Patients with COVID-19 ARDS have distinct physiological and immunological phenotypes compared to patients with non-COVID ARDS. Patients with COVID-19 ARDS (n = 32) had a significant improvement in PaO2: FiO2 ratio (p = 0.046) following low-dose steroid treatment, unlike patients with non-COVID ARDS (n = 16) (p = 0.529). Patients with COVID-19 ARDS had a greater fall in CRP compared to patients with non-COVID ARDS, albeit not statistically significant (p = 0.07). Our novel findings highlight differences in the underlying physiological and immunological phenotypes between COVID-19 and non-COVID ARDS, with implications for future ARDS studies

Arulkumaran, N

Longobardo, A

Montanari, C

Shulman, R

Singer, M

Snow, TAC

English

UCL Discovery

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Journal of Critical Care 62 (2021) 46–48Contents lists available at ScienceDirectJournal of Critical Carej ourna l homepage: www. journa ls .e lsev ie r .com/ journa l -o f -c r i t i ca l -ca reCOVID-19 and non-COVID ARDS patients demonstrate a distinctresponse to low dose steroids- A retrospective observational studyAlessia Longobardo 1, Timothy Arthur Chandos Snow 1, Cecilia Montanari, Robert Shulman,Mervyn Singer, Nishkantha Arulkumaran ⁎Bloomsbury Institute of Intensive Care Medicine, University College London, UKAbbreviation list: ARDS, Acute respiratory distress syndIL-6, interleukin-6; PaO2, FiO2 ratio: Ratio of partial pressspired oxygen; TNFR1, soluble tumour necrosis factor rece⁎ Corresponding author at: Bloomsbury Institute of InteCollege London, Gower St, London WC1E 6BT, United KingE-mail address: nisharulkumaran@doctors.org.uk (N. A1 Authors contributed equallyhttps://doi.org/10.1016/j.jcrc.2020.11.0120883-9441/© 2020 Elsevier Inc. All rights reserved.a b s t r a c ta r t i c l e i n f oKeywords:SteroidsARDSInflammationCOVID-19Patients with COVID-19 ARDS have distinct physiological and immunological phenotypes compared to patientswith non-COVID ARDS. Patients with COVID-19 ARDS (n = 32) had a significant improvement in PaO2: FiO2ratio (p = 0.046) following low-dose steroid treatment, unlike patients with non-COVID ARDS (n = 16) (p =0.529). Patientswith COVID-19ARDS had a greater fall in CRP compared to patients with non-COVIDARDS, albeitnot statistically significant (p = 0.07). Our novel findings highlight differences in the underlying physiologicaland immunological phenotypes between COVID-19 and non-COVID ARDS, with implications for future ARDSstudies.© 2020 Elsevier Inc. All rights reserved.Dear Editor,Patients with COVID-19 ARDS have distinct physiological [1,2] andimmunological [3,4] phenotypes compared to patients with non-COVID ARDS. We hypothesised that differences in immunological andphysiological phenotypes between patients with COVID-19 and non-COVID ARDS are associatedwith differences in changes to inflammationand PaO2: FiO2 ratio in response to steroid treatment.We conducted a single-centre retrospective case-control study ofCOVID-19 patients with ARDS treated with low-dose systemic steroidsat University College London Hospital between 1st March and 30thJune 2020. During the COVID-19 pandemic, methylprednisolone wasprescribed for ARDS with persistent or worsening hypoxaemia, hydro-cortisone was prescribed for septic shock. As the period of data collec-tion preceded the results of the RECOVERY study, dexamethasone wasnot routinely prescribed for patients with COVID-19. Data on consecu-tive patients with non-COVID ARDS receiving steroids between January2018 to March 2020 were used as comparison.Data were extracted from electronic healthcare records on patientdemographics, corticosteroid type and dose, and sequential C-reactiveprotein (CRP), neutrophil, and temperature. Where patients receivedmore than one course of steroid, only the first course of steroid wasrome; CRP, C-reactive protein;ure of oxygen to fraction of in-ptor superfamily member 1A.nsive CareMedicine, Universitydom.rulkumaran).considered. We included patients receiving either methylprednisolone1–2 mg/kg daily or hydrocortisone 50-100 mg four times daily. As thehalf-life of CRP is 19 h [5], we collected data on CRP change 3 days fol-lowing steroid administration. Ten patients in the non-COVID groupand 12 patients in the COVID-19 group did not survive for at least3 days following steroid administration and were therefore excluded.Haemato-oncology patients (n= 18) who had received recent chemo-therapy were excluded as the inflammatory response could be con-founded by chemotherapy.Continuous and categorical variables are reported as median (inter-quartile range) and n (%), respectively. For comparison of continuousvariables, Mann Whitney U test for comparison between 2 groups andWilcoxon sign rank test was used to assess change of CRP, PaO2: FiO2ratio, neutrophil count, and daily peak temperature. Categorical datawere compared using the chi-squared test. Statistical analysis was per-formed, and graphs constructed using Prism (GraphPad Software, Ver-sion 5.0d, San Diego, California, US).A total of 32 patients with non-COVID ARDS and 16 patients withCOVID-19 ARDS were included in the final analysis. Patients withCOVID-19 ARDS received steroids later following ICU admission (p =0.002) and had a lower PaO2: FiO2 ratio on initiation of steroids (p =0.001) compared to patients with non-COVID ARDS (Table 1). Age, gen-der, CRP on day of steroid initiation, requirement for renal replacementtherapy, vasopressors, mechanical ventilation, and hospital mortalitywere similar between patients with COVID-19 ARDS and non-COVIDARDS (Table 1).Patients with COVID-19 ARDS and non-COVID ARDS had significantreductions in CRP following initiation of steroids. Only patients withCOVID-19 ARDS had a significant improvement in PaO2: FiO2 ratio (93Table 1Demographics and baseline characteristics of patient with COVID-19 and non-COVIDARDS.COVID-19 ARDS Non-COVID ARDS P-valueN = 16 N = 32Age (years) 61 (51–65) 56 (38–68) 0.622Gender: Male 12/16 (75%) 14/32 (44%) 0.065Days from ICU admission to steroid 11 (2–14) 1 (0–5) 0.002Mechanical ventilation 14/16 (88%) 28/32 (88%) >0.999Renal replacement therapy 10/16 (63%) 20/32 (63%) >0.999Vasopressors 14/16 (88%) 23/32 (72%) 0.225Day 0 PaO2: FiO2 ratio (mmHg) 91 (75–133) 155 (127–192) 0.001Day 0 CRP (mg/L) 253 (145–365) 178 (119–302) 0.365Hospital mortality 11/16 (69%) 23/32 (72%) >0.999A. Longobardo, T.A.C. Snow, C. Montanari et al. Journal of Critical Care 62 (2021) 46–48(76–147) to 142 (85–214) mmHg; p = 0.046) following steroid treat-ment, unlike patients with non-COVID ARDS (155 (127–193) vs. 148(114-207)mmHg; p = 0.529). Only patients with non-COVID ARDShad a significant reduction in temperature with steroid treatment(Fig. 1). Patients with COVID-19 ARDS had a greater fall in CRP com-pared to patients with non-COVID ARDS following steroid treatment, al-beit not statistically significant (−56(−74 to −28)% vs. −34 (−63 to12)%; p = 0.07). Neither patients with COVID-19 ARDS or non-COVIDARDS demonstrated any change in neutrophil count following steroidtreatment (Fig. 1).We report a distinct response in CRP and PaO2: FiO2 ratio to steroidsbetween COVID-19 ARDS and non-COVID ARDS patients. The underly-ing pathophysiology of COVID-19 ARDS is distinct to non-COVIDARDS, with significant differences in serum levels of interleukin-6(IL-6) and soluble tumour necrosis factor receptor superfamilymember1A (TNFR1) between patients with COVID-19 and non-COVID ARDS [3].COVID-19 ARDS is associated with a marked vasculopathy, distinct toFig. 1. Change in CRP, PaO2: FiO2 ratio, neutrophil count, and temperature between patient (a-dsteroid treatment (either hydrocortisone (50-100 mg 6- hourly) or methylprednisolone (1-significant reduction in CRP over 3 days from steroid initiation. Only patients with (b) COVID-patients with (f) Non-COVID-19 ARDS. Core temperature however, only falls in patients wittreatment. Data represent median and interquartile range. Data are assessed using Wilcoxon s47other forms of ARDS [6]. It is unclear if has any implications on respon-siveness to steroids, given the success of steroid treatment in pulmonaryvasculopathies [7]. A higher CRP is associated with survival in patientswith non-COVID ARDS, although the opposite has been observed withCOVID-19ARDS [8,9]. As such, the ability of steroid treatment to amelio-rate the underlying inflammatory process may be more advantageousin COVID-19 compared to non-COVID ARDS. This may underpin the as-sociation between steroid use and reducedmortality among critically illpatients with COVID-19 [10]; (although heavily weighted by theRECOVERY study), whereas the benefit of steroids in non-COVID ARDShas been less clear cut.As with all retrospective analyses, we acknowledge the possibility ofresidual confounding, and that results are associative. The small numberof patients included also warrants caution in interpreting the findings.There were differences in baseline demographics between groups andthe use of steroids was confounded by indication bias and timing of ini-tiation.Wewere unable to adjust for these differences due to the limitedsample size.We describe novel findings on the distinct responses in CRP andPaO2: FiO2 ratio between ARDS patients with and without COVID-19.Our data highlight the importance of defining the underlying aetiologyand immune phenotype to enable trial enrichment, therefore targetingpatients most likely to benefit for future ARDS studies.Ethics approvalEthics to report observational data on critical care patients at UCLH iscovered by the National Research Ethics Service (14/LO/103).Consent for publicationN/A.) with and (e- h)without COVID-19 between initiation of low dose steroid and 3 days after2 mg/kg daily). Patients with (a) COVID-19 and (e) Non-COVID-19 ARDS demonstrate19 ARDS demonstrate an increase in PaO2: FiO2 ratio following steroid treatment, but noth (h) Non-COVID-19 ARDS but not in those with (d) COVID-19 ARDS following steroidign rank test.A. Longobardo, T.A.C. Snow, C. Montanari et al. Journal of Critical Care 62 (2021) 46–48Availability of data and materialsUpon reasonable request.FundingNone.Authors' contributionsStudy design (NA), data collection (AL, RS, CM), Statistics (NA),Drafting manuscript (NA, TS). All authors read and approved the finalmanuscript.Declaration of Competing InterestNone.AcknowledgementsUCLH Intensive Care.48References[1] Gattinoni L, Chiumello D, Caironi P, et al. COVID-19 pneumonia: different respiratorytreatments for different phenotypes? Intensive Care Med 2020. https://doi.org/10.1007/s00134-020-06033-2.[2] Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D. Covid-19 doesnot Lead to a “typical” acute respiratory distress syndrome. Am J Respir Crit CareMed 2020. https://doi.org/10.1164/rccm.202003-0817LE.[3] Sinha P, Calfee CS, Cherian S, et al. Prevalence of phenotypes of acute respiratory dis-tress syndrome in critically ill patients with COVID-19: a prospective observationalstudy. Lancet Respir Med 2020. https://doi.org/10.1016/S2213-2600(20)30366-0.[4] Sinha P, Matthay MA, Calfee CS. Is a “Cytokine Storm” Relevant to COVID-19? JAMAIntern Med 2020. https://doi.org/10.1001/jamainternmed.2020.3313.[5] Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003;111:1805–12. https://doi.org/10.1172/JCI18921.[6] Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular Endothelialitis,thrombosis, and angiogenesis in Covid-19. N Engl J Med 2020;120-8:383. https://doi.org/10.1056/NEJMoa2015432.[7] Frankel SK, Schwarz MI. The pulmonary vasculitides. Am J Respir Crit Care Med2012;216-24:186. https://doi.org/10.1164/rccm.201203-0539CI.[8] Bajwa EK, Khan UA, Januzzi JL, Gong MN, Thompson BT, Christiani DC. Plasma C-reactive protein levels are associated with improved outcome in ARDS. Chest2009;471-80:136. https://doi.org/10.1378/chest.08-2413.[9] Manson JJ, Crooks C, Naja M, et al. COVID-19-associated hyperinflammation and es-calation of patient care: a retrospective longitudinal cohort study. Lancet Rheumatol2020;2:e594–602. https://doi.org/10.1016/S2665-9913(20)30275-7.[10] WHO REACT Working Group, Sterne JAC, Murthy S, et al. Association Between Ad-ministration of Systemic Corticosteroids and Mortality Among Critically Ill PatientsWith COVID-19: A Meta-analysis. JAMA 2020. https://doi.org/10.1001/jama.2020.17023.

COVID-19 and non-COVID ARDS patients demonstrate a distinct response to low dose steroids- A retrospective observational study

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COVID-19 and non-COVID ARDS patients demonstrate a distinct response to low dose steroids- A retrospective observational study

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