Health & Medical Lung Health

Pulmonary Hypertension With COLD and Pulmonary Fibrosis

Pulmonary Hypertension With COLD and Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis


The occurrence of severe pulmonary hypertension in patients suffering from IPF is a rare event; however, it may significantly affect the clinical outcome. The pathophysiology of pulmonary hypertension in parenchymal lung diseases is attributable to the destruction and distortion of the vascular bed and to hypoxia. Usually, patients present with mild or moderate degrees of pulmonary hypertension; however, a severe pulmonary hypertension, which cannot be solely explained by hypoxia and parenchymal injury, may occasionally develop in patients with IPF. The pathogenesis of this event is still unclear and is an object of controversy. Interesting findings were published last year by Calabrese et al., who found that the prevalence of herpes virus infection (as detected by molecular analysis) in the lungs of 55 IPF patients was higher than that in the lungs of 44 control patients. Viral infection was also associated with a higher mPAP, suggesting the role of herpes virus in the remodeling of the lung vessels: thus, such hypothesis now takes back to the potential role of HIV and inflammation in the development of HIV-PAH and opens new interesting scenario framework for research.

Recently, as already mentioned, the proceedings of the 5th World Symposium on Pulmonary Hypertension, which was held in Nice, France, in February 2013, have been published in the Journal of the American College of Cardiology. The task force on 'Chronic Lung diseases' addressed the issue on the appropriateness of considering pulmonary hypertension as disproportionate in relation to the severity of parenchymal lung disease. The experts also add three important considerations. In fact, they stated that 'the "severe pulmonary hypertension group" includes only a minority of chronic lung disease patients who are suspected of having strong general vascular abnormalities (remodeling) accompanying the parenchymal disease and with evidence of an exhausted circulatory reserve rather than an exhausted ventilator reserve underlies the limitation of exercise capacity'. The experts also claimed that 'for discrimination between group 1 pulmonary hypertension patients with concomitant respiratory abnormalities and group 3 pulmonary hypertension patients (pulmonary hypertension caused by lung disease), patients should be transferred to a center with expertise in both pulmonary hypertension and lung diseases for comprehensive evaluation'. The task force concluded by stating that 'studies evaluating the effect of pulmonary arterial hypertension drugs currently not approved for group 3 PH patients should focus on this severe PH group'.

These concerns can also explain the disappointing results of all clinical trials carried out so far in patients with IPF and pulmonary hypertension treated with medications commonly used for PAH (e.g. ambrisentan). In fact, as patients were considered eligible even if they had a slight increase in pulmonary hypertension, two distinct disease phenotypes (one comprising IPF patients with mild-to-moderate pulmonary hypertension secondary to hypoxia and progression of the scarring process because of the fibrotic disarrangement of the vascular bed, and the other one comprising patients who presented with minor or moderate fibrotic alterations, yet had severe pulmonary hypertension) were included in the study and, thus, selection bias might have occurred.

The role of functional tests for the screening of pulmonary hypertension in IPF was evaluated in two interesting studies. In a study conducted on 38 patients with IPF, van der Plas et al. evaluated the predictive value of noninvasive exercise parameters that were associated with elevated SPAP and survival. The authors found that V'E/V'CO2 was the only cardiopulmonary exercise test (CPET) parameter associated with elevated systolic PAP (as evaluated by echocardiography) and appeared as a potentially useful noninvasive screening test to be used in IPF patients for the early detection of pulmonary hypertension development. Gläser et al. attained similar results in a multicenter study conducted on 135 IPF patients who underwent CPET, right heart catheterization, and pulmonary function test during their initial evaluation. Pulmonary hypertension (which was diagnosed in 73 patients) was best predicted by gas exchange efficiency during exercise and peak oxygen uptake; in addition, oxygen uptake at peak exercise was a good predictor of survival.

The combined pulmonary emphysema and fibrosis (CPFE) syndrome, including radiological findings of upper lobe emphysema and lower lobe fibrosis, typically occurs in male smokers and is characterized by subnormal spirometry, severely impaired DLCO and poor prognosis. CPFE has also been described as a distinct pulmonary manifestation within the spectrum of CTD-associated lung diseases, such as rheumatoid arthritis and systemic scleroderma. Cottin et al. reported that 47% of CPFE patients had systolic PAP of at least 45 mmHg, as estimated by echocardiography. Pulmonary hypertension seems to be more frequent in patients with CPFE than in IPF patients without emphysema and is a determinant of their prognosis. Drugs used for group I PAH patients such as bosentan, sildenafil or inhaled iloprost did not show any significant beneficial effect in these patients. Nowadays, the only supportive therapy for these patients is oxygen therapy and an early referral for lung transplantation is strongly recommended.

The role of pulmonary rehabilitation in patients with interstitial lung diseases has been the subject of long-standing controversy; recently, a study published in the European Respiratory Journal has helped clarify the issue. The authors evaluated 402 consecutive patients with interstitial lung disease who were admitted to a specialized pulmonary rehabilitation center (over a period of 12 months): they observed that the 6-MWT markedly improved (by 46 ± 3 m) after 30 days of rehabilitation, whereas dyspnea rating did not change and lung function tests only showed marginal improvement. In addition, patients with signs of pulmonary hypertension also seemed to benefit from rehabilitation.

In conclusion, severe pulmonary hypertension in IPF is a rare, but very severe, condition. No clinical trial specifically designed for this condition has been carried out until now. CPTE can be useful as a screening test for pulmonary hypertension in IPF, whereas rehabilitation could have a role in improving exercise capacity. In CPFE patients, early referral for lung transplantation is strongly recommended. New therapeutic approaches, which are needed to successfully treat severe pulmonary hypertension associated with IPF, are now under investigation.



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