Clinical predictors and explant lung pathology of acute exacerbation of idiopathic pulmonary fibrosis

Discussion

The main findings of our study are as follows. 1) Transplantation candidate testing including GORD studies were not associated with AE-IPF; 2) patients with higher absolute FVC decline had increased risk of developing AE-IPF; 3) AE-IPF was characterised by histopathological UIP and a diverse secondary pathologic diagnosis identified in explanted lung tissue; 4) HRCT UIP patterns and presence or absence of GGO were not associated with clinical AE-IPF, but GGO in HRCT during AE-IPF correlated with secondary pathologic diagnosis beyond UIP; and 5) patients with IPF without AE who had UIP and a secondary pathologic diagnosis could not be distinguished clinically prior to transplantation.

Given the high rate of mortality of AE-IPF, it would be of significant benefit to predict which IPF patients are more likely to suffer an acute exacerbation. Previously reported risk factors for AE-IPF included low FVC, TLC, D_LCO, 6MWD, resting oxygen saturation, cardiac disease and pulmonary hypertension. Of these, FVC is the most consistent parameter [1, 6, 9, 10, 18]. In our study, we found that patients with AE-IPF had increased absolute decline of FVC. We found that higher FVC % predicted absolute decline had increased hazard ratio for developing AE-IPF: the risk for an AE was 7.3-fold higher in patients with >15% absolute FVC decline compared to patients with <5% absolute FVC decline. This increased absolute decline can potentially be a predictor of rapid subclinical deterioration leading to clinical respiratory failure and hospitalisation for AE-IPF. Since the mortality of AE-IPF with respiratory failure is up to 90% for patients with AE-IPF and respiratory failure requiring mechanical ventilation [1, 3, 5–], fastening the process of evaluation and early listing for patients with rapid decline of FVC might prevent lung transplantation during AE-IPF, which has been shown by our group to have worse short- and long-term outcomes [19].

In our study, none of the other parameters checked were statistically significant in predicting AE-IPF. We did find that residual lung volume was lower at baseline in those who had AE-IPF, which has not been reported previously in the literature (44±15% pred versus 33±10% pred). However, the significance of this finding is unknown. The other two parameters that were statistically different between the groups were mPAP and albumin. However, these parameters lost statistical significance when AE-IPF patients who were urgently evaluated during the hospitalisation were excluded.

The cause of AE-IPF remains elusive. Proposed aetiological factors include intrinsic acceleration of the fibrotic disease or acute injury in response to external stimuli (e.g. infection, micro-aspiration, trauma, etc.) [1]. However, existing studies examining clinical, molecular, genetic, post-mortem, BAL and environmental exposure have failed to find a consistent or common aetiology of AE-IPF [12, 20–23–]. We examined most components of pre-transplantation patient characterisation and failed to identify a risk factor for AE-IPF. The use of anti-acid therapy has been shown to be associated with fewer AE-IPF, suggesting that GORD contributes to disease progression [24]. We examined the use of anti-acid therapy and GORD severity scores in those patients with and without AE-IPF. The use of anti-acid therapy was similar in both groups. The GORD severity as defined by pre-transplantation oesophageal studies was similar between the two groups.

Reported surgical lung biopsies of hospitalised AE-IPF are limited. Parambil et al. [25] described seven patients hospitalised for AE-IPF who underwent surgical lung biopsy after a median interval of 10 days following hospitalisation. All patients were receiving mechanical ventilation at the time of biopsy for a median of 8 days. They described a combination of UIP and DAD in five out of seven patients. One had DAD without UIP, although UIP and DAD were confirmed at autopsy. The other had biopsy histology of UIP and patchy zones of associated COP without features of DAD. Additional features of acute lung injury in the six patients with DAD included hyaline membranes (n=5), squamous metaplasia of bronchiolar epithelium (n=4) and fibrin thrombi (n=1). None demonstrated nonspecific interstitial pneumonia (NSIP) or DIP.

Description of explant histopathology in IPF transplantation recipients is limited to two studies and a total of 42 lungs. Of these 42 patients, AE-IPF explant pathology is limited to one clinically diagnosed AE-IPF and seven with HRCTs read as possible AE-IPF. None were hospitalised prior to transplantation. Katzenstein et al. [26] examined the histology of surgical lung biopsy and explanted lungs of 20 lung transplantation recipients at a single centre. None were reported to have been hospitalised prior to transplantation. Explant pathology showed UIP diagnosis in 19 and NSIP in one patient. 18 had UIP and focal or prominent “DIP-like reaction” and 16 had “NSIP-like areas”. The cohort included several patients with connective tissue disease-related ILD and the entire cohort was quite young, perhaps younger than a modern IPF/transplantation cohort. Rabeyrin et al. [27] examined 22 explanted lungs from patients transplanted for IPF. All explants showed UIP, 16 showed chronic inflammation, 13 showed UIP with NSIP-like areas, four showed DIP-like areas and one showed DAD. Of note, DAD and COP were rare in both studies, occurring in only two and one out of 42 explants, respectively. If these patients had been listed for transplantation in the lung allocation score era the timing of the candidate listing and transplantation would probably have been very different. Modern lung transplantation programmatic attitudes and life-support technology allow for the survival and transplantation of much sicker patients who previously did not survive hospitalisation for AE-IPF. Most of the AE-IPF patients described in our article would not have received transplantation and explant histopathology, which might affect the results showing more advanced and severe pathologic findings.

The relative paucity of DAD in our AE-IPF cohort is contrary to the widely held assumption that AE-IPF common histopathology is DAD superimposed upon UIP. We speculate that AE-IPF has several endotypes including a more protracted subacute worsening of pre-existing severe disease leading to severe hypoxaemia that cannot be supported at home. This subacute exacerbation endotype may lack a discrete acute lung injury and therefore not have DAD histology. The striking increased proportion of associated secondary histopathology including DIP and COP in our AE-IPF versus stable IPF may differentiate progressive IPF headed for hospitalisation and advanced support from a more stable IPF. DIP is known to be caused by cigarette smoke exposure and typically manifests as acute or subacute respiratory failure. However, none of the patients were actively smoking during 6 months prior to candidate evaluation or after active listing for transplantation as confirmed by serum and urine nicotine and cotinine testing. There was no correlation of smoking burden (pack-years) with DIP pattern on lung pathology. Since air pollution including passive smoke exposure is known to exacerbate chronic obstructive lung disease and asthma, and given our findings, we can only speculate that poor air quality might potentially increase AE-IPF risk [28, 29].

Our study has several limitations. First, given that this is a single-centre study, our medical management, level of experience and surgical techniques cannot necessarily be generalised. Second, despite the sample size being larger than those of previous studies, the size is still small with inherently reduced statistical power. Third, pathologic sampling error is possible and may underestimate the degree of significant pathological changes, especially with disease that is patchy in nature. Fourth, since all patients who had AE-IPF before lung transplantation were treated with supportive measures including systemic steroids, and the time gap between AE-IPF to transplantation was 22±24 days, pathologic conclusions should be cautious since systemic steroids have the potential to affect the findings, specifically the inflammatory response rather than fibrotic changes. Fifth, chest HRCT findings such as GGO are not specific to AE-IPF. GGO might represent other processes such as volume overload, infection, diffuse alveolar haemorrhage and more. Furthermore, the number of patients who had both HRCT in the 30 days before lung transplantation and explant lung pathology is small (n=9) and conclusions regarding that are of limited value. Finally, we did not characterise the baseline and change in fibrotic HRCT extent, which are two important variables potentially influencing AE-IPF.

In summary, we found that among comprehensive transplantation candidacy testing, only absolute decline of FVC was a predictor of AE-IPF. We found that patients with AE-IPF had high frequency of secondary acute pathological process beyond UIP and DAD. These processes were diverse and seen also in patients with clinical stable disease. HRCT UIP patterns and presence or absence of GGO did not predict clinical or pathological AE-IPF, but GGO during AE-IPF did predict secondary pathological process beyond UIP. We conclude that AE-IPF might be a multifactorial process with similar clinical presentation. Emerging risk factors from our study might be exposure to cigarette smoking and/or air pollution, as reflected by the high frequency of DIP in explanted lungs of patients with AE-IPF. Further clinical–pathologic studies are needed to confirm our findings.