Interstitial lung disease in patients with common variable immunodeficiency disorders: several different pathologies?

Various reports of disease-related lung pathologies in common variable immunodeficiency disorder (CVID) patients have been published, with differing histological and high-resolution computed tomography (HRCT) findings. Data were extracted from the validated Oxford Primary Immune Deficiencies  Database (PID) database (1986-2016) on adult, sporadic CVID patients with suspected interstitial lung disease (ILD). Histology of lung biopsies was studied in relation to length of follow-up, clinical outcomes, HRCT findings and chest symptoms, to look for evidence for different pathological processes. Twenty-nine CVID patients with lung histology and/or radiological evidence of ILD were followed. After exclusions, lung biopsies from 16 patients were reanalysed for ILD. There were no well-formed granulomata, even though 10 patients had systemic, biopsy-proven granulomata in other organs. Lymphocytic infiltration without recognizable histological pattern was the most common finding, usually with another feature. On immunochemistry (n = 5), lymphocytic infiltration was due to T cells (CD4 or CD8). Only one patient showed B cell follicles with germinal centres. Interstitial inflammation was common; only four of 11 such biopsies also showed interstitial fibrosis. Outcomes were variable and not related to histology, suggesting possible different pathologies. The frequent nodules on HRCT were not correlated with histology, as there were no well-formed granulomata. Five patients were asymptomatic, so it is essential for all patients to undergo HRCT, and to biopsy if abnormal HRCT findings are seen. Internationally standardized pathology and immunochemical data are needed for longitudinal studies to determine the precise pathologies and prognoses in this severe complication of CVIDs, so that appropriate therapies may be found.

When to initiate immunoglobulin replacement therapy (IGRT) in antibody deficiency: a practical approach.

Primary antibody deficiencies (PAD) constitute the majority of all primary immunodeficiency diseases (PID) and immunoglobulin replacement forms the mainstay of therapy for many patients in this category. Secondary antibody deficiencies (SAD) represent a larger and expanding number of patients resulting from the use of a wide range of immunosuppressive therapies, in particular those targeting B cells, and may also result from renal or gastrointestinal immunoglobulin losses. While there are clear similarities between primary and secondary antibody deficiencies, there are also significant differences. This review describes a practical approach to the clinical, laboratory and radiological assessment of patients with antibody deficiency, focusing on the factors that determine whether or not immunoglobulin replacement should be used. The decision to treat is more straightforward when defined diagnostic criteria for some of the major PADs, such as common variable immunodeficiency disorders (CVID) or X-linked agammaglobulinaemia (XLA), are fulfilled or, indeed, when there is a very low level of immunoglobulin production in association with an increased frequency of severe or recurrent infections in SAD. However, the presentation of many patients is less clear-cut and represents a considerable challenge in terms of the decision whether or not to treat and the best way in which to assess the outcome of therapy. This decision is important, not least to improve individual quality of life and reduce the morbidity and mortality associated with recurrent infections but also to avoid inappropriate exposure to blood products and to ensure that immunoglobulin, a costly and limited resource, is used to maximal benefit.

Chronic mucocutaneous candidiasis: characterization of a family with STAT-1 gain-of-function and development of an ex-vivo assay for Th17 deficiency of diagnostic utility.

Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent and persistent superficial infections, with Candida albicans affecting the mucous membranes, skin and nails. It can be acquired or caused by primary immune deficiencies, particularly those that impair interleukin (IL)-17 and IL-22 immunity. We describe a single kindred with CMC and the identification of a STAT1 GOF mutation by whole exome sequencing (WES). We show how detailed clinical and immunological phenotyping of this family in the context of WES has enabled revision of disease status and clinical management. Together with analysis of other CMC cases within our cohort of patients, we used knowledge arising from the characterization of this family to develop a rapid ex-vivo screening assay for the detection of T helper type 17 (Th17) deficiency better suited to the routine diagnostic setting than established in-vitro techniques, such as intracellular cytokine staining and enzyme-linked immunosorbent assay (ELISA) using cell culture supernatants. We demonstrate that cell surface staining of unstimulated whole blood for CCR6⁺ CXCR3⁻ CCR4⁺ CD161⁺ T helper cells generates results that correlate with intracellular cytokine staining for IL-17A, and is able to discriminate between patients with molecularly defined CMC and healthy controls with 100% sensitivity and specificity within the cohort tested. Furthermore, removal of CCR4 and CD161 from the antibody staining panel did not affect assay performance, suggesting that the enumeration of CCR6⁺ CXCR3⁻ CD4⁺ T cells is sufficient for screening for Th17 deficiency in patients with CMC and could be used to guide further investigation aimed at identifying the underlying molecular cause.

Therapeutic immunoglobulin should be dosed by clinical outcome rather than by body weight in obese patients.

There are currently no data to support the suggestion that the dose of therapeutic immunoglobulin (Ig) should be capped in obese patients for pharmacokinetic (PK), safety and economic reasons. We compared IgG trough levels, increment and efficiency in matched pairs of obese and lean patients receiving either replacement or immunomodulatory immunoglobulin therapy. Thirty-one obese patients were matched with a clinically equivalent lean patient across a range of indications, including primary antibody deficiency or autoimmune peripheral neuropathy. Comprehensive matching was carried out using ongoing research databases at two centres in which the dose of Ig was based on clinical outcome, whether infection prevention or documented clinical neurological stability. The IgG trough or steady state levels, IgG increments and Ig efficiencies at times of clinical stability were compared between the obese and lean cohorts and within the matched pairs. This study shows that, at a population level, obese patients achieved a higher trough and increment (but not efficiency) for a given weight-adjusted dose compared with the lean patients. However at an individual patient level there were significant exceptions to this correlation, and upon sub-group analysis no significant difference was found between obese and lean patients receiving replacement therapy. Across all dose regimens a high body mass index (BMI) cannot be used to predict reliably the patients in whom dose restriction is clinically appropriate.

A mutation in X-linked inhibitor of apoptosis (G466X) leads to memory inflation of Epstein-Barr virus-specific T cells.

Mutations in the X-linked inhibitor of apoptosis (XIAP) gene have been associated with XLP-like disease, including recurrent Epstein-Barr virus (EBV)-related haemophagocytic lymphohystiocytosis (HLH), but the immunopathogenic bases of EBV-related disease in XIAP deficiency is unknown. We present the first analysis of EBV-specific T cell responses in functional XIAP deficiency. In a family of patients with a novel mutation in XIAP (G466X) leading to a late-truncated protein and varying clinical features, we identified gradual hypogammaglobulinaemia and large expansions of T cell subsets, including a prominent CD4(+) CD8(+) population. Extensive ex-vivo analyses showed that the expanded T cell subsets were dominated by EBV-specific cells with conserved cytotoxic, proliferative and interferon (IFN)-γ secretion capacity. The EBV load in blood fluctuated and was occasionally very high, indicating that the XIAP(G466X) mutation could impact upon EBV latency. XIAP deficiency may unravel a new immunopathogenic mechanism in EBV-associated disease.

Burden of copy number variation in common variable immunodeficiency.

Common variable immunodeficiency (CVID) has been associated recently with a dramatic increase in total copy number variation burden, the cause of which is unclear. In order to explore further the origin and clinical relevance of this finding, we quantified the total genomic copy number variation (CNV) burden in affected patients and evaluated clinical details in relationship to total CNV burden. No correlation was found between total CNV burden and either patient age or time elapsed since symptom onset, and higher total burden did not correlate with incidence of malignancy or other subphenotypes. These findings suggest that the increased CNV burden is static and intrinsic to CVID as a disease.

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.

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.

Comparison of American and European practices in the management of patients with primary immunodeficiencies.

Primary immunodeficiency diseases (PIDs) comprise a heterogeneous group of rare disorders. This study was devised in order to compare management of these diseases in the northern hemisphere, given the variability of practice among clinicians in North America. The members of two international societies for clinical immunologists were asked about their management protocols in relation to their PID practice. An anonymous internet questionnaire, used previously for a survey of the American Academy of Allergy, Asthma and Immunology (AAAAI), was offered to all full members of the European Society for Immunodeficiency (ESID). The replies were analysed in three groups, according to the proportion of PID patients in the practice of each respondent; this resulted in two groups from North America and one from Europe. The 123 responses from ESID members (23·7%) were, in the majority, very similar to those of AAAAI respondents, with > 10% of their practice devoted to primary immunodeficiency. There were major differences between the responses of these two groups and those of the general AAAAI respondents whose clinical practice was composed of < 10% of PID patients. These differences included the routine use of intravenous immunoglobulin therapy (IVIg) for particular types of PIDs, initial levels of IVIg doses, dosing intervals, routine use of prophylactic antibiotics, perceptions of the usefulness of subcutaneous immunoglobulin therapy (SCIg) and of the risk to patients' health of policies adopted by health-care funders. Differences in practice were identified and are discussed in terms of methods of health-care provision, which suggest future studies for ensuring continuation of appropriate levels of immunoglobulin replacement therapies.

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.

NOD2 polymorphisms in clinical phenotypes of common variable immunodeficiency disorders.

Common variable immunodeficiency disorders (CVIDs) are a heterogeneous group of diseases characterized by hypogammaglobulinaemia and consequent susceptibility to infection. CVID patients commonly develop a variety of additional manifestations for which the causative factors are not fully understood. Two such manifestations are granulomatous disease and enteropathy. Because the ability to predict complications would aid clinical management, we continue to search for possible disease modifier genes. NOD2 acts a microbial sensor and is involved in proinflammatory signalling. Particular mutations of the NOD2 gene are associated with Crohn's disease including gly908arg, leu1007finsc and arg702trp polymorphisms. We hypothesized that NOD2 polymorphisms may be a disease modifier gene towards an enteropathic or granulomatous phenotype within CVIDs. Sequence-specific primers returned genotypes for 285 CVID patients from centres across the United Kingdom and Europe. We present the frequencies of the different phenotypes of patients within our international cohort. Arg702trp polymorphisms were significantly less frequent than wild-type (WT) (P = 0·038) among international CVID patients with splenomegaly. Gly908arg polymorphisms were more prevalent than WT in UK patients with autoimmune disorders (P = 0·049) or enteropathy (P = 0·049). NOD2 polymorphisms were not more prevalent than WT in CVID patients with clinical phenotypes of granulomata. UK allele frequencies of 0·014, 0·056 and 0·026 were found for gly908arg, arg702trp and leu1007finsc NOD2 polymorphisms, respectively. These do not differ significantly from UK immunocompetent controls confirming, as expected, that in addition these NOD2 polymorphisms do not confer susceptibility to CVIDs per se.

A novel mutation in a patient with a deficiency of the eighth component of complement associated with recurrent meningococcal meningitis.

INTRODUCTION: Complement component C8 is one of the five terminal complement components required for the formation of the membrane attack complex. Complete absence of C8 results in increased susceptibility to gram-negative bacteria such as Neisseria species. MATERIALS AND METHODS: Two functionally distinct C8 deficiency states have been described: C8 alpha-gamma deficiency has been predominantly reported amongst Afro-Caribbeans, Hispanics, and Japanese and C8beta mainly in Caucasians. RESULTS: We report a case of functional and immunochemical deficiency of the complement component C8, diagnosed in a Caucasian adult following three episodes of meningitis. Western blotting and hemolytic assay demonstrated absence of C8beta. In genetic studies, the common exon 9 C > T transition responsible for 85% of C8beta deficiencies was not found. Two mutations were identified: a novel duplication mutation, c.1047_1053 dupGGCTGTG in exon 7 that introduces a frame shift, resulting in the addition of seven novel amino acid residues and a premature stop codon, and a previously reported mutation, c.271C > T in exon 3. The parents each expressed one of these mutations, confirming compound heterozygosity. DISCUSSION: This is the first report of a duplication mutation in C8beta deficiency and extends the molecular heterogeneity of the disorder.

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.