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Highlights • Serious cardiac arrhythmias may be the consequence of direct effects of COVID-19 infection, but also the outcome of the deleterious effects of systemic illness and the adverse proarrhythmic reactions to drugs employed in the treatment of this pandemic • Drug combinations, especially of QT-prolonging agents, can lead to higher arrhythmogenicity, compared with single drug therapies • Furthermore, critically ill COVID-19 patients often have comorbidities that can trigger life-threatening ventricular arrhythmias, while acute myocardial injury increases the prevalence of arrhythmias • ECG and QTc monitoring and taking appropriate measures are of critical importance to prevent, detect and manage cardiac arrhythmias in COVID-19 patients • Contactless monitoring and telemetry for inpatients, especially those admitted to the ICU, as well as for outpatients needing continued management, has recently been facilitated by implementing digital health monitoring tools, As the coronavirus 2019 (COVID-19) pandemic marches unrelentingly, more patients with cardiac arrhythmias are emerging due to the effects of the virus on the respiratory and cardiovascular (CV) systems and the systemic inflammation that it incurs, and also as a result of the proarrhythmic effects of COVID-19 pharmacotherapies and other drug interactions and the associated autonomic imbalance that enhance arrhythmogenicity. The most worrisome of all arrhythmogenic mechanisms is the QT prolonging effect of various anti-COVID pharmacotherapies that can lead to polymorphic ventricular tachycardia in the form of torsade des pointes and sudden cardiac death. It is therefore imperative to monitor the QT interval during treatment; however, conventional approaches to such monitoring increase the transmission risk for the staff and strain the health system. Hence, there is dire need for contactless monitoring and telemetry for inpatients, especially those admitted to the intensive care unit, as well as for outpatients needing continued management. In this context, recent technological advances have ushered in a new era in implementing digital health monitoring tools that circumvent these obstacles. All these issues are herein discussed and a large body of recent relevant data are reviewed.

CAPA (COVID-19 associated pulmonary aspergillosis) is an important complication of COVID-19. It has been reported that the incidence of CAPA is as high as 19%-33% worldwide. However, its onset has not been reported in Japan. A 72-year-old Japanese man was diagnosed with COVID-19 and was transferred to our hospital due to deterioration of respiratory condition. Treatment with remdesivir, dexamethasone (DEXA), and antibiotics was performed under mechanical ventilation. Although the condition improved temporarily, a new shadow appeared in the lung, and Aspergillus fumigatus was cultured from sputum. The patient was clinically diagnosed with CAPA and treated with voriconazole. However, his progress deteriorated and he died. High-risk COVID-19 patients should be tested for Aspergillus to ensure early diagnosis of CAPA.

Highlights • After the global push for the use of Hydroxychloroquine and Chloroquine there is ongoing discussion about the effectivity of these drugs. • Findings of this observational study provide crucial data on a potential protective effect of Hydroxychloroquine in non-ICU, hospitalized COVID-19 patients. • Early treatment with HCQ on the first day of admission is associated with a reduced risk of 53% in transfer to the ICU for mechanical ventilation. • This protective effect was not observed for Chloroquine, therefore these drugs cannot be regarded as interchangeable., Background The global push for the use of hydroxychloroquine (HCQ) and chloroquine (CQ) against COVID-19 resulted in an ongoing discussion about the effectivity and toxicity of these drugs. Recent studies report no effect of (H)CQ on 28 day-mortality. We investigated the effect of HCQ and CQ in hospitalized patients on the non-ICU COVID-ward. Methods A nationwide, observational cohort study was performed in The Netherlands. Hospitals were given the opportunity to decide independently on the use of three different COVID-19 treatment strategies: HCQ or CQ, or no treatment. We compared the outcome between these groups. The primary outcomes were 1) death on the COVID-19 ward, and 2) transfer to the Intensive Care Unit (ICU). Results The analysis contained 1064 patients from 14 hospitals: 566 patients received treatment with either HCQ (n = 189) or CQ (n = 377), and 498 patients received no treatment. In a multivariate propensity matched weighted competing regression analysis, there was no significant effect of (H)CQ on mortality on the COVID-ward. HCQ however was associated with a significant decreased risk of transfer to the ICU (Hazard ratio (HR) = 0.47, 95%CI = 0.27–0.82, p = 0.008), when compared to controls. This effect was not found in the CQ group (HR = 0.80; 95%CI = 0.55–1.15, p = 0.207), and remained significant after competing risk analysis. Conclusion The results of this observational study demonstrate a lack of effect of (H)CQ on non-ICU mortality. However, we show that the use of HCQ - but not CQ - is associated with 53% decreased risk of transfer of COVID-19 patients from the regular ward to the ICU. Recent prospective studies have reported on 28 days all-cause mortality only, therefore additional prospective data on the early effect of HCQ in preventing transfer to the ICU is still needed.

In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed., Graphical abstract Unlabelled Image

Severe respiratory syncytial virus (RSV) bronchiolitis in early life is a significant risk factor for future recurrent wheeze (RW) and asthma. The goal of the Azithromycin to Prevent Wheezing following severe RSV bronchiolitis II (APW-RSV II) clinical trial is to evaluate if azithromycin treatment in infants hospitalized with RSV bronchiolitis reduces the occurrence of RW during the preschool years. The APW-RSV II clinical trial is a double-blind, placebo-controlled, parallel-group, randomized trial, including otherwise healthy participants, ages 30 days-18 months, who are hospitalized due to RSV bronchiolitis. The study includes an active randomized treatment phase with azithromycin or placebo for 2 weeks, and an observational phase of 18–48 months. Two hundred participants were enrolled during three consecutive RSV seasons beginning in the fall of 2016 and were randomized to receive oral azithromycin 10 mg/kg/day for 7 days followed by 5 mg/kg/day for an additional 7 days, or matched placebo. The study hypothesis is that in infants hospitalized with RSV bronchiolitis, the addition of azithromycin therapy to routine bronchiolitis care would reduce the likelihood of developing post-RSV recurrent wheeze (≥3 episodes). The primary clinical outcome is the occurrence of a third episode of wheezing, which is evaluated every other month by phone questionnaires and during yearly in-person visits. A secondary objective of the APW-RSV II clinical trial is to examine how azithromycin therapy changes the upper airway microbiome composition, and to determine if these changes are related to the occurrence of post-RSV RW. Microbiome composition is characterized in nasal wash samples obtained before and after the study treatments. This clinical trial may identify the first effective intervention applied during severe RSV bronchiolitis to reduce the risk of post-RSV RW and ultimately asthma.

Drug repositioning has been used extensively since the beginning of the COVID-19 pandemic in an attempt to identify antiviral molecules for use in human therapeutics. Hydroxychloroquine and azithromycin have shown inhibitory activity against SARS-CoV-2 replication in different cell lines. Based on such in vitro data and despite the weakness of preclinical assessment, many clinical trials were set up using these molecules. In the present study, we show that hydroxychloroquine and azithromycin alone or combined does not block SARS-CoV-2 replication in human bronchial airway epithelia. When tested in a Syrian hamster model, hydroxychloroquine and azithromycin administrated alone or combined displayed no significant effect on viral replication, clinical course of the disease and lung impairments, even at high doses. Hydroxychloroquine quantification in lung tissues confirmed strong exposure to the drug, above in vitro inhibitory concentrations. Overall, this study does not support the use of hydroxychloroquine and azithromycin as antiviral drugs for the treatment of SARS-CoV-2 infections.

Graphical abstract, Systemic infections is one of the major causes of mortality worldwide, and a shortage of drug approaches applied for the rapid and necessary treatment contribute to increase the levels of death in affected patients. Several drug delivery systems based in nanotechnology such as metallic nanoparticles, liposomes, nanoemulsion, microemulsion, polymeric nanoparticles, solid lipid nanoparticles, dendrimers, hydrogels and liquid crystals can contribute in the biological performance of active substances for the treatment of microbial diseases triggered by fungi, bacteria, virus and parasites. In the presentation of these statements, this review article present and demonstrate the effectiveness of these drug delivery systems for the treatment of systemic diseases caused by several microorganisms, through a review of studies on scientific literature worldwide that contributes to better information for the most diverse professionals from the areas of health sciences. The studies demonstrated that the drug delivery systems described can contribute to the therapeutic scenario of these diseases, being classified as safe, active platforms and with therapeutic versatility.