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P4 Student Creates COVID-19 Resource for Pharmacists and Health Care Providers

Published on 02 April 2020

As the global Coronavirus Disease 2019 (COVID-19) pandemic continues to impact communities around the world, health care providers, professionals and researchers are quickly learning and sharing new information about COVID-19 and the novel coronavirus that causes it.

After a review of the literature currently available, St. Louis College of Pharmacy P4 student Elizabeth Ridgway has created a COVID-19 resource for pharmacists and health care providers to provide a snapshot view of the disease’s clinical presentation, diagnosis methods, currently known strategies for prevention and management, and current Missouri Board of Pharmacy Recommendations regarding the use of drug therapies.

Ridgway completed the paper, included in full below, as part of her advanced pharmacy practice experience with President John A. Pieper, Pharm.D., FCCP, FAPhA, FFIP, president of the College.

 


COVID-19: Exploring Clinical Features, Nutritional Supplementation, and Proposed Management

Authored by Elizabeth Ridgway, Pharm.D. Candidate 2020, and John A. Pieper, Pharm.D., FCCP, FAPhA, FFIP, president of St. Louis College of Pharmacy

Introduction

Coronaviruses (CoVs) are a large subfamily of viruses which commonly cause enzootic infections in birds and mammals.1 This subfamily includes the genetic and serologic groups: α-coronavirus, β-coronavirus, γ-coronavirus, and δ-coronavirus.2 Over the last decades, β-CoVs have demonstrated their ability to cross the species barrier to infect humans.1-4 The lethality of the β-CoV in humans has previously been demonstrated by the 2002 and 2013 outbreaks of severe acute respiratory syndrome (SARS-CoV) and Middle-East respiratory syndrome (MERS-CoV), respectively.4

In December 2019, a novel enveloped β-CoV, COVID-19, emerged in Wuhan, China.4,5 Since its initial identification, COVID-19 has spread rapidly and was declared to be a global pandemic by the World Health Organization (WHO) in March 2020.3,4 The COVID-19 pandemic has caused and is expected to continue to cause severe shortages in medical products and services.6 Stockpiling of the proposed treatments for COVID-19 has become worrisome in several states leading to emergency restrictions and guidelines on the prescribing and dispensing of these drugs.7

The purpose of this review is to provide a brief overview of the evidence supporting the various proposed outpatient treatments for COVID-19 and to provide guidance for the dispensing of these drugs.

Clinical Presentation8

Incubation Period

Estimated between 2 to 14 days

Signs and Symptoms

  • Common Symptoms
    • Fever
    • Dry Cough
    • Dyspnea
    • Myalgia
    • Sore throat
    • Headache
    • Diarrhea and nausea
  • Emergency Signs
    • Shortness of breath
    • Pain/pressure in the chest
    • Altered mental status
    • Inability to arouse
    • Cyanosis
Severity

The severity of COVID-19 varies from asymptomatic to severe or fatal illness. Among 72,314 confirmed cases of COVID-19 in mainland China, 71% of patients were shown to experience only mild symptoms, however 14.5% and 4.7% of patients experienced severe or critical illness, respecitively.9

Risk Factors for Mortality

The risk factors for severe-illness and fatality are yet unclear, however a study which included 72,314 patients in mainland China found that the majority of deaths occurred in patients > 60 years of age with comorbidities, such as hypertension, cardiovascular disease, and diabetes.9

Diagnosis10

All current laboratory tests for COVID-19 use real-time Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and provide results within 4 to 6 hours.

Prevention and Management

Nonpharmacological Management

Hand-washing and Cleaning

Current evidence suggests that COVID-19 remains infectious on fomite surfaces and hands for days.11 For this reason, frequent disinfection of surfaces using products containing the following is recommended. The listed products inactivate COVID-19 within ~1 minute.12

  • 62 – 71% ethanol
  • 0.5% hydrogen peroxide
  • 0.1% sodium hypochlorite

Social Distancing and Quarantining

Mathematical models have demonstrated that interventions such as workplace distancing, school closure, and quarantining reduce the estimated number of infections. These findings were robust to sensitivity analyses.13

Facemasks

Limited studies have evaluated the use of facemasks in the community setting. Due to concern for stockpiling, the Centers for Disease Control and Prevention (CDC) currently recommend that the use of facemasks is limited to high-risk patients and to those in the medical community.14

Nutritional Interventions

Nutritional intervention and dietary supplementation have demonstrated some efficacy for the treatment and prevention of CoV infections. While these results are promising, their efficacy in the setting of COVID-19 is yet unproven.

Vitamin A

Vitamin A is a fat-soluble vitamin which has previously been shown to reduce morbidity and mortality of many infectious diseases including, measles, diarrheal diseases, measles-related pneumonia, human immunodeficiency virus, and malaria.3 Jee et al demonstrated that low vitamin A consumption in calves was associated with poorer production of IgG antibodies in response to an inactivated β-CoV vaccination, as compared to calves receiving a diet supplemented with vitamin A.15 These findings suggest that vitamin A supplementation or increased dietary intake may be beneficial for the prevention and management of COVID-19.

Vitamin B2

B vitamins are water-soluble vitamins which have a diverse array of functions.3 Keil et al demonstrated that Vitamin B2 in combination with ultraviolet light reduced MERS-CoV titer in human plasma (mean log reduction > 4.07 for the pooled donor plasma).16 No current data has evaluated the efficacy of Vitamin B2 for the management of COVID-19, however vitamin B2 may have some benefit and has been associated with minimal risk.3

Vitamin C

Vitamin C, or ascorbic acid, is a water-soluble vitamin which is known to support healthy immune function. Several studies have demonstrated the utility of Vitamin C for the prevention of lower respiratory tract infections. One study conducted by Atherton et al, demonstrated that vitamin C increased the resistance of chick embryo tracheal organ cultures to avian CoV.3 Based on this evidence, supplementation with vitamin C may have a protective effect against COVID-19.3

Zinc

Zinc is a dietary trace mineral, which is important for the maintenance and development of immune cells.3 Increased intracellular concentrations of zinc-ionophores has been shown to reduce the in vitro replication of RNA virus, including SARS-CoV.16, 17 Based upon this finding, zinc supplementation may have some utility for the treatment of COVID-19.

Other

There is a theoretical benefit associated with vitamin D, vitamin E, selenium, omega-3 polyunsaturated fatty acids, and iron supplementation. However, there is little or no evidence supporting the use of these supplements for the prevention or management of CoV infections.3

Antiviral Agents

Several antiviral agents are currently under investigation for the treatment and prevention of COVID-19.

Baloxavir

Baloxavir is an antiviral agent commonly used for the treatment of influenza A and B. Currently, two registered randomized clinical trials are examining the use of baloxavir in the setting of COVID-19 infection. At present, no data supports the use of baloxavir for the outpatient treatment of COVID-19, and therefore it is not recommended.18

Chloroquine, Hydroxychloroquine, and Azithromycin

Chloroquine (CQ) and hydroxychloroquine (HCQ) have historically been used for the treatment of lupus, rheumatoid arthritis, and malaria due to their immunomodulatory activity. Limited pre-clinical evidence suggests that CQ and HCQ may be efficacious for the treatment of COVID-19, both alone and in combination with azithromycin.18,19

In one small, open-label, non-randomized clinical trial in France, Gautret et al demonstrated that the combination of azithromycin (AZ) and HCQ significantly increased the percent of COVID-19 positive patients achieving a virological cure after 6-days of treatment (100% for AZ + HCQ, 57.1% for HCQ only, 12.5% for control; p <0.001).20 Further evaluation is needed to validate both the safety and efficacy of these drugs for the treatment of COVID-19. Additionally, optimal dosage and duration for treatment has not been established.18

Lopinavir and Ritonavir

Lopinavir and ritonavir have been suggested as potential treatments for COVID-19 due to their in vitro activity against SARS-CoV and MERS-CoV.18 A randomized, controlled, open-label trial conducted by Cao et al showed that in hospitalized patients with severe COVID-19 infection, lopinavir and ritonavir provided no benefit, as compared to standard care alone with regard to time to clinical improvement (hazard ratio (HR) 1.24, 95% confidence interval (CI) 0.9 to 1.72).21 Further investigation is needed to confirm these findings and to extend these results to patients with less severe illness.

Oseltamivir

Oseltamivir is a commonly used antiviral agent which is being evaluated for use in the treatment of COVID-19. Currently no evidence supports its use in the management of COVID-19.18

Remdesivir

Remdesivir is a broad-spectrum antiviral agent with in vitro activity against MERS-CoV and SAR-CoV.18 While this intravenous agent is not yet commercially available, it is in phase 3 clinical trials for use in the setting of both severe and moderate COVID-19 infections. Remdesivir is not available for compassionate use at this time except for children ≤18 years of age with severe disease and pregnant women. Enrollment in clinical trials is open (https://rdvcu.gilead.com).

Supportive Therapies

Presently, supportive therapies for the management of the symptoms associated with COVID-19 are unclear.

Corticosteroids

Corticosteroids may accelerate the resolution of pulmonary and systemic inflammation in the setting of pneumonia.18 While evidence appears to be conflicting in the setting of COVID-19, one retrospective cohort study found that methylprednisolone was associated with mortality benefit in patients with COVID-19 and acute respiratory distress syndrome (n = 84, HR 0.38, 95% CI 0.20 to 0.72).22 Currently, further investigation is needed to evaluate the use of low-dose corticosteroids in the outpatient setting.

Ibuprofen and Acetaminophen

Antipyretic agents such as ibuprofen and acetaminophen are commonly used for the treatment of fever. Fang et al postulated a link between ibuprofen and worsening outcomes in the setting of COVID-19 infection,23 however there is no data to support this hypothesis. Furthermore, routine administration of antipyretics to treat fever in the setting of COVID-19 is poorly supported in literature.24

Current Missouri Board of Pharmacy Recommendations25

On March 23, 2020, the Missouri State Board of Registration for the Healing Arts and the Missouri Board of Pharmacy issued a joint statement addressing reports of prophylactic prescribing of hydroxychloroquine, chloroquine, and azithromycin for the prevention of COVID-19. This prescribing has led to concern for drug shortages.

At this time, pharmacists are encouraged to use their professional judgment when dispensing these drugs. The Boards recommend that pharmacists:

  • Take appropriate steps to verify that newly issued prescriptions are for a legitimate medical purpose by verifying diagnoses prior to dispensing the drugs.
  • For the prevention and management of COVID-19, it may be appropriate to limit day-supply dispensed to 14-days.

Summary

  • COVID-19 causes mild respiratory symptoms in most patients, however it may cause severe illness in ~20% of patients.
  • Older adults and those who have comorbid conditions, including hypertension, cardiovascular disease, and diabetes appear to be at a higher risk of mortality associated with COVID-19.
  • A combination of social distancing and quarantining is recommended to reduce the transmission of COVID-19.
  • The use of face masks in a community setting has been poorly evaluated in literature, however it may be appropriate in high-risk patients and medical personnel.
  • Supplementation with ascorbic acid is likely to have a protective effect against COVID-19, while supplementation with vitamin A, vitamin B2, and zinc may have some benefit.
  • Hydroxychloroquine in combination with azithromycin may be effective for the treatment of COVID-19, however further evidence is needed to validate the efficacy and safety of this regimen.
  • The use of supportive therapies, such as corticosteroids and antipyretics, is not currently supported for the outpatient management of COVID-19 infections.
  • Pharmacists should use caution when dispensing hydroxychloroquine, chloroquine, and azithromycin in order to prevent stockpiling and drug shortages.
  • Further information for pharmacists can be found at Pharmacist.com.

 


References

  1. Schoeman D, Burtram BC. Coronavirus envelop protein: current knowledge. Virol J. 2019; 16(1): 69.
  2. Monchatre-Leroy E, Boue F, Boucher JM, et al. Identification of alpha and beta coronavirus in wildlife species in France: cats, rodents, rabbits, and hedgehogs. Viruses. 2017; 9(12). ppii: E364.
  3. Zhang L, Liu Y. Potential interventions for novel coronavirus in China: a systematic review. J Med Virol. 2020; 92(5): 479-90.
  4. Zhu N, Zhang D, Wang W. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020; 382: 727-33.
  5. Cao Y, Li L, Feng Z, et al. Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discov. 2020; 6:11.
  6. Truog RD, Mitchell C, Daley GQ. The toughest triage-allocating ventilators in a pandemic [published online ahead of print, March 23, 2020]. N Engl J Med. doi: 0.1056/NEJMp2005689.
  7. Gaber E. States say some doctors stockpile trial coronavirus drugs, for themselves. New York Times. March 24, 2020. https://www.nytimes.com/2020/03/24/business/doctors-buying-coronavirus-drugs.html?smid=em-share. Accessed March 25, 2020.
  8. Coronavirus Disease 2019 (COVID-19) Clinical Care [Internet]. Centers for Disease Control and Prevention; March 7, 2020 [cited March 25, 2020] Available from: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html#foot09
  9. Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. [The epidemiological characteristics of an outbreak of 2019 novel coronavirus disease (COVID-19) in China]. Zhonghua Lie Xing Xue Za Zhi. 2020; 41(2):145-51.
  10. Coronavirus Disease 2019 (COVID-19) Symptoms & Testing [Internet]. Centers for Disease Control and Prevention; March 13, 2020 [cited March 25, 2020] Available from: https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/index.html
  11. Van Doremalen N, Bushmaker T, Morris DH, et al. Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1 [published online ahead of print March 17, 2020]. N Engl J Med. doi: 10.1056/NEJMc2004973.
  12. Kampf G, Todt D, Pfaender S, Steinmann E. Persistence of coronavirus on inanimate surfaces and their inactivation with biocidal agents. J Hosp Inf. 2020; 104(3): 246-51.
  13. Koo JR, Cook AR, Park M, et al. Interventions to mitigate early spread of SARS-CoV-2 in Singapore: a modelling study [published online ahead of print March 23, 2020]. Lancet Infect Dis. doi: 10.1016/S1473-3099(20)30162-6.
  14. Feng S, Sehn C, Xia N, Song W, Fan M, Cowling BJ. Rational use of face masks in the COVID-19 pandemic [published online ahead of print March 20, 2020]. Lancet Respir Med. doi: 0.1016/S2213-2600(20)30134-X.
  15. Jee J, Hoet AE, Azevedo MP, et al. Effects of dietary vitamin A content on antibody responses of feedlot calves inoculated intramuscularly with an inactivated bovine coronavirus vaccine. Am J Vet Res. 2013; 74(10):1353-62.
  16. Keil SD, Bowen R, Marschner S. Inactivation of Middle East respiratory syndrome coronavirus (MERS-CoV) in plasma products using a riboflavin-based and ultraviolet light-based photochemical treatment. Transfusion. 2016; 56(12):2948-52.
  17. te Velthuis AJ, van der Worm SH, Sims AC, et al. Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 2010; 6(11):e1001176.
  18. Assessment of Evidence for COVID-19-Related Treatments [Internet]. American Society of Hospital Pharmacists; March 24, 2020 [cited March 26, 2020] Available from: https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/Coronavirus/docs/ASHP-COVID-19-Evidence-Table.ashx?la=en&hash=B414CC64FD64E1AE8CA47AD753BA744EDF4FFB8C
  19. Cortegiani A, Ingoglia G, Ippolito M, Giarratono A, Einav S. A systematic review on the efficacy and safety of chloroquine for the treatment of COVIID-19 [published online ahead of print March 10, 2020]. J Crit Care. doi: 10.1016/j.jcrc.2020.03.005
  20. Gautret P, Lagier J, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial [published online ahead of print March 20, 2020]. Int J Antimicrob Agents. doi: 0.1016/j.ijantimicag.2020.105949.
  21. 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 March 18, 2020]. N Engl J Med. doi: 10.1056/NEJMoa2001282.
  22. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China [published ahead of print March 13, 2020]. JAMA Intern Med. doi: 10.1001/jamainternmed.2020.0994.
  23. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?. Lancet Respir Med. 2020. pii:S2213-2600(20)30116-8.
  24. Park S, Brassey J, Heneghan C, Mahtani K. Managing fever in adults with possible or confirmed COVID-19 in primary care [Internet]. CEBM Research. March 19, 2020 [cited March 27, 2020] Available from: https://www.cebm.net/covid-19/managing-fever-in-adults-with-possible-or-confirmed-covid-19-in-primary-care/
  25. Joint Statement from the Missouri Board Registration for the Healing Arts and the Missouri Board of Pharmacy [Internet]. Missouri Board Registration for the Healing Arts and the Missouri Board of Pharmacy; March 2020 [cited March 25, 2020] Available from:https://content.govdelivery.com/attachments/MODIFP/2020/03/23/file_attachments/1408387/Healing%20Arts-Pharmacy%20Joint%20Statement.pdf.

 


Information on the College's ongoing response to the COVID-19 pandemic as well as additional resources and regional mandates can be found at stlcop.edu/covid19.

 

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