Care of patients with inborn errors of immunity in thirty J Project countries between 2004 and 2021

Abstract

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.

Keywords: ESID; Eastern and Central Europe, Asia; J Project; immunodeficiencies; parameters.

Figure 1

Number of patients with inborn errors of immunity reported from Eastern and Central Europe (ECE) to the ESID Registry in 2000 was less than 10 (see color coding and the scale on the left). Number of patients reported to this J Project survey at the end of 2021 is shown by numbers in ECE countries. For more details see Table 1.

Figure 2

(A) shows the cumulative number of J Project (JP) meetings organized in Eastern and Central Europe (ECE), Asia and part of Africa. The average number of meetings per country was 10.75 in 2021. (B) shows the number of countries participating in the JP between 2004 and 2021 reaching 32 by 2020. (C) shows the number of JP meetings organized yearly over 18 years. A remarkable increase of meeting number occurred over the past 4 years which was not directly related to the number of participating countries. This is indicated by the difference between 2020 and 2021 when the JP country number was equal. (D) shows the cumulative number of JP meetings in participating countries. The largest number of meetings in Russia is in concert with the population estimated 138,000,000 in this country. On the other hand, the number of meetings in Hungary (estimated population, 9,600,000) was about half of that in Russia. Further, the same number of meetings were organized in Bulgaria and Czech Republic than in Romania with a population of 20,000,000 and Republic of Moldova (2,600,000) or Slovenia (2,200,000) suggesting that the activity and interest maybe more important than the size and population of the country. Unfortunately, there are countries with permanently low number of meetings including Croatia, Bosnia & Herzegovina, Estonia, Serbia) despite longer-term membership in the JP network (see also Supplementary Table 1).

Figure 3

The total number of patients reported from 30 countries to various IUIS subgroups. The most common subgroups were predominantly antibody deficiency (11510) and combined immunodeficiencies with associated or syndromic feature (3557). The number of patients with periodic fever syndrome does not include patients reported from Armenia (3151 pts) to avoid unproportional presentation (see Table 1). The number of patients with no definitive IEI diagnosis was 734 representing 2,95% of the total number of 24,862 patients.

Figure 4

Comparable percentages of patients in different subgroups reported to the ESID-R (left columns) and the J Project (right columns). Despite slight differences in a few subgroups (subgroups 3, 4, 7 and 8), these data indicate similarly wide range of diagnosis of patients with different disease groups.

Figure 5

Total number of patients reported to the ESID-R (left columns, red) and the J Project (JP; right columns, blue) are shown. Such data were available only from 13 of the 32 JP countries indicating the lack of appropriate reporting activity. In addition, the total number of patients reported to the ESID-R was 3226 in contrast to the 15,234 patients reported in this survey.

Figure 6

Availability of basic diagnostic parameters in J Project countries is shown in green. Red indicates the lack of various parameters. Numbers in insets indicate the number of countries that are missing various diagnostic measures. Imm Chem, immunochemistry; Flow Cyt, flow cytometry; GS, gene sequencing; NGS, new generation sequencing.

Figure 7

Correlations between the number of primary immunodeficiency (PID) centers and PID experts with the replacement of intravenous immunoglobulin (IVIG) or subcutaneous Ig (SCIG) or the number of hematopoietic stem cell transplantation (HSCT) performed in various countries. Data show that higher number of centers and experts favored the treatment with IVIG and HSCT but not with SCIG.