key: cord-0851114-eerzbmvz authors: Kolilekas, Lykourgos; Loverdos, Konstantinos; Giannakaki, Styliani; Vlassi, Lamprini; Levounets, Anastasia; Zervas, Eleftherios; Gaga, Mina title: Can steroids reverse the severe COVID‐19 induced ‘cytokine storm’? date: 2020-06-12 journal: J Med Virol DOI: 10.1002/jmv.26165 sha: 19237c6ab705024f4805225c4b91a048e4e958fc doc_id: 851114 cord_uid: eerzbmvz Severe COVID‐19 is characterized by an excessive pro‐inflammatory cytokine storm, resulting in acute lung injury and development of ARDS. The role of corticosteroids is controversial in severe COVID‐19 pneumonia and associated hyper‐inflammatory syndrome. We reported a case series of six consecutive COVID‐19 patients with severe pneumonia, ARDS and laboratory indices of hyper‐inflammatory syndrome. All patients were treated early with a short course of corticosteroids, and clinical outcomes were compared before and after corticosteroids administration. All patients evaded intubation and intensive care admission, ARDS resolved within 11.8 days (median), viral clearance was achieved in 4 patients within 17.2 days (median), and all patients were discharged from the hospital in 16.8 days (median). Early administration of short course corticosteroids improves clinical outcome of patients with severe COVID‐19 pneumonia and evidence of immune hyper‐reactivity. This article is protected by copyright. All rights reserved. In addition to respiratory failure, early studies on patients with severe COVID-19 have reported significantly increased plasma levels of several cytokines and chemokines, and inflammatory markers such as C-reactive protein (CRP), interleukin 6 (IL-6), procalcitonin and ferritin, appear to correlate with respiratory failure, ARDS, altered immune status and fatal outcome 1, 2 . Based on these findings, a dysregulated host immune response to SARS-CoV-2 lung infection leading to exuberant cytokine release ('cytokine storm') and immune-mediated lung injury has been postulated as a critical pathogenetic factor in the progression to ARDS 3 . We present a small series of six consecutive hospitalized COVID-19 patients with rapidly deteriorating hypoxemia and laboratory indices of CAHS, all of which evaded intubation/ICU admission and recovered completely following a short course of high-dose CS. This article is protected by copyright. All rights reserved. From March 19 th to April 24 th 2020, 38 patients were admitted to the 7 th Department of Respiratory Medicine, "Sotiria" Chest Hospital, Athens, Greece, which was transformed to a COVID-19 only care unit. All of them had confirmed COVID-19, defined by a positive reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay for SARS-CoV-2 in a nasopharyngeal swab. Baseline characteristics and clinical, laboratory, radiological and treatment data were prospectively collected as part of an observational cohort study approved by the research ethics committee of our hospital (10685/2020). Written informed consent was obtained from all patients included in this registry. Eleven patients developed severe hypoxemia, fulfilling the diagnostic criteria of ARDS (PaO 2 /FiO 2 < 300mmHg) either at admission or shortly after. Six out of the eleven patients who developed severe hypoxemia, were middleaged (median 58, range 45-64 years), mostly male (5/6), never or ex-smokers with otherwise insignificant medical history. All presented with fever, cough and mild dyspnea on exertion as well as pulmonary infiltrates several days after symptom onset (median 7.8, range 6-12 days) and either had hypoxemia (median PaO 2 /FiO 2 190mmHg, range 113-252 mmHg) on admission or developed it shortly after (median time from admission to ARDS 1.5, range 0-3 days), thus fulfilling the diagnostic criteria of ARDS (Table 1 ). Antigen tests for influenza (nasopharyngeal swabs), Streptococcus pneumoniae and Legionella pneumophila (urine samples) and sputum cultures were performed in all patients. On admission, This article is protected by copyright. All rights reserved. lymphopenia was almost universally present (median 635, range 490-1,930 lymphocytes/μL) as well as a low lymphocyte-to-CRP ratio (LCR), while increased levels of d-dimers (median 1.19, range 0,45-3,81μg/mL) and transaminitis (median alanine aminotransferase 60.5, range 17-343 IU/L) were noticed in four patients. CRP and ferritin in contrast with procalcitonin, were already significantly elevated at presentation and increased further in parallel with the development of hypoxemia ( Figure 1 ). Patients received treatment as per local protocol (combination of azithromycin, hydroxychloroquine, beta-lactam, prophylaxis with low-molecular-weight heparin and oxygen therapy). One patient had also tested positive for influenza and received oseltamivir, while four patients did not receive hydroxychloroquine due to laboratory confirmed glucose-6-phosphate dehydrogenase deficiency (G6PD). Treatment with CS (i.v. methylprednisolone 125mg once daily) was started shortly after hypoxemia and evidence of cytokine storm had ensued. In all 6 patients, fever subsided and dyspnea alleviated within 48 hours after CS initiation and by day 3 post treatment onset, four patients had attained significant reductions in the levels of most or all of the inflammatory markers measured and CS were discontinued. A more prolonged treatment course (5 days) was followed in the other two patients, in whom inflammatory markers began to decline on day 5 of CS therapy. Oxygenation gradually improved obviating the need for intubation in all 6 patients. The inflammatory profile amelioration tended to precede PaO 2 /FiO 2 which was slow, with the time needed to reach a PaO 2 /FiO 2 >300mmHg ranging from 6 to 18 days (median 11.8 days), indicating a slower rate of the inflammatory resolution in the pulmonary compared to systemic This article is protected by copyright. All rights reserved. Accepted Article compartment ( Figure 1) . Overall, CS were well tolerated, with only one patient developing transient mild hyperglycemia, and RT-PCR to confirm viral clearance on discharge was repeated in four patients and all had two negative tests at a 24hour interval (median 17.2 days, range 14-23 days) ( Table 1 ). Of the remaining five patients out of eleven (median 74, range 62-91 years) who developed severe hypoxemia and did not receive CS, the first three were intubated and transferred to ICU, one was treated as cardiac failure and recovered, and another had terminal cancer and died of septic shock-the only fatal outcome among our patients ( Table 2 SuppInfo). In this uncontrolled case series of 6 middle-aged patients with COVID-19 associated hyper-inflammatory syndrome and without significant comorbidities, administration of CS was followed by clinical improvement, and in four patients checked on discharge, viral clearance was documented, raising question whether or not CS may prolong viral shedding. Real-life data suggest that therapeutic trials of CS have already been applied quite extensively in COVID-19, particularly in ICU patients with severe or critical disease, without clear evidence of benefit, although a recent study showed that early administration of CS reduced the need for intubation and mortality 1, 4 . This article is protected by copyright. All rights reserved. The rationale for CS use in this specific clinical phenotype of COVID-19 patients with associated hyper-inflammatory syndrome, was that the benefits of an early intervention to decrease the hyper-inflammatory response and acute lung injury, that does not initially resembles that of classic ARDS, may outweigh the adverse effects of CS 7 . Theoretically, this COVID-19 associated hyper-inflammatory syndrome (CAHS) could bear some resemblance to secondary haemophagocytic lymphohistiocytosis Clinical and immunological features of severe and moderate coronavirus disease 2019 Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study SARS-CoV-2: a storm is raging Early Short Course Corticosteroids in Hospitalized Patients with COVID-19 Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury On the use of corticosteroids for 2019-nCoV pneumonia Clinical phenotypes of SARS-CoV-2: Implications for clinicians and researchers COVID-19: consider cytokine storm syndromes and immunosuppression Recommendations for the management of hemophagocytic lymphohistiocytosis in adults Time to consider histologic pattern of lung injury to treat critically ill patients with COVID-19 infection AH: arterial hypertension, CS: corticosteroids, ARDS: acute respiratory distress syndrome, NA: not available.