Affiliations: Charleston, SC
Dr. Strange is Professor of Pulmonary and Critical Care Medicine, Medical University of South Carolina.
Correspondence to: Charlie Strange, MD, FCCP, Professor of Pulmonary and Critical Care Medicine, Medical University of South Carolina, 812 CSB, 96 Jonathan Lucas St, Charleston, SC 29425; e-mail: firstname.lastname@example.org
No therapy for idiopathic pulmonary fibrosis (IPF) has been proven to improve mortality or quality of life. However, like many diseases for which we now have cures, disease pathogenesis needed to be understood first before we could develop effective medications. Most of us have thought for a long time that pulmonary hypertension (PH) is a very bad marker of IPF severity. In this issue of CHEST (see page 2393), Nadrous et al1 report on the outcome of a large cohort of patients at the Mayo Clinic showing that PH has a significant correlation with mortality due to IPF. While not surprising, there is certainly a more positive spin to these data that needs to be explored.
The primary IPF symptom is dyspnea. Despite the fact that FVC remains the most robust correlate of IPF prognosis,2–3 the cause of exercise intolerance is not the associated limitation of exercise tidal volume. Instead, exercise intolerance is related more to cardiovascular limitations, including the oxygen desaturation associated with poor ventilation and perfusion matching.4 Maybe, if we cannot change ventilation, we should explore methods to change perfusion.
The pathogenesis of PH in IPF has not been comprehensively studied. Historically, the feeling has been that lung fibrosis also envelopes some of the vasculature. Therefore, the treatment of secondary PH is to reverse lung fibrosis. At this level of understanding, the refractoriness of secondary PH to vasodilators is no surprise.
In patients with IPF, areas of honeycomb lung at the lung bases that involve the pulmonary vasculature will transition pulmonary artery blood flow toward the lung apex, an area of the lung that is more rarely involved with fibrosis. As > 50% of the vasculature is obliterated, pulmonary artery pressure will rise. The first possible detection of elevated pulmonary artery pressure will occur when exercise increases cardiac output through an increased pulmonary vascular resistance. Only later will resting echocardiography detect disease. Using this model, the height of systolic pulmonary artery pressure should mirror the extent of lung fibrosis.
However, in the case series by Nadrous et al, the correlation between FVC and pulmonary artery pressures as detected by echocardiography did not even reach statistical significance. The correlation with the diffusing capacity of the lung for carbon dioxide was present but not robust. If this is true, then we must redefine our understanding of PH in IPF patients. Some of this discordance may relate to cigarette smoking and falsely preserved FVC through air trapping. However, there is much that is not understood about this observation.
We will continue to debate the issue of whether echocardiography is sufficiently accurate for the diagnosis of pulmonary arterial hypertension. In secondary PH, the debate is just as robust. In the Mayo Clinic series, the subgroup in which PH could not be estimated because of the lack of tricuspid regurgitation did not have the longest survival time. Therefore, should we advance to clinical trials, right heart catheterization will be needed to accurately measure both left and right heart pressures.
Another interesting but disturbing observation is the very poor mortality rate observed in the subgroup of individuals with concomitant left ventricular dysfunction. Possibly, the preservation of cardiac output is as important in patients with IPF-associated PH as in those with idiopathic pulmonary arterial hypertension.
So, what will it take to change the fatalism with which many pulmonary physicians approach IPF? Since corticosteroid and antifibrotic therapies have not yet proven to be beneficial in randomized trials, might there be other options to improve IPF outcomes? Should we begin ordering serial echocardiography or measurements of brain natriuretic peptide levels5 to define the frequency of PH with rest and exercise as a target for therapy? The answer will be realized after the next round of clinical trials directed at IPF-induced PH, targeting functional outcomes.
Because IPF and most interstitial lung diseases are heterogeneous, some healthy blood vessels likely remain. These blood vessels, which are localized in areas of preserved lung parenchyma, might be amenable to vasodilator therapy, particularly if medial hypertrophy in response to pressure overload has developed. One challenge will be to match ventilation and perfusion to avoid worsened exercise hypoxemia.
There are other diseases in which so called fixed pulmonary artery hypertension has proven amenable to drug therapy. The response of thromboembolic PH6–7 and sarcoidosis8 to epoprostenol therapy serves as an example of how those blood vessels remaining in the lung may vasodilate and marginally improve cardiac output, pulmonary vascular resistance, and symptoms. Future trials in IPF patients will use the data of Nadrous et al to risk stratifying the patients and justify medication trials. These trials seem justified in the investigation of this devastating pulmonary disease.
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