Review article
Acute exacerbation of idiopathic pulmonary fibrosis: A systematic review

https://doi.org/10.1016/j.ejim.2007.04.024Get rights and content

Abstract

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a clinical entity defined by rapid deterioration of IPF during the course of the disease that is not due to infections, pulmonary embolism, or heart failure. The condition needs to be differentiated from acute interstitial pneumonia (or Hamman–Rich syndrome), which occurs in patients with no underlying lung disease. The exact etiology and pathogenesis remain unknown, but the condition is characterized by diffuse alveolar damage (on a background of IPF) that probably occurs as a result of a massive lung injury due to some unknown etiologic agent. High-resolution computed tomography can help in prognostication and management of this condition. Once infections and other causes of worsening have been excluded, treatment involves enhanced immunosuppression with pulse doses of methylprednisolone and cytotoxic agents. Our systematic review shows that the outcome, however, is poor, with 1-month and 3-month mortality around 60% and 67%, respectively. Few studies have shown beneficial effects of cyclosporine, pirfenidone, and anticoagulants in the management and prevention of AE-IPF. The etiology, risk factors, pathogenesis, therapy, prognosis, and predictors need to be studied and the potential role of newer agents in the management and prevention of AE-IPF needs to be further clarified.

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease (ILD) of unknown etiology that is characterized clinically by relentless dyspnea, reduced lung volumes, impaired gas exchange, and a histological pattern of usual interstitial pneumonia (UIP) on surgical lung biopsy [1], [2]. This needs to be differentiated from other known causes of UIP, such as asbestosis, rheumatoid arthritis, and other connective tissue disease-related ILD, and from other causes that also have UIP on histopathology but are not categorized as IPF. IPF is the most common entity of the idiopathic interstitial pneumonias and accounts for approximately one-quarter of all interstitial lung diseases [3]. The survival time varies considerably from individual to individual, but the mean survival time is around 2–4 years [1]. Although studies have provided inconsistent results, generally the factors that predict survival include the age at presentation, gender, duration of dyspnea, pulmonary function, and radiological and histopathological findings [3].

IPF is a progressive and irreversible illness. However, its course is punctuated by acute exacerbations (AE) that are characterized by a rapid deterioration in lung function during the course of the disease that is not due to infections or heart failure. Several reviews of IPF are available [1], [2]; however, there has been no systematic review on AE-IPF.

The aim of this review was to summarize the current knowledge of acute exacerbations of IPF. For the purpose of this review, we searched the National Library of Medicine's MEDLINE database from 1980 to 2006, with no language restrictions, for fully published articles. We limited the search to human adults (19+ years) using the key words: “acute exacerbation of idiopathic pulmonary fibrosis”, “acute exacerbation of IPF”, “IPF”, “idiopathic pulmonary fibrosis”, and “idiopathic interstitial pneumonias”. We reviewed the reference lists of all identified studies and reviews and hand-searched our personal files. A total of 185 articles were reviewed for the purpose of this review. The focus was on clinical publications on epidemiology, diagnosis, and treatment, specifically on acute exacerbations of IPF, but we also studied other related reviews and publications on IPF.

Section snippets

Definitions

IPF is a fatal fibrotic lung disease of unknown etiology that is characterized by a histological pattern of usual interstitial pneumonia. In contrast, AE-IPF is characterized by rapid deterioration during the course of the disease that is not due to infection, pulmonary embolism, or heart failure.

Confusing terminologies

Numerous other terms are confused or used interchangeably with AE-IPF. They include: “acute interstitial pneumonia”, “Hamman–Rich syndrome”, “accelerated variant of interstitial pneumonitis”, “fulminant idiopathic pulmonary fibrosis”, “acute diffuse interstitial fibrosis of the lungs”, and “accelerated variant of IPF”.

Clearing the confusion

In 1935, Louis Hamman and Arnold Rich described four previously healthy patients with fatal fulminant respiratory failure that, on autopsy, was characterized by extensive pulmonary fibrosis [4], [5]. They termed this condition “acute diffuse interstitial fibrosis of the lungs”, a pattern of ILD that is not easily categorized in the subsequent classification of interstitial pneumonias. However, the eponym “Hamman–Rich syndrome” became synonymous with IPF despite clear differences in clinical

Epidemiology

The exact incidence is not known and varies in different studies. However, AE-IPF is now increasingly being recognized as a common clinical event. In one retrospective series (exploratory analyses conducted on the placebo group of 168 patients enrolled in the interferon gamma-1b trial [10]), Martinez et al. reported that, over a median period of 76 weeks, 21% of these patients died, and 47% of these deaths followed an acute deterioration in the patient's clinical status [11]. In another study

Pathogenesis

The exact pathogenesis of IPF and AE-IPF is not clear [21]. According to the traditional view, IPF is considered to be a progressive disease with a slow and steady decline in lung function that ultimately leads to respiratory failure and death. However, recent evidence suggests that IPF involves multiple microscopic injuries or ‘‘hits’’ to the lungs that are temporally distributed over many years [6]. According to this hypothesis, inflammation is subsequent to injury and IPF occurs as a result

Pathology

As alluded to in the pathogenesis, AE-IPF is an acute insult to the lung over a background of IPF, and the histopathological features also reflect the same findings, namely, the occurrence of diffuse alveolar damage over and above the underlying UIP [25], [26], [27]. The histopathological findings are also different in patients who have high-resolution computed tomographic (HRCT) evidence of only peripheral opacification of the parenchyma versus the multifocal or diffuse parenchymal

Diagnostic criteria

Acute exacerbation of IPF is characterized by acute clinical deterioration in the form of low-grade fever, worsening dyspnea and cough, worsening gas-exchange parameters, and the appearance of new opacities on radiology in the absence of alternate causes, such as infection and heart failure [26], [27]. The currently used diagnostic criteria are summarized in Table 1. Because of the importance of AE-IPF to our understanding of the natural history of the disease, a consensus definition needs to

Role of high-resolution CT

High-resolution CT (HRCT) is a useful modality in the diagnosis and management of AE-IPF. The usual findings include the presence of new-onset ground glass opacities and/or consolidation in a background of fibrosis (intralobular septal thickening, traction bronchiectasis, and bronchiolectasis) and honeycomb opacities (Figs. 2 and3). HRCT patterns seen during periods of rapid deterioration in patients with IPF can even allow predictions of prognosis and response to treatment.

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Role of surgical lung biopsy

Surgical lung biopsy remains the most sensitive and specific diagnostic procedure for diffuse pulmonary infiltrates and can influence changes in management for patients with undiagnosed pulmonary infiltrates. It can not only suggest a specific diagnosis but can also help in prognostication [30]. Moreover, a surgical lung biopsy can lead to a change in the original diagnosis in about 50–70% of the patients [30], [31], [32] and can be safely performed even in the mechanically ventilated patient

Differential diagnosis

In any patient with chronic lung disease, worsening pulmonary function and/or gas exchange can be ascribed to one of the following causes:

  • 1.

    exacerbation of underlying pulmonary disease (i.e., AE-IPF),

  • 2.

    community-acquired pneumonia superimposed on pre-existing lung disease,

  • 3.

    complications of therapy given for basic disease (e.g., opportunistic infections or drug-related lung disease secondary to immunosuppressant drugs used in the treatment of IPF),

  • 4.

    exclusion of other common causes of acute respiratory

Treatment and outcome

Our search yielded eight citations (n = 79) that specifically reported on the baseline characteristics, treatment, and outcomes (1-month and 3-months) of AE-IPF (Table 2) [12], [13], [16], [26], [33], [34], [37], [38]. We excluded studies that only reported mortality in AE-IPF as part of a complication of IPF but did not give any further details of AE-IPF [11], [14], [39], [40]; we also excluded single-patient case reports [15], [41]. Our analysis shows that most patients are elderly males with

Role of lung transplantation

Lung transplantation is the last therapeutic option for patients with IPF who have exhausted all medical therapies, and the development of AE in IPF can make prediction of time for referral for lung transplantation extra difficult. In young and middle-aged patients with AE-IPF, lung transplantation may be a treatment option. As noted above, one patient successfully received a single-lung transplant after initiation of mechanical ventilation [42]. There is also the theoretical possibility of

Future directions

Recent studies have shown that specific interventions can decrease the occurrence of AE-IPF [14], [39]. For example, in two studies that had employed pirfenidone and anticoagulants in the management of IPF, the occurrence of AE-IPF episodes was less in the experimental arms than in the controls (5/35 in placebo vs 0/72 in pirfenidone group [14] and 21/33 in placebo vs 11/23 in anticoagulant group [39]). Also, the use of cyclosporine in AE-IPF needs to be further investigated.

Conclusions

AE-IPF is an abrupt and unexpected worsening of the underlying IPF that is unrelated to infection or heart failure. There are no definite treatment guidelines because of the paucity of studies, but an increase in immunosuppression may be effective. Patients may benefit from enhanced immunosuppression including pulse doses of methylprednisolone and additional cytotoxic agents. However, larger randomized controlled trials are required to definitely clarify this issue. The etiology, risk factors,

Learning points

  • Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a clinical entity that is defined by a rapid deterioration of IPF during the course of the disease that is not due to infections, pulmonary embolism, or heart failure.

  • Acute exacerbation of IPF is characterized by an acute clinical deterioration in the form of low-grade fever, worsening dyspnea and cough, worsening gas-exchange parameters, and the appearance of new opacities on radiology in the absence of alternate causes, such as

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