Combined pulmonary fibrosis and emphysema and lung transplantation: current evidence and future directions

Introduction

Combined pulmonary fibrosis and emphysema (CPFE) is pulmonary condition that arises from the co-occurrence of lung emphysema and pulmonary fibrosis (1). Initially, the fibrotic aspect of the disease was identified as usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF). However, other fibrosis patterns have also emerged in conjunction with emphysema (1-3). Hence, the existence of IPF is not a mandatory criterion for diagnosing CPFE. A recent overview has summarized the various interstitial lung patterns observed in CPFE (4).

In individuals with severe emphysema, detecting the fibrotic aspect can be challenging. Conversely, in patients with primarily fibrotic presentations, the emphysematous component might be disregarded.

Proper categorization of individuals with CPFE holds significance in both pre- and post-transplant phases due to the following reasons:

First, the restrictive fibrotic element, may offset the emphysematous component, which is obstructive, resulting in a potential underestimation of pulmonary obstruction and a relative retention of lung function during pulmonary function tests. The ISHLT consensus document outlines the lung function criteria that should be met for a patient to be referred and considered for lung transplantation (5). In interstitial lung disease, a forced vital capacity (FVC) of <80% of predicted or diffusing capacity for carbon monoxide (DLCO) of <40% is one of the criteria for referral and consideration of lung transplantation (5). In chronic obstructive pulmonary disease (COPD), the lung function criterion is a forced expiratory volume in 1 second (FEV1) <25% (5). In case of CPFE, the lung function capacities and DLCO can appear better as the restrictive component may be underestimated due to the concurrent obstructive component, and vice versa, resulting in a relatively preserved lung function, that underestimates the severity of CPFE. Consequently, this can delay the referral of patients to a lung transplant center.

Secondly, individuals with CPFE often experience severe pulmonary hypertension (6), which has a higher mortality rate on the lung transplant waiting list compared to those without it (7-9). Furthermore, individuals with CPFE and pulmonary hypertension have an elevated risk of perioperative complications during lung transplantation (10-13). In individuals with severe emphysema, non-invasive measurements like Doppler echocardiography may underestimate the severity of pulmonary hypertension (14,15). Additionally, individuals with CPFE are at an increased risk of lung allograft dysfunction (15). However, a study conducted by Takahashi et al., which included 27 CPFE patients who underwent lung transplantation, demonstrated that this did not impact their survival (15).

Consequently, we conducted a retrospective examination of individuals who underwent lung transplantation for either interstitial lung fibrosis or emphysema. We reviewed their computed tomography (CT) scans to identify patients with CPFE who were previously undiagnosed. Our hypothesis was that our patient cohort might contain undetected cases of CPFE and that CPFE patients would have a higher incidence of pre-transplant pulmonary hypertension and post-transplant chronic lung allograft dysfunction (CLAD). We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1200/rc).

Methods

Study design and setting

This is a single-center, retrospective cohort study, performed at the University Hospital Zurich, Switzerland. Between January 1, 2013, and December 2021, a total of 133 consecutive adult bilateral lung transplantations were performed. In this cohort, all pre-transplant CT scans, initially assessed by a team of radiology consultants, in patients with either pulmonary fibrosis or pulmonary emphysema were reviewed by an expert thoracic radiologist (T.F., Head of Department).

Patients were eligible for inclusion if they provided informed consent, were at least 18 years of age and had undergone a lung transplantation with a preoperative diagnosis of interstitial lung disease, COPD/emphysema or CPFE. Patients in which a pre-transplant chest CT scan was not available were excluded. Data regarding donors and recipients were retrieved retrospectively from the medical records of the University Hospital of Zurich. All patients provided written informed consent. The protocol of the current study was approved by the Zurich branch of the Swiss Ethics Committee with the protocol number 2022-00457. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Diagnostic criteria of CPFE

CPFE was diagnosed according to the criteria by Cottin et al. (3), and the proposed research definition of CPFE according to the ATS/ERS/JRS/ALAT Research Statement (1), requiring the following two criteria:

• The presence of emphysema on CT scan, defined as well-demarcated areas of decreased attenuation in comparison with contiguous normal lung and marginated by a very thin (0.1 mm) or no wall, and/or multiple bullae (0.1 cm) with upper zone predominance, and
• The presence of a diffuse parenchymal lung disease with significant pulmonary fibrosis on CT scan, defined as reticular opacities with peripheral and basal predominance, honeycombing, architectural distortion and/or traction bronchiectasis or bronchiolectasis; focal ground-glass opacities and/or areas of alveolar condensation may be associated but should not be prominent.

Pre- and post-transplant pulmonary function testing

The pulmonary function testing was performed according to the ATS/ERS guidelines (16). The single breath diffusing capacity was measured using the ATS/ERS standards.

Pre-transplant pulmonary hypertension screening

As part of the lung transplant screening process, patients have been screened in the pre-transplant period for pulmonary hypertension by right heart catheterization (17).

CLAD

The Consensus Report from the Pulmonary Council of the ISHLT was used to define CLAD in our patient cohort (18).

Outcomes

Our hypothesis for this study was that there might be an overlooked number of patients in our cohort of ILD and COPD/emphysema who should be classified as CPFE.

The primary outcome of our study was the incidence of CPFE among ILD and COPD/emphysema patients that underwent lung transplantation. The secondary outcome of this study was to compare the pulmonary function, diffusing capacity, incidence of pulmonary hypertension by invasive measurement, and CLAD stages between CPFE and non-CPFE patients in our cohort. Additionally, we also compared the postoperative FEV1 values.

Statistical analysis

We employed descriptive statistics to present the patient characteristics and the overall results of our study. Data analyses were performed using IBM SPSS Statistics version 28.

Results

Pre-transplant radiological diagnosis

Out of the 133 individuals who underwent lung transplantation, 67 patients (50.4%) were diagnosed with COPD/emphysema based on radiological assessments, while 66 patients (49.6%) exhibited interstitial lung disease. In this cohort, 113 patients were evaluable for the study.

Table 1 displays the demographic details of the patients.

In patients with interstitial lung disease, the majority exhibited a UIP/IPF pattern (n=44, 38.9%).

Upon review of the pre-transplant chest CT scans, CPFE was identified in 12 patients (10.6%), the majority of whom had previously been diagnosed with either COPD/emphysema (n=3, 25%) or interstitial lung disease (n=3, 25%). Table 2 presents the other radiological diagnoses prior to the review.

Pre-transplant pulmonary function testing

Despite the limited number of CPFE patients and only descriptive statistical analysis has been performed, there was no apparent difference in lung functional restriction, as indicated by the total lung capacity (TLC) measured via body plethysmography, between CPFE and non-CPFE fibrosis (Table 1). The patients with emphysema (mean DLCO 28%) and CPFE (mean DLCO 28%) had the lowest diffusing capacity (DLCO), while patients with non-CPFE fibrosis had a better mean DLCO (35.3%). Nonetheless, after adjusting for alveolar volume (VA), the DLCO/VA (also referred to as KCO) was relatively preserved in CPFE patients relative to those with non-CPFE fibrosis.

Pre-transplant pulmonary hypertension screening

Table 1 illustrates that the mean invasively measured mean pulmonary artery pressure (mPAP) was comparable between patients with CPFE and those with non-CPFE fibrosis, with a propensity for mPAP to be lower in individuals with emphysema.

Pre-transplant smoking history

Patients with CPFE and emphysema had a comparable smoking history (Table 1).

Post-transplant lung function (FEV1)

We compared the baseline FEV1 across the different groups, calculated as the average of the two best post-operative FEV1 measurements taken at least three weeks apart. The FEV1 values appeared similar among patients with CPFE (mean FEV1: 2.58 L), non-CPFE fibrosis (2.49 L), non-CPFE emphysema (2.62 L), non-CPFE fibrosis and emphysema (2.59 L), and non-CPFE tree-in-bud (2.81 L).

CLAD

The most common CLAD stage in patients with CPFE, non-CPFE fibrosis and non-CPFE emphysema was stage 0, followed by stage 1. In CPFE patients, 84% had either CLAD stage 0 or 1, while in non-CPFE fibrosis and non-CPFE emphysema patients, this percentage was 81% and 75%, respectively (Table 3). In patients with CPFE, 4 individuals (33%) exhibited CLAD, with either phenotype bronchiolitis obliterans (BOS) or restrictive allograft syndrome (RAS).

Two patients were diagnosed with BOS (in CLAD stage 1 and 2, respectively). The other two patients exhibited RAS, with one in CLAD stage 1 and the other in stage 3.

Discussion

Our study aimed to investigate the potential presence of CPFE among patients who had undergone lung transplantation and were initially diagnosed with ILD or COPD/emphysema. Upon revising the radiological diagnoses of our cohort, which comprised 113 evaluable patients with ILD or COPD/emphysema, we reclassified 12 patients (10.6%) as having CPFE. This reclassification highlighted the likelihood of an underestimation of CPFE within our initial classifications of ILD and COPD/emphysema patients, signaling the imperative for further exploration into the prevalence and clinical implications of this distinct disease entity.

Following this reclassification, we conducted a comparative analysis between patients identified as CPFE and those categorized as non-CPFE within our cohort. Our analysis aimed to assess various parameters, including pulmonary function, diffusing capacity, incidence of pulmonary hypertension via invasive measurements, and the stages of CLAD.

Comparative analysis between CPFE and non-CPFE patients

In contrast to findings in the literature, we did not observe clinically relevant differences between the restriction in lung function of patients with CPFE versus non-CPFE fibrosis.

Regarding CO-diffusing capacity, CPFE exhibited greater similarity to emphysema than to non-CPFE fibrosis, and this trend was also observed for FEV1/FVC.

Regarding invasively measured pulmonary hypertension, our findings did not reveal relevant differences between the patients with CPFE, non-CPFE fibrosis and non-CPFE emphysema, which is contrary to findings in other studies. This convergence in pulmonary hypertension incidence further emphasizes the need for a comprehensive understanding of CPFE’s underlying mechanisms and clinical implications in the context of lung transplantation.

Similarly, CLAD did not differ among patients with CPFE, non-CPFE fibrosis and non-CPFE emphysema. The limited number of cases underscores the necessity for larger studies to unravel potential associations between CPFE and the development of CLAD post-lung transplantation.

Specific aspects such as epidemiology, risk factors, complications, and comorbidities warrant detailed attention, to be expounded upon in subsequent sections. Additionally, we present two cases from our study where patients initially diagnosed with COPD and UIP, respectively, were ultimately re-diagnosed with CPFE (Figures 1,2).

Figure 1 Patient initially classified as COPD. Axial CT images show apical emphysema and basal reticulation, confirming CPFE. COPD, chronic obstructive pulmonary disease; CT, computed tomography; CPFE, combined pulmonary fibrosis and emphysema.

Figure 2 Patient initially classified as UIP. Axial CT image show bulleous and paraseptal emphysema and basal reticulation and honey combing leading to reclassification. UIP, usual interstitial pneumonia; CT, computed tomography.

Epidemiology

The prevalence of CPFE in a lung transplant cohort is uncertain. However, in patients with IPF, the reported incidence ranges from 8% to 67% (1,19-28). There have been reports of geographic variation in the prevalence of CPFE, with the highest rates observed in Asia. However, since our hospital’s transplant cohort comprises only Swiss residents, who are predominantly of Caucasian descent, this may account for the relatively lower prevalence of CPFE in our study.

Risk factors

While CPFE has been reported to occur approximately nine times more frequently in males with a male predominance of 73–100%, our study demonstrated only a slightly higher proportion of males (1). Connective tissue disease (CTD) is another significant risk factor for CPFE (29,30). However, the CPFE patients in our study were found to have no evidence of CTD. Table 1 indicates that CPFE patients had a higher number of pack-years than non-CPFE fibrosis patients, highlighting smoking as another significant risk factor for CPFE. Previous research has also suggested a dose-response relationship between the number of pack-years and the risk of CPFE, as reported in several studies (1,23,31-33).

Complications and comorbidity

The two main complications in CPFE are lung cancer and pulmonary hypertension (4). Various comorbidities such as DM, coronary artery disease, and peripheral vascular disease have been reported (1,34,35). However, in our study, neither pre-transplant nor post-transplant DM was observed in CPFE patients. It should be noted that coronary artery disease and peripheral vascular disease were not assessed in our study.

Limitations of this study

The primary limitations of this study are its retrospective, single-center design, and the small sample size of CPFE patients. Additionally, potential selection bias may have occurred since older CPFE patients and those with multiorgan disease may not have been referred to our lung transplant center. However, it’s worth noting that patients with mild disease may also not have been referred to our center, which means they were not included in our study.

Future directions

New imaging techniques have facilitated early diagnosis of CPFE and improve differentiation between CPFE and both IPF and emphysema (36-39). In their study, Fleming et al. demonstrated the potential of late gadolinium-enhanced (LGE) thoracic magnetic resonance imaging (LEG-MRI) to differentiate CPFE from pure emphysema (36). They proposed that this imaging technique could be an effective supplementary test to HRCT for patients suspected of having CPFE (36). Chan et al. used MRI with inhaled hyperpolarized helium 3 (³He) to explore functional and structural imaging of the lungs. By using hyperpolarized gas diffusion weighted (DW) MRI, they could evaluate microstructural acinar changes in the lungs non-invasively and obtain quantitative measurements of such changes (37). Other experimental and quantitative imaging techniques have been reviewed extensively (38).

In addition, there is a need for histopathological criteria for CPFE, and the use of specific biomarkers could be beneficial. Accurate diagnosis of CPFE could prove valuable in patients who do not yet require lung transplantation, as it would enable the exploration of alternative treatment options, such as antifibrotics, inhaled corticosteroids, or pulmonary rehabilitation. In conclusion, further research in this area is necessary to improve the understanding of CPFE and identify effective treatment options for patients.

Conclusions

Our study highlights the potential underestimation of CPFE in patients undergoing lung transplantation initially diagnosed with ILD or COPD/emphysema. By reclassifying 12 patients (10.6%) as having CPFE, we emphasize the need for greater awareness of this disease in clinical practice. Although our comparative analysis did not reveal significant differences in pulmonary function, pulmonary hypertension, or CLAD between CPFE and non-CPFE patients, the small sample size underscores the necessity for larger studies to clarify these associations. Additionally, a smoking history was identified as a key risk factor, while other known risk factors like CTD were not observed in our cohort. Future research should focus on refining diagnostic criteria, utilizing advanced imaging techniques, and exploring alternative treatments for CPFE. Expanding our understanding of the epidemiology, complications, and comorbidities of CPFE will ultimately contribute to improved management and outcomes for affected patients.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1200/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1200/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1200/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1200/coif). T.F. reports speakers Bureau for Bracco and Bayer, Advisory Board Agta. C.F.C. reports payment from AstraZeneca, Boehringer Ingelheim, CSL Behring, Dalichi Synkyo, GlaxoSmithKline, Novartis, Sanoti, OM Pharma, MSD, Grifols, Vifor. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Zurich branch of the Swiss Ethics Committee with the protocol number 2022-00457. Informed consent for data usage was obtained from all patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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