Introduction

Strongyloidiasis is a disease caused by the intestinal nematodes Strongyloides stercoralis or Strongyloides fuelleborni. The more common agent, Stercoralis stercoralis, is a helminth transmitted by soil and can cause severe disease in immunocompromised individuals.[1][2][3]

Etiology

Strongyloides stercoralis is a nematode with a complicated life cycle that involves parasitic and free-living forms. It can cause autoinfection, which is the ability to complete a full life cycle within humans and, therefore, multiplies. Multiple migratory cycles can lead to recurrent infections. Only a complete cure can eliminate the risk of complications, so accurate diagnostic methods must be employed.[4][5][6]

Epidemiology

Endemic to the Caribbean, Latin America, Europe, Asia, and sub-Saharan Africa, strongyloidiasis mainly affects tropical and sub-tropical regions. It is estimated that S. stercoralis affects 30 to 100 million people worldwide. It is often underdiagnosed, and more appropriate and sensitive diagnostic tests would yield a higher global incidence.[7]

Environmental risk factors in endemic regions include close exposure to soil and sand for occupational needs, proximity to farm animals, overcrowding, and poor sanitation. A low socio-economic population is, therefore, more vulnerable. For the same reason, children are affected more due to poor adherence to personal hygiene. The male sex is infected twice as more due to occupational exposure. Certain soil-grown vegetables and even tap water have been identified with S. stercoralis larvae, eggs, and even adult nematodes. While prevalent in all continents, in the United States, the parasite has been particularly identified in Appalachia and the southeastern United States.[8]

Pathophysiology

The life cycle of S. stercoralis has three components: direct, indirect, and autoinfection. In the direct cycle, the rhabditiform larva from stool matures into filariform larvae in the soil and penetrates the skin to travel to the lungs and, eventually, the gastrointestinal system. The indirect cycle follows, where eggs are excreted and returned to the soil to live as free-living adults or develop into filariform larvae or reinvade the host through the perianal skin. This reinvasion characterizes the autoinfection cycle, where the infective filariform larva completes its formation in the host’s intestines.

Direct contact of intact skin with contaminated soil results in inoculation of the larva, which then migrates through lymphatics and venules to reach pulmonary circulation and then alveoli. Larvae are then coughed up proximally into the trachea and then swallowed from the upper respiratory tract into the gastrointestinal tract. Within the intestine, they mature, and eggs are produced by females.

1. Eggs may pass intact through stool
2. Eggs may hatch in the intestine and pass in stool as rhabditiform larva
3. Or produce infective filariform larva prematurely,  which then reinvades the host either via the intestinal wall or perianal skin to create a perpetual cycle of infection known as autoinfection.

The rhabditiform larva is the initial noninfective stage, whereas the filariform larva is the infective stage. The incubation period ranges between 2 to 4 weeks which is almost the same for autoinfection as well. Autoinfection usually occurs in individuals with impaired cell-mediated immunity. It is the key pathway to both hyperinfection syndrome and disseminated strongyloidiasis.

History and Physical

Among individuals who have asymptomatic chronic infection, incidental diagnosis of peripheral eosinophilia is the most common presentation. However, at the acute stage, infected individuals may have a pruritic edematous petechial rash at the site of penetration. A more pathognomonic rash is larva currens or migrans from the migration of the filariform larva under the skin resulting in a hypersensitivity response in the host. It results in a transient linear erythematous serpiginous rash that shifts at a rate of 2-10 cm/hour. The duration of the rash can be hours to days at a time, but it can be a recurrent process during the duration of parasitic autoinfection.[8][9][10]

Chronic infection can have nonspecific multiorgan symptoms predominantly of gastrointestinal, dermatological, or respiratory systems. Abdominal bloating, heartburn, constipation or diarrhea, and reduced appetite are the usual gastrointestinal symptoms. They take about 2 weeks to manifest after the initial infection. A chronic dry cough or wheezing that mimics asthma can be the respiratory manifestation, whereas constitutional symptoms of low-grade fever, weight loss, and anemia can also be the sole presenting feature. Larva migrating through pulmonary capillaries can produce alveolar hemorrhage, while their entrance into alveolar spaces causes an eosinophilic inflammatory response resulting in clinical evidence of pneumonitis.

A more ominous presentation is of hyper infection syndrome, which is characterized by an explosive increase in the multiplication of infective larvae and, thus, the worm burden within a host. Although it has occasionally been reported in immunocompetent hosts, it is usually seen in immunocompromised individuals, particularly those on high-dose systemic steroids or immunosuppressants after solid organ transplant. The initial low-grade gastrointestinal and respiratory symptoms of chronic infection suddenly progress to complications of intestinal obstruction, peritonitis, gastrointestinal bleeding, pneumonitis, alveolar hemorrhage, respiratory failure, or sepsis. Disseminated strongyloidiasis, on the other hand, involves dissemination outside locations involved in the parasite’s ordinary life cycle. Translocation can result in bloodborne infection, massive weight loss,  meningitis, encephalitis, or SIADH (syndrome of inappropriate secretion of Antidiuretic hormone). Lab findings surprisingly show a normal eosinophil count along with low serum albumin and anemia. Hyper infection syndrome and disseminated disease have a mortality rate of up to 80 to  90% [11][12][13]

Evaluation

The concept of asymptomatic screening is particularly relevant in lower socioeconomic status individuals in high endemic areas, individuals being started on planned immunosuppression with systemic steroids or post solid organ transplants, and also in individuals with hitherto unexplained persistent eosinophilia.[14]

 The microscopic examination of stool for larval forms still remains the gold standard of diagnosis. However, a single stool exam has only about 50% sensitivity.

Sporadic excretion of larva in stool makes microscopic stool testing a very unpredictable and low-yield diagnostic tool. It is somewhat mitigated by serial stool testing. The sensitivity of serial stool samples reaches 100% when 7 samples, each from different days, are tested.[15] Several techniques have been applied over the years to enhance the detection of larvae in stool, including the Baermann method and the Harada- Mori method.[16] The blood agar plate culture method has the highest sensitivity ( 96%) among stool exam techniques.[17] Serologic testing by recombinant antigens is more sensitive but suffers from a lack of availability, particularly in endemic areas in the developing world. The rSs1a recombinant antigen has demonstrated a sensitivity of 96% and specificity of 93%.[18]  Microscopic visualization of the larva can also be used for other body fluids like bronchoalveolar lavage fluid, cerebrospinal fluid, pleural fluid, or even duodenal biopsy. [19] Real-time polymerase chain reaction can also be used for body fluid samples and stool.

Diagnostic sensitivity is enhanced by combining stool testing with serologic testing by Enzyme-linked Immunosorbent assay( ELISA). ELISA  has a high negative predictive value and can thus help in ruling out infection, particularly in patients to be subjected to immunosuppressive treatment. However, it identifies IgG and thus does not distinguish between current and prior infection.

IgG antibodies can also be detected by the indirect Immunofluorescent antibody test (IFAT). A 1:20 titer or above has a sensitivity of 97.4% and a specificity of 97.9%. It is, therefore, the desired cutoff for screening. Luciferase immunoprecipitation system (LIPS)  provides the highest positive predictive value with a specificity of 100%.[20][21] It detects antibodies to a recombinant Strongyloides antigen.

The diagnosis of hyperinfection syndrome is relatively easy because of the high larval load in the stool or body fluids. 

Endoscopy and duodenal biopsy may reveal larva or signs of chronic inflammation like edematous mucosa, white villi, or erythematous mucosa.

High serum IgE levels are present in 39% to 58% of the cases. This association between elevated serum IgE levels and strongyloidiasis is, however, rarely present in  HTLV-1 co-infected individuals, indicating an inability of HTLV-I-positive patients to clear S. stercoralis.

Treatment / Management

Many studies show that the best treatment for uncomplicated strongyloidiasis is a drug called Ivermectin. The recommended treatment regimen consists of 200 mcg/kg for 2 consecutive days. For uncomplicated strongyloidiasis, the treatment is ivermectin daily until larvae can no longer be detected in stool, urine, or sputum for two weeks.[22][23][24]

• Ivermectin does not kill the Strongyloides larvae, but only the adult worms. As a result, repeat dosing is necessary.
• There is an auto-infective cycle of about 2 weeks in which ivermectin must be re-administered, and additional dosing will be necessary as it will not kill Strongyloides in the blood or larvae deep within the bowels.
• Ivermectin is metabolized by the cytochrome P450 3A4 pathway in the liver, and therefore patient with hepatobiliary impairment needs to explore other options for therapy. It targets both the adult and larval stages, while albendazole targets only the adult stage of the parasite
• Albendazole and thiabendazole (25 mg/kg twice daily for 5 days, a 400 mg maximum) are also effective.
• The optimal duration of treatment is not clear.
•  Albendazole can suppress bone marrow and thus result in pancytopenia
• Eradication can be difficult as Strongyloides has been known to live in individuals for decades, even after treatment.
• Continued treatment is often necessary, even if symptoms resolve.
• Clothes and sheets should be washed with enzyme washing powder and dried on hot days.

For patients with hyperinfection syndrome, contact precautions and isolation are recommended, as larvae may be found in all body fluids. Family members should also be screened, and healthcare workers should adopt universal precautions. Steroids and leukotriene inhibitors should be avoided as leukotrienes play a potential role in immunity against Strongyloides infection.

Ivermectin is pregnancy category C and is thus not recommended for pregnant or lactating women unless no other option of treatment is available. Albendazole is allowed by WHO in the last 2 trimesters of pregnancy, although it is also pregnancy category C in the USA. If a new treatment is being initiated, pregnancy testing should be completed.

Ivermectin is also not recommended for body weight less than 15 kg, and therefore, albendazole is the recommended treatment at a dose of 400 mg daily for 3 days between age 2 to 20 and 200 mg daily for 3 days below age 2.[25] 

Intensive Care

• Immunocompromised patients may require intensive care for disseminated infection.
• Contact isolation should be considered because sputum, stool, and vomitus may contain infective larvae.
• Patients with hyperinfection syndrome often have sepsis, shock, and acute respiratory distress syndrome (ARDS).

Differential Diagnosis

The differential diagnoses include:

• Acute respiratory distress syndrome
• Asthma
• Cholera
• Chronic obstructive pulmonary disease
• Diverticulitis
• Ileus
• Inflammatory bowel disease
• Loeffler syndrome
• Peritonitis
• Pneumonia, especially in the immunocompromised

Prognosis

The prognosis in strongyloidiasis depends on the development of complications. Strongyloidiasis can result in dermatologic, gastrointestinal, renal, pulmonary, and neurologic complications and even death.

Gastrointestinal

• Appendicitis
• Eosinophilic oophoritis
• Hemorrhage
• Ileus
• Infarction
• Intestinal obstruction
• Malabsorption
• Obstructive jaundice
• Perforation
• Peritonitis
• Pneumatosis intestinalis 

Pulmonary

• Alveolar hemorrhage
• Asthma
• ARDS
• Granulomatous lung disease
• Pneumonitis
• Respiratory failure
• Pleural effusion

Dermatologic

• Chronic urticaria
• Larva currens
• Purpura of the trunk and proximal extremities

Neurologic

• Brain abscess
• Meningitis
• Vascular Complications
• Hyperinfection syndrome presenting as bacteremia

Renal Complications

• Nephrotic syndrome
• Syndrome of inappropriate antidiuretic hormone (SIADH)

Complications

Complications may include the development of respiratory problems (Loeffler syndrome), digestive issues, and hyperinfection may result in central nervous system problems. Chronic disseminated strongyloidiasis is associated with immunodepression.[26][27]

Pearls and Other Issues

The goal in strongyloidiasis is to eradicate the infection, decrease morbidity, and prevent complications.

• Albendazole and mebendazole are sometimes used in Strongyloides stercoralis infection, but results are varied.
• Ivermectin is more effective than albendazole.
• The disseminated disease should be treated with ivermectin. For those too sick to tolerate oral ivermectin, subcutaneous or rectal dosing may be effective.
• Ivermectin should be administered daily until symptoms have resolved and larvae have not been detected for at least 2 weeks.

Parasite pathways are different from the human host and allow selective interference by chemotherapeutic agents. The effectiveness of anthelmintic agents against larvae is poor; they are more effective in established infection.

Ivermectin

• Ivermectin is the drug of choice for both acute and chronic strongyloidiasis in intestinal stages, hyperinfection syndrome, and disseminated strongyloidiasis.
• This drug has not been studied extensively in children, and it has been used as an adjuvant in patients with hyperinflation not responding to thiabendazole.
• Ivermectin is a semisynthetic macrolide that binds selectively to glutamate-gated chloride ion channels in nerve and muscle cells, increasing cell membrane permeability with hyperpolarization and causing paralysis and cell death.
• Ivermectin's half-life is 16 hours, and it is metabolized in the liver.
• The cure rate is close to 100% with a 2-day course.

Albendazole

• Albendazole is an alternative to ivermectin for acute and chronic strongyloidiasis.
• Albendazole has a high affinity for binding free beta-tubulin in the parasite's cells and inhibiting tubulin polymerization, resulting in loss of cytoplasmic microtubules and decreasing ATP production in the worm, which results in energy depletion by inhibiting glucose uptake, immobilization, then causing death.
• Albendazole should be administered with high-dose glucocorticoids and anticonvulsants to avoid a central nervous system inflammatory response.

Mebendazole

• Mebendazole has variable efficacy against strongyloidiasis.
• This agent inhibits microtubule formation and causes worm glucose depletion, and is available in chewable form for pediatric use.

Enhancing Healthcare Team Outcomes

The diagnosis and management of Strongyloides infection are done with an interprofessional team that includes an infectious disease expert, gastroenterologist, emergency department physician, and pharmacist. The key is to get rid of all larvae with ivermectin. Once discharged, the patients need to follow up with either a nurse practitioner or primary physician to ensure that all body fluids have no remnant larvae. Patients also need to be educated about handwashing and maintaining personal hygiene. For those with a simple infection of the GI tract, the outcomes are good, but in patients with multiple organ infestations, the prognosis is guarded.[28][29]