Administration of yellow fever vaccine in patients with egg allergy.

BACKGROUND: The population of large parts of Africa, South America and travellers to these areas are at risk of yellow fever (YF) with a 50% mortality risk. Yellow fever vaccine (YFV) propagated in hens' eggs confers protection in 95% of the vaccinated. The rate of anaphylaxis for YFV ranges from 0.42 to 1.8/100,000 doses with most cases considered to be due to egg allergy. Egg allergy is a contraindication for the YFV. Nevertheless, the potential fatal sequelae from YF give the incentive to protect everyone at risk irrespective of their allergic status. METHODS: Six subjects who had had a recent reaction to egg and who were travelling to endemic areas (3 adults and 3 children) underwent skin prick tests (SPT) with undiluted YFV and egg extract. Intradermal tests for YFV were undertaken at a 1:10 dilution. In 4 egg-allergic patients with a positive SPT to YFV, a 7-step desensitization protocol was used. A 2-step (10 + 90%) protocol was used in the 2 subjects with a negative YFV SPT. Premedication was not administered. RESULTS: All 6 patients were successfully vaccinated. Four patients completed desensitization: 1 developed mild local erythema at the injection site, 1 had fleeting generalized urticaria with local erythema/angioedema and 2 did not experience any adverse reactions. Patients who received YFV in 2 steps developed no adverse reactions. CONCLUSIONS: We describe the successful administration of YFV in 6 egg-allergic patients. The Cambridge Allergy 7-step protocol allows for its safe administration in patients with positive SPT to YFV. A 2-step protocol can be used in patients with negative YFV SPT.

Paracetamol hypersensitivity: clinical features, mechanism and role of specific IgE.

BACKGROUND: Paracetamol is a common antipyretic/analgesic and a component of many prescription and over- the- counter preparations. Hypersensitivity reactions to paracetamol appear to be increasing, but there are few prevalence data. The mechanism is poorly understood. We identified the clinical features of 32 patients with suspected paracetamol allergy, investigated the underlying mechanism and examined co-existing non-steroidal anti-inflammatory drug (NSAID) tolerance. METHODS: A clinical history was taken and skin tests and an oral challenge were performed in 32 patients with suspected paracetamol allergy. RESULTS: Patients presented with a combination of urticaria, angio-oedema (face, hands), erythema (cutaneous features in 94%), dyspnoea (including laryngeal oedema), rhinoconjunctivitis, cough, abdominal pain and anaphylaxis. Two patients had a positive skin prick test (SPT) and unequivocal history of acute urticaria/facial angio-oedema/conjunctivitis/cough after paracetamol with no other triggers. One patient had a positive intradermal test. Oral challenge was positive in 15 of 31 patients (including self-challenge in 4), triggering (a combination of) rhinitis, conjunctivitis, pruritus, erythema, urticaria, angio-oedema, dyspnoea and abdominal pain. Sensitivity was evident in 1 patient on the basis of the patient's history. Overall, paracetamol hypersensitivity was confirmed in 16 of the 32 patients (50%). Twelve of the 16 paracetamol-allergic patients (75%) tolerated NSAIDs (negative challenge in 6, negative history in 6). Four of these 16 patients (25%) were intolerant of NSAIDs (positive challenge in 1, self-challenge in 3). CONCLUSIONS: In past reports on paracetamol hypersensitivity, only single cases of a positive SPT and detectable specific IgE have been described. Our data confirm that specific IgE may be a mechanism underlying paracetamol hypersensitivity, as in this series 18.8% of the patients had specific IgE. In 81.2% of patients, negative skin tests did not exclude paracetamol hypersensitivity, suggesting that it may be mediated by leukotrienes. However, three quarters of our patients tolerated NSAIDs, implicating an alternative mechanism. In patients with suspected paracetamol allergy, skin tests should be performed in addition to clinical history and oral challenge.

Diagnosis and management of hymenoptera venom allergy: British Society for Allergy and Clinical Immunology (BSACI) guidelines.

This guidance for the management of patients with hymenoptera venom allergy has been prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI). The guideline is based on evidence as well as on expert opinion and is for use by both adult physicians and pediatricians practising allergy. During the development of these guidelines, all BSACI members were included in the consultation process using a web-based system. Their comments and suggestions were carefully considered by the SOCC. Where evidence was lacking, consensus was reached by the experts on the committee. Included in this guideline are epidemiology, risk factors, clinical features, diagnostic tests, natural history of hymenoptera venom allergy and guidance on undertaking venom immunotherapy (VIT). There are also separate sections on children, elevated baseline tryptase and mastocytosis and mechanisms underlying VIT. Finally, we have made recommendations for potential areas of future research.

BSACI guidelines for the investigation of suspected anaphylaxis during general anaesthesia.

Investigation of anaphylaxis during general anaesthesia requires an accurate record of events including information on timing of drug administration provided by the anaesthetist, as well as timed acute tryptase measurements. Referrals should be made to a centre with the experience and ability to investigate reactions to a range of drug classes/substances including neuromuscular blocking agents (NMBAs) intravenous (i.v.) anaesthetics, antibiotics, opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), local anaesthetics, colloids, latex and other agents. About a third of cases are due to allergy to NMBAs. Therefore, investigation should be carried out in a dedicated drug allergy clinic to allow seamless investigation of all suspected drug classes as a single day-case. This will often require skin prick tests, intra-dermal testing and/or drug challenge. Investigation must cover the agents administered, but should also include most other commonly used NMBAs and i.v. anaesthetics. The outcome should be to identify the cause and a range of drugs/agents likely to be safe for future use. The allergist is responsible for a detailed report to the referring anaesthetist and to the patient's GP as well as the surgeon/obstetrician. A shorter report should be provided to the patient, adding an allergy alert to the case notes and providing an application form for an alert-bracelet indicating the wording to be inscribed. The MHRA should be notified. Investigation of anaphylaxis during general anaesthesia should be focussed in major allergy centres with a high throughput of cases and with experience and ability as described above. We suggest this focus since there is a distinct lack of validated data for testing, thus requiring experience in interpreting tests and because of the serious consequences of diagnostic error.

British Society for Allergy and Clinical Immunology guidelines for the management of egg allergy.

This guideline advises on the management of patients with egg allergy. Most commonly, egg allergy presents in infancy, with a prevalence of approximately 2% in children and 0.1% in adults. A clear clinical history and the detection of egg white-specific IgE (by skin prick test or serum assay) will confirm the diagnosis in most cases. Egg avoidance advice is the cornerstone of management. Egg allergy often resolves and re-introduction can be achieved at home if reactions have been mild and there is no asthma. Patients with a history of severe reactions or asthma should have reintroduction guided by a specialist. All children with egg allergy should receive measles, mumps and rubella (MMR) vaccination. Influenza and yellow fever vaccines should only be considered in egg-allergic patients under the guidance of an allergy specialist. This guideline was prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI) and is intended for allergists and others with a special interest in allergy. The recommendations are evidence-based but where evidence was lacking consensus was reached by the panel of specialists on the committee. The document encompasses epidemiology, risk factors, diagnosis, treatment, prognosis and co-morbid associations.

Anaphylaxis to patent blue V: a case series and proposed diagnostic protocol.

Patent blue V is widely used in the identification of sentinel lymph nodes in patients with breast cancer and other malignancies. Individual case reports of allergy to patent blue V have been described in the medical literature since the 1960s. However, there is little data on clinical features and little experience of which allergy tests are appropriate or useful. We gathered all cases of patent blue V allergy that had been seen and diagnosed in the Department of Allergy, Addenbrooke's Hospital over a 3-year period. We collected clinical details of each case including skin test results. For comparison we recruited 12 healthy control subjects who then underwent skin testing to patent blue V. Six cases of patent blue V allergy were identified, all occurring during sentinel lymph node identification for breast carcinoma. All 6 had positive skin prick tests to neat patent blue V (25 mg/ml). Skin prick testing with a 1 : 10 dilution (2.5 mg/ml) produced positive results in 3 of 4 patients tested, and intradermal testing at a 1 : 100 dilution was (0.25 mg/ml) was positive in all patients tested. Of 12 control subjects, 11 had negative skin prick tests to both neat and 1 : 10 patent blue V with one subject showing a positive reaction to the higher concentration only. On the basis of our experience of patent blue V allergy, we propose a diagnostic protocol that can be safely and reliably utilised in centres equipped for allergy testing.

BSACI guidelines for the management of drug allergy.

These guidelines have been prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI) and are intended for allergists and others with a special interest in allergy. As routine or validated tests are not available for the majority of drugs, considerable experience is required for the investigation of allergic drug reactions and to undertake specific drug challenge. A missed or incorrect diagnosis of drug allergy can have serious consequences. Therefore, investigation and management of drug allergy is best carried out in specialist centres with large patient numbers and adequate competence and resources to manage complex cases. The recommendations are evidence-based but where evidence was lacking consensus was reached by the panel of specialists on the committee. The document encompasses epidemiology, risk factors, clinical patterns of drug allergy, diagnosis and treatment procedures. In order to achieve a correct diagnosis we have placed particular emphasis on obtaining an accurate clinical history and on the physical examination, as these are critical to the choice of skin tests and subsequent drug provocation. After the diagnosis of drug allergy has been established, communication of results and patient education are vital components of overall patient management.

Successful oral tolerance induction in severe peanut allergy.

BACKGROUND: Peanut allergy is common, potentially severe and rarely resolves causing impaired quality of life. No disease-modifying treatment exists and there is therefore a need to develop a therapeutic intervention. AIMS OF THE STUDY: The aim of this study was to investigate whether peanut oral immunotherapy (OIT) can induce clinical tolerance to peanut protein. METHODS: Four peanut-allergic children underwent OIT. Preintervention oral challenges were performed to confirm clinical allergy and define the amount of protein required to cause a reaction (dose thresholds). OIT was then administered as daily doses of peanut flour increasing from 5 to 800 mg of protein with 2-weekly dose increases. After 6 further weeks of treatment, the oral challenge was repeated to define change in dose threshold and subjects continued daily treatment. RESULTS: Preintervention challenges confirmed peanut allergy and revealed dose thresholds of 5-50 mg (1/40-1/4 of a whole peanut); one subject had anaphylaxis during challenge and required adrenaline injection. All subjects tolerated immunotherapy updosing to 800 mg protein and i.m. adrenaline was not required. Each subject tolerated at least 10 whole peanuts (approximately 2.38 g protein) in postintervention challenges, an increase in dose threshold of at least 48-, 49-, 55- and 478-fold for the four subjects. CONCLUSIONS: We demonstrated a substantial increase in dose threshold after OIT in all subjects, including the subject with proven anaphylaxis. OIT was well tolerated and conferred protection against at least 10 peanuts, more than is likely to be encountered during accidental ingestion.

Systemic absorption of inhaled epinephrine.

To determine the systemic absorption of epinephrine when it is given by inhalation, six normal volunteers were given 15 puffs, followed by 30 puffs, of epinephrine from a pressurized aerosol (160 micrograms epinephrine/puff). The peak mean (+/- SE) plasma epinephrine levels were 1.50 (+/- 0.61) and 4.22 (+/- 1.93) nmol/L 1 minute after each dose, respectively. The effect on physiologic finger tremor correlated with the plasma epinephrine level and returned to baseline 20 minutes after taking the higher dose. There was a small fall in mean plasma potassium levels of 0.45 mmol/L and a small rise in plasma glucose levels of 0.81 mmol/L. On a separate occasion an injection of 0.3 ml of 1/1000 (300 micrograms) epinephrine was given subcutaneously to the same individuals. This caused a peak plasma epinephrine level of 2.43 (+/- 0.47) nmol/L at 10 minutes, and this was still raised at 2.05 (+/- 0.41) nmol/L after 40 minutes. The maximum fall in the mean plasma potassium level was 0.43 mmol/L after the injection.

A competitive inhibition ELISA for the quantification of human interferon-gamma.

A competitive enzyme immunoassay has been developed for the measurement of human interferon-gamma (IFN-gamma) in cell culture supernatants. The assay is based on the dose-dependent inhibitory effect of liquid phase IFN-gamma on the binding of a specific monoclonal antibody to recombinant IFN-gamma (rIFN-gamma) immobilized on microtitre plate wells. The extent of monoclonal anti-IFN-gamma inhibition was determined by the uptake of alkaline phosphatase-conjugated goat anti-mouse IgG and the subsequent development of enzyme substrate colour. Absorbance readings were taken and results for test samples were extrapolated from standard rIFN-gamma inhibition curves constructed as logit-log plots. Assay performance was assessed using three different monoclonal antibodies (clones 20G7, H-22 and GZ-4). Optimum sensitivity was achieved with the antibodies of higher affinity, 20G7 and H-22, which gave reliable quantification of IFN-gamma over a wide range of concentrations from 0.4 ng/ml (3.4 IU/ml), or less, to 250 ng/ml approximately 2000 IU/ml). The inhibition assay incorporates the advantages of specificity, reproducibility and convenience of performance which are the hallmarks of monoclonal antibody-based ELISAs. However, compared to the sandwich ELISAs previously described for human IFN-gamma, it is considerably more economical in its use of monoclonal anti-IFN-gamma, requiring < 50 ng of a single antibody per 96 well plate. It also uses relatively small volumes of test samples (50 microliters/well) which is particularly advantageous where limited amounts of cell culture supernatant are available for cytokine assays.

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.

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.

The incidence, aetiology and management of anaphylaxis presenting to an accident and emergency department.

We retrospectively studied anaphylaxis in an A&E department from computerized records. In 1993 (Study A), of 55,000 patients seen in casualty, nine had severe anaphylaxis (ANA) with loss of consciousness (LOC) or fainting (about 1: 6000). Fifteen had generalized allergic reactions (GR) without LOC or fainting, but including dyspnoea due to laryngeal oedema or asthma, angioedema and/or urticaria. Thus there were 24 (about 1:2300) generalized reactions involving hypotension and/or respiratory difficulty. A further case diagnosed as hyperventilation syndrome was probably a wasp sting GR. Six cases of urticaria and/or angioedema were also identified. Of the nine with ANA, a possible cause was identified in eight (3 stings; 2 drugs; 3 foods). There was delay in arrival in A&E: hypotension was noted in three and had resolved spontaneously in six. Only 3/9 were related with adrenaline: i.v. hydrocortisone and chlorpheniramine was the mainstay of treatment. No investigation was recommended nor advice given on future management. Four patients were later referred to our allergy clinic by their GPs. In study B (aug-Oct 1994), nine cases of ANA were identified (1:1500), eight due to bee or wasp stings. The increased incidence was probably related to more detailed history-taking. Only three were treated with adrenaline. The use of adrenaline for future anaphylaxis was discussed with six patients, and five were referred to our allergy clinic. A reaction to the same allergen had occurred previously in 24%. Improved awareness of anaphylaxis and its management is necessary.

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.

Functional imaging of lung ventilation using the concept of mean transit time.

This paper describes a new way of expressing local ventilation using a scintillation gamma camera interfaced to a digital computer. From the ratio of the first to the zeroth moment of the lung clearance curve for 13N gas, a mean transit time is calculated and displayed for different regions of the lung. Lung clearance curves following intravenously administered 13N solutions, or after equilibration with 13N gas, are measured during normal breathing. Describing regional ventilation by mean transit time during clearance uses all the counts in the lung clearance curve and the improvement in statistical accuracy compared with the height over area method using a Stewart-Hamilton equation is significant. In normal subjects the average mean transit time for clearance from the total lung field is t = (61 +/- 4) s, from the upper zone tuz = (64 +/- 4) s and from the lower zone tlz = (54 +/- 5) s. These results show uneven ventilation between regions of the normal lung in general agreement with that described by previous authors. In addition, the functional image gives the mean transit time for each cell of the 64 X 64 matrix of the computer display. The fractional error in mean transit time is 3% for an area of 2-2 cm2 corresponding to 12 cells in the display. This display provides a sensitive method, functionally and spatially, of investigating local differences in ventilation, including vertical and horizontal gradients in narrow strips of lung.

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.

Clinical study of peanut and nut allergy in 62 consecutive patients: new features and associations.

OBJECTIVE: To investigate clinical features of acute allergic reactions to peanuts and other nuts. DESIGN: Analysis of data from consecutive patients seen by one doctor over one year in an allergy clinic at a regional referral centre. SUBJECTS: 62 patients aged 11 months to 53 years seen between October 1993 and September 1994. MAIN OUTCOME MEASURES: Type and severity of allergic reactions, age at onset of symptoms, type of nut causing allergy, results of skin prick tests, and incidence of other allergic diseases and associated allergies. RESULTS: Peanuts were the commonest cause of allergy (47) followed by Brazil nut (18), almond (14), and hazelnut (13). Onset of allergic symptoms occurred by the age of 2 years in 33/60 and by the age of 7 in 55/60. Peanuts accounted for all allergies in children sensitised in the first year of life and for 82% (27/33) of allergies in children sensitised by the third year of life. Multiple allergies appeared progressively with age. The commonest symptom was facial angioedema, and the major feature accounting for life threatening reactions was laryngeal oedema. Hypotension was uncommon. Of 55 patients, 53 were atopic--that is, had positive skin results of tests to common inhaled allergens--and all 53 had other allergic disorders (asthma, rhinitis, eczema) due to several inhaled allergens and other foods. CONCLUSIONS: Sensitisation, mainly to peanuts, is occurring in very young children, and multiple peanut/nut allergies appear progressively. Peanut and nut allergy is becoming common and can cause life threatening reactions. The main danger is laryngeal oedema. Young atopic children should avoid peanuts and nuts to prevent the development of this allergy.