Combined Pulmonary Fibrosis and Emphysema

Smoking increases the risk of developing IPF, and many patients exhibit features of IPF and emphysema. The prevalence of emphysema in IPF patients was 30% in a retrospective study from Mexico and 47% at the time of diagnosis and 55% during follow-up in a European cohort. Early reports describe patients with a clinical presentation of severe dyspnea, pulmonary fibrosis, preserved lung volumes, and a markedly reduced transfer factor for carbon monoxide. These patients had characteristic radiographic features including upper lobe–predominant centrilobular or periseptal emphysema and lower lobe–predominant pulmonary fibrosis ( Fig. 10.1 ). The syndrome of combined pulmonary fibrosis and emphysema (CPFE) was coined by Cottin and colleagues in 2005 to describe this subgroup of IPF patients. It is important to note that the CPFE phenotype is not limited to IPF; hypersensitivity pneumonitis, nonspecific interstitial pneumonia (NSIP), and other forms of fibrotic lung disease have also been described in CPFE.

High-resolution computed tomography images from a patient with combined pulmonary fibrosis and emphysema illustrating upper lobe emphysema (A) and lower lobe fibrosis with honeycomb change (B).

From Mejia M, Carrillo G, Rojas-Serrano J, et al. Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension. Chest . 2009;136:10–15; with permission.

The pathobiology of CPFE has not been established. Cigarette smoke is the most important trigger, but other environmental exposures, such as agrochemical compounds, may also contribute. It is not known whether CPFE develops in individuals who inherit susceptibility to both chronic obstructive pulmonary disease (COPD) and IPF or if there is a distinct genetic basis for the syndrome.

Patients with CPFE have worse survival than those with IPF alone (25 vs. 34 months). Prognosis of patients with concurrent pulmonary fibrosis and emphysema is even poorer if they develop PH. When patients develop restriction (forced vital capacity [FVC] <50% predicted) in the setting of CPFE with PH, the prognosis is grim.

Recent studies have attempted to determine models that could further help in the prognostication of patients with CPFE. Although the decline in FVC and diffusing capacity of the lungs for carbon monoxide (D lco ) are important prognostic variables for IPF patients, they are not reliable indicators of disease in CPFE patients. In a retrospective study conducted by Schmidt et al., decline in FEV ₁ by 10% was a stronger predictor of mortality in CPFE patients than FVC, D lco , or composite physiologic index. Kishaba et al. retrospectively examined ILD patients at their center; 93 had CPFE with either IPF or iNSIP as the fibrotic phenotype. The mean survival rate of these patients was 30.7 months. In this study, an overall ratio of %FEV ₁ to %FVC of more than 1.2 and presence of finger clubbing were the best predictors of poor survival in patients with CPFE.

Management of patients with CPFE should be directed to the underlying fibrotic lung disease, emphysema, and resulting aberrations in gas exchange. Smoking cessation is of paramount importance. Oral corticosteroids and immunosuppressive therapy are ineffective for the long-term management of CPFE patients, but may be considered for management of acute exacerbations. Supplemental oxygen should be provided for hypoxemic patients. Anti-PH therapy has not been specifically evaluated in this population.

Pulmonary Hypertension and Idiopathic Pulmonary Fibrosis

Multiple studies have examined PH in patients with IPF. PH is defined as a mean pulmonary arterial pressure (mPAP) ≥25 mm Hg at rest or ≥30 mm Hg with exercise. Echocardiography is recommended as a screening test for identifying patients with PH. In a study comparing echocardiographic and right-sided heart catheterization data for patients with advanced lung disease waiting for lung transplant, 48% of patients were misclassified with PH. Thus echocardiographic data must be interpreted with caution, and right-sided heart catheterization is required to accurately confirm the presence and severity of PH in the IPF population.

Recent studies have investigated the utility of echocardiographic measurements of right ventricular structure and function to predict outcomes in IPF-associated PH. A retrospective cohort study by Rivera-Lebron et al. reviewed 135 patients with IPF out of whom 29% had PH. They reported an association between the ratio of right ventricle to left ventricle diameter greater than 1, TAPSE less than 1.6 cm, presence of moderate to severe right atrial or right ventricle dilation, and right ventricle dysfunction with increased risk of death. Hence quantitative echocardiographic assessment of right ventricular structure and function can be clinically significant. Other echocardiographic parameters such as right ventricular systolic pressure have limited accuracy in patients with advanced lung disease.

Estimates of the prevalence of PH in IPF range between 31% and 85% and are derived from data from patients awaiting lung transplantation. The incidence and severity of PH increase with time, and thus the prevalence of PH in the general IPF population may be lower.

PH in IPF is associated with a higher mortality, especially in patients with combined emphysema and pulmonary fibrosis. Although mPAP ≥25 mm Hg is an accepted definition for PH, a recent analysis demonstrated that mPAP >17 mm Hg is the best discriminator of increased 5-year mortality for IPF patients. Elevated pulmonary vascular resistance has also been associated with poor outcome in patients with IPF-PH.

PH in IPF is the result of a number of proposed pathophysiologic mechanisms, including distortion and destruction of the vascular bed from fibrosis and chronic vasoconstriction due to hypoxemia. PH usually develops in patients with severe IPF and is analogous to the development of PH in other chronic lung diseases, such as COPD. However, there exists a subset of IPF patients who develop PH at earlier stages of the disease. These patients are hypothesized to represent a distinct phenotype of disproportionate PH in IPF. Patients may have disproportionate PH in IPF due to episodic hypoxemia during sleep or exercise or may have an imbalance of angiogenesis and angiostasis in the lung. Whether this represents a true novel phenotype remains to be explored, as do the underlying potential mechanisms of disproportional PH in IPF.

Recent advances in the understanding of the pathobiology of PH have resulted in the development of therapies that have greatly improved functional status and survival of select groups of patients with the disease. Early trials of endothelin receptor antagonists in IPF provided promising results ; subsequent larger trials have failed to show a statistically significant benefit. Other studies have been terminated early because of disease progression in IPF patients with PH treated with ambrisentan or riociguat. Based on a lack of evidence and potential for harm, treatment of PH in IPF is not recommended for the majority of patients.

In patients with idiopathic PAH, there is evidence supporting the use of long-term anticoagulation for prevention of venous thromboembolism. However, currently there are no studies to support the use of long-term anticoagulation in IPF patients with PH. Furthermore, a study that evaluated the use of warfarin in patients with progressive IPF was terminated early because of a trend toward higher mortality, hospitalization, and acute exacerbation of IPF in the warfarin group.

Rapidly Progressive Idiopathic Pulmonary Fibrosis

Patients with IPF may exhibit varying courses of their disease: some have slowly progressive disease, some experience acute exacerbations of IPF, and some experience a very rapid deterioration from the time of symptom onset ( Fig. 10.2 ). Patients with rapid disease progression are hypothesized to represent a distinct phenotype of IPF. A study of 26 patients with rapidly progressive disease (<6 months of symptoms) and 88 patients with slowly progressive disease (>24 months of symptoms) found differential expression of genes between the groups, with the rapid progressors exhibiting upregulation of the several genes involved in cell motility, myofibroblast differentiation, coagulation, oxidative stress, and development, including the gene for the adenosine A _2B receptor. Another study showed elevated TLR9 gene expression in surgical lung biopsies of patients with rapidly progressive IPF compared with those with more stable disease. A genomewide analysis in IPF patients identified gene expression from lung parenchyma of IPF patients that differentiated patients with rapid disease progression from those with stable disease. These results suggest biologically plausible mechanisms underlying the difference between the proposed slowly and rapidly progressive phenotypes in IPF.

Natural history of idiopathic pulmonary fibrosis. The majority of patients experience slow progression of the disease (slow progression), while some have more stable disease (stable). Patients with slow progression or stable disease may experience episodes of acute deterioration (lightning bolt; acute worsening). A subset of patients has rapidly progressive disease (rapid progression) and may encompass a distinct phenotype.

Adapted from Raghu G, Collard HR, Egan JJ, et al. An Official ATS/ERS/JRS/ALAT Statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med . 2011;183:788; with permission.

Gastroesophageal Reflux Disease

Evidence that gastroesophageal reflux disease (GERD) is associated with IPF and recurrent silent aspiration of gastric acid is associated with acute exacerbations of IPF makes GERD an attractive hypothesis for the etiology of IPF. Instillation of acid into the tracheobronchial tree produces pulmonary fibrosis in animal models, and aspiration of gastric contents can cause pulmonary fibrosis in humans.

The prevalence of GERD in IPF is estimated between 66% and 87%. It should be noted that 33–53% of patients with documented acid reflux are asymptomatic. In a study of patients with IPF being worked up for lung transplantation, symptoms of reflux were a poor predictor of acid reflux measured with esophageal pH monitoring with a sensitivity of 65% and specificity of 71%. A small case series comparing bronchoalveolar lavage (BAL) pepsin levels found that patients with acute exacerbations of IPF had higher levels of BAL pepsin than stable IPF patients. In a recent study, patients with asymmetric IPF were more likely to have GERD and have experienced acute exacerbations of IPF than patients with symmetric IPF. The authors speculate that asymmetric IPF is caused by silent nocturnal aspiration and that acute exacerbations of IPF are also caused by silent aspiration.

There are limited data describing treatment outcomes for IPF patients with silent GERD. A small series of four IPF patients with silent GERD documented by 24-h pH measurements and treated with proton pump inhibitors (PPIs) and gastric fundoplication if required showed stabilization in lung function. A retrospective study of IPF patients waiting for lung transplantation found that those who underwent Nissan fundoplication for severe symptomatic acid reflux had an improved posttransplant course compared with patients who did not undergo the procedure.

Two recent post hoc studies show contrasting results. Lee et al. examined patients who were assigned to the placebo group of the three IPFnet randomized controlled trials. Out of 242 patients in placebo arms, 124 patients (51%) were taking PPI or H2 receptor blockers (H2B) at baseline. At 30 weeks the H2B/PPI group had smaller decrease in FVC (estimated difference between groups 0.07 L (95% CI 0.00, 0.14, P -value = .05) and fewer acute exacerbations compared with the group of patients not taking antacid therapy at baseline. Kreuter et al. analyzed patients who were randomly allocated to the placebo arms in three large clinical trials of pirfenidone. Of the 624 patients included in the study cohort, 291(47%) received antacid therapy (256 [88%] PPIs, 24 [8%] H2 blockers, and 11 [4%] both PPIs and H2 blockers) and 333 (53%) patients did not. Antacid therapy users had similar disease progression at 1 year compared with no antacid therapy users (37·8% vs. 40·5%; P = .4002). There were no significant differences in percent-change in FVC from baseline, 6-min walk distance, all-cause mortality and IPF-related mortality, and adverse events between the two groups. However, there were more overall infections [107 (74%) vs. 101 (62%); P = .0174] and pulmonary infections [20 (14%) vs. 10 (6%); P = .0214] in patients with more advanced IPF treated with antacids than those who were not. These observational and retrospective studies suggest that anti-GER therapy may improve lung function, but may be associated with an increased risk of pneumonia. Randomized controlled trials are needed. The most recent ATS/ERS/JRS/ALAT IPF guidelines provide a conditional recommendation for the use of antacid therapy for the treatment of IPF, with “very low confidence in effect estimates.”

Cardiovascular Disease and Venous Thromboembolic Disease

Several studies have demonstrated that IPF patients have a higher risk of developing acute vascular disease (cardiovascular disease and venous thromboembolic disease) than those with other lung diseases or the general population. In an uncontrolled autopsy study of IPF patients, nine patients (21%) died of cardiovascular events. A cross-sectional study of 630 patients referred for lung transplantation at a tertiary hospital demonstrated that IPF patients have an increased risk of coronary artery disease identified at angiography than patients referred with other chronic lung disease (OR, 2.31; 95% CI, 1.11–4.82). More recently, a large case-controlled study showed that patients with IPF are more likely to have a history of cardiovascular disease at the time of IPF diagnosis (OR, 1.53; 95% CI, 1.15–2.03) than controls and are more likely to have an acute coronary event during follow-up (RR, 3.14; 95% CI, 2.02–4.87). IPF patients who were diagnosed with cardiovascular disease during follow-up for IPF had a greater mortality than those with preexisting cardiovascular disease at the time of IPF diagnosis (HR 4.7, 95% CI 2.0, 11.1; P < .001). IPF patients have an increased risk of angina, atrial fibrillation, deep vein thrombosis, and stroke.

Venous thromboembolic disease is also important in IPF patients. A large study of the Danish population examined whether thromboembolic disease is a risk factor for idiopathic interstitial pneumonia. This study demonstrated that patients with deep venous thrombosis and pulmonary embolism have an increased risk of idiopathic interstitial pneumonia compared with controls (HR 1.3; 95% CI, 1.2–1.4; and HR 2.4; 95% CI, 2.3–2.6, respectively) with multivariate-adjusted analyses. In a study of all decedents in the United States between 1988 and 2007, the risk of death from venous thromboembolic disease was greater for patients with pulmonary fibrosis compared with the general population (OR 1.35, 95% CI 1.29–1.38, P < .0001), patients with lung cancer (OR 1.45, 95% CI 1.39–1.48, P < .0001), or patients with COPD (OR 1.55, 95% CI 1.49–1.59, P < .0001).

Current guidelines on the management of IPF do not discuss the identification and management of comorbid vascular disease in IPF patients. However, it is reasonable to screen patients for cardiovascular or thromboembolic disease if they clinically deteriorate. In particular, when assessing a patient with a possible acute exacerbation of IPF, one must rule out cardiovascular disease and pulmonary embolism as causes of the deterioration.

Lung Cancer

The risk of lung cancer for patients with IPF is high. When compared with that of the general population, the relative risk is 7.31 (95% CI, 4.47–11.93). The prevalence of lung cancer among IPF patients followed in national registries ranges between 4.4% and 9.8%. In a retrospective cohort study, the cumulative incidence of lung cancer among IPF patients was 3.3% at 1 year, 15.4% at 5 years, and 54.7% at 10 years. The risk of developing lung cancer is greater for IPF patients who are male ever-smokers. There are three hypotheses to explain this relationship: pulmonary fibrosis causes lung cancer, lung cancer and/or its treatment causes pulmonary fibrosis, and/or common mediators cause lung cancer and pulmonary fibrosis. Interestingly, in a study of molecular phenotypes of IPF, several genes that are upregulated in IPF (but not in normal lung tissue) are also upregulated in adenocarcinoma of the lung, suggesting that the observed increased risk may be in part due to common biologic mechanisms.

Treatment of lung cancer in IPF is fraught with difficulties, including acute exacerbations of pulmonary fibrosis/acute lung injury associated with surgical resection of cancers, radiation therapy, and chemotherapy. Existing guidelines do not specifically address this issue and the decision to proceed with treatment of cancer in IPF patients should be a carefully considered one.

Depression

Quality of life in patients with pulmonary fibrosis is poor and associated with dyspnea and impaired pulmonary function. Dyspnea in IPF affects health-related quality of life differently in men and women: in men, dyspnea worsens physical quality of life domains, and in women, it worsens emotional domains. Twenty three percent of patients with pulmonary fibrosis were found to have clinically significant depression in a recent study. There is a strong correlation between depression and dyspnea in these patients; multivariate analysis suggests that depression is a major contributing factor in patients’ perception of dyspnea and thus their quality of life. Depression was found in 21% of a Danish cohort of IPF patients. Treating depression may improve patients’ dyspnea and quality of life; this hypothesis needs testing in clinical trials.

Sleep Apnea and Idiopathic Pulmonary Fibrosis

Obstructive sleep apnea (OSA) affects 2–4% of the North American population. Numerous studies show disruption of sleep architecture in ILD patients, increased breathing frequency, nocturnal cough, and oxygen desaturation especially during rapid eye movement sleep. The prevalence of OSA in IPF patients is estimated between 44% and 88%.

Early recognition and treatment of OSA are important as untreated OSA is associated with high risk of adverse clinical outcomes including cardiovascular disease, type 2 diabetes mellitus, depression, PH, and cognitive impairment. Mortality and morbidity rates increase significantly when OSA occurs concurrently with other chronic lung diseases. Several factors associated with OSA such as chronic gastroesophageal reflux, microaspiration, intermittent hypoxia, and intrathroacic mechanical strain may either contribute to the development of IPF or further promote its progression. In addition, OSA may contribute to fatigue and poor sleep quality in affected patients.

Treatment of moderate to severe OSA in IPF patients results in overall improvement in the quality of life based on the Functional Outcome of Sleep Questionnaire, daily living activities, and sleep parameters. Initiating CPAP therapy in the early stages of the disease may improve acclimation and compliance to CPAP. However, in general, there is a paucity of literature looking at CPAP initiation in this patient population; future research is needed to investigate the potential role of OSA in progression and development of IPF.

Diabetes Mellitus

A prospective Danish study of IPF patients noted that 17% of IPF patients had diabetes mellitus. Survival of IPF patients with diabetes at the time of IPF diagnosis mellitus was significantly worse than for those without diabetes after adjusting for age, gender, and FVC (HR 2.47, 95% CI 1.04–5.88; P = .041). The reason why IPF patients with diabetes mellitus have a higher risk of death than those without is not clear, and the relationship between diabetes mellitus and IPF warrants further investigation.