Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature.

BACKGROUND: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections. METHODS: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39). RESULTS: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV. CONCLUSIONS: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.

Recurrent or unusual infections in children - when to worry about inborn errors of immunity.

Recurrent infections are a common presenting feature in paediatrics and, while most times considered part of normal growing up, they are also a classical hallmark of inborn errors of immunity (IEI). We aimed to outline the value of currently used signs for IEI and the influence of the changing epidemiology of infectious diseases due to implementation of new vaccines and the effect of the COVID-19 pandemic on the assessment of children with recurrent infections. Warning signs for IEI have been developed, but the supporting evidence for their effectiveness is limited, and immune dysregulation is more commonly recognised as a feature for IEI, making reliable identification of children who should be screened for IEI on clinical grounds difficult. In addition, the epidemiology of infectious diseases is changing due to restrictions related to Covid-19 as well as immunisations, which may change the threshold to screen children for IEI. Treatments for IEI are evolving and are often more effective and less complicated when started early. Screening for IEI can be initiated by the non-immunologist and should be considered early to ensure optimal treatment outcomes.

Haploidentical CD3+ TCR αß/CD19+ depleted HSCT for MHC Class II deficiency and persistent SARS-CoV-2 pneumonitis.

Background & Objectives: SARS-CoV-2 infection leads to coronavirus disease 2019 (COVID-19), which can range from a mild illness to a severe phenotype characterised by acute respiratory distress, needing mechanical ventilation. Children with combined immunodeficiencies might be unable to mount a sufficient cellular and humoral immune response against Covid-19 and have persistent disease. The authors describe a child with combined immunodeficiency, with favorable post-HSCT course following a haploidentical haematopoietic stem cell transplant in the presence of persistent SARS-CoV-2 infection. Methods & results: A 13-month-old girl with MHC class II deficiency developed persistent pre-HSCT SARS-CoV-2 infection. Faced with a significant challenge of balancing the risk of progressive infection due to incompetent immune system with the danger of inflammatory pneumonitis peri-immune reconstitution post-HSCT, she underwent a maternal (with a recent history of Covid-19 infection) haploidentical haematopoietic stem cell transplant. The patient received Regdanvimab® (post stem cell infusion) and Remdesivir (pre and post stem cell infusion). We noted a gradual increase in the Ct (cycle threshold) values, implying reduction in viral RNA with concomitant expansion in the CD3 lymphocyte subset and clinical/radiological improvement. Conclusions: Combination of adoptive transfer of maternal CD45RO+ memory add-back T-lymphocytes after haploidentical HSCT, use of Regdanvimab® (SARS-CoV-2 neutralising monoclonal antibody) and Remdesivir may have led to the successful outcome in our patient with severe immunodeficiency, undergoing HSCT. Our case highlights the role of novel antiviral strategies (monoclonal antibodies and CD45RO+ memory T-lymphocytes) in contributing to viral clearance in a challenging clinical scenario.

Haploidentical CD3+ TCR αβ/CD19+ depleted HSCT for MHC Class II deficiency and persistent SARS-CoV-2 pneumonitis

Background & Objectives SARS-CoV-2 infection leads to coronavirus disease 2019 (COVID-19), which can range from a mild illness to a severe phenotype characterised by acute respiratory distress, needing mechanical ventilation. Children with combined immunodeficiencies might be unable to mount a sufficient cellular and humoral immune response against Covid-19 and have persistent disease. The authors describe a child with combined immunodeficiency, with favorable post-HSCT course following a haploidentical haematopoietic stem cell transplant in the presence of persistent SARS-CoV-2 infection. Methods & results A 13-month-old girl with MHC class II deficiency developed persistent pre-HSCT SARS-CoV-2 infection. Faced with a significant challenge of balancing the risk of progressive infection due to incompetent immune system with the danger of inflammatory pneumonitis peri-immune reconstitution post-HSCT, she underwent a maternal (with a recent history of Covid-19 infection) haploidentical haematopoietic stem cell transplant. The patient received Regdanvimab® (post stem cell infusion) and Remdesivir (pre and post stem cell infusion). We noted a gradual increase in the Ct (cycle threshold) values, implying reduction in viral RNA with concomitant expansion in the CD3 lymphocyte subset and clinical/radiological improvement. Conclusions Combination of adoptive transfer of maternal CD45RO+ memory add-back T-lymphocytes after haploidentical HSCT, use of Regdanvimab® (SARS-CoV-2 neutralising monoclonal antibody) and Remdesivir may have led to the successful outcome in our patient with severe immunodeficiency, undergoing HSCT. Our case highlights the role of novel antiviral strategies (monoclonal antibodies and CD45RO+ memory T-lymphocytes) in contributing to viral clearance in a challenging clinical scenario.

Cascading Risks for Preventable Infectious Diseases in Children and Adolescents during the 2022 Invasion of Ukraine.

Russia's military incursion into Ukraine triggered the mass displacement of two-thirds of Ukrainian children and adolescents, creating a cascade of population health consequences and producing extraordinary challenges for monitoring and controlling preventable pediatric infectious diseases. From the onset of the war, infectious disease surveillance and healthcare systems were severely disrupted. Prior to the reestablishment of dependable infectious disease surveillance systems, and during the early months of the conflict, our international team of pediatricians, infectious disease specialists, and population health scientists assessed the health implications for child and adolescent populations. The invasion occurred just as the COVID-19 Omicron surge was peaking throughout Europe and Ukrainian children had not received COVID-19 vaccines. In addition, vaccine coverage for multiple vaccine-preventable diseases, most notably measles, was alarmingly low as Ukrainian children and adolescents were forced to migrate from their home communities, living precariously as internally displaced persons inside Ukraine or streaming into European border nations as refugees. The incursion created immediate impediments in accessing HIV treatment services, aimed at preventing serial transmission from HIV-positive persons to adolescent sexual or drug-injection partners and to prevent vertical transmission from HIV-positive pregnant women to their newborns. The war also led to new-onset, conflict-associated, preventable infectious diseases in children and adolescents. First, children and adolescents were at risk of wound infections from medical trauma sustained during bombardment and other acts of war. Second, young people were at risk of sexually transmitted infections resulting from sexual assault perpetrated by invading Russian military personnel on youth trapped in occupied territories or from sexual assault perpetrated on vulnerable youth attempting to migrate to safety. Given the cascading risks that Ukrainian children and adolescents faced in the early months of the war-and will likely continue to face-infectious disease specialists and pediatricians are using their international networks to assist refugee-receiving host nations to improve infectious disease screening and interventions.

Case Report: Severe Acute Pulmonary COVID-19 in a Teenager Post Autologous Hematopoietic Stem Cell Transplant.

Pulmonary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children is generally described as mild, and SARS-CoV-2 infection in immunocompromised children are observed as generally mild as well. A small proportion of pediatric patients will become critically ill due to (cardio)respiratory failure and require intensive care treatment. We report the case of a teenager with Hodgkin's lymphoma who acquired SARS-CoV-2 (detected by PCR) on the day of her autologous stem cell transplant and developed acute respiratory distress syndrome, successfully treated with a combination of antivirals, immunomodulation with steroids and biologicals, and ECMO.