Recent respiratory literature has identified a new interstitial lung disorder known as combined pulmonary fibrosis and emphysema (CPFE). Scientists have observed it to behave as a clinical entity separate from idiopathic pulmonary fibrosis (IPF) and emphysema.
CPFE is heavily associated with people with a history of smoking and is characterized by the worsening of respiratory symptoms and the progressive decline of lung function. There is no specific treatment for CPFE; hence, physicians tend to treat lung fibrosis and emphysema separately with the goal of improving overall respiratory function.
The first time fibrosis and emphysema were characterized together was in an experiment with dogs subjected to cigarette smoking. In the 1990s, physicians first described the combination of emphysema and fibrosis in a series of patients. The term “CPFE” was coined in 2005 and was defined as a combination of emphysema and pulmonary fibrosis characterized by abnormal spirometry, marked impairment of gaseous exchange, and a high prevalence of pulmonary hypertension. Computed tomography (CT) is typically used to characterize these changes.
A Tale of Two Conditions
As published in Lung, Kim and colleagues conducted a study to investigate the impact of concomitant emphysema on the clinical outcomes of patients with IPF. They noted that IPF is associated with progressive lung function decline and reduced survival, while emphysema is a common comorbidity in patients with pre-existing IPF.
Nevertheless, scientists have debated whether patients with CPFE experience clinical progression distinct from IPF or emphysema alone. Some studies suggest that the mortality rate in patients with CPFE is similar to that in patients with IPF alone; other studies contradict these findings, suggesting that patients with CPFE have a higher mortality rate compared to patients with IPF.
Read more about IPF etiology
In addition, emphysema has emerged as a sort of wildcard because scientists are unsure of its impact on disease progression and survival in both patients with IPF alone and CPFE. Studies indicate that patients with CPFE have a lower diffusing capacity of the lungs for carbon dioxide (DLCO) but a higher forced vital capacity (FVC) compared to patients with IPF alone. Why this is the case remains a mystery.
Kim et al registered patients with IPF using the IPF-PRO Registry. Upon enrollment, patients were subjected to a high-resolution computed tomography (HRCT) scan; if both pulmonary fibrosis and “clinically significant emphysema” were detected, they were classified as CPFE patients. Of the 934 patients recruited, 119 had CPFE based on the HRCT scan.
The research team used Cox proportional hazard models to determine any association between emphysema and clinical outcomes. End-point measurements included hospitalizations, lung transplantation, and death.
Although this study found that CPFE was associated with poorer outcomes (such as lower quality of life and higher mortality), the authors of the study cautioned that these may be due to confounding variables not fully examined in this study, such as age and complications of smoking.
“Whether CPFE is a unique biologic entity or simply represents the additive effect of two superimposed diseases requires further study,” they concluded.
Possible Etiological Pathways
The lack of consensus around CPFE and its impact on clinical outcomes is in part due to the hazy picture surrounding lung pathology. The proverbial question applies: which came first, the chicken or the egg?
Does lung fibrosis begin first, creating unfavorable conditions that give rise to emphysema? Or is emphysema a separate entity brought on by years of smoking? How much do these conditions influence each other? Does a combination of both synergistically lead to poorer outcomes?
Let’s start with the most widely accepted theory of CPFE. Some scientists propose that lung fibrosis, especially in the basal lung, exerts traction on the upper lung, which creates the conditions for emphysema to develop. This theory is not universally accepted, since some patients develop emphysema before fibrotic changes are noted.
Read more about IPF treatment
Others contend that CPFE is an autoimmune phenomenon. A study found that a significant percentage of patients with CPFE have elevated serum levels of antinuclear antibodies (ANA) compared to patients with IPF only. In addition, patients with CPFE who had positive autoimmune markers had better survival rates compared to patients with a negative autoimmune profile.
Some scientists believe that CPFE is driven by genetic factors. Studies found that adenosine and its receptor ADORA2B are present in higher amounts in patients with chronic lung diseases. ADORA2B, in turn, leads to higher concentrations of hyaluronan, leading some scientists to speculate that elevated hyaluronan levels in CPFE is driven by ADORA2B.
It is clear that much more research is needed to further elucidate the differences between IPF, emphysema, and CPFE. New research may shed light on how various lung pathologies interact. The ultimate goal, of course, is curative, which is unfortunately out of reach for any of the lung diseases discussed in this article.
Patients who are still smokers should be referred to a smoking cessation program, given that smoking cessation results in clinical improvements that are observable almost immediately. As for emphysema and obstructive lung disease, inhaled bronchodilators are typically prescribed to open up the airways to ensure better gaseous exchange.
Antifibrotic drugs, such as pirfenidone and nintedanib, have long been used in IPF. Will these medications work to alleviate the disease burden in CPFE? The jury is still out on this matter, although many physicians prescribe antifibrotic drugs in CPFE as a matter of habit.
In the midst of discussing how lung disease should be classified, it is important to remember that our role as physicians is to educate our patients so that lung disease does not develop in the first place. Patients should be equipped with the information and the resources they need to avoid habits that may lead to lung disease in the future.
Kim HJ, Snyder LD, Neely ML, et al. Clinical outcomes of patients with combined idiopathic pulmonary fibrosis and emphysema in the IPF-PRO registry. Lung. 2022;200(1):21-29. doi:10.1007/s00408-021-00506-x
Hage R, Gautschi F, Steinack C, Schuurmans MM. Combined pulmonary fibrosis and emphysema (CPFE) clinical features and management. Int J Chron Obstruct Pulmon Dis. 2021;16:167-177. doi:10.2147/COPD.S286360