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          Abstract

          Novel coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome virus (SARS‐CoV‐2) has become a global health care crisis. The Centers for Disease Control and Prevention (CDC) lists immunocompromised patients, including those requiring immunosuppression following renal transplantation, as high risk for severe disease from SARS‐CoV‐2. Treatment for other viral infections in renal transplant recipients often includes a reduction in immunosuppression; however, no current guidelines are available recommending the optimal approach to managing immunosuppression in the patients who are infected with SARS‐CoV‐2. It is currently advised to avoid corticosteroids in the treatment of SARS‐CoV‐2 outside of critically ill patients. Recently published cases describing inpatient care of COVID‐19 in renal transplant recipients differ widely in disease severity, time from transplantation, baseline immunosuppressive therapy, and the modifications made to immunosuppression during COVID‐19 treatment. This review summarizes and compares inpatient immunosuppressant management strategies of recently published reports in the renal transplant population infected with SARS‐CoV‐2 and discusses the limitations of corticosteroids in managing immunosuppression in this patient population.

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          Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China

          Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that was first reported in Wuhan, China, and has subsequently spread worldwide. Risk factors for the clinical outcomes of COVID-19 pneumonia have not yet been well delineated.
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            Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury

            The 2019 novel coronavirus (2019-nCoV) outbreak is a major challenge for clinicians. The clinical course of patients remains to be fully characterised, little data are available that describe the disease pathogenesis, and no pharmacological therapies of proven efficacy yet exist. Corticosteroids were widely used during the outbreaks of severe acute respiratory syndrome (SARS)-CoV 1 and Middle East respiratory syndrome (MERS)-CoV, 2 and are being used in patients with 2019-nCoV in addition to other therapeutics. 3 However, current interim guidance from WHO on clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected (released Jan 28, 2020) advises against the use of corticosteroids unless indicated for another reason. 4 Understanding the evidence for harm or benefit from corticosteroids in 2019-nCoV is of immediate clinical importance. Here we discuss the clinical outcomes of corticosteroid use in coronavirus and similar outbreaks (table ). Table Summary of clinical evidence to date Outcomes of corticosteroid therapy * Comment MERS-CoV Delayed clearance of viral RNA from respiratory tract 2 Adjusted hazard ratio 0·4 (95% CI 0·2–0·7) SARS-CoV Delayed clearance of viral RNA from blood 5 Significant difference but effect size not quantified SARS-CoV Complication: psychosis 6 Associated with higher cumulative dose, 10 975 mg vs 6780 mg hydrocortisone equivalent SARS-CoV Complication: diabetes 7 33 (35%) of 95 patients treated with corticosteroid developed corticosteroid-induced diabetes SARS-CoV Complication: avascular necrosis in survivors 8 Among 40 patients who survived after corticosteroid treatment, 12 (30%) had avascular necrosis and 30 (75%) had osteoporosis Influenza Increased mortality 9 Risk ratio for mortality 1·75 (95% CI 1·3–2·4) in a meta-analysis of 6548 patients from ten studies RSV No clinical benefit in children10, 11 No effect in largest randomised controlled trial of 600 children, of whom 305 (51%) had been treated with corticosteroids CoV=coronavirus. MERS=Middle East respiratory syndrome. RSV=respiratory syncytial virus. SARS=severe acute respiratory syndrome. * Hydrocortisone, methylprednisolone, dexamethasone, and prednisolone. Acute lung injury and acute respiratory distress syndrome are partly caused by host immune responses. Corticosteroids suppress lung inflammation but also inhibit immune responses and pathogen clearance. In SARS-CoV infection, as with influenza, systemic inflammation is associated with adverse outcomes. 12 In SARS, inflammation persists after viral clearance.13, 14 Pulmonary histology in both SARS and MERS infections reveals inflammation and diffuse alveolar damage, 15 with one report suggesting haemophagocytosis. 16 Theoretically, corticosteroid treatment could have a role to suppress lung inflammation. In a retrospective observational study reporting on 309 adults who were critically ill with MERS, 2 almost half of patients (151 [49%]) were given corticosteroids (median hydrocortisone equivalent dose [ie, methylprednisolone 1:5, dexamethasone 1:25, prednisolone 1:4] of 300 mg/day). Patients who were given corticosteroids were more likely to require mechanical ventilation, vasopressors, and renal replacement therapy. After statistical adjustment for immortal time and indication biases, the authors concluded that administration of corticosteroids was not associated with a difference in 90-day mortality (adjusted odds ratio 0·8, 95% CI 0·5–1·1; p=0·12) but was associated with delayed clearance of viral RNA from respiratory tract secretions (adjusted hazard ratio 0·4, 95% CI 0·2–0·7; p=0·0005). However, these effect estimates have a high risk of error due to the probable presence of unmeasured confounders. In a meta-analysis of corticosteroid use in patients with SARS, only four studies provided conclusive data, all indicating harm. 1 The first was a case-control study of SARS patients with (n=15) and without (n=30) SARS-related psychosis; all were given corticosteroid treatment, but those who developed psychosis were given a higher cumulative dose than those who did not (10 975 mg hydrocortisone equivalent vs 6780 mg; p=0·017). 6 The second was a randomised controlled trial of 16 patients with SARS who were not critically ill; the nine patients who were given hydrocortisone (mean 4·8 days [95% CI 4·1–5·5] since fever onset) had greater viraemia in the second and third weeks after infection than those who were given 0·9% saline control. 5 The remaining two studies reported diabetes and avascular necrosis as complications associated with corticosteroid treatment.7, 8 A 2019 systematic review and meta-analysis 9 identified ten observational studies in influenza, with a total of 6548 patients. The investigators found increased mortality in patients who were given corticosteroids (risk ratio [RR] 1·75, 95% CI 1·3–2·4; p=0·0002). Among other outcomes, length of stay in an intensive care unit was increased (mean difference 2·1, 95% CI 1·2–3·1; p<0·0001), as was the rate of secondary bacterial or fungal infection (RR 2·0, 95% CI 1·0–3·8; p=0·04). Corticosteroids have been investigated for respiratory syncytial virus (RSV) in clinical trials in children, with no conclusive evidence of benefit and are therefore not recommended. 10 An observational study of 50 adults with RSV infection, in which 33 (66%) were given corticosteroids, suggested impaired antibody responses at 28 days in those given corticosteroids. 17 Life-threatening acute respiratory distress syndrome occurs in 2019-nCoV infection. 18 However, generalising evidence from acute respiratory distress syndrome studies to viral lung injury is problematic because these trials typically include a majority of patients with acute respiratory distress syndrome of non-pulmonary or sterile cause. A review of treatments for acute respiratory distress syndrome of any cause, based on six studies with a total of 574 patients, 19 concluded that insufficient evidence exists to recommend corticosteroid treatment. 20 Septic shock has been reported in seven (5%) of 140 patients with 2019-nCoV included in published reports as of Jan 29, 2020.3, 18 Corticosteroids are widely used in septic shock despite uncertainty over their efficacy. Most patients in septic shock trials have bacterial infection, leading to vasoplegic shock and myocardial insufficiency.21, 22 In this group, there is potential that net benefit might be derived from steroid treatment in severe shock.21, 22 However, shock in severe hypoxaemic respiratory failure is often a consequence of increased intrathoracic pressure (during invasive ventilation) impeding cardiac filling, and not vasoplegia. 23 In this context, steroid treatment is unlikely to provide a benefit. No clinical data exist to indicate that net benefit is derived from corticosteroids in the treatment of respiratory infection due to RSV, influenza, SARS-CoV, or MERS-CoV. The available observational data suggest increased mortality and secondary infection rates in influenza, impaired clearance of SARS-CoV and MERS-CoV, and complications of corticosteroid therapy in survivors. If it is present, the effect of steroids on mortality in those with septic shock is small, and is unlikely to be generalisable to shock in the context of severe respiratory failure due to 2019-nCoV. Overall, no unique reason exists to expect that patients with 2019-nCoV infection will benefit from corticosteroids, and they might be more likely to be harmed with such treatment. We conclude that corticosteroid treatment should not be used for the treatment of 2019-nCoV-induced lung injury or shock outside of a clinical trial.
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              Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19)

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                Author and article information

                Contributors
                kristen.johnson001@mercyhealth.com
                Journal
                Pharmacotherapy
                Pharmacotherapy
                10.1002/(ISSN)1875-9114
                PHAR
                Pharmacotherapy
                John Wiley and Sons Inc. (Hoboken )
                0277-0008
                1875-9114
                26 May 2020
                : 10.1002/phar.2410
                Affiliations
                [ 1 ] Department of Pharmacy Services Mercy Health Saint Mary’s Grand Rapids Michigan USA
                [ 2 ] Kidney Transplant Center Mercy Health Saint Mary’s Grand Rapids Michigan USA
                Author notes
                [*] [* ] Address for correspondence: Kristen M. Johnson, Department of Pharmacy Services, Mercy Health Saint Mary’s, Grand Rapids, MI, USA; e‐mail: kristen.johnson001@ 123456mercyhealth.com

                Author information
                https://orcid.org/0000-0002-4105-1811
                https://orcid.org/0000-0002-9189-0752
                Article
                PHAR2410
                10.1002/phar.2410
                7267490
                32339304
                9fe16406-9b8d-4bf7-b016-1c40916eda93
                © 2020 Pharmacotherapy Publications, Inc.

                This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

                History
                Page count
                Figures: 1, Tables: 2, Pages: 8, Words: 10513
                Categories
                Review of Therapeutics
                Review of Therapeutics
                Custom metadata
                2.0
                corrected-proof
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.3 mode:remove_FC converted:03.06.2020

                covid‐19,immunosuppression,sars‐cov‐2,coronavirus,renal transplant,corticosteroid

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