Measurement and interpretation of Salmonella typhi Vi IgG antibodies for the assessment of adaptive immunity

Response to polysaccharide vaccination can be an invaluable tool for assessing functionality of the adaptive immune system. Measurement of antibodies raised in response to Pneumovax®23 is the current gold standard test, but there are significant challenges and constraints in both the measurement and interpretation of the response. An alternative polysaccharide vaccine approach (Salmonella typhi Vi capsule (ViCPS)) has been suggested. In the present article, we review current evidence for the measurement of ViCPS antibodies in the diagnosis of primary and secondary antibody deficiencies. In particular, we review emerging data suggesting their interpretation in combination with the response to Pneumovax®23 and comment upon the utility of these vaccines to assess humoral immune responses while receiving immunoglobulin replacement therapy (IGRT)

The lung in primary immunodeficiencies: new concepts in infection and inflammation

Immunoglobulin replacement therapy (IGRT) has contributed critically to the management of primary antibody deficiencies (PAD) and the decrease in pneumonia rate. However, despite adequate IGRT and improved prognosis, patients with PAD continue to experience recurrent respiratory tract infections, leading to bronchiectasis and continuing decline in lung function with a severe impact on their quality of life. Moreover, non-infectious inflammatory and interstitial lung complications, such as granulomatous-lymphocytic interstitial lung disease, contribute substantially to the overall morbidity of PAD. These conditions develop much more often than appreciated and represent a major therapeutic challenge. Therefore, a regular assessment of the structural and functional condition of the lung and the upper airways with appropriate treatment is required to minimize the deterioration of lung function. This work summarizes the knowledge on lung complications in PAD and discusses the currently available diagnostic tools and treatment options

Secondary antibody deficiency: a complication of anti-CD20 therapy for neuroinflammation

B-cell depleting anti-CD20 monoclonal antibody therapies are being increasingly used as long-term maintenance therapy for neuroinflammatory disease compared to many non-neurological diseases where they are used as remission-inducing agents. While hypogammaglobulinaemia is known to occur in over half of patients treated with medium to long-term B-cell-depleting therapy (in our cohort IgG 38, IgM 56 and IgA 18%), the risk of infections it poses seems to be under-recognised. Here, we report five cases of serious infections associated with hypogammaglobulinaemia occurring in patients receiving rituximab for neuromyelitis optica spectrum disorders. Sixty-four per cent of the whole cohort of patients studied had hypogammaglobulinemia. We discuss the implications of these cases to the wider use of anti-CD20 therapy in neuroinflammatory disease

New insights in the use of immunoglobulins for the management of immune deficiency (PID) patients

Immunoglobulin replacement therapy (IRT) is standard treatment for patients with primary immunodeficiency (PID). Because most of the patients with PID will require long life-time immunoglobulin replacement therapy, the quality of the prescribed products is of utmost importance. The IRT is generally administered either intravenously (abbreviated IVIG), or subcutaneously (abbreviated SCIG). Both routes have been demonstrated to be effective. The preferred route may vary at different times during a given patient’s life. Options are therefore not fixed and the choice of route for immunoglobulin therapy will depend on several factors, including patient characteristics, clinical indication, venous access, side effects, rural or remote location, treatment compliance and patient preference. Many years ago, immunoglobulin therapy was associated with side effects which may compromise patient’s compliance and quality of life of the patients. Most of the side effects were related to impurities. Recently, major advances in the manufacturing process have been made and new processes, such as the Quality by design (QbD) approach were added into the manufacturing steps to ensure patients tolerability and safety. Due to the improved purity of the immunoglobulin products obtained by these processes, the incidence of side effects is lower, while the ways of administration of Ig therapy and the choice of the regimen has widened to suit patient’s preference and needs

Long-term efficacy and safety of Hizentra® in patients with primary immunodeficiency in Japan, Europe, and the United States: a Review of 7 Phase 3 Trials

Many patients with primary immunodeficiency (PID) require immunoglobulin G (IgG) replacement therapy, delivered as intravenous IgG (IVIG) or subcutaneous IgG (SCIG). We aim to identify trends in efficacy and safety that would not be evident in individual studies of small patient numbers. Seven open-label, Phase 3, prospective, multicenter studies of the efficacy and safety of Hizentra® (a SCIG), conducted in Japan, Europe, and the US were summarized. Overall, 125 unique patients received 15,013 weekly infusions during a total observation period of 250.9 patient-years. Mean weekly doses of Hizentra® were 83.22–221.3 mg/kg body weight; infusion rates per patient (total body rate) were 25.2–49.3 mL/h across studies. The rates of infections and serious bacterial infections were 3.10 and 0.03 events per patient/year, respectively. Annualized rates of days hospitalized due to infection, out of work/school, and prophylactic antibiotic use were 0.95, 5.14, and 36.78 per patient, respectively. For the equivalent monthly dose, weekly Hizentra® SCIG administration resulted in expectedly-increased serum IgG trough levels in patients switching from IVIG, and maintained levels in patients switching from previous SCIG. Adverse events (AEs) totaled 5039 (events/infusion 0.094–0.773), almost all of which were mild/moderate. Three thousand one hundred ninety-seven were considered treatment-related, the most common of which were injection site reactions (2919 events; 0.001–0.592 AEs per infusion). Systemic AEs were very uncommon. The results from these seven studies indicate that Hizentra® therapy was both efficacious and well tolerated during long-term treatment. This is particularly important in patients with PID, who may require lifelong IgG replacement therapy

Efficacy and Safety of Hizentra®, a New 20% Immunoglobulin Preparation for Subcutaneous Administration, in Pediatric Patients with Primary Immunodeficiency

Subcutaneous IgG treatment for primary immunodeficiencies (PI) is particularly well suited for children because it does not require venous access and is mostly free of systemic adverse events (AEs). In a prospective, open-label, multicenter, single-arm, Phase III study, 18 children and five adolescents with PI were switched from previous intravenous (IVIG) or subcutaneous (SCIG) IgG treatment to receive dose-equivalent, weekly subcutaneous infusions of Hizentra® for 40 weeks. Mean IgG trough levels were maintained in patients previously on SCIG, or increased in those previously on IVIG, regardless of age. No serious bacterial infections were reported during the efficacy period of the study. The rates of non-serious infections were 4.77 (children) and 5.18 (adolescents) infections per patient per year. Related AEs were observed in seven children (38.9%) and two adolescents (40%). Three serious AEs and two AEs leading to discontinuation (all unrelated) were reported in children. Hizentra® is an effective and well-tolerated treatment for pediatric patients

Quantification of human complement C2 protein using an automated turbidimetric immunoassay

Background: The measurement of complement components is clinically useful where a deficiency is suspected, or where excessive activation and consumption are present in disease. C2 deficiency carries an increased risk of developing systemic lupus erythematosus, recurrent infections and atherosclerosis. In this study, we have evaluated The Binding Site’s Human Complement C2 SPAPLUS® assay. Methods: Linearity was tested using 13 sample dilutions covering the standard measuring range. Within- and between-assay variabilities were calculated using five samples with different C2 concentrations. The correlation between C2 concentrations in EDTA-plasma and serum was assessed, as was the correlation between C2 measurements by the automated assay and radial immunodiffusion. C2 concentrations were compared with CH50 activity, and quantified in individuals with homozygous or heterozygous C2 deficiency, acquired angioedema and patients with chronic inflammatory conditions. Results: The assay was linear across the measuring range (3.8–42.3 mg/L). Intra- and interassay variability were 2.3%–3.8% and 0%–3.3%, respectively. Comparison between C2 measurements in EDTA-plasma and serum provided a strong correlation (p<0.0001, R2=0.82, slope 0.92), as did the correlation between the automated and radial immunodiffusion methods (p<0.0001, R2=0.89, slope 1.07). A positive correlation between C2 concentration and CH50 activity was demonstrated (p<0.0001, R2=0.48). Significant differences were observed between the median C2 concentrations obtained in healthy controls and the patient clinical samples, with homozygous C2-deficient patients giving below detectable results. Conclusions: This C2 SPAPLUS® assay allows the automated, rapid and precice quantification of complement C2 protein and could therefore be considered as a replacement for older, more time-consuming methods

British Lung Foundation/United Kingdom primary immunodeficiency network consensus statement on the definition, diagnosis, and management of granulomatous-lymphocytic interstitial lung disease in common variable immunodeficiency disorders

A proportion of people living with common variable immunodeficiency disorders develop granulomatous-lymphocytic interstitial lung disease (GLILD). We aimed to develop a consensus statement on the definition, diagnosis, and management of GLILD. All UK specialist centers were contacted and relevant physicians were invited to take part in a 3-round online Delphi process. Responses were graded as Strongly Agree, Tend to Agree, Neither Agree nor Disagree, Tend to Disagree, and Strongly Disagree, scored +1, +0.5, 0, −0.5, and −1, respectively. Agreement was defined as greater than or equal to 80% consensus. Scores are reported as mean ± SD. There was 100% agreement (score, 0.92 ± 0.19) for the following definition: “GLILD is a distinct clinico-radio-pathological ILD occurring in patients with [common variable immunodeficiency disorders], associated with a lymphocytic infiltrate and/or granuloma in the lung, and in whom other conditions have been considered and where possible excluded.” There was consensus that the workup of suspected GLILD requires chest computed tomography (CT) (0.98 ± 0.01), lung function tests (eg, gas transfer, 0.94 ± 0.17), bronchoscopy to exclude infection (0.63 ± 0.50), and lung biopsy (0.58 ± 0.40). There was no consensus on whether expectant management following optimization of immunoglobulin therapy was acceptable: 67% agreed, 25% disagreed, score 0.38 ± 0.59; 90% agreed that when treatment was required, first-line treatment should be with corticosteroids alone (score, 0.55 ± 0.51)

The evolution of cellular deficiency in GATA2 mutation.

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageConstitutive heterozygous GATA2 mutation is associated with deafness, lymphedema, mononuclear cytopenias, infection, myelodysplasia (MDS), and acute myeloid leukemia. In this study, we describe a cross-sectional analysis of 24 patients and 6 relatives with 14 different frameshift or substitution mutations of GATA2. A pattern of dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency (DCML deficiency) with elevated Fms-like tyrosine kinase 3 ligand (Flt3L) was observed in all 20 patients phenotyped, including patients with Emberger syndrome, monocytopenia with Mycobacterium avium complex (MonoMAC), and MDS. Four unaffected relatives had a normal phenotype indicating that cellular deficiency may evolve over time or is incompletely penetrant, while 2 developed subclinical cytopenias or elevated Flt3L. Patients with GATA2 mutation maintained higher hemoglobin, neutrophils, and platelets and were younger than controls with acquired MDS and wild-type GATA2. Frameshift mutations were associated with earlier age of clinical presentation than substitution mutations. Elevated Flt3L, loss of bone marrow progenitors, and clonal myelopoiesis were early signs of disease evolution. Clinical progression was associated with increasingly elevated Flt3L, depletion of transitional B cells, CD56(bright) NK cells, naïve T cells, and accumulation of terminally differentiated NK and CD8(+) memory T cells. These studies provide a framework for clinical and laboratory monitoring of patients with GATA2 mutation and may inform therapeutic decision-making.Lymphoma and Leukaemia Research British Society of Hematology Bright Red George Walker Trust Wellcome Trus