Respirology | 2019
In search for a predictive marker of acute exacerbations of idiopathic pulmonary fibrosis
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive disorder that has a 50% mortality rate at 2–3 years from diagnosis, worse than most cancers. There is a predominant male distribution with patients aged >50 years. The epidemiology of IPF in the Asia-Pacific region is not well known. There are several associations with the development of IPF, including genetic and family predisposition, pollution, occupational exposure and smoking. There have been several iterations to describe the classification of IPF based on radiological and pathological features. IPF is described as definite, probable, possible and unclassifiable, reflecting the heterogeneity of presentation of this disease. Recently, two anti-fibrotic agents—nintedanib and pirfenidone—have been shown to reduce the decline of IPF. There is not only an improvement in long-term outcomes with these drugs but also a reduced incidence of acute exacerbations of IPF (AEIPF). AE-IPF is a major cause of patient morbidity and mortality. This condition is characterized by worsening of IPF in <30 days duration, the presence of a new radiological abnormality on high-resolution computed tomography (CT) (i.e. bilateral ground-glass opacification/consolidation) and the exclusion of alternative aetiologies (e.g. infection, heart failure and pulmonary embolism). The pathology of AE-IPF is the infiltration of inflammatory cells into alveolar spaces, underpinned by diffuse alveolar damage (DAD). There are several causes of AE-IPF, including viral infections. Given that AE-IPF is an important cause of patient mortality, it would be rather compelling to find a marker that would predict AE-IPF. The marker should be sensitive for AE-IPF and specific for this condition as other aetiologies, such as infection and cardiac failure, are common mimics. The marker should also be cheap, reproducible and used globally. At a practical clinical level, the marker should be included as part of routine blood tests at clinical follow-up. For example, a patient on anti-fibrotics may have the marker assessed in addition to a complete blood count and liver function tests. To this end, a new study in Respirology by Yamaguchi et al. aims to address the challenge of finding a biomarker that will predict the onset of AE-IPF. The serum high-mobility box 1 (HMGB1) is a nuclear chromatin protein that facilitates the binding of transcription factors to chromatin, thus playing an important role in transcription. The authors note that HMGB1 is released during cell necrosis and by inflammatory cells and is therefore detected in the circulation during an acute inflammatory process such as AE-IPF. They examined HMGB1 levels in 76 patients with stable IPF, 17 patients with AE-IPF, 37 patients with chronic obstructive pulmonary disease (COPD) and 74 healthy controls. Serum HMGB1 levels in patients with stable IPF were significantly higher than those in healthy controls; AE-IPF had the highest levels of HMGB1, and they were even higher than levels in either of these groups—stable IPF, healthy controls and AE-IPF: 6.26 5.27, 3.42 2.69 and 19.20 16.76 ng/mL, respectively. There was no significant difference in serum HMGB1 levels between stable IPF patients and COPD patients. Notably higher levels of HMGB1 were associated with earlier onset of AE in stable IPF patients and with shorter survival in AE-IPF patients (P = 0.030 and 0.001, respectively). These interesting findings have raised more questions. The derivation of HMGB1 in this study has made the findings difficult to interpret. The authors have found elevated levels of HMGB1 in subjects with AEIPF but have then analysed the data retrospectively using Cox hazard ratios to determine the levels of HMGB1 to predict AE-IPF. Therefore, HMGB1 has not been assessed by sequential blood analysis to assess if it is a predictor of AE-IPF. This is not conclusive but will require researchers to prospectively validate HMGB1 levels in a cohort of AE-IPF. Future studies will necessitate the regular collection of blood and sequential storage and analysis of samples to validate if this marker is helpful in predicting AE-IPF. In addition, HMGB1 needs to be controlled for comparison with other potential markers such as Krebs von den Lungen-6 (KL-6). There would be several challenges in a study such as this. We would need to examine the fluctuations of HMGB1 in a longitudinal study. Furthermore, HMGB1 should be evaluated against other candidate markers. In addition, questions will be raised about how and when to act if we find a raised HMGB1 level. For example, should we escalate treatment immediately on finding a raised HMGB1 level or after a second raised level? In addition, we need to establish the interval of testing for HMGB1 and the cost-effectiveness of such testing. Finally, an enduring challenge is how to treat early AE-IPF. The therapy of AE-IPF is uniformly difficult. Systemic steroids and immunosuppressive agents have been used with little success. Recently, rituximab, methylprednisolone and plasma exchange have been used with anecdotal success.