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Strongyloidiasis

Strongyloidiasis
Authors:
Karin Leder, MBBS, FRACP, PhD, MPH, DTMH
Peter F Weller, MD, MACP
Section Editor:
Edward T Ryan, MD, DTMH
Deputy Editor:
Elinor L Baron, MD, DTMH
Literature review current through: Dec 2022. | This topic last updated: Nov 01, 2022.

INTRODUCTION — Strongyloidiasis is caused by infection with the soil-transmitted helminth Strongyloides stercoralis.

This organism is capable of completing its life cycle entirely within the human host, in contrast with all other soil-transmitted helminths that cannot replicate within hosts and require exogenous reinfections to sustain their life cycle.

As a consequence, infectious-stage larvae develop in the gastrointestinal tract and endogenously propagate ongoing infection. Therefore, chronic asymptomatic infection can be sustained for decades, and clinical manifestations can occur long after the initial infection. In addition, among patients with subclinical infections who subsequently become immunosuppressed, larval reproduction can lead to disseminated infection. (See "Evaluation for infection before solid organ transplantation" and "Evaluation for infection before hematopoietic cell transplantation".)

Issues related to other soil-transmitted helminths are discussed separately. (See "Ascariasis" and "Enterobiasis (pinworm) and trichuriasis (whipworm)" and "Hookworm infection".)

Issues related to mass drug administration for control of parasitic infections are discussed separately. (See "Mass drug administration for control of parasitic infections".)

EPIDEMIOLOGY

Geography — Strongyloidiasis occurs in areas with poor sanitation. Strongyloidiasis is endemic in areas of tropical and subtropical regions; in these areas, the overall regional prevalence may exceed 30 percent [1], and some countries (such as Peru, Kenya, Namibia, and Papua New Guinea) have prevalence >70 percent [2]. The global prevalence may be as high as 600 million cases [3]. Southeast Asia, Africa, and Western Pacific Regions account for approximately three-quarters of all infections globally [3]. Human infections with S. stercoralis occur in Australia and temperate areas such as North America, Europe, Japan, and Australia [4-11].

In the United States, infections occur among residents of the southeastern states and Appalachian regions [12,13] where S. stercoralis larvae may be present in soil in regions with poor sanitation [14]. In one report of United States hospitalizations for strongyloidiasis between 2003 and 2018, strongyloidiasis was more prevalent in the northeastern United States including the mid-Atlantic region [15]. Infections also occur among individuals who have resided in endemic areas (including internal migrations, immigrants, refugees, travelers, and military personnel) [16-18].

In a review and meta-analysis describing the prevalence of strongyloidiasis among migrants from endemic areas, the seroprevalence of strongyloidiasis was 12 percent; the prevalence was highest among migrants from East Asia and the Pacific (17 percent), followed by those from sub-Saharan Africa (14 percent) and Latin America/the Caribbean (11 percent) [19]. Another meta-analysis including migrants to Spain from sub-Saharan Africa, Latin America, and North Africa noted seroprevalence of S. stercoralis infection to be 20, 14, and 8 percent, respectively [20].

Canine infections with S. stercoralis are being recognized in Europe and elsewhere [21], but the zoonotic relevance of canine infections to human infections remains to be ascertained [22]. A related species, Strongyloides fullburn, also a soil-transmitted infection that infects non-human primates (including monkeys), has uncommonly infected humans living in proximity to monkeys [23].

Transmission — The most common mode for transmission of strongyloidiasis is via skin contact with contaminated soil. Lack of adequate sanitation facilities is an important risk factor [4]. In endemic areas, infection may be prevented by wearing shoes to avoid contact of bare feet with infected soil.

Less common modes of transmission include fecal-oral transmission and person-to-person transmission (via contact with fecally contaminated, larvae-bearing fomites or via sexual contacts [24]). Nosocomial transmission of strongyloidiasis has been described; standard precautions are sufficient for prevention [13,25,26].

Transplant recipients receiving organs or tissues from donors with epidemiologic risk for asymptomatic Strongyloides infection are at risk for donor-derived strongyloidiasis [27,28]. In addition, immunosuppressed individuals are at risk for developing Strongyloides hyperinfection/disseminated disease; this can occur as a consequence of accelerated autoinfection even in the setting of a remote history of initial infection. (See 'Severe manifestations' below.)

Issues related to prevention of infection among immunosuppressed individuals are discussed below. (See 'Asymptomatic individuals' below.)

Life cycle and autoinfection — The life cycle begins when human skin contacts filariform larvae (the infective larval stage) of S. stercoralis, which are found in soil or other materials contaminated with human stool (figure 1). The filariform larvae penetrate the skin and migrate via the bloodstream and lymphatics to the lungs, where they penetrate into the alveolar air sacs. The larvae then ascend the tracheobronchial tree and are swallowed.

The larvae mature into adult worms that burrow into the mucosa of the duodenum and jejunum. Adult worms may live for up to five years. In the apparent absence of male adults, pathogenic adult females produce eggs, from which early larvae and then noninfectious larvae (rhabditiform larvae) develop within the lumen of the gastrointestinal (GI) tract. The rhabditiform larvae (picture 1) are generally passed in the stool. The duration of the cycle from dermal penetration of filariform larvae to appearance of rhabditiform larvae in the stool is approximately three to four weeks.

In addition, autoinfection can occur; in this part of the life cycle, the rhabditiform larvae become infective filariform larvae within the human GI tract (figure 1). The filariform larvae can then penetrate the intestinal mucosa (internal autoinfection) or the perianal skin (external autoinfection) to complete the life cycle by migrating via the bloodstream and lymphatics to the lungs and then the intestine. Transformation of rhabditiform larvae to filariform larvae within the GI tract may be accelerated by constipation, diverticula, other conditions that reduce bowel motility, and use of steroids or other immunosuppressive agents. Via autoinfection, the burden of adult worms in infected humans can increase substantially in the absence of ongoing epidemiologic re-exposures.

In general, autoinfection is limited by an intact immune response; however, ongoing low levels of autoinfection may permit the infection to persist for decades and cause clinical manifestations to occur long after the initial infection [29]. Delayed onset of symptomatic infection has been observed among World War II ex-prisoners of war who worked on the Burma-Thailand railroad and presented with clinical manifestations more than 40 years after initial exposure [30].

In patients with glucocorticoid administration and/or diminished cell-mediated immunity, hyperinfection with disseminated disease may develop as a consequence of autoinfection [31,32]. (See 'Severe manifestations' below.)

Besides S. stercoralis, the only helminthic parasite capable of completing its life cycle entirely within the human host is Capillaria philippinensis. (See "Miscellaneous nematodes", section on 'Capillariasis'.)

Risk factors for severe disease — Immunosuppressed individuals are at risk for developing Strongyloides hyperinfection/disseminated disease; this can occur as a consequence of accelerated autoinfection even in the setting of a remote history of initial infection.

Risk factors include:

Conditions associated with impairment of cell-mediated immunity, including [31]:

Human T-lymphotropic virus type I (HTLV-I) infection – HTLV-I infection is an important risk factor for disseminated strongyloidiasis. One review and meta-analysis found that in regions of co-endemicity, those infected with HTLV-1 were more likely to be coinfected with S. stercoralis and, if coinfected, were more likely to fail treatment and develop severe manifestations of infection [33]. (See "Human T-lymphotropic virus type I: Disease associations, diagnosis, and treatment".)

Human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) – Disseminated strongyloidiasis can occur in patients with AIDS [34,35], but it occurs less frequently than in patients with HTLV-I and is much less common than might be predicted given the co-endemicity of the two infections [36]. In one systematic review including 7 studies and more than 2000 patients hospitalized with HTLV-I and strongyloidiasis, HIV infection was found in 41 percent of cases [33].

Malignancy

Hypogammaglobulinemia (including nephrotic syndrome and multiple myeloma) [37,38]

Congenital immunodeficiency

Alcoholism and/or malnutrition

Medical interventions associated with immunosuppression:

Administration of corticosteroids, cytotoxic drugs, or tumor necrosis factor inhibitors [31,39-49]. Hyperinfection syndrome has been described regardless of dose, duration, or route of corticosteroid administration; even short courses (eg, 6 to 17 days) have been associated with hyperinfection [4,42]. Hyperinfection has developed in patients with COVID-19-treated corticosteroids [50,51].

Solid organ transplantation, either from an infected donor to an uninfected recipient, or from an uninfected donor to an infected recipient whose subclinical infection is unmasked by immunosuppression [28].

Hematopoietic stem cell transplantation [28].

Pregnancy – Data on the risk of severe strongyloidiasis during pregnancy are limited; disseminated disease in pregnant patients has been described [52]. In one case, fatal disseminated strongyloidiasis developed in a patient who was infected with HTLV-1 and had received corticosteroids [52,53].

Issues related to prevention of Strongyloides infection prior to initiation of immunosuppressive therapy are discussed below. (See 'Asymptomatic individuals' below.)

CLINICAL MANIFESTATIONS

Signs and symptoms — Due to the capacity for internal reinfection, infection due to S. stercoralis may persist for decades. Clinical manifestations may be present in the context of chronic infection; moreover, infected individuals are at risk for severe manifestations.

Acute infection — The clinical manifestations of acute strongyloidiasis reflect the path of larval migration from the site of skin penetration to the small intestine, where new adults will develop and start producing larvae (figure 1) [4]. Clinical manifestations during larval penetrations are rarely recognized and reported.

Infected individuals may experience immediate irritation at the site of skin penetration [54]. Within a week following transmission, a dry cough may develop. Following the establishment of infection in the small intestine (as early as the third week following transmission), gastrointestinal (GI) symptoms such as diarrhea, constipation, abdominal pain, or anorexia may occur.

Approximately one month following transmission, larval production by the newly established adult worms begins; new cycles of infection may be initiated via autoinfection (either within the intestinal mucosa or the perianal skin).

Chronic infection — When present, clinical symptoms usually involve the GI tract and/or the skin; respiratory symptoms occur less commonly:

Gastrointestinal symptoms – When present, GI symptoms are usually mild. Abdominal pain may be periumbilical or mid-epigastric [55], the latter likely due to the duodenal localization of adult and larval parasites. Other symptoms may include diarrhea, constipation, intermittent vomiting, and borborygmi.

Dermatologic manifestations – Dermatologic manifestations include larva currens (picture 2), pruritus, urticaria, and angioedema.

Larva currens ("running" larva) presents as raised, pink, pruritic, evanescent streaks along the lower trunk, thighs, and buttocks, resulting from migrating larvae through the subcutaneous tissues (picture 2) [56]. Larva currens can progress approximately 1 cm in 5 minutes and 5 to 15 cm per hour. As the larvae move, they leave behind a thin red line that gradually fades to brown and disappears within 48 hours. While larva currens is pathognomonic for strongyloidiasis, it is uncommon. In contrast, urticaria is more frequent [55,57]. At times, urticaria may be the sole clinical manifestation of chronic strongyloidiasis [58]. In an allergy clinic in New York City, among 84 subjects who had positive strongyloides enzyme-linked immunosorbent assays (ELISA) tests, 52 (61.9 percent) experienced cutaneous manifestation (pruritus, urticaria, angioedema, and/or rash) and half of these experienced symptomatic improvement after treatment with ivermectin [59].

Respiratory symptoms – Respiratory symptoms include dry cough, throat irritation, dyspnea, and wheezing. Asthma that paradoxically worsens with corticosteroid use may occur [60-62].

Eosinophilia may be observed, in the presence or absence of symptoms (see 'Laboratory findings' below). While eosinophilia may be indicative of strongyloidiasis, the absence of eosinophilia does not exclude infection with strongyloides or other intestinal helminths [63].

A meta-analysis aiming to describe the pattern and frequency of clinical and laboratory characteristics associated with S. stercoralis infection showed that symptoms were reported in 50.4 percent of cases, more often in nonendemic than endemic areas (58 versus 36 percent), and almost 70 percent had eosinophilia [64].

Severe manifestations — Severe manifestations of strongyloidiasis include hyperinfection and disseminated infection; these occur in a minority of cases and are usually associated with immunosuppression. (See 'Risk factors for severe disease' above.)

Hyperinfection refers to accelerated autoinfection; signs and symptoms are attributable to increased larval migration within the organs normally involved in the autoinfection cycle (ie, the GI tract, lungs, and skin) (figure 1).

Disseminated disease consists of hyperinfection syndrome with spread of larvae to organs and tissues outside those in the autoinfection cycle; these may include the liver, gallbladder, pancreas, kidneys, ovaries, mesenteric lymph nodes, diaphragm, heart, brain, and skeletal muscle [4]. At times, adult worms localize in the bronchial tree and lay eggs that develop into larvae.

Severe manifestations involving the GI tract, respiratory tract, and skin include:

GI symptoms reflecting the presence of large quantities of larvae in the intestinal lumen; they are nonspecific and include abdominal pain (crampy or bloating in nature), watery diarrhea, constipation, anorexia, weight loss, difficulty swallowing, nausea, and vomiting. Electrolyte disturbances, inflammation, bleeding, ulceration, and small bowel obstruction may occur; fever and hemodynamic instability should prompt suspicion for perforation. Colitis and proctitis may be associated with occult or gross blood. Additional manifestations may include protein-losing enteropathy or ascites. Abdominal radiographic imaging may demonstrate paralytic ileus with dilated, thickened bowel loops (in the absence of evidence for mechanical obstruction), and/or small bowel distension with air-fluid levels.

Respiratory symptoms usually reflect the irritative responses related to the passage of larvae; these may include fever, dyspnea, cough, wheezing, choking, hoarseness, chest pain, hemoptysis, and palpitations [65]. Acute respiratory distress syndrome can occur during severe disease, usually in the setting of multiorgan failure. Chest radiographic imaging may demonstrate bilateral or focal interstitial infiltrates reflecting alveolar hemorrhage (image 1).

Dermatologic findings include larva currens on the lower trunk, thighs, and buttocks. In addition, widespread petechial and purpuric lesions may develop. Periumbilical purpura may be a pathognomonic manifestation of disseminated infection; it refers to radiation of purpura from the umbilical area and resembles thumbprints [66,67].

Migration of filariform larvae during autoinfection may facilitate entry of enteric organisms into the systemic circulation. Clinically, this may manifest as extraintestinal bacterial infection such as pneumonia, meningitis, or sepsis; therefore, presence of fever and/or hemodynamic instability should prompt evaluation for systemic bacterial infection [68]. In such cases, bacterial cultures (from the blood, sputum, spinal fluid, or other sites) may demonstrate enteric flora, and polymicrobial bacterial infection can occur.

Peripheral eosinophilia is usually absent in the setting of hyperinfection and disseminated infection. (See 'Laboratory findings' below.)

Strongyloidiasis is not common among patients with HIV infection; however, hyperinfection/disseminated strongyloidiasis has been described as a manifestation of immune reconstitution inflammatory syndrome [69,70].

Physical examination — Given the broad range of clinical manifestations, physical examination should include multisystem evaluation, particularly the chest, abdomen, skin, and central nervous system. Specific findings are described above. (See 'Signs and symptoms' above.)

Laboratory findings — In the setting of chronic infection, eosinophilia may be observed in approximately two-thirds of cases, in the presence or absence of symptoms [71,72]. In one report of refugees to the United States from Southeast Asia, eosinophilia (>400 cells/mL) was associated with a diagnosis of strongyloidiasis [71]. However, the sensitivity of eosinophilia for strongyloidiasis was low; no eosinophilia was observed among patients with positive Strongyloides polymerase chain reaction in 27 percent of cases.

In the setting of the hyperinfection syndrome, peripheral eosinophilia is usually absent; more often there is suppression of peripheral eosinophil levels, sometimes related to corticosteroid therapy or concomitant bacterial infection. The presence of peripheral eosinophilia during hyperinfection appears to predict a better prognosis [73,74].

Variable elevated serum IgE levels have been observed in 39 to 58 percent of cases [75]. This finding is generally not observed among patients with human T-lymphotropic virus type I (HTLV-I) and strongyloidiasis, however, which may be related to impaired ability of patients with HTLV-I infection to clear S. stercoralis infection [76-78].

Endoscopic findings — There is no role for routine endoscopy for diagnosis of strongyloidiasis. For patients with GI symptoms of uncertain etiology who undergo endoscopy, it may be possible to establish a diagnosis of strongyloidiasis.

Endoscopic features of strongyloidiasis include:

Duodenum – Edema, brown mucosal discoloration, erythematous spots, subepithelial hemorrhages, and megaduodenum. Biopsy may demonstrate parasites in the gastric crypts or duodenal glands and eosinophilic infiltration of the lamina propria [79-82].

Colon – Edema, loss of vascular pattern, aphthous ulcers, erosions, serpiginous ulcerations, and xanthoma-like lesions (picture 3). Strongyloides colitis may mimic ulcerative colitis [83]. (See 'Differential diagnosis' below.)

Stomach – Thickened folds and mucosal erosions [82,84].

DIAGNOSIS — Diagnosis of chronic strongyloidiasis can be challenging given the low sensitivity of stool microscopy, low specificity of serology, and the lack of wide availability deoxyribonucleic acid (DNA)-based methods. Diagnosis of hyperinfection syndrome/disseminated infection is less difficult, given the florid clinical presentation and the large numbers of larvae often seen in the stool or other body fluids.

Issues related to diagnosis of symptomatic patients are discussed in the following section; issues related to screening of asymptomatic individuals are discussed below. (See 'Asymptomatic individuals' below.)

Clinical approach — Strongyloidiasis should be suspected among patients with relevant epidemiologic exposure (eg, skin contact with contaminated soil in tropical and subtropical regions) and gastrointestinal (GI), respiratory, and/or dermatologic manifestations (with or without eosinophilia) [4,5]. The diagnosis also warrants consideration in patients with systemic infection due to enteric organisms with no obvious cause [85-87].

Laboratory tools for diagnosis of strongyloidiasis include stool testing and serology. The clinical approach depends on the clinical circumstances:

For asymptomatic patients with suspected chronic infection, the approach is discussed below. (See 'Asymptomatic individuals' below.)

For patients with dermatologic manifestations, respiratory manifestations, and/or eosinophilia (in the absence of GI symptoms), we favor serologic testing. For patients with dermatologic manifestations, skin biopsy may demonstrate larvae.

For patients with GI symptoms, we favor serologic testing as well as stool testing. Stool microscopy allows evaluation for strongyloidiasis as well as other causes of GI symptoms, although the sensitivity is low. For settings in which stool polymerase chain reaction (PCR) is available, this assay is preferable given its relatively high sensitivity and specificity. As an alternative, stool can be sent for agar plate culture. (See 'Stool studies' below.)

For patients with suspected hyperinfection syndrome, we favor serologic testing as well as stool testing. In addition, blood cultures should be obtained to rule out secondary bacterial infection. We also pursue diagnostic testing tailored to clinical manifestations:

Patients with respiratory symptoms should undergo chest radiography as well as evaluation of respiratory specimens; larvae may be observed in sputum, bronchoalveolar lavage fluid, or pleural fluid [88,89].

Patients with ascites should undergo paracentesis with evaluation for larvae in peritoneal fluid.

Patients with neurologic symptoms should undergo lumbar puncture to assess cerebrospinal fluid for larvae as well as findings consistent with meningitis (See "Clinical features and diagnosis of acute bacterial meningitis in adults".)

Stool studies — The traditional diagnostic approach consists of microscopy for direct identification of S. stercoralis larvae in stool; this is still done in many laboratories, but the sensitivity is relatively low (<50 percent) given intermittent larval excretion. Larvae may be detectable in stool three to four weeks after dermal penetration (picture 1) [90].

Other stool testing approaches include agar plate culture, sedimentation concentration, Baermann concentration with charcoal culture, and Harada-Mori filter paper technique [91,92]. These specialized techniques are rarely available in most diagnostic microbiology laboratories and have not been employed in most studies that report treatment efficacy [93].

Of the above techniques, agar plate culture is most sensitive; however, assessing the accuracy is difficult given lack of a gold standard for diagnosis [94-96]. This method involves inoculating agar plates with stool and incubating for two days at room temperature [97]; such testing can be performed at the United States Centers for Disease Control and Prevention [98]. Larvae crawl on the agar and spread bacteria in their paths, creating bacterial growth patterns on the agar surface. Larvae may be observed by macroscopic examination of the plates; their presence can be confirmed by washing the plate surface with formalin and examining the washing sediment [99].

The sensitivity of stool detection may be improved with increased number of stool samples for examination; when as many as seven stool samples are studied, the sensitivity may approach 100 percent [90,100]. However, patterns of stool detection are variable among infected individuals. In one study including 108 asymptomatic Brazilian men with strongyloidiasis, eight weekly stool exams were performed without intervening treatment [100]. Among 29 men with detectable larvae in only one of the first four specimens, all of the next four samples were negative in 76 percent of cases.

Stool nucleic acid amplification tests (NAATs) have greater specificity for diagnosis of Strongyloides than direct stool examination [4,101-103]. In one systematic review of PCR for diagnosis of strongyloidiasis, the sensitivity and specificity were 72 and 93 percent, respectively [104]. However, sensitivity estimates vary widely depending on the DNA extraction and molecular methods used [105]. In some cases, suboptimal sensitivity may be attributable to intermittent larval production and presence of PCR inhibitors in stool. Use of stool NAATs for diagnosis of Strongyloides infection is limited by availability but is increasing, particularly with use of multiplex PCR for GI pathogens.

Serology — Serologic tests may be used to overcome the limitations of stool testing, with greater sensitivity [106]. Serologic tests include enzyme-linked immunosorbent assays (ELISAs), indirect immunofluorescence microscopy, gelatin particle agglutination, and immunoblot.

Most serologic tests measure IgG or IgG4 response to a crude soluble extract of larvae obtained from experimentally infected animals or related Strongyloides species. Limitations include cross-reactivity in patients with filarial infection or infection due to other soil-transmitted helminths, diminished sensitivity in patients with hematologic malignancy or human T-lymphotropic virus type I infection, inability to distinguish between current and prior infection, and lack of standardization across centers [99,107]. Recombinant antigens have been used with improved diagnostic accuracy to overcome some of these limitations. In addition, using a combination of serologic tests may help increase specificity [95].

The negative predictive value of serologic screening is higher among migrants than returning travelers [108,109]. In one study of two commercially available ELISAs, high sensitivity (89 and 83 percent, respectively) and specificity (97 percent) for diagnosis of chronic infection were reported [110]. Another study compared two ELISA assays and a luciferase immunoprecipitation system (LIPS) assay for detection of IgG antibodies to S. stercoralis among 101 serum samples; agreement between all three assays was observed in 65 percent of cases, and each method had similar numbers of positive samples (84 to 89 percent) [111]. In another study including 86 patients with microscopically proven strongyloidiasis, serologic testing was associated with 81 percent sensitivity [108].

ELISAs for detection of Strongyloides antigens are being refined, including via multiplexed antigen detection assays [112]. Immunochromatographic tests (ICTs) for the diagnosis of S. stercoralis infection are also being developed. In one study of sera from 274 migrants from sub-Saharan Africa, ICT had a sensitivity and specificity of 82 and 74 percent, respectively, compared with stool agar plate culture and/or PCR [113]. Future optimization of ICTs may enable their use for screening purposes.

Urine testing for strongyloides-specific IgG by ELISA has also been evaluated, with studies suggesting it to have a diagnostic accuracy comparable with serologic assay, being more sensitive than fecal methods and with minimal daily variation [114,115]. Concentrated-urine ELISA testing is also being evaluated for diagnosis of Strongyloides [116].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of uncomplicated strongyloidiasis includes:

Ascariasis and hookworm – Strongyloidiasis, ascariasis, and hookworm can all cause nonspecific gastrointestinal and/or pulmonary symptoms or chronic urticaria and/or pruritus. In addition, all can be associated with eosinophilia in the presence or absence of other symptoms. Coinfection can occur; the diagnoses are distinguished by stool microscopy. (See "Approach to stool microscopy".)

Cutaneous larva migrans (CLM) – Larva currens, the dermatologic manifestation of strongyloidiasis, must be distinguished from CLM; both are associated with migratory serpiginous lesions that are erythematous, raised, and pruritic. Usually the conditions can be distinguished clinically based on the speed of advancement; larva currens can progress approximately 1 cm in 5 minutes and 5 to 15 cm per hour, while the larval track of cutaneous larva migrans progresses approximately 1 to 2 cm per day. Additionally, larva currens is typically evanescent and pink, whereas CLM is angry-looking, red, raised, and typically persists for weeks. (See "Hookworm-related cutaneous larva migrans".)

Ulcerative colitisStrongyloides colitis may mimic ulcerative colitis; distinctive features of strongyloidiasis include skip pattern of inflammation, distal attenuation of the disease, eosinophil-rich infiltrates, relatively intact crypt architecture, and frequent involvement of submucosa with erythematous nodules (picture 3) [83]. (See "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults".)

The differential diagnosis of hyperinfection syndrome/disseminated disease includes:

Loeffler syndrome – Besides S. stercoralis, other helminths with life cycles in which infecting larvae migrate the lungs via the bloodstream and penetrate into alveoli include Ascaris (A. lumbricoides, A. suum) and hookworms (Ancylostoma duodenale, Necator americanus). Loeffler syndrome refers to transient pulmonary radiographic opacities and peripheral blood eosinophilia in the setting of ascariasis. (See "Overview of pulmonary eosinophilia", section on 'Transpulmonary passage of helminth larvae (Löffler syndrome)' and "Ascariasis", section on 'Early phase: Pulmonary manifestations'.)

Tropical filarial pulmonary eosinophilia – Tropical filarial pulmonary eosinophilia occurs in the context of lymphatic filariasis; symptoms include dry cough, wheeze, and fatigue. Tropical pulmonary eosinophilia is characterized by eosinophilia above 3000/microL; the diagnosis can be confirmed by filarial antibody titers. (See "Tropical pulmonary eosinophilia".)

Meningococcal meningitis – Both meningococcal meningitis and strongyloidiasis may present with neurologic manifestations, purpura, and hemodynamic instability. The diagnosis of meningococcal meningitis is established via lumbar puncture. (See "Clinical manifestations of meningococcal infection" and "Diagnosis of meningococcal infection".)

MANAGEMENT — Treatment with anthelminthic therapy is warranted for symptomatic and asymptomatic individuals, regardless of immune status. The goal of treatment is cure, in order to prevent development of severe disease in the context of chronic autoinfection.

Issues related to treatment of symptomatic patients are discussed in the following section; issues related to treatment of asymptomatic individuals are discussed below. (See 'Asymptomatic individuals' below.)

Initial approach

Uncomplicated infection — For patients with uncomplicated strongyloidiasis, we favor treatment with ivermectin:

For immunocompetent patients, we favor a single-dose or two-dose regimen (200 mcg/kg per day for one or two days) [4,117,118]. The approach to regimen selection varies among experts; data supporting either approach are limited.

For immunocompromised patients, we favor a four-dose regimen (200 mcg/kg daily for two days, repeated at two weeks [eg, one autoinfection cycle]), given the potentially devastating nature of Strongyloides infection in the setting of immunosuppression and the high tolerability of ivermectin, even though clinical data to support this approach are lacking.

Ivermectin is lipophilic. In individuals with higher body mass index, this can result in lower plasma levels; however, this can also result in a longer half-life and time to clearance [119-121]. The clinical impact of these effects on treatment efficacy is unknown; given the lipophilicity, we favor dosing based on actual body weight.

Following treatment, follow-up monitoring should be performed as described below. (See 'Follow-up' below.)

For individuals from areas of Africa endemic for loiasis, screening for loiasis microfilaremia (via blood smear) should be performed prior to administration of ivermectin; administration of ivermectin to highly microfilaremic patients can precipitate life-threatening encephalopathy. (See "Loiasis (Loa loa infection)".)

The efficacy of ivermectin (200 mcg/kg per day for one or two days) has been shown to be greater than that of albendazole (400 mg twice a day for three to seven days) and comparable with that of thiabendazole (25 mg/kg per day for three days) [117,122]. In a meta-analysis including seven trials and more than 1100 patients with chronic strongyloidiasis, cure rates for ivermectin were superior to albendazole and comparable with thiabendazole (74 to 84 percent, 48 percent, and 69 percent, respectively) [117]. Use of thiabendazole is limited by gastrointestinal adverse effects and drug availability.

Data comparing single-dose and two-dose ivermectin regimens are limited, and the available tools to assess treatment response (stool exams and serologic titer) have limited specificity. In one randomized trial including 31 patients treated with single-dose therapy and 29 patients treated with two-dose therapy, treatment failure (assessed via stool exam) was observed in 3.2 versus 6.9 percent, respectively [122]. In another randomized trial including 16 patients treated with single-dose ivermectin and 18 patients treated with two-dose ivermectin, there were no cases of treatment failure (assessed via stool exam) [123].

Ivermectin failure has been observed, even in immunocompetent hosts. For this reason, a four-dose regimen of ivermectin (two doses administered two weeks apart) has been proposed, since the duration of the autoinfection cycle is two weeks [118,124-126]. However, thus far, available data do not suggest superior efficacy for a four-dose regimen over a one-dose regimen. In a randomized trial including more than 300 patients in nonendemic areas with positive serology (high titer) or positive serology (any titer) plus positive stool test, patients were randomly assigned to one-dose or four-dose ivermectin treatment [127]. After 12 months, the response rate (assessed via fall in serologic titer) was comparable between the groups (86 versus 85 percent, respectively). Mild adverse events occurred more frequently among those in the four-dose cohort.

Severe disease — For patients with known or suspected hyperinfection/disseminated strongyloidiasis, treatment with ivermectin (200 mcg/kg per day) should be initiated, as should empiric antibiotic therapy with activity against enteric gram-negative bacteria. In addition, patients on immunosuppressive agents should have these regimens reduced, if feasible. (See "Gram-negative bacillary bacteremia in adults".)

The optimal duration of ivermectin for hyperinfection/disseminated strongyloidiasis is uncertain; we favor treatment for at least two weeks, tailored to individual circumstances. For patients with persistent immunosuppression or critical illness in the setting of persistently positive stool examination for ≥3 days on ivermectin monotherapy, many experts would switch from ivermectin monotherapy to combination treatment with ivermectin plus albendazole until clinical improvement is observed [128].

We continue anthelminthic treatment until symptoms have resolved and daily stool examination is negative for at least two weeks (one autoinfection cycle). For patients with persistent immunosuppression whose symptoms have resolved, we favor administration of suppressive ivermectin once monthly for at least six months [129].

For patients unable to take ivermectin orally or via nasogastric tube (eg, due to severe systemic illness or paralytic ileus), ivermectin may be administered subcutaneously [130,131]. Rectal administration has also been used successfully as an alternative in such cases [132], although some data suggest that rectal suppositories of ivermectin may not achieve sufficient serum levels [133].

Patients with hyperinfection/disseminated infection that does not resolve after initial treatment should be evaluated for an underlying immune defect such as human T-lymphotropic virus type I infection. (See "Human T-lymphotropic virus type I: Disease associations, diagnosis, and treatment", section on 'Diagnosis'.)

Follow-up — Following completion of treatment, our follow-up approach is as follows:

For patients with persistent symptoms following completion of treatment, we favor repeat treatment as described below.

For patients with positive stool examination prior to treatment, we perform repeat stool examination two to four weeks after treatment. Patients with persistently positive stool examination warrant repeat treatment as described below. However, a negative stool exam is not definitive proof of parasitologic cure, since the sensitivity of stool examination is relatively low. (See 'Stool studies' above.)

For patients with positive stool polymerase chain reaction (PCR) prior to treatment, we do not favor follow-up stool PCR testing; the role of stool PCR for follow-up monitoring is uncertain [118]. (See 'Stool studies' above.)

For patients with eosinophilia prior to treatment, we perform repeat complete blood counts with differential every three months for up to twelve months. In one study including 31 patients treated for strongyloidiasis, reductions in peripheral eosinophilia was observed after an average of 96 days [134].

Persistent eosinophilia up to twelve months after following treatment may reflect failure to eradicate strongyloidiasis and/or an alternative etiology [135]. Such patients should be evaluated for alternative causes of eosinophilia; if none is identified, a repeat course of treatment for strongyloidiasis is reasonable. (See "Approach to the patient with unexplained eosinophilia".)

For patients with positive serology prior to treatment, use of serologic monitoring for follow-up should be guided by the type of assay used. For some assays, successful treatment has been associated with falling immunoreactivity at three to six months [134,136,137]; however, for other assays, use of serologic monitoring for follow-up is hampered by lack of standardization.

The optimal approach to repeat treatment in the setting of treatment failure is uncertain; reasonable approaches include a repeat two-dose ivermectin regimen (200 mcg/kg per day for two days) or a four-dose ivermectin regimen (200 mcg/kg daily for two days, repeated at two weeks).

Patients with treatment failure should be evaluated for human T-lymphotropic virus type I infection [138,139]. (See "Human T-lymphotropic virus type I: Disease associations, diagnosis, and treatment".)

PROGNOSIS — Among patients with hyperinfection/disseminated infection, the mortality rate is up to 70 to 100 percent; Factors that increase the likelihood of mortality include concomitant immunosuppression, bacteremia, and delayed diagnosis [4,140,141].

ASYMPTOMATIC INDIVIDUALS

Screening — Serologic screening of asymptomatic individuals for strongyloidiasis is warranted in the following circumstances [6,16,134,142-147]:

Patients with relevant epidemiologic exposure (eg, skin contact with contaminated soil in tropical and subtropical regions) who are undergoing medical interventions associated with immunosuppression (including solid organ transplantation, hematopoietic stem cell transplantation, or administration of corticosteroids, cytotoxic drugs, or tumor necrosis factor inhibitors). (See 'Geography' above and 'Risk factors for severe disease' above.)

Organ donors with relevant epidemiologic exposure (eg, skin contact with contaminated soil in tropical and subtropical regions). (See "Evaluation for infection before solid organ transplantation" and "Evaluation for infection before hematopoietic cell transplantation".)

Military personnel with history of service in areas where strongyloidiasis is endemic (even in the setting of remote exposure).

Immigrants and refugees. (See "Medical care of adult immigrants and refugees".)

For screening asymptomatic patients with suspected chronic infection, we favor serologic testing; stool testing is not sufficiently sensitive [94]. For asymptomatic patients who are embarking on immunosuppressive therapy, we perform serologic testing followed by prompt administration of empiric treatment (eg, before the results of serologic testing are available). (See 'Preventive treatment' below.)

For transplant candidates and transplant recipients diagnosed with strongyloidiasis, we perform serologic screening for human T-lymphotropic virus type I infection [7]. (See "Human T-lymphotropic virus type I: Disease associations, diagnosis, and treatment".)

Issues related to risk factors for severe disease are discussed above. (See 'Risk factors for severe disease' above.)

Preventive treatment — The optimal approach to preventive treatment of individuals with asymptomatic strongyloidiasis is uncertain; in general, our approach is as follows:

For patients with relevant epidemiologic exposure (eg, skin contact with contaminated soil in tropical and subtropical regions) who require prompt initiation of immunosuppression, we perform serologic testing and administer empiric preventive treatment for strongyloidiasis (ivermectin 200 mcg/kg daily for two days, repeated at two weeks) while test results are pending [7].

For patients with relevant epidemiologic exposure (eg, skin contact with contaminated soil in tropical and subtropical regions) who require immunosuppression but need not begin promptly (ie, there is sufficient time to pursue screening), we perform serologic testing; for patients with positive serologic test results, we administer preventive treatment for strongyloidiasis (ivermectin 200 mcg/kg daily for two days, repeated at two weeks) [7].

For organ transplant recipients whose organ donors have positive serologic testing for strongyloidiasis, we administer preventive treatment to the recipient (ivermectin 200 mcg/kg daily for two days, repeated at two weeks) [27,148]. For living donors (who are not otherwise immunosuppressed), we administer preventive treatment for strongyloidiasis (ivermectin 200 mcg/kg daily for two days).

For patients with positive serologic test results who do not require immunosuppression (such as military personnel, immigrants, and refugees), we administer preventive treatment for strongyloidiasis (ivermectin 200 mcg/kg daily for two days).

For asymptomatic seropositive individuals who are receiving immunosuppressive therapy, we favor a four-dose preventive treatment regimen (single dose administered on two consecutive days, then repeated after one autoinfection cycle) rather than a two-dose regimen, given the potentially devastating nature of Strongyloides infection in the setting of immunosuppression and the high tolerability of ivermectin; however, there is no clinical evidence to support this approach. For asymptomatic seropositive individuals who are not receiving immunosuppressive therapy, an empiric two-dose preventive treatment regimen (ivermectin 200 mcg/kg daily for two days) is reasonable.

SUMMARY AND RECOMMENDATIONS

General principles – Strongyloidiasis is caused by infection with the helminth Strongyloides stercoralis. This organism is capable of completing its life cycle entirely within the human host. Therefore, chronic asymptomatic infection can be sustained for decades, and clinical manifestations can occur long after the initial infection. In addition, among patients with subclinical infection who subsequently become immunosuppressed, larval reproduction can lead to disseminated infection. (See 'Introduction' above.)

Epidemiology – Strongyloidiasis is endemic in rural areas of tropical and subtropical regions; in these areas, the overall regional prevalence may exceed 25 percent. In addition, strongyloidiasis occurs sporadically in temperate areas such as North America, southern Europe, Japan, and Australia. (See 'Epidemiology' above.)

Life cycle – The life cycle begins when human skin contacts filariform larvae (the infective larval stage) of S. stercoralis, which are found in soil or other materials contaminated with human stool (figure 1). The filariform larvae penetrate the skin and migrate via the bloodstream and lymphatics to the lungs, where they penetrate into the alveolar air sacs. The larvae then ascend the tracheobronchial tree and are swallowed. In addition, autoinfection can occur; in this part of the life cycle, the rhabditiform larvae become infective filariform larvae within the human gastrointestinal (GI) tract. (See 'Life cycle and autoinfection' above.)

Risk factors for severe disease – Immunosuppressed individuals are at risk for developing Strongyloides hyperinfection/disseminated disease; this can occur as a consequence of accelerated autoinfection even in the setting of a remote history of initial infection. Risk factors include conditions associated with impairment of cell-mediated immunity and medical interventions associated with immunosuppression. (See 'Risk factors for severe disease' above.)

Clinical manifestations and laboratory findings

Acute and chronic infection – Strongyloidiasis may be asymptomatic or associated with nonspecific complaints in more than half of cases. Signs and symptoms of acute and chronic infection may include GI symptoms, respiratory symptoms, and dermatologic manifestations (picture 2). In the setting of chronic infection, eosinophilia may be observed in approximately two-thirds of cases (in the presence or absence of symptoms). (See 'Signs and symptoms' above and 'Laboratory findings' above.)

Severe manifestations – Severe manifestations of strongyloidiasis include hyperinfection and disseminated infection; these occur in a minority of cases and are usually associated with immunosuppression. Hyperinfection refers to accelerated autoinfection; signs and symptoms are attributable to increased larval migration within the organs normally involved in the autoinfection cycle (ie, the GI tract, lungs, and skin). Disseminated disease consists of hyperinfection with spread of larvae to organs and tissues outside those in the autoinfection cycle. Larval migration may facilitate entry of enteric organisms into the systemic circulation; this may manifest clinically as extraintestinal bacterial infection such as pneumonia, meningitis, or sepsis. In the setting of severe disease, peripheral eosinophilia is usually absent. (See 'Severe manifestations' above and 'Laboratory findings' above.)

Diagnosis – (see 'Diagnosis' above):

Clinical approach – Strongyloidiasis should be suspected in patients with relevant epidemiologic exposure (eg, skin contact with contaminated soil in tropical and subtropical regions) and GI, respiratory, and/or dermatologic manifestations (with or without eosinophilia). The diagnosis also warrants consideration in patients with systemic infection due to enteric organisms with no obvious cause.

Laboratory testing – Laboratory tools for diagnosis of strongyloidiasis include stool testing and serology. In general, the preferred diagnostic approach consists of serologic testing. For patients with GI symptoms and for patients with suspected hyperinfection syndrome, we also perform stool testing. Additional diagnostic testing should be tailored to clinical manifestations.

Management – For patients with strongyloidiasis, we suggest treatment with ivermectin rather than alternative agents (Grade 2B) (see 'Management' above):

Immunocompetent patients – For immunocompetent patients with uncomplicated strongyloidiasis, we suggest a single-dose or two-dose regimen over a longer regimen (Grade 2C). The approach to regimen selection varies among experts; data supporting either approach are limited. (See 'Uncomplicated infection' above.)

Immunocompromised patients – For immunocompromised patients with uncomplicated strongyloidiasis, we suggest a four-dose regimen (200 mcg/kg daily for two days, repeated at two weeks) over a shorter regimen (Grade 2C), given the potentially devastating nature of Strongyloides infection in the setting of immunosuppression and the high tolerability of ivermectin. (See 'Uncomplicated infection' above.)

Hyperinfection/disseminated infection – For patients with known or suspected hyperinfection/disseminated strongyloidiasis, the optimal duration of ivermectin is uncertain; we favor treatment for at least two weeks and continue until symptoms have resolved and daily stool examination is negative for at least two weeks (one autoinfection cycle); a longer duration of treatment may be warranted for patients with persistent immunosuppression. In addition, we initiate empiric antibiotic therapy with activity against enteric gram-negative bacteria. Patients on immunosuppressive agents should have these regimens reduced, if feasible. (See 'Severe disease' above.)

Screening – (see 'Screening' above):

Whom to screen – Serologic screening of asymptomatic individuals for strongyloidiasis is warranted for patients with relevant epidemiologic exposure who are undergoing medical interventions associated with immunosuppression, organ donors with relevant epidemiologic exposure, military personnel with history of service in endemic areas, and immigrants and refugees with relevant epidemiologic exposure. (See 'Screening' above.)

Clinical approach – For asymptomatic patients with relevant epidemiologic exposure who require prompt initiation of immunosuppression, we perform serologic testing and administer empiric preventive ivermectin while test results are pending. For asymptomatic patients with relevant epidemiologic exposure who require immunosuppression but need not begin promptly (ie, there is sufficient time to pursue screening), we perform serologic testing and administer empiric preventive ivermectin for those with positive results.

Preventive treatment – For preventive treatment of asymptomatic patients with strongyloidiasis who require immunosuppression, we suggest a four-dose ivermectin regimen over a shorter regimen (Grade 2C), given the potentially devastating nature of Strongyloides infection in the setting of immunosuppression and the high tolerability of ivermectin. For preventive treatment of asymptomatic immunocompetent patients with strongyloidiasis, we suggest a two-dose regimen (Grade 2C). (See 'Preventive treatment' above.)

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Topic 5714 Version 43.0

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