Secondary Logo

Journal Logo

Acute exacerbation of idiopathic pulmonary fibrosis

usual interstitial pneumonitis vs. possible usual interstitial pneumonitis pattern

Cao, Meng-Shu1,2; Sheng, Jian1; Wang, Tian-Zhen2; Qiu, Xiao-Hua1; Wang, Dong-Mei3; Wang, Yang3; Xiao, Yong-Long1; Cai, Hou-Rong1

Section Editor(s): Chen, Li-Min

doi: 10.1097/CM9.0000000000000422
Original Articles
Open

Background: The prognosis of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is very poor with a high mortality. The aim of this study was to describe the clinical features and survival of patients with AE-IPF with usual pulmonary fibrosis (UIP) and possible UIP (P-UIP) pattern on chest high resolution computed tomography (HRCT).

Methods: This retrospective study included 107 patients with AE-IPF admitted to Nanjing Drum Tower Hospital from January 2010 to December 2016. The subjects were divided into UIP (n = 86) and P-UIP group (n = 21) based on chest HRCT. Continuous variables were analyzed using Student's t test or Mann-Whitney U test. Categorical variables were analyzed using χ2 test. Log-rank test was used for the survival analysis. Cox proportional models evaluated the risk factors for AE occurrence and survival.

Results: The male, older patients, previous N-acetylcysteine use, elevated white blood cell (WBC) counts, and microbiology infection were more common in the UIP group than the P-UIP group (χ2 = 13.567, P < 0.001; z = −2.936, P = 0.003; χ2 = 5.901, P = 0.015; t = 2.048, P = 0.043; χ2 = 10.297, P = 0.036, respectively). The percentage of AE with UIP pattern in idiopathic interstitial pneumonia (IIP) was significantly higher than P-UIP pattern (χ2 = 40.011, P < 0.001). Smoking was the risk factor for AE within 6 months after IPF diagnosis in the UIP group. The cumulative proportion survival of 30-days was significantly higher in the UIP group compared with the P-UIP group (χ2 = 5.489, P = 0.019) despite of the similar overall survival in the two groups. Multivariate Cox regression analysis indicated WBC count, partial pressure of oxygen in artery (PaO2)/fractional concentration of inspired oxygen (FiO2), and computed tomography (CT) score were the independent predictors for survival in the UIP group (hazard ratio [HR]: 1.070, 95% confidential interval [CI]: 1.027–1.114, P = 0.001; HR: 0.992, 95% CI: 0.986–0.997, P = 0.002; and HR: 1.649, 95% CI: 1.253–2.171, P < 0.001, respectively).

Conclusions: AE occurrence of UIP patients in IIP was significantly more than P-UIP cases. The short-term survival was better in the UIP group despite of the similar overall survival in the two groups. WBC count, PaO2/FiO2, and CT score were the independent predictors for survival in UIP subjects.

1Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China

2Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, Jiangsu 210008, China

3Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China.

Correspondence to: Prof. Meng-Shu Cao, Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, Jiangsu 210008, ChinaE-Mail: mengshucao@126.com

How to cite this article: Cao MS, Sheng J, Wang TZ, Qiu XH, Wang DM, Wang Y, Xiao YL, Cai HR. Acute exacerbation of idiopathic pulmonary fibrosis: usual interstitial pneumonitis vs. possible usual interstitial pneumonitis pattern. Chin Med J 2019;00:00–00. doi: 10.1097/CM9.0000000000000422

Received 20 July, 2019

Online date: September 3, 2019

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

Back to Top | Article Outline

Introduction

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial pneumonia, occurring primarily in older adults. The median survival is only 2 to 3 years.[1] Acute exacerbation (AE) of IPF is an acute, clinically significant respiratory deterioration characterized by evidence of newly developed widespread alveolar abnormality.[2] AE occurs mostly in IPF, but it is also found in other fibrosing interstitial pneumonias, such as idiopathic non-specific interstitial pneumonitis, chronic hypersensitivity pneumonitis, and connective tissue disease-associated fibrosing interstitial lung disease (CTD-fILD).[3–5] Annual incidence of AE in patients with IPF is 4.1% in the United States,[6] 4.8% in Japan,[7] and 5.2% in South Korea.[8] The prognosis of AE-IPF is very poor, with 50.0% in-hospital mortality rate and 90% 6-month mortality.[2,3,6,9–11] In China, published reports of small series indicated the similar in-hospital mortality.[12,13] Therefore, AE is the most common cause of death in patients with IPF.[14,15]

IPF is associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonitis (UIP). New algorithm for IPF with UIP patterns is based on high resolution computed tomography (HRCT) findings; surgical lung biopsy (SLB) is not an absolute requirement in patients with a classical UIP pattern on HRCT.[1,16] Patients with possible UIP (P-UIP) pattern on chest imaging appear similar to those with UIP pattern on histopathology.[1,17,18] P-UIP pattern on HRCT has a high specificity for UIP on SLB, but positive predictive value is highly dependent on underlying prevalence.[19] Recently, Salisbury et al[18] suggested that IPF patients with P-UIP pattern had a better survival than those with definite UIP pattern and were associated with reduced hazard of death or lung transplant. However, Yunt et al[20] indicated that rheumotoidathrit is associated ILD patients with both definite UIP and P-UIP pattern which had equally poor survival. Although the clinical characteristics and survival of patients with fILD with UIP pattern were not completely consistent with P-UIP pattern, the differences of patients with AE-IPF between the two patterns on chest HRCT were not fully described. In this retrospective study, we compared the clinical features and outcomes of AE-IPF patients with UIP and P-UIP pattern on chest HRCT in our single center.

Back to Top | Article Outline

Methods

Ethical approval

This study was approved by the Ethics Committee of Nanjing Drum Tower Hospital (No. 2016-160-01) and conducted in accordance with the principles of the Declaration of Helsinki (1989). All patients or their relatives signed an informed consent.

Back to Top | Article Outline

Study subjects

We retrospectively reviewed the clinical data of 1606 new-onset patients with idiopathic interstitial pneumonia (IIP) admitted to Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School from January 2010 to December 2016 according to the international criteria.[1,16] The final study cohort included 107 AE-IPF subjects. The subjects were divided into UIP group and P-UIP group according to chest HRCT as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin America Thoracic Association (LATA) guidelines [Figure 1].[1,16] The diagnosis of IPF was based on the ATS/ERS/JRS/LATA guidelines and included in (1) exclusion of other known causes of ILD (eg, domestic and occupational environmental exposures, CTDs, and drug toxicity); and (2) the presence of a UIP or P-UIP pattern on HRCT.[1,16] AE-IPF was defined as an acute, clinically significant respiratory deterioration characterized by evidence of new widespread alveolar abnormality with: (1) previous or concurrent diagnosis of IPF,(2) acute worsening or development of dyspnea typically less than 1 month duration; (3) computed tomography (CT) with new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with UIP or P-UIP pattern; and (4) deterioration not fully explained by cardiac failure or fluid overload.[2]

Figure 1

Figure 1

The clinical and imaging data were extracted from the medical records. Vital status was obtained from medical records or telephone interview on follow-up. The time of follow-up was from 6 months to 7 years after AE. The baseline characteristics were obtained upon the admittance to hospital.

Back to Top | Article Outline

Chest imaging

All subjects accepted the examination of chest HRCT with appropriate settings (1.0–1.5 mm thick section, window width: 1600 and window level: −600) within 24 h after diagnosis of respiratory failure due to AEs. Some patients performed HRCT at the time of IPF diagnosis. UIP pattern was defined as: sub-pleural and basal predominance, reticular abnormality, honeycombing with or without traction bronchiectasis, and absence of features inconsistent with UIP pattern [Figure 2A].[1] P-UIP pattern was described as: sub-pleural and basal predominance, reticular abnormality, and absence of features inconsistent with UIP pattern [Figure 2C].[1] Each case was evaluated and categorized into UIP pattern or P-UIP pattern according to HRCT.[1] Those with inconsistent with UIP pattern were excluded from our study.[1] When new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with UIP or P-UIP pattern, it was regarded as the AE occurrence [Figure 2B and 2D].[2] The findings of chest HRCT were reviewed and scored by two senior radiologists blinded to clinical information independently. CT score of the patient with AE-IPF was calculated based on the overall extent of abnormalities (ie, ground glass chioectasis, reticulation, and honeycombing) determined for each entire lung using a four-point scale (0 = no involvement, 1 = 1%–25% involvement, 2 = 26%–50% involvement, 3 = 51%–75% involvement, and 4 = 76%–100% involvement) based on the published reports.[21,22] The total CT score of each patient was obtained by adding up the scores of both lungs.[21,22]

Figure 2

Figure 2

Back to Top | Article Outline

Statistical analysis

Continuous variables are presented as mean ± standard deviation, and analyzed using Student's t test or Mann-Whitney U test. Categorical variables are presented as percentages and analyzed using χ2 test. Patient survival was evaluated with Kaplan-Meier method and followed by the log-rank test. Bivariate correlation analysis was used to identify the relationship between the total survival and clinical variables. The risk factors for accidence or survival were analyzed using univariate and multivariate Cox proportional models. All statistical analyses were conducted by using SPSS version 23 (SPSS Inc., Chicago, IL, USA). Statistical significance was defined as P < 0.05 (two-sides).

Back to Top | Article Outline

Results

Baseline clinical characteristics

There were 107 subjects with AE-IPF (mean age: 68.52 ± 9.87 years; male/female: 81/26) included in our cohort study [Table 1]. All patients were presented with severe hypoxia (mean partial pressure of oxygen in artery (PaO2)/fractional concentration of inspired oxygen (FiO2): 123.71 ± 48.36 mmHg) and very high CT scores (mean CT score was 7.25 ± 0.92) [Table 1].

Table 1

Table 1

The male gender, older patients, N-acetylcysteine used before AE and white blood cell (WBC) counts at AE occurrences were more common in the UIP group than in the P-UIP group (P < 0.05, respectively) [Table 1]. The evidence of microbiology infection was higher in patients with P-UIP pattern than UIP pattern (χ2 = 10.297, P = 0.036). The other clinical variables and treatment after AE, such as maximal dosage of methylprednisolone, immunoglobulin (10–20 g/d for 3–5 days), immunosuppressant, caspofungin, cotrimoxazole, and mechanical ventilation (MV) did not show any difference between the two groups [Table 1].

Back to Top | Article Outline

AE occurrence in patients with IIP

The number of new-onset patients with IIP and AE-IPF was increased gradually from 2010 to 2016 in our single-center [Figure 3A], and the total percentage of AE-IPF was 6.66% in all new-onset IIP cases. The AE occurrence of UIP was higher than P-UIP in patients with IIP in the past few years, and the difference of total AE occurrence was significant between the two groups (5.35% vs. 1.31%, P < 0.001) [Figure 3B and 3C]. Univariate and multivariate Cox regression analyses showed that smoking was the significant risk factor for AE within 6 months after IPF diagnosis in UIP group after adjusting other clinical variables (hazard ratio [HR]: 1.974, 95% confidential interval [CI]: 1.140–3.419, P = 0.015). Corticosteroids reduction or discontinuation before AEs had the tendency of being a risk factor for AE (HR: 0.525, 95% CI: 0.274–1.003, P = 0.051) [Table 2]. None of these clinical variables could predict AE occurrence in P-UIP group.

Figure 3

Figure 3

Table 2

Table 2

Back to Top | Article Outline

Survival

The median survival time of all patients was only 33 days, and the in-hospital mortality was 54.2%. The cumulative proportion survival (CPS) of 30, 60, and 120-day after AE was 56.1%, 30.8%, and 14.0%, respectively. Kaplan-Meier analysis did not reveal any difference in the overall survival between the two groups (χ2 = 0.264, P = 0.608) [Figure 4], but the CPS of 30-day was significantly higher in the UIP group than in the P-UIP group (χ2 = 5.489, P = 0.019) [Table 3].

Figure 4

Figure 4

Table 3

Table 3

Back to Top | Article Outline

Risk factors for survival

Bivariate correlation analysis discovered that the survival negatively correlated to WBC count (r = −0.260, P = 0.015), C-reactive protein (CRP) (r = −0.296, P = 0.006), lactic dehydrogenase (LDH) (r = −0.235, P = 0.029), CT score (r = −0.445, P < 0.001), maximal dosage of methylprednisolone (r = −0.024, P = 0.038) and use of immunoglobulin (r = −0.231, P = 0.032), co-trimoxazole (r = −0.230, P = 0.033), and MV (r = −0.407, P < 0.001) in the UIP group, and positively correlated to PaO2/FiO2 (r = 0.234, P = 0.030). In the P-UIP group, the survival negatively correlated to D-dimer (r = −0.519, P = 0.023) and positively correlated to PaO2/FiO2 (r = 0.457, P = 0.037) [Table 4].

Table 4

Table 4

Univariate cox analysis demonstrated that the survival was associated with WBC count (HR: 1.077, 95% CI: 1.035–1.121, P < 0.001), LDH (HR: 1.002, 95% CI: 1.000–1.003, P = 0.009), PaO2/FiO2 (HR: 0.992, 95% CI: 0.987–0.997, P = 0.001), CT score (HR: 1.711, 95% CI: 1.316–2.224, P < 0.001), maximal dosage of methylprednisolone (HR: 1.001, 95% CI: 1.000–1.002, P = 0.012), use of immunoglobulin (HR: 1.939, 95% CI: 1.212–3.102, P = 0.006), caspofungin (HR: 1.992, 95% CI: 1.106–3.590, P = 0.022), and MV (HR: 2.497, 95% CI: 1.566–3.980, P < 0.001) in the UIP group [Table 5]. Only use of MV was related to the survival of subjects with P-UIP pattern (HR: 3.132, 95% CI: 1.040–9.428, P = 0.042) [Table 5]. However, in the multivariate Cox model, WBC count, PaO2/FiO2, and CT score were the independent prognostic factors for subjects in the UIP group after adjusting other clinical variables (95% CI: 1.027–1.114, P = 0.001; 95% CI: 0.986–0.997, P = 0.002; and 95% CI: 1.253–2.171, P < 0.001, respectively), none of clinical variables could predict the survival of patients in P-UIP group [Table 5].

Table 5

Table 5

Back to Top | Article Outline

Discussion

The current study showed the clinical features of patients with AE with UIP pattern differed from P-UIP pattern. AE incidence of UIP was significantly higher than P-UIP in IIP patients. Within 6 months after IPF diagnosis, smoking was the risk factor for AE occurrence in UIP group. Although the overall survival was similar in the two groups, the survival of 30-day was much better in UIP group. WBC count, PaO2/FiO2, and CT score were the independent risk factors for prognosis in patients with UIP pattern.

The positive predictive value of UIP or P-UIP pattern on chest HRCT for IPF is very high.[1,23–25] Quite a few of studies suggested that SLB was optional for diagnosis IPF patients with P-UIP pattern. In the study of Sumikawa et al,[26] SLB revealed that 23 subjects were pathological UIP-pattern among 24 patients with radiological P-UIP pattern. Lee et al[27] argued that lung biopsy was not necessary in patients with radiological P-UIP pattern when associated with typical symptoms and excluded other known causes of IPF. Arai et al[28] indicated that AE possibly occurred more often in patients with UIP pattern than those with P-UIP pattern on chest imaging. Population-based epidemiological studies have suggested that IPF tended to occur in male and older people.[1,29] AE-IPF patients with classical UIP pattern were older than P-UIP subjects.[28] Consistent with these previous studies, patients with AE in the UIP group had more men and were older than those in the P-UIP group in our study.[1,28,29] Severe hyoxmia and high CT scores at AEs meant that the conditions of these subjects included in our cohort study were quite serious.

Recent evidences indicated that infection could be an important pathogenic factor and risk factor for mortality for patients with AE-IPF.[3,30–32] In some patients with AE-IPF, death was attributed to bronchopneumonia and the causes of infection included fungus, virus, and bacteria.[33] Patients with AE-IPF had higher bacterial burden in bronchoalvolar lavage fluids than stable cases.[34] As a result, the updated international diagnostic criteria of AE-IPF no longer excluded respiratory infections, such a broader definition was more inclusive and pragmatic for clinicians who struggled with the historical requirement for exclusion of infection.[2] In current study, more higher inflammation markers and evidence of microbiology infection were shown in the UIP group when AEs occurred. These findings were consistent with the new definition and diagnostic criteria,[2] and indicated that infection could be more important in patients with P-UIP than classical UIP cases in AE.

Cohort studies generally reported a higher annual incidence of AE-IPF than clinical trials, 13.0, 14.2, and 8.6 per 100 patients with IPF in the United States, South Korean, and Japan, respectively.[3,9,35] Low forced vital capacity (FVC), low diffusing capacity for carbon monoxide (DLCO), pulmonary hypertension, poor baseline oxygenation, and increased dyspnea have been proved to be the risk factors for AE-IPF.[3,6,9,10,35] Now, nation-wide epidemiological study in China is lacking. In the current study from our single-center, the incidence of AE-IPF was 6.66% in patients with IIP, and AE incidence of UIP patients was higher than P-UIP subjects per year. The differences of epidemiological data between our center and other countries might be due to the different population of AE-IPF.[2] Smoking has been identified as a risk factor for AE-IPF by some, but not all studies.[3,36,37] Results from the current study supported the claim that smoking was a risk factor for AE. A prospective cohort study of the relationship between smoking and AE occurrence should be conducted in the future. Although the international guideline recommended that patients with IPF should not be treated with corticosteroid mono-therapy or in combination with immunosuppressant therapy,[1] we included some cases before the guideline published, part of them used corticosteroids in our study. Data analysis showed that there was a tendency of corticosteroids reduction or discontinuation as a risk factor for AE occurrence. We should be cautious with withdrawal of corticosteroids in order to avoiding the fatal events of AE in patients with IPF.

The median survival time of AE-IPF has been estimated at 3 to 4 months approximately.[3,6] The average survival time and in-hospital mortality of our cases were similar to the published reports.[3,6,9] In previous small cohort retrospective studies, the survival of patients with AE-IPF between UIP and P-UIP pattern were inconsistent with each other. Arai et al[28] reported that the prognosis of patients with AE-IIP with P-UIP pattern (n = 12) might be worse than those with UIP pattern (n = 29). However, Usui et al[38] showed a similar survival in patients with AE-IPF with UIP pattern and P-UIP pattern. In our cohort, the short-term survival in patients with UIP was much better, although the overall survival did not show significant difference between the two groups. Such discrepancy was very interesting. We suspected that the better short-term survival might be associated with more microbiology infection in the UIP group. Now, the respiratory infection has been regarded as an important factor for the development of AE-IPF.[2] We could take the effective targeted treatments once we identified some pathogens. However, it required further clinical studies of multi-center design and larger samples size.

Previous studies revealed that the following prognostic factors were associated with the survival of patients with AE-IPF, such as lower baseline FVC and DLCO,[3,9] more extensive CT abnormalities,[39] worse oxygenation,[3,40] bronchoalveolar lavage neutrophil, and lymphocyte percentages at the time of AE.[3] Several biomarkers in peripheral blood, including Krebs Von den Lungen-6 (KL-6), heat shock protein 70, LDH, CRP, and leptin have also been proposed.[37,41–43] In our study, the predictors for survival in patients with AE were also different between the two groups. WBC count, PaO2/FiO2, and CT score were the independent prognostic factors in the UIP group, but none in P-UIP group. The findings in the UIP group were generally consistent with results obtained in patients with AE-IPF in previous studies.[3,40] Fujimoto et al[39] suggested that HRCT CT scores could predict the mortality of patients with AE-IPF. We suspected that the clinical outcomes of patients with AE-UIP were mainly dependent on the degree of inflammation and the injury extents of lung at AEs. The survival of AE patients with P-UIP pattern needs to be further studied.

There is no treatment proven to be effective for AE-IPF. Systemic corticosteroids were often used by clinicians for patients with AE-IPF because the international evidence-based guidelines of the management of IPF made a weak recommendation, but the ILD experts have not reached a consensus on the regimen and dosage of corticosteroids.[1,2,44]Steroids in combination with immunosuppressant for AE-IPF appeared better than corticosteroid monotherapy.[1,2,44,45] Supportive cares, such as supplemental oxygen, immunoglobulin, and MV are usually used when AE occurs, although the use of MV is controversial.[2,46,47] In our analysis, uses of high dose methylprednisolone, immunoglobulin, co-trimoxazole, and MV for AE were associated with a shorter survival in the UIP group. So the current therapies for AE usually could not benefit patients with IPF. Nintedanib, intra-venous thrombomodulin, and polymyxin B-immobilized fiber column perfusion add-on conventional treatment might be the potential treatments for patients with AE-IPF.[40,48,49] Recently, some experts suggested translating to AE-IPF the lessons learned from the management of patients with ARDS because of the common pathophysiological abnormalities and similar clinical needs.[50]

The current study had limitations. First, it was retrospectively reviewed for patients from a single center and the sample size was small. Second, the diagnosis of AE-IPF was only based on clinical and radiological findings, without pathological evidences. Third, the definite causes of death were not clear. A prospective, multi-center and nation-wide cohort study would be helpful to understand the epidemiological features of patients with AE-IPF in China.

In summary, the clinical features of AE-IPF were different between patients with UIP pattern and P-UIP pattern. AE incidence of cases with UIP pattern was significantly higher than P-UIP pattern in patients with IIP. Within 6 months after IPF diagnosis, smoking was the independent risk factor for AE occurrence in UIP group. The short-term survival of patients with AE-UIP was better despite of the similar overall survival in the two groups. The WBC count, PaO2/FiO2, and CT score were the independent prognostic predictors for patients with UIP pattern, not P-UIP pattern.

Back to Top | Article Outline

Funding

This study was partially supported by the grants from the National Natural Science Foundation of China (No. 81200049 and No. 81670059) and the Nanjing Medical Science and Technique Development Foundation (No. ORX17005).

Back to Top | Article Outline

Conflicts of interests

None.

Back to Top | Article Outline

References

1. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183:788–824. doi: 10.1164/rccm.2009-040GL.
2. Collard HR, Ryerson CJ, Corte TJ, Jenkins G, Kondoh Y, Lederer DJ, et al. Acute exacerbation of idiopathic pulmonary fibrosis. an International Working Group Report. Am J Respir Crit Care Med 2016; 194:265–275. doi: 10.1164/rccm.201604-0801CI.
3. Song JW, Hong SB, Lim CM, Koh Y, Kim DS. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J 2011; 37:356–363. doi: 10.1183/09031936.00159709.
4. Miyazaki Y, Tateishi T, Akashi T, Ohtani Y, Inase N, Yoshizawa Y. Clinical predictors and histologic appearance of acute exacerbations in chronic hypersensitivity pneumonitis. Chest 2008; 134:1265–1270. doi: 10.1378/chest.08-0866.
5. Suda T, Kaida Y, Nakamura Y, Enomoto N, Fujisawa T, Imokawa S, et al. Acute exacerbation of interstitial pneumonia associated with collagen vascular diseases. Respir Med 2009; 103:846–853. doi: 10.1016/j.rmed.2008.12.019.
6. Collard HR, Yow E, Richeldi L, Anstrom KJ, Glazer C. Suspected acute exacerbation of idiopathic pulmonary fibrosis as an outcome measure in clinical trials. Respir Res 2013; 14:73doi: 10.1186/1465-9921-14-73.
7. Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A, Suga M, et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010; 35:821–829. doi: 10.1183/09031936.00005209.
8. Johannson KA, Vittinghoff E, Lee K, Balmes JR, Ji W, Kaplan GG, et al. Acute exacerbation of idiopathic pulmonary fibrosis associated with air pollution exposure. Eur Respir J 2014; 43:1124–1131. doi: 10.1183/09031936.00122213.
9. Kondoh Y, Taniguchi H, Katsuta T, Kataoka K, Kimura T, Nishiyama O, et al. Risk factors of acute exacerbation of idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis 2010; 27:103–110.
10. Kim DS, Park JH, Park BK, Lee JS, Nicholson AG, Colby T. Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features. Eur Respir J 2006; 27:143–150. doi: 10.1183/09031936.06.00114004.
11. Rangappa P, Moran JL. Outcomes of patients admitted to the intensive care unit with idiopathic pulmonary fibrosis. Crit Care Resusc 2009; 11:102–109.
12. Xue H, Li E, Li Z. Clinical characteristics of acute exacerbation of idiopathic pulmonary fibrosis: an analysis of 16 cases. Chin J Pract Int Med 2015; 35:946–948.
13. Liu Y, Cai L, Zhao H, Huang Q, Zhu S, Chen B, et al. Acute exacerbation of idiopathic pulmonary fibrosis: clinical analysis of 21 Cases (in Chinese). Chin J Respir Crit Care Med 2012; 11:362–366.
14. Daniels CE, Yi ES, Ryu JH. Autopsy findings in 42 consecutive patients with idiopathic pulmonary fibrosis. Eur Respir J 2008; 32:170–174. doi: 10.1183/09031936.00176307.
15. Natsuizaka M, Chiba H, Kuronuma K, Otsuka M, Kudo K, Mori M, et al. Epidemiologic survey of Japanese patients with idiopathic pulmonary fibrosis and investigation of ethnic differences. Am J Respir Crit Care Med 2014; 190:773–779. doi: 10.1164/rccm.201403-0566OC.
16. Travis WD, Costabel U, Hansell DM, King TE Jr, Lynch DA, et al. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013; 188:733–748. doi: 10.1164/rccm.201308-1483ST.
17. Flaherty KR, Travis WD, Colby TV, Toews GB, Kazerooni EA, Gross BH, et al. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med 2001; 164:1722–1727. doi: 10.1164/ajrccm.164.9.2103074.
18. Salisbury ML, Tolle LB, Xia M, Murray S, Tayob N, Nambiar AM, et al. Possible UIP pattern on high-resolution computed tomography is associated with better survival than definite UIP in IPF patients. Respir Med 2017; 131:229–235. doi: 10.1016/j.rmed.2017.08.025.
19. Brownell R, Moua T, Henry TS, Elicker BM, White D, Vittinghoff E, et al. The use of pretest probability increases the value of high-resolution CT in diagnosing usual interstitial pneumonia. Thorax 72:424–429. doi: 10.1136/thoraxjnl-2016-209671.
20. Yunt ZX, Chung JH, Hobbs S, Fernandez-Perez ER, Olson AL, Huie TJ, et al. High resolution computed tomography pattern of usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease: relationship to survival. Respir Med 2017; 126:100–104. doi: 10.1016/j.rmed.2017.03.027.
21. Akira M, Kozuka T, Yamamoto S, Sakatani M. Computed tomography findings in acute exacerbation of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2008; 178:372–378. doi: 10.1164/rccm.200709-1365OC.
22. Lynch DA, Godwin JD, Safrin S, Starko KM, Hormel P, Brown KK, et al. High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit Care Med 2005; 172:488–493. doi: 10.1164/rccm.200412-1756OC.
23. Flaherty KR, Thwaite EL, Kazerooni EA, Gross BH, Toews GB, Colby TV, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax 2003; 58:143–148. doi: 10.1136/thorax.58.2.143.
24. Sumikawa H, Johkoh T, Colby TV, Ichikado K, Suga M, Taniguchi H, et al. Computed tomography findings in pathological usual interstitial pneumonia: relationship to survival. Am J Respir Crit Care Med 2008; 177:433–439.
25. Hunninghake GW, Zimmerman MB, Schwartz DA, King TE Jr, Lynch J, Hegele R, et al. Utility of a lung biopsy for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2001; 164:193–196. doi: 10.1164/ajrccm.164.2.2101090.
26. Sumikawa H, Johkoh T, Fujimoto K, Arakawa H, Colby TV, Fukuoka J, et al. Pathologically proved nonspecific interstitial pneumonia: CT pattern analysis as compared with usual interstitial pneumonia CT pattern. Radiology 2014; 272:549–556. doi: 10.1148/radiol.14130853.
27. Lee JW, Shehu E, Gjonbrataj J, Bahn YE, Rho BH, Lee MY, et al. Clinical findings and outcomes in patients with possible usual interstitial pneumonia. Respir Med 2015; 109:510–516. doi: 10.1016/j.rmed.2015.02.008.
28. Arai T, Kagawa T, Sasaki Y, Sugawara R, Sugimoto C, Tachibana K, et al. Heterogeneity of incidence and outcome of acute exacerbation in idiopathic interstitial pneumonia. Respirology 2016; 21:1431–1437. doi: 10.1111/resp.12862.
29. Coultas DB, Zumwalt RE, Black WC, Sobonya RE. The epidemiology of interstitial lung diseases. Am J Respir Crit Care Med 1994; 150:967–972. doi: 10.1164/ajrccm.150.4.7921471.
30. Ambrosini V, Cancellieri A, Chilosi M, Zompatori M, Trisolini R, Saragoni L, et al. Acute exacerbation of idiopathic pulmonary fibrosis: report of a series. Eur Respir J 2003; 22:821–826.
31. Kondoh Y, Taniguchi H, Kawabata Y, Yokoi T, Suzuki K, Takagi K. Acute exacerbation in idiopathic pulmonary fibrosis. Analysis of clinical and pathologic findings in three cases. Chest 1993; 103:1808–1812. doi: 10.1378/chest.103.6.1808.
32. Huie TJ, Olson AL, Cosgrove GP, Janssen WJ, Lara AR, Lynch DA, et al. A detailed evaluation of acute respiratory decline in patients with fibrotic lung disease: aetiology and outcomes. Respirology 2010; 15:909–917. doi: 10.1111/j.1440-1843.2010.01774.x.
33. Oda K, Ishimoto H, Yamada S, Kushima H, Ishii H, Imanaga T, et al. Autopsy analyses in acute exacerbation of idiopathic pulmonary fibrosis. Respir Res 2014; 15:109doi: 10.1186/s12931-014-0109-y.
34. Molyneaux PL, Cox MJ, Wells AU, Kim HC, Ji W, Cookson WO, et al. Changes in the respiratory microbiome during acute exacerbations of idiopathic pulmonary fibrosis. Respir Res 2017; 18:29doi: 10.1186/s12931-017-0511-3.
35. Fernandez Perez ER, Daniels CE, Schroeder DR, St Sauver J, Hartman TE, Bartholmai BJ, et al. Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: a population-based study. Chest 2010; 137:129–137. doi: 10.1378/chest.09-1002.
36. Mura M, Porretta MA, Bargagli E, Sergiacomi G, Zompatori M, Sverzellati N, et al. Predicting survival in newly diagnosed idiopathic pulmonary fibrosis: a 3-year prospective study. Eur Respir J 2012; 40:101–109. doi: 10.1183/09031936.00106011.
37. Ohshimo S, Ishikawa N, Horimasu Y, Hattori N, Hirohashi N, Tanigawa K, et al. Baseline KL-6 predicts increased risk for acute exacerbation of idiopathic pulmonary fibrosis. Respir Med 2014; 108:1031–1039. doi: 10.1016/j.rmed.2014.04.009.
38. Usui Y, Kaga A, Sakai F, Shiono A, Komiyama K, Hagiwara K, et al. Cohort study of mortality predictors in patients with acute exacerbation of chronic fibrosing interstitial pneumonia. BMJ Open 2013; 3: doi: 10.1136/bmjopen-2013-002971.
39. Fujimoto K, Taniguchi H, Johkoh T, Kondoh Y, Ichikado K, Sumikawa H, et al. Acute exacerbation of idiopathic pulmonary fibrosis: high-resolution CT scores predict mortality. Eur Radiol 2012; 22:83–92. doi: 10.1007/s00330-011-2211-6.
40. Abe S, Azuma A, Mukae H, Ogura T, Taniguchi H, Bando M, et al. Polymyxin B-immobilized fiber column (PMX) treatment for idiopathic pulmonary fibrosis with acute exacerbation: a multicenter retrospective analysis. Intern Med 2012; 51:1487–1491. doi: 10.2169/internalmedicine.51.6965.
41. Simon-Blancal V, Freynet O, Nunes H, Bouvry D, Naggara N, Brillet PY, et al. Acute exacerbation of idiopathic pulmonary fibrosis: outcome and prognostic factors. Respiration 2012; 83:28–35. doi: 10.1159/000329891.
42. Kakugawa T, Yokota S, Ishimatsu Y, Hayashi T, Nakashima S, Hara S, et al. Serum heat shock protein 47 levels are elevated in acute exacerbation of idiopathic pulmonary fibrosis. Cell Stress Chaperones 2013; 18:581–590. doi: 10.1007/s12192-013-0411-5.
43. Cao M, Swigris JJ, Wang X, Cao M, Qiu Y, Huang M, et al. Plasma leptin is elevated in acute exacerbation of idiopathic pulmonary fibrosis. Mediators Inflamm 2016; 2016:6940480doi: 10.1155/2016/6940480.
44. Juarez MM, Chan AL, Norris AG, Morrissey BM, Albertson TE. Acute exacerbation of idiopathic pulmonary fibrosis-a review of current and novel pharmacotherapies. J Thorac Dis 2015; 7:499–519. doi: 10.3978/j.issn.2072-1439.2015.01.17.
45. Novelli L, Ruggiero R, De Giacomi F, Biffi A, Faverio P, Bilucaglia L, et al. Corticosteroid and cyclophosphamide in acute exacerbation of idiopathic pulmonary fibrosis: a single center experience and literature review. Sarcoidosis Vasc Diffuse Lung Dis 2016; 33:385–391.
46. Fumeaux T, Rothmeier C, Jolliet P. Outcome of mechanical ventilation for acute respiratory failure in patients with pulmonary fibrosis. Intensive Care Med 2001; 27:1868–1874. doi: 10.1007/s00134-001-1150-0.
47. Suzuki A, Taniguchi H, Ando M, Kondoh Y, Kimura T, Kataoka K, et al. Prognostic evaluation by oxygenation with positive end-expiratory pressure in acute exacerbation of idiopathic pulmonary fibrosis: a retrospective cohort study. Clin Respir J 2018; 985-903. doi: 10.1111/crj.12602.
48. Abe M, Tsushima K, Matsumura T, Ishiwata T, Ichimura Y, Ikari J, et al. Efficacy of thrombomodulin for acute exacerbation of idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia: a nonrandomized prospective study. Drug Des Devel Ther 2015; 9:5755–5762. doi: 10.2147/DDDT.S90739.
49. Richeldi L, Cottin V, Flaherty KR, Kolb M, Inoue Y, Raghu G, et al. Design of the INPULSIS trials: two phase 3 trials of nintedanib in patients with idiopathic pulmonary fibrosis. Respir Med 2014; 108:1023–1030. doi: 10.1016/j.rmed.2014.04.011.
50. Marchioni A, Tonelli R, Ball L, Fantini R, Castaniere I, Cerri S, et al. Acute exacerbation of idiopathic pulmonary fibrosis: lessons learned from acute respiratory distress syndrome? Crit Care 2018; 22:80doi: 10.1186/s13054-018-2002-4.
Keywords:

Idiopathic pulmonary fibrosis; Acute exacerbation; Usual interstitial pneumonitis

© 2019 by Lippincott Williams & Wilkins, Inc.