Distinct clinical and immunological features of SARS-COV-2-induced multisystem inflammatory syndrome in children

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Abstract

Background: Pediatric SARS-CoV-2 infection can be complicated by a dangerous hyperinflammatory condition termed multisystem inflammatory syndrome in children (MIS-C). The clinical and immunologic spectrum of MIS-C and its relationship to other inflammatory conditions of childhood have not been studied in detail. Methods: We retrospectively studied confirmed cases of MIS-C at our institution from March to June 2020. The clinical characteristics, laboratory studies and treatment response were collected. Data were compared with historic cohorts of Kawasaki disease (KD) and macrophage activation syndrome (MAS). Results: Twenty-eight patients fulfilled the case definition of MIS-C. Median age at presentation was 9 years (range 1 month to 17 years); 50% of patients had pre-existing conditions. All patients had laboratory confirmation of SARS-CoV-2 infection. Seventeen patients (61%) required intensive care, including 7 patients (25%) requiring inotrope support. Seven patients (25%) met criteria for complete or incomplete KD and coronary abnormalities were found in 6 cases. Lymphopenia, thrombocytopenia, and elevation in inflammatory markers, D-dimer, B-type natriuretic peptide, IL-6 and IL-10 levels were common but not ubiquitous. Cytopenias distinguished MIS-C from KD and the degree of hyperferritinemia and pattern of cytokine production differed between MIS-C and MAS. Immunomodulatory therapy given to MIS-C patients included IVIG (71%), corticosteroids (61%) and anakinra (18%). Clinical and laboratory improvement were observed in all cases, including 6 cases that did not require immunomodulatory therapy. No mortality was recorded in this cohort. Conclusion: MIS-C encompasses a broad phenotypic spectrum with clinical and laboratory features distinct from Kawasaki disease and macrophage activation syndrome. Funding: This work was supported by the National Institute of Health / National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) K08-AR074562 (PYL), K08-AR AR073339 (LAH), R01-AR065538, R01-AR073201 and P30-AR070253 (PAN); National Institute of Allergy and Infectious Diseases 5T32AI007512-34 (JL, JR, TB, AAN and RWN); Rheumatology Research Foundation Investigator Awards (PYL and LAH) and Medical Education Award (JSH); Boston Children’s Hospital Faculty Career Development Awards (PYL and LAH), the McCance Family Foundation (JWN), and the Samara Jan Turkel Center (JC, RPS, MBS).

Authors

Pui Y. Lee, Megan Day-Lewis, Lauren A. Henderson, Kevin Friedman, Jeffrey Lo, Jordan E. Roberts, Mindy S. Lo, Craig D. Platt, Janet Chou, Kacie J. Hoyt, Annette L. Baker, Tina Banzon, Margaret H. Chang, Ezra Cohen, Sarah de Ferranti, Audrey Dionne, Saddiq Habiballah, Olha Halyabar, Jonathan S. Hausmann, Melissa Hazen, Erin Janssen, Esra Meidan, Ryan W. Nelson, Alan A. Nguyen, Robert P. Sundel, Fatma Dedeoglu, Peter A. Nigrovic, Jane W. Newburger, Mary Beth F. Son

Circadian rhythm influences induction of trained immunity by BCG vaccination

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Abstract

BACKGROUND. The anti-tuberculosis vaccine Bacillus Calmette-Guérin (BCG) reduces overall infant mortality. Induction of innate immune memory, also termed trained immunity, contributes towards protection against heterologous infections. Since immune cells display oscillations in numbers and function throughout the day, we investigated the effect of BCG administration time on the induction of trained immunity. METHODS. 18 volunteers were vaccinated with BCG at 6pm and compared with 36 age- and sex-matched volunteers vaccinated between 8-9 am. Peripheral blood mononuclear cells were stimulated with Staphylococcus aureus and Mycobacterium tuberculosis before, as well as two weeks and three months after BCG vaccination. Cytokine production was measured to assess the induction of trained immunity and adaptive responses, respectively. Additionally, the influence of vaccination time on induction of trained immunity was studied in an independent cohort of 302 individuals vaccinated between 8am-12pm with BCG. RESULTS. Compared to evening vaccination, morning vaccination elicited both a stronger trained immunity and adaptive immune phenotype. In a large cohort of 302 volunteers, early morning vaccination resulted in a superior cytokine production capacity compared with later morning. A cellular, rather than soluble, substrate of the circadian effect of BCG vaccination was demonstrated by the enhanced capacity to induce trained immunity in vitro in morning compared to evening isolated monocytes. CONCLUSIONS. BCG vaccination in the morning induces stronger trained immunity and adaptive responses compared to evening vaccination. Future studies should take vaccine administration time into account when studying specific and non-specific effects of vaccines: early morning should be the preferred moment of BCG administration. FUNDING Spinoza grant of the Netherlands Organization for Scientific Research, ERC Advanced Grant (TRAIN-OLD nr. 833247), Danish National Research Foundation (DNRF108).

Authors

L. Charlotte J. de Bree, Vera P. Mourits, Valerie A.C.M. Koeken, Simone J.C.F.M. Moorlag, Robine Janssen, Lukas Folkman, Daniele Barreca, Thomas Krausgruber, Victoria Fife-Gernedl, Boris Novakovic, Rob J.W. Arts, Helga Dijkstra, Heidi Lemmers, Christoph Bock, Leo A.B. Joosten, Reinout van Crevel, Christine S. Benn, Mihai G. Netea

Toward an equitable society: building a culture of antiracism in health care

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Abstract

Addressing racism from within health care is critically important to creating an equitable society. Here, we provide an actionable framework that can be implemented to build a culture of antiracism in health care systems.

Authors

Eugenia C. South, Paris D. Butler, Raina M. Merchant

Prioritizing clinical research studies during the COVID-19 pandemic: lessons from New York City

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Abstract

A retrospective look at how clinical research trials were prioritized in New York City in the wake of the COVID-19 pandemic provides insights for future clinical research efforts.

Authors

Roy M. Gulick, Magdalena E. Sobieszczyk, Donald W. Landry, Anthony N. Hollenberg

Diagnostic accuracy of three urine lipoarabinomannan tuberculosis assays in HIV-negative outpatients

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Abstract

Background: Inadequate tuberculosis (TB) diagnostics are a major hurdle in the reduction of disease burden and accurate point-of-care tests (POCT) are urgently needed. We assessed the diagnostic accuracy of Fujifilm SILVAMP TB LAM (FujiLAM) for TB diagnosis in HIV-negative outpatients compared to Alere Determine TB LAM Ag (AlereLAM) and a laboratory-based ultrasensitive electrochemiluminescence LAM research assay (EclLAM). Methods: In this multicentre diagnostic test accuracy study, we recruited HIV-negative adults with symptoms suggestive of pulmonary TB presenting to outpatient healthcare centres in Peru and South Africa. Urine samples were tested using FujiLAM, AlereLAM and EclLAM and the diagnostic accuracy was assessed against microbiological (MRS) and composite reference standards. Results: 372 HIV-negative participants were included and the prevalence of microbiologically confirmed TB was 30%. Compared to the MRS, the sensitivities of AlereLAM, FujiLAM and EclLAM were 10.8% (95% CI 6.3to18.0), 53.2% (43.9to62.1), and 66.7% (57.5to74.7) respectively. The specificities of AlereLAM, FujiLAM and EclLAM were 92.3% (88.5to95.0), 98.9% (96.7to99.6), and 98.1% (95.6to99.2) respectively. Positive Likelihood Ratio of AlereLAM, FujiLAM and EclLAM were 1.4, 46.2, and 34.8 and positive predictive values 37.5%, 95.2%, and 93.7% respectively. Conclusion: Compared to AlereLAM, FujiLAM detected five times more TB patients in HIV-negative participants, has a high positive predictive value and has the potential to improve rapid diagnosis of TB at the point-of-care. EclLAM demonstrated that additional sensitivity gains are possible, which highlights LAMs potential as a biomarker. Additional research is required to assess FujiLAMs performance in prospective cohorts, its cost-effectiveness, and its impact in real-world clinical settings.

Authors

Tobias Broger, Mark Nicol, George Sigal, Eduardo Gotuzzo, Alexandra J. Zimmer, Shireen Surtie, Tatiana Caceres-Nakiche, Anna Mantsoki, Elena Ivanova Reipold, Rita Székely, Michael Tsionsky, Judith van Heerden, Tatiana Plisova, Kinuyo Chikamatsu, Todd L. Lowary, Abraham Pinter, Satoshi Mitarai, Emmanuel Moreau, Samuel G Schumacher, Claudia M. Denkinger

NIDDK initiatives addressing health disparities in chronic diseases

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The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) focuses on many diseases that place disparate burdens on minority groups and the poor, such as obesity, diabetes, and kidney disease. Here, we highlight the NIDDK's commitment to combating health disparities through basic, translational, and clinical research.

Authors

B. Tibor Roberts, Griffin P. Rodgers

BCG vaccination in humans inhibits systemic inflammation in a sex-dependent manner

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Abstract

Background. Induction of innate immune memory, also termed trained immunity, by the anti-tuberculosis vaccine Bacillus Calmette-Guérin (BCG) contributes to protection against heterologous infections. However, the overall impact of BCG vaccination on the inflammatory status of an individual is not known: while induction of trained immunity may suggest increased inflammation, BCG vaccination has been epidemiologically associated with a reduced incidence of inflammatory and allergic diseases. Methods. We investigated the impact of BCG (BCG-Bulgaria, InterVax) vaccination on systemic inflammation in a cohort of 303 healthy volunteers, as well as the effect of the inflammatory status on the response to vaccination. A targeted proteome platform was used to measure circulating inflammatory proteins before and after BCG vaccination, while ex vivo Mycobacterium tuberculosis and Staphylococcus aureus induced cytokine responses in peripheral blood mononuclear cells were used to assess trained immunity. Results. While BCG vaccination enhanced cytokine responses to restimulation, it reduced systemic inflammation. This effect was validated in three smaller cohorts, and was much stronger in men than in women. In addition, baseline circulating inflammatory markers were associated with ex vivo cytokine responses (trained immunity) after BCG vaccination. Conclusion. The capacity of BCG to enhance microbial responsiveness while dampening systemic inflammation should be further explored for potential therapeutic applications. Funding. This study was funded by a Spinoza grant of the Netherlands Organization for Scientific Research and an ERC Advanced Grant (TRAIN-OLD nr. 833247).

Authors

Valerie A. C. M. Koeken, L. Charlotte J. de Bree, Vera P. Mourits, Simone J.C.F.M. Moorlag, Jona Walk, Branko Cirovic, Rob J.W. Arts, Martin Jaeger, Helga Dijkstra, Heidi Lemmers, Leo A.B. Joosten, Christine Stabell Benn, Reinout van Crevel, Mihai Netea

Decreased lymphatic HIF-2α accentuates lymphatic remodeling in lymphedema

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Abstract

Pathologic lymphatic remodeling in lymphedema evolves during periods of tissue inflammation and hypoxia through poorly defined processes. In human and mouse lymphedema, there is a significant increase of hypoxia inducible factor (HIF)-1α, but a reduction of HIF-2α protein expression in lymphatic endothelial cells (LECs). We questioned whether dysregulated expression of these transcription factors contributes to disease pathogenesis and found that LEC-specific deletion of Hif-2α exacerbated lymphedema pathology. Even without lymphatic vascular injury, the loss of LEC-specific Hif-2α caused anatomic pathology and a functional decline in fetal and adult mice. These findings suggest that HIF-2α is an important mediator of lymphatic health. HIF-2α promoted protective phosphorylated TIE2 (p-TIE2) signaling in LECs, a process also replicated by upregulating TIE2 signaling through adenovirus-mediated angiopoietin-1 (Angpt1) gene therapy. Our study suggests that HIF-2α normally promotes healthy lymphatic homeostasis and raises the exciting possibility that restoring HIF-2α pathways in lymphedema could mitigate long-term pathology and disability.

Authors

Xinguo Jiang, Wen Tian, Eric J. Granucci, Allen B. Tu, Dongeon Kim, Petra Dahms, Shravani Pasupneti, Gongyong Peng, Yesl Kim, Amber H. Lim, F. Hernan Espinoza, Matthew Cribb, J. Brandon Dixon, Stanley G. Rockson, Gregg L. Semenza, Mark R. Nicolls

Immobilization after injury alters extracellular matrix and stem cell fate

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Abstract

Cells sense extracellular environment and mechanical stimuli and translate these signals into intracellular responses through mechanotransduction and alters cell maintenance, proliferation, and differentiation. Here we use a mouse model of trauma induced heterotopic ossification (HO) to examine how cell-extrinsic forces impact MPC fate. After injury, single cell (sc) RNA sequencing of the injury site reveals an early increase in MPC genes associated with pathways of cell adhesion and ECM-receptor interactions, and MPC trajectories to cartilage and bone. Immunostaining uncovers active mechanotransduction after injury with increased focal adhesion kinase signaling and nuclear translocation of transcriptional co-activator TAZ, inhibition of which mitigates HO. Similarly, joint immobilization decreases mechanotransductive signaling, and completely inhibits HO. Joint immobilization decreases collagen alignment and increases adipogenesis. Further, scRNA sequencing of the HO site after injury with or without immobilization identifies gene signatures in mobile MPCs correlating with osteogenesis, while signatures from immobile MPCs with adipogenesis. scATAC-seq in these same MPCs confirm that in mobile MPCs, chromatin regions around osteogenic genes are open, while in immobile MPCs, regions around adipogenic genes are open. Together these data suggest that joint immobilization after injury results in decreased ECM alignment, altered MPC mechanotransduction, and changes in genomic architecture favoring adipogenesis over osteogenesis, resulting in decreased formation of HO.

Authors

Amanda K. Huber, Nicole Patel, Chase A. Pagani, Simone Marini, Karthik Padmanabhan, Daniel L. Matera, Mohamed Said, Charles Hwang, Ginny Ching-Yun Hsu, Andrea A. Poli, Amy L. Strong, Noelle D. Visser, Joseph A. Greenstein, Reagan Nelson, Shuli Li, Michael T. Longaker, Yi Tang, Stephen J. Weiss, Brendon M. Baker, Aaron W. James, Benjamin Levi

Thioredoxin activity confers resistance against oxidative stress in tumor-infiltrating NK cells

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To improve the clinical outcome of adoptive NK cell therapy in patients with solid tumors, NK cells need to persist within the tumor microenvironment (TME) in which the abundance of reactive oxygen species (ROS) could dampen anti-tumor immune responses. In the present study, we demonstrated that IL-15 primed NK cells acquire resistance against oxidative stress through thioredoxin system activated by mTOR. Mechanistically, the activation of thioredoxin showed dependence on localization of thioredoxin-interacting protein. For the first time, we showed that NK cells residing in the tumor core expressed higher thiol density which could aid to protect other lymphocytes against ROS within the TME. Furthermore, the prognostic value of IL15 and NK cell gene signature in tumors may be influenced by tobacco smoking history in NSCLC patients. Collectively, the levels of reducing antioxidants in NK cells may not only predict for better tumor penetrance but even potentially response to immune therapy.

Authors

Ying Yang, Shi Yong Neo, Ziqing Chen, Weiyingqi Cui, Yi Chen, Min Guo, Yongfang Wang, Haiyan Xu, Annina Kurzay, Evren Alici, Lars Holmgren, Felix Haglund, Kai Wang, Andreas Lundqvist