Patient demographics
The most common ILD type was IPF, accounting for 58 % of the 237 patients. The median follow-up time of the patients was 4.7 years. The hospital mortality was 11 % with no statistically significant difference between IPF and non-IPF cases. The majority of the patients (87 %) had died at the end of the follow-up time, with more survivors among the non-IPF patients than in IPF. Median survival time from diagnosis in IPF patients was significantly shorter, e.g. 3.5 years, compared with non-IPF patients who had 7.8 years’ median survival (p<0.001, log rank-test). The post-hospitalization survival was also shorter in IPF patients, e.g. 1.1 years, compared with non-IPF patients with a survival time of 1.9 years (p=0.001, log rank-test). Vital capacity (VC), but not forced vital capacity (FVC), and diffusion capacity for carbon monoxide (DLCO) in the non-IPF patients at diagnosis were higher than those of IPF patients; however, these differences could no longer be observed in the PTF results examined near the hospitalization date. Slightly more than every fourth patient (26 %) had ILD diagnosed during the non-elective hospital treatment period. The median time from the ILD diagnosis date to the hospitalization date in those with a previous ILD diagnosis was more than double in non-IPF patients as compared to those with IPF, namely 5.9 years compared with 2.4 years (p<0.001). ILD types and the number of patients having experienced an AE-ILD are presented in Table 2 and the characteristics of the study subjects are shown in Table 3.
TABLE 2. Patients with interstitial lung diseases (ILD) hospitalized due to acute respiratory symptoms.
Type of ILD
|
N=237
N (%)
|
Male/Female
N=144/N=93
N/N
|
AE-ILD during follow-up N=128
N (% within ILD type/% within AE-ILD)
|
IPF
|
138 (58)
|
91 /47
|
79 (57/62)
|
Asbestosis
|
22 (9.2)
|
22/0
|
10 (45/8.6)
|
Asbestosis and RA
|
2 (0.8)
|
2/0
|
1 (50/0.8)
|
NSIP
|
19 (8.0)
|
5/14
|
10 (53/7.8)
|
CHP
|
8 (3.4)
|
4/4
|
4 (50/3.1)
|
CTD-ILD
|
33 (14)
|
13/20
|
20 (61/16)
|
RA
|
26 (11)
|
12/14
|
17 (65/13)
|
SSc
|
1 (0.4)
|
1/0
|
1 (100/0.8)
|
PM
|
1 (0.4)
|
0/1
|
0
|
MCTD
|
1 (0.4)
|
0/1
|
0
|
pSS
|
2 (0.8)
|
0/2
|
2 (100/1.6)
|
pSS + SLE
|
1 (0.4)
|
0/1
|
0
|
SLE
|
1 (0.4)
|
0/1
|
0
|
DIP
|
1 0.4)
|
0/1
|
0
|
Unclassifiable ILD
|
14 (5.9)
|
7/7
|
4 (29/3.1)
|
Abbreviations: AE-ILD, acute exacerbation of interstitial lung disease; CHP, chronic hypersensitivity pneumonitis; CTD-ILD, connective tissue disease-associated interstitial lung disease; DIP, desquamative interstitial pneumonia; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; MCTD, mixed connective tissue disease; NSIP, non-specific interstitial pneumonia; PM, polymyositis; pSS, primary Sjögren’s syndrome; RA-ILD, rheumatoid arthritis-associated ILD; SLE, systemic lupus erythematosus; SSc, systemic scleroderma.
TABLE 3. Characteristics of the patients hospitalized due to acute respiratory symptoms.
Characteristic
|
Total
N=237
|
IPF
N=138
|
Other ILD
N=99
|
P-value
|
Age at diagnosis (years)
|
69±11
|
70±10
|
68±13
|
0.155
|
Age at hospitalization (years)
|
73±9.7
|
73±9.7
|
74±9.8
|
0.603
|
Gender male
|
144 (61)
|
91 (66)
|
53 (54)
|
0.054
|
PFT at diagnosis
|
|
|
|
|
VC (% of pred)#
|
72 ±16
|
70±15
|
76±17
|
0.012
|
FVC (% of pred)¢
|
74±16
|
72±15
|
76±17
|
0.090
|
FEV1 (% of pred)¢
|
78±17
|
77±16
|
79±19
|
0.225
|
FEV1/FVC (% of pred)¤
|
106±9.3
|
107±8.9
|
105±9.4
|
0.028
|
DLCO (% of pred)§
|
53±18
|
48±17
|
58±18
|
<0.001
|
PFT at hospitalization
|
|
|
|
|
VC (% of pred)##
|
60±17
|
59±15
|
62±19
|
0.340
|
FVC (% of pred)¢¢
|
63±18
|
62±16
|
65±20
|
0.297
|
FEV1 (% of pred)£
|
68±17
|
68±15
|
69±20
|
0.650
|
FEV1/FVC (% of pred)¤¤
|
108±9.2
|
109±8.9
|
107±9.5
|
0.061
|
DLCO (% of pred)§§
|
41±14
|
39±14
|
43±15
|
0.106
|
GAP at diagnosisⱠ
|
3 (2−5)
|
4 (3−5)
|
3 (2−4)
|
0.002
|
Stage I (0−3 points)
|
109 (51)
|
51 (43)
|
58 (62)
|
0.004
|
Stage II (4−5 points)
|
79 (37)
|
52 (43)
|
27 (29)
|
0.032
|
Stage III (6−8 points)
|
25 (12)
|
17 (14)
|
8 (8.6)
|
0.211
|
No former ILD diagnosis
|
62 (26)
|
37 (27)
|
25 (25)
|
0.788
|
AE-ILD during follow-up
|
128 (54.0)
|
79 (57.2)
|
49 (49.5)
|
0.238
|
Smoking at hospitalization∞
|
|
|
|
|
Current smoker
|
16 (6.9)
|
11 (8.2)
|
5 (5.1)
|
0.356
|
Ex-smoker
|
100 (43)
|
62 (46)
|
38 (39)
|
0.255
|
Non-smoker
|
116 (50)
|
61 (46)
|
55 (56)
|
0.111
|
Pack-years of ever-smokers∞∞
|
27±17
|
29±18
|
24±14
|
0.169
|
Long-term oxygen therapy at home before hospitalization µ
|
29 (12)
|
17 (13)
|
12 (12)
|
0.931
|
Time from diagnosis to hospitalization (excluding first time diagnosis), years
|
3.4 (1.2−8.1)
|
2.4 (0.9−5.5)
|
5.9 (2.3−10.7)
|
<0.001
|
Follow-up time, years
|
4.7 (1.9−9.0)
|
3.5 (1.4−6.6)
|
6.6 (3.6−11.1)
|
<0.001
|
Time from hospitalization to last follow-up date, months
|
16.5 (2.6−42.9)
|
13.5 (1.9−29.8)
|
22.0 (4.4−58.9)
|
0.008
|
1st hospitalization led to death
|
26 (11)
|
16 (12)
|
10 (10)
|
0.717
|
Deceased during the follow- up
|
206 (87)
|
127 (92)
|
79 (80)
|
0.006
|
Lung transplantation
|
7 (3.0)
|
5 (3.6)
|
2 (2.0)
|
0.702
|
Data is expressed as numbers of patients (%), means (±standard deviation) or medians (interquartile range). Changes in PFT results were calculated as follows: (PFT at hospitalization (absolute value) minus PFT at diagnosis (absolute value)) divided by PFT result (absolute value) at diagnosis. Those patients who were diagnosed with ILD during the hospital treatment period were excluded. # Data of 50 patients was missing. ¢ Data of 19 patients was missing. ¤ Data of 22 patients was missing. § Data of 29 patients was missing. ## Data of 63 patients was missing. ¢¢ Data of 36 patients was missing. £ Data of 37 patients was missing. ¤¤Data of 39 patients was missing. §§ Data of 66 patients was missing. ⱠGAP data of 24 patients was missing. ∞Data of 5 patients was missing (4 IPF, 1 other ILD). ∞∞Pack-year data of 11 ex- or current smokers was missing. µ Data of two patients missing.
Abbreviations: Dg, diagnosis; DLCO, diffusion capacity for carbon monoxide; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; ILD, interstitial lung disease; PFT, pulmonary function test; pred, predicted; VC, vital capacity.
Most hospitalizations were due to reasons other than AE-ILD
AE-ILD accounted for 96 (41 %) of all hospitalizations with no statistically significant difference between IPF and non-IPF cases (Table 4). The AE-ILD was fatal in 20 patients (IPF n=11, other ILDs n=5). In all, 32 patients of the total 237 experienced an AE-ILD later after the first non-elective hospitalization. A lower respiratory tract infection (22 %) and CV causes (7.2 %) were the most common single causes of non-ILD-related hospitalizations. A subacute ILD progression was a more common reason for acute hospitalization among IPF patients than in their non-IPF counterparts. Non-ILD-related hospitalizations for various reasons (subcategory “other” in Table 4) were more common in non-IPF patients than in IPF. The cause for hospitalization was associated with post-hospitalization survival (Figure 2). Patients with a lower respiratory tract infection had a more favorable prognosis compared with patients with an AE-ILD (Table 5). In the subgroup of non-IPF patients with a CV or a multifactorial cause for hospitalization, the post-hospitalization survival was shorter than in patients experiencing an AE-ILD (Table 5).
TABLE 4. Causes for the first non-elective hospitalizations due to acute respiratory worsening.
Parameter, No. (%)
|
Whole Group
N=237
|
IPF
N=138
|
Other ILD
N=99
|
P-value
|
AE-ILD
|
96 (41)
|
60 (44)
|
36 (36)
|
0.271
|
Triggered AE-ILD
|
8 (3.4)
|
3 (2.2)
|
5 (5.1)
|
0.284
|
No trigger
|
88 (37)
|
57 (41)
|
31 (31)
|
0.116
|
ILD-related hospitalization other than AE-ILD*
|
46 (19)
|
31 (23)
|
15 (15)
|
0.160
|
Subacute ILD progression
|
28 (12)
|
23 (17)
|
5 (5.1)
|
0.006
|
Respiratory symptoms without explanatory findings
|
9 (3.8)
|
3 (2.2)
|
6 (6.1)
|
0.170
|
Diagnosis of ILD at subacute phase
|
9 (3.8)
|
5 (3.6)
|
4 (4.0)
|
1.000
|
Lower respiratory tract infection
|
51 (22)
|
29 (21)
|
22 (22)
|
0.823
|
Multifactorial§
|
16 (6.8)
|
7 (5.1)
|
9 (9.1)
|
0.224
|
Cardiological cause
|
17 (7.2)
|
10 (7.2)
|
7 (7.1)
|
0.959
|
Other cause Ⱡ
|
11 (4.6)
|
1 (0.7)
|
10 (10)
|
0.001
|
*Hospitalizations related to diagnosis of subacute ILD, subacute ILD progression or acute respiratory symptoms without other new, explanatory findings. § Lower respiratory tract infection concurrently with some other cause(s): cardiovascular (5 IPF, 7 other ILD), acute exacerbation of asthma (2 non-IPF ILD), acute exacerbation of COPD (1 IPF, 1 other ILD), lung cancer (1 IPF, 1 other ILD). Ⱡ One non-IPF patient had pleural effusion, one non-IPF patient had acute exacerbation of chronic obstructive lung disease (COPD), one IPF patient had haemoptysis, one non-IPF patient had escherichia coli septicemia, three non-IPF patients had pulmonary embolism, one non-IPF patient had pneumothorax and aspergilloma, one non-IPF patient had bilateral pneumothorax and one non-IPF patient was suspected of experiencing an allergic reaction to the local anesthetic used during bronchoscopy procedure.
Abbreviations: AE-ILD, acute exacerbation of interstitial lung disease; ILD, interstitial lung disease, IPF, idiopathic pulmonary fibrosis.
TABLE 5. Post-hospitalization survival of the patients with AE-ILD compared with patients hospitalized due to other cause.
Parameter
|
Total
N=237
|
IPF
N=138
|
Other ILD
N=99
|
HR (95% CI)
|
P-value
|
HR (95%CI)
|
P-value
|
HR (95%CI)
|
P-value
|
AE-ILD
|
Reference
|
|
Reference
|
|
Reference
|
|
ILD-related hospitalization other than AE-ILD*
|
0.95 (0.65−1.39)
|
0.791
|
0.80 (0.51−1.26)
|
0.331
|
1.13 (0.57−2.25)
|
0.729
|
Lower respiratory tract infection
|
0.64 (0.44−0.92)
|
0.017
|
0.58 (0.36−0.92)
|
0.021
|
0.70 (0.37−1.32)
|
0.270
|
Cardiovascular cause
|
1.38 (0.81−2.37)
|
0.240
|
0.80 (0.39−1.63)
|
0.545
|
3.29 (1.36−7.94)
|
0.008
|
Other cause Ⱡ
|
0.64 (0.31−1.33)
|
0.231
|
0.49 (0.07−3.53)
|
0.475
|
1.04 (0.45−2.39)
|
0.936
|
Multifactorial §
|
1.62 (0.95−2.78)
|
0.078
|
0.98 (0.44−2.18)
|
0.962
|
3.08 (1.42−6.67)
|
0.004
|
*Hospitalizations related to diagnosis of subacute ILD, subacute ILD progression or acute respiratory symptoms without other new, explanatory findings. Ⱡ One non-IPF patient had pleural effusion, one non-IPF patient had mild pericarditis, one IPF patient atrial fibrillation, one IPF patient had haemoptysis, one non-IPF patient had escherichia coli septicemia, two non-IPF patients had pulmonary embolism, one non-IPF patient had pneumothorax and aspergilloma, one non-IPF patient had bilateral pneumothorax and one non-IPF patient was suspected of experiencing an allergic reaction to an local anesthetic used during bronchoscopy procedure. §Two or more of the following causes occurring simultaneously: Lower respiratory tract infection, cardiovascular cause or other cause.
Abbreviations: AE-ILD, acute exacerbation of interstitial lung disease; GAP, Gender-Age-Physiology index; HR, hazard ratio.
High GAP index was a risk factor for mortality and earlier AE-ILD
A high GAP index was associated with shorter overall survival and earlier occurrence of AE-ILD in all patients (Figure 3, Table 6). The occurrence of deaths and AE-ILDs at different time points from diagnosis according to the GAP stages are presented in Figures 4 and 5 and in E-Table 1. Slightly more than half (52.6 %) of the 19 patients who survived less than one year had GAP stage III. GAP stage III patients who experienced an AE-ILD had suffered this episode in less than a year after the diagnosis of ILD; in fact, none of the GAP stage III patients had their first AE-ILD later than 1 year after the diagnosis. Survival differences in the various GAP stages were also evaluated with a multivariate model involving the occurrence of AE-ILD, which had no significant impact on the result, since HR between GAP stage II and GAP stage I was 1.97 (95% CI 1.42 to 2.73, p <0.001), while HR between GAP stage III and I was 4.52 (95 % CI 2.84 to 7.19, p < 0.001).
TABLE 6. The risk for death and acute exacerbations (Cox Univariate model).
Parameter
|
N=237
GAP N=213
|
IPF N=138
GAP N=120
|
Other ILD N=99
GAP N=93
|
HR (95% CI)
|
P-value
|
HR (95%CI)
|
P-value
|
HR (95%CI)
|
P-value
|
Risk for mortality
|
|
|
|
|
|
|
GAP at diagnosis
|
|
|
|
|
|
|
I
|
Reference
|
|
Reference
|
|
Reference
|
|
II
|
1.97 (1.42−2.73)
|
<0.001
|
2.10 (1.36−3.24)
|
0.001
|
1.51 (0.87−2.63)
|
0.146
|
III
|
4.45 (2.80−7.07)
|
<0.001
|
3.78 (2.11−6.74)
|
<0.001
|
5.29 (2.36−11.86)
|
<0.001
|
Risk for AE-ILD
|
|
|
|
|
|
|
GAP at diagnosis
|
|
|
|
|
|
|
I
|
Reference
|
|
Reference
|
|
Reference
|
|
II
|
1.96 (1.29−2.97)
|
0.002
|
1.77 (1.02−3.08)
|
0.041
|
2.05 (1.05−4.00)
|
0.036
|
III
|
2.81 (1.47−5.38)
|
0.002
|
2.40 (1.07−5.40)
|
0.034
|
3.03 (1.01−9.08)
|
0.048
|
*Hospitalization was concerned ILD-related, if hospitalization was due to AE-ILD, diagnosis of subacute ILD, subacute progression of ILD or acute respiratory symptoms without new, explanatory findings. **Hospitalizations related to diagnosis of subacute ILD, subacute ILD progression or acute respiratory symptoms without new, explanatory findings.
Abbreviations: AE-ILD, acute exacerbation of interstitial lung disease; CI, confidence interval; GAP, Gender-Age-Physiology index; HR, hazard ratio; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis.