Introduction
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing form of interstitial pneumonia with a median survival after diagnosis of three to five years [
1]-[
4]. Acute exacerbation of IPF (AE-IPF) has an extremely poor prognosis and is believed to occur in 5-10% of patients with IPF annually [
5],[
6]. In 1993, AE-IPF was first described in a case report by Kondoh et al. as acute clinical deterioration in three IPF patients in the absence of an identified infection [
7]. The American Thoracic Society and European Respiratory Society subsequently introduced the notion of AE-IPF in 2002 [
8], and Collard and colleagues focused on establishing a worldwide consensus for AE-IPF in 2007 [
9]. This consensus statement is currently the most widely used definition of AE-IPF, having been used in several clinical studies and being referred to in the 2011 IPF guidelines [
10].
Lung tissue derived from patients with IPF shows a characteristic histopathological pattern known as usual interstitial pneumonia (UIP), which includes the presence of fibroblastic foci. The pathological findings of AE-IPF comprise diffuse alveolar damage (DAD) superimposed on underlying UIP; this is the most commonly described finding on surgical lung biopsies [
9],[
11],[
12]. On the other hand, several studies have reported the detection of organizing pneumonia (OP) without evidence of organizing DAD or extensive fibroblastic foci [
13],[
14]. In addition, although previous reports have focused on the postmortem pathological findings of patients with IPF [
15],[
16], no studies have focused on the characteristics of “acute exacerbation”, and the pathological findings and clinical manifestations of AE-IPF remain only partially understood.
The current study is a retrospective review of an autopsy series designed to describe and evaluate the pathological findings, including concomitant and infectious diseases, observed during the clinical course until death in patients with AE-IPF.
Discussion
In this study, we retrospectively analyzed the autopsy findings of AE-IPF and clarified that AE-IPF exhibits a variety of pathological findings in addition to DAD. Moreover, the AE-IPF patients were diagnosed with various infectious diseases and complications during their clinical course after AE-IPF.
DAD has been reported to be the focal pathological finding of AE-IPF [
9]. DAD also accounted for many cases of AE-IPF in the present investigation, involving a mixture of pulmonary hemorrhage, pulmonary thromboembolism and OP. However, DAD was not observed in all cases. In particular, pulmonary hemorrhage was a representative pathological finding in the AE-IPF patients without DAD. Pulmonary hemorrhage is rarely encountered during the course of IPF [
20]-[
22], and it is difficult to make a premortem diagnosis in actual clinical practice without performing BAL. Nevertheless, careful attention is required in such cases, as the use of BAL in IPF patients may increase the risk of acute exacerbation [
23]. Moreover, pulmonary thromboembolism frequently occurs as a complication during the course of IPF [
24] and can be an important differential diagnosis of AE-IPF.
Regarding acute respiratory distress syndrome (ARDS), in which the diagnostic criteria are based on clinical findings, in the same manner as AE-IPF, Patel S.R. et al. reported that they investigated the pathological findings of 57 cases satisfying the diagnostic criteria for ARDS via open-lung biopsy, with DAD observed in 23 patients (40.3%) [
25]. On the other hand, another study reported specific infections in eight patients (14.0%), diffuse alveolar hemorrhage in five patients (8.8%) and bronchiolitis obliterans organizing pneumonia in five patients (8.8%). Moreover, Esteban A. et al. found that, although DAD was observed in 112 of 127 autopsy cases satisfying the diagnostic criteria for ARDS, the following diseases were observed in patients without DAD, in order of descending prevalence: pneumonia, pulmonary hemorrhage, pulmonary edema and pulmonary embolism [
26]. The findings of such diverse pathological features are very similar to the results of the present study. To date, very few investigations have been carried out regarding the pathological findings of AE-IPF, and the present study is the first report to summarize the features of autopsy cases involving the “acute exacerbation” of IPF. In this study, although the diagnosis was made while checking the findings of AE-IPF against the diagnostic criteria, in the same manner as diagnosing ARDS, not all of the patients with AE-IPF exhibited DAD, namely only 78.8% of the AE-IPF patients demonstrated DAD. Moreover, a significant number of patients who satisfied the diagnostic criteria for AE-IPF did not have remarkable DAD (11/52, 21.2%). In addition, we found no findings associated with acute fibrinous or organizing pneumonia in the AE-IPF patients without DAD [
27]. In these cases, genuine respiratory failure accompanied the progression of pulmonary fibrosis, which may constitute the natural course of IPF. Notably, the results of the present study are supported by the findings of a previous report in which only extensive fibroblastic foci were observed as a pathological finding of an acute pattern [
13]. The incidence of gastrointestinal hemorrhage and right ventricular hypertrophy, both of which are extrapulmonary findings, was 25.0% and 34.6%, respectively. Furthermore, the effects of hypoxic, physical and psychosomatic stress [
28] and high-dose corticosteroid therapy [
29] must be considered with respect to gastrointestinal hemorrhage. Right ventricular hypertrophy may be caused by pulmonary hypertension [
30] at the end stage of AE-IPF. Moreover, the relationship between IPF and pulmonary hypertension is important, and Judge and colleagues recently reported that pulmonary hypertension is associated with acute disease exacerbation as well as poor survival [
31]. Therefore, it is necessary to monitor the potential for pulmonary hypertension in patients with IPF.
Although there is no established standard therapy for AE-IPF [
10], high-dose corticosteroid therapy [
11],[
12],[
14],[
32]-[
34] and immunosuppressive agents [
35],[
36] are commonly used in clinical practice. However, a previous study [
37] suggested that these drugs increase the rates of infectious complications. In addition to the immunodeficient state caused by corticosteroids and/or immunosuppressants, the application of intensive antimicrobial treatment following the acute exacerbation of pulmonary infection may have affected the results of the present study. Regardless, similar to recently published data [
38] from a study of gene expression profiling of patients with AE-IPF, our data demonstrated that an infectious etiology may not be the main cause of AE-IPF. In fact, all patients underwent treatment with high-dose corticosteroids and/or immunosuppressive agents, excluding only one patient, with mechanical ventilation carried out in more than half of the AE-IPF patients. Moreover, the pulmonary infections detected in the present study may have affected, at least in part, the occurrence of respiratory failure leading to death, although there were no significant differences in the time interval between the diagnosis of AE-IPF and death based on the presence of infectious disease. Therefore, in addition to the detection of pathological findings based on DAD, AE-IPF eventually causes respiratory failure due to the effects of accompanying infectious diseases, with patients thus exhibiting a variety of histopathological features. The present investigation was carried out among autopsy cases only; therefore, the efficacy of high-dose corticosteroid therapy against AE-IPF cannot be debated based on our results. However, taking into consideration the fact that many patients with diabetes and pneumothorax following acute disease exacerbation underwent high-dose corticosteroid therapy, such therapy should be carefully administered based on the tolerability and efficacy of the treatment in conjunction with multidisciplinary therapies. Physicians should therefore be aware of the appropriate therapeutic strategies when treating patients with complications induced by treatment for AE-IPF. Furthermore, the results of the present study indicate that it is difficult to distinguish acute exacerbation from other disorders, even if the patient meets the diagnostic criteria for AE-IPF. Given the results of this study, it is very important for clinicians to be alert to the possibility of other treatable disorders, such as infectious diseases, as no effective treatment regimen for AE-IPF has been established to date.
There are several limitations associated with this study. First, only patients who died and underwent autopsy were included; therefore, the results may differ based on the status of onset of AE-IPF. In other words, no patients who survived after AE-IPF were included, and the present findings thus do not reflect all aspects of the entity of AE-IPF. Second, we did not perform endotracheal aspiration or bronchoalveolar lavage due to the presence of severe hypoxemia in all cases. However, we carefully excluded patients based on the findings of sputum, laboratory and physical examinations. In addition, a previous study reported that the features of clinically suspected acute exacerbation diagnosed based on the radiological and clinical course are similar to those of acute exacerbation diagnosed based on the results of several intensive examinations, including BAL [
39]. Third, this study was carried out jointly across multiple facilities, primarily university hospitals, including only Japanese IPF patients. Hence, potential biases, including racial and institutional selection, must be considered when interpreting the results. Finally, 52% of the patients with AE-IPF in the present study required mechanical ventilation on admission, which suggests that these patients had a relatively more severe condition. Therefore, the results of this study may not be extrapolated to all cases of AE-IPF.
Acknowledgements
This research was partly supported by a grant to the Diffuse Lung Diseases Research Group from the Ministry of Health, Labour and Welfare, Japan and was a Ministry of Education, Science, Sports and Culture Grant-in-Aid for Scientific Research (B), 2013–2014 (25860665, Keishi Oda).
The authors thank all test personnel for their work during the data collection at the six institutions involved in the study: University of Occupational and Environmental Health, Japan, Oita University Faculty of Medicine, Fukuoka University School of Medicine, Steel Memorial Yawata Hospital, Nagasaki University School of Medicine and Miyazaki University School of Medicine. The authors also thank Drs. Chiharu Yoshii, Yukiko Kawanami, Toshinori Kawanami, Chinatsu Nishida, Kei Yamasaki, Shingo Noguchi, Takaaki Ogoshi, Kentarou Akata, Kaori Kato, Tetsuya Hanaka, and Masahiro Tahara for their cooperation in this research.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
KO, HI and SY made substantial contributions to the conception and design of the study. KO, HK, HI, TI, TH, YI, NM and KN acquired the data. HI and KY analyzed and interpreted the data. KO, HI, MN, JK, KW, SK and HM participated in drafting the article and critically revising it for important intellectual content. All authors have read and approved the final manuscript.