The COVID-19 pandemic continues to bring society as we know it to a halt, with more than half the world’s population under stay-at-home orders. At the time of this writing, there have been >2.5 million confirmed cases and >177,000 deaths in the world, with the United States having the highest numbers of both (>800,000 confirmed cases and >45,000 deaths). This outbreak has highlighted in all too real terms how unprepared the United States—and really, the world—was for an infectious outbreak such as this. That said, some of the scientific advances have been truly remarkable, and the rapidity with which these developments have been made would have been unthinkable a decade ago. Within 4 months of initially recognizing this new disease, scientists identified and sequenced the virus, identified its host receptor, developed and implemented novel diagnostic tests worldwide, and initiated 470 interventional clinical trials (as listed on clinicaltrials.gov) including phase 2 vaccine trials. Although myriad COVID-19-related papers have been published with many more available as non-peer-reviewed preprints, there is still a paucity of high-quality data guiding clinical management of patients. A few of the major issues are highlighted below.

 

Testing

  • Numerous diagnostic tests have now been developed and are available; however, most of these have not gone through the standard review process by the U.S. Food and Drug Administration, so the actual test characteristics (e.g., sensitivity and specificity) are not well described. Moreover, although the tests have now been developed, there is a shortage of the reagents needed to run the test, which effectively prevents testing from being implemented as widely as is needed.

  • Deeper respiratory samples (e.g., bronchoalveolar lavage fluid) appear to have higher sensitivity than less invasive samples (e.g., anterior nasal swabs), and the virus is detectable for longer in stool than in respiratory samples or serum.

  • Although there is now a point-of-care test available that yields a result in <15 min, its false-negative rate may be as high as ~15% according to unpublished results from the Cleveland Clinic.

  • There are now tests available to assess SARS-CoV-2-specific antibodies, but it is not yet clear what percentage of infected individuals actually develop antibodies and whether these antibodies confer protection against disease.

 

Treatment

  • Although there was initially a great deal of excitement for the possibility that hydroxychloroquine with or without azithromycin may be effective against COVID-19, additional scrutiny of the initial reports raised questions about the study design. Moreover, early results from controlled trials evaluating hydroxychloroquine with or without azithromycin have been disappointing, with some of the trials needing to be stopped early due to cardiac side effects from the medicines.

  • Remdesivir, an adenosine analogue that causes premature termination of the viral RNA polymerase, was initially used to treat patients with severe COVID-19 under the auspices of “compassionate use.” Between January 25, 2020, and March 7, 2020, 61 patients received at least 1 dose of the drug, with analyzable data from 53. Of these patients, 36 had an improvement in oxygen-support class, with 17 of 30 patients initially receiving mechanical ventilation able to be extubated. Although these results are promising at face value, it is important to note that it is not clear how the pharmaceutical company that provided remdesivir approved patients for this compassionate use program, how many patients applied for the drug and were denied, and how these treated patients compare with a control group. Of note, the median duration of symptoms before receiving remdesivir was 12 days, which may have preselected for patients who had lower SARS-CoV-2 viral loads and were already beginning to get better (with ongoing severe disease being a result of ongoing inflammatory processes and not direct viral damage). Results from double-blind, randomized trials are expected to be available in the next few months for patients with severe and moderate disease (separate clinical trials).

 

Guidelines

  • The Infectious Disease Society of America (IDSA), the World Health Organization, and the National Institutes of Health (NIH) have each independently developed guidelines for the management of patients with COVID-19, and it is notable that the recommendations from these different groups of experts are largely similar. The main finding by all of these groups is that there is not yet any drug that has proven efficacy against COVID-19, and that all treatment regimens should be conducted within the framework of clinical trials when feasible. All groups highlight the lack of high-quality clinical data suggesting a particular treatment regimen should be recommended for or against.

  • IDSA and NIH specifically mention that certain treatment regimens (e.g., hydroxychloroquine plus azithromycin, HIV protease inhibitors) should not be used outside of a clinical trial given toxicities and/or negative clinical trial data to date.

  • There is consensus across these guidelines that systemic corticosteroids should not be used in mechanically ventilated patients with COVID-19 who do not have acute respiratory distress syndrome (ARDS). There is insufficient evidence to make any definitive statement about patients with COVID-19-related ARDS.

  • Although these guidelines provide useful background on the various approaches that are actively being studied as possible therapeutic regimens, they really highlight how little is currently known about effective management strategies for patients with moderate to severe illness. Although these guidelines encourage the use of various drugs in the setting of clinical trials, it should be noted that most practitioners do not work in a setting that actively participates in clinical trials. As such, it remains unclear what, if anything, these providers should do for patients with COVID-19 beyond supportive care.

Although there are still issues and significant unknowns with optimal testing and treatment recommendations, results from several clinical trials are expected to be published in the coming weeks to months. The hope is that these peer-reviewed, randomized clinical trials will provide a clear path forward as this pandemic continues to evolve.