Strongyloides stercoralis.

Strongyloidiasis has been estimated to affect over 600 million people worldwide. It is caused by Strongyloides stercoralis, a roundworm endemic to the tropics and subtropics, especially areas where sanitation is suboptimal Autochthonous transmission has been documented in rural areas of the USA and Europe. Humans are infected when larvae penetrate the skin or are ingested. Autoinfection, in which larvae generated in the host go on to re-infect the host, leads to a state of chronic asymptomatic infection often with eosinophilia. Hyperinfection syndrome may develop when patients develop immune suppression, due to medications such as corticosteroids or following solid-organ transplantation. Hyperinfection is characterized by exponential increase in parasitic burden, leading to tissue invasion and life-threatening disease and associated bloodstream infections due to enteric organisms. Cases following use of corticosteroids for COVID-19 pneumonia have been described. Strongyloidiasis can be diagnosed by direct visualization of larvae in stool or other body fluids, or by serology. Ivermectin is highly effective in treating the disease. Patients with exposure to endemic areas and those expected to become immune suppressed should be screened and treated before starting immune suppressive agents. Empiric treatment should be considered when timely testing is not readily available.

Introduction

Strongyloides stercoralis is a roundworm (nematode) that causes the disease known as strongyloidiasis. It has been estimated to affect over 600 million people worldwide [1], and is of particular clinical importance due to its ability to cause chronic infection that can become life-threatening in the setting of immunosuppression. Though S. fuelleborni and some other zoonotic species have been implicated as human pathogens, they are of minor medical relevance [2]. This review will focus on the epidemiology, basic parasitology, presentation, diagnosis, and management of S. stercoralis infection.

Epidemiology

Strongyloides stercoralis is endemic worldwide, but is most prevalent in tropical and subtropical climates, especially in areas with inadequate sanitary conditions. Community-based studies have estimated a prevalence of over 70% in countries such as Peru, Kenya, Namibia, and Papua New Guinea. In the USA and Europe the majority of cases are considered imported, though local transmission has been reported mainly in rural areas. A recent prospective study that enrolled patients in Cataluña (Spain) from 2003 to 2012 found seventy cases of strongyloidiasis, diagnosed either by serologic testing, or by sputum or fecal parasitology. Of these, 59% were considered to have originated in South America and the Caribbean, 26% in sub-Saharan Africa, 13% in Southeast Asia, and only 3% were considered autochthonous [3]. Infection with human immunodeficiency virus (HIV), human T-lympho-tropic virus 1 (HTLV-1), hypogammaglobulinemia, alcoholism, and malnutrition have been associated with an increased risk of strongyloidiasis [4, 5]. Institutionalized patients also seem to be more commonly affected [6]. In the USA, a seroprevalence as high as 4% has been documented in areas of rural Kentucky, with most cases occurring in American-born patients that had not traveled to endemic areas [7]. Statistical modeling has suggested that up to 16 states are at high risk of local transmission [8].

Transmission

The lifecycle of S. stercoralis is summarized in Fig. 1. S. stercoralis most commonly infects humans through the cutaneous route. Filariform larvae can be found in soil and penetrate the skin of people who go barefoot, which presents as “ground itch”. After penetration, filariform larvae migrate to the lungs, where they mature, are coughed up, and swallowed. When in the small intestine, the larvae mature into adult females, which in turn intermittently produce eggs through asexual reproduction. These then hatch into rhabditiform larvae, which are excreted in stool. The rhabditiform larvae, which are non-infectious, then give rise to the infectious filariform larvae, either in soil or in the own host’s intestine. The latter causes the unique phenomenon of autoinfection, in which filariform larvae generated in the host itself invade intestinal mucosa or perianal skin and restart the infectious cycle [9], which in turn leads to a chronic and frequently subclinical infection. Primary infection can also occur by ingestion of the filariform larvae, either by consumption of contaminated food or water, or sexually, by anal–oral contact [10]. In people with delayed fecal transport, autoinfection can be significant and cause large worm burdens. In those where fecal soilage of the skin occurs for prolonged periods of time, penetration of filariform larvae can cause local irritation as well as autoinfection. Cases of transmission following kidney transplantation have also been reported [11].

Fig. 1

Lifecycle of S. stercoralis. (1) Filariform larvae penetrate the host’s skin and migrate to pulmonary parenchyma. (2) Filariform larvae are coughed up and swallowed. (3) Filariform larvae migrate to small intestine and lay eggs, which hatch into rhabditiform larvae. (4) Rhabditiform larvae are excreted in soil and give rise to infectious filariform larvae, which are able to penetrate skin and restart the cycle. S. stercoralis also has a free-living life cycle, independent of human hosts. (5) Rhabditiform larvae may give rise to infectious filariform larvae in the host itself, leading to invasion of intestinal mucosa and/or perianal skin, process known as autoinfection. In the right host, this may lead to hyperinfection syndrome. Figure created with Biorender

Clinical Spectrum of Disease

Strongyloidiasis occurs in three forms: acute, caused by primary parasitic invasion; chronic, caused by autoinfection; and hyperinfection, which typically occurs in the setting of immunosuppression. Table 1 further outlines the wide array of manifestations that have been described in this disease. The most common pulmonary manifestations of strongyloidiasis are transient pulmonary opacities with cough, dyspnea, and bronchospasm often with associated pulmonary and peripheral eosinophilia. Chest radiographs range from being normal to showing bilateral opacities. Other manifestations that have been reported include lobar infiltrates, interstitial infiltrates, and abscess/cavitation. Strongyloidiasis may cause asthma with improvement of asthma occurring following treatment of this infection. Patients with chronic obstructive pulmonary disease (COPD) or asthma form endemic regions should be screened for strongyloidiasis, especially before starting steroids which could trigger a hyperinfection syndrome.

Table 1

Presentation, diagnosis, and management S. stercoralis infection

Phase	Host	Presentation	Diagnosis	Management
Acute strongyloidiasis	Recent exposure to endemic area	Larva currens Loeffler-like syndrome Heartburn Anorexia Abdominal pain Constipation Diarrhea	Stool positive 3 to 4 weeks after initial infection Multiple samples may be required to obtain diagnosis Limited utility of serology, typically negative	Single or multiple dose ivermectin 200 μg/kg
Chronic strongyloidiasis	Remote exposure to endemic area	Often asymptomatic May cause intermittent nausea/vomiting, diarrhea, constipation, abdominal pain Pruritus ani Urticaria Recurrent asthma Eosinophilia	Stool positive (multiple samples required may be required for diagnosis) Serology positive	Single or multiple dose ivermectin 200 μg/kg
Strongyloides hyperinfection syndrome	Remote exposure to endemic area and: Immunosuppression (corticosteroids, chemotherapy) Bone marrow transplant Solid-organ transplant Human T-Lymphotropic virus 1 (HTLV-1) infection Hypogammaglobulinemia (associated with nephrotic syndrome and multiple myeloma) Hematologic malignancies	General Fevers, chills, fatigue Eosinophilia in early stages (occasionally seen) Eosinopenia in later stages (commonly seen) Bacteremia/fungemia with enteric flora (often recurrent) Central nervous system Meningitis caused by enteric flora Cardiopulmonary Cough, wheezing, chest pain, pneumonia, recurrent asthma Gastrointestinal Abdominal pain,  nausea/vomiting,  diarrhea, constipation, ileus Other Larva currens, Pruritus ani Larval invasion of other organs (liver, pancreas, kidneys, etc.) described	Identification of larvae in bodily fluids [e.g., sputum or bronchoalveolar lavage (BAL)] Serology positive	Ivermectin 200 μg/kg/day until stool is negative (minimum 14 days) Consider rectal and subcutaneous ivermectin in severe cases or when unable to tolerate oral medications

Acute Strongyloidiasis

Acute strongyloidiasis is typically oligosymptomatic. Larval skin invasion usually occurs in the feet and may cause a serpiginous trail of dermatitis known as larva currens (“running larvae”), similar to what occurs in toxocariasis. Though pulmonary migration of larvae may cause a Loeffler-like syndrome, it is less frequent than that classically described in ascariasis [12]. Symptoms of asthma, peripheral eosinophilia, and pulmonary infiltrates on chest imaging may develop in this stage. Upper gastrointestinal symptoms, such as heartburn and bloating are commonly reported. Diarrhea and malabsorption are less frequent [13].

Chronic Strongyloidiasis

Chronic strongyloidiasis is mostly asymptomatic. It is most frequently diagnosed during workup of peripheral eosinophilia, which tends to decrease steadily following initial exposure [3]. Serology for strongyloidiasis can be used to screen for asymptomatic chronic infection. Symptomatic patients can intermittently experience dyspnea, wheezing, diarrhea, abdominal pain, constipation, vomiting, weight loss, urticaria, and/or larva currens [3, 6, 14, 15]. Migration of larvae through the lung parenchyma can cause a foreign body reaction, inflammatory pneumonitis, and pulmonary hemorrhage [16]. Rarer manifestations of chronic infection include reactive arthritis, chronic malabsorption, nephrotic syndrome, duodenal obstruction, and hepatic lesions.

Strongyloides Hyperinfection Syndrome

Strongyloides hyperinfection syndrome typically occurs when patients with chronic infection become immunosuppressed, leading to a dramatic increase in the rate of autoinfection and consequently, in parasitic burden [17]. Dissemination of larvae throughout tissues causes direct damage. Disruption of the intestinal membrane predisposes to bacteremia caused by intestinal flora. It has been suggested that the migrating larvae may also carry bacteria from the gastrointestinal tract to the lung and other organs. Though presentation is highly variable, classically strongyloides hyperinfection syndrome manifests by recurrent unexplained enterobacterial bloodstream infections, which can be polymicrobial and seed to unusual sites such as the meninges [12]. The lung is an important target organ in hyperinfection with the usual presentation being pneumonia and cough from the migrating filiform larvae in the pulmonary parenchyma. Eosinophilia is usually not seen due to steroids being the precipitating factor in the majority of cases of strongyloides hyperinfection syndrome. Chest radiographs typically show bilateral infiltrates which can be interstitial or parenchymal; however focal lobar infiltrates are also reported to occur. Hemoptysis and respiratory failure can be seen. Hyperinfection often presents with significant gastrointestinal symptoms including abdominal pain, nausea, vomiting, and ileus. The mortality of untreated strongyloides hyperinfection syndrome varies from 85 to 100% [18].

Use of corticosteroids is the most common trigger for strongyloides hyperinfection syndrome [17] and has been reported with courses as short as 6 days [19] and doses as low as 20 mg of prednisone/day [20]. Unsurprisingly, multiple cases of strongyloides hyperinfection syndrome following use of corticosteroids in the management of COVID-19 pneumonia have been reported [21, 22]. A variety of other immunosuppressive medications, such as rituximab, mycophenolate mofetil, antithymocyte globulin, and antineoplastic agents such as adriamycin, doxorubicin, and melphalan have also been implicated in strongyloides hyperinfection syndrome. Infection with HTLV-1, hypogammaglobulinemia (associated with nephrotic syndrome and multiple myeloma), hematologic malignancies, solid-organ and hematopoietic stem cell transplantation have also been associated with strongyloides hyperinfection syndrome [18]. Though initially considered an AIDS (acquired immunodeficiency syndrome) defining illness, a relatively small number of cases of strongyloides hyperinfection syndrome associated with HIV have been reported, and most of them have occurred following use of corticosteroids for conditions such as Pneumocystis pneumonia [23-25]. Strongyloides hyperinfection syndrome has been seen occasionally in immune competent individuals without other significant risk factors, for example, cases have been seen following laparoscopic surgery [26, 27]. It is thought that hypomotility of the gastrointestinal tract, i.e., prolonged transit time of stool, probably permits conversion of a higher numbers of rhabditiform larvae into infectious filariform larvae facilitating hyperinfection.

Immunopathogenesis

The innate immune response to S. stercoralis is mediated by eosinophils, granulocytes, and macrophages [28-30]. Larval killing by eosinophils depends on eosinophil major basic protein, and by granulocytes on myeloperoxidase [31]. Both cell types rely on complement-mediated mechanisms for killing [32]. Though classically not thought of as antigen-presenting cells, eosinophils have been shown to be able to act as such in animal models of strongyloidiasis [33]. The adaptive immune response to S. stercoralis is typically Th2-skewed, with interleukin (IL)-5 leading to further recruitment and activation of eosinophils, and IL-4 and IL-5 promoting class switch of immunoglobulins secreted by B cells to IgEs [34]. IL-13 causes increased peristalsis, possibly leading to increased larval expulsion [35]. Expression of regulatory T-cells (T-reg) appears to be important in the pathogenesis of hyperinfection, i.e., increased numbers of T-regs lead to decreased levels of IL-5 and IgE, and presumably impaired larval killing [36]. In HTLV-1 co-infected patients, T-reg expression is increased and is thought to contribute to the higher frequency of hyperinfection in this population [37].

Diagnosis

Strongyloidiasis should be suspected in any patient with unexplained eosinophilia especially if they have had epidemiologic exposure in areas of high disease prevalence. There is also a role for screening patients thought to be at increased risk of developing hyperinfection, such as those undergoing transplantation [38] or starting medications, such as corticosteroids, that have been implicated in strongyloides hyperinfection syndrome [39]. Screening should also be considered in those with evidence of infection with HLTV-1 [18]. Screening prior to use of corticosteroids can involve both parasitological and serological assays.

Parasitological Testing

Direct visualization of larvae is the gold-standard for diagnosis of strongyloidiasis. Sensitivity of single specimen stool microscopy is as low as 21% [40]. This is thought to be due to intermittent parasite shedding and low infectious burden. Examination of multiple specimens obtained on different dates increases sensitivity, which approaches 100% when seven samples are sent [41]. Parasitological techniques such as the modified agar plate method and the Baermann technique can be used to improve diagnostic yield, but they are seldom performed in most parasitology labs [42]. Real-time polymerase chain reaction (PCR) has been used for diagnosis of strongyloidiasis, but estimates of sensitivity of this method vary greatly and the nucleic acid probes are not yet easily available [42]. In cases of hyperinfection, the large number of worms make detection less challenging: larvae can be seen in preparations of sputum, bronchoalveolar or gastric lavage, urine, blood, and even in lung or gastrointestinal biopsies [42].

Serologic Testing

There are several commercially available serologic tests for strongyloidiasis. Though it is challenging to estimate sensitivity and specificity of these tests, as cases of chronic strongyloidiasis have low parasitic burden, which in turn decreases the sensitivity of fecal tests used as gold-standards, the negative predictive value of serology in immigrants in low prevalence settings approaches 100% [43]. The same is not true for recently acquired infections (e.g., returning traveler), in which the negative predictive value of serological screening was found to be only 72% [44]. In these cases, a negative serology is not sufficient to rule out infection and clinicians should consider stool examination and paired serologic testing if clinical suspicion is high. Cross-reactivity with other parasites such as hookworms, ascaris, and filaria has been well described, though this appears to be less of a concern in more modern test kits [45].

Management

Clinical trials of drugs for treatment of strongyloidiasis have mostly focused on the treatment of chronic infection, not on strongyloides hyperinfection syndrome. Ivermectin, a broad-spectrum antiparasitic that causes muscle paralysis in invertebrates, has emerged as the treatment of choice for strongyloidiasis. It is better tolerated than and has similar efficacy than the previously recommended drug thiabendazole [46] and is more effective in achieving larval clearance when compared to albendazole [47]. For uncomplicated S. stercoralis infections, the usual treatment in the USA is oral ivermectin 200 μg/kg/day for two consecutive days. Some experts recommend repeating the course after 2 weeks to account for the parasite’s autoinfectious cycle [48]. However, in a randomized clinical trial, single-dose ivermectin has been shown to have similar efficacy to multiple-dose regimens [49, 50]. The same treatment recommendation as used for uncomplicated S. stercoralis infection applies to patients found to have positive serology during screening, though it is important to note that the use of comparative antibody titers as markers of parasitic eradication following treatment has not been adequately evaluated. Moreover, characteristics of different serology techniques vary greatly, and laboratory protocols are not standardized [45]. Due to the high cost and long turn-around times of tests for S. stercoralis and the safe profile of ivermectin, some experts suggest empiric treatment in patients considered to be at high risk [18].

Though there is a lack of high-quality evidence for treatment of cases of hyperinfection, experts suggest that ivermectin should be given daily at 200 μg/kg/day for at least two weeks. Ideally, treatment should be extended until no more larvae are found in stool specimens. Reduction in immunosuppressive regimens should be considered in cases where the risks of strongyloides hyperinfection syndrome outweigh the benefits of immunosuppression. In cases where oral administration is not possible, or when intestinal absorption of ivermectin is thought to be impaired, alternative routes of administration may be considered. Though not approved by the US Food and Drug Administration (FDA), rectal administration of ivermectin (200 μg/kg/day) has been reported as successful. Parenteral (subcutaneous) ivermectin, only available in veterinary formulations, should be reserved as a last resort [18]. There have also been reports of successful treatment with the addition of albendazole (400 mg orally twice a day) to ivermectin [51]. Additionally, patients with strongyloides hyperinfection syndrome should be considered infectious and placed on standard contact precautions [18].

Though there have been reports of cases of severe toxicities following use of high-dose ivermectin inappropriately used to treat COVID-19, the drug is generally well-tolerated when given in recommended doses. Use should be avoided in patients with Loa loa, a filarial disease endemic to West Africa, as it has been associated development of encephalopathy [52]. Albendazole is a possible alternative for the management of these co-infection cases. Moxidectin has shown efficacy for the treatment of strongyloides infections in a phase 2 clinical trials and is a promising addition to the armamentarium for this infection [53, 54].

Conclusion

Although infection with S. stercoralis is frequently asymptomatic, it has the potential of causing life-threatening disease in the immunocompromised. Ivermectin is a well-tolerated and highly efficacious drug for treatment of strongyloidiasis. As such, screening and adequate treatment of at-risk populations, especially the immunocompromised and those receiving immunosuppressive agents such as corticosteroids, is paramount in avoiding the devastating hyperinfection syndrome. When screening is not feasible, empiric treatment of these patients should be strongly considered.