Shopping Cart

INTRODUCTION

In the middle of May 2020, the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues across the United States. Within the next week, the number of American deaths from coronavirus disease 2019 (COVID-19) could reach 100,000, according to updated projections from the Institute for Health Metrics and Evaluation (IHME) at the University of Washington. The case count is increasing by more than 25,000 per day and is approaching 1.5 million since the pandemic began in the United States. Worldwide, cases will soon number 5 million and deaths have exceeded 300,000.

The IHME model, revised on May 12, projects 147,040 U.S. deaths by August 4, and even that number assumes a decline in cases and deaths that is not certain, given the reopening of businesses and recreation areas and warmer weather calls people outside. All of which goes to say that a better understanding of this virus is needed, and better pharmacologic treatments are needed as vaccine development continues.

PATHOPHYSIOLOGY AND TRANSMISSION OF SARS-COV-2

Autopsy samples of respiratory tissue from 22 patients who died of COVID-19 had high numbers of viral copies per cell, but other tissues also had relatively high numbers, including the kidneys, liver, heart, and brain. This could account for some of the multiorgan effects seen in latter stages of severe cases. About three-fourths of the deceased patients had at least one coexisting condition, and these could have affected the virus’s affinity for these organ systems. Still, this broad “organotropism” resulted in viral levels in distal organs about the same as those in the pharynx and only a couple of logs lower than in lung tissue. [Puelles et al., 2020]

“Renal tropism is a potential explanation of commonly reported new clinical signs of kidney injury in patients with Covid-19, even in patients with SARS-CoV-2 infection who are not critically ill,” the authors concluded. “Our results indicate that SARS-CoV-2 has an organotropism beyond the respiratory tract, including the kidneys, liver, heart, and brain, and we speculate that organotropism influences the course of Covid-19 disease and, possibly, aggravates preexisting conditions.” [Puelles et al., 2020]

Assessing the case of a man with COVID-19 who developed acute kidney injury, authors examined overall management of this disease and reported clotting within the filter during continuous renal replacement therapy (CRRT) with continuous venovenous hemofiltration. “In observing patients with Covid-19 and severe acute kidney injury leading to renal replacement therapy, I am struck by the cohesion with old themes dating back to the inception of dialysis, including the specific challenges of maintaining patent circulatory access and anticoagulation, as well as the question of how to allocate care if there are limited resources,” one physician commented in discussing the case. [Sise et al., 2020]

Based on previous reports that SARS-CoV-2 could be transmitted from people to domestic cats and to lions and tigers in a zoo setting, researchers investigated transmission among cats in a controlled study. On day 0 of the study, 3 domestic cats were inoculated with SARS-CoV-2. The following day, an uninoculated cat was cohoused with each of the inoculated cats. Virus was detected in 2 of the inoculated cats on day 1 and in the third inoculated cat on day 3; they remained positive for the virus until days 5 (all cats) and 6 (2 of the 3 cats). The uninoculated cats became positive for the virus on days 3, 5, and 6 of the study. “Cats may be a silent intermediate host of SARS-CoV-2, because infected cats may not show any appreciable symptoms that might be recognized by their owners,” the researchers concluded.

PHARMACOTHERAPY OF COVID-19

If rapid shifts in stock prices of vaccine developers are any indication, progress is quite swift in finding a product to protect the world against SARS-CoV-2. Unfortunately, though, solid research results will be needed before people are confident that the virus has been controlled and disease eliminated. While we wait for one or more safe and effective vaccines, better medications and biologic agents are needed. As discussed previously with respect to remdesivir, hopeful signs are beginning to emerge.

Triple Combination Therapy for COVID-19: Three antiviral agents used together were safe and more effective than lopinavir–ritonavir alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in an open-label, randomized, phase 2 trial of 127 adult patients with mild-to-moderate COVID-19. [Hung et al., 2020]

At 6 Hong Kong hospitals, participants were randomized to combination therapy with interferon beta-1b, lopinavir–ritonavir, and ribavirin or to lopinavir–ritonavir alone for 14 days. The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal SARS-CoV-2 test (7 days [interquartile range, 5–11]) than the control group (12 days [8–15]; hazard ratio 4.37 [95% confidence interval, 1.86–10.24], P = .0010). Both groups had self-limited nausea and diarrhea with no differences in numbers of adverse events; 1 patient in the control group had biochemical hepatitis and discontinued lopinavir–ritonavir. [Hung et al., 2020]

Reacting to these results, an editorialist writes: “This study presents a step towards finding a much-needed therapy for SARS-CoV-2. However, as the authors acknowledge, future studies to examine the efficacy of interferon beta-1b alone or in combination with other drugs to treat severe or critically ill patients with confirmed COVID-19 compared with placebo are warranted.” [Shalhoub, 2020]

Hydroxychloroquine in Patients Hospitalized for COVID-19: Two observational studies failed to identify benefits from hydroxychloroquine use in patients hospitalized for COVID-19.

The first study was a retrospective, multicenter, cohort study of a random sample of all admitted patients with laboratory-confirmed COVID-19 in 25 New York City hospitals. In-hospital mortality rates were statistically similar regardless of the drug therapy received by 1,438 patients: 25.7% with both hydroxychloroquine and azithromycin, 19.9% with hydroxychloroquine alone, 10.0% with azithromycin alone, and 12.7% among those receiving neither drug. Compared with patients on neither drug, those receiving hydroxychloroquine plus azithromycin had more than twice the risk of cardiac arrest (hazard ratio, 2.13 [95% confidence interval, 1.12–4.05]; those in other treatment groups had statistically similar risks of cardiac arrest as those on neither drug. [Rosenberg et al., 2020]

Conducted at a large New York City medical center, the second study found no significant changes in a composite endpoint of intubation and death among 1,446 consecutively admitted patients with COVID-19 based on hydroxychloroquine use (hazard ratio, 1.04, 95% confidence interval, 0.82–1.32). Interpretation of results was compromised since patients placed on the drug were more severely ill at baseline than other patients.  [Geleris et al., 2020]

“This observational study is in no way a substitute for randomized, placebo-controlled trials,” editorialists wrote in response to the second trial. “The findings of this study set broad parameters around the potential good (or harm) that these drugs could do. The results leave open the possibility that these agents could have a modest benefit but do not rule out a detrimental effect, something that will probably be learned only through well-designed and well-conducted randomized, controlled trials. The value of such trials has been known for a century. It is disappointing that several months into the pandemic, we do not yet have results from controlled trials of a therapy that is being widely used. When we have little idea about appropriate therapy, we have an obligation to help by performing studies that will help us to learn together with our patients.” [Rubin et al., 2020]

In a special article, the American College of Physicians (ACP) says that evidence does not support the use of chloroquine or hydroxychloroquine alone or in combination with azithromycin to prevent COVID-19 after infection with SARS-CoV-2 or for treatment of patients with COVID-19. The ACP Practice Points also state that physicians, in light of known harms and very uncertain evidence of benefit, may choose to treat hospitalized COVID-19–positive patients with chloroquine or hydroxychloroquine alone or in combination with azithromycin in the context of a clinical trial using shared and informed decision-making with patients and their families. [Qaseem et al., 2020]

CAP Treatment During COVID-19 Pandemic: The cochairs of the recently released American Thoracic Society and Infectious Diseases Society of America Guideline for Treatment of Adults with Community-Acquired Pneumonia (CAP) offer their interpretation of the guideline as it applies to the management of patients with COVID-19. “Although most of the lung injury patients have is believed to be caused by the virus, concern over bacterial co-infection also informs current treatment approaches for patients with COVID-19–related pneumonia,” the authors write. Five principles are emphasized [Metlay & Waterer, 2020]:

• “Empirical coverage for bacterial pathogens is recommended in patients with CAP without confirmed COVID-19 but is not required in all patients with confirmed COVID-19–related pneumonia.
• “Although data are limited, it is likely that the relevant bacterial pathogens in patients with COVID-19 and pneumonia are the same as in previous patients with CAP and therefore empirical antibiotic recommendations should be the same.
• “Testing for bacterial pathogens with sputum and blood cultures is most useful when there is concern for multidrug-resistant pathogens.
• “Procalcitonin could be helpful in limiting overuse of antibiotics in patients with COVID-19–related pneumonia.
• “Although it is likely that host immunologic processes play a key role in the lung damage that leads to respiratory failure and adverse outcomes in patients with COVID-19, immunomodulating therapy is not currently recommended in patients with pneumonia.”

PEDIATRIC DISEASE ASSOCIATED WITH COVID-19

Clinicians are awaiting guidance from the Centers for Disease Control and Prevention (CDC) on how to recognize and manage a pediatric multisystem inflammatory syndrome (PIMS) in infants and children who are COVID-19–positive. With symptoms similar to Kawasaki disease and toxic shock syndrome, PIMS appears to be an overreaction of the body’s immune system to an otherwise mild or asymptomatic SARS-CoV-2 infection, according to experts interviewed by CNN and other mass media outlets.

As noted in the April 24^th “This Week in COVID-19,” pediatric cases of symptomatic SARS-CoV-19 infections have been surprisingly rare during the pandemic. It’s important to remember, though, that children and infants could be important in community-based transmission of the virus and that while the case counts are low, pediatric patients have had COVID-19 and occasionally died from the disease. In Pediatrics, authors wrote, “Many infectious diseases affect children differently than adults and understanding those differences can yield important insights into disease pathogenesis, informing management, and the development of therapeutics. This will likely be true for COVID-19, just as it was for older infectious diseases.” The authors also noted that “while children are less likely to become severely ill than older adults, there are subpopulations of children with an increased risk for more significant illness” and “the attributable risk for severe disease from COVID-19 in children is challenging to discern.” [Cruz & Zeichner, 2020]

A subsequently published analysis of 40 critically ill children with COVID-10 in the United States and Canada provides information on their clinical characteristics and outcomes. At 14 pediatric intensive-care units, 48 children were admitted between March 14 and April 3, 2020. Pre-existing medical conditions were common (83% of patients), 73% had respiratory symptoms, and 38% needed invasive ventilation. The mortality rate was 4.2%. [Shekerdemian et al., 2020]

Key questions that can inform prevention and treatment of COVID-19 across all age groups are proposed in a review article that has been accepted for publication. Sample questions include the following [Singh et al., 2020]:

• What immunological or host factors predispose children to a milder illness compared to adults? (clinical presentation)
• Does viral shedding in stool indicate potential fecal-oral route of transmission? (transmission)
• What is the risk of severe disease in immunocompromised children? (risk factors for severe disease)
• How do infant respiratory tract cells respond differently to SARS-Cov2 infection as compared to adult cells? (protective immunity)
• How soon can we include vulnerable populations including pregnant women, neonates, and children in the vaccine development process to optimally tailor vaccine design to these populations? (therapies and vaccines)

IN THE PHARMACY

On the frontlines of practice, pharmacists are dealing with everything from shortages to nasopharyngeal swabs. But that’s if you’re still working.

The irony of the pressure to care for patients hospitalized with COVID-19 is that many units within health systems have been sitting idle. That reality is hitting the pharmacy with budget cuts and reduced staffing. According to a biweekly survey of U.S. hospitals and health systems conducted on April 21–24 by the American Society of Health-System Pharmacists (ASHP), two-thirds of 260 responding pharmacies have reduced staffing in response to the pandemic, one-fifth have been unaffected, and the other 14% have increased staffing. The impact is even greater in hospitals where patients with COVID-19 occupy fewer than 50% of intensive-care beds; 77% of those facilities have reduced pharmacy staffing.

When staffing is reduced, it’s most often by reductions in hours worked (79% of respondents); temporary staff furloughs have occurred in 31% of hospitals and health systems. Remote staffing and use of telehealth technologies were reported by 205 of the responding pharmacies, most often for non-patient-care functions such as administrative work or purchasing (62%). Order verification, medication-assistance programs, and other patient-care activities have been completed remotely in 60% of responding institutions.

Shortages can be tracked at the drug class and individual agent level on the ASHP website. Supplies are low for paralytics such as atracurium and cisatracurium; inventory of propofol has improved since the previous ASHP biweekly survey when nearly half of institutions reported low (43%) or no (3%) supply of the sedative.

With California this week allowing pharmacies to begin collecting swabs and ordering COVID-19 tests, most U.S. pharmacies can now be involved in some part of the badly needed increase in assessment of how many Americans have the virus and/or have developed antibodies to it. On the National Community Pharmacists Association website, regulatory and statutory limits are summarized relative to providing COVID-19 testing services and getting paid for doing so. 

Recent actions relevant to pharmacy include the following:

• Legislation under consideration in the United Kingdom would empower pharmacists to supply some controlled drugs without prescription during the COVID-19 pandemic, according to a BMJ news report.
• FDA issued an emergency use authorization for Fresenius Propoven 2% Emulsion (propofol, Fresenius Kabi AG) use in maintaining sedation via continuous infusion in critically ill patients older than 16 who require mechanical ventilation during the COVID-19 public health emergency. This product differs from FDA-approved propofol drugs, according to FDA’s Health Care Provider Fact Sheet.
• FDA’s Coronavirus Treatment Acceleration Program has a goal of accelerating the development of prevention and treatment options for COVID-19 by providing new guidance with recommendations for innovators and researchers.

CONCLUSION

The COVID-19 pandemic has brought to the fore certain inequities of American society and increased the discussion on how to address them. One factor concerns “the striking racial/ethnic disparities reported for COVID-19 infection, testing, and disease burden, editorialists wrote recently. “[These] are a clear reminder that failure to protect the most vulnerable members of society not only harms them but also increases the risk of spread of the virus, with devastating health and economic consequences for all,” the authors noted. “COVID-19 disparities are not the fault of those who are experiencing them, but rather reflect social policies and systems that create health disparities in good times and inflate them in a crisis. The US must develop a new kind of ‘herd immunity,’ whereby resistance to the spread of poor health in the population occurs when a sufficiently high proportion of individuals, across all racial, ethnic, and social class groups, are protected from and thus ‘immune’ to negative social determinants.” [Williams & Cooper, 2020]

REFERENCES

Cruz AT, Zeichner SL. COVID-19 in children: initial characterization of the pediatric disease. Pediatrics. 2020 Apr 8: e20200834. [Epub ahead of print]

Geleris J, Sun Y, Platt J, et al. Observational study of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med. 2020 May 7. doi: 10.1056/NEJMoa2012410. [Epub ahead of print]

Hung, I F-N, Lung K-C, Tso E Y-K, et al. Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020 May 8. doi: 10.1016/S0140-6736(20)31042-4. [Epub ahead of print]

Metley JP, Waterer GW. Treatment of community-acquired pneumonia during the coronavirus disease 2019 (COVID-19) pandemic. Ann Intern Med. 2020 May 7. doi: 0.7326/M20-2189. [Epub ahead of print]

Puelles VG, Lütgehetmann M, Lindenmeyer MT, et al. Multiorgan and renal tropism of SARS-CoV-2 [letter]. N Engl J Med. 2020 May 13: doi: 10.1056/NEJMc2011400. [Epub ahead of print]

Qaseem A, Yost J, Etxeandia-Ikobaltzeta I, et al. Should clinicians use chloroquine or hydroxychloroquine alone or in combination with azithromycin for the prophylaxis or treatment of COVID-19? Living practice points from the american college of physicians (version 1). Ann Intern Med. 2020 May 13.doi: 10.7326/M20-1998. [Epub ahead of print]

Rosenberg ES, Dufort EM, Udo T, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State. JAMA. 2020 May 11. doi: 10.1001/jama.2020.8630. [Epub ahead of print]

Rubin EJ, Harrington DP, Hogan JW, et al. The urgency of care during the COVID-19 pandemic — learning as we go [editorial]. N Engl J Med. 2020 May 7. doi: 10.1056/NEJMe2015903. [Epub ahead of print]

Shalhoub S. Interferon beta-1b for COVID-19 [editorial]. Lancet. 2020 May 8. doi: 10.1016/S0140-6736(20)31101-6. [Epub ahead of print]

Shekerdemian LS, Mahmood NR, Wolfe KK, et al.  Characteristics and outcomes of children with coronavirus disease 2019 (COVID-19) infection admitted to US and Canadian pediatric intensive care units. JAMA Pediatr. 2020 May 11. doi: 10.1001/jamapediatrics.2020.1948. [Epub ahead of print]

Singh T, Heston SM, Langel SN, et al. Lessons from COVID-19 in children: key hypotheses to guide preventative and therapeutic strategies. Clin Infect Dis. 2020 May 8. doi: 10.1093/cid/ciaa547. [Accepted manuscript]

Sise ME, Baggett MV, Shepard J-A O, Stevens JS, Rhee EP. Case 17-2020: a 68-year-old man with COVID-19 and acute kidney injury. N Engl J Med. 2020 May 13: doi: 10.1056/NEJMcpc2002418. [Epub ahead of print]

Williams DR, Cooper LA. COVID-19 and health equity—a new kind of “herd immunity.” JAMA. 2020 May 11. doi: 10.1001/jama.2020.8051. [Epub ahead of print]

Back to Top