The COVID-19 pandemic has transformed lives across the world. In the UK there has been a public health driven policy of population ‘lockdown’ that had enormous personal and economic impact. We compare UK response/outcomes including excess deaths with European countries with similar levels of income/healthcare resources. We calibrate estimates of the economic costs as different %loss in GDP against possible benefits of avoiding life years lost, for different scenarios where local COVID-19 mortality/comorbidity rates were used to calculate the loss in life expectancy. We apply quality-adjusted life years (QALY) value of £30,000 (maximum under NICE guidelines). The implications for future lockdown easing policy in the UK are also evaluated. The spread of cases across European countries was extremely rapid. There was significant variation both in severity and timing of both implementation and subsequent reductions in social restrictions. There was less variation in the trajectory of mortality rates and excess deaths, which have fallen across all countries during May/June 2020. The average age at death and life expectancy loss for non-COVID-19 was 79.1 and 11.4years respectively while COVID-19 were 80.4 and 10.1years; including for life-shortening comorbidities and quality of life reduced this to 5QALY for each COVID-19 death. The lowest estimate for lockdown costs incurred was 50% higher than highest benefits from avoiding the worst mortality case scenario at full life expectancy tariff and in more realistic estimation they were over 50 times higher. Application to potential future scenarios showed in the best case a QALY value of £220k (7xNICE guideline) and in the worst-case £3.7m (125xNICE guideline) was needed to justify the continuation of the lockdown. The evidence suggests that the costs of continuing severe restrictions in the UK are so great relative to likely benefits in numbers of lives saved so that a substantial easing in restrictions is now warranted.

A document by lixing liu, written on Authorea.

Multisystem inflammatory syndrome in children (MIS-C) during the COVID-19 pandemic raised a global alert from the Centers for Disease Control and Prevention’s Health Alert Network. The main manifestations of MIS-C in the setting of a severe inflammatory state include fever, diarrhea, shock, and variable presence of rash, conjunctivitis, extremity edema, and mucous membrane changes, and in some cases it progressed to multi-organ failure. The low percentage of children with asymptomatic cases compared with mild illness and moderate illness could be correlated with the rare cases of MIS-C. One potential explanation for the progression to severe MIS-C disease despite the presence of readily detectable anti-SARS-CoV-2 antibodies could be due to potential role of antibody-dependent enhancement (ADE). We reason that the incidence of the ADE phenomenon whereby the pathogen-specific antibodies can promote pathology should be considered in vaccine development against SARS-COV-2.

The difference in morbidity and mortality between adult and pediatric COVID-19 infections is dramatic. Understanding pediatric-specific acute and delayed immune responses to SARS-CoV-2 is critical for the development of vaccination strategies, immune-targeted therapies, and treatment and prevention of MIS-C. The goal of this review is to highlight research developments in understanding of the immune responses to SARS-CoV-2 infections, with a specific focus on age-related immune responses.

To the editor,Following the online podcast recorded the 31 March 2020 by the International Committee of the American Thoracic Society Pediatrics Assembly and recently published in Pediatric Pulmonology1, we have interesting discussion with my international colleagues about the likelihood of acute bronchiolitis caused by SARS-CoV-2 infection in absence of RSV co-infection. Here, we report 2 cases of COVID-19 in infants < 3 months old admitted to our paediatric unit. The infants presented fever and neurological symptoms and after a short period, acute bronchiolitis.Case 1 : A term-born boy with unremarkable history was admitted to the emergency department with poorly tolerated high fever (38.8°C) and rhinitis. The parents, who had no history of asthma or allergy, showed clinical signs suggesting SARS-CoV-2 infection. RT-PCR for SARS-CoV-2 on a nasopharyngeal swab was positive for the father and the grandfather, who was hospitalized in the intensive care unit. Neurologic examination of the infant revealed lethargy and hypotonia with a bulging anterior fontanelle. The respiratory condition and clinical examination findings including hemodynamics were normal.The first blood test showed isolated lymphopenia (lymphocyte count 1.56 x109/L; normally 4-6x109/L) without modification of biological inflammatory parameters, as assessed by normal levels of C-reactive protein (CRP) and procalcitonin (PCT). Spinal fluid analysis, cytobacteriological urine analysis and blood culture were negative. RT-PCR of a nasopharyngeal swab was positive for SARS-CoV-2 but negative for respiratory syncytial virus (RSV) and influenza virus (IV). The patient received fluid volume expansion(20 ml/Kg of 0.9% sodium chloride solution) together with antibiotic treatment (cefotaxime, amoxicillin and gentamicin at meningeal doses) for 24 hr, that was stopped with a positive RT-PCR test for SARS-CoV-2 and negative blood culture. Favourable clinical outcome was obtained shortly thereafter, allowing the infant to return home 2 days later.Ten days later, the child returned with acute bronchiolitis. Respiratory symptoms included polypnea, shortness of breath, wheezing and hypoxia (SpO2< 92 %). Lung ultrasonography revealed signs of interstitial syndrome with thickened and irregular pleural line associated with confluent B lines and small multifocal subpleural consolidations. RT-PCR for RSV and IV remained negative. Treatment associated supplemental oxygen and enteral nutrition for 6 days. A second episode of acute bronchiolitis occurred 1 month later, but a RT-PCR test for SARS-CoV-2 was negative. The chest X-ray was normal. The child remained hospitalized for 5 days with enteral nutrition support but did not require oxygen supplementation. Long-term treatment with inhaled daily corticosteroids (fluticasone) was introduced.Case 2 : A term-born eutrophic male with otherwise unremarkable neonatal history was referred for poorly tolerated high fever at age 2 months. Both parents had clinical signs of COVID-19 but were not tested (a member of the family had a positive test). The neurologic examination revealed lethargia and hypotonia in the child; the respiratory condition and clinical examination findings including hemodynamics were normal. The first blood test showed lymphopenia (lymphocyte count: 1.86 x109/L; normally 4-6x109/L)without modification of biological inflammatory parameters. Cytobacteriological examination of urine and blood culture were negative and spinal fluid analysis was not performed. RT-PCR testing of a nasopharyngeal swab was positive for SARS-CoV-2 but negative for RSV and IV. The patient did not receive any antibiotics. On day 3 after admission, the respiratory condition progressively worsened, with retraction, wheezing, increased respiratory rate at 80/min and hypoxia (SpO2 < 92%) requiring supplemental oxygen together with enteral nutrition for 3 days. The chest X-ray was normal, and no lung ultrasonography was performed. The infant was returned to the emergency department 2 weeks later with a non-severe wheezing episode and was discharged at home.These 2 cases of COVID-19 in infants hospitalized for poorly tolerated high fever and neurological symptoms in whom acute bronchiolitis developed at a delay of 2 to 8 days suggest that SARS-CoV-2 infection may cause acute bronchiolitis in absence of viral co-infection such as RSV. Pneumonia is the most common diagnosis among symptomatic children with COVID-191. High-resolution CT scan usually shows ground-glass opacities or bilateral lung consolidations, especially in the periphery, and lung ultrasonography, as in our case 1, reveals signs of lung involvement. In contrast, to the best of our knowledge, acute bronchiolitis due to SARS-CoV-2 infection has never been reported. The wheezing episodes described in our patients were likely due to SARS-CoV-2 infection for the following reasons: first, RT-PCR tests for RSV and IV were always negative in both children, and second, the epidemic season for both viruses was over and the lockdown in France was still active at the time of the cases. Finally, previous study of virus repartition in positive respiratory samples from infants with acute bronchiolitis detected close to a 5% frequency of coronaviruses OC43 and 229E2. Moreover, a recent experimental model of COVID-19 in ferrets showed lung lesions compatible with bronchiolitis3. Our patients showed bronchiolitis symptoms several days after those of COVID-19, which may explain the lack of wheezing episodes reported in the literature. Case 2 was diagnosed with recurrent wheezing presumably due to SARS-CoV-2 infection. RSV as well as rhinovirus bronchiolitis is a risk factor for recurrent wheezing and asthma4,5,but little is known about the long-term impact of SARS-CoV-2 infection in lung function trajectory, which emphasizes the need to follow these children. Whether the infection in symptomatic or asymptomatic infants may predispose to recurrent wheezing or asthma remains to be determined.

Objective: To investigate temporal bone findings in COVID-19 Design: Retrospective study Settings: Using the database of our tertiary pandemic hospital, patients with COVID-19 infection with a positive PCR test and temporal bone tomography imaging were evaluated. Participants: 42 PCR positive COVID-19 patients with temporal bone imaging. Main outcome measures: A grading system was created to evaluate effusion in the middle ear and mastoid air cells. Also any specific sign in temporal bone imaging. Results: Patients were divided into two groups according to their chest CT findings. Group 1 had specific chest CT findings and included 26 patients, group 2 had no findings in chest CT and included 16 patients. No obvious temporal bone involvement was observed in any of the patients. Temporal bone imaging findings were compared according to a grading system and there was no difference between the groups (p=0,50). Conclusion: The SARS-CoV-2 does not affect the temporal bone. There was no sign of effusion in mastoid air cells or the middle ear or any specific sign in the temporal bone in our study group.

Intense effort is underway to evaluate potential therapeutic agents for the treatment of COVID-19. In order to respond quickly to the crisis, the repurposing of existing drugs is the primary pharmacological strategy. Despite the urgent clinical need for these therapies, it is imperative to consider potential safety issues. This is important due to the harm-benefit ratios that may be encountered when treating COVID-19, which can depend on the stage of the disease, when therapy is administered and underlying clinical factors in individual patients. Treatments are currently being trialled for a range of scenarios from prophylaxis (where benefit must greatly exceed risk) to severe life-threatening disease (where a degree of potential risk may be tolerated if it is exceeded by the potential benefit). In this perspective, we have reviewed some of the most widely-researched repurposed agents in order to identify potential safety considerations using existing information in the context of COVID-19.

At present, Corona virus disease 2019(COVID-19) has become a major concern all over the world and leads to huge medical pressure. Antibody-dependent enhancement (ADE) of viral infection has been researched extensively in many viruses. It is not yet clear whether SARS-CoV-2 infection causes ADE effects. However, there is evidence that ADE may be found in COVID-19. We have discussed the possibilities of ADE effect induced by COVID-19 and proposed a series of measures to deal with it.

Secondary pneumomediastinum in patients with ARDS is often related to invasive mechanical ventilation due to high airway pressures leading to alveolar rupture.1 The pathophysiologic mechanism through which this occurs is known as the Macklin effect which describes the idea that alveolar rupture causes a leakage of air along the bronchovascular bundle whereby it extends into the mediastinum.2 Another contributing factor to alveolar rupture is the diffuse alveolar damage seen in patients with severe ARDS.3   Here we present a case series from a major New York City academic hospital of 18 patients with Covid-19 complicated by pneumomediastinum in the setting of both invasive and noninvasive ventilation.             The data collected was obtained on April 19th during which 130 Covid-19 infected patients were intubated and in the intensive care unit since March 26th 2020. Four patients were excluded from analysis due to inability to exclude pneumomediastinum as a line-associated complication. All intubations were done by the most senior clinician available. The median age of the patients was 60 years and 55.6% were men. The most common comorbidities were hypertension (38.9%) and diabetes mellitus (33.3%). Most pneumomediastinum cases (83.3%) were in association with invasive mechanical ventilation and 46.7% occurred within the first day of intubation. An additional 40% of pneumomediastinum cases occurred between day 1 and day 6. Those intubated were placed on an average of 6.58 cc/kg of tidal volume. Only 20% of patients experienced peak inspiratory pressures greater than 35 mm Hg and 13.3% had plateau pressures greater than 30 mm Hg. High PEEP strategy defined as greater than 12 mm Hg was used in 40% of patients. The most frequent concurrent complications observed were subcutaneous emphysema (72.2%) and pneumothorax (55.6%). Figure 1 shows a single axial cut of a CT scan of the Chest of one patient who experienced severe subcutaneous emphysema, pneumomediastinum and diffuse bilateral lung infiltrates due to Covid-19. The in hospital mortality rate at the time of publication is 44.4%.             The prevalence of pneumomediastinum cases due to COVID-19 in this study was 13.8%. This is significantly more frequent than that observed with protective ventilation strategy which was as low as 7%.4 Interestingly, a previous study of SARS-Cov1 estimated a total incidence of 12% of patients with pneumomediastum.5             The large number of pneumomediastinum cases observed in this case series seems to be unexplained solely by barotrauma from mechanical ventilation in these patients treated with protective lung strategy and may be specific to the underlying pathology of Covid-19. Of note, three patients who developed this complication were receiving noninvasive ventilation further supporting this hypothesis.  Conflict of Interest: None  References:1.   Ioannidis G, Lazaridis G, Baka S, et al. Barotrauma and pneumothorax. J Thorac DIs. 2015;7(Suppl 1):S38-S43 2.   Jacobi A, Chung M, Bernheim A, Eber C. Portable chest X-ray in coronavirus disease-19 (COVID-19): A pictorial review. Clinical Imaging. 2020;64:35–42. 3. Murayama S. Spontaneous pneumomediastinum and Macklin effect: Overview and appearance on computed tomography. World Journal of Radiology. 2014;6(11):850.4. Passos Amato M, Valente Barbas C, Medeiros D, et al. Effect of a Protective-Ventilation Strategy on Mortality in the Acute Respiratory Distress Syndrome. New England Journal of Medicine. 1998;338:347-3545. Peiris J, Chu C, Cheng V, et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet. 2003;361(9371):1767–72.

Aim: We hypothesize that the efficacy of COVID-19 therapeutic candidates will be better predicted by understanding their effects at various points on a viral cell cycle, in particular, the specific rate constants, and that drugs acting independently of these specific discrete sites may not yield expected efficacy. We hypothesize that drugs, or combinations of drugs that act at specific multiple sites on the viral life cycle have the highest probability of success in the treatment of early infection phase in COVID-19 patients. Methods: Using a target cell limited model structure that had been used to characterize viral load dynamics from COVID-19 patients, we performed simulations to show that combinations of therapeutics targeting specific rate constants have greater probability of efficacy and supportive rationale for clinical trial evaluation. Results: Based on the known kinetics of the SARS-CoV-2 life cycle, we rank ordered potential targeted approaches involving repurposed, low-potency agents. We suggest that targeting multiple points central to viral replication within infected host cells or release from those cells is a viable strategy for reducing both viral load and host cell infection. In addition, we observed that the time-window opportunity for a therapeutic intervention to effect duration of viral shedding exceeds the effect on sparing epithelial cells from infection or impact on viral load AUC. Furthermore, the impact on reduction on duration of shedding may extend further in patients who exhibit a prolonged shedder phenotype. Conclusions: Our work highlights the use of model-informed tools to better rationalize effective treatments for COVID-19.

Background: The first case of COVID-19 in Israel was reported on February 21, 2020. Shaare Zedek (SZ), a 1000-bed tertiary care medical center in Jerusalem, Israel, cared for a significant number of these patients. While attention focused on COVID-19 patients, uninfected patients were admitted to decreasing numbers of available internal medicine (IM) beds as IM departments were converted to COVID-19 isolation wards. Due to the increase in COVID-19 patients, closure of IM wards, re-assignment of staff, and dynamic changes in available community placement options, we investigated the impact of the outbreak on IM patient not admitted for COVID-19. Methods: We reviewed IM admissions during March 15 – April 30, 2020 for patients without COVID-19. Characteristics assessed included number of admissions, age, length of stay, mortality rate, number of discharges, number discharged home, and functional status of the patients. Data was compared to the previous three years (2017 – 2019) during the same time period. Results: During March 15 – April 30, 2020 there were 409 patients admitted to IM compared to a mean of 557 over the previous three years. Fewer patients were admitted to the ED and the IM wards during the outbreak. There was no significant difference between the two groups with regards to gender, in-hospital mortality rate, number discharged, number discharged home, and patient functional level. Patients admitted during the outbreak to IM were younger (74.85 vs 76.86 years) and had a mean shorter hospital length of stay (5.12 vs 7.63 days) compared to the previous three years. Conclusion: While the characteristics of patients admitted to IM during the outbreak were similar, hospital length of stay was significantly shorter. Internal management processes, as well as patient preferences may have contributed to this observation. An infectious disease outbreak may have a significant effect on uninfected admitted patients.

To the Editor,We read carefully the research letter “Is asthma protective of COVID-19?” by Carli et al recently published.1Important topic for asthma patients in the coronavirus disease 2019 (COVID-19) pandemic were considered, including that until recently weak evidence that patients with chronic respiratory disorders are at a lower risk of being infected or becoming severely ill with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).Reflecting only about previous reports from China and Italy where asthma was underrepresented in COVID-19 patients, the authors accept the heterogeneous condition that it is asthma, speculating that T2-immunity, interferon-mediated immune responses and increased number of eosinophils in the airways could have a protective effect against COVID-19 severity.1The epidemiology of COVID-19 is changing rapidly with new data. More recent reports from the United States of America and from several European countries, in particular the United Kingdom (UK), states a higher asthma prevalence in patients with COVID-19, suggesting that asthma is more common in COVID-19 patients than it was previously reported in Asia and in the first European surveys.2Data from the UK Biobank, a large prospective case-control study, found an asthma prevalence of 17,9% in 605 COVID-19 hospitalized patients, mostly of them adults, surpassing the prevalence of asthma in the general population.3Besides that, in the OpenSAFELY Collaborative Study (UK), it was found a significant increased risk of severe CoViD-19 in patients with asthma, including death, in particular related with the recent use of oral corticosteroid (OCS).4 These findings can indicate an increased asthma severity and/or poor control and, in accordance with data from previous coronavirus outbreaks, that systemic corticosteroids were associated with a higher viral load.5We agree with Carli et al1 that further studies focused on asthma and its different phenotypes are needed to provide a better understanding of the impact of SARS-CoV-2 infection in patients with asthma.6 Nevertheless, for the moment, it seems crucial that patients with asthma do not stop their controller medication, that may lead to a higher risk of asthma exacerbations, increased OCS use and higher probability to emergency room access and hospitalization that represent themselves significant risk factors for coronavirus exposure and spread.In conclusion, according with the available data, patients with asthma must still be included in the high-risk groups for COVID-19 and more data are needed to understand the relationship between asthma and COVID-19.

Background: The coronavirus infection (COVID-19) was declared in January 2020 as a public health emergency of international concern. The Middle East and North Africa (MENA), like other parts of the world, suffered from several epidemics over the years. Pharmacists have vital roles to play to prevent the spread of this virus. Objectives: To assess the awareness of COVID-19 amongst pharmacists from countries located in the MENA countries, and to assess their perspectives of their role, barriers, and roles of the educational institutions and pharmaceutical associations in preparing them for their roles during the pandemic. Methods: An online survey was conducted to run a descriptive cross-sectional study in Jordan from 12th to 22th April 2020. The questionnaire was validated and put on Facebook for pharmacists’ recruitment and assessment of their awareness (20 questions with a score out of 20) about epidemics/pandemics and COVID-19, their perceived roles and barriers, and roles of the educational institutions and pharmaceutical associations. Data were analyzed using Statistical Package for the Social Science (SPSS). Results: Study participants (n= 2589) had a mean age of 29.3 (8.2) years and 1329 (51.5%) were females. Most of the participants were from Egypt 819 (40.8%), Followed by Jordan, Algeria, and Syria. As for the sources of information about coronavirus treatment among the study participants, 60.8% got their information from the social media. Fear as a consequence was identified by the majority of participants (87.7%). The majority of pharmacists identified positive roles for the pharmaceutical association and pharmaceutical associations. Conclusion: Pharmacists from the MENA countries believe they got enough education previously about epidemics/pandemics, and the majority follow on the latest coronavirus updates from social media. Fear was reported as the major barrier that requires resolution by the policymakers. Certain gaps in the awareness about COVID-19 were identified.

Aim: To assess the potential of interleukin-6 (IL-6) signaling blockade in the lung to treat SARS-CoV-2 infection via model-based simulation by exploring soluble IL-6 receptor (sIL-6R) sequestration by tocilizumab (TCZ) and IL-6 sequestration by siltuximab (SIL). Methods: Literature values of IL-6, the IL-6 antagonist SIL, sIL-6R, the IL-6R antagonist TCZ, and their respective binding constants were used to develop a model to predict the impact of treatment on IL-6 signaling. Models were used to generate simulated bronchoalveolar lavage (BAL) concentrations for normal subjects, subjects at risk of developing acute respiratory distress syndrome (ARDS), and subjects with ARDS were simulated under four conditions: without treatment, treatment with TCZ, treatment with SIL, and treatment with TCZ + SIL. Results: With TCZ intervention, IL-6 levels are unaffected and sIL-6R is reduced somewhat below the Normal case. IL-6:sIL-6R complex only slightly decreased relative to the no-intervention case. With SIL intervention, sIL-6R levels are unaffected and IL-6 is greatly reduced below the Normal case. IL-6:sIL-6R complex is greatly decreased relative to the no-intervention case. With TCZ + SIL intervention, IL-6 and sIL-6R levels are reduced below the Normal case and achieve suppression equivalent to monotherapy results for their respective targets. IL-6:sIL-6R complex reduction is predicted to be greater than monotherapy. This reflects sequestration of both components of the complex and the nonlinear binding equilibrium. Conclusion: Co-administration of both IL-6 and IL-6R sequestering products such as SIL and TCZ may be necessary to effectively treat COVID-19 patients who have or are at risk of developing ARDS.

A document by Andres Perez-Lopez, written on Authorea.

In the search to rapidly identify effective therapies that will mitigate the morbidity and mortality of COVID-19, attention has been directed towards the repurposing of existing drugs. Candidates for repurposing include drugs that target COVID-19 pathobiology, including agents that alter angiotensin signaling. Recent data indicate that key findings in COVID-19 patients include thrombosis and endothelitis Activation of PAR1 (protease activated receptor 1), in particular by the protease thrombin, is a critical element in platelet aggregation and coagulation. PAR1 activation also impacts on the actions of other cell types involved in COVID-19 pathobiology, including endothelial cells, fibroblasts and pulmonary alveolar epithelial cells. Vorapaxar is an approved inhibitor of PAR1, used for treatment of patients with myocardial infarction or peripheral arterial disease. Here, we discuss evidence implying a possible beneficial role for vorapaxar in the treatment of COVID-19 patients and in addition, other as-yet non-approved antagonists of PAR1 and PAR4.

The pandemic condition Coronavirus-disease (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can take asymptomatic, mild, moderate, and severe courses. COVID-19 affects primarily the respiratory airways leading to dry cough, fever, myalgia, headache, fatigue, and diarrhea and can end up in interstitial pneumonia and severe respiratory failure. Different clinical symptoms caused by involvement of organs outside the respiratory system have been also described. Interestingly, reports about the manifestation of various skin lesions and lesions of the vascular system in some subgroups of SARS-CoV-2 positive patients as such features outside the respiratory sphere, are rapidly emerging. However, knowledge about prevalence and pattern of skin involvement, time of onset, predilection, and its direct or indirect relation to SARS-CoV-2 is still limited. In order to update information gained, we provide a systematic overview of the skin lesions described in COVID-19 patients, discuss potential causative factors and describe differential diagnostic evaluations.

The COVID-19 pandemic has forced the transition of many traditional face-to-face classes into an online format with little time to prepare best practice guidelines. In this article we share ways to adapt a group field activity into an individual lab assignment that can be completed during shelter-in-place restrictions. We address the tactics, difficulties, successes, and ideas for future applications while staying mindful of the ways in which this pandemic has highlighted the inequities of the classroom.

COVID-19 has now become a global epidemic, prevailing over 213 countries of the world including Pakistan. To date, there have been more than 12000 cases and above 220 deaths reported in Pakistan. The outbreak is caused by a β-coronavirus called SARS-CoV-2, similar in characteristics to the SARS and MERS-CoV. It shows symptoms like pneumonia and may lead to death. Despite lockdown and possible isolation system, it is spreading rapidly. Lack of precautionary measures, specific vaccine and delayed diagnosis may be the major reasons for its spread. Several researches on COVID-19 have described its various features to extend its knowledge in order to help the scientific world in preparation of vaccine. Current review aimed to cover all essential data such as clinical characteristics, pathology, detailed morphology and structure, antigenicity of COVID-19 virus, role of structural proteins in anti-viral drug development and possible treatments being used. This manuscript would be helpful to select the best possible treatment depending on the availability and condition of the patient. Moreover, further research is needed for assistance in designing a virus-specific drug or vaccine.

The current pandemic of the novel coronavirus SARS-CoV-2 infection has affected over 6 million humans around the planet. The clinical manifestations of Coronavirus disease 2019 (COVID-19) are diverse, ranging from asymptomatic or mild flu-like symptoms to atypical pneumonia, severe respiratory distress syndrome, systemic inflammation, immune dysregulation and dyscoagulation.Inborn errors of immunity (IEI) are a heterogenous group of more than 430 rare congenital disorders with increased susceptibility to infection, autoimmunity, atopy, hyperinflammation and cancer. Autosomal recessive ARPC1B deficiency is an actinopathy, as are DOCK8 deficiency and the Wiskott-Aldrich Syndrome. Defective actin polymerization affects hematopoietic cells, impairing their migration and immunological synapse1, which results in a combined immune deficiency characterized by leukocytosis, eosinophilia, platelet abnormalities and hypergammaglobulinemia; and clinically, by eczema and food allergy, infections caused by bacteria, fungi and viruses, vasculitis, and bleeding diathesis2.Here, we describe a male infant patient with known ARPC1B deficiency who was hospitalized for COVID-19 pneumonia and improved without requiring intensive care or mechanical ventilation.An 8-month-old infant was brought to the emergency department with high-grade fever. His family history is remarkable for one brother who died as a newborn from intracranial bleeding, and an 11-year-old sister with the same genetic defect who underwent hematopoietic stem-cell transplantation twice without success, and is currently on antimycobacterial treatment, antimicrobial prophylaxis and regular subcutaneous immunoglobulin. The patient was first seen at age 1-month old for eczema and rectal bleeding attributed to cow milk protein allergy. At age 4 months, he developed bronchiolitis caused by respiratory syncytial virus (RSV) and oral candidiasis. Laboratory workup revealed leukocytosis (17,500-33,600/mm3), eosinophilia (5,600-20,100/mm3) and a marginally high (467,000) platelet count; as well as high serum IgG (737 mg/dL) and IgA (165 mg/dL) with normal IgM (37.7 mg/dL). CD8+ T lymphocytes were low at 3% (257 cells) and B cells were elevated at 48% (4,116 cells). Whole exome sequencing identified a homozygous 46 base-pair deletion in exon 8 of ARPC1B(chr7:99,392,784 hg38; p.Glu300fs).Upon his arrival to the emergency department he was febrile with tachycardia and signs of septic shock requiring rapid fluid resuscitation. He showed no respiratory or gastrointestinal signs. He also had a post-traumatic ulcerated lesion under the tongue with dark discoloration, which raised a concern for fungal infection. Intravenous antibiotics (ciprofloxacin) with antifungal coverage were started within the first hour, and a dose of intravenous immunoglobulin (IVIG) at 1g/kg. Blood counts revealed leukocytosis, neutrophilia, and mild eosinophilia without lymphopenia, while platelets were initially found within normal limits. A day later, blood culture had grownPseudomonas aeruginosa .During his second day of hospitalization, the patient persisted febrile, tachycardic and tachypneic, with oxygen desaturation into the low 80s. Chest X-ray showed nonspecific bilateral interstitial opacities in the perihilar regions (Figure 1 ). Real-time Polymerase chain reaction (RT-PCR) for SARS-Cov2 came back positive, and he was then transferred to a COVID-19 isolation area. The potassium hydroxide (KOH) test for oral thrush was negative for yeast cells, after which amphotericin was switched to fluconazole. Supplemental oxygen was discontinued on day 6 of hospitalization, when mild thrombocytopenia and a prolonged thromboplastin time (aPTT) (but normal fibrinogen and ferritin serum levels) were reported. After completing 14 days of antimicrobial treatment, the patient was discharged without ever requiring intensive care unit admission or mechanical ventilation.The behavior of COVID-19 in patients with IEI might help dissect the immune response to SARS-Cov2. A few cases of adults with COVID-19 and predominantly antibody deficiencies have been reported3,4; some of them developed acute respiratory distress syndrome (ARDS), while some had a milder course of illness. Based on what we know, innate immune defects in genes involved in type 1 interferon response (such as IRF7, IRF9, TLR3) are the most likely candidates to result in severe disease and death in patients with flu-like virus infection5. In a few cases of fatal influenza A (H1N1), variants in genes associated with familial hemophagocytic lymphohistiocytosis (FHL) and a decreased cytolytic function of NK cells, were also reported6.Our patient was on monthly supplemental IVIG treatment, and he received an additional dose during his hospital stay. This, and his young age, might have ameliorated the clinical course7. He had a favorable evolution, despite the known susceptibility to viral infection and immune dysregulation in ARPC1B deficient patients1. There were no signs of severe infection, ARDS, hyperinflammation or of “cytokine storm” unleashed by SARS-CoV-2. Despite his having a combined immune deficiency, our patient fully recovered without the need of additional supportive measures other than IVIG, supplemental oxygen and antibiotic treatment directed against the documented bacteremia.Although pediatric cases of COVID-19 are fewer compared to adults, some severe presentations and deaths among children have been reported. The presence of a restricted repertoire of IgG (since infants have no previous exposure to coronaviruses) might play a role in the better outcome seen in pediatric patients. Antibody-dependent enhancement has been implicated in the development of severe COVID-19 in the elderly8. Additionally, lung cells from children and women show a lower expression of membrane-bound ACE-2, which may also be protective against severe pneumonia.Conceivably, some immune defects could protect patients with certain IEIs from mounting a full uncontrolled inflammatory response against SARS-Cov2. The cytoskeleton is a regulator of gene transcription, coupling cell mechanics with the activity of NF-κB. Coronaviruses are thought to alter the cytoskeleton architecture to facilitate viral replication and output9. Thus, ARPC1B deficiency and other actinopathies might limit SARS-CoV-2 replication. Furthermore, Th2 cytokines modulate ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 expression in airway epithelial cells10, and children with allergies (asthma and/or allergic rhinitis) have a lower expression of ACE211. Patients with ARPC1B deficiency often have allergic diseases; their Th2-biased response could help explain the milder presentation seen in our patient. Insights from protective mechanisms in children, with and without certain immune defects, could facilitate the identification of therapeutic targets.Lina Maria Castano-Jaramillo1, MDMarco Antonio Yamazaki-Nakashimada1, MDSelma Cecilia Scheffler Mendoza1, MD, MSJuan Carlos Bustamante-Ogando2, MD, MSSara Elva Espinosa-Padilla2, MD, PhDSaul O. Lugo Reyes2, MD, MS.From the (1) Clinical Immunology Service, and the (2) Immunodeficiencies Research Unit, at the National Institute of Pediatrics, Mexico City, Mexico.Conflict of interests: NoneEthical statement: The patient and his family gave written informed consent for the diagnostic procedures and for publication of the case report.KEY WORDS: Primary immune deficiency, inborn errors of immunity, combined immune deficiency, ARPC1B deficiency, actinopathy, children, COVID-19, SARS-Cov-2, allergy, pneumonia, sepsis.

The outbreak of the Covid-19 pandemic obliged us all to handle many dilemmas, some of which we took upon ourselves as philosophers, ethicists, doctors and nurses to discuss around four key ethical notions : responsibility, dignity, fairness and honouring death. The following collection of the symposium acts held online in May 2020 with the Paris Global Center of Columbia University and Columbia Global Centers, attempts to testify to the ongoing pandemic emergency and difficult challenges while evaluating whether the ethical principles in the official recommendations were able to meet the lived reality. Looking at accountability and consistency in regard to the context of exercise, it seemed equally important to examine, through an international exchange, whether the contextuality of Coronavirus across countries and cultures affected the ethical decision making processes. We hope that our discussion can serve as a resource for advanced care planning, helping medical providers and other specialists to consider the shared important aspects of medical ethics in times of great uncertainty.

In this issue of BJOG, Mendoza and colleagues report in an observational study the occurrence of a preeclampsia-like syndrome in six out of eight pregnant patients with novel coronavirus disease (COVID-19) who were admitted to the Intensive Care Unit (ICU) with severe pneumonia (Mendoza M, et al. BJOG 2020). There were no symptoms of preeclampsia amongst the 34 pregnant women who had mild forms of COVID-19. Importantly, the authors recorded not only routine laboratory test results, but also measured biophysical and biochemical markers that are typically altered in women with preeclampsia (uterine artery pulsatility index on Doppler ultrasound, serum soluble fms-like tyrosine kinase-1 [sFLT-1] and placental growth factor [PlGF]). Such markers were normal in five of the six cases, in whom the symptoms of preeclampsia resolved after improvement of the maternal clinical situation.The intriguingly high cumulative incidence of preeclampsia symptoms in women with severe coronavirus disease needs to be interpreted with caution due to the observational nature of the study, the small number of pregnant women with severe infection and the possible role of confounding factors. The normal biomarker results in most cases, nevertheless, suggest that severe coronavirus disease can lead to symptoms that mimic those of preeclampsia in the absence of defective placentation, which is further corroborated by the resolution of the symptoms without the delivery of the placenta when overall clinical improvement occurs. It is plausible that such manifestations are the result of widespread inflammation and endothelial damage, in a process that has been denominated “cytokine storm”, responsible for many of the symptoms of the coronavirus-related organ injury (Mehta P, et al. Lancet 2020;395:1033-34) This mechanism includes activation of inflammation pathways that convert arachidonic acid to prostaglandins, thromboxane and eicosanoids, ultimately provoking significant cytokine release. The cascade of events, however, does not appear to influence the levels of specific preeclampsia angiogenic and anti-angiogenic markers such as sFLT-1 and PlGF.A normal sFLT-1: PlGF ratio in women with clinically suspected preeclampsia can be reliably used predict the short-term absence of disease (Zeisler H, et al. N Engl J Med 2016;374:13-22). Although the definition of preeclampsia has changed over the last 20 years to incorporate less specific clinical features of end-organ damage, biomarkers will likely become part of the disease definition in the years to come or, at least, a valuable tool to select subgroups of women at higher risk of preeclampsia-related morbidity and mortality who require closer monitoring or immediate delivery.While larger cohorts derived from national datasets or international registries of coronavirus disease in pregnancy will be essential to confirm or refute this association, the preliminary data published in this study indicate that delivery during severe coronavirus disease should not be based on preeclampsia symptoms alone, particularly at early gestational ages, and that the use of ultrasound and serum biomarkers such as the sFLT-1: PlGF ratio might help to guide clinical management by distinguishing hypertension and endothelial dysfunction caused by COVID-19-related inflammation from true preeclampsia.No disclosures: A completed disclosure of interest form is available to view online as supporting information.

Under the unprecedented pressures of the global coronavirus disease 2019 (COVID-19) pandemic, there is an urgent requisite for successful strategies to safely deliver cardiac surgery. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first described in early December 2019, and the rapid spread and emergence of this virus has caused significant disruptions in the delivery of healthcare services worldwide.1,2 In particular, provision of cardiac surgery has been disproportionally affected due to reallocation of intensive care resources, such as ventilators.2Additionally, patients with pre-existing cardiovascular disease are likely to have comorbidities which are associated with poorer clinical outcomes in confirmed SARS-CoV-2 cases.3,4 Despite this, Yandrapalli and colleagues have reported the first case of a successful coronary artery bypass graft (CABG) operation in a patient with asymptomatic SARS-CoV-2 infection, which offers insights into how cardiac surgery could be adapted to solve the challenges of this pandemic.5In response to the burden of COVID-19 on healthcare systems in the United Kingdom (UK), elective cardiac surgeries have been delayed owing to the redistribution of intensive care resources and the unquantifiable risk of acquiring COVID-19.2 Likewise, cardiac surgery services have undergone structural remodelling into a centralised system in an attempt to continue provisions of emergency surgery alongside hospital management of COVID-19 patients.2Unsurprisingly, most cardiac surgery units across the globe have seen a sharp decline in surgeries as a result, and one unit reported an 83% reduction in cardiac index cases between 23rd March to 4th May 2020.2 Similar models have been used in Europe to manage healthcare services and increase intensive care capacity. For example in the Lombardy region of Italy, 16 out of 20 cardiac surgical units discontinued services and all urgent cases have been consequently diverted to the remaining four units for centralised services.6 Whilst these measures have been beneficial for supporting the focused management of COVID-19 patients, it is important to reflect upon the future consequences of delayed elective cardiac surgery. Indeed, such patients are likely to have progressive conditions and further work is needed to investigate the long-term impact of COVID-19 on mortality and morbidity in this cohort.The case report by Yandrapalli and colleagues highlight the importance of routine SARS-CoV-2 testing for all patients requiring cardiac surgery, especially for detecting asymptomatic or subclinical infections.5 Active SARS-CoV-2 infection may precipitate an overproduction of early response proinflammatory cytokines in post-operative period, leading to unfavourable surgical outcomes.7,8 Moreover, preliminary studies have shown that patients with established cardiovascular diseases may have a greater risk of increased SARS-CoV-2 infection severity and prognosis.9 Taken together, assessment for active infection is crucial for risk stratification. In addition, clinicians should consider the threshold for surgery when selecting patients for cardiac surgery. An international, multi-centre cohort study by COVIDSurg Collaborative which included 1128 confirmed SARS-CoV-2 patients undergoing a broad range of surgeries revealed that 30-day mortality risk was significantly associated with the patient demographics of male sex, an age of 70 years or older, and poor preoperative physical health status.10 Collectively, the risks and benefits of cardiac surgery should be carefully considered in such patients due to higher mortality risk.10Alternative therapeutic procedures with rapid discharge, such as percutaneous intervention or medical therapy, may be more appropriate to reduce SARS-CoV-2 related mortality and nosocomial infection risk.11Current evidence is limited for postoperative outcomes in cardiac surgery cases. In the aforementioned cohort study by COVIDSurg Collaborative, the 30-day mortality rate was 23.8%.10In addition, the study reported that 51.2% of patients had postoperative pulmonary complications, which was associated with a higher mortality rate of 38.0%.10 In another case report describing an emergency CABG operation, the asymptomatic patient succumbed to pulmonary complications arising from a SARS-CoV-2 infection confirmed postoperatively.12 The authors acknowledge that the undiagnosed infection may have triggered a refractory pathological response after cardiac surgery. Indeed, recent literature has suggested that patients with SARS-CoV-2 are at higher risk of developing thromboembolisms, possibly mediated by the interaction with angiotensin-converting enzyme 2 (ACE2) receptors.13Similarly, there is a consensus that SARS-CoV-2 has direct adverse effects on the myocardium due to high expression of ACE2.14 As such, SARS-CoV-2 can potentially trigger multisystem complications which require vigilant monitoring, especially in patients requiring cardiopulmonary bypass and at high risk of developing thromboembolisms. Cardiac surgery patients represent a vulnerable patient population, and this cohort may experience worse outcomes with SARS-CoV-2 infection based on the current available evidence. In the latest recommendation, UK currently advises all patients who are listed for elective cardiac surgery to self-isolate for 14 days prior to surgery date, in a measure to limit and contain the exposure of such cohort to the smallest possibilities of acquiring COVID-19.Currently, the future of cardiac surgery after the pandemic is unclear as the evidence is still emerging. However, the lessons learnt from these unprecedented times can be taken forward to inform future service planning. Moving forwards, routine screening of patients for SARS-CoV-2 infection will undoubtedly play a key role in identifying asymptomatic or subclinical infections. The preoperative UK National Health Service testing recommendations should be broadened so that all patients undergoing cardiac surgery are screened, given the higher risk of postoperative complications in this population. Similarly, repeat testing is important for monitoring patients for concomitant infections. Alongside changes to hospital protocol, service delivery will inevitably shift. The successful application of telemedicine during the pandemic has already been reported in the delivery of oncology services.15 Moreover, the benefits of telecardiology outside of the COVID-19 era have been previously reported, and cardiology services will likely embrace the utilisation of telemedicine for managing outpatient consultations.16 Units will also have to address the vast backlog of surgeries caused by cancellation of elective cardiac operations in a sustainable manner, with adequate hospital space and personal protective equipment availability.17 In order to resume success services, planning for this eventuality should begin now and patients at significant mortality risk due to delayed surgery need to be prioritised.Ultimately, clear guidelines should be implemented to ensure safe resumption of surgical services, whilst also reassuring patients concerned about safety.3 Whilst the future trajectory of this pandemic is uncertain, the insights from the impact of COVID-19 on cardiac surgery will undoubtedly shape the future delivery of cardiac surgery.

The outbreak of the Covid-19 pandemic obliged us all to handle many dilemmas, some of which we took upon ourselves as philosophers, ethicists, doctors and nurses to discuss around four key ethical notions : responsibility, dignity, fairness and honouring death. The following collection of the symposium acts held online in May 2020 with the Paris Global Center of Columbia University and Columbia Global Centers, attempts to testify to the ongoing pandemic emergency and difficult challenges while evaluating whether the ethical principles in the official recommendations were able to meet the lived reality. Looking at accountability and consistency in regard to the context of exercise, it seemed equally important to examine, through an international exchange, whether the contextuality of Coronavirus across countries and cultures affected the ethical decision making processes. We hope that our discussion can serve as a resource for advanced care planning, helping medical providers and other specialists to consider the shared important aspects of medical ethics in times of great uncertainty.