COVID-19 and Dexamethasone: A Potential Strategy to Avoid Steroid-Related Strongyloides Hyperinfection | Critical Care Medicine | JAMA | JAMA Network
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July 30, 2020

COVID-19 and Dexamethasone: A Potential Strategy to Avoid Steroid-Related Strongyloides Hyperinfection

Author Affiliations
  • 1Center for Global Health and Social Responsibility, University of Minnesota, Minneapolis
  • 2Department of Medicine, Global Medicine, University of Minnesota, Minneapolis
  • 3HealthPartners Institute, Bloomington, Minnesota
  • 4HealthPartners Travel and Tropical Medicine Center, St Paul, Minnesota
JAMA. 2020;324(7):623-624. doi:10.1001/jama.2020.13170

A widely publicized press release and subsequent preliminary report of the RECOVERY trial, a randomized study conducted in the UK, noted a survival benefit with the use of dexamethasone in hospitalized patients with coronavirus disease 2019 (COVID-19).1 The use of dexamethasone for management of COVID-19 has already increased, particularly given the recent National Institutes of Health COVID-19 Treatment Panel guidelines that recommend its use.2

Although clinicians are familiar with the most common adverse effects associated with dexamethasone, a corticosteroid, they may be less familiar with a potentially severe, but preventable, less common complication: Strongyloides hyperinfection or dissemination syndrome (hyperinfection).3

Strongyloidiasis is caused by a nematode (roundworm) infection, with most human disease associated with Strongyloides stercoralis. Strongyloides infection is predominantly acquired through contact with soil contaminated with free-living larvae, which penetrate the skin and migrate to the intestine, where they lay eggs. Eggs are excreted into the environment where they hatch. Larvae complete the life cycle by penetrating the skin of a new host. Unlike other soil-transmitted infections, eggs of Strongyloides may hatch into filariform larvae in the intestines and directly autoinoculate, reinfecting their human host (autoinfection) without an environmental stage. This unique characteristic perpetuates chronic infection, often lasting for decades.

Although a majority of individuals with strongyloidiasis are asymptomatic, a severe disease manifestation is hyperinfection syndrome. This frequently fatal iatrogenic complication is usually associated with use of an immunosuppressive drug in persons with unrecognized chronic infection. The most common precipitator is use of a corticosteroid agent, which appears to be independent of dose or duration of treatment.3-5 Coinfection with human T-lymphotropic virus type 1, which is disproportionately found in immigrant and refugee populations, is also associated with hyperinfection syndrome.3,4

Although prevalence data are lacking from many regions of the world, Strongyloides is estimated to infect hundreds of millions of people worldwide,3,6 with studies suggesting that 10% to 40% of populations in tropical and subtropical regions may be infected.6,7 A 2019 meta-analysis of studies involving migrants worldwide found a pooled strongyloidiasis seroprevalence of 12.2%; the prevalence was 17.3% among migrants from Asia, 14.6% among migrants from sub-Saharan Africa, and 11.4% among those from Latin America and the Caribbean.8 The prevalence among certain populations of refugees from Africa and Asia arriving in the US is estimated to approach 50%.9 Although there are no incidence or prevalence estimates of Strongyloides hyperinfection, there are hundreds of case reports, and the condition is likely underreported because of challenges in diagnostic testing and lack of clinician awareness of the syndrome.3-7 Given the high prevalence rate in refugees, underrecognition of infection in the US, and a lifetime risk associated with Strongyloides infection, presumptive treatment of all at-risk US-bound refugees was initiated in 2011.9 In 2016, the Committee to Advise on Tropical Medicine and Travel for Canada (CATMAT) issued similar evidence-based screening and preventive treatment guidelines for at-risk immigrant and refugee populations in Canada5 and, in 2018, the European Centre for Disease Prevention and Control issued guidance.

With more than 44 million first-generation immigrants residing in the US, many of whom work essential jobs and live in environments less conducive to social distancing, the convergence of risk for both chronic strongyloidiasis and COVID-19 infection could be common and is concerning. In addition, it is likely that dexamethasone use will increase for COVID-19 in Stronglyoides-endemic low- and middle-income countries because corticosteroids are inexpensive and widely available. The most proactive approach to avoid the risk of iatrogenic Strongyloides hyperinfection is to address infection in asymptomatic persons prior to the use of immunosuppressant therapy, particularly corticosteroids. Most patients with chronic strongyloidiasis are asymptomatic. Peripheral eosinophilia may be associated with parasitic infection and is commonly believed to be a good clinical marker for Strongyloides infection. However, eosinophilia has poor sensitivity, specificity, and predictive value, particularly in predicting hyperinfection syndrome.3,4 Therefore, suspicion of underlying chronic infection must be made independent of signs and symptoms and instead based on factors such as country of origin and long-term residence. Additionally, risk should be weighted for patients by demographic risk factors associated with transmission (eg, history of rural residence, labor associated with exposure to soil) and duration of exposure. Because infection may be lifelong, suspicion should not be based on duration outside an endemic area; fatal cases have been reported more than 50 years after leaving an endemic area.

How should clinicians evaluate and manage the risk of Strongyloides hyperinfection among patients with COVID-19 with increased use of dexamethasone? The current recommended dexamethasone dose from the COVID-19 Treatment Panel is 6 mg/d (≈40 mg of prednisone) for 10 days.2 A study that reviewed 133 individuals with Strongyloides hyperinfection found that hyperinfection was associated with corticosteroid administration in 83% of cases, with an average dose of 40 mg per day of prednisone.10 In addition, cases have occurred within 5 days of administration of the first dose of corticosteroids, following doses as low as 20 mg of prednisone and following a single dose of dexamethasone, leading experts to assert that the occurrence is independent of dose, duration, or route of administration.3

Based on the available data, it is likely that the benefit of dexamethasone outweighs the risk of possible Strongyloides hyperinfection, an uncommon complication. However, due to the high mortality associated with this syndrome and the availability of inexpensive and effective therapy, ivermectin could be used as a preventive strategy for at-risk patients. Ivermectin is considered extremely safe and is used in many settings for parasite control programs (mass treatment) because of a low adverse event profile. In vitro data suggest that ivermectin has direct activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), although no current data are available to support its use for management of COVID-19, and no group has recommended its use.

A possible strategy to avoid hyperinfection syndrome for patients at moderate to high risk for strongyloidiasis in anticipation of widespread use of dexamethasone during the COVID-19 pandemic is presented in the Figure. The 2016 CATMAT recommendations has stratified risk categories into high, moderate, and low, which may be used for this purpose.5 A test-and-treat strategy is suggested for the outpatient setting and for patients with mild COVID-19 when serologic testing is available. For patients with COVID-19 who are, or may become, candidates for dexamethasone, it is reasonable to consider presumptive treatment with ivermectin for moderate- to high-risk patients not previously tested or treated for Strongyloides. When serologic testing is unavailable or delayed and when treatment with steroids is imminent, waiting for serologic results to guide treatment decisions is not advisable. Although this suggested treatment approach has not been formally studied, many clinical experts advocate a similar approach for select patients (eg, before organ transplant).

Figure.  Approach to Reducing Risk for Strongyloides Hyperinfection/Dissemination in Persons at Moderate to High Risk of Infection5 During the Coronavirus Disease 2019 (COVID-19) Pandemica
Approach to Reducing Risk for Strongyloides Hyperinfection/Dissemination in Persons at Moderate to High Risk of Infection During the Coronavirus Disease 2019 (COVID-19) Pandemica

aThis strategy has not been evaluated in patients with COVID-19 who are candidates for corticosteroid therapy.

bSerologic testing is preferred. When testing is not available, presumptive treatment is acceptable if there are no contraindications to ivermectin.

cIf the patient previously tested negative for strongyloidiasis or has documented treatment with ivermectin, no screening or treatment is needed.

dIvermectin 200 μg/kg once per day orally for 1 or 2 days. Possible contraindications include possible Loa loa infection (endemic to West and Central Africa), pregnancy, and weight <15 kg.

eGenerally includes testing of multiple specimens for ova and parasites or pathologic examination of other sites of suspected infection.

In patients at risk of strongyloidiasis who receive dexamethasone without being tested or treated for Strongyloides, clinicians should include Strongyloides hyperinfection syndrome on the differential diagnosis for patients who experience acute clinical decompensation, especially if gram-negative rod bacteremia or central nervous system infection is detected.3

Strongyloides hyperinfection syndrome is potentially catastrophic to patients. It is possible that as dexamethasone becomes more widely prescribed for individuals with COVID-19, a substantial number of patients may be at risk. This iatrogenic potentially fatal complication is avoidable. Clinicians and health care systems should consider implementing a strategy to prevent hyperinfection syndrome in patients with COVID-19 who are at risk for strongyloidiasis and are candidates for dexamethasone therapy.

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Article Information

Corresponding Author: William M. Stauffer, MD, MSPH, Department of Medicine, University of Minnesota, 420 Delaware St SE, MMC 250, Minneapolis, MN 55455 (stauf005@umn.edu).

Published Online: July 30, 2020. doi:10.1001/jama.2020.13170

Conflict of Interest Disclosures: Dr Stauffer reported serving as the lead medical advisor of the Immigrant, Refugee, and Migrant Health Branch at the CDC, where he has been an author on the refugee predeparture and postarrival parasitic screening and presumptive treatment guidelines, and has received royalties from UpToDate. Dr Walker reported receiving royalties from Elsevier and UpToDate outside the submitted work. No other disclosures were reported.

Disclaimer: The views expressed herein are the opinions of the authors and do not represent the position of the CDC, which did not participate in the development of this article, or any organization with which the authors are affiliated.

References
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The RECOVERY Collaborative Group.  Dexamethasone in hospitalized patients with Covid-19—preliminary report.   N Engl J Med. Published online July 17, 2020. doi:10.1056/NEJMoa2021436PubMedGoogle Scholar
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Corticosteroids (including dexamethasone). NIH website. Updated July 17, 2020. Accessed July 22, 2020. https://www.covid19treatmentguidelines.nih.gov/dexamethasone/
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Krolewiecki  A, Nutman  TB.  Strongyloidiasis: a neglected tropical disease.   Infect Dis Clin North Am. 2019;33(1):135-151. doi:10.1016/j.idc.2018.10.006PubMedGoogle ScholarCrossref
4.
Requena-Méndez  A, Buonfrate  D, Gomez-Junyent  J,  et al.  Evidence-based guidelines for screening and management of strongloidiasis in non-endemic countries.   Am J Trop Med Hyg. 2017;97(3):645-652.PubMedGoogle ScholarCrossref
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Boggild  AK, Libman  M, Greenaway  C,  et al.  CATMAT statement on disseminated strongyloidiasis: prevention, assessment and management guidelines.   Can Commun Dis Rep. 2016;42(1):12-19. doi:10.14745/ccdr.v42i01a03PubMedGoogle ScholarCrossref
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Puthiyakunnon  S, Boddu  S, Li  Y,  et al.  Strongyloidiasis–an insight into its global prevalence and management.   PLoS Negl Trop Dis. 2014;8(8):e3018. doi:10.1371/journal.pntd.0003018PubMedGoogle Scholar
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Olsen  A, van Lieshout  L, Marti  H,  et al.  Strongyloidiasis—the most neglected of the neglected tropical diseases?   Trans R Soc Trop Med Hyg. 2009;103(10):967-972.PubMedGoogle ScholarCrossref
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Asundi  A, Beliavsky  A, Liu  XJ,  et al.  Prevalence of strongyloidiasis and schistosomiasis among migrants.   Lancet Glob Health. 2019;7(2):e236-e248. PubMedGoogle ScholarCrossref
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Presumptive treatment and screening for strongyloidiasis, infections caused by other soil-transmitted helminths, and schistosomiasis among newly arrived refugees. CDC website. Accessed July 5, 2020. https://www.cdc.gov/immigrantrefugeehealth/guidelines/domestic/intestinal-parasites-domestic.html
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Geri  G, Rabbat  A, Mayaux  J,  et al.  Strongyloides stercoralis hyperinfection syndrome.   Infection. 2015;43(6):691-698.PubMedGoogle ScholarCrossref
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    4 Comments for this article
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    Ivermectin in Latin America
    Carlos Alvarez, MD; FIDSA; PhD; DTM&H | Porfessor of Medicine at Infectious Diseases at Tropical medicine. Facultad de Medicina; Universidad Nacional de Colombia. Clinica Universitaria Colombia, Clinica Colsanitas
    I have carefully read the Viewpoint on use of ivermectin proposed by Dr. Stauffer et al. to avoid the hyperinfection of Strongyloides stercoralis (S. stercoralis). In countries endemic for this intestinal parasitosis it is mandatory to start deworming before starting the use of steroids, since the presence of cases of S. stercoralis hyperinfestation is not uncommon. Besides, given the endemicity, the use of serological tests is not useful, and the usefulness of the stool test is weak due to its sensitivity to detect this parasite (1,2). At this time when regions such as Latin America are on the epidemic curve of COVID-19, clinical practice guidelines of several countries have routinely introduced using dexamethasone based on the data from the RECOVERY trial, and previous administration of ivermectin is recommended as an antiparasitic encouraged by the title of a paper recently published in Antiviral Research, "The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro" (3). The study reports that ivermectin, a medication widely used for treatment of certain parasitic diseases in humans, inhibits replication of SARS-CoV-2 in cell culture. The search for a simple therapeutic treatment of COVID-19 has led to extensive use of ivermectin not only as a treatment but also as a prophylactic in several Latin American countries, and in countries like Peru and Honduras the drug is promoted in national clinical guidelines; This has led to a shortage in some regions of ivermectin, including veterinary presentations. Since its use and method of administration for this indication is not clear, despite the safety of ivermectin, its administration at high doses or repeated use could lead to unexpected consequences. Finally, I consider that repurposing ivermectin for COVID-19 could be encouraging, but this cannot be massively recommended without having carried out controlled clinical studies

    REFERENCES
    1. Kalantari N, Chehrazi M, Ghaffari S, Gorgani-Firouzjaee T. Serological assays for the diagnosis of Strongyloides stercoralis infection: a systematic review and meta-analysis of diagnostic test accuracy. Trans R Soc Trop Med Hyg. 2020;114(6):459-469.
    2. Campo Polanco L, Gutiérrez LA, Cardona Arias J. Infección por Strongyloides stercoralis: metanálisis sobre evaluación de métodos diagnósticos convencionales (1980-2013) [Diagnosis of Strongyloides Stercoralis infection: meta-analysis on evaluation of conventional parasitological methods (1980-2013)]. Rev Esp Salud Publica. 2014;88(5):581-600.
    3. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;178:104787. doi:10.1016/j.antiviral.2020.104787
    CONFLICT OF INTEREST: None Reported
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    Strongyloides Hyperinfection Prophylaxis Is Not Necessary in COVID-19 Patients Given Dexamethasone
    Joseph Santos, MD; PhD | Unidade de Terapia Intensiva, Hospital Governador Israel Pinheiro - IPSEMG - Hospital Universitário Ciências Médicas - FELUMA - Belo horizonte Minas Gerais - Brazil
    Dr. Stauffer et al. proposes the use of ivermectin as a potential strategy to avoid steroid-related Strongyloides hyperinfection in patients with severe COVID-19 treated with dexamethasone (6mg per day for 10 days), as demonstrated in the RECOVERY trial. However in several other clinical situations corticosteroids are used without such prophylaxis as in the case of hydrocortisone for treatment of septic shock. The guidelines of the Surviving Sepsis Campaign (SSC) do not recommend such prophylaxis for patients given hydrocortisone, which has been widely used for sepsis worldwide for almost 20 years (1). The recommended dose in the SSC guideline, 200 mg hydrocortisone per day, is equivalent to the dose of 6.7 mg of dexamethasone, similar to that used by the RECOVERY study. It is estimated that 48.9 million cases of sepsis occur worldwide, and that 2 to 20% progress to septic shock, and a significant number of them use hydrocortisone, without prophylaxis for strongyloides hyperinfection (1). Studies that tested hydrocortisone in septic shock considered the occurrence of strongyloides hyperinfection to be irrelevant in this situation, so much so that they did not include the use of antiparasitic agents in the research protocols prior to its use, and in these same studies there was no report of any case (2). Systematic reviews of the use of corticosteroids in sepsis do not mention an indication for the use of prophylaxis for strongyloides hyperinfection. Furthermore, we did not find any report in the literature of strongyloides hyperinfection in patients who received hydrocortisone in order to treat septic shock. On the contrary, systematic reviews of case studies of strongyloides hyperinfection show no reports in septic patients who used corticosteroids, but only in patients who received immunosuppressive therapy with corticosteroids, or in patients who used high doses (equivalent dose of prednisone above 30 mg / day) and for a prolonged period (greater than 4 weeks) (3). These data show that if there is any case of strongyloides hyperinfection in patients with septic shock, this is an extremely rare event. A guideline for the treatment of patients with COVID-19, recently published, does not provide a recommendation for prophylaxis in patients who need corticosteroids (4). As a concluding remark, there is no need or indication for the use of any antiparasitic to prevent strongyloides hyperinfection in patients with COVID-19 using dexamethasone.

    REFERÊNCIAS:
    1 – Rhodes A, Evans L, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016, Crit Care Medicine. 2017. 45(3):486-552
    2 – Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008;358:111-24
    3 - Geri, G., Rabbat, A., Mayaux, J. et al. Strongyloides stercoralis hyperinfection syndrome: a case series and a review of the literature. Infection. 2015. 43:691–698
    4 – Alhazzani W, Møller M H, Arabi, YM, et al. Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19), Crit Care Medicine. 2020. 48(6):e440-e469
    CONFLICT OF INTEREST: None Reported
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    Steroids and Immunotherapy
    David Spigel, MD | Sarah Cannon Research Institute
    Thanks for the heads up on this interesting potential medical complication of using steroids for COVID-19. It is odd that this has not been an issue with steroids and cancer treated with immunotherapy - where steroids are frequently used (and perhaps more than ever) to mitigate toxicities. Perhaps that is because it is under-recognized or due to regional use/risk.
    CONFLICT OF INTEREST: None Reported
    Can It Be About Strongyloides?
    Akshar Dash, MD | University of Texas at Houston, McGovern Medical School
    In response to the timely article COVID-19 and Dexamethasone: A Potential Strategy to Avoid Steroid-Related Strongyloides Hyperinfection published in JAMA in the August 18 2020 issue, we would like to suggest including Human T-Lymphotropic Virus-1 (HTLV-1) antibody co-testing to the strategy of screening and treatment of Strongyloides infection in COVID-19 patients being considered for corticosteroid treatment in the hospital setting algorithm (1). HTLV-1 coinfection with Strongyloides is a risk factor for Strongyloides Hyperinfection Syndrome. The pathophysiology in this illness is well defined (2). However as noted, the majority of Strongyloides hyperinfection syndrome cases tend to be in the case report format, and it is difficult to quantify the contribution and impact of the HTLV-1 virus toward the severity of the hyper infection illness. It must be noted that besides Adult T-Cell Leukemia/Lymphoma (ATLL), the virus does cause other illness; the well-documented HTLV 1 associated myelopathy, and HTLV-1 associated bronchoalveolar disorder among others (3).

    Thus, in patients that have tested positive for HTLV-1 and have Strongyloides antibodies who have been treated for Strongyloides but are not recovering from SARS-CoV-2 infection as expected, the deleterious effects of HTLV-1 associated disease should be considered and diagnostic work-up needs to performed. In the case reported by Baez et. al, Strongyloides hyperinfection syndrome was diagnosed in a 42-year old Colombian woman on upper gastrointestinal endoscopy after she was found to have meningitis due to enteric organisms (4). Due to a persistence of findings suggestive of meningitis, despite CSF bacterial cultures turning negative, Western Blot analysis of CSF for HTLV-1 was done and was found to be positive suggesting a lingering viral meningitis. The patient needed treatment for the bacterial meningitis based on bacterial culture and sensitivity results and was also on prolonged courses of oral Prednisone and Ivermectin. Upon discharge, repeat CSF Western Blot analysis was reported as being equivocal for HTLV-1, not negative. From this case and literature review, our understanding is HTLV-1 can be a confounding factor in the severity, spectrum, and duration of illness in a SARS-CoV-2 infected hospitalized patient with presumed Strongyloides infection treated with corticosteroids. Needless to say, treatment of a case with suspected HTLV-1 associated illness will need to be undertaken with the guidance of infectious disease specialists.

    Dash, Akshar, MD
    Chernis, Julia MD
    Stone, David MD
    Bhattacharjee, Gitanjali MS,
    Bhattacharjee, Modushudan MD

    References:
    1. Stauffer WM, Alpern JD, Walker PF. COVID-19 and Dexamethasone: A Potential Strategy to Avoid Steroid-Related Strongyloides Hyperinfection. JAMA. 2020;324(7):623–624. doi:10.1001/jama.2020.13170

    2. Carvalho, E. M, and A Da Fonseca Porto. “Epidemiological and Clinical Interaction Between HTLV-1 and Strongyloides Stercoralis.” Parasite immunology 26.11-12 (2004): 487–497.

    3. Nozuma, Satoshi, and Steven Jacobson. “Neuroimmunology of Human T-Lymphotropic Virus Type 1-Associated Myelopathy/Tropical Spastic Paraparesis.” Frontiers in microbiology 10 (2019): 885.

    4. Báez-Vallecillo, Luis et al. “Strongyloides Hyperinfection as a Mimic of Inflammatory Bowel Disease.” The American journal of gastroenterology 108.4 (2013): 622–623.
    CONFLICT OF INTEREST: None Reported
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