Effectiveness and economic impact of Dupilumab in asthma: a population-based cohort study.

RATIONALE: Severe asthma is burdened by relevant socio-economic and clinical impact. Randomized controlled trials on Dupilumab showed efficacy and a good safety profile, but post-market studies are needed. OBJECTIVES: To evaluate the impact of Dupilumab on (i) the use of anti-asthmatic drugs, including oral corticosteroids (OCS), (ii) the rates of asthma exacerbation-related hospital admissions, and (iii) the healthcare costs in patients with asthma. METHODS: Data were retrieved from Healthcare Utilization database of Lombardy region (Italy). We compared healthcare resources use between the 6 months after Dupilumab initiation ("post-intervention period") and (i) the 6 months before Dupilumab initiation ("wash-out period") and (ii) the corresponding 6 months of the prior year ("pre-intervention period"). MAIN RESULTS: In a cohort of 176 patients, Dupilumab significantly reduced anti-asthmatic drugs use (including OCS and short-acting ß2-agonists, inhaled corticosteroids (ICS)/long-acting ß2-agonists and ICS alone) when comparing the "pre-intervention" to the "post-intervention" period. When considering hospital admissions, we observed a not statistically or marginally significant reduction between both periods before Dupilumab and the post-intervention period. Six-months discontinuation rate was 8%. Overall healthcare costs had a tenfold increase between the "pre-intervention" and "post-intervention" period, which was mainly led by the biologic drug cost. Conversely, expenditures connected to hospital admissions did not change. CONCLUSIONS: Our real-world investigation suggests that Dupilumab reduced anti-asthmatic drugs use, including OCS, in comparison to a corresponding period in the prior year. However, long-term healthcare sustainability remains an open issue.

Cluster Analysis to Explore Clinical Subphenotypes of Eosinophilic Granulomatosis With Polyangiitis.

OBJECTIVE: Previous studies suggested that distinct phenotypes of eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome) could be determined by the presence or absence of antineutrophil cytoplasmic antibodies (ANCA), reflecting predominant vasculitic or eosinophilic processes, respectively. This study explored whether ANCA-based clusters or other clusters can be identified in EGPA. METHODS: This study used standardized data of 15 European centers for patients with EGPA fulfilling widely accepted classification criteria. We used multiple correspondence analysis, hierarchical cluster analysis, and a decision tree model. The main model included 10 clinical variables (musculoskeletal [MSK], mucocutaneous, ophthalmological, ENT, cardiovascular, pulmonary, gastrointestinal, renal, central, or peripheral neurological involvement); a second model also included ANCA results. RESULTS: The analyses included 489 patients diagnosed between 1984 and 2015. ANCA were detected in 37.2% of patients, mostly perinuclear ANCA (85.4%) and/or antimyeloperoxidase (87%). Compared with ANCA-negative patients, those with ANCA had more renal (P < 0.001) and peripheral neurological involvement (P = 0.04), fewer cardiovascular signs (P < 0.001), and fewer biopsies with eosinophilic tissue infiltrates (P = 0.001). The cluster analyses generated 4 (model without ANCA) and 5 clusters (model with ANCA). Both models identified 3 identical clusters of 34, 39, and 40 patients according to the presence or absence of ENT, central nervous system, and ophthalmological involvement. Peripheral neurological and cardiovascular involvement were not predictive characteristics. CONCLUSION: Although reinforcing the known association of ANCA status with clinical manifestations, cluster analysis does not support a complete separation of EGPA in ANCA-positive and -negative subsets. Collectively, these data indicate that EGPA should be regarded as a phenotypic spectrum rather than a dichotomous disease.

The role of chest CT in deciphering interstitial lung involvement: systemic sclerosis versus COVID-19.

OBJECTIVE: The aim of this study was to identify the main CT features that may help in distinguishing a progression of interstitial lung disease (ILD) secondary to SSc from COVID-19 pneumonia. METHODS: This multicentric study included 22 international readers grouped into a radiologist group (RADs) and a non-radiologist group (nRADs). A total of 99 patients, 52 with COVID-19 and 47 with SSc-ILD, were included in the study. RESULTS: Fibrosis inside focal ground-glass opacities (GGOs) in the upper lobes; fibrosis in the lower lobe GGOs; reticulations in lower lobes (especially if bilateral and symmetrical or associated with signs of fibrosis) were the CT features most frequently associated with SSc-ILD. The CT features most frequently associated with COVID- 19 pneumonia were: consolidation (CONS) in the lower lobes, CONS with peripheral (both central/peripheral or patchy distributions), anterior and posterior CONS and rounded-shaped GGOs in the lower lobes. After multivariate analysis, the presence of CONs in the lower lobes (P < 0.0001) and signs of fibrosis in GGOs in the lower lobes (P < 0.0001) remained independently associated with COVID-19 pneumonia and SSc-ILD, respectively. A predictive score was created that was positively associated with COVID-19 diagnosis (96.1% sensitivity and 83.3% specificity). CONCLUSION: CT diagnosis differentiating between COVID-19 pneumonia and SSc-ILD is possible through a combination of the proposed score and radiologic expertise. The presence of consolidation in the lower lobes may suggest COVID-19 pneumonia, while the presence of fibrosis inside GGOs may indicate SSc-ILD.

Long-term evaluation of the safety and efficacy of recombinant human pentraxin-2 (rhPTX-2) in patients with idiopathic pulmonary fibrosis (IPF): an open-label extension study.

BACKGROUND: Recombinant human pentraxin-2 (rhPTX-2) significantly decreased decline in percent predicted forced vital capacity (FVC) and stabilized 6-min walk distance (6MWD) in patients with idiopathic pulmonary fibrosis (IPF) during the 28-week, placebo-controlled, randomized period of the Phase II PRM-151-202 study. Interim (76-week) data from the open-label extension (OLE) demonstrated sustained safety and efficacy with rhPTX-2 treatment. Here, we present the entire long-term OLE safety and efficacy data to 128 weeks. METHODS: Patients who completed the randomized PRM-151-202 study period were eligible for the OLE, during which all patients received rhPTX-2, having started rhPTX-2 (i.e., crossed from placebo) or continued rhPTX-2 after Week 28. rhPTX-2 was administered in 28-week cycles, with 10 mg/kg intravenous infusions (60 min) on Days 1, 3, and 5 in the first week of each cycle, then one infusion every 4 weeks up to Week 128. The OLE primary objective was to assess the long-term safety and tolerability of rhPTX-2. Other outcomes included FVC, 6MWD, and patient-reported outcomes (descriptive analysis). RESULTS: All 111 patients who completed the randomized period entered the OLE (n = 37 started rhPTX-2; n = 74 continued rhPTX-2); 57 (51.4%) completed to Week 128. The treatment-emergent adverse event (TEAE) profile was consistent with the randomized period, with the majority of TEAEs graded mild or moderate. Serious TEAEs occurred in 47 patients (42.3%), most frequently IPF (n = 11; 9.9%), pneumonia (n = 7; 6.3%), and acute respiratory failure (n = 3; 2.7%). Three patients underwent lung transplantation. Most serious TEAEs (and all 14 fatal events) were considered unrelated to rhPTX-2 treatment. For patients starting vs continuing rhPTX-2, mean (95% confidence interval) changes from baseline to Week 128 were, respectively, - 6.2% (- 7.7; - 4.6) and - 5.7% (- 8.0; - 3.3) for percent predicted FVC and - 36.3 m (- 65.8; - 6.9) and - 28.9 m (- 54.3; - 3.6) for 6MWD; however, conclusions were limited by patient numbers at Week 128. CONCLUSIONS: Long-term treatment (up to 128 weeks) with rhPTX-2 was well tolerated in patients with IPF, with no new safety signals emerging in the OLE. The limited efficacy data over 128 weeks may suggest a trend towards a treatment effect. Trial registration NCT02550873; EudraCT 2014-004782-24.

Sarcopenia in idiopathic pulmonary fibrosis: a prospective study exploring prevalence, associated factors and diagnostic approach.

BACKGROUND: Sarcopenia gained importance in the evaluation of patients with chronic respiratory diseases, including idiopathic pulmonary fibrosis (IPF), since it may impact negatively on clinical outcomes. AIM: Aim of this study is to evaluate the prevalence and factors associated with sarcopenia, defined according to the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) 2019 definition, and to evaluate the prevalence of the single criteria that define the EWGSOP2 definition (muscle strength, muscle quantity and physical performance), in a cohort of consecutive patients with IPF prospectively followed up in 9 hospitals in Northern Italy between December 2018 and May 2021. METHODS: Enrolled patients underwent an extensive pulmonary and nutritional assessment, including bioelectrical impedance analysis, dynamometry and 4-m gait speed test, both at IPF diagnosis and at 6-month follow-up. RESULTS: Out of the 83 patients (81% males, mean age 72.5 years) with IPF at disease diagnosis enrolled in the study, 19 (22.9%) showed sarcopenia, including 2 (2.4%) with severe sarcopenia, 5 (6.0%) with confirmed sarcopenia and 12 (14.5%) with probable sarcopenia. Sarcopenia was associated with a significantly higher severity of the disease and sedentary lifestyle, while no differences were observed in regards to body mass index, history of weight loss and comorbidities between patients with and without sarcopenia. Out of the 64 patients without sarcopenia at baseline, 16 cases showed alteration of muscle quantity and/or physical performance. In the 51 patients with complete data at 6-month follow-up, there were no cases of severe sarcopenia, 1 case (2.0%) showed confirmed sarcopenia, while the prevalence of probable sarcopenia was 19.6% (10 cases). No differences in regards to antifibrotic treatment received and onset of gastrointestinal side effects were observed between patients with and without sarcopenia at follow-up. CONCLUSIONS: The prevalence of sarcopenia in patients with IPF both at diagnosis and at 6-month follow-up was low but not negligible and was associated with higher severity of the disease and sedentary lifestyle. In IPF patients, a comprehensive diagnostic work-up including all the criteria defining the EWGSOP2 definition might be more useful than a series testing for prompt recognition of nutritional and physical performance abnormalities.

One-year pulmonary impairment after severe COVID-19: a prospective, multicenter follow-up study.

BACKGROUND: Long-term pulmonary sequelae following hospitalization for SARS-CoV-2 pneumonia is largely unclear. The aim of this study was to identify and characterise pulmonary sequelae caused by SARS-CoV-2 pneumonia at 12-month from discharge. METHODS: In this multicentre, prospective, observational study, patients hospitalised for SARS-CoV-2 pneumonia and without prior diagnosis of structural lung diseases were stratified by maximum ventilatory support ("oxygen only", "continuous positive airway pressure (CPAP)" and "invasive mechanical ventilation (IMV)") and followed up at 12 months from discharge. Pulmonary function tests and diffusion capacity for carbon monoxide (DLCO), 6 min walking test, high resolution CT (HRCT) scan, and modified Medical Research Council (mMRC) dyspnea scale were collected. RESULTS: Out of 287 patients hospitalized with SARS-CoV-2 pneumonia and followed up at 1 year, DLCO impairment, mainly of mild entity and improved with respect to the 6-month follow-up, was observed more frequently in the "oxygen only" and "IMV" group (53% and 49% of patients, respectively), compared to 29% in the "CPAP" group. Abnormalities at chest HRCT were found in 46%, 65% and 80% of cases in the "oxygen only", "CPAP" and "IMV" group, respectively. Non-fibrotic interstitial lung abnormalities, in particular reticulations and ground-glass attenuation, were the main finding, while honeycombing was found only in 1% of cases. Older patients and those requiring IMV were at higher risk of developing radiological pulmonary sequelae. Dyspnea evaluated through mMRC scale was reported by 35% of patients with no differences between groups, compared to 29% at 6-month follow-up. CONCLUSION: DLCO alteration and non-fibrotic interstitial lung abnormalities are common after 1 year from hospitalization due to SARS-CoV-2 pneumonia, particularly in older patients requiring higher ventilatory support. Studies with longer follow-ups are needed.

Clinical spectrum time course in non-Asian patients positive for anti-MDA5 antibodies.

OBJECTIVES: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. METHODS: We conducted a multicentre, international, retrospective cohort study. RESULTS: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. CONCLUSIONS: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.

Nintedanib in IPF: Post hoc Analysis of the Italian FIBRONET Observational Study.

BACKGROUND: The FIBRONET study was an observational study of patients with idiopathic pulmonary fibrosis (IPF) in Italy. OBJECTIVES: In this post hoc descriptive analysis, we describe changes in lung function, anxiety/depression, coughing, exacerbations, and adverse events (AEs) in patients receiving nintedanib treatment. METHODS: Patients with IPF from 20 centers in Italy, aged ≥40 years who received nintedanib for ≥7 months, were followed up for 12 months from study enrollment, attending clinic visits every 3 months. Outcomes included change in forced vital capacity (FVC)% predicted from baseline to 12 months, anxiety/depression measured by the Hospital Anxiety and Depression Scale (HADS), and the proportion of patients with cough, AEs, and exacerbations. RESULTS: In total, 52 patients received nintedanib (mean duration of 11.6 months). Ten patients had dose reductions from 150 mg to 100 mg twice daily, due to AEs. FVC% predicted was unchanged in the overall nintedanib population (78.7% at baseline; 79.8% at 12 months) and those with a reduced dose (77.7% at baseline; 81.0% at 12 months). HADS score was low at baseline and throughout the study. The proportion of patients with cough decreased from 50.0% to 21.2% over 12 months. Two patients experienced exacerbations, 2 patients discontinued treatment, and 27 (51.9%) reported AEs. The most common AE was diarrhea (34.6%). CONCLUSIONS: In patients with IPF who received nintedanib in the FIBRONET study, FVC% predicted was stable over 12 months, and the proportion of patients with cough decreased. The safety profile was consistent with the known safety profile for nintedanib in IPF.

Prolonged exposure to welding fumes as a novel cause of systemic iron overload.

BACKGROUND & AIMS: Inhalation of welding fume may cause pulmonary disease known as welder's lung. At our centre we came across a number of welders with systemic iron overload and prolonged occupational history and we aimed at characterizing this novel clinical form of iron overload. METHODS: After exclusion of other known causes of iron overload, 20 welders were fully evaluated for working history, hepatic, metabolic and iron status. MRI iron assessment was performed in 19 patients and liver biopsy in 12. We included 40 HFE-HH patients and 24 healthy controls for comparison. RESULTS: 75% of patients showed lung HRCT alterations; 90% had s-FERR > 1000 ng/mL and 60% had TSAT > 45%. Liver iron overload was mild in 8 and moderate-severe in 12. The median iron removed was 7.8 g. Welders showed significantly lower TSAT and higher SIS and SIS/TIS ratio than HFE-HH patients. Serum hepcidin was significantly higher in welders than in HFE-HH patients and healthy controls. At liver biopsy, 50% showed liver fibrosis that was mild in four, and moderate-severe in two. Liver staging correlated with liver iron overload. CONCLUSIONS: Welders with prolonged fume exposure can develop severe liver iron overload. The mechanism of liver iron accumulation is quite different to that of HFE-HH suggesting that reticuloendothelial cells may be the initial site of deposition. We recommend routine measurement of serum iron indices in welders to provide adequate diagnosis and therapy, and the inclusion of prolonged welding fume exposure in the list of acquired causes of hyperferritinemia and iron overload.

Helmet CPAP to treat hypoxic pneumonia outside the ICU: an observational study during the COVID-19 outbreak.

BACKGROUND: Respiratory failure due to COVID-19 pneumonia is associated with high mortality and may overwhelm health care systems, due to the surge of patients requiring advanced respiratory support. Shortage of intensive care unit (ICU) beds required many patients to be treated outside the ICU despite severe gas exchange impairment. Helmet is an effective interface to provide continuous positive airway pressure (CPAP) noninvasively. We report data about the usefulness of helmet CPAP during pandemic, either as treatment, a bridge to intubation or a rescue therapy for patients with care limitations (DNI). METHODS: In this observational study we collected data regarding patients failing standard oxygen therapy (i.e., non-rebreathing mask) due to COVID-19 pneumonia treated with a free flow helmet CPAP system. Patients' data were recorded before, at initiation of CPAP treatment and once a day, thereafter. CPAP failure was defined as a composite outcome of intubation or death. RESULTS: A total of 306 patients were included; 42% were deemed as DNI. Helmet CPAP treatment was successful in 69% of the full treatment and 28% of the DNI patients (P < 0.001). With helmet CPAP, PaO2/FiO2 ratio doubled from about 100 to 200 mmHg (P < 0.001); respiratory rate decreased from 28 [22-32] to 24 [20-29] breaths per minute, P < 0.001). C-reactive protein, time to oxygen mask failure, age, PaO2/FiO2 during CPAP, number of comorbidities were independently associated with CPAP failure. Helmet CPAP was maintained for 6 [3-9] days, almost continuously during the first two days. None of the full treatment patients died before intubation in the wards. CONCLUSIONS: Helmet CPAP treatment is feasible for several days outside the ICU, despite persistent impairment in gas exchange. It was used, without escalating to intubation, in the majority of full treatment patients after standard oxygen therapy failed. DNI patients could benefit from helmet CPAP as rescue therapy to improve survival. TRIAL REGISTRATION: NCT04424992.

Six-Month Pulmonary Impairment after Severe COVID-19: A Prospective, Multicentre Follow-Up Study.

BACKGROUND: Long-term pulmonary sequelae following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia are not yet confirmed; however, preliminary observations suggest a possible relevant clinical, functional, and radiological impairment. OBJECTIVES: The aim of this study was to identify and characterize pulmonary sequelae caused by SARS-CoV-2 pneumonia at 6-month follow-up. METHODS: In this multicentre, prospective, observational cohort study, patients hospitalized for SARS-CoV-2 pneumonia and without prior diagnosis of structural lung diseases were stratified by maximum ventilatory support ("oxygen only," "continuous positive airway pressure," and "invasive mechanical ventilation") and followed up at 6 months from discharge. Pulmonary function tests and diffusion capacity for carbon monoxide (DLCO), 6-min walking test, chest X-ray, physical examination, and modified Medical Research Council (mMRC) dyspnoea score were collected. RESULTS: Between March and June 2020, 312 patients were enrolled (83, 27% women; median interquartile range age 61.1 [53.4, 69.3] years). The parameters that showed the highest rate of impairment were DLCO and chest X-ray, in 46% and 25% of patients, respectively. However, only a minority of patients reported dyspnoea (31%), defined as mMRC ≥1, or showed restrictive ventilatory defects (9%). In the logistic regression model, having asthma as a comorbidity was associated with DLCO impairment at follow-up, while prophylactic heparin administration during hospitalization appeared as a protective factor. The need for invasive ventilatory support during hospitalization was associated with chest imaging abnormalities. CONCLUSIONS: DLCO and radiological assessment appear to be the most sensitive tools to monitor patients with the coronavirus disease 2019 (COVID-19) during follow-up. Future studies with longer follow-up are warranted to better understand pulmonary sequelae.

Molecular Biomarkers in Idiopathic Pulmonary Fibrosis: State of the Art and Future Directions.

Idiopathic pulmonary fibrosis (IPF), the most lethal form of interstitial pneumonia of unknown cause, is associated with a specific radiological and histopathological pattern (the so-called "usual interstitial pneumonia" pattern) and has a median survival estimated to be between 3 and 5 years after diagnosis. However, evidence shows that IPF has different clinical phenotypes, which are characterized by a variable disease course over time. At present, the natural history of IPF is unpredictable for individual patients, although some genetic factors and circulating biomarkers have been associated with different prognoses. Since in its early stages, IPF may be asymptomatic, leading to a delayed diagnosis. Two drugs, pirfenidone and nintedanib, have been shown to modify the disease course by slowing down the decline in lung function. It is also known that 5-10% of the IPF patients may be affected by episodes of acute and often fatal decline. The acute worsening of disease is sometimes attributed to identifiable conditions, such as pneumonia or heart failure; but many of these events occur without an identifiable cause. These idiopathic acute worsenings are termed acute exacerbations of IPF. To date, clinical biomarkers, diagnostic, prognostic, and theranostic, are not well characterized. However, they could become useful tools helping facilitate diagnoses, monitoring disease progression and treatment efficacy. The aim of this review is to cover molecular mechanisms underlying IPF and research into new clinical biomarkers, to be utilized in diagnosis and prognosis, even in patients treated with antifibrotic drugs.

Progressive Fibrosing Interstitial Lung Diseases: Prevalence and Characterization in Two Italian Referral Centers.

BACKGROUND: The prevalence and natural history of progressive fibrosing interstitial lung diseases (PF-ILDs), and their response to commonly used treatments in real life are largely unknown. OBJECTIVES: The aim of the study was to describe the prevalence, clinical characteristics, management, and outcomes of PF-ILD patients attending 2 Italian referral centers (San Gerardo Hospital, Monza, and San Giuseppe Hospital, Milan) from January 1, 2011, to July 31, 2019. METHODS: From a cohort of non-idiopathic pulmonary fibrosis fibrosing ILD patients with at least 2-year follow-up, we selected only those with progressive disease, defined as per the INBUILD trial, collecting their demographical, clinical, and functional data. RESULTS: Out of the 245 fibrosing ILD patients, 75 (31%) were classified as PF-ILDs (median age 66 years, 60% males), most frequently idiopathic non-specific interstitial pneumonia (28%), followed by connective tissue disease-associated ILD (20%), chronic hypersensitivity pneumonitis, and sarcoidosis (17% each). Most patients (81%) were categorized as PF-ILDs because of forced vital capacity (FVC) decline ≥10%, while 19% experienced a marginal FVC decline (between 5 and 10%) associated with worsening respiratory symptoms or increasing extent of fibrotic changes on high-resolution computed tomography. Disease progression occurred after a median of 18 months from ILD diagnosis. The vast majority (93%) of PF-ILD patients received prednisolone, alone (40%) or associated with steroid-sparing agents (52%), and 35% of treated patients developed treatment-related adverse events. After ILD progression, the median survival was 3 (interquartile range (IQR) 2-5) years, with a 2- and 3-year mortality rate of 4 and 20%, respectively. CONCLUSIONS: In a real-life setting, approximately one-third of the fibrosing ILD patients showed a progressive course despite treatment. Studies aimed to better phenotype this subgroup of patients are needed.

Psychometric properties and minimal important differences of SF-36 in Idiopathic Pulmonary Fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a rare disease with a median survival of 3-5 years after diagnosis with limited treatment options. The aim of this study is to assess the psychometric characteristics of the Short Form 36 Health Status Questionnaire (SF-36) in IPF and to provide disease specific minimally important differences (MID). METHODS: Data source was the European IPF Registry (eurIPFreg). The psychometric properties of the SF-36 version 2 were evaluated based on objective clinical measures as well as subjective perception. We analysed acceptance, feasibility, discrimination ability, construct and criterion validity, responsiveness and test-retest-reliability. MIDs were estimated via distribution and anchor-based approaches. RESULTS: The study population included 258 individuals (73.3% male; mean age 67.3 years, SD 10.7). Of them 75.2% (194 individuals) had no missing item. The distribution of several items was skewed, although floor effect was acceptable. Physical component score (PCS) correlated significantly and moderately with several anchors, whereas the correlations of mental component score (MCS) and anchors were only small. The tests showed mainly significant lower HRQL in individuals with long-term oxygen therapy. Analyses in stable individuals did not show significant changes of HRQL except for one dimension and anchor. Individuals with relevant changes of the health status based on the anchors had significant changes in all SF-36 dimensions and summary scales except for the dimension PAIN. PCS and MCS had mean MIDs of five and six, respectively. Mean MIDs of the dimensions ranged from seven to 21. CONCLUSION: It seems that the SF-36 is a valid instrument to measure HRQL in IPF and so can be used in RCTs or individual monitoring of disease. Nevertheless, the additional evaluation of longitudinal aspects and MIDs can be recommended to further analyse these factors. Our findings have a great potential impact on the evaluation of IPF patients. TRIAL REGISTRATION: The eurIPFreg and eurIPFbank are listed in https://clinicaltrials.gov ( NCT02951416 ).

Management of Chronic Respiratory Failure in Interstitial Lung Diseases: Overview and Clinical Insights.

Interstitial lung diseases (ILDs) may be complicated by chronic respiratory failure (CRF), especially in the advanced stages. Aim of this narrative review is to evaluate the current evidence in management of CRF in ILDs. Many physiological mechanisms underlie CRF in ILDs, including lung restriction, ventilation/perfusion mismatch, impaired diffusion capacity and pulmonary vascular damage. Intermittent exertional hypoxemia is often the initial sign of CRF, evolving, as ILD progresses, into continuous hypoxemia. In the majority of the cases, the development of CRF is secondary to the worsening of the underlying disease; however, associated comorbidities may also play a role. When managing CRF in ILDs, the need for pulmonary rehabilitation, the referral to lung transplant centers and palliative care should be assessed and, if necessary, promptly offered. Long-term oxygen therapy is commonly prescribed in case of resting or exertional hypoxemia with the purpose to decrease dyspnea and improve exercise tolerance. High-Flow Nasal Cannula oxygen therapy may be used as an alternative to conventional oxygen therapy for ILD patients with severe hypoxemia requiring both high flows and high oxygen concentrations. Non-Invasive Ventilation may be used in the chronic setting for palliation of end-stage ILD patients, although the evidence to support this application is very limited.

Molecular Pathways and Respiratory Involvement in Lysosomal Storage Diseases.

Lysosomal storage diseases (LSD) include a wide range of different disorders with variable degrees of respiratory system involvement. The purpose of this narrative review is to treat the different types of respiratory manifestations in LSD, with particular attention being paid to the main molecular pathways known so far to be involved in the pathogenesis of the disease. A literature search was conducted using the Medline/PubMed and EMBASE databases to identify studies, from 1968 through to November 2018, that investigated the respiratory manifestations and molecular pathways affected in LSD. Pulmonary involvement includes interstitial lung disease in Gaucher's disease and Niemann-Pick disease, obstructive airway disease in Fabry disease and ventilatory disorders with chronic respiratory failure in Pompe disease due to diaphragmatic and abdominal wall muscle weakness. In mucopolysaccharidosis and mucolipidoses, respiratory symptoms usually manifest early in life and are secondary to anatomical malformations, particularly of the trachea and chest wall, and to accumulation of glycosaminoglycans in the upper and lower airways, causing, for example, obstructive sleep apnea syndrome. Although the molecular pathways involved vary, ranging from lipid to glycogen and glycosaminoglycans accumulation, some clinical manifestations and therapeutic approaches are common among diseases, suggesting that lysosomal storage and subsequent cellular toxicity are the common endpoints.

The European IPF registry (eurIPFreg): baseline characteristics and survival of patients with idiopathic pulmonary fibrosis.

BACKGROUND: Since 2009, IPF patients across Europe are recruited into the eurIPFreg, providing epidemiological data and biomaterials for translational research. METHODS: The registry data are based on patient and physician baseline and follow-up questionnaires, comprising 1700 parameters. The mid- to long-term objectives of the registry are to provide clues for a better understanding of IPF phenotype sub-clusters, triggering factors and aggravating conditions, regional and environmental characteristics, and of disease behavior and management. RESULTS: This paper describes baseline data of 525 IPF subjects recruited from 11/2009 until 10/2016. IPF patients had a mean age of 68.1 years, and seeked medical advice due to insidious dyspnea (90.1%), fatigue (69.2%), and dry coughing (53.2%). A surgical lung biopsy was performed in 32% in 2009, but in only 8% of the cases in 2016, possibly due to increased numbers of cryobiopsy. At the time of inclusion in the eurIPFreg, FVC was 68.4% ± 22.6% of predicted value, DLco ranged at 42.1% ± 17.8% of predicted value (mean value ± SD). Signs of pulmonary hypertension were found in 16.8%. Steroids, immunosuppressants and N-Acetylcysteine declined since 2009, and were replaced by antifibrotics, under which patients showed improved survival (p = 0.001). CONCLUSIONS: Our data provide important insights into baseline characteristics, diagnostic and management changes as well as outcome data in European IPF patients over time. TRIAL REGISTRATION: The eurIPFreg and eurIPFbank are listed in ClinicalTrials.gov( NCT02951416 ).

A Real-Life Multicenter National Study on Nintedanib in Severe Idiopathic Pulmonary Fibrosis.

BACKGROUND: Two therapeutic options are currently available for patients with mild-to-moderate idiopathic pulmonary fibrosis (IPF): pirfenidone and nintedanib. To date, there is still insufficient data on the efficacy of these 2 agents in patients with more severe disease. OBJECTIVES: This national, multicenter, retrospective real-life study was intended to determine the impact of nintedanib on the treatment of patients with severe IPF. METHODS: All patients included had severe IPF and had to have at least 6 months of follow-up before and at least 6 months of follow-up after starting nintedanib. The aim of the study was to compare the decline in lung function before and after treatment. Patient survival after 6 months of therapy with nintedanib was assessed. RESULTS: Forty-one patients with a forced vital capacity (FVC) ≤50% and/or a diffusing capacity of the lung for carbon monoxide (DLCO) ≤35% predicted at the start of nintedanib treatment were enrolled. At the 6-month follow-up, the decline of DLCO (both absolute and % predicted) was significantly reduced compared to the pretreatment period (absolute DLCO at the -6-month, T0, and +6-month time points (5.48, 4.50, and 5.03 mmol/min/kPa, respectively, p = 0.03; DLCO% predicted was 32.73, 26.54, and 29.23%, respectively, p = 0.04). No significant beneficial effect was observed in the other functional parameters analyzed. The 1-year survival in this population was 79%, calculated from month 6 of therapy with nintedanib. CONCLUSIONS: This nationwide multicenter experience in patients with severe IPF shows that nintedanib slows down the rate of decline of absolute and % predicted DLCO but does not have significant impact on FVC or other lung parameters.

Management of acute respiratory failure in interstitial lung diseases: overview and clinical insights.

BACKGROUND: Interstitial lung diseases (ILDs) are a heterogeneous group of diseases characterized by widespread fibrotic and inflammatory abnormalities of the lung. Respiratory failure is a common complication in advanced stages or following acute worsening of the underlying disease. Aim of this review is to evaluate the current evidence in determining the best management of acute respiratory failure (ARF) in ILDs. METHODS: A literature search was performed in the Medline/PubMed and EMBASE databases to identify studies that investigated the management of ARF in ILDs (the last search was conducted on November 2017). RESULTS: In managing ARF, it is important to establish an adequate diagnostic and therapeutic management depending on whether the patient has an underlying known chronic ILD or ARF is presenting in an unknown or de novo ILD. In the first case both primary causes, such as acute exacerbations of the disease, and secondary causes, including concomitant pulmonary infections, fluid overload and pulmonary embolism need to be investigated. In the second case, a diagnostic work-up that includes investigations in regards to ILD etiology, such as autoimmune screening and bronchoalveolar lavage, should be performed, and possible concomitant causes of ARF have to be ruled out. Oxygen supplementation and ventilatory support need to be titrated according to the severity of ARF and patients' therapeutic options. High-Flow Nasal oxygen might potentially be an alternative to conventional oxygen therapy in patients requiring both high flows and high oxygen concentrations to correct hypoxemia and control dyspnea, however the evidence is still scarce. Neither Non-Invasive Ventilation (NIV) nor Invasive Mechanical Ventilation (IMV) seem to change the poor outcomes associated to advanced stages of ILDs. However, in selected patients, such as those with less severe ARF, a NIV trial might help in the early recognition of NIV-responder patients, who may present a better short-term prognosis. More invasive techniques, including IMV and Extracorporeal Membrane Oxygenation, should be limited to patients listed for lung transplant or with reversible causes of ARF. CONCLUSIONS: Despite the overall poor prognosis of ARF in ILDs, a personalized approach may positively influence patients' management, possibly leading to improved outcomes. However, further studies are warranted.

Effect of Recombinant Human Pentraxin 2 vs Placebo on Change in Forced Vital Capacity in Patients With Idiopathic Pulmonary Fibrosis: A Randomized Clinical Trial.

Importance: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Approved therapies do not halt disease progression. Objective: To determine the effect of recombinant human pentraxin 2 vs placebo on change from baseline to week 28 in mean forced vital capacity (FVC) percentage of predicted value. Design, Setting, and Participants: Phase 2, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 7 countries of eligible patients with IPF (N = 117; aged 40-80 years; FVC ≥50% and ≤90% predicted; ratio of forced expiratory volume in the first second/FVC >0.70; diffusing capacity for carbon monoxide [Dlco] ≥25% and ≤90% predicted; and distance of ≥150 m on the 6-minute walk test). Study period was August 2015-May 2017. Interventions: Patients were randomized to receive either recombinant human pentraxin 2 (10 mg/kg intravenous every 4 weeks, n = 77) or placebo (n = 39) for 24 weeks, and stratified by concurrent IPF treatment status. Main Outcomes and Measures: The primary end point was the least-squares mean change in FVC percentage of predicted value from baseline to week 28 (minimal clinically important difference, decline of 2%-6%). Secondary end points included mean change in lung volumes (total, normal, and interstitial lung abnormalities) on high-resolution computed tomography (HRCT) and 6-minute walk distance (minimal clinically important difference, 24-45 m). Results: Of 117 randomized patients, 116 received at least 1 dose of study drug (mean age, 68.6 years; 81.0% men; mean time since IPF diagnosis, 3.8 years), and 111 (95.7%) completed the study. The least-squares mean change in FVC percentage of predicted value from baseline to week 28 in patients treated with recombinant human pentraxin 2 was -2.5 vs -4.8 for those in the placebo group (difference, +2.3 [90% CI, 1.1 to 3.5]; P = .001). No significant treatment differences were observed in total lung volume (difference, 93.5 mL [90% CI, -27.7 to 214.7]), quantitative parenchymal features on HRCT (normal lung volume difference, -1.2% [90% CI, -4.4 to 1.9]; interstitial lung abnormalities difference, 1.1% [90% CI, -2.2 to 4.3]), or measurement of Dlco (difference, -0.4 [90% CI, -2.6 to 1.7]). The change in 6-minute walk distance was -0.5 m for patients treated with recombinant human pentraxin 2 vs -31.8 m for those in the placebo group (difference, +31.3 m [90% CI, 17.4 to 45.1]; P < .001). The most common adverse events in the recombinant human pentraxin 2 vs placebo group were cough (18% vs 5%), fatigue (17% vs 10%), and nasopharyngitis (16% vs 23%). Conclusions and Relevance: In this preliminary study, recombinant human pentraxin 2 vs placebo resulted in a slower decline in lung function over 28 weeks for patients with idiopathic pulmonary fibrosis. Further research should more fully assess efficacy and safety. Trial Registration: clinicaltrials.gov Identifier: NCT02550873.