Fatal Coronavirus Disease 2019 Research Articles

Life-prolonging treatment restrictions and outcomes in patients with cancer and COVID-19: an update from the Dutch Oncology COVID-19 Consortium

Aim of the studyThe coronavirus disease 2019 (COVID-19) pandemic significantly impacted cancer care. In this study, clinical patient characteristics related to COVID-19 outcomes and advanced care planning, in terms of non-oncological treatment restrictions (e.g. do-not-resuscitate codes), were studied in patients with cancer and COVID-19. MethodsThe Dutch Oncology COVID-19 Consortium registry was launched in March 2020 in 45 hospitals in the Netherlands, primarily to identify risk factors of a severe COVID-19 outcome in patients with cancer. Here, an updated analysis of the registry was performed, and treatment restrictions (e.g. do-not-intubate codes) were studied in relation to COVID-19 outcomes in patients with cancer. Oncological treatment restrictions were not taken into account. ResultsBetween 27th March 2020 and 4th February 2021, 1360 patients with cancer and COVID-19 were registered. Follow-up data of 830 patients could be validated for this analysis. Overall, 230 of 830 (27.7%) patients died of COVID-19, and 60% of the remaining 600 patients with resolved COVID-19 were admitted to the hospital. Patients with haematological malignancies or lung cancer had a higher risk of a fatal outcome than other solid tumours. No correlation between anticancer therapies and the risk of a fatal COVID-19 outcome was found. In terms of end-of-life communication, 50% of all patients had restrictions regarding life-prolonging treatment (e.g. do-not-intubate codes). Most identified patients with treatment restrictions had risk factors associated with fatal COVID-19 outcome. ConclusionThere was no evidence of a negative impact of anticancer therapies on COVID-19 outcomes. Timely end-of-life communication as part of advanced care planning could save patients from prolonged suffering and decrease burden in intensive care units. Early discussion of treatment restrictions should therefore be part of routine oncological care, especially during the COVID-19 pandemic.

Profiling of lung SARS-CoV-2 and influenza virus infection dissects virus-specific host responses and gene signatures.

BackgroundThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which emerged in late 2019 has spread globally, causing a pandemic of respiratory illness designated coronavirus disease 2019 (COVID-19). A better definition of the pulmonary host response to SARS-CoV-2 infection is required to understand viral pathogenesis and to validate putative COVID-19 biomarkers that have been proposed in clinical studies.MethodsHere, we use targeted transcriptomics of formalin-fixed paraffin-embedded tissue using the NanoString GeoMX platform to generate an in-depth picture of the pulmonary transcriptional landscape of COVID-19, pandemic H1N1 influenza and uninfected control patients.ResultsHost transcriptomics showed a significant upregulation of genes associated with inflammation, type I interferon production, coagulation and angiogenesis in the lungs of COVID-19 patients compared to non-infected controls. SARS-CoV-2 was non-uniformly distributed in lungs (emphasising the advantages of spatial transcriptomics) with the areas of high viral load associated with an increased type I interferon response. Once the dominant cell type present in the sample, within patient correlations and patient–patient variation, had been controlled for, only a very limited number of genes were differentially expressed between the lungs of fatal influenza and COVID-19 patients. Strikingly, the interferon-associated gene IFI27, previously identified as a useful blood biomarker to differentiate bacterial and viral lung infections, was significantly upregulated in the lungs of COVID-19 patients compared to patients with influenza.ConclusionCollectively, these data demonstrate that spatial transcriptomics is a powerful tool to identify novel gene signatures within tissues, offering new insights into the pathogenesis of SARS-COV-2 to aid in patient triage and treatment.

High infectious disease burden as a basis for the observed high frequency of asymptomatic SARS-CoV-2 infections in sub-Saharan Africa

Following the coronavirus outbreaks described as severe acute respiratory syndrome (SARS) in 2003 and the Middle East respiratory syndrome (MERS) in 2012, the world has again been challenged by yet another corona virus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infections were first detected in a Chinese Province in December 2019 and then declared a pandemic by the World Health Organization in March 2020. An infection caused by SARS-CoV-2 may result in asymptomatic, uncomplicated or fatal coronavirus disease 2019 (COVID-19). Fatal disease has been linked with the uncontrolled “cytokine storm” manifesting with complications mostly in people with underlying cardiovascular and pulmonary disease conditions. The severity of COVID-19 disease and the associated mortality has been disproportionately lower in terms of number of cases and deaths in Africa and also Asia in comparison to Europe and North America. Also, persons of colour residing in Europe and North America have been identified as a highly susceptible population due to a combination of several socioeconomic factors and poor access to quality healthcare. Interestingly, this has not been the case in sub-Saharan Africa where majority of the population are even more deprived of the aforementioned factors. On the contrary, sub-Saharan Africa has recorded the lowest levels of mortality and morbidity associated with the disease, and an overwhelming proportion of infections are asymptomatic. Whilst it can be argued that these lower number of cases in Africa may be due to challenges associated with the diagnosis of the disease such as lack of trained personnel and infrastructure, the number of persons who get infected and develop symptoms is proportionally lower than those who are asymptomatic, including asymptomatic cases that are never diagnosed. This review discusses the most probable reasons for the significantly fewer cases of severe COVID-19 disease and deaths in sub-Saharan Africa.

Carica papaya leaf water extract promotes innate immune response via MAPK signaling pathways

The emergence and rapid spread of the potentially fatal coronavirus disease 2019, caused due to infection by severe acute respiratory syndrome coronavirus-2, has led to worldwide interest in developing functional bioactive ingredients that act as immunomodulatory agents. In this study, we aimed to characterize Carica papaya extract and explore its potential as an immuno-modulator by performing in vitro cell screening. Papaya leaf water extract (PLW) was found to significantly increase the levels of nitric oxide (NO) and prostaglandin E2 (PGE2) by upregulating inducible nitric oxide synthase and cyclo-oxygenase-2 activity, respectively. Additionally, PLW increased the production of tumor necrosis factor-α and interleukin 1β in RAW 264.7 cells. Furthermore, PLW activated the expression of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) but not that of p38 mitogen-activated protein kinase. These results indicate that PLW increased the production of NO, PGE2, and pro-inflammatory cytokines by activating the JNK and ERK pathways in macrophages, thus demonstrating immunomodulatory properties. Finally, high-performance liquid chromatography fingerprint analysis indicated the presence of rutin, narirutin, and ρ-coumaric acid in PLW (6.30, 119.76, and 47.25 ppm, respectively). Treating cells with these compounds at non-toxic concentrations had no effect on NO production. Taken together, these results suggest that PLW may have potential as an immunity-enhancing supplement. © The Korean Society for Applied Biological Chemistry 2021.

Does diabetes mellitus mitigate the gender gap in COVID-19 mortality?

In this SARS-COV2-pandemic, diabetes mellitus (DM) soon emerged as one of the most prominent risk factors for a severe course of corona virus disease-2019 (COVID-19) and increased mortality due to hyperglycemia/insulin resistance, obesity, inflammation, altered immune status, and cardiovascular complications. In general, men are at a higher risk of severe or fatal COVID-19 disease irrespective of age, region and despite comparable infection rates in both sexes. In COVID-19, there is also a male predominance among hospitalized patients with diabetes, however, overall, data among patients with diabetes are ambiguous so far. Of note, similar to cardiovascular complications, women with type 2 diabetes (DM2) appear to lose their biological female advantage resulting in comparable death rates to those of men. The complex interplay of biological and behavioral factors, which may put men at greater risk of a severe or fatal course of COVID-19, and gender-related psychosocial factors, which may cause disadvantage to women concerning the infection rates, might explain why sex-disaggregated data among infected patients with diabetes are conflicting. Better knowledge on biological factors leading to functionally different immune responses and of gender-sensitive sociocultural determinants of COVID-19 infection rates may help to optimize prevention and management in the high-risk groups of men and women with diabetes.

Variation of COVID-19 Specific Immunoglobulin's and Some Inflammatory Factors in COVID-19 Patients in the Sabratha Isolation Center, Western Libya

Background: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic causing significant mortality and morbidity and implementation of strict isolation measures. Serological testing can diagnose illness by detecting antibodies (IgM and IgG). Testing antibodies against SARS-CoV-2 is rapid and sensitive for the auxiliary diagnosis of COVID-19. The serum levels of CRP, D-dimers, and ferritin, which may be used in risk stratification to predict severe and fatal COVID-19 in hospitalized patients. Objectives The present study aimed to investigate the variations in COVID-19 Specific Immunoglobulin's and Some Inflammatory factors in COVID-19 Patients in Sabratha isolation center, Western Libya. Subjects and Methods: Sixty Confirmed COVID-19 patients hospitalized in the Isolation Centre located in Sabratha city, Libya from the 2nd October 2020 to the 2nd June 2021, were enrolled in this prospective study. Covid-19 patients were defined as positive cases after the detection of SARS-CoV-2 RNA in oro-nasopharyngeal swab samples. Data collected included demographic, clinical, and biological factors. Also, 30 healthy individuals without any chronic disease or respiratory symptoms were recruited for the control group. Blood samples were collected by vein puncture 5 ml of venous blood was withdrawn from each participant in the study by using disposable syringes under the aseptic technique; they were then transferred to a sterile tube for estimating biochemical parameters. Biochemical parameters were determined using automated COBAS E411 and INTEGRA 400 machines in the Sabratha Isolation Centre laboratory. The statistical significance of differences between groups was evaluated with the Kruskal-Wallis H test. Results: The results showed that patients with COVID-19 had a significant (P<0.0001) increase in IgM levels at 0 day, 14 days, and 21 days, respectively compared with the healthy individuals. Also, IgG levels were showed a gradual significantly (P<0.0001) increase during COVID-19 Virus Infection among COVID-19 patients at 0 day, 14 days, and 21 days compared with the controls. In addition, coronavirus infection caused a significant (P<0.0001) increase in D-dimer, CRP, and Ferritin levels compared with the healthy control individuals. Conclusion: It can be concluded that coronavirus infection caused a significant increase in IgM, IgG, D-dimer, CRP, and Ferritin levels at different periods compared to the controls. Further studies are needed to confirm these results. COVID-19 Specific Immunoglobulin's and Some Inflammatory factors in COVID-19 Patients These changes in IgM, IgG, D-dimer, CRP, and Ferritin levels during COVID-19 Virus Infection among COVID-19 patients may help the clinicians to better understand the COVID-19 and provide more clinical treatment options.

The Association of Asthma With COVID-19 Mortality: An Updated Meta-Analysis Based on Adjusted Effect Estimates

BackgroundThe association of asthma with the risk for mortality among coronavirus disease 2019 (COVID-19) patients is not clear.ObjectiveTo investigate the association between asthma and the risk for mortality among COVID-19 patients.MethodsWe performed systematic searches through electronic databases including PubMed, EMBASE, and Web of Science to identify potential articles reporting adjusted effect estimates on the association of asthma with fatal COVID-19. A random-effects model was conducted to estimate pooled effects. Sensitivity analysis, subgroup analysis, meta-regression, Begg's test and Egger's test were also performed.ResultsBased on 62 studies with 2,457,205 cases reporting adjusted effect estimates, COVID-19 patients with asthma had a significantly reduced risk for mortality compared with those without it (15 cohort studies: 829,670 patients, pooled hazard ratio [HR] = 0.88, 95% confidence interval [CI], 0.82-0.95, I2 = 65.9%, P < .001; 34 cohort studies: 1,008,015 patients, pooled odds ratio [OR] = 0.88, 95% CI, 0.82-0.94, I2 = 39.4%, P = .011; and 11 cross-sectional studies: 1,134,738 patients, pooled OR = 0.87, 95% CI, 0.78-0.97, I2 = 41.1%, P = .075). Subgroup analysis based on types of adjusted factors indicated that COVID-19 patients with asthma had a significantly reduced risk for mortality among studies adjusting for demographic, clinical, and epidemiologic variables (pooled OR = 0.87, 95% CI, 0.83-0.92, I2 = 36.3%, P = .013; pooled HR = 0.90, 95% CI, 0.83-0.97, I2 = 69.2%, P < .001), but not among studies adjusting only for demographic variables (pooled OR = 0.88, 95% CI, 0.70-1.12, I2 = 40.5%, P = .097; pooled HR = 0.82, 95% CI, 0.64-1.06, I2 = 0%, P = .495). Sensitivity analysis proved that our results were stable and robust. Both Begg's test and Egger's test indicated that potential publication bias did not exist.ConclusionsOur data based on adjusted effect estimates indicated that asthma was significantly related to a reduced risk for COVID-19 mortality.

Case Report: Severe COVID-19 in a Kidney Transplant Recipient Without Humoral Response to SARS-CoV-2 mRNA Vaccine Series.

Supplemental Digital Content is available in the text.

Computed tomography findings and clinical manifestations in different clinical types of coronavirus disease 2019

OBJECTIVE: Since the coronavirus disease 2019 (COVID-19) outbreak in Wuhan in 2019, the virus has spread rapidly. We investigated the clinical and computed tomography (CT) characteristics of different clinical types of COVID-19. MATERIALS AND METHODS: We retrospectively analyzed clinical and chest CT findings of 89 reverse transcription polymerase chain reaction confirmed cases from five medical centers in China. All the patients were classified into the common (n = 65), severe (n = 18), or fatal (n = 6) type. CT features included lesion distribution, location, size, shape, edge, density, and the ratio of lung lesions to extra-pulmonary lesions. A COVID-19 chest CT analysis tool (uAI-discover-COVID-19) was used to calculate the number of infections from the chest CT images. RESULTS: Fatal type COVID-19 is more common in older men, with a median age of 65 years. Fever was more common in the severe and fatal type COVID-19 patients than in the common type patients. Patients with fatal type COVID-19 were more likely to have underlying diseases. On CT examination, common type COVID-19 showed bilateral (68%), patchy (83%), ground-glass opacity (48%), or mixed (46%) lesions. Severe and fatal type COVID-19 showed bilateral multiple mixed density lesions (56%). The infection ratio (IR) increased in the common type (2.4 [4.3]), severe type (15.7 [14.3]), and fatal type (36.9 [14.2]). The IR in the inferior lobe of both lungs was statistically different from that of other lobes in common and severe type patients (P &lt; 0.05). However, in the fatal type group, only the IR in the right inferior lung (RIL) was statistically different from that in the right superior lung(RUL), right middle lung (RML), and the left superior lung (LSL) (P &lt; 0.05). CONCLUSION: The CT findings and clinical features of the various clinical types of COVID-19 pneumonia are different. Chest CT findings have unique characteristics in the different clinical types, which can facilitate an early diagnosis and evaluate the clinical course and severity of COVID-19.

Distinctive features of SARS-CoV-2-specific T cells predict recovery from severe COVID-19.

Although T cells are likely players in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunity, little is known about the phenotypic features of SARS-CoV-2-specific T cells associated with recovery from severe coronavirus disease 2019 (COVID-19). We analyze T cells from 34 individuals with COVID-19 with severity ranging from mild (outpatient) to critical, culminating in death. Relative to individuals who succumbed, individuals who recovered from severe COVID-19 harbor elevated and increasing numbers of SARS-CoV-2-specific T cells capable of homeostatic proliferation. In contrast, fatal COVID-19 cases display elevated numbers of SARS-CoV-2-specific regulatory T cells and a time-dependent escalation in activated bystander CXCR4+ T cells, as assessed by longitudinal sampling. Together with the demonstration of increased proportions of inflammatory CXCR4+ T cells in the lungs of individuals with severe COVID-19, these results support a model where lung-homing T cells activated through bystander effects contribute to immunopathology, whereas a robust, non-suppressive SARS-CoV-2-specific T cell response limits pathogenesis and promotes recovery from severe COVID-19.

Fatal COVID-19 is Characterized by Distinct Vasculopathic Features and Increased Congestion of the Alveolar Capillary-Bed

Background: Clinical and radiologic studies investigating Coronavirus disease 2019 (COVID-19) indicate that a possible cause of severe hypoxia is marked ventilation-perfusion (VA/Q) mismatch. Published histopathology reports diffuse alveolar damage (DAD) in fatal COVID-19 is indistinguishable from other causes of DAD. We compared lung parenchymal and vascular alterations between COVID-19 and DAD of other etiologies using a multidimensional approach. Methods: This autopsy cohort consisted of consecutive COVID-19 patients (n=20) and patients with clinical acute respiratory distress syndrome and histologic DAD (n=21; non-COVID-19 viral and non-viral etiologies). Premortem chest CTs were evaluated for mosaic attenuation and vascular changes. Postmortem lung tissues were compared using histopathological, immunohistochemical, transcriptomics and computational analyses. Machine-learning-derived morphometric analysis of microvasculature was performed, with a random forest classifier quantifying vascular congestion (VSCong), in different microscopic compartments. Findings: On premortem CT, COVID-19 patients showed more mosaic attenuation (p<0·020), and subsegmental dilated vasculature (p=0·003) compared to controls. Histopathology revealed vasculopathic changes including: capillary-congestion and hemangiomatosis-like changes (p=0·043), microthrombi (p=0·026), thromboemboli (p=0·0036), infarcts (p=0·048), and perivascular inflammation(p <0·001). Immunohistochemistry revealed increased CD4+ T-cells(p=0·023), TIM3+ lymphocytes/macrophages (p=0·037/0·019), and PD-1+ cells(p=0·008). Morphometric analysis in COVID-19 revealed significantly higher bronchiolar VS Cong (p <0·0001) and alveolar-septal VSCong (p<0·0001), with larger overall VSCong range (p=0·002). Septal-congestion was associated with a significantly shorter time-to-death from symptom onset (p=0·02). Interpretation: Severe COVID-19 is characterized by significant vasculopathy and aberrant alveolar septal-congestion, which may be associated with shorter time-to-death. Dilated sublobar vessels and heterogeneously increased septal-congestion may translate to VA/Q mismatch in COVID-19. These findings warrant further investigation in larger multi-institutional autopsy cohorts. Funding Information: Supported by Internal Sundry, and Vickery-Colvin Award from the Department of Pathology, Massachusetts General Hospital. Declaration of Interests: LPH reports grants from Boehringer Ingelheim and has received personal consulting fees from Boehringer Ingelheim, Pliant Therapeutics, and Biogen Idec, all of which are not related to this study. SET have received CDC funding for other COVID-related work which are not related to this study. JAB has received grant support from Zeus Scientific, bioMerieux, Immunetics, the Bay Area Lyme Foundation and the Lyme Disease Biobank Foundation for work not related to this study, and has been a consultant for T2 Biosystems, DiaSorin and Roche Diagnostics, not related to this study. BPL reports royalties from Elsevier, Inc. for his work as an associate textbook editor, not related to this study. MMK has served as a compensated consultant for H3 Biomedicine and AstraZeneca and has received research (institutional) funding from Novartis and loyalty from Elsevier, all of which are not related to this study. The other authors declare no competing interests. Ethics Approval Statement: Analysis of patient autopsy material was reviewed and approved by the Partners Human Research IRB (Protocol #: 2020P001146).

Clinical Characteristics and Histopathology of Coronavirus Disease 2019-Related Deaths in African Children.

Globally, very few childhood deaths have been attributed to coronavirus disease 2019 (COVID-19). We evaluated clinical, microbiologic and postmortem histopathologic findings in childhood deaths in whom severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified antemortem or postmortem. Surveillance of childhood deaths was ongoing during the initial COVID-19 outbreak in South Africa from April 14, 2020, to August 31, 2020. All children hospitalized during this time had a SARS-CoV-2 test done as part of standard of care. Postmortem sampling included minimally invasive tissue sampling (MITS) of lung, liver and heart tissue; blood and lung samples for bacterial culture and molecular detection of viruses (including SARS-CoV-2) and bacteria. The cause of death attribution was undertaken by a multidisciplinary team and reported using World Health Organization framework for cause of death attribution. SARS-CoV-2 was identified on antemortem and/or postmortem sampling in 11.7% (20/171) of deceased children, including 13.2% (12/91) in whom MITS was done. Eighteen (90%) of 20 deaths with SARS-CoV-2 infection were <12 months age. COVID-19 was attributed in the causal pathway to death in 91.7% (11/12) and 87.5% (7/8) cases with and without MITS, respectively. Lung histopathologic features in COVID-19-related deaths included diffuse alveolar damage (n = 6, 54.5%), type 2 pneumocyte proliferation (n = 6, 54.5%) and hyaline membrane formation (n = 5, 36.4%). Culture-confirmed invasive bacterial disease was evident in 54.5% (6/11) of COVID-19 attributed deaths investigated with MITS. COVID-19 was in the causal pathway of 10.5% (18/171) of all childhood deaths under surveillance. The postmortem histopathologic features in fatal COVID-19 cases in children were consistent with reports on COVID-19 deaths in adults; although there was a high prevalence of invasive bacterial disease in the children.

High infectious disease burden as a basis for the observed high frequency of asymptomatic SARS-CoV-2 infections in sub-Saharan Africa.

Following the coronavirus outbreaks described as severe acute respiratory syndrome (SARS) in 2003 and the Middle East respiratory syndrome (MERS) in 2012, the world has again been challenged by yet another corona virus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infections were first detected in a Chinese Province in December 2019 and then declared a pandemic by the World Health Organization in March 2020. An infection caused by SARS-CoV-2 may result in asymptomatic, uncomplicated or fatal coronavirus disease 2019 (COVID-19). Fatal disease has been linked with the uncontrolled "cytokine storm" manifesting with complications mostly in people with underlying cardiovascular and pulmonary disease conditions. The severity of COVID-19 disease and the associated mortality has been disproportionately lower in terms of number of cases and deaths in Africa and also Asia in comparison to Europe and North America. Also, persons of colour residing in Europe and North America have been identified as a highly susceptible population due to a combination of several socioeconomic factors and poor access to quality healthcare. Interestingly, this has not been the case in sub-Saharan Africa where majority of the population are even more deprived of the aforementioned factors. On the contrary, sub-Saharan Africa has recorded the lowest levels of mortality and morbidity associated with the disease, and an overwhelming proportion of infections are asymptomatic. Whilst it can be argued that these lower number of cases in Africa may be due to challenges associated with the diagnosis of the disease such as lack of trained personnel and infrastructure, the number of persons who get infected and develop symptoms is proportionally lower than those who are asymptomatic, including asymptomatic cases that are never diagnosed. This review discusses the most probable reasons for the significantly fewer cases of severe COVID-19 disease and deaths in sub-Saharan Africa.

COVID-19: Autopsy findings in six patients between 26 and 46 years of age

ObjectivesStudies on coronavirus disease 2019 (COVID-19) usually focus on middle-aged and older adults. However, younger patients may present with severe COVID-19 with potentially fatal outcomes. For optimized, more specialized therapeutic regimens in this particular patient group, a better understanding of the underlying pathomechanisms is of utmost importance. MethodsOur study investigated relevant, pre-existing medical conditions, clinical histories, and autopsy findings, together with SARS-CoV-2-RNA, determined by qPCR, and laboratory data in six COVID-19 decedents aged 50 years or younger, who were autopsied at the Charité University Hospital. ResultsFrom a total of 76 COVID-19 patients who underwent an autopsy at our institution, six (7.9%) were 50 years old or younger. Most of these younger COVID-19 decedents presented with pre-existing medical conditions prior to SARS-CoV-2 infection. These included overweight and obesity, arterial hypertension, asthma, and obstructive sleep apnea, as well as graft-versus-host disease following cancer and bone marrow transplantation. Furthermore, clinical histories and autopsy results revealed a disproportionally high prevalence of thromboembolism and ischemic organ damage in this patient cohort. Histopathology and laboratory results indicated coagulopathies, signs of immune dysregulation, and liver damage. ConclusionsIn conclusion, pre-existing health conditions may increase the risk of severe and fatal COVID-19 in younger patients, who may be especially prone to developing thromboembolic complications, immune dysregulation, and liver damage.

A fatal toxic shock-like syndrome post COVID-19 infection in a child

BackgroundChildren affected by Coronavirus disease 2019 (COVID-19) showed various manifestations. Some of them were severe cases presenting with multi-system inflammatory syndrome (MIS-C) causing multiple organ dysfunction.Case presentationWe report the case of a 12-year-old girl with recent COVID-19 infection who presented with persistent fever, abdominal pain and other symptoms that meet the definition of MIS-C. She had lymphopenia and a high level of inflammatory markers. She was admitted to pediatric intensive care unit since she rapidly developed refractory catecholamine-resistant shock with multiple organ failure. Echocardiography showed a small pericardial effusion with a normal ejection fraction (Ejection Fraction = 60%) and no valvular or coronary lesions. The child showed no signs of improvement even after receiving intravenous immunoglobulin, fresh frozen plasma, high doses of Vasopressors and corticosteroid. His outcome was fatal.ConclusionPediatric patients affected by the new COVID-19 related syndrome may show severe life-threatening conditions similar to Kawasaki disease shock syndrome. Hypotension in these patients results from heart failure and the decreased cardiac output. We report a new severe clinical feature of SARS-CoV-2 infection in children in whom hypotension was the result of refractory vasoplegia.

Delayed production of neutralizing antibodies correlates with fatal COVID-19.

Recent studies have provided insights into innate and adaptive immune dynamics in coronavirus disease 2019 (COVID-19). However, the exact features of antibody responses that govern COVID-19 disease outcomes remain unclear. In this study, we analyzed humoral immune responses in 229 patients with asymptomatic, mild, moderate and severe COVID-19 over time to probe the nature of antibody responses in disease severity and mortality. We observed a correlation between anti-spike (S) immunoglobulin G (IgG) levels, length of hospitalization and clinical parameters associated with worse clinical progression. Although high anti-S IgG levels correlated with worse disease severity, such correlation was time dependent. Deceased patients did not have higher overall humoral response than discharged patients. However, they mounted a robust, yet delayed, response, measured by anti-S, anti-receptor-binding domain IgG and neutralizing antibody (NAb) levels compared to survivors. Delayed seroconversion kinetics correlated with impaired viral control in deceased patients. Finally, although sera from 85% of patients displayed some neutralization capacity during their disease course, NAb generation before 14 d of disease onset emerged as a key factor for recovery. These data indicate that COVID-19 mortality does not correlate with the cross-sectional antiviral antibody levels per se but, rather, with the delayed kinetics of NAb production.

Tissue-based SARS-CoV-2 detection in fatal COVID-19 infections: Sustained direct viral-induced damage is not necessary to drive disease progression

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although viral infection is known to trigger inflammatory processes contributing to tissue injury and organ failure, it is unclear whether direct viral damage is needed to sustain cellular injury. An understanding of pathogenic mechanisms has been handicapped by the absence of optimized methods to visualize the presence and distribution of SARS-CoV-2 in damaged tissues. We first developed a positive control cell line (Vero E6) to validate SARS-CoV-2 detection assays. We then evaluated multiple organs (lungs, kidneys, heart, liver, brain, intestines, lymph nodes, and spleen) from fourteen COVID-19 autopsy cases using immunohistochemistry (IHC) for the spike and the nucleoprotein proteins, and RNA in situ hybridization (RNA ISH) for the spike protein mRNA. Tissue detection assays were compared with quantitative polymerase chain reaction (qPCR)-based detection. SARS-CoV-2 was histologically detected in the Vero E6 positive cell line control, 1 of 14 (7%) lungs, and none (0%) of the other 59 organs. There was perfect concordance between the IHC and RNA ISH results. qPCR confirmed high viral load in the SARS-CoV-2 ISH-positive lung tissue, and absent or low viral load in all ISH-negative tissues. In patients who die of COVID-19-related organ failure, SARS-CoV-2 is largely not detectable using tissue-based assays. Even in lungs showing widespread injury, SARS-CoV-2 viral RNA or proteins were detected in only a small minority of cases. This observation supports the concept that viral infection is primarily a trigger for multiple-organ pathogenic proinflammatory responses. Direct viral tissue damage is a transient phenomenon that is generally not sustained throughout disease progression.

Cellular Immune Response to COVID-19 and Potential Immune Modulators.

Coronavirus disease 2019 (COVID-19) is a respiratory infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Droplets and contacts serve as the main route of transmission of SARS-CoV-2. The characteristic of the disease is rather heterogeneous, ranging from no symptoms to critical illness. The factors associated with the outcome of COVID-19 have not been completely characterized to date. Inspired by previous studies on the relevance of infectious diseases, viral and host factors related to clinical outcomes have been identified. The severity of COVID-19 is mainly related to host factors, especially cellular immune responses in patients. Patients with mild COVID-19 and improved patients with severe COVID-19 exhibit a normal immune response to effectively eliminate the virus. The immune response in patients with fatal severe COVID-19 includes three stages: normal or hypofunction, hyperactivation, and anergy. Eventually, the patients were unable to resist viral infection and died. Based on our understanding of the kinetics of immune responses during COVID-19, we suggest that type I interferon (IFN) could be administered to patients with severe COVID-19 in the hypofunctional stage, intravenous immunoglobulin (IVIG) and glucocorticoid therapy could be administered in the immune hyperactivation stage. In addition, low molecular weight heparin (LMWH) anticoagulation therapy and anti-infective therapy with antibiotics are recommended in the hyperactivation stage.

SARS-CoV-2 Induces Lymphocytopenia by Promoting Inflammation and Decimates Secondary Lymphoid Organs.

While lymphocytopenia is a common characteristic of coronavirus disease 2019 (COVID-19), the mechanisms responsible for this lymphocyte depletion are unclear. Here, we retrospectively reviewed the clinical and immunological data from 18 fatal COVID-19 cases, results showed that these patients had severe lymphocytopenia, together with high serum levels of inflammatory cytokines (IL-6, IL-8 and IL-10), and elevation of many other mediators in routine laboratory tests, including C-reactive protein, lactate dehydrogenase, α-hydroxybutyrate dehydrogenase and natriuretic peptide type B. The spleens and hilar lymph nodes (LNs) from six additional COVID-19 patients with post-mortem examinations were also collected, histopathologic detection showed that both organs manifested severe tissue damage and lymphocyte apoptosis in these six cases. In situ hybridization assays illustrated that SARS-CoV-2 viral RNA accumulates in these tissues, and transmission electronic microscopy confirmed that coronavirus-like particles were visible in the LNs. SARS-CoV-2 Spike and Nucleocapsid protein (NP) accumulated in the spleens and LNs, and the NP antigen restricted in angiotensin-converting enzyme 2 (ACE2) positive macrophages and dendritic cells (DCs). Furthermore, SARS-CoV-2 triggered the transcription of Il6, Il8 and Il1b genes in infected primary macrophages and DCs in vitro, and SARS-CoV-2-NP+ macrophages and DCs also manifested high levels of IL-6 and IL-1β, which might directly decimate human spleens and LNs and subsequently lead to lymphocytopenia in vivo. Collectively, these results demonstrated that SARS-CoV-2 induced lymphocytopenia by promoting systemic inflammation and direct neutralization in human spleen and LNs.

Clinical features of 141 fatal cases of coronavirus disease in Jinyintan Hospital in Wuhan, China

Objective: To describe the epidemiological characteristics and clinical features of patients with fatal coronavirus disease (COVID-19), in order to provide evidence for clinical diagnosis and treatment. Methods: In this retrospective study, we analyzed data on 141 fatal cases of confirmed COVID-19 that occurred among patients in Jinyintan Hospital in Wuhan, China, from January 20 to March 6, 2020. We analyzed their epidemiological characteristics, clinical and radiological features, laboratory results, and treatment. Results: Of the 141 patients (49 females, 92 males), the median age was 77 years (range: 24-92 years). The most likely source of exposure included the Huanan seafood market (n=3, 2%), family members (n=6, 4%), and hospital-acquired infection (n=8, 6%). The remaining 116 patients (72%) had no known source of exposure. Of the patients, 101 (72%) had chronic diseases. The most common comorbidities were hypertension, diabetes and coronary heart disease. The most common clinical manifestations were fever (n=121, 85%), dry cough (n=77, 54%), shortness of breath (n=23, 16%), and chest pain (n=15, 10%). Less common clinical manifestations included fatigue (n=7, 4%), headache (n=3, 2%), disorders of consciousness (n=2, 1%), diarrhea (n=2, 1%) and lumbago (n=1, 0.7%). In terms of laboratory tests, the absolute value of lymphocytes in most patients was reduced (n=132, 94%), but C-reactive protein (n=141, 100%), procalcitonin(n=121, 89%), serum amyloid (n=140, 99%) were significantly increased. The most common findings on imaging of the lungs were bilateral multiple mottling and ground-glass opacity (n=101, 72%), mainly in the lower lobes (n=15, 10%), with lesions being more common on the right. Other imaging findings included diffuse consolidation (n=4, 3%), ground-glass opacity and consolidation (n=20, 14%), and pneumothorax (n=1, 0.7%). All patients were treated with antibiotics and antiviral drugs. Other treatments included immunoglobulin (n=49, 35%), corticosteroids (n=45, 32%), continuous renal replacement therapy (n=24, 17%), and extracorporeal membrane oxygenation (n=12, 9%). All patients were treated with oxygen therapy. The mode of administration included invasive mechanical ventilation (n=61, 43%), noninvasive mechanical ventilation (n=65, 46%), and nasal catheter oxygen inhalation (n=15, 11%). The direct causes of death were acute respiratory distress syndrome (n=90, 64%), multiple organ failure (n=24, 17%), sudden cardiac arrest (n=11, 8%), viral myocarditis (n=8, 5%), acute myocardial infarction (n=4, 3%), cerebrovascular accident (n=3, 2%), and acute gastrointestinal bleeding (n=1, 0.7%). Conclusions: Risk factors for death due to COVID-19 included older age, male sex, and the presence of comorbidities. The most common direct causes of death were acute respiratory distress syndrome, multiple organ failure, sudden cardiac arrest, and viral myocarditis.