COVID-19 Monthly Update: Delta Variant Dominates


Nearly 20 months into the coronavirus disease 2019 (COVID-19) pandemic, nearly 200 million cases resulting in more than 4 million deaths worldwide have occurred as of late July 2021. As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ravaged the world, the National Center for Health Statistics, a part of the U.S. Centers for Disease Control and Prevention (CDC), reported that life expectancy in the United States decreased from 78.8 years in 2019 to 77.3 years in 2020. This was the largest 1-year drop since World War II, with nearly 75% of the decline attributed to COVID-19 disease.

Similar to previously documented outcomes with COVID-19, the mortality effects of the disease have been most pronounced on minority populations. COVID-19 was responsible for 90% of the decline in life expectancy in Latinos, 68% among non-Hispanic White population, and 59% among the non-Hispanic Black population. Also contributing to the lower life expectancy were a record 93,000 deaths attributable to drug overdoses driven by fentanyl, methamphetamine, and cocaine. COVID-19 and the overdose fatalities together produced a 3-year decline in life expectancy for people of Hispanic ethnicity and 2.9-year decline in life expectancy for non-Hispanic Blacks compared with a 1.2-year decline in life expectancy for non-Hispanic Whites.

Because of the way these life expectancy estimates are calculated, the declines should reverse quickly, given the drop in pandemic deaths since vaccines became available and many of those in high-risk groups received them. As of July 2021, 3 vaccines have been authorized by the FDA for use: the Pfizer/BioNTech and Moderna mRNA vaccines as well as the Janssen/Johnson & Johnson adenovirus vector vaccine. More than 188 million total doses have been administered, with more than 163 million people fully vaccinated, mostly with the mRNA vaccines. This equates to nearly 90% of older adults (³65 years), who are at highest risk of morbidity and mortality, and 69% of adults (³18 years) receiving at least 1 dose. Approximately 80% of older adults and 60% of all adults in the United States have been fully vaccinated.

However, a major impediment toward a return to prepandemic life has been emergence and spread of, B.1.617.2, better known as the SARS-CoV-2 delta variant. The CDC has classified delta as a variant of concern, joining the B.1.1.7 (alpha), B.1.351 (beta), and P.1 (gamma) variants. The CDC designates problematic strains as variants of concern to improve coordination among federal agencies in monitoring and responding to the SARS-CoV-2 pandemic.

A number of questions about the delta variant are important for pharmacists and pharmacy technicians to address with patients in order to give truthful, trustworthy information in the era of internet and social media “news.” The following questions and answers address a number of the pressing questions regarding the delta variant. This program also covers other developments of concern to the pharmacy community, including recent research on antiviral therapies.

Question: What is the delta variant?

Answer: The delta variant was first identified in India in October 2020, where it was responsible for the tremendous increases in cases over the ensuing months. This variant is different from the parent strain in that it has diverse spike protein mutations in the N-terminal domain and the receptor binding domain. The delta variant also has increased affinity for its binding domain on the angiotensin-converting enzyme 2 (ACE 2) receptor, which increases its ability to evade antibodies.1

Of note, the delta plus variant, also named B.1.617.2.1 or AY.1, is considered a subvariant of delta. Its mutation allows for increased virulence in lung cells and potentially the ability to evade vaccines. While delta plus has been found in the United States, the CDC and the World Health Organization (WHO) have yet to name it a variant of concern as they have with the delta strain.

Question: How does the delta variant compare to previous variants or the parent strain with regard to spread and clinical presentation?

Answer: The delta variant is much more contagious than previous variants or the parent strain. The WHO has described the delta variant as “the fastest and the fittest.” While the pathophysiology is being further delineated for these traits, this increased transmissibility results from production of more than 1,000 times the viral load than with the parent strain. “It’s actually quite dramatic how the growth rate will change” with this variant, said Dr. F. Perry Wilson, physician at Yale Medicine. “In a completely unmitigated environment — where no one is vaccinated or wearing masks —it’s estimated that the average person infected with the original coronavirus strain will infect 2.5 other people. In the same environment, delta would spread from one person to maybe 3.5 or 4 other people. Because of the math, it grows exponentially and more quickly. So, what seems like a fairly modest rate of infectivity can cause a virus to dominate very quickly.” The delta variant’s basic reproductive number, or R0, is similar to that of smallpox (or in some cases higher) and lower than only mumps and measles, which have R0 of 12 and 18, respectively.

The symptoms of the delta variant are overall similar to those with previously circulating strains. While some reports out of the United Kingdom state that cough and loss of smell are less common with the delta variant, other symptoms — headache, sore throat, rhinorrhea, fever — are similar to those of older strains. Increased severity of illness with the delta variant has not been demonstrated definitively. While a study out of Scotland showed patients with the delta variant to be twice as likely to be hospitalized compared with the alpha strain, this observation has not been confirmed elsewhere.

Question: How common is the delta variant in the United States at this time?

Answer: The delta variant has rapidly become the dominant strain in the United States. As of late July, this variant was identified in an estimated 83% of new coronavirus cases in the United States, up from just over 50% a few weeks earlier. These data were cited by Dr. Rochelle Walensky, CDC director, during a Senate health committee hearing. The strain is rapidly spreading through most areas of the country, especially those with the lowest vaccination rates, primarily in the southern parts of the country, including the states of Arkansas, Florida, and Missouri. Because of the rapidity and efficiency of the spread, health systems in these states are quickly being overwhelmed, resulting in diversion of patients to other hospitals, similar to early in the pandemic.

The United Kingdom, where the delta strain became the dominant strain earlier than in the United States, is seeing a rapid 7-day decrease in cases of more than 30%. This could portend positively for the United States if the surge of cases that began in July 2021 peaks and subsides in a few weeks. The better than average vaccination rate among Americans compared with other countries could also result in a lower peak for the delta strain surge.

To get ahead of the transmission curve with the delta variant, the CDC on July 27,2021, reversed its previous advice relaxation of masking for fully vaccinated individuals. The newly revised recommendation is that everyone, including those who are fully vaccinated, should wear a mask in indoor public places when in a geographic area with “substantial or high transmission.” Such areas can be identified on the CDC’s COVID data tracker.

Question: How effective are current vaccines at preventing infections of the delta variant?

Answer: Vaccines represent the best way for people to protect themselves from the delta variant. However, breakthrough infections with the delta strain can occur even after being fully vaccinated. It is important to remember that no vaccine is 100% effective in preventing disease and illness. A small percentage of fully vaccinated people will test positive for SARS-CoV-2, and some will develop symptoms of COVID-19. Even though this risk is very small, people must aware that a small percentage of the hundreds of millions of Americans who have been vaccinated means that they will hear about – or even know – people with these so-called “breakthrough” infections. That is to be expected with mass immunization campaigns.

Data for 2 of the 3 available vaccines show durable responses that will protect most people against the delta variant. The adenovirus vaccine by Janssen/Johnson & Johnson produces high titers of neutralizing antibody to the delta variant, with antibody and T-cell responses durable for at least 8 months.2 A recently published New England Journal of Medicine study used a case–control design to estimate the effectiveness of vaccination with BNT162b2, the Pfizer/BioNTech mRNA vaccine, against symptomatic COVID-19 caused by the delta variant. Effectiveness of 1 dose of BNT162b2 was significantly lower against the delta variant compared to the alpha variant (30.7% vs. 48.7%, respectively). However, the 2-dose regimen provided vaccine effectiveness against the delta variant similar to the alpha variant (88.0% vs 93.7%, respectively).3 Efforts to administer the full 2-dose regimen of this vaccine are therefore optimal to maximize vaccine effectiveness.

Despite those encouraging figures, data from Israel suggest the Pfizer vaccine is less effective versus the delta variant than previously studied, showing a 39% effectiveness rate against symptomatic disease. Breakthrough infections and symptoms in the United States are being reported, including highly publicized outbreaks such as the one involving the New York Yankees, whose athletes who received full vaccination with the Janssen/Johnson & Johnson vaccine. Other athletes have also had positive tests and/or breakthrough symptoms. Jon Rahm, professional golfer, has had especially bad luck. After receiving the Janssen/Johnson & Johnson vaccine in June a few days before the Memorial Tournament, Rahm tested positive for COVID-19 during the match while holding a 6-shot lead and in line to win $1.7 million. In July, he again tested positive for COVID-19 before he was to travel to Tokyo for the Olympic games.

In Minnesota, rates of breakthrough cases for the Pfizer/BioNTech, Moderna, and Janssen/Johnson & Johnson vaccine were 0.13% (2,074 of 1,626,557 patients), 0.09% (976 of 1,125,919 patients), and 0.30% (813 of 266,975 patients), respectively. This report did not include variant-specific breakthrough rates; that is important to evaluate going forward.

A recent article in the Morbidity and Mortality Weekly Report described an outbreak of COVID-19 in a seaside Barnstable County, Massachusetts, town over a 2-week period that included “densely packed indoor and outdoor events at venues that included bars, restaurants, guest houses, and rental homes.” Of the 469 identified cases, 74% occurred in fully vaccinated individuals. Testing identified the delta variant in 90% of specimens from 133 residents or tourists who visited Provincetown, Massachusetts, during this time. These data show that vaccinated people have less protection against the delta strain than against previously identified strains, even though full vaccination still provides the best means for protection in general and against severe disease.

Question: How effective are current vaccines at preventing severe COVID-19 caused by the delta variant?

Answer: As illustrated by the Provincetown report, breakthrough infections with the delta variant occur in fully vaccinated people. It is important to note some vaccinated populations, such as most Olympic and other athletes, are tested early and often to decrease viral spread. This can lead to identification of SARS-CoV-2 infections even when there are no signs/symptoms of COVID-19.

The great news is that the currently authorized vaccines do an excellent job of preventing severe disease including hospitalization and death. For the previously discussed Israeli study, overall vaccine effectiveness was 39% for symptomatic disease, but prevention of severe disease, including hospitalizations and death, was much higher at 91% for BNT162b2. This has been demonstrated in several other studies, some published and some online but yet to be peer reviewed.

A noted researcher, Eric Topol of the Scripps Research Translational Institute, tweeted that the vaccine effectiveness of BNT162b2 was 96% for preventing hospital admissions among people in the United Kingdom infected by the delta variant. This is similar to the 95% figure reported for the alpha variant. Data for the Moderna vaccine are limited to 1-dose studies, Topol wrote, but they show a 96% vaccine effectiveness with respect to hospitalizations and deaths in Canada and the United Kingdom. Outside of limited laboratory data, Janssen/Johnson & Johnson have few outcome data regarding prevention of severe disease caused by the delta variant. A preprint article suggests that this vaccine‘s protection decreased significantly over time, possibly indicating that a booster shot may be needed, but more study is needed to evaluate these findings.

Question: What are risks of the delta variant to unvaccinated patients?

Answer: While overall COVID-19 vaccination rates in the United States are better than the majority of countries due to access, trends in vaccination have not been favorable in recent months. The peak day of vaccination recorded in the United States was April 8, 2021, with 4,433,136 doses administered. Since then, 7-day averages have consistently decreased to approximately 400,000–500,000 doses daily in early July. Spreading of the delta variant has leveled off this decline, and some locales are reporting renewed interest in vaccinations.

Fortunately, those most at risk from COVID-19 severe disease have been vaccinated, with nearly 90% of Americans aged 65 years or older receiving at least 1 dose of vaccine and about 80% fully vaccinated. However, a surge in severe disease, primarily in unvaccinated patients has occurred, demonstrating the transmissibility potential of this strain within the unvaccinated population. The “delta wave” has hit states such as Florida, Alabama, Mississippi, and Arkansas hardest, with hospitalization rates in late July 4–5 times those in early July; this has the potential to overwhelm health care systems in those states. Nationally, more than 95% of hospitalizations due to COVID-19 are occurring in unvaccinated individuals. Unfortunately, in conjunction with these increased hospitalization rates, increased mortality is also being documented due to severe COVID-19 illness.

Questions: Is the delta variant affecting the pediatric population differently that previous strains? How will this affect children as the school year begins soon?

Answer: This is a question on the minds of parents and guardians everywhere as the summer comes to a close. While data demonstrating increased or decreased severity of disease caused by the delta variant in children are lacking at this point, transmissibility is definitely increased compared with previous strains. The delta variant appears to be at least 50% more transmissible that the parent strain. This is an important risk factor for children in an indoor classroom setting with 20 or more of their peers, many if not most of whom lack immunity against SARS-CoV-2.

The Pfizer/BioNTech vaccine is indicated only for those 12 years of age and up, limiting the development of herd immunity in the classroom setting. Vaccine rates among adolescents have been limited because of parental concern about short- and long-term safety of the vaccine, particularly the increased risk of myocarditis in adolescents and young adults. Moderna has submitted data with the FDA for approval in those ages 12 or older, and trials are under way for younger children.

Children should pose minimal risk to parents or grandparents who are vaccinated. The small percentage of vaccinated parents who experience reinfection should have limited symptoms and little chance of severe disease, assuming they are not immunocompromised. Vaccinated parents and grandparents produce smaller numbers of SARS-CoV-2, limiting transmission to others. However, with the transmissibility of the delta variant greater than with other strains, these reinfections are a concern.

While overall pediatric risk appears to be minimal, rare cases of multisystem inflammatory syndrome in children (MIS-C) have been reported. Inflammation of the heart, lungs, kidneys, brain, eyes, skin, stomach, small bowel, or colon can occur, leading to serious manifestations such as hypotension and shock. If this is suspected, the parent or guardian should seek medical care for the child immediately. In addition, long-term COVID-19 symptoms have occurred in children following COVID-19 infection. Data specific to the delta strain and “long COVID” have not been published to date. Current data suggest that long COVID symptoms are more prevalent in adults compared to children, especially those with the most severe disease presentations.

Until vaccines are authorized for use in younger children (assuming that occurs), the CDC is recommending children 2 years and older wear a mask in public settings. The CDC also recognizes that students benefit significantly from in-person learning, and returning to this form of instruction this autumn is a major priority. A physical distance of 3 feet is recommended between students within the classroom setting to reduce transmission of SARS-CoV-2. Important measures to implement to decrease the overall risk of transmission and subsequent infection include appropriate screening and testing, ventilation, handwashing, contact tracing with quarantine and isolation when appropriate, and cleaning/disinfection. It is important to remember that while overall risk to children is minimal for severe COVID-19 illness, adults who interact with students at schools may be immunocompromised and even when fully vaccinated may not have the robust immune response compared with immunocompetent people overall. Immunocompromised people could include patients being actively treated for malignancy or receiving medications such as monoclonal antibodies for rheumatoid arthritis or immunosuppressive agents for prevention of transplant rejection, such as mycophenolate mofetil or tacrolimus.

Question: With the delta variant circulating, should I be vaccinated even if I had confirmed COVID-19 illness previously?

Answer:The current recommendation from the CDC is for people aged 12 years or older to receive COVID-19 vaccination, irrespective of whether they have had COVID-19 illness. It is currently unknown how long protection from natural immunity endures. Data are limited comparing natural and vaccine-induced immunity to overall long-term outcomes. Observational data cannot be used to inform recommendations for natural immunity due to differing populations, different variants circulating when studies were conducted, and various methods for case adjudication. Several studies have shown that risk of reinfection was similarly low in patients who had previous documented infection, but these were not head-to-head comparisons with vaccine-protected individuals. Emerging data have demonstrated that immune responses following mild natural infections may not generate as robust an immune response against variants such as the delta strain.

With regard to timing of vaccine administration, if someone had COVID-19 and received either a monoclonal antibody, such as casirivimab and imdevimab, or were treated for convalescent plasma, they should wait 90 days before receiving the first dose of COVID-19 vaccine.

Question: How are immunocompromised patients affected by the delta variant?

Answer: In addition to people who are unvaccinated, the largest population of patients at potential risk for the delta or other variants are people who are immunocompromised. Approximately 2.7% of the U.S. adult population is moderately to severely immunocompromised. This population comprises patients with solid tumors or hematologic cancers, persons living with human immunodeficiency syndrome, those with severe primary immunodeficiencies, and patients who have undergone stem cell or solid-organ transplants or are being treated with immunosuppressive medications.4 Other varying degrees of immunosuppression can occur with other comorbid conditions such as chronic kidney disease or asplenia.

A number of publications have examined outcomes with COVID-19 in immunocompromised patients, who are more likely to become severely ill. They also are higher risk for prolonged shedding and infection and to have low antibody titers to SARS-CoV-2 variants such as delta. They are more likely to transmit SARS-CoV-2 to household contacts and to have breakthrough infections.

Studies from the United States and Israel demonstrated that 44% and 40%, respectively, of hospitalized breakthrough cases occurred in immunocompromised patients.,6 The U.S. study is currently only available in preprint form and is awaiting peer review.5 In the Israeli study, BNT162b2 vaccine effectiveness (defined as preventing hospitalization) was 59% in immunocompromised patients compared with 91% in immunocompetent patients.6

A small study of 63 patients demonstrated that the 2 mRNA vaccinations produce an antibody response in most patients undergoing hemodialysis, about half of those being treated for cancer or receiving immunosuppressive therapies, and fewer than half of those who have received organ transplants.

Emerging data suggest an improved antibody response upon receipt of a third mRNA COVID-19 dose with tolerability similar to the first 2 doses. France announced in April 2021 that a third dose 4 weeks after the second dose would be an option for “severely immunocompromised” patients. Israel announced in early July 2021 that patients with organ/stem cell transplants, blood cancers, or autoimmune diseases, and those receiving specific immunosuppressive medications would be eligible for a third dose. Nevertheless, at the time this program was prepared, FDA had not approved third doses of either of the mRNA vaccines available in the United States or booster doses for the Janssen/Johnson & Johnson vaccine.

Question: Beyond issues related to the delta variant, is their a need for booster shots of currently available vaccines?

Answer: There are 2 major reasons for potentially needing “booster” doses of any vaccine: to extend the duration of an immune response (as with pertussis) and to overcome microbial immune evasion secondary to mutations or other adaptive changes (as with influenza).

Human immune response occurs in a highly variable fashion depending on the host and the pathogen targeted by the vaccine. Viruses and other pathogens mutate often. The more rapid the mutation, the quicker they may be able to evade the immune system. The mutations currently present in the delta variant spike protein can lead to some immune evasion, but no variant fully evades the immune system because of production of neutralizing antibody, vaccine-induced changes in T-cells, and priming of memory B-cells. T-cells respond to vaccination and while not routinely measured, they are active against all variants and are likely the component of the immune system preventing severe COVID-19 illness. In addition, while levels of neutralizing antibody concentrations decrease or “wane” over time, memory B-cells can ramp up production through somatic hypermutation. if they are later re-exposed to pathogens such as SARS-CoV-2.

Pfizer has released data demonstrating that getting a third dose of its COVID-19 vaccine at least 6 months after the second dose produced neutralizing antibodies 5-fold and 11-fold higher against both the beta and delta variants compared with a second dose in participants aged 18–55 years of age and 65–85 years of age, respectively. Trials with this schedule were scheduled to begin in August 2021. While further study is warranted to help determine indication and ultimate role for booster shots, especially in the immunocompromised patient population, current focus should be on unvaccinated patients who are eligible to receive a COVID-19 vaccine.

Treatment of COVID-19 Illness

When prevention of SARS-CoV-2 infections fails, attention turns to treatment of the viral disease. Therapies of current interest include remdesivir, monoclonal antibodies, ivermectin, azithromycin, tofacitinib, and canakinumab.


Two studies of remdesivir in hospitalized patients with COVID-19 add to the evidence that initial perceived benefits of this agent are not holding up.

Ohl et al. conducted a retrospective cohort study evaluating 2,344 U.S. veterans hospitalized for treatment of COVID-19. Mortality at 30 days was statistically similar with and without remdesivir treatment (12.2% vs. 10.6%, respectively; P = 0.26). Median length of stay was significantly longer in the remdesivir patient population compared to those receiving standard care (6 days vs. 3 days; P <0.001), likely because they had to finish the 5-day course of infusions indicated for treatment.8

A smaller study at 23 Norwegian hospitals demonstrated no significant differences in viral load or mortality among patients receiving remdesivir, hydroxychloroquine, or standard of care.9

Monoclonal Antibodies

The National Institutes of Health (NIH) COVID-19 guidelines recommend combination therapy with casirivimab plus imdevimab (marketed as REGEN-COV, Regeneron) or monotherapy with sotrovimab (GlaxoSmithKline) for treatment of patients with mild-to-moderate COVID-19 not requiring hospitalization or supplemental oxygen who are at high risk of clinical progression.

Sotrovimab is an anti-SARS-CoV-2 monoclonal antibody that targets a highly conserved isotope that does not overlap with mutation sites identified among SARS-CoV-2 variants of concern, including B.1.1.7 (alpha), B.1.351 (beta), and the delta variant.10

Conditions found in high-risk patients that were well represented in clinical trials are listed in Table 1 along with conditions occurring in limited numbers of participants. The NIH guidelines make no delineation on which antibody product to use as these products have not been compared in head-to-head trials. The Infectious Diseases Society of America (IDSA) guidelines state that local variant susceptibility should be considered in choice of most appropriate agent. Treatment with either agent should occur within 10 days of symptom onset or upon positive SARS-CoV-2 antigen test or nucleic acid amplification test.

Of note, the NIH panel recommends against the use of bamlanivimab plus etesevimab due to increases in the proportion of variants (specifically noting the beta and gamma variants) that have reduced susceptibility to these monoclonal antibodies. The IDSA guidelines recommend against bamlanivimab for patients hospitalized for COVID-19.

Table 1. CDC Recommendations for Treatment With SARS-CoV-2 Monoclonal Antibodies Based on Criteria From FDA Emergency Use Authorizations

Medical Conditions Well Represented In Clinical Trials

Conditions With Limited Trial Representation But Considered Risk Factors for Progression by CDC

Older age (≥65 years)

Immunocompromising condition or immunosuppressive treatment

Obesity (body mass index >30 kg/m2)

Overweight (body mass index, 25–30 kg/m2) as sole risk factor


Chronic kidney disease

Cardiovascular disease (including congenital heart disease) or hypertension


Chronic lung diseases (e.g., chronic obstructive pulmonary disease, moderate-to-severe asthma, interstitial lung disease, cystic fibrosis, pulmonary hypertension)

Sickle cell disease

Neurodevelopmental disorder (e.g., cerebral palsy) or other conditions that confer medical complexity (e.g., genetic or metabolic syndromes and severe congenital abnormalities)


Medical-related technological dependence (e.g., tracheotomy, gastrostomy, positive pressure ventilation not related to COVID-19)


Source: NIH Treatment Guidelines.
Abbreviations: CDC, Centers for Disease Control and Prevention; COVID-19, coronavirus disease 2019; FDA, U.S. Food and Drug Administration; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.


Ivermectin’s role in treating COVID-19 has been the subject of discussion. While approved by FDA for treatment of intestinal strongyloidiasis and onchocerciasis, ivermectin inhibits SARS-CoV-2 in vitro, possibly through inhibition of host nuclear transport proteins. While some clinical data have been published, most studies are of poor quality. Two recent reports are worth noting.

A study by Elgazzar et al. generated much discussion but was later withdrawn, reportedly because of plagiarism and concerns about the raw data. In the trial, researchers investigated ivermectin treatment of 400 symptomatic patients with mild-to-moderate and severe COVID-19 as well as prophylaxis of 200 health care workers or household contacts of patients with COVID-19 in Egypt. Compared with hydroxychloroquine plus standard of care, ivermectin plus standard of care reduced mortality in those with active disease and decreased infections in close contacts.

A second study was of higher quality — a randomized, double-blind, placebo-controlled trial evaluating ivermectin for preventing hospitalizations in patients with early COVID-19 in Argentina. Patients were invited within 48 hours by phone after a positive SARS-CoV-2 nasal swab. The treatment group received weight-based ivermectin doses: up to 80 kg (12 mg at inclusion followed by 12 mg 24 hours after initial dose), 80–110 kg (18 mg at inclusion followed by 18 mg 24 hours after initial dose), and >110 kg (24 mg at inclusion followed by 24 mg 24 hours after initial dose). Hospitalization rates were lower but not statistically significant in the ivermectin group (5.6% vs. 8.4%; odds ratio 0.65; 95% confidence interval [CI] 0.32–1.31; P = 0.227). Patients who received ivermectin were also intubated sooner than those in the standard-of-care arm (5.25 days vs. 10 days; P = 0.019).11

Data from ongoing or future randomized trials, such as the PRINCIPLE trial out of the University of Oxford in United Kingdom, will help ultimately delineate role of ivermectin for COVID-19.


Azithromycin was used extensively in the initial phases of the pandemic to help counter the effects of any bacterial coinfections that might be present in patients with COVID-19 and for its anti-inflammatory and antiviral effects. While data did not support the need for bacterial coverage, azithromycin was thought to reduce cytokines and thereby prevent transition to tissue damage and severe manifestations of COVID-19, especially if given early in the course of the infection.

A randomized trial recently published in JAMA evaluated azithromycin in remotely recruited adult outpatients with confirmed SARS-CoV-2 infection. The primary outcome was absence of COVID-19 self-reported symptoms (e.g., fever, cough, diarrhea, and an open-ended “other” category) at day 14 after treatment with a single dose of azithromycin 1200 mg. Myriad secondary clinical endpoints were included, 23 in all, including all-cause hospitalization at day 21. The trial was terminated early by the data and safety monitoring committee for futility after the interim analysis showed no significant difference between groups.12


Tofacitinib, a Janus kinase inhibitor, was recently evaluated in patients hospitalized with COVID-19 pneumonia for less than 72 hours. Exclusion criteria included use of noninvasive or invasive ventilation or extracorporeal membrane oxygenation (ECMO). Participants were randomized to either oral tofacitinib 10 mg or placebo twice daily for up to 14 days or until hospital discharge, whichever occurred earliest among 15 sites in Brazil. A lower tofacitinib dose (5 mg twice daily) was used in patients with an estimated glomerular filtration rate of 50 mL/minute or moderate hepatic impairment or in those using strong CYP3A4 inhibitors or moderate CYP3A4 inhibitors plus strong CYP2C19 inhibitors. All patients received other local standard of care treatments, such as glucocorticoids (~80% in both groups). The primary outcome was death or respiratory failure at day 28 of follow-up.13

Published in the New England Journal of Medicine, a study showed that tofacitinib significantly reduced mortality compared with placebo (18.1% vs. 29%; risk ratio 0.63; 95% CI 0.41–0.97; P = 0.04). This outcome was primarily driven by respiratory failure events, as death occurred in only 12 of 289 patients evaluated.13

It remains to be seen how the IDSA guidelines will incorporate tofacitinib, as baricitinib is currently recommended for patients with severe COVID-19 with elevated inflammatory markers who are not on invasive mechanical ventilation. Patients hospitalized with severe COVID-19 who cannot receive standard-of-care corticosteroids should receive baricitinib plus remdesivir instead of remdesivir monotherapy, IDSA recommends.

Canakinumab and Tocilizumab

Canakinumab, a human anti-human-IL-1β monoclonal antibody, is approved by FDA for a number of indications, including adult-onset Still’s disease and systemic juvenile idiopathic arthritis in patients aged 2 years and older. In vitro data demonstrate SARS-CoV-2 triggers activation of the inflammasome as well as anti-human-IL-1β monoclonal antibody growth and release.

A phase 3, randomized, double-blind, placebo-controlled trial conducted in 454 patients with severe COVID-19 at 39 hospitals in Europe and the United States was recently published in JAMA. Patients were included if they had elevated C-reactive protein (20 mg/L or greater) or ferritin concentrations (600 mcg/L or greater) and were not receiving invasive mechanical ventilation. Patients were randomly assigned to receive a single dose infusion of canakinumab (weight-based) or placebo along with other standard-of-care therapies. The primary outcome of survival without invasive mechanical ventilation was not significantly different between those receiving canakinumab or placebo (88.8% vs. 85.7%; odds ratio 1.39; 95% CI 0.76–2.54; P = 0.29).13

Tocilizumab, an IL-6 monoclonal antibody, is currently recommended in the IDSA guidelines for use in hospitalized patients with progressive severe or critical COVID-19 who have elevated markers of systemic inflammation in addition to standard of care including corticosteroids. Critical COVID-19 includes those patients who are receiving invasive mechanical ventilation and ECMO.


Patients are already asking lots of questions of pharmacy staff about the delta-variant resurgence in SARS-CoV-2 infections, and those can only increase as the influenza vaccination season gets under way this fall. In the next COVID-19 update, other topics of current interest will be covered, including the risks of myocarditis with the mRNA vaccines and current thinking on mixing and matching COVID-19 vaccines.


  1. Planas D, Veyer D, Baidaliuk A, et al. Reduced sensitivity of SARS-CoV-2 variant delta to antibody neutralization. Nature. 2021 Jul 7. doi: 10.1038/s41586-021-03777-9
  2. Barouch DH, Stephenson KE, Sadoff J, et al. Durable humoral and cellular immune responses 8 months after Ad26.COV2.S vaccination. N Engl J Med. 2021 Jul 14. doi: 10.1056/NEJMc2108829
  3. Bernal JL, Andrews N, Gower C, et al. Effectiveness of covid-19 vaccines against the B.1.617.2 (delta) variant. N Engl J Med. Published 2021 Jul 21. doi: 10.1056/NEJMoa2108891
  4. Harpaz R, Dahl RM, Dooling KL. Prevalence of immunosuppression among US adults, 2013. JAMA. 2016;316:2547–2548.
  5. Tenforde MW, Patel MM, Ginde AA, et al. Effectiveness of SARS-CoV-2 mRNA vaccines for preventing COVID-19 hospitalizations in the United States. 2021: 10.1101/2021.07.08.21259776.
  6. Brosh-Nissimov T, Orenbuch-Harroch E, Chowers M, et al. BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully vaccinated hospitalized COVID-19 patients in Israel. Clin Micro Infect. 2021 Jul 7; S1198-743X(21)00367-0. doi: 10.1016/j.cmi.2021.06.036
  7. Khan N, Mahmud N. Effectiveness of SARS-CoV-2 vaccination in a Veterans Affairs cohort of patients with inflammatory bowel disease with diverse exposure to immunosuppressive medications. Gastroenterology. 2021 May 25. Online ahead of print. doi: 10.1053/j.gastro.2021.05.044.
  8. Ohl ME, Miller DR, Lund BC, et al. Association of remdesivir treatment with survival and length of hospital stay among US veterans hospitalized with COVID-19. JAMA Netw Open. 2021;4:e2114741.
  9. Barratt-Due A, Olsen IC, Nezvalova-Henriksen K, et al. Evaluation of the effects of remdesivir and hydroxychloroquine on viral clearance in COVID-19. Ann Intern Med. 2021 Jul 13: M21:0653.
  10. Cathcart AL, Havenar-Daughton C, Lempp FA, et al. The dual function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2. 2021 Jul 26. doi: 10.1101/2021.03.09.434607.
  11. Vallejos J, Zoni R, Bangher M, et al. Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial. BMC Infect Dis. 2021;21:635. doi: 10.1186/s12879-021-06348-5
  12. Oldenburg CE, Pinsky BA, Brogdon J, et al. Effect of oral azithromycin vs placebo on COVID-19 symptoms in outpatients with SARS-CoV-2 infection: a randomized clinical trial. JAMA. 2021 July 16. Published online ahead of print. Doi: 10.1001/jama.2021.11517
  13. Guimaraes PO, Quirk D, Furtado RH, et al. Tofacitinib in patients hospitalized with covid-19 pneumonia. N Engl J Med. 2021;385:406–415. doi: 10.1056/NEJMoa2101643
  14. Caricchio R, Abbate A, Gordeev I, et al. Effect of canakinumab vs placebo on survival without invasive mechanical ventilation in patients hospitalized with severe COVID-19: a randomized clinical trial. JAMA. 2021;326:230–239.

Back to Top