Acute exacerbations of interstitial lung disease: what is the best treatment?

Abstract

with various forms of chronic fibrosing interstitial lung diseases (CFILD) are at risk for an acute exacerbation (AE) of their disease that can rapidly lead to death (1). While acute exacerbations of Idiopathic pulmonary fibrosis (AE-IPF) appear to be more common than acute exacerbations for other forms of CFILD and a considerable number of manuscripts have been published on risk factors, pathogenesis and treatments, no randomized and adequately powered clinical trials of therapies for AE-CFILD have been published to date. But because only a relatively small number of patients at any single center develop an AE over time, such a study would be very difficult to perform. Furthermore, funding entities with adequate resources to support a large clinical trial of licensed drugs are reluctant to support an evaluation drugs that are off patent. Treatment approaches to fibrotic lung diseases and, especially, IPF have evolved considerably over the past two decades. The first clinical practice guideline on the diagnosis and management of patients with IPF (2) suggested that cytotoxic drugs such as azathioprine or cyclophosphamide (CYC) could be useful to diminish or stop the progression of IPF. But these drugs had never been tested in randomized controlled trials that were adequately powered with robust endpoints. But over a decade later a key National Institutes of Health (NIH) sponsored study provided results that went against the assumption that the cytotoxic agent, azathioprine, was beneficial in treating patients with IPF (3). In contrast to the perception that azathioprine in combination with low-dose corticosteroids may be a useful therapy for IPF, treatment with azathioprine was shown by the PANTHER-IPF trial to actually be detrimental to a substantial number of patients and associated with a significantly increased risk of adverse events including hospitalization and death when compared to controls. Additionally, a prospective study of CYC for patients with progressive IPF did not find benefit, and drug-related adverse events occurred in two-thirds of this study cohort (4). Recently updated clinical practice guidelines on the management of patients with IPF do not support the use of cytotoxic drugs for the treatment of IPF (5). The advent of anti-fibrotic therapy with pirfenidone or nintedanib has had a significant impact on disease progression in IPF, and new data support anti-fibrotic therapy using nintedanib for patients with CFILD (,7). Nonetheless, significant numbers of patients with IPF as well as those with CFILD other than IPF can suffer acute exacerbations of their fibrotic lung disease despite treatment with anti-fibrotic drugs. While many retrospective case series that examined different drug therapies for acute exacerbations of IPF have been published in the literature (8), no therapy other than lung transplantation has been shown to provide long-term survival in a randomized clinical trial. However, despite a lack of clinical trial evidence, current international consensus guidelines make a weak recommendation, based on very low quality evidence, that corticosteroids should be used to treat the majority of patients with Acute exacerbations of interstitial lung disease: what is the best treatment?