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      Risk Factors for Mortality after COVID-19 in Patients with Preexisting Interstitial Lung Disease

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          To the Editor: Patients with preexisting interstitial lung disease (ILD) may be at high risk for severe coronavirus disease (COVID-19) because of impaired lung function, propensity to develop acute exacerbation of pulmonary fibrosis, or immunomodulatory medications that may interact with viral clearance or pathogenesis (1, 2). Previous studies found that patients with ILDs had an increased risk of death compared with control subjects matched for age, sex, comorbidities, and/or race (3, 4). However, whether the type of ILD may influence the outcome of COVID-19 is unknown. Here, we aimed to compare mortality of COVID-19 between patients with fibrotic idiopathic ILD, including idiopathic pulmonary fibrosis (IPF), with those with other types of ILD. In this multicentric observational survey of specialized centers, we analyzed the survival of COVID-19 in patients with ILDs and compared mortality rates among those with fibrotic idiopathic ILDs, including IPF, with those with other ILDs. Patients were eligible if they had preexisting ILD and if they had COVID-19 during the study period confirmed by RT-PCR or definite clinical manifestations (acute onset of fever, flu-like symptoms, headache, and anosmia), typical features on chest computed tomography and positive serology for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with lung transplantation were excluded. Consecutive cases were collected using a deidentified case report form through the French rare lung disease network (OrphaLung) between the onset of the outbreak in France to May 28, 2020. Data collected included demographics, medical history, comorbidities, last available lung function in stable condition, and treatment received at the time of COVID-19. The primary outcome was death, censored at Day 30 of COVID-19. No imputation was applied for missing data. Univariable and multivariable Cox regression analyses were used to investigate predictors of mortality. For multivariable analysis, we included into the model variables that were associated with mortality in univariable analysis with a P value of less than 0.10, as well as glucocorticoid therapy used to treat COVID-19, as it was considered clinically relevant. Medications to treat ILD were excluded from the prediction model to limit collinearity with the underlying diagnosis. This study was formally approved by the institutional review boards of the French learned society for respiratory medicine (Comité d’Ethique Pour la Recherche Observationnelle 2020-036; August 25, 2020) and the Hospices Civils de Lyon (May 13, 2020), which waived the need for written informed consent (April 14, 2020). A total of 123 patients were included (Table 1), with a median age of 64 years (interquartile range, 58–74 yr), and 66% were of male sex. Forty-eight patients (39%) had fibrotic idiopathic ILD, including IPF (n = 20; median age, 72 yr), idiopathic nonspecific pneumonia (n = 8; median age, 66.5 yr), and other fibrotic idiopathic ILDs (n = 20; median age, 73.5 yr). Other diagnostic categories included connective tissue disease–associated ILD (n = 27; median age, 57 yr), systemic vasculitis (n = 7; median age, 61 yr), sarcoidosis (n = 16; median age, 56 yr), and other ILDs (n = 25; median age, 64.5 yr). Patients were receiving antifibrotic drugs (10%), glucocorticoids (38%), or other immunosuppressive drugs (37%). COVID-19 was confirmed by RT-PCR in 91% of patients and by symptoms, computed tomography scan, and serology in 9% of patients. COVID-19–related medications were prescribed for COVID-19 in 35% of cases. Table 1. Main Characteristics of the Study Population and Outcomes by ILD Diagnosis   Fibrotic Idiopathic ILD (n = 48) Other ILDs (n = 75) All (N = 123) P Value Patient characteristics          Sex, n (%)       0.04   F 11 (23) 31 (41) 42 (34)   M 37 (77) 44 (59) 81 (66)  Age, mean ± SD, yr 71 ± 11 60 ± 18 64 ± 16 0.02  Body mass index, mean ± SD, kg ⋅ m−2 26 ± 4 27 ± 3 27 ± 5 0.29 Comorbidities, n (%)          Obesity 8 (17) 16 (21) 24 (20) 0.55  Hypertension 24 (50) 29 (39) 53 (43) 0.26  Cardiovascular disease 16 (33) 12 (16) 28 (23) 0.03  Diabetes mellitus 17 (35) 19 (25) 36 (29) 0.27  Chronic kidney disease 4 (8) 7 (9) 11 (9) 0.81  Cancer or hemopathy 3 (6) 4 (5) 7 (6) 0.86  Pulmonary hypertension 7 (15) 8 (11) 15 (12) 0.50 Pulmonary characteristics          mMRC, mean ± SD 1.9 ± 1.0 1.7 ± 1.1 1.7 ± 1.1 0.26  FVC% predicted, mean ± SD 76 ± 22 81 ± 25 79 ± 24 0.28  FVC% categories, n (%)       0.14   <50 7 (15) 4 (5) 11 (15)*   50–70 8 (17) 19 (25) 27 (36)*   >70 27 (56) 45 (60) 72 (96)*  Corrected Dl CO% predicted, mean ± SD 46 ± 17 54 ± 21 51 ± 20 0.06  Dl CO% categories, n (%)       0.62   <40 12 (25) 15 (20) 27 (22)   40–60 13 (27) 22 (29) 35 (28)   >60 12 (25) 25 (33) 37 (30)  Oxygen supplementation at home, n (%) 12 (25) 10 (13) 22 (18) 0.12 Treatment at baseline, n (%)          Antifibrotic medication 12 (25) 0 (0) 12 (10) <0.01  Glucocorticoids 11 (23) 36 (48) 47 (38) 0.01  Immunosuppressive drugs 10 (21) 35 (47) 45 (37) <0.01 COVID-19–related medications, n (%)          Any medication 18 (37) 25 (33) 43 (35) 0.64  Lopinavir/ritonavir 2 (4) 6 (8) 8 (7) 0.40  Azithromycine 8 (17) 6 (8) 14 (11) 0.14  Hydroxychloroquine 7 (15) 8 (11) 15 (12) 0.52  Glucocorticoids 5 (10) 9 (12) 14 (11) 0.79 Outcomes, n (%)          Hospital admission       0.37   Not hospitalized 5 (10) 15 (20) 20 (16)   Hospitalized, not in ICU 32 (67) 45 (60) 77 (63)   Hospitalized in ICU 11 (23) 15 (20) 26 (21)  Dead at Day 30 17 (35) 14 (19) 31 (25) 0.04 Definition of abbreviations: COVID-19 = coronavirus disease; ILD = interstitial lung disease; mMRC = modified Medical Research Council. Comparisons used χ2 or Student’s t test when appropriate. Bold indicates P < 0.05. * These percentages were calculated from available data. Hospital admission was required in 84% of patients (90% of those with fibrotic idiopathic ILD and 80% of those with other ILDs), including 21% in ICUs. According to the reporting physician, admission modalities were appropriate in all cases (i.e., no patient was denied admission because of bed unavailability). At Day 30 of COVID-19, 17 of 48 (35%) patients with fibrotic idiopathic ILD had died compared with 14 of 75 (19%) of those with other ILDs (P = 0.04). The median time between diagnosis and death was 8 days (interquartile range, 4–15 d). Death was related to COVID-19 in all cases, including four in whom COVID-19 triggered an acute exacerbation of IPF. On univariable Cox regression analysis, mortality was significantly associated with male sex, increasing age, an underlying diagnosis of fibrotic idiopathic ILD compared with other ILDs, comorbidities (hypertension, cardiovascular disease, cancer or hemopathy, and pulmonary hypertension), lower FVC, lower Dl CO, chronic use of oxygen supplementation at home (at rest or exercise), and treatment with antifibrotic drugs (Table 2). On Cox multivariable analysis, increasing age, male sex, history of cancer/hemopathy, and the chronic use of oxygen supplementation at home remained independently predictive of mortality (Table 2). Table 2. Association with Mortality of Clinical Characteristics, Comorbidities, Lung Function, and Treatment by Cox Regression Analysis   Univariable Analysis Multivariable Analysis   HR (95% CI) P Value HR (95% CI) P Value Sex, M/F 4.22 (1.47–12.06) 0.01 3.90 (1.17–13.04) 0.03 Age, yr 1.07 (1.03–1.10) <0.01 1.07 (1.04–1.11) <0.01 Body mass index, kg ⋅ m−2 1.02 (0.96–1.09) 0.51 — — Underlying ILD, fibrotic/other 2.15 (1.06–4.35) 0.04 — — Comorbidities, yes/no          Obesity 1.01 (0.41–2.47) 0.99 — —  Hypertension 2.48 (1.18–5.21) 0.02 — —  Cardiovascular disease 3.20 (1.55–6.59) <0.01 — —  Diabetes mellitus 1.46 (0.69–3.06) 0.32 — —  Chronic kidney disease 1.81 (0.63–5.20) 0.27 — —  Cancer or hemopathy 3.21 (1.12–9.21) 0.03 5.82 (1.88–18.08) <0.01  Pulmonary hypertension 2.88 (1.22–6.83) 0.02 — — Pulmonary characteristics          FVC% predicted 0.98 (0.96–0.99) 0.02 — —  Corrected Dl CO% predicted 0.96 (0.94–0.99) <0.01 — —  Oxygen supplementation at home 4.25 (2.02–8.91) <0.01 4.56 (2.13–9.78) <0.01 Treatment at baseline, yes/no          Antifibrotic medication 3.09 (1.27–7.55) 0.01 — —  Glucocorticoids 1.06 (0.51–2.18) 0.88 — —  Immunosuppressive drugs 0.58 (0.26–1.30) 0.19 — — COVID-19–related medications, yes/no          Any 1.43 (0.70–2.92) 0.32 — —  Lopinavir/ritonavir 1.61 (0.49–5.30) 0.43 — —  Azithromycine 0.23 (0.03–1.72) 0.15 — —  Hydroxychloroquine 1.58 (0.60–4.11) 0.35 — —  Glucocorticoids 1.15 (0.40–3.28) 0.80 — — Definition of abbreviations: CI = confidence interval; COVID-19 = coronavirus disease; HR = hazard ratio; ILD = interstitial lung disease. Bold indicates P < 0.05. Here, we report a series of 123 patients with ILD who had COVID-19 and were followed in the French network of rare pulmonary disease expert centers. This relatively low number likely reflects that patients with ILD stayed at home during the lockdown period and rigorously adopted preventive measures to protect themselves from infection (5). The case fatality rate was 35% among subjects with idiopathic fibrotic ILD and was 19% in those with another ILD. Of note, the mortality among subjects with an ILD other than fibrotic idiopathic ILD was comparable with that reported in the global French population hospitalized for COVID-19 (18.1%) (6). Multivariable analysis indicated that the greater mortality among subjects with fibrotic idiopathic ILD was attributable to age and comorbidities already identified as risk factors of severity in COVID-19 (7, 8). Chronic home oxygen supplementation was also associated with greater mortality, reflecting the severity of the underlying ILD, independently of the ILD diagnostic subgroup. This finding is consistent with that of a large prospective observational cohort study, in which peripheral oxygen saturation on room air lower than 92% was significantly associated with in-hospital mortality (7), and with a study of patients with ILD before developing COVID-19, in which an FVC of <80% predicted was associated with mortality (4). Mortality in our cohort was directly related to COVID-19 and followed an acute exacerbation of fibrotic ILD triggered by the viral infection in four cases. However, distinguishing an infection from a triggered acute exacerbation can be challenging (9). Long-term treatment with glucocorticoids or immunosuppressive drugs was not associated with a worse prognosis, in contrast to previous suggestions (10). This study has limitations, including the small sample size, retrospective design, and absence of model validation. Individuals who were not hospitalized may have been missed; however, this does not influence the case fatality rate among patients who were admitted. A longer follow-up is required to assess potential irreversible pulmonary fibrosis secondary to COVID-19 (11) because delayed improvement may occur (12). In conclusion, this study found a high mortality rate due to COVID-19 in patients with preexisting fibrotic idiopathic ILD compared with those with other ILDs, which was mostly attributable to age, male sex, history of cancer, and severity of the underlying ILD as reflected by the chronic use of supplemental oxygen. The potential long-term impact of COVID-19 on the course of ILD remains to be determined.

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          Predictors of Mortality for Patients with COVID-19 Pneumonia Caused by SARS-CoV-2: A Prospective Cohort Study

          To identify factors associated with the death for patients with COVID-19 pneumonia caused by a novel coronavirus SARS-CoV-2. All clinical and laboratory parameters were collected prospectively from a cohort of patients with COVID-19 pneumonia who were hospitalised to Wuhan Pulmonary Hospital, Wuhan City, Hubei Province, China, between December 25, 2019 and February 7, 2020. Univariate and multivariate logistic regression was performed to investigate the relationship between each variable and the risk for death of COVID-19 pneumonia patients. A total of 179 patients with COVID-19 pneumonia (97 male and 82 female) were included in the present prospective study, of whom 21 died. Univariate and multivariate logistic regression analysis revealed that age ≥65 years (odd ratio, 3.765; 95% confidence interval, 1.146‒17.394; p=0.023), preexisting concurrent cardiovascular or cerebrovascular diseases (2.464; 0.755‒8.044; p=0.007), CD3+CD8+ T cells ≤75 cell·μL−1 (3.982; 1.132‒14.006; p<0.001), and cardiac troponin I≥0.05 ng·mL−1 (4.077; 1.166‒14.253; p<0.001) were associated with an increase in risk of mortality of COVID-19 pneumonia. In the sex‒, age‒, and comorbid illness-matched case study, CD3+CD8+ T cells ≤75 cell·μL−1 and cardiac troponin I≥0.05 ng·mL−1 remained to be the predictors for high mortality of COVID-19 pneumonia. We identified four risk factors, age ≥65 years, preexisting concurrent cardiovascular or cerebrovascular diseases, CD3+CD8+ T cells ≤75 cell·μL−1, and cardiac troponin I≥0.05 ng·mL−1, especially the latter two factors, were predictors for mortality of COVID-19 pneumonia patients.
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            Estimating the burden of SARS-CoV-2 in France

            France has been heavily affected by the SARS-CoV-2 epidemic and went into lockdown on the 17 March 2020. Using models applied to hospital and death data, we estimate the impact of the lockdown and current population immunity. We find 3.6% of infected individuals are hospitalized and 0.7% die, ranging from 0.001% in those 80ya. Across all ages, men are more likely to be hospitalized, enter intensive care, and die than women. The lockdown reduced the reproductive number from 2.90 to 0.67 (77% reduction). By 11 May 2020, when interventions are scheduled to be eased, we project 2.8 million (range: 1.8–4.7) people, or 4.4% (range: 2.8–7.2) of the population, will have been infected. Population immunity appears insufficient to avoid a second wave if all control measures are released at the end of the lockdown.
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              Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy

              Summary In December, 2019, reports emerged from Wuhan, China, of a severe acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). By the end of April, 2020, over 3 million people had been confirmed infected, with over 1 million in the USA alone, and over 215 000 deaths. The symptoms associated with COVID-19 are diverse, ranging from mild upper respiratory tract symptoms to severe acute respiratory distress syndrome. The major risk factors for severe COVID-19 are shared with idiopathic pulmonary fibrosis (IPF), namely increasing age, male sex, and comorbidities such as hypertension and diabetes. However, the role of antifibrotic therapy in patients with IPF who contract SARS-CoV-2 infection, and the scientific rationale for their continuation or cessation, is poorly defined. Furthermore, several licensed and potential antifibrotic compounds have been assessed in models of acute lung injury and viral pneumonia. Data from previous coronavirus infections such as severe acute respiratory syndrome and Middle East respiratory syndrome, as well as emerging data from the COVID-19 pandemic, suggest there could be substantial fibrotic consequences following SARS-CoV-2 infection. Antifibrotic therapies that are available or in development could have value in preventing severe COVID-19 in patients with IPF, have the potential to treat severe COVID-19 in patients without IPF, and might have a role in preventing fibrosis after SARS-CoV-2 infection.
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                Author and article information

                Journal
                Am J Respir Crit Care Med
                Am J Respir Crit Care Med
                ajrccm
                American Journal of Respiratory and Critical Care Medicine
                American Thoracic Society
                1073-449X
                1535-4970
                15 January 2021
                15 January 2021
                15 January 2021
                15 January 2021
                : 203
                : 2
                : 245-249
                Affiliations
                [ 1 ]Hospices Civils de Lyon and Université Claude Bernard Lyon 1

                Lyon, France
                [ 2 ]Assistance Publique-Hôpitaux de Paris and Université Sorbonne Paris Nord

                Bobigny, France
                [ 3 ]Assistance Publique-Hôpitaux de Paris Hôpital Bichat and Université

                Bichat-Claude Bernard

                Paris, France
                [ 4 ]Lausanne University Hospital and University of Lausanne

                Lausanne, Switzerland
                [ 5 ]Assistance Publique-Hôpitaux de Paris Hôpital Tenon and Sorbonne

                Université

                Paris, France
                [ 6 ]Centre Hospitalier Universitaire de Tours

                Tours, France
                [ 7 ]Hôpitaux Universitaires de Strasbourg

                Strasbourg, France
                [ 8 ]Hôpital Européen Georges Pompidou

                Paris, France

                and
                [ 9 ]Centre Hospitalier Régional Universitaire de Lille

                Lille, France
                Author notes
                [* ]Corresponding author (e-mail: vincent.cottin@ 123456chu-lyon.fr ).
                Article
                202007-2638LE
                10.1164/rccm.202007-2638LE
                7874431
                33252997
                902b1810-140b-4630-8e6b-02de8bda0a74
                Copyright © 2021 by the American Thoracic Society

                This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 ( http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints, please contact Diane Gern ( dgern@ 123456thoracic.org ).

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