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1.  Wheal and flare reactions in skin prick tests of patients treated with montelukast alone or in combination with antihistamines 
Inflammation Research  2013;63(3):191-195.
Because antileukotrienes may inhibit inflammation, it is plausible that montelukast administered for a long time could suppress skin wheal and flare reaction, and thus, it should be discarded prior to the tests. This study assessed the effect of long-lasting treatment with montelukast alone or in combination with antihistamines on wheal and flare in skin pricks tests (SPT) in patients sensitized to perennial allergens.
We conducted a 32-week, double-blind, placebo-controlled, cross-over and randomized trial that implicated two arms: arm A, 20 patients received levocetirizine, montelukast with or without levocetirizine or placebo; arm B, 20 patients received desloratadine, montelukast with or without desloratadine or placebo. All treatment periods lasted 6 weeks and were separated by 2-week washouts. At baseline and on the last day of each treatment period, SPT were performed in all participants.
Both levocetirizine and desloratadine in monotherapy, or in combination with montelukast, were effective in reducing wheal and flare in SPT. Monotherapy with montelukast did not change the size of the wheal for either histamine or for house dust mites, in either arm of the study, but significantly reduced the size of flare for histamine in arm A. Addition of montelukast to antihistamine did not exceed efficacy of monotherapy with antihistamine in both arms of the study.
Since the size of wheal determines the results of SPT, montelukast, even taken for a long time, does not have to be discarded prior to the tests.
PMCID: PMC3921455  PMID: 24281730
Allergic rhinitis; Montelukast; Antihistamine; Skin prick test; Inflammation
2.  Adjusting wheal size measures to correct atopy misclassification 
Skin prick testing (SPT) is fundamental to the practice of clinical allergy identifying relevant allergens and predicting the clinical expression of disease. Wheal sizes on SPT are used to identify atopic cases, and the cut-off value for a positive test is commonly set at 3 mm. However, the measured wheal sizes do not solely reflect the magnitude of skin reaction to allergens, but also skin reactivity (reflected in the size of histamine reaction) and other random or non-random factors. We sought to estimate wheal sizes exclusively due to skin response to allergens and propose gender-specific cutoff points of atopy.
We developed a Bayesian method to adjust observed wheal sizes by excluding histamine and other factor effects, based on which revised cutoff points are proposed for males and females, respectively. The method is then applied to and intensively evaluated using a study population aged 18, at a location on the Isle of Wight in the United Kingdom. To evaluate the proposed approach, two sample t-tests for population means and proportion tests are applied.
Four common aeroallergens, house dust mite (HDM), grass pollen, dog dander, and alternaria are considered in the study. Based on 3 mm cutoff, males tend to be more atopic than females (P-values are between 0.00087 and 0.062). After applying the proposed methods to adjust wheal sizes, our findings suggest that misclassifications of atopy occur more often in males. Revised allergen-specific cutoff values are proposed for each gender.
To reduce the gender discrepancy, we may have two potentially convenient solutions. One way is to apply allergen-specific and gender-specific cutoff values following the proposed method. Alternatively, we can revise the concentration of allergens in the SPT solutions but keep the cutoff values unchanged, which may be more convenient to clinicians.
PMCID: PMC3160870  PMID: 21887114
SPT; atopy; Bayesian method; joint modeling; misclassification
3.  570 Atopy Patch Test to Aeroallergens Extracts is Useful In Allergic Diseases Diagnosis When Skin Prick Test is Negative 
The World Allergy Organization Journal  2012;5(Suppl 2):S197-S198.
The atopic diseases are generally diagnosed by performing skin prick tests (SPTs) to different aeroallergens. However, when this study results negative, it is possible to perform atopy patch test (APT). This technique has been introduced to evaluate sensitization to aeroallergens in patients with atopic eczema dermatitis syndrome. Nevertheless, its role in other allergic diseases has not been proved. Objective: Evaluate aeroallergens response using skin prick test (SPT) and atopy patch test (APT) in patients with allergic diseases.
Retrospective cohort study of individuals who performed SPT and APT as part of allergic diseases study. The study subjects were patch and skin prick tested to house dust mite (Dermatophagoides), trees, grass and fungi mix, cat and dog dander, among others. The tests were performed at the respiratory allergic disease center of Santa Maria Clinic in Santiago, Chile, between January 2010 and April 2011.
Fifty-five patients were included, 18 (33%) males and 37 (67%) females, median age 6 years (range from 3 months to 62 years), with the following diagnosis: atopic dermatitis syndrome (60%), allergic rhinitis (58%), contact allergic dermatitis (16%), asthma (9%), recurrent bronchial obstructive syndrome (7%), allergic rhinoconjuctivitis (4%), chronic cough (4%), recurrent acute otitis media (2%) and recurrent laryngitis (2%). They underwent usual SPTs and APTs with multiple aeroallergens extracts. Of the 55 patients, 22 showed a positive SPT and 32 a positive APT; in 14 (25%) both, SPT and APT were positive. In 8 (15%) the SPT was positive and APT negative, while in 18 (33%) the SPT was negative, but the APT positive. Fifteen (27%) were negative to both tests.
Our results show that APT might be a useful diagnosis test in patients with allergic diseases and that its routine use can improve their diagnosis.
PMCID: PMC3513076
4.  Kidney Bean: A Major Sensitizer among Legumes in Asthma and Rhinitis Patients from India 
PLoS ONE  2011;6(11):e27193.
The prevalence of IgE mediated food allergies has increased over the last two decades. Food allergy has been reported to be fatal in highly sensitive individuals. Legumes are important food allergens but their prevalence may vary among different populations. The present study identifies sensitization to common legumes among Indian population, characterizes allergens of kidney bean and establishes its cross reactivity with other legumes.
Patients (n = 355) with history of legume allergy were skin prick tested (SPT) with 10 legumes. Specific IgE (sIgE) and total IgE were estimated in sera by enzyme-linked immunosorbent assay. Characterization of kidney bean allergens and their cross reactivity was investigated by immunobiochemical methods. Identification of major allergens of kidney bean was carried out by mass spectrometry.
Principal Findings
Kidney bean exhibited sensitization in 78 (22.0%) patients followed by chickpea 65 (18.0%) and peanut 53 (15%). SPT positive patients depicted significantly elevated sIgE levels against different legumes (r = 0.85, p<0.0001). Sera from 30 kidney bean sensitive individuals exhibited basophil histamine release (16–54%) which significantly correlated with their SPT (r = 0.83, p<0.0001) and sIgE (r = 0.99, p<0.0001). Kidney bean showed eight major allergens of 58, 50, 45, 42, 40, 37, 34 and 18 kDa on immunoblot and required 67.3±2.51 ng of homologous protein for 50% IgE inhibition. Inhibition assays revealed extensive cross reactivity among kidney bean, peanut, black gram and pigeon pea. nLC-MS/MS analysis identified four allergens of kidney bean showing significant matches with known proteins namely lectin (phytohemagglutinin), phaseolin, alpha-amylase inhibitor precursor and group 3 late embryogenesis abundant protein.
Among legumes, kidney bean followed by chick pea and peanut are the major allergic triggers in asthma and rhinitis patients in India. Kidney bean showed eight major allergens and cross reacted with other legumes. A combination of SPT, sIgE and histamine release assay is helpful in allergy diagnosis.
PMCID: PMC3212544  PMID: 22096535
5.  128 Colour Change in the Human Histamine Wheal; a Sign of Desensitized Histamine Vasoconstrictory Receptors 
The aim was to find the cause and consequences of a colour change in histamine wheals found after ordinary histamine skin prick tests (SPTs) (10 mg/mL). A rapid change to a darker red colour from the 18th and to the 20th minute has been demonstrated by using a digital image-processing technique called LYYN and ImageJ to yield numerical values.1
Repeated histamine SPTs in the middle of the site for earlier performed histamine SPTs in humans. Calculations of the sizes of photographed wheals. Histamine solutions perfused in isolated rabbit ears.
Histamine SPT performed 90 minutes or 6 hours apart from initial histamine SPTs evoked a ring of wheal peripherally around the site of the initial wheal or no wheal at all. The initial wheals had at those times disappeared. Histamine perfusion in isolated rabbit ears indicated first vasoconstriction and after a mean of 17 minutes vasodilatation in post-capillary vessels despite continued histamine perfusion.
The results indicate that total desensitization of histamine-1 receptors in the wheal is the cause of the colour change in human histamine SPTs and that such desensitization lasts long time. If histamine released at allergen provocations also evokes such a long-lasting desensitization and post-capillary vasodilatation it opens new aspects on vascular events in allergic reactions.
PMCID: PMC3512879
6.  410 Epidemiological and Clinical Characteristics of Allergic Conjunctivitis Patients in a Reference Center of Mexico City 
In our country (Mexico) there are few reports about epidemiological characteristics of allergic conjunctivitis patients; despite these studies give us some information about patient profile, in most cases these studies are not always comparable due to the use of different methodologies, that is, Include only a portion of the population (elderly, infants) or there are limited to one region of the city. The purpose of this study was to know the epidemiological and clinical characteristics of allergic conjunctivitis (AC)-patients in the biggest reference center of ocular diseases in Mexico (Institute of Ophthalmology “Conde de Valenciana”)
Data were obtained from clinical records. Six hundred fifteen patients with diagnosis of AC were included. Epidemiological characteristics included sex, age, residence; clinical-immunological characteristics included atopy, coexistence of other allergies, total IgE, cutaneous reactivity to skin prick test (SPT), sixty allergens were evaluated. Descriptive statistics were performed to obtain frequencies and t test was used to find significant differences, P < 0.05 was considered statistically significant.
AC-Patients who received medical consultation at the Institute of Ophthalmology where predominantly from State of Mexico (47.25%), Mexico City (37.5%), and in less frequency Hidalgo, Puebla, Tlaxcala, Michoacan, Veracruz, Oaxaca, Guerrero, Chiapas and Guanajuato. 88% of AC-patients were positive to SPT (SPT+), while 12% were negative to SPT (SPT-). Age of diagnosis was significant different between SPT-AC-patients and SPT+AC-patients (14.5-years vs 17.9-years, P = 0.02). Male SPT-AC-patients were diagnosed younger than male SPT+AC-patients (P = 0.001). IgE concentration was significant increased in male SPT+AC-patients than female SPT+AC-patients (P = 0.006). The most common skin reactivity was against Dermatophagoides sp (59.1%), Aedes sp(54.55%) and Blatella-Periplaneta sp.(31.14%); we did not observe significant differences in skin reactivity between male or female SPT+AC-patient.
It was considered that AC-patients were negative to SPT; contrary to reported, this study showed that most of AC-patients were positive to some allergen; this result is relevant because open the possibility to offer specific desensitization as conventional treatment instead anti-histamine drugs in SPT+ population. This is the first study covering the central and southern part of our country.
PMCID: PMC3512601
7.  The rate of epinephrine administration associated with allergy skin testing in a suburban allergy practice from 1997 to 2010 
Allergy & Rhinology  2012;3(2):e55-e60.
Allergy skin testing is considered a safe method for testing for IgE-mediated allergic responses although anaphylactic events can occur. Reported rates of anaphylaxis per patient are not consistent and range from 0.008 to 4%. The aim of this study was to determine the rate of epinephrine use associated with allergy skin-prick testing (SPT) and intradermal testing (IDT) in a suburban practice over 13 years. This retrospective chart review used billing and procedure coding records during the time period from January 1997 to June 2010 to identify encounters where epinephrine was administered after SPT or IDT. Patient encounters with procedure codes for skin testing plus either parenteral epinephrine, corticosteroid, antihistamine, or i.v. fluid administration were identified. These patient charts were reviewed to determine if epinephrine was administered, whether systemic reactions developed, and rates of epinephrine administration were calculated. There were 28,907 patient encounters for SPT and 18,212 for IDT. Epinephrine was administered in six patient encounters (0.02%) where SPT was performed; no IDT encounters led to epinephrine administration. There were no fatalities. Allergy skin testing to a variety of allergens, when administered by well-trained personnel, is a safe procedure. This study, involving the largest population to date, showed a rate of systemic reactions requiring epinephrine of 20 per 100,000 SPT visits. No epinephrine was given after IDT.
PMCID: PMC3548609  PMID: 23342290
Adverse reactions; allergic rhinitis; anaphylactoid reactions; anaphylaxis; food allergy testing; idiopathic anaphylaxis; intradermal testing; skin-prick testing; systemic reactions; venom allergy testing
8.  Oil body-associated hazelnut allergens including oleosins are underrepresented in diagnostic extracts but associated with severe symptoms 
Oil body-associated allergens such as oleosins have been reported for important allergenic foods such as peanut, sesame and hazelnut. Here we investigate whether oil body associated proteins (OAPs) are linked with specific clinical phenotypes and whether they are represented in skin prick test (SPT) reagents.
A hazelnut OAP fraction was characterized by mass-spectrometry (MS) to identify its major constituents. Polyclonal rabbit antibodies were generated against hazelnut OAPs. The presence of OAPs in commercially available hazelnut SPTs was studied by immunoblot and spiking experiments. OAP-specific IgE antibodies were measured in sera from patients with a convincing history of hazelnut allergy by RAST (n = 91), immunoblot (n = 22) and basophil histamine release (BHR; n = 14).
Hazelnut OAPs were analysed by MS and found to be dominated by oleosins at ~14 and ~17 kDa, and a 27 kDa band containing oleosin dimers and unidentified protein. In 36/91 sera specific IgE against hazelnut OAPs was detected, and confirmed to be biologically active by BHR (n = 14). The majority (21/22) recognized the oleosin bands at 17 kDa on immunoblot, of which 11 exclusively. These OAP-specific IgE responses dominated by oleosin were associated with systemic reactions to hazelnut (OR 4.24; p = 0.015) and negative SPT (χ2 6.3, p = 0.012). Immunoblot analysis using OAP-specific rabbit antiserum demonstrated that commercial SPT reagents are virtually devoid of OAPs, sometimes (3/9) resulting in false-negative SPT. Spiking of SPT reagents with OAP restored serum IgE binding of these false-negative patients on immunoblot at mainly 17 kDa.
Hazelnut allergens found in oil bodies dominated by oleosin are associated with more severe systemic reactions and negative SPT. Defatted diagnostic extracts are virtually devoid of these allergens, resulting in poor sensitivity for detection of IgE antibodies against these clinically relevant molecules.
PMCID: PMC4015814  PMID: 24484687
Food allergy; IgE-mediated; Oil bodies; Oleosins; Hazelnut
9.  Intradermal Tests for Diagnosis of Drug Allergy are not Affected by a Topical Anesthetic Patch 
The use of topical anesthesia to perform intradermal tests (IDTs) for drug allergy diagnosis was never investigated. We aimed to determine the effects of a topical anesthetic patch containing prilocaine-lidocaine on wheal size of IDT with drugs. Patients who had positive IDT as part of their investigation process of suspected drug hypersensitivity were selected. IDT were performed according to guidelines. Anesthetic patch (AP) was placed and the same prior positive IDT, as well as positive histamine skin prick test (SPT) and negative (saline IDT) controls, were performed in the anesthetized area. Patients with negative IDT were also included to check for false positives with AP. Increase in wheals after 20 minutes both with and without AP was recorded and compared. 45 IDT were performed (36 patients), of which 37 have been previously positive (14 antibiotics, 10 general anesthetics, 6 non-steroidal anti-inflammatory drugs, 3 iodinated contrasts, 3 anti-Hi-histamines and 1 ranitidine). Mean histamine SPT size without the AP was 4.7 mm [95%CI (4.4-5.1]), and 4.6 mm [95%CI(4.2-5.0)] with anesthesia. Mean wheal increase in IDT for drugs without the anesthesia was 4.5 mm [95%CI(3.3-5.7)] and with anesthesia was 4.3 mm [95%CI(2.8-5.8)]. No statistical significant differences were observed between skin tests with or without AP for histamine SPT (P=0.089), IDT with saline (P=0.750), and IDT with drugs (P=0.995). None of the patients with negative IDT showed positivity with the AP, or vice-versa. The use of an AP containing prilocaine-lidocaine does not interfere with IDT to diagnose drug allergy, and no false positive tests were found.
PMCID: PMC4161688  PMID: 25229004
Drug allergy; intradermal tests; topical anesthesia
10.  Enhanced prostaglandin synthesis after ultraviolet injury is mediated by endogenous histamine stimulation. A mechanism for irradiation erythema. 
Journal of Clinical Investigation  1990;86(2):566-574.
Acute ultraviolet light B (UVB) injury is associated with dermal mast cell histamine release. The possibility that histamine-stimulated prostaglandin (PG) synthesis could be a mechanism for irradiation erythema was therefore examined using human skin explants. Explants responded to UV irradiation (120 mJ/cm2) with a fivefold increase in synthesis of prostaglandins E2, F2 alpha and 6-keto PGF1 alpha. Incubating explants with the H1 antihistamines brompheniramine (50 microM) or pyrilamine (30 microM) inhibited PG release from irradiated explants 63 +/- 4.9% (mean +/- SEM) 6 h after UV exposure. Antihistamines did not affect PG synthesis in control explants. Irradiation increased the histamine concentration in explant conditioned medium only 50% over basal values, suggesting that irradiation enhanced histamine responsiveness. Explants were therefore incubated with exogenous histamine. In irradiated explants, PG synthesis was stimulated threefold by 3 microM histamine. Unirradiated explants' PG synthesis was unaffected by histamine. Enhanced histamine sensitivity was also examined in epidermal cell cultures. In irradiated cultures, histamine sensitivity was again markedly potentiated: as little as 1 microM histamine stimulated significant PGE2 release and the response to 10-30 microM histamine was increased six to eight times compared with that of unirradiated cultures. These studies demonstrate that endogenous histamine stimulates PG synthesis in human skin after UV injury by potentiation of histamine-induced prostaglandin release. Potentiated agonist responses induced by UV exposure may contribute to the effects of UVB irradiation injury and in particular to irradiation erythema.
PMCID: PMC296762  PMID: 1696589
11.  A case of anaphylaxis to peppermint 
Anaphylaxis, a form of IgE mediated hypersensitivity, arises when mast cells and possibly basophils are provoked to secrete mediators with potent vasoactive and smooth muscle contractile activities that evoke a systemic response. We report a case of IgE mediated anaphylaxis to peppermint (Mentha piperita) in a male shortly after sucking on a candy.
Case presentation
A 69 year old male developed sudden onset of lip and tongue swelling, throat tightness and shortness of breath within five minutes of sucking on a peppermint candy. He denied lightheadedness, weakness, nausea, vomiting, or urticaria. He took 25 mg of diphenhydramine, but his symptoms progressed to onset of cough, wheeze and difficulty with talking and swallowing. He was rushed to the nearest emergency department, where he was treated with intramuscular epinephrine, antihistamines and steroids. On history, he reported recent onset of mouth itchiness and mild tongue and lip swelling after using Colgate peppermint toothpaste. He denied previous history of asthma, allergic rhinitis, food or drug allergies. His past medical history was remarkable for hypercholesterolemia, gastroesophageal reflux and gout. He was on simvastatin, omeprazole, aspirin, and was carrying a self-injectable epinephrine device. He moved to current residence three years ago and cultivated mint plants in his backyard. He admitted to develop nasal congestion, cough and wheeze when gardening. Physical examination was unremarkable apart from slightly swollen pale inferior turbinates. Skin prick test (SPT) was strongly positive to a slurry of peppermint candy and fresh peppermint leaf, with appropriate controls. Same tests performed on five healthy volunteers yielded negative results. Skin testing to common inhalants including molds and main allergenic foods was positive to dust mites. Strict avoidance of mint containing items was advised. Upon reassessment, he had removed mint plants from his garden which led to resolution of symptoms when gardening.
IgE mediated anaphylaxis to peppermint is rare. This case demonstrates a systemic reaction to a commonly consumed item, incapable of triggering anaphylaxis in the far majority of the population, yet causing a severe episode for our patient.
PMCID: PMC3912937  PMID: 24472564
Anaphylaxis; Peppermint; Menthol; IgE mediated
12.  Randomized, single-blind, crossover comparison of two rupatadine tablet formulations on histamine-induced cutaneous response in healthy adult volunteers 
Background: Rupatadine is a histamine receptor type 1 antagonist that has been used to treat allergic rhinitis and urticaria.
Objective: The aim of this study was to compare the effect of 2 rupatadine tablet formulations on the inhibition of histamine-induced wheal-and-flare cutaneous responses.
Methods: In this single-blind, single oral dose, crossover study, healthy male volunteers were randomized to receive 10 mg of either a rupatadine reference or test formulation after an overnight fast. After a 10-day washout period, the subjects were crossed over to receive the other formulation. Subjects were asked to sit with their arm resting on the table while histamine was injected intradermally. The skin prick test was performed on the upper half of the volunteers' forearms before administration and at 1, 2, 4, 6, 12, and 24 hours after study drug administration. Fifteen minutes after each skin prick test, the wheal-and-flare responses were visualized under a bright lamp. AUC0–24 was the primary end point.The 90% CI of least squares mean ratio (%) of the test: reference formulations for maximum inhibition of histamine-induced wheal-and-flare response (Imax%), Tmax, AUC0–24 mm2/h, and AUC0–24%/hr were expected to be within 80% to 125% of untransformed data and 80% to 120% of log-transformed data for the 2 formulations to be considered pharmacodynamically equivalent. Subjects were monitored for any spontaneously reported adverse event (AE) throughout the study. In addition, they were specifically asked about the occurrence of any AEs on a checklist (ie, drowsiness, dizziness, dryness of mouth, itching sensation, headache, nausea) throughout the study.
Results: Of the 15 subjects assessed for inclusion, 12 healthy male volunteers (mean [SD] age, 30 [5] years; height, 162 [6] cm; weight, 58 [6] kg) participated in the study. Administration of reference and test formulations of rupatadine significantly inhibited the histamine-induced cutaneous responses in all subjects (P <0.001). Wheal Imax% with the reference and test formulations was 67.97% (11.57%) and 66.76% (9.40%), respectively. Flare Imax% was 59.06% (11.95%) and 56.92% (16.31%), respectively. None of the subjects withdrew from the study due to AEs. Both formulations were well tolerated except for an itching sensation on injection of histamine in all patients; no subject complained of any adverse drug reaction.
Conclusion: In this small study of healthy adult males, the test formulation of the rupatadine tablet was found to be pharmacodynamically equivalent to the reference formulation, as measured by inhibition of histamine-induced cutaneous wheal-and-flare responses.
PMCID: PMC3969931  PMID: 24692771
rupatadine; healthy subjects; pharmacodynamic equivalence; histamine-induced cutaneous response
13.  MEDICAL PROGRESS: Histamine and the Antihistaminic Drugs 
California Medicine  1950;72(5):377-389.
The tissues affected by histamine and anaphylactic reactions are identical. Epinephrine antagonizes the action of histamine by acting on effector cells in a direction opposite to that of histamine. The so-called antihistaminic drugs block rather than antagonize the action of histamine. The injection into the human body of epinephrine or certain antihistaminic substances provokes the release of histamine and thereby produces a rise in the histamine blood level.
There is a remarkable conformity of potency of antihistaminics as determined by Dale experiments and by histamine intoxication experiments in the intact guinea pig. Neoantergan, Pyribenzamine and Histadyl are usually superior to other compounds when potency is assayed by these methods.
All antihistaminics provide similar protection again animal anaphylaxis. Larger doses are necessary to protect against anaphylaxis than against histamine intoxication.
The differences in potency as determined by Dale experiments and histamine experiments in animals are not found in clinical use. One compound is not generally superior to all others in the treatment of any one or several allergic disorders.
The antihistaminic drugs are beneficial in the symptomatic treatment of allergic rhinitis, acute urticaria and angioneurotic edema, and mild non-infective bronchial asthma. Their effectiveness in the management of moderately severe and severe non-infective bronchial bronchial asthma; infective bronchial asthma; migraine; atopic dermatitis (disseminated neurodermatitis), and pruritus of skin disorders other than acute urticaria and angioneurotic edema, is not worthy of particular commendation.
The size of the dose of any antihistaminic substance influences the incidence of but not the type of side-effect that may accompany its usage. The quality of side effects varies according to the drug, although there is an individuality of response for each patient which must be reckoned with. In selecting an antihistaminic compound it is necessary to consider the percentage of cases in which side effects occur, as well as the percentage of good results. Optimal results are obtained by employing combinations of compounds and changing from one to the other as the case demands.
PMCID: PMC1520402  PMID: 15414437
14.  Clinical Availability of Component-Resolved Diagnosis Using Microarray Technology in Atopic Dermatitis 
Annals of Dermatology  2014;26(4):437-446.
Various allergens play a role in the elicitation or exacerbation of eczematous skin lesions in atopic dermatitis (AD), and much research effort has been focused on improving diagnostic tests to identify causative allergens.
The purpose of this study was to evaluate the diagnostic effectiveness of a newly introduced microarray-based specific immunoglobulin E detection assay, ImmunoCAP ISAC, for use in AD patients.
The serum samples of 25 AD patients were tested by using ISAC and a multiple allergen simultaneous test-enzyme immunoassay (MAST-EIA). In addition, 10 of the 25 patients underwent skin prick testing (SPT). The positive reaction rates to allergens in each test and the agreements, sensitivities, and specificities of ISAC and MAST-EIA were evaluated versus the SPT results.
For ISAC versus SPT, the overall results were as follows: sensitivity, 90.0%; specificity, 98.2%; positive predictive value (PPV), 90.0%; and negative predictive value (NPV), 98.2%. The total agreement and κ value for ISAC versus SPT were 96.9% and 0.882, respectively. For MAST-EIA versus SPT, the sensitivity was 80.0%, specificity 92.7%, PPV 66.7%, and NPV 96.2%. The total agreement and κ value for MAST-EIA versus SPT were 90.8% and 0.672, respectively. The overall agreement between the ISAC and MAST-EIA results was 88%.
The ISAC results in AD correlated well with the SPT results, and compared favorably to the MAST-EIA results. This study demonstrates the potential of ISAC as a convenient allergic diagnostic method in AD patients.
PMCID: PMC4135097  PMID: 25143671
Atopic dermatitis; Microarray-based specific IgE detection assay
15.  BAM8–22 peptide produces itch and nociceptive sensations in humans independent of histamine release 
Chronic itch accompanying many dermatological, neurological and systemic diseases is unresponsive to antihistamines. Our knowledge of endogenous chemicals that evoke histamine-independent itch and their molecular targets is very limited. Recently it was demonstrated in behavioral and cellular experiments that bovine adrenal medulla 8–22 peptide (BAM8–22), a proteolytically cleaved product of proenkephalin A, is a potent activator of Mas-related G protein-coupled receptors (Mrgprs), MrgprC11 and hMrgprX1, and induces scratching in mice in a Mrgpr-dependent manner. To study the sensory qualities that BAM8–22 evokes in humans we tested the volar forearm of 15 healthy volunteers with heat-inactivated cowhage spicules previously soaked in the peptide. BAM8–22 produced itch in each subject, usually accompanied by sensations of pricking/stinging and burning. The sensations were occasionally accompanied by one or more mechanically evoked dysesthesias, namely alloknesis, hyperknesis, and hyperalgesia, but no wheal or neurogenic flare in the skin surrounding the application site. The inactive truncated peptide BAM8–18 produced weak or no sensations. Pretreatment of the tested skin with an antihistamine cream (doxepin) inhibited the histamine-induced sensations, dysesthesias and skin reactions but not the sensations and dysesthesias evoked by BAM8–22. We show that BAM8–22 produces itch and nociceptive sensations in humans in a histamine-independent manner. Thus, BAM8–22 may be an endogenous itch mediator that activates, in humans, MrgprX1, a novel target for potential anti-itch treatments.
PMCID: PMC3111068  PMID: 21593341
16.  How Stress and Anxiety Can Alter Immediate and Late Phase Skin Test Responses in Allergic Rhinitis 
Psychoneuroendocrinology  2009;34(5):670.
Allergic rhinitis (AR) is the fifth most common chronic disease, and the association between allergic disorders and anxiety is well-documented. To investigate how anxiety and stressors modulate skin prick test (SPT) responses and associated inflammatory responses, 28 men and women with AR were selected by clinical history and skin test responses. The participants were admitted twice to a hospital research unit for 4 hours in a crossover trial. Changes in SPT wheals were assessed before and after a standardized laboratory speech stressor, as well as again the following morning; skin responses assessed twice during a lab session without a stressor and again the following morning served as the contrast condition. Anxiety heightened the magnitude of allergen-induced wheals following the stressor. As anxiety increased, SPT wheal diameters increased after the stressor, compared to a slight decrease following the control task. Anxiety also substantially enhanced the effects of stress on late phase responses: even skin tests performed the day after the stressor reflected the continuing impact of the speech stressor among the more anxious participants. Greater anxiety was associated with more IL-6 production by Con A-stimulated leukocytes following the stressor compared to the control visit. The data suggest that stress and anxiety can enhance and prolong AR symptoms.
PMCID: PMC2819057  PMID: 19150180
Allergies; psychoneuroimmunology; stress; anxiety; allergic rhinitis; skin tests
17.  Effects of first and second generation antihistamines on muscarinic induced mucus gland cell ion transport 
BMC Pharmacology  2005;5:8.
The first generation antihistamines, such as diphenhydramine, are fairly potent muscarinic antagonists in addition to being H1 selective antihistamines. The antimuscarinic action is often not desirable since it is in part responsible for the drying of secretions in the airways and the sedative effect. We therefore examined a number of antihistamines for antimuscarinic effects on ion transport by mucus gland cells isolated from the airways of swine. Enzymatically isolated airway mucus gland cells were purified utilizing density gradients and grown in culture on porous inserts (Millicell HA™) at an air interface. Cells grown in this manner maintain phenotype and polarity. Transport of ions, as short-circuit current measured under voltage-clamp, was measured in response to acetylcholine (ACh) or histamine applied to the serosal side of the gland cell layers. Concentration-response relationships for ACh or histamine were generated in the presence and absence of various drugs. The potencies against muscarinic receptor activation were estimated using the dose-ratio method of Schild.
Three known muscarinic antagonists were used to validate the system. Atropine had a pA2 of 9.4 ± 0.1 (n = 9). 4-DAMP and methoctramine had pA2 values of 8.6 ± 0.1 and 5.6 ± 0.1, respectively (n = 12, 11) all consistent with inhibition of an M3 subtype muscarinic receptor. The rank order of potency of the antihistamines against the inhibition of M3 receptors was desloratadine = diphenhydramine > hydroxyzine (pA2; 6.4, 6.2, 4.8, respectively). pA2 values for fexofenadine, loratadine and cetirizine were not determined since they had no effect on the cholinergic response at the highest drug concentrations tested (10, 10 and 100 μM, respectively). The pA2 values for the antihistamines against the histamine response could not be calculated, but the estimates of the rank order of potency were estimated to be desloratadine> cetirizine ≈ hydroxyzine > fexofenadine > loratadine > diphenhydramine.
The rank order of selectivity for histamine receptors over muscarinic receptors was estimated to be cetirizine ≈ fexofenadine > loratadine > desloratadine ≥ hydroxyzine ≥ diphenhydramine.
PMCID: PMC1079883  PMID: 15790419
18.  Suppression of Basophil Histamine Release and Other IgE-dependent Responses in Childhood Schistosoma mansoni/hookworm Coinfection 
The Journal of Infectious Diseases  2014;210(8):1198-1206.
Background. The poor correlation between allergen-specific immunoglobulin E (asIgE) and clinical signs of allergy in helminth infected populations suggests that helminth infections could protect against allergy by uncoupling asIgE from its effector mechanisms. We investigated this hypothesis in Ugandan schoolchildren coinfected with Schistosoma mansoni and hookworm.
Methods. Skin prick test (SPT) sensitivity to house dust mite allergen (HDM) and current wheeze were assessed pre-anthelmintic treatment. Nonspecific (anti-IgE), helminth-specific, and HDM-allergen-specific basophil histamine release (HR), plus helminth- and HDM-specific IgE and IgG4 responses were measured pre- and post-treatment.
Results. Nonspecific- and helminth-specific-HR, and associations between helminth-specific IgE and helminth-specific HR increased post-treatment. Hookworm infection appeared to modify the relationship between circulating levels of HDM-IgE and HR: a significant positive association was observed among children without detectable hookworm infection, but no association was observed among infected children. In addition, hookworm infection was associated with a significantly reduced risk of wheeze, and IgG4 to somatic adult hookworm antigen with a reduced risk of HDM-SPT sensitivity. There was no evidence for S. mansoni infection having a similar suppressive effect on HDM-HR or symptoms of allergy.
Conclusions. Basophil responsiveness appears suppressed during chronic helminth infection; at least in hookworm infection, this suppression may protect against allergy.
PMCID: PMC4176447  PMID: 24782451
Schistosoma mansoni; schistosomiasis; hookworm; helminth infection; allergy; skin prick test; wheeze; basophils; histamine release; house dust mite
19.  Clinical relevance is associated with allergen-specific wheal size in skin prick testing 
Clinical and Experimental Allergy  2014;44(3):407-416.
Within a large prospective study, the Global Asthma and Allergy European Network (GA2LEN) has collected skin prick test (SPT) data throughout Europe to make recommendations for SPT in clinical settings.
To improve clinical interpretation of SPT results for inhalant allergens by providing quantitative decision points.
The GA2LEN SPT study with 3068 valid data sets was used to investigate the relationship between SPT results and patient-reported clinical relevance for each of the 18 inhalant allergens as well as SPT wheal size and physician-diagnosed allergy (rhinitis, asthma, atopic dermatitis, food allergy). The effects of age, gender, and geographical area on SPT results were assessed. For each allergen, the wheal size in mm with an 80% positive predictive value (PPV) for being clinically relevant was calculated.
Depending on the allergen, from 40% (blatella) to 87–89% (grass, mites) of the positive SPT reactions (wheal size ≥ 3 mm) were associated with patient-reported clinical symptoms when exposed to the respective allergen. The risk of allergic symptoms increased significantly with larger wheal sizes for 17 of the 18 allergens tested. Children with positive SPT reactions had a smaller risk of sensitizations being clinically relevant compared with adults. The 80% PPV varied from 3 to 10 mm depending on the allergen.
These ‘reading keys’ for 18 inhalant allergens can help interpret SPT results with respect to their clinical significance. A SPT form with the standard allergens including mm decision points for each allergen is offered for clinical use.
PMCID: PMC4215109  PMID: 24283409
allergy diagnostics; common allergens; sensitization; skin prick test
20.  Variability in Skin Prick Test Results Performed by Multiple Operators Depends on the Device Used 
The variability of skin prick test results when carried out by multiple users has not previously been assessed across different devices or between different sites on the body. Such multiuser variability has important implications for clinical practice.
We assessed the variability of measurements from 4 commonly used single-headed skin test devices when used by multiple operators and examined whether the variability in performance was different on the back compared with the forearm.
Eight adult volunteer "operators" were trained in the use of 4 devices: Greer Pick, Quintip, Stallergenes Lancet, and Feather Lancet. Each operator performed a histamine skin prick test with all devices on the backs and forearms of 5 volunteer "receivers." Variability in results was assessed using a multilevel (random effects) regression model.
After controlling for variation between users and receivers, the residual variability or "measurement error" was least for the Stallergenes Lancet, closely followed by the Quintip. The Greer Pick had the greatest variability. There was greater variability in measurements on the arm compared with the back.
The devices using the "puncture" method (Stallergenes Lancet, Quintip) provide less variability in results than those using a "prick" method when carried out by multiple users (Greer Pick and Feather Lancet). Testing on the back also gives less variable results compared with the arm.
PMCID: PMC3651175  PMID: 23282421
device; skin prick test; variability
21.  533 Viral Respiratory Infections and the Development of Atopy and Asthma 
There is an association between severe RSV bronchiolitis in early childhood, recurrent wheezing, asthma, and allergy in later childhood. And also becomes increasingly evident that other viruses such as RV, also showed association with the development of asthma. The objective of this study is to know the relationship between viral respiratory infections in the first 5 years of age and the development of atopy and asthma.
This study is a prospective follow-up study in 2 communities, 9 years after a respiratory infection study was performed. Assessment included questionnaires, physical examination, skin prick tests (SPT), pulmonary function test (PFT), and reversibility testing.
Three hundred thirty-two children, age 7 to 14 years, including 182 (54.8%) boys, were enrolled in the study. In 86 children, histories of viral respiratory infections (RSV, RV, and hMPV) were detected. The rate of positive SPT was high (81.6%), and 15 (4.5%) children showed dermatographism. The percentage of positive SPT among children with and without viral respiratory infections was almost similar (83.4% vs 85.4%). The positive SPT > 1 in children with history of viral respiratory infections was 65.9%; 5.9% with 1 positive, 27.1% with 2 to 3 positive, 20% with 4 to 5 positive and 18.8% with > 5 positive; while the positive SPT > 1 in the non viral respiratory infections was 75,3%; 9.3%, 23.9%, 30.4%, and 21.1%, respectively. The difference between those 2 groups of children was not significant (P = 0.076). History of asthma in the children with history of respiratory infections was higher compared with the non infections group (19.7% vs 8.1%). However, the spirometry results show no difference (P > 0.05) of FEV1 < 80%, FVC < 80%, FEV1/FVC < 80% and bronchodilator response > 12%, between those 2 groups.
The positive rate of SPT in the children is high, but no difference is found between history of viral respiratory infections in early life in relation to the later development of atopy and asthma. The spirometry test results show no difference between the 2 groups.
PMCID: PMC3512968
22.  370 Correlation Between Skin Prick Test and Mast Results in Patients with Chronic Rhinitis 
The World Allergy Organization Journal  2012;5(Suppl 2):S135-S136.
Among methods to confirm the allergic causes of chronic rhinitis, the most common and the most reliable method is skin prick test, followed by MAST, which is reported to be compatible to skin prick test, with acceptable sensitivity and specificity. This study was designed to confirm whether MAST is reliable test in diagnosing allergic rhinitis.
Retrospective chart review was conducted with chronic rhinitis patients who visited Yeouido St. Mary's Hospital between January 2010 and June 2011. Subjects were selected with whom the results of skin prick test and MAST were found.
One hundred and ninety three subjects, 111 male and 82 females, were included and the mean age was 30.08 (range 6∼77). MAST was performed for 42 inhalant allergens and skin prick test was performed for 56 allergens including histamine and control.
Subjects who have one or more positive allergen in skin prick test were 132, and positive in MAST were 104. Sensitivity was 63.16%, specificity was 65.57% and efficiency was 63.92%.
Number of positive allergen in skin prick test was 2.42 in average and among positive subjects, 3.53. In MAST, positive allergen count was 2.1 in average and among positive subjects, 4.0. Positive rates per common allergens in skin prick test were as follow; Dermatophagoides farinae 79.69% (106 subjects), Dermatophagoides pteronyssinus 68.42% (91 subjects), oak pollen 12.78% (17 subjects). Positive rates per common allergens in MAST were as follow; Dermatophagoides farinae 69.52% (73 subjects), Dermatophagoides pteronyssinus 59.05% (62 subjects), housedust 50.48% (53 subjects).
Skin prick test result was analyzed as from negative to 6+, according to relative size of the allergen wheal compared with histamine wheal and MAST result was analyzed as from negative to class 6, according to the concentration of the solution. When we defined correlation as difference between positive count in skin prick test and class in MAST were less than 2, the correlation rate in Df was 65.80%, 59.07% in Dp.
The correlation between MAST and skin prick test is not high enough to use MAST as a diagnostic test for allergic rhinitis. The more study to confirm the reliability of MAST should be conducted.
PMCID: PMC3512731
23.  A study on the immunological basis of the dissociation between type I-hypersensitivity skin reactions to Blomia tropicalis antigens and serum anti-B. tropicalis IgE antibodies 
BMC Immunology  2011;12:34.
Two conditions are used as markers of atopy: the presence of circulating anti-allergen IgE antibodies and the presence of positive skin prick test (SPT) reactions to allergenic extracts. The correlation between these conditions is not absolute. This study aimed at investigating immunological parameters that may mediate this lack of correlation. Individuals whose sera contained anti-B. tropicalis extract IgE antibodies (α-BtE IgE) were divided into two groups, according to the presence or absence of skin reactivity to B. tropicalis extract (BtE). The following parameters were investigated: total IgE levels; α-BtE IgE levels; an arbitrary α-BtE IgE/total IgE ratio; the proportion of carbohydrate-reactive α-BtE IgE; the proportion of α-BtE IgE that reacted with Ascaris lumbricoides extract (AlE); the production of IL-10 by BtE- and AlE-stimulated peripheral blood cells (PBMC).
Total IgE levels were similar in the two groups, but α-BtE IgE was significantly higher in the SPT-positive group (SPT+). A large overlap of α-BtE IgE levels was found in individuals of both groups, indicating that these levels alone cannot account for the differences in SPT outcome. Individuals of the two groups did not differ, statistically, in the proportion of α-BtE IgE that reacted with carbohydrate and in the production of IL-10 by BtE- and AlE-stimulated PBMC. Both groups had part of α-BtE IgE activity absorbed out by AlE, indicating the existence of cross-reactive IgE antibodies. However, the α-BtE IgE from the SPT-negative individuals (SPT-) was more absorbed with AlE than the α-BtE IgE from the SPT+ individuals. This finding may be ascribed to avidity differences of the α-BtE IgE that is present in the two groups of individuals, and could occur if at least part of the α-BtE IgE from the SPT- individuals were elicited by A. lumbricoides infection.
The present results suggest that a low ratio of specific IgE to total IgE levels (in a minority of individuals), and differences in α-BtE IgE avidities (which would have high affinities for A. lumbricoides antigens in SPT- than in SPT+ individuals) may play a role in the down-modulation of type-I hypersensitivity reaction against aeroallergens described in helminth-infected individuals.
PMCID: PMC3118201  PMID: 21631925
24.  Role of skin prick test and serological measurement of specific IgE in the diagnosis of occupational asthma resulting from exposure to vinyl sulphone reactive dyes 
Park, J | Kim, C | Kim, K | Choi, S | Kang, D | Ko, S | Won, J | Yang, J | Hong, C
OBJECTIVES—Some patients with occupational asthma resulting from exposure to reactive dyes have skin reactivity to the causative dyes and specific IgE to reactive dyes have been found in these patients. However, the usefulness of skin prick tests (SPTs) and serological measurement of specific IgE in screening, diagnosis, and monitoring the occupational asthma resulting from exposure to reactive dyes have not yet been assessed. In this study, the clinical validation of SPTs and measurement of specific IgE to vinyl sulphone reactive dyes by enzyme linked immunosorbent assay (ELISA) was evaluated.
METHODS— 42 Patients with occupational asthma from reactive dyes (true positive group) were enrolled. In these the causative reactive dye was confirmed by bronchial challenge test. 93 Asymptomatic factory workers with negative challenge to the reactive dye (true negative group) and 16 unexposed controls with negative challenge to the reactive dye were also enrolled. Skin prick tests were done with 10 mg/ml reactive dye in 0.4% phenol/0.9% saline. IgE specific to reactive dye conjugated to human serum albumin (HSA) was measured with enzyme linked immunosorbent assays (ELISAs).
RESULTS—None of the unexposed controls had a positive response to SPTs. The sensitivity (76.2% v 53.7%), specificity (91.4% v 86.0%), positive predictive value (80.0% v 62.9%), and negative predictive value (89.5% v 80.8%) of SPTs were higher than those of ELISAs. The mean weal size of reaction to reactive dye was weakly correlated with the ELISA optical density of IgE to reactive dye conjugate in patients with occupational asthma from reactive dyes (n=41, r=0.337, p<0.05). In four patients with occupational asthma from reactive dyes and eight control subjects exposed to reactive dye, IgE specific to reactive dye conjugated to HSA was detected with ELISA even though they showed negative skin reactivity. Six patients completely avoided the reactive dye for a mean (SD) 27.8 (10.3) months, IgE specific to reactive dyes decreased in all six patients (p<0.05) during this time.
CONCLUSIONS—Both SPTs and detection of IgE specific to reactive dye in serum samples could be valuable for screening, diagnosis, and monitoring occupational asthma resulting from exposure to reactive dyes. These two tests would complement each other.

Keywords: reactive dye; occupational asthma; skin prick test
PMCID: PMC1740145  PMID: 11351058
25.  293 Sensitization of Severe Allergic Asthma Patients 
The prevalence of asthma is high, the worldwide average being estimated at 10%, which makes it a public health problem. Many studies show a clear relationship between asthma and specific allergens. With sensitization to aeroallergens identified as a dominant risk factor for asthma.
The present study of asthma reports the allergic sensitization of patients with severe persistent asthma followed in the Division of Clinical Immunology and Allergy of University of São Paulo Medical School.
A total of 61 patients with severe persistent asthma defined according to the criteria of the Global Initiative for Asthma (GINA) were enrolled. Total IgE levels (IU/mL) were measured in serum and levels up to 120 IU/mL were considered within normal range. A battery of 7 aeroantigens (Dermatophagoides pteronyssinus, Blomia tropicalis, Aspergillus fumigatus, Penicillium nonatum, Lolium perenne, Felis domesticus, Canis familiaris, Blatela germanica and Periplaneta americana) was used in skin prick tests (SPTs), which were performed in each subject, on the volar side of the forearm. Histamine hydrochloride and normal saline solutions were used as positive and negative controls, respectively. The SPTs were read after 15 minutes and, a wheal at least 3 mm greater than the negative control was considered positive.
The asthmatic patients had a mean age of 48 years and 75% were female. We found that mean total serum IgE levels were 518.4 IU/mL (between 17 and 4720 UI/mL). SPTs positivity was 91.8% for D pteronyssinus, 67.2% for Blomia tropicalis, 4.9% for P nonatum and A fumigatus, 6.5% L perene and Felis domesticus, 16.3% for Canis familiaris, 21.3% Blatela germanica, 13.1% for Periplaneta americana. Twelve patients were monosensitized and 23 patients were polysensitized to 3 or more allergens.
Most patients with severe allergic asthma were polysensitized, and dust mites, followed by cockroaches, were the main allergens.
PMCID: PMC3512694

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