Treating Strongyloides with ivermectin in patients with COVID-19
by Government of Canada
Published by: The Public Health Agency of Canada
Issue: Volume 47-7/8: Infant Botulism in Canada, 1979–2019
Date published: July/August 2021
ISSN: 1481-8531
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Volume 47-7/8: Infant Botulism in Canada, 1979–2019
Rapid Communication
Ivermectin treatment for Strongyloides infection in patients with COVID-19
Ontario COVID-19 Science Advisory Table and the Drugs & Biologics Clinical Practice Guidelines Working Group
Correspondence
Suggested citation
Abstract
Ivermectin, an antiparasitic agent, is not recommended for prophylaxis or treatment of coronavirus disease 2019 (COVID-19). Inappropriate use of ivermectin for treatment of COVID-19 may make it less available for patients with serious parasitic infections who could benefit from its use and worsen the current shortage of ivermectin in Canada. However, patients with COVID-19 who are candidates to receive immunomodulatory therapies (e.g. corticosteroids and interleukin-6 inhibitors) may be at risk of hyperinfection syndrome and disseminated disease from Strongyloides stercoralis. These complications can be severe and even fatal. It is important to recognize and screen patients who may be at risk of strongyloidiasis, as these patients may require treatment with ivermectin to avoid the potential for a hyperinfection syndrome and disseminated disease, which is frequently deadly. Clinicians should follow evidence-based recommendations to screen and treat for Strongyloides infection in patients with COVID-19 who are under consideration to receive specific COVID-19 therapies that alter immune response and may lead to hyperinfection syndrome or disseminated disease.
Introduction
Ivermectin is an oral drug approved in Canada for the treatment of certain parasitic infections (e.g. strongyloidiasis and onchocerciasis)Footnote 1. In vitro data have demonstrated that ivermectin has antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and can prevent viral proteins from binding to and entering cellsFootnote 2. This has contributed to the view that ivermectin may have antiviral effects in vivo. However, the plasma concentrations that are required to achieve antiviral effect are significantly higher than the maximum achievable plasma concentrations with tolerable doses in humansFootnote 3. Ivermectin is currently not recommended for prophylaxis or treatment of coronavirus disease 2019 (COVID-19)Footnote 4, as current evidence does not show clinical benefitFootnote 5. In the absence of evidence showing a clinical benefit for ivermectin in the treatment of COVID-19, there are compelling reasons to conserve limited national and provincial supplies of ivermectin by only using it for evidence-based indications.
It is important to note that the primary and approved use of ivermectin is as an antiparasitic agent. One parasite of interest is Strongyloides stercoralis. Strongyloides infection ranges in presentation from asymptomatic intestinal infection to hyperinfection and severe disseminated disease. Patients with chronic asymptomatic S. stercoralis infection and impaired immunity may develop "accelerated auto-infection", known as hyperinfection. These patients may also experience disseminated disease secondary to larval migration outside their usual anatomic reservoir, with varying presentations (e.g. pneumonia, central nervous system infection, recurrent gram-negative or polymicrobial bacteremia and sepsis). Immunosuppression, in particular corticosteroid use, has been associated with increased risk of hyperinfection syndrome in patients with chronic Strongyloides infection.
Clinicians can refer to the Ontario Science Advisory Table Science Brief "Ivermectin as Empiric Treatment for Strongyloides in Patients with COVID-19 Disease" for full details to further support the recommendations submitted in this article. The Science Table full brief is available online.
Current situation
In patients with strongyloidiasis (including asymptomatic Strongyloides infection), immunosuppression can lead to a worsening of the parasitic infection including hyperinfection and disseminated disease, which is a devastating illness with mortality rates approaching 90% if left untreatedFootnote 6Footnote 7. Although most reports of hyperinfection syndrome implicate corticosteroids as the main risk factor, there are also reports with other immunosuppressive or immunomodulatory agents including tumour necrosis factor (TNF), interleukin-1 (IL-1) and other non-steroid lymphocyte depleting agentsFootnote 6Footnote 7. A recent European Society of Clinical Microbiology and Infectious Diseases review on the safety of biological therapies did not identify Strongyloides as a major infectious risk with IL-6 inhibitors (including tocilizumab)Footnote 8. However, there have been case reports of Strongyloides hyperinfection developing in patients who received concomitant corticosteroid therapy with tocilizumabFootnote 9Footnote 10Footnote 11.
Dexamethasone and tocilizumab, two evidence-based therapies for the treatment of moderately and critically-ill patients with COVID-19, are both anti-inflammatory agents with immunosuppressive effects. There is no clear relationship between a threshold dose and duration of immunosuppression at which the risk of disseminated Strongyloides infection may occur. It is also currently not well described how concomitant immunosuppressive medications may interact to affect hyperinfection risk, or whether those who receive multiple immunosuppressive therapies are at additional risk for disseminated disease.
Current limited supply of ivermectin
Ivermectin is an essential medication for treatment of strongyloidiasis (and is an important component of combination therapy for hyperinfection syndrome and fulminant, disseminated disease). As of January 21, 2021, ivermectin has been listed on shortage by Drug Shortages Canada, with only limited quantities available due to increased demand for the drug; the estimated shortage end date is December 31, 2021, which is subject to change based on supply and demandFootnote 12. Therefore, clinicians are currently encouraged to use ivermectin only when necessary for evidence-based clinical indications, and may need to be prepared to consider using substitute agents if ivermectin becomes locally unavailable. In this brief review, we discuss the application of existing Strongyloides screening recommendations to patients with COVID-19, and suggested Strongyloides treatment strategies to preserve ivermectin supply while ensuring appropriate treatment for patients with COVID-19 at risk for hyperinfection (see Appendix Table 1).
Assessment of Strongyloides risk in patients with COVID-19
The rate of Strongyloides infection in Canada is not well described, but the Committee to Advise on Tropical Medicine and Travel (CATMAT) estimates that as many as 2.5 million individuals in Canada have simple intestinal strongyloidiasis (assuming a prevalence rate of 40% in the patient country of origin, although seroprevalence has been noted to be above 60% among immigrants from endemic regions). In 2016, CATMAT noted that almost seven million Canadians were foreign-born, and 85% of this population were from a country where S. stercoralis is endemic; therefore, the risk of strongyloidiasis in Canada is not negligibleFootnote 6.
For patients with COVID-19 who are under consideration to receive immunosuppressive therapy, the first step is to assess their risk for progressing to severe strongyloidiasis based on both epidemiologic and clinical factors. We recommend following the CATMAT guidelines Step 1—epidemiologic assessment (based on country of prior residence or extended exposure)Footnote 6Footnote 13. Of note, the CATMAT guidelines outline risk related to a corticosteroid dose "equivalent to 20 mg/day of prednisone for ≥2 weeks", and we assume that the dose of corticosteroid recommended for COVID-19 treatment is similar to this relatively arbitrary cutoff. Hyperinfection syndrome has been reported with a range of corticosteroid doses and durations, and it is still unknown whether concomitant immunosuppressive therapies contribute to a higher relative risk of hyperinfection.
We also recognize that geographic epidemiologic risk alone may place many patients in the moderate risk category (if not the high risk category), and this may also overlap with patient demographics in neighbourhoods and communities which have been highly and disproportionately impacted by the COVID-19 pandemicFootnote 14.
We also recommend following CATMAT guidelines Step 2—assessment of clinical risk and suspected clinical syndrome. This Step will identify what diagnostic tests should be done to screen for strongyloidiasis. Ideally, S. stercoralis testing is performed prior to administration of immunosuppressive therapy, but often this is not possible in patients with COVID-19. Patients at moderate or high epidemiologic risk of Strongyloides infection should proceed to serologic testing as soon as possible (even if immunosuppression has already been initiated), while patients at low epidemiologic risk of Strongyloides infection do not require diagnostic screening unless there is clinical suspicion of Strongyloides hyperinfection or dissemination. Clinicians should note that any patients who have clinical signs/symptoms of active strongyloidiasis, hyperinfection or dissemination will require additional diagnostic testing, empiric treatment, and expert consultationFootnote 6.
Treatment of strongyloidiasis in patients with COVID-19
Ivermectin dosing for treatment of strongyloidiasis differs depending on the clinical syndrome. Less severe forms of strongyloidiasis (e.g. mild intestinal or asymptomatic strongyloidiasis) are now mostly treated with a single weight-based dose of ivermectin (200 μg per kilogram), based on emerging evidence that a single dose is as effective as multiple dosesFootnote 15. Clinicians may consider repeating serology after a single dose regimen if treatment failure is suspected. When a two-dose regimen of ivermectin is used, the doses are typically administered on consecutive days or separated by 14 days. When a two-dose regimen is administered, the separated-dose regimen is preferred to consecutive doses due to the risk of prepatent infection arising from auto-infection although consecutive doses may be used if medication adherence is a concern (e.g. healthcare system challenges related to increased frequency of intra and inter-hospital patient transfers during the COVID-19 pandemic). Severe forms of strongyloidiasis (e.g. hyperinfection and disseminated Strongyloides infection) often require daily weight-based dosing of ivermectin, sometimes given in combination with other antihelminthic agents such as albendazoleFootnote 6.
We recommend following CATMAT guidelines Step 3 to decide whether a patient should be screened and/or treated with ivermectin for strongyloidiasis. This approach takes into account both the epidemiologic (Step 1) and clinical risks (Step 2) assessments. Most patients with an epidemiologic risk for Strongyloides infection, and for whom immunomodulatory therapies (either dexamethasone, tocilizumab, or both) are being considered during their hospitalization for COVID-19, are at risk for asymptomatic strongyloidiasis. As outlined earlier, many of these patients may also meet the "high" or "moderate" category of geographic epidemiologic risk. In these cases, it is important that clinicians send the appropriate specimens for diagnostic testing and also monitor the patient after receipt of immunomodulatory therapy for any signs/symptoms of Strongyloides infection which could potentially progress to hyperinfection syndrome and disseminated disease if not treated promptly.
The CATMAT guidelines (prior to COVID-19) indicate that empiric treatment with two doses of ivermectin may be given "in the rare circumstance where the patient is deemed high risk for strongyloidiasis and immunosuppression cannot await definitive diagnostic testing"Footnote 6. However, given the current limited national supply of ivermectin, we recommend waiting for Strongyloides serology results (if results can be obtained reasonably quickly—e.g. within 24 hours) before initiating ivermectin for treatment of asymptomatic strongyloidiasis. Patients with a reactive or indeterminate Strongyloides serology result should be treated for asymptomatic strongyloidiasis as described earlier. If laboratory results cannot be expedited, it is reasonable to wait for serology results if the patient is clinically stable and only administer empiric ivermectin therapy if the patient is clinically unstable. If there is suspicion for hyperinfection at the time of COVID-19 presentation, infectious disease specialist consultation is recommended.
Finally, an important consideration before any ivermectin therapy is initiated, is screening for the presence of concurrent loiasis (infection with the filarial nematode Loa loa), due to the risk of severe reactions, including fatal encephalopathy, if ivermectin is administered to a patient with untreated loiasis. Clinicians should consult with an infectious diseases/tropical medicine expert for recommendations on Strongyloides treatment in patients who are from Loa loa endemic areas; namely West and Central AfricaFootnote 6Footnote 16. Recommended testing includes a daytime blood film examination for Loa loa microfilaria.
Serologic testing expected turn-around-time
In the absence of immunosuppression, screening for Strongyloides by microscopic examination of stool or sputum for ova and parasites (OAP) may only produce a positive result if the patient has a high burden of infection (e.g. if the patient is symptomatic or already experiencing hyperinfection syndrome). Therefore, although CATMAT guidelines recommend screening with both serology and stool OAP, we do not recommend sending stool OAP to screen for asymptomatic strongyloidiasis—especially given increased healthcare resource demands during the COVID-19 pandemic. Therefore, the ideal test to screen for Strongyloides (including asymptomatic infection) is a serologic testFootnote 17. S. stercoralis IgG serology testing is available through provincial laboratories and the turnaround time for results can be up to 10 days from receipt of blood sample by the laboratoryFootnote 18. In situations where serology results will impact urgent treatment decisions, laboratories may be able to expedite serology test results. For example, in the most recent third wave of Ontario infections, the Public Health Ontario Laboratory has provided expedited Strongyloides serology testing results within 24 hours from receipt by the laboratory, for specimens marked as coming from a patient with COVID-19. A coordinated laboratory strategy can help to preserve limited ivermectin supplies while ensuring that patients at high risk of progression to hyperinfection are identified rapidly.
Conclusion
COVID-19 mild illness: In patients who have mild COVID-19 there is currently insufficient evidence to support the use of immunomodulatory therapies (dexamethasone and tocilizumab). If patients who are mildly ill are to receive immunomodulatory therapy for COVID-19 or for other established non-COVID-19 indications, clinicians may use the CATMAT guidance recommendations to guide screening and/or treatment decisions.
COVID-19 moderate illness and critical illness: Patients who have moderate or critical COVID-19 are likely to be candidates to receive immunomodulatory therapies for treatment of COVID-19, and should therefore be screened for Strongyloides exposure/infection and may require treatment with ivermectin based on geographic epidemiologic risk and suspected Strongyloides clinical syndrome (Appendix Table 1).
Authors' statement
- EL — Wrote the first draft of the Science Brief
- EL, SR, BL, CG, NA, AMM, and MP — Contributed to the conception of the Science Brief
All authors revised it critically for important intellectual content and approved the final version.
The content and view expressed in this article are those of the authors and do not necessarily reflect those of the Government of Canada.
Competing interests
None.
Acknowledgements
E Leung, S Raybardhan, C Graham, C Nott, BJ Langford, N Andany, W Ciccotelli, S Chakrabarti, II Bogoch, WL Gold, M Pai, AM Morris, A McCarthy (on behalf of the Ontario COVID-19 Science Advisory Table Drugs & Biologics Clinical Practice Guidelines Working Group).
The Ontario COVID-19 Science Advisory Table is a group of scientific experts and health system leaders who evaluate and report on emerging evidence relevant to the COVID-19 pandemic, to inform Ontario's response. Our mandate is to provide weekly summaries of relevant scientific evidence for the COVID-19 Health Coordination Table of the Province of Ontario, integrating information from existing scientific tables, Ontario's universities and agencies, and the best global evidence. The Science Table summarizes its findings for the Health Coordination Table and the public in Science Briefs.
The Drugs & Biologics Clinical Practice Guidelines Working Group is a group of clinicians and scientists with recognized expertise in drugs, biologics and clinical care. The Working Group evaluates existing scientific data, disease epidemiology, drug availability and implementation issues in order to develop Clinical Practice Guidelines for the treatment of COVID-19 using drugs and biologics. The Working Group reports its findings to the public and the Science Table. Its findings are also summarized in Science Briefs.
The authors thank M Deilgat and P Huston for their helpful comments and correspondence regarding this manuscript, given the urgent nature of this topic as related to the increasing COVID-19 case numbers across Canada.
Funding
None.
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Appendix: Therapeutic recommendations
For therapeutic recommendations, we used the following definitions for COVID-19 severity:
Critically ill: Patients requiring ventilatory and/or circulatory support, including high-flow nasal oxygen, non-invasive ventilation, invasive mechanical ventilation or extracorporeal membrane oxygenation. These patients are usually managed in an intensive care setting.
Moderately ill: Patients newly requiring low-flow supplemental oxygen. These patients are usually managed in hospital wards.
Mildly ill: Patients who do not require new or additional supplemental oxygen from their baseline status, intravenous fluids, or other physiological support. These patients are usually managed in an ambulatory/outpatient setting.
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