Sofia Grigoriadou

The United Kingdom Primary Immune Deficiency (UKPID) Registry: report of the first 4 years' activity 2008-2012

This report summarizes the establishment of the first national online registry of primary immune deficency in the United Kingdom, the United Kingdom Primary Immunodeficiency (UKPID Registry). This UKPID Registry is based on the European Society for Immune Deficiency (ESID) registry platform, hosted on servers at the Royal Free site of University College, London. It is accessible to users through the website of the United Kingdom Primary Immunodeficiency Network (www.ukpin.org.uk). Twenty‐seven centres in the United Kingdom are actively contributing data, with an additional nine centres completing their ethical and governance approvals to participate. This indicates that 36 of 38 (95%) of recognized centres in the United Kingdom have engaged with this project. To date, 2229 patients have been enrolled, with a notable increasing rate of recruitment in the past 12 months. Data are presented on the range of diagnoses recorded, estimated minimum disease prevalence, geographical distribution of patients across the United Kingdom, age at presentation, diagnostic delay, treatment modalities used and evidence of their monitoring and effectiveness.

Hypogammaglobulinaemia after rituximab treatment— incidence and outcomes

BACKGROUND Rituximab, a chimeric monoclonal antibody against CD20, is increasingly used in the treatment of B-cell lymphomas and autoimmune conditions. Transient peripheral B-cell depletion is expected following rituximab therapy. Although initial clinical trials did not show significant hypogammaglobulinaemia, reports of this are now appearing in the literature. METHODS We performed a retrospective review of patients previously treated with rituximab that were referred to Clinical Immunology with symptomatic or severe hypogammaglobulinaemia. Patient clinical histories, immunological markers, length of rituximab treatment and need for intravenous immunoglobulin replacement therapy (IVIG) were evaluated. An audit of patients receiving rituximab for any condition in a 12-month period and frequency of hypogammaglobulinaemia was also carried out. RESULTS We identified 19 post-rituximab patients with persistent, symptomatic panhypogammaglobulinaemia. Mean IgG level was 3.42 ± 0.4 g/l (normal range 5.8-16.3 g/l). All patients had reduced or absent B-cells. Haemophilus Influenzae B, tetanus and Pneumococcal serotype-specific antibody levels were all reduced and patients failed to mount an immune response post-vaccination. Nearly all of them ultimately required IVIG. The mean interval from the last rituximab dose and need for IVIG was 36 months (range 7 months-7 years). Of note, 23.7% of 114 patients included in the audit had hypogammaglobulinaemia. CONCLUSION With the increasing use of rituximab, it is important for clinicians treating these patients to be aware of hypogammaglobulinaemia and serious infections occurring even years after completion of treatment and should be actively looked for during follow-up. Referral to clinical immunology services and, if indicated, initiation of IVIG should be considered.

A UK national audit of hereditary and acquired angioedema

Hereditary angioedema (HAE) and acquired angioedema (AAE) are rare life‐threatening conditions caused by deficiency of C1 inhibitor (C1INH). Both are characterized by recurrent unpredictable episodes of mucosal swelling involving three main areas: the skin, gastrointestinal tract and larynx. Swelling in the gastrointestinal tract results in abdominal pain and vomiting, while swelling in the larynx may be fatal. There are limited UK data on these patients to help improve practice and understand more clearly the burden of disease. An audit tool was designed, informed by the published UK consensus document and clinical practice, and sent to clinicians involved in the care of HAE patients through a number of national organizations. Data sets on 376 patients were received from 14 centres in England, Scotland and Wales. There were 55 deaths from HAE in 33 families, emphasizing the potentially lethal nature of this disease. These data also show that there is a significant diagnostic delay of on average 10 years for type I HAE, 18 years for type II HAE and 5 years for AAE. For HAE the average annual frequency of swellings per patient affecting the periphery was eight, abdomen 5 and airway 0·5, with wide individual variation. The impact on quality of life was rated as moderate or severe by 37% of adult patients. The audit has helped to define the burden of disease in the UK and has aided planning new treatments for UK patients.

Clinical Immunology Review Series: An approach to the management of pulmonary disease in primary antibody deficiency

The sinopulmonary tract is the major site of infection in patients with primary antibody deficiency syndromes, and structural lung damage arising from repeated sepsis is a major determinant of morbidity and mortality. Patients with common variable immunodeficiency may, in addition, develop inflammatory lung disease, often associated with multi‐system granulomatous disease. This review discusses the presentation and management of lung disease in patients with primary antibody deficiency.

Primary vs. Secondary Antibody Deficiency: Clinical Features and Infection Outcomes of Immunoglobulin Replacement

Secondary antibody deficiency can occur as a result of haematological malignancies or certain medications, but not much is known about the clinical and immunological features of this group of patients as a whole. Here we describe a cohort of 167 patients with primary or secondary antibody deficiencies on immunoglobulin (Ig)-replacement treatment. The demographics, causes of immunodeficiency, diagnostic delay, clinical and laboratory features, and infection frequency were analysed retrospectively. Chemotherapy for B cell lymphoma and the use of Rituximab, corticosteroids or immunosuppressive medications were the most common causes of secondary antibody deficiency in this cohort. There was no difference in diagnostic delay or bronchiectasis between primary and secondary antibody deficiency patients, and both groups experienced disorders associated with immune dysregulation. Secondary antibody deficiency patients had similar baseline levels of serum IgG, but higher IgM and IgA, and a higher frequency of switched memory B cells than primary antibody deficiency patients. Serious and non-serious infections before and after Ig-replacement were also compared in both groups. Although secondary antibody deficiency patients had more serious infections before initiation of Ig-replacement, treatment resulted in a significant reduction of serious and non-serious infections in both primary and secondary antibody deficiency patients. Patients with secondary antibody deficiency experience similar delays in diagnosis as primary antibody deficiency patients and can also benefit from immunoglobulin-replacement treatment.

An Artemis polymorphic variant reduces Artemis activity and confers cellular radiosensitivity

Artemis is required for V(D)J recombination and the repair of a subset of radiation-induced DNA double strand breaks (DSBs). Artemis-null patients display radiosensitivity (RS) and severe combined immunodeficiency (SCID), classified as RS-SCID. Strongly impacting hypomorphic Artemis mutations confer marked infant immunodeficiency and a predisposition for EBV-associated lymphomas. Here, we provide evidence that a polymorphic Artemis variant (c.512C > G: p.171P > R), which has a world-wide prevalence of 15%, is functionally impacting. The c.512C > G mutation causes an approximately 3-fold decrease in Artemis endonuclease activity in vitro. Cells derived from a patient who expressed a single Artemis allele with the polymorphic mutational change, showed radiosensitivity and a DSB repair defect in G2 phase, with Artemis cDNA expression rescuing both phenotypes. The c.512C > G change has an additive impact on Artemis function when combined with a novel C-terminal truncating mutation (p.436C > X), which also partially inactivates Artemis activity. Collectively, our findings provide strong evidence that monoallelic expression of the c.512C > G variant impairs Artemis function causing significant radiosensitivity and a G2 phase DSB repair defect. The patient exhibiting monoallelic c.512C > G-Artemis expression showed immunodeficiency only in adulthood, developed bilateral carcinoma of the nipple and myelodysplasia raising the possibility that modestly decreased Artemis function can impact clinically.

Secondary antibody deficiency.

Secondary antibody deficiencies are defined by a quantitative or qualitative decrease in antibodies that occur most commonly as a consequence of renal or gastrointestinal immunoglobulin loss, hematological malignancies and corticosteroid, immunosuppressive or anticonvulsant medications. Patients with hematological malignancies or requiring immunosuppressive medications are known to be at increased risk of infection, but few studies directly address this relationship in the context of antibody deficiency. Immunoglobulin replacement therapy has been shown to be effective in reducing infections in primary and some secondary antibody deficiencies. The commonly encountered causes of secondary antibody deficiencies and their association with infection-related morbidity and mortality are discussed. Recommendations are made for screening and clinical management of those at risk.

In pursuit of excellence: an integrated care pathway for C1 inhibitor deficiency

There are estimated to be approximately 1500 people in the United Kingdom with C1 inhibitor (C1INH) deficiency. At BartsHealth National Health Service (NHS) Trust we manage 133 patients with this condition and we believe that this represents one of the largest cohorts in the United Kingdom. C1INH deficiency may be hereditary or acquired. It is characterized by unpredictable episodic swellings, which may affect any part of the body, but are potentially fatal if they involve the larynx and cause significant morbidity if they involve the viscera. The last few years have seen a revolution in the treatment options that are available for C1 inhibitor deficiency. However, this occurs at a time when there are increased spending restraints in the NHS and the commissioning structure is being overhauled. Integrated care pathways (ICP) are a tool for disseminating best practice, for facilitating clinical audit, enabling multi‐disciplinary working and for reducing health‐care costs. Here we present an ICP for managing C1 inhibitor deficiency.

Immune deficiency: changing spectrum of pathogens

Current UK national standards recommend routine bacteriology surveillance in severe antibody‐deficient patients, but less guidance exists on virology screening and viral infections in these patients. In this retrospective audit, we assessed the proportion of positive virology or bacteriology respiratory and stool samples from patients with severe, partial or no immune deficiency during a 2‐year period. Medical notes were reviewed to identify symptomatic viral infections and to describe the course of persistent viral infections. During the 2‐year period, 31 of 78 (39·7%) severe immune‐deficient patients tested had a positive virology result and 89 of 160 (55.6%) had a positive bacteriology result. The most commonly detected pathogens were rhinovirus (12 patients), norovirus (6), Haemophilus influenzae (24), Pseudomonas spp. (22) and Staphylococcus aureus (21). Ninety‐seven per cent of positive viral detection samples were from patients who were symptomatic. Low serum immunoglobulin IgA levels were more prevalent in patients with a positive virology sample compared to the total cohort (P = 0·0078). Three patients had persistent norovirus infection with sequential positive isolates for 9, 30 and 16 months. Virology screening of symptomatic antibody‐deficient patients may be useful as a guide to anti‐microbial treatment. A proportion of these patients may experience persistent viral infections with significant morbidity.

Use of recombinant C1 inhibitor in patients with resistant or frequent attacks of hereditary or acquired angioedema

BackgroundConestat alfa (Ruconest, rhC1INH) is the first recombinant human C1 inhibitor protein (C1INH) for the treatment of acute attacks of hereditary angioedema (HAE).ObjectiveTo assess clinical experience of the first 11 adult patients who received rhC1INH in clinical practice in the UK.MethodsEleven patients (nine HAE type 1, one HAE type 2 and one acquired angioedema with C1 inhibitor deficiency) received between one and six, mostly self-administered, doses of rhC1INH for acute HAE attacks. They were asked to record their time to first response and complete resolution following the treatment. This cohort included our most severely affected and difficult to treat patients.ResultsIn most cases, time to first improvement following rhC1INH and complete resolution was recorded as comparable to their typical response to pdC1INH, although 4/11 patients reported that the time to first improvement was much quicker than their average pdC1INH response. Five of the 11 patients continued with rhC1INH as their preferred rescue treatment. Of those who chose not to continue the treatment, four reported a recurrence or early return of symptoms with rhC1INH.ConclusionIn our experience, rhC1INH is a beneficial treatment for patients with preference for a C1INH that is not plasma derived and it is suitable for home treatment. In some cases it demonstrates cost saving, especially for heavier patients who require higher doses. In some patients rhC1INH may result in faster resolution of symptoms. It may be associated with an early return of symptoms in patients with exceptionally frequent attacks.