The Toxicology of COVID

Since 2020, the COVID-19 pandemic has run rampant in the United States, significantly altering many facets of everyday life.

Since its onset, the world has been looking for preventative measures and treatments. As emergency physicians, we have seen the changing landscape of treatment modalities used in the hospitals over time and have watched with excitement the rapid development of COVID-19 vaccines.

However, while we were watching the rapid scientific development, there was a concurrent wave of misguided therapeutic misadventures among the general population.

A quick internet search will reveal myriad therapies, all with varying degrees of potential risk. Many proposed therapies have been widely publicized by prominent public figures and news outlets and have gained widespread popularity without sufficient scientific evidence to demonstrate their efficacy and safety. Perhaps the most widely discussed treatments or preventative measures in the mainstream media were bleach, chloroquine/hydroxychloroquine, and, most recently, ivermectin.

Bleach and household cleaners
During the COVID-19 pandemic, the use of disinfectants increased dramatically. There were many news stories describing people ingesting bleach or attempting other self-decontamination methods to help fight off the virus. How true were these stories? National Poison Center data demonstrate a 20.4% increase in calls about bleach and other disinfectants from January 2020 to March 2020 compared to the same time period the year prior.¹ One survey described 60% of respondents had increased household cleaning frequency due to the pandemic.² Of the respondents, 39% reported using household disinfectants, including bleach, inappropriately. Methods included ingestion, application on skin, inhalation, and cleaning produce with disinfectant or household cleaners. In addition to the adult misuse of these products, a large percentage of the calls to the Poison Centers during the Covid pandemic have been accidental exposures in children, as has been the case in years before the pandemic.¹

Many household cleaners and disinfectants are caustic agents. Important considerations for risk of significant damage include the amount ingested and the pH of the substance. Initial management of a patient exposed to a caustic agent includes a rapid assessment of the patient’s airway. If there is concern for potential airway compromise (significant swelling, stridor, inability to tolerate secretions), emergent intubation should be considered for airway protection. Once the patient is stabilized, the next question is whether the patient requires endoscopic evaluation.³ As a rule, any intentional ingestion requires endoscopy, as the volume in these ingestions is potentially larger. In addition, those with intentional ingestions are less likely to report the development of symptoms, including pain, which could indicate significant damage has occurred. In unintentional ingestions (i.e. children), endoscopy is indicated if the patient has stridor or two of the following: pain, vomiting, or drooling.^3,4 Patients with ingestions that meet the concerning parameters should be admitted for monitoring and GI should be consulted.

Chloroquine/Hydroxychloroquine
Early in the pandemic, hydroxychloroquine was used for some COVID-19 patients based on early data. However, further studies demonstrated its lack of benefit and potential harm.^5,6 Despite the changing science, the general population continued to ask for and search out hydroxychloroquine or its counterpart, chloroquine. One high-profile case involved a husband and wife who ingested aquarium cleaner containing chloroquine. Sadly, the husband died, and the wife became critically ill.⁷

Of the proposed COVID-19 treatments, chloroquine or hydroxychloroquine are perhaps the most likely to cause life-threatening toxicity in overdose. These drugs are best known as malarial and rheumatologic treatments.⁸ In overdose, patients can develop toxicity quickly. They can develop significant hypokalemia, QRS prolongation, QTc prolongation, hypotension, respiratory depression, seizures, and coma. Management of these patients is complicated and requires early aggressive intervention.⁹ This can include gastrointestinal decontamination if appropriate, early intubation, and treatment with high dose diazepam and epinephrine, in addition to supportive care. For chloroquine and hydroxychloroquine toxicity, epinephrine is the vasopressor of choice as it is the best studied. Interestingly, high dose diazepam is also shown to be effective (2 mg/kg IV over 30 minutes then 1-2 mg/kg/day for 2-4 days).⁸ The mechanism is yet to be elucidated, but several theories have been proposed that are beyond the scope of this short review.

Ivermectin
A more recent drug discussed in the media for potential use against COVID-19 is the anthelmintic ivermectin. Much of the recent fanfare resulted from an Egyptian study that was purported to show a significant mortality benefit.¹⁰ However, this preprint article was retracted due to concerns about its data.¹¹ Despite the retraction, the article has been widely viewed, and ivermectin is being discussed regularly in the media. This has led to an uptick in calls to Poison Centers, as noted by the Mississippi State Department of Health.¹²

Although ivermectin has not been shown to be effective against COVID-19, it is generally well-tolerated in overdose. There are scant case reports of significant toxicity. Therapeutic use can result in gastrointestinal symptoms.¹³ Overdose can cause encephalopathy and CNS depression.^13,14 Management is supportive. Many news articles describe individuals purchasing veterinary preparations of ivermectin, some of which are higher concentrations. We may learn more about this drug in overdose because of this recent misuse by the public.

Conclusion
The COVID-19 pandemic and the myriad questions surrounding it have led individuals to search for prevention and treatment modalities with questionable scientific backing. It is important for emergency medicine providers to be aware of the potential toxicity from exposure to these xenobiotics.

Poison Control Centers are available 24/7 to assist in the management of poisoned patients. Please do not hesitate to call us: (800) 222-1222.

References

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2. Gharpure R, Hunter CM, Schnall AH, Barrett CE, Kirby AE, Kunz J, Kirsten B, Mercante JW, Murphy JL, Garcia-WIlliams AG. Knowledge and practices regarding safe household cleaning and disinfection for COVID-19 prevention – United States, May 2020. Morbidity and Mortality Weekly Report. 2020, 69(23): 705-709.
3. Wightman RS, Fulton JA. Wightman R.S., & Fulton J.A. Wightman, Rachel S., and Jessica A. Fulton.In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. Nelson L.S., & Howland M, & Lewin N.A., & Smith S.W., & Goldfrank L.R., & Hoffman R.S.(Eds.),Eds. Lewis S. Nelson, et al.eds. Goldfrank's Toxicologic Emergencies, 11e. McGraw Hill; 2019. Accessed September 13, 2021. https://accessemergencymedicine.mhmedical.com/content.aspx?bookid=2569&sectionid=210275165
4. Crain, E. F. (1984). Caustic ingestions. American Journal of Diseases of Children, 138(9), 863. https://doi.org/10.1001/archpedi.1984.02140470061020 
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6. Fiolet, T., Guihur, A., Rebeaud, M. E., Mulot, M., Peiffer-Smadja, N., & Mahamat-Saleh, Y. Effect of HYDROXYCHLOROQUINE with or without AZITHROMYCIN on the mortality of CORONAVIRUS disease 2019 (COVID-19) patients: A systematic review and meta-analysis. Clinical Microbiology and Infection. 2021, 27(1), 19–27. https://doi.org/10.1016/j.cmi.2020.08.022 
7. Neuman S. Coronavirus Updates: Man dies, woman hospitalized after taking form of chloroquine to prevent COVID-19. National Public Radio. March 24, 2020.
8. Barry J. Barry J Barry, James David.In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. Nelson L.S., & Howland M, & Lewin N.A., & Smith S.W., & Goldfrank L.R., & Hoffman R.S.(Eds.),Eds. Lewis S. Nelson, et al.eds.Goldfrank's Toxicologic Emergencies, 11e. McGraw Hill; 2019. Accessed September 13, 2021. https://accessemergencymedicine.mhmedical.com/content.aspx?bookid=2569&sectionid=210273082
9. Riou B., Barriot P., Rimailho A., Baud F. Treatment of severe chloroquine poisoning. New England Journal of Medicine. 1988, 318 (1): 1-6.
10. Elgazzar, A., Eltaweel, A., Youssef, S. A., Hany, B., Hafez, M., & Moussa, H. (2020). Efficacy and safety of ivermectin for treatment and prophylaxis of covid-19 pandemic. https://doi.org/10.21203/rs.3.rs-100956/v3 
11. Reardon, S. (2021). Flawed ivermectin preprint highlights challenges of covid drug studies. Nature, 596(7871), 173–174. https://doi.org/10.1038/d41586-021-02081-w  
12. Byers P. MS Health Alert Network (HAN) Alert: Increased poison control calls due to ivermectin ingestion and potential toxicity. Mississippi State Department of Health. August 20, 2021.
13. In: Baselt RC, eds. Disposition of Toxic Drugs and Chemicals in Man. 12^th ed. Biomedical Publications; 2020:1098-1099.
14. Baudou E, Lespine A, Durrieu G, et al. Serious ivermectin toxicity and human abcb1 nonsense mutations. New England Journal of Medicine. 2020;383(8):787-789. doi:10.1056/nejmc1917344