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.