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INTRODUCTION

The fifth month of worldwide spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is dawning. While cases decline in the hard-hit New York City area and parts of Europe, outbreaks continue there and in other places around the world. As public health officials and medical researchers attempt to figure out the virus and pathophysiology and clinical symptoms of coronavirus disease 2019 (COVID-19), two glimmers of hope have appeared in the form of an antiviral drug that has activity against the virus and the shift of a vaccine candidate into human trials.

This article provides a concise summary of activity in COVID-19 over the April 24–30 time period and updates to content in previous continuing pharmacy education articles on this topic, posted to the Power-Pak website (COVID-19: An Update for Pharmacists and Pharmacy Technicians on the Frontlines; This Week in COVID-19: April 24, 2020)

Changing Ideas About COVID-19

Disease Symptoms: The Centers for Disease Control and Prevention (CDC) has revised its “watch for symptoms” list for COVID-19 to include 6 new possible presentations. The agency also moved fever into a secondary category, leaving two cardinal symptoms that can indicate presence of the disease. The revised definition says symptoms may appear 2 to 14 days after exposure to SARS-CoV-2 and present as these symptoms or combinations of these symptoms:

• Cough
• Shortness of breath or difficulty breathing

Or at least 2 of these symptoms:

• Fever
• Chills
• Repeated shaking with chills
• Muscle pain
• Headache
• Sore throat
• New loss of taste or smell

CDC also said children can have similar symptoms as adults but generally have mild illness. (On the other hand, older adults can present with different, often nonspecific symptoms – see the below section on long-term care facilities.)

Large-Vessel Stroke in Young People With COVID-19: Accounts in the mass media are reporting new and troubling complications of COVID-19 in people under age 50 years. In the Washington Post, reporters described young patients with clots forming even as surgeons were operating on primary lesions.

Five cases of large-vessel stroke among New Yorkers with COVID-19 who were younger than 50 years of age are reported in a letter to the editor of the New England Journal of Medicine [Oxley et al., 2020]: “Over a 2-week period from March 23 to April 7, 2020, a total of five patients … who were younger than 50 years of age presented with new-onset symptoms of large-vessel ischemic stroke,” the authors report. “All five patients tested positive for Covid-19. By comparison, every 2 weeks over the previous 12 months, our service has treated, on average, 0.73 patients younger than 50 years of age with large-vessel stroke.”

Hypercoagulable states are known to occur in severely ill patients, and Chinese researchers had previously proposed coagulation disorders and vascular endothelial dysfunction as complications of COVID-19. [Zhou et al., 2020] More research will be needed to determine how often these occur and how many strokes and deaths may have already occurred without the recognition they were related to COVID-19.

The importance of watching for symptoms of stroke should be reinforced with all patients, including those in young and middle adulthood who do not think of themselves as at risk for stroke or COVID-19. Acting F.A.S.T. is important in stroke, the CDC says:

F—Face: Ask the person to smile. Does one side of the face droop?

A—Arms: Ask the person to raise both arms. Does one arm drift downward?

S—Speech: Ask the person to repeat a simple phrase. Is the speech slurred or strange?

T—Time: If you see any of these signs, call 9-1-1 right away.

In particular, some people have delayed seeking care because of the fear of acquiring the virus in health care settings. If stroke symptoms are occurring, patients and family members need to know how important it is to get treatment quickly.

A study from Georgia reinforces the need to consider COVID-19 even in people not in the groups thought to be most affected (e.g., older adults, those with underlying medical conditions). Among people hospitalized in that state with COVID-19, one-fourth (26.2% of 305 patients) were younger than 65 years of age and had no underlying medical conditions. Non-Hispanic black patients were overrepresented among hospitalized patients. [Gold et al., 2020]

TREATMENT UPDATES: REMDESIVIR A NEW STANDARD OF CARE?

Remdesivir: Hospitalized patients with advanced COVID-19 and lung involvement who received Gilead’s investigational nucleotide analogue remdesivir recovered faster than similar patients who received placebo, according to a preliminary data analysis from a randomized, controlled trial involving 1,063 patients, the National Institute of Allergy and Infectious Diseases (NIAID) reported this week. The results, included in an interim analysis of data from the Adaptive COVID-19 Treatment Trial (ACTT), have not yet been peer reviewed.

FDA has issued an emergency use authorization (EUA) for remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease. The EUA requires that fact sheets that provide important information about using remdesivir in treating COVID-19 be made available to health care providers and patients, including dosing instructions, potential side effects, and drug interactions.

In remarks from the Oval Office, NIAID Director Anthony S. Fauci, MD, noted that patients who received remdesivir had a 31% faster time to recovery than those who received placebo, a significant difference (P <0.001). The median time to recovery was 11 days for patients treated with remdesivir compared with 15 days for those who received placebo. Results also suggested a survival benefit but failed to reach significance, with a mortality rate of 8.0% for the group receiving remdesivir versus 11.6% for the placebo group (P = 0.059).

Fauci described the results as changing the standard of care for COVID-19 in hospitalized patients who can receive the intravenous drug. He compared a meeting in which these data were reviewed to one in 1986 during which he and others realized that azidothymidine (AZT) was the first agent with activity against the human immunodeficiency virus. Similar to AZT, whether remdesivir proves to be a “game changer” in the pandemic, this evidence does indicate that we can use antiviral agents to interrupt the infectious process, Fauci said.

Fauci indicated that the next step in research would be to combine remdesivir with other agents, possibly anti-inflammatory monoclonal antibodies, that can complement the antiviral actions by decreasing the body’s harmful overresponse to the viral attack.

Topline results were reported by Gilead Sciences for a second study, the unpublished open-label, phase 3 SIMPLE trial. It evaluated 5-day and 10-day dosing durations of remdesivir in hospitalized patients with severe manifestations of COVID-19 disease. The study demonstrated that patients receiving a 10-day treatment course of remdesivir achieved similar improvement in clinical status compared with those taking a 5-day treatment course (OR, 0.75 [95% CI 0.51–1.12] on day 14), the company said. No new safety signals were identified with remdesivir across either treatment group.

Pulmonary Phenotypes. Similar to information in the April 24 weekly update, patients with COVID-19 acute respiratory distress syndrome (CARDS) should be managed differently based on whether their pulmonary phenotype is L or H, Marini et al. [2020] wrote in a JAMA article: “Soon after onset of respiratory distress from COVID, patients initially retain relatively good [lung] compliance despite very poor oxygenation. Minute ventilation is characteristically high. Infiltrates are often limited in extent and, initially, are usually characterized by a ground-glass pattern on [computed tomography (CT)] that signifies interstitial rather than alveolar edema. Many patients do not appear overtly dyspneic. These patients can be assigned, in a simplified model, to ‘type L,’ characterized by low lung elastance (high compliance), lower lung weight as estimated by CT scan, and low response to [positive end-expiratory pressure (PEEP)]. For many patients, the disease may stabilize at this stage without deterioration while others, either because of disease severity and host response or suboptimal management, may transition to a clinical picture more characteristic of typical ARDS. These can be defined as ‘type H,’ with extensive CT consolidations, high elastance (low compliance), higher lung weight, and high PEEP response. Clearly, types L and H are the conceptual extremes of a spectrum that includes intermediate stages, in which their characteristics may overlap. Another feature consistently reported is a highly activated coagulation cascade, with widespread micro- and macro-thromboses in the lung and in other organs; very elevated serum D-dimer levels are a consistent finding associated with adverse outcomes.”

While remdesivir provides the first therapeutic option for patients severe COVID-19, the question remains on how to manage those with mild or moderate disease. In a New England Journal of Medicine clinical practice article, authors review available agents being tested for usefulness in COVID-19 and advise clinicians to get symptomatic patients involved in clinical trials when possible. [Gandhi et al., 2020]

Use of Hydroxychloroquine/Chloroquine: To decrease the risk of potentially life-threatening arrhythmias, the U.S. Food and Drug Administration (FDA) warned the public that hydroxychloroquine and chloroquine, either alone or combined with azithromycin, when used for COVID-19 should be limited to clinical trial settings or for treating certain hospitalized patients under the agency’s emergency use authorization (EUA). Hydroxychloroquine and chloroquine have not been shown to be safe and effective for treating or preventing COVID-19, FDA said. The drugs are being studied in clinical trials for COVID-19, and FDA authorized their temporary use during the pandemic for treatment of COVID-19 in hospitalized patients when clinical trials are not available, or participation is not feasible.

Arrhythmias associated with administration of these drugs include QT-interval prolongation and ventricular tachycardia. In study of 90 patients with COVID-19 pneumonia who were treated with hydroxychloroquine, 53 also received azithromycin. The most common comorbid conditions were hypertension (53.3%) and diabetes (28.9%). Median baseline QTc was 455 milliseconds; this increased by a median of 5.5 milliseconds with hydroxychloroquine alone and 23 milliseconds in patients on both drugs, a significant difference. Prolonged QTc values of 500 milliseconds or more developed in 13% of patients on hydroxychloroquine alone and 21% of those who also received azithromycin. Adverse drug events (intractable nausea, hypoglycemia, and 1 case of torsades de pointes) caused 10 patients on hydroxychloroquine alone to discontinue treatment. [Mercuro et al., 2020]

In a French study, 37 of 40 patients on hydroxychloroquine with or without azithromycin had increased QT intervals. Prolonged QTc was observed in 14 patients; 10 patients had a prolonged QTc of greater than 60 msec and 7 had QTc of 500 msec or more. [Bessière et al., 2020] This and the above study, coupled with other published data, “underscore the potential risk associated with widespread use of hydroxychloroquine and azithromycin in ambulatory patients with known or suspected COVID-19. [Bonow et al., 2020]

Vaccine Progress: On the preventive front of COVID-19 research, the University of Oxford announced rapid progress in moving its vaccine candidate into human trials. By working from a vaccine platform previously confirmed as safe in people, the ChAdOx1 nCoV-19 trial was approved by British drug authorities for testing the efficacy of a COVID-19 vaccine in 1,110 adults aged 18 to 55 years old. Further safety data will be generated, as will immunogenicity characteristics of the vaccine. It is being compared in healthy volunteers against a meningococcal control vaccine. The vaccine combines an adenovirus vector with the SARS-CoV-2 spike protein “S” that binds to ACE2 receptors to gain entry into human cells.

An important part of any successful pandemic vaccine candidate is being able to ramp up production for worldwide distribution. That requires involvement of one of the half dozen major vaccine manufacturers. Oxford has announced an agreement with AstraZeneca, which is based in the United Kingdom, to develop large-scale manufacturing and distribution capability for the COVID-19 vaccine. Under the new agreement, as well as providing U.K. access as early as possible if the vaccine candidate is successful, AstraZeneca will work with global partners on the international distribution of the vaccine, particularly working to make it available and accessible for low and medium income countries, the university said.

COVID-19 IN LONG-TERM CARE FACILITIES

Because of differences in the way states count COVID-19 cases and deaths, the exact toll of the disease in the nation’s long-term care facilities (LTCFs) is not known. At least 10,000 residents and staff had died as April 23, 2020, the Kaiser Family Foundation estimates, in the 23 states that report fatality data; that is 27% of the deaths in those states attributed to COVID-19. LTCF residents and staff account for more than half of COVID-19 deaths in 6 states (Delaware, Massachusetts, Oregon, Pennsylvania, Colorado, and Utah), the article states. The possibility of many other deaths during the influenza season being incorrectly attributed to other causes is great, and we will never know for sure how many had COVID-19.

That’s not the only reason COVID-19 can be unrecognized or underdiagnosed in this population. Older adults can present with atypical symptoms, Kaiser Health News reports: “Seniors may seem ‘off’ — not acting like themselves — early on after being infected by the coronavirus. They may sleep more than usual or stop eating. They may seem unusually apathetic or confused, losing orientation to their surroundings. They may become dizzy and fall. Sometimes, seniors stop speaking or simply collapse.”

“The pandemic of [COVID-19] is having a global impact unseen since the 1918 worldwide influenza epidemic,” authors write in the Journal of the American Geriatrics Society. [D’Adamo et al., 2020] “All aspects of life have changed dramatically for now. The group most susceptible to COVID-19 are older adults and those with chronic underlying medical disorders. The population residing in long-term care facilities generally are those who are both old and have multiple comorbidities.…

“This is an opportunity for the field of geriatrics to shine and play a critical role in the vast team of people and organizations involved in managing this crisis. Awareness of potential key clinical differences of COVID-19 in this population; quickly initiating appropriate behaviors to manage the infection clinically in LTCFs; implementing containment strategies to disrupt further spread of the virus, as well as preventive interventions in an LTCF; and being knowledgeable about the decisions being made at the local, state, and federal level will help achieve this goal.” [D’Adamo et al., 2020]

The American Society of Consultant Pharmacists (ASCP) has an excellent COVID-19 resource center. It includes tools such as the following:

• ASCP COVID-19 (SARS-CoV-2) Medication Management FAQ
• Field Guide to Reduce Medication Burden during COVID-19
• Sample Pharmacy and Facility COVID-19 Policy & Procedures (member login required)
• U.S. Deprescribing Network – Optimizing Medication Management During the COVID-19 Pandemic: Implementation Guide for the Post-Acute and Long-Term Care
• ASCP’s Remote MRR and Restocking CMS Guidance
• COVID-19 Discussion Board (member login required)

IN THE PHARMACY

In addition to the possibility of emerging as important COVID-19 testing centers, pharmacies are feeling the brunt of the COVID-19 pandemic in many ways. Frontline pharmacists and pharmacy technicians are involved in clinical trials of antiviral agents, including remdesivir, editorialists write in the Journal of the American College of Clinical Pharmacy. They also have important roles to play in antiviral stewardship during the pandemic, management of marketed drugs being repurposed for off-label use in preventing or treating COVID-19, ensuring availability of needed agents and dealing with product shortages, supporting the health care team and infection preventionists in conservation of personal protective equipment (e.g., aligning medication administration times to reduce the number of daily entries into patient rooms), and providing accurate information to professionals and patients. [Gross & MacDougall, 2020]

The Centers for Medicare & Medicaid Services issued an interim final rule with comment period clarifying that provision of medication therapy management services by pharmacists are considered within the definition of auxiliary personnel during the public health emergency. In a notification to members, the American Pharmacists Association (APhA) wrote, “In response to APhA’s request for clarity on pharmacists providing services and billing for Medicare beneficiaries incident to the professional services of a physician, CMS clarified:

• “Medication management is covered under both Medicare Part B and Part D.
• “Pharmacists are considered ‘auxiliary personnel’ under the regulations and can provide these services under the appropriate level of supervision under Part B if payment for the services is not made under the Medicare Part D benefit.
• “Clinical services shall be in accordance with the pharmacist’s state scope of practice and applicable law.
• “CMS did not address APhA’s billing concerns and stated that the regulation does not alter current payment policy for pharmacist services furnished incident to the professional services of a physician.”

State boards of pharmacy have taken many actions related to COVID-19 situations. FDA, the Drug Enforcement Agency, and the United States Pharmacopeia have also issued statements and relaxed some requirements during the public health emergency. The COVID-19 micro site of the American Society of Health-System Pharmacists is a good resource for tracking federal updates.

In recent announcements, FDA warned that the use of denatured alcohol in the manufacturing of hand sanitizer is important to make the product more bitter and less appealing to ingest, particularly for young children. It pointed to a 79% year-over-year increase in poison center calls related to the product in March 2020, most for ingestion by young children. The agency also issued a guidance explaining a temporary policy regarding the repackaging or combining of FDA-approved propofol injectable emulsion products during the COVID-19 public health emergency.

REFERENCES

Bessière F, Roccia H, Delinière A, et al. Assessment of QT intervals in a case series of patients with coronavirus disease 2019 (COVID-19) infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit. JAMA Cardiol. 2020(May 1). doi: 10.1001/jamacardio.2020.1787. [Epub ahead of print]

Bonow RO, Hernandez AF, Turakhia M. Hydroxychloroquine, coronavirus disease 2019, and QT prolongation [editorial]. JAMA Cardiol. 2020(May 1). doi: 10.1001/jamacardio.2020.1787. [Epub ahead of print]

D’Adamo H, Yoshikawa T, Ouslander JG. Coronavirus disease 2019 in geriatrics and long‐term care: the ABCDs of COVID‐19. J Am Geriatr Soc. 2020(Mar 25). doi: 10.1111/jgs.16445. [Epub ahead of print]

Gandhi RT, Lynch JB, del Rio C. Mild or moderate Covid-19. N Engl J Med. 2020 Apr 24. doi: 10.1056/NEJMcp2009249. [Epub ahead of print]

Gold JAW, Wong KK, Szablewski CM, et al. Characteristics and clinical outcomes of adult patients hospitalized with COVID-19 — Georgia, March 2020. Morb Mortal Wkly Rep. 2020(Apr 29);69. Available at: https://www.cdc.gov/mmwr/volumes/69/wr/mm6918e1.htm. [Epub ahead of print]

Gross AE, MacDougall C. Roles of the clinical pharmacist during the COVID-19 pandemic. J Am Coll Clin Pharm. 2020(Mar 30). doi: 10.1002/jac5.1231. [Epub ahead of print]

Marini JJ, Gattinoni L. Management of COVID-19 respiratory distress. JAMA. 2020(Apr 24). doi: 10.1001/jama.2020.6825. [Epub ahead of print]

Mercuro NJ, Yen CF, Shim DJ, et al. Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020(May 1). doi: 10.1001/jamacardio.2020.1787. [Epub ahead of print]

Oxley TJ, Mocco J, Majidi S, et al. Large-vessel stroke as a presenting feature of covid-19 in the young. N Engl J Med. 2020(Apr 28). doi: 10.1056/NEJMc2009787. [Epub ahead of print]

Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054-1062.

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