Clinical Course of Acute Exacerbation of Fibrosing Interstitial Lung Disease

doi:10.21203/rs.3.rs-1658658/v1

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Clinical Course of Acute Exacerbation of Fibrosing Interstitial Lung Disease

https://doi.org/10.21203/rs.3.rs-1658658/v1

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No large-scale studies have reported on the clinical course of acute exacerbation of fibrosing interstitial lung disease (AE-FILD). We aimed to elucidate the clinical course of AE-FILD. We retrospectively included patients admitted with AE-FILD diagnosis. The clinical courses of AE-FILD were classified as consistent improvement after response to treatment (responder group); no response to treatment (non-responder group); improvement after treatment followed by worsening respiratory status not attributable to AE-FILD (complication group); and improvement after treatment followed by worsening respiratory status attributable to AE-FILD relapse (second-attack group). Among 340 patients, 123 died within 90 days, 265 responded, and 75 were refractory to initial treatment. Among patients who responded to treatment, 191, 26, 46, and 2 belonged to the responder, complication, second-attack, and unknown groups, respectively. Multivariate analysis revealed that high lactate dehydrogenase, high C-reactive protein, and low PaO₂/FiO₂ were associated with 90-day mortality (odds ratio [OR] 2.27, p = 0.002; OR 2.01, p = 0.008; and OR 1.70, p = 0.042, respectively). Of patients who responded to treatment, a second attack was strongly associated with 90-day mortality (OR 18.54, p < 0.001). AE-FILD has a heterogeneous clinical course. Importantly, worsening of respiratory condition despite an initial response to treatment is common.

interstitial lung disease

acute exacerbations

lung fibrosis

Interstitial lung disease (ILD) is characterized by fibrosis and inflammation of the lung parenchyma¹. ILD has a heterogeneous etiology; among the possible underlying conditions, fibrosing ILD (FILD), including idiopathic pulmonary fibrosis (IPF), can cause deterioration of respiratory function and quality of life due to the progression of fibrosis^2,3. FILD is relatively common among smokers in nonspecific populations, with an increasing prevalence^4–6. Furthermore, IPF-related mortality increased by 9.85% in age-adjusted mortality from 2000 to 2017^7–8.

Acute exacerbation of FILD (AE-FILD) is characterized by rapid progressive worsening of imaging and clinical symptoms^9,10. The annual incidence of AE-FILD is 5–20%; moreover, it can occur at any time during the disease course^10–13. AE-FILD has a very high mortality rate (30–50%); however, even if the patient survives, deterioration of the quality of life remains a possibility due to decreased respiratory function^11,14−16. AE is the most common cause of mortality (40%), especially in patients with IPF, with the median post-AE survival ranging from 1–4 months^14,17. Steroid and immunosuppressive drugs are customarily used for treatment; however, we have no firm evidence of efficacy, despite the clinical importance of this condition^10,11.

Several studies have reported on the prognostic factors and devastating impact of AE-FILD; however, few reports have described the clinical course of AE-FILD^10,11. In clinical settings, the heterogeneous clinical courses of AE-FILD have been described, with some cases responding to treatment and improving, some not responding to treatment, and others improving but subsequently worsening. Inadequate assessment of the clinical course of AE-FILD impedes individualized treatment and counseling of the patients and their families. Therefore, a better understanding of these clinical patterns is needed to facilitate shared decision-making regarding AE-FILD treatment and improve future management.

This study aimed to elucidate the clinical course of AE-FILD and identify areas of patient management requiring improvement.

Study design and patients

This multicenter, retrospective, hospital-based cohort study enrolled patients diagnosed with primary AE-FILD at the Wakayama Medical University Hospital and the Kobe City Medical Center General Hospital between January 2012 and December 2019. The clinical data for each patient were extracted from medical charts and entered into a database.

FILD diagnosis was based on the clinical history, physical examination, laboratory data, and computed tomography (CT) imaging¹¹. Based on the classification of usual interstitial pneumonia (UIP) patterns by the ATS/ERS/JRS/ALAT Clinical Practice Guideline, the FILD imaging results were classified as UIP, probable UIP, indeterminate for UIP, and alternative diagnosis¹⁸. Among the patients without high-resolution CT images before AE-FILD, those with no findings suggestive of UIP at the time of AE-FILD diagnosis were classified under alternative diagnosis. Interstitial pneumonia with autoimmune features was diagnosed based on patient background and previous reports¹⁹. AE-FILD was defined based on the definition proposed by Collard et al. in 2016 with modification to include FILD, rather than UIP, as a background lung pattern. The criteria were as follows: (1) previous or concurrent diagnosis of FILD; (2) acute worsening or development of dyspnea, typically within 1 month; (3) CT with new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with FILD; and (4) deterioration not fully attributable to cardiac failure or fluid overload⁹. Heart failure was ruled out through physical examination, laboratory data, and if necessary, transthoracic echocardiography and consultation with a cardiologist. At least two experienced pulmonologists made the decisions regarding imaging patterns and clinical diagnoses.

The clinical courses within 90 days after AE-FILD development were categorized as follows: (1) consistent improvement after response to treatment (responder group); (2) no response to treatment (non-responder group); (3) improvement observed at least once after treatment followed by worsening respiratory status not attributable to AE-FILD but rather to conditions such as pneumothorax, infectious disease, or heart disease (complication group); and (4) improvement observed at least once after treatment followed by worsening respiratory status attributable to AE-FILD relapse (second-attack group). A second attack was defined as a repeat acute exacerbation within the first 90 days post-treatment despite visible improvement at least once after initiating the initial treatment. We defined improvement (including temporary improvement) after treatment as cases without worsening of chest imaging and showing a decrease in the required oxygen levels to maintain the SpO₂, for at least 48 hours.

Steroid pulse therapy was defined as methylprednisolone administration at a dose of ≥ 500 mg. In patients who underwent steroid pulse therapy, the dose administered after the steroid pulse was used as the initial dose. Steroid doses were expressed as prednisolone equivalents. Additionally, we defined a high steroid dose as a prednisolone equivalent dose of ≥ 0.5 mg/kg²⁰. Patients who used immunosuppressants during AE-FILD were included in the immunosuppressive group even if they had been using them prior to the diagnosis of AE-FILD.

This study was approved by the Wakayama Medical University Hospital Institutional Review Board and Kobe city medical center general hospital certified review board. All methods were performed in accordance with the relevant guidelines and regulations. The requirement for informed consent was waived given the retrospective design of the study by Wakayama Medical University Hospital Institutional Review Board and Kobe city medical center general hospital certified review board.

Statistical analysis

Continuous variables were presented as median and interquartile range (IQR) and analyzed using the Wilcoxon rank-sum test. Categorical variables were presented as number and percentage and analyzed using a chi-square or Fisher’s exact test, as appropriate. The Kaplan–Meier method was used to estimate the 90-day survival outcomes in all patients. Logistic regression models were fitted to identify the factors associated with 90-day mortality. A multivariate logistic regression model was developed for all clinically important factors to identify the associations between patient characteristics and 90-day mortality in all included patients^{11,14,21− 24}. When we conducted subgroup analysis on patients who responded to treatment at least once, because of the small number of events, a similar multivariate model was constructed using variables from the univariate analysis (p < 0.1). To evaluate the impact of a second attack on mortality, we performed a 21-day landmark analysis that only included patients who responded to treatment at least once and those who were alive 21 days after a diagnosis of AE-FILD. The analysis was based on a landmark assessment of a second attack that developed within the first three weeks. Any second attack occurring after the landmark date was not counted in the second-attack group. Statistical significance was set at a two-tailed p-value < 0.05. Statistical analyses were performed using JMP PRO® 14 (SAS Institute Inc., Cary, NC, USA).

Patient characteristics

We included 340 patients with AE-FILD. Table 1 summarizes their clinical characteristics. The median age was 76.5 (IQR, 70.0–81.0) years and 72.6% (n = 247) had a history of smoking. Approximately 26.2% (n = 89) of the patients had a UIP pattern. At the onset of AE-FILD, the median PaO₂/FiO₂ (P/F) was 203.8 (IQR, 135.0–291.7); further, steroid pulse therapy was administered to 84.7% (n = 288) of the patients. The initial steroid dose was high and low in 304 (89.4%) and 6 (1.8%) cases, respectively; moreover, 13 (3.8%) patients did not receive steroid therapy while 17 (5.0%) patients died during pulse therapy. Among the 304 patients who initially started high-dose steroids, 215 (70.7%) were able to reduce the dose to 0.5 mg/kg within a median of 19.0 days (IQR, 11.0–29.0). Immunosuppressive drugs were used in 149 patients (43.8%).

Table 1

Baseline characteristics of the patients.
Patient characteristics	All patients (N = 340)
Age, years
Median (IQR)	76.5 (70.0–81.0)
Sex, n (%)
Male	257 (75.6)
Smoking status, n (%)
Current	29 (8.5)
Former	218 (64.1)
Never	93 (27.4)
Emphysema, n (%)	105 (30.9)
Baseline ILD pattern, n (%)
UIP	89 (26.2)
Probable UIP	98 (28.8)
Indeterminate UIP	49 (14.4)
Alternative diagnosis	104 (30.6)
Treatment for baseline ILD, n (%)
Steroids	100 (29.4)
Immunosuppressants	48 (14.1)
Antifibrotic drug	39 (11.5)
None	215 (63.2)
Collagen disease, n (%)	55 (16.2)
IPAF, n (%)	43 (12.6)
AE with causes, n (%)	81 (23.8)
P/F at the AE, Median (IQR)	203.8 (135.0–291.7)
Laboratory data at the time of AE diagnosis; median (IQR)
LDH	340.0 (276.3–436.0)
CRP	7.9 (3.9–14.0)
KL-6	1192.0 (745.0–2000.0)
Treatment for AE, n (%)
Steroid pulse	288 (84.7)
Initial steroid
High dose	304 (89.4)
Low dose	6 (1.8)
None	30 (8.8)
Immunosuppressants	149 (43.8)
Abbreviations: IQR, interquartile range; ILD, interstitial lung disease; UIP, usual interstitial pneumonia; IPAF, interstitial pneumonia with autoimmune features; P/F, PaO₂/FIO₂ ratio; AE, acute exacerbation; KL-6, Krebs von den Lungen-6; LDH, lactate dehydrogenase; CRP, C-reactive protein.

Clinical courses of AE-FILD

Two-hundred and sixty-five (77.9%) patients responded to treatment at least once, while 75 (22.1%) patients were completely refractory to treatment and died within 90 days (non-responder group). Among the patients who responded to treatment at least once, 191 (72.1%) maintained improvement (responder group), while 72 (27.2%) showed worsening of respiratory status. Two patients (0.8%) responded to treatment but died after discharge, and had an unclear clinical course. Among the patients whose respiratory status worsened, 26 (36.1%) had worsening attributable to complications (complication group), while 46 (63.9%) had a second attack (second-attack group) (Fig. 1). In the complication group, infection (n = 5, 19.2%) was the most common cause, followed by pneumothorax (n = 4, 15.4%) and heart failure (n = 4, 15.4%). Among the patients with worsening after temporary improvement, the median time of relapse was 20 days after the start of treatment (IQR 9–33).

Ninety-day mortality and risk factors

Out of all 340 patients, 123 (36.2%) died within 90 days; among these, 75 (61.0%), 18 (14.6%), 28 (22.8%), and two (1.6%) cases were in the non-responder, complication, second-attack, and unknown groups, respectively (Fig. 1, Table 2). Univariate analysis revealed that the following factors were associated with 90-day mortality: older age (odds ratio [OR], 1.66; 95% confidence interval [CI], 1.05–2.60; p = 0.029), higher serum lactate dehydrogenase level (LDH) (OR, 2.93; 95% CI, 1.85–4.66; p < 0.001), higher serum C-reactive protein level (CRP) (OR, 2.63; 95% CI, 1.66–4.15; p < 0.001), and a low P/F ratio (< 200) at AE diagnosis (OR, 2.42; 95% CI, 1.53–3.80; p < 0.001). Multivariate analysis identified the following factors as independent risk factors for 90-day mortality: higher serum CRP (OR, 2.02; 95% CI, 1.21–3.38; p = 0.007), higher serum LDH (OR, 2.29; 95% CI, 1.38–3.80; p = 0.001), and a low P/F ratio (OR, 1.71; 95% CI, 1.03–2.84; p = 0.040). The all-patients survival curve after AE diagnosis is shown in Fig. 2A.

Table 2

Odds ratios for 90-day mortality in all patients
Variables	Univariate analysis		Multivariate analysis
Variables	Odds ratio (95% CI)	p-value	Odds ratio (95% CI)	p-value
Age (≥ 75/<75)	1.66 (1.05–2.60)	0.029	1.49 (0.90–2.47)	0.13
Sex (male/female)	1.07 (0.64–1.80)	0.79	1.17 (0.63–2.19)	0.61
Emphysema (+/-)	0.89 (0.55–1.44)	0.63	0.77 (0.44–1.35)	0.36
Baseline ILD pattern
UIP/others	1.37 (0.83–2.24)	0.22	1.29 (0.73–2.27)	0.39
Collagen disease (+/-)	1.11 (0.61–2.01)	0.74	0.98 (0.49–1.94)	0.95
IPAF (+/-)	0.83 (0.42–1.64)	0.60	1.00 (0.46–2.16)	0.99
P/F (< 200/≥200)	2.42 (1.53–3.80)	< 0.001	1.71 (1.03–2.84)	0.040
LDH at AE
≥ 340 (median)/<	2.93 (1.85–4.66)	< 0.001	2.29 (1.38–3.80)	0.001
CRP at AE
≥ 7.9 (median)/<	2.63 (1.66–4.15)	< 0.001	2.02 (1.21–3.38)	0.007
KL-6 at AE
≥ 1192 (median)/<	1.04 (0.67–1.62)	0.86	1.12 (0.68–1.84)	0.67
Abbreviations: CI, confidence interval; ILD, interstitial lung disease; UIP, usual interstitial pneumonia; IPAF, interstitial pneumonia with autoimmune features; P/F, PaO₂/FIO₂ ratio; AE, acute exacerbation; KL-6, Krebs von den Lungen-6; LDH, lactate dehydrogenase; CRP, C-reactive protein.

Analysis of patients who responded to treatment at least once

Among the 265 patients who responded to treatment at least once, 191 (72.1%), 26 (9.8%), 46 (17.4%), and two (0.8%) were in the responder, complication, second-attack, and unknown groups, respectively. Forty-eight died within 90 days. These fatalities comprised 18 (37.5%), 28 (58.3%), and two (4.2%) cases in the complication, second-attack, and unknown groups, respectively. The most common complications leading to death were pneumothorax and infection (Table S1). Among the patients who responded to treatment at least once, comparisons between the second-attack group and others showed that a second attack was an independent risk factor for 90-day mortality (OR, 19.30; 95% CI, 8.04–46.35; p < 0.001) (Table 3). The survival curve of patients who responded to treatment at least once after a diagnosis of AE is shown in Fig. 2B.

Table 3

Odds ratios for 90 days mortality in patients who responded to treatment at least once.
Variables	Univariate analysis
Variables	Odds ratio (95% CI)	p-value	Odds ratio (95% CI)	p-value
Age (≥ 75/<75)	1.34 (0.71–2.52)	0.37
Sex (male/female)	1.26 (0.59–2.70)	0.55
Emphysema (+/-)	0.97 (0.50–1.91)	0.94
Baseline ILD pattern Baseline ILD pattern
UIP/others	0.94 (0.45–1.98)	0.88
Collagen disease (+/-)	0.36 (0.11–1.22)	0.10
IPAF (+/-)	1.30 (0.55–3.05)	0.55
P/F (< 200/≥200)	1.16 (0.62–2.19)	0.64
LDH at AE
≥ 340 (median)/<	3.23 (1.65–6.29)	< 0.001	1.91 (0.88–4.16)	0.10
CRP at AE
≥ 7.9 (median)/<	1.98 (1.05–3.72)	0.035	1.81 (0.85–3.89)	0.13
KL-6 at AE
≥ 1192 (median)/<	1.33 (0.71–2.49)	0.37
2nd-attack	15.48 (7.31–32.76)	< 0.001	13.85 (6.36–30.14)	< 0.001
Abbreviations: CI, confidence interval; ILD, interstitial lung disease; UIP, usual interstitial pneumonia; IPAF, interstitial pneumonia with autoimmune features; P/F, PaO₂/FIO₂ ratio; AE, acute exacerbation; KL-6, Krebs von den Lungen-6; LDH, lactate dehydrogenase; CRP, C-reactive protein.

Analysis of patients who experienced a second attack

Given the relatively high incidence and negative prognostic impact of this condition, we investigated the patients who experienced a second attack. The median time to a second attack was 19.5 days after AE-FILD onset (IQR, 9.8–32.3). The median steroid dose at the second attack was 45.0 mg (IQR, 25.0–60.0). In the second-attack group, 43 (93.5%) patients had initially been started on high-dose steroids at the time of diagnosis of AE-FILD. The 90-day mortality rate in the second-attack group was 60.9% (n = 28). A 21-day landmark analysis showed that the survival time was significantly shorter in patients with a second attack than that in other groups (p < 0.001) (Fig. 2C). To isolate the predictors of a second attack, we compared the patient characteristics between the responder group (n = 191) and the second-attack group (n = 46) (Table 4). The second-attack group showed a significantly higher serum LDH level at the time of AE (390.0 vs. 306.0 IU/L; p < 0.001). As for the initial steroid therapy, there was no significant between-group difference in steroid pulse therapy (p = 0.30) and steroid dose as the initial treatment for AE (p = 1.00).

Table 4

Patient characteristics of the second-attack and responder groups
Patient characteristics	Second-attack (N = 46)	Responder (N = 191)	p-value
Age, years
Median (IQR)	75.0 (67.0–80.0)	74.0 (68.0–80.0)	0.63
Sex, n (%)
Male	34 (73.9)	142 (74.3)	1.00
Smoking status, n (%)
Current	2 (4.3)	18 (9.4)	0.71^a
Former	33 (71.7)	121 (63.4)
Never	11 (23.9)	52 (27.2)
Emphysema, n (%)	11 (23.9)	62 (32.5)	0.29
Baseline ILD pattern, n(%)
UIP	14 (30.4)	43 (22.5)	0.26^a
Probable UIP	16 (34.8)	54 (28.3)
Indeterminate UIP	3 (6.5)	26 (13.6)
Alternative diagnosis	13 (28.3)	68 (35.6)
Treatment for baseline ILD, n(%)
Steroids	18 (39.1)	50 (26.2)
Immunosuppressants	10 (21.7)	28 (14.7)
Antifibrotic drug	10 (21.7)	18 (9.4)
None	22 (47.8)	129 (67.5)
Collagen disease, n (%)	9 (19.6)	28 (14.7)	0.50
IPAF, n (%)	5 (10.9)	28 (14.7)	0.64
AE with causes, n (%)	11 (23.9)	44 (23.0)	1.00
P/F at the AE,
Median (IQR)	216.1 (126.8–287.2)	238.6 (162.5–318.2)	0.19
Laboratory data at the AE
Median (IQR)
LDH	390.0 (329.8–476.0)	306.0 (251.0–398.0)	< 0.001
CRP	7.9 (5.9–15.1)	6.3 (2.5–11.8)	0.060
KL-6	1463.5 (813.0–2081.3)	1133.0 (756.0–1950.0)	0.38
Abbreviations: IQR, interquartile range; ILD, interstitial lung disease; UIP, usual interstitial pneumonia; IPAF, interstitial pneumonia with autoimmune features; AE, acute exacerbation; P/F, PaO₂/FIO₂ ratio; KL-6, Krebs von den Lungen-6; LDH, lactate dehydrogenase; CRP, C-reactive protein.
^a Patients were compared after stratification into smokers and never-smokers, as well as UIP and others.

The present study demonstrated the clinical courses and outcomes of AE-FILD and included one of the largest published cohorts of patients with AE-FILD. To our knowledge, this is the first study to describe the clinical course of AE-FILD with a focus on patients experiencing a second attack.

Our study revealed a high mortality rate and a heterogeneous course of AE-FILD. Approximately 40% of patients who developed AE-FILD died within 90 days, which is consistent with previous reports^11,14,15. Notably, approximately 80% of patients with AE-FILD responded to treatment at least once; however, approximately 30% of these patients experienced a relapse of their respiratory condition. This indicates the need for careful attention to a possible deterioration of the respiratory condition even after improvement following treatment for AE-FILD.

We identified two major courses leading to death in patients with AE-FILD: cases without a response to initial steroid therapy and those that responded to treatment at least once but died due to a second attack or complications. Among the patients who experienced second attacks or complications, 63.9% (n = 46) died within 90 days. Of all the patients who died of AE-FILD, approximately 40% responded to treatment at least once. Considering these results, we identified a need to differentially treat these disease courses to improve the prognosis of AE-FILD. For patients who do not respond to treatment, it is necessary to consider drugs other than steroids, which are commonly used in the initial treatment of AE-FILD²⁵. It is of interest that a clinical trial of new agents for AE-IPF has recently appeared²⁶. For patients who respond to treatment at least once, we identified a need to improve early preventive treatment against a second attack. This might require studies on prednisolone dose reduction or new therapies, including antifibrotic drugs. In addition to such clinical studies, mechanistic studies are needed to determine the cause of the observed relapses.

Our findings revealed several prognostic factors for AE-FILD. Low P/F ratio, high serum LDH level at AE diagnosis, and high serum CRP level at AE diagnosis were associated with 90-day mortality, which is consistent with previous findings^11,22,27,28. Furthermore, multivariate analysis revealed that a second attack was an independent prognostic factor in patients who responded to treatment at least once. Moreover, the second attacks occurred in the early period after initial treatment and were strongly associated with early death; specifically, 28 patients in the second-attack group who died within 90 days died 10.5 days (median) after the onset of the second attack. This phenomenon has not been studied. Given their relatively high incidence and extremely high mortality rate, there is a need to consider the importance of second attacks.

Compared with the responder group, the second-attack group showed significantly higher serum LDH levels at AE onset. The median serum LDH was 328.0 IU/L in patients who responded at least once, with an IQR of 263.0–419.5 IU/L. Patients were divided into four quartiles (≤ 419.5, ≥ 328.0 and < 419.5, ≥ 263.0 and < 328.0, and < 263.0). In each group, 19 (28.8%), 18 (26.5%), five (7.6%), and four (6.2%) patients had second attacks, respectively. The precise reason for the association of LDH with a second attack is unclear. However, we identified a need for increased vigilance for respiratory deterioration if the baseline LDH levels are found to be high, even if the patient initially responds to treatment.

This study has several limitations. First, the fact that this study was conducted at only two institutions introduced a potential selection bias. Second, this was a retrospective study and included some cases (n = 2, 0.6%) with early loss to follow-up. Third, almost all included patients were of a single ethnicity (Japanese), which may limit the generalizability of the results. However, a strength of our study was the use of a large sample.

AE-FILD has a heterogeneous clinical course. Worsening of the respiratory condition after an initial response to treatment is relatively common. Specifically, a second attack tended to occur in the early period after treatment and was associated with a high mortality rate. Clinicians should remain vigilant for a worsening respiratory condition even after a positive response to treatment. Further, we identify a need for clinical studies on patients who respond to treatment, as well as basic research to investigate the mechanism of relapses of this condition, to improve the outcomes of AE-FILD.

DATA AVAILABILITY

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

ACKNOWLEDGEMENTS

We thank the staff at all the sites involved in this study, as well as the data manager and other support staff.

FUNDING

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

DECLARATION OF INTEREST

KF received honoraria from Boehringer Ingelheim Japan, Inc. DF received grants from AstraZeneca KK and Boehringer Ingelheim Japan, Inc., and honoraria from AstraZeneca KK, Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Boehringer Ingelheim Japan, Inc., Eli Lilly Japan KK, and Novartis Pharma KK. DF served on the advisory boards of AstraZeneca KK and Chugai Pharmaceutical Co., Ltd. KT received payment for presentations from Boehringer Ingelheim Japan, Inc. and Shionogi & Co., Ltd. NY received honoraria from and served on the advisory board of Boehringer Ingelheim Japan, Inc. Other co-authors have no conflicts of interest to declare.

AUTHOR CONTRIBUTIONS

K.F.: Conceptualization, Data curation, Formal analysis, Investigation, Writing-original draft. D.F.: Conceptualization, Project administration, Methodology, Writing-original draft. A.M.: Conceptualization, Data curation, Investigation. T.M.: Formal analysis, Methodology, Writing-review and editing. M.T.: Conceptualization, Investigation, Writing-review and editing. R.S.: Conceptualization, Methodology, Writing-review and editing. Y.S.: Investigation, Writing-review and editing. K.N.: Methodology, Writing-review and editing. K.T.: Methodology, Writing-review and editing. N.Y.: Conceptualization, Supervision, Writing-review and editing.

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Competing interest reported. KF received honoraria from Boehringer Ingelheim Japan, Inc. DF received grants from AstraZeneca KK and Boehringer Ingelheim Japan, Inc., and honoraria from AstraZeneca KK, Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Boehringer Ingelheim Japan, Inc., Eli Lilly Japan KK, and Novartis Pharma KK. DF served on the advisory boards of AstraZeneca KK and Chugai Pharmaceutical Co., Ltd. KT received payment for presentations from Boehringer Ingelheim Japan, Inc. and Shionogi & Co., Ltd. NY received honoraria from and served on the advisory board of Boehringer Ingelheim Japan, Inc. Other co-authors have no conflicts of interest to declare.

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Clinical Course of Acute Exacerbation of Fibrosing Interstitial Lung Disease

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Abstract

Figures

Introduction

Methods

Study design and patients

Statistical analysis

Results

Patient characteristics

Clinical courses of AE-FILD

Ninety-day mortality and risk factors

Analysis of patients who responded to treatment at least once

Analysis of patients who experienced a second attack

Discussion

Conclusions

Declarations

References

Additional Declarations

Supplementary Files

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