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Concept: Primary immunodeficiency

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Patients with primary immunodeficiency disease (PIDD) typically require life-long intravenous (IV) or subcutaneous (SC) immunoglobulin (Ig) replacement therapy to prevent recurrent infections. The efficacy, safety, and pharmacokinetics of a highly concentrated (20 %) Ig preparation for SC administration (IGSC 20 %) were evaluated in a prospective trial in patients with PIDD. A total of 74 patients (aged 3-83 years) received 4327 IGSC 20 % infusions over a median of 380.5 days. The rate of validated serious bacterial infections was 0.012 event/patient-year (p < 0.0001 compared with the historical control), and the annualized rate of infection was 2.41 events/patient. Median IgG trough levels were >14.5 g/l. The median maximum infusion rate was 60 ml/h/site (range 4.4-180), resulting in a median infusion duration of 0.95 h. A volume ≥30 ml was infused per site in 74.8 % of IGSC 20 % infusions. Most (84.9 %) infusions were administered using ≤2 infusion sites; for 99.8 % of infusions, there was no need to interrupt/stop administration or reduce the infusion rate. No related serious adverse event (AE) occurred during IGSC 20 % treatment; related non-serious AEs occurred at a rate of 0.036 event/infusion. The incidence of related local AEs was 0.015 event/infusion and of related systemic AEs was 0.021 event/infusion; most were mild in severity, none severe. Increased infusion rates or volumes were not associated with higher AE rates. The investigated IGSC 20 % treatment was shown to be effective and safe, enabling higher infusion rates and volumes per site compared to conventional SC treatments, resulting in fewer infusion sites and shorter infusion durations.

Concepts: Immune system, Infectious disease, Bacteria, Infection, Immunodeficiency, Infusion, Primary immunodeficiency, Infusion pump

170

There is a need for neonatal screening tools to improve the long-term clinical outcome of patients with primary immunodeficiency diseases (PID). Recently, a PCR-based screening method for both TRECs and KRECs using Guthrie card samples has been developed. However, the applicability of these excision circle assays is limited to patients with severe T or B cell lymphopenia (SCID, XLA and A-T), whereas the most common forms of PID are not detected. Absence of serum IgA is seen in a major fraction of patients with immunological defects. As serum IgA in newborns is considered to be of fetal origin, eluates from routinely collected dried blood spot samples might thus be suitable for identification of children with PID. To assess the applicability of such screening assays, stored Guthrie card samples were obtained from 47 patients with various forms of primary immunodeficiency diseases (SCID, XLA, A-T, HIGM and IgAD), 20 individuals with normal serum IgA levels born to IgA-deficient mothers and 51 matched healthy newborns. Surprisingly, normal serum IgA levels were found in all SCID, XLA, A-T and HIGM patients and, additionally, in all those IgAD patients born to IgA-sufficient mothers. Conversely, no serum IgA was found in any of the 16 IgAD patients born by IgA-deficient mothers. Moreover, half of the IgA-sufficient individuals born by IgA-deficient mothers also lacked IgA at birth whereas no IgA-deficient individuals were found among the controls. IgA in neonatal dried blood samples thus appears to be of both maternal and fetal origin and precludes its use as a reliable marker for neonatal screening of primary immunodeficiency diseases.

Concepts: Immune system, Infant, Fetus, Maternal bond, Pediatrics, Immunodeficiency, Primary immunodeficiency, Dried blood spot testing

28

Our understanding of immunity has historically been informed by studying heritable mutations in both the adaptive and innate immune responses, including primary immunodeficiency and autoimmune diseases. Recent advances achieved through the application of genomic and epigenomic approaches are reshaping the study of immune dysfunction and opening up new avenues for therapeutic interventions. Moreover, applying genomic techniques to resolve functionally important genetic variation between individuals is providing new insights into immune function in health. This review describes progress in the study of rare variants and primary immunodeficiency diseases arising from whole-exome sequencing (WES), and discusses the application, success, and challenges of applying genome-wide association studies (GWAS) to disorders of immune function and how they may inform more rational use of therapeutics. In addition, the application of expression quantitative-trait mapping to immune phenotypes, progress in understanding MHC disease associations, and insights into epigenetic mechanisms at the interface of immunity and the environment are reviewed.

Concepts: Immune system, Medicine, Genetics, Evolution, Innate immune system, Immunology, Immunodeficiency, Primary immunodeficiency

28

OBJECTIVE: Common Variable Immunodeficiency Disorder (CVID) is a complex disorder that predisposes patients to recurrent and severe infections. Immunophenotypic classification schemes were developed to categorise CVID patients into phenotypic and prognostic groups based on different memory B cell subsets. Whether the B cell subset analysis is stable over time has not been investigated. METHODS: B cell phenotyping in CVID patients (n=15) and sex- and age-matched controls (n=26) were carried out according to the three B cell classifications. CVID patients were evaluated monthly over six months. Controls were assessed once during the study. RESULTS: We scored how often each patient was assigned to the same group within each classification. The Freiburg classification assigned patients to the same group at a rate of 73% and the Paris classification at 88%. The EUROclass classification of smB- vs smB+ was at 90%. The two sub-classifications [(smB-21low or smB-21norm) and transitional B] were at 87% and 97% respectively. The level of naïve B cells measured in all CVID patients during the 6 month evaluation was the most stable B cell subset. CONCLUSION: We conclude that all classifications systems show considerable variability but the EUROclass classification was the most reliable scheme for our 15 CVID and 26 healthy cohorts. Our results indicate that phenotypic classifications within CVID will be difficult while there is variability of commonly used assays.

Concepts: Immune system, Gene, B cell, Immunodeficiency, Memory B cell, Primary immunodeficiency, Common variable immunodeficiency

28

Common variable immunodeficiency (CVID) is an inherited disease characterized by hypogammaglobulinaemia and impaired humoural immunoresponse and is mainly associated with recurrent infections of the airway and the digestive tract. An 18-year old female with a diagnosis of CVID associated with a devastating necrotizing periodontitis, ultimately resulting in complete destruction of the periodontium and loss of all teeth, is reported. Clinical, biochemical, microbiological and radiographic examinations are presented. The report highlights the likely importance of immunoglobulin replacement and intensive dental hygiene in CVID patients, and the devastating effect of non-compliance in such patients.

Concepts: Immune system, Disease, Infectious disease, Immunodeficiency, Oral hygiene, Primary immunodeficiency, Common variable immunodeficiency, Hypogammaglobulinemia

28

Common variable immunodeficiency (CVID) describes a heterogeneous subset of hypogammaglobulinemias of unknown etiology. Typically, patients present with recurrent bacterial infections of the respiratory and gastrointestinal tract. A significant proportion of CVID patients develops additional autoimmune, inflammatory or lymphoproliferative complications. CVID is the most frequent symptomatic primary immunodeficiency encountered in adults. Informative monogenetic defects have been found in single patients and families but in most cases the pathogenesis is still elusive. Numerous immunological studies have demonstrated phenotypic and functional abnormalities of T cells, B cells and antigen-presenting cells. A hallmark is the impaired memory B-cell formation that has been taken advantage of for classifying CVID patients. Clinical multi-center studies have demonstrated a correlation between immunological markers and clinical presentation. Long-term outcome is significantly influenced by delay of diagnosis and treatment and the presence of chronic inflammatory complications. While immunoglobulin replacement therapy plus antibiotics can control infections in most cases, patients with non-infectious inflammatory complications such as granulomatous inflammation, interstitial lung disease, inflammatory bowel disease, lymphoproliferation and developing malignancies still represent a therapeutic challenge. In this review we provide a systematic overview of the immunological, clinical, diagnostic and therapeutic aspects of CVID and highlight recent developments in these fields.

Concepts: Immune system, Inflammation, Lymphocyte, Protein, Medicine, Bacteria, Immunodeficiency, Primary immunodeficiency

26

Granulomas may develop as a response to a local antigenic trigger, leading to the activation of macrophages and T lymphocytes. Primary immune deficiency (PID) is associated with the development of extensive cutaneous granulomas, which etiology remains unknown. We performed High-Throughput Sequencing of the transcriptome of cutaneous granuloma lesions on two consecutive index cases and RT-PCR in a third consecutive patient. The RA27/3 vaccine strain of Rubella virus - the core component of a universally used pediatric vaccine - was present in the cutaneous granuloma of these three out of three consecutive PID patients. Controls included the healthy skin of two patients, non-granulomatous cutaneous lesions of patients with immunodeficiency, and skin biopsy samples of healthy individuals and were negative. Expression of viral antigens was confirmed by immunofluorescence. Persistence of the Rubella vaccine virus was also demonstrated in granuloma lesions sampled 4 to 5 years earlier. The persistence of rubella virus vaccine strain in three out of three consecutive cutaneous granuloma patients with PID strongly suggests a causal association between RV and granuloma in this setting. This article is protected by copyright. All rights reserved.

Concepts: HIV, Immune system, Antibody, Vaccine, Anatomical pathology, Immunodeficiency, Copyright, Primary immunodeficiency

7

Background The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe combined immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth. Methods We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009). Results Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infection that had resolved (82%). Among actively infected infants without a matched sibling donor, survival was best among recipients of haploidentical T-cell-depleted transplants in the absence of any pretransplantation conditioning. Among survivors, reduced-intensity or myeloablative pretransplantation conditioning was associated with an increased likelihood of a CD3+ T-cell count of more than 1000 per cubic millimeter, freedom from immunoglobulin substitution, and IgA recovery but did not significantly affect CD4+ T-cell recovery or recovery of phytohemagglutinin-induced T-cell proliferation. The genetic subtype of SCID affected the quality of CD3+ T-cell recovery but not survival. Conclusions Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection. All available graft sources are expected to lead to excellent survival among asymptomatic infants. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Concepts: HIV, Immune system, Infectious disease, Opportunistic infection, Infection, Immunodeficiency, Severe combined immunodeficiency, Primary immunodeficiency

5

Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide.

Concepts: AIDS, Immune system, Medicine, Immunology, Immunity, World Health Organization, Immunodeficiency, Primary immunodeficiency

4

Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells.

Concepts: DNA, Genetics, Genetic disorder, Somatic hypermutation, Immunodeficiency, Primary immunodeficiency, Common variable immunodeficiency, Hypogammaglobulinemia