Causes of acute respiratory hospitalizations predict survival in fibrosing interstitial lung diseases

DOI: https://doi.org/10.21203/rs.3.rs-29692/v1

Abstract

Background

Acute exacerbation of ILD (AE-ILD) is a common reason for hospitalization; it is also associated with significant mortality. Less is known about the prognostic significance of other events causing acute, non-elective hospitalizations in ILD patients.

Methods

ILD patients hospitalized due to acute respiratory worsening were collected from medical records. Reasons for respiratory deterioration were classified into AE-ILDs and other causes. Clinical features and survival data of idiopathic pulmonary fibrosis (IPF) and other types of ILDs were evaluated and compared.

Results

In all, 237 patients (138 with IPF and 99 with other ILD) fulfilled the inclusion criteria. Of the non-IPF ILD types, the most prevalent subgroups were connective tissue disease-associated ILD (n = 33) and asbestosis (n = 22). The most common cause for hospitalization was AE-ILD explaining 41% of hospitalizations. Lower respiratory tract infection (22%), subacute progression of ILD (12%) and cardiovascular causes (7.2%) were other common reasons for hospital treatment. Patients with a lower respiratory tract infection had a more favorable prognosis compared with patients with AE-ILD. AE-ILDs were less fatal than cardiovascular or concurrent non-ILD-related causes for hospitalizations in non-IPF patients. High Gender-Age-Physiology (GAP) index was a marker for shortened survival and earlier AE-ILDs in all patients. IPF patients had a significantly shorter overall and post-hospitalization survival time compared with other ILDs.

Conclusions

Most respiratory hospitalizations in ILD patients were related to causes other than AE-ILD, which highlights the importance of accurate differential diagnosis in order to target the appropriate treatment for each ILD patient.

Background

Idiopathic pulmonary fibrosis (IPF) and other progressive fibrosing interstitial lung diseases (ILD) are serious, often fatal conditions also causing a high burden for health care systems. In a Spanish study, the numbers of hospitalizations related to IPF almost doubled between 2004 and 2013 from 3.82/100 000 inhabitants to 6.98/100 000 inhabitants [1].

Based on the results of the epidemiological studies, a significant proportion of hospitalizations in ILD patients were related to ILD or other reasons causing respiratory symptoms [1-4], and the majority of ILD patients had experienced some kind of event requiring hospitalization during their disease history [4]. Most of the register-based studies have investigated solely patients with IPF, while those of other ILDs are sparse. Table 1 presents data from previously published epidemiological studies and real-world data (RWD) studies on hospitalizations of ILD patients [5-11].

Table 1 here

Acute exacerbation (AE) is a severe complication of ILD, which seems to cause significant mortality in all types of ILDs [12,13]. The current diagnostic criteria for AE-IPF have been suggested to be applied for other ILDs as well [12,13]. The diagnosis of AE-ILD requires a detailed evaluation of clinical symptoms and high-resolution computed tomography (HRCT) images of chest [12]. One substantial problem in AE-ILD research is the fact that no specific diagnosis code exists for AE-ILD. As a consequence, the large epidemiological studies mentioned above do not provide detailed information on the number of AE-ILDs [1-4]. In other studies with access to the patient data, the proportion of AE-ILDs out of all the hospitalizations caused by an acute respiratory deterioration has ranged between 29-55% [5,6,10,11], when only two of these investigations included patients with non-IPF ILDs [5,11]. In the previous studies, which have not presented the exact data on the number of AE-ILDs, it was claimed that respiratory or cardiopulmonary hospitalizations increased the mortality of ILD patients more than hospitalization due other illnesses [7,9].

The aim of this present study was to evaluate fibrosing ILD patients hospitalized non-electively due to an acute deterioration of respiratory symptoms in two Finnish hospitals, namely Oulu University Hospital (OUH) and Oulaskangas Hospital (OH). The causes for hospitalizations were evaluated and classified as either AE-ILDs or other reasons, and the risk factors for mortality and AE-ILDs were compared between IPF and non-IPF patients.

Methods

Patient and data collection

The study material consists of ILD patients who were non-electively hospitalized due to acute respiratory symptoms in OUH or OH between 1/1/2008 and 31/12/2017. A total of 128 of these patients were also included in our previous study [14]. The flowchart of the study and criteria used to define AE-ILD are presented in Fig. 1. We performed a search with International Classification of Diseases version 10 (ICD-10) codes J84.1, J84.8 and J84.9 to identify the patients and their treatment periods from medical records as described previously [14]. Another search was performed with ICD-10 codes J61, J99, J99.0* and J99*M05.1 to find the hospitalizations related to asbestosis and rheumatoid arthritis-associated ILD (RA-ILD). However, there were no matches for the search with J99 codes, because J84 codes had been used for all RA-ILD patients in our cohort. The type of ILD was re-evaluated according to the current international criteria [15, 16]. The clinical information was collected systematically from electronic patient records dating back about 20 years in OUH and OH in a form specially designed for the present study. A detailed description of the data collection and evaluation of ILD types has been provided in our previous study [14].

For this current study, we categorized the reasons for hospitalizations to AE-ILDs and other reasons, as presented in Fig. 1. The data on hospitalizations was collected related to the first non-elective hospitalization after or at the time of ILD diagnosis, if the diagnosis of ILD was made during a non-elective hospitalization. The information on the patients having experienced an AE-ILD after their first respiratory hospitalization was gathered as described previously [14]. Thus, we had the data of both the patients with AE-ILD as the cause for the first non-elective hospital treatment period and the data on those patients who were first hospitalized due to some other reason but experienced an AE-ILD later during the follow-up. Subacute progression of ILD was defined as increased fibrotic changes either in HRCT or chest x-ray compared with previous images. A subclass “respiratory symptoms without explanatory findings” was used for patients hospitalized non-electively due to acute respiratory symptoms, but whose investigations did not reveal any acute findings in clinical status, HRCT, chest x-ray or laboratory tests. A lower respiratory tract infection, e.g. pneumonia or acute bronchitis, was recorded as the reason for hospitalization if the patient had elevated C-reactive protein level, increased cough and mucus production with or without new infiltrate in chest x-ray or HRCT. The treatment periods caused by heart failure, coronary atherosclerosis, myocardial infarction or atrial fibrillation were considered to be cardiovascular (CV). Heart failure was documented as the reason for hospitalization if at least two of the following criteria were met: congestion in HRCT or chest x-ray, elevated B-type natriuretic peptide (BNP), swollen limbs or a finding compatible with heart failure in the echocardiogram. High Gender-Age-Physiology (GAP) index and GAP stage were defined as in our previous study [17]. Overall survival time was calculated from diagnosis date to death, transplantation or last follow-up date (31/8/2019). Post-hospitalization survival was determined from the first hospitalization date to death, transplantation or last follow-up date.

Statistical analysis

IBM SPSS Statistics for Windows, Version 25.0 (Armonk, NY: IBM Corp.) was used to perform statistical analysis and Origin(Pro), Version 2019b (OriginLab Corporation, Northampton, MA, USA) was utilized for graphs. Means and standard deviation were calculated for continuing variables, which were normally distributed. Medians and inter-quartile range (IQR) were utilized for continuing variables which were not normally distributed. Group differences of continuous variables were tested by using independent samples t-test and variance analyses or Mann-Whitney U-test. Differences in the categorized variables were calculated with Chi-Square or Fisher’s Exact test. Survival was estimated by using Kaplan-Meier curves and the groups were compared with each other by using log rank tests. Log rank test with a linear trend for factor levels was used, when the survival differences of patients were evaluated according to the cause of the hospitalization. Cox regression model was utilized for the assessment of risk factors for death and AE-ILD.

Ethics

As this was a register-based retrospective study and the majority of study subjects were deceased, no patient consent forms were gathered in accordance with Finnish legislation. The study protocol was approved by the Ethical Committee of the Northern Ostrobothnia Hospital District (statement 2/2015). Permission to use death certificates was given by Statistics Finland (Dnro: TK-53-515-15). The study was conducted in compliance with the Declaration of Helsinki.

Results

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 diagnosisâ± 

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. â± GAP 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 â± 

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). â±  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 â± 

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. â±  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.

Discussion

We have investigated RWD in 237 ILD patients that were hospitalized non-electively due to acute worsening of respiratory symptoms. All of the data of each patient was re-assessed in a very detailed manner. Acute exacerbations of ILD explained about 41% of the hospitalizations whereas the majority of the hospitalizations were explained by other causes. The cause for hospitalization was associated with survival time in all patients, patients with lower respiratory infection having the most favorable prognosis. A high GAP index was associated with both shortened survival and earlier occurrence of AE-ILDs and was a more specific indicator for earlier AE-ILDs than for deaths.

Non-IPF patients were found to have a lower GAP stage and higher VC and DLCO levels at the time of diagnosis as compared with IPF patients, indicative of a less progressed disease of non-IPF patients at baseline. However, at the time of hospitalization, the differences in VC and DLCO between IPF and non-IPF patients had disappeared. As can be seen in E-Table 2, in comparison with most other studies, here the median time from diagnosis to hospitalization seemed to be longer [5, 6, 9] and patients were older [57, 9], even though the baseline pulmonary function test (PFT) values in our study and those of others were approximately at the same level. A Japanese study has reported the PFT results of the investigated subjects near the first hospitalization date were higher than in our material, even though the patients in that study and our own were approximately the same age [11]. These differences may be attributable to the different genetic and ethnic backgrounds of the study subjects and also to the heterogeneity of the non-IPF patients in the above publications.

AE-ILD has been reported to be the most common individual cause for a respiratory deterioration in different types of ILDs accounting for 29–55% [5, 6, 10, 11] of respiratory hospitalizations, values consistent with our own findings. Lower respiratory tract infections were observed in 20–33% of respiratory hospitalizations in previous studies, which is in line with our result of 22% [5, 6, 10, 11]. Furthermore, a subacute progression was the reason for hospitalization in 12% of patients in our study, again in accordance with earlier investigations reporting proportions of 15% and 17% [5, 10]. Given the challenges concerning the diagnostic practices of ILD patients with acute respiratory worsening, which make retrospective studies extremely demanding to perform, the results of the previous and the present study are amazingly consistent.

AE-ILD has been reported to be associated with a poor outcome in various types of ILDs [5, 6, 10, 1821]. The treatment of AE-ILDs usually includes high doses of corticosteroids and/or other immunosuppressive therapies, even though the evidence of their efficacy is limited [12, 13]. Our results together with earlier investigations suggest that it is crucial to be meticulous in the differential diagnostics in ILD patients with acute respiratory symptoms. Based on the present results and those of other investigators, most hospitalizations were due to some reasons other than AE-ILD. Patients deserve to be treated according to the actual cause, thus avoiding the potentially harmful effects of the treatments targeted at AE-ILD.

In our study population, those patients hospitalized due to AE-ILD had a shorter survival compared with patients with a lower respiratory tract infection, the difference was more distinct in IPF patients in comparison to those with other ILDs. A similar result has also been presented by Teramachi et al. in a recent study on IPF patients, in which a respiratory tract infection was associated with decreased 90-day post-hospitalization mortality as compared with other causes for hospitalization. It can be speculated that the occurrence of a respiratory tract infection, if not fulfilling the criteria for a triggered AE-ILD, may be a marker of an ILD phenotype associated with a slow disease progression.

Interestingly, in the subgroup of non-IPF patients with a CV cause for hospitalization or a lower respiratory tract infection concurrent with some other cause, the post-hospitalization survival time was shorter than in non-patients with AE-ILD. Moua et al. have observed that in non-IPF patients, an AE-ILD did not cause increased mortality in comparison with other types of hospitalizations in a multivariate model [5]. These findings may reflect the fact that AE-ILDs are less fatal for non-IPF patients than for those patients with IPF, which was also supported by our previous study, where IPF patients had a significantly shorter survival after an AE in comparison with non-IPF patients [14].

In our study, the GAP index was a risk factor for both death and AE-ILD. At least one of these findings has been described in earlier investigations [18, 2227], even though this has not been verified in all studies [9, 28]. We also demonstrated that AE-ILDs can occur at any phase of the disease in a cohort involving both IPF and non-IPF patients, a finding which is a known feature of IPF, making the disease course difficult to predict [12, 29].

The occurrence of AE-ILD was relatively high, e.g. 54%, in our study population. In the previous studies, presenting data on GAP and its effect on mortality, the prevalence of AE-ILD has varied between 20–40% [18, 22, 23], these discrepancies may be caused by different types of study protocols, e.g. we included only non-electively hospitalized patients. Our results indicate that the GAP index is a functional prognostic marker even in a cohort enriched with AE-ILDs. Nonetheless, almost half of the patients survived less than one year from diagnosis had GAP stage I or II at baseline, suggesting that GAP alone did not provide an exact prognosis for these patients, a result consistent with earlier studies presenting data on the accuracy of GAP in the prognostic evaluation of IPF patients [24, 26]. However, GAP stage III seemed to be quite a specific predictor of early AE-ILDs, since all the patients with GAP stage III disease at diagnosis experienced an AE-ILD within 1 year after the diagnosis, whereas those GAP stage III patients who survived the first year without an AE-ILD did not experience the episode later. To our knowledge, there is no earlier published data demonstrating similar findings.

Our study has some limitations in common in retrospective studies, namely some missing patient data and possible incorrect use of ICD-10 diagnosis codes by clinicians, which might have led to the exclusion of a few potential cases. However, the careful and systematic evaluation of the data as well as re-classification of ILD types according to the current international guidelines are the strengths of our study. It should be noted that differential diagnostics in hospitalized patients with progressed ILD would be challenging even in a prospective study protocol, because AE-ILD, respiratory infections and heart failure often share similar and even concurrent clinical and radiological features.

Conclusions

To conclude, although AE-ILD was the most common single cause for hospitalization, a relatively large proportion of hospitalizations, e.g. 59 %, was attributable to causes other than AE-ILD. In view of the potentially harmful effects of the therapies targeted at managing an AE-ILD, clinicians should be aware that there are multiple possible etiologies other than an AE-ILD when treating ILD patients with acute respiratory worsening, some of them may be potentially even more serious for patients than an AE. 

List Of Abbreviations

AE, acute exacerbation; AE-ILD, acute exacerbation of interstitial lung disease; AE-IPF, acute exacerbation of idiopathic pulmonary fibrosis; CT, computed tomography; DLCO, diffusion capacity for carbon monoxide; FVC, forced vital capacity; GAP, gender-age-physiology index; ICD-10, International Classification of Diseases, version 10; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; OH, Oulaskangas Hospital; OUH, Oulu University hospital, PFT, pulmonary function test; VC, vital capacity.

Declarations

Ethics approval

The study protocol was approved by the Ethical Committee of the Northern Ostrobothnia Hospital District (statement 2/2015).

Consent to participate and consent for publication

No consents for the participation and publication were gathered since this was a retrospective study and the majority of the patients were deceased.

Availability of data and materials

The datasets generated and analyzed during the current study are not publicly available due to the relatively small population of Northern Finland, we could not guarantee individuals’ anonymity as the data was collected in a detailed manner, but it is available from the corresponding author on reasonable request.

Competing interests

JS reports congress fees and travel costs from Boehringer-Ingelheim, GlaxoSmithKline, Novartis, Orion Pharma, Ratiopharm and Roche, and lecture fees from Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Mundipharma, Orion Pharma and Roche outside the submitted work. HV has nothing to disclose.  MP reports a lecture fee from Boehringer-Ingelheim Finland Ltd and a congress fee and travel costs from Roche, outside the submitted work. RK reports consultant fees from GlaxoSmithKline and Boehringer-Ingelheim, lecture fees from Roche and Boehringer-Ingelheim, and a congress travel subsidy from Orion pharma outside the submitted work.

Authors’ contributions

JS collected the study material and interpreted and analyzed the data. JS prepared the draft of the manuscript. HV participated in the statistical analysis. RK and MP participated in planning the data collection, study design and in the interpretation of the data. RK managed the study and contributed substantially to data interpretation by re-evaluating the study patients and data from medical records. All authors participated in the preparation of the manuscript, read and approved the final manuscript.

Funding

 JS has received personal grants for scientific work from Foundation of the Finnish Anti-Tuberculosis Association and the Research Foundation of the Pulmonary Diseases HES. RK has received grants for the study group from Foundation of the Finnish Anti-Tuberculosis Association, the Research Foundation of the Pulmonary Diseases, Jalmari and Rauha Ahokas Foundation and the Research Foundation of North Finland.

Acknowledgements

We would like to thank for Dr. Ewen MacDonald for the language and editorial assistance and Seija Leskelä for the help in editing the images

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Table 1

TABLE 1. Previous studies investigating hospitalizations of patients with interstitial lung diseases (ILD).

Study

Setting

Number of patients and/or treatment periods

Causes for hospitalization (%)

Epidemiologic studies based on diagnosis codes without an evaluation of clinical data

 

Yu et al, 2016, USA[2]

Commercial administrative claims data between 2006-2011, 1-year follow-up. ICD-9-CM code 516.3 and additional criteria used to identify IPF patients.

1735 patients (516.3)

Proportions of patients:

All-cause 38.6 %

IPF-related 10.8 %

Cottin et al, 2017, France [3]

French national hospital discharge database between 2008-2013. Over 50-year-old patients with ICD-10 code J84.1

6476 patients (J84.1)

16 106 treatment periods

Proportions of patients:

Acute event (respiratory or other) 87 %

Respiratory infection 43.7 %

Acute respiratory worsening 36.5 %

Cardiac event 51.7 %

Pedraza-Serrano et al 2017,

Spain [1]

Hospitalized patients from the Spanish National Hospital Database between 2004-2013. Patients with ICD-9-CM code 516.3

22 214 treatment periods (516.3)

Most common diagnoses combined with ICD-9-CM 516.3 (proportions of treatment periods):

Acute and chronic respiratory failure 18.4 %

Other disease of respiratory system 14.3 %

Acute respiratory failure 13.2 %

Pneumonia 6.4 %

Heart failure 5.1 %

Wälscher et al, 2020, Germany [4]

German claims data from 2009 to 2014. Patients with ICD-10 codes J84.1, J84.0, J84.9, D48.1, D86.0-D86.9, J70.2-J70.4, J62.0-J62.8, J63.2, J70.1, J82, J67.9 and J99.1.

154 109 hospitalizations

14 453 patients (J84.1)

22 364 patients with other codes

Proportions of patients:

ILD-related 56.6 %

Non-ILD-related 71.2 %

Retrospective real-world-data studies investigating hospitalizations of patients with an evaluation of clinical data

 

Moua et al, 2016, USA [5]

Retrospective data on ILD patients hospitalized due to acute respiratory worsening in one center between 2000 and 2014.

311 hospital admissions

100 IPF patients

120 Non-IPF patients

 

Proportions of hospital admissions:

AE-ILD  52 %

Infection 20 %

Subacute progression 15 %

Cardiac 6 %

Thromboembolic 4 %

Multifactorial <1 %

Teramachi et al 2018,

Japan [10]

Retrospective data on IPF patients with respiratory hospitalization from one center between 2008 and 2017.

122 IPF patients

Data concerning first hospitalization:

AE-IPF 29 %

Subacute progression 17 %

Pneumonia 23 %

Lower respiratory tract infection 9 %

Other parenchymal cause 9 %

Extra-parenchymal cause 13 %

Song et al, 2011, South Korea [6]

Retrospective data on IPF patients from one center between 1990 and 2009

461 IPF patients

Proportions of patients:

Respiratory (total) 35.4 %

AE-IPF 19.5 %

Lower respiratory tract infection 11.1%

Heart failure 1.1%

Yamazaki et al, 2020, Japan [11]

Retrospective data on IPF and chronic idiopathic interstitial pneumonia (c-IIP) patients with respiratory hospitalizations from one center between 2008 and 2018.

138 IPF patients

105 c-IIP patients

Total 243

Proportions of patients (first hospitalization):

AE-ILD 48 %

Pulmonary infection 33%

Pneumothorax and/or mediastinal emphysema 10 %

Heart failure 3.3 %

 

Ratwani et al, 2019,

USA [7]

Retrospective data on connective tissue disease associated interstitial lung diseases (CTD-ILD) patients from one center between 2010 and 2017

137 CTD-ILD patients

 

Proportions of patients:

No hospitalizations 32%

Cardiopulmonary 51%

Non-cardiopulmonary 17 %

AE-ILD: NA

Behr et al, 2015,

Germany [8]

Data from multicenter national INSIGHT-IPF-registry collected between 2012-2014

502 IPF patients

Proportions of the patients hospitalized within the last 12 months:

IPF-related 42.9 %

Non-IPF-related 3.9 %

AE-IPF: NA

Brown et al, 2015, USA [9]

Retrospective data on IPF patients from one center between 1997 and 2012.

592 IPF patients

Proportions of patients:

No hospitalizations 74.7 %

Respiratory 19.6 %

Non-respiratory 5.7 %

AE-IPF: NA

Abbreviations: AE-ILD, acute exacerbation of interstitial lung disease; AE-IPF, acute exacerbation of idiopathic pulmonary fibrosis; c-IIP, chronic idiopathic interstitial pneumonia; CTD-ILD, connective tissue disease-associated interstitial lung disease; ICD-9CM, International Classification of Diseases, ninth revision, Clinical Modification; ICD-10, International Classification of Diseases, version 10; IPF, idiopathic pulmonary fibrosis; NA, not applicable.