Jason C. Gallagher, PharmD, FCCP, FIDP, FIDSA, BCPS*

Jason Gallagher is an active member of the Society of Infectious Disease Pharmacists.

Of all the issues that coronavirus disease 2019 (COVID-19) has unmasked, one of the biggest may be the power of wishful thinking. Perhaps one of the better-defined examples of this has been the different interpretations on the utility of hydroxychloroquine, an agent that has been polarized in bizarre ways.

Even before the first small study of hydroxychloroquine for COVID-19 was published, hydroxychloroquine was getting attention from clinicians facing early outbreaks. There was a reason for hope, since both hydroxychloroquine and chloroquine have in vitro activity against SARS-CoV-2. They are generally well-tolerated and hydroxychloroquine is widely-available in the US. But in vitro activity does not always predict clinical success, the agents have problematic pharmacokinetics, and the record of effectively treating respiratory viruses with antiviral therapies is unimpressive. Nevertheless, it was worth a look.

The first widely reported study started a whirlwind of effects with which that we are still dealing. It was a report by Gautret and colleagues of virologic outcomes of 26 patients who received hydroxychloroquine compared to 16 who were treated at another hospital and did not.

 Six patients who also received azithromycin “to prevent bacterial superinfection” were included, and these had the most rapid virologic response. No clinical outcomes were reported, though of the 6 patients excluded from analysis, 3 were transferred to the ICU and another 1 died. However, this was enough to capture the interest of a scared public and desperate healthcare professionals looking for any possible therapy.

As use increased, retrospective cohort studies followed, reporting variable results. Since more severely ill patients were often more likely to receive hydroxychloroquine with or without azithromycin, the results of non-randomized studies were highly dependent on the quality of analysis performed. Some found a benefit, more found no effect, and some suggested harm.

 Meanwhile, the politicization of the drug was well-underway. The announcement by the president that the Gautret results could be a “game-changer” drove prescriptions for hydroxychloroquine and azithromycin to the point of shortages and turned a 70-year-old, 18-letter drug into a polarizing household topic. The publication and of a Lancet paper that concluded that the drugs were actually harmful was cheered by one side, then derided by the other after it was retracted. Hydroxychloroquine was stuck in the middle.

Randomized, blinded clinical trials have since been performed that in my mind have put this issue to rest, at least scientifically. The RECOVERY trial in the UK found no difference in mortality between hydroxychloroquine and usual care in over 4600 hospitalized patients.

 Two randomized studies in less severely ill patients found no difference between groups

and perhaps most damning, a study of hydroxychloroquine as post-exposure prophylaxis did not prevent COVID-19 developing any better than placebo.

As the pandemic has progressed, so has our knowledge about COVID-19 therapy. Unfortunately, the early excitement about hydroxychloroquine has not been warranted, and the time has come to abandon it and move on to explore other possible therapies. At this point the threshold for new data evaluating hydroxychloroquine must be raised to prospective, randomized, blinded studies designed to remove the bias that non-randomized studies inherently create, while we need to revert to using retrospective studies for the hypothesis-generation for which they are intended.

 Published online March 20, 2020. doi: 10.1016/j.ijantimicag.2020.105949 

Magagnoli et al., Outcomes of Hydroxychloroquine Usage in United States Veterans Hospitalized with COVID- 19, Med (2020), https://doi.org/10.1016/j.medj.2020.06.001 

Published online May 7, 2020. doi: 10.1056/NEJMoa2012410

Arshad S et al. IJID: https://doi.org/10.1016/j.ijid.2020.06.099 

https://doi.org/10.1101/2020.07.15.20151852

Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in nonhospitalized adults with early COVID-19. A randomized trial. Ann Intern Med. 16 July 2020. [Epub ahead of print]. doi:10.7326/M20-4207 

Boulware D et al. NEJM. DOI: 10.1056/NEJMoa2016638

Articles

Hydroxychloroquine for COVID-19: A Lesson in Study Quality

Coronavirus disease 2019 (COVID-19) is taxing us in so many ways. In some parts of the country, our health system has been pushed to the brink of capacity or beyond. Our economy has been decimated as a result of the widespread closures enacted to decrease the spread of the severe acute respiratory syndrome coronavirus 2 and prevent health-system collapse. Misinformation about COVID-19 has circulated farther and faster than the actual infection, confusing individuals and forcing health care practitioners to constantly counter myths being mentioned by patients, friends, and family. Finally, the flow of literature about COVID-19 has been unending, tiring those of us who look to it for guidance to improve patient outcomes. I want to focus on this last point for this month’s column.

The saga of 2020 will have many subtitles. One of them could be “The rise of the preprint.” Keeping up with newly available literature on COVID-19 feels like drinking from a firehose, except that only a percentage of the contents is actually clean water. Preprints have moved from a mostly unused venue for scientists to gather feedback on studies they are finalizing to a primary method for sharing “breaking data” as fast as possible. When these data are in the basic sciences and largely remain within a self-policing circle of scientists, they are probably fine. However, now there are millions of clinicians desperately looking for ways to more effectively treat patients with COVID-19. The media are reporting on unreviewed preprints that are often flawed, pushing catchy narratives that miss major points and the nuances that need emphasis. Reacting to preprints of clinical and translational science without critique is potentially dangerous. It is also understandable.

Many professional schools in the health sciences have curricula that include literature interpretation. We all know better than to “just read the abstract,” accept results at face value, or accept conclusions of papers without vetting the methods. Remaining steadfast to sound practice is much harder when we are constantly reacting to a continuous influx of new information. We are all looking for that golden paper that will help us improve our standard of care to something more satisfying than the largely watch-and-wait approach that we are stuck with now.

Peer review has flaws, but its absence has highlighted its utility. Ironically, it has become harder to find peer reviewers recently, as clinical scientists face long hours on busy clinical services. This column is a reminder that when you read a preprint, remember that you serve as your own reviewer and possibly the only reviewer that paper will see before you. In the past issue, I wrote about taking notes for the sake of posterity during the COVID-19 pandemic. Examining the influence of preprints should be one of them.

In his June Editor-in-Chief letter, Dr. Jason Gallagher explores the influence of preprints amid the COVID-19 pandemic.

COVID-19 Preprints: Reader, Beware

Temple University Hospital campus. Boyer Pavilion is on the left side, and Rock Pavilion is on the right.

The first case of coronavirus disease 2019 (COVID-19) in Philadelphia was 

 on March 10. Prior to this, Temple University Health System was preparing for the inevitable influx of patients suffering from COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Temple University Hospital is a 700-plus—bed urban, level 1 trauma center on the Health Sciences Campus of Temple University. Temple provides care to many of the city’s most vulnerable populations—those 

 by the coronavirus pandemic. Temple is also a center of excellence for lung diseases, making the hospital suited to care for patients with a deadly pulmonary disease. As of early May, Temple University Hospital has provided care to the largest number of patients with COVID-19 among hospitals in Philadelphia. Through multidisciplinary planning, thoughtful triage, follow-up of mild cases, and anticipation of future needs, Temple has been able to cope with a significant burden of disease while maintaining a high level of care for its patients. This article outlines the hospital’s response to the pandemic.

The keys to an effective response to a crisis are leadership and organization. A multidisciplinary approach has been fundamental in the preparation for and navigation through this public health crisis. Voices from internal medicine, nursing, pulmonary/thoracic medicine, infectious diseases, emergency medicine, pharmacy, respiratory therapy, ventilator management, and those involved in infection control/procuring personal protective equipment (PPE) were all present in task forces and planning groups. The hospital administration let the voices of frontline clinicians guide policy decisions.

Clinical leadership for the COVID-19 response has come from Gerard J. Criner, MD, FACP, FACCP, director of the Temple Lung Center and chair of the Department of Thoracic Medicine and Surgery. His relationship with scientists in Wuhan, China, has helped inform Temple’s COVID-19 response by enabling frontline practitioners with experience to guide those who lacked it before our first patient was admitted. Dr. Criner has also been holding interdisciplinary systemwide daily video calls 6 days a week to allow clinicians, infection control, laboratory management, informatics personnel, and supply management to weigh in on evolving outcomes, policies, and treatment protocols. Each call begins with a COVID-19 update on the Philadelphia region, followed by expectations for the next week, specifics on Temple logistics, status, and anticipated needs.

Multiple groups have become leaders in the Temple COVID-19 response. The Section of Infectious Diseases has guided policy for infection control, PPE, and testing. An infectious disease attending is on call as the “COVID czar” 24 hours a day to answer clinical questions about testing and other policy questions. A designated hospitalist administrator handles questions about transfers, bed management, and patient disposition. Kathleen Reeves, MD, director of the Center for Urban Bioethics and senior associate dean of Health Equity, Diversity and Inclusion, has also been working to meet of the needs of Temple’s underserved patient population in the face of the pandemic. She has been leading efforts to deliver food to city residents, connect people to social services, and maintain utilities for the city’s residents.

To allow essential services to continue and to decrease the risk of nosocomial COVID-19 acquisition, hospital leadership took advantage of Temple University Hospital’s facility to create functional COVID-19 and non—COVID-19 hospitals. Temple University Hospital’s physical layout proved fortuitous for our response; Temple comprises 2 separate hospital buildings connected by a covered bridge. The main hospital building (the Rock Pavilion) has operated with normal services at reduced volumes. Meanwhile, Temple transformed the Boyer Pavilion, which usually houses several outpatient offices as well as a few inpatient floors and intensive care units (ICUs), into a separate 250-bed COVID-19 hospital. Physicians first admit patients with suspected COVID-19 to a service in Boyer as their status is determined.  If they are polymerase chain reaction (PCR) negative and clinical suspicion subsides with an alternative diagnosis, for instance, staff transfer patients from Boyer to Rock (COVID-19 to non–COVID-19). If Rock patients are suspected of having COVID-19, as with an atypical or delayed presentation, staff transfer them to Boyer. With the canceling of elective procedures and decreased patient volumes in Rock, Temple has scaled up staffing in Boyer to accommodate patient volume. There is also a designated CT scanner in Boyer dedicated to patients with COVID-19, making diagnosis quicker and decreasing likelihood of nosocomial spread.

One of the keys to Temple’s approach has been triage, which starts with emergency department personnel.  Clinical leadership created triage algorithms to facilitate consistency in patient care and bed management using clinical, radiological, and needs-based criteria (

). As the need for beds increased, administration quickly facilitated coversion of office spaces and lobbies in the building into patient wards and post anesthesia care units into ICUs. The capacity of the Boyer Pavilion has more than doubled.

Patients who present with mild disease and are treated with outpatient care are offered monitoring with the HGE COVID symptom tracking application, a website on which patients can log symptoms daily. This allows occupational health and primary care clinicians to assess outpatients based on patient-reported symptoms and act to redirect them to inpatient care if necessary. 

Shortly before patients with COVID-19 were admitted to Temple, hospital administration instructed nonessential and off-duty personnel to work from home, and experiential training for health sciences students ended. To maintain a viable, healthy workforce, medical residents had elective rotations canceled, and services included essential personnel only. Remote support using the electronic health record (EHR) has allowed clinical services to continue, even for essential services. Temple enacted a universal masking policy and temperature checks for anyone entering the hospital buildings.

As the crisis has progressed, Temple has had to adapt its staffing needs. An unanticipated increase in patients requiring renal replacement led to around-the-clock shifts for dialysis personnel. Laboratory leadership modified logistics in the microbiology lab to allow for increased frequencies of SARS-CoV-2 assays.  

To allow our emergency department providers to effectively triage and manage cases of patients presenting with symptoms of COVID-19, the hospital has created various “pods” staffed by other specialties to triage and see patients with non—COVID-19 complaints. Triagers funnel patients presenting with chest pain and acute coronary syndrome  to a “cardiology pod” staffed directly by cardiologists; a surgeon sees patients presenting with abdominal pain. This team approach extends to inpatient services as well. As inpatient volume has increased, Temple has created more COVID-19 care teams, and specialists have staffed these teams in several day blocks to relieve hospitalists. For example, a gastroenterologist or a nephrologist may oversee a COVID-19 floor team with the help of an internal medicine resident. Behind the scenes, outpatient providers embraced the use of telemedicine for the vast majority of patient needs.

Temple has been subject to the nationwide shortage of testing supplies for COVID-19. As in many institutions, Temple’s lab took advantage of Emergency Use Authorization to create and quickly validate in-house PCR-based testing. The lab also increased testing capacity through technician training and by running multiple testing shifts per day. Shortages of testing supplies have created challenges intermittently, and Temple has responded in several ways. When the ability to run assays became limited, send-out testing was used for situations in which turnaround time (TAT) was less urgent, as for confirming negative assays before removal from isolation. Temple has pursued alternative platforms as well. Laboratory leadership investigated Abbott’s ID Now platform for outpatient settings, but they were ultimately unable to procure the system. The recent addition of the Cepheid platform to the laboratory’s toolset has allowed for a rapid TAT of the SARS-CoV-2 assay when time was essential. Infectious Diseases is also using diagnostic stewardship by fielding clinical questions regarding testing and developing a retesting policy for the institution that conserves both testing resources and PPE.

Temple’s pulmonary and critical care physicians have been the frontline managers in the treatment of patients with COVID-19 infection. As mentioned, we created tiers for patient management and escalation of level of care to quickly identify the need for escalating care. Temple has 

 early strategies for noninvasive ventilation, including use of high-flow oxygen and prone positioning to decrease rates of intubation.

Temple developed its treatment algorithm for COVID-19 with input from many disciplines, and it has evolved continuously. To preserve PPE, principles of the algorithm are to preferentially use less frequently dosed regimens (eg, enoxaparin over heparin) and those that do not require specific laboratory blood draws (eg, linezolid over vancomycin). Informatics created a panel in our EHR specifically for monitoring patients with COVID-19, including vitals, laboratory values, and pertinent biomarkers.

With a lack of established therapies for COVID-19, early enrollment in clinical trials has been a primary therapeutic modality for our patients. We facilitate this through several means, including placement of available clinical trials in treatment pathways, prioritization of COVID-19 protocols by the Temple institutional review board, and the use of multiple personnel for consent. Because overlap exists between some of the inclusion criteria for studies, clinicians need to make decisions on enrollment based on clinical indication, not just eligibility.

Given the cytokine storm often seen in patients with COVID-19, Temple has used immunomodulatory therapies inside and outside clinical trials, including those that inhibit IL-1, IL-6, and granulocyte-macrophage colony-stimulating factor. Because both therapies are associated with increased risk of infection and blunt diagnostic markers of infection, infectious diseases physicians follow all patients who are prescribed or enrolled to receive one.

A healthy workforce is necessary to adequately care for the surge of patients with COVID-19, and Temple has created policies and procedures with employee health in mind. Physicians on the COVID-19 services work 8-hour shifts to decrease provider fatigue, which can compromise patient and provider safety. Temple created an in-hospital testing site, which now primarily provides testing for symptomatic employees. Occupational health has also increased their capacity based on workforce need and has been flexible with workforce guidelines as institutional needs and circumstances have changed. The aforementioned HGE COVID symptom tracker is available for employees so they can track symptoms daily. Temple has also provided several services focusing on wellness, including provision of dorms at the undergraduate campus for health care workers to stay, free shuttle service in the city, and free mental health resources.

Despite many challenges, Temple, the largest COVID-19 hospital in Philadelphia, has succeeded in providing high-quality care to those most in need. Although the differences between hospitals in the United States are considerable, we believe that aspects of Temple’s approach can offer our medical peers examples to follow and adapt for their own institutions.

Sedlock is a first-year fellow in infectious diseases at Temple University Hospital.

Gallagher, editor-in-chief of Contagion®, is a clinical professor at Temple University School of Pharmacy and clinical pharmacy specialist in infectious diseases at Temple University Hospital, both in Philadelphia, Pennsylvania. He is also the director of the PGY2 Residency in Infectious Diseases Pharmacy at Temple. *He is an active member of the Society of Infectious Diseases Pharmacists. 

The health system’s response could be used as a teaching model for addressing future infectious disease threats.

COVID-19: How Temple University Hospital Is Addressing the Pandemic

As my deadline for this issue’s column approached, I had no doubt what its topic would be. Anyone who follows me on Twitter knows that coronavirus disease 2019 (COVID-19) bumped antimicrobial resistance as the focus of my attention over the past 3 months. However, narrowing this piece to something specific would be much more difficult, and I knew that whatever I wrote would be immediately out-of-date in this fast-moving pandemic. That concern in itself has become the focus. As we address the challenges ahead, let’s take care to record the history to guide us next time.

Our readers know that COVID-19 does not present our first pandemic, nor will it be our last. It presents a disease caused by a unique, readily spread respiratory virus. As the pandemic presses on, each day brings more updates. Practitioners forced to make quick patient care and policy decisions while following new developments and keeping up with advancing literature, plus monitoring their own health, will be hard-pressed to do anything else. However, to the extent possible, I believe it is crucial that we document the advance of COVID-19 and our successes and failures in dealing with it along the way.

We are encountering COVID-19 with a highly interconnected, international society that presents new opportunities and obstacles for its citizenry. Social media is ubiquitous, offering a platform for the dissemination of good ideas (such as a shared Google document on treatment possibilities, started by Section Editor Conan MacDougall), clinicians describing situations they encounter, patient experiences, and rapid distribution of new literature. However, it also accelerates the propagation of fear, anxiety, and misinformation. Preprints of new findings about SARS—CoV-2 and clinical experience treating COVID-19 provide information more quickly to frontline clinicians looking for help. Also, more people have the capability of teleworking than ever before, and educational institutions can offer classes virtually. Telemedicine has become more common and may see rapid uptake for nonurgent needs during the pandemic. All will affect our management in new ways that should be noted.

What’s the point? History shows us that we are doomed to repeat our mistakes if we do not learn from them, and we are relearning past lessons right now. Our national infrastructure to respond to infectious threats has been degraded through policy decisions, budget cuts, and open positions at the Centers for Disease Control and Prevention. Private industry has little incentive to develop anti-infectives for threats that fizzle out, so therapeutics that were beginning to be developed to treat earlier coronaviruses did not come to fruition. As COVID-19 progresses, we will learn many more lessons, not only in the obvious topics of epidemiology, therapeutics, public health, and infection control, but also in psychology, sociology, and political science.

During the time that I’ve had the pleasure of serving as Editor-in-Chief, 

 has grown considerably. My goal has always been to deliver a product that offers true utility to the infectious diseases community, and now is a key time for us to step up and deliver. You will see an increase in COVID-19 content on our pages and the web as we cover multiple aspects of this emerging challenge. This issue contains an interview on COVID-19 with Christina Tan, MD, MPH, from the New Jersey Department of Health. We also feature an article on measures taken against the Ebola virus disease in Congo.

*Gallagher is an active member of the Society of Infectious Diseases Pharmacists. 

COVID-19 does not present our first pandemic, nor will it be our last. What should we take note of? 