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.

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.

Improving Survival in Lymphangioleio-myomatosis: A 16-Year Observational Study in a Large Cohort of Patients.

BACKGROUND: Over the last 2 decades, great progress has been made in the understanding of the clinical aspects and pathogenesis of lymphangioleiomyomatosis (LAM), leading to publication of guidelines and approval of an effective therapy. OBJECTIVES: Aim of our study was to describe how the management and the natural history of this rare disease have changed after the publication of the ERS and American Thoracic Society/Japanese Respiratory Society guidelines and the introduction of sirolimus. METHODS: We examined 162 LAM patients followed at our center between 2001 and 2017, reporting clinical characteristics and diagnostic approach. Response to sirolimus in patients undergoing long-term treatment and mortality risk, estimated in terms of cumulative incidence taking into account organ transplantation as a competing cause of the event, were evaluated. The difference in the cumulative incidence between the patients admitted to the observation before 2011 and after 2011, year of the publication of the MILES trial for the efficacy of sirolimus, has also been estimated. RESULTS: Sixty-one patients had a histological diagnosis (22 from 2010 onward). 101 patients received a radiological diagnosis according to the guidelines criteria. Pulmonary function tests remained stable over a 3-year treatment period in patients who received sirolimus for over 12 months. The cumulative incidence of mortality after 10 years in the whole population was 25.5%. The cumulative incidence of mortality after 5 years was significantly lower in patients who entered the study since 2011 (after publication of the MILES trial) than in patients who entered the study before. CONCLUSIONS: We provide the data supporting the long-term efficacy of sirolimus therapy in a large cohort of patients with functional impairment and other manifestations of the disease. Our results also suggest that the advent of sirolimus and the publication of international guidelines changed the natural history of the disease lowering the mortality and reducing the need of invasive diagnostic techniques.

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.

Chest-CT mimics of COVID-19 pneumonia-a review article.

Coronavirus disease 2019 (COVID-19) emerged in early December 2019 in China, as an acute lower respiratory tract infection and spread rapidly worldwide being declared a pandemic in March 2020. Chest-computed tomography (CT) has been utilized in different clinical settings of COVID-19 patients; however, COVID-19 imaging appearance is highly variable and nonspecific. Indeed, many pulmonary infections and non-infectious diseases can show similar CT findings and mimic COVID-19 pneumonia. In this review, we discuss clinical conditions that share a similar imaging appearance with COVID-19 pneumonia, in order to identify imaging and clinical characteristics useful in the differential diagnosis.

Older Idiopathic Pulmonary Fibrosis Male Patients Are at a Higher Risk of Nintedanib Dose Reduction.

BACKGROUND: Two pharmaceutical agents have been approved for treatment of idiopathic pulmonary fibrosis (IPF): pirfenidone and nintedanib. OBJECTIVES: We investigated the need of dose reduction in consecutive patients treated with nintedanib in relation to gender and body max index, comparing the population over and under 80 years of age. METHODS: We retrospectively reviewed the data of all consecutive IPF patients treated with nintedanib for at least 3 months. Data on age, gender, body max index, side effects, and duration of therapy after enrolment were recorded. RESULTS: A total of 82 patients has been evaluated. All dose reductions were related to side effects and/or toxicities. The need for a dose reduction was significantly more frequent in patients aged 80 years or older (50 vs. 26.8%, p = 0.039), independently from their body mass index. A total of 52% of males >80 years and only 16% of males <80 years reduced the dose (p = 0.002). CONCLUSIONS: Male gender and not body mass index in IPF patients aged ≥80 years treated with nintedanib seems to influence dose reduction.

Lung Cryobiopsy for the Diagnosis of Interstitial Lung Diseases: A Series Contribution to a Debated Procedure.

Introduction: Transbronchial cryobiopsy is an alternative to surgical biopsy for the diagnosis of fibrosing interstitial lung diseases, although the role of this relatively new method is rather controversial. Aim of this study is to evaluate the diagnostic performance and the safety of transbronchial cryobiopsy in patients with fibrosing interstitial lung disease. Materials and methods: The population in this study included patients with interstitial lung diseases who underwent cryobiopsy from May 2015 to May 2018 at the Division of Pneumology of San Giuseppe Hospital in Milan and who were retrospectively studied. All cryobiopsy procedures were performed under fluoroscopic guidance using a flexible video bronchoscope and an endobronchial blocking system in the operating room with patients under general anaesthesia. The diagnostic performance and safety of the procedure were assessed. The main complications evaluated were endobronchial bleeding and pneumothorax. All cases were studied with a multidisciplinary approach, before and after cryobiopsy. Results: Seventy-three patients were admitted to this study. A specific diagnosis was reached in 64 cases, with a diagnostic sensitivity of 88%; 5 cases (7%) were considered inadequate, 4 cases (5%) were found to be non-diagnostic. Only one major bleeding event occurred (1.4%), while 14 patients (19%) experienced mild/moderate bleeding events while undergoing bronchoscopy; 8 cases of pneumothorax (10.9%) were reported, of which 2 (2.7%) required surgical drainage. Conclusions: When performed under safe conditions and in an experienced center, cryobiopsy is a procedure with limited complications having a high diagnostic yield in fibrotic interstitial lung disease.

The association between air pollution and the incidence of idiopathic pulmonary fibrosis in Northern Italy.

Acute exacerbations and worsening of idiopathic pulmonary fibrosis (IPF) have been associated with exposure to ozone (O3), nitrogen dioxide (NO2) and particulate matter, but chronic exposure to air pollution might also affect the incidence of IPF. We investigated the association between chronic exposure to NO2, O3 and particulate matter with an aerodynamic diameter <10 µm (PM10) and IPF incidence in Northern Italy between 2005 and 2010.Daily predictions of PM10 concentrations were obtained from spatiotemporal models, and NO2 and O3 hourly concentrations from fixed monitoring stations. We identified areas with homogenous exposure to each pollutant. We built negative binomial models to assess the association between area-specific IPF incidence rate, estimated through administrative databases, and average overall and seasonal PM10, NO2, and 8-hour maximum O3 concentrations.Using unadjusted models, an increment of 10 µg·m-3 in NO2 concentration was associated with an increase between 7.93% (95% CI 0.36-16.08%) and 8.41% (95% CI -0.23-17.80%) in IPF incidence rate, depending on the season. After adjustment for potential confounders, estimated effects were similar in magnitude, but with larger confidence intervals.Although confirmatory studies are needed, our results trace a potential association between exposure to traffic pollution and the development of IPF.

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.

Smoking-related idiopathic interstitial pneumonia: A review.

For many years, cigarette smoking has been considered as the leading cause of chronic obstructive pulmonary disease and lung cancer. Recently, however, it has also been associated with the development of diffuse interstitial lung diseases. In the latest classification of the major idiopathic interstitial pneumonias (IIP), the term smoking-related IIP has been introduced, including two entities, namely desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis-interstitial lung disease (RB-ILD). Other entities in which smoking has a definite or suggested role include pulmonary Langerhan's cell histiocytosis, smoking-related interstitial fibrosis, combined pulmonary fibrosis and emphysema syndrome and idiopathic pulmonary fibrosis. In this review, we will focus on the mechanisms of smoking-related lung damage and on the clinical aspects of these disorders with the exception of idiopathic pulmonary fibrosis, which will be reviewed elsewhere in this review series.

Lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is an ultra-rare, slowly progressive neoplastic cystic disease, belonging to the group of PEComas. It can occur sporadically or associated to tuberous sclerosis complex disease and affects mainly women in child-birth age. Dyspnoea is the most frequent symptom referred to the time of diagnosis, however spontaneous pneumothorax may be a typical presentation associated to extrathoracic manifestations, such as renal angiomyolipomas. In the last decade, important advances in understanding molecular mechanisms underlying the LAM pathogenesis have been reached. It has allowed to obtain improvements in the research of novel biomarkers, treatment and a better management of the disease.

Comparison of clinical scoring to predict mortality risk in mild-to-moderate idiopathic pulmonary fibrosis.

BACKGROUND: During the last decade, a number of clinical scores, such as Gender-Age-Physiology (GAP) Index, TORVAN Score and Charlson Comorbidity Index (CCI), have been separately used to measure comorbidity burden in idiopathic pulmonary fibrosis (IPF). However, no previous study compared the prognostic value of these scores to assess mortality risk stratification in IPF patients with mild-to-moderate disease. METHODS: All consecutive patients with mild-to-moderate IPF who underwent high-resolution computed tomography, spirometry, transthoracic echocardiography and carotid ultrasonography at our Institution, between January 2016 and December 2018, were retrospectively analyzed. GAP Index, TORVAN Score and CCI were calculated in all patients. Primary endpoint was all-cause mortality, whereas secondary endpoint was the composite of all-cause mortality and rehospitalizations for all-causes, over medium-term follow-up. RESULTS: Seventy IPF patients (70.2±7.4 yrs, 74.3% males) were examined. At baseline, GAP Index, TORVAN Score and CCI were 3.4±1.1, 14.7±4.1 and 5.3±2.4, respectively. A strong correlation between coronary artery calcification (CAC) and common carotid artery (CCA) intima-media thickness (IMT) (r=0.88), CCI and CAC (r=0.80), CCI and CCA-IMT (r=0.81), was demonstrated in the study group. Follow-up period was 3.5±1.2 years. During follow-up, 19 patients died and 32 rehospitalizations were detected. CCI (HR 2.39, 95% CI: 1.31-4.35) and heart rate (HR 1.10, 95% CI: 1.04-1.17) were independently associated with primary endpoint. CCI (HR 1.54, 95% CI: 1.15-2.06) predicted secondary endpoint, also. A CCI ≥6 was the optimal cut-off for predicting both outcomes. CONCLUSIONS: Due to the increased atherosclerotic and comorbidity burden, IPF patients with CCI ≥6 at an early-stage disease have poor outcome over medium-term follow-up.

Images in Sarcoidosis: new section of our Journal.

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Prognostic role of CHA2DS2-VASc score for mortality risk assessment in non-advanced idiopathic pulmonary fibrosis: a preliminary observation.

During the last decade, the CHA2DS2-VASc score has been used for stratifying the mortality risk in both atrial fibrillation (AF) and non-AF patients. However, no previous study considered this score as a prognostic indicator in non-AF patients with mild-to-moderate idiopathic pulmonary fibrosis (IPF). All consecutive non-AF patients with mild-to-moderate IPF, diagnosed between January 2016 and December 2018 at our Institution, entered this study. All patients underwent physical examination, blood tests, spirometry, high-resolution computed tomography and transthoracic echocardiography. CHA2DS2-VASc score, Gender-Age-Physiology (GAP) index and Charlson Comorbidity Index (CCI) were determined in all patients. Primary endpoint was all-cause mortality, while the secondary endpoint was the composite of all-cause mortality and rehospitalizations for all causes over mid-term follow-up. 103 consecutive IPF patients (70.7 ± 7.3 yrs, 79.6% males) were retrospectively analyzed. At the basal evaluation, CHA2DS2-VASc score, GAP index and CCI were 3.7 ± 1.6, 3.6 ± 1.2 and 5.5 ± 2.3, respectively. Mean follow-up was 3.5 ± 1.3 yrs. During the follow-up period, 29 patients died and 43 were re-hospitalized (44.2% due to cardiopulmonary causes). On multivariate Cox regression analysis, CHA2DS2-VASc score (HR 2.15, 95% CI 1.59-2.91) and left ventricular ejection fraction (LVEF) (HR 0.91, 95% CI 0.86-0.97) were independently associated with all-cause mortality in IPF patients. CHA2DS2-VASc score (HR 1.66, 95% CI 1.39-1.99) and LVEF (HR 0.94, 95% CI 0.90-0.98) also predicted the secondary endpoint in the same study group. CHA2DS2-VASc score > 4 was the optimal cut-off for predicting both outcomes. At mid-term follow-up, a CHA2DS2-VASc score > 4 predicts an increased risk of all-cause mortality and rehospitalizations for all causes in non-AF patients with mild-to-moderate IPF.

Influence of chest wall conformation on spirometry parameters and outcome in mild-to-moderate idiopathic pulmonary fibrosis.

Extrinsic causes of restrictive lung syndrome in idiopathic pulmonary fibrosis (IPF) patients have been poorly investigated. We aimed to investigate the influence of the anterior chest wall deformity, noninvasively assessed by modified Haller index (MHI), on spirometry parameters and outcome in a consecutive population of patients with mild-to-moderate IPF. Sixty consecutive IPF patients (73.8 ± 6.6 years, 45 males) were included in this retrospective study. All patients underwent physical examination, spirometry, blood tests, conventional transthoracic echocardiography and MHI assessment (chest transverse diameter over the distance between sternum and spine) at basal evaluation. During follow-up, we evaluated the composite endpoint of (1) pulmonary or cardiovascular hospitalizations and (2) all-cause mortality. IPF patients with concave-shaped chest wall (MHI > 2.5) (36.7% of total) and those with normal chest shape (MHI ≤ 2.5) (63.3%) were separately analyzed. In comparison to IPF patients with MHI ≤ 2.5, those with MHI > 2.5: were less likely to be men and smokers; had a more severe restrictive pattern; had significantly smaller cardiac chamber dimensions and significantly higher systolic pulmonary artery pressure (51.9 ± 15.1 vs 42.4 ± 14.3 mmHg, p = 0.02). Mean follow-up time was 2.5 ± 1.4 years. During follow-up, 13 deaths and 16 pulmonary or cardiovascular hospitalizations were detected. At multivariate Cox regression analysis, concave-shaped chest wall (MHI > 2.5) (HR 4.55, 95% CI 1.02-20.4), increased C-reactive protein (HR 1.68, 95% CI 1.08-2.61) and absence of beta-blocker therapy (HR 0.13, 95% CI 0.01-0.26) were independently associated to the investigated outcome. MHI assessment and implementation may help the clinician to identify, among IPF patients, those with poorer prognosis over a medium-term follow-up.

Incremental prognostic value of arterial elastance in mild-to-moderate idiopathic pulmonary fibrosis.

Previous reports suggested that poor pulmonary function was associated with increased arterial elastance (Ea) in patients with chronic obstructive pulmonary disease and systemic sclerosis. The mechanisms connecting pulmonary function and Ea have not yet been accurately studied in patients with idiopathic pulmonary fibrosis (IPF). The present study was designed to assess Ea in IPF patients without chronic severe pulmonary hypertension and to determine its prognostic role over a medium-term follow-up. This retrospective study included 60 consecutive patients with mild-to-moderate IPF (73.8 ± 6.6 years, 75% males) and 60 controls matched by age, sex and cardiovascular risk factors. All patients underwent physical examination, spirometry, blood tests, modified Haller index (MHI, chest transverse diameter over the distance between sternum and spine) assessment, conventional transthoracic echocardiography implemented with speckle tracking analysis of left atrial positive global strain (LA-GSA+ ) and finally carotid Doppler ultrasonography, at basal evaluation. The effective arterial elastance index (EaI) was calculated as the ratio of end-systolic pressure to stroke volume index. During follow-up period, we evaluated the composite endpoint of (1) pulmonary or cardiovascular hospitalizations; (2) all-cause mortality. At baseline, EaI was significantly higher in IPF patients than controls (4.1 ± 1.3 vs 3.5 ± 1.0 mmHg/ml/m2, p = 0.01). EaI was strongly correlated to the following variables: C-reactive protein (CRP) (r = 0.86), forced vital capacity (FVC) (r = - 0.91), E/e' ratio (r = 0.91), LA-GSA+ (r = - 0.92), common carotid artery-cross sectional area (CCA-CSA) (r = 0.89) and MHI (r = 0.86), in IPF patients. Mean follow-up time was 2.4 ± 1.3 years. During follow-up, 12 patients died and 17 were hospitalized due to major adverse clinical events. At univariate Cox analysis, CRP (HR 1.51, 95% CI 1.25-1.82), FVC (HR 0.88, 95% CI 0.85-0.91), LA-GSA+ (HR 0.85, 95% CI 0.77-0.94), CCA-CSA (HR 1.12, 95% CI 1.03-1.22) and EaI (HR 2.43, 95% CI 1.75-3.37) were significantly associated with outcome. At multivariate Cox analysis, only EaI (HR 1.60, 95% CI 1.03-2.50) retained statistical significance. An EaI ≥ 4 mmHg/ml/m2 showed 100% sensitivity and 99.4% specificity for predicting outcome (AUC = 0.98). In patients with mild-to-moderate IPF, an EaI ≥ 4 mmHg/ml/m2 is a negative prognostic factor over a medium-term follow-up.