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Concept: Immunodeficiency

179

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

67

In July 1996, researchers, policymakers, and activists involved in the fight against HIV-AIDS met in Vancouver, Canada, for the 11th International Conference on AIDS. During that historic meeting, practitioners and patients heard evidence regarding a powerful weapon to stop the relentless onslaught of the human immunodeficiency virus (HIV): combination antiretroviral therapy (ART), with a protease inhibitor as the centerpiece of the regimen. In the nearly 20 years since that watershed meeting, the early promise of durable effects from combination therapy has been realized for many patients: between 2000 and 2014, the rollout of ART saved an estimated 7.8 million lives . . .

Concepts: Antiretroviral drug, HIV, AIDS, Protease inhibitor, Immune system, Tuberculosis, South Africa, Immunodeficiency

48

Human immunodeficiency virus (HIV) disproportionately impacts minority youth. Interventions to decrease HIV sexual risk are needed.

Concepts: HIV, AIDS, Immune system, Sexual intercourse, Genome, Randomized controlled trial, Human sexual behavior, Immunodeficiency

34

Patients with cancer who are infected with the human immunodeficiency virus (HIV) are less likely to receive cancer treatment compared with HIV-uninfected individuals. However, to the authors' knowledge, the impact of insurance status and comorbidities is unknown.

Concepts: HIV, AIDS, Immune system, Infectious disease, Genome, Immunodeficiency

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

To evaluate the association between oral candidiasis and tuberculosis (TB) in human immunodeficiency virus (HIV) infected individuals in sub-Saharan Africa, and to investigate oral candidiasis as a potential tool for TB case finding.

Concepts: HIV, AIDS, Immune system, Africa, Sub-Saharan Africa, Tuberculosis, Candidiasis, Immunodeficiency