Other Comorbidities and Complications

Comorbidities especially related to tobacco smoking are frequent in CPFE [8]. As in IPF [230] and chronic obstructive pulmonary disease, patients with CPFE may present with cardiovascular disease (including ischemic heart disease, arterial hypertension, cerebral infarction, atrial brillation, etc.), diabetes mellitus, sleep apnea syndrome, gastro-­ esophageal refux disease, venous thromboembolism, depression, and osteoporosis. The respective frequency and contribution to morbidity and mortality has not been studied speci cally in CPFE.

Management

There are no guidelines for a speci c treatment of pulmonarybrosis or emphysema in the setting of CPFE. It is unknown if treating these separate components of disease infuences clinical outcomes.

General Measures and Treatment of Emphysema

Smoking cession should be strongly encouraged and is the cornerstone of treatment for emphysema. Inhaled bronchodilators may be bene cial on dypsnea and cough, and seem to be underutilized [13]. Long-term oxygen therapy is often required [231], especially when severe PH is present [8, 25]. Regular exercise and pulmonary rehabilitation may be useful for most patients with CPFE [232]. Infuenza, pneumococcal, and COVID-19 vaccination are also recommended as per standard intervals, unless contraindicated [233, 234]. Patients with severe disease and especially with PH should be referred for lung transplantation [235], however, it is contraindicated in most patients by age and comorbidities [8, 13, 25].

Treatment of Pulmonary Fibrosis

Decisions about pharmacologic treatment are guided by the underlying diagnosis of brosing ILD [234]. Management of pulmonary brosis in the setting of CPFE is informed by the landmark clinical trials of nintedanib and pirfenidone [236– 241]. Management of pulmonary brosis in CPFE generally may follow that of IPF or that of brosing ILD with a progressive phenotype. Anti brotic medications may have ben- e t in IPF patients with CPFE, and in other forms of pulmonary brosis with CPFE, progressing despite management.

As most patients with signi cant emphysema on HRCT or signi cant airfow obstruction were excluded from these

studies, no de nite conclusion can be drawn regarding the potential ef cacy of pirfenidone and nintedanib in the CPFE syndrome. It can be speculated, however, that similar ef - cacy may be obtained, at least in those patients with typical IPF associated with emphysema, with however less change in lung physiology over time. A post-hoc study of the INPULSIS trial that demonstrated the ef cacy of nintedanib in patients with IPF, found that the presence of emphysema at baseline did not infuence the study results [242]. Therapeutic trials should be designed speci cally to include patients with CPFE, likely using endpoints that do not rely on physiologic surrogates such as FVC [12, 243]. Although data from the PANTHER trial have recommended against combination therapy with prednisone, azathioprine, and N-acetylcysteine in patients with de nite diagnosis of IPF, oral corticosteroids and occasionally immunosuppressive therapy may be considered in patients with HRCT patterns more suggestive of NSIP, desquamative interstitial pneumonia, or hypersensitivity pneumonitis [234]. Gastro-­ esophageal refux disease when present might enhance progression of pulmonary brosis [244] and should be treated actively.

Management of Pulmonary Hypertension

Management of PH in chronic respiratory disease including the CPFE syndrome is mostly based on the optimal treatment of the underlying disease. A comprehensive review of PH in the setting of ILD including CPFE is beyond the scope of this chapter. Controlled data do not support the use of oral PH speci c therapies in CPFE [208, 245], including endothelin receptor antagonists (bosentan, ambrisentan), phos- phodiesterase-­5 inhibitors (sildena l, tadala l), or stimulator of soluble guanylate cyclase (riociguat) [246], although uncontrolled observational studies show possible bene t from PH therapies [25, 247–251] with improvement of hemodynamic parameters, and there are encouraging secondary endpoint trends in trials using sildena l in IPF [240, 252, 253]. Furthermore, treatment with ambrisentan and riociguat are deleterious in patients with brotic ILD [254, 255] and especially those with CPFE [256]. Treatment with PH drugs may occasionally worsen gas exchange in patients with chronic respiratory disease. Interestingly, nebulized treprostinil improved 6-min walk distance, decreased NT-pro-brain natriuretic peptide levels, improved FVC, and reduced the risk of clinical worsening compared to placebo in patients with ILD and group 3 precapillary PH con rmed by right heart catheterization including patients with CPFE [257, 258]; however, clinical implementation remains limited due to multiple challenges.

Further research is needed to evaluate the potential clinical bene t of PH therapy especially in patients with pre-