Studies of chest computed tomography (CT) in patients with primary antibody deficiency syndromes (ADS) suggest a broad range of bronchial pathology. However, there are as yet no multicentre studies to assess the variety of bronchial pathology in this patient group. One of the underlying reasons is the lack of a consensus methodology, a prerequisite to jointly document chest CT findings. We aimed to establish an international platform for the evaluation of bronchial pathology as assessed by chest CT and to describe the range of bronchial pathologies in patients with antibody deficiency. Ffteen immunodeficiency centres from 9 countries evaluated chest CT scans of patients with ADS using a predefined list of potential findings including an extent score for bronchiectasis. Data of 282 patients with ADS were collected. Patients with common variable immunodeficiency disorders (CVID) comprised the largest subgroup (232 patients, 82.3%). Eighty percent of CVID patients had radiological evidence of bronchial pathology including bronchiectasis in 61%, bronchial wall thickening in 44% and mucus plugging in 29%. Bronchiectasis was detected in 44% of CVID patients aged less than 20 years. Cough was a better predictor for bronchiectasis than spirometry values. Delay of diagnosis as well as duration of disease correlated positively with presence of bronchiectasis. The use of consensus diagnostic criteria and a pre-defined list of bronchial pathologies allows for comparison of chest CT data in multicentre studies. Our data suggest a high prevalence of bronchial pathology in CVID due to late diagnosis or duration of disease.
- MeSH
- běžná variabilní imunodeficience patologie MeSH
- bronchiektazie patologie MeSH
- bronchy patologie MeSH
- dítě MeSH
- dospělí MeSH
- hrudní stěna patologie MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- počítačová rentgenová tomografie metody MeSH
- předškolní dítě MeSH
- senioři MeSH
- spirometrie metody MeSH
- syndromy imunologické nedostatečnosti patologie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- Klíčová slova
- sekundární imunodeficience,
- MeSH
- antitumorózní látky škodlivé účinky terapeutické užití MeSH
- glukokortikoidy škodlivé účinky terapeutické užití MeSH
- iatrogenní nemoci MeSH
- lidé MeSH
- monoklonální protilátky škodlivé účinky terapeutické užití MeSH
- radioterapie škodlivé účinky MeSH
- splenektomie škodlivé účinky MeSH
- syndromy imunologické nedostatečnosti * chemicky indukované diagnóza patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Imunitný systém patrí k základným mechanizmom organizmu udržiavajúcim rovnováhu. Protilátkové imunodeficiencie sú poruchy, vyplývajú z absencie alebo nedostatočnej funkcie jednej alebo viacerých zložiek imunitného systému. V súčasnosti sa viac preferuje subkutánne podávanie imunoglobulínov, pretože pacientovi zvyšujú kvalitu života, vzhľadom na aplikáciu v domácom prostredí. Pacientove obmedzenia sú v porovnaní s intravenóznou aplikáciou menšie. Subkutánne podávanie liečivých prípravkov predstavuje menej častý, ale veľmi významný parenterálny spôsob podávania liečivých látok do podkožného tkaniva.
The immune system is one of the basic mechanisms of the organism that maintains balance. Immunodeficiency conditions are disorders of any component of immune defence, resulting from the absence or insufficiency of function of one or more components of the immune system. At present, subcutaneous administration of immunoglobulins is preferred because it improves the quality of life of the patient due to being applied in the home. The limitations on the patient are fewer than in comparison with intravenous administration. Subcutaneous administration of drug preparations is a less frequent, but very important, parenteral route for administration of medicinal substances to the subcutaneous tissue.
- Klíčová slova
- selektivní deficit IgM,
- MeSH
- alergie MeSH
- autoimunitní nemoci MeSH
- imunoglobulin M * imunologie krev nedostatek MeSH
- infekce MeSH
- lidé MeSH
- syndromy imunologické nedostatečnosti * diagnóza komplikace patologie terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Pathogenic gain-of-function variants in the genes encoding phosphoinositide 3-kinase δ (PI3Kδ) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy, and immune deficiency (activated PI3Kδ syndrome [APDS]). Knowing the genetic etiology of APDS afforded us the opportunity to explore PI3Kδ inhibition as a precision-medicine therapy. Here, we report in vitro and in vivo effects of inhibiting PI3Kδ in APDS. Treatment with leniolisib (CDZ173), a selective PI3Kδ inhibitor, caused dose-dependent suppression of PI3Kδ pathway hyperactivation (measured as phosphorylation of AKT/S6) in cell lines ectopically expressing APDS-causative p110δ variants and in T-cell blasts derived from patients. A clinical trial with 6 APDS patients was conducted as a 12-week, open-label, multisite, within-subject, dose-escalation study of oral leniolisib to assess safety, pharmacokinetics, and effects on lymphoproliferation and immune dysregulation. Oral leniolisib led to a dose-dependent reduction in PI3K/AKT pathway activity assessed ex vivo and improved immune dysregulation. We observed normalization of circulating transitional and naive B cells, reduction in PD-1+CD4+ and senescent CD57+CD4- T cells, and decreases in elevated serum immunoglobulin M and inflammatory markers including interferon γ, tumor necrosis factor, CXCL13, and CXCL10 with leniolisib therapy. After 12 weeks of treatment, all patients showed amelioration of lymphoproliferation with lymph node sizes and spleen volumes reduced by 39% (mean; range, 26%-57%) and 40% (mean; range, 13%-65%), respectively. Thus, leniolisib was well tolerated and improved laboratory and clinical parameters in APDS, supporting the specific inhibition of PI3Kδ as a promising new targeted therapy in APDS and other diseases characterized by overactivation of the PI3Kδ pathway. This trial was registered at www.clinicaltrials.gov as #NCT02435173.
- MeSH
- aktivace lymfocytů účinky léků MeSH
- chemokiny krev MeSH
- cílená molekulární terapie * MeSH
- demografie MeSH
- dítě MeSH
- fenotyp MeSH
- fosfatidylinositol-3-kinasy třídy I antagonisté a inhibitory imunologie metabolismus MeSH
- imunoglobulin M krev MeSH
- inhibitory proteinkinas farmakologie MeSH
- kojenec MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- lymfatické uzliny účinky léků patologie MeSH
- mutace genetika MeSH
- předškolní dítě MeSH
- pyridiny farmakokinetika farmakologie MeSH
- pyrimidiny farmakokinetika farmakologie MeSH
- slezina účinky léků patologie MeSH
- syndromy imunologické nedostatečnosti farmakoterapie enzymologie imunologie patologie MeSH
- T-lymfocyty účinky léků imunologie MeSH
- TOR serin-threoninkinasy antagonisté a inhibitory metabolismus MeSH
- transfekce MeSH
- velikost orgánu MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, N.I.H., Intramural MeSH
Schimke immuno-osseous dysplasia (SIOD) is a rare multisystem disorder with early mortality and steroid-resistant nephrotic syndrome (SRNS) progressing to end-stage kidney disease. We hypothesized that next-generation gene panel sequencing may unsurface oligosymptomatic cases of SIOD with potentially milder disease courses. We analyzed the renal and extrarenal phenotypic spectrum and genotype-phenotype associations in 34 patients from 28 families, the largest SMARCAL1-associated nephropathy cohort to date. In 11 patients the diagnosis was made unsuspectedly through SRNS gene panel testing. Renal disease first manifested at median age 4.5 yrs, with focal segmental glmerulosclerosis or minimal change nephropathy on biopsy and rapid progression to end-stage kidney disease (ESKD) at median age 8.7 yrs. Whereas patients diagnosed by phenotype more frequently developed severe extrarenal complications (cerebral ischemic events, septicemia) and were more likely to die before age 10 years than patients identified by SRNS-gene panel screening (88 vs. 40%), the subgroups did not differ with respect to age at proteinuria onset and progression to ESKD. Also, 10 of 11 children diagnosed unsuspectedly by Next Generation Sequencing were small at diagnosis and all showed progressive growth failure. Severe phenotypes were usually associated with biallelic truncating mutations and milder phenotypes with biallelic missense mutations. However, no genotype-phenotype correlation was observed for the renal disease course. In conclusion, while short stature is a reliable clue to SIOD in children with SRNS, other systemic features are highly variable. Our findings support routine SMARCAL1 testing also in non-syndromic SRNS.
- MeSH
- arterioskleróza diagnóza genetika patologie MeSH
- dítě MeSH
- DNA-helikasy genetika MeSH
- dospělí MeSH
- fenotyp MeSH
- genetické testování MeSH
- genotyp MeSH
- kohortové studie MeSH
- kojenec MeSH
- ledviny patologie MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace MeSH
- nefrotický syndrom diagnóza genetika patologie MeSH
- osteochondrodysplazie diagnóza genetika patologie MeSH
- plicní embolie diagnóza genetika patologie MeSH
- předškolní dítě MeSH
- syndromy imunologické nedostatečnosti diagnóza genetika patologie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
