Shereen M. Reda

Characterization of T and B cell repertoire diversity in patients with RAG deficiency

Differences in B and T cell repertoires in patients with RAG deficiency associate with clinical severity. Taking SCID genetics to the clinic Mutations that lead to deficiencies in the recombination-activating genes RAG1 and RAG2 result in a spectrum of immunodeficiencies ranging from loss of T and/or B cell repertoire diversity to a complete lack of T and B cells—severe combined immunodeficiency (SCID). Here, Lee et al. perform next-generation B and T cell repertoire sequencing on 12 patients with RAG mutations who have immunodeficiencies of varying severity. They found that the level of repertoire skewing was associated with the severity of disease and that specific repertoire deficiencies were associated with particular phenotypes. These data support a genotype-phenotype connection for primary immunodeficiencies. 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 the 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 immunodeficiency (SCID) with lack of T and B cells, Omenn syndrome, leaky SCID, and combined immunodeficiency with granulomas or autoimmunity (CID-G/AI). Using next-generation sequencing, we analyzed the TCR and B cell receptor (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 to better understand the phenotypic heterogeneity of RAG deficiency.

Poliovirus Excretion among Persons with Primary Immune DeficiencyDisorders: Summary of Data from Enhanced Poliovirus Surveillance in Egypt,2011-2014

Background: If exposed to oral poliovirus vaccine (OPV), persons with primary immune deficiency disorders (PID) are at increased risk of paralytic poliomyelitis; and can chronically excrete poliovirus. However, the risk of excretion of vaccine derived poliovirus among immunodeficient persons (iVDPV) is not well characterized. We present summary of data from poliovirus surveillance project among PID patients collected between 2011 and 2014 from 11 Egyptian Governorates. Methods: Stool was tested for polioviruses in suspected or confirmed PID children regardless of whether Acute Flaccid Paralysis (AFP) was present or not. Those excreting poliovirus were followed until three consecutive negative stool samples were obtained. Results: There were 122 patients with suspected or confirmed PID identified; 13/122 (11%) excreted poliovirus; of these, 6 excreted iVDPVs, the remaining 7 excreted Sabin virus. The duration of iVDPV excretion ranged from 1 to 21 months. AFP was detected in 3/6 (50%) of those excreting iVDPVs. All iVDPV excretors had history of receiving OPV. Conclusions: Chronic poliovirus excretion in PID patients is rare, however, poliovirus eradication requires removal of all polioviruses from circulation; and because PID individuals are not necessarily paralyzed they might be missed by current poliovirus surveillance based on detection of AFP. To achieve poliovirus eradication, surveillance for polioviruses among PID patients should be routinely conducted in all countries, and poliovirus antiviral therapy must be made available for those with chronic excretion.

Erratum to: Emerging Infections and Pertinent Infections Related to Travel for Patients with Primary Immunodeficiencies

In today’s global economy and affordable vacation travel, it is increasingly important that visitors to another country and their physician be familiar with emerging infections, infections unique to a specific geographic region, and risks related to the process of travel. This is never more important than for patients with primary immunodeficiency disorders (PIDD). A recent review addressing common causes of fever in travelers provides important information for the general population Thwaites and Day (N Engl J Med 376:548-560, 2017). This review covers critical infectious and management concerns specifically related to travel for patients with PIDD. This review will discuss the context of the changing landscape of infections, highlight specific infections of concern, and profile distinct infection phenotypes in patients who are immune compromised. The organization of this review will address the environment driving emerging infections and several concerns unique to patients with PIDD. The first section addresses general considerations, the second section profiles specific infections organized according to mechanism of transmission, and the third section focuses on unique phenotypes and unique susceptibilities in patients with PIDDs. This review does not address most parasitic diseases. Reference tables provide easily accessible information on a broader range of infections than is described in the text.

Could recurrent otitis media predict primary antibody deficiencies in Egyptian children

Background Recurrent ear infection is a significant warning sign of primary immunodeficiency diseases. Objective To estimate the frequency of IgA deficiency among children presenting to the outpatient clinic with recurrent otitis media (ROM > 4 times/year) and identify other possible risk factors of ROM in our community. Materials and methods Three hundred children (154 males and 146 females), who presented to the outpatient clinic of Childrens Hospital, Ain Shams University with ROM, were consecutively enrolled in the study over a 1-year period. According to the age of enrollment, children were classified into two groups: group A (1-6 years) and group B (>6-12 years). The demographic features of both groups were evaluated together with assessment of serum IgA level. Results Of all patients studied, only two (0.7%) had a low serum IgA level for normal age-reference values. None of the patients had neutropenia or lymphopenia. Iron-deficiency anemia was diagnosed in 76 cases, with higher rates among the patients in group A than group B. All patients received several courses of various empirical broad-spectrum antibiotics, but with either an incomplete course (n = 192) or a poor response (n = 49). Conclusion The current study showed a relatively low incidence of IgA deficiency among children with ROM and indicated other environmental risk factors that participated in the occurrence of OM in our community.