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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.  Prevention of pruritus with ethyl-chloride in skin prick test: a double-blind placebo-controlled prospective study 
Ethyl-chloride (EC) spray was recently shown to be an effective antipruritic agent, when given 15 min after histamine skin-prick test (SPT), without changing the wheal and flare reaction. We aimed to investigate the antipruritic effect of EC on SPT, when given prior to SPT.
A double-blind placebo-controlled prospective study. Overall, 44 volunteers underwent histamine SPT on both arms to trigger local pruritus. Prior to test, they were randomly treated with EC spray on one arm and saline spray (placebo) on the other. Subjects as well as researchers were blinded to the type of applied sprays. The wheal and flare reaction was measured after the SPT and subjects reported the intensity of pruritus following EC/placebo using a validated pruritus questionnaire (indexes 1–3) and a visual analog scale (VAS).
Significant improvement in pruritus was reported following treatment with EC compared with placebo for all four studied parameters. Index 1 in EC 3.7 ± 2.3 versus 5 ± 3.5 (p = 0.007) in placebo, index 2 in EC 2.6 ± 2.1 versus 3.8 ± 2.8 (p = 0.002) in placebo, index 3 of EC 6.3 ± 3.8 versus 8.8 ± 5.8 (p = 0.03) and VAS in EC 3.7 ± 1.9 versus 4.4 ± 2.3 (p = 0.003). There were no significant differences between EC and placebo in terms of the wheal and flare indurations area.
Ethyl-chloride has an effective antipruritic agent, when given before histamine SPT. Its use did not change the wheal and flare reaction, making it ideal for prevention of pruritus, secondary to allergy skin test, without masking the results.
PMCID: PMC4558967  PMID: 26339253
Ethyl-chloride spray; Histamine skin-prick test
3.  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
4.  Measurement and interpretation of skin prick test results 
There are several methods to read skin prick test results in type-I allergy testing. A commonly used method is to characterize the wheal size by its ‘average diameter’. A more accurate method is to scan the area of the wheal to calculate the actual size. In both methods, skin prick test (SPT) results can be corrected for histamine-sensitivity of the skin by dividing the results of the allergic reaction by the histamine control. The objectives of this study are to compare different techniques of quantifying SPT results, to determine a cut-off value for a positive SPT for histamine equivalent prick -index (HEP) area, and to study the accuracy of predicting cashew nut reactions in double-blind placebo-controlled food challenge (DBPCFC) tests with the different SPT methods.
Data of 172 children with cashew nut sensitisation were used for the analysis. All patients underwent a DBPCFC with cashew nut. Per patient, the average diameter and scanned area of the wheal size were recorded. In addition, the same data for the histamine-induced wheal were collected for each patient. The accuracy in predicting the outcome of the DBPCFC using four different SPT readings (i.e. average diameter, area, HEP-index diameter, HEP-index area) were compared in a Receiver-Operating Characteristic (ROC) plot.
Characterizing the wheal size by the average diameter method is inaccurate compared to scanning method. A wheal average diameter of 3 mm is generally considered as a positive SPT cut-off value and an equivalent HEP-index area cut-off value of 0.4 was calculated. The four SPT methods yielded a comparable area under the curve (AUC) of 0.84, 0.85, 0.83 and 0.83, respectively. The four methods showed comparable accuracy in predicting cashew nut reactions in a DBPCFC.
The ‘scanned area method’ is theoretically more accurate in determining the wheal area than the ‘average diameter method’ and is recommended in academic research. A HEP-index area of 0.4 is determined as cut-off value for a positive SPT. However, in clinical practice, the ‘average diameter method’ is also useful, because this method provides similar accuracy in predicting cashew nut allergic reactions in the DBPCFC.
Trial registration: Trial number NTR3572
PMCID: PMC4763448  PMID: 26909142
Allergy; Cut-off value; Histamine equivalent index; Mean wheal diameter; Skin prick test
5.  The Role of Helminth Infection and Environment in the Development of Allergy: A Prospective Study of Newly-Arrived Ethiopian Immigrants in Israel 
PLoS Neglected Tropical Diseases  2016;10(1):e0004208.
Helminth infection may be protective against allergy and account for the low prevalence of allergy in developing countries. We studied prospectively the prevalence of allergy in Ethiopian immigrants with heavy helminth infection on arrival in Israel, and again after a year of adjustment to an urban industrialized setting, to explore the roles of helminth infection, changed environment and background immunity on the manifestations of allergy. 126 newly arrived Ethiopian immigrants were studied at baseline and 115 after a year of follow up in Israel. Allergic symptoms, Skin prick tests (SPT), Tuberculin (PPD) skin tests, stool and blood samples were obtained for determining parasites, blood IgE and eosinophil levels, respectively. Anti-helminthic therapy was offered to the entire infected individuals, but only 50/108 (46.3%) took the medication. At baseline, there was a significant negative association between helminth infection and allergy, 4/18 (22.2%) of uninfected participants were allergic compared to 7/108 (6.5%) of helminth-infected participants (p = 0.028), as well as between helminth infection and SPT reactivity, 12/18 (66.6%) of uninfected participants compared to 43/108 (39.8%) of helminth-infected participants (p = 0.033). After one year, a significant general increase in allergy and SPT was observed. While only 11/126 (8.7%) were allergic at baseline, 30/115 (26.1%) became allergic at follow-up (p<0.0001), and while 55/126 (43.7%) were SPT+ at baseline, 79/115 (68.7%) became SPT+ at follow-up (p<0.001). A twofold increase in allergen sensitization was also observed after one year in Israel, particularly for dust mites, grasses and olive tree (p<0.001). These results show that: a) Helminth infection is significantly associated with low allergy and low SPT reactivity; b) One year after immigration to Israel, allergy and SPT reactivity increased significantly in all immigrants; c) Higher increases in positive SPT and allergy were observed after a year in the group that remained infected with helminths, even though they had a lowered helminth load; d) The reasons for the increased allergy one year after immigration needs further investigation but probably reflects the combined influence of the decreased helminth load and novel environmental factors.
Author Summary
The role of intestinal parasitic infections in allergy is of great interest since it has been suggested that they suppress the development of allergy. Urbanization has also been claimed to cause allergy because of air pollution and higher exposure to allergens. The present study took advantage of the special opportunity presented by the recent Ethiopian immigration to Israel in order to study this question. A cohort of newly arrived Ethiopian immigrants to Israel, highly infected with parasites, was studied prospectively for the presence of allergy and response to allergens on arrival and after a year of follow up in Israel. The results showed clearly a significant inverse association between the presence of parasitic infections and allergy on arrival, while after a year of living in Israel, accompanied by a lowered parasitic infection load, a general increase of allergy was observed in all immigrant groups, and not only in those that had parasitic infections on arrival. These results lend support to the suppressive effect of intestinal parasites on allergy, but suggest that additional factors, most probably environmental, also play a role in the generation of allergy.
PMCID: PMC4709081  PMID: 26752538
6.  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
7.  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
8.  The Lancet Weight Determines Wheal Diameter in Response to Skin Prick Testing with Histamine 
PLoS ONE  2016;11(5):e0156211.
Skin prick test (SPT) is a common test for diagnosing immunoglobulin E-mediated allergies. In clinical routine, technicalities, human errors or patient-related biases, occasionally results in suboptimal diagnosis of sensitization.
Although not previously assessed qualitatively, lancet weight is hypothesized to be important when performing SPT to minimize the frequency of false positives, false negatives, and unwanted discomfort.
Accurate weight-controlled SPT was performed on the volar forearms and backs of 20 healthy subjects. Four predetermined lancet weights were applied (25 g, 85 g, 135 g and 265 g) using two positive control histamine solutions (1 mg/mL and 10 mg/mL) and one negative control (saline). A total of 400 SPTs were conducted. The outcome parameters were: wheal size, neurogenic inflammation (measured by superficial blood perfusion), frequency of bleeding, and the lancet provoked pain response.
The mean wheal diameter increased significantly as higher weights were applied to the SPT lancet, e.g. from 3.2 ± 0.28 mm at 25 g to 5.4 ± 1.7 mm at 265 g (p<0.01). Similarly, the frequency of bleeding, the provoked pain, and the neurogenic inflammatory response increased significantly. At 265 g saline evoked two wheal responses (/160 pricks) below 3 mm.
Conclusion and clinical relevance
The applied weight of the lancet during the SPT-procedure is an important factor. Higher lancet weights precipitate significantly larger wheal reactions with potential diagnostic implications. This warrants additional research of the optimal lancet weight in relation to SPT-guidelines to improve the specificity and sensitivity of the procedure.
PMCID: PMC4877047  PMID: 27213613
9.  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
10.  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
11.  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
12.  Astemizole, a potent histamine H1-receptor antagonist: effect in allergic rhinoconjunctivitis, on antigen and histamine induced skin weal responses and relationship to serum levels. 
The efficacy of astemizole, a new, long acting, oral histamine H1-receptor antagonist was compared to placebo for the treatment of allergic rhinitis and conjunctivitis during the grass pollen season of 1982. Sixty-three patients with a positive skin prick test to grass pollen and current symptoms participated in an 8 week, double-blind, randomized study. Astemizole, 10 mg, was significantly better than placebo in alleviating both nose (P less than 0.05) and eye (P less than 0.01) symptoms despite significantly greater use of the reserve medication, clemastine, by the placebo group (P less than 0.003). There was a lag period of 5 days after initiation of therapy before treatment benefit became manifest. Subdivision of nasal symptoms indicated significant improvement compared to placebo over the 8 weeks for sneezing (P less than 0.05) and runny nose (P less than 0.05) but not blocked nose. The absence of effect on nasal blockage was confirmed by parallel measurement of nasal calibre by body plethysmography. The antihistaminic potency of astemizole was indicated by an 80% inhibition of the histamine induced skin weal response after 8 weeks therapy. A positive correlation was found between serum drug levels and % inhibition of histamine skin weal (r = 0.64, P less than 0.001). Astemizole was free from adverse sedative or anticholinergic effects but did cause a mean increase in weight of 1.3 kg (P less than 0.01) after 8 weeks therapy, not found with placebo.
PMCID: PMC1463581  PMID: 6146346
13.  Are allergen batch differences and the use of double skin prick test important? 
Skin prick tests (SPT) are widely used both in clinical diagnostics and in research. The standardization of allergen extracts is well documented to be crucial for the validity of SPT, whereas less emphasis has been placed on reproducibility and the SPT procedure itself. The objectives of this study are to clarify how the double skin prick test procedure influence the sensitivity and specificity of the test and to analyse the differences in weal size in skin prick tests between two batches of allergen extracts from the same vendor.
The association between rhinitis and SPT was assessed among 1135 persons from a general population sample. SPT was performed twice with 10 common aeroallergens. In a subsample of 90 persons SPT was performed simultaneously with five of the allergens using different batches.
Thirty percent had at least one positive SPT. Among asthmatics this number was 62%. Only minor differences were seen between the sizes of two weals from the same batch. A second SPT with the same batch did not change the association between rhinitis and sensitization. When performing SPT with two different batches disagreement was observed in 2% (Birch) to 11% (Cat) of the subjects.
Performing SPT twice with the same allergen batch does not enhance the validity of the test, and value of double testing can be questioned. Considerable differences in SPT response with different batches from the same manufacturer were observed. Thus inter batch differences in allergen extracts might be a source of variability.
PMCID: PMC4397883  PMID: 25886946
Skin prick test; Aeroallergens; Population based study; Validity; Rhinitis
14.  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
15.  Optimizing diagnostic tests for persulphate-induced respiratory diseases 
Persulphates from hair bleaching products are considered the major cause of occupational-rhinitis and asthma in hairdressers. The specific inhalation challenge (SIC) is considered ‘reference standard’ for diagnosing persulphate-induced asthma and rhinitis; however, the currently validated method of performing SIC with persulphate powder is time consuming with a duration of up to 4 days. The value of skin prick tests (SPTs) and histamine release tests (HRTs) with persulphates is unknown. The aim of this study was to establish a novel rapid SIC with persulphate powder to test for both rhinitis and asthma simultaneously in 1 day. In addition, we assessed the suitability of SPTs and HRTs for detecting persulphate-induced respiratory diseases.
The study population included 19 hairdressers with a history of work-related rhinitis and/or asthma symptoms, 12 symptomatic controls (10 with concurrent allergic asthma and rhinitis and two with non-allergic asthma), and 40 healthy controls. A previous severe asthmatic reaction and/or anaphylactic reaction to persulphates was considered an exclusion criterion for hairdressers. The 19 hairdressers and 12 symptomatic controls had SIC performed with 3 × 5 min exposures to potassium persulphate powder in a provocation chamber. All participants, including the 40 healthy controls, were subjected also to SPTs and HRTs with three persulphate salts at concentrations of 2–20 % and 0.03–1 %, respectively.
None of the symptomatic controls had a nasal or bronchial response to SIC with potassium persulphate. Six hairdressers presented a nasal and two a bronchial response. No severe reactions occurred. No positive SPTs were recorded, neither among hairdressers, symptomatic controls, nor healthy controls. All three groups showed nonspecific non-IgE mediated histamine release to persulphates in HRT.
The proposed method for performing SIC showed a high specificity for detecting persulphate-induced asthma and rhinitis. The rapid SIC was able to produce positive nasal and bronchial responses in symptomatic hairdressers without any severe reactions occurring. SPTs and HRTs cannot predict asthma or rhinitis caused by persulphates.
PMCID: PMC4955245  PMID: 27446529
Specific inhalation challenge; Persulphates; Persulphate salts; Histamine release test; Skin prick tests; Occupational asthma; Occupational rhinitis
16.  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
17.  Inhibition of allergen-induced wheal and flare reactions by levocetirizine and desloratadine 
To evaluate the inhibitory activity of the new-generation antihistamines levocetirizine and desloratadine at their therapeutic doses on the allergen-induced wheal and flare reaction at 1.5 h, 4 h, 7 h, 12 h and 24 h postdose, and to measure their plasma and skin concentrations.
A double-blind, randomized, cross-over, placebo-controlled study in 18 allergic subjects was carried out. The time–response of the wheal and flare reaction areas under the curve (AUC) were compared by anova.
Both antihistamines significantly (P < 0.001) inhibited the allergen-induced wheal and flare reactions compared with placebo. Levocetirizine was significantly more potent than desloratadine. Mean ± SEM wheal AUC(0–24 h) was 506.4 ± 81.0 with levocetirizine and 995.5 ± 81.0 mm2 h with desloratadine as compared with placebo (1318.5 ± 361.0 mm2 h). Flare AUC(0–24 h) was 5927.3 ± 1686.5 and 15838.2 ± 1686.5 mm2 h, respectively [P < 0.001 for both compared with placebo (22508.2 ± 7437.1 mm2 h)]. Levocetirizine showed significant inhibition of wheal and flare already at 1.5 h postdose compared with placebo (P ≤ 0.001); desloratadine achieved a significant effect only after 4 h. The mean total plasma concentration at 12 h and 24 h after intake was higher for levocetirizine (58.1 ± 13.4 and 20.0 ± 8.1 ng ml−1, respectively) as compared with desloratadine (0.82 ± 0.24 and 0.45 ± 0.16 ng ml−1). Similarly, higher mean unbound skin concentrations were observed for levocetirizine 24 h after intake (1.80 ng g−1) than for desloratadine (0.07 ng g−1). This was associated with greater receptor occupancy for levocetirizine (54%) than desloratadine (34%) at 24 h.
Levocetirizine suppressed the cutaneous allergic reactions with a higher potency than desloratadine, which correlated with its high receptor occupancy. Receptor occupancy rather than drug affinity or plasma half-life is more representative of antihistamine potency.
What is already known about this subject The reproducible and standardized histamine-induced wheal and flare model helps identify the objective effectiveness of antihistamines in humans, as well as their differences in onset and duration of action.Some of the newest antihistamines have already been compared in a head-to-head setting using this model. However, their objective action at inhibiting the allergen-induced wheal and flare response has not been reported yet.
What this study adds The time–response study presented here shows the objective activity of two of the newest generation of antihistamines, levocetirizine and desloratadine, at inhibiting the allergen-induced wheal and flare response in a randomized, cross over, placebo-controlled trial.This model is interesting to the clinical setting since allergic subjects are recruited, and the response to allergen involves mast cell degranulation and release of numerous vasoactive and pro-inflammatory mediators additionally to histamine.In addition, this study reports receptor occupancy for both antihistamines at therapeutic dosage, leading to analysis of potential differences in activity.This study clearly shows the potential anti-inflammatory properties of desloratadine and levocetirizine in their skin activity when allergen is the challenging agent as occurs in the clinical situation.
PMCID: PMC2253696  PMID: 17953719
allergen; antihistamine; desloratadine; levocetirizine; pharmacokinetics; skin; wheal and flare reactions
18.  Non-invasive instrumental techniques to detect terfenadine and temelastine induced suppression of histamine weals in man. 
1. The effectiveness of chronic dosing with temelastine (SK&F 93944) 75 mg twice daily and terfenadine 60 mg twice daily compared with placebo in inhibiting the weal and flare response to intradermal histamine was assessed using non-invasive objective assessment techniques. 2. The mean weal thickness, as measured by the A-scan pulsed ultrasound device, was significantly decreased by both temelastine and terfenadine when compared with placebo. 3. There was a significant reduction in both the areas of the weal and the weal and flare, as measured by a digitizing tablet linked to a microcomputer, following treatment with temelastine and terfenadine compared with placebo and also between temelastine and terfenadine. 4. No significant difference was found in blood flow in the weal or flare as measured by the laser doppler flowmeter among any of the groups tested. 5. The ultrasound and digitizer techniques aid objectivity and precision in the investigation of the effects of drugs on histamine induced weals. 6. Temelastine and terfenadine were found to possess antihistaminic effects on histamine induced weal and flare in the skin.
PMCID: PMC1386301  PMID: 2891368
19.  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
20.  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
21.  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
22.  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
23.  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
24.  Facial thermography is a sensitive tool to determine antihistaminic activity: comparison of levocetirizine and fexofenadine 
To assess the antihistaminic activity of levocetirizine and fexofenadine 2 h and 24 h after drug administration using facial thermography and to compare the results with those using well-established parameters of antihistaminic activity in the nose and skin.
This was a randomized, double-blind, three-treatment, three-period, single-dose, cross-over study in healthy males taking levocetirizine 5 mg, fexofenadine 120 mg or placebo. The primary endpoint was nasal skin temperature after nasal histamine challenge recorded for 20 min at 2 and 24 h after drug intake. The secondary endpoints were nasal symptoms and a histamine skin prick test.
Thirty subjects were randomized. At 2 h after drug intake the inhibition of the nasal temperature increase from baseline was not significantly different between levocetirizine and fexofenadine. At 24 h it was significantly more pronounced after levocetirizine than fexofenadine (difference: least-squares mean: −0.13 °C; P ≤ 0.024, 95% CI −0.24, −0.02). Both drugs significantly reduced (P≤ 0.001) the mean temperature increase from baseline compared with placebo at 2 and 24 h (least-squares mean increase and (95% CI): levocetirizine, −0.28 °C (−0.42, −0.14) and −0.32 °C (−0.43, −0.21); fexofenadine −0.35 °C (−0.49, −0.21) and −0.19 °C (−0.30, −0.08), respectively). Results of nasal symptom score and wheal and flare were consistent with the thermography results.
Facial thermography is an objective, non-invasive and sensitive method to study antihistaminic activity at the nose level. Levocetirizine and fexofenadine demonstrate the same activity at 2 h after drug intake, but levocetirizine has a more sustained activity at 24 h.
PMCID: PMC1885088  PMID: 16842390
facial thermography; fexofenadine; healthy subjects; levocetirizine; nasal histamine provocation; nasal skin temperature; wheal and flare
25.  Comparative Study of Positive Versus Negative Autologous Serum Skin Test in Chronic Spontaneous Urticaria and its Treatment Outcome 
Chronic urticaria (CU) is defined as urticaria persisting daily or almost daily for more than 6 weeks and affecting 0.1% of the population. Mast cell degranulation and histamine release are of central importance in the pathogenesis of CU. About 40-50% of the patients with chronic idiopathic urticaria (CIU) or chronic spontaneous urticaria (CSU) demonstrates an immediate wheal and flare response to intradermal injected autologous serum. This led to the concept of autoimmune urticaria (AIU).
To determine the occurrence, clinical features, associated clinical conditions, comorbidities of AIU, and to compare this with CSU. This study aimed to find the frequency of autologous serum skin test (ASST)-positive patients among patients with CSU and to identify the clinical and laboratory parameters associated with positive ASST and to compare the treatment outcome.
Materials and Methods:
A prospective correlation study in 110 patients with CSU was conducted, after screening 200 CU patients attending the outpatient Department of Dermatology during from January 2012 to May 2013. Patients were subjected to ASST, complete blood counts, urine routine examination, liver function tests, renal function tests, thyroid function tests (T3, T4, and TSH), and urine analysis.
Out of 200 CU patients screened, 90 patients had excludable causes based on detailed history and skin prick test, and the remaining 110 patients were considered to have CSU. These 110 patients were further subjected to ASST, serum immunoglobulin E (IgE), and peripheral blood eosinophilia. ASST was positive in 48 patients and negative in 62 patients. Frequency of urticarial attacks and associated diseases such as abnormal thyroid function tests in both ASST-positive and ASST-negative patients did not show any statistical significance. Only attacks of angioedema in ASST-positive individuals were higher and were statistically significant. In the ASST-positive group, 31 (81.25%) patients showed improvement with first-line antihistamines, along with oral prednisolone and injection Histaglobulin and 10 (10.41%) patients did not show any improvement. Thirty-three (43.54%) patients in the ASST-negative group showed improvement while 13 (30.62%) patients did not show improvement.
ASST is considered a screening test for AIU, which decreases the rate of diagnosis of idiopathic form of CU. ASST-positive patients in addition to antihistamines, were treated with short course of oral steroids and weekly Histaglobulin injections for 5 weeks followed by the 3rd and 6th months.
PMCID: PMC4784180  PMID: 27011944
Autoimmune; autologous serum skin test; chronic spontaneous urticaria (CSU)

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