LAUSR

Severe COVID‐19 is distinct from ARDS and cytokine‐release syndromes Published data [1, 2], anecdotal observations, and discussions with colleagues worldwide indicate that COVIDinduced respiratory phenotypes are distinct from typical ARDS in several ways [2]. COVID-19 patients develop profound hypoxemia early in their disease course. However, overt respiratory dysfunction at these early stages is unusual. Pulmonary compliance in intubated COVID19 patients appears to be only modestly decreased, and patients are therefore relatively easy to ventilate [1]. Gattinoni et al. [1] described hyperperfusion of poorly ventilated lung, perhaps due to vasodilation and the loss of hypoxic vasoconstriction. While benefit from low-tomoderate levels of PEEP and prone positioning have been noted, these authors suggest that they result more from hemodynamics effects than lung recruitment [1]. Later in the course of COVID-19, some patients develop a phenotype more consistent with ARDS [1, 2]. The reported inflammatory response in COVID19 is also not consistent with either typical ARDS or cytokine-release syndromes (CRS) or “cytokine storm.” Qin et al. [3] report mean interleukin-6 levels were 25 (SD: 10–55) pg/mL (normal range: 7 pg/mL). Other smaller COVID-19 reports have ranged from 7 to 125 pg/ mL. These findings contrast with interleukin-6 elevations seen in typical ARDS and in CRS. Sinha et al. report mean interleukin-6 levels of 282 (111–600) pg/mL in “hypoinflammatory” ARDS [9] and 1618 (517–3205) pg/mL in hyperinflammatory ARDS [4], 10to 60-fold higher than reported in the Wuhan data. Among CRS patients, mean interleukin-6 levels are frequently as high as 10,000 pg/mL [5]. Other inflammatory cytokines (e.g., interleukin-8, interleukin-1β) demonstrate similar patterns. In summary, COVID-19 is associated with only mild inflammatory cytokine elevation and demonstrates physiology and immunology that are difficult to reconcile with ARDS or CRS. An alternative mechanism of disease therefore seems likely.