Lesson of the week: Depot corticosteroid treatment for hay fever causing avascular necrosis of both hips.
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Administration, Topical↗
Biomedical subjects
P W Ewan
Publications and source records attributed to P W Ewan.
Long-term prospective observational study of patients with peanut and nut allergy after participation in a management plan.
BACKGROUND: Peanut and nut allergy is common and the most frequent cause of severe or fatal reactions to foods. Current advice is poor--doctors give an epinephrine injector to patients, without training or advice on nut avoidance--so that further reactions are common and deaths occur. We devised and assessed a management programme providing advice on nut avoidance and emergency medication. METHODS: Unselected referrals with confirmed peanut or tree-nut allergy were recruited. Severity of nut allergy was graded 1-5 and emergency medication allocated accordingly: oral antihistamine with or without inhaled or injected epinephrine. Patients, parents, and school staff received verbal and written advice on nut avoidance as well as training in recognition and self-treatment of reactions, with a written treatment plan. At follow-up (more than 13610 patient months) retraining was given and details of further reactions obtained. FINDINGS: 88 (15%) of 567 patients had a follow-up reaction of reduced severity. 62 of 88 were mild (grades 1-3, mainly cutaneous) and 49 patients used oral antihistamine, six inhaled adrenaline, and ten took no treatment. 12 of 12 patients with a moderate follow-up reaction improved after inhaled epinephrine. Only three (0.5%) of 567 patients, aged 27-40 years, had a severe follow-up reaction (involving dyspnoea) compared with 12% initially. Only one of 567 changed from a mild index reaction to a severe follow-up reaction. Patients with a moderate/severe (grade 4-5) reaction were older (median 18 years vs 9 years; p=0.03) and nine of 26 received injected epinephrine which was always effective. 85% of patients had no further reactions. Severity was related to the amount of nut eaten. INTERPRETATION: Self-treatment was effective (inhaled epinephrine for early laryngeal oedema and an epinephrine injector for severe reactions) but provision of this treatment, including who should carry epinephrine, required assessment of allergy severity. Our management plan was effective, and our results indicate that patients should be referred to specialist allergy centres for advice on nut avoidance.
Adolescent↗
Interleukin-10 levels increase in cutaneous biopsies of patients undergoing wasp venom immunotherapy.
We have studied the influence of wasp venom immunotherapy (VIT) on cellular recruitment and cytokine mRNA expression during allergen-induced cutaneous late-phase responses (LPR). Nine subjects with a history of wasp sting anaphylaxis, and specific IgE in their sera underwent wasp VIT. Skin biopsies were taken 24 h after intradermal diluent and allergen before and after 3 months VIT. Pre-immunotherapy, there were significant allergen-induced increases in EG2(+) eosinophils, elastase(+) neutrophils, CD68(+) macrophages and IL-10 protein(+) cells, and increased expression of mRNA for IL-4, IL-13, IFN-gamma, IL-12, IL-10, TGF-beta, RANTES and eotaxin. When these allergen-induced changes in cytokine mRNA and cellular profiles were compared with those obtained after 3 months VIT there was a significant reduction in IL-4 mRNA (p=0.012) and increase in IL-10 protein(+) cells (p=0.004) with a trend to an increase in IL-10 mRNA (p=0.054). There were also significant reductions in eosinophils (p<0.004) and the size of the cutaneous LPR (p<0.01) but no change in mRNA to IFN-gamma, IL-13 or IL-12. Therefore, VIT is associated with a significant increase in cells positive for IL-10 protein but not IL-12 or IFN-gamma. These results suggest that induction of IL-10 may be important in VIT and occur independently of the switch to a Th1 phenotype. IL-10 generation may down-regulate IL-4 expression and eosinophil recruitment.
Adult↗
Differential effect of thalidomide and dexamethasone on the transcription factor NF-kappa B.
Thalidomide was initially used as a sedative during pregnancy but was withdrawn from the market due to its teratogenic effects. In vitro studies have shown that thalidomide inhibits tumour necrosis factor alpha (TNF-alpha) mRNA expression and protein production by mitogen-stimulated macrophages and activated T cells. Even at the highest concentration (10-1 mM) tested, however, TNF-alpha levels are inhibited only partially and the mechanism of action is unknown. In the present investigations, we have examined the influence of thalidomide on nuclear levels of NF-kappa B in human peripheral blood mononuclear cells (PBMC) following activation with mitogen or phorbol myristate acetate (PMA)/ionophore. Dexamethasone was used as a positive control due to its well-characterised mechanism of action and NF-kappa B-mediated effects on TNF-alpha expression. PBMC from healthy human volunteers were stimulated optimally with phytohemagglutinin (PHA) or PMA/ionophore in the presence of 10(-1)-10(-5) mM thalidomide or dexamethasone, concentrations that displayed a range of inhibitory effects on TNF-alpha production. Cells were harvested at varying time points and nuclear extracts prepared. Nuclear levels of NF-kappa B were measured using electrophoretic mobility shift assays (EMSA) with a radiolabelled DNA probe specific for NF-kappa B. Results were analysed using optical densitometry. Nuclear levels of NF-kappa B were found to be unaffected by thalidomide at all concentrations tested, including concentrations (10(-1)-10(-3) mM) that exhibited significant inhibition of TNF-alpha protein and mRNA expression. In concurrent experiments, dexamethasone was found to reduce NF-kappa B expression in a dose-dependent manner with maximal inhibition at the highest dose tested (10(-1) mM). TNF-alpha gene expression is controlled by at least three separate transcription factors that are involved in binding to the promoter region. These observations suggest that thalidomide does not act directly on NF-kappa B and therefore inhibits TNF-alpha production through another independent mechanism.
Adult↗
Opiate-sensitivity: clinical characteristics and the role of skin prick testing.
BACKGROUND: The value of skin prick testing in opiate-sensitive individuals is uncertain as opiates cause non-specific weals by direct degranulation of mast cells. OBJECTIVE: To define whether skin prick test (SPT) responses to opiates in opiate-sensitive individuals are different to those seen in the normal population and to describe the clinical characteristics of this group of subjects. METHODS: The SPT responses of eight opiate-sensitive subjects to morphine 10 mg/mL, pethidine (meperidine) 50 mg/mL and papaveretum 15.4 mg/mL at four different concentrations (undiluted, 1/10, 1/50 and 1/100) were compared with the responses of 100 (32 atopic) non-opiate-sensitive control subjects. Four of the opiate-sensitive subjects had a clinical history of asthma, rhinitis or urticaria on occupational exposure to morphine. One subject developed urticaria with codeine, one developed urticaria and asthma with morphine and diamorphine and two subjects reacted to intravenous papaveretum with anaphylaxis or urticaria. Five out of the eight cases had opiate sensitivity confirmed by single-blind placebo-controlled oral challenge. RESULTS: Skin prick tests to all three opiates were not significantly different when the eight opiate-sensitive subjects were compared with either the entire normal control group or the subgroup of 47 definite opiate-tolerant controls that had previously received opiates for clinical indications. Furthermore, there were no significant differences in size of opiate SPT responses between atopic and non-atopic control subjects. In the control subjects, there was a positive correlation in SPT weal size between the three opiates. CONCLUSION: Skin prick testing is not useful in the diagnosis of opiate sensitivity and placebo-controlled challenge should be considered.
Adult↗
New insight into immunological mechanisms of venom immunotherapy.
The early production of IL-10 appears to induce T cell anergy and is an important step in venom immunotherapy. This results in the loss of the abnormal venom-specific T helper type 2 response (reduced proliferation and cytokine production) and a switch from a T helper type 2 dominant to a T helper type 1 dominant cytokine response. As a consequence, there is an increase in specific IgG4, an increase in the specific IgG4:IgE ratio, and over the longer term a decrease in specific IgE. IL-10 is initially produced by allergen-specific T cells, but later by B cells and monocytes. IL-10 initiates anergy in T cells by blocking tyrosine phosphorylation of CD28 and inhibiting the CD28 co-stimulatory signal. IL-10 also inhibits cytokine gene transcription and messenger RNA production. That clinical protection in venom immunotherapy occurs earlier than antibody changes suggests that additional mechanisms may be operative. Decreased basophil mediator release is a candidate and has been demonstrated: it is induced by IL-10 and possibly also related to changes in chemokines and other cytokines. Proliferation and cytokine secretion in anergic T cells can be restored depending on the cytokine milieu. Restimulation in the presence of IL-2, IL-15 and possibly IL-12 leads to a T helper type 1 cytokine pattern (immunity:effective immunotherapy) and with IL-4 a T helper type 2 pattern (persistence of allergy:relapse). The cytokine microenvironment in tissues can thus influence outcome. A variety of new approaches to immunotherapy is being investigated, including peptide therapy. Preliminary data from DNA vaccines, largely in animal models, hold great promise. Immunostimulatory DNA sequences have an adjuvant effect and induce T helper type 1 cytokines, independent of antigen. They may be co-administered with allergen and used to redirect allergen-specific T helper type 2 responses.
Allergens↗
Position statement: UEMS- Section of Allergology and Clinical Immunology. European specialist care in allergology and clinical immunology in the new millennium.
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Allergy and Immunology↗
Anaphylaxis caused by neostigmine.
A patient developed anaphylaxis during anaesthesia, towards the end of surgery, 30 s after intravenous administration of neostigmine. Anaphylaxis to neostigmine was confirmed by demonstrating an elevated mast cell tryptase and a strongly/positive skin prick test, showing the presence of drug-specific IgE (skin prick tests to neostigmine were negative in normal subjects). This is a rare cause of anaphylaxis during anaesthesia.
Anaphylaxis↗
Provision of allergy care for optimal outcome in the UK.
Allergy is common and the prevalence has increased substantially in the last 2-3 decades. There has been a particular increase in severe allergic disease, including anaphylaxis, food, drug and latex rubber allergy. Provision of allergy services in the NHS is extremely poor and there is a huge unmet need. Allergy is a full speciality, but there are few consultants and few trainees. Whilst other specialists have a role in the management of allergy, it is no longer adequate to devolve most of allergy care to them. Provision of allergy care must be lead by allergy specialists so that adequate standards of care can be achieved. The lack of care leads to morbidity, mortality and substantial cost to the NHS, much of which is avoidable. There is an urgent need for the creation of more consultant posts in allergy and this requires recognition by Trust Managers, Regional Commissioners and the Department of Health.
Adolescent↗
Selective down-regulation of T cell- and non-T cell-derived tumour necrosis factor alpha by thalidomide: comparisons with dexamethasone.
Both thalidomide and dexamethasone have been shown to inhibit the production of tumour necrosis factor alpha (TNF-alpha), but little is known of their cellular selectivity. Inhibition of monocyte TNF-alpha expression has been implicated in the clinical efficacy of thalidomide, and it has been suggested that the drug modulates only monocyte-derived cytokines. Given the importance of T lymphocyte responses in immunological disorders in which treatment with thalidomide has been successful, it is pertinent to study the effects of this drug on T cell-derived TNF-alpha. In the present investigations we have examined the influence of both thalidomide and dexamethasone on mitogen-induced elaboration of TNF-alpha by CD3+ peripheral blood mononuclear cells (PBMC) and the T cell line MOLT-4. PBMC from healthy human volunteers were stimulated optimally with phytohaemagglutinin (PHA) in the presence of varying concentrations of thalidomide or dexamethasone, and supernatants assayed for TNF-alpha and interleukin 2 (IL-2). Concurrently, PHA-stimulated PBMC were treated with 1 x 10(-1) mM thalidomide or dexamethasone and the cells fixed, permeabilised, stained with anti-CD3 and anti-TNF-alpha fluorescently labelled antibodies and analysed by flow cytometry. MOLT-4 cells were cultured in the presence or absence of the drugs following activation with phorbol myristate acetate (PMA)/ionophore, and supernatants analysed by enzyme-linked immunosorbent assay (ELISA) for cytokine expression. Thalidomide was found to inhibit PBMC-derived TNF-alpha, but not IL-2. In contrast, dexamethasone down-regulated both TNF-alpha and IL-2 in a dose-dependent manner. Thalidomide and dexamethasone both suppressed intracellular levels of TNF-alpha in CD3+ PBMC, reducing percentages of double positive staining cells by 28 and 52%, respectively, compared with controls. In addition, TNF-alpha production by CD3- PBMC was inhibited by 31% by thalidomide and by 47% by dexamethasone. In order to determine whether thalidomide was acting directly on T cells, or indirectly through effects on accessory cells, TNF-alpha production in the T cell line MOLT-4 was investigated. TNF-alpha secretion by PMA/ionophore activated MOLT-4 cells was reduced by 80% following thalidomide treatment and close to background levels following dexamethasone treatment. To verify that thalidomide was acting selectively to down-regulate TNF-alpha, IL-2 production by MOLT-4 cells was also measured and found to be unaffected by the drug. In contrast, dexamethasone reduced MOLT-4-derived IL-2 levels by 20%. These observations suggest that thalidomide, in addition to its known inhibitory effect on monocyte-derived TNF-alpha, is capable also of down-regulating T cell-derived TNF-alpha in a direct and selective manner. In addition, the inhibition of intracellular levels of TNF-alpha strengthens the evidence that the inhibitory effect of thalidomide is at the level of transcription and/or translation and does not reduce cellular TNF-alpha secretion. Such effects could explain the efficacy of thalidomide treatment in various immunological disorders where T cell activation plays an important role in the pathogenesis of the disease.
CD3 Complex↗
Granulomatous interstitial pneumonitis in association with primary hypogammaglobulinemia: computed tomography appearances.
The authors describe the computed tomographic appearances of nonspecific granulomatous interstitial pneumonitis in two patients with primary hypogammaglobulinemia. Their purpose is to show that it is important to consider this entity in the differential diagnosis of multiple pulmonary nodules in patients with this disease.
Adult↗
Differential regulation by thalidomide and dexamethasone of cytokine expression in human peripheral blood mononuclear cells.
Immunosuppressive drugs are used routinely to reduce the inappropriate production of cytokines in an immune response. Recent attention has focused on drugs that selectively inhibit specific cytokines. Both thalidomide and dexamethasone have been reported to exhibit immunomodulatory effects on cytokines in vitro. We wished to examine the effects of thalidomide and dexamethasone on the production of cytokines by peripheral blood mononuclear cells (PBMC), following mitogenic stimulation, at the level of both secreted product and mRNA production. PBMC from healthy human volunteers were stimulated optimally with phytohaemagglutinin (PHA) in the presence of varying concentrations of thalidomide and dexamethasone using dimethyl sulphoxide (DMSO) as the solvent. Analysis of supernatants by enzyme-linked immunosorbent assay (ELISA) showed that thalidomide caused a dose-dependent inhibition of the pro-inflammatory cytokines interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-alpha), maximally reducing production by 20 (P < 0.05) and 30% (P < 0.01), respectively, compared with controls. However, thalidomide did not affect either proliferation or the production of interleukin 2 (IL-2), interleukin 4 (IL-4) or interleukin 10 (IL-10). A slight bell shaped inhibition of interferon gamma (IFN-gamma) was seen which was statistically significant (P < 0.05). In contrast, dexamethasone inhibited markedly the expression of all cytokines tested (IL-2, IL-4, IL-6, IL-10, IFN-gamma and TNF-alpha) in dose-dependent fashion, reducing levels to near to background. Reverse transcription-polymerase chain reaction (RT-PCR) analyses showed that thalidomide inhibited selectively the expression of TNF-alpha and IL-6 mRNA, whereas dexamethasone inhibited mRNA levels of all cytokines examined. The data indicate that dexamethasone is a broad range immunosuppressant inhibiting all cytokines tested in a dose-dependent manner at the level of both secreted product and mRNA. Conversely, thalidomide selectively inhibits the production of IL-6 and TNF-alpha. Due to their markedly different effects on cytokine production, and the fact that both drugs act at the level of transcription, we believe they influence separate pathways involved in cytokine gene regulation.
Anti-Inflammatory Agents↗
The frequency and clinical significance of specific IgE to both wasp (Vespula) and honey-bee (Apis) venoms in the same patient.
BACKGROUND: Changeover from Phadebas RAST to Pharmacia AutoCAP increased double-positivity to both honey-bee and common wasp (vespula) venom in our patients. OBJECTIVE: We examined the frequency of IgE double-positivity, its clinical relevance and utility in investigating potentially allergic patients. METHODS: One hundred and eighty-two patients with hymenoptera allergy were tested using RAST (n = 51) and AutoCAP (n = 131) assays over 4 years. Patients had a history of reactions to vespulae (22), honey-bee (10) and unidentified hymenoptera (vespinae) (7). RESULTS: After changing from RAST to AutoCAP double-positivity increased from 10 (5/ 51) to 30% (39/131) (P < 0.01). RAST and CAP assays gave similar median class results (vespula = 3, honey-bee = 2). Thirty-six CAP patients had systemic reactions of Mueller grade II and above. In vespula-allergic double-positive subjects, high CAP classes (> or = class 3) to honey-bee were common (30%). In 25% the CAP classes were equal. In honey-bee-allergic subjects, all vespula venom CAP IgE was low titre (class 1 or 2) and 20% were equal for both venoms. In 43% of vespinae-allergic patients the CAP class was equal to both (class 2 and 3). In contrast, intradermal skin test double-positivity was uncommon. Double-negative skin test results were common in the CAP double-positive population (22% of honey-bee-allergic, 13% of vespula-allergic and 43% of vespinae-allergic patients). Vespula allergic patients have higher bee-venom IgE than vice versa. Twenty-seven per cent of CAP double-positive patients (representing 8% of all venom allergic patients tested over this period) had equal class IgE to both venoms which was not helpful in diagnosis. Combination of skin testing and CAP is unhelpful in only 5/37 (14%) of patients with double-positive serology. CONCLUSION: If used in isolation CAP may be misleading, especially if only one venom is tested. Identification of the causative venom must utilize both clinical history and skin testing in these double-positive patients, and challenge testing if indicated.
Adolescent↗
Specific IgE antibodies in the diagnosis of atopic disease. Clinical evaluation of a new in vitro test system, UniCAP, in six European allergy clinics.
A new immunoassay system utilizing new automatic instrumentation, new software for evaluation of data, and reagents updated for increased speed and accuracy was evaluated. Six clinical studies included 894 consecutive patients. Major symptoms were rhinoconjunctivitis, asthma, atopic dermatitis, and urticaria. The prevalence of inhalant allergy was 54-69%. Phadiatop, detecting atopic sensitization to common inhalant allergens, agreed with clinical diagnosis in 764/836 cases (91.4%). The clinical sensitivity and specificity were 93% and 89%, respectively. The clinical sensitivity and specificity of UniCAP specific IgE derived from 5170 comparisons with clinical diagnosis were 89% and 91%, respectively. Specific IgE measurements in UniCAP and in the Pharmacia CAP System agreed in 266/274 cases (97%). A comparison of the sensitivity and specificity of Pharmacia CAP System RAST in 1987 and with UniCAP specific IgE in 1995 showed equivalent performance without change of efficacy or degradation of IgE antibodies after 8 years. The systems were equivalent also in terms of measured values (r=0.96, slope=1.12), confirming the standardization of allergens and of assay calibration. UniCAP is an efficient laboratory system for routine diagnostic testing of allergy and a valuable tool for basic studies on allergens and antibodies.
Administration, Inhalation↗