I. Introduction
Chronic Obstructive Pulmonary Disease (COPD) and Idiopathic Interstitial Pneumonias (IIPs) have traditionally been considered distinct respiratory conditions, each with unique radiological, pathological, functional, and prognostic profiles. However, medical understanding has evolved, increasingly recognizing the concurrent existence of emphysema and pulmonary fibrosis within individuals. This combination, termed “Combined Pulmonary Fibrosis and Emphysema” (CPFE) syndrome by Cottin in 2005, presents a distinct clinical challenge. CPFE is characterized by exertional dyspnea, upper-lobe emphysema alongside lower-lobe fibrosis, surprisingly preserved lung volumes, and a significant reduction in gas exchange capacity. Furthermore, CPFE often leads to severe complications such as pulmonary hypertension, acute lung injury, and lung cancer, resulting in a poor prognosis. Current treatments, particularly for CPFE patients suffering from severe pulmonary hypertension, offer limited efficacy, with lung transplantation often considered the only viable option. Despite its clinical significance, CPFE has not yet garnered widespread attention among clinicians, and comprehensive research comparing CPFE with emphysema/COPD and IIP is lacking. This article aims to provide a detailed review of the current knowledge surrounding CPFE, contrasting it with emphysema/COPD and IIP. The objective is to enhance awareness of CPFE syndrome and explore potential avenues for more effective diagnostic and therapeutic strategies in clinical practice. While our website, xentrydiagnosis.store, focuses on automotive repair, understanding complex diagnostic challenges like CPFE highlights the importance of meticulous analysis and comprehensive problem-solving – skills valuable across disciplines.
II. Defining CPFE: Distinguishing Key Terms
To effectively understand Cpfe Diagnosis, it’s crucial to differentiate it from related respiratory conditions. Terms such as emphysema, smoking-related interstitial lung fibrosis (SRIF), idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), and non-specific interstitial pneumonia (NSIP) are frequently encountered in the context of CPFE and require clear definitions.
CPFE: Radiographic and Functional Definition
The term CPFE, initially defined by Cottin et al., is characterized radiographically by the presence of centrilobular and/or paraseptal emphysema in the upper lobes and pulmonary fibrosis, predominantly of the IPF/UIP pattern, in the lower lobes. Pulmonary function tests in CPFE patients typically reveal a mixed pattern with a notable reduction in diffusing capacity for carbon monoxide (DLco), a feature strongly associated with a high incidence of pulmonary hypertension. Although UIP is the most commonly observed fibrotic pattern in CPFE, cases exhibiting desquamative interstitial pneumonia (DIP) or unclassified interstitial pneumonia have also been reported. Consequently, some cases classified as CPFE might fall under the spectrum of SRIF.
Emphysema: Structural Lung Damage
Emphysema is pathologically defined by the abnormal and permanent enlargement of air spaces distal to the terminal bronchioles, accompanied by the destruction of alveolar walls, without obvious fibrosis. Emphysema caused by smoking is typically centrilobular. On High-Resolution Computed Tomography (HRCT), it often appears as localized areas of low attenuation within the central portion of the secondary pulmonary lobule. Emphysema can lead to an obstructive pattern, characteristic of COPD, due to these structural changes in the lung.
SRIF: Smoking-Related Interstitial Fibrosis
Smoking-related interstitial lung fibrosis (SRIF) describes chronic unclassified interstitial fibrosis that develops in smokers. Key diagnostic features of SRIF include fibrosis primarily composed of hyalinized, eosinophilic collagen deposition thickening alveolar septa, often associated with enlarged airspaces of emphysema and respiratory bronchiolitis (RB). Fibrosis in SRIF predominantly affects the subpleural parenchyma and often exhibits a centrilobular distribution in deeper parenchyma. Differentiating SRIF from other fibrotic interstitial lung diseases, particularly UIP and NSIP, is essential for accurate CPFE diagnosis and management.
IPF/UIP: Idiopathic Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia of unknown etiology, primarily affecting older adults. IPF is characterized by progressive dyspnea, declining lung function, and a poor prognosis. The hallmark histologic pattern of IPF is usual interstitial pneumonia (UIP). HRCT findings in UIP typically include subpleural and basal predominance, reticular opacities, and honeycombing, with or without traction bronchiectasis. Histopathologically, UIP is characterized by significant architectural distortion due to interstitial destruction by extensive irregular scars and well-formed honeycombing, predominantly in a subpleural/paraseptal distribution.
NSIP: Non-Specific Interstitial Pneumonia
Non-specific interstitial pneumonia (NSIP) is an uncommon interstitial pneumonia associated with collagen vascular diseases, hypersensitivity pneumonitis, and drug-induced lung injury. Fibrotic NSIP on HRCT presents variably, but characteristically shows symmetric bilateral areas of ground-glass opacity with superimposed fine reticular opacities, with or without traction bronchiectasis and bronchiolectasis, but minimal or absent honeycombing. Fibrosis in NSIP typically has a diffuse distribution. Even in severely fibrotic NSIP, chronic inflammatory cells are usually present alongside collagen.
III. Epidemiology of CPFE
While the prevalence of emphysema and IPF are relatively well-documented, the specific prevalence of CPFE remains less defined. Emphysema affects approximately 21.5 per 1,000 individuals in the general population, whereas IPF prevalence ranges from 14 to 42.7 cases per 100,000, indicating IPF is considerably rarer than emphysema. However, studies utilizing HRCT scans to detect CPFE in IPF patients have reported proportions ranging from 8% to 51%. This wide variation in CPFE prevalence may be attributed to differing criteria for evaluating the extent of emphysema on HRCT. Conversely, estimates of pulmonary fibrosis prevalence in emphysema patients, as detected by HRCT, range from 4.4% to 8%.
CPFE patients are typically older, predominantly male, and have a significant smoking history. Most studies report heavy smoking histories in almost all CPFE patients, suggesting smoking as a primary risk factor. While smoking history is similar between CPFE and COPD patients, both CPFE and COPD patients generally have more pack-years compared to IPF patients. The male predominance observed in CPFE could be partially explained by greater historical smoking exposure in men, or other occupational or environmental factors. Although both emphysema and IPF are more common in male smokers, further research is needed to determine if gender is an independent risk factor for CPFE.
IV. Pathogenesis of CPFE: Unraveling the Mechanisms
The precise pathogenesis of CPFE is not yet fully understood. It remains unclear whether emphysematous and fibrotic lesions develop independently or if one condition predisposes to the other. Current hypotheses suggest that shared mechanisms, potentially involving various cytokines and signaling pathways, may lead to both emphysema and pulmonary fibrosis in genetically susceptible individuals following exposure to environmental triggers, such as cigarette smoke.
Cigarette Smoking: A Major Etiological Factor
Cigarette smoking is a well-established major risk factor for both COPD and IPF. Studies using HRCT scans in smokers have shown interstitial lung abnormalities in approximately 8% of subjects. Given the prevalent heavy smoking history among CPFE patients, smoking is considered a dominant risk factor for CPFE. Animal studies have demonstrated that tobacco exposure can induce both emphysema and pulmonary fibrosis concurrently. Research on lobectomy specimens from smokers with lung cancer has revealed interstitial fibrosis in over half, even in patients without clinical ILD evidence and sometimes with emphysema as the sole CT finding. However, the specific mechanisms and processes through which smoking contributes to CPFE development require further investigation.
Occupational Exposures: Environmental Triggers
Besides tobacco smoke, other environmental exposures may act as potential triggers for lung injury in CPFE. Mineral dust exposure could explain some CPFE cases. Case reports have linked CPFE to agrochemical compound exposure in agricultural workers and to occupations like tyre industry work and welding. In these contexts, CPFE may be considered an occupational disease.
Connective Tissue Disease (CTD) Association
Initially, patients with CTD-associated ILDs were excluded from CPFE studies. However, CPFE syndrome has since been documented in patients with CTDs, particularly smokers or former smokers with rheumatoid arthritis and systemic sclerosis. CTD-associated CPFE patients are more likely to be female, younger, and tend to have less severe outcomes compared to idiopathic CPFE. The lower prevalence of pulmonary hypertension in CTD-associated CPFE might contribute to their better survival. Imaging and pulmonary function features in CTD-associated CPFE are similar to idiopathic CPFE but differ from typical CTD-associated ILD. This suggests CPFE may represent a novel pulmonary manifestation within the spectrum of CTD-ILDs. Recent research has found elevated serum antinuclear antibodies and positive p-ANCA more frequently in CPFE patients than IPF patients. CPFE patients with positive autoimmune markers show greater CD20+ B cell infiltration in fibrotic lung tissue and improved survival compared to those with negative autoimmune profiles.
Genetic Susceptibility: Inherited Predisposition
Genetic predisposition may explain why not all smokers develop CPFE. Gene expression studies have shown differences between fibrotic and emphysematous lesions in CPFE patients. Immune system-related genes are highly expressed in fibrotic lesions, while genes related to cellular fraction, membrane biology, and vascular biology are prominent in emphysematous lesions. These distinct gene expression patterns may contribute to the development of coexisting lesions in CPFE, indicating a potential genetic susceptibility.
Specific genetic pathways are implicated in CPFE. Case reports have identified CPFE in non-smokers with mutations in the surfactant protein C gene and the ABCA3 gene. These mutations disrupt surfactant homeostasis and damage alveolar epithelial type II cells. Both pulmonary fibrosis and COPD are linked to accelerated aging due to oxidative stress and telomere shortening. Telomere length is associated with familial and sporadic IIPs. Mutations in telomerase genes (hTERT or hTR), causing telomere shortening, are risk factors for pulmonary fibrosis in familial cases. Short telomeres may lower the threshold for cigarette smoke-induced damage, acting as a genetic susceptibility factor for emphysema, possibly contributing to age-related onset. Cases of early-onset CPFE in families with lung disease history and inherited hTR or hTERT mutations further support the role of telomerase abnormalities in CPFE.
In summary, CPFE pathogenesis is complex and likely involves multiple cytokines and signaling pathways. Inflammatory mediators such as PDGF, TNF-α, and TGF-β are implicated in both emphysema and fibrosis lesions. Analysis of bronchoalveolar lavage fluid from IPF patients revealed higher concentrations of CXCL5 and CXCL8 in those with concomitant emphysema, suggesting neutrophil accumulation and a cycle of alveolar regeneration attempts and uncontrolled fibrosis activation. Elevated alveolar fraction of exhaled nitric oxide in CPFE patients, similar to IPF but higher than emphysema alone, indicates that pulmonary inflammation in CPFE is more akin to IPF, and fibrotic lesions may play a more significant role in CPFE progression.
V. Clinical Symptoms of CPFE
Cough and dyspnea are common respiratory symptoms shared by patients with CPFE, COPD, and IPF. However, there are notable differences in symptom presentation. COPD is typically characterized by chronic cough with variable sputum production and progressive dyspnea, with chronic cough and sputum often preceding airflow limitation. In IPF, dyspnea is the primary symptom, present in over 90% of patients at diagnosis, followed by a dry, nonproductive cough in 73-86% of patients in later stages. CPFE symptoms appear more similar to IPF. Progressive shortness of breath, particularly exertional dyspnea, is the most common and prominent symptom in CPFE, often severe (functional class III-IV NYHA). Other respiratory symptoms like cough, wheezing, perioral cyanosis, and asthenia may also occur. Physical examination of CPFE patients often reveals inspiratory dry crackles (“velcro sounds”) on chest auscultation, indicative of underlying pulmonary fibrosis (reported in 87-100% of cases), and finger clubbing in a significant proportion (43-45%).
VI. High-Resolution Computed Tomography (HRCT) in CPFE Diagnosis
Currently, a universally accepted definition of CPFE is lacking. However, High-Resolution Computed Tomography (HRCT) is indispensable for CPFE diagnosis. Diagnostic criteria for CPFE, as proposed by Cottin et al., include HRCT findings of upper-lobe centrilobular and/or paraseptal emphysema with multiple bullae, and lower-lobe honeycombing with subpleural reticular opacities, traction bronchiectasis, and sometimes ground-glass opacities.
Emphysematous Lesions on HRCT
Upper-lobe emphysematous lesions in CPFE predominantly include centrolobular emphysema, paraseptal emphysema, and bullae. Studies report prevalences of 97% for centrolobular emphysema, 93% for paraseptal emphysema, and 54% for bullae in CPFE patients. While emphysema in COPD is typically centrilobular, this type is also common in CPFE, with no significant difference in prevalence between CPFE and COPD. However, paraseptal emphysema is significantly more frequent in CPFE than COPD and is considered a more characteristic feature of CPFE.
Thick-Walled Cystic Lesions (TWCLs)
Thick-walled cystic lesions (TWCLs) are considered unique radiological and pathological features of CPFE. Enlargement of TWCLs may indicate interstitial pneumonia progression. Recent research has observed TWCLs in 72.7% of CPFE patients, but not in patients with IPF or emphysema alone. The extent of emphysema was also found to be greater in CPFE patients with TWCLs compared to those without.
Fibrotic Lesions on HRCT
Lower-lobe fibrotic lesions in CPFE are characterized by honeycombing, reticulation, and traction bronchiectasis as the most frequent imaging features, with reported prevalences of 75.6-95% for honeycombing, 84.4-87% for reticulation, and 40-69% for traction bronchiectasis. Ground-glass opacities are also common in CPFE (62.2-66%), suggesting smoking-related ILD such as desquamative interstitial pneumonia.
HRCT Scoring and Phenotypes
HRCT scoring reveals that total emphysema scores are highest in COPD, and higher in CPFE than IPF. Emphysema scores in CPFE are similar to mild to moderate COPD and lower than severe COPD. Fibrosis scores are generally higher in CPFE and IPF compared to COPD. However, the difference in fibrosis scores between CPFE and IPF remains debated, with some studies showing no difference and others reporting lower fibrosis scores in CPFE, consistent across lung zones.
Recent research comparing CPFE patients with and without airflow obstruction (CPFE OB+ and CPFE OB− groups) has shown that the degree of emphysema, measured by LAA scores on HRCT, is significantly lower in the CPFE OB− group than CPFE OB+ and COPD groups. Conversely, pulmonary fibrosis severity is greater in the CPFE OB− group than CPFE OB+ group. These findings suggest different mechanisms may underlie CPFE clinical phenotypes, potentially classifying them as “emphysema-dominant” or “fibrosis-dominant.”
Distribution Patterns and Diagnostic Challenges
The distribution of emphysema and fibrosis in CPFE patients is not always independent. Distribution patterns in CPFE can include a progressive apical-to-basal transition from emphysema to fibrosis, paraseptal emphysema with fibrosis areas, or separate, independent areas of fibrosis and emphysema. Differentiating emphysema from pulmonary fibrosis on HRCT can be challenging. Wall-thickened emphysematous changes can mimic honeycomb cysts. Furthermore, only about 50% of CPFE patients present with simultaneous emphysema and fibrosis at diagnosis; others may develop the second lesion later. Regular follow-up is therefore essential for patients with suspected CPFE.
These findings highlight CPFE as a heterogeneous disease with potentially distinct phenotypes. The relative contributions of emphysema and fibrosis vary among patients. While Cottin et al.’s diagnostic criteria for CPFE on HRCT emphasize upper-lobe emphysema and lower-lobe fibrosis, they lack specific quantitative methods to assess the degree of each. Standardized quantitative methods for diagnostic criteria in CPFE are needed to improve diagnostic effectiveness and accuracy.
VII. Pulmonary Function Tests (PFTs) in CPFE
CPFE exhibits a distinctive pulmonary function profile, differing from pure emphysema and IPF. It is characterized by unexpectedly preserved lung volumes contrasted with a severely reduced diffusing capacity. Forced Vital Capacity (FVC) and Total Lung Capacity (TLC) values in CPFE are often within relatively normal ranges, while DLco is significantly diminished. The preserved lung volumes may result from the counteracting effects of emphysema-induced hyperinflation and fibrosis-induced restriction. The severe reduction in diffusing capacity likely stems from the combined negative impact of both emphysema and pulmonary fibrosis on gas exchange.
PFT Differences Compared to COPD and IPF
In emphysema/COPD, PFTs typically show increased lung compliance, enlarged lung volumes and residual capacity (RV), reduced maximal expiratory flows, and decreased DLco. Studies generally show that CPFE patients have lower Forced Expiratory Volume in one second (FEV1) and FEV1/FVC ratios, lower RV and TLC, and lower DLco compared to COPD patients. Longitudinal studies on lung function changes reveal that annual decreases in lung volumes (VC and FVC) and gas exchange (DLco and DLco/VA) are significantly greater in CPFE than COPD. However, the annual decrease in airflow limitation (FEV1/FVC) is less in CPFE than COPD. This may be attributed to traction from pulmonary fibrosis in CPFE preventing expiratory airway collapse typical of emphysema, thus supporting small airways.
In pulmonary fibrosis, PFTs typically show decreased lung compliance, reduced TLC, RV, and RV/TLC ratio, with preserved or increased maximal expiratory flow rates and reduced DLCO. CPFE patients generally have higher lung volumes, lower FEV1/FVC ratios, and lower DLco compared to IPF patients. Despite a lower baseline DLco in CPFE, annual rates of decline in DLco and FVC may be lower in CPFE than IPF. The presence and extent of emphysema are significant factors influencing pulmonary function decline in IPF, particularly FEV1/FVC. Longitudinal studies have shown that FEV1/FVC ratio in CPFE decreases over time, while remaining stable in IPF, suggesting CPFE is associated with a progressively obstructive pattern, highlighting the importance of bronchodilator therapy in CPFE.
PFTs and CPFE Phenotypes
Differences in pulmonary function impairment have been reported between CPFE patients with and without airflow obstruction. Diffusion capacity impairment is severe in both groups. Lung hyperinflation and respiratory resistance are lowest in the CPFE OB− group and lower in CPFE OB+ than COPD. CPFE OB+ patients with more emphysema may have worse survival than CPFE OB− patients.
It’s important to note that a normal lung volume with severely reduced DLco pattern on PFTs is not exclusively diagnostic of CPFE. Other conditions such as pulmonary vascular disease, emphysema alone, and ILD alone can also present with this pattern. Only a minority of patients with severely diminished gas exchange capacity may have CPFE; the majority may have emphysema, ILD, or PAH.
VIII. Blood Gas Analysis in CPFE
Resting and exercise hypoxemia are common in CPFE patients due to severely impaired gas exchange capacity. Hypercapnia, however, is rare, with PaCO2 levels usually within normal average ranges. Hypoxemia in CPFE is typically moderate to severe at rest and worsens with exercise. Blood gas analysis in CPFE is distinct from COPD and more similar to IPF. In advanced COPD, gas exchange abnormalities often result in both hypoxemia and hypercapnia, with carbon dioxide retention due to reduced ventilation from severe obstruction and hyperinflation. IPF patients typically present with hypoxemia and increased alveolar-arterial oxygen difference [P(A-a)O2], important diagnostic indicators of IPF. Hypercapnia is uncommon in IPF due to the restrictive, rather than obstructive, pattern.
IX. Other Diagnostic Methods for CPFE
Recent advancements explore novel diagnostic methods for CPFE. M-mode ultrasonography has been proposed as a method to differentiate CPFE. Studies have shown that CPFE patients have the least diaphragmatic motion during deep breathing compared to COPD and IPF patients, with IPF patients showing motion similar to healthy controls. Diaphragmatic motion measurement by M-mode ultrasonography may thus be a useful tool in CPFE diagnosis.
Biomarker research is also exploring specific markers for CPFE differential diagnosis. Club cell secretory protein (CC16), a lung secretory protein, is found to be significantly elevated in CPFE patients and, when combined with KL-6 testing, can effectively differentiate CPFE from emphysema alone. Serum CC16 is known to be elevated in IIP but decreased in COPD smokers. Increased CC16 levels in CPFE further suggest that pulmonary inflammation in CPFE is more similar to pulmonary fibrosis than emphysema, warranting further research to confirm and elucidate the underlying pathogenesis.
X. Complications of CPFE
CPFE is associated with several severe complications that significantly impact prognosis and management.
Pulmonary Arterial Hypertension (PAH)
Pulmonary arterial hypertension (PAH), defined as mean pulmonary arterial pressure (mPAP) >25 mmHg, is a major complication in COPD and IPF, associated with poorer survival. PAH prevalence is reported around 50% in COPD and 31-46% in advanced IPF. In CPFE, PAH prevalence is significantly higher, ranging from 47-90% in studies, exceeding both COPD and IPF. PAH may be present in nearly half of CPFE patients at diagnosis and increase during follow-up. Most CPFE patients develop moderate to severe PAH, while PAH in COPD or IPF is typically mild to moderate. This may be due to the synergistic effect of hypoxic pulmonary vasoconstriction and reduced capillary beds from combined pulmonary fibrosis and emphysema in CPFE.
PAH contributes to the severe dyspnea, impaired gas transfer, and exercise hypoxemia in CPFE, and is a significant predictor of poor prognosis. Higher pulmonary vascular resistance, heart rate, lower cardiac index, and lower DLco are associated with worse outcomes in CPFE-associated PAH. One-year survival rates in CPFE patients with PAH can be as low as 60%. CPFE-associated PAH carries a poorer prognosis than PAH associated with IPF or COPD. Median survival times are shorter in CPFE-PAH compared to IPF-PAH. Five-year survival rates are significantly lower in CPFE-PAH compared to CPFE patients without PAH and COPD-associated PAH.
Lung Cancer
Emphysema and IPF are independent risk factors for lung cancer. Lung cancer incidence is reported at 22.4-31.3% in IPF and 6.8-10.8% in COPD. CPFE, combining features of both and associated with smoking, is also an independent risk factor for lung cancer. Lung cancer prevalence is much higher in CPFE (35.8-46.8%) than in either condition alone, with squamous cell carcinoma being the most common histological type, likely related to the heavy smoking history in CPFE patients.
Lung cancer prevalence is significantly higher in CPFE than COPD and also higher than IPF in some studies. Conversely, CPFE prevalence is higher in lung cancer populations compared to isolated pulmonary fibrosis. Retrospective studies have shown increased lung cancer risk in CPFE and IPF groups compared to emphysema, but no significant difference in lung cancer risk between CPFE and IPF.
CPFE patients with lung cancer have a significantly poorer prognosis than those with emphysema or IPF alone. Median overall survival is shorter in CPFE patients with lung cancer compared to emphysema patients. Lung cancer is also a more frequent cause of death in CPFE compared to IPF.
Lung cancer location differs among CPFE, IPF, and emphysema. Lung cancers in CPFE and IPF predominantly occur in the subpleural area, while in emphysema, they are typically in the upper lung. The similar location in CPFE and IPF suggests emphysema might not have an additive impact on lung cancer development in CPFE, potentially explaining the similar lung cancer risk between CPFE and IPF.
Acute Lung Injury
CPFE may increase the risk of acute lung injury following lung resection surgery or chemotherapy. Studies have shown a high proportion of post-lobectomy ARDS cases occurring in patients with CPFE. A significant percentage of CPFE patients with lung cancer develop acute lung injury during treatment, particularly surgery, chemotherapy, and radiation. Prognosis for these patients is poor, with high mortality rates and short median survival times after acute lung injury onset. Lower transfer factor for carbon monoxide (TLCO), FVC values, and higher fibrosis on HRCT are predictors of acute lung injury after surgery. Preoperative cardiopulmonary function and HRCT assessment are crucial for CPFE patients undergoing lung cancer treatment, along with careful monitoring during surgery, chemotherapy, and radiation due to their lung vulnerability.
XI. Prognosis of CPFE
CPFE syndrome generally carries a poor prognosis, with 5-year survival rates ranging from 35-80%. Median survival times reported in studies vary from 2.1 to 8.5 years. Major causes of death in CPFE include chronic respiratory failure, PAH, acute exacerbation, and lung cancer. Elevated KL-6 levels are predictive of acute exacerbations in CPFE. Pulmonary hypertension is a major determinant of poor prognosis in CPFE, with high mPAP, pulmonary vascular resistance, heart rate, and low DLco associated with worse outcomes.
Mortality in CPFE is higher than in emphysema alone. In patients without malignancy, CPFE has a significantly higher mortality risk than emphysema. However, whether CPFE mortality is higher or lower than IPF alone is less clear. Some studies report worse survival in CPFE compared to IPF, while others show no significant difference. Some research even suggests emphysema might be protective in CPFE, and that pulmonary fibrosis lesions contribute more to CPFE progression than emphysema lesions.
Inconsistent results in prognosis comparisons between CPFE and IPF may be due to the inclusion of heterogeneous chronic interstitial pneumonias in CPFE cohorts, varying enrollment criteria, complications, and the extent and distribution of fibrosis and emphysema. Retrospective data analysis and lead-time bias might also contribute to these inconsistencies.
Predictors of mortality in CPFE include finger clubbing, FEV1/FVC ratio greater than 1.2, and lower FVC. Longitudinal FEV1 decline over 12 months is a strong mortality predictor in CPFE. Composite physiologic index (CPI), useful in IPF prognosis, is less effective in CPFE due to the opposing effects of FEV1 and FVC on CPI calculation.
Paraseptal emphysema has been proposed as a strong independent factor for mortality in CPFE, particularly associated with high estimated systolic pulmonary arterial pressure (esPAP). It’s hypothesized that smoking-induced centrilobular emphysema, with its associated inflammatory cytokines, may have antifibrotic properties, protecting against fibrosis, while paraseptal emphysema represents a different lung response to smoking, leading to more severe fibrosis. Some studies suggest better prognosis in pulmonary fibrosis combined with advanced centrilobular or mixed emphysema compared to paraseptal emphysema or no emphysema. However, these conclusions are debated, and potential biases in research methodologies are considered.
XII. Treatment Strategies for CPFE
Currently, there are no specific, effective treatments for CPFE syndrome. Treatment decisions are generally based on guidelines for emphysema and pulmonary fibrosis individually. Given the role of cytokines in CPFE pathogenesis, cytokine antagonists or alternative therapies might be explored in different disease stages, although clinical validation is needed.
Smoking cessation is paramount for CPFE patients, as it is for COPD and IPF, to potentially halt disease progression. Avoiding other environmental exposures is crucial for those with occupational triggers. Long-term oxygen therapy and vaccinations against influenza and streptococcus pneumonia are recommended to manage hypoxemia and prevent exacerbations and infections. Oxygen therapy is essential for hypoxemia and pulmonary hypertension in CPFE. Inhaled bronchodilators may be used for patients with obstructive or mixed ventilation dysfunction, similar to COPD management. However, bronchodilator efficacy in CPFE remains uncertain and may vary between CPFE patients with and without airflow obstruction. Further research is needed to clarify the relationship between bronchodilator efficacy and airflow obstruction in CPFE.
Systemic corticosteroids and immunosuppressant therapy may be considered for CTD-associated CPFE. However, randomized controlled trials are lacking, and high mortality risks due to infections have been reported with corticosteroid use in CPFE. Immunosuppressive therapy might be reasonable for patients with evidence of active inflammation, such as ground-glass opacities. N-acetylcysteine has been suggested for CPFE patients with UIP patterns, but evidence for its efficacy is limited. Triple therapy with N-acetylcysteine, prednisolone, and azathioprine, once considered for IPF, is now discouraged due to increased risks of death and hospitalization.
Pirfenidone, an approved treatment for mild to moderate IPF, has shown promise in improving progression-free survival and slowing FVC decline in IPF. It is generally well-tolerated in IPF patients, including those with cardiovascular diseases and emphysema. However, its efficacy in CPFE is not well-established and requires further prospective studies.
Nintedanib, a multi-tyrosine kinase inhibitor, is also approved for IPF treatment. Clinical trials have shown it reduces annual FVC decline in IPF, including patients with early disease, no honeycombing, and/or concomitant emphysema, with a trend towards reduced mortality. While promising for IPF management, its effectiveness in CPFE remains unknown and requires clinical trials.
Specific pulmonary hypertension therapies like endothelin-1 receptor antagonists, prostanoids, or phosphodiesterase type 5 inhibitors have been used for PAH in CPFE, but clinical trials have generally shown no benefit and may worsen hypoxemia. Long-term oxygen therapy remains the primary recommended treatment for PAH in CPFE. Lung transplantation may be the only effective option for advanced CPFE to improve survival.
XIII. Conclusions: Enhancing CPFE Diagnosis and Awareness
Whether CPFE is merely a coincidence of smoking-related lung diseases or a distinct clinical entity with shared genetic or environmental factors is still debated. However, most researchers lean towards considering CPFE a unique entity. CPFE remains under-recognized and may be overlooked due to unexpectedly normal lung volumes. Clinicians should be vigilant for CPFE in patients presenting with severely impaired diffusing capacities disproportionate to lung volumes, or pulmonary hypertension with mixed obstructive/restrictive lung function, particularly in smokers or former smokers. Establishing specific clinical diagnostic and classification criteria for CPFE is crucial. Further research into CPFE pathogenesis, pathophysiology, and prognostic factors is urgently needed to develop novel and effective diagnostic and therapeutic strategies for this complex syndrome.
XIV. Acknowledgements
Funding: This study was supported by the National Natural Science Foundation of China (Grant No. 81370120) and by the Guangdong Natural Science Foundation (Grant No. S2013010014803).
Disclosure: The authors declare no conflict of interest.
