American Journal of Respiratory and Critical Care Medicine

To the Editor:

We read with great interest the update on acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) by Collard and colleagues, recently published in the Journal (1).

Although this update is of great interest to the readers of the Journal, given the numerous studies published since 2007 dealing with pulmonary issues (2), we would like to add three comments.

Our first comment refers to excluding infection as diagnostic criterion. Collard and colleagues argued that “exclusion of infection or any other potential trigger is no longer required for AE diagnosis” (1). Infection can provoke diffuse alveolar damage (DAD) and act as a trigger of AE, even if treated adequately. In an IPF setting, infection can, however, mimic AE, with the occurrence of ground-glass opacities or consolidations, and solely be responsible for the clinical degradation. Despite our inability to confidently rule out an underlying infection, it appears crucial to fully investigate patients using microbiological tests on a case-by-case basis. In our opinion, removing “exclusion of pulmonary infection” from the diagnostic criteria may be confusing for clinicians.

Our second comment concerns the proposal of changing the onset criterion “within the previous 30 days” into “typically less than 1 month.” Of note is that patients with a more gradual clinical presentation may experience a better prognosis. Morawiec and colleagues reported on 18 patients with IPF suffering from AE (3). Time from symptom onset to hospital admission was 7 (range, 3–18) days for 11 patients, and 47 (range, 39–62) days for another 7 (3), all receiving the same treatment. At 3 months, only 55% of patients from the first group were still alive versus all from the second group (P < 0.05). Until this issue is better understood, it appears relevant for future prospective research trials to distinguish between AEs that occur within a 30-day interval and those occurring at longer time intervals, in an attempt to reduce the risk of prognostic factor imbalance between comparative therapeutic arms.

Our third comment applies to the role of corticosteroids in AE management. Corticosteroids are justified not only because of anecdotal reports of benefits but also owing to pathological features. In the IPF setting, AE histologically manifests as DAD or, less commonly, as organizing pneumonia superimposed on underlying usual interstitial pneumonia, commonly associated with biological inflammatory responses. The efficacy of corticosteroids has been demonstrated in the organizing pneumonia setting. Clinical trials using corticosteroids in acute respiratory distress syndrome, histologically characterized by DAD, suggested these agents exert beneficial effects on patient respiratory status with down-regulation of systemic inflammation (4). Adding immunosuppressive treatment to corticosteroids in IPF-related AE has, however, been questioned by several groups. Along with others, we recently suggested based on two independent French cohorts that cyclophosphamide (CYC) might improve the prognosis of IPF-related AE (3, 5). In a first study, 3-month mortality rate under CYC and methylprednisolone pulse therapy was 45% (3). In a second study, 3-month mortality rates were 33 and 55%, with and without CYC, respectively (5). In a third Korean retrospective study on AE, the authors compared the treatment regimens all together and found that the treatments did not affect patient outcome. However, the in-hospital mortality was 56% in patients treated with corticosteroids alone (>0.5 mg/kg/d or corticosteroid pulse 500 mg/d for 3 days followed by high-dose corticosteroids) versus 32% in those receiving corticosteroids plus immunosuppressive therapy (i.e., cyclosporine, azathioprine, or CYC) (6). There is a need for randomized prospective trials before the role of immunosuppressive treatment can be definitely confirmed.

For this reason, the French health ministry has approved and given a grant to the EXAFIP (Exacerbation de Fibrose Pulmonaire Idiopathique) study (NCT02460588), a placebo-controlled randomized phase III trial evaluating the efficacy of CYC in adjunction to corticosteroids in IPF-related AE.

1. Collard HR, Ryerson CJ, Corte TJ, Jenkins G, Kondoh Y, Lederer DJ, Lee JS, Maher TM, Wells AU, Antoniou KM, et al. Acute exacerbation of idiopathic pulmonary fibrosis: an international working group report. Am J Respir Crit Care Med 2016;194:265275.
2. Collard HR, Moore BB, Flaherty KR, Brown KK, Kaner RJ, King TE Jr, Lasky JA, Loyd JE, Noth I, Olman MA, et al.; Idiopathic Pulmonary Fibrosis Clinical Research Network Investigators. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2007;176:636643.
3. Morawiec E, Tillie-Leblond I, Pansini V, Salleron J, Remy-Jardin M, Wallaert B. Exacerbations of idiopathic pulmonary fibrosis treated with corticosteroids and cyclophosphamide pulses. Eur Respir J 2011;38:14871489.
4. Meduri GU, Golden E, Freire AX, Taylor E, Zaman M, Carson SJ, Gibson M, Umberger R. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest 2007;131:954963.
5. Simon-Blancal V, Freynet O, Nunes H, Bouvry D, Naggara N, Brillet PY, Denis D, Cohen Y, Vincent F, Valeyre D, et al. Acute exacerbation of idiopathic pulmonary fibrosis: outcome and prognostic factors. Respiration 2012;83:2835.
6. 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;37:356363.

Author disclosures are available with the text of this letter at www.atsjournals.org.

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