COVID-19 Management: Classical Treatments for a New Disease

Given the global pandemic of the novel SARS-CoV-2, clinical trials are underway to elucidate an effective treatment. Be aware of the potential risks.

Case
You are working a shift when a 34-year-old Caucasian woman presents to your ED with altered mental status (AMS), hypotension and tachycardia. An emergent EKG shows a sinus tachyarrhythmia at 119 beats/min with a prolonged QTc interval 600 ms. Labs are significant for hypokalemia 2.1 mEq/L, and CT scan of the brain shows no acute findings. You find out the patient self-medicated prophylactically with approximately 15 pills of hydroxychloroquine (HCQ) (7.5 g) in an attempt to prevent symptoms of COVID-19. Suddenly, the nurse calls you to the bedside, where the patient’s cardiac monitor indicates a rate of 220 with polymorphic ventricular tachycardia; you’re contemplating torsades de pointes.

Case reports illustrate this hypothetical. A female patient presented to the ED with AMS and VTach after ingesting approximately 30 g of HCQ purchased online in an attempt to prevent COVID-19.¹ A couple in their sixth decade of life from Arizona presented to the ED in critical condition after ingesting fish tank cleaner that contained chloroquine (CQ) phosphate in an attempt to prevent COVID-19 symptoms.² It is important for emergency physicians to recognize the narrow therapeutic index and increased incidence of toxidromes globally from COVID-19 treatments.

CURRENT PROPOSED TREATMENTS

Given the global pandemic of the novel SARS-CoV-2, clinical trials are underway to elucidate an effective treatment. Several treatment options for COVID-19 are being used in the ED and across hospitals, such as the low-cost antimalarial drug CQ, its derivative HCQ, macrolides, antivirals, monoclonal antibodies (MABs), and convalescent plasma (used first in the 1890s for diphtheria). Countries across the globe have begun clinical trials involving these agents, including both CQ and HCQ.³

CQ and HCQ are used as treatment and prophylaxis of malaria, but there are chloroquine resistant strains of malaria and HCQ is a less toxic derivative.⁴ HCQ is also therapeutic for several autoimmune diseases, including systemic lupus erythematous, rheumatoid arthritis, Sjogren’s syndrome, and dermatomyositis.The molecular mechanism of action suggested by in vitro studies of CQ and HCQ against COVID-19 occur at multiple steps in the viral pathway. These drugs alter cellular entry and exit, alter intracellular pH, and induce endoplasmic reticulum stress, which retards the formation of essential viral proteins⁴. Both medications have narrow therapeutic windows. There are many factors that can alter drug bioavailability such as the patient’s genome, metabolism, drug-drug interactions, kidney function, and dose.

In addition to their antibacterial properties, macrolides (erythromycin, clarithromycin, and azithromycin) also have immunomodulatory effects. They have been shown to have viral reduction efficacy in treatment of rhinovirus, influenza, zika and ebola; azithromycin reduced influenza virus replication in vitro.⁵ A recent study illustrated that treating COVID-19 patients with HCQ, along with azithromycin, for six days showed significant viral reduction via polymerase chain reaction (PCR) nasopharyngeal swab; in comparison with HCQ alone.⁶ The mechanism is currently not well understood however studies suggest it to be promising in treatment of COVID-19. Research is being released daily with new data to be analyzed.

Antiviral agents are being considered. These include RNA-dependent RNA polymerase inhibitor Remdesivir (RDV), neuraminidase inhibitor Oseltamivir (OTV), and protease inhibitor Lopinavir (LPV). RDV has recently been approved by the FDA for treatment of COVID-19 as Emergency Use Authorization.⁷ RDV resembles adenosine triphosphate (ATP) and is used as a substrate for viral RNA polymerase resulting in termination of viral RNA production.^8-9 OTV is also currently being investigated as a treatment option as it is known to reduce viral shedding in respiratory secretions.¹⁰ LPV has shown to be a strong inhibitor of the protease enzyme present in SARS-CoV-1 which is a key enzyme for the viral life cycle.¹⁰

CLINICAL MANIFESTATIONS      
CQ is rapidly absorbed from the GI tract and symptoms can present within 1-3 hours of ingestion. Common side effects at therapeutic CQ doses (500 mg-2500 mg per day) for malaria prophylaxis and treatment are nausea, vomiting, headache, and vision changes. Of particular concern is the development of hemolysis in G6PD-deficient patients in particular¹¹. Rarely at therapeutic concentrations, hypoglycemia, sensorineural deafness, and retinal damage may be seen (bull’s eye retina; image 2). Symptoms at supratherapeutic levels can be lethal and can include apnea, hypotension, and cardiovascular collapse. EKG abnormalities include QRS prolongation, atrioventricular block, ST-T depression, presence of U waves, and QT prolongation.¹¹ Significant hypokalemia can be secondary to CQ-induced intracellular shifts and exacerbate any direct chloroquine-induced QT prolongation.¹²

HCQ overdose is relatively rare and most of the current understanding of toxicity and management of HCQ overdose comes from its related compound, CQ.⁴ Observed side effects with routine HCQ dosing (400 mg) for malaria prophylaxis are similar to CQ.¹¹ The current literature demonstrates a wide range of outcomes with varying doses of HCQ ingested, with death occurring with as little as 5 g and survival after 20 g.¹² Studies suggest that HCQ mortality is primarily due to rapid cardiovascular collapse with refractory hypotension and ventricular arrhythmias.¹³ Several case reports also provide echocardiogram (using pulse doppler of the mitral inflow analyzing the E-wave to A-wave ratio) and magnetic resonance evidence of this restrictive cardiomyopathy (image 3).¹⁴

Acute oral overdoses of macrolides are usually not life-threatening and comprise mainly of gastrointestinal symptoms. Rarely, macrolides cause QT prolongation and torsades de pointes. The risk of macrolide-induced arrhythmias is increased when combined with other drugs, cardiac disease, cardiac channelopathies that prolong the QT interval.¹⁵ A score for Drug Induced QTc Prolongation is published by the American College of Cardiology.¹⁴

RDV has mild adverse effects including nausea and vomiting. Patients treated with RDV should have liver enzymes monitored as there have been cases that suggest RDV-induced liver injury. The most common adverse reactions (incidence at least 5%) for the IL-6 inhibitor tocilizumab are upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT, and injection site reactions.¹⁶ Convalescent plasma transfusions have adverse risk factors such as transfusion related acute lung injury, transfusion associated circulatory overload, and allergic/anaphylaxis.¹⁷

WORK UP
A thorough history and physical exam is especially essential in patients presenting with altered mental status to verify history through bystanders, such as family, friends, EMS personnel, law enforcement, pharmacies, and available pill bottles. Diagnostics should begin with a basic metabolic panel evaluating for emergent electrolyte abnormalities and an EKG. Specific drug concentrations may help with diagnosis and directing treatment depending on the drug of concern. All intentional overdoses should include an acetaminophen concentration.¹⁸ Use the available history, physical, and laboratory findings to narrow the differential as much as possible.

CLINICAL MANAGEMENT PEARLS
Initial treatment for any potential overdose should be focused on the primary survey (airway, breathing, and circulation). Supportive care is critical to enhance survival. Current recommendations for CQ/HCQ overdose, based on assessment of patient, include the following main points. Diazepam 2 mg/kg IV (or 0.5 mg/kg midazolam) should be given over 30 minutes for seizure and sedation. Diazepam has been shown in porcine animal models to improve vitals and shorten QT duration indicating cardioprotective effects.¹⁹ Higher doses of diazepam has been shown to reduce mortality in other animal models and one prospective, multi-center, double-blind, placebo-controlled study showed that low dose diazepam (0.5 mg/kg loading dose then 1 mg/kg infusion over 24 hrs) did not affect serial ECGs in overdose CQ patients.^20-21 Early intubation and mechanical ventilation should be planned. Other medical intervention include the following: epinephrine 0.25 µg/kg/min IV targets vasodilation and myocardial depression; potassium repletion (if below 2 mEq/L) along with magnesium and calcium repletion; and activated charcoal 1 g/kg PO, for gastrointestinal decontamination if ingestion occurred within one to two hours of presentation.^22-27 Consider sodium bicarbonate in the setting of QRS prolongation.²³ Always consult with your local poison control center for specific recommendations. The efficacy of currently recommended treatment modalities may differ in patients affected by COVID-19. Further research is needed to elucidate optimal treatment in this patient population.

TAKE-HOME POINTS

• Multiple medications, MABs, and transfusion products are being used to treat COVID-19.
• Recognize the toxidromes above.
• Assess and treat the patient.
• Be aware of your available treatments at your institution, ranging from benzodiazepines to ECMO.
• Main treatment is supportive care.
• As of this publication, prepublished studies on HCQ are showing questionable mortality benefits, peer review is pending.²⁸
• Clinical trials are underway, including with the World Health Organization, called the Solidarity Trials.²⁹
• Research is ongoing. Critique the literature using basic research skills, using resources such as the ACEP EMBRS Webinars or the SAEM Research Learning Series.^30-31

REFERENCES

1. Xuan Z. A woman in Wuhan has not been infected with the new crown, but was ordered online and overdose prescription drugs were sent to ICU. The Paper. February 25, 2020. https://www.thepaper.cn/news. Accessed April 17, 2020.
2. Waldrop T. Fearing coronavirus, Arizona man dies after taking a form of chloroquine used to treat aquariums. CNN Health. March 25, 2020. https://www.cnn.com. Accessed April 17, 2020.
3. Marmor MF. COVID-19 and Chloroquine/Hydroxychloroquine: is there Ophthalmological Concern? Am J Ophthalmol. 2020 Mar 25. pii: S0002-9394(20)30132-X. 
4. Keshtkar-Jahromi M, Bavari S. A Call for Randomized Controlled Trials to Test the Efficacy of Chloroquine and Hydroxychloroquine as Therapeutics against Novel Coronavirus Disease (COVID-19). Am J Trop Med Hyg. 2020 Apr 3. 
5. Tran DH, Sugamata R, Hirose T, et al. Azithromycin, a 15-membered macrolide antibiotic, inhibits influenza A(H1N1)pdm09 virus infection by interfering with virus internalization process. J Antibiot. 2019;72:759–768. 
6. Ohe M, Shida H. Macrolide treatment for COVID-19: Will this be the way forward? Biosci Trends. 2020 Apr 5. 
7.  Liao J, Way G, Madahar V. Target Virus or Target Ourselves for COVID-19 Drugs Discovery?-Lessons learned from anti-influenzas virus therapies [published online ahead of print, 2020 Apr 13]. Med Drug Discov. 2020;100037. 
8. Gordon CJ. Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. J Biol Chem. 2020 Apr 13. pii: jbc.RA120.013679. 
9. Hillaker E. Delayed Initiation of Remdesivir in a COVID-19 Positive Patient. Pharmacotherapy. 2020 Apr 13. doi: 10.1002/phar.2403
10. Agrawal S, Goel AD, Gupta N. (2020). Emerging prophylaxis strategies against COVID-19. Monaldi Archives for Chest Disease. 2020;90(1). https://doi.org/10.4081/monaldi.2020.1289
11. Hoffman R, Nelson L, Howland M. Goldfrank’s Manual of Toxicological Emergencies. 10th ed. McGraw- Hill Education; 2015. ISBN: 978-0-07-180185-0
12. Chansky PB, Werth VP. Accidental hydroxychloroquine overdose resulting in neurotoxic vestibulopathy. BMJ Case Rep. 2017;2017:bcr2016218786. Published 2017 Apr 12. 
13. Gunja N, Roberts D, McCoubrie D, et al. . Survival after massive hydroxychloroquine overdose. Anaesth Intensive Care. 2009;37:130–3.
14. Joyce E, Fabre A, Mahon N. Hydroxychloroquine cardiotoxicity presenting as a rapidly evolving biventricular cardiomyopathy: key diagnostic features and literature review. Eur Heart J Acute Cardiovasc Care. 2013;2(1):77–83. 
15. Pillay; VV. In Modern Medical Toxicology. 4th ed. Jaypee Brothers; 2013. ISBN: 978-9350259658
16. Greentech, Inc. Actemra (tocilizumab) [package insert]. U.S. Food and Drug Administration. Revised June 2019. Accessed April 2020.
17. Pandey S, Vyas GN. Adverse effects of plasma transfusion. Transfusion. 2012;52 Suppl 1(Suppl 1):65S–79S. doi:10.1111/j.1537-2995.2012.03663.x
18. Dazhe Cao J. A Medical Toxicologist’s Approach to the Overdosed Patient. Website http://www.emdocs.net/a-medical-toxicologists-approach-to-the-overdosed-patient/. July 2019. Accessed April 2020.
19. Riou B, Rimailho A, Galliot M, et al. Protective cardiovascular effects of diazepam in experimental acute chloroquine poisoning. Intensive Care Med 1988;14:610–616.
20. Crouzette J, Vicaut E, Palombo S, Girre C, Fournier PE. Experimental assessment of the protective activity of diazepam on the acute toxicity of chloroquine. J Toxicol Clin Toxicol. 1983;20(3):271–9.
21. Clemessy J, Angel G, Borron SW, et al. Therapeutic trial of diazepam versus placebo in acute chloroquine intoxications of moderate gravity. Intensive Care Med. 1996;22:1400–1405.
22. Marquardt K, Albertson TE. Treatment of hydroxychloroquine overdose. Am J Emerg Med. 2001;19:420–4. 
23. Syed Minhaj F. Chloroquine and Hydroxychloroquine: Old Drugs, Still Just as Toxic. Website.https://mdpoison.com/media/SOP/mdpoisoncom/ToxTidbits/2020/March%202020%20ToxTidbits.pdf. March 2020. Accessed April 2020.
24. ACMT Antidote Card. Website.https://www.acmt.net/_Library/Membership_Documents/ ACMT_Antidote_Card_May_2015.pdf. February 2015. Accessed April 2020.
25. Emergency Medicine Residents' Association. COVID-19: Toxicology - Treatments on the Frontline [Live online webinar] April 2020. Website. https://vimeo.com/407598642. Accessed April 2020
26. de Olano J. Toxicokinetics of hydroxychloroquine following a massive overdose. Am J Emerg Med. 37(12):2264.e5 - 2264.e8
27. Clemessy J, Angel G, Borron SW, et al. Therapeutic trial of diazepam versus placebo in acute chloroquine intoxications of moderate gravity. Intensive Care Med. 1996;22:1400–1405.
28. Magagnoli J, Narendran S. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. medRxiv 2020.04.16.20065920; doi: https://doi.org/10.1101/2020.04.16.20065920
29. Solidarity Clinical Trial for COVID-19 Treatments. World Health Organization website. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments. March 2020. Accessed April 2020.
30. COVID-19 . American College of Emergency Physicians website. https://www.acep.org/corona/COVID-19/. April 2020. Accessed April 2020
31. COVID-19. Society of American Emergency Medicine website. https://www.saem.org/saem-foundation/events/educational/webinars. April 2020. Accessed April 2020