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

The expanding field of secondary antibody deficiency: causes, diagnosis, and management

Antibody deficiency or hypogammaglobulinemia can have primary or secondary etiologies. Primary antibody deficiency (PAD) is the result of intrinsic genetic defects, whereas secondary antibody deficiency may arise as a consequence of underlying conditions or medication use. On a global level, malnutrition, HIV, and malaria are major causes of secondary immunodeficiency. In this review we consider secondary antibody deficiency, for which common causes include hematological malignancies, such as chronic lymphocytic leukemia or multiple myeloma, and their treatment, protein-losing states, and side effects of a number of immunosuppressive agents and procedures involved in solid organ transplantation. Secondary antibody deficiency is not only much more common than PAD, but is also being increasingly recognized with the wider and more prolonged use of a growing list of agents targeting B cells. SAD may thus present to a broad range of specialties and is associated with an increased risk of infection. Early diagnosis and intervention is key to avoiding morbidity and mortality. Optimizing treatment requires careful clinical and laboratory assessment and may involve close monitoring of risk parameters, vaccination, antibiotic strategies, and in some patients, immunoglobulin replacement therapy (IgRT). This review discusses the rapidly evolving list of underlying causes of secondary antibody deficiency, specifically focusing on therapies targeting B cells, alongside recent advances in screening, biomarkers of risk for the development of secondary antibody deficiency, diagnosis, monitoring, and management

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

Clozapine-associated secondary antibody deficiency

Purpose of review Clozapine has recently been described as a novel cause of secondary antibody deficiency (SAD), associated with long-term therapy. Here we critically review the evidence linking clozapine use to an increased infection risk, describe immunological alterations, and discuss potential mechanisms. Recent findings Individuals with schizophrenia are at two to five times more likely to develop pneumonia than the general population, in particular, when receiving clozapine. Delayed-onset distinguishes clozapine-associated hypogammaglobulinaemia from agranulocytosis or neutropenia that occur at lesser frequency. Biomarker searches in treatment-resistant schizophrenia highlight an immune signature associated with long-term clozapine use. This includes reduction in class-switched memory B cells, echoing common variable immunodeficiency. Recent identification of a role for dopamine in T follicular helper–B cell interactions may inform future clinical studies. Summary The detrimental impact of the increased infection risk associated with clozapine necessitates a re-evaluation of the current monitoring strategies as well as further studies to better understand the underlying mechanisms of SAD in this setting. On the basis of available evidence, we suggest simple modifications to clozapine monitoring including integration of routine vaccination, smoking cessation, and assessment of humoral immunity. Further studies are required to understand the role of clozapine in neuroinflammation as well as other potentially autoantibody-mediated diseases

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

Editorial: The complexity of primary antibody deficiencies

Primary antibody deficiencies represent by far the largest group of primary immunodeficiencies (PID) at 56% (ESID Registry), however the proportion of patients in whom antibody deficiency represents a component of their condition is greater still at around 75% (1). It has become clear over recent years that while the vast majority of such patients experience recurrent infections a significant proportion are also affected by non-infectious dysregulatory complications which include malignancy, autoimmunity, inflammation and allergy (Figure 1). The increasingly complex manifestations of Primary Antibody Deficiencies have a major impact on the clinical management of patients and raise diagnostic and therapeutic challenges (2). This Research Topic draws together a series of reports focusing on a range of these non-infectious complications and their clinical implications

Bioavailability of IgG Administered by the subcutaneous route

Purpose US licensing studies of subcutaneous IgG (SCIG) calculate dose adjustments necessary to achieve area under the curve (AUC) of serum IgG vs. time on SCIG that is non-inferior to that on intravenous IgG (IVIG), within the FDA-set limit of ±20 %. The results are interpreted as showing that different SCIGs differ in bioavailability. We used three approaches to determine if the bioavailabilities were actually different. Methods Dose adjustments and AUCs from published licensing studies were used to calculate bioavailabilities using the formula: Bioavailability (% of IVIG) = AUC(SCIG) ÷ AUC(IVIG) x 1/Dose Adjustment. We also compared the increment in serum IgG concentration achieved with varying doses of SCIG in recent meta-analyses with the increment with different doses of IVIG, and determined the serum IgG concentrations when patients switched SCIG products at the same dose. Results The actual bioavailabilities were: Gamunex® 65.0 %, Hizentra® 65.5 %, Gammagard® 67.2 %, Vivaglobin® 69.0 %. Regression analyses of serum IgG vs. dose showed that the mean increase in serum IgG resulting from a 100 mg/kg/month increment in SCIG dosing was 69.4 % of the increase with the same increment in IVIG dosing (84 mg/dL vs. 121 mg/dL). Patients switching SCIG preparations at the same dose had no change in serum IgG levels, confirming that bioavailabilities of the SCIG preparations did not differ. Conclusions Decreased bioavailability appears to be a basic property of SCIG and not a result of any manufacturing process or concentration. Because serum IgG levels do not vary with different SCIG products at the same dose, adjustments are not necessary when switching products