Off balance: Interferons in COVID-19 lung infections.

Interferons are innate and adaptive cytokines involved in many biological responses, in particular, viral infections. With the final response the result of the balance of the different types of Interferons. Cytokine storms are physiological reactions observed in humans and animals in which the innate immune system causes an uncontrolled and excessive release of pro-inflammatory signaling molecules. The excessive and prolonged presence of these cytokines can cause tissue damage, multisystem organ failure and death. The role of Interferons in virus clearance, tissue damage and cytokine storms are discussed, in view of COVID-19 caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The imbalance of Type I, Type II and Type III Interferons during a viral infection contribute to the clinical outcome, possibly together with other cytokines, in particular, TNFα, with clear implications for clinical interventions to restore their correct balance.

Mutants of human ACE2 differentially promote SARS-CoV and SARS-CoV-2 spike mediated infection.

SARS-CoV and SARS-CoV-2 encode spike proteins that bind human ACE2 on the cell surface to enter target cells during infection. A small fraction of humans encode variants of ACE2, thus altering the biochemical properties at the protein interaction interface. These and other ACE2 coding mutants can reveal how the spike proteins of each virus may differentially engage the ACE2 protein surface during infection. We created an engineered HEK 293T cell line for facile stable transgenic modification, and expressed the major human ACE2 allele or 28 of its missense mutants, 24 of which are possible through single nucleotide changes from the human reference sequence. Infection with SARS-CoV or SARS-CoV-2 spike pseudotyped lentiviruses revealed that high ACE2 cell-surface expression could mask the effects of impaired binding during infection. Drastically reducing ACE2 cell surface expression revealed a range of infection efficiencies across the panel of mutants. Our infection results revealed a non-linear relationship between soluble SARS-CoV-2 RBD binding to ACE2 and pseudovirus infection, supporting a major role for binding avidity during entry. While ACE2 mutants D355N, R357A, and R357T abrogated entry by both SARS-CoV and SARS-CoV-2 spike proteins, the Y41A mutant inhibited SARS-CoV entry much more than SARS-CoV-2, suggesting differential utilization of the ACE2 side-chains within the largely overlapping interaction surfaces utilized by the two CoV spike proteins. These effects correlated well with cytopathic effects observed during SARS-CoV-2 replication in ACE2-mutant cells. The panel of ACE2 mutants also revealed altered ACE2 surface dependencies by the N501Y spike variant, including a near-complete utilization of the K353D ACE2 variant, despite decreased infection mediated by the parental SARS-CoV-2 spike. Our results clarify the relationship between ACE2 abundance, binding, and infection, for various SARS-like coronavirus spike proteins and their mutants, and inform our understanding for how changes to ACE2 sequence may correspond with different susceptibilities to infection.

Low dose lung radiotherapy for COVID-19 pneumonia: A potential treatment.

The covid-19 pandemic has been affecting many countries across the world and lost precious lives. Most patients suffer from respiratory disease which progresses to the severe acute respiratory syndrome, termed as SARS-CoV-2 pneumonia. A systemic inflammatory response occurs in SARS-CoV-2 pneumonia severely ill patients, The inflammation process if uncontrolled has a detrimental effect, and the release of cytokines play an important role leading to lung fibrosis. Radiation therapy used in low doses has an anti-inflammatory and immunomodulatory effect. Its low cost, wider availability, and decreased risk of acute side effects can reduce the burden on the health care system.

Severe Acute Respiratory Syndrome due to COVID-19 among children and adolescents in Brazil: profile of deaths and hospital lethality as at Epidemiological Week 38, 2020. / Síndrome respiratória aguda grave por COVID-19 em crianças e adolescentes no Brasil: perfil dos óbitos e letalidade hospitalar até a 38ᵃ Semana Epidemiológica de 2020.

OBJECTIVE: To describe the profile of deaths and the lethality of Severe Acute Respiratory Syndrome (SARS) due to COVID-19 in hospitalized children and adolescents in Brazil. METHODS: This was a cross-sectional study conducted with data from the SARS notification forms of children and adolescents (0 to 19 years old) with laboratory-confirmed COVID-19. Notifications with complete progression of SARS due to COVID-19 were included, up to the 38th Epidemiological Week of 2020. RESULTS: 6,989 hospitalizations were investigated, 661 died, resulting in 9.5% hospital lethality. Higher lethality rates were observed among children under 1 year of age (14.2%), female children and adolescents (9.7%), the indigenous (23.0%), and those living in rural areas (18.1 %), as well as in the Northeast (15.4%) and North (9.7%) regions of Brazil. CONCLUSION: Differences in hospital mortality were found according to sociodemographic characteristics and marked regional inequalities.

Acute Immune Signatures and Their Legacies in Severe Acute Respiratory Syndrome Coronavirus-2 Infected Cancer Patients.

Given the immune system's importance for cancer surveillance and treatment, we have investigated how it may be affected by SARS-CoV-2 infection of cancer patients. Across some heterogeneity in tumor type, stage, and treatment, virus-exposed solid cancer patients display a dominant impact of SARS-CoV-2, apparent from the resemblance of their immune signatures to those for COVID-19+ non-cancer patients. This is not the case for hematological malignancies, with virus-exposed patients collectively displaying heterogeneous humoral responses, an exhausted T cell phenotype and a high prevalence of prolonged virus shedding. Furthermore, while recovered solid cancer patients' immunophenotypes resemble those of non-virus-exposed cancer patients, recovered hematological cancer patients display distinct, lingering immunological legacies. Thus, while solid cancer patients, including those with advanced disease, seem no more at risk of SARS-CoV-2-associated immune dysregulation than the general population, hematological cancer patients show complex immunological consequences of SARS-CoV-2 exposure that might usefully inform their care.

Congenital SARS-CoV-2 Infection in a Neonate With Severe Acute Respiratory Syndrome.

Coronavirus disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is mainly transmitted through droplets, but other ways of transmission have been hypothesized. We report a case of vertical transmission of SARS-CoV-2 in a preterm born to an infected mother, confirmed by the presence of the virus in the neonatal blood, nasopharyngeal and oropharyngeal swabs collected in the first half an hour of life. The neonate presented with acute respiratory distress, similar to the findings in severely affected adults. This case highlights the importance of pregnancy, labor and neonatal period surveillance of affected mothers and their newborns.

No Evidence of SARS-CoV-2 Circulation in Rome (Italy) during the Pre-Pandemic Period: Results of a Retrospective Surveillance.

In March 2020, the World Health Organization (WHO) declared that the COVID-19 outbreak recorded over the previous months could be characterized as a pandemic. The first known Italian SARS-CoV-2 positive case was reported on 21 February. In some countries, cases of suspected "COVID-19-like pneumonia" had been reported earlier than those officially accepted by health authorities. This has led many investigators to check preserved biological or environmental samples to see whether the virus was detectable on dates prior to those officially stated. With regard to Italy, the results of a microbiological screening in sewage samples collected between the end of February and the beginning of April 2020 from wastewaters in Milan (Northern Italy) and Rome (Central Italy) showed presence of SARS-CoV-2. In the present study, we evaluated, by means of a standardized diagnostic method, the SARS-CoV-2 infection prevalence amongst patients affected by severe acute respiratory syndrome (SARI) in an academic hospital located in Central Italy during the period of 1 November 2019-1 March 2020. Overall, the number of emergency room (ER) visits during the investigated period was 13,843. Of these, 1208 had an influenza-like syndrome, but only 166 matched the definition of SARI as stated in the study protocol. A total of 52 SARI cases were laboratory confirmed as influenza: 26 as a type B virus, 25 as a type A, and 1 as both viruses. Although about 17% of the total sample had laboratory or radiological data compatible with COVID-19, all the nasopharyngeal swabs stored underwent SARS-CoV-2 RT-PCR and tested negative. Based on our result, it is confirmed that the COVID-19 pandemic spread did not start prior to the "official" onset in central Italy. Routine monitoring of SARI causative agents at the local level is critical for reporting epidemiologic and etiologic trends that may differ from one country to another and also among different influenza seasons. This has a practical impact on prevention and control strategies.

Severity of respiratory failure at admission and in-hospital mortality in patients with COVID-19: a prospective observational multicentre study.

OBJECTIVES: COVID-19 causes lung parenchymal and endothelial damage that lead to hypoxic acute respiratory failure (hARF). The influence of hARF severity on patients' outcomes is still poorly understood. DESIGN: Observational, prospective, multicentre study. SETTING: Three academic hospitals in Milan (Italy) involving three respiratory high dependency units and three general wards. PARTICIPANTS: Consecutive adult hospitalised patients with a virologically confirmed diagnosis of COVID-19. Patients aged <18 years or unable to provide informed consent were excluded. INTERVENTIONS: Anthropometrical, clinical characteristics and blood biomarkers were assessed within the first 24 hours from admission. hARF was graded as follows: severe (partial pressure of oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) <100 mm Hg); moderate (PaO2/FiO2 101-200 mm Hg); mild (PaO2/FiO2 201-300 mm Hg) and normal (PaO2/FiO2 >300 mm Hg). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the assessment of clinical characteristics and in-hospital mortality based on the severity of respiratory failure. Secondary outcomes were intubation rate and application of continuous positive airway pressure during hospital stay. RESULTS: 412 patients were enrolled (280 males, 68%). Median (IQR) age was 66 (55-76) years with a PaO2/FiO2 at admission of 262 (140-343) mm Hg. 50.2% had a cardiovascular disease. Prevalence of mild, moderate and severe hARF was 24.4%, 21.9% and 15.5%, respectively. In-hospital mortality proportionally increased with increasing impairment of gas exchange (p<0.001). The only independent risk factors for mortality were age ≥65 years (HR 3.41; 95% CI 2.00 to 5.78, p<0.0001), PaO2/FiO2 ratio ≤200 mm Hg (HR 3.57; 95% CI 2.20 to 5.77, p<0.0001) and respiratory failure at admission (HR 3.58; 95% CI 1.05 to 12.18, p=0.04). CONCLUSIONS: A moderate-to-severe impairment in PaO2/FiO2 was independently associated with a threefold increase in risk of in-hospital mortality. Severity of respiratory failure is useful to identify patients at higher risk of mortality. TRIAL REGISTRATION NUMBER: NCT04307459.

[Quick review: air pollution and morbi-mortalityby Covid-19.] / Revisión rápida: contaminación del aire y morbimortalidad por Covid-19.

OBJECTIVE: To analyze the evidence on the relationship between air pollution and an increased risk of morbidity and mortality from Covid-19. MATERIALS AND METHODS: An adaptation of the Cochrane rapid review methodology was used. The search was performed in PubMed and MedRxiv and was limited until April 28 and 26, respectively. The titles and abstracts were reviewed by five researchers who, in turn, reviewed the full texts of the final selection. RESULTS: 450 manuscripts were found, 15 met the inclusion criteria. The evidence reports that the incidence and risk of morbidity and mortality from Covid-19 increase with chronic and acute exposure to air pollution, particularly to particulate matter (PM2.5, P M10) and nitrogen dioxide. CONCLUSIONS: More studies are required especially in Latin American cities. It is necessary to strengthen the recommendations in cities with higher levels of pollutants and to reduce their emissions.

OBJETIVO: Analizar la evidencia sobre la relación entre la contaminación del aire y un riesgo mayor de morbimor-talidad por Covid-19. MATERIAL Y MÉTODOS: Se utilizó una adaptación de la metodología de revisiones rápidas de Cochrane. La búsqueda se realizó en PubMed y MedRxiv y se limitó hasta el 28 y 26 de abril, respectivamente. Los títu-los y resúmenes fueron revisados por cinco investigadores que, a su vez, revisaron los textos completos de la selección final. RESULTADOS: Se encontraron 450 manuscritos, 15 cumplieron los criterios de inclusión. La evidencia encon-trada reporta que la incidencia y el riesgo de morbilidad y mortalidad por Covid-19 se incrementan con la exposición crónica y aguda a la contaminación del aire, particularmente a material particulado (PM2.5, P M10) y dióxido de nitrógeno. CONCLUSIONES: Se requieren más estudios especialmente en ciudades latinoamericanas. Es necesario fortalecer las recomendaciones en las ciudades con mayores niveles de contaminantes y reducir sus emisiones.

Analysis of the clinical characteristics of 77 COVID-19 deaths.

The COVID-19 outbreak is becoming a public health emergency. Data are limited on the clinical characteristics and causes of death. A retrospective analysis of COVID-19 deaths were performed for patients' clinical characteristics, laboratory results, and causes of death. In total, 56 patients (72.7%) of the decedents (male-female ratio 51:26, mean age 71 ± 13, mean survival time 17.4 ± 8.4 days) had comorbidities. Acute respiratory failure (ARF) and sepsis were the main causes of death. Increases in C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer and lactic acid and decreases in lymphocytes were common laboratory results. Intergroup analysis showed that (1) most female decedents had cough and diabetes. (2) The proportion of young- and middle-aged deaths was higher than elderly deaths for males, while elderly decedents were more prone to myocardial injury and elevated CRP. (3) CRP and LDH increased and cluster of differentiation (CD) 4+ and CD8+ cells decreased significantly in patients with hypertension. The majority of COVID-19 decedents are male, especially elderly people with comorbidities. The main causes of death are ARF and sepsis. Most female decedents have cough and diabetes. Myocardial injury is common in elderly decedents. Patients with hypertension are prone to an increased inflammatory index, tissue hypoxia and cellular immune injury.

A comparative overview of COVID-19, MERS and SARS: Review article.

Following the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), a third, highly pathogenic coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appearing at end of 2019 led to a pandemic, increased panic and attracted global attention. This review analyzes the epidemiology, etiology, clinical characteristics, treatment and sequelae of the severe acute respiratory syndrome (SARS), the Middle East respiratory syndrome (MERS) and the 2019 novel coronavirus disease (COVID-19) to help provide direction for further studies that can help understand COVID-19.

Neurological Disorders Identified during Treatment of a SARS-CoV-2 Infection.

A 69-year-old man was admitted to our hospital under diagnosis of pneumonia due to severe acute respiratory syndrome-corona virus 2 (SARS-CoV-2) (Day 0). He underwent endotracheal intubation from Day 3. Although his respiratory condition improved and anesthetic drugs were discontinued, no cough reflex was observed despite intubation having been performed until Day 17. His tendon reflexes were also diminished. We suspected that he had developed Guillain-Barré syndrome (GBS), and administered intravenous immunoglobulin from Day 18. The absence of cough reflex improved and extubation was successfully performed on Day 23. Neurological disorders including GBS should be considered when intubated SARS-CoV-2 patients present with a loss of cough reflex during the treatment period.

Veno-venous extracorporeal membrane oxygenation for COVID-19-associated pediatric acute respiratory distress syndrome.

BACKGROUND: The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) coronavirus has emerged as a highly contagious respiratory pathogen causing severe acute lung injury. Extracorporeal membrane oxygenation is a standard tool for the management of life-threatening acute respiratory distress syndrome, but the use of this resource-intensive therapy has come into question due to strained medical systems and limited proven treatments for COVID-19. CASE SUMMARY: A 16-year-old female with obesity presented with fever, myalgias, cough, and tachypnea and was diagnosed with COVID-19. She progressed to severe pediatric acute respiratory distress syndrome requiring intubation on hospital day 4 and cannulation to veno-venous extracorporeal membrane oxygenation on hospital day 6. The patient received remdesivir, steroids, and anakinra. The patient was successfully decannulated on hospital day 12 and was discharged home on hospital day 21. CONCLUSION: We report the use of veno-venous extracorporeal membrane oxygenation as a bridge to lung recovery in a pediatric patient with severe pediatric acute respiratory distress syndrome due to COVID-19.

Intubation and mechanical ventilation of patients with COVID-19: what should we tell them?

Severe COVID-19 illness is characterised by the development of Acute Respiratory Distress Syndrome (ARDS), for which the mainstay of treatment is represented by mechanical ventilation. Mortality associated with ARDS due to other causes is in the range of 40-60%, but currently available data are not yet sufficient to draw safe conclusions on the prognosis of COVID-19 patients who require mechanical ventilation. Based on data from cohorts of the related coronavirus-associated illnesses, that is to say Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), prognosis would seem to be worse than ARDS due to other causes such as trauma and other infections. Discussion of prognosis is central to obtaining informed consent for intubation, but in the absence of definitive data it is not clear exactly what this discussion should entail.

Serological and molecular findings during SARS-CoV-2 infection: the first case study in Finland, January to February 2020.

The first case of coronavirus disease (COVID-19) in Finland was confirmed on 29 January 2020. No secondary cases were detected. We describe the clinical picture and laboratory findings 3-23 days since the first symptoms. The SARS-CoV-2/Finland/1/2020 virus strain was isolated, the genome showing a single nucleotide substitution to the reference strain from Wuhan. Neutralising antibody response appeared within 9 days along with specific IgM and IgG response, targeting particularly nucleocapsid and spike proteins.

A new coronavirus associated with human respiratory disease in China.

Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health1-3. Despite intense research efforts, how, when and where new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 January 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 December 2019. Epidemiological investigations have suggested that the outbreak was associated with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 December 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing4 of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here 'WH-Human 1' coronavirus (and has also been referred to as '2019-nCoV'). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China5. This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.