MESSAGE
| DATE | 2020-04-20 |
| FROM | Ruben Safir
|
| SUBJECT | Subject: [Hangout - NYLXS] sars-cov2 info
|
this was passed to the Pharmacist community this week and you might be
interested
COVID-19: An Update for Pharmacists and Pharmacy Technicians on the
Frontlines
INTRODUCTION
At the Smithsonians 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
20022003 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 cells 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
Remdesivira
Interference with host factors involved in replication and
transcription
Assembly of viral components (4 structural proteinsenvelope,
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
aInvestigational agent
Case 1
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 familys
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)
EPIDEMIOLOGY
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 2044-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 12March 16, 2020
% Patientsa
Age Group (yrs) (no. cases) Hospitalization ICU Admission
Case-Fatality
019 (123) 1.62.5 0 0
2044 (705) 14.320.8 2.04.2 0.10.2
4554 (429) 21.128.3 5.410.4 0.50.8
5564 (409) 20.530.1 4.711.2 1.42.6
6574 (210) 28.643.5 8.118.8 2.74.9
7584 (144) 30.558.7 10.531.0 4.310.5
85 (144) 31.370.3 6.329.0 10.427.3
Total (2,449) 20.731.4 4.911.5 1.83.4
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 dallIstituto Superiore di Sanità,
2020; KCDC, 2020]
Case 2
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
citys 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 20192020 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.
PATHOPHYSIOLOGY
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,
granulocytemacrophage 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.
SARS-CoV-2 Vaccines
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
Case 3: Hannah is a 43-year-old woman living in San Francisco
and working in Silicon Valley. Following onset of fever
(38.5C), 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 39C and remains there for 3 days during times when
acetaminophen doses wear off. Hannahs 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 peoples 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.
Small-Molecule Drugs
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.
Protease Inhibitors
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)
Remdesivir
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]
Chloroquine/Hydroxychloroquine
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.
[2020] 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]
Anti-inflammatory Agents
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.
Immunomodulators
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 38.7C, 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 Sams
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
peoples 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 fathers
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 Brandons 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 Hannahs 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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