Molecular Profiling of Tissue Samples with Chronic Rejection from Patients with Chronic Lung Allograft Dysfunction: A Pilot Study in Cystic Fibrosis Patients.

Chronic rejection (CR) is the main culprit for reduced survival and quality of life in patients undergoing lung transplantation (Ltx). High-throughput approaches have been used to unveil the molecular pathways of CR, mainly in the blood and/or in bronchoalveolar lavage. We hypothesized that a distinct molecular signature characterizes the biopsies of recipients with clinically confirmed histological signs of CR. Eighteen cystic fibrosis patients were included in the study and RNA sequencing was performed in 35 scheduled transbronchial biopsies (TBBs): 5 with acute cellular rejection, 9 with CR, and 13 without any sign of post-LTx complication at the time of biopsy; 8 donor lung samples were used as controls. Three networks with 33, 26, and 36 differentially expressed genes (DEGs) were found in TBBs with CR. Among these, seven genes were common to the identified pathways and possibly linked to CR and five of them (LCN2, CCL11, CX3CL1, CXCL12, MUC4) were confirmed by real-time PCR. Immunohistochemistry was significant for LCN2 and MUC4. This study identified a typical gene expression pattern in TBBs with histological signs of CR and the LCN2 gene appeared to play a central role. Thus, it could be crucial in CR pathophysiology.

The pathogenesis, epidemiology and biomarkers of susceptibility of pulmonary fibrosis in COVID-19 survivors.

Pulmonary fibrosis (PF), a pathological outcome of chronic and acute interstitial lung diseases associated to compromised wound healing, is a key component of the "post-acute COVID-19 syndrome" that may severely complicate patients' clinical course. Although inconclusive, available data suggest that more than a third of hospitalized COVID-19 patients develop lung fibrotic abnormalities after their discharge from hospital. The pathogenesis of PF in patients recovering from a severe acute case of COVID-19 is complex, and several hypotheses have been formulated to explain its development. An analysis of the data that is presently available suggests that biomarkers of susceptibility could help to identify subjects with increased probability of developing PF and may represent a means to personalize the management of COVID-19's long-term effects. Our review highlights the importance of both patient-related and disease-related contributing risk factors for PF in COVID-19 survivors and makes it definitely clear the possible use of acute phase and follow-up biomarkers for identifying the patients at greatest risk of developing this disease.

Correlation between α1-Antitrypsin Deficiency and SARS-CoV-2 Infection: Epidemiological Data and Pathogenetic Hypotheses.

The most common hereditary disorder in adults, α1-antitrypsin deficiency (AATD), is characterized by reduced plasma levels or the abnormal functioning of α1-antitrypsin (AAT), a major human blood serine protease inhibitor, which is encoded by the SERine Protein INhibitor-A1 (SERPINA1) gene and produced in the liver. Recently, it has been hypothesized that the geographic differences in COVID-19 infection and fatality rates may be partially explained by ethnic differences in SERPINA1 allele frequencies. In our review, we examined epidemiological data on the correlation between the distribution of AATD, SARS-CoV-2 infection, and COVID-19 mortality rates. Moreover, we described shared pathogenetic pathways that may provide a theoretical basis for our epidemiological findings. We also considered the potential use of AAT augmentation therapy in patients with COVID-19.

Prone Positioning Is Safe and May Reduce the Rate of Intubation in Selected COVID-19 Patients Receiving High-Flow Nasal Oxygen Therapy.

BACKGROUND: Patients with COVID-19 may experience hypoxemic Acute Respiratory Failure (hARF) requiring O2-therapy by High-Flow Nasal Cannula (HFNO). Although Prone Positioning (PP) may improve oxygenation in COVID-19 non-intubated patients, the results on its clinical efficacy are controversial. The present study aims to prospectively investigate whether PP may reduce the need for endotracheal intubation (ETI) in patients with COVID-19 receiving HFNO. METHODS: All consecutive unselected adult patients with bilateral lung opacities on chest X-ray receiving HFNO after admission to a SARS-CoV-2 Respiratory Intermediate Care Unit (RICU) were considered eligible. Patients who successfully passed an initial PP trial (success group) underwent PP for periods ≥ 2 h twice a day, while receiving HFNO. The study's primary endpoint was the intubation rate during the stay in the RICU. RESULTS: Ninety-three patients were included in the study. PP was feasible and safe in 50 (54%) patients. Sixteen (17.2%) patients received ETI and 27 (29%) escalated respiratory support, resulting in a mortality rate of 9/93 (9.7%). The length of hospital stay was 18 (6-75) days. In 41/50 (80%) of subjects who passed the trial and underwent PP, its use was associated with clinical benefit and survival without escalation of therapy. CONCLUSIONS: PP is feasible and safe in over 50% of COVID-19 patients receiving HFNO for hARF. Randomized trials are required to confirm that PP has the potential to reduce intubation rate.

Short- and Long-Term Impact of Smoking Donors in Lung Transplantation: Clinical and Pathological Analysis.

BACKGROUND: The use of smoking donors (SD) is one strategy to increase the organ pool for lung transplantation (LT), but the benefit-to-risk ratio has not been demonstrated. This study aimed to evaluate the impact of SD history on recipient outcomes and graft alterations. METHODS: LTs in 293 patients were retrospectively reviewed and divided into non-SD (n = 225, group I), SD < 20 pack-years (n = 45, group II), and SD ≥ 20 pack-years (n = 23, group III) groups. Moreover, several lung donor biopsies before implantation (equally divided between groups) were evaluated, focusing on smoking-related lesions. Correlations were analyzed between all pathological data and smoking exposure, along with other clinical parameters. RESULTS: Among the three groups, donor and recipient characteristics were comparable, except for higher Oto scores and age in group III. Group III showed a longer intensive care unit (ICU) and hospital stay compared with the other two groups. This finding was confirmed when SD history was considered as a continuous variable. However, survival and other mid- and long-term major outcomes were not affected by smoking history. Finally, morphological lesions did not differ between the three groups. CONCLUSIONS: In our study, SDs were associated with a longer post-operative course, without affecting graft aspects or mid- and long-term outcomes. A definition of pack-years cut-off for organ refusal should be balanced with the other extended criteria donor factors.

Dyspnea, effort and muscle pain during exercise in lung transplant recipients: an analysis of their association with cardiopulmonary function parameters using machine learning.

BACKGROUND: Despite improvement in lung function, most lung transplant (LTx) recipients show an unexpectedly reduced exercise capacity that could be explained by persisting peripheral muscle dysfunction of multifactorial origin. We analyzed the course of symptoms, including dyspnea, muscle effort and muscle pain and its relation with cardiac and pulmonary function parameters during an incremental exercise testing. METHODS: Twenty-four bilateral LTx recipients were evaluated in an observational cross-sectional study. Recruited patients underwent incremental cardio-pulmonary exercise testing (CPET). Arterial blood gases at rest and peak exercise were measured. Dyspnea, muscle effort and muscle pain were scored according to the Borg modified scale. Potential associations between the severity of symptoms and exercise testing parameters were analyzed using a Forest-Tree Machine Learning approach, which accomplishes for a ratio between number of observations and number of screened variables less than unit. RESULTS: Dyspnea score was significantly associated with maximum power output (WR, watts), and minute ventilation (VE, L/min) at peak exercise. In a controlled subgroup analysis, dyspnea score was a limiting symptom only in LTx recipients who reached the higher levels of WR (≥ 101 watts) and VE (≥ 53 L/min). Muscle effort score was significantly associated with breathing reserve as percent of maximal voluntary ventilation (BR%MVV). The lower the BR%MVV at peak exercise (< 32) the higher the muscle effort perception. Muscle pain score was significantly associated with VO2 peak, arterial [HCO3-] at rest, and VE/VCO2 slope. In a subgroup analysis, muscle pain was the limiting symptom in LTx recipients with a lower VO2 peak (< 15 mL/Kg/min) and a higher VE/VCO2 slope (≥ 32). CONCLUSIONS: The majority of our LTx recipients reported peripheral limitation as the prevalent reason for exercise termination. Muscle pain at peak exercise was strictly associated with basal and exercise-induced metabolic altered pathways. The onset of dyspnea (breathing effort) was associated with the intensity of ventilatory response to meet metabolic demands for increasing WR. Our study suggests that only an accurate assessment of symptoms combined with cardio-pulmonary parameters allows a correct interpretation of exercise limitation and a tailored exercise prescription. The role and mechanisms of muscle pain during exercise in LTx recipients requires further investigations.

Nintedanib Treatment for Idiopathic Pulmonary Fibrosis Patients Who Have Been Switched from Pirfenidone Therapy: A Retrospective Case Series Study.

BACKGROUND: The efficacy and effectiveness of nintedanib as a first-line therapy in idiopathic pulmonary fibrosis (IPF) patients have been demonstrated by clinical trials and real-life studies. Our aim was to examine the safety profile and effectiveness of nintedanib when it is utilized as a second-line treatment in subjects who have discontinued pirfenidone. METHODS: The medical charts of 12 patients who were switched from pirfenidone to nintedanib were examined retrospectively. The drug's safety was defined by the number of adverse events (AEs) that were reported; disease progression was evaluated based on the patient's vital status and changes in forced vital capacity (FVC) at 12-month follow-up. RESULTS: The numbers of patients experiencing AEs and of the AEs per patient in our study group didn't significantly differ with respect to a group of 56 individuals who were taking nintedanib as a first-line therapy during the study period (5/12 vs. 22/56; p = 0.9999, and 0.00 (0.00-1.00) vs. 0.00 (0.00-3.00); p = 0.517, respectively). Two out of the 3 patients who had been switched to nintedanib due to a rapid disease progression showed stabilized FVC values. CONCLUSIONS: Nintedanib was found to have an acceptable safety profile in the majority of the IPF patients switched from pirfenidone. Prospective studies are warranted to determine if the drug can effectively delay disease progression in these patients.

Geographical Overlap Between Alpha-1 Antitrypsin Deficiency and COVID-19 Infection in Italy: Casual or Causal? / Superposición geográfica entre la deficiencia de alfa-1 antitripsina y la infección por COVID-19 en Italia: casual o causal?

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High-flow nasal cannula oxygen therapy to treat acute respiratory failure in patients with acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Some patients with idiopathic pulmonary fibrosis (IPF) develop acute exacerbation (AE-IPF) leading to severe acute respiratory failure (ARF); despite conventional supportive therapy, the mortality rate remains extremely high. The aim of this study was to assess how a treatment algorithm incorporating high-flow nasal cannula (HFNC) oxygen therapy affects the short-term mortality of patients with AE-IPF who develop ARF. METHOD AND DESIGN: A retrospective cohort analysis was conducted. PATIENTS AND INTERVENTIONS: The study consisted of 17 patients with AE-IPF admitted to a respiratory intensive care unit (RICU) for ARF managed using a treatment algorithm incorporating HFNC. The outcome measure was mortality rate during their stay in the RICU. RESULTS: Implementation of the treatment algorithm led to a successful outcome in nine patients and to a negative one in eight patients (47.1%) who died within 39 days of being admitted to the RICU. The survival rate was 70.6% (±0.1 %) at 15 days, 52.9% (±0.1%) at 30 days, 35.3% (±0.1%) at 90 days, and 15.6% (±9.73 %) at 365 days. Overall, 4 out of 10 patients who did not respond to conventional oxygen therapy showed a satisfactory response to HFNC. CONCLUSIONS: Short-term mortality fell to below 50% when a treatment algorithm incorporating HFNC was implemented in a group of patients with AE-IPF admitted to a RICU for ARF. Patients not responding to conventional oxygen therapy seemed to benefit from HFNC. The reviews of this paper are available via the supplementary material section.

Pirfenidone improves the survival of patients with idiopathic pulmonary fibrosis hospitalized for acute exacerbation.

Objective: To examine the effect of pirfenidone on the survival of patients hospitalized due to acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). Methods: The outcomes of 11 consecutive AE-IPF patients who were receiving pirfenidone treatment when they were admitted to a respiratory intensive care unit (RICU) for acute respiratory failure (ARF) (treatment group) were retrospectively compared with those of 9 patients who were not on pirfenidone treatment at admission (control group). The study's primary outcome measure was survival following RICU admission; the patients' mortality rate and the length of time spent in the RICU were also assessed. Results: The treatment group had significantly longer survival than the control group (median survival time: 137.0 [95% CI, 39.0-373.0] versus 16.0 [95% CI, 14.0-22.0] days; p = .0009); the hazard ratio for death was 0.2896 (95% CI, 0.09541-0.8791). The treatment group also tended to have a lower RICU mortality rate (3/11 vs. 7/9; p = .0698). Conclusions: Pirfenidone significantly improved survival in IPF patients hospitalized for severe acute exacerbation compared to controls.

Spontaneous pneumomediastinum complicating severe acute asthma exacerbation in adult patients.

Objectives: The real incidence of pneumomediastinum (PNM) in adult patients with severe acute asthma exacerbation continues to be unknown. The current study aims to investigate the occurrence of PNM in an adult population of patients presenting a severe asthma attack and to evaluate the risk factors associated to its development. Methods: The 45 consecutive subjects who were admitted to our Division between January 1, 2015 and December 31, 2016 for severe acute asthma exacerbation underwent a diagnostic protocol including a standard chest X-ray and continuous monitoring of arterial oxygen saturation (SaO2) during the first 24 hours following admission. The patients showing persistence or deterioration of oxyhemoglobin desaturation were prescribed a chest Computed Tomographic (CT) scan. Results: Five out of the 45 patients (11.1%) with severe acute asthma exacerbation were diagnosed with PNM, in one case on the basis of an X-ray image and in four on the basis of a chest CT scan. Data analysis showed that the PNM patients were younger [21 (17-21) vs 49.5 (20-73) yrs; p < 0.001] and more likely to show sensitization to Alternaria (2/5 vs 0/40; p = 0.0101) with respect to their non-PNM counterparts. The duration of hospital stay was similar in the two groups [8 (4-12) vs 7 (3-15) days; p = 0.6939]. Conclusions: PNM is a common clinical entity in young adults with severe acute asthma exacerbation, particularly in those with unsatisfactory response to initial medical therapy. Although generally benign, patients with suspected PNM should be closely monitored because of the risk of developing severe hypoxemia.

Recent advances in the diagnosis and management of obstructive sleep apnea.

Affecting a large number of middle-aged, frequently overweight subjects, obstructive sleep apnea (OSA) is the most common sleep related breathing disorder. Partial or complete upper airway (UA) collapse during sleep causing repeated apneic episodes, which is the leading pathophysiological mechanism underlying the disorder, results in arterial oxygen desaturation and recurrent arousals from sleep to re-establish airway patency. Untreated OSA is commonly associated with a range of adverse consequences, including cardiovascular complications, such as arterial and/or pulmonary hypertension, arrhythmias, stroke, as well as diabetes mellitus and metabolic syndrome, and motor vehicle accidents. Evidence-based guidelines are presently available for the diagnosis and management of OSA, and a variety of updated testing and treatment procedures and devices including some that are able to identify the site and degree of airway obstruction are becoming increasingly available. As the "one size fits all" approach falls to the wayside, a tailored personal therapeutic strategy is becoming increasingly popular in the field of sleep medicine. The aim of this review is to provide an overview for practicing clinicians on recent advances in the evaluation and management of obstructive sleep apnea in adults.

Cardiopulmonary exercise testing responses to different external portable drivers in a patient with a CardioWest Total Artificial Heart.

Management of patients treated with CardioWest Total Artificial Heart (CW-TAH) as a bridge to heart transplantation (HTx) is complicated by difficulties in determining the optimal timing of transplantation. We present a case of a 53-year-old man supported as an outpatient with a CW-TAH, whose condition deteriorated following exchange of the portable driver. The patient was followed-up with serial cardiopulmonary exercise testing (CPET) which demonstrated a fall of peak VO2 to below 12 ml/kg/min following driver substitution, and the patient was subsequently treated with urgent orthotopic HTx. This case highlights the potential utility of CPET as a means for monitoring and indicating timing of HTx in patients with CW-TAH, as well as the potential for clinical deterioration following portable driver substitution.

Changes in pulmonary function tests predict radiological response to chemotherapy in malignant pleural mesothelioma.

OBJECTIVES: Response to chemotherapy in malignant pleural mesothelioma (MPM) is usually evaluated by radiological criteria, but no common agreement exists on their validity, yet. The cytoreductive effect of chemotherapy on pleural thickening may make the lung more expansible, reducing the restrictive ventilatory impairment. The aim of this study was to evaluate the changes in pulmonary function following chemotherapy in patients with MPM and to correlate these findings with radiological changes. METHODS: Between 2004 and 2011, 62 consecutive patients (74% males, median age 63 years) were prospectively investigated. Modified RECIST criteria were used for radiological evaluation of response to chemotherapy. All patients underwent pulmonary function tests before and after three cycles of platinum-based chemotherapy. Changes between baseline and post-chemotherapy pulmonary function values (Δ) and their differences were assessed by means of Student's paired and unpaired t-test, respectively. Receiver operating characteristic (ROC) curve analysis was performed on spirometric parameters significantly associated with response. RESULTS: Thirty (48.4%) patients had a radiological stable disease (S), 23 (37.1%) a partial response (R) and 9 (14.5%) a progressive disease (P). ΔFEV1%pred (R: 18.1 ± 18.5%; S: 0.5 ± 9.3%; P: -11 ± 13.5%; P < 0.0001), ΔFVC%pred (R: 16.1 ± 11.8%; S: 0.4 ± 11.2%; P: -9.2 ± 14.6%; P < 0.0001) and ΔVC%pred (R: 12.9 ± 15.7%; S: 1.5 ± 12.1%; P: -6.1 ± 13.2%; P = 0.001) were significantly associated with radiological response. A significant correlation was observed between ΔFEV1%pred (r = 0.46, P = 0.01), ΔFVC%pred (r = 0.43, P = 0.02) and % change in linear tumour measurement. ROC curve analysis using dichotomized radiological response (P/S vs R) as classification variables showed AUC = 0.88 (95%CI: 0.77-0.95) for ΔFEV1%pred (optimal cut-off value: +7%, sensitivity: 83%, specificity: 82%, PPV: 73%, NPV: 89%) and AUC = 0.86 (95%CI: 0.75-0.94) for ΔFVC%pred (optimal cut-off value: +6%, sensitivity: 82%, specificity: 74%, PPV: 64%, NPV: 88%). CONCLUSIONS: Dynamic lung volumes and radiological changes after chemotherapy seem directly related. Lung function changes could be an additional tool to better evaluate the response to chemotherapy in MPM.

Noninvasive positive pressure ventilation in the management of acute respiratory failure due to osteogenesis imperfecta.

The development of acute respiratory failure (ARF) secondary to respiratory tract infection is a common event in patients affected with osteogenesis imperfecta type III. Noninvasive positive pressure ventilation (NPPV) is increasingly administered to treat severe ARF of various origin. The use of NPPV in two patients with severe ARF secondary to osteogenesis imperfecta type III is presented.

Undifferentiated connective tissue disease presenting with prevalent interstitial lung disease: case report and review of literature.

Undifferentiated connective tissue diseases (UCTDs) are clinical entities characterised by signs and symptoms suggestive of a systemic autoimmune disease, which do not fulfil the diagnostic criteria for a defined connective tissue disease. Lung involvement can complicate the course and management of the disease, often determining a worse outcome. Respiratory dysfunction as the first clinical manifestation has seldom been reported.We describe a case of a female patient who developed significant respiratory dysfunction as the principal clinical sign. Video-assisted thoracoscopy was performed and a histological pattern of nonspecific interstitial pneumonia (NSIP) was found. A pathological diagnosis suggested careful follow-up with extensive immunological screening which then detected Raynaud's phenomenon and positivity of antinuclear antibodies. After a multidisciplinary discussion (pneumologist, radiologist, pathologist and rheumatologist) a final diagnosis of NSIP associated with UCTD was made. The diagnosis of UCTD should be considered when NSIP is diagnosed even in cases with evident first clinical manifestations of severe respiratory dysfunction. A multidisciplinary approach in the field of interstitial lung disease with NSIP, also including rheumatologic expertise, is fundamental to achieve a prompt and correct diagnosis.