COVID-19: An Update for Pharmacists and Pharmacy Technicians on the Frontlines
At the Smithsonian’s National Museum of Natural History in Washington, DC, a current exhibit describes a life-threatening pathogen that jumped from animals to humans in an Asian market with live animals, quickly spread locally, and was transported by planes, trains, and automobiles before anyone comprehended what was happening. “Outbreak: Epidemics in a Connected World” is scheduled to close in 2021, but the museum itself closed to the public in early 2020 because of the exact situation depicted in the prescient exhibit.[Smithsonian, 2020]
Within a few weeks after the December 2019 emergence of a previously unknown human coronavirus in Wuhan, China, the number of people diagnosed with infections and the number of associated deaths had far eclipsed those associated with the 2003 severe acute respiratory syndrome (SARS) and the 2012 Middle East respiratory syndrome (MERS). The World Health Organization (WHO) named the disease coronavirus disease 2019 (COVID-19), and the International Committee on the Taxonomy of Viruses designated the causative organism as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
This article describes what frontline pharmacy professionals need to know as this disease spreads around the world. The information is accurate as of late March 2020; updates will be published quarterly as more becomes known about the virus, the disease it causes, and the epidemiology, etiology, diagnosis, prevention, and treatment of COVID-19.
CLASSIFICATIONS AND STRUCTURE/FUNCTION OF CORONAVIRUSES
As their name suggests (“corona” is Latin for “crown”), coronaviruses are in an upper echelon among the positive-strand RNA viruses; they are the biggest, have the largest genome, and are the most complex. This complexity creates opportunities for finding ways to disrupt or stop the virus, but it also gives the virus multiple pathways for infection, replication, and viral release. [Denison, 2020]
The Coronaviridae family is within the Nidovirales order. The large number of proteins produced by coronaviruses provide several potential therapeutic targets. They have protein spikes and crowns on the outer envelope that could be targets in vaccine development. Coronaviruses check the accuracy of their replication phase, a function more commonly found in higher organisms. That accuracy could also prove fortuitous in vaccine development, since it means the organism might mutate less often than other viruses. However, some research indicates that coronaviruses have mechanisms that increase its mutation rates under certain conditions. [Koppaka, 2020; Baric, 2020]
Four subgroupings of coronaviruses have been identified, designated as alpha, beta, gamma, and delta. These viruses can be spread between animal species and humans (zoonotic). Seven human coronaviruses (HCoV) have been identified. Two alpha strains, HCoV-229E and -OC43, and two beta strains, HCoV-NL63 and -HKU1, are in wide circulation and routinely infect people, causing mild-to-moderate symptoms similar to the common cold (rhinorrhea, headache, cough). Infants, older adults, and people with immunocompromising conditions are most often infected, and most people have at least one coronavirus infection sometime during their lives. Infections are more common in the colder seasons but can occur year round. [Koppaka, 2020; Baric, 2020]
From an evolutionary perspective, these common HCoV strains may have adapted to humans, but humans have also adapted to the virus. The strains of HCoV that reproduce most effectively are those that produce disease but not death in people; a deceased host does not pass the virus along as much as living hosts. Likewise, since HCoV most often infect infants and young children, the virus exerts a selective pressure for people who can survive its infection; younger people who are susceptible do not live to reproduce. [Ye et al., 2020; Vijgen et al., 2005]
Three beta HCoVs have been identified within the past two decades that cause more severe and even lethal disease in humans. Severe acute respiratory syndrome coronavirus (SARS-CoV) was first recognized in 2002–2003 in China, and Middle East respiratory syndrome (MERS-CoV) was identified in 2012 in Saudi Arabia. The most recently identified HCoV, SARS-CoV-2, was identified in Wuhan, China, in December 2019, and retrospective analysis shows cases were occurring at least a month before then. [Koppaka, 2020; Baric, 2020]
The genetic composition of SARS-CoV-2 is 22% different from SARS-CoV, placing it in an entirely new clade of SARS-like viruses; it differs by more than 5,000 to 6,000 nucleotides from previously identified HCoV clades. Its closest known relative is a bat coronavirus originally obtained from a cave in the Yunnan province of China; the SARS-CoV-2 genome is 96% identical, differing by about 1,200 nucleotides. SARS-CoV-2 likely was harbored in bats and passed to humans, possibly directly but more likely through an intermediate host. Researchers are focusing on the role of a reptile species, the pangolin, as a possible intermediate host in which the virus mutated and amplified before passage to humans through butchering or meat consumption. [Ye et al., 2020; Koppaka, 2020; Baric, 2020]
The life cycle of a virus is straightforward: attach to a host cell, make entry, take over the cell’s ribosomal processes, generate viral proteins that will begin viral replication, have the host cell produce the viral components through transcription of the genetic material (RNA or DNA) and translation into proteins, assemble the structural and nucleic acid components, and release the new viruses. Based on the proteins coded for in the RNA of SARS-CoV-2, these processes provide several opportunities for therapeutic intervention, as shown in Table 1.
|Table 1. Potential Therapeutic Targets in the Coronavirus Life Cycle
|Essential Viral Functions/Components
||Potential Therapeutic Interventions/Agents
|Entry via the coronavirus spike attachment to the human angiotensin 2 receptor in lungs, small intestines
||• Broad entry inhibitors (primarily hydroxychloroquine and chloroquine)
• ACE inhibitors and ARBs (effects unclear — see text)
• Interference with host factors involved in entry
|Translation of viral RNA and production of 2 large polyproteins
||• Interference with host factors involved in translation
|Proteolysis of the polyproteins into 16 nonstructural proteins, including 2 proteases, RNA-dependent RNA polymerase, helicase, and exonuclease, which checks accuracy of replication of viral RNA
||• Inhibition of proteolysis
|Replication and transcription of viral RNA
||• Protease inhibitors
• Interference with host factors involved in replication and transcription
|Assembly of viral components (4 structural proteins—envelope, membrane, spike, nucleocapsid) with genomic RNA
||• Interference with host factors involved in viral assembly
|Release of new virions
||• Interference with host factors involved in virion release
|Source: Denison, 2020; de Wit et al., 2016, Guo Y-R et al., 2020.
Abbreviations: ACE, angiotensin converting enzyme; ARBs, angiotensin 2 receptor blockers
Case 1: Hannah is a 27-year-old woman working at an advertising agency in Manhattan. Before the pandemic of COVID-19 worsened in New York City, she was commuting each day by subway from her family’s home in Queens. She has been asymptomatic and began teleworking when mandatory stay-at-home orders were issued. About that time, her 53-year-old father begins having fever, cough, and fatigue, and later her 79-year-old grandmother becomes symptomatic. The father and grandfather test positive for SARS-CoV-2. Is Hannah the source of the virus?
What is your assessment? (see end of text for possible responses)
Much has been learned about COVID-19 and its epidemiology since identification of the novel beta-coronavirus, later designated as SARS-CoV-2. As the epidemic spread and the pandemic developed, research intensified and media attention increased. As a result, health professionals must look beyond mixed messages in the mass and social media and examine original studies and assess the quality of the research.
Because many of the people hospitalized during the first wave worked at or had visited a Wuhan, China, seafood market, the initial assumption was that the virus was transmitted from wild animals sold illegally by vendors (hence the attention on the pangolin mentioned above); whether this is the origin of the virus is unclear, as cases have been identified in patients hospitalized in November 2019, and some initial patients had no link to the market. [Wang et al., 2020]
Regardless of its origins, the virus and the disease it causes, COVID-19, soon spread into the community, where it was easily transmitted to other people, especially in family clusters. The new virus is likely transmitted primarily through airborne droplets following coughs and sneezes and on surfaces, where it is reported to remain viable for a few days. [van Doremalen et al., 2020] The virus is transmitted by asymptomatic and symptomatic patients through shedding that results from initial infection of the upper respiratory tract. [Woelfel et al., 2020; Ji et al., 2020; Fan et al., 2020]
One published report illustrates how transmission of SARS-CoV-2 can occur and how epidemiologic tools can be used to identify a “super spreader” — someone who transmits the virus to more than the usual number of people. A 20-year-old woman who lived in Wuhan spread the virus to five individuals after traveling to a town about 700 km (435 m) away where no other cases had been identified previously. Those five individuals developed COVID-19 and its characteristic fever, respiratory symptoms, and/or sore throat; the young woman showed no symptoms during a 30-day follow-up. [Bai et al., 2020] Other reports of early local transmission of the virus came from Taiwan, [Liu et al., 2020] Thailand, [Pongpirul et al., 2020] and Vietnam. [Phan et al., 2020; Thanh et al., 2020]
The spread of SARS-CoV and MERS-CoV was limited to fewer than 30 countries each and about 8,000 and 2,500 patients, respectively. In comparison, SARS-CoV-2 infections were reported in about 180 countries and approaching 1 million people by the end of March 2020 — less than 4 months after health professionals in Wuhan began noticing an unusual pattern of cases of pneumonia of unknown origin. The incubation period of the new virus has been estimated at 2 to 14 days, with a mean of 5 to 6 days elapsing between exposure to the virus and appearance of symptoms. [Baric, 2020]
SARS-CoV-2 is easily transmitted, and patients shed the virus readily and in higher numbers for a median of 20 days in survivors and until death in nonsurvivors. Calculation of the reproduction number, R0, has been hampered by a lack of testing among asymptomatic individuals to determine the extent of viral spread. The World Health Organization (WHO) has estimated an R0 of 1.4 to 2.9 based on data from the initial outbreak in China [Li et al., 2020]; others have estimated R0 at 2.5 to 3.8, meaning 1 infected person would spread the virus to an average of 2.5 to 3.8 other people. [Baric, 2020; Zhou et al., 2020]
Older adults and people with multiple disease states and/or immunocompromised conditions are at increased risk of developing COVID-19. Initial public health messaging and recommendations to “shelter in place” focused on these risk factors. Mortality from COVID-19 has disproportionately affected older and middle-aged adults and those with comorbidities. However, children and young people, including some who are otherwise healthy, have acquired the virus and developed the disease; as SARS-CoV-2 spreads around the world and the numbers of infected people climb, the morbidity and mortality in young people cannot be ignored. [CDC COVID-19 Response Team, 2020]
Data for 2,449 Americans with COVID-19 and whose ages were known reinforce this point. As shown in Table 2, 29% of those with SARS-CoV-2 were in the 20–44-year-old age range. Of the 508 patients who needed hospitalization, 20% were in this age range, and 2% to 4% of these young adults required intensive care. [CDC COVID-19 Response Team, 2020]
|Table 2. Hospitalization, ICU Admission, and Case-Fatality Percentages for Reported COVID-19 Cases With Known Ages, United States, February 12–March 16, 2020
|Age Group (yrs) (no. cases)
|Source: CDC COVID-19 Response Team, 2020
Abbreviation: ICU, intensive care unit
a Data are from 49 states, the District of Columbia, and 3 U.S. territories; the ranges shown are the lowest and highest reported percentages from these jurisdictions.
The low numbers of infants and children with COVID-19 is intriguing, especially since the HCoV strains in general circulation primarily infect children. As noted by Fauci et al. (2020), if children are not widely infected by SARS-CoV-2, that has epidemiologic implications. If their symptoms are so mild that the infections are escaping detection, that has implications for determining an accurate number of community infections for the denominator of epidemiologic calculations.
Another trend in the data generated thus far is that men are affected more often than women, and even in cases where more women have COVID-19, men die from it more often. In Italy through March 12, 2020, COVID-19 was occurring predominantly in men, and the case-fatality rate was 7.2% in men, compared with 4.1% in women. South Korea reported more cases in women through March 20, 2020, but the case-fatality rates were 1.53% in men and 0.81% in women. [Prodotto dall’Istituto Superiore di Sanità, 2020; KCDC, 2020]
Case 2: Brandon is a 43-year-old man living near New Orleans. On March 2, 2020, he presents to the emergency department of a suburban hospital with cough and malaise. His temperature is normal, and he is positive for influenza. He has no known exposure to people with diagnosed SARS-CoV-2 infections or who have traveled outside the country, but he participated in the city’s Mardi Gras celebrations, including parties in private homes the weekend of February 22. The test for SARS-CoV-2 is not available for a patient with these symptoms. Can COVID-19 be ruled out for Brandon?
What is your assessment? (see end of text for possible responses)
CLINICAL PRESENTATION AND DISEASE COURSE
Emerging during the 2019–2020 influenza season in the Northern Hemisphere, COVID-19 has presented diagnostic challenges to clinicians. Its presenting symptoms range from mild to severe; lacking a specific treatment and sufficient supplies of diagnostic tests, most clinicians have had to rule out all other possible causes (influenza A and B, respiratory syncytial virus, adenoma, parainfluenza virus, Mycoplasma pneumoniae, Chlamydia pneumoniae), perhaps take a chest radiograph, make a presumptive diagnosis of COVID-19 when no other cause could be confirmed, and recommend the patient take precautions to avoid secondary spread. [Wu et al., 2020]
The clinical course of COVID-19 often begins with malaise, dry cough, dyspnea, fatigue, and subjective feeling of fever. It progresses over an 11- to 14-day period. Some patients have had nausea, vomiting, and diarrhea. Fever was more consistently reported in patients in Wuhan than among a group of 21 critically ill, mostly older adults in Washington State. In contrast to the sudden onset people report with influenza, progression of symptoms with SARS-CoV-2 have a slower onset. During early phases of viral spread, symptoms began an average of 3.5 days before patients sought medical or emergent care. [Arentz et al., 2020; Wang et al., 2020; Guo Y-R et al., 2020]
The great majority of people have few symptoms requiring medical intervention. While testing of asymptomatic patients has thus far been limited, about 80% of people testing positive for SARS-CoV-2 have had symptoms mild enough to be managed at home. Fever occurs in almost all symptomatic patients (89%), cough is very common (68%), and some patients have fatigue (38%), sputum production (33%), shortness of breath (19%), sore throat (14%), and headache (14%). [Guo Y-R et al., 2020]
Symptoms have been categorized as typical (fever, cough, shortness of breath) and atypical (chills, malaise, sore throat, increased confusion, rhinorrhea, myalgia, dizziness, headache, nausea, diarrhea). In a study of skilled-nursing facility residents in Washington State, symptom screening failed to identify at least one-half of residents with SARS-CoV-2, and about one-quarter of residents who tested negative for the virus had symptoms suggestive of COVID-19. [Kimball et al., 2020]
Loss or reductions in smell (anosmia, hyposmia) or distortions in taste (dysgeusia) have been reported anecdotally, particularly in people with no other symptoms who eventually test positive for SARS-CoV-2. [American Academy of Otolaryngology, 2020]
In the 20% of patients requiring hospitalization, chest radiographs show bilateral nodular and ground-glass opacities in nearly all patients with COVID-19; other types of pneumonia are more likely involve a single lung and to lack the ground-glass appearance. Blood tests in patients with COVID-19 have shown decreases in absolute lymphocyte counts and elevations in liver enzymes and prothrombin times; white blood cell counts are often elevated but remain normal in many patients. Those whose symptoms become severe can recover, while others who seem to be doing fine can decline precipitously and have life-threatening respiratory, cardiac, cardiopulmonary, or multi-organ failure. [Arentz et al., 2020; Wang et al., 2020; Zhao et al., 2020; Woelfel et al., 2020]
About 5% of patients with COVID-19 (one-fourth of those needing hospitalization) present with advanced symptoms or become critically ill as viral damage in the lungs results in acute respiratory distress syndrome (ARDS). Many of these patients can survive if oxygen and supportive therapy provides time for their immune systems to fight off the virus. Patients with advanced age and those with comorbidities have a worse prognosis if ARDS develops. Some patients get better and recover; some get better before sudden declines necessitate rapid intubation or cardiopulmonary resuscitation. Patients have experienced fatal cytokine storms, and others have died of respiratory failure as alveolar damage compromises gas exchange. Evidence of direct cardiac damage is emerging in Chinese cohorts and anecdotal reports in the United States. Patients who recover from ARDS frequently have residual lung damage and reduced lung function permanently. [Arentz et al., 2020; Wang et al., 2020; Zhao et al., 2020; Woelfel et al., 2020; Guo T et al., 2020b; Bonow et al., 2020]
Patients with refractory episodes of COVID-19 infection have been reported. In one series of 155 patients, 55% of patients did not reach clinical or radiographic improvement by 10 days. Compared with those who recovered, patients with refractory COVID-19 were more likely to be men and to be older, have anorexia, and lack elevated temperature on admission. [Mo et al., 2020]
Stress, anxiety, and depression are common in society in general as the COVID-19 pandemic creates a need to maintain physical distance and separation from others. These can be accentuated in patients with the virus and should be assessed when patients initially present and during the course of the infection (or follow-up, in the case of initially negative tests). [Lim et al., 2020]
After infection with SARS-CoV-2, people are expected to have immunity to the virus. Whether this occurs and how long any immunity lasts are unknown. Antibody tests coming onto the market will give insights into important questions about reinfection, whether people can return to work, and which health care workers are more susceptible to infection.
Pathophysiologic changes are progressive during an episode of SARS-CoV-2 infection. The abnormal laboratory findings as described above for initial presentation of patients with mild-to-moderate symptoms are accelerated and accompanied by more severe pathophysiologic changes as the virus invades the lower respiratory tract and affects other body systems. [Rothan & Byrareddy, 2020; Guo Y-R et al., 2020]
SARS-CoV-2 infection of the lower respiratory tract produces severe pneumonia and ARDS, and viral RNA segments in the blood (RNAemia) produces systemic inflammatory responses. Among the elevated cytokines and chemokines found in the limited number of patients studied thus far are interleukin (IL) 1-beta, IL1 receptor antagonist, IL-7, IL-8, IL-10, fibroblast growth factor, granulocyte colony stimulating factor, granulocyte–macrophage colony stimulating factor, interferon (IFN)–gamma, and tumor necrosis factor alpha. [Rothan & Byrareddy, 2020; Xu Z et al., 2020; Guo Y-R et al., 2020; Bonow et al., 2020]
Reports of cardiac injury have been mixed; autopsy of one patient who died of severe COVID-19 with respiratory failure showed no direct injury to the heart, but tissues had a few interstitial mononuclear inflammatory infiltrates. As noted above, evidence of direct cardiac damage is emerging in Chinese cohorts and anecdotal reports in the United States. [Rothan & Byrareddy, 2020; Xu L et al., 2020; Guo Y-R et al., 2020]
In severe cases of COVID-19, liver injury has been reported. Changes are similar to those seen in past coronaviral epidemics, but whether these result from the disease or drugs used in efforts to manage fever and other symptoms or contain the virus is not clear. [Xu L et al., 2020; Guo Y-R et al., 2020]
In patients who die of COVID-19, cytopathic effects and cytokine storm lead to multi-organ failure, septic shock, difficult-to-correct metabolic acidosis, and coagulation dysfunction. [Guo Y-R et al., 2020]
PUBLIC HEALTH RESPONSES
As awareness of the SARS-CoV-2 grew, the U.S. Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH) began work on developing assays and vaccines. When cases emerged, beginning in Washington State in mid-January 2020, containment of the virus was attempted through traditional public health techniques (contact tracing, quarantine, restrictions on immigration from affected areas), but a delay in availability of a test complicated these efforts. Community spread ensued, and mitigation efforts were put into place in areas of the United States with higher case counts; these included recommendations for social distancing and self-isolation based on exposure through travel or contact with known cases. Finally, broad stay-at-home orders were issued by governors and local authorities.
While these efforts may have succeeded in delaying the spread of COVID-19, by late March 2020, hospitals in the New York City metropolitan area were fully engaged in caring for patients with this disease. Various states took different approaches to manage the pandemic and identify locally effective ways of slowing the spread and “bending the curve.”
Based on the skilled-nursing facility experience from Washington State described above, the CDC investigators suggested that as soon as a facility has a case of COVID-19, broad strategies should be implemented to prevent transmission, including restriction of resident-to-resident interactions, universal facemasks for all health care personnel while in the facility, and use of full personal protective equipment when possible during the care of all residents, including gown, gloves, eye protection, and when available, an N95 respirator (or face mask if that is not available). [Kimball et al., 2020] Hospital workers are accustomed to using such equipment, but with surges in COVID-19 cases, shortages of personal protective equipment have occurred in many health care settings.
Dozens of potential vaccines are in development or early clinical trials (phase 1 as of March 2020). The virus provides several vaccine targets, and companies are testing a variety of vaccine platforms and adjuvants for their safety and efficacy. Previous efforts to develop vaccines against SARS had limited success because immunity waned in a few months or a year; MERS vaccine produced longer-lasting immunity, but no one knows why it was better. [Poland, 2020]
For beta-coronaviruses, the spikes on viral protein coats are an obvious target for drugs and vaccines, and most current vaccine candidates are focusing on the S protein located there. The supporting stems might be even better, as they do not mutate as frequently as the spikes. Another approach would be vaccines that include additional surface proteins – the E, M, or HE proteins — to avoid the vaccine selection pressure on mutations affecting a single vaccine. [Baric, 2020; Poland, 2020]
In past trials of vaccines for coronaviruses, substantial heterogeneity has limited vaccine efficacy, and use of adjuvants has led to adverse effects after vaccination. In addition, older adults have been affected greatly by COVID-19, and that group responds less to vaccines in general. [Baric, 2020]
Case 3: Hannah is a 43-year-old woman living in San Francisco and working in Silicon Valley. Following onset of fever (38.5°C), cough, and malaise of 3 days’ duration, she contacts her primary care physician by email and is instructed on how to obtain a drive-through SARS-CoV-2 test. Her temperature soon increases to 39°C and remains there for 3 days during times when acetaminophen doses wear off. Hannah’s SARS-CoV-2 test comes back positive, and her cough worsens and becomes productive. She is admitted to a San Francisco hospital, where her chest radiograph shows bilateral ground-glass infiltrates. Her oxygen saturation declines as she becomes lethargic and confused. She is transferred to intensive care, where she is sedated and intubated. Drug therapy includes corticosteroids and acetaminophen. After 4 to 5 days, Hannah begins to improve, and she is placed on positive-pressure oxygen and sedation is withdrawn. She recovers, has a negative SARS-CoV-2 test, and is discharged 15 days after admission. What does Hannah need to know as she leaves the hospital?
What is your assessment? (see end of text for possible responses)
DRUG THERAPY IN COVID-19
At this time, any discussion of treatment (or prevention) of COVID-19 must start with a single fact: No treatment has been shown effective and safe in controlled clinical trials. While a number of small-molecule compounds, biologic agents, and immunomodulators might be beneficial in patients with or at risk for COVID-19, nothing is proven at this point.
Notwithstanding this fact, a pandemic is raging, the initial public health containment of the pathogenic virus came too late initially in China and most other countries, and the blunt tool of social distancing with home confinement is creating economic havoc around the globe. In China, the virus was eventually controlled through severe restrictions on people’s activities and movements for 2 or more months, universal mask use while in public places, tracking and monitoring people through facial recognition and mobile phone locations, and cultural tendencies to obey governmental directives; such approaches are not likely to be effective or even tolerated in European and American democracies.
Given the long lag time involved in vaccine development, the only foreseeable way of reducing the rolling impact of SARS-CoV-2 over the next year to 18 months is identification of a miracle cure along the lines of penicillin in the middle of the 20th century and rapid testing of this agent in valid studies conducted in real-world settings. That fact has spurred research and clinical investigations into dozens of existing compounds and examination of interactions of the virus with the host in an effort for one that could be disrupted by monoclonal antibodies or immunomodulators. [Zimmer, 2020; Gordon et al., 2020]
This section provides an overview of several of the most promising agents with actions that could prove useful in patients with COVID-19. These include repurposed marketed agents and investigational products in development and clinical trials.
An ideal antiviral agent targeting SARS-CoV-2 and future coronaviruses that are “outbreak ready” in bats would have these characteristics [Denison, 2020]:
- Target viral functions or proteins that are highly conserved (ones that do not change much as a result of mutation) or host proteins and structures involved in viral entry, translation, replication, transcription, and/or virion assembly and release
- Have a high barrier to resistance, with limited genetic paths that can mutate and/or high fitness costs to the virus when mutations occur (i.e., organisms that have the mutation are not as “fit” as wild-type viruses)
- Have an extended therapeutic window, with roles in prevention, amelioration of the damaging effects of viral infection on the host tissues, and treatment of HCoV diseases
- Be useful for decreasing transmission in situations such as a cruise ship and if possible be administered orally
Certain antiviral agents are unlikely to be useful. Use of neuraminidase inhibitors (e.g., oseltamivir, peramivir, zanamivir) is not logical, since coronaviruses do not have a gene for neuraminidase. Nucleoside analogues (e.g., acyclovir, ganciclovir, ribavirin) would be expected to exert effects only at high levels since the coronavirus has an exonuclease that would recognize and remove the analogues when incorporated into the viral genome. [Tan et al., 2004; Guo Y-R et al., 2020]
Available drugs or drug classes with potential usefulness in the SARS-CoV-2 pandemic include protease inhibitors, the investigational drug remdesivir, chloroquine/hydroxychloroquine, angiotensin receptor modulators, and immunomodulators.
The SARS-CoV-2 RNA codes for a pair of protease enzymes that are essential to production of viable virions upon release. Protease inhibitors have been highly effective for treating patients with infections of human immunodeficiency virus (HIV) or hepatitis C virus. Lopinavir interrupts viral maturation of HIV-1 and HIV-2 by inhibiting the cleavage of a polyprotein, thereby resulting in production of immature, noninfectious virions. It is marketed in combination with ritonavir, a weaker protease inhibitor that increases serum concentrations of lopinavir by reducing its metabolism through inhibition of the hepatic and gut 3A isoenzyme. (Anderson et al., 2020)
The therapeutic success of protease inhibitors in HIV led researchers to see whether these agents could be effective in patients with COVID-19. In the first clinical trial of a protease inhibitor in this setting, 199 hospitalized adult patients with confirmed SARS-CoV-2 infection and an oxygen saturation of 94% or less while breathing ambient air or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen of less than 300 mm Hg were randomized to lopinavir/ritonavir 400/100 mg twice a day for 14 days plus standard care or standard care alone. (Cao et al., 2020)
Based on a primary end point of the time to clinical improvement, the two groups were not significantly different (hazard ratio for clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72). There was a notable but not significant reduction in mortality at 28 days with lopinavir/ritonavir, but this finding was offset by a higher rate of gastrointestinal adverse events with the protease inhibitors, some of them severe enough to necessitate termination of therapy in 13.8% of patients. Because the patient population in this study turned out to have severe cases of COVID-19 — and it is difficult to treat patients once the damage is done to the lungs — there is some thought that further testing of protease inhibitors is warranted. Lopinavir also may not have been the best choice for use against SARS-CoV-2, as “the concentration necessary to inhibit viral replication is relatively high as compared with the serum levels found in patients treated,” authors of an accompanying editorial noted. (Cao et al., 2020; Baden & Rubin, 2020)
Under development by Gilead, remdesivir is a novel antiviral agent originally developed for treating Ebola virus. While very promising in both in vitro tests and clinical trials against that virus and other HCoVs, it has not yet been approved for any condition in any country. [Denison, 2020]
Remdesivir is a nucleotide analogue that acts through chain termination during RNA replication. When a single molecule is incorporated into the growing strand, the process stops and the resulting virion is not infective. At low concentrations, remdesivir reduces viral titers in vitro by several logs. [Denison, 2020]
In January 2020, clinical trials of intravenous remdesivir began in China in patients with COVID-19. At least 5 additional trials began subsequently, including one at the National Institutes of Health and others in combination with chloroquine or interferon beta. Results are not yet available. [Denison, 2020; Shereen et al., 2020]
Broad antiviral properties of chloroquine and hydroxychloroquine have long been recognized. However, the evidence supporting use of these agents as an inhibitor of viral entry into host cells is primarily preclinical, with much of it in vitro. An in vitro study also showed that chloroquine and remdesivir inhibit SARS-CoV-2. That said, some clinical evidence is now appearing with respect to SARS-CoV-2, and numerous additional trials are underway. In addition, FDA issued an emergency use authorization and coordinated donation of hydroxychloroquine sulfate and chloroquine phosphate products to the states for use in hospitalized patients with COVID-19. [Cortegiani et al., 2020; Wang M et al., 2020; FDA, 30 March 2020]
A French study of 36 patients with COVID-19 of hydroxychloroquine and azithromycin has received much attention. Conducted “in a hospital setting,” some patients were asymptomatic (n = 6), most had upper respiratory tract infection symptoms (n = 22), and others had lower respiratory tract infection symptoms (n = 8). While the stated purpose of the study was to assess the effects of hydroxychloroquine 200 mg three times daily for 10 days on viral load as assessed with nasopharyngeal swabs, the researchers added azithromycin to patient regimens “depending on their clinical presentation.” Assignment to groups was not random. [Gautret et al., 2020]
Six patients in the treatment group were to follow-up because 3 patients were transfered to intensive care and 1 patient each because of death, left hospital, and adverse effects (nausea). Results showed that 13 of remaining 20 patients treated with hydroxychloroquine had negative nasal swabs by day 6 of treatment, compared with 1 of 16 control patients. All 6 patients who received both hydroxychloroquine and azithromycin had negative swabs on day 6, leading to the authors’ conclusion that the antibiotic “reinforced” the effects of hydroxychloroquine. [Gautret et al., 2020]
In a systematic review, Cortegiani et al.  showed that the rationale for use of chloroquine is sound and there is preclinical evidence for its effectiveness against SARS-CoV-2. Support for its safety comes primarily from long-time clinical use for other indications. The available evidence justifies clinical research into its use in patients with COVID-19, the authors concluded, but current use should be restricted to ethically approved trials or emergency use situations.
Hydroxychloroquine is being studied in clinical trials of patients with COVID-19, according to information posted on the CDC website and clinicaltrials.gov. These include studies looking at both pre-exposure and postexposure situations and in patients with mild, moderate, or severe COVID-19. Given the possibility of creating shortages of hydroxychloroquine being used in patients for labeled indications and causing adverse effects in unmonitored ambulatory patients (QT prolongation), use of this drug is not recommended outside the clinical trial setting. [ASHP, 2020; CDC, 2020; Kalil, 2020; Kim et al., 2020]
Coadministration of azithromycin with hydroxychloroquine increases the risk of QT prolongation, an adverse effect of both drugs. This can be monitored in the hospital but not generally in ambulatory settings. With the lack of both rationale and evidence for adding azithromycin to a chloroquine-based regimen, its use is not recommended.
Angiotensin Receptor Modulation
The process of SARS-CoV-2 entry into cells of the lower respiratory tract involves tissue angiotensin-2 receptors and angiotensin converting enzyme 2 (ACE2). This has led to speculation about whether use of angiotensin converting enzyme (ACE) inhibitors and/or angiotensin-2 receptor blockers (ARBs) is beneficial or harmful. At this time, evidence is lacking to support either possibility. [Patel & Verma, 2020]
Epidemiological studies from the early phase of the pandemic in China indicated that patients with hypertension who developed COVID-19 were at greater risk of death and ARDS. This led to a general concern that ACE inhibitors and ARBs might increase viral entry or patient susceptibility to the virus. Others have pointed to theoretical mechanisms and evidence with other HCoVs in advocating for use of these agents during treatment of COVID-2 in patients with hypertension. [Patel & Verma, 2020]
At this time, the current consensus is that patients on these agents should continue taking them if they test positive for SARS-CoV-2 or develop COVID-19. Unless patients are part of a clinical trial, they should not begin treatment with these agents to prevent or treat SARS-CoV-2 or COVID-19. [Anonymous, 2020; Patel & Verma, 2020]
Use of nonsteroidal anti-inflammatory drugs (NSAIDs) during the pandemic has been controversial, but drawing any conclusion is impossible given current evidence and the widespread use of these drugs for fever (a common symptom in patients with COVID-19) and other diseases commonly present in those with severe cases (diabetes, hypertension). Speculation about ibuprofen began after a letter in Lancet Respiratory Medicine suggested research into the potential for ACE inhibitors and ARBs to increase the number of ACE2 receptors in lung tissue and thereby facilitate viral entry. [Fang et al., 2020] Since NSAIDs are involved in one of the processes by which this could occur, speculation began that NSAIDs could worsen COVID-19; the media amplified this concern.
FDA soon issued a statement confirming the safety of ibuprofen, given current evidence. [FDA, 2020 March 19] For those concerned about using NSAIDs, acetaminophen is a rational alternative for reducing elevated temperatures. Given the effects of COVID-19 on the liver, acetaminophen doses should be as low as feasible, and the drug should not be used without a clear indication. A danger in treating low-grade fevers is that patients may inadvertently (or deliberately) mask the presence of fever through use of NSAIDs and other antipyretics, complicating diagnosis and increases the spread of SARS-CoV-2 to susceptible family members and other contacts.
A variety of immunomodulators and agents that affect the host response to SARS-CoV-2 are under investigation. The viral proteins and nucleic acids listed in Table 1 interact with cells in the body, providing targets for antibodies and drugs both old and new. A manuscript submitted for publication proposes an interaction map of human and viral proteins that provide drug targets and potential drug repurposing. [Gordon et al., 2020]
Media reports list at least 50 small-molecule drugs being tested in high-throughput laboratories that can detect activity for exploration in other in vitro, preclinical, and clinical trials. These include already-marketed agents and investigational agents that may or may not have been studied previously in people. [Zimmer et al., 2020]
The IL-6 receptor antagonist sarilumab, already approved for use in rheumatoid arthritis, is being studied in patients with COVID-19, according to company statements and media reports. Another IL-6 antagonist, tocilizumab, is in clinical trials for use in patients with COVID-19 in China and the United States. [Chinese Clinical Trial Registry, 2020; Genentech, 2020; Sanofi, 2020]
While anecdotal reports of product shortages have surfaced regarding patients needing the agents for labeled indications, the companies say they have ample products in the supply chain. Until results of clinical trials demonstrate efficacy and safety of these and other immunomodulators in COVID-19, clinicians should not prescribe these agents— which themselves can make patients more susceptible to infections — for prophylaxis or treatment of SARS-CoV-2.
Critical Care of Severe COVID-19
Patients with severe symptoms of COVID-19 have much higher mortality rates — 22% to 62% in some early reports from Hubei province in China — compared with all infected patients (0.5% to 4%). Because of this increased risk of death and the lack of any drugs approved for this condition, many therapeutic interventions have been used in heroic efforts to save patients’ lives. These include neuraminidase inhibitors, which are unlikely to be of any benefit, and corticosteroids, which should be used selectively as outlined below. [Murthy et al., 2020]
The Surviving Sepsis Campaign (SSC) has issued recommendations for management of the 5% to 10% of patients with COVID-19 who require intensive care and mechanical ventilation, and these provide a useful overview of care in intensive care units. Recommendations are categorized as infection control and testing, hemodynamic support, ventilatory support, and therapy. For therapy, the three recommendations are as follows (emphasis added) [Poston et al., 2020]:
* In adults receiving mechanical ventilation who do not have ARDS, routine use of systematic corticosteroids is suggested against (weak recommendation, low quality evidence [LQE]). In those with ARDS, use of corticosteroids is suggested (weak recommendation, LQE).
* In COVID-19 patients receiving mechanical ventilation who have respiratory failure, use of empiric antimicrobial/antibacterial agents is suggested (no evidence rating); assess for de-escalation.
* In critically ill adults with fever, use of pharmacologic agents for temperature control is suggested over nonpharmacologic agents or no treatment. Routine use of standard intravenous immunoglobulins is not suggested. Convalescent plasma is not suggested. There is insufficient evidence to issue a recommendation on use of any of the following: antiviral agents, recombinant interferons, chloroquine/hydroxychloroquine, or tocilizumab.
Case 4: Enclose in box
Case 4: Sam is an 83-year-old man who resides in an assisted-living facility with his wife of 64 years. His medical history includes diabetes and mild cognitive impairment. He develops symptoms of COVID-19 with rapid onset and decline. When he is transferred to a local hospital during the height of the pandemic, his temperature is 38.7°C, his oxygen saturation values are low, nail beds blue, and breathing is labored and punctuated by deep productive coughs. All the intensive-care beds are full at this hospital and throughout the city, and no ventilators are available. What options do Sam’s hospitalist and pulmonologist have?
What is your assessment? (see end of text for possible responses)
CHALLENGES FOR FRONTLINE PHARMACY PROFESSIONALS
The COVID-19 pandemic has occurred rapidly and dramatically in the clinical setting, and its impact on society and the economy have been equally disconcerting. Mass media and the millions of people posting on social media have sometimes created panic buying of hand sanitizer as well as drugs and other therapies with unproven efficacy and safety. A statement issued jointly by the American Medical Association, the American Society of Health-System Pharmacists, and American Pharmacists Association expressed concern about shortages and hoarding of chloroquine, hydroxychloroquine, and other emerging therapies for COVID-19. [American Medical Association et al., 2020]
Personal protective equipment has been in short supply, leading to advice from United States Pharmacopeia (USP) on conserving garb needed in sterile compounding. [United States Pharmacopeia, 2020 March 18] USP also provided formulations for compounding alcohol-based hand sanitizer during the pandemic. [United States Pharmacopeia, 2020 March 25]
In the community pharmacy, patients may be seeking or asking about alcohol for use in making their own hand sanitizer or use of non-pharmaceutical-grade chloroquine. Patients must understand the need to use denatured alcohol (regular alcohol products are highly toxic to young children and others who ingest even small amounts of these products if not made with denatured alcohol). Fatalities and poisonings from non-pharmaceutical-grade chloroquine products have also been publicized. [USP, 2020; Shepherd, 2020; FDA, 2020 March 27]
A number of administrative and practical problems are also being addressed on the frontlines, including the need for redundant systems to ensure operability when workers test positive, become sick, need to address family situations or child-care gaps, or otherwise cannot continue in their usual roles. All staff should have access to email and other communication systems from outside the institution or pharmacy. Staff training about how to respond (or not respond) to the media should be reinforced. Senior-level administrators and human resources staff will need to review workers compensation policies and relevant state and federal laws to determine what will happen when health care professionals and other workers become positive for the virus and the source is unclear; with shortages of personal protective equipment likely to continue and worsen, this will be an area of controversy.
As this pandemic goes on and the possibility of hot spots continues or restarts in the fall or winter, pharmacists and pharmacy technicians will be essential health professionals needed to meet the needs of a worried populace. Medications, monoclonal antibodies, and vaccines will hopefully end this pandemic and people’s susceptibility to SARS-CoV-2. Until then, pharmacy professionals will need to care for patients who think they have the virus or are worried about it. As they do, pharmacy professionals will need to keep in mind their own worries and concerns and remember to take care of themselves first so they can continue taking care of others.
POSSIBLE ASSESSMENTS FOR CASES IN TEXT
Case 1 Assessment: That is one possibility, but there is no way to tell where the virus was acquired once community spread is occurring. Since Hannah is asymptomatic and tests were in short supply at that time, she would not likely have been tested if she presented for care. While the pandemic had passed the point when epidemiologists might have used contact tracing to identify and confine a source, that technique would be used to find possible sources, probably starting with the father’s contacts, since he was the first symptomatic member of this family cluster of COVID-19.
Case 2 Assessment: A point of confusion concerns whether the presence of influenza rules out the possibility of COVID-19. Coinfection with both viruses is possible and has been reported. One would expect fever with both influenza and COVID-19, but its absence is not sufficient for ruling out COVID-19. Even without the influenza factor, many people have COVID-19 with no symptoms at all or mild presentations that do not include fever. Thus, COVID-19 cannot be ruled out. A chest radiograph would be useful if Brandon’s symptoms worsen. In the meantime, it is reasonable to recommend that Brandon self-isolate himself for 14 days based on the potential exposure to SARS-CoV-2 during Mardi Gras.
Case 3 Assessment: Thanks to the supportive care that allowed Hannah’s immune system to overcome COVID-19, she is being discharged from the hospital. Areas unique to this condition about which patients have questions include whether they are infective to their family and friends, immune to reinfection, and fully recovered. Since Hannah has tested negative, the current thinking is that she should not be shedding virus and therefore is not infective to others. Since antibodies have likely developed in response to the virus, she should have immunity. However, it is currently unknown how long those antibodies remain in the body and whether viral mutations have or will create strains that can elude these antibodies. Patients recovering from severe COVID-19 can expect some reduction in lung function because of the damage to the lungs from the virus and immune responses of the body, and some believe there could be cardiac damage. How these lung and heart changes will affect people in the long-term is unknown.
Case 4 Assessment: Various institutions are approaching an imbalance between patient load and availability of beds and ventilators differently. Beyond the usual triaging of patients needed during disasters to identify those at greatest need who are also most likely to respond to interventions, hospitals and health systems are developing procedures for decision making when demand exceeds supply for patients with similar clinical findings. These include decisions by upper-level administrators or clinicians, committees, or lotteries.
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COVID Tracking Project (state- and county-level case, death, and testing data)
The Covid-19 Tracker (STAT News; very good visualizations of worldwide and U.S. data)
U.S. Centers for Disease Control and Prevention
U.S. Food and Drug Administration
U.S. Government Coronavirus site
JAMA Coronavirus Resource Center
Johns Hopkins Coronavirus Resource Center
New England Journal of Medicine Coronavirus page
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