Abstracts
Combined pulmonary fibrosis and emphysema (CPFE) has been increasingly recognized in the literature. Patients with CPFE are usually heavy smokers or former smokers with concomitant lower lobe fibrosis and upper lobe emphysema on chest HRCT scans. They commonly present with severe breathlessness and low DLCO, despite spirometry showing relatively preserved lung volumes. Moderate to severe pulmonary arterial hypertension is common in such patients, who are also at an increased risk of developing lung cancer. Unfortunately, there is currently no effective treatment for CPFE. In this review, we discuss the current knowledge of the pathogenesis, clinical characteristics, and prognostic factors of CPFE. Given that most of the published data on CPFE are based on retrospective analysis, more studies are needed in order to address the role of emphysema and its subtypes; the progression of fibrosis/emphysema and its correlation with inflammation; treatment options; and prognosis.
Pulmonary fibrosis; Emphysema; Hypertension, pulmonary; Lung diseases, interstitial
A combinação de fibrose pulmonar e enfisema (CFPE) é cada vez mais reconhecida na literatura. Os pacientes são geralmente fumantes pesados ou ex-fumantes nos quais a TCAR de tórax revela enfisema nos lobos superiores e, concomitantemente, fibrose nos lobos inferiores. Esses pacientes comumente apresentam dispneia grave e baixa DLCO, não obstante os volumes pulmonares relativamente preservados em exames espirométricos. Hipertensão arterial pulmonar de moderada a grave e aumento da incidência de câncer de pulmão também são comuns nesses pacientes. Infelizmente, ainda não existe um tratamento eficaz para a CFPE. O objetivo desta revisão é discutir o que se sabe atualmente a respeito da patogênese, das características clínicas e dos fatores prognósticos da CFPE. Como a maioria dos dados publicados baseia-se em análise retrospectiva, são necessários mais estudos sobre o papel do enfisema e seus subtipos, a progressão da fibrose/enfisema e sua correlação com a inflamação, as opções de tratamento e o prognóstico em pacientes com CFPE.
Fibrose pulmonar; Enfisema; Hipertensão pulmonar; Doenças pulmonares intersticiais
Introduction
Idiopathic pulmonary fibrosis (IPF) and pulmonary emphysema are distinct clinicopathological entities that pulmonologists have long been familiar with. Since the advent of HRCT, the combination of these two conditions has been increasingly described and has been proven to be a prevalent and distinct entity rather than a rare coincidence.
The association of IPF and emphysema was initially described in 1990 by Wiggins et
al.,(
11. Wiggins J, Strickland B, Turner-Warwick M. Combined cryptogenic
fibrosing alveolitis and emphysema: the value of high resolution computed tomography
in assessment. Respir Med. 1990;84(5):365-9.
http://dx.doi.org/10.1016/S0954-6111(08)...
) who described eight heavy smokers with fibrosis and upper lobe emphysema on
HRCT scans, together with severe breathlessness, strikingly low DLCO, and preserved lung
volumes. In 2005, Grubstein et al.(
22. Grubstein A, Bendayan D, Schactman I, Cohen M, Shitrit D, Kramer MR.
Concomitant upper-lobe bullous emphysema, lower-lobe interstitial fibrosis and
pulmonary hypertension in heavy smokers: report of eight cases and review of the
literature. Respir Med. 2005;99(8):948-54.
http://dx.doi.org/10.1016/j.rmed.2004.12...
) reported an association of fibrosis with emphysema in eight patients, their
clinical and functional findings being similar to those of the aforementioned study. The
authors also found moderate to severe pulmonary arterial hypertension (PAH) and
postulated that smoking is a factor linking emphysema, pulmonary fibrosis, and pulmonary
vascular disease.(
22. Grubstein A, Bendayan D, Schactman I, Cohen M, Shitrit D, Kramer MR.
Concomitant upper-lobe bullous emphysema, lower-lobe interstitial fibrosis and
pulmonary hypertension in heavy smokers: report of eight cases and review of the
literature. Respir Med. 2005;99(8):948-54.
http://dx.doi.org/10.1016/j.rmed.2004.12...
) The term combined pulmonary fibrosis and emphysema (CPFE) was first used in
2005 by Cottin et al.,(
33. Cottin V, Nunes H, Brillet PY, Delaval P, Devouassoux G,
Tillie-Leblond I et al. Combined pulmonary fibrosis and emphysema: a distinct
underrecognised entity. Eur Respir J. 2005;26(4):586-93.
http://dx.doi.org/10.1183/09031936.05.00...
) who characterized a homogeneous group of 61 patients with CT findings of
emphysema in the upper zones and interstitial lung disease (ILD) with pulmonary fibrosis
in the lower lobes.
When CPFE was first described, patients with other ILDs were excluded from the
study.(
33. Cottin V, Nunes H, Brillet PY, Delaval P, Devouassoux G,
Tillie-Leblond I et al. Combined pulmonary fibrosis and emphysema: a distinct
underrecognised entity. Eur Respir J. 2005;26(4):586-93.
http://dx.doi.org/10.1183/09031936.05.00...
) Later on, CPFE was described in patients with other ILDs, such as
connective tissue disease (CTD)-associated ILD,(
44. Cottin V, Nunes H, Mouthon L, Gamondes D, Lazor R, Hachulla E, et al.
Combined pulmonary fibrosis and emphysema syndrome in connective tissue disease.
Arthritis Rheum. 2011;63(1):295-304.
http://dx.doi.org/10.1002/art.30077...
5. Lubatti C, Zeni S, Ingegnoli F. Combined pulmonary fibrosis and
emphysema syndrome in systemic sclerosis. Int J Rheum Dis.
2012;15(5):e122-3.
http://dx.doi.org/10.1111/j.1756-185X.20...
6. Cottin V, Freymond N, Cabane J, Cordier JF. Combined pulmonary
fibrosis and emphysema syndrome in a patient age 28 years with severe systemic
sclerosis. J Rheumatol. 2011;38(9):2082-3
http://dx.doi.org/10.3899/jrheum.101365...
-
77. Cottin V, Cordier JF. Combined pulmonary fibrosis and emphysema in
connective tissue disease. Curr Opin Pulm Med. 2012;18(5):418-27.
http://dx.doi.org/10.1097/MCP.0b013e3283...
) as well as in patients with microscopic polyangiitis.(
88. Tzouvelekis A, Zacharis G, Oikonomou A, Koulelidis A, Steiropoulos P,
Froudarakis M, et al. Combined pulmonary fibrosis and emphysema associated with
microscopic polyangiitis. Eur Respir J. 2012;40(2):505-7.
http://dx.doi.org/10.1183/09031936.00216...
)
Studies have shown that patients with CPFE associated with CTDs (especially rheumatoid
arthritis and systemic sclerosis) are significantly younger than their idiopathic CPFE
counterparts, are predominantly female, and have less DLCO impairment.(
44. Cottin V, Nunes H, Mouthon L, Gamondes D, Lazor R, Hachulla E, et al.
Combined pulmonary fibrosis and emphysema syndrome in connective tissue disease.
Arthritis Rheum. 2011;63(1):295-304.
http://dx.doi.org/10.1002/art.30077...
) One group of authors found elevated serum antinuclear antibodies with or
without positive perinuclear antineutrophil cytoplasmic antibodies in CPFE patients when
compared with IPF patients without emphysema, those with positive autoimmune markers
exhibiting greater infiltration of CD20+ B cells forming lymphoid follicles in fibrotic
lung tissue and improved survival when compared with those with negative autoimmune
markers.(
99. Tzouvelekis A, Zacharis G, Oikonomou A, Mikroulis D, Margaritopoulos
G, Koutsopoulos A, et al. Increased incidence of autoimmune markers in patients with
combined pulmonary fibrosis and emphysema. BMC Pulm Med. 2013;13:31.
http://dx.doi.org/10.1186/1471-2466-13-3...
)
Given that tobacco exposure seems to modulate an underlying inflammatory response in patients with ILD, CPFE should be categorized as a pattern associated with other pulmonary diseases rather than as a primary idiopathic syndrome, a classification similar to the usual interstitial pneumonia (UIP) pattern in other fibrotic ILDs. In other words, the recognition of a CPFE pattern should also prompt the investigation of secondary autoimmune diseases and CTDs.
Patients with CPFE are predominantly male, with a history of heavy tobacco exposure, and
usually present with severe breathlessness and cough. Physical examination reveals
"Velcro" crackles at the lung bases and digital clubbing.(
33. Cottin V, Nunes H, Brillet PY, Delaval P, Devouassoux G,
Tillie-Leblond I et al. Combined pulmonary fibrosis and emphysema: a distinct
underrecognised entity. Eur Respir J. 2005;26(4):586-93.
http://dx.doi.org/10.1183/09031936.05.00...
,
1010. Kishaba T, Shimaoka Y, Fukuyama H, Yoshida K, Tanaka M, Yamashiro S,
et al. A cohort study of mortality predictors and characteristics of patients with
combined pulmonary fibrosis and emphysema. BMJ Open. 2012;15:2(3).
) Pulmonary hypertension is a hallmark of the syndrome and determines poor
prognosis.(
1010. Kishaba T, Shimaoka Y, Fukuyama H, Yoshida K, Tanaka M, Yamashiro S,
et al. A cohort study of mortality predictors and characteristics of patients with
combined pulmonary fibrosis and emphysema. BMJ Open. 2012;15:2(3).
) Between January of 2006 and December of 2013, 17 patients were diagnosed
with CPFE at our interstitial lung disease outpatient clinic, and the data are
summarized in Table 1. In accordance with the
literature, our patients were predominantly male (88%), the mean age at diagnosis being
68 years. All of the patients presented with tobacco exposure and dyspnea at diagnosis.
Almost half of the patients had pulmonary hypertension diagnosed by echocardiography.
Few (6%) had a diagnosis of lung cancer, and 12% died during the follow-up period.
- Characteristics of 17 patients with combined pulmonary fibrosis and emphysema treated at the Interstitial Lung Disease Outpatient Clinic of the University of São Paulo School of Medicine Hospital das Clínicas between 2006 and 2013, together with the clinical manifestations of the disease.a
Pathogenesis
The pathogenesis of CPFE has yet to be elucidated. Tobacco exposure per se can be an important fibrogenic stimulus, smoking having been shown to play a key role in the pathogenesis of several ILDs, including respiratory bronchiolitis-associated ILD (RB-ILD), desquamative interstitial pneumonia, pulmonary Langerhans cell histiocytosis, and, possibly, IPF.
Washko et al. conducted a lung cancer screening study involving a large cohort of
COPD patients and found interstitial lung abnormalities on HRCT scans in up to 8% of
smokers.(
1111. Washko GR, Hunninghake GM, Fernandez IE, Nishino M, Okajima Y,
Yamashiro T, et al. Lung volumes and emphysema in smokers with interstitial lung
abnormalities. N Engl J Med. 2011;364(10):897-906.
http://dx.doi.org/10.1056/NEJMoa1007285...
) Likewise, Katzenstein et al. reported frequent and severe interstitial
fibrosis in over half of lobectomy specimens excised for lung cancer from smokers
with no clinical evidence of ILD, even in those patients in whom emphysema was the
only CT finding.(
1212. Katzenstein AL, Mukhopadhyay S, Zanardi C, Dexter E. Clinically
occult interstitial fibrosis in smokers: classification and significance of a
surprisingly common finding in lobectomy specimens. Hum Pathol.
2010;41(3):316-25.
http://dx.doi.org/10.1016/j.humpath.2009...
)
Those histological findings characterized a distinct, non-classifiable ILD, which
Katzenstein et al. designated "smoking related-interstitial fibrosis", characterized
by thickening of alveolar septa by fibrosis composed mostly of hyalinized
eosinophilic collagen bundles and surrounding enlarged airspaces of emphysema, as
well as by signs of respiratory bronchiolitis.(
1212. Katzenstein AL, Mukhopadhyay S, Zanardi C, Dexter E. Clinically
occult interstitial fibrosis in smokers: classification and significance of a
surprisingly common finding in lobectomy specimens. Hum Pathol.
2010;41(3):316-25.
http://dx.doi.org/10.1016/j.humpath.2009...
) Although follow-up was short, the clinical progression seemed to be
particularly different from that of IPF, with indolent fibrosis and better survival
rates, reinforcing the idea of a different disease.(
1212. Katzenstein AL, Mukhopadhyay S, Zanardi C, Dexter E. Clinically
occult interstitial fibrosis in smokers: classification and significance of a
surprisingly common finding in lobectomy specimens. Hum Pathol.
2010;41(3):316-25.
http://dx.doi.org/10.1016/j.humpath.2009...
)
It is reasonable to assume that the lung parenchyma shows different patterns of
injury and repair in response to tobacco exposure. The different phenotypes of
lesions secondary to tobacco exposure depend on the balance of apoptosis,
proteolysis, and fibrosis. Patients in whom genes related to connective tissue
synthesis, structural constituents of the cytoskeleton, and cell adhesion are
overexpressed typically display a fibrogenic phenotype, such as that found in
patients with UIP; however, a different inflammatory response to smoking-associated
cellular damage (destruction and repair of cells, vessels, and pneumocytes) leads to
destruction of lung parenchyma, culminating in pulmonary emphysema.(
1313. Hanaoka M, Ito M, Droma Y, Ushiki A, Kitaguchi Y, Yasuo M, et al.
Comparison of gene expression profiling between lung fibrotic and emphysematous
tissues sampled from patients with combined pulmonary fibrosis and emphysema.
Fibrogenesis Tissue Repair. 2012;5(1):17.
http://dx.doi.org/10.1186/1755-1536-5-17...
) A combination of these two patterns of response can be found in patients
with CPFE and has recently been demonstrated by gene expression analysis of fibrotic
and emphysematous lesions in such patients.(
1313. Hanaoka M, Ito M, Droma Y, Ushiki A, Kitaguchi Y, Yasuo M, et al.
Comparison of gene expression profiling between lung fibrotic and emphysematous
tissues sampled from patients with combined pulmonary fibrosis and emphysema.
Fibrogenesis Tissue Repair. 2012;5(1):17.
http://dx.doi.org/10.1186/1755-1536-5-17...
)
The role of environmental exposure as a potential trigger of lung injury is also
plausible, given that some CPFE patients have had significant exposure to
agrochemical compounds that cause airway damage and ILD in genetically susceptible
smokers.(
1414. Daniil Z, Koutsokera A, Gourgoulianis K. Combined pulmonary fibrosis
and emphysema in patients exposed to agrochemical compounds. Eur Respir J.
2006;27(2):434.
http://dx.doi.org/10.1183/09031936.06.00...
) Some authors have described CPFE as an occupational disease, e.g., in
patients exposed to talc(
1515. Karkhanis VS, Joshi JM. Combined pulmonary fibrosis and emphysema in
a tyre industry worker. Lung Índia. 2012;29(3):273-6.
http://dx.doi.org/10.4103/0970-2113.9911...
) and in welders.(
1616. Roshan R, Guptal M, Kulshrestha R, Menon B, Chhabra SK. Combined
pulmonary fibrosis and emphysema in a welder. Monaldi Arch Chest Dis.
2012;77(1):26-8.
)
The signaling pathways to these responses are unknown. Laboratory animal studies have
demonstrated that oxidative stress inducing inflammatory cell activation, elevated
matrix metalloproteinase levels causing proteolytic activity,(
1717. Rogliani P, Mura M, Mattia P, Ferlosio A, Farinelli G, Mariotta S,
et al. HRCT and histopathological evaluation of fibrosis and tissue destruction in
IPF associated with pulmonary emphysema. Respir Med.
2008;102(12):1753-61.
http://dx.doi.org/10.1016/j.rmed.2008.07...
,
1818. Portillo Carroz K, Roldán Sánchez J, Morera Prat J. Combined
pulmonary fibrosis and emphysema [Article in Spanish]. Arch Bronconeumol.
2010;46(12):646-51.
http://dx.doi.org/10.1016/j.arbres.2010....
) and overexpression of other mediators, such as PDGF,(
1919. Hoyle GW, Li J, Finkelstein JB, Eisenberg T, Liu JY, Lasky JA, et
al. Emphysematous lesions, inflammation, and fibrosis in the lungs of transgenic mice
overexpressing platelet-derived growth factor. Am J Pathol.
1999;154(6):1763-75.
http://dx.doi.org/10.1016/S0002-9440(10)...
) TNF-α, and TGF-β,(
2020. Lundblad LK, Thompson-Figueroa J, Leclair T, Sullivan MJ, Poynter
ME, Irvin CG, et al. Tumor necrosis factor-alpha overexpression in lung disease: a
single cause behind a complex phenotype. Am J Respir Crit Care Med.
2005;171(12):1363-70.
http://dx.doi.org/10.1164/rccm.200410-13...
,
2121. Lee CG, Cho S, Homer RJ, Elias JA. Genetic control of transforming
growth factor-beta1-induced emphysema and fibrosis in the murine lung. Proc Am Thorac
Soc. 2006;3(6):476-7.
http://dx.doi.org/10.1513/pats.200603-04...
) are potential pathways explaining the lesions that lead to emphysema and
fibrosis. A study analyzing inflammatory mediators in BAL fluid from patients with
IPF showed significantly higher concentrations of chemokine (C-X-C motif) ligand 5
and chemokine (C-X-C motif) ligand 8 in those with concomitant HRCT findings of
emphysema.(
2222. Tasaka S, Mizoguchi K, Funatsu Y, Namkoong H, Yamasawa W, Ishii M,
et al. Cytokine profile of bronchoalveolar lavage fluid in patients with combined
pulmonary fibrosis and emphysema. Respirology. 2012;17(5):814-20.
http://dx.doi.org/10.1111/j.1440-1843.20...
) These chemokines are associated with neutrophil accumulation in
airspaces and suggest a different pathway of inflammation leading to the development
of emphysematous changes superimposed on pulmonary fibrosis.(
2222. Tasaka S, Mizoguchi K, Funatsu Y, Namkoong H, Yamasawa W, Ishii M,
et al. Cytokine profile of bronchoalveolar lavage fluid in patients with combined
pulmonary fibrosis and emphysema. Respirology. 2012;17(5):814-20.
http://dx.doi.org/10.1111/j.1440-1843.20...
)
Genetic mutations have been described in CPFE patients with and without a significant
smoking history.(
66. Cottin V, Freymond N, Cabane J, Cordier JF. Combined pulmonary
fibrosis and emphysema syndrome in a patient age 28 years with severe systemic
sclerosis. J Rheumatol. 2011;38(9):2082-3
http://dx.doi.org/10.3899/jrheum.101365...
,
2323. Cottin V, Reix P, Khouatra C, Thivolet-Béjui F, Feldmann D, Cordier
JF. Combined pulmonary fibrosis and emphysema syndrome associated with familial SFTPC
mutation. Thorax. 2011;66(10):918-9.
http://dx.doi.org/10.1136/thx.2010.15140...
) This indicates that risk factors other than tobacco smoking are
associated with the development of CPFE or that tobacco smoking can be a triggering
factor in susceptible patients. Plausible genetic pathways have been confirmed in
case reports in which mutations in the surfactant protein C gene were identified in a
32-year-old female who had never smoked(
23
) and an ABCA3 mutation was identified in a 41-year-old male
nonsmoker,(
2424. Epaud R, Delestrain C, Louha M, Simon S, Fanen P, Tazi A. Combined
pulmonary fibrosis and emphysema syndrome associated with ABCA3 mutations. Eur Respir
J. 2014;43(2):638-41.
http://dx.doi.org/10.1183/09031936.00145...
) with CT findings identical to those in CPFE patients. These mutations
are known to cause dysfunction of surfactant homeostasis and, consequently, injury or
death of alveolar epithelial type II cells and myofibroblast
proliferation.(
2323. Cottin V, Reix P, Khouatra C, Thivolet-Béjui F, Feldmann D, Cordier
JF. Combined pulmonary fibrosis and emphysema syndrome associated with familial SFTPC
mutation. Thorax. 2011;66(10):918-9.
http://dx.doi.org/10.1136/thx.2010.15140...
) Finally, reports have described CPFE features in a family with inherited
telomerase mutations.(
2525. Nunes H, Monnet I, Kannengiesser C, Uzunhan Y, Valeyre D,
Kambouchner M, et al. Is telomeropathy the explanation for combined pulmonary
fibrosis and emphysema syndrome?: report of a family with TERT mutation. Am J Respir
Crit Care Med. 2014;189(6):753-4.
http://dx.doi.org/10.1164/rccm.201309-17...
)
These findings reinforce the idea of a combination of genetic predisposition and a
triggering exposure (smoking) in susceptible individuals leading to continued damage
to alveolar epithelial cells that cannot be properly repaired, initiating a vicious
cycle of attempts at alveolar regeneration and uncontrolled activation of fibrosis
proliferation and parenchymal destruction.(
2626. Chilosi M, Carloni A, Rossi A, Poletti V. Premature lung aging and
cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and
COPD/emphysema. Transl Res. 2013;162(3):156-73.
http://dx.doi.org/10.1016/j.trsl.2013.06...
)
Imaging studies in CPFE
Imaging studies are essential for the diagnosis of CPFE. Although routine chest X-rays are not as sensitive as HRCT scans, they can reveal an interstitial pattern predominantly in the subpleural and basal lung regions, with hyperlucency in the lung apices corresponding to emphysematous areas.
The mainstay of the diagnosis of CPFE, HRCT scans typically show centrilobular or
paraseptal emphysema in the upper lobes, as well as reticular opacities, traction
bronchiectasis, septal thickening, ground-glass opacities, and honeycombing in the
lower lobes(33. Cottin V, Nunes H, Brillet PY, Delaval P, Devouassoux G,
Tillie-Leblond I et al. Combined pulmonary fibrosis and emphysema: a distinct
underrecognised entity. Eur Respir J. 2005;26(4):586-93.
http://dx.doi.org/10.1183/09031936.05.00...
) (Figures 1 and 2). Although UIP is
the most common CT pattern, some patients have ground-glass opacities that are more
extensive than expected for a UIP pattern and are therefore suggestive of nonspecific
interstitial pneumonia, RB-ILD, and even desquamative interstitial
pneumonia.(
33. Cottin V, Nunes H, Brillet PY, Delaval P, Devouassoux G,
Tillie-Leblond I et al. Combined pulmonary fibrosis and emphysema: a distinct
underrecognised entity. Eur Respir J. 2005;26(4):586-93.
http://dx.doi.org/10.1183/09031936.05.00...
)
CT scan of the chest of a 67-year-old female patient with combined pulmonary fibrosis and emphysema, showing centrilobular and paraseptal emphysema in the upper lobes (A and B), as well as ground-glass opacities, traction bronchiectasis, and honeycombing in the lower lobes (C and D). Note an aspergilloma in one of the paraseptal bullae in the right upper lobe (black arrow, in B)
CT scan of the chest of a 70-year-old male patient with combined pulmonary fibrosis and emphysema and acute exacerbation of interstitial disease. Note predominantly paraseptal emphysema in the lung apices, with architectural destruction of the lung parenchyma (A and B). Extensive areas of ground-glass opacity and honeycombing can be seen in the lower lobes (C and D)
Brillet et al.(
2727. Brillet PY, Cottin V, Letoumelin P, Landino F, Brauner MW, Valeyre
D, et al. Combined apical emphysema and basal fibrosis syndrome (emphysema/fibrosis
syndrome): CT imaging features and pulmonary function tests [Article in French]. J
Radiol. 2009;90(1 Pt 1):43-51.
http://dx.doi.org/10.1016/S0221-0363(09)...
) described patterns of distribution of fibrosis and emphysema in patients
with CPFE other than those initially described: a progressive transition from apical
emphysema to a zone of transition between bullae and honeycombing; paraseptal
emphysema with areas of fibrosis; and separate processes with independent areas of
fibrosis and emphysema.(
2727. Brillet PY, Cottin V, Letoumelin P, Landino F, Brauner MW, Valeyre
D, et al. Combined apical emphysema and basal fibrosis syndrome (emphysema/fibrosis
syndrome): CT imaging features and pulmonary function tests [Article in French]. J
Radiol. 2009;90(1 Pt 1):43-51.
http://dx.doi.org/10.1016/S0221-0363(09)...
)
Lung function in CPFE
Regarding the lung function of patients with CPFE, spirometry can be normal or show
mild abnormalities, FVC, FEV1, and TLC values usually being within normal
ranges or slightly altered.(
33. Cottin V, Nunes H, Brillet PY, Delaval P, Devouassoux G,
Tillie-Leblond I et al. Combined pulmonary fibrosis and emphysema: a distinct
underrecognised entity. Eur Respir J. 2005;26(4):586-93.
http://dx.doi.org/10.1183/09031936.05.00...
,
2828. Cottin V, Cordier JF. The syndrome of combined pulmonary fibrosis
and emphysema. Chest. 2009;136(1):1-2
http://dx.doi.org/10.1378/chest.09-0538...
) The FEV1/FVC ratio can be within or slightly below the normal
range. Severely impaired DLCO and hypoxemia during exercise are common.(
33. Cottin V, Nunes H, Brillet PY, Delaval P, Devouassoux G,
Tillie-Leblond I et al. Combined pulmonary fibrosis and emphysema: a distinct
underrecognised entity. Eur Respir J. 2005;26(4):586-93.
http://dx.doi.org/10.1183/09031936.05.00...
,
2828. Cottin V, Cordier JF. The syndrome of combined pulmonary fibrosis
and emphysema. Chest. 2009;136(1):1-2
http://dx.doi.org/10.1378/chest.09-0538...
)
Silva et al. reported similar findings in a retrospective cohort of 11 Brazilian
patients, spirometry having revealed normal lung volumes in 7.(
2929. Silva DR, Gazzana MB, Barreto SS, Knorst MM. Idiopathic pulmonary
fibrosis and emphysema in smokers. J Bras Pneumol.
2008;34(10):779-86.
http://dx.doi.org/10.1590/S1806-37132008...
) At our facility, 17 CPFE patients were evaluated, and spirometry showed
normal lung function and lung volumes in 12%, an obstructive pattern in 18%, and a
restrictive pattern in 47%. All patients had reduced DLCO (Table 2).
In a five-year follow-up study of 16 CPFE patients, the annual decline in FVC, DLCO,
and DLCO/alveolar volume was significantly higher than was that found in a group of
COPD patients. (
3030. Kitaguchi Y, Fujimoto K, Hayashi R, Hanaoka M, Honda T, Kubo K.
Annual changes in pulmonary function in combined pulmonary fibrosis and emphysema:
over a 5-year follow-up. Respir Med. 2013;107(12):1986-92.
http://dx.doi.org/10.1016/j.rmed.2013.06...
) In another study, the rate of decline in lung volume was found to be
considerably lower in patients with CPFE than in those with IPF.(
3131. Akagi T, Matsumoto T, Harada T, Tanaka M, Kuraki T, Fujita M, et al.
Coexistent emphysema delays the decrease of vital capacity in idiopathic pulmonary
fibrosis. Respir Med. 2009;103(8):1209-15.
http://dx.doi.org/10.1016/j.rmed.2009.02...
) Although DLCO values were lower in the patients with CPFE than in those
with IPF, the annual rate of decline in DLCO was also significantly lower in the
former. There were no differences between the two groups in terms of
survival.(
3131. Akagi T, Matsumoto T, Harada T, Tanaka M, Kuraki T, Fujita M, et al.
Coexistent emphysema delays the decrease of vital capacity in idiopathic pulmonary
fibrosis. Respir Med. 2009;103(8):1209-15.
http://dx.doi.org/10.1016/j.rmed.2009.02...
)
One possible explanation for normal or subnormal spirometry results despite severe impairment in DLCO is that hyperinflation and greater lung compliance as a result of loss of elasticity in the areas of emphysema can compensate for the losses in volume and lung compliance caused by fibrosis. Another plausible explanation is that fibrosis prevents the early small airway closure observed in patients with emphysema.
Although a single spirometry test can underestimate the severity of the disease,
Schmidt et al. demonstrated that a progressive approach, with a longitudinal decline
in FEV1, can accurately define disease progression and predict mortality
in CPFE patients.(
3232. Schmidt SL, Nambiar AM, Tayob N, Sundaram B, Han MK, Gross BH et al.
Pulmonary function measures predict mortality differently in IPF versus combined
pulmonary fibrosis and emphysema. Eur Respir J. 2011;38(1):176-83.
http://dx.doi.org/10.1183/09031936.00114...
) In addition, the authors found a correlation between the extent of
emphysema on HRCT scans and the decline in FEV1.(
3232. Schmidt SL, Nambiar AM, Tayob N, Sundaram B, Han MK, Gross BH et al.
Pulmonary function measures predict mortality differently in IPF versus combined
pulmonary fibrosis and emphysema. Eur Respir J. 2011;38(1):176-83.
http://dx.doi.org/10.1183/09031936.00114...
)
PAH in CPFE
The prevalence of PAH is exceedingly high in patients with CPFE, and PAH correlates
with worse survival.(
33. Cottin V, Nunes H, Brillet PY, Delaval P, Devouassoux G,
Tillie-Leblond I et al. Combined pulmonary fibrosis and emphysema: a distinct
underrecognised entity. Eur Respir J. 2005;26(4):586-93.
http://dx.doi.org/10.1183/09031936.05.00...
,
3333. Cottin V, Le Pavec J, Prévot G, Mal H, Humbert M, Simonneau G, et
al. Pulmonary hypertension in patients with combined pulmonary fibrosis and emphysema
syndrome. Eur Respir J. 2010;35(1):105-11.
http://dx.doi.org/10.1183/09031936.00038...
,
3434. Mejía M, Carrillo G, Rojas-Serrano J, Estrada A, Suárez T, Alonso D,
et al. Idiopathic pulmonary fibrosis and emphysema: decreased survival associated
with severe pulmonary arterial hypertension. Chest.
2009;136(1):10-5.
http://dx.doi.org/10.1378/chest.08-2306...
) The prevalence of PAH in CPFE patients varies from 47% to 90%, being
considerably higher than that in patients with COPD or IPF alone.(
1818. Portillo Carroz K, Roldán Sánchez J, Morera Prat J. Combined
pulmonary fibrosis and emphysema [Article in Spanish]. Arch Bronconeumol.
2010;46(12):646-51.
http://dx.doi.org/10.1016/j.arbres.2010....
) Indeed, the five-year survival rate in a study involving CPFE patients
was 25% in those with PAH (as measured by transthoracic echocardiography), being 75%
in those without PAH.(
2828. Cottin V, Cordier JF. The syndrome of combined pulmonary fibrosis
and emphysema. Chest. 2009;136(1):1-2
http://dx.doi.org/10.1378/chest.09-0538...
) In another study, the finding of severe PAH on echocardiography was
associated with an increased risk of death.(
3535. Sergiacomi G, Bolacchi F, Cadioli M, Angeli ML, Fucci F, Crusco S,
et al. Combined pulmonary fibrosis and emphysema: 3D time-resolved MR angiographic
evaluation of pulmonary arterial mean transit time and time to peak enhancement.
Radiology. 2010;254(2):601-8.
http://dx.doi.org/10.1148/radiol.0908154...
)
Mejia et al. conducted a study in Mexico, in which PAH was assessed by transthoracic
echocardiography in a cohort of patients with IPF (with and without emphysema). Not
only was PAH more prevalent in the patients with CPFE, but it was also responsible
for a worse prognosis. Another important finding was that the amount of emphysema on
CT scans was directly correlated with a higher estimated systolic pulmonary artery
pressure.(
3434. Mejía M, Carrillo G, Rojas-Serrano J, Estrada A, Suárez T, Alonso D,
et al. Idiopathic pulmonary fibrosis and emphysema: decreased survival associated
with severe pulmonary arterial hypertension. Chest.
2009;136(1):10-5.
http://dx.doi.org/10.1378/chest.08-2306...
)
Although transthoracic echocardiography is an operator-dependent imaging modality and
lacks accuracy in the diagnosis of PAH in patients with advanced lung disease,
including COPD and IPF, it seems to have a good correlation with right heart
catheterization studies in CPFE patients, being therefore an effective screening tool
for PAH in such patients.(
1818. Portillo Carroz K, Roldán Sánchez J, Morera Prat J. Combined
pulmonary fibrosis and emphysema [Article in Spanish]. Arch Bronconeumol.
2010;46(12):646-51.
http://dx.doi.org/10.1016/j.arbres.2010....
,
3434. Mejía M, Carrillo G, Rojas-Serrano J, Estrada A, Suárez T, Alonso D,
et al. Idiopathic pulmonary fibrosis and emphysema: decreased survival associated
with severe pulmonary arterial hypertension. Chest.
2009;136(1):10-5.
http://dx.doi.org/10.1378/chest.08-2306...
)
Cottin et al. retrospectively characterized PAH by means of right heart
catheterization in 40 patients with CPFE. Higher pulmonary vascular resistance,
higher HR, lower cardiac index, and lower DLCO were associated with a worse
prognosis, the one-year survival rate being 60%. Although an evaluation of the effect
of treatment was not the primary objective of the study, none of the available
treatments improved survival.(
3333. Cottin V, Le Pavec J, Prévot G, Mal H, Humbert M, Simonneau G, et
al. Pulmonary hypertension in patients with combined pulmonary fibrosis and emphysema
syndrome. Eur Respir J. 2010;35(1):105-11.
http://dx.doi.org/10.1183/09031936.00038...
)
Novel noninvasive methods for the diagnosis and quantification of PAH in CPFE
patients have been proposed, including time-resolved magnetic resonance
angiography,(
3535. Sergiacomi G, Bolacchi F, Cadioli M, Angeli ML, Fucci F, Crusco S,
et al. Combined pulmonary fibrosis and emphysema: 3D time-resolved MR angiographic
evaluation of pulmonary arterial mean transit time and time to peak enhancement.
Radiology. 2010;254(2):601-8.
http://dx.doi.org/10.1148/radiol.0908154...
) which allows anatomic imaging of the pulmonary vasculature and
evaluation of hemodynamic parameters.(
3535. Sergiacomi G, Bolacchi F, Cadioli M, Angeli ML, Fucci F, Crusco S,
et al. Combined pulmonary fibrosis and emphysema: 3D time-resolved MR angiographic
evaluation of pulmonary arterial mean transit time and time to peak enhancement.
Radiology. 2010;254(2):601-8.
http://dx.doi.org/10.1148/radiol.0908154...
) Using this technique, Sergiacomi et al. prospectively studied 18 CPFE
patients using pulmonary arterial mean transit time and time to peak enhancement as
surrogate parameters for hemodynamic data (mean pulmonary artery pressure and
pulmonary vascular resistance), which were obtained through right heart
catheterization performed three days before time-resolved magnetic resonance
angiography was performed.(
3535. Sergiacomi G, Bolacchi F, Cadioli M, Angeli ML, Fucci F, Crusco S,
et al. Combined pulmonary fibrosis and emphysema: 3D time-resolved MR angiographic
evaluation of pulmonary arterial mean transit time and time to peak enhancement.
Radiology. 2010;254(2):601-8.
http://dx.doi.org/10.1148/radiol.0908154...
) Pulmonary arterial mean transit time and time to peak enhancement showed
good correlation with the invasive parameters.(
3535. Sergiacomi G, Bolacchi F, Cadioli M, Angeli ML, Fucci F, Crusco S,
et al. Combined pulmonary fibrosis and emphysema: 3D time-resolved MR angiographic
evaluation of pulmonary arterial mean transit time and time to peak enhancement.
Radiology. 2010;254(2):601-8.
http://dx.doi.org/10.1148/radiol.0908154...
)
Treatment and prognosis
As is the case with IPF, there is currently no effective treatment for CPFE, with the
exception of smoking cessation and lung transplantation (for patients with advanced
disease). Bronchodilators, however, can be prescribed to patients with a positive
response to bronchodilators in pulmonary function tests. Cottin et al.(
44. Cottin V, Nunes H, Mouthon L, Gamondes D, Lazor R, Hachulla E, et al.
Combined pulmonary fibrosis and emphysema syndrome in connective tissue disease.
Arthritis Rheum. 2011;63(1):295-304.
http://dx.doi.org/10.1002/art.30077...
) recommended the use of N-acetylcysteine (1.8 g/day) on the basis of the
results of studies investigating IPF. Oral corticosteroids and immunosuppressants
have been considered an option in the setting of CTD-associated CPFE; however, no
randomized trials have been conducted.(
44. Cottin V, Nunes H, Mouthon L, Gamondes D, Lazor R, Hachulla E, et al.
Combined pulmonary fibrosis and emphysema syndrome in connective tissue disease.
Arthritis Rheum. 2011;63(1):295-304.
http://dx.doi.org/10.1002/art.30077...
) Lung transplantation is the only option that can improve survival.
The major causes of death in patients with CPFE are chronic respiratory failure,
PAH,(
2525. Nunes H, Monnet I, Kannengiesser C, Uzunhan Y, Valeyre D,
Kambouchner M, et al. Is telomeropathy the explanation for combined pulmonary
fibrosis and emphysema syndrome?: report of a family with TERT mutation. Am J Respir
Crit Care Med. 2014;189(6):753-4.
http://dx.doi.org/10.1164/rccm.201309-17...
,
2626. Chilosi M, Carloni A, Rossi A, Poletti V. Premature lung aging and
cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and
COPD/emphysema. Transl Res. 2013;162(3):156-73.
http://dx.doi.org/10.1016/j.trsl.2013.06...
) acute exacerbation,(
33. Cottin V, Nunes H, Brillet PY, Delaval P, Devouassoux G,
Tillie-Leblond I et al. Combined pulmonary fibrosis and emphysema: a distinct
underrecognised entity. Eur Respir J. 2005;26(4):586-93.
http://dx.doi.org/10.1183/09031936.05.00...
,
44. Cottin V, Nunes H, Mouthon L, Gamondes D, Lazor R, Hachulla E, et al.
Combined pulmonary fibrosis and emphysema syndrome in connective tissue disease.
Arthritis Rheum. 2011;63(1):295-304.
http://dx.doi.org/10.1002/art.30077...
) and lung cancer.(
3636. Usui K, Tanai C, Tanaka Y, Noda H, Ishihara T. The prevalence of
pulmonary fibrosis combined with emphysema in patients with lung cancer. Respirology.
2011;16(2):326-31.
http://dx.doi.org/10.1111/j.1440-1843.20...
,
3737. Kwak N, Park CM, Lee J, Park YS, Lee SM, Yim JJ, et al. Lung cancer
risk among patients with combined pulmonary fibrosis and emphysema. Respir Med.
2014;108(3):524-30.
http://dx.doi.org/10.1016/j.rmed.2013.11...
) Usui et al. found an 8.9% prevalence of CPFE in 1,143 consecutive
patients with primary lung cancer in Japan.(
3636. Usui K, Tanai C, Tanaka Y, Noda H, Ishihara T. The prevalence of
pulmonary fibrosis combined with emphysema in patients with lung cancer. Respirology.
2011;16(2):326-31.
http://dx.doi.org/10.1111/j.1440-1843.20...
) The authors showed that, in comparison with patients with fibrosis or
emphysema alone, CPFE patients had a worse survival and an increased incidence of
acute exacerbation after surgery.(
3636. Usui K, Tanai C, Tanaka Y, Noda H, Ishihara T. The prevalence of
pulmonary fibrosis combined with emphysema in patients with lung cancer. Respirology.
2011;16(2):326-31.
http://dx.doi.org/10.1111/j.1440-1843.20...
)
Variations in DLCO, hypoxemia, digital clubbing,(
1010. Kishaba T, Shimaoka Y, Fukuyama H, Yoshida K, Tanaka M, Yamashiro S,
et al. A cohort study of mortality predictors and characteristics of patients with
combined pulmonary fibrosis and emphysema. BMJ Open. 2012;15:2(3).
) mean pulmonary artery pressure,(
2626. Chilosi M, Carloni A, Rossi A, Poletti V. Premature lung aging and
cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and
COPD/emphysema. Transl Res. 2013;162(3):156-73.
http://dx.doi.org/10.1016/j.trsl.2013.06...
,
2727. Brillet PY, Cottin V, Letoumelin P, Landino F, Brauner MW, Valeyre
D, et al. Combined apical emphysema and basal fibrosis syndrome (emphysema/fibrosis
syndrome): CT imaging features and pulmonary function tests [Article in French]. J
Radiol. 2009;90(1 Pt 1):43-51.
http://dx.doi.org/10.1016/S0221-0363(09)...
) and decline in FEV1
(
3232. Schmidt SL, Nambiar AM, Tayob N, Sundaram B, Han MK, Gross BH et al.
Pulmonary function measures predict mortality differently in IPF versus combined
pulmonary fibrosis and emphysema. Eur Respir J. 2011;38(1):176-83.
http://dx.doi.org/10.1183/09031936.00114...
) are considered better surrogates for disease progression and higher risk
of mortality, allowing earlier evaluation for transplantation. Recently, Chiba et al.
demonstrated that two biomarkers of fibrosis, namely KL-6 and surfactant protein D,
are good indicators of the extent of fibrosis in patients with CPFE.(
3838. Chiba S, Ohta H, Abe K, Hisata S, Ohkouchi S, Hoshikawa Y, et al.
The diagnostic value of the interstitial biomarkers KL-6 and SP-D for the degree of
fibrosis in combined pulmonary fibrosis and emphysema. Pulm Med.
2012;2012:492960.
http://dx.doi.org/10.1155/2012/492960...
) High KL-6 and surfactant protein D levels were found to correlate
negatively with all lung volumes and with DLCO.(
3838. Chiba S, Ohta H, Abe K, Hisata S, Ohkouchi S, Hoshikawa Y, et al.
The diagnostic value of the interstitial biomarkers KL-6 and SP-D for the degree of
fibrosis in combined pulmonary fibrosis and emphysema. Pulm Med.
2012;2012:492960.
http://dx.doi.org/10.1155/2012/492960...
) Kishaba et al. demonstrated that high levels of KL-6 are predictors of
acute exacerbations in patients with CPFE.(
1010. Kishaba T, Shimaoka Y, Fukuyama H, Yoshida K, Tanaka M, Yamashiro S,
et al. A cohort study of mortality predictors and characteristics of patients with
combined pulmonary fibrosis and emphysema. BMJ Open. 2012;15:2(3).
)
The prognosis and overall mortality of CPFE patients in comparison with those of IPF and COPD patients is still a matter of debate. Different enrollment criteria, duration of follow-up, heterogeneity of patients (including type of emphysema), retrospective data analysis, and lead-time bias might explain the heterogeneity of results.
Todd et al.(
3939. Todd NW, Jeudy J, Lavania S, Franks TJ, Galvin JR, Deepak J, et al.
Centrilobular emphysema combined with pulmonary fibrosis results in improved
survival. Fibrogenesis Tissue Repair. 2011;4(1):6.
http://dx.doi.org/10.1186/1755-1536-4-6...
) and Todd & Atamas(
4040. Todd NW, Atamas SP. Survival in pulmonary fibrosis combined with
emphysema: likely defined by characteristics of specific patient subpopulations.
Fibrogenesis Tissue Repair. 2011;4:17.
http://dx.doi.org/10.1186/1755-1536-4-17...
) examined the extent and type of emphysema in a subset of patients with
pulmonary fibrosis and found that patients with a combination of fibrosis with
centrilobular or mixed (centrilobular and paraseptal) emphysema had better survival
rates than did those with pulmonary fibrosis without emphysema, those with trivial
emphysema, and those with advanced paraseptal emphysema.(
3939. Todd NW, Jeudy J, Lavania S, Franks TJ, Galvin JR, Deepak J, et al.
Centrilobular emphysema combined with pulmonary fibrosis results in improved
survival. Fibrogenesis Tissue Repair. 2011;4(1):6.
http://dx.doi.org/10.1186/1755-1536-4-6...
,
4040. Todd NW, Atamas SP. Survival in pulmonary fibrosis combined with
emphysema: likely defined by characteristics of specific patient subpopulations.
Fibrogenesis Tissue Repair. 2011;4:17.
http://dx.doi.org/10.1186/1755-1536-4-17...
) The pattern of emphysema and its extent seem to correlate with disease
severity. The reasons for these findings remain unknown. One possible explanation is
that patients with CPFE tend to have somewhat preserved lung volumes compared with
patients with fibrosis alone; however, no retrospective studies found any correlation
between preserved lung volumes (as determined by pulmonary function tests) and better
survival in patients with CPFE. In addition, there were no differences in DLCO among
those groups of patients.(
3939. Todd NW, Jeudy J, Lavania S, Franks TJ, Galvin JR, Deepak J, et al.
Centrilobular emphysema combined with pulmonary fibrosis results in improved
survival. Fibrogenesis Tissue Repair. 2011;4(1):6.
http://dx.doi.org/10.1186/1755-1536-4-6...
,
4040. Todd NW, Atamas SP. Survival in pulmonary fibrosis combined with
emphysema: likely defined by characteristics of specific patient subpopulations.
Fibrogenesis Tissue Repair. 2011;4:17.
http://dx.doi.org/10.1186/1755-1536-4-17...
)
Another hypothesis for centrilobular emphysema acting as a "protective factor" is
based on the fact that centrilobular emphysema is essentially caused by tobacco
exposure. Some in vitro studies have shown that the proinflammatory cytokines seen in
cases of cigarette smoking and emphysema have antifibrotic properties; therefore,
such patients might have smaller areas of fibrosis and a better
prognosis.(
1919. Hoyle GW, Li J, Finkelstein JB, Eisenberg T, Liu JY, Lasky JA, et
al. Emphysematous lesions, inflammation, and fibrosis in the lungs of transgenic mice
overexpressing platelet-derived growth factor. Am J Pathol.
1999;154(6):1763-75.
http://dx.doi.org/10.1016/S0002-9440(10)...
) Paraseptal emphysema might represent another lung response to smoking,
leading to severe pulmonary fibrosis, or simply reflect a greater extent of fibrosis
in lower lung zones, exerting traction on lung tissue located in the apices. However,
the fibrotic areas seen on chest X-rays do not precede the onset of emphysema,
indicating that both processes probably occur simultaneously.
Corroborating this theory, Kurashima et al. found that a greater extent of emphysema
on CT scans correlated with better pulmonary function parameters and a better
prognosis in comparison with those in a group of patients with IPF.(
4141. Kurashima K, Takayanagi N, Tsuchiya N, Kanauchi T, Ueda M, Hoshi T,
et al. The effect of emphysema on lung function and survival in patients with
idiopathic pulmonary fibrosis. Respirology. 2010;15(5):843-8.
http://dx.doi.org/10.1111/j.1440-1843.20...
) The authors did not classify emphysema into subtypes and suggested that
emphysema is a protective factor in patients with CPFE.(
4141. Kurashima K, Takayanagi N, Tsuchiya N, Kanauchi T, Ueda M, Hoshi T,
et al. The effect of emphysema on lung function and survival in patients with
idiopathic pulmonary fibrosis. Respirology. 2010;15(5):843-8.
http://dx.doi.org/10.1111/j.1440-1843.20...
) Similar findings were reported by Ando et al.(
4242. Ando K, Sekiya M, Tobino K, Takahashi K. Relationship between
quantitative CT metrics and pulmonary function in combined pulmonary fibrosis and
emphysema. Lung. 2013;191(6):585-91.
http://dx.doi.org/10.1007/s00408-013-951...
) in a study examining the relationship between pulmonary function and CT
quantification of emphysema and fibrosis in CPFE, the authors having concluded that
pulmonary fibrotic changes contribute more to the progression of CPFE than does
emphysema.(
4242. Ando K, Sekiya M, Tobino K, Takahashi K. Relationship between
quantitative CT metrics and pulmonary function in combined pulmonary fibrosis and
emphysema. Lung. 2013;191(6):585-91.
http://dx.doi.org/10.1007/s00408-013-951...
)
The mortality rates for CPFE and IPF are similar. (
4343. Jankowich MD, Polsky M, Klein M, Rounds S. Heterogeneity in combined
pulmonary fibrosis and emphysema. Respiration. 2008;75(4):411-7.
http://dx.doi.org/10.1159/000107048...
,
4444. Jankowich MD, Rounds S. Combined pulmonary fibrosis and emphysema
alters physiology but has similar mortality to pulmonary fibrosis without emphysema.
Lung. 2010;188(5):365-73.
http://dx.doi.org/10.1007/s00408-010-925...
) Recently, Ryerson et al. compared CPFE-IPF patients with non-CPFE IPF
patients.(
4544. Jankowich MD, Rounds S. Combined pulmonary fibrosis and emphysema
alters physiology but has similar mortality to pulmonary fibrosis without emphysema.
Lung. 2010;188(5):365-73.
http://dx.doi.org/10.1007/s00408-010-925...
) Although the patients with CPFE had a more extensive smoking history,
greater oxygen requirements, higher pulmonary artery pressure, less restrictive
physiology, and lower diffusing capacity, there was no significant difference in
mortality between the two groups.(
4545. Ryerson CJ, Hartman T, Elicker BM, Ley B, Lee JS, Abbritti M et al.
Clinical features and outcomes in combined pulmonary fibrosis and emphysema in
idiopathic pulmonary fibrosis. Chest. 2013;144(1):234-40.
http://dx.doi.org/10.1378/chest.12-2403...
)
Final considerations
Pulmonologists have been accustomed to recognizing fibrosis and emphysema as two well-defined diseases. However, a large body of evidence has shown that an overlap can exist, CPFE being therefore a new entity, with unique features. In view of the fact that most studies investigating CPFE have had a retrospective design, more studies are needed to address the role of emphysema and its subtypes, the progression of fibrosis/emphysema and its correlation with inflammation, treatment options (including the treatment of PAH), and prognosis in CPFE patients. A deeper understanding of the pathophysiology and progression of CPFE is urgently required in order to improve its management, given that there is currently no effective treatment for the disease.
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*
Study carried out in the Department of Pulmonology, Instituto do Coração - InCor, Heart Institute - University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.
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**
A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br
Publication Dates
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Publication in this collection
May-Jun 2014
History
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Received
06 May 2014 -
Accepted
19 May 2014