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.

High-flow nasal cannula oxygen therapy to treat patients with hypoxemic acute respiratory failure consequent to SARS-CoV-2 infection.

This observational study aims to assess the outcome and safety of O2-therapy by high-flow nasal cannula (HFNC) in 28 consecutive patients with severe hypoxemic acute respiratory failure (hARF) consequent to SARS-CoV-2 infection, unresponsive to conventional O2-therapy. Nineteen patients had a positive response. Nine patients required escalation of treatment to non-invasive ventilation (five subsequently intubated). None of the staff had a positive swab testing during the study period and the following 14 days. Severity of hypoxemia and C reactive protein level were correlated with HFNC failure. These data suggest HFNC to be a safe treatment for less severe patients with SARS-CoV-2 hARF and efficacy will need to be assessed as part of a clinical trial.

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.

Immune activation in α1-antitrypsin-deficiency emphysema. Beyond the protease-antiprotease paradigm.

RATIONALE: α1-Antitrypsin (AAT) is a potent protease inhibitor, deficiency of which is associated with the presence of emphysema. An imbalance of elastase and antielastase, along with innate inflammation in the lung, is believed to cause lung destruction in α1-antitrypsin deficiency (AATD). It is now apparent that AAT has important immune-regulatory roles that would be lost in AATD, yet adaptive immune responses in the lung have not been investigated in patients with AATD. OBJECTIVES: To assess the adaptive immune response in severe AATD emphysema and compare it with that present in "usual" chronic obstructive pulmonary disease (COPD). METHODS: The immune inflammatory response in explanted lungs from 10 subjects with AATD was characterized and quantified, and the results were compared with those of 26 subjects with usual COPD and those of 17 smoking and 11 nonsmoking control subjects with normal lung function. MEASUREMENTS AND MAIN RESULTS: Lymphoid follicles (LFs) in AATD and usual COPD were markedly increased when compared with control groups. Molecular analysis of B lymphocytes in LFs showed predominantly mono/oligoclonality. LF number correlated negatively with FEV1/FVC. B lymphocytes and CD4(+) and CD8(+) T lymphocytes were significantly increased in AATD and usual COPD when compared with control groups. IL-32, an important cytokine in induction of autoimmunity, was markedly up-regulated in AATD and usual COPD. CONCLUSIONS: An important adaptive immune inflammation, comprising B, CD4(+), and CD8(+) lymphocytes, and LFs, is a prominent feature in AATD. These results change the paradigm of the mechanism of AATD-induced emphysema from a pure elastase-antielastase imbalance to a much more complex one involving the adaptive immune system, similarly to what occurs in usual COPD.

Ex Vivo Signaling Protein Mapping in T Lymphocytes in the Psoriatic Arthritis Joints.

We assessed signaling protein mapping in total T cells, to analyze the proportions of T regulatory (Treg) and TCD4+ effector (Teff) cell phenotypes, and the respective interleukin 6Rα (IL-6Rα) expression in the inflammatory microenvironment of synovial fluid (SF) of patients with sustained psoriatic arthritis (PsA). Our approach was to measure the IL-6 level in SF using a multiplex bead immunoassay. Reverse-phase protein array was used to assess Janus kinase (JAK) 1 and JAK2, extra-cellular regulated kinase (ERK) 1 and 2, protein kinase Cδ (PKCδ), signal transducer and activator and transcription (STAT) 1, STAT3, and STAT5 phosphoproteins in total T cell lysates from SF of patients with PsA. Frequencies of CD4+IL-17A-F+IL-23+ CD4+ Th cells producing IL-17A and IL-17F (Th17) and CD4+CD25high intracellular forkhead box transcription factor+ (FOXP3+) phenotypes, and the percentage of Treg- and Teff- cells were quantified in SF and matched peripheral blood (PB) of patients with PsA and PB of healthy controls (HC) by flow cytometry. Our results were the following: In PsA SF samples, a coordinate increase of JAK1, ERK1/2, STAT1, STAT3, and STAT5 phosphoproteins was found in total T cells in SF of PsA; where IL-6 levels were higher than in PB from HC. Expanded CD4+IL-17A-F+IL-23+ Th17, CD4+ CD25- Teff- and CD4+CD25(high) FoxP3+Treg subsets, showing similar levels of enhanced IL-6Rδ expression, were confined to PsA joints. In our studies, the transcriptional network profile identified by ex vivo signaling protein mapping in T lymphocytes in PsA joints revealed the complex interplay between IL-1, IL-6, and IL-23 signaling and differentiation of Th17 cells and CD4+Tregs in sustained joint inflammation in PsA.

The Safety of a High-Flow Nasal Cannula in Neuromuscular Disease Patients with Acute Respiratory Failure: A Retrospective Case-Series Study.

(1) Background: Although Non-Invasive Ventilation (NIV) is effective in preventing mortality and endotracheal intubation in patients with Acute Respiratory Failure (ARF) linked to a neuromuscular disorder, its efficacy can be affected by patient intolerance. A High-Flow Nasal Cannula (HFNC) appears to have a significant advantage over NIV as far as patient tolerance is concerned. The aim of the study was to investigate HFNC's safety profile in a group of consecutive Neuromuscular Disease (NMD) patients intolerant to NIV who were admitted to an Intermediate Respiratory Care Unit (IRCU) for ARF. (2) Methods: The clinical course of nine NMD patients intolerant to NIV and switched to HFNC was reported. HFNC was provided during daytime hours and NIV during the night-time to the NIV-intolerant patients. HFNC was utilized 24 h a day in those patients who were intolerant of even nocturnal NIV. (3) Results: HFNC was simple to use and it was well tolerated by all of the patients. Three out of nine patients experienced treatment failure, consisting of the need for ETI and/or death during their IRCU stay. The remaining 6 had a favorable outcome. Treatment failure was linked to the utilization of HFNC 24 h a day. (4) Conclusion: HFNC during the daytime hours, together with nocturnal NIV, seems to be a safe therapeutic approach for NMD patients with ARF. A round-the-clock use of HFNC tends to be linked to a high likelihood of failure.

High-Flow Tracheal Oxygen for Tracheostomy Tube Removal in Lung Transplant Recipients.

(1) Background: Because of a complicated intraoperative course and/or poor recovery of graft function, approximately 15% of lung transplant (LT) recipients require prolonged mechanical ventilation (PMV) and receive a tracheostomy. This prospective study aimed to assess the effect of High-Flow Tracheal Oxygen (HFTO) on tracheostomy tube removal in LT recipients receiving PMV postoperatively. (2) Methods: The clinical course of 14 LT recipients receiving HFTO was prospectively evaluated and compared to that of 13 comparable controls receiving conventional oxygen therapy (COT) via tracheostomy. The study's primary endpoint was the number of patients whose tracheostomy tube was removed at discharge from an Intermediate Respiratory Care Unit (IRCU). (3) Results: Setting up HFTO proved easy, and it was well tolerated by all the patients. The number of patients whose tracheostomy tube was removed was significantly higher in the HFOT group compared to the COT group [13/14 vs. 6/13 (p = 0.0128)]. (4) Conclusions: HFTO is an effective, safe therapy that facilitates tracheostomy tube removal in LT recipients after weaning from PMV.

Synovial biomarkers in psoriatic arthritis.

OBJECTIVE: To find candidate biomarkers of psoriatic arthritis (PsA). A panel of synovial fluid (SF) and synovial tissue (ST) biomarkers was analyzed in patients with resistant peripheral PsA, in relation to clinical and imaging outcomes of synovitis response following serial intraarticular (IA) etanercept injections (12.5 mg). METHODS: Fourteen PsA patients with resistant knee joint synovitis were treated with 4 IA etanercept injections in a single knee joint, once every 2 weeks. Primary outcome (Thompson's knee index: THOMP) and secondary outcomes were assessed at baseline and end of study: C-reactive protein, Knee Joint Articular Index (KJAI), Health Assessment Questionnaire disability index, maximal synovial thickness (MST) by gray-scale ultrasonography, contrast-enhanced magnetic resonance imaging (C+MRI), ST-cluster differentiation (CD)45+ mononuclear cell, ST-CD31+ vessels, and ST-CD105+ angiogenic endothelial cells, along with levels of SF interleukin 1ß (IL-1ß), IL-1 receptor antagonist (Ra), and IL-6. RESULTS: At the end of the study, clinical and imaging outcomes, ST and SF biological markers were significantly reduced compared to baseline. There was a significant association between IL-6 and either THOMP or KJAI; between either ST-CD31+ or ST-CD105+ or ST-CD45+; between ST and SF biomarkers expression (CD45+ and IL-1ß) and between ST-CD45+ and both KJAI and MRI-MST. Comparing pre- versus post-IA etanercept injection changes (Δ), Δ IL-1ß was significantly correlated with both Δ IL-6 and with Δ IL-1Ra and Δ IL-6 with Δ IL-1Ra. CONCLUSION: The association to disease activity and the changes following IA treatment indicate that ST-CD45+ and ST-CD31+, along with SF-IL-6 and SF-IL-1ß, may represent candidate biomarkers of the knee synovitis response to IA tumor necrosis factor-α blockade.

Clinical Outcomes in Patients Aged 80 Years or Older Receiving Non-Invasive Respiratory Support for Hypoxemic Acute Respiratory Failure Consequent to COVID-19.

As the clinical outcome of octogenarian patients hospitalised for COVID-19 is very poor, here we assessed the clinical characteristics and outcomes of patients aged 80 year or older hospitalised for COVID-19 receiving non-invasive respiratory support (NIRS). A multicentre, retrospective, observational study was conducted in seven hospitals in Northern Italy. All patients aged ≥80 years with COVID-19 associated hypoxemic acute respiratory failure (hARF) undergoing NIRS between 24 February 2020, and 31 March 2021, were included. Out of 252 study participants, 156 (61.9%) and 163 (64.6%) died during hospital stay and within 90 days from hospital admission, respectively. In this case, 228 (90.5%) patients only received NIRS (NIRS group), while 24 (9.5%) were treated with invasive mechanical ventilation (IMV) after NIRS failure (NIRS+IMV group). In-hospital mortality did not significantly differ between NIRS and NIRS+IMV group (61.0% vs. 70.8%, respectively; p = 0.507), while survival probability at 90 days was significantly higher for NIRS compared to NIRS+IMV patients (0.379 vs. 0.147; p = 0.0025). The outcome of octogenarian patients with COVID-19 receiving NIRS is quite poor. Caution should be used when considering transition from NIRS to IMV after NIRS failure.

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.

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.

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.

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.

Effect of a passive exhalation port on tracheostomy ventilation in amyotrophic lateral sclerosis patients: a randomized controlled trial.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) patients often require long-term tracheostomy ventilation (LT-TV) because of progressive ventilatory failure. Although widely used for non-invasive ventilation (NIV), passive exhalation port systems have not been gaining popularity for TV because of the possibility of carbon dioxide (CO2) rebreathing. The current study set out to investigate the effect of a Whisper Swivel connector in comparison to an active exhalation valve on gas exchange and symptoms in ALS patients requiring LT-TV. METHODS: A prospective randomized controlled trial was carried out to compare the clinical outcome of ten ALS patients receiving LT-TV by means of a Trilogy 100 ventilator with a Whisper Swivel passive exhalation port (group A) and of 10 ALS patients connected to an Airox Legendair ventilator with an active exhalation valve (group B). The study's main outcome measure was CO2 retention at the 30-day follow-up assessment. RESULTS: One patient in each of the two cohorts showed significant CO2 retention. At the 30-day assessment, scores on the following measures were not significantly different in the two groups: the Borg dyspnea scale {2 [1-3] vs. 1 [1-3]; P=0.2891}, the visual analogue scale (VAS) dyspnea {20 [10-85] vs. 20 [0-50]; P=0.8571}, the Epworth sleepiness scale (ESS) {8 [4-10] vs. 5.5 [0-12]; P=0.1443}, the EuroQol-VAS (EQ-VAS) {55 [50-80] vs. 50 [30-80]; P=0.4593} and the relative stress scale (RSS) {49 [30-65] vs. 52 [25-64]; P=0.8650}. At the 3-month follow-up assessment, the numbers of hospitalizations and deaths were likewise similar in the two groups. CONCLUSIONS: The efficacy of the Whisper Swivel connector is similar to that of an active exhalation valve in ALS patients undergoing LT-TV.

Functional VEGF and VEGF receptors are expressed in human medulloblastomas.

Vascular endothelial growth factor (VEGF) is one of the key regulators of tumor neoangiogenesis. It acts through two types of high-affinity tyrosine kinase receptors (VEGF receptor-1 [VEGFR-1]/fms-related tyrosine kinase 1 [Flt-1] and VEGFR-2/kinase domain receptor [KDR]) expressed on endothelial cells. VEGFRs have also been detected on cancer cells, suggesting a possible autocrine effect of VEGF on their growth. We studied the expression of VEGF, VEGFR-1, and VEGFR-2 in human medulloblastoma cell lines (DAOY, D283Med, and D341Med) and investigated the possible autocrine mechanisms of VEGF on medulloblastoma cell proliferation. Reverse transcriptase PCR analysis showed the presence of VEGF and VEGFR mRNAs in all cell lines studied. Of the three VEGF isoforms, VEGF(121) and VEGF(189) were detected by Western blot analysis in all three medulloblastoma cell lines, whereas VEGF(165) was identified only in DAOY cells. Medulloblastoma cell lines expressed both VEGFR-1 and VEGFR-2. We also demonstrated expression of VEGF and its receptors in medulloblastoma tumor specimens. Exogenous VEGFR-2 inhibitor reduced the VEGF-dependent cell proliferation of DAOY and D283Med cells. In DAOY cells, VEGF(165) induced phosphorylation of VEGFR-2/KDR and of downstream proteins in the signal transduction pathway. These data suggest a possible autocrine role for VEGF in medulloblastoma growth. Targeting VEGF signaling may represent a new therapeutic option in the treatment of medulloblastoma.

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.