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.

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.

Beneficial effects of L-Arginine in patients hospitalized for COVID-19: New insights from a randomized clinical trial.

We have recently demonstrated in a double-blind randomized trial the beneficial effects of L-Arginine in patients hospitalized for COVID-19. We hypothesize that one of the mechanisms underlying the favorable effects of L-Arginine is its action on inflammatory cytokines. To verify our hypothesis, we measured longitudinal plasma levels of pro-inflammatory and anti-inflammatory cytokines implied in the pathophysiology of COVID-19 in patients randomized to receive oral L-Arginine or placebo. The study was successfully completed by 169 patients. Patients in the L-Arginine arm had a reduced respiratory support evaluated at 10 and 20 days; moreover, the time to hospital discharge was significantly shorter in the L-Arginine group. The assessment of circulating cytokines revealed that L-Arginine significantly reduced the circulating levels of pro-inflammatory IL-2, IL-6, and IFN-γ and increased the levels of the anti-inflammatory IL-10. Taken together, these findings indicate that adding L-Arginine to standard therapy in COVID-19 patients markedly reduces the need of respiratory support and the duration of in-hospital stay; moreover, L-Arginine significantly regulates circulating levels of pro-inflammatory and anti-inflammatory cytokines.

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.].

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.

Three Month Follow-Up of Patients With COVID-19 Pneumonia Complicated by Pulmonary Embolism.

Background: Previous studies have demonstrated persistent dyspnoea and impairment of respiratory function in the follow-up of patients who have recovered from COVID-19 pneumonia. However, no studies have evaluated the clinical and functional consequences of COVID-19 pneumonia complicated by pulmonary embolism. Objective: The aim of our study was to assess the pulmonary function and exercise capacity in COVID-19 patients 3 months after recovery from pneumonia, either complicated or not by pulmonary embolism. Methods: This was a retrospective, single-centre, observational study involving 68 adult COVID-19 patients with a positive/negative clinical history of pulmonary embolism (PE) as a complication of COVID-19 pneumonia. Three months after recovery all patients underwent spirometry, diffusion capacity of the lungs for carbon monoxide (DLCO), and 6 minute walk test (6MWT). In addition, high-resolution computed tomography (HRCT) of the lung was carried out and CT-pulmonary angiography was conducted only in the PE+ subgroup. Patients with a previous diagnosis of PE or chronic lung diseases were excluded from the study. Results: Of the 68 patients included in the study, 24 had previous PE (PE+) and 44 did not (PE-). In comparison with the PE- subgroup, PE+ patients displayed a FVC% predicted significantly lower (87.71 ± 15.40 vs 98.7 ± 16.7, p = 0.009) and a significantly lower DLCO% predicted (p = 0.023). In addition, a higher percentage of patients were dyspnoeic on exercise, as documented by a mMRC score ≥1 (75% vs 54.3%, p < 0.001) and displayed a SpO2 <90% during 6MWT (37.5% vs 0%, p < 0.001). HRCT features suggestive of COVID-19 pneumonia resolution phase were present in both PE+ and PE- subjects without any significant difference (p = 0.24) and abnormalities at CT pulmonary angiography were detected in 57% of the PE+ subgroup. Conclusion: At the 3 month follow-up, the patients who recovered from COVID-19 pneumonia complicated by PE showed more dyspnoea and higher impairment of pulmonary function tests compared with those without PE.

Acute Pancreatitis and COVID-19: A Single-Center Experience.

Gastrointestinal involvement in SARS-CoV-2 disease (COVID-19) can occur and evolve fatally. Reports are emerging that SARS-CoV-2 virus attacks the pancreatic cells, causing the boost of amylase and lipase serum activity and rarely frank pancreatitis. We retrospectively assessed all the patients admitted to the respiratory sub-intensive care and evaluated pancreatitis cases and their course. In our study, we included all patients admitted to our respiratory sub-intensive care unit from 1st to 30th November. All patients had a confirmed diagnosis of COVID-19 and a CT finding of interstitial pneumonia associated with signs of respiratory failure. We observed the course and evaluated who developed acute pancreatitis according to standard definitions. In this study, etiology of acute pancreatitis was defined on the basis of risk factors (ie, biliary pancreatitis was defined in presence of common bile duct stone or sludge at CT or MR). According to the Revised Atlanta Classification, we diagnosed and classified the patients and evaluated the radiological severity according to the Balthazar index and a computed tomography severity index. We found that 19% (15 of 78 patients) met the criteria for acute pancreatitis. The mortality rate among patients with pancreatitis was 20%. Interestingly, in our population, cholelithiasis' imaging findings were found in only 7% of the patients, whereas no patient-reported alcohol consumption. Considering that alcohol and biliary stones represent the two major causes of AP in the general population, it is reasonable to hypothesize that SARS-CoV-2 could play a role in the etiology of acute pancreatitis in a subgroup of these patients.

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.

BACKGROUND: We and others have previously demonstrated that the endothelium is a primary target of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and L-arginine has been shown to improve endothelial dysfunction. However, the effects of L-arginine have never been evaluated in coronavirus disease 2019 (COVID-19). METHODS: This is a parallel-group, double-blind, randomized, placebo-controlled trial conducted on patients hospitalized for severe COVID-19. Patients received 1.66 g L-arginine twice a day or placebo, administered orally. The primary efficacy endpoint was a reduction in respiratory support assessed 10 and 20 days after randomization. Secondary outcomes were the length of in-hospital stay, the time to normalization of lymphocyte number, and the time to obtain a negative real-time reverse transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2 on nasopharyngeal swab. This clinical trial had been registered at ClinicalTrials.gov, identifier: NCT04637906. FINDINGS: We present here the results of the initial interim analysis on the first 101 patients. No treatment-emergent serious adverse events were attributable to L-arginine. At 10-day evaluation, 71.1% of patients in the L-arginine arm and 44.4% in the placebo arm (p < 0.01) had the respiratory support reduced; however, a significant difference was not detected 20 days after randomization. Strikingly, patients treated with L-arginine exhibited a significantly reduced in-hospital stay vs placebo, with a median (interquartile range 25th,75th percentile) of 46 days (45,46) in the placebo group vs 25 days (21,26) in the L-arginine group (p < 0.0001); these findings were also confirmed after adjusting for potential confounders including age, duration of symptoms, comorbidities, D-dimer, as well as antiviral and anticoagulant treatments. The other secondary outcomes were not significantly different between groups. INTERPRETATION: In this interim analysis, adding oral L-arginine to standard therapy in patients with severe COVID-19 significantly decreases the length of hospitalization and reduces the respiratory support at 10 but not at 20 days after starting the treatment. FUNDING: Both placebo and L-arginine were kindly provided by Farmaceutici Damor S.p.A., Naples.

The Angiotensin Converting Enzyme Deletion/Deletion Genotype Is a Risk Factor for Severe COVID-19: Implication and Utility for Patients Admitted to Emergency Department.

Background and objective: Insertion/deletion polymorphisms of angiotensin-converting enzyme (ACE) have been previously described in association with adult respiratory distress syndrome (ARDS) and correlated to outcome. The ACE deletion/deletion(D/D)genotype represents a marker of thrombosis in subjects apparently without predisposing factors and/or traditional thrombophilic alterations and increases the risk of venous thromboembolism in subjects in whom a thrombogenic condition occurs. Thrombosis seems to play a role very early in the disease caused by SARS-CoV-2, in particular in those with severe COVID-19 pneumonia. The counterbalance between angiotensin-converting enzyme (ACE) and ACE2 activities in COVID-19 disease may play a crucial role in the thrombo-inflammatory process. We hypothesised that a genetic predisposition could condition the severity and complications of SARS-CoV-2 infection. Materials and methods: We conducted a spontaneous, single centre observational study in the Sub-Intensive Care Unit of A.O.R.N. Ospedali dei Colli, Cotugno Hospital, Naples (Italy). In this study, we performed genetic screening for ACE D/D genotype and other thrombophilic mutations in 20 patients affected by ARDS related to COVID-19 pneumonia, compared to 19 age- and sex-matched healthy controls. Results: All tested patients had multiple polymorphisms and, in particular, a significantly higher prevalence of ACE D/D polymorphism in severe COVID-19 patients Conclusion: We found that the majority of patients who tested positive for ACE D-D genotype and who were not associated with other risk factors for VTE showed an evolution to ARDS. This finding could have a predicting role in the selection of patients more prone to developing severe COVID-19 during clinical observation in emergency department.

The Role of High Flow Nasal Cannula in COVID-19 Associated Pneumomediastinum and Pneumothorax.

BACKGROUND: Pneumomediastinum, subcutaneous emphysema and pneumothorax are not rarely observed during the COVID-19 pandemic. Such complications can worsen gas exchange and the overall prognosis in critical patients. The aim of this study is to investigate what predisposing factors are related to pneumomediastinum and pneumothorax in SARS-CoV2-Acute Respiratory Distress Syndrome (ARDS), what symptoms may predict a severe and potentially fatal complication and what therapeutical approach may provide a better outcome. METHODS: In this single center cohort study, we recorded data from 45 critically ill COVID-19 patients who developed one or more complicating events among pneumomediastinum, subcutaneous emphysema and pneumothorax. All patients showed ARDS and underwent non-invasive ventilation (NIV) at baseline. Patients with mild to moderate ARDS and pneumomediastinum/pneumothorax (n = 25) received High Flow Nasal Cannula (HFNC), while patients with severe ARDS and pneumomediastinum/pneumothorax underwent HFNC (n = 10) or invasive mechanical ventilation (IMV) (n = 10). RESULTS: Pneumomediastinum/pneumothorax developed in 10.5% of subjects affected by SARS-coV2-ARDS. Dyspnea affected 40% and cough affected 37% of subjects. High resolution computed tomography of the chest showed bilateral diffuse ground glass opacities (GGO) in 100% of subjects. Traction bronchiolectasis, reticulation, crazy paving and distortion were observed in 64%. Furthermore, 36% showed subcutaneous emphysema. Non-severe ARDS cases received HFNC, and 76% patients recovered from pneumomediastinum/pneumothorax over a median follow up of 5 days. Among severe ARDS cases the recovery rate of pneumomediastinum/pneumothorax was 70% with the HFNC approach, and 10% with IMV. CONCLUSION: HFNC is a safe and effective ventilatory approach for critical COVID-19 and has a positive role in associated complications such as pneumomediastinum and pneumothorax.

Alpha-1 Antitrypsin Deficiency: Home Therapy.

While available in only a few countries, home therapy is a possible strategy for the treatment of alpha-1 antitrypsin deficiency. We want to describe our experience in the management of human alpha-1 antitrypsin using home care intravenous augmentation therapy during this emergency period caused by SARS-CoV2 infection. We assessed the safety of the home treatment and the quality of life of patients enrolled in the program.

Bleeding events in COVID-19: the other side of the coin?

We present three cases of patients affected by severe SARS-CoV-2-related pneumonia treated with a low molecular weight heparin for prevention or treatment of pulmonary embolism, who presented a major bleed, in particular an ileopsoas haematoma that caused severe anaemia; in one case it was fatal. In the recent outbreak of novel coronavirus infection, significantly abnormal coagulation parameters in SARS-CoV-2 infection occur very often, but complications in the opposite direction such as bleeding diathesis are very rare. In these cases, there are different levels of gravity: for one patient the major bleed required the anticoagulant therapy to be stopped until bleeding stabilized, one patient needed interventional radiology and one patient died.

Home Management of Patients with Moderate or Severe Respiratory Failure Secondary to COVID-19, Using Remote Monitoring and Oxygen with or without HFNC.

BACKGROUND: Home treatment of patients affected by COVID-19 is still a matter of daily debate. During the clinical evolution of the disease, there are high risks of lung failure, which requires oxygen therapy. Here, we report our clinical experience with at-home treatment using high-flow nasal cannula in non-hospitalised patients with confirmed COVID-19. PATIENTS AND METHODS: In this study, 18 patients with moderate-to-severe respiratory failure secondary to COVID-19 were monitored at home daily for temperature and SpO2 measurements. Other parameters such as saturation of peripheral oxygen (SpO2), SpO2/FiO2 (fraction of inspired oxygen), temperature, and lung performance were monitored periodically. Depending on oxygen requirements, the patients also received either standard oxygen via a face mask or, if higher FiO2 required, high-flow nasal cannula (HFNC). RESULTS: All 18 patients had favourable outcomes and recovered from COVID-19. No death was recorded in this group. CONCLUSION: Our clinical experience proves that high-flow nasal cannula oxygen therapy may be considered for at-home treatment of COVID-19 patients with moderate lung failure. This could be useful for further treatment during the pandemic and may also be considered in future epidemics.

ACE Gene I/D Polymorphism and Acute Pulmonary Embolism in COVID19 Pneumonia: A Potential Predisposing Role.

Most recent studies have stressed a high risk of thromboembolism in patients with SARS-CoV-2 infection, particularly in those with severe COVID-19 pneumonia. Counterbalance between angiotensin-converting-enzyme (ACE) and ACE2 activities in COVID-19 disease may be crucially involved in the thrombo-inflammatory process. Currently, no study has investigated ACE I/D polymorphism involvement in COVID-19 disease complicated by pulmonary embolism, hence the aim of the present pilot study. This is a retrospective, single-center observational case-control study, conducted at the Sub-Intensive Care Unit of A.O.R.N. Ospedali dei Colli, Cotugno Hospital, Naples (Italy). We included 68 subjects with severe/critical COVID-19 pneumonia. COVID-19 patients were divided according to occurrence of PE (PE+, n = 25) or absence of thromboembolic complications (PE-, n = 43). Assessment of ACE I/D polymorphisms showed a statistically significant difference between PE+ and PE- patients (p = 0.029). Particularly, prevalence of D/D homozygous polymorphism was significantly higher in PE+ COVID-19 patients than in PE- (72 vs. 46.5%; p = 0.048), while heterozygote I/D polymorphism was significantly lower expressed in PE+ patients than in PE- (16 vs. 48.8%; p = 0.009). Computed tomographic pulmonary angiography showed predominantly mono/bilateral sub-segmental embolisms. In conclusion, our findings let us hypothesize a genetic susceptibility to thromboembolism in COVID-19 disease. ACE D/D polymorphism might represent a genetic risk factor, although studies on larger populations are needed.

Dyspnea in COVID-19: not just pneumonia

We present five cases of patients affected by severe SARS-CoV-2 pneumonia (COVID-19) complicated by acute pulmonary embolism (APE). The clinical presentation, D-dimer levels, and the time of appearance of the acute pulmonary embolism were different in every single case. First case was a 46-year-old man affected by bilateral pneumonia COVID-19 with a high D-dimer serum value on the first day of hospitalization. Computed tomography pulmonary angiography (CTPA) showed bilateral pulmonary embolism. Second case was a 51-year-old man affected by acute respiratory failure from bilateral pneumonia-COVID-19 with a significant and sudden increase of D-dimer levels on the twelfth day of illness, CTPA showed widespread bilateral embolism. Third case was a 62-year-old man affected by acute respiratory failure due to COVID-19 with persistently low D-dimer values but with HRCT evidence of vascular dilatation that is characteristic for the presence of thrombosis. The CTPA practiced subsequently ascertained the presence of diffuse segmental embolism. Fourth case was a 35year-old woman, with respiratory failure and severe dyspnea due to COVID-19. No elevation of D-dimer levels. Blood gas analysis (BGA) showed middle hypoxemia and normocapnia;on fifth day she performed CT angiography for persistent dyspnea and chest pain, that documented bilateral pulmonary embolism. Finally, fifth case was a 47 years old man, affected by acute respiratory failure due to bilateral pneumonia COVID-19 related, and normal D-dimer levels. CT angiography showed bilateral pulmonary embolism.