Washington University Emergency Medicine Journal Club
Having gone to bed in a normal world, you have since woken up in the middle of a
global pandemic. COVID-19, the disease caused by the novel coronavirus virus SARSCoV2, was first identified in Wuhan, China in December of 2019. It has since spread
to the rest of world, with nearly 1.4 million cases worldwide and nearly 400,000
cases in the US alone as of April 7th. While Missouri has been relatively insulated
from the worst of the crisis (with 2700 cases across the state) you have seen several
patients in your ED with a high suspicion for the disease. Several of these have been
critically ill with varying degrees of hypoxia, and many have required intubation.
With this being a fairly new disease, little is known about the optimal treatment
(aside from supportive case). Several adjunct medications have been touted in the
lay press, including the anti-malarial drugs hydroxychloroquine and chloroquine
(heavily favored by the President of the United States), adenosine analogue and HIV
medication Remdesivir, and the antibiotic azithromycin. You are wary of the way the
media has presented these options, given the novelty of the disease and the paucity
of evidence supporting any treatment, but given the limited options you are willing
to consider anything to reduce the morbidity and mortality of COVID-19. You decide
to perform a literature search, looking not only for any evidence supporting the
efHicacy of these medications, but for any information on the course of the disease.
Though little evidence has managed to appear in the mere 5 months the disease has
been known to exist, you somehow manage to Hind a few reasonable articles to dive
No single PICO question was chosen. Instead, a review of various therapies, clinical
Findings, and personal protective strategies was chosen.
For articles evaluating hydroxychloroquine as a therapy, PubMed was searched
using the terms “hydroxychloroquine AND (coronavirus OR COVID)”(https://
tinyurl.com/ybnwtrqc) and the most relevant articles and reviews were chosen. The
article on N-95 respirators was recommended by a colleague, and a brief search for
COVID-19 on PubMed identified the meta-analysis on clinical, laboratory, and
Article 1: Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin
as a treatment of COVID-19: results of an open-label non-randomized clinical trial.
Int J Antimicrob Agents. 2020 Mar 20:105949. Answer Key.
Article 2: Singh AK, Singh A, Shaikh A, Singh R, Misra A. Chloroquine and
hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A
systematic search and a narrative review with a special reference to India and other
developing countries. Diabetes Metab Syndr. 2020 Mar 26;14(3):241-246. Answer
Article 3: Bartoszko JJ, Farooqi MAM, Alhazzani W, Loeb M. Medical masks vs N95
respirators for preventing COVID-19 in healthcare workers: A systematic review and
meta-analysis of randomized trials. Influenza Other Respir Viruses. 2020 Apr 4.
Article 4: Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, et al;
Latin American Network of Coronavirus Disease 2019-COVID-19 Research
(LANCOVID-19). Electronic address: https://www.lancovid.org. Clinical, laboratory
and imaging features of COVID-19: A systematic review and meta-analysis. Travel
Med Infect Dis. 2020 Mar 13:101623. Answer Key.
SARS-CoV-2, the novel coronavirus responsible for COVID-19, was first isolated in
December of 2019, a mere 6 months ago. As a result, we are still learning about the
disease and studying potential treatments. Given the need to rapidly accumulate and
disseminate information, researchers and medical providers have largely bypassed
the typical knowledge translation pathway, at times to the detriment of medical care.
Early studies reporting clinical, laboratory, and imaging findings (collated in a
systematic narrative review) suggested a more typical, if deadly, viral illness
presenting with fevers, cough, and shortness of breath with abnormal chest x-ray
findings of pneumonia observed in nearly 3 of every 4 patients admitted to the
hospital. With time, we have found this virus to be anything but typical, with
growing reports of multiple adverse consequences, including cardiomyopathy,
coagulopathy, and encephalopathy. The various dermatologic findings alone are
enough to require astute clinical observation and heightened awareness in the face
of this pandemic.
By ignoring the principles of evidence-based medicine, chloroquine and
hydroxychloroquine were at one point touted by some as highly effective treatments
against COVID-19 (including the President of the United States). This reaction was
based in part on the results of an observational French study that demonstrated
rapid clearance of viral RNA from the nasopharynx among patients treated with
hydroxychloroquine, with a synergistic effect when combined with azithromycin.
Despite a very small sample size and a failure to demonstrate any improvement in
patient-centered outcomes, the authors concluded their study by recommending
“that COVID-19 patients be treated with hydroxychloroquine and azithromycin to
cure their infection and to limit the transmission of the virus to other people in
order to curb the spread of COVID-19 in the world.”
These preliminary results seemed to be confirmed by the findings of an early systematic
review of this topic. At the time, the authors were only able to identify one other
research article. An observational Chinese study involving more than 100 patients
found that treatment with chloroquine led to more rapid reduction in symptom
duration and radiological improvement of pneumonia, while also promoting higher
rates of virus-negative seroconversion when compared to a control group. Since
then, a handful additional studies have been published contradicting these findings.
These include a retrospective study from the Veterans Administration that found no
benefit with regards to several patient-centered outcomes (including death and
need for mechanical ventilation), and a French study in which patients with
COVID-19 who required supplemental oxygen were enrolled. In this latter study,
patients who received hydroxychloroquine were equally likely to die or be
transferred to the ICU when compared to those who did not receive
hydroxychloroquine. While more rigorous randomized controlled trials are still
ongoing, the current evidence does not seem to support the routine use of
hydroxychloroquine in the management of COVID-19 at this time.
One deleterious aspect of the COVID-19 pandemic has been a shortage of necessary
personal protective equipment (PPE) both in the US and abroad. Given this shortage,
the CDC has relaxed its recommendations, allowing for extended use of N-95
respirators, while the World Health Organization recommends medical masks alone
for healthcare providers caring for patients with COVID-19, reserving N95
respirators for aerosol-generating procedures. A systematic review and meta-analysis of studies comparing medical masks to N-95 respirators found no difference
in the prevention of laboratory-confirmed viral respiratory infection, laboratory confirmed influenza, influenza-like illness, or clinical respiratory illness among
healthcare workers. While none of the included studies involved COVID-19, one
study found no difference in transmission of other coronaviruses.
Further research is ongoing at this time, not only to continue establishing
hydroxychloroquine’s place as a potential treatment, but also looking at
convalescent serum and a variety of antiviral and immunosuppressive medications
in the management of COVID-19. While still unpublished, early reports from the
manufacturer suggest significant benefit with the antiviral drug, remdesivir. As more
research is reported, it will be important not to forego the principles of evidence based medicine in our search for more therapies, but rather to use sound judgment
in applying these principles to select the most appropriate treatments and prevent
further harm to our patients.