Combined pulmonary fibrosis and emphysema: The many aspects of a cohabitation contract

Accepted Manuscript Combined pulmonary fibrosis and emphysema: The many aspects of a cohabitation contract Andriana I. Papaioannou, Konstantinos Kostikas, Effrosyni D. Manali, Georgia Papadaki, Aneza Roussou, Likurgos Kolilekas, Raphaël Borie, Demosthenis Bouros Prof, Spyridon A. Papiris PII:

S0954-6111(16)30081-6

DOI:

10.1016/j.rmed.2016.05.005

Reference:

YRMED 4910

To appear in:

Respiratory Medicine

Received Date: 29 November 2015 Revised Date:

20 March 2016

Accepted Date: 5 May 2016

Please cite this article as: Papaioannou AI, Kostikas K, Manali ED, Papadaki G, Roussou A, Kolilekas L, Borie R, Prof DB, Papiris SA, Combined pulmonary fibrosis and emphysema: The many aspects of a cohabitation contract, Respiratory Medicine (2016), doi: 10.1016/j.rmed.2016.05.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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ACCEPTED MANUSCRIPT Title: Combined Pulmonary Fibrosis and Emphysema: The many aspects of a cohabitation contract Andriana I Papaioannou MD1, Konstantinos Kostikas MD1, Effrosyni D Manali MD1, Georgia Papadaki MD1, Aneza Roussou MD1, Likurgos Kolilekas MD2,

1 nd

2

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Raphaël Borie MD3, Demosthenis Bouros Prof4, and Spyridon A Papiris Prof1 Respiratory Medicine Department, “Attikon” University Hospital, Athens

Medical School, National and Kapodistrian University of Athens, Greece [email protected],

[email protected],

[email protected],

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[email protected], [email protected], [email protected] 2 th

7 Department of Pneumonology, “Sotiria” Chest Diseases Hospital, Athens, Greece,

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[email protected]

APHP, Hôpital Bichat, DHU FIRE Service de Pneumologie A, Centre de

compétence des maladies pulmonaires rares, INSERM, Unité 1152, Université Paris Diderot, Paris, France, [email protected] 4 st

1 Respiratory Medicine Department, “Sotiria” Chest Diseases Hospital, Athens,

Medical School, National and Kapodistrian University of Athens, Greece,

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[email protected], [email protected] Corresponding author

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Prof Spyridon A Papiris

2nd Respiratory Medicine Department Attikon” University Hospital, Athens Medical

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School, National and Kapodistrian University of Athens, Greece Email: [email protected]

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ACCEPTED MANUSCRIPT Abstract Combined pulmonary fibrosis and emphysema (CPFE) is a clinical entity characterized by the coexistence of upper lobe emphysema and lower lobe fibrosis. Patients with this condition experience severe dyspnea and impaired gas exchange with preserved lung volumes. The diagnosis of the CPFE syndrome is based on

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HRCT imaging, showing the coexistence of emphysema and pulmonary fibrosis both in varying extent and locations within the lung parenchyma. Individual genetic background seem to predispose to the development of the disease. The risk of the development of pulmonary hypertension in patients with CPFE is high and related to

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poor prognosis. CPFE patients also present a high risk of lung cancer. Mortality is significant in patients with CPFE and median survival is reported between 2.1 and 8.5

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years. Currently, no specific recommendations are available regarding the management of patients with CPFE. In this review we provide information on the existing knowledge on CPFE regarding the pathophysiology, clinical manifestations, imaging, complications, possible therapeutic interventions and prognosis of the

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disease.

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ACCEPTED MANUSCRIPT Introduction Pulmonary emphysema and idiopathic pulmonary fibrosis (IPF) are two distinct entities defined by different clinical, functional, radiological, and pathological criteria 1

. IPF is the most common of the idiopathic interstitial lung diseases (i-ILD) and has

the histopathologic and/or radiologic pattern of usual interstitial pneumonia (UIP) 2.

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Emphysema is defined as an enlargement of the air spaces distal to the terminal bronchioles due to the destruction of tissues forming their walls 3. These two distinct entities coexist in a condition characterized by upper lobe emphysema and lower lobe pulmonary fibrosis and it is therefore called combined pulmonary fibrosis and

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emphysema (CPFE). The coexistence of the two conditions which are considered to have different pathophysiological and functional characteristics, results in the development of a separate disease entity with distinct clinical and functional

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characteristics and different prognosis compared to its individual components4 . (Figure 1)

The histopathologic co-existence of pulmonary fibrosis and emphysema was first reported in 1974 by Auerbach and colleagues 5 who first described the presence of both entities in the lungs of smokers at autopsy. Following this, in 1990 Wiggins et

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al described eight patients noticing not only the combination of the two different entities in CT but also that these patients were characterized by low diffusing capacity for carbon monoxide (DLCO) and preserved lung volumes 6. In the following years, several reports described patients with the coexistence of the two diseases7,8,

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supporting the idea that this was the coincidental occurrence of first emphysema and at later age of IPF, in smokers with great smoking history7. However, it was only on

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2005, that the combination of pulmonary fibrosis and emphysema was characterized as a distinct entity1 and nowadays several studies are taking place for the better understanding of the pathophysiology of this condition as well as the possible genetic predisposing factors and the biological pathways which probably lead to its development.

Although several review papers on CPFE have been already published, the aim of the present review is to update recent information in this field, and to systematically describe the many aspects of CPFE discovered as the scientific community gets clinically better acquainted with the syndrome.

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ACCEPTED MANUSCRIPT Prevalence and Clinical manifestations CPFE is a disease that is increasingly recognized during the latest years 9. It has been reported that emphysema complicates IPF in approximately 30% of patients

10,11

. On

the other hand, in the COPD Gene Study Group (a mass screening study on smokers in the United States) it has been reported the presence of interstitial shadowing or

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radiologically overt interstitial pneumonia on HRCT of a great percentage of subjects with COPD 12,13

CPFE seems to occur most often in males after the sixth decade of life (mean 6,14,15

. Usually patients are current or ex-smokers with a smoking

history greater than 40 pack years

15,16

. However, CPFE has been also described in 17,18

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age of 65 years)

non-smokers in which was found to be related to mutations

. The association of

predisposition to the disease 19

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CPFE with connective tissue diseases even in non-smokers also shows the genetic

Patients usually present with severe dyspnea, mainly on exertion, which is associated with significant functional limitation and desaturation during exercise 1. Other manifestations, including cough, sputum production, and chest pain, are less often 1. Physical examination might reveal basal crackles and finger clubbing, while

Pathogenesis

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wheezes can also occur in some cases 1,14

The exact mechanism which leads to the coexistence of pulmonary fibrosis and

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pulmonary emphysema is not fully understood. It is still unclear whether the coexistence of two different entities is nothing more than a “cohabitation” or if there

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is a result of common mechanisms which lead to the development of both types of lesions. It has been supported that CPFE might be the result of the interaction of an environmental trigger (such as cigarette smoking) in patients with a genetic predisposition20,21. Smoking is known as the main cause of the development of emphysema and pulmonary fibrosis22 and also the majority of CPFE patients seem to be current or ex-smokers

15,16

. Studies have shown that smoking causes induction of

several epigenetic changes in the methylation of DNA which has been found to occur in both emphysema and IPF 23,24 while CPFE patients seem to have a greater smoking history compared to patients with lone IPF 10,25-27. It is worth to mention that there are few case reports that associate the development of CPFE in patients with certain occupational exposures such as in welders and coal workers28,29.

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ACCEPTED MANUSCRIPT Oxidative stress seems to be another probable risk factor for the development of both conditions

30,31

. In the case of emphysema, oxidative stress mainly caused by

cigarette smoking results in the development of cellular injury and apoptosis31, while in the case of pulmonary fibrosis cellular injury results in activation of fibroblasts and myofibroblasts as well as in the deposition of extracellular matrix32.

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Accelerated lung aging has been also proposed as a possible mechanism of the development of both pulmonary fibrosis and pulmonary emphysema22, and markers of senescence such as telomere shortening have been described in both conditions33

34

.

Another common mediator in both diseases is transforming growth factor- β (TGF-β) and although is known as a major regulator of fibrosis, it has been recently found to

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also play a significant role in the development of emphysema35. Finally, neutrophil elastases have been suggested to represent a common pathogenic link between

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emphysema and fibrosis by acting as a regulatory factor which leads to the expression of soluble cytokines with mitogenic activity for mesenchymal cells resulting either in

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emphysema or in fibrosis or both36.

Radiological characteristics/Imaging studies Characteristically, on chest x-rays of CPFE patients lung volume is maintained although there is obvious reticulation in bilateral lower lung fields 37. The diagnosis of

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the CPFE syndrome is based on HRCT imaging which shows the coexistence of emphysema (mainly in the upper zones of the lungs) and pulmonary fibrosis subpleural

reticular

opacities,

honeycomb

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(including

images

and

traction

bronchiectasis) in the lower lung zones 1. Emphysematous lesions in CPFE patients include the presence of either diffuse (centrilobular and/or bullous) emphysema or paraseptal emphysema with predominance in the subpleural areas

38,39

. While UIP

seems to be the most common reported finding in the assessment of the fibrotic aspect of CPFE, studies have shown that the imaging findings are heterogeneous 40. Patients with CPFE except from HRCT patterns of UIP, might also have patterns of fibrotic non-specific interstitial pneumonia (f-NSIP)

1,20,37

. A study of Cottin et al has shown

that the most frequent observations in HRCT of patients with CPFE were honeycombing (present in 95% of cases), reticular intralobular opacities (present in

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ACCEPTED MANUSCRIPT 87% of cases) and traction bronchiectasis (present in 73% of cases) 1. The zones of fibrosis and emphysema might be completely separated (emphysema in the upper zones and fibrosis in the bases (Figure 2 a-c), or to have a progressive transition between them (Figure 3 a-c). Finally, paraseptal emphysematous lesions might be also present at the bases of the lungs within the fibrotic lesions38 (Figure 4 a-c). Ground 1

and seem to be more frequent in CPFE patients

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glass opacities may be present

compared to patients with fibrosis only16 and could be attributed to smoking-related changes like desquamative interstitial pneumonia (DIP). Air-space consolidation and micronodules although reported, are rare

1

and could represent respiratory

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bronchiolitis-interstitial lung disease (RB-ILD) lesions related to smoking.

A distinct radiological feature of CPFE is the presence of large thick-walled cystic lesions

41

. These cysts are larger than honeycombing (they measure at least 1

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cm in diameter) and are delineated by a 1-mm-thick wall. They can be situated either in the upper lungs just beneath the chest wall or grow within the areas of reticulation 37

and/or honeycombing

(Figure 5 a-c and Figure 6 a-c). These thick-walled large

cysts probably represent the development of pulmonary fibrosis within the emphysematous lung, and seem to be enlarged due to retraction forces in the fibrotic

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lesions 38. It is important to note that these cystic lesions do not seem to be present in patients with IPF or emphysema alone and thus, they should probably be considered as an important radiological feature of CPFE 41. Finally, it has been also reported that the extent of emphysema in CPFE patients with these large thick-walled cystic lesions

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was greater than that in patients without such lesions 41. In a previous study Matsuoka et al have shown that the morphological disease

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progression in CPFE differed significantly from that of emphysema alone or fibrosis alone, whereas CPFE provided a more rapid increase in the emphysematous low attenuation lesions and the percentage of destructed area 42. Other findings of CPFE in HRCT include centrilobular nodules which

correspond to airway-centered fibrosis, (i.e. fibrotic changes along the respiratory bronchioles) and subpleural curvilinear opacities

37

. Since CPFE is often related to

lung cancer, possible nodules or masses which might appear in the lung parenchyma should be carefully interpreted

37

. Finally, since CPFE is also related to the

development of pulmonary hypertension, important findings in the CT scans might be the dilatation of the central pulmonary arteries, the enlargement of the right heart, the reduction of peripheral branches of the pulmonary arteries and the mosaic appearance

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ACCEPTED MANUSCRIPT of the pulmonary parenchyma.

37,43

. The later however, might be difficult to observe

because of the fibrotic lesions in the pulmonary parenchyma

37,43

The main

radiological characteristics of CPFE are summarized in Table 1

Pathophysiology (lung volumes, pulmonary function tests)

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The pulmonary function tests of patients with CPFE are characterized by the preservation of spirometric values and static lung volumes and the significant reduction of the diffusion capacity of carbon monoxide (DLCO)

16,44,45

. The reason

for the relatively normal spirometric values observed in CPFE is the result of a

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counterbalance between the restrictive effects of pulmonary fibrosis and the hyperinflation caused by emphysematous lesions. Thus, the increased traction caused by pulmonary fibrosis supports the small airways and prevents the airway collapse,

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which is normally seen in emphysema, resulting in this way to the preservation of the forced expiratory volume in one second (FEV1)

46

. On the other hand, the severe

impairment of gas exchange observed in CPFE is the result of the reduced vascular surface area and pulmonary capillary blood volume, caused by both fibrotic and emphysematous lesions, in combination with the alveolar membrane thickening

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caused by the fibrotic lesions 46. The degree of the preservation of spirometric values depends on the extent of the emphysematous and fibrotic lesions and it has been shown that some CPFE patients have airflow obstruction (defined as a postbronchodilation FEV1/FVC ratio ≤70%)

44

. Furthermore, the extent of fibrosis and

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emphysema seems to correlate with the reduction in DLCO and the degree of pulmonary hypertension while the different patterns of the disease on HRCT

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correspond to specific changes on pulmonary function tests.38 In order to predict mortality in patients with IPF Wells et al have developed a

composite physiologic index (CPI) 47 .The formula for the CPI was as follows: extent of disease on CT = 91.0 - (0.65 x percent predicted diffusing capacity for carbon monoxide [DLCO]) - (0.53 x percent predicted FVC) + (0.34 x percent predicted FEV1). However, in a study which included patients with CPFE the CPI was not able to predict mortality and FEV1 was found to be the best predictor of mortality 48. Regarding the annual changes of pulmonary function CPFE patients show a significantly more rapid decrease in FEV1/FVC compared to patients with IPF only 49 and a significantly higher decrease in VC and FVC compared to patients with

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ACCEPTED MANUSCRIPT emphysema only 50. FVC values seem to decline rapidly over time and are affected by the extent of the fibrotic lesions 51. Annual decrease in FEV1/FVC in patients with CPFE seems to be lower than in those with only emphysema

50

. Although the annual decrease in DLCO does not

CPFE patients compared to patients with only emphysema 50.

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differ between patients with CPFE and those with IPF only 49, it seems to be higher in

In CPFE patients there is a significant correlation between DLCO% predicted and both the extent of emphysema in the upper lobe or the degree of fibrosis in the lower lobe suggesting that both fibrosis and emphysema contribute to the 51

. However, there is no correlation

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disproportionate reduction in gas exchange

between the degree of diffusion impairment and degree of dyspnea 52.

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Regarding lung mechanics, the measurement of multifrequency forced oscillation technique has shown that whole-breath resistance is significantly lower in patients with CPFE compared to patients with fibrotic interstitial pneumonia or emphysema alone and this difference occurred irrespectively of the severity of airflow limitation although expiratory flow limitation in CPFE patients is significantly higher than in those with fibrotic interstitial pneumonia and lower than in patients with only 53

. When diaphragmatic motions were measured using M-mode

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emphysema

ultrasonographic images, CPFE patients showed lower diaphragmatic motions compared both to patients with only emphysema and to those with only fibrosis both during quiet breathing and deep breathing. Emphysema and not fibrosis seemed to be

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the main cause of limited diaphragmatic motion in patients with CPFE 54.

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Pathological findings

The radiological characteristics of CPFE correspond to pathologic features of

destructive pulmonary alterations seen in smokers (i.e. emphysema and fibrosis) Wright et al.

55

37

.

described 2 main types of smoking-related interstitial lung disease.

The first, the so-called diffuse form, includes an overlap of pulmonary emphysema and fibrotic interstitial pneumonia (either UIP or f-NSIP). The second, named as the localized form, includes the presence of emphysema with fibrosis, air space enlargement with fibrosis, or occult fibrosis of smokers

55

. Although pulmonary

emphysema is by definition air space enlargement without fibrosis, Wright described

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ACCEPTED MANUSCRIPT frequently varying degrees of pulmonary fibrosis in the alveolar septa around the emphysema wall

55

. Fibrotic lesions can be also identified along bronchioles around

the emphysematous areas 56. Post-mortem observations have shown the presence of thick-walled cystic lesions involving one or more acini. These cystic lesions are characterized by dense

normal alveoli

41

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wall fibrosis and occasional fibroblastic foci surrounded by honeycombing and and have been previously described as lesions of emphysema with

fibrosis 55 or as air space enlargement with fibrosis 57.

In a previous study, Katzenstein et al.58 described the presence of varying

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degrees of alveolar septal widening by collagen deposition along with emphysema and respiratory bronchiolitis in the lungs of smokers; a change that they designated as

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occult fibrosis of smokers or smoking-related interstitial fibrosis (SRIF). This lesions of fibrosis occurred both in subpleural and in deeper parenchyma and surrounded emphysematous lesions, but they also involved non-emphysematous parenchyma 58. In summary, although the clinical definition of CPFE pathologically is characterized by the coexistence of emphysema and fibrotic interstitial pneumonia (UIP and f-NSIP patterns), pathological studies have also shown a multiplicity of

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fibrotic and non-fibrotic lesions such as SRIF, characterized by airspace enlargement with fibrosis known as desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis- interstitial lung disease (RBILD) 1,40,46,56. Pathological characteristics of

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CPFE are summarized in Table 2

Cytokines in CPFE

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Several cytokines have been studied regarding their role and expression in patients with CPFE. Animal studies have shown that overexpression of mediators such as tumor necrosis factor-a (TNF-a), platelet-derived growth factor-b (PDGF) transforming growth factor beta (TGF-β)

60

59

and

can result to airspace dilatation and

fibrosis 61.

CPFE patients seem to have lower LDH levels and higher levels of CRP in serum compared to patients with IPF only, while these two groups do not seem to differ regarding the levels of KL-6 and Surfactant Protein D (SP-D) 11. On the other hand, patients with CPFE have been found to express higher serum concentrations of CC16, SP-D, and KL-6 compared to healthy controls and patients with only

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ACCEPTED MANUSCRIPT emphysema

62

. In CPFE patients, SP-D levels correlate to FEV1 and mean systolic

pulmonary artery pressure

62

whereas the combination of KL-6 and SP-D was found

to correlate with markers of pulmonary function tests 63. Serum KL-6 levels have been also found to be predictors of acute exacerbations in patients with CPFE

64

. Finally,

the combination of CC16 and KL-6 levels was a good predictor of CPFE 62.

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Patients with CPFE have been found to have increased absolute numbers of neutrophils and increased concentrations of CXCL5 and CXCL8 in BAL compared to patients with IPF alone11. Furthermore, CXCL8 concentrations in BAL fluid significantly correlated to the extent of emphysema on HRCT and to the number of

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accumulation in the airspaces of CPFE patients 11.

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neutrophils in BAL suggesting a possible role of this chemokine on neutrophil

Genetics

Studies suggest that the development of CPFE is the result of the combination of genetic predisposition and environmental exposure (such as smoking) in susceptible individuals. More specifically, the continued damage of alveolar epithelial cells leads to attempts of alveolar regeneration and uncontrolled fibrosis proliferation fibrosis 9.

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and parenchymal destruction resulting in a vicious cycle of continuous damage and

Individual genetic backgrounds seem to predispose to the development of CPFE. A polymorphism in the promoter of the matrix metalloproteinase-1 gene, has

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been identified in smokers 65 and it has been hypothesized that such pathway might be dysfunctional in patients with CPFE. However, CPFE has been also described in non-

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smokers in which was found to be related to genetic mutations of surfactant proteins, whereas mutation in the telomerase complex could predisposed smokers to CPFE 17,18,66

. A heterozygous mutation in the gene which encodes surfactant protein C has

been reported in a young female nonsmoker with CPFE 17. A heterozygous mutation of the ATP-binding cassette subfamily member 3 gene (ABCA3, MIM 601615) has been described in an adult nonsmoker patient 18. These mutations are known to cause dysfunction of surfactant homeostasis and result to the injury or death of alveolar epithelial type II cells and to the proliferation of myofibroblasts 17. In Figure 7a-c we provide the CT scan of a 19 year-old female patient with a 8 year history of ILD which was found to have an of ABCA3 mutation. Finally, whereas both fibrosis and

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ACCEPTED MANUSCRIPT emphysema are associated with telomere shortening

66-68

, inherited telomerase

complex mutations were until recently associated only with fibrosis

69

CPFE features

have been described in a family with inherited telomerase mutations and further associated with a specific risk of COPD and emphysema particularly in women <50

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years-old 66,70.

Pulmonary hypertension

The risk of the development of pulmonary hypertension (PH) in patients with CPFE is higher than this of patients with only IPF or only emphysema [1]. It is

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possible that the prevalence and severity of PH in CPFE is the result of an additive effect of the two separate disease processes which are known to be independently 71

. Both emphysema and fibrosis cause reduction of the

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associated with PH

pulmonary capillary bed, while hypoxia further results in the increase of pulmonary vascular resistance 72. However, it has been suggested that PH in CPFE is a common process in susceptible individuals, probably mediated through chronic inflammation induced by cigarette smoke that results in vascular remodeling in addition to fibrosis and emphysema 71. Many of the symptoms of patients with CPFE are largely related

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to the development of severe precapillary PH 10,73. PH occurs early after the diagnosis of CPFE 73, while the onset of PH in CPFE is a predictor of increased mortality (one year survival of approximately 60%) 10,73.

The physiologically consistent pattern of PH in CPFE is characterized by

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increased pressure in the pulmonary artery (Ppa), elevated pulmonary vascular resistance (PVR), increased heart rate, and lower cardiac index73. Pathological

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findings include intimal fibrosis and medial hypertrophy of the pulmonary artery and thickening and fibrosis of the pulmonary veins resulting in marked luminal narrowing74,75. Modest venopathy, can be present but without obvious capillary changes74. Interestingly, obstruction of small muscular pulmonary arteries can be present even in areas of normal lung75. It is important to note that there is no evidence of plexiform lesions 75. Since the prognosis of patients with CPFE is affected from the development of PH, follow up should include regular assessments of pulmonary artery pressures

71

.

Transthoracic echocardiography is not accurate on the estimation of systolic Ppa especially in patients with lung diseases

76

and right heart catheterization (RHC)

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ACCEPTED MANUSCRIPT should be performed in cases where the accurate measurement of pulmonary hemodynamics is necessary

71

for example in cases where specific treatment is

considered. There are no specific recommendations regarding the treatment of PH in patients with CPFE although several case reports indicate that specific therapy for PH may improve haemodynamics, in these patients

73,77,78

but without clear evidence for

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clinical and survival benefit.

Lung Cancer in CPFE

Though cigarette smoking is known as the most important risk factor for lung cancer,

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both emphysema and IPF (which are smoking-related diseases) have been recognized as independent risk factors for the development of lung cancer

79-81

. Repeated lung

injury and chronic inflammation are thought to contribute to genetic mutations which

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lead to the development of lung cancer in both emphysema and IPF 82. CPFE is also associated with smoking and several studies have shown that the prevalence of lung cancer is high in CPFE patients 82,83. Finally, although the risk of lung cancer in CPFE patients has been shown to be greater compared to patients with emphysema only, no significant difference has been found between CPFE and IPF 82.

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The location of lung cancer development differs between IPF and emphysema. In patients with emphysema, lung cancer most frequently occurs in the upper lung 79. On the contrary, in patients with IPF, lung cancer tends to occur in the subpleural

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areas mainly in the lower lobes 82,84. In patients with CPFE, lung cancer tends to occur more frequently in the subpleural area similarly to IPF, which leads to the hypothesis that probably the development of lung cancer in these patients is mostly related to the

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fibrotic abnormalities whereas emphysema does not have any additive impact on tumorigenesis 82.

In a recent study which included patients with lung cancer, CPFE has been

found to be more prevalent than fibrosis only, and patients with CPFE had a poorer prognosis

85

. The most frequent histological types of lung cancer in CPFE are

squamous cell carcinoma and adenocarcinoma whereas small cell lung cancer occurs in a minority of cases

86

. CPFE is also an unfavorable prognostic factor in patients

with non-small cell lung cancer after complete tumour resection

87

. Figure 8 a and b

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ACCEPTED MANUSCRIPT and Figure 9 a and b show characteristic CT images of lung cancer in two patients with CPFE.

CPFE in Connective Tissue Diseases (CTD)

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CPFE may also be encountered as a pulmonary manifestation within the spectrum of connective tissue disease-associated lung diseases, with generally similar features as ‘idiopathic’ CPFE19. Patients with CTD are usually younger and although there is still a male predominance (approximately 68%) this is not as strong as in idiopathic CPFE

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where more than 90% of patients are male4,19. Furthermore, in patients with CTD, CPFE can also occur in only mild or no smoking history, suggesting that the

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underlying CTD may contribute to the development of emphysema 4,88. CPFE can occur in almost any type of CTD although less frequently than in IPF89. The predominant CTD associated with the development of CPFE are rheumatoid arthritis and systemic sclerosis (SSc), however, CPFE has also been reported in patients with polymyositis, Sjögren’s syndrome, mixed connective tissue disease and overlapping CTDs, with consistent antibody profiles4,19. Usually, the

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diagnosis of CPFE follows that of CTD although in some patients the two conditions might be diagnosed at the same time19.

The imaging features of patients with CPFE and CTD are similar to those with idiopathic CPFE and include areas of reticulation, architectural distortion,

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honeycombing and traction bronchiectasis4 which are mainly situated in the lower lung zones and in subpleural areas. Other HRCT findings include ground-glass

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opacities. The imaging pattern of UIP is observed more frequently than NSIP. The emphysematous changes in CPFE include mainly paraseptal emphysema while panlobular emphysema is rare. Thick-walled large cysts of the lower zones of the lungs can be also observed 4. Patients with CPFE in CTD have better survival compared to patients with

idiopathic CPFE 19. However, the survival of patients with CPFE syndrome according to the type of CTD is not known. Similarly to idiopathic CPFE, the development of PH is a poor prognostic factor and pulmonary pressures seem to be higher in patients with CPFE and CTD than in patients with ILDs related to CTD but without emphysema. 4,19

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ACCEPTED MANUSCRIPT Acute exacerbations in patients with CPFE Patients with CPFE might experience the development of diffuse alveolar damage (DAD) upon the emphysema-UIP histology, clinically manifesting as an acute lung injury–adults respiratory distress syndrome (ALI-ARDS) upon CPFE, a condition

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similar to the so-called acute exacerbations of IPF 4. Predictors of acute exacerbations in patients with CPFE were the increased dyspnea level and higher baseline serum KL-6

64

. Although the presence of emphysema was found to be a predictor of acute

exacerbation in patients with IPF90 acute exacerbations of IPF seem to be more fatal compared to those observed in patients with CPFE25 although the latter are still

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related to increased mortality64. In CPFE acute exacerbations, it is very important to investigate all possible conditions that might precipitate a subacute-acute

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deterioration, such as lower respiratory tract infections, heart failure, pulmonary embolism or pneumothorax and provide appropriate treatment91. CPFE patients may also be at increased risk of ALI after lung resection surgery 46,92 (Figures 10 a-d). A previous study has shown that in patients with CPFE and lung cancer, chemotherapy may also induce ALI 85 although this finding was not

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confirmed in a recent study93.

Prognosis

Mortality is significant in patients with CPFE and median survival has been reported 1,10,25,94,95

while 5 year survival ranges between 38

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to be between 2.1 and 8.5 years. and 55% 1,16,96.

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The rate of decline in lung function seems to differ between patients with only fibrosis and those with CPFE. Patients with CPFE show a slower decline in both FVC, TLC and DLCO over time, and unlike IPF patients, which show an increase in the FEV1/FVC ratio, in CPFE patients this ratio may decrease overtime 26. Regarding prognosis, although in IPF the annual rate of decline in FVC, DLCO or the CPI are known to be independent predictors of survival, in patients with CPFE survival is strongly related to the decline of FEV1 48. Furthermore, CPFE progresses more rapidly in active smokers compared to patients that have quit smoking clubbing seems to be also an independent predictor of mortality.64

97

. Finally, finger

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ACCEPTED MANUSCRIPT It has been debated whether survival in patients with CPFE is better or not, compared to patients with lone fibrosis. Several studies have shown a better survival in CPFE patients

25,98

, although others failed to demonstrate differences in mortality 27,94

between these two groups 10,99

or have reported a worse survival in CPFE patients

. These differences are probably associated to the great heterogeneity of patients

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with CPFE regarding the extent of the fibrotic and emphysematous lesions 16,40, and to the fact that probably some studies included not only patients with UIP but also patients with f-NSIP hypertension

1,10,99

100

. Furthermore, both the development of pulmonary

and lung cancer are associated with reduced survival

in CPFE

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patients.

87

In CPFE the extent of fibrosis in HRCT has been reported to be a significant predictor of survival

96

. Furthermore, patients with CPFE related to centrilobular or

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mixed emphysema have better survival not only compared to patients with only IPF but also compared to patients with CPFE and minor emphysema or with advanced paraseptal emphysema 95,99. These findings suggest that in CPFE patients, prognosis is mostly related to the fibrotic component whereas emphysema seems to influence

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survival only in cases that is very extensive or progressive.

Therapeutic interventions

Currently, no specific recommendations are available regarding the management of patients with CPFE. The general measures that should be taken are smoking cessation

EP

for patients who continue to smoke and oxygen therapy for patients with respiratory failure. Since patients who continue to smoke have a worst prognosis compared to 97

CPFE patients are in an urgent need to stop

AC C

patients who have quit smoking

smoking and all efforts should be made to help patients to quit using all available interventions

101

. Oxygen therapy is known to improve survival in patients with

COPD and in those with pulmonary hypertension who experience respiratory failure 102,103

. Vaccination against influenza viruses and S. pneumoniae might also be a

reasonable intervention 20. In patients with airflow obstruction inhaled bronchodilators might be also prescribed

16

. In the presence of pulmonary hypertension, specific

therapy might result to the improvement of haemodynamics 73,77,78 although the use of these therapies in CPFE-related pulmonary hypertension needs to be further evaluated.

16

ACCEPTED MANUSCRIPT Novel treatments for IPF such as pirfenidone and the novel tyrosine kinase inhibitor nintedanib, might be beneficial for CPFE patients as well. In a recent study it has been shown that patients with CPFE tolerated pirfenidone well and had a stable course of disease during treatment

104

. Pulmonary function alterations during

pirfenidone treatment were not different between patients with CPFE and those with 104

. However, more studies are needed in order to define the response of

RI PT

IPF only

CPFE patients on the treatment with pirfenidone. The possible beneficial effects of nintedanib on disease progression and survival of CPFE patients remains unknown. Finally, patients with severe disease should also be considered for lung transplantation and the well preserved lung volumes should not work against these patients in their

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46

The many faces of CPFE

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lung allocation score.

Current evidence shows that patients with CPFE might express different degree of its two components (i.e. pulmonary fibrosis and pulmonary emphysema) and might develop one or more of different comorbidities or complications (Figure 12). CPFE patients show great heterogeneity regarding the extent of the fibrotic and

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emphysematous lesions and this might be associated to the different decline of lung function and survival rates as well as the recognition of slow and rapid progressors of the disease which have been reported in different patient series16,40. Patients who develop pulmonary hypertension are characterized by poorer survival10,73. A subgroup

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of CPFE patients develop lung cancer and their prognosis is also poor85. Some patients are susceptible to exacerbations and require hospital admission and

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aggressive treatment. Finally, CPFE might appear in patients with genetic mutations17,18 or might be related to connective tissue disease19. This disease heterogeneity leads to the need of further understanding of the pathophysiological mechanisms behind its development in order to allow to the better characterization of the patient’s needs and to help the establishment of more personalized treatment.

Conclusions Available data show that CPFE, irrespective of its origin, or whether it is a cohabitation or the result of common pathogenetic mechanisms of two different

17

ACCEPTED MANUSCRIPT smoking related diseases, it appears to be a distinct clinical entity with its own phenotypes, clinical course and complications, related to the interaction of specific genetic and environmental factors. CPFE is an increasingly recognized condition and seems to be related to different natural history and prognosis than IPF. CPFE should be suspected in smokers with interstitial lung disease and severely reduced DLCO

RI PT

with preserved lung volumes and diagnosis should be confirmed via HRCT. Early recognition of this disease and early diagnosis of its complications (i.e. development of pulmonary hypertension or lung cancer) is of great importance for providing to the patient the best care and support. Finally, further research is needed for the better

SC

understanding of the underline mechanisms, related to the pathogenesis and pathophysiology of the disease, which will help to the development of novel and

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effective therapies.

Acknowledgements

The authors would like to greatly thank for their contribution Professors B. Crestani and H.Mal (Hôpital Bichat, Paris) and A. Cuvelier (CHU Rouen) and acknowledge

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the precious contribution and thank very much Dr Caroline Kannengiesser (Genetic Laboratory Hôpital Bichat, Paris), Dr Nadia Nathan and Dr Serge Amselem (Genetic Laboratory Hôpital Armand Trousseau, Paris) for the genetic analysis of the patient of Figure 7

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Finally, the authors would like to thank Ms Tina Panagiotopoulou for her help with the artistic creation of Figure 1.

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The manuscript has been supported by the Greek State Scholarship Foundation Fellowships of Excellence- Siemens.

18

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ACCEPTED MANUSCRIPT Figure Legends Figure 1 IPF

CPFE

Emphysema

FEV1

↓

↓ or N

↓

FVC

↓

↓ or N

↓

FEV1/FVC

↑

↓ or ↑ or N

↓

TLC

↓

↓ or ↑ or N

↑

FRC

↓

↓ or ↑ or N

↑

RV

↓

↓ or ↑ or N

↑

DLCO

↓

↓↓

↓

Desaturation during exercise

+

++

+

+

+

+

-

UIP

UIP or f-NSIP + Emphysema

Emphysema

+

++

+

++

+

Emphysema

-

Fibrosis

+

Pathological findings

Lung cancer risk

SC

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Pulmonary Hypertension

M AN U

CT findings

RI PT

Pulmonary function tests

++

Abbreviations: IPF: Idiopathic Pulmonary Fibrosis , CPFE: Combined Pulmonary Fibrosis and Emphysema, UIP: Usual Interstitial Pneumonia, f-NSIP: fibrotic Non

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Specific Interstitial Pneumonia, FEV1: Forced Expiratory Volume in 1 second, FVC; Forced exhaled Vital Capacity, TLC: Total Lung Capacity, FRC: Functional Residual Capacity, RV: Residual Volume, DLCO: Diffusing capacity for Carbon Monoxide.

AC C

CT: computed tomography, N: Normal

Figures 2-6

Different distribution of the zones of fibrosis and emphysema in patients with CPFE Figure 2 (a-c) Fibrosis and emphysema are completely separated (emphysema in the upper zones and fibrosis in the bases)

26

ACCEPTED MANUSCRIPT Figure 3 (a-c) Progressive transition between fibrosis and emphysema. Figure 4 (a-c) Paraseptal emphysematous lesions are also present at the bases of the lungs within the

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fibrotic lesions Figure 5 (a-c)

Thick walled cysts situated in the upper lung zones just beneath the chest wall

SC

Figure 6 (a-c)

Thick walled cysts grow within the areas of reticulation and/or honeycombing

M AN U

Figure 7 (a-c)

A CT scan of a 19 year old girl with an 8 years history of ILD. The CT revealed ground glass opacities and emphysema a diagnosis of a ABCA3 mutation was made. Figure 8 (a and b) and Figure 9 (a and b)

Figure 10 (a-d)

TE D

Lung cancer in two patients with CPFE

Acute exacerbation in a CPFE patient with lung cancer who underwent lobectomy of

Figure 11

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the right lower lobe, a and b: CT before surgery, c and d: CT after surgery.

AC C

Schematic representation of the different CPFE phenotypes. Abbreviations: CPFE: Combined Pulmonary Fibrosis and Emphysema, DAD: Diffuse Alveolar Damage, PH: Pulmonary Hypertension,

ACCEPTED MANUSCRIPT

27

Table 1

RI PT

Radiological characteristics of CPFE

AC C

EP

TE D

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Radiographic characteristic Emphysema in the upper zones and fibrosis in the bases Progressive transition between emphysema and fibrosis Paraseptal emphysematous lesions at the bases of the lungs within the fibrotic lesions Large thick-walled cystic lesions (diameter ≥ 1 cm) delineated by a 1-mm-thick wall. These cysts can be situated either in the upper lungs just beneath the chest wall or grow within the areas of reticulation and/or honeycombing Centrilobular nodules which correspond to airway-centered fibrosis, (i.e. fibrotic changes along the respiratory bronchioles) Subpleural curvilinear opacities Ground Glass opacities Findings suggestive of pulmonary hypertension (i.e. dilatation of the central pulmonary arteries, enlargement of the right heart, reduction of peripheral branches of the pulmonary arteries and mosaic appearance of the pulmonary parenchyma)

References 38 38 38 37,38

37 37 1,16 37,43

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Pathological characteristics of CPFE

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Pathological findings Diffuse form of smoking-related interstitial lung disease: Overlap of pulmonary emphysema and fibrotic interstitial pneumonia (UIP or f-NSIP) Localized form of smoking-related interstitial lung disease: Presence of emphysema with fibrosis, air space enlargement with fibrosis, or occult fibrosis of smokers Fibrotic lesions along bronchioles around the emphysematous areas

References 55

55

56 41,55,57

Occult fibrosis of smokers or smoking related interstitial fibrosis (SRIF): Alveolar septal widening by collagen deposition along with emphysema and respiratory bronchiolitis both in subpleural areas and in deeper parenchyma, surrounded or not by emphysematous lesions

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Thick-walled cystic lesions involving one or more acini characterized by dense wall fibrosis, and occasional fibroblastic foci, surrounded by honeycombing and normal alveoli

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In this review we provide information on the existing knowledge CPFE

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Patients experience severe dyspnea, impaired gas exchange and preserved lung volumes

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HRCT shows coexistence of emphysema and fibrosis in varying extent and locations Individual genetic background seems to predispose to the development CPFE

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There is increased risk of developing pulmonary hypertension and lung cancer

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