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Although it is estimated that COVID-19 life-threatening conditions may be diagnosed in less than 1:1000 infected individuals below the age of 50, but the real impact of this pandemic on pediatric patients with different types of primary immunodeficiency (PID) is not elucidated. The current prospective study on a national registry of PID patients showed that with only 1.23 folds higher incidence of infections, these patients present a 10-folds higher mortality rate compared to population mainly in patients with combined immunodeficiency and immune dysregulation. Therefore, further management modalities against COVID-19 should be considered to improve the survival rate in these two PID entities using hematopoietic stem cell transplantation and immunomodulatory agents.

BACKGROUNDWarts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a primary immunodeficiency disorder caused by heterozygous gain-of-function CXCR4 mutations. Myelokathexis is a kind of neutropenia caused by neutrophil retention in bone marrow and in WHIM syndrome is associated with lymphopenia and monocytopenia. The CXCR4 antagonist plerixafor mobilizes leukocytes to the blood; however, its safety and efficacy in WHIM syndrome are undefined.METHODSIn this investigator-initiated, single-center, quadruple-masked phase III crossover trial, we compared the total infection severity score (TISS) as the primary endpoint in an intent-to-treat manner in 19 patients with WHIM who each received 12 months treatment with plerixafor and 12 months treatment with granulocyte CSF (G-CSF, the standard of care for severe congenital neutropenia). The treatment order was randomized for each patient.RESULTSPlerixafor was nonsuperior to G-CSF for TISS (P = 0.54). In exploratory endpoints, plerixafor was noninferior to G-CSF for maintaining neutrophil counts of more than 500 cells/μL (P = 0.023) and was superior to G-CSF for maintaining lymphocyte counts above 1,000 cells/μL (P < 0.0001). Complete regression of a subset of large wart areas occurred on plerixafor in 5 of 7 patients with major wart burdens at baseline. Transient rash occurred on plerixafor, and bone pain was more common on G-CSF. There were no significant differences in drug preference or quality of life or the incidence of drug failure or serious adverse events.CONCLUSIONPlerixafor was not superior to G-CSF in patients with WHIM for TISS, the primary endpoint. Together with wart regression and hematologic improvement, the infection severity results support continued study of plerixafor as a potential treatment for WHIM syndrome.TRIAL REGISTRATIONClinicaltrials.gov NCT02231879.FUNDINGThis study was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases.

The most recent updated classification of inborn errors of immunity/primary immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee, was published in January 2020. Within days of completing this report, it was already out of date, evidenced by the frequent publication of genetic variants proposed to cause novel inborn errors of immunity. As the next formal report from the IUIS Expert Committee will not be published until 2022, we felt it important to provide the community with a brief update of recent contributions to the field of inborn errors of immunity. Herein, we highlight studies that have identified 26 additional monogenic gene defects that reach the threshold to represent novel causes of immune defects.

Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies 1 – 3 . Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed 4 ) identified multiple new candidate PID-associated genes, including IVNS1ABP . We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of—and interplay between—novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans. Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

Primary immunodeficiencies (PIDs) comprise a diverse group of over 400 genetic disorders that result in clinically apparent immune dysfunction. Although PIDs are classically considered as Mendelian disorders with complete penetrance, we now understand that absent or partial clinical disease is often noted in individuals harboring disease-causing genotypes. Despite the frequency of incomplete penetrance in PID, no conceptual framework exists to categorize and explain these occurrences. Here, by reviewing decades of reports on incomplete penetrance in PID we identify four recurrent themes of incomplete penetrance, namely genotype quality, (epi)genetic modification, environmental influence, and mosaicism. For each of these principles, we review what is known, underscore what remains unknown, and propose future experimental approaches to fill the gaps in our understanding. Although the content herein relates specifically to inborn errors of immunity, the concepts are generalizable across genetic diseases.

WHIM syndrome is a rare combined primary immunodeficiency disease named by acronym for the diagnostic tetrad of warts, hypogammaglobulinemia, infections, and myelokathexis. Myelokathexis is a unique form of non-cyclic severe congenital neutropenia caused by accumulation of mature and degenerating neutrophils in the bone marrow; monocytopenia and lymphopenia, especially B lymphopenia, also commonly occur. WHIM syndrome is usually caused by autosomal dominant mutations in the G protein-coupled chemokine receptor CXCR4 that impair desensitization, resulting in enhanced and prolonged G protein- and β-arrestin-dependent responses. Accordingly, CXCR4 antagonists have shown promise as mechanism-based treatments in phase 1 clinical trials. This review is based on analysis of all 105 published cases of WHIM syndrome and covers current concepts, recent advances, unresolved enigmas and controversies, and promising future research directions.

PurposePatients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying “at-risk” patient profiles.MethodsWe performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included.ResultsA total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus–induced lymphoma in 1 case. Patients with a central venous catheter (n = 19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (p = 0.04).ConclusionOur data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode.

Backgrounds Children with primary immunodeficiency (PID) may develop severe infections after BCG vaccination. There is limited information on the long-term prognosis and management of these BCG-induced diseases. Methods Data were gathered from a cohort study on BCG-induced diseases at the Shanghai Public Health Clinical Center, spanning from January 2007 to August 2022. The study enrolled patients with confirmed PIDs, and information was obtained via personal interviews with patients or their guardians, as well as from their medical records. This allowed us to gather clinical and genetic details, treatment history, and the outcomes of their PIDs. We evaluated antimycobacterial outcomes and analyzed the impact of HSCT and IFN-γ therapy on the risk of death. Results Out of 422 patients with BCG-induced diseases, 109 patients with confirmed PID were included in the analysis. Of these, 88.1% had developed distant or disseminated BCG infection, and the median duration of illness documented in the study was 57 months (IQR 31–79). The three most common PIDs in this cohort were MSMD (47/109, 43.1%), CGD (28/109, 25.7%), and CID (19/109 or 17.4%). The estimated five-year and ten-year survival rates were 80.3% (95%CI, 72.1%-88.5%) and 69.3% (95%CI, 56.8%-81.8%). Patients who received hematopoietic stem cell transplantation therapy (HSCT) had a significantly higher success rate with antimycobacterial treatment (75.8% vs. 0%). The survival benefit of HSCT varies across immunodeficiency types but is clearly beneficial for CID ( p  < 0.001). IFN-γ therapy presented no significant effect on the survival of CGD and MSMD. The initial STRONGkids nutritional score (HR = 2.27 per point, 95%CI 1.65–3.13) and gender (HR for male = 4.89, CI 1.36–17.57) are significant predictors of survival. Mutations in 6 genes ( IL12RB1 , CYBB , IFNGR1 , IL2RG , STAT1 , and RAG1 ) account for 66% of BCG-associated immunodeficiency mutations. Conclusions PID complicated by BCG infection may cause persistent and severe conditions. Patients with severe nutritional risk in the early stages of infection have a higher risk of death and should prioritize HSCT.

A global gold standard framework for primary immunodeficiency (PID) care, structured around six principles, was published in 2014. To measure the implementation status of these principles IPOPI developed the PID Life Index in 2020, an interactive tool aggregating national PID data. This development was combined with a revision of the principles to consider advances in the field of health and science as well as political developments since 2014. The revision resulted in the following six principles: PID diagnosis, treatments, universal health coverage, specialised centres, national patient organisations and registries for PIDs. A questionnaire corresponding to these principles was sent out to IPOPI’s national member organisations and to countries in which IPOPI had medical contacts, and data was gathered from 60 countries. The data demonstrates that, regardless of global scientific progress on PIDs with a growing number of diagnostic tools and better treatment options becoming available, the accessibility and affordability of these remains uneven throughout the world. It is not only visible between regions, but also between countries within the same region. One of the most urgent needs is medical education. In countries without immunologists, patients with PID suffer the risk of remaining undiagnosed or misdiagnosed, resulting in health implications or even death. Many countries also lack the infrastructure needed to carry out more advanced diagnostic tests and perform treatments such as hematopoietic stem cell transplantation or gene therapy. The incapacity to secure appropriate diagnosis and treatments affects the PID environment negatively in these countries. Availability and affordability also remain key issues, as diagnosis and treatments require coverage/reimbursement to ensure that patients with PID can access them in practice, not only in theory. This is still not the case in many countries of the world according to the PID Life Index. Although some countries do perform better than others, to date no country has fully implemented the PID principles of care, confirming the long way ahead to ensure an optimal environment for patients with PID in every country.

The Primary Immunodeficiency Database in Japan (PIDJ) is a registry of primary immunodeficiency diseases (PIDs) that was established in 2007. The database is a joint research project with research groups associated with the Ministry of Health, Labor and Welfare; the RIKEN Research Center for Allergy and Immunology (RCAI); and the Kazusa DNA Research Institute (KDRI). The PIDJ contains patient details, including the age, sex, clinical and laboratory findings, types of infections, genetic analysis results, and treatments administered. In addition, web-based case consultation is also provided. The PIDJ serves as a database for patients with PIDs and as a patient consultation service connecting general physicians with PID specialists and specialized hospitals. Thus, the database contributes to investigations related to disease pathogenesis and the early diagnosis and treatment of patients with PIDs. In the 9 years since the launch of PIDJ, 4,481 patients have been enrolled, of whom 64% have been subjected to genetic analysis. In 2017, the Japanese Society for Immunodeficiency and Autoinflammatory Diseases (JSIAD) was established to advance the diagnosis, treatment, and research in the field of PIDs and autoinflammatory diseases (AIDs). JSIAD promotes the analysis of the pathogenesis of PIDs and AIDs, enabling improved patient care and networking via the expansion of the database and construction of a biobank obtained from the PIDJ. The PIDJ was upgraded to “PIDJ ver.2” in 2019 by JSIAD. Currently, PIDJ ver.2 is used as a platform for epidemiological studies, genetic analysis, and pathogenesis evaluation for PIDs and AIDs.