Continuing Education Activity

Despite its ability to cause life-threatening diseases, strongyloidiasis is one of the most neglected tropical diseases. Moreover, Strongyloides infection can last the host's lifetime due to its ability to cause autoinfection of the host. The helminth S. stercoralis mainly infects humans but also occurs naturally in domestic dogs, cats, and primates. Manifestations of infection can range from asymptomatic to life-threatening complications and require a high degree of suspicion to make the diagnosis. This activity examines the pathogenesis, disease manifestations, and management of strongyloidiasis and highlights the role of the interprofessional team in caring for patients affected by this disease.

Objectives:

• Review the life cycle and mechanism of infection of Strongyloides stercoralis.

• Describe the clinical presentation of a patient infected with Strongyloides stercoralis.

• Summarize the medical management of a patient infected with Strongyloides stercoralis.

• Outline the importance of the interprofessional team in advancing care for patients infected by Strongyloides stercoralis.

Introduction

Strongyloides stercoralis, commonly known as threadworm, is a soil-transmitted human parasite belonging to a group of nematodes called roundworms. Although prevalent almost worldwide, except only in the far north and south, the global burden of this parasitic infection is still underestimated because of the unavailability of precise data from endemic areas.[1] S. stercoralis, therefore, becomes one of the most overlooked parasitic infections among the "neglected tropical diseases" (NTDs).[2]

The helminth, S. stercoralis, mainly infects humans but also occurs naturally in domestic dogs, cats, and primates.[3] The feature that makes it unique among other human nematodes is the ability to give rise to a progeny of free-living worms from rhabditiform larvae shed in human feces, which reproduce to form infective, skin-penetrating filariform larvae in the external environment.[3] Humans infected with S. stercoralis present with varying degrees of clinical manifestations ranging from asymptomatic carriers to acute strongyloidiasis and disseminated infections.[3]

Strongyloidiasis is the term used to indicate infection by Strongyloides stercoralis. It differs from other helminth infections by its ability to cause overwhelming hyperinfection in immunocompromised individuals.[4] Strongyloides infection can last the host's lifetime due to its autoinfection life cycle and cause a wide spectrum of diseases ranging from asymptomatic eosinophilia to severe, life-threatening disseminated disease in immunocompromised patients.[5]

Etiology

Strongyloides stercoralis is a soil-transmitted helminth. It is classified as a roundworm or nematode. There are more than 50 species of Strongyloides. Most of them do not infect humans. Strongyloidiasis, the disease caused by S. stercoralis in humans, is contracted mainly through the transcutaneous route.[3] Other modes of transmission include the fecal-oral and anal-oral routes. It can also be transmitted through organ transplantation from an infected donor.[6]

Host factors such as HIV infection, human T-lymphotropic virus type 1 (HTLV-1) infection, and alcoholism have been reported as risk factors for Strongyloidiasis. The most prominent risk factors for severe disease include immunosuppressive therapies (including corticosteroid use), diseases like diabetes, HIV, HTLV infection, and alcoholism.[7] Poor sanitation of households and walking barefoot have been postulated to play an important role in the etiology of this infection as well.[7] Contrary to popular belief, HIV does not seem to be a risk factor for superinfection. This is likely secondary to HIV-induced CD4 cell immunosuppression predisposing more to bacterial and viral infections than parasitic infections.[8]

Epidemiology

Strongyloides stercoralis is prevalent in almost every part of the world except Antarctica. According to one study, this soil-transmitted nematode is estimated to have infected 370 million people globally, especially in the tropical and subtropical regions, where 10 to 40% of the population is affected.[7] A 2021 systemic review revealed the highest prevalence of this infection in the Western Pacific region (affecting 9 to 21% of the population).[9] The Eastern Mediterranean Region was noted to have the highest seroprevalence, with as high as 40% of the population being affected.[9]

Worldwide and local prevalence of Strongyloides is seriously underestimated because of the low sensitivity of tests and poor reporting in high-incidence countries. It is more frequently found in warm, moist areas and areas with poor sanitary conditions. Some studies have reported incidences as high as 91% in Gabon and 75% in Peru, but the prevalence varies widely depending on the diagnostic methods used.[1] Studies identifying the incidence of this disease are non-existent.[1]

In developed countries, Strongyloidiasis is more frequently seen in farmers and miners, as well as immigrant populations, tourists, and military personnel returning from high-prevalence areas. In the United States, the highest incidence is in immigrants from Africa and Asia (46% in one study evaluating Sudanese refugees), followed by Central and Latin America.[10] It is important to note that refugee populations receive deworming therapy when entering the United States.

There is a slight predilection for the male sex. This is thought to be due to increased exposure to the source of infection due to involvement in farming, fieldwork, etc.[11]

Pathophysiology

Life Cycle of Strongyloides stercoralis

The distinctive nature of the life cycle of this human parasite is attributed to its ability to cause autoinfection. Its life cycle comprises a free-living phase and a parasitic phase.[12] The free-living phase begins when rhabditiform larvae passed in stools grow into infective skin-penetrating filariform larvae or develop into adult worms which reproduce sexually to give rise to the second generation of filariform larvae.[12] The parasitic phase of the life cycle begins with skin penetration by the filariform larvae. These larvae then migrate via the bloodstream or lymphatics to reside in the gut. Within the small intestine, these larvae mature into adult females, which reproduce by parthenogenesis and give rise to rhabditiform larvae which are either excreted in feces or develop into filariform larvae to cause autoinfection.[13]

Parasitic Phase

Infection occurs through skin contact with soil containing filariform (infective) larvae. After penetrating the skin, larvae travel to the lungs, where they mature. It then travels up the trachea and is eventually swallowed. In the alimentary canal, the larvae invade the mucosa of the proximal small intestine. Here they mature and lay eggs.[13] The adult form can live in the intestinal mucosa for up to 5 years. The eggs hatch inside the intestinal mucosa and release rhabditiform (non-infective) larvae that travel to the intestinal lumen. They are eventually excreted in the feces. The larvae excreted in the soil may mature into an ineffective filariform larva or complete a free-living cycle where the male and female produce rhabditiform larvae that can later mature into filariform larvae.[1]

Autoinfection

Some rhabditiform larvae mature inside the intestinal lumen into filariform larvae. These newly hatched larvae can then penetrate the intestinal mucosa or the perianal skin and complete an autoinfection cycle. This allows the organism to perpetuate the infection inside the host.[13] Autoinfection is generally limited by an intact immune response. However, even in an immunocompetent host, a low level of autoinfection can occur and, subsequently, cause chronic infections for decades and may only lead to clinical manifestations when superimposed immunosuppression exists.[14]

Hyperinfection

Hyperinfection syndrome is the most severe manifestation of the disease, with high mortality rates. This occurs in chronically infected individuals that become immunosuppressed or in acutely infected immunosuppressed patients.[1] It stems from uncontrolled and accelerated autoinfection resulting in the dissemination of the larvae to end organs like the liver or brain. Sepsis is a common complication caused by bacterial translocation from the intestinal wall in patients suffering from hyperinfection syndrome.

History and Physical

In most cases, Strongyloidiasis is asymptomatic, especially in immunocompetent individuals.[1] Often, the only sign of infection is unexplained peripheral eosinophilia. Some studies report nonspecific symptoms in more than 50% of the affected patients.[15]

Acute Infection

Acute infection may show an itchy serpiginous skin rash in the area where the larvae penetrate the skin. When filariform larvae in fecal-contaminated soil enter the body through skin penetration, intense pruritus, congestion, and edema is noted at the portal of entry.[3] This is known as ground itch and is usually present in feet or hands but can be perianal, abdominal, or virtually anywhere in the body. This intense urticaria can last for up to 3 weeks.[16] Intradermal migration is very fast (5 cm to 15 cm an hour), and the rash it causes is known as larva currens.[3] 

Larva currens or “running” larva is a pathognomonic dermatologic manifestation of strongyloidiasis and can be seen with autoinfection as well. Larva currens manifest as a raised, pink, pruritic, serpiginous streak and can progress approximately 5 to 15 cm per hour.[17]

Passage of the larvae through the lungs can give a dry cough and cause a Loeffler-like syndrome with dyspnea, wheezing, eosinophilia, and migratory pulmonary infiltrates. The larvae travel through venules and lymphatics to enter pulmonary circulation producing pulmonary hemorrhages and cough. Eosinophilic infiltration of the alveolar spaces often results in pneumonitis as well.[18] 

Intestinal symptoms include diarrhea, vomiting, and epigastric pain.

Hyperinfection syndrome presents with fever, gram-negative bacteremia, and sepsis with signs of end-organ damage (hemoptysis, gastrointestinal bleeding, ileus, hyponatremia).

Chronic Infection

Strongyloides stercoralis can also cause chronic infections, which can persist for years in humans. Chronic Strongyloides stercoralis infections present with cough, rhonchi, dyspnea, abdominal pain, anorexia, diarrhea, and/or constipation.[19] Respiratory and gastrointestinal symptoms tend to be mild in chronic forms, and dermatologic manifestations such as urticaria and larva currents can still be seen.[20] 

Hyperinfection

Hyperinfection is caused by accelerated autoinfection of the parasite within the host leading to a high parasite burden and severe disease. The signs and symptoms of hyperinfection are similar to symptoms of increased larval migration within the organs. Disseminated disease occurs with hyperinfection syndrome leading to the spread of larvae to distant organs such as the liver, pancreas, kidneys, mesenteric lymph nodes, brain, and skeletal muscles.[21] 

Evaluation

Definitive diagnosis of Strongyloides stercoralis requires the detection of larvae in the stool specimen; however, this method is limited due to scanty and intermittent excretion of larvae in most cases of strongyloidiasis. Intestinal biopsy, when performed, can sometimes demonstrate parasites in the gastric crypts or duodenal glands, as well as eosinophilic infiltration of the lamina propria.[21] However, it must be noted that routine endoscopy has no role in evaluating a patient suspected to have strongyloidiasis. Cell-free DNA of the parasite can also be detected in urine specimens of infected individuals.[22] On sputum culture, Gram staining and routine acid-fast staining can reveal strongyloidiasis.[23] Serologic testing is also available for the diagnosis of this disease. 

The sensitivity and specificity of these tests, however, are not high. The standard stool examination has a sensitivity of only 21%. Stool concentration methods, such as the Baermann technique (72% sensitive) or agar plate culture (89% sensitive), can still fail to yield a diagnosis despite consecutive samples.[24] Serologic tests (IFAT, ELISA, NIE-LIPS) tend to have better sensitivity.[25] The disadvantage of serologic techniques is the lack of specificity because of cross-reactivity with other helminthic antigens, specially filariasis. The ELISA test has the benefit of being able to detect coproantigen and thus works as a marker of current infection.

With the above limitations in mind, the gold standard tests for S. stercoralis diagnosis are yet to be developed. In most cases, both stool and serologic evaluation is indicated. PCR and RT-PCR tests have been developed and show promising results with nearly 100% specificity and very high sensitivity, but they are not widely available.[26]

Peripheral eosinophilia is a common finding in patients with chronic infections.[27] However, the sensitivity of eosinophilia for strongyloidiasis is low. Moreover, in patients with hyperinfection syndrome, peripheral eosinophilia is usually absent.[28] 

The diagnosis of chronic strongyloidiasis is especially challenging due to low parasitic load, which results in low sensitivity of stool microscopy and low specificity of serology.

As discussed above, the sensitivity of stool microscopy and serology is low, especially in patients with acute or chronic infections. It is useful to note that serologic tests have a high negative predictive value and are quite useful in excluding strongyloidiasis.[29] A 2019 study from the UK evaluating the performance of standard diagnostic techniques for this condition in patients with microscopically proven infection reported that patients with proven infection had lower serology values than those who were diagnosed based on serology and eosinophilia alone, suggesting a correlation between immunologic control of strongyloidiasis and the amplitude of the humoral response.[29]

Hyperinfection can be diagnosed by studying stool, body fluids, and/or tissue with adequate sensitivity because, in this state, the host generally has a high burden of readily detectable parasites. 

Treatment / Management

The goal of treatment is to eradicate the parasite completely and is indicated for symptomatic and asymptomatic individuals regardless of their immune status.

Uncomplicated strongyloidiasis is treated with ivermectin (200 micrograms/kg for two days), thiabendazole (25 mg/kg/day for three days), or albendazole (400 mg twice a day for 3-7 days).[30][3] Response to treatment should be ensured with serial stool testing or anti-Strongyloides titer testing for one to two years in all patients.[31]

Patients with evidence of hyperinfection syndrome are treated with ivermectin for at least two weeks or until stool is negative for two consecutive weeks.[3] Broad-spectrum antibiotics with coverage for enteric bacteria should also be added to ivermectin in these patients. Of note, for individuals from areas of Africa that are endemic to loiasis, screening for loiasis microfilaremia is indicated prior to treatment with ivermectin, as administration of this drug in such patients can lead to encephalopathy. 

Of the agents outlined above, the preferred therapy is ivermectin.[32] This regimen has shown the best efficacy, and the side effect profile is similar to albendazole, as demonstrated by the latest meta-analysis.[32] Second-line therapy is albendazole because it has lower efficacy than ivermectin.[32] For the most part, thiabendazole has fallen out of favor due to the increased incidence of adverse events, although it remains as effective as ivermectin.[32]

Treatment may be prolonged in immunocompromised individuals. Stopping or decreasing immunosuppressive therapy should be considered, and treatment should ideally be continued until larvae are undetectable in stool, urine, and sputum for at least 14 days.

Differential Diagnosis

For pulmonary symptoms:

• Acute respiratory distress syndrome (ARDS)
• Pneumonia
• Bronchial asthma
• Pneumonitis

For gastrointestinal symptoms:

• Acute appendicitis
• Intestinal obstruction
• Inflammatory bowel syndrome
• Proctitis
• Loffler syndrome
• Peritonitis

Prognosis

With treatment, the prognosis of acute and chronic infections is generally favorable. However, in patients with hyperinfection syndrome and disseminated infection, the mortality rate is reported to be as high as 70 to 100%.[33] Risk factors for increased mortality in patients affected with this disease include underlying immunosuppression (due to underlying illness and/or immunosuppressive therapy), concomitant bacteremia, and delayed diagnosis.[34][21]

A 2006 study from Hong Kong evaluated the clinical course and outcome of disseminated strongyloidiasis over a 10-year period. Seven patients were identified, of which 5 had pulmonary involvement at the time of presentation and subsequently died despite anthelmintic therapy and aggressive supportive therapy. Pulmonary and bowel symptoms were prominent in this series, and peripheral eosinophilia was universally absent.[33]

Complications

As outlined above, the most dreaded consequence of Strongyloides stercoralis infection is hyperinfection syndrome, which is associated with severe disseminated disease and frequently leads to multiorgan failure with eventual death despite anthelmintic therapy.[33] Additionally, patients with severe diseases are also at risk of gram-negative bacteremia and sepsis, which is why broad-spectrum antibiotics are recommended in addition to antihelminthic therapy in patients with severe disease. 

Deterrence and Patient Education

Prevention of chronic and disseminated strongyloidiasis should be considered in patients at high risk for the disease. This includes the screening of asymptomatic patients, especially those with exposure to endemic areas. Serologic testing in asymptomatic individuals is warranted in patients:[35]

• Patients with exposure to endemic areas that now require immunosuppressive therapies
• Those who have relevant environmental exposure and are now becoming organ donors
• Military personnel with a history of service in endemic areas, regardless of how remote the exposure was
• Immigrants and refugees from endemic areas

As with other soil-transmitted helminth infections, prevention of disease incidence in endemic areas is undertaken by sanitation, access to clean water, hand washing, and general hygiene.[36]

Enhancing Healthcare Team Outcomes

The diagnosis and management of strongyloidiasis require a high degree of clinical suspicion and careful care coordination among interprofessional healthcare team members to ensure early diagnosis, appropriate treatment, and effective eradication of the disease. The pharmacist plays a crucial role in ensuring medication compliance to ensure eradication occurs with the first treatment course. Subsequent monitoring of all patients is required to ensure that larvae are no longer detectable in the body fluids; nurses participate extensively in monitoring, answering patient questions, reporting/charting therapy progress for the clinician team, and educating patients regarding the need for effective therapy despite minimal symptoms. Response to treatment should be followed up with serial stool exams or anti-Strongyloides titers for one to two years in all patients.[31] This requires extensive patient counseling by clinical providers and specialty nurses to ensure patients remain compliant with the treatment plan. A well-coordinated interprofessional team of nurses, pharmacists, and clinical providers can significantly reduce the burden of this disease and ensure better clinical outcomes. [Level 5]