Editorial
Controversies in Fibrosis and Emphysema
Controversias en la fibrosis y el enfisema
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Antoniou, Eleni Bibaki, George A. Margaritopoulos" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Katerina M." "apellidos" => "Antoniou" "email" => array:1 [ 0 => "kantoniou@med.uoc.gr" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Eleni" "apellidos" => "Bibaki" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "George A." "apellidos" => "Margaritopoulos" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Department of Thoracic Medicine, Faculty of Medicine, University of Crete, Heraklion, Greece" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Interstitial Lung Disease Unit, Royal Brompton Hospital, London, UK" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Controversias en la fibrosis y el enfisema" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The clinical entity of combined pulmonary fibrosis and emphysema (CPFE) is characterized by the admixture of fibrosis and emphysema on high resolution computed tomography (HRCT). It can be observed in the context of idiopathic interstitial pneumonias such as idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP) and in interstitial lung diseases associated with connective tissue disorders (CTD-ILDs) such as rheumatoid arthritis (RA) and systemic sclerosis (SSc).<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">1–3</span></a> It is still unclear whether this entity represents a distinct syndrome, a specific subtype of fibrosis, or a coincidental co-existence of two processes.</p><p id="par0010" class="elsevierStylePara elsevierViewall">In contrast to isolated pulmonary fibrosis and emphysema, no specific pathogenic pathways which could lead to different treatment approach for CPFE have yet been identified. However, common pathogenetic pathways, such as increase in oxidative stress, accelerated lung aging associated with genetic abnormalities (for example, mutations in the telomerase genes), and increased neutrophil elastases are involved in both disorders.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">4</span></a> Historically, the presence of radiologic emphysema was associated with smoking. Interestingly, in smokers with IPF, NSIP, rheumatoid and pulmonary scleroderma, the development of emphysema was associated with a lower pack-year smoking history than in smokers without fibrosis.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">1–3</span></a> This could be viewed as indirect evidence of an interaction between fibrosis and smoking in the development of emphysema in this subgroup of patients. More intriguingly, in a large cohort of 333 patients with pulmonary scleroderma, 15/41 patients with CPFE were non-smokers, raising the possibility of an autoimmune origin of emphysema in this subgroup.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">3</span></a> Obviously, in the absence of a control cohort, these results should be interpreted with caution, and need to be confirmed at the cellular and biological level.</p><p id="par0015" class="elsevierStylePara elsevierViewall">CPFE poses significant difficulties in the diagnosis of the radiologic pattern of pulmonary fibrosis. It is generally accepted that in ILDs, diagnosis means prognosis. In clinical practice, the main concern is to distinguish IPF, the most common and severe form of ILD, from other fibrotic lung disease such as NSIP, some subtypes of chronic hypersensitivity pneumonitis, and unclassifiable ILD, which generally have a better prognosis. In CPFE, it is often difficult to distinguish between honeycombing cysts, the main characteristic of usual interstitial pneumonia (UIP) which is the radiologic counterpart of IPF, and pseudocysts due to admixture of emphysema and fibrosis. This difficulty was underlined in a recent study in the diagnosis of UIP among thoracic radiologists with special interest in ILDs.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">5</span></a> Quantification of the extent of both processes is also problematic. Some experts have suggested using density masking, but the main constraint in this case is that areas of low density could correspond to either emphysema, or honeycombing, or traction bronchiectasis. The likely contamination of CPFE cohorts with entities like NSIP, and the difficulty in including patients with the same extent of emphysema and fibrosis has led to conflicting results regarding the prognostic significance of CPFE.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">6–8</span></a> Mejia et al. reported an interesting finding, namely, that worse prognosis in CPFE was due to the high prevalence of pulmonary hypertension (PH).<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">6</span></a> Although this could facilitate early diagnosis of PH, it is clinically irrelevant because no effective treatment is available for PH associated with IPF or CPFE. In scleroderma lung, which exhibits different clinical behavior from IPF, the presence of trivial emphysema did not influence the prevalence of PH on echocardiography at presentation compared to patients with isolated fibrosis.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">3</span></a> After adjustment for the extent of fibrosis on HRCT, emphysema was associated with an additional average reduction of 24.1% from baseline DLco levels and a 34.8% increase in the FVC/DLco ratio, but there was no overall significant effect on forced vital capacity (FVC) levels. These effects did not differ between smokers and nonsmokers, and on multivariate analysis pulmonary function tests were not influenced by either smoking status or total pack-years after adjusting for the extent of pulmonary fibrosis or the presence of emphysema. The FVC/DLco ratio is used in SSc as a marker of PH, and a value greater than 1.6 calls for an echocardiogram. However, this study showed that in the presence of emphysema, the ratio is not a reliable marker for echocardiographic features of PH.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The coexistence of emphysema and fibrosis has a significant attenuating effect on serial FVC decline, with major implications for routine IPF monitoring and the use of serial FVC as a primary endpoint in IPF treatment trials. In a well-defined pharmaceutical IPF cohort, patients with IPF and concurrent emphysema had a significantly slower rate of decline of FVC than patients with IPF only when the extent of emphysema on HRCT was greater than 15%.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">9</span></a> It should also be stressed that the coexistence of emphysema with IPF leads to spurious preservation of FVC, which has implications in the approval of antifibrotic drugs in countries where an upper limit for FVC is used to assess eligibility for treatment. There is still insufficient evidence to support the use of the composite physiolocic index (cpi), which takes into account the presence of emphysema, as an end-point in these patients. Baseline cpi correlates with the extent of IPF disease on CT and is superior to individual lung function variables in predicting survival in patients with concomitant radiologic emphysema, whereas in IPF patients without emphysema, baseline cpi has the same predictive value as baseline DLco.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">10</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In the context of CTD-ILDs, the impact of concurrent emphysema on serial changes in FVC, which is also used as the primary end-point in clinical trials in SSc-ILD,<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">11</span></a> has not yet been studied. Recently though, it was observed that the presence of limited emphysema had no effect on baseline FVC after adjustment for the extent of ILD.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">3</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">In conclusion, the coexistence of emphysema with fibrosis remains controversial. This entity is not characterized by the activation of any particular pathways that can lead to the development of disease-specific treatment. In the case of IPF, the presence of emphysema causes difficulties in monitoring the behavior of the disease and the response to treatment due to the attenuating effect on serial FVC decline. Moreover, the preservation of FVC precludes the use of antifibrotic drugs in countries where an upper limit of FVC is used. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 7 | 4 | 11 |
| 2024 October | 40 | 20 | 60 |
| 2024 September | 48 | 21 | 69 |
| 2024 August | 64 | 42 | 106 |
| 2024 July | 41 | 21 | 62 |
| 2024 June | 61 | 28 | 89 |
| 2024 May | 80 | 21 | 101 |
| 2024 April | 45 | 19 | 64 |
| 2024 March | 61 | 19 | 80 |
| 2024 February | 30 | 37 | 67 |
| 2023 July | 2 | 4 | 6 |
| 2023 March | 12 | 4 | 16 |
| 2023 February | 41 | 11 | 52 |
| 2023 January | 31 | 22 | 53 |
| 2022 December | 81 | 29 | 110 |
| 2022 November | 82 | 21 | 103 |
| 2022 October | 58 | 32 | 90 |
| 2022 September | 51 | 26 | 77 |
| 2022 August | 37 | 38 | 75 |
| 2022 July | 25 | 40 | 65 |
| 2022 June | 31 | 27 | 58 |
| 2022 May | 28 | 33 | 61 |
| 2022 April | 46 | 41 | 87 |
| 2022 March | 49 | 48 | 97 |
| 2022 February | 41 | 35 | 76 |
| 2022 January | 46 | 38 | 84 |
| 2021 December | 35 | 31 | 66 |
| 2021 November | 26 | 44 | 70 |
| 2021 October | 29 | 39 | 68 |
| 2021 September | 23 | 40 | 63 |
| 2021 August | 20 | 51 | 71 |
| 2021 July | 25 | 35 | 60 |
| 2021 June | 31 | 46 | 77 |
| 2021 May | 33 | 36 | 69 |
| 2021 April | 94 | 90 | 184 |
| 2021 March | 38 | 25 | 63 |
| 2021 February | 49 | 25 | 74 |
| 2021 January | 34 | 13 | 47 |
| 2020 December | 35 | 18 | 53 |
| 2020 November | 41 | 23 | 64 |
| 2020 October | 28 | 22 | 50 |
| 2020 September | 26 | 18 | 44 |
| 2020 August | 37 | 26 | 63 |
| 2020 July | 50 | 22 | 72 |
| 2020 June | 33 | 21 | 54 |
| 2020 May | 31 | 15 | 46 |
| 2020 April | 20 | 17 | 37 |
| 2020 March | 23 | 17 | 40 |
| 2020 February | 23 | 24 | 47 |
| 2020 January | 35 | 26 | 61 |
| 2019 December | 25 | 25 | 50 |
| 2019 November | 31 | 20 | 51 |
| 2019 October | 22 | 24 | 46 |
| 2019 September | 23 | 26 | 49 |
| 2019 August | 26 | 23 | 49 |
| 2019 July | 30 | 19 | 49 |
| 2019 June | 31 | 20 | 51 |
| 2019 May | 52 | 26 | 78 |
| 2019 April | 31 | 25 | 56 |
| 2019 March | 33 | 20 | 53 |
| 2019 February | 21 | 21 | 42 |
| 2019 January | 26 | 17 | 43 |
| 2018 December | 27 | 22 | 49 |
| 2018 November | 45 | 14 | 59 |
| 2018 October | 71 | 14 | 85 |
| 2018 September | 34 | 5 | 39 |
| 2018 June | 2 | 0 | 2 |
| 2018 May | 33 | 0 | 33 |
| 2018 April | 26 | 7 | 33 |
| 2018 March | 23 | 9 | 32 |
| 2018 February | 38 | 6 | 44 |
| 2018 January | 35 | 8 | 43 |
| 2017 December | 37 | 11 | 48 |
| 2017 November | 41 | 8 | 49 |
| 2017 October | 29 | 21 | 50 |
| 2017 September | 47 | 22 | 69 |
| 2017 August | 83 | 25 | 108 |
| 2017 July | 4 | 3 | 7 |
| 2017 June | 8 | 5 | 13 |
| 2017 May | 65 | 21 | 86 |
| 2017 April | 5 | 4 | 9 |
| 2017 March | 0 | 3 | 3 |
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