This Week in COVID-19: April 24, 2020
Only 4 months after the world learned of a novel coronavirus spreading in Wuhan, China, the worldwide case count for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is approaching 3 million. In the United States on April 24, 2020, confirmed cases are poised to reach 1 million any day, and the number of deaths from coronavirus disease 2019 (COVID-19) will exceed 50,000. Americans have been dying of this disease this week at the rate of about 2 each minute.
Several guidelines are now out with the latest best thinking on clinical management of COVID-19. As these are combined with knowledge of COVID-19 coming from clinical experience, population testing and research are showing that many presumptions about this virus have been incorrect. Clinically, it is not just another pulmonary pathogen. COVID-19 can have an insidious onset, one sometimes not recognized until it is too late. It affects the heart, coagulation system, kidneys, and gastrointestinal tract.
On the epidemiological front, first cases, first deaths, and beginning of community spread occurred much earlier than was assumed before this week. It has been around much longer than suspected. A presumed difficult influenza season may have been the beginning of the COVID-19 pandemic. If testing confirms that large swaths of the population have acquired immunity while asymptomatic or during mild disease, everything changes — the public health response, the need to shelter in place, and the drastic limits on economic activity.
With those thoughts in mind, let’s look at the specifics of what is happening with COVID-19 as we approach the end of April 2020.
New Guidelines Available
The good news is that two major guidelines have been published for treatment of COVID-19. The bad news is they recommend no specific therapies for routine use at this point. Some agents are promising, while others are not performing well clinically. Care remains primarily supportive.
COVID-19 Guidelines: On April 21, the National Institutes of Health released COVID-19 treatment guidelines covering critical care, therapeutic options under investigation, and concomitant medications. Their primary definitive conclusion was to put to rest the idea that combining two agents known to prolong the QT interval — hydroxychloroquine and azithromycin — is safe and useful in patients with COVID-19. [COVID-19 Treatment Guidelines Panel, 2020]
The treatment guidelines panel concluded that insufficient data are available to make a recommendation regarding use of chloroquine or hydroxychloroquine as single agents outside clinical trials. Lopinavir/rotinavir should not be used outside clinical trials, the group recommended, and data are insufficient to recommend for or against use of the investigational nucleotide analogue remdesivir. No difference was identified between use of NSAIDs or acetaminophen for fever reduction. Statins or ACE inhibitors/ARBs should not be started as treatment for COVID-19; those on the drugs for other reasons should continue therapy. Advice about systemic corticosteroids is similar to other guidelines — no routine use other than in the acute respiratory distress syndrome (ARDS) setting.
The other major guideline comes from the Infectious Diseases Society of America. “Guidelines on the Treatment and Management of Patients with COVID-19 Infection” is published online in Clinical Infectious Diseases. Its recommendations largely agree with those that came later from NIH. [Bhimraj et al., 2020]
Chloroquine/Hydroxychloroquine: Reports of results of clinical trials of these closely associated antimalarial agents in patients with COVID-19 are beginning to appear in the mass media and on websites that post preprints (unreviewed, unpublished drafts of potential journal articles). The one getting the most attention is a Veterans Health Administration retrospective analysis of patients with confirmed SARS-CoV-2 treated in VHA facilities through April 11, 2020. Among 368 patients whose records were reviewed, mortality rates were 27.8% of 97 patients on hydroxychloroquine only, 22.1% of 113 patients treated with hydroxychloroquine + azithromycin, 11.4% of 158 patients who received neither drug. “These findings highlight the importance of awaiting the results of ongoing prospective, randomized, controlled studies before widespread adoption of these drugs,” the authors concluded. [Magagnoli et al., 2020]
In a randomized phase 2b trial, 81 critically ill patients with COVID-19 in a Brazilian tertiary care facility had worse outcomes when treated with chloroquine 600 mg twice daily for 10 days than with a lower 450 mg twice daily on day 1 and once daily for 4 days. All patients also received azithromycin, and most were on oseltamivir. Mortality was 27.2% in the high-dose group and 15.0% in the low-dose group. Age was an important confounder that compromises data interpretation. Viral RNA was present in most decedents — 14 of 16 people in the high-dose group and 5 of 6 in the low-dose group. The investigators recommend that higher doses of chloroquine not be used for treatment of severe COVID-19 because of safety concerns, and they note “no apparent benefit” of the drug on mortality thus far (the study is continuing with the lower dose). [Borba et al., 2020]
FDA, after issuing an emergency use authorization allowing distribution and use of hydroxychloroquine/chloroquine in hospitals and clinical trials, warned health professionals of these drugs’ serious effects on heart rhythms in an April 24 drug safety communication. “These risks, which are in the drug labels for their approved uses, may be mitigated when health care professionals closely screen and supervise these patients such as in a hospital setting or a clinical trial,” the agency said.
Consumers anxious to protect themselves against SARS-CoV-2 have ingested veterinary products containing chloroquine with adverse results, including death in 1 case. Federal agencies have issued an alert cautioning consumers that the products should not be taken by people or used to prevent SARS-CoV-2 infections in their animals.
Remdesivir: Remdesivir, an agent known to inhibit coronaviruses in vitro, continues to be promising in clinical trials. A STAT news article reports “rapid recoveries” among patients with COVID-19 who received remdesivir at a Chicago hospital. Previously, uncontrolled data from 53 patients hospitalized for severe COVID-19 who were treated on a compassionate-use basis showed clinical improvement in two-thirds of the group. [Grein et al., 2020]
A COVID-19 drug therapy review from JAMA reinforces the point: “No proven effective therapies for this virus currently exist. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a significant number of potential drug targets. The most promising therapy is remdesivir. Remdesivir has potent in vitro activity against SARS-CoV-2, but it is not US Food and Drug Administration approved and currently is being tested in ongoing randomized trials.…” Those authors go on to note that oseltamivir has not been shown to have efficacy and that corticosteroids are currently not recommended. [Sanders et al., 2020]
Angiotensin Receptor Modulators: Since the SARS-CoV-2 virus is known to enter human cells using through interactions with tissue angiotensin-2 receptors and angiotensin converting enzyme 2, researchers have been working to determine whether ACE inhibitors (ACEIs) and angiotensin-2 receptor blockers (ARBs) might block the virus or assist it in some way. “Current clinical evidence does not support stopping [ACEIs or ARBs] in patients with COVID-19,” JAMA Cardiology authors wrote. “All guidelines recommend continuing ACEIs/ARBs in patients with COVID-19 unless clinically indicated. Furthermore, they do not suggest initiation of ACEIs/ARBs in those without another clinical indication (eg, hypertension, heart failure, diabetes), given the lack of strong evidence showing benefit of these medications in COVID-19. We agree with these recommendations, given the current state of evidence. However, the biological plausibility of salutary effects of ACEIs/ARBs in those with COVID-19 is intriguing.…” [Bavishi et al., 2020]
COVID-19 in Children and Infants: 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]
Mental Health Support: Finally, mental health is important to monitor in all patients during this time of dual disease and economic crises; this includes health professionals, who face the added stress of the exposure and deaths in the workplace. “This difficult moment in time nonetheless offers the opportunity to advance our understanding of how to provide prevention-focused, population-level, and indeed national-level psychological first aid and mental health care, and to emerge from this pandemic with new ways of doing so,” Viewpoint authors wrote in JAMA Internal Medicine in discussing the need for prevention and early intervention during and following the COVID-19 pandemic. “The worldwide COVID-19 pandemic, and efforts to contain it, represent a unique threat, and we must recognize the pandemic that will quickly follow it—that of mental and behavioral illness—and implement the steps needed to mitigate it.” The authors recommend 3 actions [Galea et al., 2020]:
• Plan for the inevitability of loneliness and its sequelae as populations physically and socially isolate and to develop ways to intervene.
• Have in place mechanisms for surveillance, reporting, and intervention when it comes to domestic violence and child abuse.
• Bolster the mental health system in preparation for inevitable challenges precipitated by the COVID-19 pandemic.
Changing Ideas About the SARS-CoV-2 Pathogen
What causes rapid decline in patients with COVID-19? Why are some people dying at home with the disease without seeking care or seemingly even realizing they have the virus? If people were dying of COVID-19 in California starting in early February, can we rely on the epidemiological models predicting peaks and ends to current wave in different cities and states?
Those are some of the questions now emerging as more becomes known about SARS-CoV2 and COVID-19. Even without the sheer numbers of patients treated in diverse parts of the world, clinicians would be struggling to understand this new disease while simultaneously finding out what works to treat it. With the volume of patients, it’s been like the proverbial “drinking from the firehose.” Presented here are some of the changing ideas pharmacists and pharmacy technicians should be aware of as they engage patients and other health professionals.
The different clinical presentations of patients with COVID-19 and its divergent clinical courses have baffled clinicians. They are moving to readjust supportive measures they have been using. In news accounts, physicians describe a “silent hypoxia” similar to altitude sickness; patients with severely depressed oxygen levels that would usually cause patients to be unconscious or struggling to get air into their lungs, or to have altered mental status. Instead, patients with COVID-19 are in little distress despite oxygen saturation levels as low as 50% (normal is 95% or more) and pneumonia on chest imaging, emergency physician Richard Levitan wrote in the New York Times.
Similar concerns are appearing in the medical literature. In an Intensive Care Medicine editorial, Gattinoni et al. propose 2 phenotypes of COVID-19. One set of patients, type L, have low lung elastance (high compliance), low ventilation-to-perfusion ratio, low lung weight, and low recruitability (the amount of nonaerated lung tissue is very low). Those with type H have the opposite characteristics; features of the chest images can help clinicians differentiate between these types. Type L patients with dyspnea are better treated with noninvasive options such as nasal cannulas and continuous positive airway pressure. For type H patients, usual ARDS care is appropriate, these authors write. [Gattinoni et al., 2020]
Another unexpected complication of COVID-19 is increased risk of emboli. According to a Washington Post report, some medical groups are discussing the possible need for all patients with COVID-19 to be on anticoagulants, including those at home or in the hospital. [Cha, 2020]
Available data on thrombosis are summarized on the website of the American College of Cardiology — including a reminder that 8% to 10% of patients with critical illnesses have increased risk of venous thromboembolism (VTE). Studies from China [Cui et al., 2020], the Netherlands [Klok et al., 2020], and France [Helms et al., 2020] have presented data on thrombotic risks in patients with COVID-19. Pearls from these studies include these: Patients with elevated D-dimer levels on admission to the intensive care unit have a worse prognosis, and higher-than-usual anticoagulation targets may be needed in those with COVID-19.
Pharmacists’ Roles in COVID-19 Pandemic
Testing and potential drug therapies for COVID-19 are the big questions in the near future as the nation seeks to get a handle on possible relaxation of physical distancing restrictions and ways of treating the disease in moderate and severe cases. Pharmacists are assisting in both areas. Here is compilation of activity on the ground and at the national level:
- The Centers for Disease Control and Prevention has posted guidance for community and outpatient pharmacies with precautions to follow while filling prescriptions, strategies to use minimizing close contact between staff and patients, and administrative controls such as use of drive-through windows, curbside pick-up, home delivery, and limits on the number of people allowed in the pharmacy at a given time.
- Executives at 12 national pharmacy organizations issued a joint statement calling for involvement of pharmacists during the pandemic in infectious disease testing, treating, and immunizing; allowing pharmacists and pharmacy technicians to practice across state lines, including through telehealth; authorizing pharmacists who are providing direct patient care to use therapeutic interchange and substitution when product shortages arise; and providing direct reimbursement to pharmacists for services within scope of practice and covered for other health care providers.
- Following on last week’s U.S. Department of Health and Human Service , the National Community Pharmacists Association (NCPA) has posted a video on how to apply for the CLIA certificate of waiver needed to conduct tests and a “test vetting” algorithm to use in determining which tests can be performed at the pharmacy. NCPA is building a coronavirus information center on its website.
- The American Society of Health-System Pharmacists (ASHP) launched a coronavirus microsite that pulls together an evidence table with detailed, referenced information on drugs with potential use in COVID-19, information on educational webinars, news articles, the CEO blog, and ASHP podcasts. Webinars are being conducted with pharmacists on the frontlines, and the Society has opened access to its AHFS Drug Information resource for the next 60 days.
- At the American Pharmacists Association (APhA), information and resources are compiled on the Pharmacists’ Guide to Coronavirus page of pharmacist.com. A series of short, continuing pharmacy education presentations, 15 on COVID-19, is presenting information on convalescent plasma, tocilizumab, remdesivir, and other topics. APhA President Michael Hogue is moderating a weekly webinar series. In a virtual meeting, the 2020 APhA House of Delegates passed policies on protecting pharmaceuticals as a strategic asset, protecting pharmacy personnel during a public health crisis and pharmaceutical safety and access during emergencies.
- Pharmacists have an important role to play in advising patients on appropriate actions during the pandemic. Poison control centers and emergency workers are concerned about bleach and alcohol ingestions after the President mentioned of internal treatment with those agents during yesterday’s White House COVID-19 briefing, according to articles in the New York Times and the Washington Post. Calls to poison centers related to cleaners and disinfectants were already up, according to an MMWR report, including bleaches, nonalcohol disinfectants, and hand sanitizers. [Chang et al., 2020]
Lessons for the Next Pandemic
Vaccines, diagnostics, and antiviral drugs will be the “big medical breakthroughs” emerging from the COVID-19 pandemic, Microsoft pioneer Bill Gates predicts in an invited article in The Economist. Medical researchers — “the most important people in the world” for the next year, Gates says — have already made “giant leaps in vaccinology.” That progress will accelerate as research focuses on vaccine platforms such as mRNA that can be repurposed quickly to induce immunity against emerging pathogens.
Gates closes his article with a well-known quote Winston Churchill from 1942. Following Britain’s first World War II land victory, Churchill said: “This is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.”
Bavishi C, Maddox TM, Messerli FH. Coronavirus disease 2019 (COVID-19) infection and renin angiotensin system blockers. JAMA Cardiol. 2020:10.1001/jamacardio.2020.1282. [Epub in advance of print, April 3, 2020].
Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19. Infectious Diseases Society of America. 2010 Apr 11. Available at: https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/. Accessed on: April 23, 2020.
Borba MGS, Almeida FFA, Sampaio VS, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection a randomized clinical trial. JAMA Netw Open. 2020;3(4.23):e208857.
Chang A, Schnall AH, Law R, et al. Cleaning and disinfectant chemical exposures and temporal associations with COVID-19 — National Poison Data System, United States, January 1, 2020–March 31, 2020. Morb Mortal Wkly Rep. 2020;69:496–498.
COVID-19 Treatment Guidelines Panel. COVID-19 Treatment Guidelines. U.S. National Institutes of Health. 2020 Apr 21. Available at: https://covid19treatmentguidelines.nih.gov. Accessed on: April 23, 2020.
Cruz AT, Zeichner SL. COVID-19 in children: initial characterization of the pediatric disease. Pediatrics. 2020:e20200834. [Epub in advance of print, April 8, 2020]
Cui S, Chen S, Li X, et al. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemostas. 2020:10.1111/jth.14830. [Epub in advance of print, April 9, 2020]
Galea S, Merchant RM, Lurie N. The mental health consequences of COVID-19 and physical distancing: the need for prevention and early intervention. JAMA Intern Med. 2020: 10.1001/jamainternmed.2020.1562. [Epub in advance of print, April 10, 2020]
Gattinoni L, Chiumello D, Caironi P, et al. COVID-19 pneumonia: different respiratory treatment for different phenotypes? Intens Care Med. 2020:10.1007/s00134-020-06033-2. [Released online as accepted, unedited proof]
Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med. 2020: 10.1056/NEJMoa2007016. [Epub in advance of print, April 10, 2020]
Helms J, Tacquard C, Sevarac F, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intens Care Med. 2020:10.1007/s00134-020-06062-x. [Released online as accepted, unedited proof]
Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020:10.1016/j.thromres.2020.04.013. [Epub in advance of print]
Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19. Available at: https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v1.full.pdf. Accessed April 23, 2020.
Sanders JM, Monogue ML, Jodlowski TZ, et al. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. JAMA. 2020: 10.1001/jama.2020.6019. [Epub in advance of print, April 13, 2020]
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