A parasitic infection that can turn fatal with administration of corticosteroids

Healthcare workers in tropical and sub-tropical settings where strongyloidiasis is prevalent or caring for patients who have travelled to such areas, need to maintain a high level of awareness about the use of corticosteroids, including when this class
of anti-inflammatories is given to patients suspected of infection with SARS-CoV-2.

Strongyloidiasis – a parasitic worm infection – is estimated to affect millions of people and is associated with marginalized communities who often walk barefoot. While it is frequently subclinical, immunosuppression resulting from diseases such
as AIDS, lymphoma and leukemia or from continued use of corticosteroids can convert it into a severe and deadly “hyperinfection” syndrome.

Risks in an era of COVID-19

The current COVID-19 pandemic serves to highlight the risk of using systemic corticosteroids and, to a lesser extent, other immunosuppressive therapy, in populations with significant risk of underlying strongyloidiasis. Cases of strongyloidiasis hyperinfection
in the setting of corticosteroid use as COVID-19 therapy have been described^1,2 and draw attention to the necessity of addressing the risk of iatrogenic strongyloidiasis hyperinfection syndrome in infected individuals prior to
corticosteroid administration.

Although this has gained importance in the midst of a pandemic where corticosteroids are one of few therapies shown to improve mortality³, its relevance is much broader given that corticosteroids and other immunosuppressive therapies have become
increasingly common in treatment of chronic diseases (e.g. asthma or certain rheumatologic conditions).

The risk of strongyloidiasis and corticosteroid use further becomes globally relevant as at-risk populations include not only those residing in endemic areas but also migrant communities in non-endemic areas.

The disease and immunosuppression

Strongyloidiasis, most commonly due to Strongyloides stercoralis in humans, is a parasitic (nematode) infection endemic throughout much of the tropical and subtropical regions of the world with an overall global prevalence of 8% and highest burden
in South-East Asia, Western Pacific, and African WHO Regions⁴.

Humans acquire the infection via contact with contaminated soil when larvae penetrate the skin and then migrate to the intestine. The eggs (or larvae) are then excreted back into the environment where they may infect a new host. Unlike other nematode
intestinal infections, S. stercoralis has a unique ability to auto-inoculate (re-infect) their human host without requiring passage through the soil, giving the parasite the ability to chronically infect the host for decades.

Most infections are asymptomatic or subclinical, although they can be associated with abdominal discomfort, skin rashes, cough, constipation or other less common complications. However, the feared complication, hyperinfection syndrome or dissemination,
occurs when a patient becomes immunosuppressed, most commonly from corticosteroid treatment⁵.

In addition to pharmacological immunosuppression, co-infection with human T-lymphotropic virus type 1 (HTLV-1), another common tropical/subtropical chronic infection, increases the risk of hyperinfection.

Prevention is crucial

The most common clinical presentation of hyperinfection syndrome is the acute decompensation of a patient who is noted to have a gram-negative bacteremia or central nervous system infection (meningitis). In areas of the world without access to dependable
diagnostics, including microbiologic cultures, the underlying condition of strongyloidiasis is under-recognized. Even in areas with advanced diagnostics the etiology is frequently overlooked, and when diagnosed, is incidentally found. While eosinophilia
can aid in diagnosis of chronic strongyloidiasis, it is frequently absent in cases of hyperinfection which accentuates the importance of high clinical acumen in recognizing this process. Prevention is paramount given that, even in treated cases, mortality
far exceeds 50%.

Treatment

Treatment of chronic strongyloidiasis with ivermectin 200 µg/kg per day orally x 1-2 days is considered safe with potential contraindications including possible Loa loa infection (endemic in West and Central Africa), pregnancy, and weight
<15kg.

Given ivermectin’s safety profile, the United States has utilized presumptive treatment with ivermectin for strongyloidiasis in refugees resettling from endemic areas, and both Canada and the European Centre for Disease Prevention and Control have
issued guidance on presumptive treatment to avoid hyperinfection in at risk populations^6–8. Screening and treatment, or where not available, addition of ivermectin to mass drug administration programs should be studied and considered.

Presumptive treatment

Corticosteroids are extremely inexpensive, widely available, and effective treatment for a myriad of conditions. The actual risk of hyperinfection syndrome in any given individual placed on corticosteroids is unknown. However, when it occurs, it generally
has a devastating outcome.

Risk stratification for chronic strongyloidiasis places those receiving corticosteroid therapy (or have HTLV-1 infection) at high risk for hyperinfection if they were born, resided,
or had long-term travel in Southeast Asia, Oceania, sub-Saharan Africa, South America, or the Caribbean. Similarly, the risk is considered  moderate   in Central America, Eastern Europe,
Mediterranean, Mexico, Middle East, North Africa, Indian sub-continent, or Asia (with low risk being those in Australia, Canada, United States, or Western Europe)⁸.

When initiating corticosteroid therapy, including for COVID-19, presumptive treatment (with or without laboratory screening) with ivermectin is advisable for those at high or moderate risk of hyperinfection⁹.

High level of awareness by clinicians

When prescribing corticosteroids, including when treating COVID-19 patients, clinicians need to maintain a high level of awareness for strongyloidiasis which causes chronic, subclinical infections that can become fatal in the setting of hyperinfection
from immunosuppression.

Due to the high endemicity of S. stercoralis in tropical and subtropical areas of the globe, people with a history of living or extensively traveling in these areas should be considered for presumptive treatment with ivermectin prior to corticosteroid
administration to prevent hyperinfection.

Further study and data are needed regarding presumptive treatment and the possible addition of ivermectin to other existing mass drug administration programs. Diagnosis and management of suspected or established strongyloidiasis hyperinfection system
should be discussed with an expert.

 

References:

1. Case Report: Disseminated Strongyloidiasis in a Patient with COVID-19. The American Journal of Tropical Medicine and Hygiene. 2020;103(4):1590-1592. doi:10.4269/ajtmh.20-0699
2. Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. Infection. Published online September 10, 2020:1-4. doi:10.1007/s15010-020-01522-4
3. The Recovery Collaborative Group. Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. New England Journal of Medicine. 2020;0(0):null. doi:10.1056/NEJMoa2021436
4. Buonfrate D, Bisanzio D, Giorli G, et al. The Global Prevalence of Strongyloides stercoralis Infection. Pathogens. 2020;9(6). doi:10.3390/pathogens9060468
5. Krolewiecki A, Nutman TB. Strongyloidiasis: A Neglected Tropical Disease. Infectious Disease Clinics of North America. 2019;33(1):135-151. doi:10.1016/j.idc.2018.10.006
6. Centers for Disease Control and Prevention. Division of Global Migration and Quarantine: Guidelines for Overseas Presumptive Treatment of Strongyloidiasis, Schistosomiasis, and Soil-Transmitted Helminth Infections | Immigrant and Refugee Health |
   CDC. Published 2019. Accessed November 13, 2020. https://www.cdc.gov/immigrantrefugeehealth/guidelines/overseas/intestinal-parasites-overseas.html
7. ECDC issues migrant screening and vaccination guidance. European Centre for Disease Prevention and Control. Published December 5, 2018. Accessed December 1, 2020. https://www.ecdc.europa.eu/en/news-events/ecdc-issues-migrant-screening-and-vaccination-guidance
8. Boggild A, Libman M, Greenaway C, McCarthy A. CATMAT statement on disseminated strongyloidiasis: Prevention, assessment and management guidelines. Can Commun Dis Rep. 2016;42(1):12-19. doi:10.14745/ccdr.v42i01a03
9. Stauffer WM, Alpern JD, Walker PF. COVID-19 and Dexamethasone: A Potential Strategy to Avoid Steroid-Related Strongyloides Hyperinfection. JAMA. 2020;324(7):623. doi:10.1001/jama.2020.13170