Distribution of PIDs in the IPINet Registry
The IPINet registry currently includes 3352 patients affected with PIDs (male vs female: 59.6% vs 40.4%). A progressive increase in the number of registered patients was noted over these 20 years, as shown in Fig. 1. Evaluation of the regional distribution pattern in Italy revealed that the minimal prevalence of PIDs based on patients’ residence is higher in Lombardy and Lazio, followed by Emilia Romagna, Tuscany, and Campania (Fig. 2). The distribution of PIDs, based on the latest IUIS classification [1, 2] within the IPINet registry, is depicted in Fig. 3a. Almost two-thirds of registered patients are affected with predominantly antibody deficiencies (63%), in line with previously published data [5,6,7,8,9,10,11,12,13,14,15,16,17,18]. Combined immunodeficiencies with associated or syndromic features represent a smaller portion of the IPINet registry (22.5%), followed by immunodeficiencies affecting cellular and humoral immunity (8.5%) and congenital defects of phagocyte number or function (4.9%) (Fig. 3a).
More in detail (Fig. 3b), predominantly antibody deficiencies within the IPINet registry can be divided in Common Variable Immunodeficiency (CVID) (27.2%, 913 patients), Selective IgA Deficiency (SIgAD) (25%, 839 patients), X-linked Agammaglobulinemia (XLA) (5.6%, 189 patients), Transient Hypogammaglobulinemia of the Infancy (THI) (4.1%, 138 patients), and Autosomal Recessive Agammaglobulinemia (ARA) (1%, 34 patients) (Fig. 3b and Table 1). Combined immunodeficiencies with associated or syndromic features included patients affected with Wiskott-Aldrich Syndrome (WAS) (4.2%, 139 patients), partial DiGeorge Syndrome (pDGS) (14.4%, 482 patients), Ataxia-Telangiectasia (A-T) (2.5%, 85 patients), and Hyper-IgE Syndrome (HIES) (1.5%, 49 patients) (Fig. 3b and Table 1). The group of immunodeficiency affecting cellular and humoral immunity included only SCID/CID patients (8.5%, 285 patients). Congenital defects of phagocyte number or function included Chronic Granulomatous Disease (CGD) (4.3%, 144 patients) and Congenital Neutropenia (CN) (0.6%, 19 patients). We found a small amount of patients affected with diseases of immune dysregulation that comprised Chediak-Higashi Syndrome (CHS) (0.3%, 11 patients), Autoimmune Lymphoproliferative Syndrome (ALPS) (0.4%, 13 patients), and Immunodysregulation Polyendocrinopathy Enteropathy X-linked (IPEX) (0.1%, 2 patients) (Fig. 3b and Table 1). Finally, in the group of bone marrow failure, a small number of patients with Dyskeratosis Congenita (DKC) was registered (0.3%, 10 patients) (Fig. 3b and Table 1).
Table 1 PID distribution in the IPINet registry. Detailed distribution of affected patients in the IPINet registry based on disease, sex, and age at diagnosis classified according to the latest IUIS classification (2019) [1, 2] Age at Diagnosis of PID Patients in the IPINet Registry
Age at diagnosis was younger among male patients compared with the female ones (4 vs 6 years respectively; median values) (Table 1). More in detail, among predominantly antibody deficiencies, CVID is the only one with a diagnosis more frequent in adult age (> 18 years) (636 patients) rather than in childhood (< 18 years) (277 patients) (Table 1), with a median age at diagnosis of 25 years (Table 1). XLA on the other hand was mainly diagnosed before adulthood (176 out of 189 patients) (median age at diagnosis: 3 years), and a similar trend was observed for both ARA (26 out of 34) (median age at diagnosis: 2 years) and SIgAD (804 out of 839 patients) (median age at diagnosis: 5 years) (Table 1). By definition, THI was only diagnosed during childhood, with a median age at diagnosis of 1 year. SCID/CID were almost exclusively diagnosed in childhood (284 out of 285 patients), with a median age at diagnosis of 0 year (Table 1). Combined immunodeficiency with associated or syndromic features (WAS, pDGS, A-T) followed the same pattern of diagnosis before adulthood (Table 1). In slight contrast with this trend, HIES was diagnosed during adulthood in almost one-third of affected patients (14 out of 49 patients) (median age at diagnosis: 11 years) (Table 1). Finally, diseases of immune dysregulation, congenital defects of phagocyte number or function, and bone marrow failure were all diagnosed in childhood (Table 1). Of note, median age of diagnosis before and after the establishment of the IPINet registry did not show significant differences in most cases (Table 1).
Treatment and Survival of PID Patients in the IPINet Registry
Less than one-third of the patient cohort was under regular immunoglobulin replacement treatment, with an evident prevalence of the endovenous route (20.6%) contrary to what observed in other countries, where the subcutaneous route is preferred [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19].
The majority of patients within the IPINet registry (92.6%) were alive during the last follow-up with 4.2% of deaths (140 patients) (Fig. 4a). With the exception of pDGS where the majority of deceased patients were males (66.7%), no significant sex-related differences were observed for the other PIDs (Table 1). Comparison with available data from other PID registries showed that this percentage of mortality is in line with several European registries, remaining inferior to the high mortality rates reported from Tunisia, Morocco, Kuwait, Slovenia, and France (Fig. 4b). Finally, 3.2% of patients were lost during follow-up (Fig. 4a).
Prevalence of PIDs in Italy
The real prevalence of PIDs is not well defined and may depend upon various factors, such as form of PID, ethnic background, and consanguinity [5,6,7,8,9,10,11,12,13,14,15,16,17,18]. In recent years for example, the introduction of newborn screening (NBS) for SCID/CID in several countries has redefined the prevalence of these disorders [21].
Considering the large cohort of the IPINet registry, we wanted to calculate the minimal prevalence of PIDs in the Italian territory. The minimal prevalence of PIDs in Italy in 2019 is higher (5.1 per 100.000) than the one reported from most European PID registries, with the exception of published data from Iceland, Slovenia, Norway, and the United Kingdom (Fig. 5). It also resulted higher than the PID minimal prevalence reported from Morocco, Spain, Germany, Ireland, Netherlands, Switzerland, Tunisia, and France while it was similar than the ones reported from Kuwait, Australia and New Zealand, and Israel (Fig. 5).
The minimal prevalence of predominantly antibody deficiencies within the IPINet registry (3.28 per 100.000) was higher from what reported so far from most registries, with the exception of the United Kingdom and Iceland (Table 2). The minimal prevalence of combined immunodeficiencies with associated or syndromic features within the IPINet registry (1.17 per 100.000) resulted again higher when compared with the minimal prevalence from other registries, with the exception of Kuwait and Iceland (Table 2). Regarding the remaining PIDs, their minimal prevalence in Italy showed an intermediate collocation in relation to other countries (Table 2).
Table 2 Minimal prevalence of PIDs in Italy and comparison with other countries. Minimal prevalence (per 105 inhabitants) of PIDs in Italy calculated on alive patients based on the latest IUIS classification (2019) and comparison with previously published data from other national PID registries. Numbers in parentheses represent total number of registered patients (bold) and total number of alive patients (italic)