Wiskott-Aldrich syndrome: a study of 577 patients defines the genotype as a biomarker for disease severity and survival.

ABSTRACT: Wiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is a biomarker to predict the outcome for patients with WAS.

A multicentre observational study to investigate feasibility of a direct oral penicillin challenge in de-labelling 'low risk' patients with penicillin allergy by non-allergy healthcare professionals (SPACE study): Implications for healthcare systems.

OBJECTIVE: The huge burden of inaccurate penicillin allergy labels (PALs) is an important driver of antimicrobial resistance. This is magnified by insufficient allergy specialists and lack of 'point-of-care' tests. We investigated the feasibility of non-allergy healthcare professionals (HCPs) delivering direct oral penicillin challenges (DPCs) for penicillin allergy de-labelling. METHODS: This prospective observational study was conducted in three hospitals in England across three settings (acute medical, pre-surgical and haematology-oncology). Patients with a PAL were screened and stratified as low risk/high risk. Low risk patients (non-immune mediated symptoms, benign rash, tolerated amoxicillin since and family history) underwent a DPC. RESULTS: N = 2257 PALs were screened, 1054 were eligible; 643 were approached, 373 declined, 270 consented and 259 risk stratified (low risk = 155; high risk = 104). One hundred and twenty-six low risk patients underwent DPC, 122 (96.8%) were de-labelled with no serious allergic reactions. Conversion rate from screening-to-consent was 12% [3.3% and 17.9% in acute and elective settings respectively; odds ratios for consent were 3.42 (p < 0.001) and 5.53 (p < 0.001) in haematology-oncology and pre-surgical setting respectively. Common reasons for failure to progress in the study included difficulty in reaching patients, clinical instability/medical reasons, lacking capacity to consent and psychological factors. INTERPRETATION: DPCs can be delivered by non-allergy HCPs. A high proportion of patients with PALs did not progress in the study pathway. Strategies to deliver DPC at optimal points of the care pathway are needed to enhance uptake. Elective settings offer greater opportunities than acute settings for DPC. The safety and simplicity of DPCs lends itself to adoption by healthcare systems beyond the UK, including in resource-limited settings.

Peri-Operative Anaphylaxis-An Investigational Challenge.

Patients with suspected peri-operative anaphylaxis (POP) require thorough investigation to identify underlying trigger(s) and enable safe anesthesia for subsequent surgery. The changing epidemiology of POP has been striking. Previous estimates of the incidence of POP have ranged between 1:6,000 and1:20,000 anesthetics, but more recent data from France and the United Kingdom suggest an estimated incidence of 1:10,000. Other important changes include a change in the hierarchy of well-recognized triggers, with antibiotics (beta-lactams) supplanting neuromuscular blockers (NMB) as the leading cause of POP. The emergence of chlorhexidine, patent blue dye, and teicoplanin as important triggers have also been noteworthy findings. The mainstay of investigation revolves around critical analysis of the time-line of events leading up to anaphylaxis coupled with judicious skin testing. Skin tests have limitations with respect to unknown predictive values for most drugs/agents and therefore, knowledge of background positivity in healthy controls, test characteristics of individual drugs and the use of non-irritant concentrations is essential to avoid both false-positive and false-negative results. Specific IgE assays for individual drugs are available only for a limited number of agents and are not a substitute for skin testing. Acute serum total tryptase has a high specificity and positive predictive value in IgE-mediated POP anaphylaxis but is limited by its moderate sensitivity and negative predictive value. Planning for safe anesthesia in this group of patients is particularly challenging and consequently anesthetists need to be alert to the possibility of repeat episodes of anaphylaxis. Because of the limitations of current investigations for POP, collecting systematic data on the outcome of repeat anesthesia is valuable in validating current investigatory approaches. This paper reviews the changing epidemiology of POP with reference to the main triggers, and the investigation and outcome of subsequent anesthesia.

Treatment stratification of respiratory syncytial virus infection in allogeneic stem cell transplantation.

BACKGROUND: Due to paucity of evidence to guide management of allogeneic haematopoietic stem cell transplantation (allo-HSCT) patients with respiratory syncytial virus (RSV) infections national and international guidelines make disparate recommendations. METHODS: The outcomes of allo-HSCT recipients with RSV infection between 2015 and 2017 were assessed using the following treatment stratification; upper respiratory tract infections (URTI) being actively monitored and lower respiratory tract infections (LRTI) treated with short courses of oral ribavirin combined with intravenous immunoglobulin (IVIG, 2 g/kg). RESULTS: During the study period 49 RSV episodes were diagnosed (47% URTI and 53% LRTI). All patients with URTI recovered without pharmacological intervention. Progression from URTI to LRTI occurred in 15%. Treatment with oral ribavirin given until significant symptomatic improvement (median 7 days [3-12]) and IVIG for LRTI was generally well tolerated. RSV-attributable mortality was low (2%). CONCLUSIONS: In this cohort study, we demonstrate that active monitoring of allo-HSCT patients with RSV in the absence of LRTI was only associated with progression to LRTI in 15% of our patients and therefore appears to be a safe approach. Short course oral ribavirin in combination with IVIG was effective and well-tolerated for LRTI making it a practical alternative to aerosolised ribavirin. This approach was beneficial in reducing hospitalisation, saving nursing times and by using oral as opposed to nebulised ribavirin.

Prognosis of Good syndrome: mortality and morbidity of thymoma associated immunodeficiency in perspective.

Good syndrome (GS) or thymoma-associated immunodeficiency, is a rare condition that has only been studied in retrospective case series. General consensus was that GS has a worse prognosis than other humoral immunodeficiencies. In this study, physicians of GS patients completed two questionnaires with a two year interval with data on 47 patients, 499 patient years in total. Results on epidemiology, disease characteristics, and outcome are presented. Mean age at diagnosis was 60years and median follow-up from onset of symptoms was 9years. There was a high frequency of respiratory tract infections due to encapsulated bacteria. Median survival was 14years. Survival was reduced compared to age-matched population controls (5-year survival: 82% versus 95%, p=0.008). In this cohort survival was not associated with gender (HR 0.9, 95% CI 0.3-3.0), autoimmune diseases (HR 2.9, 95% CI 0.8-10.1) or immunosuppressive use (HR 0.3, 95% CI: 0.1-1.2).

Secondary antibody deficiencies.

PURPOSE OF REVIEW: Antibody deficiency can occur in the context of primary immune deficiency due to inherited genetic defects or secondary to a variety of causes. This review aims to summarize current data concerning the causes of secondary antibody deficiency and where possible evidence regarding the use of prophylactic replacement immunoglobulin. (Figure is included in full-text article.) RECENT FINDINGS: Advances in immune-mediated therapies ranging from monoclonal antibodies to novel B-cell-targeted therapeutics are responsible for an expansion in the possible iatrogenic causes of antibody deficiency. SUMMARY: Causes of secondary antibody deficiency include B-cell lymphoproliferative disease, notably chronic lymphocytic leukaemia and multiple myeloma, protein losing states, disorders of lymphatic circulation, increased immunoglobulin catabolism and a growing number of therapeutic agents. At-risk patients should be closely monitored for the development of hypogammaglobulinaemia, B-cell function should be defined where appropriate with specific antibody responses to immunization antigens and where there is a significant burden of infections patients should be treated with prophylactic antibiotics and/or replacement immunoglobulin.

Antibody deficiency secondary to chronic lymphocytic leukemia: Should patients be treated with prophylactic replacement immunoglobulin?

Hypogammaglobulinemia is a common finding in chronic lymphocytic leukemia (CLL). Its incidence increases with disease duration and stage such that it is present in up to 85 % of patients at some point in their disease course. It is therefore important to monitor patients for the development of an antibody deficiency. However, not all patients with antibody deficiency secondary to CLL are symptomatic with bacterial infections. In addition patients are susceptible to viral, fungal and opportunistic infections as a result of iatrogenic immunosuppression and through a variety of disease-related mechanisms, which affect cellular immunity and phagocytes. Published guidelines suggest that patients with a history of recurrent bacterial infections and a documented failure of antibody production should be treated with antibiotic prophylaxis in the first instance, with replacement immunoglobulin reserved for those who continue to suffer with significant bacterial infections. Here we present a review of the existing literature in order to provide a practical approach, based on best available evidence, to the investigation, monitoring and treatment of patients with antibody failure secondary to CLL; and we highlight areas in which further studies are needed.

Is rheumatoid factor useful in primary care? A retrospective cross-sectional study.

Rheumatoid factor (RF) is frequently tested in general practice where its utility as a diagnostic test for rheumatoid arthritis (RA) is not known. We undertook a retrospective cross-sectioal study to determine the utility and cost of RF in a primary care population. We compared RF with recorded clinical features based on the American College of Rheumatology (ACR) criteria as a diagnostic test for RA in 235 patients in general practice using receiver operating characteristic curves and calculated the cost of testing per case of RA. We analysed 36,191 RF requests made to one laboratory from 2003-2009 at a mean annual cost of £58,164 and the variation and annual cost of RF testing between 77 practices. The sensitivity and specificity of RF at the optimal cut-off value of 20 U/ml were 0.6 and 0.96 and that of two documented clinical ACR criteria were 0.9 and 0.92, respectively. No ACR criteria were documented in 150 (63.8%) patients who had RF tested. The overall cost of RF testing per case of seropositive RA was £708.75. Of all RF requests, 66.6% was made by GPs, 7.0% by rheumatologists and 26.4% by other hospital departments. The proportion of positive tests was 5.8% in primary care and 17.7% in rheumatology. The mean number of tests performed annually in primary care was 4.65 (SD 2.7) per 1,000 patients. RF is less sensitive for RA than clinical features in primary care and is frequently requested in cases without clinical evidence of the disease, adding to the overall cost.

The diagnostic significance of serum IgG4 levels in patients with autoimmune pancreatitis: a UK study.

BACKGROUND: Autoimmune pancreatitis (AIP) is recognised as an end organ manifestation of the systemic condition known as IgG4-sclerosing disease. One major characteristic of this disease, regardless of its location in the body, is the presence of high levels of circulating serum IgG, in particular IgG4 antibody. In the case of AIP, differential diagnosis from other conditions of the pancreas and biliary system, particularly cancers, can be difficult, but could result in avoiding invasive procedures and surgery. Earlier studies have evaluated the use of checking IgG4 levels in AIP diagnosis; these have produced variable results. OBJECTIVE: To further assess the diagnostic significance of serum IgG4 levels in AIP and investigate its value in differentiating from cancer of the gastroenterological system. METHODS: A retrospective study of 196 IgG4-requested samples from a 24-month period was examined. Samples were sorted into confirmed AIP, cancer or other pancreatic conditions including primary sclerosing cholangitis. RESULTS: Patients with AIP possessed a mean serum IgG level that was significantly higher compared with all other groups (mean serum IgG level=19.0 g/l+/-2.5, P<0.001). The mean serum IgG4 level of AIP patients was also significantly higher compared with all other conditions including cancer patients (mean IgG4 level=3.7 g/l+/-0.5, P<0.001). CONCLUSION: This data lends support to circulating IgG4 levels only being used as an accompanying diagnostic marker to imaging, histology and clinical presentation. In particular, this may help in differentiating between AIP and pancreatic carcinoma.

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.

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

INTRODUCTION: The 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. METHODS: This 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. RESULTS: In 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.