What should I, as a pharmacist, know about COVID-19?

Background

Coronavirus disease 2019 (COVID-19) affects the respiratory tract and is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which originated in Wuhan, China, in December 2019.¹ The disease is highly contagious and has spread quickly on a global level.² The exact origin of SARS-CoV-2 is unknown but most likely stems from an animal, similar to other coronaviruses such as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV).

Common signs and symptoms of COVID-19 consist of fever (77% to 98%), cough (46% to 82%), myalgia/fatigue (11% to 52%), and shortness of breath (3% to 31%).³ Other symptoms may include sore throat, headache, and gastrointestinal symptoms such as diarrhea and/or nausea. Older patients and patients with chronic medical conditions including cardiovascular disease, diabetes, chronic respiratory disease, hypertension, and cancer are at a higher risk for severe presentation of COVID-19.

At this point, the clinical course of the disease remains unclear due to its novelty.³ Based on the current information,  the disease may progress towards hospitalization over 8 to 9 days (hospitalization typically occurring during the second week after symptom onset), with pneumonia and dyspnea serving as the main reasons for the hospital admission. Ribonucleic acid (RNA) of SARS-CoV-2 may be detected in nose, throat, upper and lower respiratory tract, blood, and stool potentially for weeks.³ About 14% of patients diagnosed with COVID-19 require hospitalization and 5% of patients will be admitted to intensive care units (ICUs).¹ About 20% to 30% of patients who are hospitalized may require respiratory support, some through mechanical ventilation.^1,3 Clinical progression of severe COVID-19 may lead to acute respiratory disease syndrome (ARDS), sepsis, septic shock, and multiorgan failure such as acute kidney injury and/or cardiac injury.¹

Treatment

For healthcare professionals in the United States, Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) provide recommendations for managing patients with COVID-19.^1,3 According to the CDC interim clinical guidance, updated on March 7, 2020, providers should monitor patients with mild COVID-19 symptoms closely because the disease may progress rapidly resulting in hospitalization during the second week after symptom onset.³ At this point, the definitive treatment for COVID-19 is lacking, and efforts should be focused on effective infection prevention and control and supportive care. Several investigational therapies and vaccines are currently being explored. The WHO interim guidance, updated on March 13, 2020, recommends isolating patients presenting with mild symptoms of COVID-19 to prevent virus transmission.¹ Patients with mild symptoms may take antipyretics for fever. The rest of the guidance focuses on providing supportive care and managing complications such as co-infections, ARDS, and septic shock. Similar to the CDC guidance, the WHO guidance states that several agents are being investigated for COVID-19 treatment.

Corticosteroids

Both the CDC and WHO interim guidances recommend avoiding systemic corticosteroids in patients with COVID-19, because they may prolong viral replication.^1,3 A study involving 309 ICU patient with MERS revealed that administering corticosteroids did not affect 90-day mortality after adjusting for time-dependent confounders but delayed MERS-CoV RNA clearance.⁴ A Cochrane review of 19 observational studies with 3,459 influenza patients showed increased mortality with corticosteroids (odds ratio (OR), 3.06; 95% confidence interval (CI), 1.58 to 5.92), but the quality of evidence was very low.⁵ An observational cohort study of 607 ICU patients affected by 2009 pandemic H1N1 influenza suggested a potential increase in mortality with using corticosteroids (25.5% vs16.4%, p=0.007) compared with avoiding corticosteroids, but a statistically significant association between using corticosteroids and mortality disappeared after adjusting for time-dependent differences.⁶ Per both guidances, using corticosteroids may be appropriate for other indications in patients with COVID-19 such as exacerbation of asthma or chronic obstructive pulmonary disease or presence of septic shock.^1,3

NSAIDs versus acetaminophen

The CDC and WHO guidances do not list preferred agents (eg, preferred antipyretics) for managing mild symptoms of COVID-19.^1,3 On March 14, 2020, French officials and some scientists stated that nonsteroidal anti-inflammatory drugs (NSAIDs) may worsen symptoms of COVID-19, and acetaminophen should be preferred for managing mild symptoms of COVID-19.⁷ These informal statements were released after 4 young patients with COVID-19 developed more severe symptoms after using NSAIDs for their initial mild symptoms. A letter by Fang and colleagues hypothesized that SARS-CoV-2 binds to target cells through angiotensin-converting enzyme 2 (ACE2), present in the epithelial cells of the lung, intestine, kidney, and blood vessels.⁸ Medications such as ACE inhibitors and angiotensin II receptors blockers,  commonly prescribed to patients with diabetes and hypertension, thiazolidinediones, and ibuprofen may upregulate ACE2 expression and put patients at risk for severe symptoms of COVID-19. To date, the evidence for using NSAIDs versus acetaminophen in COVID-19 is lacking. An exploratory analysis of data for 683 adults and 838 pediatric critically ill patients during the 2009 pandemic H1N1 influenza found no association between using NSAIDs or aspirin and increased mortality.⁹ On March 19, 2020, the Food and Drug Administration (FDA) released communication that the agency is aware of the reports regarding ibuprofen but the scientific evidence is missing.¹⁰ The agency is investigating this issue further.

Investigational treatments

The effective pharmacological treatment for COVID-19 is unknown due to the novelty of the disease, but several agents are under investigation. The CDC guidance mentions that numerous clinical trials with remdesivir, an RNA polymerase inhibitor, are underway due to its in vitro efficacy against SARS-CoV-2.^2,3 Other agents that have been used for COVID-19 in China consist of oseltamivir (75 mg every 12 h orally), ganciclovir (0.25 g every 12 h intravenously), lopinavir/ritonavir (400/100 mg twice daily orally), interferon a (INF-a; 5 million units twice daily via inhalation), ribavirin (500 mg 2 to 3 times daily, intravenous in combination with INF-a or lopinavir/ritonavir), chloroquine (500 mg [300 mg base] twice daily orally), and arbidol (200 mg 3 times daily orally).^11,12 Some of these agents and certain formulations are not available in the United States. Robust data from clinical trials specifically in patients with COVID-19 are missing for all of these agents. For example, a most recent trial showed a lack of benefit of lopinavir/ritonavir in patients with COVID-19.¹³ Based on in vitro studies, chloroquine, an anti-malarial and anti-inflammatory agent for lupus and rheumatoid arthritis, may be effective in controlling COVID-19, but clinical trials with human patients are lacking.^14,15 A letter by Gao and colleagues stated that chloroquine decreased exacerbation of pneumonia, improved findings on lung imaging, and shortened the disease course in 100 patients with COVID-19.¹⁵ However, the full data and details from this trial have not been published.  Hydroxychloroquine, commonly used for rheumatic diseases, has a similar structure but with less ocular toxicity than chloroquine.¹⁶ Many countries have access only to hydroxychloroquine, which may be an appropriate substitution for chloroquine. On March 28, 2020, the FDA granted emergency use authorization for hydroxychloroquine and chloroquine from the strategic national stockpile to treat adolescents and adults with COVID-19, if clinical trials are unavailable or not feasible.¹⁷

Resources for COVID-19 outbreak for pharmacists

As more information regarding COVID is updated and released, pharmacists should stay up to date with any new guidances or developments. Table 1 provides key resources that may be helpful to pharmacists.

Conclusion

Coronavirus disease 2019 is a viral respiratory disease that has spread quickly and globally. The common symptoms of COVID-19 include fever, cough, and shortness of breath. The definitive treatment for COVID-19 is lacking and mostly focuses on supportive care. The CDC and WHO interim guidances recommend avoiding systemic corticosteroids. The medical and scientific communities continue to explore effective treatment agents and/or vaccines against COVID-19 and whether NSAIDs such as ibuprofen contribute to worsening symptoms in patients with this condition. The available information is rapidly changing – please check the most up-to-date WHO and CDC guidances before treating patients with COVID-19.

References:

1. Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected. World Health Organization website. https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected. Published March 13, 2020. Accessed March 24, 2020.
2. Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Di Napoli R. Features, evaluation and treatment coronavirus (COVID-19). In. StatPearls. Treasure Island (FL): StatPearls Publishing LLC.; 2020.
3. Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19). Centers for Disease Control and Prevention website. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html. Updated March 7, 2020. Accessed March 24, 2020.
4. Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid therapy for critically ill patients with Middle East Respiratory Syndrome. Am J Respir Crit Care Med. 2018;197(6):757-767.
5. Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Lim WS. Corticosteroids as adjunctive therapy in the treatment of influenza. Cochrane Database Syst Rev. 2016;3:CD010406.
6. Delaney JW, Pinto R, Long J, et al. The influence of corticosteroid treatment on the outcome of influenza A(H1N1pdm09)-related critical illness. Crit Care. 2016;20:75.
7. Day M. COVID-19: ibuprofen should not be used for managing symptoms, say doctors and scientists. 2020;368:m1086.
8. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? [published online ahead of print Mar 11, 2020]. Lancet Respir Med. doi: 10.1016/s2213-2600(20)30116-8.
9. Epperly H, Vaughn FL, Mosholder AD, Maloney EM, Rubinson L. Nonsteroidal anti-inflammatory drug and aspirin use, and mortality among critically ill pandemic H1N1 influenza patients: an exploratory analysis. Jpn J Infect Dis. 2016;69(3):248-251.
10. FDA advises patients on use of non-steroidal anti-inflammatory drugs (NSAIDs) for COVID-19. US Food and Drug Administration website. https://www.fda.gov/drugs/drug-safety-and-availability/fda-advises-patients-use-non-steroidal-anti-inflammatory-drugs-nsaids-covid-19. Published March 19, 2020. Accessed March 24, 2020.
11. Cunningham AC, Goh HP, Koh D. Treatment of COVID-19: old tricks for new challenges [published online ahead of print, 2020]. Crit Care. doi: 10.1186/s13054-020-2818-6.
12. Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov Ther. 2020;14(1):58-60.
13. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19 [published online ahead of print Mar 18, 2020]. N Engl J Med. doi: 10.1056/NEJMoa2001282.
14. Touret F, de Lamballerie X. Of chloroquine and COVID-19 [published online ahead of print Mar 5, 2020]. Antiviral Res. doi: 10.1016/j.antiviral.2020.104762.
15. Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020;14(1):72-73.
16. Sahraei Z, Shabani M, Shokouhi S, Saffaei A. Aminoquinolines against coronavirus disease 2019 (COVID-19): chloroquine or hydroxychloroquine [published online ahead of print Mar 16, 2020]. Int J Antimicrob Agents. doi: 10.1016/j.ijantimicag.2020.105945.
17. Emergency use authorization. US Food and Drug Administration website. https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization. Updated March 31, 2020. Accessed April 1, 2020.

Prepared by:
Janna Afanasjeva, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois At Chicago College of Pharmacy

April 2020

The information presented is current as March 24, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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