Combined pulmonary fibrosis and emphysema: A new horizon of smoker’s lung disease with obstructive and restrictive lung functions!

INTRODUCTION

Combined pulmonary fibrosis and emphysema (CPFE) is an underrecognized syndrome characterized by chronic, progressive disease with a dismal prognosis. Frequent comorbidities with a higher incidence than in idiopathic pulmonary fibrosis (IPF) or emphysema alone are pulmonary hypertension (World Health Organization group 3) in 47–90% of the patients and lung cancer in 46.8% of the patients.^[1] According to the definition of emphysema, the presence of excess fibrosis has been historically excluded from the diagnosis of emphysema.^[2] Therefore, chronic obstructive pulmonary disease (COPD) and idiopathic interstitial pneumonias, with different radiological, pathological, functional, and prognostic characteristics, have been regarded as separate entities for a long time. However, there is an increasing recognition of the coexistence of emphysema and pulmonary fibrosis in individuals. Whether the combination of emphysema and pulmonary fibrosis is a distinct clinical entity or not remains unknown. Some consider it as a coincidence of two smoking-related diseases in one person, comparable to the coexistence of lung cancer and COPD. However, previous data had suggested that interstitial lung abnormalities were inversely associated with emphysema in smokers.^[3] Actually, most former smokers with IPF do not have radiographic evidence of emphysema. Likewise, most patients with emphysema/COPD do not have overt evidence of interstitial fibrosis. Therefore, the combination of pulmonary fibrosis and emphysema may be a distinct consequence of smoking that reflects unique individual susceptibilities.

In 2005, Cottin et al. first time put forward a defined syndrome termed “combined pulmonary fibrosis and emphysema (CPFE),” which is characterized by heavy smoking history, exercise hypoxemia, upper lobe emphysema and lower lobe fibrosis, unexpected subnormal lung volumes and severe reduction of carbon monoxide transfer.^[4] The CPFE syndrome comprises a heterogeneous population of patients and a consistent definition of CPFE has not been put forward. High-resolution computed tomography (HRCT) is the mandatory tool to diagnose this syndrome. CPFE is frequently complicated by pulmonary hypertension, acute lung injury and lung cancer and the prognosis of it is poor. Treatments for CPFE patients with severe pulmonary hypertension are less effective than lung transplantation.^[5] Identification of patients with CPFE is important because this disorder has its unique natural history. However, unfortunately CPFE has not yet attracted wide attention of clinicians and there is no research systematically contrasting the differences among CPFE, emphysema/COPD and pulmonary fibrosis alone at the same time.

BASIC ASPECTS OF CPFE AND PATHOGENETIC MECHANISMS

CPFE is a clinical entity characterized by the combination of the upper lobe emphysema and lower lobe fibrosis. The advent of computed tomography permitted recognition of the coexistence of pulmonary fibrosis and emphysema (CPFE). Although most cases of CPFE likely represent the common fibrotic pattern of usual interstitial pneumonia (UIP), few cases have been reported as showing desquamative interstitial pneumonia (DIP) or unclassified interstitial pneumonia.^[6] Emphysema is defined as an enlargement of the air spaces distal to the terminal bronchioles due to the destruction of the tissues forming their walls. Emphysema secondary to smoking is typically centrilobular, which commonly manifests as small, localized areas of low attenuation within the central portion of the secondary pulmonary lobule on HRCT.^[2] IPF is a chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, characterized by progressive worsening of dyspnea and lung function and associated with a poor prognosis. It is the most common ILD with a characteristic histologic pattern of UIP, which is characterized on HRCT by the presence of subpleural and basal predominance, reticular opacities, and honeycombing with or without traction bronchiectasis.^[7]

PATHOGENESIS: FOUR DIFFERENT THEORIES

The pathogenesis of CPFE has not been fully elucidated to date. It is still unclear whether emphysematous and fibrotic lesions progress independently or if one results from the other. Perhaps there are some undiscovered mechanisms, which may involve a variety of cytokines and shared signaling pathways, resulting in both emphysema and pulmonary fibrosis in genetically susceptible individuals after the exposure to environmental triggers such as smoking.

CLINICAL SYMPTOMS

Cough and dyspnea are common symptoms in patients with CPFE or COPD or IPF. However, some differences exist among them. The characteristic symptoms of COPD are chronic cough with daily variable sputum production and progressive dyspnea. Chronic cough and sputum production usually precede airflow limitation by many years.^[14] As for patients with IPF, dyspnea is the primary symptom existing in over 90% of patients at the time of diagnosis, followed by frequent dry and non-productive cough experienced by 73– 86% of patients in the late stage.^[15]

The symptoms of CPFE seem more similar to that of IPF. Progressive shortness of breath is the most common and classical symptom and is usually more severe, especially exertional dyspnea (exists in almost all the patients; functional class III–IV of the New York Heart Association). Other common signs and symptoms of respiratory tract, such as cough, wheezing, perioral cyanosis, asthenia and so on, may also appear in some patients. On physical examination, patients with CPFE usually have inspiratory dry crackles named “Velcro sounds” from the underlying pulmonary fibrosis on chest auscultation, as reported in 87– 100% of cases, and a number of them (43–45%) have finger clubbing.^[16]

HIGH-RESOLUTION COMPUTED TOMOGRAPHY (HRCT)

At present, there is no consistent definition of CPFE. HRCT scanning is essential for the diagnosis of CPFE. The diagnostic criteria of CPFE described by Cottin et al. included radiological findings of the upper-lobe centrilobular and/or paraseptal emphysema with multiple bullae and lower-lobe honeycombing with subpleural reticular opacities and traction bronchiectasis, and sometimes ground-glass opacities.^[4,5] The upper-lobe emphysematous lesions in CPFE mainly include centrilobular emphysema, paraseptal emphysema and bullae, with the prevalence 97%, 93%, and 54%, described, respectively, in a study by Cottin et al.^[5] There are differences in the distribution of emphysema between CPFE and COPD. Emphysema secondary to smoking was reported typically centrilobular in COPD. However, paraseptal emphysema was much more frequent in the CPFE group than the COPD group and was considered as the most typical presentation of CPFE.^[16]

Thick-walled cystic lesions (TWCLs) are considered as unique radiological and pathological features of CPFE as well.^[11] Enlargement of TWCLs is probably an indication of interstitial pneumonia deterioration. In recent research, both radiological and pathological TWCLs were observed in 72.7% of the CPFE patients, but not in any patient with IPF or emphysema alone. The authors also found that the extent of emphysema was greater in the CPFE patients with TWCLs than that in the patients without TWCLs.^[16]

As for the lower-lobe fibrosis lesions, honeycombing, reticulation and traction bronchiectasis are the top-three common imaging features, with the prevalence of 75.6–95%, 84.4–87% and 40–69% reported in cases with CPFE.^[16,17] Except the abnormalities mentioned above, areas of ground glass attenuation are also common in CPFE, as reported by 62.2–66%, being the unique feature suggesting possible smoking-related ILD, such as DIP.^[18]

In the aspect of HRCT scores, the total emphysema scores were reported highest in COPD and higher in CPFE than in IPF. Besides, the total emphysema scores of CPFE were similar to that of mild to moderate COPD and lower than that of severe COPD.^[19] Fibrosis scores are generally higher in CPFE and IPF than that in COPD. However, the difference of fibrosis scores between CPFE and IPF was still controversial. Some reports found no difference while others showed the lower total fibrosis scores in CPFE than IPF and found the difference was consistent in the upper, mid, and lower lung zones.^[19,20]

Recently, there is a new report about the comparison of CPFE patients with and without airflow obstruction (CPFE OB+ group and CPFE OB− group). The degree of emphysema represented by LAA scores on HRCT was significantly lower in the CPFE OB− group than the CPFE OB+ and COPD groups, while the severity of pulmonary fibrosis was greater in the CPFE OB− group than the CPFE OB + group. Different mechanisms may be involved in the development of clinical phenotypes of CPFE, which might be classified into “emphysema-dominant” phenotype or “fibrosis-dominant” phenotype.^[17]

The distribution of emphysema and fibrosis in patients with CPFE are not completely independent from each other. Brillet et al. had described three patterns of distribution in CPFE: A progressive transition from apical emphysema to a zone of transition between bullae and honeycombing; paraseptal emphysema with areas of fibrosis; separate processes with independent areas of fibrosis and emphysema.^[21] Sometimes differentiating emphysema from pulmonary fibrosis may be complex and difficult. For example, wall-thickened emphysematous changes may be mistaken for honeycomb cysts. Moreover, as reported by Cottin et al. only 50% of patients with CPFE had simultaneous emphysema and pulmonary fibrosis at diagnosis; others might develop another lesion after a long history of emphysema or pulmonary fibrosis.^[5] Hence, patients with suspected CPFE should be followed up on a regular basis.

PULMONARY FUNCTION TESTS (PFTS)

CPFE has a characteristic pulmonary function feature different from pure emphysema and IPF, which is characterized by the unexpected relatively normal lung volumes contrasted by a severely reduced diffusing capacity. In many research, mean values of forced vital capacity (FVC) and total lung capacity (TLC) in CPFE are usually within a relatively normal range, whereas Diffusing capacity of lung for carbon monoxide (DLCO) is severely diminished.^[17,20,22] The preserved lung volumes may be attributed to the counterbalanced effects of the hyperinflation defect of emphysema and the restrictive defect of pulmonary fibrosis. And the reduced diffusing capacity may be due to the overlapping negative effects of both emphysema and pulmonary fibrosis on the gas exchange.^[3,22,23]

For emphysema/COPD, it tends to increase lung compliance, enlarge lung volumes and residual volume (RV) with reduced maximal expiratory flows and decreased DLco. In most research, higher forced expiratory volume in the first second (FEV1) and FEV1/FVC, lower RV and TLC, and lower DLco are usually observed in patients with CPFE than in patients with COPD.^[20,24] In one study showing annual changes of lung function between CPFE and COPD, Kitaguchi et al. reported that annual decreases in lung volumes (VC and FVC) and gas-exchange (DLco) were significantly higher in the CPFE group than the COPD group. However, the annual decrease in airflow limitation represented as FEV1/FVC was significantly lower in the CPFE group than the COPD group. This may be explained by the traction caused by pulmonary fibrosis in CPFE, which prevents the typical expiratory airway collapse seen in emphysema and strengthens the support of the small airways.^[23]

For pulmonary fibrosis, it tends to decrease lung compliance and reduce TLC, RV and RV/TLC ratio with preserved or increased maximal expiratory flow rates and reduced DLCO. In general, patients with CPFE usually have higher lung volumes, lower FEV1/FVC ratio and lower DLco than patients with IPF.^[3,25] In spite of a lower baseline DLco in the CPFE group than that in the IPF group, Akagi et al. reported that the annual rates of decline in DLco and FVC were also significantly lower in the CPFE group.^[26] The existence and range level of emphysema are important factors promoting decline in the pulmonary function of IPF, such as FEV1/ FVC. In several studies showing annual changes of lung function between CPFE and IPF, the FEV1/FVC ratio in CPFE significantly decreased during the follow-up period while that in IPF remained nearly consistent over time.^[24,26,27] These results suggest that CPFE is more associated with a progressively obstructive pattern over time and highlight the importance of bronchodilator therapy in CPFE.

The different pulmonary function impairment between CPFE patients with and without airflow obstruction has been recently reported.^[24] Impairment of diffusion capacity was severe in both CPFE OB− and CPFE OB+ groups. Although there were no significant differences in the dynamic hyperinflation between CPFE OB− and CPFE OB + groups, lung hyperinflation and respiratory resistance were significantly lowest in CPFE OB− group and lower in CPFE OB+ group than the COPD group. In addition, CPFE OB+ patients with more emphysema were also found to have a worse survival than CPFE OB− patients.

In the end, it is worth noting that the pattern of normal lung volume with severely decreased DLco in PFTs does not necessarily mean CPFE syndrome. It may be explained by other abnormalities, such as pulmonary vascular disease, emphysema and ILD. In a report, only 16% of patients with severely diminished capacity of gas exchange had CPFE, with the remainder having emphysema (46%), ILD (28%) or pulmonary arterial hypertension (PAH) (8%).^[28]

BLOOD GAS ANALYSIS

Resting and exercise hypoxemia are most frequent in patients with CPFE because of the severely damaged capacity of gas exchange, whereas hypercapnia hardly appears, usually with normal average levels of PaCO₂.^[3] Hypoxemia in the CPFE syndrome is generally moderate or above at rest and gets worse during exercise.^[29] The blood gas analysis of CPFE is different from that of COPD and seems more similar to IPF. For patients with advanced COPD, gas exchange abnormalities usually result in hypoxemia and hypercapnia. The carbon dioxide retention in COPD can be explained by reduced ventilation due to severe obstruction and hyperinflation with ventilator muscle impairment.^[14]

COMPLICATION

TREATMENT OPTIONS IN CPFE

There are no specific effective treatments for the CPFE syndrome at present. It seems logical to make treatment decisions based on recommendations separately for emphysema and pulmonary fibrosis.

1. Smoking cessation, which is the first recommended treatment for COPD and IPF, should be encouraged for CPFE as well because it may stop the progression of disease. For those who are associated with other environmental exposures, keeping away from the exposures is the most important.^[14,35]

2. To lessen acute exacerbations and infections, patients are suggested to accept a long-term oxygen therapy and take vaccination against influenza viruses and streptococcus pneumonia. Oxygen therapy is known as the most appropriate treatment for hypoxemia and pulmonary hypertension in CPFE. Supplemental oxygen therapy is used in the context of resting hypoxemia and may also have benefits when prescribed only for hypoxemia that occurs during exercise and nocturnally, even in those patients who are normoxemic at rest^[36]

3. Regular exercise and pulmonary rehabilitation are provided to most patients with CPFE. Although no studies have evaluated pulmonary rehabilitation in CPFE, pulmonary rehabilitation and regular exercise are a cornerstone of management of patients with emphysema and are increasingly used in patients with fibrosing ILD (fILD)^[37]

4. As most exacerbations of both COPD and fILD are thought to be triggered by a respiratory tract infection (either from a virus or bacteria), influenza, pneumococcal, and coronavirus disease vaccination are also provided at standard intervals, unless contraindicated.

PREDICTORS OF SURVIVAL OR OUTCOME

Different longitudinal measurements such as lung function (FEV1, FVC, DLCO), symptoms and radiological studies (HRCT scans), are used to classify disease severity. However, none of these parameters are fully satisfactory in predicting prognosis in CPFE patients. Wells et al. tried to develop a more reliable predictor of prognosis in IPF patients, by using the composite physiologic index (CPI).^[48] This index was derived to represent the extent of fibrosis in IPF patients, with adjustment for the emphysema component. In IPF patients, the extent of IPF on CT was calculated by a formula incorporating multiple components of pulmonary function: the extent of disease on CT = 91.0 – (0.65 × percent predicted DLCO) – (0.53 × percent predicted FVC) + (0.34 × percent predicted FEV1). In IPF patients, CPI and longitudinal changes in DLCO were more predictive than FVC and FEV1.^[49] However, CPI is not helpful in predicting prognosis in CPFE patients: Schmidt et al. demonstrated that longitudinal change in FEV1 was most predictive of mortality in CPFE patients, whereas a significant increase (i.e., by at least five points over 6 or 12 months) in CPI was the best predictor in patients with IPF without emphysema.^[49]

The clinicoradiological patterns of the fibrotic disease of CPFE are also relevant in the estimation of the prognosis. The study of Alsumrain et al. showed that the overall mortality for the study period (11 years) was greatest in those with CPFE with UIP/IPF pattern, compared to other classifiable and unclassifiable ILD patterns (69% vs. 45% vs. 38%, respectively, P = 0.016).^[50]

CONCLUSIVE REMARKS AND CLINICAL LESSONS

Progressive shortness of breath with partial response to inhaled bronchodilator and antimuscarinic needs prompt evaluation in COPD to rule out other causes of failure of treatment. Chest X-ray gives definite clues for alternate diagnosis in cases with partial response to inhaled medicines in COPD. Chest radiology showing blurred cardiac and diaphragmatic margins needs interstitial disease to rule out. In fact, loss of demarcation of cardiac and diaphragmatic margins in chest X-ray is “earliest marker” of ILD. Velcro crepitations on auscultation in COPD cases are “clinical clues” to suspect IPF in cases with chronic tobacco exposure.

HRCT is the gold standard test to evaluate ILD. Honeycombing, tractional bronchiectasis, and reticular opacities in bilateral lower lobes with peripheral, subpleural distribution suggestive of UIP pattern. Combination of UIP pattern in lower lobes with emphysema in upper lobe is CPFE in cases with chronic smokers. With the typical radiological pattern of CPFE, lung biopsy is not necessary for further confirmation.

Large number of CPFE cases with poor exercise tolerance (i.e., 6-min walk distance) necessitates echocardiography to rule out pulmonary hypertension which is common but underestimated cause of persistent dyspnea in these cases. Although DLCO is decreased in both emphysema and ILD independently, it can be assessed with lung volumes. Normal lung volumes with reduced DLCO are rare in CPFE.

Proportionately large number of CPFE cases are having rheumatological symptoms with positive RA factor. ANA blot needs strict evaluation in all cases of CPFE to rule out concurrent CTD. Myositis and undifferentiated CTDs are common in CPFE. Bronchodilators, antifibrotics with or without pulmonary vasodilators and oxygen supplementing as per oxygen saturation and echocardiography findings is mainstay therapy for CPFE.