key: cord-278406-n5e3a09i
authors: Macauley, Precious; Martin, Alvaro; Epelbaum, Oleg
title: CORTICOSTEROIDS IN THE TREATMENT OF SEVERE COVID-19 LUNG DISEASE: THE PULMONOLOGY PERSPECTIVE FROM THE FIRST UNITED STATES EPICENTER
date: 2020-08-21
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.08.051
sha: 
doc_id: 278406
cord_uid: n5e3a09i

The SARS-CoV-2 pandemic has introduced the medical community to a lung disease heretofore unknown to most clinicians. In much of the discourse about COVID-19 lung disease, the more familiar clinical entity of ARDS has been used as the guiding paradigm. Reflecting on studies in ARDS, particularly that due to influenza, and on data from the SARS-CoV and MERS epidemics, many authorities, including within the discipline of infectious diseases, were initially passionate in their opposition to the use of corticosteroids for lung involvement in COVID-19. The voice of the pulmonology community—the community of lung experts—has continued to be among the quietest in this conversation. Herein we offer our perspective as academic pulmonologists who encountered COVID-19 in its first United States epicenter of New York City. We encourage a conceptual separation between early COVID-19 lung involvement and ARDS. We draw on history with other immune cell-mediated lung diseases, on insights from the SARS-CoV experience, and on frontline observations in an attempt to allay the skepticism towards corticosteroids in COVID-19 lung disease that is likely to persist even as favorable study results emerge.

As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic first swept across the globe in the first quarter of 2020, the management of the associated clinical entity termed coronavirus disease 2019 became the subject of institutional recommendations (Massachusetts General Hospital, 2020), societal guidelines (Bhimarj et al, 2020), and position statements (Russell et al, 2020) . Because acute respiratory failure (ARF) in COVID-19 is triggered by a viral pathogen, it is understandable that the discussion of this potentially devastating illness has centered on its infectious disease and epidemiologic implications. However, as pulmonologists who treated severe COVID-19 patients in the first United States epicenter of New York City, we believe that something important has been underemphasized in this discourse. At the "heart" of COVID-19 is a lung disease, and a question that has still not been raised often enough is: what exactly is the nature of the lung disease caused by SARS-CoV-2? More specifically, when progression to lung involvement appears, what would one see under the microscope in a section of lung tissue? This hypothetical question is of utmost importance because frontline experience indicates that reversal of COVID-19 lung disease and avoidance of prolonged invasive mechanical ventilation (IMV) is pivotal. All too frequently, the features of lung involvement in severe COVID-19 have been conflated with the acute respiratory distress syndrome (ARDS), a clinically defined entity intended to correspond to the histological lung injury pattern known as diffuse alveolar damage (DAD). The correlation between ARDS and pathological DAD is highly imperfect (Thille et al, 2013) , and ARDS has a number of well-described mimics among diffuse lung diseases with acute presentations (Schwarz et al 2004) . The importance of differentiating ARDS from its mimics is that, unlike DAD, many histological patterns in the mimic category are exquisitely corticosteroid-sensitive. Early in the pandemic, it was recognized that the physiological behavior of COVID-19 lung disease is often J o u r n a l P r e -p r o o f distinct from that typically encountered in ARDS/DAD (Gattinoni et al, 2020) . To the trained eye of a pulmonologist, the thoracic imaging appearance of early COVID-19 lung disease is less reminiscent of corticosteroid-resistant ARDS/DAD and more reminiscent of corticosteroidsensitive substrates such as organizing pneumonia (OP), acute eosinophilic pneumonia (AEP), and vasculitis (Hani et al, 2020; Nemec et al 2013) . Although both influenza and coronavirus infect respiratory epithelial cells, there is histopathological evidence from the 2003 severe acute respiratory syndrome coronavirus (SARS-CoV) epidemic to suggest that the former has a more dramatic propensity than the latter for catastrophic lung injury in the form of DAD (Ng et al, 2006 ). Clinicoradiological differences between COVID-19 lung disease and that of influenza are likewise emerging to support the histopathological observations (Tang et al, 2020) . This is consistent with our clinical experience in COVID-19. Figure 1 depicts the chest radiographs (CXR) of three representative patients with COVID-19 admitted to the intensive care unit (ICU) of our institution; each row of the panel corresponds to a single patient. The CXRs on the left (panels A, C, E) were obtained on the day of ICU admission while the CXRs on the right (panels B, D, F) were obtained less than 24 hours later. In each case, the only pharmacological intervention these patients received between the two CXRs that could account for a dramatic improvement in lung consolidation within such a short period of time is a single one gram "pulse" dose of methylprednisolone. This type of radiographic behavior is decidedly uncharacteristic of ARDS/DAD but is quite characteristic of the corticosteroid-sensitive ARDS/DAD mimics mentioned above. While caring for scores of severe COVID-19 lung disease patients and repeatedly witnessing a striking clinicoradiographic response to pulse corticosteroids, we were disheartened by the initial negativity towards corticosteroids expressed by, among others, our infectious disease colleagues (Massachusetts General Hospital, 2020; the use of corticosteroids in pulmonary medicine, including at pulse dose, for certain diffuse lung diseases, a practice that is readily applied even to novel entities such as e-cigarette or vaping product-use associated lung injury (EVALI) that lack any evidence base (Layden et al, 2020) . Many of the studies labeled inconclusive were never intended to specifically examine the role of corticosteroids. If one restricts the view to just those English-language studies designed to investigate corticosteroid regimens, an overall optimistic picture emerges, particularly considering that the survival figures include critically ill patients (Table 1 ) (Fowler et al 2003) . The most discouraging study in this group is a retrospective analysis of critically ill MERS patients showing a very high mortality with no survival advantage attributable to corticosteroids (Arabi et al, 2018) . It is worth considering that corticosteroids were administered based on clinicians' discretion a median of three days into ICU stay at a median dose in methylprednisolone equivalents of 60mg, very different from the one gram of methylprednisolone starting on the day of ICU arrival and continued for three days that has been our practice with severe COVID-19 lung disease. This study, along with another from the SARS-CoV era , implicated corticosteroids in persistence of viral RNA. 

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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

This manuscript preparation did not require ethical approval.

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