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.

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.

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.

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.

New Insights into the Identification of Metabolites and Cytokines Predictive of Outcome for Patients with Severe SARS-CoV-2 Infection Showed Similarity with Cancer

SARS-CoV-2 infection is characterized by several clinical manifestations, ranging from the absence of symptoms to severe forms that necessitate intensive care treatment. It is known that the patients with the highest rate of mortality develop increased levels of proinflammatory cytokines, called the "cytokine storm”, which is similar to inflammatory processes that occur in cancer. Additionally, SARS-CoV-2 infection induces modifications in host metabolism leading to metabolic reprogramming, which is closely linked to metabolic changes in cancer. A better understanding of the correlation between perturbed metabolism and inflammatory responses is necessary. We evaluated untargeted plasma metabolomics and cytokine profiling via 1H-NMR (proton nuclear magnetic resonance) and multiplex Luminex assay, respectively, in a training set of a limited number of patients with severe SARS-CoV-2 infection classified on the basis of their outcome. Univariate analysis and Kaplan–Meier curves related to hospitalization time showed that lower levels of several metabolites and cytokines/growth factors, correlated with a good outcome in these patients and these data were confirmed in a validation set of patients with similar characteristics. However, after the multivariate analysis, only the growth factor HGF, lactate and phenylalanine retained a significant prediction of survival. Finally, the combined analysis of lactate and phenylalanine levels correctly predicted the outcome of 83.3% of patients in both the training and the validation set. We highlighted that the cytokines and metabolites involved in COVID-19 patients' poor outcomes are similar to those responsible for cancer development and progression, suggesting the possibility of targeting them by repurposing anticancer drugs as a therapeutic strategy against severe SARS-CoV-2 infection.

New Insights into the Identification of Metabolites and Cytokines Predictive of Outcome for Patients with Severe SARS-CoV-2 Infection Showed Similarity with Cancer.

SARS-CoV-2 infection is characterized by several clinical manifestations, ranging from the absence of symptoms to severe forms that necessitate intensive care treatment. It is known that the patients with the highest rate of mortality develop increased levels of proinflammatory cytokines, called the "cytokine storm", which is similar to inflammatory processes that occur in cancer. Additionally, SARS-CoV-2 infection induces modifications in host metabolism leading to metabolic reprogramming, which is closely linked to metabolic changes in cancer. A better understanding of the correlation between perturbed metabolism and inflammatory responses is necessary. We evaluated untargeted plasma metabolomics and cytokine profiling via 1H-NMR (proton nuclear magnetic resonance) and multiplex Luminex assay, respectively, in a training set of a limited number of patients with severe SARS-CoV-2 infection classified on the basis of their outcome. Univariate analysis and Kaplan-Meier curves related to hospitalization time showed that lower levels of several metabolites and cytokines/growth factors, correlated with a good outcome in these patients and these data were confirmed in a validation set of patients with similar characteristics. However, after the multivariate analysis, only the growth factor HGF, lactate and phenylalanine retained a significant prediction of survival. Finally, the combined analysis of lactate and phenylalanine levels correctly predicted the outcome of 83.3% of patients in both the training and the validation set. We highlighted that the cytokines and metabolites involved in COVID-19 patients' poor outcomes are similar to those responsible for cancer development and progression, suggesting the possibility of targeting them by repurposing anticancer drugs as a therapeutic strategy against severe SARS-CoV-2 infection.

Aerosol delivery through high-flow nasal therapy: Technical issues and clinical benefits.

High-flow nasal cannula (HFNC) therapy is an oxygen delivery method particularly used in patients affected by hypoxemic respiratory failure. In comparison with the conventional "low flow" oxygen delivery systems, it showed several important clinical benefits. The possibility to nebulize drugs via HFNC represents a desirable medical practice because it allows the administration of inhaled drugs, mostly bronchodilators, without the interruption or modification of the concomitant oxygen therapy. HFNC, by itself has shown to exert a small but significant bronchodilator effect and improves muco-ciliary clearance; thus, the nebulization of bronchodilators through the HFNC circuit may potentially increase their pharmacological activity. Several technical issues have been observed which include the type of the nebulizer that should be used, its position within the HFNC circuit, and the optimal gas flow rates to ensure an efficient drug delivery to the lungs both in "quiet" and "distressed" breathing patterns. The aim of this review has been to summarize the scientific evidence coming from "in vitro" studies and to discuss the results of "in vivo" studies performed in adult subjects, mainly affected by obstructive lung diseases. Most studies seem to indicate the vibrating mesh nebulizer as the most efficient type of nebulizer and suggest to place it preferentially upstream from the humidifier chamber. In a quite breathing patterns, the inhaled dose seems to increase with lower flow rates while in a "distressed" breathing pattern, the aerosol delivery is higher when gas flow was set below the patient's inspiratory flow, with a plateau effect seen when the gas flow reaches approximately 50% of the inspiratory flow. Although several studies have demonstrated that the percentage of the loaded dose nebulized via HFNC reaching the lungs is small, the bronchodilator effect of albuterol seems not to be impaired when compared to the conventional inhaled delivery methods. This is probably attributed to its pharmacological activity. Prospective and well-designed studies in different cohort of patients are needed to standardize and demonstrate the efficacy of the procedure.

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.

High-flow nasal oxygen versus conventional oxygen therapy in patients with COVID-19 pneumonia and mild hypoxaemia: a randomised controlled trial.

RATIONALE: In patients with COVID-19 pneumonia and mild hypoxaemia, the clinical benefit of high-flow nasal oxygen (HFNO) remains unclear. We aimed to examine whether HFNO compared with conventional oxygen therapy (COT) could prevent escalation of respiratory support in this patient population. METHODS: In this multicentre, randomised, parallel-group, open-label trial, patients with COVID-19 pneumonia and peripheral oxygen saturation (SpO2) ≤92% who required oxygen therapy were randomised to HFNO or COT. The primary outcome was the rate of escalation of respiratory support (ie, continuous positive airway pressure, non-invasive ventilation or invasive mechanical ventilation) within 28 days. Among secondary outcomes, clinical recovery was defined as the improvement in oxygenation (SpO2 ≥96% with fractional inspired oxygen (FiO2) ≤30% or partial pressure of arterial carbon dioxide/FiO2 ratio >300 mm Hg). RESULTS: Among 364 randomised patients, 55 (30.3%) of 181 patients assigned to HFNO and 70 (38.6%) of 181 patients assigned to COT underwent escalation of respiratory support, with no significant difference between groups (absolute risk difference -8.2% (95% CI -18% to +1.4%); RR 0.79 (95% CI 0.59 to 1.05); p=0.09). There was no significant difference in clinical recovery (69.1% vs 60.8%; absolute risk difference 8.2% (95% CI -1.5% to +18.0%), RR 1.14 (95% CI 0.98 to 1.32)), intensive care unit admission (7.7% vs 11.0%, absolute risk difference -3.3% (95% CI -9.3% to +2.6%)), and in hospital length of stay (11 (IQR 8-17) vs 11 (IQR 7-20) days, absolute risk difference -1.0% (95% CI -3.1% to +1.1%)). CONCLUSIONS: Among patients with COVID-19 pneumonia and mild hypoxaemia, the use of HFNO did not significantly reduce the likelihood of escalation of respiratory support. TRIAL REGISTRATION NUMBER: NCT04655638.

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.

Clinical evaluation of the safety and efficacy of enoxaparin in patients with COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), increases thrombotic risk in hospitalised patients. The rate of thrombosis in patients with COVID-19 is unclear. The role of heparin, frequently used in the management of hospitalised patients, also needs to be clarified. In this study, we investigated the efficacy and safety of enoxaparin given at prophylactic or therapeutic dose in hospitalised patients with COVID-19, and evaluated its role in the development of disease in terms of mortality, and incidence of thrombotic and bleeding events. MATERIAL AND METHODS: We included 141 patients with SARS-CoV-2 infection, admitted to five different wards (one intensive care unit, 2 sub-intensive care units, and 2 general infectious disease units) of Cotugno Hospital, a tertiary care hospital in Naples, Italy, between March and May 2020. RESULTS: Over a median time of 17 days (IQR 11-25), enoxaparin was given to 90/141 patients (63.8%) of whom 65 took a prophylactic and 25 a therapeutic dose. We documented 14 episodes of thrombosis (9.9%); almost all were cases of pulmonary embolism. No significant difference in terms of thromboembolic prevention was found between those patients not receiving anticoagulants and those on prophylactic or therapeutic dose of enoxaparin. Five episodes of major bleeding occurred (3.5%); therapeutic dose of enoxaparin was associated with a greater bleeding risk than prophylactic dose (p=0.002). During follow-up, 31 patients (22%) died; these were mostly elderly men with two or more comorbidities at admission. No advantages of enoxaparin, either as prophylaxis or at high doses, in terms of mortality were observed. At multivariate analysis, low estimated glomerular filtration rate, and high total bilirubin and fasting hyperglycemia were independently associated with a higher mortality. DISCUSSION: We did not observe advantages in terms of either thromboembolic prevention or mortality of enoxaparin, which however was more frequently used in patients with more severe disease. Prophylactic enoxaparin was not seen to be associated with bleeding risk.

Prognosis of Spontaneous Pneumothorax/Pneumomediastinum in Coronavirus Disease 2019: The CoBiF Score.

Objectives: Pneumothorax and pneumomediastinum are associated with high mortality in invasively ventilated coronavirus disease 2019 (COVID-19) patients; however, the mortality rates among non-intubated patients remain unknown. We aimed to analyze the clinical features of COVID-19-associated pneumothorax/pneumomediastinum in non-intubated patients and identify risk factors for mortality. Methods: We searched PubMed Scopus and Embase from January 2020 to December 2021. We performed a pooled analysis of 151 patients with no invasive mechanical ventilation history from 17 case series and 87 case reports. Subsequently, we developed a novel scoring system to predict in-hospital mortality; the system was further validated in multinational cohorts from ten countries (n = 133). Results: Clinical scenarios included pneumothorax/pneumomediastinum at presentation (n = 68), pneumothorax/pneumomediastinum onset during hospitalization (n = 65), and pneumothorax/pneumomediastinum development after recent COVID-19 treatment (n = 18). Significant differences were not observed in clinical outcomes between patients with pneumomediastinum and pneumothorax (±pneumomediastinum). The overall mortality rate of pneumothorax/pneumomediastinum was 23.2%. Risk factor analysis revealed that comorbidities bilateral pneumothorax and fever at pneumothorax/pneumomediastinum presentation were predictors for mortality. In the new scoring system, i.e., the CoBiF system, the area under the curve which was used to assess the predictability of mortality was 0.887. External validation results were also promising (area under the curve: 0.709). Conclusions: The presence of comorbidity bilateral pneumothorax and fever on presentation are significantly associated with poor prognosis in COVID-19 patients with spontaneous pneumothorax/pneumomediastinum. The CoBiF score can predict mortality in clinical settings as well as simplify the identification and appropriate management of patients at high risk.

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 [...].

Optical Coherence Tomography Angiography Analysis of Vessel Density Indices in Early Post-COVID-19 Patients.

Purpose: A hypercoagulable state has been reported to cause potential sight-threatening ischemia in patients suffering from Coronavirus disease 2019 (COVID-19). This study aimed to determine whether vessel density (VD), as measured by optical coherence tomography angiography (OCT-A), has insights into retinal and choriocapillaris vascular changes in patients affected by SARS-CoV-2 infection. Methods: Hundred and fifty two patients positive for SARS-CoV-2 infection were enrolled in this observational, retrospective, controlled study. A control group of 60 healthy subjects was selected for statistical comparisons. Raw OCT and OCT-A data were exported and 3D datasets were analyzed to determine VD. Results: Hundred and forty eyes (92.1%) were included for final analysis. The VD of the superficial capillary plexus (SCP) did not differ between the two groups. The mean VD of the deep capillary plexus (DCP) and the choriocapillaris (CC) was significantly lower in the foveal sector of the COVID-19 group compared to healthy controls. Within the post-COVID-19 group, the lowest DCP and CC foveal VD values were recorded in patients treated with antiviral therapy; no differences were observed among COVID-19 patients with other comorbidities (hypertension, diabetes, thyroid disease) or taking antiplatelet therapy. DCP and CC foveal VD were significantly lower in patients hospitalized in an intensive care unit (ICU) than asymptomatic patients. Conclusion: Foveal vessel density at the level of DCP and CC was reduced in post-COVID-19 patients. Further studies evaluating these changes over time will be needed to corroborate the hypothesis of a microvascular retinal impairment in individuals who have recently recovered from SARS-CoV-2 infection.

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.