasis in high- and middle-income countries (Posey et al. Reference Posey, Blackburn, Weinberg, Flagg, Ortega, Wilson, Secor, Sanders-Lewis, Won and Maguire2007; Schar et al. Reference Schar, Trostdorf, Giardina, Khieu, Muth, Marti, Vounatsou and Odermatt2013).
Prevalence and global distribution
There is little consensus about prevalence rates and the global distribution of human infections with S. stercoralis. There is, however, a great degree of consensus about the fact that the prevalence of strongyloidiasis has long been underestimated (Olsen et al. Reference Olsen, van Lieshout, Marti, Polderman, Polman, Steinmann, Stothard, Thybo, Verweij and Magnussen2009; Schar et al. Reference Schar, Trostdorf, Giardina, Khieu, Muth, Marti, Vounatsou and Odermatt2013; Khieu et al. Reference Khieu, Schar, Forrer, Hattendorf, Marti, Duong, Vounatsou, Muth and Odermatt2014; Toledo et al. Reference Toledo, Munoz-Antoli and Esteban2015). Although prevalence and global distribution patterns have been recently examined, aggregated detailed distribution maps and country by country data [cf. (Schar et al. Reference Schar, Trostdorf, Giardina, Khieu, Muth, Marti, Vounatsou and Odermatt2013; Toledo et al. Reference Toledo, Munoz-Antoli and Esteban2015)] are beyond the scope of this review
Transmission
While Strongyloides is most commonly acquired transcutaneously, high prevalence rates in institutionalized subjects raise speculation about alternate routes of transmission (Yoeli et al. Reference Yoeli, Most, Hammond and Scheinesson1972; Gatti et al. Reference Gatti, Lopes, Cevini, Ijaoba, Bruno, Bernuzzi, de Lio, Monco and Scaglia2000; Robson et al. Reference Robson, Welch, Beeching and Gill2009). A Japanese study found support to this claim by observing a higher prevalence of Strongyloides infection in patients with Blastocystis hominis, a protozoan acquired by the fecal oral route (Czachor and Jonas, Reference Czachor and Jonas2000). However, standard rather than strict contact precautions appear sufficient for prevention of nosocomial transmission based on case reports of patients with disseminated disease (Sugiyama et al. Reference Sugiyama, Hasegawa, Nagasawa and Hitomi2006). Transmission of Strongyloides infection after transplantation of kidneys, pancreatic allograft or intestines has been suggested by several reports where donors but not recipients had a history of travel to a Strongyloides endemic regions of the world (Ben-Youssef et al. Reference Ben-Youssef, Baron, Edson, Raghavan and Okechukwu2005; Said et al. Reference Said, Nampoory, Nair, Halim, Shetty, Kumar, Mokadas, Elsayed, Johny, Samhan and Al-Mousawi2007; Patel et al. Reference Patel, Arvelakis, Sauter, Gondolesi, Caplivski and Huprikar2008) (see section below).
CLINICAL MANIFESTATIONS
Acute Strongyloidiasis
The clinical manifestations of acute strongyloidiasis are associated with the path of larval migration to the small intestine. Infected individuals may experience irritation at the site of skin penetration by larvae followed occasionally by localized oedema or urticaria. Within a week following infection, a dry cough and/or tracheal irritation may occur. Gastrointestinal symptoms such as diarrhoea, constipation, abdominal pain, or anorexia can occur (Keiser and Nutman, Reference Keiser and Nutman2004) following the establishment of the infection in the small intestine.
Chronic Strongyloidiasis
Chronic infection with S. stercoralis is most often clinically asymptomatic (Grove, Reference Grove1989). Since up to 75% of persons may have peripheral eosinophilia or elevated IgE levels (Rossi et al. Reference Rossi, Takahashi, Partel, Teodoro and da Silva1993), Strongyloides should be considered in the differential diagnosis of high grade and/or persistent eosinophilia in travellers or expatriates from endemic areas (O'Connell and Nutman, Reference O'Connell and Nutman2015).
Symptomatic individuals may complain of diarrhoea, constipation, intermittent vomiting or borborygmus. Dermatologic manifestations such as recurrent urticaria can occur (Leighton and MacSween, Reference Leighton and MacSween1990) as can larva currens (pruritic linear streaks located along the lower trunk, thighs and buttocks) as a result of migrating larvae (Pelletier, Reference Pelletier1984; Pelletier and Gabre-Kidan, Reference Pelletier and Gabre-Kidan1985; Grove, Reference Grove1996). Unusual manifestations of chronic strongyloidiasis include arthritis (Richter et al. Reference Richter, Muller-Stover, Strothmeyer, Gobels, Schmitt and Haussinger2006); nephrotic syndrome (Hsieh et al. Reference Hsieh, Wen and Chen2006), chronic malabsorption (Atul et al. Reference Atul, Ajay, Ritambhara, Harsh and Ashish2005), duodenal obstruction (Harish et al. Reference Harish, Sunilkumar, Varghese and Feroze2005; Suvarna et al. Reference Suvarna, Mehta, Sadasivan, Raj and Balakrishnan2005), focal hepatic lesions (Gulbas et al. Reference Gulbas, Kebapci, Pasaoglu and Vardareli2004) and recurrent asthma (Tullis, Reference Tullis1970; Dunlap et al. Reference Dunlap, Shin, Polt and Ho1984).
Hyperinfection syndrome/disseminated infections
Hyperinfection describes the syndrome of accelerated autoinfection, generally – although not always (Husni et al. Reference Husni, Gordon, Longworth and Adal1996; Tiwari et al. Reference Tiwari, Rautaraya and Tripathy2012; Dogan et al. Reference Dogan, Gayaf, Ozsoz, Sahin, Aksel, Karasu, Aydogdu and Turgay2014) – the result of an alteration in immune status. The distinction between autoinfection and hyperinfection is quantitative and not strictly defined. Therefore, hyperinfection syndrome implies the presence of signs and symptoms attributable to increased larval migration. Development or exacerbation of gastrointestinal and pulmonary symptoms is seen, and the detection of increased numbers of larvae in stool and/or sputum is the hallmark of hyperinfection. Larvae in non-disseminated hyperinfection are increased in numbers but confined to the organs normally involved in the pulmonary autoinfective cycle (i.e. gastrointestinal tract, peritoneum and lungs), although enteric bacteria, that can be carried by the filariform larvae or gain systemic access through intestinal ulcers, may affect any organ system.
The term disseminated infection is often used to refer to migration of larvae to organs beyond the range of the pulmonary autoinfective cycle. This does not necessarily imply a greater severity of disease. Extra-pulmonary migration of larvae has been shown to occur routinely during the course of chronic S. stercoralis infections in experimental dogs (Schad et al. Reference Schad, Aikens and Smith1989) and has been reported to cause symptoms in humans without other manifestations of hyperinfection syndrome (Lai et al. Reference Lai, Hsu, Wang and Lin2002). Similarly, many cases of hyperinfection are fatal without larvae being detected outside the pulmonary autoinfective route.
General features
The clinical manifestations of S. stercoralis hyperinfection vary widely. The onset may be acute (Thomas and Costello, Reference Thomas and Costello1998) or insidious (Wurtz et al. Reference Wurtz, Mirot, Fronda, Peters and Kocka1994). Fever and chills are not uniformly present and should prompt a search for an associated bacterial infection. Other constitutional symptoms include fatigue (Liepman, Reference Liepman1975), weakness (Chu et al. Reference Chu, Whitlock and Dietrich1990) and total body pain (Chaudhuri et al. Reference Chaudhuri, Nanos, Soco and McGrew1980). Blood counts performed during hyperinfection may show eosinophilia but more often show a suppressed eosinophil count (Grove, Reference Grove1996). Patients who have increased peripheral eosinophilia during hyperinfection appear to have a better prognosis (Jamil and Hilton, Reference Jamil and Hilton1992).
Gastrointestinal manifestations
Gastrointestinal symptoms are common but are non-specific. Some case reports do not mention any gastrointestinal symptoms (Liepman, Reference Liepman1975). Abdominal pain (Celedon et al. Reference Celedon, Mathur-Wagh, Fox, Garcia and Wiest1994), often described as crampy or bloating in nature, watery diarrhoea, constipation anorexia, weight loss (Scowden et al. Reference Scowden, Schaffner and Stone1978), difficulty swallowing (Yee et al. Reference Yee, Boylen, Noguchi, Klatt and Sharma1987), sore throat, nausea (Liepman, Reference Liepman1975), vomiting and gastrointestinal bleeding, and small bowel obstruction (Newton et al. Reference Newton, Limpuangthip, Greenberg, Gam and Neva1992; Thomas and Costello, Reference Thomas and Costello1998) may result, with diffuse abdominal tenderness and hypoactive bowel sounds. Protein-losing enteropathy may give rise to acute or worsening hypoalbuminaemia with peripheral oedema (Ho et al. Reference Ho, Luk, Chan and Yuen1997; Yoshida et al. Reference Yoshida, Endo, Tanaka, Ishikawa, Kondo and Nakamura2006) or ascites (Liepman, Reference Liepman1975). Hypokalaemia (Jain et al. Reference Jain, Agarwal and el-Sadr1994) or other electrolyte abnormalities may reflect these gastrointestinal disturbances. Direct stool exam usually shows numerous rhabditiform and filariform larvae. Occasionally, adult worms (Ho et al. Reference Ho, Luk, Chan and Yuen1997) and eggs (Armignacco et al. Reference Armignacco, Capecchi, De Mori and Grillo1989; Cahill and Shevchuk, Reference Cahill and Shevchuk1996) are also seen. Occult or gross blood is a common finding. Esophagitis and gastritis are reported, in addition to duodenitis, jejunitis, ileitis, colitis, including pseudomembranous colitis and proctitis. Mucosal ulceration is most common in the small intestine, but can occur at any level from the oesophagus (Levi et al. Reference Levi, Kallas and Ramos Moreira Leite1997) and stomach (Wurtz et al. Reference Wurtz, Mirot, Fronda, Peters and Kocka1994) to the rectum. Larvae may be seen in these ulcers on biopsy (Gompels et al. Reference Gompels, Todd, Peters, Main and Pinching1991; Wurtz et al. Reference Wurtz, Mirot, Fronda, Peters and Kocka1994; Ho et al. Reference Ho, Luk, Chan and Yuen1997). Crypts are often distorted by the numerous larvae (Wurtz et al. Reference Wurtz, Mirot, Fronda, Peters and Kocka1994) Inflammatory infiltrates (Mori et al. Reference Mori, Konishi, Matsuoka, Deguchi, Ohta, Mizuno, Ueno, Okinaka, Nishimura, Ito and Nakano1998) or areas of necrosis (Neefe et al. Reference Neefe, Pinilla, Garagusi and Bauer1973; Yee et al. Reference Yee, Boylen, Noguchi, Klatt and Sharma1987) in involved intestinal mucosa may be present (Newton et al. Reference Newton, Limpuangthip, Greenberg, Gam and Neva1992). The appendix may also be invaded by larvae (Scowden et al. Reference Scowden, Schaffner and Stone1978; Kramer et al. Reference Kramer, Gregg, Goldstein, Llamas and Krieger1990). Abdominal imaging may show small bowel distension with air-fluid levels (Newton et al. Reference Newton, Limpuangthip, Greenberg, Gam and Neva1992; Celedon et al. Reference Celedon, Mathur-Wagh, Fox, Garcia and Wiest1994). Mucosal oedema (Neefe et al. Reference Neefe, Pinilla, Garagusi and Bauer1973; Mori et al. Reference Mori, Konishi, Matsuoka, Deguchi, Ohta, Mizuno, Ueno, Okinaka, Nishimura, Ito and Nakano1998) and findings consistent with protein-losing enteropathy may also be demonstrated radiographically. Computed tomography scans can occasionally reveal intra-abdominal lymphadenopathy (Thomas and Costello, Reference Thomas and Costello1998).
Cardiopulmonary manifestations
Cardiopulmonary manifestations range from none at all to cough (Nomura and Rekrut, Reference Nomura and Rekrut1996), wheezing (Kramer et al. Reference Kramer, Gregg, Goldstein, Llamas and Krieger1990), (Yee et al. Reference Yee, Boylen, Noguchi, Klatt and Sharma1987), a choking sensation (Cahill and Shevchuk, Reference Cahill and Shevchuk1996), hoarseness (Yee et al. Reference Yee, Boylen, Noguchi, Klatt and Sharma1987), chest pain (Chaudhuri et al. Reference Chaudhuri, Nanos, Soco and McGrew1980; Cahill and Shevchuk, Reference Cahill and Shevchuk1996), haemoptysis, palpitations, atrial fibrillation (Gordon et al. Reference Gordon, Gal, Solomon and Bryan1994), dyspnoea (Nomura and Rekrut, Reference Nomura and Rekrut1996), and, rarely, respiratory collapse. Respiratory alkalosis is common (Thompson and Berger, Reference Thompson and Berger1991). Pneumothorax is rarely seen (McNeely et al. Reference McNeely, Inouye, Tam and Ripley1980). Sputum may demonstrate filariform or rhabditiform larvae and even, occasionally, eggs (Kennedy et al. Reference Kennedy, Campbell, Lawrence, Nichol and Rao1989). These findings suggest that filariform larvae develop into adults in the lungs, and a new generation of rhabditiform larvae is produced locally (Cirioni et al. Reference Cirioni, Giacometti, Burzacchini, Balducci and Scalise1996). This hypothesis is supported by reports of adult parasites being expectorated post treatment (McLarnon and Ma, Reference McLarnon and Ma1981) and autopsy studies showing adult worms in lung tissue (Cahill and Shevchuk, Reference Cahill and Shevchuk1996). Chest imaging most frequently show bilateral or focal interstitial infiltrates. Lung tissues may show alveolar haemorrhage. Petechial haemorrhage or hyperaemia of the bronchial, tracheal and laryngeal mucosa has also been reported (Yee et al. Reference Yee, Boylen, Noguchi, Klatt and Sharma1987; Cahill and Shevchuk, Reference Cahill and Shevchuk1996).
Dermatologic manifestations
Pruritic linear streaks of the lower trunk, thighs and buttocks (larva currens) frequently accompany hyperinfection (Ho et al. Reference Ho, Luk, Chan and Yuen1997). Petechial and purpuric rashes of these same areas, in which larvae have been demonstrated on skin biopsy is common (Ronan et al. Reference Ronan, Reddy, Manaligod, Alexander and Fu1989; Stewart et al. Reference Stewart, Ramanathan, Mahanty, Fedorko, Janik and Morris2011). Skin manifestations of vasculitis (Harcourt-Webster et al. Reference Harcourt-Webster, Scaravilli and Darwish1991) or of disseminated intravascular coagulation seen associated with
Gram-negative sepsis (Neefe et al. Reference Neefe, Pinilla, Garagusi and Bauer1973) may, of course, also present during hyperinfection.
Central nervous system (CNS) manifestations
Meningeal signs and symptoms (Kramer et al. Reference Kramer, Gregg, Goldstein, Llamas and Krieger1990) are the most common manifestation of CNS involvement in hyperinfection syndrome. Hyponatremia may accompany meningitis (Harcourt-Webster et al. Reference Harcourt-Webster, Scaravilli and Darwish1991; Jain et al. Reference Jain, Agarwal and el-Sadr1994). In patients with meningitis, spinal fluid may show parameters of aseptic meningitis [i.e. pleocytosis, elevated protein, normal glucose, negative bacterial cultures (Scowden et al. Reference Scowden, Schaffner and Stone1978; Vishwanath et al. Reference Vishwanath, Baker and Mansheim1982)] or demonstrate characteristics of a Gram-negative bacterial infection. Larvae have been found in spinal fluid (Dutcher et al. Reference Dutcher, Marcus, Tanowitz, Wittner, Fuks and Wiernik1990), meningeal vessels (Cahill and Shevchuk, Reference Cahill and Shevchuk1996), dura, epidural, subdural and subarachnoid spaces (Neefe et al. Reference Neefe, Pinilla, Garagusi and Bauer1973). Eosinophilic meningitis has not been reported.
Sepsis
Hyperinfection syndrome/disseminated are often complicated, and rarely preceded by infections caused by gut flora that gain access to extraintestinal sites, presumably through ulcers induced by the filariform larvae or by virtue of being carried on the surface or in the intestinal tract of larvae themselves. Organisms that have been reported to cause sepsis in such patients include Group D Streptococci, Candida Streptococcus bovis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas, Enterococcus faecalis, coagulase negative staphylococci and Streptococcus pneumoniae. Polymicrobial infections can also occur (Link and Orenstein, Reference Link and Orenstein1999).
Disseminated infections
Organs to which larvae have disseminated include skin, mesenteric lymph nodes, gallbladder, liver, diaphragm, heart, pancreas, skeletal muscle, kidneys, ovaries and brain (Keiser and Nutman, Reference Keiser and Nutman2004) based largely on autopsy studies. Chronic inflammation or necrosis frequently surrounds the larvae, but tissue reactions are also frequently absent (Neefe et al. Reference Neefe, Pinilla, Garagusi and Bauer1973; Takayanagui et al. Reference Takayanagui, Lofrano, Araugo and Chimelli1995).
Conditions associated with hyperinfection syndrome and dissemination (Table 1)
Corticosteroids and other agents
Corticosteroids (most commonly prednisone and methyl-prednisilone) have a particularly strong and specific association with the development of hyperinfection syndrome and dissemination. Beyond their known (and broad) effects on the host immune system, it has been postulated that corticosteroids have a direct effect on the S. stercoralis parasite (Genta, Reference Genta1992; Ramanathan et al. Reference Ramanathan, Varma, Ribeiro, Myers, Nolan, Abraham, Lok and Nutman2011) though this has not been shown definitively. Other immunosuppressive therapies and underlying conditions (Table 1) may also predispose to dissemination. However, the concomitant administration of corticosteroids in most of these other conditions makes it difficult to assign a direct causal association. Hyperinfection syndrome has been described regardless of dose, duration or route of administration of corticosteroids. Even short courses (6–17 days) of corticosteroids in immunocompetent patients without underlying immunosuppressive conditions have even been associated with hyperinfection syndrome and death (Ghosh and Ghosh, Reference Ghosh and Ghosh2007).
Table 1. Conditions associated with hyperinfection syndrome
HTLV-1 Infection
Human T-cell lymphotropic virus type 1 (HTLV-1) represents a significant risk factor for the development of hyperinfection syndrome or disseminated strongyloidiasis (Carvalho and Da Fonseca Porto, Reference Carvalho and Da Fonseca Porto2004) that may be related to HTLV-I driven alterations in IgE or associated Type-2 responses (Neva et al. Reference Neva, Filho, Gam, Thompson, Freitas, Melo and Carvalho1998; Porto et al. Reference Porto, Neva, Bittencourt, Lisboa, Thompson, Alcantara and Carvalho2001; Mitre et al. Reference Mitre, Thompson, Carvalho, Nutman and Neva2003; Santos et al. Reference Santos, Porto, Muniz, Jesus and Carvalho2004). A growing body of evidence points to the synergistic relationship between HTLV-1 and S. stercoralis. Higher rates of S. stercoralis infection have been found in HTLV-1 patients (Carvalho and Da Fonseca Porto, Reference Carvalho and Da Fonseca Porto2004). Strongyloides stercoralis infection has been shown to influence the natural history of HTLV-1 infection (Marcos et al. Reference Marcos, Terashima, Canales and Gotuzzo2011) and has been considered a co-factor in the development of HTLV-1-associated diseases (Gotuzzo et al. Reference Gotuzzo, Arango, de Queiroz-Campos and Isturiz2000).
HIV
Strongyloidiasis was once considered an AIDS defining illness (Keiser and Nutman, Reference Keiser and Nutman2004) yet there is no evidence that a low CD4 count will increase the risk of dissemination or decrease the chance of clearing an infection (Walson et al. Reference Walson, Stewart, Sangare, Mbogo, Otieno, Piper, Richardson and John-Stewart2010). Severe infection with Strongyloides has not been observed frequently with HIV-infected patients (Celedon et al. Reference Celedon, Mathur-Wagh, Fox, Garcia and Wiest1994). Hyperinfection syndrome is associated with the use of corticosteroids in the treatment of immune reconstitution inflammatory syndrome (IRIS) (Brown et al. Reference Brown, Cartledge and Miller2006; Mascarello et al. Reference Mascarello, Gobbi, Angheben, Gobbo, Gaiera, Pegoraro, Lanzafame, Buonfrate, Concia and Bisoffi2011). Whether IRIS occurs after the initiation of antiretroviral therapy in patients with single infections with S. stercoralis remains unclear.
Strongyloides infection in the transplanted patient
Solid organ transplants (Stone and Schaffner, Reference Stone and Schaffner1990; Lichtenberger et al. Reference Lichtenberger, Rosa-Cunha, Morris, Nishida, Akpinar, Gaitan, Tzakis and Doblecki-Lewis2009; Mokaddas et al. Reference Mokaddas, Shati, Abdulla, Nampoori, Iqbal, Nair, Said, Abdulhalim and Hira2009) haematopoietic stem cell transplants (HSCT) and their pre-conditioning regimens and subsequent immunosuppression have been linked to dissemination of S. stercoralis. Among the different types of transplants, HSCT has the highest incidence of fatal dissemination with a higher mortality than in other types of transplants (Wirk and Wingard, Reference Wirk and Wingard2009). A unique complication of transplants is the development of graft vs host disease (GVHD). In HSCT the risk of GVHD is greater than for other types of transplants because of the use of allogeneic stem cells (non-ablative conditioning). Because the main therapy for acute GVHD is corticosteroids, it is at the time that steroids are given in the setting of chronic strongyloidiasis that the risk for dissemination is high (Choi and Reddy, Reference Choi and Reddy2014).
The geographical proximity to either North America or Europe by immigrants from Central and South America and Africa that are being transplanted are a sizeable ‘at risk’ population for dissemination of S. stercoralis (Wolfe et al. Reference Wolfe, Roys and Merion2010; Guermani et al. Reference Guermani, Potenza, Isnardi, Peluso, Bosco and Donadio2013). Organ donors have also been shown to transmit Strongyloides infection with cases of solid organ transplant-associated S. stercoralis infections having been reported (Weiser et al. Reference Weiser, Scully, Bulman, Husain and Grossman2011).
Other
Several case reports have supported an association between S. stercoralis infection hypogammaglobulinaemia associated with multiple myeloma and nephrotic syndrome (Seet et al. Reference Seet, Lau and Tambyah2005; Hsieh et al. Reference Hsieh, Wen and Chen2006; Yassin et al. Reference Yassin, El Omri, Al-Hijji, Taha, Hassan, Aboudi and El-Ayoubi2010).
HUMAN IMMUNE RESPONSES AND PROTECTIVE IMMUNITY
The human immune response to S. stercoralis has not been studied in great detail. Most of our knowledge about immune responsiveness and protective immunity has come from animal studies [reviewed in this issue (Breloer and Abraham, Reference Breloer and Abraham2016)]. These studies, that have as an added benefit the knowledge of exactly when the infection was initiated, have suggested a role for antibodies (of many isotypes) as well as for innate and adaptive immune responses in mediating resistance to infection (Fig. 1).
Fig. 1. Immune responses in Strongyloides stercoralis infection as a function of time after infection initiation. The infective L3 larval parasites initiate infection at skin sites and activate a variety of different cell types such as innate lymphoid cells (ILCs), macrophages (MAC), dendritic cells (DCs), natural killer cells (NK), eosinophils (Eos) and basophils/mast cells (Baso/MC). At this relatively early phase of infection (or by the time the adult worms are established in the small intestine) the parasite induces the differentiation of a small number of effector Th1/Th17 and a relatively larger number of Th2 cells which together with IgE antibody, may lead to attrition of some of the parasites. At the time of patency (when larval production occurs) there is an expansion of Th2/Th9 CD4+ cells, a further contraction of Th1/Th17 cells and the induction of alternatively activated macrophages (AAM). With the evolution of chronic longstanding infection, there is an associated expansion of IL-10- and/or TGFβ-producing regulatory T cells (Tregs) and a small contraction of Th2/Th9 cells.
In humans, it has been shown, however, that Th2 response are essential to protect against hyperinfection (Porto et al. Reference Porto, Neva, Bittencourt, Lisboa, Thompson, Alcantara and Carvalho2001; Iriemenam et al. Reference Iriemenam, Sanyaolu, Oyibo and Fagbenro-Beyioku2010) and that individuals with strongyloidiasis develop S. stercoralis-specific antibodies of the IgM, IgG, IgA and IgE isotypes (McRury et al. Reference McRury, De Messias, Walzer, Huitger and Genta1986; Genta and Lillibridge, Reference Genta and Lillibridge1989; Atkins et al. Reference Atkins, Lindo, Lee, Conway, Bailey, Robinson and Bundy1997; Rodrigues et al. Reference Rodrigues, de Oliveira, Sopelete, Silva, Campos, Taketomi and Costa-Cruz2007).
The evolution of the antibody response in S. stercoralis infection has been difficult to discern given that only cross-sectional studies of infected people have been performed. Nevertheless, these studies of S. stercoralis infection have suggested that there is rapid induction of parasite-specific IgE, IgG1, IgG2 and IgG3 antibodies directed against crude S. stercoralis soluble extracts that is followed (often weeks to months later) with a rise in parasite-specific IgG4. In that the IgE and IgG4 antibodies often are directed at a similar, but restricted, set of antigens (Genta and Lillibridge, Reference Genta and Lillibridge1989), it is the IgG4 antibodies that allow for the blocking of IgE-mediated effector responses (Genta et al. Reference Genta, Ottesen, Poindexter, Gam, Neva, Tanowitz and Wittner1983; Barrett et al. Reference Barrett, Neva, Gam, Cicmanec, London, Phillips and Metcalfe1988; Genta and Lillibridge, Reference Genta and Lillibridge1989) thereby modulating some of the Type-2-mediated inflammation.
Recent work has suggested that once S. stercoralis establishes patency [usually within 6–7 weeks following infection (Freedman, Reference Freedman1991)] that the infection drives a systemic cytokine response that is dominated by Th2-associated and anti-inflammatory cytokines (Anuradha et al. Reference Anuradha, Munisankar, Bhootra, Jagannathan, Dolla, Kumaran, Shen, Nutman and Babu2015a ) (Fig. 1). This systemic response appears to reflect an expansion of antigen-specific Th2/Th9 cells with a concomitant contraction of Th1 and Th17 cells, the latter being dependent on IL-10 (George et al. Reference George, Anuradha, Kumar, Sridhar, Banurekha, Nutman and Babu2014; Anuradha et al. Reference Anuradha, Munisankar, Bhootra, Jagannathan, Dolla, Kumaran, Nutman and Babu2016, Reference Anuradha, Munisankar, Dolla, Kumaran, Nutman and Babu2015b ). With appropriate anthelmintic therapy leading to cure of the S. stercoralis infection, many of these cytokine levels and T-cell perturbations return to their homeostatic state (Anuradha et al. Reference Anuradha, Munisankar, Bhootra, Jagannathan, Dolla, Kumaran, Shen, Nutman and Babu2015a , Reference Anuradha, Munisankar, Dolla, Kumaran, Nutman and Babu b ).
Like many other systemic helminth infections (e.g. Schistosoma mansoni, Wuchereria bancrofti), S. stercoralis also, given its capacity for chronic longstanding infection, can modulate responses to bystander antigens particularly in the context of infection with other pathogens such as Mycobacterium tuberculosis (George et al. Reference George, Pavan Kumar, Jaganathan, Dolla, Kumaran, Nair, Banurekha, Shen, Nutman and Babu2015) and HTLV-1 (Mitre et al. Reference Mitre, Thompson, Carvalho, Nutman and Neva2003; Montes et al. Reference Montes, Sanchez, Verdonck, Lake, Gonzalez, Lopez, Terashima, Nolan, Lewis, Gotuzzo and White2009; Salles et al. Reference Salles, Bacellar, Amorim, Orge, Sundberg, Lima, Santos, Porto and Carvalho2013).
DIAGNOSIS
For the chronically infected, asymptomatic individual, diagnosis of strongyloidiasis can be challenging (Levenhagen and Costa-Cruz, Reference Levenhagen and Costa-Cruz2014; Buonfrate et al. Reference Buonfrate, Formenti, Perandin and Bisoffi2015; Toledo et al. Reference Toledo, Munoz-Antoli and Esteban2015). Diagnosis of hyperinfection syndrome/disseminated S. stercoralis infection is much less difficult given the large numbers of larvae often seen in the stool or other bodily fluids including CSF, pleural fluid, bronchoalveolar lavage fluid.
Parasitological methods
Definitive diagnosis relies on detection of larvae in the stool. However, intermittent and scanty excretion of larvae limits the utility of standard stool studies. Various investigators have attempted to improve the diagnostic yield of stool examination using techniques such as direct smear of feces in saline/Lugol's iodine stain, Baermann concentration, Harada-Mori filter paper culture, quantitative formalin ethyl acetate concentration technique and nutrient agar plate cultures [see (Sato et al. Reference Sato, Kobayashi, Toma and Shiroma1995)]. Sensitivity improved to 100% when seven stool samples were studied (Siddiqui and Berk, Reference Siddiqui and Berk2001). Duodenal aspiration, while more sensitive than stool examination, is an invasive procedure that makes it a less favourable option. Duodenal biopsy, when performed, can demonstrate parasites nested in the gastric crypts or duodenal glands, as well as eosinophil infiltration of the lamina propria (Rivasi et al. Reference Rivasi, Pampiglione, Boldorini and Cardinale2006).
Immunological methods
Antibody detection
A number of immunoassays, most notably enzyme-linked immunosorbent assays (ELISAs), have been increasingly used in conjunction with stool studies to increase diagnostic sensitivity. The high negative predictive value of these immunoassays can be particularly useful in excluding S. stercoralis infection as part of the differential diagnosis. Despite their utility, antibody-based immunoassays have several limitations including: (1) cross-reactivity in patients with active filarial infections; (2) lower sensitivity in patients with haematologic malignancies or HTLV-1 infection; and (3) the inability to distinguish between current and past infection. Moreover, the current available immunoassays [see (Levenhagen and Costa-Cruz, Reference Levenhagen and Costa-Cruz2014; Buonfrate et al. Reference Buonfrate, Formenti, Perandin and Bisoffi2015; Toledo et al. Reference Toledo, Munoz-Antoli and Esteban2015) for a comprehensive discussion] relies on the preparation of S. stercoralis larval antigen from stool samples of heavily infected humans or experimentally infected animals or from related (but not S. stercoralis) Strongyloides species (e.g. S. ratti).
To overcome some of these drawbacks, S. stercoralis-specific recombinant antigens, such as NIE (Ravi et al. Reference Ravi, Ramachandran, Thompson, Andersen and Neva2002) and SsIR (Ramachandran et al. Reference Ramachandran, Thompson, Gam and Neva1998), were proposed as alternatives to the crude antigen-based immunoassays currently in use. Using a number of formats including ELISA [(Krolewiecki et al. Reference Krolewiecki, Ramanathan, Fink, McAuliffe, Cajal, Won, Juarez, Di Paolo, Tapia, Acosta, Lee, Lammie, Abraham and Nutman2010), luciferase immunoprecipitation systems (Ramanathan et al. Reference Ramanathan, Burbelo, Groot, Iadarola, Neva and Nutman2008; Krolewiecki et al. Reference Krolewiecki, Ramanathan, Fink, McAuliffe, Cajal, Won, Juarez, Di Paolo, Tapia, Acosta, Lee, Lammie, Abraham and Nutman2010; Bisoffi et al. Reference Bisoffi, Buonfrate, Sequi, Mejia, Cimino, Krolewiecki, Albonico, Gobbo, Bonafini, Angheben, Requena-Mendez, Munoz and Nutman2014)] and diffraction-based biosensors (Pak et al. Reference Pak, Vasquez-Camargo, Kalinichenko, Chiodini, Nutman, Tanowitz, McAuliffe, Wilkins, Smith, Ward, Libman and Ndao2014) the use of recombinant NIE and/or SsIR has improved greatly the diagnostic accuracy and utility of these antibody-based assays (Bisoffi et al. Reference Bisoffi, Buonfrate, Sequi, Mejia, Cimino, Krolewiecki, Albonico, Gobbo, Bonafini, Angheben, Requena-Mendez, Munoz and Nutman2014; Levenhagen and Costa-Cruz, Reference Levenhagen and Costa-Cruz2014; Buonfrate et al. Reference Buonfrate, Formenti, Perandin and Bisoffi2015; Toledo et al. Reference Toledo, Munoz-Antoli and Esteban2015).
Antigen detection
Coproantigen detection assays have the ability to overcome some of the limitations seen in immunoassays that measure antibody (see above). There have been several capture ELISA assays developed for S. stercoralis coproantigen detection (El-Badry, Reference El-Badry2009; Sykes and McCarthy, Reference Sykes and McCarthy2011), and both of these assays have been performed on relatively few samples and are only available in a research setting.
Molecular diagnosis
Molecular diagnostics – using standard (and/or nested-) PCR, qPCR or loop-mediated isothermal amplification assays – have been increasingly gaining traction for use stool-based assays given their high degree of specificity and sensitivity (ten Hove et al. Reference ten Hove, van Esbroeck, Vervoort, van den Ende, van Lieshout and Verweij2009; Verweij et al. Reference Verweij, Canales, Polman, Ziem, Brienen, Polderman and van Lieshout2009; Taniuchi et al. Reference Taniuchi, Verweij, Noor, Sobuz, Lieshout, Petri, Haque and Houpt2011; Mejia et al. Reference Mejia, Vicuna, Broncano, Sandoval, Vaca, Chico, Cooper and Nutman2013; Sultana et al. Reference Sultana, Jeoffreys, Watts, Gilbert and Lee2013; Watts et al. Reference Watts, James, Sultana, Ginn, Outhred, Kong, Verweij, Iredell, Chen and Lee2014; Easton et al. Reference Easton, Oliveira, O'Connell, Kepha, Mwandawiro, Njenga, Kihara, Mwatele, Odiere, Brooker, Webster, Anderson and Nutman2016; Llewellyn et al. Reference Llewellyn, Inpankaew, Nery, Gray, Verweij, Clements, Gomes, Traub and McCarthy2016). Indeed, the improved specificity relies on the specific DNA targets used [18S rRNA, IST1, cytochrome c oxidase subunit 1 or the highly repetitive interspersed repeat sequence (Moore et al. Reference Moore, Ramachandran, Gam, Neva, Lu, Saunders, Williams and Nutman1996)] and the improved sensitivity has resulted from better methods for DNA extraction in stool (ten Hove et al. Reference ten Hove, van Esbroeck, Vervoort, van den Ende, van Lieshout and Verweij2009; Taniuchi et al. Reference Taniuchi, Verweij, Noor, Sobuz, Lieshout, Petri, Haque and Houpt2011; Liu et al. Reference Liu, Gratz, Amour, Kibiki, Becker, Janaki, Verweij, Taniuchi, Sobuz, Haque, Haverstick and Houpt2013; Mejia et al. Reference Mejia, Vicuna, Broncano, Sandoval, Vaca, Chico, Cooper and Nutman2013; Sultana et al. Reference Sultana, Jeoffreys, Watts, Gilbert and Lee2013; Easton et al. Reference Easton, Oliveira, O'Connell, Kepha, Mwandawiro, Njenga, Kihara, Mwatele, Odiere, Brooker, Webster, Anderson and Nutman2016). These molecular diagnostic techniques likely identify active S. stercoralis infection as positivity has been shown to be lost following definitive treatment.
TREATMENT
The goals for therapy for S. stercoralis infection are to: (1) clear the organism completely thereby eliminating the possibility of autoinfection: (2) treat symptomatic infection; and (3) prevent complications associated with asymptomatic infection. Oral ivermectin (200 µg kg−1 for 2 days) remains the treatment of choice for uncomplicated S. stercoralis infections (Keiser and Nutman, Reference Keiser and Nutman2004; Suputtamongkol et al. Reference Suputtamongkol, Premasathian, Bhumimuang, Waywa, Nilganuwong, Karuphong, Anekthananon, Wanachiwanawin and Silpasakorn2011; Mejia and Nutman, Reference Mejia and Nutman2012; Toledo et al. Reference Toledo, Munoz-Antoli and Esteban2015; Henriquez-Camacho et al. Reference Henriquez-Camacho, Gotuzzo, Echevarria, White, Terashima, Samalvides, Perez-Molina and Plana2016) as it targets both adults and larvae. Albendazole at 400 mg twice a day for 3–7 days has been shown to be slightly less effective than ivermectin for the treatment of uncomplicated S. stercoralis (Suputtamongkol et al. Reference Suputtamongkol, Premasathian, Bhumimuang, Waywa, Nilganuwong, Karuphong, Anekthananon, Wanachiwanawin and Silpasakorn2011; Henriquez-Camacho et al. Reference Henriquez-Camacho, Gotuzzo, Echevarria, White, Terashima, Samalvides, Perez-Molina and Plana2016) and should be considered an alternative therapy. This is likely because albendazole primarily targets only the adult parasites. Thiabendazole (25 mg kg−1 day−1) for three days can also be used, but because of gastrointestinal side effects, its use has been supplanted by ivermectin.
Hyperinfection syndrome should be considered a potential medical emergency. Thus, treatment should be started immediately if this diagnosis is being considered. Although no controlled trials have been performed in hyperinfection syndrome, daily ivermectin has been the de facto treatment with the length of treatment being for a minimum of 2 weeks (and often until there has been evidence of two full weeks of negative stool examination). Reduction of immunosuppressive therapy should also be an important part of treatment, but obviously needs to be weighed against long-term outcomes of the underlying condition. There have been case reports of the improved efficacy of combination treatment with ivermectin and albendazole (Pornsuriyasak et al. Reference Pornsuriyasak, Niticharoenpong and Sakapibunnan2004) but no randomized trials have been done.
Other methods of ivermectin administration may have to be used, particularly when patients are unable to take oral medication (even through a nasogastric tube) because of severe systemic illness or paralytic ileus. These include per rectal and parenteral formulations (Grein et al. Reference Grein, Mathisen, Donovan and Fleckenstein2010). The parenteral formulation is a veterinary formulation of ivermectin and should be reserved for extreme situations with no other options for clearing the Strongyloides infection (Marty et al. Reference Marty, Lowry, Rodriguez, Milner, Pieciak, Sinha, Fleckenstein and Baden2005; Salluh et al. Reference Salluh, Feres, Velasco, Holanda, Toscano and Soares2005; Turner et al. Reference Turner, Maclean, Fleckenstein and Greenaway2005; Suputtamongkol et al. Reference Suputtamongkol, Kungpanichkul, Silpasakorn and Beeching2008; Lichtenberger et al. Reference Lichtenberger, Rosa-Cunha, Morris, Nishida, Akpinar, Gaitan, Tzakis and Doblecki-Lewis2009; Marcos et al. Reference Marcos, Terashima, Canales and Gotuzzo2011; Moura et al. Reference Moura, Maia Mde, Ghazi, Amorim and Pinhati2012; Donadello et al. Reference Donadello, Cristallini, Taccone, Lorent, Vincent, de Backer and Jacobs2013; Barrett et al. Reference Barrett, Broderick, Soulsby, Wade and Newsholme2016).
In conclusion, the gaps in our understanding of human strongyloidiasis, among the most neglected of the neglected tropical diseases (NTDs) (Olsen et al. Reference Olsen, van Lieshout, Marti, Polderman, Polman, Steinmann, Stothard, Thybo, Verweij and Magnussen2009) are extraordinary given the rapid pace of scientific and clinical advances seen in related areas of parasitic and other tropical infectious diseases. Given its increasing importance as a significant public health problem (in high-, middle- and low-income countries) and the lack of a public health response (Krolewiecki et al. Reference Krolewiecki, Lammie, Jacobson, Gabrielli, Levecke, Socias, Arias, Sosa, Abraham, Cimino, Echazu, Crudo, Vercruysse and Albonico2013), harnessing the insights made, to date, in our understanding of the basic biology and genetic makeup of Strongyloides (Hunt et al. Reference Hunt, Tsai, Coghlan, Reid, Holroyd, Foth, Tracey, Cotton, Stanley, Beasley, Bennett, Brooks, Harsha, Kajitani, Kulkarni, Harbecke, Nagayasu, Nichol, Ogura, Quail, Randle, Xia, Brattig, Soblik, Ribeiro, Sanchez-Flores, Hayashi, Itoh, Denver, Grant, Stoltzfus, Lok, Murayama, Wastling, Streit, Kikuchi, Viney and Berriman2016), the host response to this long-lived parasite (Breloer and Abraham, Reference Breloer and Abraham2016), and molecularly based approaches to diagnosis and intervention must be made an imperative if we are to consider a world free of soil transmitted helminths (of which S. stercoralis is one of the most important).
FINANCIAL SUPPORT
This work was supported by the Division of Intramural Research (DIR) of the National Institute of Allergy and Infectious Diseases.
