Alpha-1 Antitrypsin PI M Heterozygotes with Rare Variants: Do They Need a Clinical and Functional Follow-Up?

(1) Background: Few data are available on the risk of airway dysfunction in protease inhibitor (PI*) M heterozygotes carrying rare null or deficient allelic variants of the gene SERPINA-1 (PI*MR). (2) Methods: In this observational study, in a cohort of PI*MR heterozygotes, we evaluated respiratory functional parameters at baseline and at one-year follow-up. Moreover, we compared such parameters with those of the PI*MZ and PI*MS patients. (3) Results: A total of 60 patients were recruited; 35 PI*MR, 11 PI*MZ and 14 PI*MS. At the annual follow-up, the PI*MR and PI*MZ patients demonstrated a significantly higher FEV1 decline than the PI*MS group (p = 0.04 and p = 0.018, respectively). The PI*MR patients showed a significant increase in DLCO annual decline in comparison with the PI*MS group (p = 0.02). At baseline, the PI*MR smoking patients, compared with nonsmokers, showed statistically significant lower values of FEV1, FEV1/FVC and DLCO (p = 0.0004, p < 0.0001, p = 0.007, respectively) and, at the one-year follow-up, they displayed a significantly higher FEV1 and DLCO decline (p = 0.0022, p = 0.011, respectively). PI*MR heterozygotes with COPD showed a significantly higher FEV1, FEV1/FVC and DLCO annual decline in comparison with healthy PI*MR (p = 0.0083, p = 0.043, p = 0.041). (4) Conclusions: These results suggest that PI*MR heterozygotes, particularly smokers with COPD, have a greater annual decline in respiratory functional parameters and need to be monitored.

An unusual way to improve lung function in congenital myopathies: the power of singing.

Congenital myopathies (CMs) are a clinically and genetically heterogeneous group of disorders characterized by early onset weakness, hypotonia and characteristic structural abnormalities in muscle fibres. Hypotonia and weakness can be present at birth or appear in infancy, and a static or slowly progressive clinical course may present with muscle weakness, loss of spontaneous movement, involuntary muscle activity, and muscle atrophy. Often patients develop a restrictive syndrome and respiratory failure and require respiratory support In our case, we described lung improvement and respiratory muscle training due to singing in a young patient, affected by CMs with a poor adherence to non-invasive mechanical ventilation.

Transplant with MZ genotype liver: what is the clinical pulmonary picture after 30 years? a case report and review of the literature.

BACKGROUND: Alpha-1 antitrypsin, also known as alpha1 proteinase inhibitor, is a protein 90% synthesized by hepatocytes. Alpha-1 antitrypsin deficiency should be suspected if patients have unexplained emphysema or liver disease in the absence of others recognized causes. The diagnosis is based on tests that measure the amount of the enzyme in the blood and confirm by molecular analysis. CASE PRESENTATION: We present the case of a man of Caucasian ethnicity, who started experiencing difficulty in breathing 20 years after liver transplantation. After about 30 years since transplantation, an intermediate alpha-1 antitrypsin deficiency is diagnosed with evidence of air trapping, pulmonary emphysema and bronchiectasis. CONCLUSION: The presence of a Z-variant synthesized from the donor liver may have contribute to the onset of respiratory disease.

Psychological Factors Influencing Adherence to NIV in Neuromuscular Patients Dependent on Non Invasive Mechanical Ventilation: Preliminary Results.

BACKGROUND: Non-invasive ventilation (NIV) is associated with improvement of both morbility and mortality in patients affected by neuromuscular diseases with chronic respiratory failure. Several studies have also shown that long-term NIV positively impacts the patient's quality of life and perception of disease status. Its effectiveness is likely related to the adherence to NIV. Several factors, patient- and not patient-related, may compromise adherence to NIV, such as physical, behavioral, familiar, and social issues. Few data are currently available on the role of psychological factors in influencing NIV adherence. MATERIALS AND METHODS: In this pilot study, we evaluated the adherence to NIV in a group of 15 adult patients with neuromuscular diseases (Duchenne muscular dystrophy, myotonic dystrophy, and amyotrophic lateral sclerosis) in relation to their grade of depression assessed by the Beck Depression Inventory (BDI) questionnaire. Other data were collected, such as clinical features (age and sex), use of anxiolytic drugs, the presence of a family or professional caregiver, the quality of patient-physician relationship, the beginning of psychological support after BDI screening, and the family acceptance of NIV. NIV adherence was definied as the use of NIV for at least 4 h per night on 70% of nights in a month. RESULTS: The overall rate of NIV adherence was 60%. Based on the BDI questionnaire, patients who were non-adherent to NIV had a higher rate of depression, mainly observed in the oldest patients. The acceptance of NIV by the family and positive physician-patient interaction seem to favor NIV adherence. CONCLUSION: Depression can interfere with NIV adherence in patients with neuromuscolar diseases.

The role of dexmedetomidine in ARDS: an approach to non-intensive care sedation.

Introduction: Severe COVID-19 is a life-threatening condition characterized by complications such as interstitial pneumonia, hypoxic respiratory failure, and acute respiratory distress syndrome (ARDS). Non-pharmacological intervention with mechanical ventilation plays a key role in treating COVID-19-related ARDS but is influenced by a high risk of failure in more severe patients. Dexmedetomidine is a new generation highly selective α2-adrenergic receptor (α2-AR) agonist that provides sedative effects with preservation of respiratory function. The aim of this study is to assess how dexmedetomidine influences gas exchange during non-invasive ventilation (NIV) and high-flow nasal cannula (HFNC) in moderate to severe ARDS caused by COVID-19 in a non-intensive care setting. Methods: This is a single center retrospective cohort study. We included patients who showed moderate to severe respiratory distress. All included subjects had indication to NIV and were suitable for a non-intensive setting of care. A total of 170 patients were included, divided in a control group (n = 71) and a treatment group (DEX group, n = 99). Results: A total of 170 patients were hospitalized for moderate to severe ARDS and COVID-19. The median age was 71 years, 29% females. The median Charlson comorbidity index (CCI) was 2.5. Obesity affected 21% of the study population. The median pO2/FiO2 was 82 mmHg before treatment. After treatment, the increase of pO2/FiO2 ratio was clinically and statistically significant in the DEX group compared to the controls (125 mmHg [97-152] versus 94 mmHg [75-122]; ***p < 0.0001). A significative reduction of NIV duration was observed in DEX group (10 [7-16] days vs. 13 [10-17] days; *p < 0.02). Twenty four patients required IMV in control group (n = 71) and 16 patients in DEX group (n = 99) with a reduction of endotracheal intubation of 62% (OR 0.38; **p < 0.008). A higher incidence of sinus bradycardia was observed in the DEX group. Conclusion: Dexmedetomidine provides a "calm and arousal" status which allows spontaneous ventilation in awake patients treated with NIV and HFNC. The adjunctive therapy with dexmedetomidine is associated with a higher pO2/FiO2, lower duration of NIV, and a lower risk of NIV failure. A higher incidence of sinus bradycardia needs to be considered.

Diagnosis of Paediatric Obstructive Sleep-Disordered Breathing beyond Polysomnography.

Obstructive sleep-disordered breathing (SDB) has significant impacts on health, and therefore, a timely and accurate diagnosis is crucial for effective management and intervention. This narrative review provides an overview of the current approaches utilised in the diagnosis of SDB in children. Diagnostic methods for SDB in children involve a combination of clinical assessment, medical history evaluation, questionnaires, and objective measurements. Polysomnography (PSG) is the diagnostic gold standard. It records activity of brain and tibial and submental muscles, heart rhythm, eye movements, oximetry, oronasal airflow, abdominal and chest movements, body position. Despite its accuracy, it is a time-consuming and expensive tool. Respiratory polygraphy instead monitors cardiorespiratory function without simultaneously assessing sleep and wakefulness; it is more affordable than PSG, but few paediatric studies compare these techniques and there is optional recommendation in children. Nocturnal oximetry is a simple and accessible exam that has high predictive value only for children at high risk. The daytime nap PSG, despite the advantage of shorter duration and lower costs, is not accurate for predicting SDB. Few paediatric data support the use of home testing during sleep. Finally, laboratory biomarkers and radiological findings are potentially useful hallmarks of SDB, but further investigations are needed to standardise their use in clinical practice.

Intermittent abdominal pressure ventilation management in neuromuscular diseases: a Delphi panel Consensus.

BACKGROUND: Intermittent abdominal pressure ventilator (IAPV) use started in the 1930s for ventilatory assistance with muscular dystrophy patients. Later, the device was perfected and expanded for other neuromuscular disorders (NMD). In recent years, the morbidity and mortality tracheotomies and trach tubes related renewed the interest around IAPV. However, there are no guidelines for its use. This study aimed to establish a consensus among physicians involved in its practice to provide IAPV suggestions for the treatment of patients with NMD. METHOD: A 3-step modified Delphi method was used to establish consensus. Fourteen respiratory physicians and one psychiatrist with strong experience in IAPV use and/or who published manuscripts on the topic participated in the panel. A systematic review of the literature was carried out according to the PRISMA to identify existing evidence on IAPV for patients with neuromuscular disorders. RESULTS: In the first round, 34 statements were circulated. Panel members marked 'agree' or 'disagree' for each statement and provided comments. The agreement was reached after the second voting session for all 34 statements. CONCLUSIONS: Panel members agreed and IAPV indications, parameter settings (including procedure protocol), potential limitations, contraindications, complications, monitoring, and follow-up are described. This is the first expert consensus on IAPV.

Effects on Right Ventricular Function One Year after COVID-19-Related Pulmonary Embolism.

The aim of this study was to investigate the presence of subclinical cardiac dysfunction in recovered coronavirus disease 2019 (COVID-19) patients, who were stratified according to a previous diagnosis of pulmonary embolism (PE) as a complication of COVID-19 pneumonia. Out of 68 patients with SARS-CoV-2 pneumonia followed up for one year, 44 patients (mean age 58.4 ± 13.3, 70% males) without known cardiopulmonary disease were divided in two groups (PE+ and PE-, each comprising 22 patients) and underwent clinical and transthoracic echocardiographic examination, including right-ventricle global longitudinal strain (RV-GLS), and RV free wall longitudinal strain (RV-FWLS). While no significant differences were found in the left- or right-heart chambers' dimensions between the two study groups, the PE+ patients showed a significant reduction in RV-GLS (-16.4 ± 2.9 vs. -21.6 ± 4.3%, p < 0.001) and RV-FWLS (-18.9 ± 4 vs. -24.6 ± 5.12%, p < 0.001) values compared to the PE- patients. According to the ROC-curve analysis, RV-FWLS < 21% was the best cut-off with which to predict PE diagnosis in patients after SARS-CoV-2 pneumonia (sensitivity 74%, specificity 89%, area under the curve = 0.819, p < 0.001). According to the multivariate logistic regression model, RV-FWLS < 21% was independently associated with PE (HR 34.96, 95% CI:3.24-377.09, p = 0.003) and obesity (HR 10.34, 95% CI:1.05-101.68, p = 0.045). In conclusion, in recovered COVID-19 patients with a history of PE+, there is a persistence of subclinical RV dysfunction one year after the acute phase of the disease, detectable by a significant impairment in RV-GLS and RV-FWLS. A reduction in RV-FWLS of lower than 21% is independently associated with COVID-related PE.

Long-Term High Flow Nasal Cannula Therapy in Primary and Secondary Bronchiectasis.

BACKGROUND: Bronchiectasis is the consequence of chronic bronchial inflammation, inappropriate mucus clearance, bacterial colonization, and recurrent or chronic infection. High flow therapy (HFT) is a type of non-invasive respiratory therapy, usually delivered through a nasal cannula interface (HFNC). It delivers heated and humidified air with a stable fraction of inspired oxygen and a wide range of possible flow rates. AIM OF THE STUDY: Determine the effectiveness of HFNC as add-on therapy in adult primary and secondary bronchiectasis with frequent acute exacerbations (AEs) and/or hospitalizations. METHODS: This is a single-center crossover study on long-term home therapy with HFNC in adult bronchiectasis. Pharmacological therapy included pulse therapy with mucolytics and bronchodilators. After one year, all patients were switched to additional HFNC. The temperature range was 31-37 °C. The flow range was 35-60 L/m. FiO2 was 0.21. RESULTS: Seventy-eight patients completed the follow-up; 54% were females; the median age was 70 years (IQR 60-76). The etiology of bronchiectasis was mainly post-infective (51%), COPD related (26%), and congenital (11%). AEs at baseline were 2.81 (±2.15). A significant reduction in AEs was observed after 24 months with a mean of 0.45 (±0.66) (f-ratio value 79.703. p-value < 0.00001). No significant difference was observed after HFNC therapy on FEV1 (2.39 ± 0.87 vs. 2.55 ± 0.82; f-ratio 0.79. p-value 0.45) and FVC (2.73 ± 0.88 vs. 2.84 ± 0.90; f-ratio 0.411. p-value 0.66). A significant reduction in mMRC score was observed after HFNC therapy (2.40 ± 0.81 vs. 0.97 ± 0.97 at 2 months vs. 0.60 ± 0.78 at 24 months; f-ratio value 95.512. p-value < 0.00001). CONCLUSIONS: HFNC is a well-tolerated add-on therapy for adult bronchiectasis. Dyspnea improved after 2 months and further after 2 years. The exacerbation rate decreased during the 2 years follow-up. No significant difference was observed in lung function.

Remdesivir treatment and clinical outcome in non-severe hospitalized COVID-19 patients: a propensity score matching multicenter Italian hospital experience.

INTRODUCTION: Remdesivir exerts positive effects on clinical improvement, even though it seems not to affect mortality among COVID-19 patients; moreover, it was associated with the occurence of marked bradycardia. METHODS: We retrospectively evaluated 989 consecutive patients with non-severe COVID-19 (SpO2 ≥ 94% on room air) admitted from October 2020 to July 2021 at five Italian hospitals. Propensity score matching allowed to obtain a comparable control group. Primary endpoints were bradycardia onset (heart rate < 50 bpm), acute respiratory distress syndrome (ARDS) in need of intubation and mortality. RESULTS: A total of 200 patients (20.2%) received remdesivir, while 789 standard of care (79.8%). In the matched cohorts, severe ARDS in need of intubation was experienced by 70 patients (17.5%), significantly higher in the control group (68% vs. 31%; p < 0.0001). Conversely, bradycardia, experienced by 53 patients (12%), was significantly higher in the remdesivir subgroup (20% vs. 1.1%; p < 0.0001). During follow-up, all-cause mortality was 15% (N = 62), significantly higher in the control group (76% vs. 24%; log-rank p < 0.0001), as shown at the Kaplan-Meier (KM) analysis. KM furthermore showed a significantly higher risk of severe ARDS in need of intubation among controls (log-rank p < 0.001), while an increased risk of bradycardia onset in the remdesivir group (log-rank p < 0.001). Multivariable logistic regression showed a protective role of remdesivir for both ARDS in need of intubation (OR 0.50, 95%CI 0.29-0.85; p = 0.01) and mortality (OR 0.18, 95%CI 0.09-0.39; p < 0.0001). CONCLUSIONS: Remdesivir treatment emerged as associated with reduced risk of severe acute respiratory distress syndrome in need of intubation and mortality. Remdesivir-induced bradycardia was not associated with worse outcome.

Is Intermittent Abdominal Pressure Ventilation Still Relevant? A Multicenter Retrospective Pilot Study.

Non-invasive ventilatory support (NVS) is a technique used to reduce respiratory work in neuromuscular diseases, preventing the progression of respiratory failure. NVS is usually administered via a nasal or an oronasal mask, causing discomfort, especially in patients ventilated for more than 16 h/day. Intermittent abdominal pressure ventilation (IAPV) differs completely from conventional NVS and consists of a portable ventilator and a corset with Velcro closures as the interface. In our study, the practicability and efficacy of IAPV were studied in three Italian centers monitoring 28 neuromuscular patients using IAPV who were then retrospectively analyzed. The primary outcomes were an improvement in hypoxemia and the normalization of hypercapnia, and the secondary outcome was an improvement in quality of life. Data were collected at baseline (T0) and after two hours of ventilation (T1), with follow-ups at three months (T2) and six months (T3). Statistical significance was found for PaCO2 over time (F (2.42) = 7.63, p = 0.001) and PaO2 (W = 0.539, p = 0.033). The time of NVS usage also significantly affected the quality of life (F (2.14) = 6.90, p = 0.010), as seen when comparing T0 and T3. As an alternative ventilation method, IAPV is still relevant today and could become a key part of daytime support, especially for patients who do not tolerate standard daytime NVS with an oral interface.

Targeted genetic analysis unveils novel associations between ACE I/D and APO T158C polymorphisms with D-dimer levels in severe COVID-19 patients with pulmonary embolism.

Only a percentage of COVID-19 patients develop thrombotic complications. We hypothesized that genetic profiles may explain part of the inter-individual differences. Our goal was to evaluate the genotypic distribution of targeted DNA polymorphisms in COVID-19 patients complicated (PE+) or not (PE-) by pulmonary embolism. We designed a retrospective observational study enrolling N = 94 consecutive patients suffering severe COVID-19 with pulmonary embolism (PE+, N = 47) or not (PE-, N = 47) during hospitalization. A panel of N = 13 prothrombotic DNA polymorphisms (FV R506Q and H1299R, FII G20210A, MTHFR C677T and A1298C, CBS 844ins68, PAI-1 4G/5G, GPIIIa HPA-1 a/b, ACE I/D, AGT T9543C, ATR-1 A1166C, FGB - 455G > A, FXIII103G > T) and N = 2 lipid metabolism-related DNA polymorphisms (APOE T 112C and T158C) were investigated using Reverse Dot Blot technique. Then, we investigated possible associations between genotypic subclasses and demographic, clinical, and laboratory parameters including age, obesity, smoking, pro-inflammatory cytokines, drug therapy, and biomarkers of thrombotic risk such as D-dimer (DD). We found that 58.7% of PE+ had homozygous mutant D/D genotype at ACE I/D locus vs. PE- (40.4%) and 87% of PE+ had homozygous mutant C/C genotype at APOE T158C locus vs. PE- (68.1%). In PE+ group, DD levels were significantly higher in D/D and I/D genotypes at ACE I/D locus (P = 0.00066 and P = 0.00023, respectively) and in C/C and T/C genotypes at APOE T158C locus (P = 1.6e-06 and P = 0.0012, respectively) than PE- group. For the first time, we showed significant associations between higher DD levels and ACE I/D and APOE T158C polymorphisms in PE+ vs. PE- patients suggesting potential useful biomarkers of poor clinical outcome.

Respiratory Intensive Care Unit management and efficacy during the COVID-19 outbreak in Naples, Italy.

The World Health Organization declared the Coronavirus Diseases 2019 (COVID-19) outbreak a global pandemic on March 11, 2020. COVID-19 had an impact on over 500 million people worldwide. According to the American Thoracic Society criteria, the respiratory spectrum of this disease ranges from mild illness to severe pneumonia, with the latter occurring in a not insignificant 15% of patients. A rapid increase in the incidence of COVID-19 pneumonia cases has been observed all over the world, resulting in a saturation of the Intensive Care Unit's capacity (ICUs). Because of this impressive outbreak, the ICU beds and invasive mechanical ventilators reached their capacity. Non-invasive supportive care has become an important option for keeping respiratory conditions under control. As a result, proper healthcare resource management was required to ensure adequate patient care. Respiratory Intensive Care Units (RICUs) have become a useful resource for managing complex patients due to a shortage of ICU capacity. This highlighted the importance of RICUs, where patients with moderate to severe respiratory failure can be treated with non-invasive respiratory support rather than being admitted to the ICU. The clinical outcomes and baseline characteristics of patients admitted to the RICU of Cotugno Hospital, a tertiary referral center in Naples (Italy), from January 2021 to October 2021 are described in this report.

Corrigendum to "Effects of adding L-arginine orally to standard therapy in patients with COVID-19: A randomized, double-blind, placebo-controlled, parallel-group trial. Results of the first interim analysis."

[This corrects the article DOI: 10.1016/j.eclinm.2021.101125.].

Editorial Comment on Special Issue-COVID-19 after One Year of Clinical Experience: Unexpected Clinical Presentations or Complications and Post-COVID-19 Clinical Features.

Beginning in 2020, the COVID-19 pandemic caused by SARS-CoV-2 remains ongoing [...].

Evolution of the Clinical Profile and Outcomes of Unvaccinated Patients Affected by Critical COVID-19 Pneumonia from the Pre-Vaccination to the Post-Vaccination Waves in Italy.

The vaccination campaign and the new SARS-CoV-2 variants may have changed the clinical profile and outcomes of patients admitted to sub-intensive unit care. We conducted a retrospective study aimed to compare the clinical and radiological features of unvaccinated critical COVID-19 patients hospitalized during the last pandemic wave (December 2021−February 2022, No-Vax group) and before starting the vaccination campaign (March−December 2020, Pre-Vax group). The No-Vax group was also compared with vaccinated patients of the same pandemic wave (Vax group). With respect to the Pre-Vax group, the No-Vax group contained a higher percentage of smokers (p = 0.0007) and a lower prevalence of males (p = 0.0003). At admission, the No-Vax patients showed both a higher CT score of pneumonia and a worse severe respiratory failure (p < 0.0001). In the No-Vax group, a higher percentage of deaths occurred, though this was not significant. In comparison with the No-Vax group, the Vax patients were older (p = 0.0097), with a higher Charlson comorbidity index (p < 0.0001) and a significantly lower HRCT score (p = 0.0015). The percentage of deaths was not different between the two groups. The No-Vax patients showed a more severe disease in comparison with the Pre-Vax patients, and were younger and had fewer comorbidities than the Vax patients.

Versatility of Intermittent Abdominal Pressure Ventilation in a Case of Complicated Restrictive Respiratory Failure and COVID-19.

BACKGROUND: The intermittent abdominal pressure ventilation (IAPV) is a non-invasive ventilation (NIV) technique that avoids facial interfaces and is a diurnal ventilatory support alternative for neuromuscular patients during stable chronic phases of the disease. Coronavirus disease 2019 (COVID-19) is a novel infection possibly causing acute respiratory distress syndrome (ARDS). Neuromuscular diseases (NMD) and preexisting respiratory failure can be exacerbated by respiratory infection and progress to severe disease and ICU admission with a poor prognosis. AIM: To report on the versatility and feasibility of IAPV in acute restrictive respiratory failure exacerbated by COVID-19. PATIENT: We describe the case of a 33-year-old man with spastic tetraparesis, kyphoscoliosis, and impaired cough, eventually leading to a restrictive ventilation pattern. COVID-19 exacerbated respiratory failure and seizures. An NIV trial failed because of inadequate interface adhesion and intolerance. During NIV, dyspnea and seizures worsened. He underwent a high flow nasal cannula (HFNC) with a fluctuating benefit on gas exchange. IAPV was initiated and although there was a lack of cooperation and inability to sit; the compliance was good and a progressive improvement of gas exchange, respiratory rate, and dyspnea was observed. CONCLUSIONS: IAPV is a versatile type of NIV that can be adopted in complicated restrictive respiratory failure. COVID-19 exacerbates preexisting conditions and is destined to be a disease of frailty. COVID-19 is not a contraindication to IAPV and this kind of ventilation can be employed in selected cases in a specialistic setting. Moreover, this report suggests that IAPV is safe when used in combination with HFNC. This hybrid approach provides the opportunity to benefit from both therapies, and, in this particular case, prevented the intubation with all connected risks.

Negative-Pressure Ventilation in Neuromuscular Diseases in the Acute Setting.

Mechanical ventilation started with negative-pressure ventilation (NPV) during the 1950s to assist patients with respiratory failure, secondary to poliomyelitis. Over the years, technological evolution has allowed for the development of more comfortable devices, leading to an increased interest in NPV. The patients affected by neuromuscular diseases (NMD) with chronic and acute respiratory failure (ARF) may benefit from NPV. The knowledge of the available respiratory-support techniques, indications, contraindications, and adverse effects is necessary to offer the patient a personalized treatment that considers the pathology's complexity.