Although Research is Progressing, Many Questions Remain About COVID-19


It is especially important to better understand the interactions between COVID-19 and acute respiratory distress syndrome.

Despite quickly developing research on coronavirus disease 2019 (COVID-19), investigators still do not know why some patients develop respiratory failure whereas others have minimal symptoms, and questions still remain about the beset treatment options.

A new editorial published in JAMA Internal Medicine outlined management options and lingering questions for patients with acute respiratory distress syndrome (ARDS), a severe condition defined by bilateral radiographic opacities and a high degree of hypoxemia. There are no specific pharmacologic therapies for ARDS, but research has shown that supportive care and lung-protective ventilation can improve outcomes.

According to the authors, most reports suggest that the respiratory physiology of ARDS both associated and not associated with COVID-19 are similar. For patients with COVID-19 and ARDS, experts recommend providing sedation and analgesia at the minimum level required for patient comfort and ventilator synchrony; a conservative strategy for administering fluids; prone positioning; and venovenous extracorporeal membrane oxygenation in severe cases.

“The COVID-19 pandemic has reinforced the fundamental teaching that treatment of the underlying cause of ARDS is essential to improving outcomes,” the editorial authors wrote.

Although treatment of COVID-19 with remdesivir has been shown to shorten the time to recovery, the use of this drug in patients with mechanical ventilation is still uncertain. According to the article, the RECOVERY trial found a survival benefit when using dexamethasone in patients with COVID-19 who require oxygen or mechanical ventilation, but further research is still needed.

The authors urged caution when using unproven therapies for COVID-19. Although medications such as hydroxychloroquine and lopinavir/ritonavir were touted as potential therapeutics at the beginning of the pandemic, research has shown they are largely ineffective, according to the article.

Similarly, although many patients have been treated with interleukin-6 (IL-6)-blocking agents, evidence has shown little benefit. Furthermore, the authors noted increasing evidence of opportunistic infections associated with these investigative therapies.

“The lessons are that unproven therapies for COVID-19 may provide more harm than benefit and that there are no substitutes or short-cuts for well-conducted randomized clinical trials,” the authors said.

A multitude of questions still need to be answered about COVID-19 and how it interacts with ARDS, and the authors concluded by outlining their major issues. Although patients have a wide degree of key pathways of injury, COVID-19 has a single causal etiology, likely resulting in a more specific and more uniform clinical and biological phenotype of ARDS. Because of this, the authors said it is vital to understand the distinct pathways of injury that are shared between patients with severe COVID-19 and which are specifically treatable.

Some autopsies have found evidence that endothelial injury and coagulopathy are central mediators of lung injury in patients with COVID-19, but this must be confirmed in order to safely use therapies that target endothelial activation or coagulopathy.

Finally, the authors noted many questions linger even for patients who recover from COVID-19. The long-term sequelae must be investigated in order to understand the functional and psychological consequences of the disease. A better understanding of these conditions could also help medical providers care for the large number of patients who survive.


Bos LDJ, Brodie D, Calfee CS. Severe COVID-19 Infections—Knowledge Gained and Remaining Questions. JAMA Internal Medicine; September 18, 2020. Accessed September 25, 2020.

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