Objective: Children with COVID-19 are reported to get the infection from an adult contact, with minimal secondary transmission from children. Children do not appear to be efficient transmitters of infection. Common symptoms in adults infected with COVID-19 include fever, dry cough and fatigue. The symptoms in children are more atypical than in adults, and coughing is lighter. Methods: Children aged 0-18 who was admitted to the emergency department from March 20 to September 15, 2020 and had confirmed diagnosis of COVID-19 with a positive real-time reverse-transcriptase polymerase chain reaction (RT-PCR) were included in the study. Results: RT-PCR tests were done in 835 children with suspected SARS-CoV-2 infection and the test was positive in 178 (21.3%) children. The most common symptoms at the onset of illness were fever (67.4%), headache (41.1%), cough (36.6%), sore throat (25.7%), fatigue (22.9%), myalgia (22.9%) and diarrhea (20.6%). One hundred and seven (61.1%) of the patients were infected by close contact with family members diagnosed with COVID-19, 35 (20%) of the patients were infected via close contact with non-family members diagnosed with COVID-19, 11 (6.3%) of the patients had a history of exposure in an epidemic area, including wedding hall, condolence house and shopping center and 23 (13.1%) of the patients with unknown source of infection. Conclusion: COVID-19 infection is seen to be milder and cause less hospitalizations and patient deaths in children. Crowded indoor environments are the main centers of the spread of the outbreak and children are unlikely to be the main source of infection of the pandemic.

At present, the epidemic of Coronavirus Disease 2019 (COVID-19) is spreading worldwidely. Humans may be compelled to live with the viruses for a long time. The asymptomatic infections are contagious and the most difficult to control, easy to cause the accumulation of infection sources in the community. More and more asymptomatic cases have brought great challenges to the control of the epidemic. This review provides relatively comprehensive and updated information about asymptomatic cases of COVID-19. We find most of asymptomatic carriers are young people, and there are more asymptomatic infections in children compared with adult patients. Some asymptomatic carriers especially children have a longer communicable period than the confirmed cases. There is a risk of reoccurrence of positive result of nucleic acid test in asymptomatic cases. The chest CT findings of asymptomatic infections were mainly GGO , mostly peripheral distribution and restored quickly. Aerosol and fomite transmission of SARS-CoV-2 by asymptomatic carriers is plausible, so every person releases potentially infectious aerosols all the time. All countries in the world should raise public awareness of protection and strengthen social security measures to prevent second outbreak caused by the asymptomatic infections.

SARS-CoV-2 causes a hypercoagulable state that predisposes patients to thromboembolic events. We report two adolescents with Sickle Cell Disease (SCD) who developed pulmonary embolism (PE) during acute chest syndrome (ACS) episode associated with a possible SARS-CoV-2 infection. Both SCD and SARS-CoV-2 infection predisposes to thromboembolic disease. Thromboprophylaxis with LMWH should be considered in adolescent with ACS, related or not to COVID-19 disease.

After a complete symptomatic recovery after COVID-19 pneumonia, the second phase of desaturation is a new phenomenon that is being increasingly observed. Two possible mechanisms behind it can be a continued subclinical infection and lung fibrosis. We have presented a case with the former mechanism, who responded well to steroids.

Dear Sir, Whilst the primary focus of our commentary was to reflect upon the multitude of clinical and institutional changes prompted by COVID-19 to help adopt a more streamlined approach to healthcare,1we thank Herron et al for highlighting the importance of partner support during labour.2 However, we note that even during the peak of the first wave of infections, the Royal College of Obstetricians and Gynaecologists (RCOG) continued to advocate the presence of a single birth partner throughout labour. Many obstetric units, including our own, managed to successfully adhere to this practice throughout the pandemic. However, guidance from the RCOG for women attending antenatally, for face to face clinic appointments or ultrasound scans, was to attend alone. This was subsequently implemented in most hospitals in order to reduce the number of visitors.1 Whilst necessary during the initial fear and uncertainty surrounding COVID-19, moving forward it is important to consider the potential negative impact of partner non-attendance antenatally, as well as intrapartum. Partners often positively encourage women to seek care and prepare for birth complications, thereby preventing delay in treatment and helping to manage expectations, which have been shown to positively impact outcomes.3 Whilst undoubtedly an exciting time for many, pregnancy and the prospect of motherhood is daunting to others. Partners provide support and facilitate decision making throughout the antenatal process, particularly in difficult circumstances such as following the diagnosis of a missed miscarriage, during counselling for pregnancies affected by genetic abnormalities, or after an intrauterine death. The restrictions on partner attendance may therefore inadvertently prevent a number of women seeking care during pregnancy, for fear of having to face procedures or receiving bad news alone. Evidence from a London hospital supports this notion after demonstrating a significant increase in stillbirth rate during the pandemic compared to pre-pandemic (9.31 per 1000 births Vs 2.38 per 1000 births; p=0.01). Of significance, no cases were affected by COVID-19, nor were there any post-mortem findings suggestive of the virus.4The utilisation of remote consultations with a woman and her partner offers a suitable option in appropriately triaged cases.1 Even in remote consultations where inadvertent difficult decisions arise, the presence and support of their partner facilitates collaborative decision making. Ironically, those with high risk enough pregnancies to warrant in person consultations, where additional support could offer significant value, are those whereby partners are not permitted. Prior to the pandemic, partners often reported feeling excluded, fearful of the uncertainty of pregnancy and labour and frustrated by perceived lack of support from healthcare professionals.5 This may subsequently negatively impact their relationship because of the inability to adequately support their partners. Their exclusion from the majority of antenatal care therefore, may not only negatively impact psychological wellbeing of women which may in turn result in suboptimal outcomes, but also negatively impact their future relationship. As such, we agree with Herron et al and support their notion that attempts should be made towards delivering individualised patient centred care both antenatally and intrapartum.Lorraine S Kasaven1,2, Srdjan Saso1,2, Jen Barcroft1,2, Joseph Yazbek1,2, Karen Joash1, Catriona Stalder1, Jara Ben Nagi,2 J Richard Smith,1,2 Christoph Lees1,2, Tom Bourne1,2, Benjamin P Jones1,21 Queen Charlotte’s and Chelsea Hospital, Department of Cancer and Surgery, Imperial College NHS Trust, W12 0HS London, UK.2 Imperial College London, Department of Cancer and Surgery, London W12 0NN, UK.

Objective: The aim of this study is to find out the potential risk factors including Charlson Comorbidity index (CCI) score associated with death in COVID-19 cases hospitalized due to pneumonia and try to find a novel COVID-19 mortality score for daily use. Methods: All patients diagnosed as confirmed or probable COVID-19 pneumonia whom hospitalized in our Chest Diseases Education and Research Hospital between March 11, 2020 and May 15,2020 were enrolled. The optimal cut-off values, sensitivity and specificity values and odds ratios to be used in mortality prediction of the novel scoring system created from these parameters were calculated by ROC analysis according to the area under the curve and Youden index. Results: Over 383 patients (n:33 deceased, n:350 survivors) univariate and multivariate regression analysis showed that CCI and lymphocyte ratio were prognostic factors for COVID-19 related mortality. Using this analysis, a novel scoring model CoLACD (CoVID-19 Lymphocyte ratio, Age, CCI score, Dyspnea) was established. The cut-off value of this scoring system, which determines the mortality risk in patients, was 2.5 points with 82% sensitivity and 73% specificity (AUC = 0.802, 95% CI 0.777-0.886, p <0.001). The risk of mortality was 11.8 times higher in patients with a CoLACD mortality score higher than 2.5 points than patients with a score lower than 2.5 (OR = 11.8 95% CI 4.7-29.3 p <0.001). Conclusion: This study showed that by using the CoLACD mortality score, clinicians may achieve a prediction of mortality in COVID-19 patients hospitalized for pneumonia.

To explore the association between pulmonary artery systolic pressure (PASP) and success to wean from mechanical ventilation in COVID-19 patients.Thirty-four critically ill COVID-19 patients who had been placed on ventilator support were enrolled in this retrospective study and were divided into two groups: the weaning success group (group I) and the weaning failure group (group II). Physical examination, echocardiography, and routine laboratory test data were collected. The levels of troponin I, myoglobin, interleukin 6, and D-dimer were significantly lower in group I than in group II. The interventricular septum end-diastolic thickness (IVSd) was thicker (14.00 [13.50‒15.00] mm) and the PASP was higher (61.63 ± 13.53 mmHg) in group II. Logistic regression analysis showed that D-dimer and IVSd were factors associated with ventilator weaning. The odds ratio (OR) of D-dimer was 0.81 (95% CI 0.69‒0.95) and the OR of IVSd was 0.16 (95% CI 0.045‒0.59). Cox analysis revealed that the adjusted hazard ratio (HR) for a 1-mmHg increase in PASP was 0.94 (95% CI 0.90‒0.97) for weaning events (P < 0.001). PASP was negatively correlated with the PaO2:FiO2 (r = -0.48, P < 0.01). A receiver operating characteristic curve showed that the best cutoff value of PASP for ventilator weaning was 39.50 mmHg, with a sensitivity of 100% and a specificity of 96.15% PASP was an independent risk factor for the difficulty of weaning severely ill COVID-19 patients off mechanical ventilation. PASP can be used as one of the indicators for evaluating the condition of COVID-19 patients.

Aims: The recently described SARS-CoV-2 has led to a pandemia which has severe consequences for the global community. Hydroxychloroquine has been repurposed for the treatment of COVID-19 but conflicting information on its efficacy and safety has since emerged. Our group designed a trial on the use of high-dose hydroxychloroquine in a high-risk ambulatory population with mild COVID-19 (NCT04351620) and summarizes herein the clinical data of hydroxychloroquine in COVID-19. Methods: Single-arm and single-center study evaluating the tolerability of high-dose hydroxychloroquine, 600 mg twice daily for 5 days, in patients with mild COVID-19 and risk factors for clinical decompensation and hospitalization. Secondary objectives included maintenance of ambulatory status, defervescence, and symptom relief. Results: Over a six-week period, 59 patients met eligibility criteria out of 314 contacted (18.7%). Out of these 59 potentially eligible patients, 44 (74.5%) patients declined to be screened further due to concerns about its risks and unproven efficacy, referencing media accounts and politization of the medication. Out of the 9 patients consented, 2 did not complete the therapy plan, 1 due to headaches, 1 did not follow up. Two of the 7 patients who completed the study continued to have fevers, one was admitted for pneumonia. Study was terminated early due to recruitment difficulties. Conclusions: The trial met pre-defined primary outcome of tolerability, but sample size was too small to allow further interpretation. The political climate and media coverage might have negatively impacted patient recruitment, which has ultimately led to its early interruption.

An amino acid supplement containing 700 mg of cystine and 280 mg of theanine was administered to 4 patients during the treatment of SARS-CoV-2 virus infection. Negative reactions on polymerase chain reaction (PCR) testing were promptly obtained. Oral ingestion of cysteine and theanine (C/T) may promote SARS-CoV-2 virus elimination.

Coronavirus-2019 (COVID-19) pandemic is a global health challenge where pregnant women are potentially more vulnerable to respiratory infections. We describe the successful management of a case a 35 years old pregnant woman, G3, P1, with a history of caesarian section who tested positive for COVID-19 and required critical care support

The role of editors or a team of editors has two important tasks: deciding a paper for review or not, and writing editorials for disseminating messages to the world.

Background: Many arguments suggest that neutrophils could play a prominent role in COVID-19. However, the role of key components of neutrophil innate immunity in severe forms of COVID-19 has deserved insufficient attention. We aimed to evaluate the involvement of Neutrophil Elastase, histone-DNA, and DNases in systemic and multi-organ manifestations of COVID-19. Methods: We performed a multicenter study of markers of neutrophil innate immunity in 155 cases consecutively recruited in a screening center (ambulatory subjects), local hospitals, and two regional university hospitals. The case were evaluated according to clinical and biological markers of severity and multi-organ manifestations and compared to 35 healthy controls. Results: Blood Neutrophil Elastase, histone-DNA, myeloperoxidase-DNA and free dsDNA were dramatically increased, and DNase activity decreased by 10-fold, compared to controls. Neutrophil Elastase and histone-DNA were associated with intensive care admission, body temperature, lung damage and markers of cardiovascular outcomes, renal failure and increased IL-6, IL-8 and CXCR2. Neutrophil Elastase was an independent predictor of the computed tomography score of COVID-19 lung damage and the number of affected organs, in multivariate analyses. The increased blood concentrations of NE and neutrophil extracellular traps were related to exacerbation of neutrophil stimulation through IL8 and CXCR2 increased concentrations and increased serum DAMPs, and to impaired degradation of NETs as a consequence of the dramatic decrease of blood DNase activity. Conclusion: Our results point out the key role of neutrophil innate immunity exacerbation in COVID-19. Neutrophil Elastase and DNase could be potential biomarkers and therapeutic targets of severe systemic manifestations of COVID-19.

Background: Coronavirus Disease 2019 (COVID-19) is associated with many clinical manifestations including respiratory failure and cardiovascular compromise. Objectives: We examine outcomes in critically ill individuals with COVID-19 who develop atrial tachyarrhythmias (ATA). Methods: We collected data from electrocardiograms and the electronic medical record of COVID-19 positive (COVID+) and negative (COVID-) individuals admitted to our medical intensive care unit between February 29 and June 28, 2020. We compared clinical and demographic characteristics, new onset ATA, hemodynamic compromise (HC) following ATA, and in-hospital mortality in those who were COVID+ vs. COVID-. HC was defined as having a new or increased vasopressor requirement or the need for direct current cardioversion for hemodynamic instability within 1 hour of ATA onset. Results: Of 300 individuals included, 200 were COVID+ and 100 were COVID-. Mean age was 60±16 years, 180 (60%) were males, and 170 (57%) were African American. New onset ATA occurred in 16% of COVID+ and 19% of COVID- individuals (p=0.51). When compared to COVID- participants without ATA, COVID+ individuals with new onset ATA had higher mortality after multivariable adjustment (OR 5.0, 95% CI 1.9-13.5). New onset ATA was followed by HC in 18 COVID+ but no COVID- participants (P=0.0001). COVID+ individuals with HC after ATA were requiring high levels of ventilatory support at the time of ATA onset. Conclusions: ATA may be an important mediator of HC in critically ill individuals with COVID-19, especially for those mechanically ventilated. Recognition of this could assist with clinical care and prognostication for individuals with COVID-19.

There are three types of proteins in the coronaviruses; nonstructural, structural and accessory proteins. The coronaviruses proteins are essential for the viral replication and for the binding, invasion and regulation of the host cells metabolism and immunity. This article investigated the amino acid sequence similarity and identity percentages of 10 proteins present in SARS-CoV-2, SARS-CoV and the Rhinolophus affinis bat coronavirus (BatCoV RaTG13). The investigated proteins were 1ab polyprotein, spike protein, orf3a, envelope protein, membrane protein, orf6, orf7a, orf7b, orf8, and ncleocapsid protein. The online sequence alignment service of The European Molecular Biology Open Software Suite (EMBOSS) was used to determine the similarity and identity percentages of the three viruses proteins. The results showed that the similarity and identity percentages of the SARS-CoV-2 and BatCoV RaTG13 proteins are above 95% while the identity and similarity percentages of the SARS-CoV-2 and SARS-CoV are above 38%. The proteins of the SARS-CoV-2 and the BatCoV RaTG13 are of high identity and similarity percentages compared to those of the SARS-CoV-2 and the SARS-CoV.

Abstract: Background: Spain is one of the European countries affected by the COVID-19 pandemic with a high number of recorded cases and deaths in Europe. Aim: To describe clinical characteristics and outcome of patients with COVID-19 hospitalized in a regional hospital in Spain. Methods: Clinical characteristics of the first COVID-19 patients hospitalised in the early days of the epidemic were recorded upon admission. A logistic regression multivariate analysis was performed to determine factors independently associated with a composite endpoint (death or ICU admission). Results: We included 100 patients, median age was 75 years and 52% were men. The most common comorbidities were hypertension (63%), diabetes (22%) and cardiovascular diseases (28%). The most common symptoms were fever (80%), cough (69%), fatigue (59%) and dyspnoea (52%) and 64% had respiratory insufficiency. Bilateral interstitial infiltrates (65%) and bilateral vertical “B-kerley” lines (82.6%) were the most common findings in chest radiographs and lung ultrasound. All patients received supplementary oxygen, 69% received medical treatment (hydroxychloroquine plus azithromycin the most common regimen) and 12% glucocorticoids. During hospitalization, 26% died, 10% were transferred to ICU and the remaining 62% were discharged at home. In the multivariate analysis a higher comorbidity burden (OR 1.4; 95% CI: 1.1-1.8) and higher C-reactive protein values on admission (OR 1.2; 95%CI: 1.1-1.4) were independent risk factors for the composite endpoint. Conclusions: Case-fatality rate of patients hospitalized with COVID-19 in the early days of the Spanish epidemic was 26%. A high comorbidity burden is associated to an increased risk of death or ICU admission.

Aims We aim to reveal the effect of the crisis period and normalization process after COVID-19 on dermatology practice, to anticipate future health problems, and demonstrate the necessity of teledermatology as a solution. Results The number of patients in the normalization (32.3%) increased compared to the crisis period (11.5%) but also it was found significantly lower than before the pandemic (56.2%). It was remarkable that the change in the distribution of stress-related diseases, such as idiopathic generalized pruritus, alopecia areata, and zona zoster, stably paralleled each other and the trend of increase and decrease during the crisis period and the normalization process, respectively. The increase in the frequency of contact dermatitis, which was not reflected in the crisis period, became evident in the normalization process (p<0.001). There was no significant change in the rate of scabies but a decrease in the number of patients (p=0.276). Discussion The decrease in stress-related diseases indicates that social stress started to decrease with normalization. Rates and the number of patients give an idea about the problems we may encounter aftermath pandemic. Scabies and venereal diseases, which concern public health, should not be neglected. We predicted that much more significant increases in the frequency of scabies will be recorded aftermath of COVID-19. Conclusion The extraordinary conditions that occur after the pandemic will make the management of some diseases, especially scabies, difficult in the future. The chaos that will occur when the unusually decreasing number of patients returns to normal can be alleviated by teledermatology.

Spirometry, a gold standard technique for measuring lung functions, has been restricted to a select cohort of patients in current COVID-19 pandemic due to the enhanced risk of disease dissemination. To monitor pulmonary functions in various obstructive (e.g., asthma) and restrictive diseases (e.g., COVID-19 pneumonia) on in- and out-patients serially, there is an urgent requirement of an alternate reliable test. Impulse Oscillometry (IOS) measures lung functions by working at tidal volumes and thus reduces the risk of potential aerosol generation. Feasibility of IOS in smaller children and its ability to detect parenchymal and peripheral airway involvement are other advantages over conventional spirometry. IOS could be a potential solution to periodically monitor lung functions in current pandemic situation to keep a check on diseases affecting lung functionality.

Background: The ongoing acute respiratory disease pandemic termed COVID-19 caused by a newly emerged coronavirus has jeopardized the world’s health and economic sectors. As of July 20, 2020, the virus now known as SARS-CoV-2 has already infected more than 14 million individuals and killed 612,815 patients with a mortality rate of 4.12% around the world regardless of age, gender and race. Main body: Bangladesh has become one of its worst sufferers, with 207,453 infected people and 2,668 related deaths with a mortality rate of 1.29% until July 20, 2020. More than 50% of COVID-19 patients in Bangladesh are aged between 21 and 40 but elderly people aged more than 60 have the highest mortality rate (44.7%). Male individuals are also more susceptible to the virus than females and consist of 71% and 79% among the infected and deceased patients respectively. The most prevalent clinical features following the virus incubation period are fever, fatigue and dry cough. A phylogenetic analysis study elucidated that the virus strain found in the country has 9 single-nucleotide variants, mostly in the ORF1ab gene, and a sequence containing 3 successive variants in the N protein, which reflects a weaker strain of SARS-CoV-2, implicating a possibility of its lower mortality rate. Another investigation of 184 genome samples of SARS-CoV-2 across the country implicated a close homology with a European haplotype of SARS-CoV-2. The country has also joined the race of vaccine development and started phase-III clinical trials of a candidate vaccine developed by Sinovac Research and Development Co Ltd, China. Conclusion: Bangladesh, as a developing country, still struggles with the pandemic and needs to scale up its response operation and improve health care facilities such as testing capacity, institutional quarantine and isolation centers and promote awareness. Preventive measures such as strict lockdown, social distancing and boosting the existing immune system are thus considered the only contrivances.

COVID-19 pandemic continues to spread across the world in late September 2020. To date, total cases of COVID-19 exceed 33 million including 996.342 deaths according to the WHO data. Although hydroxychloroquine, oseltamivir, remdesivir, favipiravir have been reported as an anti-SARS-CoV-2 effect, it is still unclear the fully effective protective drug and treatment. Herein, we report a woman under Tenofovir diphosphate who live and close contact with his COVID-19 positive husband. Although she had close contact with his husband without measure in the home she did not show any symptoms and signs of COVID-19 and her PCR test along with antibody test negative. Given the high reproduction number of SARS-CoV-2 and long-term close contact of the case, it can be speculated that Tenofovir could interfere with the transmission of COVID-19.

Objective COVID-19 mortality and outcomes differ significantly across the globe. Limited data exists from low-middle income countries (LMICs) on risk-factors for COVID-19 severity and mortality. We describe the clinical spectrum and predictors of mortality and severity of illness in COVID-19 from a single center in Karachi, Pakistan. Methods Retrospective cohort study of adults admitted with COVID-19 between February-June 2020 were reviewed and logistic regression applied on admission related risk-factors for severity and mortality. Results A total of 445 patients [66.97% males, mean age 51.6 (18-91) years] were admitted with PCR confirmed COVID-19 during the study period. Asymptomatic and severe/critical disease occurred in 55 (12.36%) and 137 (30.79%) patients, respectively. The proportion of severe disease increased with time and most (268, 60.22%) had ≥ 1 co-morbid. Disease severity was associated with age ≥ 60 (OR:1.92), shortness of breath (OR:4.43) , CRP ≥150mg/L (OR:1.77), LDH ≥ 500 I.U/L (OR:1.98), Neutrophil to Lymphocyte ratio (NLR) ≥5 (OR:2.80) and unit increase in serum creatinine (OR:1.32). All-cause mortality was 13%. Mortality was associated with septic shock (AOR= 13.2), age ≥ 60 (AOR: 3.25), Ferritin ≥ 1500ng/ml (AOR: 3.78) and NLR ≥ 5 (AOR: 4.04). Conclusion We describe the experience with COVID-19 from a tertiary-care hospital in a LMIC. Our study found a comparatively low inpatient mortality, high proportion of diabetics, and neutrophil to lymphocyte ratio of greater than 5 as a predictor of both severity of illness and as poor prognostic marker in COVID-19.

Background: The Coronavirus Disease 2019 (COVID-19) is causing of the new global pandemic and is responsible for millions of infections and thousands of deaths in the world. The lung ultrasound is a non-invasive and easily repeatable tool and can be carried out by the pediatrician at the bedside of children with a consequent reduction in the risk of transmission of the virus. Objective: To determine whether the lung ultrasound is a useful tool in identifying the signs of lung involvement in children with COVID-19 and whether can monitor the course of the disease. Methods: The study was made in the emergency department in a tertiary level pediatric hospital. All patients with swab-confirmed COVID-19 infection were subjected a lung ultrasound within 6 hours from admission and after 96 hours. Results: Among a total of 30 children, 18 (60%) were males, 4 reported exertional dyspnea and only 1 chest pain. The mean oxygen saturation was 98.8 ± 1.0 % in ambient air in emergency department and no patient needed oxygen therapy during hospitalization. After 96 hours we had observed ultrasound abnormality al the lung ultrasound only in 20% of the children. We found a statistically significant reduction in pleural irregularities (30% vs 16.7; p: .001) and in B lines (50% vs 20%; p: .008). Conclusions: lung ultrasound is safe and useful tool in detecting lung involvement in children with COVID-19 and in monitoring these patients during the course of disease.

In May 2020, Deng et al. (2020) published their article providing the evidence that no SARS-CoV-2-specific antibodies were detected in 1,914 samples which excluded the possibility of 35 animal species as intermediate host for SARS-CoV-2 in Transboundary and Emerging Diseases. In order to ensure the stability of SARS-CoV-2-specific antibodies in storage serum samples, we strongly suggest that standard serum banks should be established.

We report 2 imported cases of COVID 19 in patients with type 1 diabetes. The viral shedding duration was 18 and 22 days in the two cases. Both patients had maintained correct blood glucose levels without ketoacidosis decompensation with regular medical follow-up by telephone.

Sacubitril/valsartan: potential impact of ARNi “beyond the Wall” of ACE2 on treatment and prognosis of heart failure patients with COVID-19Speranza Rubattu 1,2, Giovanna Gallo1, Massimo Volpe 1,21 Cardiology Unit, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Sant’Andrea Hospital, Rome, Italy.2 IRCCS Neuromed, Pozzilli (IS), ItalyRunning title: ARNi and COVID-19 in HFrEFTotal word count (excluding references): 835Corresponding address:Speranza Rubattu, M.D.Department of Clinical and Molecular Medicine,School of Medicine and Psychology,Sapienza University of Rome;IRCCS Neuromed, Pozzilli (Isernia), Italye-mail: speranzadonatella.rubattu@uniroma1.itFrom the beginning of the SARS-CoV-2 pandemic and of its related COVID-19 outbreak, the angiotensin-converting enzyme 2 (ACE2), probably the most “unloved and neglected” member of the renin-angiotensin-aldosterone system (RAAS) family, has attracted increasing attention since it has been shown as the cell receptor through which the virus enters into the cells (Iaccarino, Grassi et al., 2020).The physiological action of ACE2 consists in degrading angiotensin II (Ang II) to angiotensin (1-7), a heptapeptide with a potent vasodilator function through the Mas receptor able to counterbalance the Ang II effects on vasoconstriction, sodium retention, and fibrosis (Gallagher, Ferrario et al., 2014).Previous studies have shown that angiotensin type 1 receptor (AT1R) blockers (ARBs), ACE inhibitors (ACEI) and mineralocorticoid receptor antagonists (MRA) may up-regulate the expression of ACE2 both in acute and chronic settings of cardiovascular diseases (CVDs) such as hypertension, heart failure (HF) and myocardial infarction (MI) (Gallagher, Ferrario et al., 2014).These data have generated concern during the early phases of the pandemic, since it has been speculated that the increase in ACE2 level may have contributed to disease virulence and to adverse outcomes particularly in those subjects affected by chronic coexisting CVDs who commonly received treatment with RAAS inhibitors and who were characterized by a worse clinical course (Iaccarino, Grassi et al., 2020).On the other hand, it has been observed that the binding between coronavirus and ACE2 leads toACE2 downregulation, resulting in an unopposed production of angiotensin II by ACE, contributing to lung damage as a consequence of AT1R mediated inflammation, fibrosis, thrombosis, vasoconstriction and increased vascular permeability. According to these findings, RAAS inhibitors and in particular ARBs may even protect against COVID-19 acute lung injury (Iaccarino, Grassi et al., 2020). As a matter of fact, epidemiological studies conducted in large populations of COVID-19 patients demonstrated that ARBs or ACEI had no association with a severe or fatal course of the disease (Iaccarino, Grassi et al., 2020).In such a context, natriuretic peptides (NPs), which include atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), along with their N-terminal counterparts, may play an important protective role in COVID-19 disease. NPs are released as a consequence of increased volume overload and myocytes stress and, through their vasorelaxant, diuretic and natriuretic effects, are able to counterbalance RAAS and sympathetic nervous system actions, ultimately regulating blood pressure, electrolytes and water homeostasis (Volpe, Rubattu et al, 2014). At the vascular level, NPs reduce cellular growth and proliferation, preserving endothelial function and integrity as well as vascular tone, and they oppose blood clotting, inflammation, angiogenesis and atherosclerosis progression (Volpe, Rubattu et al, 2014). Besides their well-described systemic haemodynamic and autocrine/paracrine functions within the cardiovascular system, NPs play an important protective role in the lungs. It fact, ANP is able to reduce lung endothelial permeability caused by inflammation and oxidative stress, avoiding the development of acute respiratory distress syndrome and improving arterial oxygenation during mechanical ventilation. According to these evidences, it has been proposed that COVID-19 patients with deficiencies in the NP system, mainly obese and black subjects, may have an increased risk of developing severe lung complications.A bidirectional interaction between ANP and ACE2 has been demonstrated in experimental models. ANP, through cyclic guanosine monophosphate (cGMP) production, inhibited the Ang II-mediated decrease of ACE2 mRNA synthesis. On the other hand, Ang-(1-7), the product of ACE2 activity, stimulated ANP secretion (Gallagher, Ferrario et al., 2014).In such a context, a field of great interest is represented by the potential impact on the clinical course of the COVID-19 disease and on its outcome of a treatment with sacubitril/valsartan (S/V), a member of the new pharmacological class of AT1R/neprilysin inhibitors (ARNi) and currently recognized as a cornerstone of the therapeutic management of HF with reduced ejection fraction (HFrEF). With regard to the trend of different NPs levels after the initiation of S/V, NT-proBNP level decreases as a consequence of the improvement of cardiac function; BNP level slightly increases due to its relatively low affinity to neprilysin, whereas ANP level consistently and substantially increases, mediating most of the benefits of neprilysin inhibition (Ibrahim, McCarthy et al., 2019).According to these evidences, an approach based on early administration of S/V has been proposed in the therapeutic management of COVID-19 hospitalized patients (Acanfora, Ciccone at al., 2020). This intriguing hypothesis appears devoid of any practical value in non CVD patients, due to the undesirable haemodynamic effects of this drug and to the lack of indication for S/V administration in the absence of HFrEF.In our opinion, a more specific and rational approach to test the expected beneficial role of S/V would be to retrospectively investigate in existing registries of hospitalized COVID-19 patients whether, among subjects affected by HFrEF, those who were treated with S/V presented a lower disease incidence, a better prognosis and clinical course, compared to patients who received other medications, including ACEI/ARBs. A call to action is required to test the potential benefits of S/V in HFrEF patients affected by COVID-19 through new prospective randomized clinical trials.