Low Penetrance, Broad Resistance, and Favorable Outcome of Interleukin 12 Receptor β1 Deficiency: Medical and Immunological Implications

The clinical phenotype of interleukin 12 receptor β1 chain (IL-12Rβ1) deficiency and the function of human IL-12 in host defense remain largely unknown, due to the small number of patients reported. We now report 41 patients with complete IL-12Rβ1 deficiency from 17 countries. The only opportunistic infections observed, in 34 patients, were of childhood onset and caused by weakly virulent Salmonella or Mycobacteria (Bacille Calmette-Guérin -BCG- and environmental Mycobacteria). Three patients had clinical tuberculosis, one of whom also had salmonellosis. Unlike salmonellosis, mycobacterial infections did not recur. BCG inoculation and BCG disease were both effective against subsequent environmental mycobacteriosis, but not against salmonellosis. Excluding the probands, seven of the 12 affected siblings have remained free of case-definition opportunistic infection. Finally, only five deaths occurred in childhood, and the remaining 36 patients are alive and well. Thus, a diagnosis of IL-12Rβ1 deficiency should be considered in children with opportunistic mycobacteriosis or salmonellosis; healthy siblings of probands and selected cases of tuberculosis should also be investigated. The overall prognosis is good due to broad resistance to infection and the low penetrance and favorable outcome of infections. Unexpectedly, human IL-12 is redundant in protective immunity against most microorganisms other than Mycobacteria and Salmonella. Moreover, IL-12 is redundant for primary immunity to Mycobacteria and Salmonella in many individuals and for secondary immunity to Mycobacteria but not to Salmonella in most

The diagnosis of type one cytokine defects : a clinical, functional and genetic assessment

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

‘It’s not an illness, it’s just bad luck’: The impact of anaphylaxis on quality of life in adults

Background: An increasing number of adults are being diagnosed with anaphylaxis, but its impact on health-related quality of life (HRQol) is not known. Objective: The aim of this study was to explore the impact of anaphylaxis on HRQoL of newly diagnosed adults. Methods: Interviews were conducted with 13 adults (aged 40-71; five males) with anaphylaxis (meeting WAO diagnostic criteria) to drugs, food, venom or spontaneous anaphylaxis, recruited using purposive sampling from allergy clinics in Birmingham, UK. Data were transcribed verbatim and analysed using thematic analysis. Results: Four themes were generated from the analysis: the journey from fear to frustration; the need to maintain a healthy identity; control over uncertainty; and the supportive role of others. Participants described their first experiences of anaphylaxis as frightening. Managing the condition was associated with frustration and anxiety, in part due to uncertainty regarding when anaphylaxis might occur. Participants did not consider their allergy as an illness and wanted to retain an identity as a healthy person. They felt a strong need to have control over their anaphylaxis so that it did not take over their lives. The support from others was extremely important, but a lack of understanding of anaphylaxis sometimes hindered that support. Conclusions and Clinical Relevance: Anaphylaxis has an adverse impact on the HRQoL of adults irrespective of the cause. More information about anaphylaxis and its management from healthcare professionals may help patients gain a sense of control over their condition and reduce the worry and anxiety associated with it

A Retrospective Critical Analysis and Risk Stratification of Penicillin Allergy De-labelling in a UK Specialist Regional Allergy Service.

BACKGROUND A spurious label of penicillin allergy (Pen-A) negatively impacts on antibiotic stewardship and healthcare costs. Recent studies have proposed a guideline-steered direct penicillin challenge without undertaking allergy tests when 'true allergy' is unlikely. OBJECTIVE Critically analyse Pen-A clinical presentation, perform risk stratification and determine clinical predictors for 'true allergy'. METHOD Retrospective data extraction from clinical and electronic patient records. RESULTS 231 patients (M= 82; F=149; mean age 51.22 (SD ± 18.07 years) were analysed. Based on clinical history, patients were categorised as likely type I hypersensitivity [HSR] (n=27), likely type IV HSR (n=65), indeterminate (n=111) and HSR unlikely (n=28). Based on index reaction and co-morbidities, patients were classified into 'low risk' (n=143) and 'high risk' (n=78). Pen-A was excluded in 74% of patients assessed having likely type I HSR, 91% with likely type IV HSR, 93% of indeterminate and 100% of HSR unlikely patients. Negative predictive value for successful de-labelling in the 'low risk' group was 94% (odds ratio [OR] - 2.9; p= 0.02). Predictors for 'true Pen-A' were history of anaphylaxis (OR - 30.6; p < 0.001), hospitalization (OR - 7; p<0.001), ≤5 years since index reaction (OR - 3; p= 0.04). CONCLUSION Systematic clinical characterisation and risk stratification has an important role in Pen-A de-labelling. These data provide proof of concept for a guideline-based selection of patients labelled with Pen-A for a direct penicillin challenge. Patients in the 'low risk' group seem suitable for this intervention, although a rigorous prospective evaluation is needed in a multi-centre study

Biliary cirrhosis in a child with inherited interleukin-12 deficiency

Interleukin-12 (IL-12) is a key cytokine in the defense against intracellular bacteria notably Mycobacteria and Salmonella species. We report a case of disseminated mycobacterial infection, following BCG vaccination, in a child who later developed tuberculosis. Functional tests and a novel diagnostic polymerase chain reaction (PCR) assay, revealed a loss-of-function deletion in the IL12 gene. Analysis of samples from the parents and siblings of the patient indicated an autosomal recessive inheritance pattern with varying degrees of phenotypic expression in identical genotypes. Interferon-γ (INF-γ) therapy was associated with marked clinical improvement. Biliary cirrhosis, a hitherto unreported complication of IL-12 deficiency, developed later and required liver transplantation. A defect in the IL-12-INF-γ pathway should be suspected in patients presenting with multiple, repeated or persistent infection with intracellular bacteria. The diagnostic work-up and the immuno-genetic assay described here can aid in the quick and reliable diagnosis of IL-12 deficiency resulting from genetic defects and its subsequent management

Empty mast cell syndrome: fallacy or fact?

Post-anaphylaxis mast cell anergy (PAMA), commonly referred to as 'empty mast cell (MC) syndrome', is a state of temporary loss of cutaneous MC reactivity in the immediate aftermath of anaphylaxis. Data relating to this condition are sparse and the incidence rate is currently unknown. PAMA has been described only in a few published case reports in the context of hymenoptera venom allergy and perioperative anaphylaxis. Best practice guidelines regarding optimal timing for performing skin tests postanaphylaxis are largely based on expert opinion, and allergy work-up has been recommended after 4-6 weeks postanaphylaxis to avoid false-negative results.This article provides a review of clinical literature surrounding PAMA, critically evaluates intracellular events in MCs from in vitro data and hypothesises regarding plausible immune mechanisms. There are no published data to directly explain molecular mechanisms underlying this phenomenon. Although not evidence based, PAMA has been attributed to depletion of MC granules following anaphylaxis. It is also plausible that exposure to high allergen concentrations in anaphylaxis can induce a temporary shift in MCs towards dominance of inhibitory signalling pathways, thus contributing to a state of transient hyporesponsiveness observed in some patients. Other potential contributory factors for reduced MC reactivity include downregulation of FcεRI expression, cross-linking of FcεRI to the inhibitory, low-affinity IgG receptors and administration of pharmacotherapeutic agents for anaphylaxis treatment. It is likely that this interesting phenomenon can be explained by a combination of these proposed mechanisms in addition to other genetic/host factors that have not yet been identified