Primary immunodeficiencies (PI) are genetic defects of the immune system that result in chronic, serious, and often life-threatening infections, if not diagnosed and treated. Many patients with PI are undiagnosed, underdiagnosed, or misdiagnosed. In fact, recent studies have shown that PI may be more common than previously estimated and that as many as 1% of the population may be affected with a PI when all types and varieties are considered. In order to raise awareness of PI with the overall goal of reducing associated morbidity and mortality, the Jeffrey Modell Foundation (JMF) established a network of specialized centers that could better identify, diagnose, treat, and follow patients with PI disorders. Over the past decade, the Jeffrey Modell Centers Network (JMCN) has provided the infrastructure to accept referrals, provide diagnosis, and offer treatments. Currently, the network consists of 792 Expert Physicians at 358 institutions, in 277 cities, and 86 countries spanning 6 continents. JMF developed an annual survey for physician experts within the JMCN, using the categories and gene defects identified by the International Union of Immunological Societies Expert Committee for the Classification of PI, to report on the number of patients identified with PI; treatment modalities, including immunoglobulins, transplantation, and gene therapy; and data on gender and age. Center Directors also provided physician-reported outcomes and differentials pre- and post-diagnosis. The current physician-reported data reflect an increase in diagnosed patients, as well as those receiving treatment. Suspected patients are being identified and referred so that they can receive early and appropriate diagnosis and treatment. The significant increase in patients identified with a PI is due, in part, to expanding education and awareness initiatives, newborn screening, and the expansion of molecular diagnosis and sequencing. To our knowledge, this is the most extensive single physician report on patients with PI around the world.

A large population of patients with recurring infections are undiagnosed or under diagnosed and Primary Immunodeficiency (PI) is more common than had been previously estimated. The results strongly indicate the measurable impact of Physician Education and Public Awareness in identifying patients with an underlying PI. The Jeffrey Modell Centers Network (JMCN) provides the infrastructure for referral, diagnosis and appropriate treatment. All disease classifications and identified defects increased significantly over the study period. Quality of Life for referred and diagnosed patients dramatically improved compared to undiagnosed patients. There is a substantial cost savings for diagnosed patients compared to undiagnosed, even if regular IgG is required. The SPIRIT(®) Software successfully identified patients with PI in a large database and at three pilot sites. The Software was successfully tested for specificity and sensitivity.

Introduction: During the last 4 decades, registration of patients with primary immunodeficiencies (PID) has played an essential role in different aspects of these diseases worldwide including epidemiological indexes, policymaking, quality controls of care/life, facilitation of genetic studies and clinical trials as well as improving our understanding about the natural history of the disease and the immune system function. However, due to the limitation of sustainable resources supporting these registries, inconsistency in diagnostic criteria and lack of molecular diagnosis as well as difficulties in the documentation and designing any universal platform, the global perspective of these diseases remains unclear. Areas covered: Published and unpublished studies from January 1981 to June 2020 were systematically reviewed on PubMed, Web of Science and Scopus. Additionally, the reference list of all studies was hand-searched for additional studies. This effort identified a total of 104614 registered patients and suggests identification of at least 10590 additional PID patients, mainly from countries located in Asia and Africa. Molecular defects in genes known to cause PID were identified and reported in 13852 (13.2% of all registered) patients. Expert opinion: Although these data suggest some progress in the identification and documentation of PID patients worldwide, achieving the basic requirement for the global PID burden estimation and registration of undiagnosed patients will require more reinforcement of the progress, involving both improved diagnostic facilities and neonatal screening.

Primary immunodeficiencies (PI) are defects of the immune system that cause severe infections if not diagnosed and treated appropriately. Many patients with PI are undiagnosed, under-diagnosed, or misdiagnosed. Over the last decade, the Jeffrey Modell Foundation has implemented a Physician Education and Public Awareness Campaign (PEPAC) to raise awareness, assure early diagnosis, appropriate treatment, and management, with the overall goal to reduce morbidities and mortalities related to PI. In order to evaluate the PEPAC program, data are requested annually from physician experts within the Jeffrey Modell Centers Network (JMCN). The JMCN, consisting of 556 expert physicians, at 234 academic institutions, in 196 cities, and 78 countries spanning six continents, provides the infrastructure for referral, diagnosis, and appropriate treatment for patients with PI. In addition, the JMCN has made a significant contribution to the field of immunology with the discovery of new genes at the centers. These advancements have led to an overall better understanding of the immune system and will continue to improve quality of life of those with PI.

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.

Primary immunodeficiencies (PI) are defects of the immune system that cause severe, sometimes life-threatening, infections if not diagnosed and treated appropriately. Many patients with PI are undiagnosed, under-diagnosed, or misdiagnosed. To raise awareness and assure earliest diagnosis, appropriate treatment, and proper care management, the Jeffrey Modell Foundation (JMF) implemented a physician education and public awareness program beginning in 2003. Data are requested annually from physician experts within the Jeffrey Modell Centers Network (JMCN), consisting of 602 expert physicians, at 253 academic institutions, in 206 cities, and 84 countries spanning six continents. Center Directors reported on patients' specific PI defects and treatment modalities including immunoglobulins, transplantation, and gene therapy as well as data on gender and age. Center Directors also provided physician-reported patient outcomes as well as pre- and post-diagnosis differences. Costs were assigned to these factors. In collaboration with the Network, JMF advocated, funded, and implemented population-based newborn screening for severe combined immunodeficiency and T cell lymphopenia, covering 96.2 % of all newborns in the US. Finally, 21 JMF Centers participated in a polio surveillance study of patients with PI who either received or have been exposed to the oral polio vaccine. These initiatives have led to an overall better understanding of the immune system and will continue to improve quality of life for those with PI.

Severe combined immunodeficiency (SCID) is a group of syndromes resulting from genetic defects causing absence in T-cell and B-cell function, leading to serious and life-threatening infections. SCID is often fatal in the first 2 years of life if not identified and properly treated. While additional laboratory methods are being developed, the current T-cell receptor excision circle assay has proven to have outstanding specificity and sensitivity to accurately identify infants with SCID and other T-cell lymphopenia. The Jeffrey Modell Foundation (JMF) has a long history of advocacy and continues to promote newborn screening for SCID to be implemented in the United States and worldwide. Based on reports provided by California, New York, Texas, and Wisconsin on the results of their population based newborn screening programs, the overall incidence of SCID averaged 1:33,000 and T-cell lymphopenia averaged 1:6,600. JMF has developed a working algorithm or "decision tree", validated by peer-reviewed scientific literature, to be used by Public Health Departments and Health Ministries in states, countries, and regions throughout the world. This decision tool allows for local or regional data to be applied to measure the threshold and economic impact of implementing newborn screening for SCID and T-cell lymphopenia.

Background Inborn errors of immunity (IEIs) are a heterogeneous group of genetic defects of immunity, which cause high rates of morbidity and mortality mainly among children due to infectious and non-infectious complications. The IEI burden has been critically underestimated in countries from middle- and low-income regions and the majority of patients with IEI in these regions lack a molecular diagnosis. Methods We analyzed the clinical, immunologic, and genetic data of IEI patients from 22 countries in the Middle East and North Africa (MENA) region. The data was collected from national registries and diverse databases such as the Asian Pacific Society for Immunodeficiencies (APSID) registry, African Society for Immunodeficiencies (ASID) registry, Jeffrey Modell Foundation (JMF) registry, J Project centers, and International Consortium on Immune Deficiency (ICID) centers. Results We identified 17,120 patients with IEI, among which females represented 39.4%. Parental consanguinity was present in 60.5% of cases and 27.3% of the patients were from families with a confirmed previous family history of IEI. The median age of patients at the onset of disease was 36 months and the median delay in diagnosis was 41 months. The rate of registered IEI patients ranges between 0.02 and 7.58 per 100,000 population, and the lowest rates were in countries with the highest rates of disability-adjusted life years (DALY) and death rates for children. Predominantly antibody deficiencies were the most frequent IEI entities diagnosed in 41.2% of the cohort. Among 5871 patients genetically evaluated, the diagnostic yield was 83% with the majority (65.2%) having autosomal recessive defects. The mortality rate was the highest in patients with non-syndromic combined immunodeficiency (51.7%, median age: 3.5 years) and particularly in patients with mutations in specific genes associated with this phenotype (RFXANK, RAG1, and IL2RG). Conclusions This comprehensive registry highlights the importance of a detailed investigation of IEI patients in the MENA region. The high yield of genetic diagnosis of IEI in this region has important implications for prevention, prognosis, treatment, and resource allocation.