Treatment of Acute Exacerbation of Idiopathic Pulmonary Fibrosis. A Call to Arms.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease with an unfavorable prognosis (1). Different from many other chronic lung diseases, deaths of individuals with IPF are primarily related to progression of lung fibrosis rather than occurring due to comorbidities (2). Acute exacerbations (AEs) of IPF (AE-IPF), characterized by the development of widespread acute lung injury, are an important cause of IPF-related disease progression and mortality, which may even occur in individuals with limited fibrosis and well-preserved lung function (3). When it comes to AE-IPF, there are important lacunae in knowledge, including understanding of pathogenesis and triggers, optimal strategies for prevention, and best approaches to (early) diagnosis. Although considerable progress has been made in the management of IPF, optimal treatment of AEs has yet to be defined, and varies considerably across the globe (4). Despite current international guidelines giving a (weak) positive recommendation for the use of glucocorticoids to treat AE-IPF, there are no proven, effective therapies for this devastating complication of IPF (1, 3). Currently used therapeutic approaches, usually glucocorticoids or immunosuppressants, are based on expert consensus and small, uncontrolled, or retrospective studies (3, 4). Before now, with the exception of a trial examining a procalcitonin-guided antibiotic treatment approach, prospective, clinical randomized placebo-controlled trials (RCTs) have been nonexistent in AE-IPF (3, 5).

Given the uncertainty around best management of AE-IPF, in this issue of the Journal, the article by Kondoh and colleagues (pp. 1110–1119) is very timely (6). Kondoh and colleagues report the outcomes of a multicenter RCT of recombinant thrombomodulin alfa in AE-IPF. This drug has been used in Japan for a number of years on the strength of several small, uncontrolled, observational, and retrospective clinical studies, all of which were conducted in Asia, which suggested efficacy of thrombomodulin alfa in improving outcomes for patients hospitalized with AE-IPF (7–13). Thrombomodulin alfa is a recombinant and soluble protein, which inhibits thrombin, high-mobility group box 1 protein, and the complement system, while also stimulating protein C. As such, in preclinical experiments, thrombomodulin alfa is associated with anticoagulant, antiinflammatory, and cytoprotective properties (14). The coagulation cascade has been shown to be involved in lung inflammation and fibrosis; thus, inhibition of key clotting pathways combined with the other effects of thrombomodulin provides a strong rationale for assessing its use in the treatment of AE-IPF (15). Kondoh and colleagues (6) are to be highly commended, as they have made strenuous efforts to conduct a rigorous trial on a lethal complication of an already deadly disease. This reflects the major strength of their study, demonstrating that it is possible to perform a multicenter RCT studying a relatively infrequent complication of a rare disease. Furthermore, they overcame the not-inconsiderable obstacle of studying a therapy that was already established in Japan for treatment of AE-IPF. In reporting a negative outcome, Kondoh and colleagues provide an important reminder of the need for establishing the efficacy of expensive and/or potentially harmful therapies before adopting them into routine clinical practice. This underscores the fact that retrospective, observational, and open-label trials, while providing information on safety and tolerability, should be treated as hypothesis generating at best when it comes to assessing efficacy. Appropriately designed and conducted RCTs remain the gold standard for assessing drug efficacy.

A number of limitations relating to the trial should, however, be kept in mind. Thrombomodulin was tested on the background of high-dose corticosteroid pulse therapy. Although corticosteroids are (weakly) recommended by international guidelines (1), they also lack evidence of efficacy, and may potentially be associated with detrimental outcomes. In addition, there was a clinically important imbalance with regard to disease severity between groups (a consequence, in part, of stratification by site, but not by disease severity), which favored the placebo group. A further weakness of the study design was the exclusion of patients who, in the opinion of the investigator, had significantly impaired survival probability. Furthermore, acute exacerbations were not classified into “triggered” and “idiopathic” (3); it is therefore unknown whether such a distinction might have altered study outcomes. Finally, it should be acknowledged that this trial was conducted in Japan, where, when compared with non-Asian countries, acute exacerbations are diagnosed more frequently in patients with IPF, and are treated differently compared with many other countries, including the United States (3, 4). Thus, the results might not be entirely generalizable.

In conclusion, Kondoh and colleagues provide us with the first blinded, randomized, prospective, and placebo-controlled trial on AE-IPF. In itself, this undertaking is of huge importance, given the need to develop evidence-based therapies for this life-threatening complication of IPF. However, the negative outcome of this trial demonstrates clearly that the management of AE-IPF still represents an area of major unmet medical need. Fundamentally, this can only be improved through the delivery of further large-scale, well-designed clinical trials. This should be seen as a call to arms for all health care professional caring for patients with IPF!