Invasive meningococcal diseases (IMD) caused by Neisseria meningitidis are generally rare. They affect mostly selected age categories and risk groups of patients (in terms of age, comorbidities, or applied therapy), and the immune system and its defects may play an important modifying role. Meningococcal infections could be the first and only clinical sign of unrecognised immunodeficiency. IMD are a typical clinical presentation of inborn errors of immunity with low concentrations or dysfunction of the terminal components of complement cascade. Meningitis is present in approximately 40% of the patients with terminal complement components deficiencies and in 6% of the patients with properdin deficiency. Despite evident advances in the understanding of the pathogenesis of meningococcal infections and the mechanisms of immune defence against this pathogen, patients with defects in the alternative or terminal complement pathway are highly predisposed to invasive and recurrent meningococcal infections, usually with a mild course. Therefore, it is recommended that each patient with IMD, especially recurrent, should undergo an immunological examination to rule out complement deficiencies.

• Klíčová slova
• Neisseria meningitides, Neisseria meningitidis, complement immunodeficiencies, complement system, immunodeficiency, immunological examination, invasive meningococcal diseases,
• MeSH
• lidé MeSH
• meningokokové infekce * imunologie   diagnóza   MeSH
• recidiva MeSH
• syndromy imunologické nedostatečnosti komplikace   imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Inborn errors of immunity (IEI) are genetically and clinically heterogeneous disorders that, in addition to infection susceptibility and immune dysregulation, can have an enhanced cancer predisposition. The increasing availability of upfront next-generation sequencing diagnostics in immunology and oncology have uncovered substantial overlap of germline and somatic genetic conditions that can result in immunodeficiency and cancer. However, broad application of unbiased genetics in these neighboring disciplines still needs to be deployed, and joined therapeutic strategies guided by germline and somatic genetic risk factors are lacking. We illustrate the current difficulties encountered in clinical practice, summarize the historical development of pathophysiological concepts of cancer predisposition, and review select genetic, molecular, and cellular mechanisms of well-defined and illustrative disease entities such as DNA repair defects, combined immunodeficiencies with Epstein-Barr virus susceptibility, autoimmune lymphoproliferative syndromes, regulatory T-cell disorders, and defects in cell intrinsic immunity. We review genetic variants that, when present in the germline, cause IEI with cancer predisposition but, when arising as somatic variants, behave as oncogenes and cause specific cancer entities. We finally give examples of small molecular compounds that are developed and studied to target genetically defined cancers but might also proof useful to treat IEI.

• Klíčová slova
• Autoimmune lymphoproliferative syndrome, Cancer predisposition, DNA repair defect, Defect in cell intrinsic immunity, EBV susceptibility, Genomics, Germline genetic variant, Inborn error of immunity, Oncogene, Regulatory T-cell disorder, Small molecular compound, Somatic genetic variant,
• MeSH
• genetická predispozice k nemoci MeSH
• genomika MeSH
• infekce virem Epsteina-Barrové * MeSH
• lidé MeSH
• nádory * diagnóza   genetika   terapie   MeSH
• virus Epsteinův-Barrové MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Inborn errors of IL-12/IL-23-IFNγ immunity underlie Mendelian susceptibility to mycobacterial diseases (MSMD), a group of immunodeficiencies characterized by a highly selective susceptibility to weakly virulent strains of mycobacteria, such as non-tuberculous mycobacteria (NTM) and bacillus Calmette-Guérin (BCG). Cutaneous mycobacterial infections are common in MSMD and may represent a red flag for this immunodeficiency. OBJECTIVES: We present a case series of four paediatric patients with MSMD, specifically with IFNγR1 and STAT1 deficiencies, and cutaneous NTM/BCG infections to increase awareness of this immunodeficiency, which may, in some cases, be intercepted by the dermatologist and thus timely referred to the immunologist. MATERIALS & METHODS: Clinical, laboratory and genetic investigations of the four paediatric patients with MSMD are presented. RESULTS: All four presented patients experienced early complications after BCG vaccination. Two patients suffered recurrent mycobacteriosis, one patient experienced delayed BCG reactivation, and one patient died of disseminated avian mycobacteriosis. The dermatological manifestation in these patients included destructive nasal ulcerations, scrofuloderma of various sites and lupus vulgaris. All patients had a normal basic immune phenotype. CONCLUSION: The presented cases demonstrate that NTM/BCG infections in otherwise seemingly immunocompetent patients should raise suspicion of MSMD. This is of utmost importance as specific therapeutic approaches, such as IFNγ treatment or haematopoietic stem cell transplantation, may be employed to improve the disease outcome.

• Klíčová slova
• MSMD, mendelian susceptibility to mycobacterial diseases, IFNγR1, STAT1, inborn error of immunity, non-tuberculous mycobacteria, BCG, necrotizing granulomas, antituberculotics,
• MeSH
• bakteriální nemoci kůže * MeSH
• BCG vakcína škodlivé účinky   MeSH
• genetická predispozice k nemoci MeSH
• interferon gama MeSH
• interleukin-12 MeSH
• interleukin-23 MeSH
• lidé MeSH
• mykobakteriózy * genetika   MeSH
• syndromy imunologické nedostatečnosti * komplikace   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• BCG vakcína MeSH
• interferon gama MeSH
• interleukin-12 MeSH
• interleukin-23 MeSH

Inborn errors of immunity (IEI) are a group of disorders caused by genetically determined defects in the immune system, leading to infections, autoimmunity, autoinflammation and an increased risk of malignancy. In some cases, a malignancy might be the first sign of an underlying IEI. As therapeutic strategies might be different in these patients, recognition of the underlying IEI by the pediatric hemato-oncologist is important. This article, written by a group of experts in pediatric immunology, hemato-oncology, pathology and genetics, aims to provide guidelines for pediatric hemato-oncologists on how to recognize a possible underlying IEI and what diagnostic tests can be performed, and gives some consideration to treatment possibilities.

• Klíčová slova
• Inborn errors of immunity, investigation, malignancy, pediatric, primary immunodeficiency,
• MeSH
• dítě MeSH
• lékařská onkologie MeSH
• lidé MeSH
• nádory * diagnóza   MeSH
• onkologové * MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Despite the progress in the understanding how COVID-19 infection may impact immunocompromised patients, the data on inborn errors of immunity (IEI) remain limited and ambiguous. Therefore, we examined the risk of severe infection course and hospital admission in a large cohort of patients with IEI. In this multicenter nationwide retrospective survey-based trial, the demographic, clinical, and laboratory data were collected by investigating physicians from 8 national referral centers for the diagnosis and treatment of IEI using a COVID-19-IEI clinical questionnaire. In total, 81 patients with IEI (including 16 with hereditary angioedema, HAE) and confirmed SARS-CoV-2 infection were enrolled, and were found to have a 2.3-times increased (95%CI: 1.44-3.53) risk ratio for hospital admission and a higher mortality ratio (2.4% vs. 1.7% in the general population). COVID-19 severity was associated with the presence of clinically relevant comorbidities, lymphopenia, and hypogammaglobulinemia, but not with age or BMI. No individuals with HAE developed severe disease, despite a hypothesized increased risk due to perturbed bradykinin metabolism. We also demonstrated a high seroconversion rate in antibody-deficient patients and the safety of anti-spike SARS CoV-2 monoclonal antibodies and convalescent plasma. Thus, IEI except for HAE, represent significant risk factors for a severe COVID-19. Therefore, apart from general risk factors, immune system dysregulation may also be involved in the poor outcomes of COVID-19. Despite the study limitations, our results support the findings from previously published trials.

• Klíčová slova
• COVID-19, SARS-CoV-2, hospital admission, inborn errors of immunity, mortality, risk factors,
• MeSH
• COVID-19 epidemiologie   MeSH
• dospělí MeSH
• hospitalizace statistika a číselné údaje   MeSH
• komorbidita MeSH
• lidé středního věku MeSH
• lidé MeSH
• primární imunodeficience epidemiologie   MeSH
• průzkumy a dotazníky MeSH
• retrospektivní studie MeSH
• rizikové faktory MeSH
• SARS-CoV-2 fyziologie   MeSH
• stupeň závažnosti nemoci MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH

BACKGROUND: Inborn errors of immunity (IEI) with dysregulated JAK/STAT signaling present with variable manifestations of immune dysregulation and infections. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but initially reported outcomes were poor. JAK inhibitors (JAKi) offer a targeted treatment option that may be an alternative or bridge to HSCT. However, data on their current use, treatment efficacy and adverse events are limited. OBJECTIVE: We evaluated the current off-label JAKi treatment experience for JAK/STAT inborn errors of immunity (IEI) among European Society for Immunodeficiencies (ESID)/European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party (IEWP) centers. METHODS: We conducted a multicenter retrospective study on patients with a genetic disorder of hyperactive JAK/STAT signaling who received JAKi treatment for at least 3 months. RESULTS: Sixty-nine patients (72% children) were evaluated (45 STAT1 gain of function [GOF], 21 STAT3-GOF, 1 STAT5B-GOF, 1 suppressor of cytokine signaling 1 [aka SOCS1] loss of function, 1 JAK1-GOF). Ruxolitinib was the predominantly prescribed JAKi (80%). Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients. We documented highly heterogeneous dosing and monitoring regimens. The response rate and time to response varied across different diseases and manifestations. Adverse events including infection and weight gain were frequent (38% of patients) but were mild (grade I-II) and transient in most patients. At last follow-up, 52 (74%) of 69 patients were still receiving JAKi treatment, and 11 patients eventually underwent HSCT after receipt of previous JAKi bridging therapy, with 91% overall survival. CONCLUSIONS: Our study suggests that JAKi may be highly effective to treat symptomatic JAK/STAT IEI patients. Prospective studies to define optimal JAKi dosing for the variable clinical presentations and age ranges should be pursued.

• Klíčová slova
• JAK inhibitor, JAK/STAT signaling, autoimmunity, baricitinib, chronic mucocutaneous candidiasis, gain of function, immune dysregulation, inborn error of immunity, primary immunodeficiency, ruxolitinib,
• MeSH
• dítě MeSH
• inhibitory Janus kinas * terapeutické užití   MeSH
• lidé MeSH
• prospektivní studie MeSH
• retrospektivní studie MeSH
• syndromy imunologické nedostatečnosti * terapie   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitory Janus kinas * MeSH

BACKGROUND: Allergies have long been observed in Inborn Errors of Immunity (IEI) and might even be the first presentation resulting in delayed diagnosis or misdiagnosis in some cases. However, data on the prevalence of allergic diseases among IEI patients are limited and contradictory. OBJECTIVE: To provide a worldwide view of allergic diseases, across a broad spectrum of IEI, and their impact on the timely diagnosis of IEI. METHODS: This is a worldwide study, conceived by the World Allergy Organization (WAO) Inborn Errors of Immunity Committee. A questionnaire was developed and pilot-tested and was sent via email to collect data from 61 immunology centers known to treat pediatric and/or adult IEI patients in 41 countries. In addition, a query was submitted to The United States Immunodeficiency Network (USIDNET) at its website. RESULTS: Thirty centers in 23 countries caring for a total 8450 IEI patients responded. The USIDNET dataset included 2332 patients. Data from responders showed that a median (IQR) of 16.3% (10-28.8%) of patients experienced allergic diseases during the course of their IEI as follows: 3.6% (1.3-11.3%) had bronchial asthma, 3.6% (1.9-9.1%) atopic dermatitis, 3.0% (1.0-7.8%) allergic rhinitis, and 1.3% (0.5-3.3%) food allergy. As per the USIDNET data, the frequency of allergy among IEI patients was 68.8% (bronchial asthma in 46.9%). The percentage of IEI patients who presented initially with allergic disorders was 8% (5-25%) and diagnosis delay was reported in 7.5% (0.9-20.6%). Predominantly antibody deficiencies had the highest frequency of allergic disease followed by combined immunodeficiency with a frequency of 40.3% (19.2-62.5%) and 20.0% (10-32%) respectively. As per the data of centers, anaphylaxis occurred in 25/8450 patients (0.3%) whereas per USIDNET dataset, it occurred in 249/2332 (10.6%); drugs and food allergy were the main causes in both datasets. CONCLUSIONS: This multinational study brings to focus the relation between allergic diseases and IEI. Major allergies do occur in IEI patients but were less frequent than the general population. Initial presentation with allergy could adversely affect the timely diagnosis of IEI. There is a need for policies to raise awareness and educate primary care and other referring specialties on the association of allergic diseases with IEI. This study provides a network among centers for future prospective studies in the field.

• Klíčová slova
• Allergic rhinitis, Anaphylaxis, Asthma, Atopic dermatitis, IVIG, Omalizumab, Primary immunodeficiency,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking. OBJECTIVES: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS. METHODS: Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs. RESULTS: The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS. CONCLUSIONS: APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients.

• Klíčová slova
• APDS, CTLA4, ESID, IEI, NFKB1, PI3K, PIK3CD, PIK3R1, STAT3, immunodeficiency,
• MeSH
• 1-fosfatidylinositol-3-kinasa * genetika   MeSH
• antigen CTLA-4 genetika   MeSH
• fosfatidylinositol-3-kinasy třídy I MeSH
• fosfatidylinositol-3-kinasy genetika   MeSH
• lidé MeSH
• mutace MeSH
• primární imunodeficience * genetika   MeSH
• registrace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1-fosfatidylinositol-3-kinasa * MeSH
• antigen CTLA-4 MeSH
• fosfatidylinositol-3-kinasy třídy I MeSH
• fosfatidylinositol-3-kinasy MeSH

INTRODUCTION: The J Project (JP) physician education and clinical research collaboration program was started in 2004 and includes by now 32 countries mostly in Eastern and Central Europe (ECE). Until the end of 2021, 344 inborn errors of immunity (IEI)-focused meetings were organized by the JP to raise awareness and facilitate the diagnosis and treatment of patients with IEI. RESULTS: In this study, meeting profiles and major diagnostic and treatment parameters were studied. JP center leaders reported patients' data from 30 countries representing a total population of 506 567 565. Two countries reported patients from JP centers (Konya, Turkey and Cairo University, Egypt). Diagnostic criteria were based on the 2020 update of classification by the IUIS Expert Committee on IEI. The number of JP meetings increased from 6 per year in 2004 and 2005 to 44 and 63 in 2020 and 2021, respectively. The cumulative number of meetings per country varied from 1 to 59 in various countries reflecting partly but not entirely the population of the respective countries. Altogether, 24,879 patients were reported giving an average prevalence of 4.9. Most of the patients had predominantly antibody deficiency (46,32%) followed by patients with combined immunodeficiencies (14.3%). The percentages of patients with bone marrow failure and phenocopies of IEI were less than 1 each. The number of patients was remarkably higher that those reported to the ESID Registry in 13 countries. Immunoglobulin (IgG) substitution was provided to 7,572 patients (5,693 intravenously) and 1,480 patients received hematopoietic stem cell therapy (HSCT). Searching for basic diagnostic parameters revealed the availability of immunochemistry and flow cytometry in 27 and 28 countries, respectively, and targeted gene sequencing and new generation sequencing was available in 21 and 18 countries. The number of IEI centers and experts in the field were 260 and 690, respectively. We found high correlation between the number of IEI centers and patients treated with intravenous IgG (IVIG) (correlation coefficient, cc, 0,916) and with those who were treated with HSCT (cc, 0,905). Similar correlation was found when the number of experts was compared with those treated with HSCT. However, the number of patients treated with subcutaneous Ig (SCIG) only slightly correlated with the number of experts (cc, 0,489) and no correlation was found between the number of centers and patients on SCIG (cc, 0,174). CONCLUSIONS: 1) this is the first study describing major diagnostic and treatment parameters of IEI care in countries of the JP; 2) the data suggest that the JP had tremendous impact on the development of IEI care in ECE; 3) our data help to define major future targets of JP activity in various countries; 4) we suggest that the number of IEI centers and IEI experts closely correlate to the most important treatment parameters; 5) we propose that specialist education among medical professionals plays pivotal role in increasing levels of diagnostics and adequate care of this vulnerable and still highly neglected patient population; 6) this study also provides the basis for further analysis of more specific aspects of IEI care including genetic diagnostics, disease specific prevalence, newborn screening and professional collaboration in JP countries.

• Klíčová slova
• ESID, Eastern and Central Europe, Asia, J Project, immunodeficiencies, parameters,
• MeSH
• imunoglobulin G * MeSH
• intravenózní podání MeSH
• lidé MeSH
• novorozenec MeSH
• stupeň vzdělání MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Egypt MeSH
• Evropa MeSH
• Názvy látek
• imunoglobulin G * MeSH

Specific diagnostic markers are the key to effective diagnosis and treatment of inborn errors of metabolism (IEM). Untargeted metabolomics allows for the identification of potential novel diagnostic biomarkers. Current separation techniques coupled to high-resolution mass spectrometry provide a powerful tool for structural elucidation of unknown compounds in complex biological matrices. This is a proof-of-concept study testing this methodology to determine the molecular structure of as yet uncharacterized m/z signals that were significantly increased in plasma samples from patients with phenylketonuria and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. A hybrid linear ion trap-orbitrap high resolution mass spectrometer, capable of multistage fragmentation, was used to acquire accurate masses and product ion spectra of the uncharacterized m/z signals. In order to determine the molecular structures, spectral databases were searched and fragmentation prediction software was used. This approach enabled structural elucidation of novel compounds potentially useful as biomarkers in diagnostics and follow-up of IEM patients. Two new conjugates, glutamyl-glutamyl-phenylalanine and phenylalanine-hexose, were identified in plasma of phenylketonuria patients. These novel markers showed high inter-patient variation and did not correlate to phenylalanine levels, illustrating their potential added value for follow-up. As novel biomarkers for 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, three positional isomers of 3-methylglutaconyl carnitine could be detected in patient plasma. Our results highlight the applicability of current accurate mass multistage fragmentation techniques for structural elucidation of unknown metabolites in human biofluids, offering an unprecedented opportunity to gain further biochemical insights in known inborn errors of metabolism by enabling high confidence identification of novel biomarkers.

• Klíčová slova
• 3-hydroxy-3-methylglutaryl coenzyme a lyase deficiency, Biomarkers, Metabolomics, Next generation metabolic screening, Phenylketonuria, Structural elucidation,
• MeSH
• acetyl-CoA-C-acetyltransferasa krev   nedostatek   MeSH
• biologické markery analýza   krev   chemie   MeSH
• chemická frakcionace metody   MeSH
• chromatografie kapalinová MeSH
• fenylketonurie krev   diagnóza   MeSH
• lidé MeSH
• metabolické nemoci krev   diagnóza   MeSH
• metabolom MeSH
• metabolomika metody   MeSH
• molekulární konformace MeSH
• reprodukovatelnost výsledků MeSH
• software MeSH
• tandemová hmotnostní spektrometrie metody   MeSH
• vrozené poruchy metabolismu aminokyselin krev   diagnóza   MeSH
• vrozené poruchy metabolismu krev   diagnóza   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetyl-CoA-C-acetyltransferasa MeSH
• biologické markery MeSH