Case of a 33-Year-Old Woman With Hemoptysis and Migrant Nodular Cavitary Lesions.

We describe the case of a young 33-year-old woman that was referred to our clinic for evidence of migrant cavitary nodules at CT scan, dyspnea, and blood sputum. Her physical examination showed translucent and thin skin, evident venous vascular pattern, vermilion of the lip thin, micrognathia, thin nose, and occasional Raynaud phenomenon. We prescribed another CT scan that showed multiple pulmonary nodules in both lungs, some of which had evidence of cavitation. Because bronchoscopy was not diagnostic, we decided to perform surgical lung biopsy. At histologic examination, we found the presence of irregularly shaped, but mainly not dendritic, foci of ossification that often contained bone marrow and were embedded or surrounded by tendinous-like fibrous tissue. After incorporating data from the histologic examination, we decided to perform genetic counseling and genetic testing with the use of whole-exome sequencing. The genetic test revealed a heterozygous de novo missense mutation of COL3A1 gene, which encodes for type III collagen synthesis, and could cause vascular Ehlers-Danlos syndrome.

Determinants of response to hypercapnia and to progressive and transient hypoxia in obstructive sleep apnea patients.

BACKGROUND: The knowledge regarding the control of breathing during wakefulness in patients affected by obstructive sleep apnea (OSAS) is still challenging. The aim of this study is firstly to analyze hypoxic and hypercapnic ventilatory response in OSA patients in comparison to controls and secondly, to investigate correlations between chemosensivity and both lung function tests, such as arterial blood gas analysis and spirometric parameters, and clinical characteristics, such as age and BMI. METHODS: Seventeen never treated OSA patients (16M; 53±13.2 years; BMI=34.5±8.1; AHI=45±14.7) underwent nocturnal cardiopulmonary monitoring test, complete lung function tests (spirometry, lung volumes and arterial blood gas analysis on room air). Read's rebreathing test was used to evaluate hypercapnic ventilatory response (HVRCO2); hypoxic ventilatory response (HVRO2) was studied through progressive and transient methods. The response was expressed in terms of slope of linear regression for HVRCO2 and of hyperbolic curve for HVRO2 between minute ventilation (VE) or mean inspiratory flow (VT/Ti) and PetCO2 or PetO2. RESULTS: The OSA group showed increased transient, but not progressive, HVRO2 and a lower HVRCO2. A lower HVRCO2 was predicted by greater values of BMI (P<0.01). Progressive HVRO2 increased with age and lower FEV1/VC, while transient HVRO2 (P<0.05) was inversely correlated with the nocturnal lowest SaO2 (P<0.01). CONCLUSIONS: Nocturnal intermittent hypoxic stimuli increases daytime glomic reactivity to transient hypoxia, while BMI is the main independent determinants of the bulbar response to hypercapnia in normocapnic OSAS patients.

Road Toward a New Model of Care for Idiopathic Pulmonary Fibrosis in the Lazio Region.

A timely, confirmed diagnosis of Idiopathic Pulmonary Fibrosis (IPF) has a significant impact on the evolution of the disease. The current model of care in the Lazio region (in Italy) was assessed on the basis of real-world data provided by the four reference centers responsible for diagnosing and treating IPF. The 5-year, population-based, retrospective longitudinal study provided the data that is at the basis of the current proposal for a new clinical and therapeutic pathway (DTCP) and has been shared with regional decision makers. A DTCP must be defined and based on four pillars: GPs, pulmonologists, IPF centers, and telemedicine. Each must play a role within a sort of hub-and-spoke model. IPF centers remain the hubs, while spokes are identified in trained GPs and pulmonologists.

Residual respiratory impairment after COVID-19 pneumonia.

INTRODUCTION: The novel coronavirus SARS-Cov-2 can infect the respiratory tract causing a spectrum of disease varying from mild to fatal pneumonia, and known as COVID-19. Ongoing clinical research is assessing the potential for long-term respiratory sequelae in these patients. We assessed the respiratory function in a cohort of patients after recovering from SARS-Cov-2 infection, stratified according to PaO2/FiO2 (p/F) values. METHOD: Approximately one month after hospital discharge, 86 COVID-19 patients underwent physical examination, arterial blood gas (ABG) analysis, pulmonary function tests (PFTs), and six-minute walk test (6MWT). Patients were also asked to quantify the severity of dyspnoea and cough before, during, and after hospitalization using a visual analogic scale (VAS). Seventy-six subjects with ABG during hospitalization were stratified in three groups according to their worst p/F values: above 300 (n = 38), between 200 and 300 (n = 30) and below 200 (n = 20). RESULTS: On PFTs, lung volumes were overall preserved yet, mean percent predicted residual volume was slightly reduced (74.8 ± 18.1%). Percent predicted diffusing capacity for carbon monoxide (DLCO) was also mildly reduced (77.2 ± 16.5%). Patients reported residual breathlessness at the time of the visit (VAS 19.8, p < 0.001). Patients with p/F below 200 during hospitalization had lower percent predicted forced vital capacity (p = 0.005), lower percent predicted total lung capacity (p = 0.012), lower DLCO (p < 0.001) and shorter 6MWT distance (p = 0.004) than patients with higher p/F. CONCLUSION: Approximately one month after hospital discharge, patients with COVID-19 can have residual respiratory impairment, including lower exercise tolerance. The extent of this impairment seems to correlate with the severity of respiratory failure during hospitalization.

Suggestions for lung function testing in the context of COVID-19.

The 2019 coronavirus disease (COVID-19) pandemic is currently a challenge worldwide. Due to the characteristics of lung function tests, the risk of cross infection may be high between health care workers and patients. The role of lung function testing is well defined for the diagnosis of various diseases and conditions. Lung function tests are also indispensable in evaluating the response to medical treatment, in monitoring patient respiratory and systemic pathologies, and in evaluating preoperative risk in cardiothoracic and major abdominal surgeries. However, lung function testing represents a potential route for COVID-19 transmission, due to the aerosol generated during the procedures and the concentration of patients with pulmonary diseases in lung function laboratories. Currently, the opportunities for COVID-19 transmission remain partially unknown, and data are continuously evolving. This review provides useful information on the risks and recommendations for lung function testing, which have varied according to the phase of the pandemic. This information may support national and regional boards and the health authorities to which they belong. There is a need for rapid re-opening of lung function laboratories, but maximum safety is required in the COVID-19 era.

Obstructive sleep apnea in sarcoidosis and impact of cpap treatment on fatigue.

RATIONALE: An increased incidence of Obstructive Sleep Apnea (OSA) in sarcoidosis has been described in small sample size studies. Fatigue is common in sarcoidosis and OSA could be a relevant, treatable comorbidity. To date, the effect of Continuous Positive Airway Pressure (CPAP) on fatigue has never been assessed. OBJECTIVES: To investigate the prevalence of OSA in sarcoidosis, fatigue status and daytime sleepiness in patients of our center. To explore the effect of CPAP in fatigue and daytime sleepiness after 3 months using validated questionnaires. METHOD: Single group, one center, open-label prospective cohort study. MEASUREMENTS AND MAIN RESULT: We enrolled 68 patients and OSA was diagnosed in 60 (88.2%): 25 (36.8%) were mild while 35 (51.5%) were moderate-to-severe. 38 (55.9%) patients received CPAP but only 20 (30.9%) were compliant at 3-month evaluation. Questionnaires demonstrated fatigue in 34 (50%) and daytime sleepiness in 21 (30.9%). In multivariate regression analysis, Scadding stage and FAS behave as predictors of Apnea-Hypopnea Index (AHI) severity while sleepiness and steroids weren't associated. FAS score (ΔFAS = 6.3; p = 0.001) and ESS score (ΔESS = 2.8; p = 0.005) improved after three months of CPAP. CONCLUSIONS: OSA is highly prevalent in patients affected by sarcoidosis. ESS questionnaire is not reliable for OSA screening and other pre-test probability tool should be evaluated in further studies. CPAP leads to a significative reduction of fatigue and daytime sleepiness at three-month. Further studies are needed to confirm the high prevalence of OSA in sarcoidosis and the positive role of CPAP in fatigue. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 169-178).

Multidisciplinary Evaluation of Interstitial Lung Diseases: New Opportunities Linked to Rheumatologist Involvement.

Multidisciplinary team (MDT) discussion is the gold standard in the management of interstitial lung disease (ILD). The rheumatologist is not routinely involved in MDT, even if up to 20% of ILD are related to systemic autoimmune rheumatic diseases (SARD). The study aims to assess the agreement and its variation over time between rheumatologists and pulmonologists in the screening of SARD and between rheumatologists and an MDT extended to rheumatologists (eMDT) in evaluating the progression of SARD. We computed the agreement between the pulmonologist and rheumatologist in the identification of red flags for SARDs of 81 ILD cases and between the rheumatologist alone and eMDT in the confirmation of 70 suspected SARD-ILD progressions. The agreement between rheumatologists and pulmonologists was moderate for the detection of autoimmunity test positivity (κ = 0.475, p < 0.001) and family history of SARD (κ = 0.491, p < 0.001) and fair for the identification of extrapulmonary symptoms (κ = 0.225, p = 0.064) or routine laboratory abnormalities consistent with SARD. The average agreement between the rheumatologist and eMDT in the identification of ILD progression was moderate (κ = 0.436, p < 0.001). The class of agreement improved from the first to the third semester. The average agreement with the rheumatologist ranged from fair to moderate, suggesting that a shared evaluation of SARD-ILD in eMDT could improve the diagnostic work-up and the evaluation of ILD progression.

Mediastinal lymph node enlargement in idiopathic pulmonary fibrosis: relationships with disease progression and pulmonary function trends.

BACKGROUND AND OBJECTIVES: Evidence of mediastinal Lymph Node Enlargement (LNE) on CT scan is a common finding in idiopathic pulmonary fibrosis (IPF). We sought to investigate whether the involvement of mediastinal lymph nodes is associated with accelerated disease progression, and explored the changes occurring in mediastinal lymph nodes during the radiological follow up of these patients. METHODS: This retrospective study included IPF patients referred to a single ILD centre in Italy. A consensus-based assessment of mediastinal LNE on chest CT scan was performed by two thoracic radiologists. Kaplan-Meier curves and multivariate Cox proportional hazards regression were used to assess hazard ratios for mortality and disease progression (defined as categorical FVC decline ≥10%). The annualized rates of change in functional parameters for each patient were calculated using mixed linear models. RESULTS: The study population consisted of 152 IPF patients, of whom 135 (89%) received antifibrotic treatment for IPF during the study follow up. Patients having evidence of 3 or more enlarged mediastinal lymph nodes on baseline CT scan showed increased rates of mortality (HR 5.03, 95% CI 1.86-13.62, p ≤ 0.001) and significant disease progression (HR 2.99, 95% CI 1.22-7.33, p = 0.17) as compared to patients without LNE, after adjusting for GAP stage. Among 62 patients with LNE who underwent a follow up CT scan of the chest and received antifibrotic treatment, 57 (92%) maintained evidence mediastinal LNE over time. CONCLUSIONS: Diffuse mediastinal lymph node involvement predicts clinically meaningful functional deterioration in patients with IPF.

Restless legs syndrome: A new comorbidity in idiopathic pulmonary fibrosis.

OBJECTIVE: Sleep disorders have a high prevalence among patients with idiopathic pulmonary fibrosis (IPF). The prevalence of restless legs syndrome (RLS) is not known in these patients, neither is its clinical impact as a comorbidity. We investigated the association of RLS with IPF and characterized the clinical features of RLS in a cohort of IPF patients. METHODS: Fifty patients with diagnosis of IPF were prospectively enrolled. RLS was diagnosed using the validated 5-item RLS criteria. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index. The prevalence of RLS in the IPF group was compared to that observed in a group of 293 patients referred for suspect of sleep disorders. The relationships between RLS and clinical parameters were determined using multivariate logistic regression. RESULTS: Prevalence of RLS in the IPF group was significantly higher than in the control population of patients referred for sleep disorders (IPF: 24%, controls 10%: χ2 6.49, p = 0.011). Higher PSQI score confirmed to be associated with RLS after adjusting for demographics and clinical parameters of disease severity (OR = 1.38, 95%CI 1.08-1.76; p = 0.01). CONCLUSIONS: RLS is highly prevalent in IPF and significantly worsen sleep quality in these patients. The benefit/risk ratio of a specific therapeutic intervention for RLS in IPF should be assessed in further prospective research.

Fibrotic Hypersensitivity Pneumonitis: Diagnosis and Management.

Fibrotic hypersensitivity pneumonitis is a complex interstitial lung disease that is not entirely understood. In its chronic and fibrotic form, hypersensitivity pneumonitis is one of the main mimickers of idiopathic pulmonary fibrosis (IPF). Distinguishing between these two conditions is challenging but is of particular clinical relevance. Two approved therapies are available for IPF, and a considerable number of clinical trials are now exploring newer pharmacological options. This impressive research effort is a consequence of new pathogenetic understanding, updated diagnostic criteria and a long history of pharmacological trials. Conversely, current knowledge gaps on pathogenesis of chronic hypersensitivity pneumonitis, coupled with lack of validated diagnostic criteria, make the management of this disease an unsolved clinical challenge. This also reflects the paucity of therapeutic clinical trials in this field. In this review, we describe the current evidence and the possible future options to approach this complex disease.

Disease progression across the spectrum of idiopathic pulmonary fibrosis: A multicentre study.

BACKGROUND AND OBJECTIVE: In clinical practice, a working diagnosis of IPF may be performed to provide effective antifibrotic treatment to patients who cannot undergo SLB. In this study, we compared the disease course across IPF diagnostic categories in a real-life clinical setting to clarify the appropriateness of a working diagnosis of IPF and treatment initiation in these patients. METHODS: Longitudinal data from IPF patients receiving antifibrotic treatment (pirfenidone or nintedanib) were retrospectively collected at three tertiary centres in Italy. Univariate and multivariate analyses were performed to compare time to death and to a composite endpoint of disease progression between two diagnostic subgroups, that is, patients with UIP on HRCT and/or SLB, and patients with possible UIP and no histological confirmation. RESULTS: A total of 249 IPF patients were included in the analysis. Among patients with a possible UIP pattern on HRCT, 41 (55%) were prescribed antifibrotic treatment (either nintedanib or pirfenidone) despite absence of histological confirmation. This group demonstrated similar mortality and disease progression as compared to patients with a definite diagnosis of IPF as per diagnostic guidelines (log-rank test P = 0.771 and P = 0.139, respectively). Such findings were confirmed on multivariate analysis (HR: 1.19, 95% CI: 0.49-2.89, P = 0.7 for death; HR: 1.42, 95% CI: 0.83-2.44, P = 0.201 for disease progression). CONCLUSION: In patients receiving antifibrotics following a working diagnosis of IPF, disease progression rates were similar to patients with a confident diagnosis of IPF according to consensus guidelines, supporting the rationale for treatment initiation in these patients by expert multidisciplinary teams.

Idiopathic pulmonary fibrosis: pathogenesis and management.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease characterized by the aberrant accumulation of fibrotic tissue in the lungs parenchyma, associated with significant morbidity and poor prognosis. This review will present the substantial advances achieved in the understanding of IPF pathogenesis and in the therapeutic options that can be offered to patients, and will address the issues regarding diagnosis and management that are still open. MAIN BODY: Over the last two decades much has been clarified about the pathogenic pathways underlying the development and progression of the lung scarring in IPF. Sustained alveolar epithelial micro-injury and activation has been recognised as the trigger of several biological events of disordered repair occurring in genetically susceptible ageing individuals. Despite multidisciplinary team discussion has demonstrated to increase diagnostic accuracy, patients can still remain unclassified when the current diagnostic criteria are strictly applied, requiring the identification of a Usual Interstitial Pattern either on high-resolution computed tomography scan or lung biopsy. Outstanding achievements have been made in the management of these patients, as nintedanib and pirfenidone consistently proved to reduce the rate of progression of the fibrotic process. However, many uncertainties still lie in the correct use of these drugs, ranging from the initial choice of the drug, the appropriate timing for treatment and the benefit-risk ratio of a combined treatment regimen. Several novel compounds are being developed in the perspective of a more targeted therapeutic approach; in the meantime, the supportive care of these patients and their carers should be appropriately prioritized, and greater efforts should be made toward the prompt identification and management of relevant comorbidities. CONCLUSIONS: Building on the advances in the understanding of IPF pathobiology, the further investigation of the role of gene variants, epigenetic alterations and other molecular biomarkers reflecting disease activity and behaviour will hopefully enable earlier and more confident diagnosis, improve disease phenotyping and support the development of novel agents for personalized treatment of IPF.

Nintedanib for the treatment of idiopathic pulmonary fibrosis.

INTRODUCTION: Idiopathic Pulmonary Fibrosis (IPF) is an interstitial lung disease characterized by the progressive loss of pulmonary function, ultimately leading to respiratory failure and death. Two novel compounds, nintedanib and pirfenidone, have shown efficacy in reducing the rate of decline of lung function in IPF patients. The multiple tyrosine kinase inhibitor nintedanib has extensively being studied as a potential angiogenesis inhibitor in clinical against various neoplastic disorders. Afterwards, this compound was successfully tested in IPF. Areas covered: Herein, the authors review the working mechanisms of nintedanib, its pharmacological profile, and its efficacy and safety for patients with IPF. Expert opinion: Nintedanib has shown to be safe and effective in patients with IPF, with a favorable long-term safety profile. There is a lack of comparative trials of pirfenidone and nintedanib, and the choice of treatment is left to the physicians' judgement. Future directions of nintedanib use are represented by the treatment of progressive fibrosing interstitial lung disease other than IPF, IPF with advanced functional impairment, and lung fibrosis secondary to connective tissue diseases. A promising safety profile for the combinational use of nintedanib and pirfenidone in IPF has also recently emerged.

Investigational drugs for idiopathic pulmonary fibrosis.

INTRODUCTION: IPF is a specific form of chronic fibrosing interstitial pneumonia of unknown cause, characterized by progressive worsening in lung function and an unfavorable prognosis. Current concepts on IPF pathogenesis are based on a dysregulated wound healing response, leading to an over production of extracellular matrix. Based on recent research however, several other mechanisms are now proposed as potential targets for novel therapeutic strategies. Areas covered: This review analyzes the current investigational strategies targeting extracellular matrix deposition, tyrosine-kinase antagonism, immune and autoimmune response, and cell-based therapy. A description of the pathogenic rationale implied in each novel therapeutic approach is summarized. Expert opinion: New IPF drugs are being evaluated in the context of phase 1 and 2 clinical trials. Nevertheless, many drugs that have shown efficacy in preclinical studies, failed to exhibit the same positive effect when translated to humans. A possible explanation for these failures might be related to the known limitations of animal models of the disease. The recent development of 3D systems composed of cells from individual patients that recreate an ex-vivo model of IPF, could lead to significant improvements in disease pathogenesis and treatment. New drugs could be tested on more genuine models and clinicians could tailor therapy based on patient's response.

Idiopathic Pulmonary Fibrosis: Molecular Endotypes of Fibrosis Stratifying Existing and Emerging Therapies.

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown causes. Current diagnostic criteria are based on radiological, clinical, and histopathological features but, unfortunately, still many patients remain undiagnosed. Two currently approved therapies, pirfenidone and nintedanib, slow down disease progression but failed to block or revert it. On the other hand, many of the therapeutic agents tested in several clinical trials have not given satisfactory answers, probably due to the pathological heterogeneity of the disease. A growing number of studies show that IPF phenotype is the common clinical outcome of a variety of different pathophysiological mechanisms that identify disease subgroups characterised by specific genetic and molecular biomarkers (endotypes). The precision medicine approach is identifying and analysing the complex system of genetic, molecular, environmental, and behavioural variables underlying the development of the disease and the response to therapy. These molecular pathways are potential targets for novel agents and useful diagnostic, prognostic, and theragnostic biomarkers. We outline the status of knowledge in this field by discussing the complex pathogenetic pathways underlying different disease subgroups and assessing a stratification approach to novel therapeutic agents based on these endotypes.