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 DlCO% predicted, mean ± SD | 46 ± 17 | 54 ± 21 | 51 ± 20 | 0.06 |
| DlCO% 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 DlCO, 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 DlCO% 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.
Supplementary Material
Footnotes
Supported by the Hospices Civils de Lyon and the University of Lyon.
Author Contributions: Substantial contributions to the conception or design of the work, analysis of the data, and drafting the manuscript: L.G. and V.C. Acquisition and interpretation of data for the work: all authors. Critically revising the manuscript for important intellectual content: all authors. Final approval of the version submitted for publication: all authors. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: all authors.
OrphaLung Network Collaborators: Kaïs Ahmad (Lyon), Melisande Baravalle (Marseille), Philippe Bonniaud (Dijon), Jacques Cadranel (Paris), Mathieu Canuet (Strasbourg), Bruno Crestani (Paris), Jean-Christophe Dubus (Marseille), Antoine Froidure (Bruxelles, Belgium), Sarah Froidure (Lille), Frédéric Gagnadoux (Angers), Clément Gauvain (Lille), Benoit Godbert (Metz), Anne Gondouin (Besançon), Violaine Giraud (Boulogne), Tiphaine Guy (Vannes), Mouhamad Nasser (Lyon), Hilario Nunes (Bobigny), Julie Perrin (Metz), Stéphane Raymond (Metz), Yasmine Rebaïne (Lyon), Martine Reynaud-Gaubert (Marseille), Frédéric Schlemmer (Créteil), and Julie Traclet (Lyon).
Originally Published in Press as DOI: 10.1164/rccm.202007-2638LE on November 30, 2020
Author disclosures are available with the text of this letter at www.atsjournals.org.
Contributor Information
Collaborators: on behalf of the OrphaLung Network
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