We aimed to assess BCG (Bacillus Calmette-Guérin) complications in patients with Inborn Errors of Immunity (IEI), according to the inherited disorders and associated immunological defects, as well as ...the different BCG substrains.
We studied adverse reactions to the locally-produced BCG Moreau vaccine, analyzed in patients with IEI diagnosed between 1980 and 2020 in the Department of Immunology, Children's Memorial Health Institute (CMHI), Warsaw. These results were compared with previously published studies.
Significantly fewer disseminated BCG infections (BCGosis) were found in 11 of 72 (15%) SCID (Severe Combined Immunodeficiency) NK (Natural Killer)-phenotype patients, when compared with the 119 out of 349 (34%) (
= 0.0012) patients with SCID with BCG in other countries. Significantly fewer deaths caused by BCGosis were observed (
= 0.0402). A significantly higher number of hematopoietic stem cell transplantations (HSCTs) were performed in the CMHI study (
= 0.00001). BCGosis was found in six patients with Mendelian susceptibility to mycobacterial diseases (MSMD). Other patients with IEI prone to BCG complications, such as CGD (Chronic Granulomatous Disease), showed no case of BCGosis.
The BCG Moreau substrain vaccine, produced in Poland since 1955, showed genetic differences with its parental Brazilian substrain together with a superior clinical safety profile in comparison with the other BCG substrains, with no BCGosis in patients with IEI other than SCID and MSMD. Our data also confirmed significantly fewer cases of BCGosis and deaths caused by BCG infection in patients with SCID with this vaccine substrain. Finally, they confirmed the protecting role of NK cells, probably
their production of IFN-γ.
The aim of our study was to evaluate redox status, enzymatic and non-enzymatic antioxidant barriers, oxidative damage of proteins, lipids and DNA, as well as concentration of coenzyme Q10 and ...vitamins A and E in patients with chronic granulomatous disease (CGD). The study was performed on fifteen Caucasian individuals (median age 24 years and seven months) diagnosed with CGD. The mutation in the
gene was confirmed in ten patients, and in the
gene in five patients. We demonstrated high levels of total oxidant status (TOS) and oxidative stress index (OSI), lipids (↑8-isoprostanes (8-isoP), ↑4-hydroxynonenal (4-HNE)), proteins (↑advanced oxidation protein products (AOPP)) and DNA (↑8-hydroxy-2'-deoxyguanosine (8-OHdG)) oxidation products in CGD individuals as compared to sex- and age-matched healthy controls. We showed enhanced serum enzymatic activity of catalase (CAT) and superoxide dismutase-1 (SOD) and significantly decreased coenzyme Q10 concentration. Our study confirmed redox disturbances and increased oxidative damage in CGD patients, and indicated the need to compare redox imbalance depending on the type of mutation and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The question regarding effectiveness of antioxidant therapy in patients with CGD is open, and the need to establish guidelines in this area remains to be addressed.
Purpose
Nijmegen Breakage Syndrome (NBS) is a rare inherited condition, characterized by microcephaly, chromosomal instability, immunodeficiency, and predisposition to malignancy. This retrospective ...study, characterizing the clinical and immunological status of patients with NBS at time of diagnosis, was designed to assess whether any parameters were useful in disease prognosis, and could help determine patients qualified for hematopoietic stem cell transplantation.
Methods
The clinical and immunological characteristics of 149 NBS patients registered in the online database of the European Society for Immune Deficiencies were analyzed.
Results
Of the 149 NBS patients, 91 (61 %), of median age 14.3 years, remained alive at the time of analysis. These patients were clinically heterogeneous, with variable immune defects, ranging from negligible to severe dysfunction. Humoral deficiencies predisposed NBS patients to recurrent/chronic respiratory tract infections and worsened long-term clinical prognosis. Eighty malignancies, most of lymphoid origin (especially non-Hodgkin’s lymphomas), were diagnosed in 42 % of patients, with malignancy being the leading cause of death in this cohort. Survival probabilities at 5, 10, 20 and 30 years of age were 95, 85, 50 and 35 %, respectively, and were significantly lower in patients with than without malignancies.
Conclusions
The extremely high incidence of malignancies, mostly non-Hodgkin’s lymphomas, was the main risk factor affecting survival probability in NBS patients. Because treatment of NBS is very difficult and frequently unsuccessful, the search for an alternative medical intervention such as hematopoietic stem cell transplantation is of great clinical importance.
Variants in recombination-activating genes (
) are common genetic causes of autosomal recessive forms of combined immunodeficiencies (CID) ranging from severe combined immunodeficiency (SCID), Omenn ...syndrome (OS), leaky SCID, and CID with granulomas and/or autoimmunity (CID-G/AI), and even milder presentation with antibody deficiency.
We aim to estimate the incidence, clinical presentation, genetic variability, and treatment outcome with geographic distribution of patients with the
defects in populations inhabiting South, West, and East Slavic countries.
Demographic, clinical, and laboratory data were collected from
-deficient patients of Slavic origin via chart review, retrospectively. Recombinase activity was determined
by flow cytometry-based assay.
Based on the clinical and immunologic phenotype, our cohort of 82 patients from 68 families represented a wide spectrum of
deficiencies, including SCID (
= 20), OS (
= 37), and LS/CID (
= 25) phenotypes. Sixty-seven (81.7%) patients carried
and 15 patients (18.3%) carried
biallelic variants. We estimate that the minimal annual incidence of
deficiency in Slavic countries varies between 1 in 180,000 and 1 in 300,000 live births, and it may vary secondary to health care disparities in these regions. In our cohort, 70% (
= 47) of patients with
variants carried p.K86Vfs
33 (c.256_257delAA) allele, either in homozygous (
= 18, 27%) or in compound heterozygous (
= 29, 43%) form. The majority (77%) of patients with homozygous
p.K86Vfs
33 variant originated from Vistula watershed area in Central and Eastern Poland, and compound heterozygote cases were distributed among all Slavic countries except Bulgaria. Clinical and immunological presentation of homozygous
p.K86Vfs
33 cases was highly diverse (SCID, OS, and AS/CID) suggestive of strong influence of additional genetic and/or epigenetic factors in shaping the final phenotype.
We propose that
p.K86Vfs
33 is a founder variant originating from the Vistula watershed region in Poland, which may explain a high proportion of homozygous cases from Central and Eastern Poland and the presence of the variant in all Slavs. Our studies in this cohort of
founder variants confirm that clinical and immunological phenotypes only partially depend on the underlying genetic defect. As access to HSCT is improving among RAG-deficient patients in Eastern Europe, we anticipate improvements in survival.
Summary
In order to build a common data pool and estimate the disease burden of primary immunodeficiencies (PID) in Europe, the European Society for Immunodeficiencies (ESID) has developed an ...internet‐based database for clinical and research data on patients with PID. This database is a platform for epidemiological analyses as well as the development of new diagnostic and therapeutic strategies and the identification of novel disease‐associated genes. Since its start in 2004, 13 708 patients from 41 countries have been documented in the ESID database. Common variable immunodeficiency (CVID) represents the most common entity with 2880 patients or 21% of all entries, followed by selective immunoglobulin A (sIgA) deficiency (1424 patients, 10·4%). The total documented prevalence of PID is highest in France, with five patients per 100 000 inhabitants. The highest documented prevalence for a single disease is 1·3 per 100 000 inhabitants for sIgA deficiency in Hungary. The highest reported incidence of PID per 100 000 live births was 16·2 for the period 1999–2002 in France. The highest reported incidence rate for a single disease was 6·7 for sIgA deficiency in Spain for the period 1999–2002. The genetic cause was known in 36·2% of all registered patients. Consanguinity was reported in 8·8%, and 18·5% of patients were reported to be familial cases; 27·9% of patients were diagnosed after the age of 16. We did not observe a significant decrease in the diagnostic delay for most diseases between 1987 and 2010. The most frequently reported long‐term medication is immunoglobulin replacement.
The dynamic development of clinical immunology in Europe began in mid 1980s, and was continued in Poland shortly thereafter. In 1993 the first national consultant in the field of clinical immunology ...was appointed in Poland. A milestone was the establishment of the Polish Working Group for Primary Immunodeficiencies (PGR for PID) in 2005. Since then, a network of numerous paediatric and internal medicine centres has been created within the Group, facing and resolving new challenges in the field. The study presents the organization of care for patients with primary and secondary immunodeficiencies in Poland, analyzes the staffing situation and patients' access to diagnostics and treatment between late 1980’s and 2024. The summary presents the achievements resulting in improved diagnostic efficiency, shortening the delay in the diagnosis of Inborn Errors of Immunity (IEI)/primary immunodeficiencies (PID), and better access of patients to therapy within drug programs, largely carried out at home. The causes hindering the development of specialization are also analyzed. The most important among them are the lack of systemic support on the part of medical care organizers and the lack of motivation of young doctors to pursue specialization. The main goal is to improve diagnostic and therapeutic procedures for PID patients, including newborn screening, highly specialized, genetic test regardless where they are implemented. It can be only achieved with their better financing. An essential problem is the lack of an epidemiological or clinical IEI registry.
Immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) have been isolated from primary immunodeficiency (PID) patients exposed to oral poliovirus vaccine (OPV). Patients may excrete ...poliovirus strains for months or years; the excreted viruses are frequently highly divergent from the parental OPV and have been shown to be as neurovirulent as wild virus. Thus, these patients represent a potential reservoir for transmission of neurovirulent polioviruses in the post-eradication era. In support of WHO recommendations to better estimate the prevalence of poliovirus excreters among PIDs and characterize genetic evolution of these strains, 635 patients including 570 with primary antibody deficiencies and 65 combined immunodeficiencies were studied from 13 OPV-using countries. Two stool samples were collected over 4 days, tested for enterovirus, and the poliovirus positive samples were sequenced. Thirteen patients (2%) excreted polioviruses, most for less than 2 months following identification of infection. Five (0.8%) were classified as iVDPVs (only in combined immunodeficiencies and mostly poliovirus serotype 2). Non-polio enteroviruses were detected in 30 patients (4.7%). Patients with combined immunodeficiencies had increased risk of delayed poliovirus clearance compared to primary antibody deficiencies. Usually, iVDPV was detected in subjects with combined immunodeficiencies in a short period of time after OPV exposure, most for less than 6 months. Surveillance for poliovirus excretion among PID patients should be reinforced until polio eradication is certified and the use of OPV is stopped. Survival rates among PID patients are improving in lower and middle income countries, and iVDPV excreters are identified more frequently. Antivirals or enhanced immunotherapies presently in development represent the only potential means to manage the treatment of prolonged excreters and the risk they present to the polio endgame.
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.
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).
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.
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