OBJECTIVE: Pulmonary involvement in chronic nonbacterial osteomyelitis (CNO) is rare. Limited awareness results in diagnostic challenges, especially because malignancy or infection needs to be considered. METHODS: Based on a survey shared among centers participating in the Kerndokumentation Deutsches Rheumaforschungszentrum (Germany), this study investigated clinical and imaging presentations, demographic features, treatment response and outcomes of pulmonary involvement in CNO (pCNO). Magnetic resonance imaging and computed tomography images were read centrally by an experienced pediatric radiologist. RESULTS: Twenty-two patients with pCNO were included in this study. Among patients with CNO, pulmonary involvement was more common in girls (91% vs 62.8%, P = 0.006) and patients with multifocal bone lesions (95% vs 65%, P <0.001) but was not associated with systemic inflammation or additional organ involvement. Forty-two pulmonary lesions were counted with a median of two per patient (two to six). They displayed a median size of 1.8 cm (0.3-4.0 cm) and followed mono- (40%) and oligo-focal (60%) patterns representing consolidations or nodules, abutting the pleura in 50%. Although prominent hilar lymph nodes were present (in 19% of patients), no pathologic enlargement (>1 cm) was seen. When available (3 of 22 patients), histology revealed granulomatous inflammation with lymphocyte infiltration. Development and courses of pCNO did not associate with treatments chosen. Complete remission was reported in 60% of patients, partial remission in 20%. CONCLUSION: pCNO is usually asymptomatic. Although more common in girls and patients with multifocal CNO, pCNO is not associated with systemic parameters of inflammation or specific organ involvement. Prognosis of pCNO is favorable, and most lesions resolve over time. Thus, a careful watch-and-wait strategy may be appropriate.
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Inborn errors of immunity are genetic disorders characterized by various degrees of immune dysregulation that can manifest as immune deficiency, autoimmunity, or autoinflammation. The routine use of next-generation sequencing in the clinic has facilitated the identification of an ever-increasing number of inborn errors of immunity, revealing the roles of immunologically important genes in human pathologies. However, despite this progress, treatment is still extremely challenging. OBJECTIVE: We sought to report a new monogenic autoinflammatory disorder caused by a de novo activating mutation, p.Tyr515∗, in hematopoietic cell kinase (HCK). The disease is characterized by cutaneous vasculitis and chronic pulmonary inflammation that progresses to fibrosis. METHODS: Whole-exome sequencing, Sanger sequencing, mass spectrometry, and western blotting were performed to identify and characterize the pathogenic HCK mutation. Dysregulation of mutant HCK was confirmed ex vivo in primary cells and in vitro in transduced cell lines. RESULTS: Mutant HCK lacking the C-terminal inhibitory tyrosine Tyr522 exhibited increased kinase activity and enhanced myeloid cell priming, migration and effector functions, such as production of the inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α, and production of reactive oxygen species. These aberrant functions were reflected by inflammatory leukocyte infiltration of the lungs and skin. Moreover, an overview of the clinical course of the disease, including therapies, provides evidence for the therapeutic efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in inflammatory lung disease. CONCLUSIONS: We propose HCK-driven pulmonary and cutaneous vasculitis as a novel autoinflammatory disorder of inborn errors of immunity.
We present a case of complete deficiency of the interferon alpha/beta receptor alpha chain (IFNAR1) in a child with fatal systemic hyperinflammation, apparently provoked by live-attenuated viral vaccination. Such pathologic hyperinflammation, fulfilling criteria for hemophagocytic lymphohistiocytosis, is an emerging phenotype accompanying inborn errors of type I interferon immunity.
Cíl studie: Chronická granulomatózní nemoc (CGD) je vzácná primární imunodeficience s X-vázanou nebo autosomálně recesivní dědičností způsobená defekty v genech kódujících podjednotky fagocytárních oxidáz z komplexu nikotinamid adenin dinukleotid fosfát (NADPH) oxidázy. Tento komplex je v buňce zodpovědný za respirační vzplanutí, což vede k usmrcení mikrobů požitých fagocytovými buňkami. NADPH oxidáza také hraje klíčovou roli v regulaci imunity, a proto je CGD též charakterizována autoimunitními a autoinflamačními projevy. Transplantace hematopoetických kmenových buněk (HSCT) je jedinou definitivní kurativní léčebnou metodou. Uvádíme zde výsledky pacientů s CGD, kteří podstoupili v letech 2007–2019 alogenní HSCT v dětských transplantačních centrech v Praze a Bratislavě. Metodika: Čtrnáct pacientů s chronickou granulomatózou podstoupilo první transplantaci hematopoetických kmenových buněk v mediánu věku 6,4 let (1,0–17,8). Genová mutace genu CYBB (X-vázaná dědičnost) byla identifikována u třinácti z nich. Zdrojem kmenových buněk byla kostní dřeň (n = 10) nebo periferní kmenové buňky (n = 4) HLA identického nepříbuzného dárce (n = 13) nebo zdravého HLA identického sourozence (n = 1). Výsledky: U všech 14 pacientů po transplantaci došlo k primárnímu přihojení štěpu. Pět pacientů, kteří později odhojili primární štěp, úspěšně podstoupili druhou transplantaci. Jeden pacient zemřel šest měsíců po HSCT v důsledku cerebrálního krvácení po opakovaném chirurgickém zákroku pro aspergilom mozku, u jiného pacienta byla diagnostikována sekundární akutní myeloidní leukémie osm let po HSCT a před 12 měsíci podstoupil druhou transplantaci. 13/14 pacientů žije s mediánem sledování 6,1 (0,1–12,2) let po poslední HSCT. Závěry: Alogenní HSCT byly provedeny bez závažnějších komplikací souvisejících s transplantací. Klíčovým bodem této terapie zůstává včasná indikace, stupeň postižení orgánů před transplantací a výběr vhodných dárců a přípravných režimů s cílem snížit riziko pozdních odhojení štěpů a potřebu re-transplantací.
Objective: Chronic Granulomatous Disease (CGD) is a rare primary immunodeficiency with X-linked or autosomal recessive inheritance caused by defects in the genes encoding phagocyte oxidase subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. This complex is responsible for the respiratory burst inside the cell, which leads to the killing of microbes ingested by phagocytic cells. NADPH oxidase also plays key role in regulating immunity and therefore CGD is also characterized by autoimmune and autoinflammatory manifestations. Hematopoietic stem cell transplant (HSCT) is the only definitive curative treatment. Here we present the outcome of patients with CGD who from 2007 till 2018 underwent allogeneic HSCT at pediatric transplant centers in Prague and Bratislava. Methods: Fourteen patients with chronic granulomatous disease received first hematopoietic stem cell transplant at a medium age of 6.4 years (1.0-17.8). CYBB gene mutation (X-linked) was identified in thirteen of them. The stem cell source was bone marrow (n=10) or peripheral stem cells (n=4) from a human leukocyte antigen identical unrelated (n=13) or healthy sibling (n=1) donor. Results: Primary engraftment was obtained in all 14 patients. Five patients, who later lost the primary graft, were successfully re-grafted following second HSCT. One patient died six months after HSCT due to cerebral bleeding following repeated surgery for cerebral aspergilloma, one developed secondary acute myeloid leukemia eight years after HSCT and 12 months ago underwent second transplant. 13/14 patients are alive with median follow-up 6.1 (range 0.1-12.2) years after the last HSCT. Conclusions: Allogeneic HSCT were safely performed without serious transplant-related complications. Early indication, pre-transplant organ involvement, donor selection and conditioning regimens remain the key points with the aim to decrease the risk of late graft failure and need for re-HSCT.
- MeSH
- chronická granulomatózní nemoc * terapie MeSH
- dítě MeSH
- infekce MeSH
- klinická studie jako téma MeSH
- kvalita života MeSH
- lidé MeSH
- transplantace kmenových buněk metody MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. CONCLUSION: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.
- MeSH
- dítě MeSH
- kojenec MeSH
- kombinované imunodeficience vázané na chromozom X mortalita terapie MeSH
- lidé MeSH
- ligand CD40 nedostatek MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- transplantace hematopoetických kmenových buněk * MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Specific granule deficiency (SGD) is a rare disorder characterized by abnormal neutrophils evidenced by reduced granules, absence of granule proteins, and atypical bilobed nuclei. Mutations in CCAAT/enhancer-binding protein-ε (CEBPE) are one molecular etiology of the disease. Although C/EBPε has been studied extensively, the impact of CEBPE mutations on neutrophil biology remains elusive. Here, we identified two SGD patients bearing a previously described heterozygous mutation (p.Val218Ala) in CEBPE. We took this rare opportunity to characterize SGD neutrophils in terms of granule distribution and protein content. Granules of patient neutrophils were clustered and polarized, suggesting that not only absence of specific granules but also defects affecting other granules contribute to the phenotype. Our analysis showed that remaining granules displayed mixed protein content and lacked several glycoepitopes. To further elucidate the impact of mutant CEBPE, we performed detailed proteomic analysis of SGD neutrophils. Beside an absence of several granule proteins in patient cells, we observed increased expression of members of the linker of nucleoskeleton and cytoskeleton complex (nesprin-2, vimentin, and lamin-B2), which control nuclear shape. This suggests that absence of these proteins in healthy individuals might be responsible for segmented shapes of neutrophilic nuclei. We further show that the heterozygous mutation p.Val218Ala in CEBPE causes SGD through prevention of nuclear localization of the protein product. In conclusion, we uncover that absence of nuclear C/EBPε impacts on spatiotemporal expression and subsequent distribution of several granule proteins and further on expression of proteins controlling nuclear shape.
- Publikační typ
- časopisecké články MeSH
BACKGROUND: X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. OBJECTIVES: We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT. METHODS: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression. RESULTS: Twenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 ± 7.2 years (range, 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation. CONCLUSION: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964-2013). However, survivors treated with HCT experienced somewhat greater well-being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates.
- MeSH
- čas MeSH
- dítě MeSH
- dospělí MeSH
- imunodeficience s hyper-IgM mortalita terapie MeSH
- Kaplanův-Meierův odhad MeSH
- kohortové studie MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- následné studie MeSH
- předškolní dítě MeSH
- proporcionální rizikové modely MeSH
- retrospektivní studie MeSH
- transplantace hematopoetických kmenových buněk mortalita MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- pozorovací studie MeSH
GATA-2 deficiency was recently described as common cause of overlapping syndromes of immunodeficiency, lymphedema, familiar myelodysplastic syndrome or acute myeloid leukemia. The aim of our study was to analyze bone marrow and peripheral blood samples of children with myelodysplastic syndrome or aplastic anemia to define prevalence of the GATA2 mutation and to assess whether mutations in GATA-2 transcription factor exhibit specific immunophenotypic features. The prevalence of a GATA2 mutation in a consecutively diagnosed cohort of children was 14% in advanced forms of myelodysplastic syndrome (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and myelodysplasia-related acute myeloid leukemia), 17% in refractory cytopenia of childhood, and 0% in aplastic anemia. In GATA-2-deficient cases, we found the most profound B-cell lymphopenia, including its progenitors in blood and bone marrow, which correlated with significantly diminished intronRSS-Kde recombination excision circles in comparison to other myelodysplastic syndrome/aplastic anemia cases. The other typical features of GATA-2 deficiency (monocytopenia and natural killer cell lymphopenia) were less discriminative. In conclusion, we suggest screening for GATA2 mutations in pediatric myelodysplastic syndrome, preferentially in patients with impaired B-cell homeostasis in bone marrow and peripheral blood (low number of progenitors, intronRSS-Kde recombination excision circles and naïve cells).
- MeSH
- aplastická anemie diagnóza etiologie MeSH
- B-lymfocyty metabolismus MeSH
- biologické markery MeSH
- buňky kostní dřeně metabolismus patologie MeSH
- diferenciální diagnóza MeSH
- dítě MeSH
- fenotyp MeSH
- imunofenotypizace MeSH
- kojenec MeSH
- kostní dřeň metabolismus patologie MeSH
- lidé MeSH
- lymfopenie diagnóza MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace MeSH
- myelodysplastické syndromy diagnóza genetika MeSH
- myeloidní buňky metabolismus MeSH
- počet lymfocytů MeSH
- předškolní dítě MeSH
- prekurzorové B-lymfoidní buňky metabolismus MeSH
- ROC křivka MeSH
- T-lymfocyty - podskupiny imunologie metabolismus MeSH
- transkripční faktor GATA2 nedostatek MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
