Strongyloidiasis

An infection that is caused by nematodes of the genus strongyloides, most commonly strongyloides stercoralis, which is a soil-transmitted helminth, and which is characterized by a variety of gastrointestinal, dermatologic, and, occasionally, pulmonary manifestations. The worm's auto-infective life cycle can lead to hyper-infection and life-threatening dissemination in immunocompromised hosts decades after initial infection.

Strongyloides stercoralis larva

Strongyloidiasis was first described in French troops who had returned from modern day Vietnam during the late 19th century who were suffering from severe, persistent diarrhea. It is a parasitic disease caused by nematodes, or roundworms, in the genus Strongyloides. The parasites enter the body through exposed skin, such as bare feet. Strongyloides is most common in tropical or subtropical climates. Most people who are infected with Strongyloides do not know they are infected and have no symptoms. Others, particularly those who are on some immunosuppressive therapies, may develop a severe form and, if untreated, become critically ill and possibly die.

Epidemiology & Risk Factors

Strongyloides is known to exist on all continents except for Antarctica, but it is most common in the tropics, subtropics, and in warm temperate regions. The global prevalence of Strongyloides infection is unknown, but experts estimate that there are between 30–100 million infected persons worldwide.

Strongyloidiasis

In the United States, a series of small studies in select populations have shown that between 0–6.1% of persons sampled were infected. Studies in immigrant populations have shown a much higher percentage of infected persons ranging from 0–46.1%.

Strongyloides infection is found more frequently in the socioeconomically disadvantaged, in institutionalized populations, and in rural areas. It is often associated with agricultural activities.

The most common way of becoming infected with Strongyloides is by contacting soil that is contaminated with Strongyloides larvae. Therefore, activities that increase contact with the soil increase the risk of becoming infected, such as

Walking with bare feet

Contact with human waste or sewage Occupations that increase contact with contaminated soil such as farming and coal mining Furthermore, many studies have shown an association with Strongyloides and infection with Human T-Cell Lymphotropic Virus-1 (HTLV-1). These studies have shown that people infected with HTLV-1 are more likely to become infected with Strongyloides, and that once infected, are more likely to develop severe cases of strongyloidiasis.

Of note, HIV/AIDS infection has not been shown to be a risk factor for acquiring strongyloidiasis or having a worse clinical course.

Causal Agents

The rhabditid nematode (roundworm) Strongyloides stercoralis is the major causative agent of strongyloidiasis in humans. Rarer human-infecting species of Strongyloides are the zoonotic S. fuelleborni (fülleborni) subsp. fuelleborni and S. fuelleborni subsp. kellyi, for which the only currently known host is humans. Strongyloides spp. are sometimes called “threadworms” (although in some countries this common name refers to Enterobius vermicularis).

Other animal-associated Strongyloides spp., including S. myopotami (nutria), S. procyonis (raccoons), and possibly others, may produce mild short-lived cutaneous infections in human hosts (larva currens, “nutria itch”), but do not cause true strongyloidiasis.

Strongyloides

Life Cycle

Strongyloides stercoralis

The Strongyloides stercoralis life cycle is complex, alternating between free-living and parasitic cycles and involving autoinfection. In the free-living cycle: Rhabditiform larvae are passed in the stool of an infected definitive host, develop into either infective filariform larvae (direct development)or free-living adult males and females that mate and produce eggs, from which rhabditiform larvae hatchand eventually become infective filariform (L3). The filariform larvae penetrate the human host skin to initiate the parasitic cycle. This second generation of filariform larvae cannot mature into free-living adults and must find a new host to continue the life cycle.

Parasitic cycle: Filariform larvae in contaminated soil penetrate human skin when skin contacts soil, and migrate to the small intestine. It has been thought that the L3 larvae migrate via the bloodstream and lymphatics to the lungs, where they are eventually coughed up and swallowed. However, L3 larvae appear capable of migrating to the intestine via alternate routes (e.g. through abdominal viscera or connective tissue). In the small intestine, the larvae molt twice and become adult female worms. The females live embedded in the submucosa of the small intestine and produce eggs via parthenogenesis (parasitic males do not exist), which yield rhabditiform larvae. The rhabditiform larvae can either be passed in the stool(see “Free-living cycle” above), or can cause autoinfection.

Duodenum Strongyloides

Rhabditiform larvae in the gut become infective filariform larvae that can penetrate either the intestinal mucosa or the skin of the perianal area, resulting in autoinfection. Once the filariform larvae reinfect the host, they are carried to the lungs, pharynx and small intestine as described above, or disseminate throughout the body. The significance of autoinfection in Strongyloides is that untreated cases can result in persistent infection, even after many decades of residence in a non-endemic area, and may contribute to the development of hyperinfection syndrome.

Life cycle of Strongyloides stercoralis,

Strongyloides fuelleborni

Strongyloides fuelleborni follows the same life cycle as S. stercoralis, with the important distinction that eggs (rather than larvae) are passed in the stool. Eggs hatch shortly after passage into the environment, releasing rhabditiform larvae, that develop to either infective filariform larvae (direct development)or free-living adult males and females. The free-living adults mate and produce eggs, from which more rhabditiform larvae hatch and eventually become infective filariform larvae. The filariform larvae penetrate the human host skin to initiate the parasitic cycle. These larvae migrate via the bloodstream to the lungs, where they are eventually coughed up and swallowed, or reach the intestine via migration through connective tissue or abdominal viscera. In the small intestine, larvae molt twice and become adult female worms. Parasitic females embedded in the submucosa of the small intestine and produce eggs via parthenogenesis (parasitic males do not exist).

Since eggs do not hatch within the host as with S. stercoralis, autoinfection is believed to be impossible. Transmission of S. fuelleborni subsp. kellyi to infants as a result of breastfeeding has been reported.

Hosts Strongyloides spp. are generally host-specific, and S. stercoralis is primarily a human parasite. However, patent infections with parasitic females have been detected in other primates (chimpanzees, monkeys, etc.) and domestic dogs. Two genetic populations have been found in domestic dogs, one that appears to only infect dogs and one that may infect both dogs and humans; all human infections have been attributed to this second genetic population. Domestic cats are experimentally susceptible to S. stercoralis infections although it is unknown if they have a role as a natural reservoir.

Strongyloides fuelleborni subsp. fuelleborni is a parasite of Old World apes and monkeys. The only identified host of S. fuelleborni subsp. kellyi is humans.

Geographic Distribution

Strongyloides stercoralis is broadly distributed in tropical and subtropical areas across the globe. Transmission has been reported during summer months in temperate areas. Infections are most common in areas with poor sanitation, rural and remote communities, institutional settings, and among socially marginalized groups.

S. fuelleborni subsp. fuelleborni occurs in non-human primates throughout the Old World. The vast majority of human infections are reported from sub-Saharan Africa. Sporadic cases have been reported from Southeast Asia. S. fuelleborni subsp. kellyi is found in Papua New Guinea, and has not been reported elsewhere thus far.

Clinical Presentation

The initial sign of acute strongyloidiasis, if noticed at all, is a localized pruritic, erythematous rash at the site of skin penetration. Patients may then develop tracheal irritation and a dry cough as the larvae migrate from the lungs up through the trachea. After the larvae are swallowed into the gastrointestinal tract, patients may experience diarrhea, constipation, abdominal pain, and anorexia. Chronic strongyloidiasis is generally asymptomatic, but a variety of gastrointestinal and cutaneous manifestations may occur. Rarely, patients with chronic strongyloidiasis may develop other complications (e.g. arthritis, cardiac arrhythmias, chronic malabsorption, duodenal obstruction, nephrotic syndrome, recurrent asthma). Up to 75% of people with chronic strongyloidiasis have mild peripheral eosinophilia or elevated IgE levels.

Hyperinfection syndrome

Hyperinfection syndrome and disseminated strongyloidiasis are most frequently associated with subclinical infection in patients receiving high-dose corticosteroids. Subsequent impaired host immunity leads to accelerated autoinfection and an overwhelming number of migrating larvae. In chronic strongyloidiasis and in hyperinfection syndrome, the larvae are limited to the GI tract and the lungs, whereas in disseminated strongyloidiasis the larvae invade numerous organs. A variety of systemic, gastrointestinal, pulmonary, and neurologic signs/symptoms have been documented; complications can be severe. Left untreated, the mortality rates of hyperinfection syndrome and disseminated strongyloidiasis can approach 90%.

Strongyloidiasis

The subcutaneous migration of filariform larvae in the autoinfective cycle, or “larva currens”, presents as a recurrent serpiginous maculopapular or urticarial rash along the buttocks, perineum, and thighs due to repeated autoinfection. This rash usually advances very rapidly (up to 10 cm/hr).

In infants infected with S. fuelleborni subsp. kellyi, a severe, often fatal, systemic illness involving protein-losing enteropathy has been described, which sometimes presents with peritoneal ascites (“swollen belly syndrome”).

Disease

Most people infected with Strongyloides do not know they are infected. If they do feel sick the most common complaints are the following:

Abdominal

• Stomachache, bloating, and heartburn
• Intermittent episodes of diarrhea and constipation
• Nausea and loss of appetite

Respiratory

• Dry cough
• Throat irritation

Skin

• An itchy, red rash that occurs where the worm entered the skin
• Recurrent raised red rash typically along the thighs and buttocks

Rarely, severe life-threatening forms of the disease called hyperinfection syndrome and disseminated strongyloidiasis can occur. These forms of the disease are more common in people who are on corticosteroids (for example, prednisone) or other immunosuppressive therapies or who are infected with HTLV-1. In this situation, people become critically ill, and should be taken to the hospital immediately.

The symptomatic spectrum of Strongyloides infection ranges from subclinical in acute and chronic infection to severe and fatal in hyperinfection syndrome and disseminated strongyloidiasis, which have case-fatality rates that approach 90%. In either case, patients’ symptoms are a result of the parasite’s larval form migrating through various organs of the body.

Acute strongyloidiasis

The initial sign of acute strongyloidiasis, if noticed at all, is a localized pruritic, erythematous rash at the site of skin penetration. Patients may then develop tracheal irritation and a dry cough as the larvae migrate from the lungs up through the trachea. After the larvae are swallowed into the gastrointestinal tract, patients may experience diarrhea, constipation, abdominal pain, and anorexia.

Chronic strongyloidiasis

Chronic strongyloidiasis is generally asymptomatic, but in patients with clinical disease gastrointestinal and cutaneous manifestations are the most common. Of the gastrointestinal complaints, epigastric pain, postprandial fullness, heartburn, and brief episodes of intermittent diarrhea and constipation are the most frequent. Less commonly, patients may present with fecal occult blood, or massive colonic and gastric hemorrhage. Presentations resembling inflammatory bowel disease, specifically ulcerative colitis, are rare. Also rare, but documented, are endoscopic exams revealing pathology similar to pseudopolyposis.

Cutaneous symptoms include chronic urticaria and larva currens- a recurrent serpiginous maculopapular or urticarial rash along the buttocks, perineum, and thighs due to repeated auto-infection. It has been described as advancing as rapidly as 10cm/hr.

Rarely, patients with chronic strongyloidiasis have complained of arthritis, cardiac arrhythmias, and signs and symptoms consistent with chronic malabsorption, duodenal obstruction, nephrotic syndrome, and recurrent asthma.

Up to 75% of people with chronic strongyloidiasis have mild peripheral eosinophilia or elevated IgE levels.

Hyperinfection syndrome and disseminated strongyloidiasis Hyperinfection syndrome and disseminated strongyloidiasis are most frequently associated with subclinical infection in patients receiving high-dose corticosteroids for the treatment of asthma or chronic obstructive pulmonary disease (COPD) exacerbations. Subsequent impaired host immunity leads to accelerated autoinfection and an overwhelming number of migrating larvae. In chronic strongyloidiasis and in hyperinfection syndrome the larvae are limited to the GI tract and the lungs whereas in disseminated strongyloidiasis the larvae invade numerous organs. Left untreated, the mortality rates of hyperinfection syndrome and disseminated strongyloidiasis can approach 90%.

The following are signs and symptoms that can be seen with hyperinfection syndrome and disseminated strongyloidiasis:

Gastrointestinal manifestations

• Abdominal pain, nausea, vomiting, diarrhea
• Ileus, bowel edema, intestinal obstruction
• Mucosal ulceration, massive hemorrhage, and subsequent peritonitis or bacterial sepsis

Pulmonary manifestations and findings

• Cough, wheezing, dyspnea, hoarseness
• Pneumonitis
• Hemoptysis
• Respiratory failure
• Diffuse interstitial infiltrates or consolidation on chest radiographs

Neurologic findings

• Aseptic or gram-negative meningitis
• Larvae have been reported in the CSF, meningeal vessels, dura, epidural, subdural, and subarachnoid spaces
• Systemic signs and symptoms

• Peripheral edema and ascites secondary to hypoalbuminemia from protein losing enteropathy
• Recurrent gram negative bacteremia or sepsis from larvae carrying bacteria that penetrate mucosal walls
• Syndrome of inappropriate secretion of anti-diuretic hormone (SIADH)
• Peripheral eosinophilia is frequently absent

Cutaneous manifestations

• Recurrent maculopapular or urticarial rash that can be found anywhere on the skin but is most commonly found along the buttocks, perineum, and thighs due to repeated auto-infection
• Larva currens—serpiginous or urticarial rash that advances as rapidly as 10cm/hr.

Diagnosis

The gold standard for the diagnosis of Strongyloides infection is serial stool examination. However, traditional stool examinations are insensitive and require up to seven stool exams to reach a sensitivity of 100%. Specialized stool exams include Baermann concentration, Horadi-Mori filter paper culture, quantitative acetate concentration technique, and nutrient agar plate cultures. Duodenal aspirate is more sensitive than stool examination, and duodenal biopsy may reveal parasites in the gastric crypts, in the duodenal glands, or eosinophilic infiltration in the lamina propria. Frequently, larvae can be seen by a simple wet-mount in fluid from a bronchoalveolar lavage (BAL).

Many of the serologic tests that are available are quite sensitive, but cross-react with other filarial parasites, schistosomes, and Ascaris lumbricoides, decreasing the specificity of the tests. Furthermore, it can be difficult to distinguish between active cases and historical cases since antibodies can persist for some time. A significant proportion of people become antibody negative within 6 months after successful treatment. More sensitive and specific serologic tests using recombinant antigens have been developed.

Of note, CDC performs reference serologic testing only to confirm test results, which are occasionally difficult to interpret or equivocal.

Treatment

• Acute and chronic strongyloidiasis
• First line therapy
• Ivermectin, in a single dose, 200 µg/kg orally for 1—2 days

Relative contraindications include the following:

Confirmed or suspected concomitant Loa loa infection Persons weighing less than 15kg Pregnant or lactating women Oral ivermectin is available for human use in the United States.

Alternative

Albendazole, 400 mg orally two times a day for 7 days.

Relative contraindications

Hypersensitivity to benzimidazole compounds or any component of product Use should be avoided in the 1st trimester of pregnancy Oral albendazole is available for human use in the United States.

In patients with positive stool examination for Strongyloides and persistent symptoms, follow-up stool exams should be performed 2—4 weeks after treatment to confirm clearance of infection. If recrudescence of larvae is observed, retreatment is indicated.

Hyperinfection syndrome/Disseminated strongyloidiasis

If possible, immunosuppressive therapy should be stopped or reduced, and:

Ivermectin, 200 µg/kg per day orally until stool and/or sputum exams are negative for 2 weeks.

For patients unable to tolerate oral therapy, such as those with ileus, obstruction, or known or suspected malabsorption, published case reports have demonstrated efficacy with rectal administration.

If oral and/or rectal administrations are not possible, there have been instances where Investigational New Drug (IND) exemptions for the veterinary subcutaneous formulation of ivermectin have been granted by the FDA.

Screening

Physicians should be particularly diligent to consider Strongyloides in patients:

• Who are on or about to begin corticosteroid therapy or other immunosuppressants
• Known to have HTLV-1 infection
• With hematologic malignancies including leukemias and lymphomas
• Who have had or are being considered for organ transplantation
• With persistent peripheral or unexplained eosinophilia
• With recent or remote travel histories to endemic areas.

Of note, though persons with HIV/AIDS can have disseminated strongyloidiasis or hyperinfection syndrome, observational studies have not shown an increased risk in this population.

Precautions

Standard precautions should be observed for patients hospitalized with strongyloidiasis. Wearing gloves and gowns, good hygiene, and diligent handwashing is important when coming into contact with the patient’s feces.

• Ivermectin
• Albendazole

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