Vasilios Tzilas

Inherent weaknesses of the current ICD coding system regarding idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most prevalent of the idiopathic interstitial pneumonias (IIPs). It carries an ominous prognosis with a median survival of 3 years. Its epidemiology is poorly described because of its rarity and lack of unanimity in diagnostic and coding practices [1]. However, during the last few years, significant improvement has been achieved in our understanding of the pathogenesis, diagnosis and management of IPF and IIP in general. This is reflected in the 2011 American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society/ALAT consensus statement on IPF [2] and the 2013 ATS/ERS update of the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias [3]. To obtain a robust understanding of the epidemiology of IPF is important, especially as novel therapies are emerging. The International Classification of Disease (ICD) coding system represents a great opportunity to create such registries that will expand our knowledge on IPF epidemiology. However, under its current formation, the 10th edition (ICD-10) coding system has severe deficiencies regarding the accurate classification of IPF. ICD-10 does not adequately classify IPF http://ow.ly/HHNqD

Pirfenidone in Idiopathic Pulmonary Fibrosis “RECAP-itulating Safety into the Real World”

duced respiratory-related hospitalizations indicating a beneficial impact on acute exacerbations of the disease [8] . Major drug-related side effects were nausea, respiratory tract infections, photosensitivity, and diarrhea [9] . Although phase 3 clinical trials set the basis for marketing authorization approval and commercial availability of the drug, they present with inherent limitations on generalizability of the results since they cannot map risks in the real-world setting. Moreover, thorough knowledge that we have about well-established therapeutic agents is acquired after the drug has been approved and marketed and thousands of patients have been exposed to it. In this issue of Respiration , Costabel et al. [10] report longitudinal safety outcomes of the RECAP study, a large simple trial in a cohort of patients with IPF who had previously completed a phase 3 randomized controlled trial. The study enrolled 1,058 patients who had been followed up for almost 5 years. Almost all patients reported at least one treatment-related adverse event. The majority of those were associated with disease progression (33.6%) and respiratory tract infections (52.5%). Cough and dyspnea were also reported in about 1/3 of participants. On the other hand, the most frequent adverse reactions were Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disease that is characterized by progressive lung scarring, ultimately leading to respiratory failure and death within 2.5–3 years of diagnosis [1] . With a gradually increasing incidence, its clinical course being largely unpredictable and the pathogenesis elusive, IPF treatment still represents a major bottleneck for clinicians and researchers [2] . Pirfenidone was the first drug to be approved for the treatment of IPF in the European Union [3] . Pirfenidone is a pleiotropic molecule with antifibrotic, anti-inflammatory and antioxidant properties. It has been demonstrated to inhibit major antifibrotic signaling pathways including those of transforming growth factor-β1, fibroblast growth factor and interleukin-1β [4] . Importantly, pirfenidone has been clinically evaluated and has shown beneficial effects in patients with IPF in 5 randomized controlled trials comprising an overall of 1,710 patients [5–7] . In particular, it was shown that pirfenidone was able to slow down the annual functional decline and reduce the risk of death at 1 year by 48% in a prespecified pooled analysis including data from 3 independent cohorts of patients with IPF [5, 6] . In addition, a recent study showed that pirfenidone significantly rePublished online: September 5, 2017

Idiopathic Pulmonary Fibrosis and Emphysema: Between Scylla and Charybdis.

cific interstitial pneumonia, which has a better prognosis compared to IPF. In this issue of Respiration, Kohashi et al. [14] add further information on the impact of emphysema on IPF prognosis. The novelty of their study lies in the fact that they strictly included patients with biopsy-proven IPF. A total of 47 patients with biopsy-proven IPF were analyzed. For the assessment of emphysema and fibrosis, high-resolution computed tomography scans were evaluated semiquantitatively by visual scoring. The lungs were divided into six zones (upper, middle, and lower zones bilaterally) and each zone was evaluated separately according to the following: score 0 = none; score 0.5 = <5%; score 1 = 5–24%; score 2 = 25–49%; score 3 = 50–74%, and score 4 = ≤ 75%. IPF-emphysema was defined as IPF cases with a total emphysema score greater than 3.0, with mean scores of all 6 zones greater than 0.50. Eight patients fulfilled the previous criteria forming the group of IPF-emphysema. Patients with IPF-emphysema had a statistically significantly worst survival compared to IPF alone patients by Kaplan-Meier analysis (median survival 1,734 vs. 2,229 days, respectively, p = 0.007). As expected, emphysema had upper lobe predominance. Regarding other prognostic parameters on univariate analysis, Krebs von Idiopathic pulmonary fibrosis (IPF) is the commonest of the idiopathic interstitial pneumonias and carries the most ominous prognosis with a median survival of 3 years [1] . IPF often coexists with emphysema. The coexistence of IPF and emphysema is intriguing as they share common pathogenetic mechanisms [2] and alongside lung cancer they have been considered as different manifestations of smoking on a susceptible genetic background [3] . But also from a clinical view the coexistence of IPF and emphysema is very interesting [4] . Firstly, it represents a characteristic case in which the presence of slightly subnormal or even normal forced vital capacity does not exclude the possibility of underlying fibrosis. Secondly, it has opened the question of whether combined pulmonary fibrosis and emphysema (CPFE) patients exhibit worse survival in comparison to sole IPF patients. Literature so far has exhibited contradicting results regarding the survival of CPFE versus sole IPF patients with some of the studies showing worsened survival [5, 6] and other studies showing no difference [7, 8] or even improved survival [9, 10] . Several reasons could be implicated for the discrepant results of the studies so far [11–13] . One of these reasons could be the inclusion in the pulmonary fibrosis group of patients with nonspePublished online: September 8, 2016

Crazy paving pattern as a rare radiological manifestation of peripheral T-cell lymphoma (PTCL) with lung involvement: A case report

Abstract We report on a 70-year old woman with dyspnea, systemic lymphadenopathy and abnormal chest computed tomography (CT) findings. A complete laboratory testing as well as mediastinal tissue sampling via Endobronchial Ultrasound (EBUS)-guided Transbronchial Needle Biopsy (TBNB) did not reveal a definite diagnosis. After experiencing acute respiratory failure which led to intensive care unit, the patient underwent a cervical lymph node biopsy which revealed peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). A CT-guided trans-thoracic lung biopsy was performed that showed involvement of the lung parenchyma in the context of PTCL-NOS. Lung involvement is a rare extra-nodal manifestation of PTCL. The imaging patterns of this lymphoma have not been well described. We conclude that the finding of crazy paving pattern is a rare manifestation of this disease. In patients with pre-existing lymphoma, lung involvement should be included in the differential due to high pre-test probability.

Corrigendum: Longitudinal “Real-World” Outcomes of Pirfenidone in Idiopathic Pulmonary Fibrosis in Greece

[This corrects the article on p. 213 in vol. 4, PMID: 29238708.].

Metsovo Lung: A Story of Episteme, Techne, and Phronesis

to alternative sources of asbestos after abandoning luto as whitewashing material. Asbestos exposure was based on two elements: the presence of pleural plaques on chest computed tomography and the presence of asbestos bodies in bronchoalveolar lavage (BAL). In the absence of both elements, no clinically significant exposure to asbestos was inferred. Gogali et al. used an active surveillance group that consisted of Metsovites born between 1960 and 1980 with recruitment taking place between 2007 and the end of 2011. The rationale for choosing this particular age window was that the „latent period” for the development of pleural plaques recognizable with chest CT is about 30 years, thus excluding residents born after 1980 from the study. It was deemed unnecessary to examine residents born before 1960 because the domestic use of luto at that time was actually universal in the area of Metsovo. Hence, exposure, even if not reported, could not be reliably excluded. The active surveillance group comprised of 36 Metsovites; 22 were evaluated prospectively while the remaining 14 retrospectively. Exposure to luto was reported by 5 individuals (3 during toddler years and 2 until adolescence). Chest CT data were available from all the individuals in the active surveillance group. Eight individuals gave their consent to undergo BAL. Data from previous studies regarding Metsovo Lung, as well as chest CTs of older Metsovites at the time of the current study, served as a comparison group. Metsovo Lung is a classical world-known example of domestic asbestos exposure that led to an “epidemic” of pleural calcifications and malignant pleural mesothelioma. About 40 years ago, the prevalence of pleural calcifications on chest X-rays was almost 50% with increasing rates at older ages (81% above the age of 70 [1]). Between 1981 and 1985, 7 patients from the Metsovo area, with a population of 5,000, were diagnosed with pleural malignant mesothelioma. The incidence of pleural mesothelioma in the area of Metsovo was 280 times greater than the expected incidence of 1/1,000,000/year [2]. The source of asbestos exposure was the white soil (luto) which the residents of Metsovo (Metsovites) used to whitewash their houses during the last century. Luto contained tremolite (a member of the amphibole group of silicate minerals). Preparation of luto involved crushing it to a thin powder that resulted in the release to ambient air of more than 200 asbestos fibers/cm3. This way, the whole family (including children) was domestically exposed to asbestos. Oryctological studies confirmed that tremolite fibers contained in luto were identical to tremolite fibers found in transbronchial biopsies from Metsovites [3, 4]. The domestic use of luto has been abandoned since the mid-eighties because the residents moved on to modern, user-friendly whitewashing materials and not because it was considered dangerous at that time. In this issue of Respiration, Gogali et al. [5] aimed to investigate whether the residents in the region of Metsovo were still exposed Published online: October 13, 2017

Guidelines for Idiopathic Pulmonary Fibrosis: Everything Flows

level of consensus was scored as “perfect” (all respondents agreed), “very good” (median and middle 50% of respondents were found at 1 interval or 80% of respondents were within 1 interval of the median), “good” (50% of respondents were within 1 interval of the median or 80% of the respondents were within 2 intervals of the median), “some” (50% of respondents were within 2 intervals of the median or 80% of respondents were within 3 intervals of the median), and “no consensus” in the remaining cases. The study contains 24 recommendations and the overall consensus agreement was very good (“good” in 1, “very good” in 19, and “perfect” in 4 statements, respectively). In addition, due to the multiple languages used in Switzerland, the Swiss guidelines were compared to current international [2, 3] , German [4] , and French [5] guidelines. There are some recommendations that are worth mentioning. The Swiss report has been differentiated from the ATS/ERS/JRS/ALAT guidelines regarding the use of bronchoalveolar lavage. Bronchoalveolar lavage is not routinely recommended by the ATS/ERS guidelines [2] . However, it can offer information that can drastically alter the diagnostic and consequently therapeutic approach. Hypersensitivity pneumonitis is a characteristic example. It represents a major feature in the differential diagnosis Idiopathic pulmonary fibrosis (IPF) represents a field of constant research and breakthroughs in several areas, from pathogenesis to diagnosis and treatment [1] . This is reflected by the plethora of papers regarding IPF published during the 21st century that led to the official ATS/ ERS/JRS/ALAT evidence-based guidelines for diagnosis and management of IPF [2] . This rapid evolution is further emphasized by the fact that, in 2015, there was a need to publish updated clinical practice guidelines regarding treatment options [3] . Indeed, a number of national societies published their own guidelines in order to keep up with the increasing flow of data [4, 5] . Such an example is the Position Paper of the Working Group for Interstitial and Rare Lung Diseases of the Swiss Respiratory Society on diagnosis and treatment of IPF [6] . The authors have to be commented not only for their initiative but also for their methodology and willingness to decide on controversial questions. An initial list of questions was distributed to the members of the Working Group, and each question was classified as “very important,” “important,” “of limited interest,” and as “unimportant.” Questions considered by the majority as “very important” and “important” formed the basis for this consensus paper. A statement regarding each question was scored from 1 (fully disagree) to 9 (fully agree). The Published online: April 27, 2017

Cardiopulmonary Exercise Testing in Systemic Sclerosis: ‘Ars longa, vita brevis'

the case, and there is also the possibility of co-existent pathophysiologic mechanisms. In the latter case, it is important to identify the primary cause of the symptoms. Another important parameter is the ability to recognize organ and type of involvement at an early stage in the course of the disease that will enable early intervention. In the latest issue of Respiration , Boutou et al. [5] demonstrated that maximal cardiopulmonary exercise testing (CPET) on a cyclic ergometer can provide a useful tool in assessing the main cause of exercise limitation. Their study included a large number of clinically stable SSc patients (both diffuse and limited) who presented due to perceived exertional dyspnea or decreased physical performance and were referred for functional evaluation. The vast majority of patients were able to successfully complete CPET (78 out of 82, 95%). The reasons for not successfully completing CPET were discoordination with the bike (1 patient) and joint pain and stiffness (3 patients). Thus, performing CPET is feasible in everyday clinical practice. Using a modified algorithm [6] , it was possible to categorize the patients into 4 distinct subgroups: (a) normal exercise capacity or subnormal but not limited by evident heart or lung disease (N), (b) respiratory limitation (RL), (c) left ventricular dysfunction (LVD), and (d) pulmonary vasculopathy (PV) and define True knowledge exists in knowing that you know nothing. Socrates