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Thoracic air leak syndromes (TALS) are very rare among the noninfectious pulmonary complications (PCs). They can either be idiopathic or have several risk factors such as allogeneic hematopoietic stem cell transplantation (allo-HSCT), graft versus host disease and rarely pulmonary aspergillosis. We present a 14-year-old girl with hypoplastic myelodysplastic syndrome who developed graft versus host disease on day 60, TALS on day 150, bronchiolitis obliterans syndrome on day 300, pulmonary aspergillosis on day 400 and COVID-19 pneumonia on day 575 after allo-HSCT. This is the first report of a child who developed these subsequent PCs after allo-HSCT. Therefore, the manifestations of these unfamiliar PCs like TALS and COVID-19 pneumonia, and concomitant pulmonary aspergillosis with management options are discussed., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: In addition to the lungs, the placenta and the endothelium can be affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are markers of endothelial dysfunction and could potentially serve as predictors of severe coronavirus disease 2019 (COVID-19). We aimed to investigate the association of serum concentrations of sFlt-1 and PlGF with the severity of COVID-19 in pregnancy., Methods: This was a prospective cohort study carried out in a tertiary care hospital in Mexico City, Mexico. Symptomatic pregnant women with a positive reverse-transcription quantitative polymerase chain reaction test for SARS-CoV-2 infection who fulfilled the criteria for hospitalization were included. The primary outcome was severe pneumonia due to COVID-19. Secondary outcomes were intensive care unit (ICU) admission, viral sepsis and maternal death. sFlt-1 levels were expressed as multiples of the median (MoM). The association between sFlt-1 and each adverse outcome was explored by logistic regression analysis, adjusted for gestational age for outcomes occurring in more than five patients, and the predictive performance was assessed by receiver-operating-characteristics-curve analysis., Results: Among 113 pregnant women with COVID-19, higher sFlt-1 MoM was associated with an increased probability of severe pneumonia (adjusted odds ratio (aOR), 1.817 (95% CI, 1.365-2.418)), ICU admission (aOR, 2.195 (95% CI, 1.582-3.047)), viral sepsis (aOR, 2.318 (95% CI, 1.407-3.820)) and maternal death (unadjusted OR, 5.504 (95% CI, 1.079-28.076)). At a 10% false-positive rate, sFlt-1 MoM had detection rates of 45.2%, 66.7%, 83.3% and 100% for severe COVID-19 pneumonia, ICU admission, viral sepsis and maternal death, respectively. PlGF values were similar between women with severe and those with non-severe COVID-19 pneumonia., Conclusion: sFlt-1 MoM is higher in pregnant women with severe COVID-19 and has the capability to predict serious adverse pregnancy events, such as severe pneumonia, ICU admission, viral sepsis and maternal death. © 2021 International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)

Critically ill patients, such as those in intensive care units (ICUs), can develop herpes simplex virus (HSV) pneumonitis. Given the high prevalence of acute respiratory distress syndrome (ARDS) and multiple pre-existing conditions among ICU patients with HSV pneumonitis, factors predicting mortality in this patient population require further investigation. In this retrospective study, the bronchoalveolar lavage or sputum samples of ICU patients were cultured or subjected to a polymerase chain reaction for HSV detection. Univariable and multivariable Cox regressions were conducted for mortality outcomes. The length of hospital stay was plotted against mortality on Kaplan-Meier curves. Among the 119 patients with HSV pneumonitis (age: 65.8 ± 14.9 years), the mortality rate was 61.34% (73 deaths). The mortality rate was significantly lower among patients with diabetes mellitus (odds ratio [OR] 0.12, 95% confidence interval [CI]: 0.02-0.49, p = 0.0009) and significantly higher among patients with ARDS (OR: 4.18, 95% CI: 1.05-17.97, p < 0.0001) or high (≥30) Acute Physiology and Chronic Health Evaluation II scores (OR: 1.08, 95% CI: 1.00-1.18, p = 0.02). Not having diabetes mellitus (DM), developing ARDS, and having a high Acute Physiology and Chronic Health Evaluation II (APACHE II) score were independent predictors of mortality among ICU patients with HSV pneumonitis.

Respirovirus such as influenza virus infection induces pulmonary anti-viral immune response, orchestration of innate and adaptive immunity restrain viral infection, otherwise causes severe diseases such as pneumonia. Chemokines regulate leukocyte recruitment to the inflammation site. One chemokine CXCL5, plays a scavenging role to regulate pulmonary host defense against bacterial infection, but its role in pulmonary influenza virus infection is underdetermined. Here, using an influenza (H1N1) infected CXCL5 -/- mouse model, we found that CXCL5 not only responds to neutrophil infiltration into infected lungs at the innate immunity stage, but also affects B lymphocyte accumulation in the lungs by regulating the expression of the B cell chemokine CXCL13. Inhibition of CXCL5-CXCR2 axis markedly induces CXCL13 expression in CD64 + CD44 hi CD274 hi macrophages/monocytes in infected lungs, and in vitro administration of CXCL5 to CD64 + alveolar macrophages suppresses CXCL13 expression via the CXCL5-CXCR2 axis upon influenza challenge. CXCL5 deficiency leads to increased B lymphocyte accumulation in infected lungs, contributing to an enhanced B cell immune response and facilitating induced bronchus-associated lymphoid tissue formation in the infected lungs during the late infection and recovery stages. These data highlight multiple regulatory roles of CXCL5 in leukocyte chemotaxis during pulmonary influenza infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Guo, Li, Yang, Li, Zheng, Yang, Chen, Zhao, Mei, Shi, Worthen and Liu.)

The coronavirus disease 2019 (COVID-19) is presently the most pressing public health concern worldwide. Cytokine storm is an important factor leading to death of patients with COVID-19. This study aims to characterize serum cytokines of patients with severe or critical COVID-19. Clinical records were obtained from 149 patients who were tested at the Sino-French New City Branch of Tongji Hospital from 30 January to 30 March 2020. Data regarding the clinical features of the patients was collected and analyzed. Among the 149, 45 (30.2%) of them had severe conditions and 104 (69.8%) of that presented critical symptoms. In the meantime, 80 (53.7%) of that 149 died during hospitalization. Of all, male patients accounted for 94 (69.1%). Compared with patients in severe COVID-19, those who in critical COVID-19 had significantly higher levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-8, and IL-10. Moreover, the passed-away patients had considerably higher levels of TNF-α, IL-6, IL-8, and IL-10 than those survived from it. Regression analysis revealed that serum TNF-α level was an independent risk factor for the death of patient with severe conditions. Among the proinflammatory cytokines (IL-1β, TNF-α, IL-8, and IL-6) analyzed herein, TNF-α was seen as a risk factor for the death of patients with severe or critical COVID-19. This study suggests that anti-TNF-α treatment allows patients with severe or critical COVID-19 pneumonia to recover.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted through respiratory droplets, aerosols and close contact. Cross infections occur because viruses spread rapidly among humans. Nineteen percent (19%) of the infected patients developed severe pneumonia and acute respiratory distress syndrome (ARDS). Hypoxemia usually occurs and patients may require oxygen therapy or mechanical ventilation (MV) support. In this article, recently published clinical experience and observational studies were reviewed. Corresponding respiratory therapy regarding different stages of infection is proposed. Infection control principles and respiratory strategies including oxygen therapy, non-invasive respiratory support (NIRS), intubation evaluation, equipment preparation, ventilator settings, special maneuvers comprise of the prone position (PP), recruitment maneuver (RM), extracorporeal membrane oxygenation (ECMO), weaning and extubation are summarized. Respiratory equipment and device disinfection recommendations are worked up. We expect this review article could be used as a reference by healthcare workers in patient care while minimizing the risk of environmental contamination., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Respiratory tract infections constitute a significant public health problem, with a therapeutic arsenal that remains relatively limited and that is threatened by the emergence of antiviral and/or antibiotic resistance. Viral-bacterial co-infections are very often associated with the severity of these respiratory infections and have been explored mainly in the context of bacterial superinfections following primary influenza infection. This review summarizes our current knowledge of the mechanisms underlying these co-infections between respiratory viruses (influenza viruses, RSV, and SARS-CoV-2) and bacteria, at both the physiological and immunological levels. This review also explores the importance of the microbiome and the pathological context in the evolution of these respiratory tract co-infections and presents the different in vitro and in vivo experimental models available. A better understanding of the complex functional interactions between viruses/bacteria and host cells will allow the development of new, specific, and more effective diagnostic and therapeutic approaches.

Background: The coronavirus disease (COVID-19) pandemic has caused ongoing challenges in health services worldwide. Despite the growing body of literature on COVID-19, reports on perinatal care in COVID-19 cases are limited., Case Presentation: We describe a case of severe acute respiratory distress syndrome (ARDS) in a 36-year-old G5/P2 pregnant woman with morbid obesity, confirmed severe acute respiratory syndrome coronavirus 2 infection, and fulminant respiratory failure. At 28 + 1 gestational weeks, the patient delivered an uninfected newborn. Using ImmunoCAP ISAC® technology, we found no immunoglobulin (Ig) M antibodies, suggesting that no mother-to-child viral transmission occurred during pregnancy or delivery. The maternal respiratory state improved rapidly after delivery; both maternal and neonatal outcomes were encouraging given the early gestational age and fulminant course of respiratory failure in our patient., Conclusions: The management of ARDS in pregnant women with COVID-19 is complex and requires an individualized, multidisciplinary approach, while considering maternal and fetal outcomes., (© 2021. The Author(s).)

Background: The aim of the study is to estimate the prevalence of atelectasis assessed with computer tomography (CT) in SARS-CoV-2 pneumonia and the relationship between the amount of atelectasis with oxygenation impairment, Intensive Care Unit admission rate and the length of in-hospital stay., Patients and Methods: Two-hundred thirty-seven patients admitted to the hospital with SARS-CoV-2 pneumonia diagnosed by clinical, radiology and molecular tests in the nasopharyngeal swab who underwent a chest computed tomography because of a respiratory worsening from Apr 1 to Apr 30, 2020 were included in the study. Patients were divided into three groups depending on the presence and amount of atelectasis at the computed tomography: no atelectasis, small atelectasis (< 5% of the estimated lung volume) or large atelectasis (> 5% of the estimated lung volume). In all patients, clinical severity, oxygen-therapy need, Intensive Care Unit admission rate, the length of in-hospital stay and in-hospital mortality data were collected., Results: Thirty patients (19%) showed small atelectasis while eight patients (5%) showed large atelectasis. One hundred and seventeen patients (76%) did not show atelectasis. Patients with large atelectasis compared to patients with small atelectasis had lower SatO 2 /FiO 2 (182 vs 411 respectively, p = 0.01), needed more days of oxygen therapy (20 vs 5 days respectively, p = 0,02), more frequently Intensive Care Unit admission (75% vs 7% respectively, p < 0.01) and a longer period of hospitalization (40 vs 14 days respectively p < 0.01)., Conclusion: In patients with SARS-CoV-2 pneumonia, atelectasis might appear in up to 24% of patients and the presence of larger amount of atelectasis is associated with worse oxygenation and clinical outcome., (© 2021. The Author(s).)

Previous studies have suggested that COVID-19 pneumonia is associated with an increased risk of venous thromboembolism (VTE). This study aimed to investigate the incidence of VTE among mechanically ventilated adults with COVID-19 pneumonia, compared to patients with respiratory failure related to other causes. Prospective study that enrolled critically ill adults with suspected COVID-19 pneumonia between June 2, 2020 and August 11, 2020. Critically ill adults with suspected COVID-19 pneumonia who required mechanical ventilation within 24 h after hospital admission were followed until death or hospital discharge. Sequential ultrasonography screening of the lower extremities and catheter insertion sites, as well as testing for plasma biochemical markers, were performed at the intensive care unit admission, day 3, day 7, and day 14. The primary outcome was a composite of deep venous thrombosis, pulmonary embolism, and thrombosis at the central catheter insertion sites. We enrolled 70 patients, including 57 patients with COVID-19 and 13 patients without COVID-19, and all patients completed follow-up. The incidence of the primary outcome was higher among patients with COVID-19 than among patients with respiratory failure related to other etiologies (36.8% vs. 0%, p = 0.023). Multivariate regression analysis revealed that VTE was independently associated with a COVID-19 diagnosis (odds ratio: 6.28, 95% confidence interval: 1.19-68.07) and D-dimer concentration (1-ng/mL increase, odds ratio: 1.15, 95% confidence interval: 1.05-1.30). The incidence of VTE was higher among critically ill mechanically ventilated patients, relative to among patients with respiratory failure related to other causes., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Purpose: Severe pneumonia and acute respiratory distress syndrome (ARDS) have been described in patients with severe coronavirus disease 2019 (COVID-19). Recently, early clinical data reported the feasibility of low doses of radiation therapy (RT) in the treatment of ARDS in patients with severe COVID-19. However, the involved mechanisms remained unknown., Methods and Materials: Here, we used airways-instilled lipopolysaccharide (LPS) and influenza virus (H1N1) as murine models of pneumonia, and toll-like receptor (TLR)-3 stimulation in human lung macrophages., Results: Low doses of RT (0.5-1 Gray) decreased LPS-induced pneumonia, and increased the percentage of nerve- and airway-associated macrophages producing interleukin (IL) 10. During H1N1 viral infection, we observed decreased lung tissue damage and immune cell infiltration in irradiated animals. Low doses of RT increased IL-10 production by infiltrating immune cells into the lung. Irradiation of TLR-3 ligand-stimulated human lung macrophages ex vivo increased IL-10 secretion and decreased interferon γ production in the culture supernatant. The percentage of human lung macrophages producing IL-6 was also decreased., Conclusions: Our data highlight a mechanism by which low doses of RT regulate lung inflammation and skew lung macrophages toward an anti-inflammatory profile. These data provide a preclinical mechanistic support to clinical trials evaluating low doses of RT, such as COVID-19-induced ARDS., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Abstract: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, keeps spreading globally. Evidence suggests that a subgroup of patients with severe symptomatology might have cytokine storms, which increases mortality. The use of interleukin-6 (IL-6) inhibitors may help in controlling the pathological immune response to the virus. Tocilizumab, a monoclonal antibody against IL-6, stands as an optional treatment for COVID-19 patients presenting this inflammatory hyper-response.We conducted a retrospective, observational, cohort study including 50 patients affected by COVID-19 with severe pneumonia and poor prognosis criteria, who have also undergone standard treatment; 36 of these patients additionally received tocilizumab in an early stage. The need for intensive care unit (ICU) admission, mortality, recovery of respiratory function, and improvement of biochemical and hematological parameters were compared between cohorts.Most patients were men, non-smokers and the most frequently reported comorbidities were hypertension and diabetes. Recurrent symptoms were fever, cough, and dyspnoea. 54.8% of patients from the tocilizumab group needed intubation, while in the control group 85.7% needed it. Treatment with tocilizumab significatively increased IL-6 levels, (554.45; CI 95% 186.69, 1032.93; P < .05) while C-reactive protein mean levels were reduced (-108.19; CI 95% -140.15, -75.33; P < .05), but no significant difference was found between cohorts. In comparison with the controls, tocilizumab reduced mortality (25.0% vs 42.9%, P = .021) and the number of ICU admissions (63.9% vs 100.0%, P = .021). 44.1% of patients treated with tocilizumab showed favorable radiological evolution, when compared with 15.4% of patients from the control group.Tocilizumab may improve clinical symptoms and mitigate deterioration observed in severe COVID-19 patients, and could be considered as an effective therapeutic option in subjects experiencing a significant inflammatory response to the disease., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

The coronavirus disease 2019 (COVID-19) pandemic is among the most important public health crises of our generation. Despite the promise of prevention offered by effective vaccines, patients with severe COVID-19 will continue to populate hospitals and intensive care units for the foreseeable future. The most common clinical presentation of severe COVID-19 is hypoxemia and respiratory failure, typical of the acute respiratory distress syndrome (ARDS). Whether the clinical features and pathobiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia differ from those of pneumonia secondary to other pathogens is unclear. This uncertainty has created variability in the application of historically proven therapies for ARDS to patients with COVID-19. We review the available literature and find many similarities between patients with ARDS from pneumonia attributable to SARS-CoV-2 versus other respiratory pathogens. A notable exception is the long duration of illness among patients with COVID-19, which could result from its unique pathobiology. Available data support the use of care pathways and therapies proven effective for patients with ARDS, while pointing to unique features that might be therapeutically targeted for patients with severe SARS-CoV-2 pneumonia.

Purpose: Older adults are more likely to be vitamin D deficient. The aim of the study was to determine whether these patients have worse outcomes with COVID-19., Methods: We conducted a prospective cohort study between 1 March and 30 April 2020 to assess the importance of vitamin D deficiency in older patients with COVID-19. The cohort consisted of patients aged ≥65 years presenting with symptoms consistent with COVID-19 (n=105). All patients were tested for serum 25-hydroxyvitamin D (25(OH)D) levels during acute illness. Diagnosis of COVID-19 was confirmed via viral reverse transcriptase PCR swab or supporting radiological evidence. COVID-19-positive arm (n=70) was sub-divided into vitamin D-deficient (≤30 nmol/L) (n=39) and -replete groups (n=35). Subgroups were assessed for disease severity using biochemical, radiological and clinical markers. Primary outcome was in-hospital mortality. Secondary outcomes were laboratory features of cytokine storm, thoracic imaging changes and requirement of non-invasive ventilation (NIV)., Results: COVID-19-positive arm demonstrated lower median serum 25(OH)D level of 27 nmol/L (IQR=20-47 nmol/L) compared with COVID-19-negative arm, with median level of 52 nmol/L (IQR=31.5-71.5 nmol/L) (p value=0.0008). Among patients with vitamin D deficiency, there was higher peak D-dimer level (1914.00 μgFEU/L vs 1268.00 μgFEU/L) (p=0.034) and higher incidence of NIV support and high dependency unit admission (30.77% vs 9.68%) (p=0.042). No increased mortality was observed between groups., Conclusion: Older adults with vitamin D deficiency and COVID-19 may demonstrate worse morbidity outcomes. Vitamin D status may be a useful prognosticator., Competing Interests: Competing interests: All authors understand the policy of declaration of interests. CGM is a former member of the Fellowship of Postgraduate Medicine (FPM) council and is currently an FPM Fellow. VB, TH, NP, SS, PK, KVdA, AKJM all declare that they have no competing interests., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

In this era, the novel Coronavirus, referred to as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a life-threatening virus with a high mortality rate (4.2%) and with no absolute treatment as of yet, may ultimately result in acute respiratory distress syndrome (ARDS). ARDS is one of the fatal complications, highlighted by pulmonary infiltration and severe hypoxemia. This condition can be developed from primary lung inflammation caused by various viruses, particularly influenza viruses, some of the most common human pathogens. Due to this issue, many studies explored several approaches for ARDS treatment. Lung transplantation has been claimed as an efficient cure for severe ARDS and Influenza, which can also be offered for treating critical lung complications of SARS-CoV-2. Thereupon, to the best of our knowledge for the first time, we aimed to review all available data about capability of lung transplantation for the treatment of critically ill patients with ARDS, Influenza, and SARS-CoV-2.

Rhinovirus (RV) is commonly detected in asymptomatic children; hence, its pathogenicity during childhood pneumonia remains controversial. We evaluated RV epidemiology in HIV-uninfected children hospitalized with clinical pneumonia and among community controls. PERCH was a case-control study that enrolled children (1-59 months) hospitalized with severe and very severe pneumonia per World Health Organization clinical criteria and age-frequency-matched community controls in seven countries. Nasopharyngeal/oropharyngeal swabs were collected for all participants, combined, and tested for RV and 18 other respiratory viruses using the Fast Track multiplex real-time PCR assay. RV detection was more common among cases (24%) than controls (21%) (aOR = 1.5, 95%CI:1.3-1.6). This association was driven by the children aged 12-59 months, where 28% of cases vs. 18% of controls were RV-positive (aOR = 2.1, 95%CI:1.8-2.5). Wheezing was 1.8-fold (aOR 95%CI:1.4-2.2) more prevalent among pneumonia cases who were RV-positive vs. RV-negative. Of the RV-positive cases, 13% had a higher probability (>75%) that RV was the cause of their pneumonia based on the PERCH integrated etiology analysis; 99% of these cases occurred in children over 12 months in Bangladesh. RV was commonly identified in both cases and controls and was significantly associated with severe pneumonia status among children over 12 months of age, particularly those in Bangladesh. RV-positive pneumonia was associated with wheezing.

A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically, Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections., Competing Interests: Declaration of interests T.A.C., H.H., M.B., P.S.L., P.C., and R.D.P. are inventors on provisional patent application US 63/038,186 titled “Methods and Compositions for treating coronavirus infectious disease.” H.H. and T.A.C. are co-founders of and hold equity in Alcea Therapeutics., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Patients with community-acquired pneumonia display enhanced levels of lipopolysaccharides (LPS) compared with controls, suggesting that low-grade endotoxemia may be implicated in vascular disturbances. It is unknown whether this occurs in patients with coronavirus 2019 (COVID-19) and its impact on thrombotic complications., Methods: We measured serum levels of zonulin, a marker of gut permeability, LPS, and D-dimer in 81 patients with COVID-19 and 81 healthy subjects; the occurrence of thrombotic events in COVID-19 during the intrahospital stay was registered., Results: Serum LPS and zonulin were higher in patients with COVID-19 than in control subjects and, in COVID-19, significantly correlated (R = 0.513; P < 0.001). Among the 81 patients with COVID-19, 11 (14%) experienced thrombotic events in the arterial (n = 5) and venous circulation (n = 6) during a median follow-up of 18 days (interquartile range 11-27 days). A logistic regression analysis showed that LPS (P = 0.024) and D-dimer (P = 0.041) independently predicted thrombotic events., Discussion: The study reports that low-grade endotoxemia is detectable in patients with COVID-19 and is associated with thrombotic events. The coexistence of low-grade endotoxemia with enhanced levels of zonulin may suggest enhanced gut permeability as an underlying mechanism., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Abstract: Herpes simplex virus (HSV) is a disease usually characterized by lesions within the epidermis or mucosa of children and adults. However, this infection can also cause complications to many systems of the body, including the peripheral and central nervous system, respiratory system, and hepatobiliary system. In this case, we present a 43-year-old man with a history of substance abuse, who presented with fever, cough, and headache, and within days, progressed into fulminant hepatitis and hypoxic failure. Bacterial and fungal cultures were negative, as well as the workup for human immunodeficiency virus. However, the presence of HSV was detected in a bronchial lavage culture after the patients had expired. This result, along with the findings at autopsy, including viral cytopathic effect in the lung and liver, which were confirmed with immunohistochemical stains for HSV, strongly suggest that the cause of death is from disseminated herpes virus infection with hepatitis and viral pneumonitis. This disseminated infection occurred in an immunocompetent host without any evidence of mucocutaneous lesions., Competing Interests: The authors report no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: In-hospital mortality rates from COVID-19 are high but appear to be decreasing for selected locations in the United States. It is not known whether this is because of changes in the characteristics of patients being admitted., Objective: To describe changing in-hospital mortality rates over time after accounting for individual patient characteristics., Design, Setting, and Participants: This was a retrospective cohort study of 20 736 adults with a diagnosis of COVID-19 who were included in the US American Heart Association COVID-19 Cardiovascular Disease Registry and admitted to 107 acute care hospitals in 31 states from March through November 2020. A multiple mixed-effects logistic regression was then used to estimate the odds of in-hospital death adjusted for patient age, sex, body mass index, and medical history as well as vital signs, use of supplemental oxygen, presence of pulmonary infiltrates at admission, and hospital site., Main Outcomes and Measures: In-hospital death adjusted for exposures for 4 periods in 2020., Results: The registry included 20 736 patients hospitalized with COVID-19 from March through November 2020 (9524 women [45.9%]; mean [SD] age, 61.2 [17.9] years); 3271 patients (15.8%) died in the hospital. Mortality rates were 19.1% in March and April, 11.9% in May and June, 11.0% in July and August, and 10.8% in September through November. Compared with March and April, the adjusted odds ratios for in-hospital death were significantly lower in May and June (odds ratio, 0.66; 95% CI, 0.58-0.76; P < .001), July and August (odds ratio, 0.58; 95% CI, 0.49-0.69; P < .001), and September through November (odds ratio, 0.59; 95% CI, 0.47-0.73)., Conclusions and Relevance: In this cohort study, high rates of in-hospital COVID-19 mortality among registry patients in March and April 2020 decreased by more than one-third by June and remained near that rate through November. This difference in mortality rates between the months of March and April and later months persisted even after adjusting for age, sex, medical history, and COVID-19 disease severity and did not appear to be associated with changes in the characteristics of patients being admitted.

Background: Published reports on tocilizumab in COVID-19 pneumonitis show conflicting results due to weak designs or heterogeneity in critical methodological issues., Methods: This open-label trial, structured according to Simon's optimal design, aims to identify factors predicting which patients could benefit from anti-IL6 strategies and to enhance the design of unequivocal and reliable future randomized trials. A total of 46 patients with COVID-19 pneumonia needing of oxygen therapy to maintain SO2 > 93% and with recent worsening of lung function received a single infusion of tocilizumab. Clinical and biological markers were measured to test their predictive values. Primary end point was early and sustained clinical response., Results: Twenty-one patients fulfilled pre-defined response criteria. Lower levels of IL-6 at 24 h after tocilizumab infusion (P = 0.049) and higher baseline values of PaO2/FiO2 (P = 0.008) predicted a favourable response., Conclusions: Objective clinical response rate overcame the pre-defined threshold of 30%. Efficacy of tocilizumab to improve respiratory function in patients selected according to our inclusion criteria warrants investigations in randomized trials., (© 2020 The Association for the Publication of the Journal of Internal Medicine.)

Background: Venous thromboembolic events have been one of the main causes of mortality among hospitalized patients with coronavirus disease 2019 (COVID-19) pneumonia. The aim of our study was to describe the prevalence of deep vein thrombosis (DVT) in noncritically ill patients with COVID-19 pneumonia and correlate such observations with the thromboprophylaxis received., Methods: We performed a prospective cohort study of 67 patients admitted to the hospital for COVID-19 pneumonia. The diagnosis was confirmed using polymerase chain reaction testing of nasopharyngeal specimens. The deep veins were examined using compression duplex ultrasonography with the transducer on B-mode. The patients were separated into two groups for statistical analysis: those receiving low-molecular-weight heparin prophylaxis and those receiving intermediate or complete anticoagulation treatment. Risk analysis and logistic regression were performed., Results: Of the 67 patients, 57 were included in the present study after applying the inclusion and exclusion criteria; 49.1% were women, and the patient mean age was 71.3 years. All 57 patients had undergone compression duplex ultrasonography. Of these 57 patients, 6 were diagnosed with DVT, for an in-hospital rate of DVT in patients with COVID-19 pneumonia of 10.5%. All the patients who had presented with DVT had been receiving low-molecular-weight heparin prophylaxis. The patients receiving prophylactic anticoagulation treatment had a greater risk of DVT (16.21%; 95% confidence interval, 0.04-0.28; P = .056) compared with those receiving intermediate or complete anticoagulation treatment. We also found a protective factor for DVT in the intermediate or complete anticoagulation treatment group (odds ratio, 0.19; 95% confidence interval, 0.08-0.46; P < .05)., Conclusions: Noncritically ill, hospitalized patients with COVID-19 pneumonia have a high risk of DVT despite receipt of correct, standard thromboprophylaxis., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, which has caused extensive mortality and morbidity and wreaked havoc on socioeconomic structures. The urgent need to better understand SARS-CoV-2 biology and enable continued development of effective countermeasures is aided by the production of laboratory tools that facilitate SARS-CoV-2 research. We previously created a directly accessible SARS-CoV-2 toolkit containing user-friendly reverse genetic (RG) infectious clones of SARS-CoV-2. Here, using K18-human ACE2 (hACE2) mice, we confirmed the validity of RG-rescued SARS-CoV-2 viruses to reproduce the infection profile, clinical disease, and pathogenesis already established in mice infected with natural SARS-CoV-2 isolates, often patient derived. RG-rescued SARS-CoV-2-infected K18-hACE2 mice developed substantial clinical disease and weight loss by day 6 postinfection. RG-rescued SARS-CoV-2 was recovered from the lungs and brains of infected K18-hACE2 mice, and infection resulted in viral pneumonia with considerable changes in lung pathology, as seen previously with natural SARS-CoV-2 infection. In mice infected with RG-rescued SARS-CoV-2-mCherry, mCherry was detected in areas of lung consolidation and colocalized with clinically relevant SARS-CoV-2-assocated immunopathology. RG-rescued SARS-CoV-2 viruses successfully recapitulated many of the features of severe COVID-19 associated with the K18-hACE2 model of SARS-CoV-2 infection. With utility in vivo , the RG-rescued SARS-CoV-2 viruses will be valuable resources to advance numerous areas of SARS-CoV-2 basic research and COVID-19 vaccine development. IMPORTANCE To develop COVID-19 countermeasures, powerful research tools are essential. We produced a SARS-COV-2 reverse genetic (RG) infectious clone toolkit that will benefit a variety of investigations. In this study, we further prove the toolkit's value by demonstrating the in vivo utility of RG-rescued SARS-CoV-2 isolates. RG-rescued SARS-CoV-2 isolates reproduce disease signs and pathology characteristic of the K18-hACE2 mouse model of severe COVID-19 in infected mice. Having been validated as a model of severe COVID-19 previously using only natural SARS-CoV-2 isolated from patients, this is the first investigation of RG-rescued SARS-CoV-2 viruses in K18-hACE2 mice. The RG-rescued SARS-CoV-2 viruses will facilitate basic understanding of SARS-CoV-2 and the preclinical development of COVID-19 therapeutics., (Copyright © 2021 Liu et al.)

Background: To estimate the prevalence of symptoms and signs related to a COVID-19 case series confirmed by polymerase chain reaction (PCR) for SARS-CoV-2. Risk factors and the associated use of health services will also be analysed., Methods: Observational, descriptive, retrospective case series study. The study was performed at two Primary Care Health Centres located in Madrid, Spain. The subjects studied were all PCR SARS-CoV-2 confirmed cases older than 18 years, diagnosed from the beginning of the community transmission (March 13) until April 15, 2020. We collected sociodemographic, clinical, health service utilization and clinical course variables during the following months. All data was gathered by their own attending physician, and electronic medical records were reviewed individually., Statistical Analysis: A descriptive analysis was carried out and a Poisson regression model was adjusted to study associated factors to Health Services use., Results: Out of the 499 patients studied from two health centres, 55.1% were women and mean age was 58.2 (17.3). 25.1% were healthcare professionals. The most frequent symptoms recorded related to COVID-19 were cough (77.9%; CI 95% 46.5-93.4), fever (77.7%; CI95% 46.5-93.4) and dyspnoea (54.1%, CI95% 46.6-61.4). 60.7% were admitted to hospital. 64.5% first established contact with their primary care provider before going to the hospital, with a mean number of 11.4 Healthcare Providers Encounters with primary care during all the follow-up period. The number of visit-encounters with primary care was associated with being male [IRR 1.072 (1.013, 1.134)], disease severity {from mild respiratory infection [IRR 1.404 (1.095, 1.801)], up to bilateral pneumonia [IRR 1.852 (1.437,2.386)]}, and the need of a work leave [IRR 1.326 (1.244, 1.413]., Conclusion: Symptoms and risk factors in our case series are similar to those in other studies. There was a high number of patients with atypical unilateral or bilateral pneumonia. Care for COVID has required a high use of healthcare resources such as clinical encounters and work leaves.

Background: COVID-19 is a new pneumonia. It has been hypothesized that tobacco smoking history may increase severity of this disease in the patients once infected by the underlying coronavirus SARS-CoV-2 because smoking and COVID-19 both cause lung damage. However, this hypothesis has not been tested., Objective: Current study was designed to focus on smoking history in patients with COVID-19 and test this hypothesis that tobacco smoking history increases risk for severe COVID-19 by damaging the lungs., Methods and Results: This was a single-site, retrospective case series study of clinical associations, between epidemiological findings and clinical manifestations, radiographical or laboratory results. In our well-characterized cohort of 954 patients including 56 with tobacco smoking history, smoking history increased the risk for severe COVID-19 with an odds ratio (OR) of 5.5 (95% CI: 3.1-9.9; P = 7.3 × 10 -8 ). Meta-analysis of ten cohorts for 2891 patients together obtained an OR of 2.5 (95% CI: 1.9-3.3; P < 0.00001). Semi-quantitative analysis of lung images for each of five lobes revealed a significant difference in neither lung damage at first examination nor dynamics of the lung damage at different time-points of examinations between the smoking and nonsmoking groups. No significant differences were found either in laboratory results including D-dimer and C-reactive protein levels except different covariances for density of the immune cells lymphocyte (P = 3.8 × 10 -64 ) and neutrophil (P = 3.9 × 10 -46 )., Conclusion: Tobacco smoking history increases the risk for great severity of COVID-19 but this risk is achieved unlikely by affecting the lungs., (© 2020 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Objective: We aimed to investigate whether the stratification of outpatients with coronavirus disease 2019 (COVID-19) pneumonia by body mass index (BMI) can help predict hospitalization and other severe outcomes., Patients and Methods: We prospectively collected consecutive cases of community-managed COVID-19 pneumonia from March 1 to April 20, 2020, in the province of Bergamo and evaluated the association of overweight (25 kg/m 2 ≤ BMI <30 kg/m 2 ) and obesity (≥30 kg/m 2 ) with time to hospitalization (primary end point), low-flow domiciliary oxygen need, noninvasive mechanical ventilation, intubation, and death due to COVID-19 (secondary end points) in this cohort. We analyzed the primary end point using multivariable Cox models., Results: Of 338 patients included, 133 (39.4%) were overweight and 77 (22.8%) were obese. Age at diagnosis was younger in obese patients compared with those overweight or with normal weight (P<.001), whereas diabetes, dyslipidemia, and heart diseases were differently distributed among BMI categories. Azithromycin, hydroxychloroquine, and prednisolone use were similar between BMI categories (P>.05). Overall, 105 (31.1%) patients were hospitalized, and time to hospitalization was significantly shorter for obese vs over- or normal-weight patients (P<.001). In the final multivariable analysis, obese patients were more likely to require hospitalization than nonobese patients (hazard ratio, 5.83; 95% CI, 3.91 to 8.71). Results were similar in multiple sensitivity analyses. Low-flow domiciliary oxygen need, hospitalization with noninvasive mechanical ventilation, intubation, and death were significantly associated with obesity (P<.001)., Conclusion: In patients with community-managed COVID-19 pneumonia, obesity is associated with a higher hospitalization risk and overall worse outcomes than for nonobese patients., (Copyright © 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Regulatory T (Treg) cells orchestrate resolution and repair of acute lung inflammation and injury after viral pneumonia. Compared with younger patients, older individuals experience impaired recovery and worse clinical outcomes after severe viral infections, including influenza and SARS coronavirus 2 (SARS-CoV-2). Whether age is a key determinant of Treg cell prorepair function after lung injury remains unknown. Here, we showed that aging results in a cell-autonomous impairment of reparative Treg cell function after experimental influenza pneumonia. Transcriptional and DNA methylation profiling of sorted Treg cells provided insight into the mechanisms underlying their age-related dysfunction, with Treg cells from aged mice demonstrating both loss of reparative programs and gain of maladaptive programs. Strategies to restore youthful Treg cell functional programs could be leveraged as therapies to improve outcomes among older individuals with severe viral pneumonia.

Purpose: To analyze the chest CT imaging findings of patients with initial negative RT-PCR and to compare with the CT findings of the same sets of patients when the RT-PCR turned positive for SARS-CoV-2 a few days later. Materials and methods: A total of 32 patients (8 males and 24 females; 52.9±7years old) with COVID-19 from 27 January and 26 February 2020 were enrolled in this retrospective study. Clinical and radiological characteristics were analyzed. Results: The median period (25%, 75%) between initial symptoms and the first chest CT, the initial negative RT-PCR, the second CT and the positive RT-PCR were 7(4.25,11.75), 7(5,10.75), 15(11,23) and 14(10,22) days, respectively. Ground glass opacities was the most frequent CT findings at both the first and second CTs. Consolidation was more frequently observed on lower lobes, and more frequently detected during the second CT (64.0%) with positive RT-PCR than the first CT with initial negative RT-PCR (53.1%). The median of total lung severity score and the number of lobes affected had significant difference between twice chest CT (P=0.007 and P=0.011, respectively). Conclusion: In the first week of disease course, CT was sensitive to the COVID-19 with initial negative RT-PCR. Throat swab test turned positive while chest CT mostly demonstrated progression., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Competing Interests: Intérêts concurrents: William Murk est consultant pour Aetion, Inc., où il détient également des actions. Monica Gierada, Andrew Weckstein et Jeremy Rassen sont des employés d’Aetion, Inc., où ils détiennent aussi des options d’achat d’actions ou des actions. Reyna Klesh est une employée de HealthVerity, Inc., qui a fourni les données pour cette étude. Aucun autre intérêt concurrent déclaré.

Background: Cytokine storm triggered by Severe Coronavirus Disease 2019 (COVID-19) is associated with high mortality. With high Interleukin -6 (IL-6) levels reported in COVID-19 related deaths in China, IL-6 is considered to be the key player in COVID-19 cytokine storm. Tocilizumab, a monoclonal antibody against IL-6 receptor, is used on compassionate grounds for treatment of COVID-19 cytokine storm. The aim of this study was to assess effect of tocilizumab on mortality due to COVID-19 cytokine storm., Method: This retrospective, observational study included patients of severe COVID-19 pneumonia with persistent hypoxia (defined as saturation 94% or less on supplemental Oxygen of 15 L per minute through non-rebreathing mask or PaO2/FiO2 ratio of less than 200) who were admitted to a tertiary care center in Mumbai, India, between 31st March to 5th July 2020. In addition to standard care, single Inj. Tocilizumab 400 mg was given intravenously to 151 consecutive COVID-19 patients with persistent hypoxia, from 13th May to 5th July 2020. These 151 patients were retrospectively analysed and compared with historic controls, ie consecutive COVID-19 patients with persistent hypoxia, defined as stated above (N = 118, from our first COVID-19 admission on 31st March to 12th May 2020 i.e., till tocilizumab was available in hospital). Univariate and multivariate Cox regression analysis was performed for identifying predictors of survival. Statistical analysis was performed using IBM SPSS version 26., Results: Out of 269 (151 in tocilizumab group and 118 historic controls) patients studied from 31st March to 5th July 2020, median survival in the tocilizumab group was significantly longer than in the control group; 18 days (95% CI, 11.3 to 24.7) versus 9 days (95% CI, 5.7 to 12.3); log rank p 0.007. On multivariate Cox regression analysis, independent predictors of survival were use of tocilizumab (HR 0.621, 95% CI 0.427-0.903, P 0.013) and higher oxygen saturation., Conclusion: Tocilizumab may improve survival in severe COVID-19 pneumonia with persistent hypoxia. Randomised controlled trials on use of tocilizumab as rescue therapy in patients of severe COVID-19 pneumonia with hypoxia (PaO2/FiO2 less than 200) due to hyperinflammatory state, are warranted.

Background: CT is thought to play a key role in coronavirus disease 2019 (COVID-19) diagnostic workup. The possibility of comparing data across different settings depends on the systematic and reproducible manner in which the scans are analyzed and reported. The COVID-19 Reporting and Data System (CO-RADS) and the corresponding CT severity score (CTSS) introduced by the Radiological Society of the Netherlands (NVvR) attempt to do so. However, this system has not been externally validated., Research Question: We aimed to prospectively validate the CO-RADS as a COVID-19 diagnostic tool at the ED and to evaluate whether the CTSS is associated with prognosis., Study Design and Methods: We conducted a prospective, observational study in two tertiary centers in The Netherlands, between March 19 and May 28, 2020. We consecutively included 741 adult patients at the ED with suspected COVID-19, who received a chest CT and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR (PCR). Diagnostic accuracy measures were calculated for CO-RADS, using PCR as reference. Logistic regression was performed for CTSS in relation to hospital admission, ICU admission, and 30-day mortality., Results: Seven hundred forty-one patients were included. We found an area under the curve (AUC) of 0.91 (CI, 0.89-0.94) for CO-RADS using PCR as reference. The optimal CO-RADS cutoff was 4, with a sensitivity of 89.4% (CI, 84.7-93.0) and specificity of 87.2% (CI, 83.9-89.9). We found a significant association between CTSS and hospital admission, ICU admission, and 30-day mortality; adjusted ORs per point increase in CTSS were 1.19 (CI, 1.09-1.28), 1.23 (1.15-1.32), 1.14 (1.07-1.22), respectively. Intraclass correlation coefficients for CO-RADS and CTSS were 0.94 (0.91-0.96) and 0.82 (0.70-0.90)., Interpretation: Our findings support the use of CO-RADS and CTSS in triage, diagnosis, and management decisions for patients presenting with possible COVID-19 at the ED., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Musculoskeletal symptoms are often unrecognised as a prominent feature of COVID-19 infection. This study hypothesised that viral arthralgia is an uncommon but distinct manifestation of COVID-19 infection. In addition, it aimed to characterise the other musculoskeletal presentations of COVID-19 infection and study their prognostic implications., Methods: Patients hospitalised with COVID-19 infection were divided into two groups: those with and without musculoskeletal symptoms. Those with musculoskeletal symptoms were subdivided according to four patterns of musculoskeletal involvement: myalgia, arthralgia, backache and generalised body ache. Using binary regression logistic analysis, the risk of developing a viral pneumonia in patients with and without musculoskeletal complaints was compared., Results: Of 294 hospitalised patients with COVID-19, 88 (30%) reported musculoskeletal complaints. Among these 88 patients, 37.5% had myalgia, 5.7% arthralgia, 6.8% new-onset backache and 50% generalised body ache. The presence of musculoskeletal complaints was not associated with the risk of developing viral pneumonia (6.8% vs. 9.7%, OR 0.68, 95% CI 0.26-1.76, p = 0.426). COVID-19 arthralgia was often more severe and had variable onset, while generalised body ache and myalgia were milder and coincided with the occurrence of fever or respiratory symptoms., Conclusion: Viral arthralgia is a novel clinical manifestation of COVID-19, and untypical of a viral prodrome or a reactive arthropathy. While musculoskeletal symptoms were not associated with developing a pneumonia, to avoid missing a diagnosis of COVID-19, clinicians should be aware of its variable onset, particularly when respiratory symptoms are absent at the time of presentation., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Interleukin-6 (IL-6)-mediated hyperinflammation may contribute to the mortality of coronavirus disease 2019 (COVID-19). The IL-6 receptor-blocking monoclonal antibody tocilizumab has been repurposed for COVID-19, but prospective trials and dose-finding studies in COVID-19 have not yet fully reported. We conducted a single-arm phase II trial of low-dose tocilizumab in nonintubated hospitalized adult patients with COVID-19, radiographic pulmonary infiltrate, fever, and C-reactive protein (CRP) ≥ 40 mg/L. We hypothesized that doses significantly lower than the emerging standards of 400 mg or 8 mg/kg would resolve clinical and laboratory indicators of hyperinflammation. A dose range from 40 to 200 mg was evaluated, with allowance for one repeat dose at 24 to 48 hours. The primary objective was to assess the relationship of dose to fever resolution and CRP response. Thirty-two patients received low-dose tocilizumab, with the majority experiencing fever resolution (75%) and CRP decline consistent with IL-6 pathway abrogation (86%) in the 24-48 hours following drug administration. There was no evidence of a relationship between dose and fever resolution or CRP decline over the dose range of 40-200 mg. Within the 28-day follow-up, 5 (16%) patients died. For patients who recovered, median time to clinical recovery was 3 days (interquartile range, 2-5). Clinically presumed and/or cultured bacterial superinfections were reported in 5 (16%) patients. Low-dose tocilizumab was associated with rapid improvement in clinical and laboratory measures of hyperinflammation in hospitalized patients with COVID-19. Results of this trial provide rationale for a randomized, controlled trial of low-dose tocilizumab in COVID-19., (© 2020 The Authors. Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

Here, we report a 54-year-old man who underwent double-sleeve left upper lobectomy for lung cancer and his postoperative course was complicated with COVID-19 pneumonia. Five days after his discharge from hospital, he was re-admitted with mild fever and bilateral multiple ground glass opacities on his chest CT. PCR testing confirmed COVID-19 infection and he was treated according to policies established by our nation's health authority. He is still receiving adjuvant chemotherapy and remains well at 3 months after the operation.

Background: Convalescent plasma is frequently administered to patients with Covid-19 and has been reported, largely on the basis of observational data, to improve clinical outcomes. Minimal data are available from adequately powered randomized, controlled trials., Methods: We randomly assigned hospitalized adult patients with severe Covid-19 pneumonia in a 2:1 ratio to receive convalescent plasma or placebo. The primary outcome was the patient's clinical status 30 days after the intervention, as measured on a six-point ordinal scale ranging from total recovery to death., Results: A total of 228 patients were assigned to receive convalescent plasma and 105 to receive placebo. The median time from the onset of symptoms to enrollment in the trial was 8 days (interquartile range, 5 to 10), and hypoxemia was the most frequent severity criterion for enrollment. The infused convalescent plasma had a median titer of 1:3200 of total SARS-CoV-2 antibodies (interquartile range, 1:800 to 1:3200). No patients were lost to follow-up. At day 30 day, no significant difference was noted between the convalescent plasma group and the placebo group in the distribution of clinical outcomes according to the ordinal scale (odds ratio, 0.83; 95% confidence interval [CI], 0.52 to 1.35; P = 0.46). Overall mortality was 10.96% in the convalescent plasma group and 11.43% in the placebo group, for a risk difference of -0.46 percentage points (95% CI, -7.8 to 6.8). Total SARS-CoV-2 antibody titers tended to be higher in the convalescent plasma group at day 2 after the intervention. Adverse events and serious adverse events were similar in the two groups., Conclusions: No significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo. (PlasmAr ClinicalTrials.gov number, NCT04383535.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: In this COVID-19 pandemic, the differential diagnosis of viral pneumonia is still challenging. We aimed to assess the classification performance of computed tomography (CT)-based CT signs and radiomics features for discriminating COVID-19 and influenza pneumonia., Methods: A total of 154 patients with confirmed viral pneumonia (COVID-19: 89 cases, influenza pneumonia: 65 cases) were collected retrospectively in this study. Pneumonia signs and radiomics features were extracted from the initial unenhanced chest CT images to build independent and combined models. The predictive performance of the radiomics model, CT sign model, the combined model was constructed based on the whole dataset and internally invalidated by using 1000-times bootstrap. Diagnostic performance of the models was assessed via receiver operating characteristic (ROC) analysis., Results: The combined models consisted of 4 significant CT signs and 7 selected features and demonstrated better discrimination performance between COVID-19 and influenza pneumonia than the single radiomics model. For the radiomics model, the area under the ROC curve (AUC) was 0.888 (sensitivity, 86.5%; specificity, 78.4%; accuracy, 83.1%), and the AUC was 0.906 (sensitivity, 86.5%; specificity, 81.5%; accuracy, 84.4%) in the CT signs model. After combining CT signs and radiomics features, AUC of the combined model was 0.959 (sensitivity, 89.9%; specificity, 90.7%; accuracy, 90.3%)., Conclusions: CT-based radiomics combined with signs might be a potential method for distinguishing COVID-19 and influenza pneumonia with satisfactory performance.

Reactivation of cytomegalovirus (CMV) or Epstein-Barr virus (EBV) is common after hematopoietic stem cell transplantation (HSCT). Previous researches have demonstrated that either CMV or EBV reactivation is associated with poor outcomes of HSCT. However, few studies investigate the impact of CMV and EBV co-reactivation after HSCT. In this study, we described the clinical characteristics of HSCT recipients with CMV and EBV co-reactivation (defined as CMV and EBV viremia occur at the same period of time). We conducted a longitudinal study of 247 patients who underwent HSCT in our center. A total of 24 (9.7%) patients had CMV and EBV co-reactivation. These patients showed higher incidence of viral pneumonitis (P=0.005). Patients with CMV and EBV co-reactivation had significant lower 1-year overall survival (OS) (P=0.004) and lower 1-year leukemia free survival (LFS) (P=0.016). Our further analysis suggested that duration of CMV (P=0.014), EBV (P<0.001), and CD4+CD25+ T cell counts at day 30 post-transplantation (P=0.05) are independent risk factors of virus co-reactivation. In conclusion, patients who developed co-reactivation of CMV and EBV had poor prognosis in terms of lower 1-year OS and LFS, and the CMV and EBV co-reactivation was associated with prolonged CMV or EBV duration and poor CD4+CD25+ T cell reconstitution at day 30 post-transplantation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhou, Shi, Wei, Wang, Yan, Zhang, Xu, Liu, Huang and Sun.)

Objective: To study the clinical and etiological characteristics of viral pneumonia in patients with chronic obstructive pulmonary disease(VP-COPD), and to identify the risk factors associated with poor prognosis. Methods: From August 1, 2017 to August 1, 2019, totally 235 patients in a general hospital in Beijing were prospectively enrolled in this research, and all patients were diagnosed with viral pneumonia by imaging and etiology. The patients were divided into VP-COPD group( n =60) and VP-nCOPD(viral pneumonia in non-COPD patients) group( n =175). Pathogen detection and clinical characteristics were compared between the two groups.Finally, the binomial logistic regression was used to explore the risk factors associated with severe VP-COPD. Results: Compared with the VP-nCOPD group, the VP-COPD group was older(76.5 vs 66.0 years, P =0.001), and the CURB-65 score(2 vs 1, P = 0.001) and the PSI score(111 vs 85, P <0.001) were higher at admission. Pseudomonas aeruginosa ( χ²= 10.308, P = 0.001) and Staphylococcus aureus(χ²= 5.953, P =0.028) were the most common co-infection bacteria. In the VP-COPD group type Ⅱ respiratory failure was more common(23.3% vs 6.8%, P <0.001), the number of severely ill patients was larger(48.3% vs 30.3%, P =0.011), the length of hospital stay was longer(13 vs 8, P <0.001), and the mortality rate during hospitalization was higher(18.3% vs 7.4%, P =0.016) in the VP-nCOPD group. Multivariate analysis showed that the level of blood glucose( OR : 1.73, 95% CI : 1.22-2.44, P = 0.002) and pleural effusion( OR : 133.12, 95% CI : 7.57-2 340.36, P =0.001) were risk factors for severe VP-COPD patients. Conclusion: Viral pneumonia in patients with COPD tended to develop into severe cases and had a poor prognosis.

Background: Many studies reporting coronavirus disease 2019 (COVID-19) complications have involved case series or small cohorts that could not establish a causal association with COVID-19 or provide risk estimates in different care settings. We sought to study all possible complications of COVID-19 to confirm previously reported complications and to identify potential complications not yet known., Methods: Using United States health claims data, we compared the frequency of all International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) diagnosis codes occurring before and after the onset of the COVID-19 pandemic in an exposure-crossover design. We included patients who received a diagnosis of COVID-19 between Mar. 1, 2020, and Apr. 30, 2020, and computed risk estimates and odds ratios (ORs) of association with COVID-19 for every ICD-10-CM diagnosis code., Results: Among 70 288 patients with COVID-19, 69 of 1724 analyzed ICD-10-CM diagnosis codes were significantly associated with COVID-19. Disorders showing both strong association with COVID-19 and high absolute risk included viral pneumonia (OR 177.63, 95% confidence interval [CI] 147.19-214.37, absolute risk 27.6%), respiratory failure (OR 11.36, 95% CI 10.74-12.02, absolute risk 22.6%), acute kidney failure (OR 3.50, 95% CI 3.34-3.68, absolute risk 11.8%) and sepsis (OR 4.23, 95% CI 4.01-4.46, absolute risk 10.4%). Disorders showing strong associations with COVID-19 but low absolute risk included myocarditis (OR 8.17, 95% CI 3.58-18.62, absolute risk 0.1%), disseminated intravascular coagulation (OR 11.83, 95% CI 5.26-26.62, absolute risk 0.1%) and pneumothorax (OR 3.38, 95% CI 2.68-4.26, absolute risk 0.4%)., Interpretation: We confirmed and provided risk estimates for numerous complications of COVID-19. These results may guide prognosis, treatment decisions and patient counselling., Competing Interests: Competing interests: William Murk is a consultant to and holds stocks in Aetion, Inc. Monica Gierada, Andrew Weckstein and Jeremy Rassen are employees of and hold stock options or stocks in Aetion, Inc. Reyna Klesh is an employee of HealthVerity, Inc., which provided the data for this study. No other competing interests were declared., (© 2021 Joule Inc. or its licensors.)

Background: For better understanding of the pathological changes of COVID-19, benefiting clinical management of the disease and the preparation for future waves of similar pandemics., Methods: Hematology parameters from a total of 52 cases of COVID-19 admitted for treatment in a designated hospital were retrospectively analyzed. Data were analyzed by SPSS statistical software., Results: Pre-treatment T-cell subsets, total lymphocytes, red blood cell distribution width (RDW), eosinophils, and basophils were significantly lower than that of post-treatment, while the inflammatory indexes neutrophils, neutrophil to lymphocyte ratio (NLR), and C-reactive protein (CRP) levels, as well as red blood cell (RBC) and hemoglobin, were significantly reduced after treatment. The T-cell subsets, total lymphocytes, and basophils in severely and critically ill patients were significantly lower than those in moderately ill patients. Neutrophils, NLR, eosinophils, procalcitonin (PCT), and CRP was significantly higher in severely and critically ill patients than in moderately ill patients. CD3+, CD8+, total lymphocytes, platelets, and basophils in patients older than 50 were lower than that of those younger than 50, while neutrophils, NLR, CRP, and RDW in patients older than 50 were higher than that of younger than 50. There was a positive correlation among prothrombin time (PT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in severely and critically ill patients., Conclusions: T-cell subsets, lymphocyte count, RDW, neutrophils, eosinophils, NLR, CRP, PT, ALT, and AST are important indicators in the management especially for severely and critically ill patients with COVID-19., (© 2020 The Authors. Journal of Clinical Laboratory Analysis Published by Wiley Periodicals LLC.)

Objective: The orf8b protein of the coronavirus SARS-CoV, analogous to SARS-CoV-2, triggers the NLRP3 inflammasome in macrophages in vitro. Deregulated inflammasome-mediated release of interleukin-1 family cytokines is important in hyper-inflammatory syndromes, like happens in SARS-CoV-2-mediated cytokine release syndrome. We propose that an intense inflammasome formation characterizes the lungs of patients with fatal COVID-19 disease due to pneumonia and acute respiratory distress syndrome (ARDS)., Methods: Samples from four patients with confirmed COVID-19 pneumonia who had been hospitalized at the Hospital of the University of Trieste (Italy) and died of ARDS and four lung samples from a historical repository from subjects who had died of cardiopulmonary arrest and had not been placed on mechanical ventilation and without evidence of pulmonary infection at postmortem examination were collected. Pathology samples had been fixed in formalin 10% at time of collection and subsequently embedded in paraffin. We conducted staining for ASC (Apoptosis-associated Speck-like protein containing a Caspase recruitment domain), NLRP3 (NACHT, LRR, and PYD domains-containing protein 3), and cleaved caspase-1., Results: Intense expression of the inflammasome was detected, mainly in leukocytes, within the lungs of all patients with fatal COVID-19 in the areas of lung injury. The number of ASC inflammasome specks per high power fields was significantly higher in the lungs of patients with fatal COVID-19 as compared with the lungs of control subjects (52 ± 22 vs 6 ± 3, P = 0.0064)., Conclusions: These findings identify the presence of NLRP3 inflammasome aggregates in the lungs of fatal COVID-19 pneumonia thus providing the potential molecular link between viral infection and cytokine release syndrome.

Background: Although platelet mean volume/platelet count ratio (MPR) is considered to be a crucial marker of inflammatory and infectious diseases, the relationship between MPR and novel coronavirus infectious disease 2019 (COVID-19) remains unclear., Methods: In this retrospective study, 85 patients with confirmed COVID-19 were enrolled and divided into low and high MPR group. Data from repeated measures were compared by the generalized estimating equations. Cox regression analyses were performed to assess the impact of MPR on the incidence of severe pneumonia (SP), with inverse probability of treatment weighting (IPTW) used to reduce confounding bias. The primary outcome is the incidence of SP of COVID-19., Results: During follow-up, 17 (20.0%) patients were developed to SP. Compared with mild patients, patients with SP developed showed a higher MPR level at baseline, day 1, day 2, and day 3 after admission (P = .005, P = .015, P = .009, and P = .032, respectively). Kaplan-Meier method showed a higher incidence of SP in the high MPR group than the low MPR group (log-rank test = 10.66, P = .001). After adjustment, high MPR was associated with an elevated incidence of SP (HR, 5.841, 95% CI, 1.566-21.791, P = .009). The IPTW method also suggested that MPR was a significant factor related to the incidence of SP (HR, 8.337, 95% CI, 4.045-17.182, P < .001)., Conclusion: High MPR level is an independent risk factor for severe pneumonia in patients with COVID-19., (© 2020 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Background: Coronavirus disease-2019 (COVID-19) is a worldwide pandemic. We present the clinical characteristics and outcomes of 28 COVID-19 patients treated in our hospital in Taiwan., Methods: Patients with COVID-19, confirmed by positive real-time reverse-transcriptase polymerase chain reaction results for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral nucleic acids from oropharyngeal swab specimens between February 4, 2020 and July 6, 2020, were enrolled. Their clinical characteristics and outcomes were reviewed., Results: Seventeen of the 28 patients (60.7%) had pneumonia. The most frequent symptoms were cough (n = 23, 82.1%) and fever (n = 17, 60.7%). The development of pneumonia was associated with age ≥40 years (p < 0.024), body mass index (BMI) ≥25 kg/m 2 (p = 0.014), fever (p = 0.007), shortness of breath (p = 0.036), chills ((p = 0.047), and lower platelet counts (<200,000/μL) (p = 0.007). Increased quarantine duration was associated with age ≥40 years (p = 0.026), Charlson index ≥1 (p = 0.037), lower lymphocyte (<1500/uL; p = 0.028) or platelet counts (<200,000/μL) (p = 0.016), lower serum sodium (<140 mEq/L; p = 0.006), and higher C-reactive protein (CRP) level (≥1 mg/dl; p = 0.04). Treatment with hydroxychloroquine or in combination with other medicines did not reduce the quarantine duration. All 28 patients recovered with a median quarantine duration of 27.2 days., Conclusion: COVID-19 patients with older age, higher BMI, fever, chills or shortness of breath, lower serum sodium level, lower platelet or lymphocyte count, and higher CRP level may be associated with developing pneumonia or longer quarantine duration., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article., (Copyright © 2020 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Acute viral pneumonia, hypoxemic respiratory failure and severe inflammatory response are hallmarks of severe coronavirus disease 2019 (COVID-19). The COVID-19-associated inflammatory state may further lead to symptomatic thromboembolic complications despite prophylaxis. We report a 66-year-old female patient with post-mortem diagnosis of COVID-19 who presented progressive livedo racemosa, acute renal failure and myocardial injury, as well as an absence of respiratory symptoms. Transthoracic echocardiography showed severe spontaneous echo contrast in the right cardiac chambers and right-sided cardiac overload presumed to result from pulmonary microvascular thrombosis or embolism. D-dimer levels were increased. The patient developed an acute ischemic stroke and died 2 days following presentation despite therapeutic anticoagulation. Her predominantly thromboembolic presentation supports the concept of coronavirus infection of endothelial cells and hypercoagulability, or COVID-19 endotheliitis. The case we report highlights that COVID-19-associated hyperacute multi-organ thromboembolic storm may precede or present disproportionately to respiratory involvement.

COVID-19 pneumonia has a significant case fatality rate and no effective antiviral drugs are available even after 9 months of the pandemic. The spectrum of COVID-19 disease ranges from asymptomatic cases to severe ARDS with myriad manifestations. Here we report a case of a male patient with severe COVID-19 ARDS who improved after receiving standard therapy but again 'deteriorated' after being stepped down to ward. He complained of worsening shortness of breath and hypoxemia which was found to be mainly positional. After ruling out other causes, he was labeled as a case of platypnea-orthodeoxia syndrome due to underlying lung involvement.  It is important to be aware of this condition in the context of COVID-19 which can be easily diagnosed bedside with pulse oximetry.