Abstract
Vascular disarrangement as a possible central event in disease progression in idiopathic pulmonary fibrosis (IPF) http://ow.ly/hln3307TyBk
To the Editor:
The article by Jacob et al. [1], reporting a computer-based computed tomography (CT) approach able to provide a precise quantification of disease extension in idiopathic publmonary fibrosis (IPF) patients by means of specific computer algorithm, CALIPER, is very interesting.
The authors show that with this algorithm it is possible to evaluate typical interstitial lung disease features, such as honeycombing, reticular pattern, ground-glass opacities and emphysema and, in addition, an innovative parameter represented by pulmonary vessel volume (PVV). CALIPER-derived measures, together with conventional visual CT scores and pulmonary function measures of disease severity, were tested for their ability to predict mortality. Surprisingly PVV, and in particular PVV5, defined as the volume of small vessels with a diameter <5 mm2 expressed as percentage of total lung volume, at univariate analysis showed the strongest prediction ability among all considered variables. At multivariable analysis PVV, CALIPER-derived honeycombing extent and the composite physiology index were confirmed to be independent predictors of mortality and were incorporated in a new three-group staging system that was powerfully predictive of mortality in the analysed cohort of IPF patients.
The unexpected signal provided by PVV in this study was acutely discussed by the authors although it remains not fully comprehensible. The authors provide three plausible explanations related to: 1) blood-flow diversion from advanced fibrotic areas to relatively spared lung regions with aberrant dilatation of capacitance vessel resulting in increased PVV; 2) to the dilatation effect on blood vessels of increased negative pressure during inspiration due to increased lung stiffness in IPF patients; and 3) the effect of pleuro-parenchymal and bronchial-pulmonary arterial anastomosis previously described in studies performed on IPF histological lung specimens [2].
In our opinion, the results of this study could have a further explanation. Some lines of evidence suggest that vascular alterations might play a role in IPF pathogenesis and progression. In this regard, three independent histological studies [3–5] have demonstrated the presence in IPF lungs of vascular abnormalities that include aspects of pulmonary venous occlusive disease (PVOD) and aberrant capillary multiplication defined as increased alveolar septa capillary density, that are consistent with aspects of the condition known as pulmonary capillary haemangiomatosis (PCH). Interestingly, these alterations are consistently reported in those areas of lung parenchyma less affected by the fibrosing process and whose presence, alternately with more fibrotic and honeycombing areas, is a distinguished hallmark of the usual interstitial pneumonia pattern characterising IPF histology. Those observations may lead to speculate that vascular alterations might be the first pathological lesions in the IPF lung on which fibrosis might eventually build up by an unclear mechanism. Idiopathic forms of PVOD and PCH are uncommon causes of pulmonary hypertension, hard to distinguish from idiopathic arterial pulmonary hypertension, and are characterised by post-capillary involvement of small pulmonary venules that cause increased pressure in pulmonary capillaries, red blood cell leakage through the alveolar–capillary barrier and, as a consequence, occult alveolar haemorrhage with the accumulation of haemosiderin-laden macrophages in the alveolar spaces [6]. Differential diagnosis between other forms of pulmonary hypertension and PVOD/PCH is difficult and bronchoalveolar lavage (BAL) with haemosiderin-laden macrophage count has been proposed as an effective tool in this setting [6]. Based on this result, we recently performed a BAL study showing an increased iron burden in the alveolar milieu of IPF patients, which correlated with echocardiographic estimation of pulmonary hypertension and with disease progression and prognosis evaluated by a composite staging system [7]. Intriguingly, in a subsequent study we demonstrated an iron-dependent increased production of oxygen reactive species by alveolar macrophages of IPF patients that may represent one of the mechanisms of recurring epithelial injury thought to be involved in the fibrogenic process of the disease [8].
We believe that the discussed pieces of evidence [3–5, 7, 8] are consistent and might represent an alternative plausible explanation of the interesting results by Jacob et al. [1], where, similarly to previous findings, the reported increased vascular volume was found in less-affected areas of the lung and showed a linear correlation with pulmonary pressure estimated by echocardiography.
The innovative results of the study by Jacob et al. [1] are of high interest not only because they offer a new powerful tool for staging IPF patients, but also because they strongly suggest that we should reconsider the current predominant “epithelial- and mesenchymal-centric” view of the disease in favour of a more inclusive view that takes into account pulmonary vascular disarrangement as a possible central event in the pathogenesis and progression of IPF.
Footnotes
Conflict of interest: None declared.
- Received November 29, 2016.
- Accepted December 9, 2016.
- Copyright ©ERS 2017