Background SCID is a syndrome characterized by profound T cell deficiency. BCG vaccine is contraindicated in SCID patients. Because most countries encourage BCG vaccination at birth, a high percent of SCID patients are vaccinated before their immune defect is detected. Objectives To describe the complications and risks associated with BCG vaccination in SCID patients. Methods An extensive standardized questionnaire evaluating complications, therapeutics, and outcome regarding BCG in patients diagnosed with SCID was widely distributed. Summary statistics and association analysis was performed. Results Data on 349 BCG vaccinated SCID patients from 28 centers in 17 countries was analyzed. Fifty-one percent of the patients developed BCG complications, 34% disseminated and 17% localized (a 33,000 and 400 fold increase, respectively, over the general population). Patients receiving early vaccination (≤ 1 month) showed an increased prevalence of complications (p=0.006) and death due to BCG complications (p<0.0001). The odds of experiencing complications among patients with T cells ≤ 250/uL at diagnosis was 2.1 times higher (95% CI, 1.4-3.4; p = 0.001) than among those with T cells > 250/uL. BCG complications were reported in 2/78 patients who received anti-mycobacterial therapy while asymptomatic and no deaths due to BCG complications occurred in this group. In contrast 46 BCG-associated deaths were reported among 160 patients treated with anti-mycobacterial therapy for a symptomatic BCG infection (p<0.0001). Conclusions BCG vaccine has a very high rate of complications in SCID patients, which increase morbidity and mortality rates. Until safer and more efficient anti-tuberculosis vaccines become available, delay in BCG vaccination should be considered to protect highly vulnerable populations from preventable complications.

Background The recombination-activating gene (RAG) 1/2 proteins play a critical role in the development of T and B cells by initiating the VDJ recombination process that leads to generation of a broad T-cell receptor (TCR) and B-cell receptor repertoire. Pathogenic mutations in the RAG1/2 genes result in various forms of primary immunodeficiency, ranging from T−B− severe combined immune deficiency to delayed-onset disease with granuloma formation, autoimmunity, or both. It is not clear what contributes to such heterogeneity of phenotypes. Objective We sought to investigate the molecular basis for phenotypic diversity presented in patients with various RAG1 mutations. Methods We have developed a flow cytometry–based assay that allows analysis of RAG recombination activity based on green fluorescent protein expression and have assessed the induction of the Ighc locus rearrangements in mouse Rag1−/− pro-B cells reconstituted with wild-type or mutant human RAG1 (hRAG1) using deep sequencing technology. Results Here we demonstrate correlation between defective recombination activity of hRAG1 mutant proteins and severity of the clinical and immunologic phenotype and provide insights on the molecular mechanisms accounting for such phenotypic diversity. Conclusions Using a sensitive assay to measure the RAG1 activity level of 79 mutations in a physiologic setting, we demonstrate correlation between recombination activity of RAG1 mutants and the severity of clinical presentation and show that RAG1 mutants can induce specific abnormalities of the VDJ recombination process.

Recombination Activating Genes 1 and 2 (RAG1 and RAG2) play a critical role in T and B cell development by initiating the recombination process that controls expression of T cell receptor (TCR) and immunoglobulin genes. Mutations in the RAG1 and RAG2 genes in humans cause a broad spectrum of phenotypes, including severe combined immune deficiency (SCID) with lack of T and B cells, Omenn syndrome, leaky SCID, and combined immune deficiency with granulomas or autoimmunity (CID-G/AI). Using next generation sequencing, we analyzed the T and B cell receptor (TCR, BCR) repertoire in 12 patients with RAG mutations presenting with Omenn syndrome (n=5), leaky SCID (n=3), or CID-G/AI (n=4). Restriction of repertoire diversity skewed usage of Variable (V), Diversity (D), and Joining (J) segment genes, and abnormalities of CDR3 length distribution were progressively more prominent in patients with a more severe phenotype. Skewed usage of V,D and J segment genes was present also within unique sequences, indicating a primary restriction of repertoire. Patients with Omenn syndrome had a high proportion of class-switched immunoglobulin heavy chain transcripts and increased somatic hypermutation rate, suggesting in vivo activation of these B cells. These data provide a framework for better understanding the phenotypic heterogeneity of RAG deficiency.

Primary immunodeficiency disorders are not rare in Egyptian children. The observed frequency of combined T- and B-cell immunodeficiencies in our cohort is relatively higher than other countries. It is a prerequisite to establish a national registry of primary immunodeficiency in Egypt.

Large differences in COVID‐19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage were associated with low death rates in European countries. SARS‐CoV‐2 binds to its receptor, the angiotensin converting enzyme 2 (ACE2). As a result of SARS‐Cov‐2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT 1 R) axis associated with oxidative stress. This leads to insulin resistanceas well as lung and endothelial damage, two severe outcomes of COVID‐19. The nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) is the most potent antioxidant in humans and can block the AT 1 R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are given: Kimchi in Korea, westernized foods and the slum paradox. It is proposed that fermented cabbage is a proof‐of‐concept of dietary manipulations that may enhance Nrf2‐associated antioxidant effects helpful in mitigating COVID‐19 severity.

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PurposeTo promote awareness of primary immunodeficiency (PID), the "10 warning signs" of PID and an immunodeficiency-related (IDR) score were developed. However, their efficiency in identifying PID cases was not sufficiently evaluated in clinical practice. The objective of this study was to test the validity of the 10 warning signs and IDR score in identifying PID among children with recurrent infections at a tertiary pediatric hospital in Egypt.MethodsA retrospective analysis of the medical records of 204 patients was performed. Of these patients, 92 had defined PID diseases and 112 were considered non-PID cases because investigations were inconclusive.ResultsDemonstrating two warning signs and an IDR score of 6 led to sensitivities of 94 and 66%, respectively, and specificities of 64 and 75%, respectively, in identifying PID cases. The strongest predictor of PID was family history that, if combined with the need for intravenous antibiotics, recurrent deep-seated infections, and failure to thrive, could identify 81% of PID patients. A family history of PID, sibling death, and/or parental consanguinity would predict 92% of combined immunodeficiencies, 92% of phagocyte defects, 87% of well-identified immunodeficiency syndromes, and 84% of antibody deficiency if the need for intravenous antibiotics is considered in the latter.ConclusionsThe 10 warning signs and IDR score do not aid in an early diagnosis of severe PID. Educational campaigns should target pediatricians aiming to increase PID awareness and to address family history of PID, parental consanguinity, and previous sibling death as key predictors of PID in communities with a high prevalence of consanguineous marriages.

The tremendous increase in allergy in the African continent cannot simply be explained by the change in public hygiene. There are many "prehygiene" communities with sewage-contaminated water supplies, helminth infestations, bare footedness, and poor housing, and still there is a high prevalence of allergic disease. Africans can be exposed to many risk factors facilitating severe asthma and wheezing, including airborne viruses, smoke, indoor dampness, cockroaches, and poor access to health care. Although the reporting on food allergy is inadequate to perform systematic reviews or meta-analyses, the available data suggest that food allergy is underdiagnosed. The rate of new HIV infections in high-prevalence settings in Africa remains unacceptably high. Although the annual number of new HIV infections in Sub-Saharan Africa has decreased lately, new HIV infections in the Middle East and North Africa region have increased; however, the current prevalence of 0.1% is still among the lowest globally. Africa is densely populated, and consanguineous mating is high in some areas of North and Sub-Saharan Africa. This allows for emergence of many autosomal recessive primary immunodeficiency diseases. There is urgent need for the establishment of primary immunodeficiency disease registries, stem cell transplantation facilities, and neonatal screening programs. To address these expanding problems and perform local cutting-edge research, Africans need to be empowered by motivated governments, dedicated funds, and compassionate scientific partnership.