How we approach thrombosis risk in children with COVID-19 infection

Thrombosis within the microvasculature and medium to large vessels is a serious and common complication among critically ill individuals with COVID-19. While children are markedly less likely to develop severe disease than adults, they remain at risk for thrombosis during acute infection and with the post-acute inflammatory illness termed multisystem inflammatory syndrome in children. Significant knowledge deficits in understanding COVID-19 associated coagulopathy and thrombotic risk pose clinical challenges for pediatric providers who must incorporate expert opinion and personal experience to manage individual patients. We discuss clinical scenarios to provide framework for characterizing thrombosis risk and thromboprophylaxis in children with COVID-19.

Download Full-text

Contribution of the Elevated Thrombosis Risk of Males to the Excess Male Mortality Observed in COVID-19: An Observational Study

10.21203/rs.3.rs-1097336/v1 ◽

2021 ◽

Author(s):

Kenneth R Cohen ◽

David Anderson BSAE ◽

Sheng Ren ◽

David J. Cook

Keyword(s):

Mortality Rate ◽

Observational Study ◽

P Value ◽

Male Mortality ◽

Thrombotic Risk ◽

Biological Sex ◽

Thrombosis Risk ◽

Exposure Variable ◽

Hospital Systems ◽

Risk For Thrombosis

Abstract Background: The mortality rate of COVID-19 is elevated in males compared to females.Objective: Determine the extent that the elevated thrombotic risk in males relative to females contributes to excess COVID-19 mortality in males.Design: Observational study.Setting: Data sourced from electronic medical records from over 200 US hospital systems.Participants: 60,877 patients hospitalized with COVID-19.Exposure: Exposure variable: biological sex; key variable of interest: thrombosis.Main outcome measures: Primary outcome was COVID-19 mortality. We measured: 1) mortality rate of males relative to females, 2) rate of thrombotic diagnoses occurring during hospitalization for COVID-19 in both sexes, and 3) mortality rate when evidence of thrombosis was present.Results: The COVID-19 mortality rate of males was 29.9% higher than that of females. Males had a 35.8% higher rate of receiving a thrombotic diagnosis compared to females. The mortality rate of all patients with a thrombotic diagnosis was 40.0%— over twice that of COVID-19 patients without a thrombotic diagnosis (adjusted OR 2.50 [2.37 to 2.64], p-value < .001). When defining thrombosis as either a documented thrombotic diagnosis or a D-dimer level ≥ 3.0 μg/mL, 16.4% of the excess mortality in male patients could be explained by increased thrombotic risk. Conclusions and Relevance: Our findings suggest the higher COVID-19 mortality rate in males may be significantly accounted for by the elevated risk for thrombosis among males. Understanding the mechanisms that underlie increased male thrombotic risk may allow for the advancement of effective anticoagulation strategies that reduce COVID-19 mortality in males.

Download Full-text

COVID-19 in Children: Expressions of Type I/II/III Interferons, TRIM28, SETDB1, and Endogenous Retroviruses in Mild and Severe Cases

International Journal of Molecular Sciences ◽

10.3390/ijms22147481 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7481

Author(s):

Pier-Angelo Tovo ◽

Silvia Garazzino ◽

Valentina Daprà ◽

Giulia Pruccoli ◽

Cristina Calvi ◽

...

Keyword(s):

Viral Infections ◽

Severe Disease ◽

Endogenous Retroviruses ◽

Type I ◽

Human Endogenous Retroviruses ◽

Moderate Disease ◽

Amplification Assay ◽

Positive Correlations ◽

Inducible Genes ◽

Inflammatory Syndrome

Children with the new coronavirus disease 2019 (COVID-19) have milder symptoms and a better prognosis than adult patients. Several investigations assessed type I, II, and III interferon (IFN) signatures in SARS-CoV-2 infected adults, however no data are available for pediatric patients. RIM28 and SETDB1 regulate the transcription of multiple genes involved in the immune response as well as of human endogenous retroviruses (HERVs). Exogenous viral infections can trigger the activation of HERVs, which in turn can induce inflammatory and immune reactions. Despite the potential cross-talks between SARS-CoV-2 infection and TRIM28, SETDB1, and HERVs, information on their expressions in COVID-19 patients is lacking. We assessed, through a PCR real time Taqman amplification assay, the transcription levels of six IFN-I stimulated genes, IFN-II and three of its sensitive genes, three IFN-lIIs, as well as of TRIM28, SETDB1, pol genes of HERV-H, -K, and -W families, and of env genes of Syncytin (SYN)1, SYN2, and multiple sclerosis-associated retrovirus (MRSV) in peripheral blood from COVID-19 children nd in control uninfected subjects. Higher expression levels of IFN-I and IFN-II inducible genes were observed in 36 COVID-19-infected children with mild or moderate disease as compared to uninfected controls, whereas their concentrations decreased in 17 children with severe disease and in 11 with multisystem inflammatory syndrome (MIS-C). Similar findings were found for the expression of TRIM-28, SETDB1, and every HERV gene. Positive correlations emerged between the transcriptional levels of type I and II IFNs, TRIM28, SETDB1, and HERVs in COVID-19 patients. IFN-III expressions were comparable in each group of subjects. This preserved induction of IFN-λs could contribute to the better control of the infection in children as compared to adults, in whom IFN-III deficiency has been reported. The upregulation of IFN-I, IFN-II, TRIM28, SETDB1, and HERVs in children with mild symptoms, their declines in severe cases or with MIS-C, and the positive correlations of their transcription in SARS-CoV-2-infected children suggest that they may play important roles in conditioning the evolution of the infection.

Download Full-text

COVID-19 induces a hyperactive phenotype in circulating platelets

10.1101/2020.07.24.20156240 ◽

2020 ◽

Cited By ~ 1

Author(s):

Shane P Comer ◽

Sarah Cullivan ◽

Paulina B Szklanna ◽

Luisa Weiss ◽

Steven Cullen ◽

...

Keyword(s):

Intensive Care ◽

Platelet Function ◽

Clinical Laboratory ◽

Platelet Reactivity ◽

Severe Disease ◽

Blood Parameters ◽

Full Blood Count ◽

Specific Marker ◽

Platelet Activity ◽

Thrombotic Risk

Background Coronavirus disease 2019 (COVID-19), caused by novel coronavirus SARS-CoV-2, has to date affected over 13.3 million globally. Although high rates of venous thromboembolism and evidence of COVID-19-induced endothelial dysfunction have been reported, the precise aetiology of the increased thrombotic risk associated with COVID-19 infection remains to be fully elucidated. Objectives Here, we assessed clinical platelet parameters and circulating platelet activity in patients with severe and non-severe COVID-19. Methods An assessment of clinical blood parameters in patients with severe COVID-19 disease (requiring intensive care), patients with non-severe disease (not requiring intensive care), general medical in-patients without COVID-19 and healthy donors was undertaken. Platelet function and activity were also assessed by secretion and specific marker analysis. Results We show that routine clinical blood parameters including increased MPV and decreased platelet:neutrophil ratio are associated with disease severity in COVID-19 upon hospitalisation and intensive care unit admission. Strikingly, agonist-induced ADP release was dramatically higher in COVID-19 patients compared with non-COVID-19 hospitalized patients and circulating levels of PF4, sP-selectin and TPO were also significantly elevated in COVID-19. Conclusion Distinct differences exist in routine full blood count and other clinical laboratory parameters between patients with severe and non-severe COVID-19. Moreover, we have determined that COVID-19 patients possess hyperactive circulating platelets. These data suggest that abnormal platelet reactivity may contribute to hypercoagulability in COVID-19. Further investigation of platelet function in COVID-19 may provide additional insights into the aetiology of thrombotic risk in this disease and may contribute to the optimisation of thrombosis prevention and treatment strategies.

Download Full-text

Dissemination of extreme levels of extracellular vesicles: tissue factor activity in patients with severe COVID-19

Blood Advances ◽

10.1182/bloodadvances.2020003308 ◽

2021 ◽

Vol 5 (3) ◽

pp. 628-634

Author(s):

Christophe Guervilly ◽

Amandine Bonifay ◽

Stephane Burtey ◽

Florence Sabatier ◽

Raphaël Cauchois ◽

...

Keyword(s):

Septic Shock ◽

Tissue Factor ◽

Extracellular Vesicles ◽

Severe Disease ◽

Plasminogen Activator Inhibitor ◽

Hospitalized Patients ◽

Plasminogen Activator Inhibitor 1 ◽

Thrombotic Risk ◽

Public Health Challenges ◽

Inflammatory State

Abstract Coronavirus disease 2019 (COVID-19) has become one of the biggest public health challenges of this century. Severe forms of the disease are associated with a thrombo-inflammatory state that can turn into thrombosis. Because tissue factor (TF) conveyed by extracellular vesicles (EVs) has been implicated in thrombosis, we quantified the EV-TF activity in a cohort of hospitalized patients with COVID-19 (n = 111) and evaluated its link with inflammation, disease severity, and thrombotic events. Patients with severe disease were compared with those who had moderate disease and with patients who had septic shock not related to COVID-19 (n = 218). The EV-TF activity was notably increased in patients with severe COVID-19 compared with that observed in patients with moderate COVID-19 (median, 231 [25th to 75th percentile, 39-761] vs median, 25 [25th to 75th percentile, 12-59] fM; P < .0001); EV-TF was correlated with leukocytes, D-dimer, and inflammation parameters. High EV-TF values were associated with an increased thrombotic risk in multivariable models. Compared with patients who had septic shock, those with COVID-19 were characterized by a distinct coagulopathy profile with significantly higher EV-TF and EV-fibrinolytic activities that were not counterbalanced by an increase in plasminogen activator inhibitor-1 (PAI-1). Thus, this article is the first to describe the dissemination of extreme levels of EV-TF in patients with severe COVID-19, which supports the international recommendations of systematic preventive anticoagulation in hospitalized patients and potential intensification of anticoagulation in patients with severe disease.

Download Full-text

Distorted TCR repertoires define multisystem inflammatory syndrome in children

10.1101/2021.04.12.21255098 ◽

2021 ◽

Author(s):

Amna Malik ◽

Eszter N. Tóth ◽

Michelle S. Teng ◽

Jacob Hurst ◽

Eleanor Watt ◽

...

Keyword(s):

T Cell ◽

Severe Acute Respiratory Syndrome ◽

Severe Disease ◽

Clinical Manifestations ◽

High Confidence ◽

T Cell Clones ◽

Severity Of Disease ◽

Cell Clones ◽

Inflammatory Syndrome ◽

Independent Expansion

While the majority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) display mild or no symptoms, rare individuals develop severe disease presenting with multisystem inflammatory syndrome (MIS-C). The reason for variable clinical manifestations is not understood. Here, we carried out TCR sequencing and conducted comparative analyses of TCR repertoires between children with severe (n=12) or mild (n=8) COVID-19. We compared these repertoires with unexposed individuals (samples collected pre-COVID-19 pandemic: n=8) and with the Adaptive Biotechnologies MIRA dataset, which includes over 135,000 high-confidence SARS-CoV-2-specific TCRs. We show that the repertoires of severely ill children are characterised by the expansion of TRBV11-2 chains with high junctional and CDR3 diversity. Moreover, the CDR3 sequences of TRBV11-2 clones shift away from SARS-CoV-2 specific T cell clones, resulting in distorted TCR repertoires. In conclusion, our study reports that CDR3-independent expansion of TRBV11-2+ cells, lacking SARS-CoV-2 specificity, defines severity of disease in children.

Download Full-text

Increased frequencies of CD4+CD25high regulatory T cells in acute dengue infection

Journal of Experimental Medicine ◽

10.1084/jem.20061381 ◽

2007 ◽

Vol 204 (5) ◽

pp. 979-985 ◽

Cited By ~ 95

Author(s):

Kerstin Lühn ◽

Cameron P. Simmons ◽

Edward Moran ◽

Nguyen Thi Phuong Dung ◽

Tran Nguyen Bich Chau ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Severe Disease ◽

Acute Infection ◽

Dengue Infection ◽

Hemorrhagic Fever ◽

Severe Dengue ◽

Effector T Cell ◽

Cell Effector

Dengue virus infection is an increasingly important tropical disease, causing 100 million cases each year. Symptoms range from mild febrile illness to severe hemorrhagic fever. The pathogenesis is incompletely understood, but immunopathology is thought to play a part, with antibody-dependent enhancement and massive immune activation of T cells and monocytes/macrophages leading to a disproportionate production of proinflammatory cytokines. We sought to investigate whether a defective population of regulatory T cells (T reg cells) could be contributing to immunopathology in severe dengue disease. CD4+CD25highFoxP3+ T reg cells of patients with acute dengue infection of different severities showed a conventional phenotype. Unexpectedly, their capacity to suppress T cell proliferation and to secrete interleukin-10 was not altered. Moreover, T reg cells suppressed the production of vasoactive cytokines after dengue-specific stimulation. Furthermore, T reg cell frequencies and also T reg cell/effector T cell ratios were increased in patients with acute infection. A strong indication that a relative rise of T reg cell/effector T cell ratios is beneficial for disease outcome comes from patients with mild disease in which this ratio is significantly increased (P < 0.0001) in contrast to severe cases (P = 0.2145). We conclude that although T reg cells expand and function normally in acute dengue infection, their relative frequencies are insufficient to control the immunopathology of severe disease.

Download Full-text

Microangiopathic Anemia of Acute Brucellosis – is it a True TTP?

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2010.031 ◽

2010 ◽

Vol 2 (3) ◽

pp. e2010031 ◽

Cited By ~ 4

Author(s):

Amir Kuperman

Keyword(s):

Thrombotic Microangiopathy ◽

Neutralizing Antibodies ◽

Molecular Mechanisms ◽

Brucella Melitensis ◽

Present Report ◽

Severe Disease ◽

Acute Infection ◽

High Dose ◽

Microangiopathic Anemia ◽

Work Up

Thrombotic thrombocytopenic purpura (TTP) is a severe disease, potentially fatal, if not diagnosed and treated promptly. TTP is clinically characterized by the pentad of thrombocytopenia, Coombs-negative hemolytic anemia, fever, renal abnormalities and neurological disturbances. Advances in recent years have delineated the molecular mechanisms of acquired and hereditary TTP.Many infectious organisms have been reported to be associated with TTP, especially mycoplasma, but only 6 cases of Brucella infection associated with thrombotic microangiopathy were reported.We describe a young woman who presented clinically with TTP following acute infection with both Brucella melitensis and Brucella abortus. The patient completely recovered after an aggressive therapy with plasmapharesis, high-dose corticosteroids and appropriate antimicrobial therapy.Since measurement of ADMTS13 activity and neutralizing antibodies is now available, and in none of the reported cases of brucellosis with thrombotic microangiopathy (including the present report) were tested, we recommend this work-up in future cases for better understanding of this rare association.

Download Full-text

X-Linked Lymphoproliferative Disease Mimicking Multisystem Inflammatory Syndrome in Children—A Case Report

Frontiers in Pediatrics ◽

10.3389/fped.2021.691024 ◽

2021 ◽

Vol 9 ◽

Author(s):

Seraina Prader ◽

Nicole Ritz ◽

Frédéric Baleydier ◽

Maya C. Andre ◽

Noémie Stähli ◽

...

Keyword(s):

Case Report ◽

Severe Disease ◽

Intravenous Immunoglobulins ◽

Lymphoproliferative Disease ◽

Number Of Children ◽

Barr Virus ◽

Reactive Protein ◽

Fatal Liver Failure ◽

Epstein Barr ◽

Inflammatory Syndrome

Most children with a SARS-CoV-2 infection are asymptomatic or exhibit mild symptoms. However, a small number of children develop features of substantial inflammation temporarily related to the COVID-19 also called multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), clinically similar to Kawasaki disease, toxic shock syndrome and hemophagocytic lymphohistiocytosis (HLH). It is well-known that genetic pre-disposition plays an important role in virally-triggered diseases such as Epstein-Barr virus (EBV)-associated HLH, while this has not yet been established for patients with MIS-C. Here we describe a male patient fulfilling the diagnostic criteria of MIS-C, who was initially treated according to current consensus guidelines. Presence of hypofibrinogenemia, normal lymphocyte counts and C-reactive protein, but substantial hyperferritinemia distinguish this patient from others with MIS-C. The clinical course following initial presentation with acute respiratory distress syndrome was marked by fatal liver failure in the context of EBV-associated HLH despite treatment with steroids, intravenous immunoglobulins, interleukin (IL)-1 receptor blockade and eventually HLH-directed treatment. X-linked lymphoproliferative disease type 1 (XLP1), a subtype of primary HLH was diagnosed in this patient post-mortem. This case report highlights the importance of including HLH in the differential diagnosis in MIS-C with severe disease course to allow specific, risk-adapted treatment and genetic counseling.

Download Full-text

Pediatric COVID-19: Immunopathogenesis, Transmission and Prevention

Vaccines ◽

10.3390/vaccines9091002 ◽

2021 ◽

Vol 9 (9) ◽

pp. 1002 ◽

Cited By ~ 1

Author(s):

Geraldine Blanchard-Rohner ◽

Arnaud Didierlaurent ◽

Anne Tilmanne ◽

Pierre Smeesters ◽

Arnaud Marchant

Keyword(s):

Respiratory Tract Infections ◽

Rapid Development ◽

Severe Disease ◽

Innate Immune ◽

The Other ◽

High Susceptibility ◽

Relative Resistance ◽

Tract Infections ◽

Inflammatory Syndrome ◽

The Impact

Children are unique in the context of the COVID-19 pandemic. Overall, SARS-CoV-2 has a lower medical impact in children as compared to adults. A higher proportion of children than adults remain asymptomatic following SARS-CoV-2 infection and severe disease and death are also less common. This relative resistance contrasts with the high susceptibility of children to other respiratory tract infections. The mechanisms involved remain incompletely understood but could include the rapid development of a robust innate immune response. On the other hand, children develop a unique and severe complication, named multisystem inflammatory syndrome in children, several weeks after the onset of symptoms. Although children play an important role in the transmission of many pathogens, their contribution to the transmission of SARS-CoV-2 appears lower than that of adults. These unique aspects of COVID-19 in children must be considered in the benefit–risk analysis of vaccination. Several COVID-19 vaccines have been authorized for emergency use in adolescents and clinical studies are ongoing in children. As the vaccination of adolescents is rolled out in several countries, we shall learn about the impact of this strategy on the health of children and on transmission within communities.

Download Full-text

The Application of Inorganic Optical Nanoprobes in Bacterial Infection

Journal of Innovative Optical Health Sciences ◽

10.1142/s1793545821300044 ◽

2021 ◽

pp. 2130004

Author(s):

Linyu Ding ◽

Lai Jiang ◽

Gang Liu

Keyword(s):

Bacterial Infection ◽

Bacterial Infections ◽

Early Stage ◽

Imaging Techniques ◽

Severe Disease ◽

Acute Infection ◽

Antibacterial Properties ◽

Efficient Treatment ◽

Optical Nanoprobes ◽

Biomedical Field

Bacterial infection is an acute infection caused by pathogens or conditional pathogens, which leads to severe disease and even death. It has become a significant reason for diseases and deaths worldwide. Therefore, rapid and precise detection, diagnosis, and treatment in the early stage are the key to deal with bacterial infections. Over recent years, along with the advances in biomaterials and nanotechnology, numerous nanomaterial-based multifunctional probes have been extensively explored in the biomedical field. Because of their excellent optical properties, inorganic optical nanoprobes are used to rapidly detect bacterial infection in the early stage and show excellent antibacterial properties, which has a great application prospect in antibacterial therapy expected to reduce the risk of bacterial infection. In this mini-review, we generally overviewed and summarized recent progress on inorganic nanoparticle-based optical imaging techniques as a platform to construct functional theranostics for the efficient treatment of bacterial infections. The opportunities and challenges in the application of fluorescent optical nanoprobes are prospected.

Download Full-text