Mary Lucas

Infection outcomes in patients with common variable immunodeficiency disorders: Relationship to immunoglobulin therapy over 22 years

BACKGROUND Common variable immunodeficiency disorders (CVIDs) are the most common forms of symptomatic primary antibody failure in adults and children. Replacement immunoglobulin is the standard treatment, although there are few consistent data on optimal dosages and target trough IgG levels required for infection prevention. OBJECTIVE To provide data to support the hypothesis that each patient requires an individual dose of therapeutic immunoglobulin to prevent breakthrough infections and that efficacious trough IgG levels vary between patients. METHODS Data, collected prospectively from a cohort of 90 patients with confirmed CVIDs from 1 center over a follow-up period of 22 years, was validated and analyzed. Immunoglobulin doses had been adjusted in accordance with infections rather than to achieve a particular trough IgG level. Doses to achieve infection-free periods were determined and resultant trough levels analyzed. A smaller group of patients with X-linked agammaglobulinemia was analyzed for comparison. RESULTS Patients with a CVID had a range of trough IgG levels that prevented breakthrough bacterial infections (5-17 g/L); viral and fungal infections were rare. Doses of replacement immunoglobulin to prevent breakthrough infections ranged from 0.2 to 1.2 g/kg/mo. Those with proven bronchiectasis or particular clinical phenotypes required higher replacement doses. Patients with X-linked agammaglobulinemia showed a similar range of IgG levels to stay infection-free (8-13 g/L). CONCLUSION These data offer guidance regarding optimal doses and target trough IgG levels in individual patients with CVIDs with or without bronchiectasis and for particular clinical phenotypes. The goal of replacement therapy should be to improve clinical outcome and not to reach a particular IgG trough level.

Abnormal liver function in common variable immunodeficiency disorders due to nodular regenerative hyperplasia.

Patients with common variable immunodeficiency disorders are monitored for liver function test abnormalities. A proportion of patients develop deranged liver function and some also develop hepatomegaly. We investigated the prevalence of abnormalities and types of liver disease, aiming to identify those at risk and determine outcomes. The local primary immunodeficiency database was searched for patients with a common variable immunodeficiency disorder and abnormal liver function and/or a liver biopsy. Patterns of liver dysfunction were determined and biopsies reviewed. A total of 47 of 108 patients had deranged liver function, most commonly raised alkaline phosphatase levels. Twenty‐three patients had liver biopsies. Nodular regenerative hyperplasia was found in 13 of 16 with unexplained pathology. These patients were more likely to have other disease‐related complications of common variable immunodeficiency disorders, in particular non‐coeliac (gluten insensitive) lymphocytic enteropathy. However, five had no symptoms of liver disease and only one died of liver complications. Nodular regenerative hyperplasia is a common complication of common variable immunodeficiency disorders but was rarely complicated by portal hypertension.

Confirmation and improvement of criteria for clinical phenotyping in common variable immunodeficiency disorders in replicate cohorts

To the Editor: The clinical diversity of common variable immunodeficiency disorders (CVIDs) required division of these patients into distinct clinical phenotypes to provide more homogeneous groups for immunopathologic studies as well as individual patient prognosis. By using data on clinical complications and disease progression from 334 patients with CVID from 7 European centers including Oxford (‘‘Northern European cohort’’), distinct clinical phenotypes were defined with relatively little overlap: 83% of the patients had only 1 clinical phenotype. The prognostic significance of the defined phenotypes was confirmed by significant correlation with survival. Comparison of data in 2 independent databases (DEFI and Mount Sinai) (see this article’s Online Repository at www. jacionline.org) showed that it was feasible to confirm clinical phenotyping criteria in replicate cohorts, using identical definitions for each clinical complication and laboratory finding. In addition, further associations were sought to improve the criteria for clinical phenotyping and survival. Predictors of clinical phenotypes were previously limited to IgM serum levels for the lymphoproliferative (LP) phenotype and malignancy as well as low peripheral CD8 counts for autoimmunity. Further searches for predictive laboratory measurements were undertaken on the combined cohorts. Since the dates of diagnosis for complications in patients in 2 cohorts (Oxford and the DEFI study) were known, the interval from the diagnoses of CVID and the first disease-related complication was calculated to search for the earliest date for reliable prognosis. Initially, it was important to confirm the concept of clinical phenotyping in CVIDs. The proportions of patients in the independent replicate cohorts with features of only 1 clinical phenotype were similar between cohorts when the original criteria were used (see Fig E1 in this article’s Online Repository at www.jacionline.org). By using the discovery (Northern European; n 5 334) cohort, further associations between complications were found to improve the phenotyping criteria. Considering the LP phenotype, no significant correlation was found between granuloma or lymphoid interstitial pneumonitis (LIP) and hepatomegaly, and so hepatomegaly was discarded. Lymphadenopathy remained as a criterion for LP, since although only 1 patient of 11 in the extended Oxford cohort did not also have granuloma or LIP, there were 29 patients with persistent lymphadenopathy in the Mount Sinai cohort of whom 10 had no obvious symptoms of granuloma and/or LIP.When autoimmunity was split into 2 categories, autoimmune cytopenias and organ-specific autoimmune diseases, only cytopenias showed decreased survival (P 5 .0001); organ-specific autoimmunity was not associated with cytopenias or the other clinical phenotypes. Lymphoid malignancies were excluded in the revised phenotyping criteria since CVID may not be the primary event. Thus, the revised phenotyping criteria were as follows:

Review of gastric cancer risk factors in patients with common variable immunodeficiency disorders, resulting in a proposal for a surveillance programme

Common variable immunodeficiency disorders (CVIDs) are the most frequent symptomatic primary immunodeficiencies in adults. They comprise a heterogeneous group of pathologies, with frequent non‐infectious complications in addition to the bacterial infections that usually characterize their presentation. Complications include a high risk of malignancy, especially lymphoma and gastric cancer. Helicobacter pylori infection and pernicious anaemia are risk predictors for gastric cancer in the general population and probably in patients with CVIDs. Screening for gastric cancer in a high‐risk population appears to improve survival. Given the increased risk of gastric cancer in patients with CVIDs and prompted by a case of advanced gastric malignancy in a patient with a CVID and concomitant pernicious anaemia, we performed a review of the literature for gastric cancer and conducted a cohort study of gastric pathology in 116 patients with CVIDs under long‐term follow‐up in Oxford. Regardless of the presence of pernicious anaemia or H. pylori infection, patients with CVIDs have a 10‐fold increased risk of gastric cancer and are therefore a high‐risk population. Although endoscopic screening of all patients with CVIDs could be considered, a more selective approach is appropriate and we propose a surveillance protocol that should reduce modifiable risk factors such as H. pylori, in order to improve the management of patients with CVIDs at risk of gastric malignancy.

T cell phenotypes in patients with common variable immunodeficiency disorders: associations with clinical phenotypes in comparison with other groups with recurrent infections.

Common variable immunodeficiency disorders (CVID) are a group of heterogeneous conditions that have in common primary failure of B cell function, although numerous T cell abnormalities have been described, including reduced proliferative response and reduced regulatory T cells. This study compared the T cell phenotype of CVID patients subdivided into clinical phenotypes as well as patients with partial antibody deficiencies [immunoglobulin (Ig)G subclass deficiency and selective IgA deficiency], X‐linked agammaglobulinaemia (XLA) and healthy and disease controls. Absolute numbers of T cell subpopulations were measured by four‐colour flow cytometry: naive T cells, central and effector memory and terminally differentiated (TEM) T cells, using CD45RA and CCR7 expression. Early, intermediate and late differentiation status of T cells was measured by CD27/CD28 expression. Putative follicular T cells, recent thymic emigrants and regulatory T cells were also assessed. Significant reduction in naive CD4 T cells, with reduced total CD4 and recent thymic emigrant numbers, was observed in CVID patients, most pronounced in those with autoimmune cytopenias or polyclonal lymphoproliferation. These findings suggest a lack of replenishment by new thymically derived cells. CD8 naive T cells were reduced in CVID patients, most significantly in the autoimmune cytopenia subgroup. There was a reduction in early differentiated CD4 and CD8 T cells and increased CD8 TEM in the CVID patients, particularly autoimmune cytopenia and polyclonal lymphoproliferation subgroups, suggesting a more activated T cell phenotype, due perhaps to an antigen‐driven process. XLA patients had significantly reduced putative follicular T cells, which may depend on B cells for survival, while no significant alterations were observed in the T cells of those with IgG subclass deficiency or selective IgA deficiency.

Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients

Splenectomy has been used in patients with common variable immunodeficiency disorders (CVID), mainly in the context of refractory autoimmune cytopenia and suspected lymphoma, but there are understandable concerns about the potential of compounding an existing immunodeficiency. With increasing use of rituximab as an alternative treatment for refractory autoimmune cytopenia, the role of splenectomy in CVID needs to be re‐examined. This retrospective study provides the largest cohesive data set to date describing the outcome of splenectomy in 45 CVID patients in the past 40 years. Splenectomy proved to be an effective long‐term treatment in 75% of CVID patients with autoimmune cytopenia, even in some cases when rituximab had failed. Splenectomy does not worsen mortality in CVID and adequate immunoglobulin replacement therapy appears to play a protective role in overwhelming post‐splenectomy infections. Future trials comparing the effectiveness and safety of rituximab and splenectomy are needed to provide clearer guidance on the second‐line management of autoimmune cytopenia in CVID.

Efficiency of immunoglobulin G replacement therapy in common variable immunodeficiency: correlations with clinical phenotype and polymorphism of the neonatal Fc receptor

Treatment of common variable immunodeficiency disorders (CVID) is based on replacement therapy using intravenous (i.v.) or subcutaneous (s.c.) immunoglobulin (Ig)G. Interindividual variation of IgG dose is common. A total of 380 CVID patients on stable IgG replacement from two prospective cohorts were analysed. An ‘efficiency’ index was defined as the ratio of serum IgG trough level minus IgG residual to the average weekly dose of IgG infusion. A reduced efficiency of IgG was associated independently with the i.v. route (P < 0·001) and with the presence of at least one CVID disease‐related phenotype (lymphoproliferation, autoimmune cytopenia or enteropathy) (P < 0·001). High IgG efficiency was noted in patients homozygotes for the variable number tandem repeat (VNTR) 3/3 polymorphism of the neonatal Fc receptor gene [IgG Fc fragment receptor transporter alpha chain (FCGRT)] promoter, and this was particularly significant in patients treated with IVIG (P < 0.01). In a multivariate analysis, FCGRT VNTR 3/3 genotype (P = 0·008) and high serum albumin (P < 0·001) were associated independently with increased efficiency of i.v. Ig.

Immunomodulatory therapy to achieve maximum efficacy: doses, monitoring, compliance, and self-infusion at home.

IntroductionThe Oxford Programme for Immunomodulatory Immunoglobulin Therapy has been operating since 1992 at Oxford Radcliffe Hospitals in the UK. Initially, this program was set up for patients with multifocal motor neuropathy or chronic inflammatory demyelinating poly-neuropathy to receive reduced doses of intravenous immunoglobulin (IVIG) in clinic on a regular basis (usually every 3 weeks). The program then rapidly expanded to include self-infusion at home, which monitoring showed to be safe and effective. It has been since extended to the treatment of other autoimmune diseases in which IVIG has been shown to be efficacious.MethodsThis review includes details of the program such as the training of patients, dosing with immunoglobulin, and monitoring and compliance for self-infusion at home, with cases to illustrate these points.ResultsIn addition, the Evidence for efficacy and the effects of confounding morbidities will be are included described. More recently, subcutaneous immunoglobulin therapy (SCIG) has been used in several chronic autoimmune peripheral neuropathies and in epidermolysis bullosa acquisita, with equally good effect. Trials of SCIG in other autoimmune diseases are planned.

Application of whole genome and RNA sequencing to investigate the genomic landscape of common variable immunodeficiency disorders

Common Variable Immunodeficiency Disorders (CVIDs) are the most prevalent cause of primary antibody failure. CVIDs are highly variable and a genetic causes have been identified in <5% of patients. Here, we performed whole genome sequencing (WGS) of 34 CVID patients (94% sporadic) and combined them with transcriptomic profiling (RNA-sequencing of B cells) from three patients and three healthy controls. We identified variants in CVID disease genes TNFRSF13B, TNFRSF13C, LRBA and NLRP12 and enrichment of variants in known and novel disease pathways. The pathways identified include B-cell receptor signalling, non-homologous end-joining, regulation of apoptosis, T cell regulation and ICOS signalling. Our data confirm the polygenic nature of CVID and suggest individual-specific aetiologies in many cases. Together our data show that WGS in combination with RNA-sequencing allows for a better understanding of CVIDs and the identification of novel disease associated pathways.

Lymphoid Proliferations of Indeterminate Malignant Potential arising in Adults with Common Variable Immunodeficiency Disorders: Unusual Case Studies and Immunohistological Review in the Light of Possible Causative Events

Patients with common variable immunodeficiency disorders (CVIDs) who developed B cell lymphoproliferation of indeterminate malignant potential are described in order to raise a discussion of the relationship between infection and lymphoproliferation in infection prone patients. Those with CVID are at risk of developing either polyclonal or monoclonal lymphoproliferation in part due to the dysregulation of their adaptive immune systems. The aetiologies of the lymphoproliferations are unknown but intriguing; the relevance of infection being particularly problematic. The patients described here demonstrate variability in preceding infection, age at presentation, response to antibiotics and other types of therapy as well as outcome. The question of treatment is also controversial; issues include whether antibiotics or chemotherapy are the first line of therapy in all patients and whether transformation to aggressive B cell malignancy is inevitable or depends on other factors and if so, the length of time for such progression.