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Abstract Introduction Obstructive sleep apnea (OSA) is often observed in subjects with interstitial lung disease (ILD). It may have a negative impact on the course of ILD, but its prognostic significance in relation to other known indicators of poor outcome is unclear. Methods After a detailed work-up, including overnight unattended type III polygraphy, all subjects newly diagnosed with ILDs referred to our clinics were followed-up for at least 1.5 years or until death or progression of disease [> 10% decline in forced vital capacity (FVC) below baseline]. We analyzed relationships between some prespecified variables of interest, including sleeping results, to establish parameters predictive of progressive course. Results Our population consisted of 46 subjects (mean age 59.6 years; males 61%); 23.9% and 41% had idiopathic pulmonary fibrosis and ILD associated with systemic diseases, respectively. Mean baseline forced vital capacity and diffusion capacity of carbon monoxide were 83% and 57% of predicted, respectively. Mean (± SE) Apnea–Hypopnea Index (AHI) was 17 (± 3) events/h. AHI in the ranges 5–14.9, 15–29.9, and ≥ 30 was recorded in 14 (31%), 6 (13%), and 9 (20%) subjects, respectively. Mean distance covered in the 6-MWG walk test (6MWT) was 302 (± 19) m and 26 subjects (57%) showed exertional oxyhemoglobin desaturation. The median follow-up was about 18 months. Multivariate logistic regression analysis showed that exertional desaturation (HR 8.2; 1.8–36.5 95% CI; p = 0.006) and AHI ≥ 30, namely the threshold of severe OSA (HR 7.5; 1.8–30.6; p = 0.005), were the only independent variables related to progressive disease course. Conclusion We conclude that exertional desaturation and elevated AHI had independent negative prognostic significance in our ILD population.

Introduction: Patients with pulmonary fibrosis experience early oxyhemoglobin desaturation under effort, which limits their ability to exercise and their quality of life. Recent studies have shown that in resting normoxaemic patients who become hypoxemic under exertion, administration of outpatient oxygen significantly improves stress dyspnoea and quality of life. It is unclear how this happens, since oxygen administration does not act directly on dyspnoea, and does not appear to have much effect on the heart rate and pulmonary artery pressure. We tested the hypothesis that correcting the hypoxaemia could reduce the increase in respiratory effort during the 6 min walking test, recording the breathing pattern during administration of oxygen or placebo. Methods: We evaluated 20 patients with fibrotic interstitial lung diseases (17 males and 3 females; mean age 72 ± 2 years; M ± SE) with a resting SpO2 ≥92 that fell to ≤88% during the 6 min walk test (6MWT). After first establishing the oxygen flow necessary to prevent desaturation, the patients underwent two further 6MWT, 15–20 min apart, one with administration of medical air and one with oxygen at the same flow, in randomized double-blind order. During the test, SpO2, heart rate, respiratory rate, tidal volume and minute ventilation (VE) were recorded, using a Spiropalm spirometer (Cosmed, Rome, Italy). Results: Oxygen saturation during the 6MWT decreased to a minimum value of 82.3% (95% CI 80.1–84.5%) during placebo and to 92% (90.3–93.7%) during oxygen with an average difference of 9.7% (7.8–11.6%, p < 0.0001). On the contrary, heart rate showed an increasing trend with walking time reaching a significantly higher maximum rate during placebo, with a difference of 5.4 bpm (2.9–8.7, p < 0.005) compared to oxygen. The distance walked was slightly but significantly greater after oxygen by 28 m (2–53, p < 0.05) and end of test dyspnoea after placebo by 0.6 points (0.1–1.1, p < 0.05). Respiratory rate increased over time, without differences between oxygen and placebo in the first minute of walking, then increasing significantly more during placebo (p < 0.0005). With placebo, tidal volume increased rapidly reaching a plateau at about 48% of FVC after 3 min, while with oxygen, the increase was slower, reaching a maximum of about 45% of FVC at the end of the test. Nevertheless, the difference was highly significant (p < 0.0005) at all the time points. Minute ventilation also increased significantly with walking time but remained at a highly significant lower level during oxygen than placebo at all the time points. Mean reduction in VE during the test with oxygen compared to placebo was 4.4 L/min (3.9–4.9, p < 0.0005). Conclusion: In our ILD patients, administration of outpatient oxygen during walking was related to a reduced increase in heart rate, respiratory rate, tidal volume and minute ventilation necessary to meet increased oxygen requirements, resulting in a lower workload on the cardiovascular system and on respiratory muscles and a consequent reduction in dyspnoea.

The pathogenetic mechanism of post-Covid-19 pulmonary fibrosis is currently a topic of intense research interest, but still largely unexplored. The aim of this work was to carry out a systematic exploratory search of the literature (Scoping review) to identify and systematize the main pathogenetic mechanisms that are believed to be involved in this phenomenon, in order to highlight the same molecular aspect of the lung. These aims could be essential in the future for therapeutic management. We identified all primary studies involving in post COVID19 syndrome with pulmonary fibrosis as a primary endpoint by performing data searches in various systematic review databases. Two reviewers independently reviewed all abstracts (398) and full text data. The quality of study has been assess through SANRA protocol. A total of 32 studies involving were included, included the possible involvement of inflammatory cytokines, concerned the renin-angiotensin system, the potential role of galectin-3, epithelial injuries in fibrosis, alveolar type 2 involvement, Neutrophil extracellular traps (NETs) and the others implied other specific aspects (relationship with clinical and mechanical factors, epithelial transition mesenchymal, TGF-β signaling pathway, midkine, caspase and macrophages, genetics). In most cases, these were narrative reviews or letters to the editor, except for 10 articles, which presented original data, albeit sometimes in experimental models. From the development of these researches, progress in the knowledge of the phenomenon and hopefully in its prevention and therapy may originate.

Abstract Background Serum chitotriosidase is a promising biomarker that has shown high specificity and sensitivity in patients with sarcoidosis. The aim of this study was to investigate correlations between serum chitotriosidase, clinical phenotypes, disease localizations and different radiological lung involvement and to identify clinical features associated with over-expression of chitotriosidase in a large cohort of sarcoidosis patients. Methods Chitotriosidase activity was evaluated in a population of 694 consecutive patients (males 39%, age 55.8 ± 12.8 years). Clinical and respiratory functional characteristics, Clinical Outcome Scale (COS) classification, clinical phenotypes proposed by the GenPhenResA project, and radiological assessment, including CT scan, were collected. Serum sampling and clinical and functional assessments at follow-up were also included. Results Significantly higher chitotriosidase activity was observed in sarcoidosis patients than in healthy controls (p

Background: Nintedanib is an oral multitarget tyrosine kinase inhibitor approved for the treatment of patients with idiopathic pulmonary fibrosis (IPF). Recent evidence demonstrated that nintedanib reduced functional disease progression also in subjects with non-IPF progressive fibrosing interstitial lung disease (PF-ILD). However, real-life data on the effectiveness of nintedanib in PF-ILD and familial pulmonary fibrosis (FPF) are lacking. Methods: this retrospective monocentric study enrolled 197 patients affected with IPF, PF-ILD and FPF treated with nintedanib at the Referral Centre of Siena from 2014 to 2021. Pulmonary functional tests and survival data were collected throughout the observation period for the evaluation of mortality and disease progression outcomes. Results: nintedanib treatment significantly reduced the FVC decline rate in IPF and PF-ILD subgroups, but not in FPF subjects. No significant differences were observed among the subgroups in terms of survival, which appeared to be influenced by gender and impaired lung function (FVC < 70% of predicted value). Concerning disease progression rate, a diagnosis of FPF is associated with more pronounced FVC decline despite nintedanib treatment. Conclusions: our research studies the effectiveness and safety of nintedanib in reducing functional disease progression of IPF and PF-ILD. FPF appeared to be less responsive to nintedanib, even though no differences were observed in terms of survival.

Introduction: Cytomegalovirus (CMV) is the leading opportunistic infection in lung transplant (LTx) recipients. CMV is associated with graft failure and decreased survival. Recently, new antiviral therapies have been proposed. The present study aimed to investigate NK and T cell subsets of patients awaiting LTx. We analyzed the cellular populations between reactive and non-reactive QuantiFERON (QF) CMV patients for the prediction of immunological response to infection. Methods: Seventeen pre-LTx patients and 15 healthy controls (HC) have been enrolled. QF and IFN-γ ELISA assay detections were applied. NK cell subsets and T cell and proliferation assay were detected before and after stimulation with pp-65 and IE-1 CMV antigens after stratification as QF+ and QF−. Furthermore, we quantified the serum concentrations of NK− and T-related cytokines by bead-based multiplex analysis. Results: CD56brCD16lowNKG2A+KIR+ resulted in the best discriminatory cellular subsets between pre-LTx and HC. Discrepancies emerged between serology and QF assay. Better proliferative capability emerged from patients who were QF+, in particular in CD8 and CD25-activated cells. CD56brCD16low, adaptive/memory-like NK and CD8Teff were highly increased only in QF+ patients. Conclusions: QF more than serology is useful in the detection of patients able to respond to viral infection. This study provides new insights in terms of immunological responses to CMV in pre-LTX patients, particularly in NK and T cells biology.

Introduction: ILDs are a varied group of diffuse parenchymal lung diseases associated with high morbidity and mortality. Current treatments can only slow their progression but not cure the disease. Other treatments such as oxygen therapy can also be used as support. We know very little about the effects of oxygen therapy on patients with ILDs. The aim of this study was to collect data from the literature in order to determine whether oxygen therapy can actually decrease the mortality rate or whether it is only suitable for supportive therapy for patients with ILDs. Methods: We reviewed the literature since 2010 on oxygen therapy during exercise in patients with ILDs. Studies that used cardio-pulmonary tests were excluded. We only reviewed those that used the 6 min walking test (6MWT) or the free walking test. We located 11 relevant articles. Results: All the articles except a Japanese study showed an augmentation in oxyhaemoglobin saturation during exercise when oxygen was supplied. A 2018 study called AmbOx provided important data on the effects of oxygen therapy during daily activities, showing significant improvements in quality of life. Conclusions: This review showed that the literature on the benefits of oxygen therapy in patients with ILDs does not provide sufficient evidence to draft specific guidelines. It was not possible to conclude whether oxygen therapy has an effect on mortality or can only play a supportive role.

Background: Changes in calcium metabolism are quite common in sarcoidosis: hypercalciuria is linked to a persistent clinical phenotype and more active disease. No data is yet available on the specificity of parameters of calcium metabolism as biomarkers for distinguishing different chronic interstitial lung diseases (ILD). Here we assessed calcium metabolism in an Italian population of sarcoidosis patients, which included a group with stage IV fibrotic disease, and compared the results with those of idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis (cHP) patients.Population and Methods: We recruited sarcoidosis, IPF and cHP patients retrospectively. All patients were diagnosed through multidisciplinary discussion and were monitored at the Regional ILD Referral Centre in Siena. Clinical, radiological, functional, immunological and laboratory parameters were collected and entered in an electronic database for data analysis.Results: A total of 305 patients (237 sarcoidosis, 40 IPF and 28 cHP) were enrolled. Sarcoidosis patients included a predominance of females and were significantly younger than IPF and cHP patients (p < 0.0001 for both). In the sarcoidosis population, 17 patients (7.2%) showed radiological evidence of lung fibrosis, according the Scadding classification; fibrotic disease was also confirmed by CT scan. Concerning calcium metabolism, sarcoidosis patients showed significantly higher serum and urinary concentrations of calcium than IPF and cHP patients (p = 0.0004 and p < 0.0001, respectively). These findings were also confirmed when comparing groups with fibrotic sarcoidosis, IPF and cHP (p = 0.0237 and p = 0.0138). According to receiver operating characteristics (ROC) curve analysis, urinary calcium showed better diagnostic accuracy than serum calcium in discriminating sarcoid and non-sarcoid lung fibrosis (AUC 0.7658 vs. 0.6205; p = 0.0026 vs. p = 0.1820).Discussion: Our results confirmed that changes in calcium metabolism, particularly hypercalciuria, occur in a substantial percentage of patients with sarcoidosis. Higher serum and urinary concentrations of calcium were found than in IPF and cHP; the same results were observed when the comparison was limited to patients with fibrotic sarcoidosis, supporting the hypothesis that dysregulation of calcium metabolism may be a special feature of sarcoid granulomas. Hypercalciuria distinguished fibrotic sarcoidosis from IPF and cHP, suggesting that assessment of calcium metabolism may be useful in the diagnostic pathway of ILDs.

BackgroundPirfenidone and nintedanib are the sole pharmacological therapies currently approved for idiopathic pulmonary fibrosis (IPF). Limited comparison data is available in literature, despite they are both prescribed for mild-to-moderate disease. Here, we describe our almost 10 years real-life experience with antifibrotic treatment to investigate potential differences in terms of efficacy.Population and MethodsWe retrospectively recruited patients diagnosed with IPF and treated with pirfenidone or nintedanib at Siena Referral Center. Clinical, functional, safety and radiological data was collected at baseline and during the follow-up, according to our Center protocol.ResultsWe retrospectively recruited 263 IPF patients (139 treated with pirfenidone and 124 with nintedanib) in the study. After 885.3 ± 559.5 days of observation, the median survival was 1224 days. No significant differences were found between pirfenidone and nintedanib in terms of survival and time to decline of forced vital capacity >10% (p = 0.8786 and p = 0.1677, respectively). A smaller lung diffusion for carbon monoxide (DLCO) decrease was found after 1 year of therapy with nintedanib in respect to pirfenidone (p = 0.0167). Overall, 21 patients permanently discontinued antifibrotic treatment due to side effects (14 with pirfenidone, 7 with nintedanib); no fatal adverse events were recorded.DiscussionOur results showed a similar effectiveness between pirfenidone and nintedanib in terms of mortality and functional disease progression. Both drugs confirmed their good tolerability profile and no new safety alerts were observed. Nintedanib was associated with a smaller reduction of DLCO after 1 year of follow-up compared with pirfenidone, maybe due to its antiangiogenic properties.

Background: Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia and has a median survival after diagnosis of 2–5 years. Pirfenidone is the first approved antifibrotic drug for the treatment of IPF. Here we report the functional progress, side effects and survival data of a population of patients with IPF, diagnosed at our centre and treated with pirfenidone. Methods: We enrolled 91 patients with IPF (71 males) treated with pirfenidone. Clinical, survival and functional details were collected retrospectively at start of therapy and after 12, 24, 36 and 48 months of treatment. Lung function tests at least 12 months before starting therapy were available for 40 patients and were entered in the database, as well as side effects. Results: During the observation period (922 ± 529 days), 27 patients died, 5 patients underwent lung transplant and 10 patients interrupted therapy due to adverse events or IPF progression. The median survival was 1606 days. There was a significant reduction in disease progression rate, as measured by trend of forced vital capacity, after 1 year of therapy with respect to before treatment ( p = 0.0085). Forced vital capacity reduction rate was progressively higher in the subsequent years of treatment. Treatment-related side effects were reported in 25 patients and were predominantly mild. Overall, four patients discontinued therapy due to severe photosensitivity. Conclusions: Our findings confirm the efficacy of pirfenidone in reducing functional progression of IPF and its excellent safety profile in a real-life setting. This study, designed on a long-term follow up, contributes to the growing evidence on safety, tolerability and efficacy of pirfenidone in IPF. The reviews of this paper are available via the supplemental material section.

Severe acute respiratory syndrome caused by coronavirus 2 emerged in Wuhan (China) in December 2019 and has severely challenged the human population. NK and T cells are involved in the progression of COVID-19 infection through the ability of NK cells to modulate T-cell responses, and by the stimulation of cytokine release. No detailed investigation of the NK cell landscape in clinical SARS-CoV-2 infection has yet been reported. A total of 35 COVID-19 hospitalised patients were stratified for clinical severity and 17 healthy subjects were enrolled. NK cell subsets and T cell subsets were analysed with flow cytometry. Serum cytokines were detected with a bead-based multiplex assay. Fewer CD56dimCD16brightNKG2A+NK cells and a parallel increase in the CD56+CD69+NK, CD56+PD-1+NK, CD56+NKp44+NK subset were reported in COVID-19 than HC. A significantly higher adaptive/memory-like NK cell frequency in patients with severe disease than in those with mild and moderate phenotypes were reported. Moreover, adaptive/memory-like NK cell frequencies were significantly higher in patients who died than in survivors. Severe COVID-19 patients showed higher serum concentrations of IL-6 than mild and control groups. Direct correlation emerged for IL-6 and adaptive/memory-like NK. All these findings provide new insights into the immune response of patients with COVID-19. In particular, they demonstrate activation of NK through overexpression of CD69 and CD25 and show that PD-1 inhibitory signalling maintains an exhausted phenotype in NK cells. These results suggest that adaptive/memory-like NK cells could be the basis of promising targeted therapy for future viral infections.

Since SARS-CoV-2 emerged in 2019, strict monitoring of post-COVID-19 patients in order to ensure the early detection of sequelae and/or chronic organ damage that could been associated with the infection has been essential. Potential involvement of the NO pathway in the development of post-COVID-19 lung fibrotic alterations is feasible, since the majority of respiratory cells can produce NO, and fractional exhaled NO (FeNO) represents a biomarker of airway inflammation. The aim of this study was to investigate the potential utility of multiple-flow FeNO parameters in a post-COVID-19 population and to compare it with other indicators of lung damage proposed in the literature. We enrolled 20 patients hospitalized for COVID-19, who underwent clinical, respiratory functional (including PFTs and FeNO) and radiological follow-up after discharge. Compared with age- and sex-matched healthy controls, post-COVID-19 patients showed significantly higher FeNO 350 mL/s and CaNO levels. Moreover, among the parameters included in the follow-up, CaNO showed the best accuracy in indicating predominant fibrotic changes and GGO at CT scan. To our knowledge, this preliminary study has investigated for the first time multiple-flow FeNO parameters in a post-COVID-19 population. The evidence of increased CaNO values may imply the persistence of alveolar and bronchiolar inflammation and/or a mild impairment of the alveolar-capillary membrane in these patients.

Abstract Background Fibrotic interstitial lung diseases (ILDs) are chronic and often progressive conditions resulting in substantial morbidity and mortality. Shortness of breath, a symptom often linked to oxygen desaturation on exertion, is tightly linked to worsening quality of life in these patients. Although ambulatory oxygen is used empirically in their treatment, there are no ILD-specific guidelines on its use. To our knowledge, no studies are available on the effects of ambulatory oxygen on day-to-day life in patients with ILD. Methods/design Ambulatory oxygen in fibrotic lung disease (AmbOx) is a multicentre, randomised controlled crossover trial (RCT) funded by the Research for Patient Benefit Programme of the National Institute for Health Research. The trial will compare ambulatory oxygen used during daily activities with no ambulatory oxygen in patients with fibrotic lung disease whose oxygen saturation (SaO2) is ≥94% at rest, but drops to ≤88% on a 6-min Walk Test. The randomised controlled trial (RCT) will evaluate the effects on health status (measured by the King’s Brief ILD Questionnaire: K-BILD) of ambulatory oxygen used at home, at an optimal flow rate determined by titration at screening visit, and administered for a 2-week period, compared to 2 weeks off oxygen. Key secondary outcomes will include breathlessness on activity scores, as measured by the University of California San Diego Shortness of Breath Questionnaire, global patient assessment of change scores, as well as quality of life scores (St George’s Respiratory Questionnaire), anxiety and depression scores (Hospital Anxiety and Depression Scale), activity markers measured by SenseWear Armbands, pulse oximetry measurements, patient-reported daily activities, patient- and oxygen company-reported oxygen cylinder use. The study also includes a qualitative component and will explore in interviews patients’ experiences of the use of a portable oxygen supply and trial participation in a subgroup of 20 patients and carers. Discussion This is the first RCT of the effects of ambulatory oxygen during daily life on health status and breathlessness in fibrotic lung disease. The results generated should provide the basis for setting up ILD-specific guidelines for the use of ambulatory oxygen. Trial registration National Clinical Trials Registry, identifier: NCT02286063 . Registered on 8 October 2014 (retrospectively registered).

Background: The immune mechanisms occurring during acute rejection (AR) and chronic lung allograft dysfunction are a challenge for research and the balance between effector and regulatory cells has not been defined completely. In this study, we aimed to elucidate the interaction of effector cells, mainly Th17, Th1 and Th2, and regulatory cells including (CD4+CD25+CD127low/−) T reg cells and phenotypes of B regs, CD19+CD24hiCD38hi, CD19+CD24hiCD27hi and CD19+CD5+CD1d+. Methods: Bronchoalveolar lavage cells (BAL) and peripheral blood mononuclear cells (PBMCs) from stable lung transplanted (LTx )subjects (n = 4), AR patients (n = 6) and bronchiolitis obliterans syndrome (BOS) (n = 6) were collected at the same time. Cellular subsets were detected through flow cytometry. Results: A predominance of Th17 cells subtypes in the PBMCs and BAL and a depletion of Tregs, that resulted in decrease Treg/Th17 ratio, was observed in the AR group. CD19+CD24hiCD38hi Bregs resulted increased in BAL of AR patients. Th1 cells predominance and a reduction of Tregs cells was observed in BAL from AR patients. Moreover, multivariate analysis showed interdependences within studied variables revealing that effector cells and regulatory cells can effectively discriminate patients’ immunological status. Conclusions: In AR, BOS and stable lung transplant, regulatory and effector cells clearly demonstrated different pathways of activation. Understanding of the balance of T cells and T and B regulatory cells can offers insights into rejection.

Fractional exhaled nitric oxide (FeNO) is a well-known and widely accepted biomarker of airways inflammation that can be useful in the therapeutic management, and adherence to inhalation therapy control, in asthmatic patients. However, the multiple-flows assessment of FeNO can provide a reliable measurement of bronchial and alveolar production of NO, supporting its potential value as biomarker also in peripheral lung diseases, such as interstitial lung diseases (ILD). In this review, we first discuss the role of NO in the pathobiology of lung fibrosis and the technique currently approved for the measurement of maximum bronchial flux of NO (J’awNO) and alveolar concentration of NO (CaNO). We systematically report the published evidence regarding extended FeNO analysis in the management of patients with different ILDs, focusing on its potential role in differential diagnosis, prognostic evaluation and severity assessment of disease. The few available data concerning extended FeNO analysis, and the most common comorbidities of ILD, are explored too. In conclusion, multiple-flows FeNO analysis, and CaNO in particular, appears to be a promising tool to be implemented in the diagnostic and prognostic pathways of patients affected with ILDs.

After publication of our article [1] the authors have notified us that one of the names has been incorrectly tagged.

RESUMO Objetivo A fibrose pulmonar familiar (FPF) é definida como uma doença pulmonar intersticial idiopática que afeta dois ou mais membros da mesma família. Nesses pacientes, os resultados têm sido insatisfatórios, apresentando alto risco de morte e disfunção crônica do enxerto pulmonar (CLAD) após o transplante de pulmão. O objetivo do presente estudo foi comparar o resultado de curto e longo prazo do transplante de pulmão em pacientes com FPF e pacientes transplantados por outras doenças pulmonares intersticiais. Métodos Foram coletados retrospectivamente dados clínicos pré e pós-transplante de 83 pacientes com fibrose pulmonar submetidos a transplante de pulmão. Os pacientes foram divididos em aqueles com fibrose pulmonar familiar (n = 9, grupo FPF) e aqueles com fibrose pulmonar não familiar (n = 74, grupo controle). Resultados O grupo FPF foi composto de quatro mulheres e cinco homens, sendo 44,5% ex-fumantes. A maioria apresentou tomografia computadorizada e evidência patológica de pneumonia intersticial usual. Os pacientes com FPF tiveram níveis significativamente menores de hemoglobina e hematócrito. Não foram observadas outras diferenças nas características pré e pós-transplante em relação ao grupo controle. A evolução clínica pós-operatória foi semelhante nos dois grupos. Não foi constatada diferença significativa na sobrevida de um ano livre de CLAD e na sobrevida em geral. Conclusão A evolução pós-transplante de pacientes com FPF foi semelhante à dos pacientes com fibrose pulmonar não familiar, embora mais pacientes com FPF tivessem anemia pré-transplante. O resultado a curto e longo prazo foi comparável em ambos os grupos. O transplante de pulmão provou ser uma opção válida para pacientes com FPF, assim como para pacientes com outros tipos de fibrose pulmonar.

A letter to the editor is presented in response to the article "The Need for Expertise and the Scientific Base of Evidence-Based Medicine," that was published in the previous issue.