Multisystem inflammatory syndrome in children (MIS-C) is a rare, but severe complication of coronavirus disease 2019 (COVID-19). It develops approximately 4 weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and involves hyperinflammation with multisystem injury, commonly progressing to shock. The exact pathomechanism of MIS-C is not known, but immunological dysregulation leading to cytokine storm plays a central role. In response to the emergence of MIS-C, the European Academy of Allergy and Clinical Immunology (EAACI) established a task force (TF) within the Immunology Section in May 2021. With the use of an online Delphi process, TF formulated clinical statements regarding immunological background of MIS-C, diagnosis, treatment, follow-up, and the role of COVID-19 vaccinations. MIS-C case definition is broad, and diagnosis is made based on clinical presentation. The immunological mechanism leading to MIS-C is unclear and depends on activating multiple pathways leading to hyperinflammation. Current management of MIS-C relies on supportive care in combination with immunosuppressive and/or immunomodulatory agents. The most frequently used agents are systemic steroids and intravenous immunoglobulin. Despite good overall short-term outcome, MIS-C patients should be followed-up at regular intervals after discharge, focusing on cardiac disease, organ damage, and inflammatory activity. COVID-19 vaccination is a safe and effective measure to prevent MIS-C. In anticipation of further research, we propose a convenient and clinically practical algorithm for managing MIS-C developed by the Immunology Section of the EAACI.

• Klíčová slova
• Delphi, MIS-C, SARS-CoV-2, children, clinical algorithm, clinical guidance, hyperinflammation, intravenous immunoglobulin, management, steroids,
• MeSH
• COVID-19 * MeSH
• dítě MeSH
• lidé MeSH
• SARS-CoV-2 MeSH
• syndrom systémové zánětlivé reakce diagnóza   terapie   MeSH
• vakcíny proti COVID-19 MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• vakcíny proti COVID-19 MeSH

Our study presents a novel germline c.1715G>T (p.G572V) mutation in the gene encoding Toll-like receptor 8 (TLR8) causing an autoimmune and autoinflammatory disorder in a family with monozygotic male twins, who suffer from severe autoimmune hemolytic anemia worsening with infections, and autoinflammation presenting as fevers, enteritis, arthritis, and CNS vasculitis. The pathogenicity of the mutation was confirmed by in vitro assays on transfected cell lines and primary cells. The p.G572V mutation causes impaired stability of the TLR8 protein, cross-reactivity to TLR7 ligands and reduced ability of TLR8 to attenuate TLR7 signaling. This imbalance toward TLR7-dependent signaling leads to increased pro-inflammatory responses, such as nuclear factor-κB (NF-κB) activation and production of pro-inflammatory cytokines IL-1β, IL-6, and TNFα. This unique TLR8 mutation with partial TLR8 protein loss and hyperinflammatory phenotype mediated by TLR7 ligands represents a novel inborn error of immunity with childhood-onset and a good response to TLR7 inhibition.

• MeSH
• autoimunitní hemolytická anemie genetika   imunologie   MeSH
• cytokiny genetika   imunologie   MeSH
• dvojčata monozygotní MeSH
• HEK293 buňky MeSH
• lidé MeSH
• mutace * MeSH
• posouzení stavu pacienta MeSH
• toll-like receptor 7 genetika   imunologie   MeSH
• toll-like receptor 8 genetika   imunologie   MeSH
• zánět genetika   imunologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• studie na dvojčatech MeSH
• Názvy látek
• cytokiny MeSH
• TLR7 protein, human MeSH Prohlížeč
• TLR8 protein, human MeSH Prohlížeč
• toll-like receptor 7 MeSH
• toll-like receptor 8 MeSH

• MeSH
• aktivační mutace imunologie   MeSH
• COVID-19 imunologie   MeSH
• imunogenicita vakcíny imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mRNA vakcíny škodlivé účinky   imunologie   MeSH
• protilátky virové imunologie   MeSH
• SARS-CoV-2 imunologie   MeSH
• syntetické vakcíny škodlivé účinky   imunologie   MeSH
• transkripční faktor STAT1 imunologie   MeSH
• vakcíny proti COVID-19 škodlivé účinky   imunologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH
• Názvy látek
• mRNA vakcíny MeSH
• protilátky virové MeSH
• STAT1 protein, human MeSH Prohlížeč
• syntetické vakcíny MeSH
• transkripční faktor STAT1 MeSH
• vakcíny proti COVID-19 MeSH

We present a case of a 42-year-old woman with Mendelian susceptibility to mycobacterial disease. The disease was diagnosed at an adult age with relatively typical clinical manifestations; the skeleton, joints, and soft tissues were affected by nontuberculous mycobacteria: Mycobacterium lentiflavum, M. kansasii, and M. avium. A previously published loss-of-function and functionally validated variant NM_000416.2:c.819_822delTAAT in IFNGR1 in a heterozygous state was detected using whole-exome sequencing. After interferon-γ therapy was started at a dose of 200 µg/m2 three times a week, there was significant clinical improvement, with the need to continue the macrolide-based combination regimen. In the last 4 months, she has been in this therapy without the need for antibiotic treatment.

• Publikační typ
• kazuistiky MeSH

PURPOSE: Signal transducer and activator of transcription 1 gain-of-function (STAT1 GOF) mutations are the most common cause of chronic mucocutaneous candidiasis (CMC). We aim to report the effect of oral ruxolitinib, the Janus kinase (JAK) family tyrosine kinase inhibitor, on clinical and immune status of a 12-year-old boy with severe CMC due to a novel STAT1 GOF mutation. METHODS: Clinical features and laboratory data were analyzed, particularly lymphocyte subsets, ex vivo IFNγ- and IFNα-induced STAT1, 3, 5 phosphorylation dynamics during the course of JAK1/2 inhibition therapy, and Th17-related, STAT1- and STAT3-inducible gene expression before and during the treatment. Sanger sequencing was used to detect the STAT1 mutation. Literature review of ruxolitinib in treatment of CMC is appended. RESULTS: A novel STAT1 GOF mutation (c.617T > C; p.L206P), detected in a child with recalcitrant CMC, was shown to be reversible in vitro with ruxolitinib. Major clinical improvement was achieved after 8 weeks of ruxolitinib treatment, while sustained suppression of IFNγ- and IFNα-induced phosphorylation of STAT1, STAT3, and STAT5, as well as increased STAT3-inducible and Th17-related gene expression, was demonstrated ex vivo. Clinical relapse and spike of all monitored phosphorylated STAT activity was registered shortly after unplanned withdrawal, decreasing again after ruxolitinib reintroduction. No increase of peripheral CD4+ IL17+ T cells was detected after 4 months of therapy. No adverse effects were noted. CONCLUSION: JAK1/2 inhibition with ruxolitinib represents a viable option for treatment of refractory CMC, if HSCT is not considered. However, long-term administration is necessary, as the effect is not sustained after treatment discontinuation.

• Klíčová slova
• Chronic mucocutaneous candidiasis, Janus kinase inhibitor, candida, ruxolitinib, signal transducer and activator of transcription 1,
• MeSH
• aktivační mutace * MeSH
• biologické markery MeSH
• CD4-pozitivní T-lymfocyty imunologie   metabolismus   MeSH
• cytokiny metabolismus   MeSH
• dítě MeSH
• fosforylace MeSH
• genetická predispozice k nemoci MeSH
• imunofenotypizace MeSH
• inhibitory proteinkinas aplikace a dávkování   terapeutické užití   MeSH
• Janus kinasy antagonisté a inhibitory   MeSH
• kandidóza chronická mukokutánní diagnóza   farmakoterapie   genetika   metabolismus   MeSH
• lidé MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• nitrily MeSH
• pyrazoly aplikace a dávkování   terapeutické užití   MeSH
• pyrimidiny MeSH
• T-lymfocyty - podskupiny imunologie   metabolismus   MeSH
• transkripční faktor STAT1 genetika   metabolismus   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH
• cytokiny MeSH
• inhibitory proteinkinas MeSH
• Janus kinasy MeSH
• nitrily MeSH
• pyrazoly MeSH
• pyrimidiny MeSH
• ruxolitinib MeSH Prohlížeč
• STAT1 protein, human MeSH Prohlížeč
• transkripční faktor STAT1 MeSH