Marihuana Allergy: Beyond the Joint

Full text

J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82© 2015 Esmon Publicidad
PRACTITIONER'S CORNER
Allergen Characterization of Chia Seeds
(Salvia hispanica), a New Allergenic Food
García Jiménez S1, Pastor Vargas C2, de las Heras M3, Sanz Maroto
A2, Vivanco F2, Sastre J3
1Immunology Department, Fundación Jiménez Díaz-IDC Salud,
Madrid, Spain
2Immunology Department, Instituto de Investigación Sanitaria de
la Fundación Jiménez Díaz, Madrid, Spain
3Allergy Department, Fundación Jiménez Díaz-IDC Salud,
Madrid, Spain
Key words: Occupational asthma. Sodium metabisulphite. Seafood
allergy. Squid.
Palabras clave: Asma ocupacional. Metabisulfito sódico. Alergia
pescados. Calamari.
Salvia hispanica, known also by its popular name, chia,
is a plant of the Lamiaceae family. The plant is considered a
pseudocereal and has a high oil and protein content. Mayans
and Aztecs used it as a medicinal product and food supplement
for added endurance. Its nutraceutical properties are due
to high content in dietary ber, natural antioxidants, and
unsaturated fatty acids (60% α-linolenic acid). The protein
content of chia is higher than that of most traditional grains.
The plant contains storage proteins such as11S globulin (also
known as α-conglutin, legumin, and glycinin), 7S globulin
(also known as β-conglutin, vicilin, convicilin, and vicilin-
type), 7S basic globulin (also known as γ-conglutin), and 2S
sulphur-rich albumin (also known as δ-conglutin). The rest of
the proteins are albumins, prolamins, glutelins, and insoluble
proteins [1]. Although chia is not well known as a dietary
supplement, its global production has increased in recent years
due to its health properties and growing popularity.
To our knowledge, there are no cases in the medical
literature describing allergic reactions due to chia seeds.
There have, however, been a few cases of hypersensitivity
reactions to plants from the same family (Lamiaceae),
including anaphylaxis induced by menthol in toothpaste [2],
contact dermatitis due to Salvia ofcinalis extract in cosmetic
products [3], and a systemic allergic reaction following the
ingestion of oregano and thyme [4]. In this article, we describe
an anaphylactic reaction to chia seeds and characterize its
allergens.
We report the case of a 54-year-old man with a previous
diagnosis of rhinitis and asthma with sensitization to grass
pollen and cat dander. A few days after starting to consume
chia seeds—as a recommended means of lowering cholesterol
levels—the patient noticed pruritus in his mouth and on the
third day he developed generalized urticaria, and experienced
facial angioedema, shortness of breath, and dizziness. He
required emergency medical treatment to recover from these
symptoms. He was evaluated in our outpatient clinic 2 weeks
after the most recent episode. Skin prick tests were positive
for allergy to pollen (grass, cypress, plane), prolin, and cat
dander (ALK). Skin prick testing was negative for sesame,
puried lipid transfer protein (Bial), and other commercial
food extracts. The patient’s tryptase levels were normal. Total
IgE was 1592 kU/L. Prick-prick testing with chia seeds was
positive (5x6 mm). Specic IgE results (in ISU units) (ISAC,
Thermo Fisher Scientic) were as follows: rPhl p 1, 33; rPhl
p 2, 50; rPhl p 4, 5.9; rPhl p 5, 0.6; nCyn d 1, 8; nCup a 1, 37;
nCryj 1, 7.9; rFel d 1, 3.1; rVes v 5, 3.3; rPol d 5, 6; rBet v 2, 6.7;
rHev b 8, 7.4; rMer a 1, 9.5; rPhl p 12, 2.7. The results for
the rest of the allergens, including Ses a1, were negative. The
ImmunoCAP results were <0.35 k/UL for Thymus vulgaris
and Menta piperita, 0.43 k/UL for Salvia ofcinalis, and 0.61
for Origanum majorana. The patient reported no reactions to
hymenoptera stings and stated that he had only experienced
oral pruritus on eating sesame seeds, but not on all occasions.
Chia extract was prepared from the seeds of a commercial
product. The seeds were dissolved in phosphate buffered saline
and the proteins were extracted overnight at 4ºC with constant
stirring. After centrifugation at 15000 g for 15 minutes, the
supernatant (water soluble extract [WSE]) was collected. The
pellet fraction was resuspended in water and stirred for 1 hour
at 4ºC to remove any residual salt, and then centrifuged for 10
minutes at 15000 g. The pellet fraction was stirred for 1hour
in 70% (vol/vol) aqueous ethanol at 4ºC and centrifuged. The
supernatant was designated as the liposoluble extract (LE).
The WSE was dialyzed against 100 mM NH4HCO3 and later
lyophilized. The LE extract was concentrated and puried using
the Amicon system (Milipore). The protein concentration was
determined according to the method published by Bradford.
SDS-PAGE, immunoblot, and identication of proteins by
tandem mass spectrometry (MS/MS) were performed as
previously described [5]. MS/MS analysis was performed in
the proteomics department of the Universidad Complutense in
Madrid (Spain), a member of the ProteoRed Network. SDS-
PAGE of chia extracts revealed multiple protein bands with
an apparent molecular weight ranging from 15 to 60 kDa and
a common band around 31 kDa (Figure A,B). The liposoluble
chia extract showed 3 IgE-binding bands with molecular sizes
of around 15, 17, and 29 kDa (Figure A). The water-soluble
chia extract showed 2 IgE-binding bands with molecular sizes
around 25 and 46 kDa (Figure B). A common band around
31 kDa was detected in both extracts. The peptide sequences of
the 29-kDa protein (LE) yielded a high match with lectins from
related species such as Phaseolus coccineus and Phaseolus
vulgaris, with a match identity of around 86% (Figure C).
Peptide sequences of the 46-kDa IgE-binding band (WSE)
exhibited a high degree of homology with elongation factor
Tu from species such as Medicago trucantula, with a match

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82 © 2015 Esmon Publicidad
IgE-Binding Peptide Sequence Identication Amino Acid Amino Acid
Band Similarity Similarity and
Conserved Substitution
29 kDa (LE) AVEFDTLYNTNDPNYR LECTIN 12/14 (86%) 12/14
with Phaseolus coccineus (85%)
and Phaseolus vulgaris
46 kDa (WSE) FDAEVYVLSKEEGGR ELONGATION 12/15 (80%) 15/1S
FACTOR TU with Medicago truncatula (100%)
31 kDa (WSE) ESWDPNMR 11S GLOBULIN 6/8 (75%) 6/8
(Cupin-1) with Ricinus communis, (75%)
Quercus robur, Ficus
pumila and Juglans regia
19 and GLDIDPYALLR No
17 kDa (LE) VADIDPYAEPR No
25 kDa (WSE) No sequence found No
identity of around 80% (Figure C). Peptide sequences of the
31-kDa IgE-binding band exhibited a high degree of homology
with a legumin precursor (11S globulin) from species such as
Ricinus communis, Quercus robur, Ficus pumila, and Juglans
regia, with an identity match of around 75% (Figure C). No
signicant homologies were found for 25-, 17-, or 19-kDa
IgE-binding proteins.
In summary, we have described the rst case of an IgE-
mediated anaphylactic reaction induced by chia seeds. The
allergens involved are water-soluble and liposoluble and
include a lectin, an elongation factor, and an 11S globulin as
known allergens in addition to another 3 as yet undescribed
allergens. Based on the negative IgE determinations to
legumins, vicillins, and conglutins included in the ISAC
platform [6] (Ana o 2, Ber e 1, Cor a 9, Cor a 14, Jug r 1,
Jug r 2, Sesi 1, Ara h 1, Ara h 2, Ara h 3, Ara h 6, Gly m 5,
Gly m 6, and Fag e 2), we suggest that the chia allergens
described have no cross-reactivity with these proteins.
Acknowledgments
Oliver Shaw for editorial assistance.
Funding
This study was partly funded by the Instituto de
Investigación Sanitaria-Fundación Jimenez Diaz, Madrid,
Spain.
Conicts of Interest
Joaquín Sastre has served as a consultant to Thermo
Fisher Scientific, Schering-Plough, Merck, FAESFarma,
Novartis, Roche, Sano, Gennetech, and GlaxoSmithKline;
has been paid speaker fees by Novartis, GSK, Stallergenes,
FAESFARMA, and UCB; and has received grant support from
Thermo Fisher Scientic, GlaxoSmithKline, and ALK-Abelló.
None of above relationships had any inuence on this research.
The other authors declare that they have no conicts of interest.
References
1. Sandoval-OlverosMR, Paredes-López O. Isolation and
characterization of proteins from chia seeds (
Salvia hispanica
).
J Agric Food Chem. 2013;61:193-201.
2. Paiva M, Piedade S, Gaspar A. Toothpaste-induced anaphylaxis
caused by mint (Mentha) allergy. Allergy. 2010: 65(9):1201-2.
3. Mayer E, Gescheidt-Shoshany H, Welfriend S. Allergic contact
dermatitis caused by Salvia Ofcinalis extract. Contact
Dermatitis. 2011;64:237-8.
4. Benito M, Jorro G, Morales C, Peláez A, Fernández A. Labiatae
allergy: systemic reactions due to ingestion of oregano and
thyme. Ann Allergy Asthma Immunol. 1996,76: 416-8.
5. Pastor C, Cuesta-Herranz J, Cases B, Pérez-Gordo M, Figueredo
E, de las Heras M, Vivanco F Identication of majorallergens in
watermelon. Int Arch Allergy Immunol. 2009;149:291-8.
6. Sastre J. Molecular diagnosis in allergy. Clin Exp Allergy.
2010;40(10):1442-60.
Figure. A, Liposoluble fraction from
Salvia hispanica
. Lane 1,SDS-PAGE immunoblots of liposoluble extract under reducing conditions. Lane 2, Patient
serum. Lane 3, Control serum. B, Water-soluble fraction from
Salvia hispanica
. Lane 1,SDS-PAGE immunoblots of water-soluble extract under reducing
conditions. Lane 2, Patient serum. Lane 3, Control serum. C, Identication of peptides from IgE-binding proteins by mass spectrometry. MW indicates
molecular weight; LE, liposoluble extract; WSE, water-soluble extract.
A C
3MW
116
97
45
31
21
14
1 2
B3MW
116
97
45
31
21
66
1 2
Manuscript received November 24, 2013; accepted for
publication, March 5, 2014.
Joaquín Sastre
Servicio de Alergia
Fundación Jiménez Díaz
Av. Reyes Católicos 2
28040 Madrid, Spain
E-mail: jsastre@fjd.es
56

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82© 2015 Esmon Publicidad
Domestic Mites on the Hair/Scalp, Pillows, and
Mattresses of Mite-Sensitized Children in a
Subtropical Area
Iraola V1, Carrillo-Díaz T2, Cruz-Niesvaara D2, García-Dumpiérrez
A2, Suarez Lorenzo I2, Hernández Suarez H2, Fernández-Caldas E1
1R&D Department, Laboratorios LETI, Tres Cantos, Spain
2Allergy Unit, Hospital Universitario Dr. Negrín, Las Palmas de
Gran Canaria, Spain
Key words: Domestic mites. Dermatophagoides. Allergen exposure.
Human hair.
Palabras clave: Ácaros domésticos. Dermatophagoides. Exposición a
alérgenos. Pelo.
Mites have colonized most ecological systems of the world,
including human habitats, where they exist as parasites or live
in human dwellings. House dust mites (HDMs) are currently
Table. Mite species, Mite Population, and Allergen Levels in Hair/Scalp, Pillow, and Mattress Samples
Hair (n=43) Pillow (n=42) Mattress (n=43)
Positive Geometric mean Positive Geometric mean Positive Geometric mean
Samples No. of mites Samples No. of mites or Samples No. of mites or
(%) (%) mg allergen (%) mg allergen
per sample per gram per sample per gram per sample per gram
Total Mites 81.4 3.87 783.7 92.9 130.5 2020.0 97.7 495.6 864.1
Dermatophagoides
pteronyssinus 81.4 3.65 737.9 92.9 103.6 1603.0 95.4 360.6 645.9
Dermatophagoides
farinae 2.3 2 714.3 19.1 13.7 199.5 27.9 88.4 200.7
Euroglyphus maynei 7.0 1 131.4 23.8 44.4 515.1 23.3 62.5 114.2
Blomia tropicalis 2.3 1 454.5 14.3 32.0 314.5 32.6 106.6 161.2
Tyrophagus
putrescentiae 7.0 1 224.2 7.1 6.2 100.3 9.3 36.4 81.8
Chortoglyphus arcuatus 2.4 11.6 37.7 2.3 883.5 575
Histiostoma feroniarum 2.4 12.1 59.9
Lepidoglyphus
destructor 4.7 9.7 82.4
Suidasia reticulata 4.7 38.9 47.9
Carpoglyphus sp. 2.3 14.1 32
Cheyletus spp. 2.3 1 61 9.5 12.5 78.4 32.6 41.2 58.7
Tarsonemus spp. 4.8 33.7 73.6 14.0 56.9 104.8
Prostigmata 2.4 4.3 47.8
Oribatida 2.4 32.7 54.3 2.3 304.6 328.4
Mesostigmata 4.7 12.2 32
Der p 1 100 1.6 15.2 100 7.9 13.5
Der f 1 96.6 1.1 8.0 82.9 3.3 8.1
the most common species in indoor environments because
the environmental conditions of this habitat have evolved to
become drier and cleaner, and skin scales are now the most
abundant organic component in domestic dust. HDMs are able
to feed on skin scales, an inheritance from their ancestors living
in bird nests [1], and therefore have practically no competitors
for food in homes [2].
Records of HDMs on skin predate those of HDMs in
domestic dust, and the rst report was of Dermatophagoides
pteronyssinus on the skin of individuals with scabies [3].
Since then, different mite species, and particularly HDM
species, have been reported on human skin, mainly in
patients with dermatitis [4]. It is now generally accepted
that mites are simple bystanders that feed on the slough
from skin scales [5].
Of particular interest was the discovery of mites on the
hair and scalp of asthmatic children in tropical regions [6,7].
The clinical signicance of this nding has, however, been
questioned [8], since extrapolation of mite numbers to grams
of dust overestimates exposure. However, the presence of
mites on hair could be important in terms of transfer and
contamination of the human environment.
57

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82 © 2015 Esmon Publicidad
The objectives of this study were to evaluate the presence
of mites on the hair/scalp of mite-allergic children and to
determine the correlation with the mite population on the
children’s pillows and mattresses.
Forty-three boys aged 4 to 18 years (mean age, 7.2 years)
with positive skin tests to D pteronyssinus were selected at
the allergy unit of Hospital Dr. Negrín in Las Palmas de Gran
Canaria, Spain. All the children had rhinitis and 31 (72.1%) had
asthma. None had atopic dermatitis. The study was approved
by the ethics committee of the hospital, and informed oral
consent was obtained from the children and their parents or
legal representatives.
The children’s hair was vacuumed for 1 minute with
a standard 2000-W vacuum cleaner equipped with a dust
trap and a paper lter. The children were asked not to wash
their hair for 3 days prior to collection of the samples. Dust
samples were collected from pillows and mattresses by
vacuuming the entire surface for 1 minute. After collection,
the samples were weighed and separated into 50-mg aliquots
to determine mites and allergens, following a previously
described method [9]. When the weight of the sample
was less than 50 mg, the entire sample was used for mite
determination. Allergens were quantied using monoclonal
antibody kits (Indoor Biotechnologies) according to the
manufacturer’s instructions. Hair, pillow, and mattress
samples were obtained from all children except 1, who had
no pillow. Allergens were not evaluated in hair/scalp samples
or in 13 pillows due to the small amount of dust collected.
The mean (SD) weight (g) of the samples was 0.008 (0.002)
for hair/scalp, 0.139 ( 0.025) for pillows, and 0.822 (0.115)
for mattresses.
The results were expressed as µg of allergen or number
of mites per 1) gram of dust or 2) amount of dust collected
in the sample. This second analysis does not extrapolate to
grams of dust and reects the allergen and mite content in the
collected sample.
The Spearman rank order test was used to determine the
correlation between variables. A P value of less than .05 was
considered statistically signicant.
The Table shows the results obtained. Sixteen mite species
were identied. The most frequent species in the 3 habitats was
D pteronyssinus. Worthy of note was the presence of intact
adults and immature forms of D pteronyssinus on the hair/scalp
and the presence of Blomia tropicalis in high numbers on
mattresses but not on the hair/scalp.
Positive correlations were found between the number of
D pteronyssinus on the hair/scalp and on pillows or mattresses.
This correlation was signicant on pillows when analyzed
per sample (r=0.363, P=.018) and on mattresses (r=0.441,
P=.004) when the results were extrapolated to grams of dust.
No correlation was found for other mite species (P>.05).
Positive and signicant correlations were found between
mite numbers on pillows and mattresses for D pteronyssinus,
Dermatophagoides farinae, and Euroglyphus maynei
regardless of how the results were expressed (P<.05). A
positive and signicant correlation between mite populations
and allergen levels when results were expressed per sample
was found on pillows for D pteronyssinus-Der p 1 (r=0.567,
P<.001) and for D farinae-Der f 1 (r=0.475, P=.032). However,
when results were extrapolated to grams, this correlation
remained signicant only for D farinae-Der f 1 (r=0.601,
P<.001). Hair/scalp mites were not correlated with allergen
levels on mattresses or pillows.
Our results conrm that the human hair/scalp is a suitable
habitat for dust mites [6,7], and for Dermatophagoides
species in particular. This may be due to morphological
adaptations stemming from the mite's parasitic ancestors [10].
We compared results expressed per gram of dust and per
sample, and found the results varied greatly depending on
the estimation method used. When the weight of samples is
less than 0.5 g, extrapolating results per gram of dust leads to
exaggerated estimates of mite and allergen levels [9].
The presence of immature D pteronyssinus in hair/scalp
samples suggests that the mites were alive when the samples
were collected, and the significant association between
D pteronyssinus on the hair/scalp and on pillows and mattresses
indicates that transfer may occur between these surfaces and
that hair could act as a reservoir. Other studies have found no
correlation between mites on the skin and on bedding [4], but
this discrepancy may be due to a closer association between
the head and pillows, facilitating the transfer of mites from
hair to pillow and vice versa.
In conclusion, our results support the importance of the
hair/scalp as a contaminating source of mites. However, its
importance as a source of allergens is more difcult to ascertain.
Although we did not determine allergens in hair samples, the
small quantity of mites suggest low allergen levels, which
would conrm previous ndings [8]. More studies are needed
to verify the clinical signicance of these results.
Funding
The authors declare that no funding was received for the
current study.
Conicts of Interest
The authors declare that they have no conicts of interest.
Previous Presentation
Part of these results were presented on a poster at the XIX
European Congress of Allergy and Clinical Immunology in
Lisbon, Portugal in July 2000.
References
1. O’Connor BM. Evolutionary origins of Astigmatid mites
inhabiting stored products. Recent advances in Acarology
Academic Press Inc. 1979; 1: 273-8.
2. Crowther D, Wilkinson T. House dust mites. In: Public Health
Signicance of Urban Pests. Bonnefoy X, Kampen H, Sweeney
K (Eds). Bonn: World Health Organization. 2008: 85-130.
3. Bogdanov A. Deus acariens trouvés par M. Scheremetevsky
sur l’homme. Bull Soc Imp Natur Moscou. 1864; 37: 341-5.
4. Teplitsky V, Mumcuoglu KY, Babai I, Dalal I, Cohen R, Tanay
A. House dust mites on skin, clothes, and bedding of atopic
dermatitis patients. Int J Dermatol. 2008; 7: 790-5.
58

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82© 2015 Esmon Publicidad
Occupational Asthma in Seafood Manufacturing and
Food Allergy to Seafood
Uriarte SA1, Fernández-Nieto M1,2, Arochena L1, Sastre J1,2
1Fundación Jiménez Díaz, Allergy Department, Madrid, Spain
2CIBER de Enfermedades Respiratorias, Instituto de salud,
Carlos III, Spain
Key words: Occupational asthma. Sodium metabisulphite. Seafood
allergy. Squid.
Palabras clave: Asma ocupacional. Metabisulto sódico. Alergia a
mariscos. Calamar.
Fish and seafood are valuable sources of allergenic
proteins, and large quantities of fresh and packaged products
are consumed worldwide. To preserve nutrients and ensure
proper conservation, a number of chemicals such as sodium
metabisulphite are used as preservatives and nutrients during
manufacture and packaging.
A 38-year-old woman with latex allergy and contact
dermatitis to black rubber, carba, and thiuram who had been
working as a seafood-packing assistant for 10 years was seen
at our clinic. Her duties consisted of handling squid, octopus,
shrimp, cod, and catsh while wearing nitrile gloves. These
food items were removed from baskets, weighed on scales,
and put in iceboxes to which sodium metabisulphite was added
as a chemical treatment for conservation. She worked 5 days
a week, 8 hours a day, and never used protective clothing or
a mask at work.
She had experienced chest tightness, wheezing, and
progressive dyspnea during working hours for the previous
3 years; these symptoms improved partially following the
use of beclomethasone/formoterol on demand. Her clinical
condition improved considerably during vacation time.
Over the last 7 years, when she ate shrimp, octopus, squid,
or sh, she immediately experienced intense oral pruritus,
nausea, abdominal pain, and dizziness, which subsided in
a matter of hours without medication. She thus avoided
intake of these food products. The physical examination
was normal.
Skin tests (prick by prick) with shrimp, octopus,
squid, hake, cod, and trout were positive. Specific IgE
(ImmunoCAP, Phadia) was positive to octopus (1.63 kU/L),
squid (12.8 kU/L), sardines (1.23 kU/L), sole (2.43 kU/L),
and latex (8.47 kU/L), and negative to shrimp (<0.35 kU/L)
and anisakis (<0.35 kU/L). Baseline spirometry was normal,
the bronchodilator test was negative, the baseline fraction
of exhaled nitric oxide (FENO) was 32 ppb, and the baseline
methacholine test was positive (concentration required to
produce a 20% reduction in forced expiratory volume in the
rst second [FEV1] [PC20], 9.5 mg/mL).
After obtaining written informed consent, we performed a
specic inhalation challenge (SIC) with sodium metabisulphite
in a 7-m3 chamber in which the patient had to pass the sodium
metabisulphite from one tray to another, producing a cloud of
Manuscript received January 22, 2014; accepted for publication,
March 5, 2014.
Victor Iraola
Research & Development Department
Laboratorios LETI, S.L.
C/ Sol, 5 28760 – Tres Cantos
Madrid, Spain
E-mail: viraola@leti.com
5. Fain A. Le genre Dermatophagoides Bogdanov, 1864. Son
importance dans les allergies respiratoires et cutanées chez
l’homme. Acarologia. 1967; 9: 179-225.
6. Naspitz CK, Diniz C, Cândida Rizzo M, Fernández-Caldas E,
Solé D. Human scalps as a reservoir of domestic mites. The
Lancet. 1997, 349: 179-80.
7. Diniz CR, Rizzo MC, Naspitz CK et al. Human scalp as a
possible reservoir of domestic mites. J. Allergy Clin Immunol
1999; 103: 26-7.
8. Siebers RW, Rains N, Fitzharris P, Crabe J. House dust mite
allergen (Der p 1) in human hair. J Allergy Clin Immunol 1998;
101: 421-2.
9. Arlian LG, Morgan MS, Goelz JF. Quantitation of dust mites
and allergen in small dust samples. J Allergy Clin Immunol
1999; 104: 707-9.
10. Klimov PB, O’Connor BM. Is permanent parasitism reversible?
– Critical evidence from early evolution of house dust mites.
Syst Biol 2013; 63: 411-23.
59

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82 © 2015 Esmon Publicidad
dust. The cumulative exposure time was 30 minutes and the
mean concentration of sodium metabisulphite was 1.5 mg/m3.
The concentration of aerosolized particles was measured
on a DustTrak Aerosol Monitor (model 8520) (TSI) with a
threshold limit value to sodium metabisulphite of 5 mg/m3.
The SIC was positive with a late asthmatic response. Thirteen
hours after exposure to sodium metabisulphite, there was a fall
in FEV1 of 17.3% and the patient developed cough and chest
tightness. FEV1 and peak expiratory ow were monitored
with a computerized asthma monitor (Amos, Jaeger) every
hour except when the patient was sleeping. The methacholine
test 24 hours after the SIC was positive (PC20, 1.58 mg/mL),
with a decrease of more than 2 concentrations relative to the
previous fall. The FENO 24 hours after the SIC was 27 ppb,
showing no signicant changes.
On a different day, we performed another SIC simulating
the patient’s working conditions in a 7-m3 chamber. The patient
was asked to clean and handle raw squid, without sodium
metabisulphite, for a cumulative exposure time of 60 minutes.
The challenge elicited a late asthmatic response, with a fall
in FEV1 of 12% 10 hours after exposure. At the same time,
the patient also developed cough and chest tightness, which
were brought under control with salbutamol. The methacholine
test performed 24 hours after the SIC with squid was positive
(PC20, 0.5 mg/mL), with a signicant decrease with respect to
the baseline value. There were no changes in FENO.
Prior to these tests a bronchial challenge with placebo
(lactose) was performed, with monitoring of FEV1 over 24
hours using the same technique as above; no changes were
observed. The whole study was performed over the course of
8 weeks, during the patient’s sick leave.
We have reported a case of occupational asthma to sodium
metabisulphite and other seafood products (cephalopods, sh,
and crustaceans) in conjunction with food allergy to these
foods. Asthma was demonstrated by SICs and variations in
nonspecic airway hyperresponsiveness.
Only a few cases of asthma induced by sodium
metabisulphite have been reported to date, namely in the
sh-processing industry [1] and in radiographers [2]. This is
the rst case to be reported in Spain. Occupational asthma in
the sh and seafood industry is well known [3,4], but no cases
have been reported to date with double sensitization to sodium
metabisulphite and seafood allergens.
Funding
The authors declare that no funding was received for the
present study.
Conicts of Interest
The authors declare that they have no conicts of interest.
References
1. Steiner M, Scaife A, Semple S, Hulks G, Ayres JG. Sodium
metabisulphite induced airways disease in the shing and sh-
processing industry. Occup Med (Lond). 2008 Dec;58(8):545-
50.
Manuscript received December 1, 2013; accepted for
publication, March 11, 2014.
Silvia Uriarte
Fundación Jiménez Díaz
Avda. Reyes Católicos 2
28040 Madrid, Spain
E-mail: sauriarte@fjd.es
2. Merget R, Korn M. Metabisulphite-induced occupational
asthma in a radiographer. Eur Respir J. 2005 Feb;25(2):386-8.
3. Wiszniewska M, Tymoszuk D, Pas-Wyroslak A, Nowakowska-
Swirta E, Chomiczewska-Skóra D, Palczynski C, Walusiak-
Skorupa J. Occupational allergy to squid (Loligo vulgaris).
Occup Med (Lond). 2013 Jun;63(4):298-300.
4. Rosado A, Tejedor MA, Benito C, Cárdenas R, González-
Mancebo E. Occupational asthma caused by octopus particles.
Allergy. 2009 Jul;64(7):1101-2.
60

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82© 2015 Esmon Publicidad
Occupational Asthma and Eosinophilic Esophagitis in
a Patient With Egg-Bird Syndrome
Gomez Torrijos E1, García Rodriguez C1, Rodriguez J2, De la Roca
F1, Cárdenas R1, Alfaya F1, Pineda F3, Feo Brito JF1
1Allergy Section, Hospital General Universitario, Ciudad Real, Spain
2Digestive Section, Hospital Gutierrez Ortega, Valdepeñas,
Ciudad Real, Spain
3Diater Laboratorios, Leganés, Madrid, Spain
Key words: Bird-egg syndrome. Occupational eosinophilic esophagitis.
Occupational asthma. Gal d 5.
Palabras clave: Síndrome ave-huevo. Esofagitis eosinofílica ocupacional.
Asma ocupacional. Gal d 5.
A 39-year-old nonsmoking woman who had been working
as a daycare cook for 15 years reported a history of egg allergy
since childhood. When she ingested egg as a hidden allergen she
experienced oropharyngeal pruritus, vomiting, diarrhea, dyspnea,
and dysphagia. Fifteen years ago, she had similar symptoms when
she ate chicken but she now tolerates this meat and other poultry.
She has had perennial asthma for 20 years; on one occasion,
she had an asthma attack after being in a dovecote. She has
experienced dysphagia and food impactions in the last 7 years.
She told us that a year earlier she had experienced dry cough and
breathlessness when cooking raw egg at work. Furthermore, when
cooking chicken, she had mild symptoms of asthma.
After 2 months of treatment with omeprazole 40 mg, we
requested an upper endoscopy with sectional biopsies of the
esophagus, stomach, and duodenum, which showed over 25
eosinophils per high power eld (Eos/HPF) in the 3 sections
of the esophagus. The stomach and duodenum were normal.
Eosinophilic esophagitis (EoE) was diagnosed, and an egg-
and poultry-free diet was prescribed. At 6 weeks, we conducted
a second endoscopy and observed that the eosinophils had
disappeared in the 3 sections of the esophagus.
After the second endoscopy, the patient ate rice with
chicken and immediately developed oral allergy syndrome,
dysphagia, coughing, choking, nausea, vomiting, and colicky
abdominal pain that required emergency care. In just a month
and a half, she had lost tolerance to chicken.
The patient was asked to perform peak ow measurements
before and after cooking egg and her records showed values
ranging from 40% to 50%. She subsequently began to
experience dysphagia and the sensation of a lump in her neck.
We repeated the endoscopy, taking biopsies of the 3 sections
of the esophagus, each of which had over 15 Eos/HPF.
On reviewing the history, we observed that the patient
had adhered to the diet during vacation time (2012), and had
therefore not been exposed to egg. After returning to work the
EoE was reactivated, suggesting an occupational origin. The
same examination was repeated after vacations (2013) and no
eosinophils were detected in the esophagus.
An allergy study showed positive skin tests (mean wheal
in mm) to Dermatophagoides pteronyssinus (3 mm), egg
white (7 mm), egg yolk (10 mm), and chicken (5.5 mm).
Skin prick tests to lipid transfer protein, prolin, epithelia,
pollens, fungi, and mites gave negative results. Specic IgE
(InmunoCAP, Phadia) was positive to egg white (5.83 kU/L),
egg yolk (31.3 kU/L), feathers (1.96 kU/L), and chicken
(1.30 kU/L). Negative results were obtained with cow’s milk,
cereals, nuts, legumes, sh and shellsh, pollens, fungi, mites,
and epithelia. The chest x-ray and spirometry were normal
(forced expiratory volume [FEV] in the rst second, 3.24; forced
vital capacity, 3.74; peak expiratory ow, 7.21; FEV25-75, 3.78).
A methacholine test using the abbreviated cumulative method
was positive with a cumulative dose of 0.682 mg.
The literature describes extensively the association
between respiratory allergy to bird allergens and food allergy
due to ingestion of egg yolk [1,2]. Patients with this syndrome
are sensitized to egg protein of avian origin (feathers, bird
droppings, and sera) [2]. RAST-inhibition studies have
described livetin (water soluble fraction of yolk proteins) as
the allergen responsible for cross-reactivity between poultry
and egg yolk proteins [3]. Subsequently, it was found that there
are common allergens in the feathers of parakeet and hen, hen
serum, and alpha-livetin (chicken serum albumin [CSA]),
indicating that this protein was the offending allergen [4]. This
was later corroborated in a study of 8 patients with double
sensitization (bird feathers and egg yolk) by Quirce et al [5],
who proposed the designation of Gal d 5 for alpha-yolk.
Most often, respiratory symptoms appear rst, followed
by food allergy to egg yolk. However, prior allergy to yolk
may sometimes predispose to respiratory symptoms caused
by exposure to birds [5]; our patient belongs to this subgroup,
since she was rst allergic to egg and later developed asthma.
Based on the order of appearance of the symptoms, the
syndrome would be classied as egg-bird syndrome, which
is more common in adults and women, but has also been
described in children [6].
This case highlights the systemic involvement of allergic
disease. Our patient probably developed allergy to chicken
meat years ago when she began to experience oropharyngeal
pruritus; by continuing to ingest this meat, however, she was
probably spontaneously desensitized and able to tolerate
chicken for years. When she stopped eating poultry, she lost
tolerance, with symptoms appearing later [6-7]. If our patient
had stopped eating poultry and if she had not been a cook,
she might not have developed EoE, since by prohibiting the
consumption of chicken and removing exposure to the allergen
while on vacation, we induced clinical and pathological
remission [8-9]. Remission of EoE during vacations (twice)
and reactivation at work indicate an occupational origin.
The allergen (CSA) triggered the EoE rst through the
digestive tract and then by inhalation [10].
A detailed history including information on the patient’s
habitat, hobbies, and occupation is crucial for the etiological
diagnosis of bronchial asthma and must be performed before
the asthma is categorized as nonallergic and once the causal
allergen has been identied; it is also important to consider
the possibility of cross-reactivity. Therefore, in our patient,
although the allergen responsible for asthma has always been
the same (CSA), at rst the source was birds, but now, due to
her profession, it is chicken egg [5].
61

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82 © 2015 Esmon Publicidad
We have reported the rst case in the literature in which
a patient with egg-bird syndrome developed asthma (inhaled
egg) and occupational EoE due to allergy to Gal d 5 or CSA
(due to ingestion of poultry and subsequently inhalation of egg
proteins when handling egg). In addition, EoE was reactivated
through the digestive tract and through inhalation.
Funding
The authors declare that no funding was received for this
study.
Conicts of Interest
The authors declare that they have no conicts of interest.
References
1. Añibarro Bausela B, Martin Esteban M, Mártinez F, Pascual
C, Ojeda JA. Egg protein sensitization in patients with bird
feather allergy. Allergy. 1991; 46:614-8.
2. Quirce S, Diez ML, Eiras P, Cuevas M, Baz G, Losada E. Inhalant
allergy to egg white proteins. Clin Exp Allergy. 1998;28:278-
85.
3. Mandallaz MM, de Weck AL, Dahinden CA, Bird-egg
syndrome. Cross-reactivity between bird antigen and egg-yolk
livetins in IgE-mediated hypersensitivity. Int Arch Allergy Appl
Immunol. 1988;87:143-50.
4. Szépfalusi Z, Ebner C, Pandjaitan R, Orlicek F, Sneider O, Boltz-
Nitelescu G, Kraft D, Ebner H. Egg yolk alfa-livetin (chicken
serum albumin) is a cross reactive allergen in the bird-egg
syndrome. J Allergy Clin Immunol. 1994;93: 932-42.
5. Quirce S, Marañon F, Umpierrez A, de la Heras M, Fernández-
Caldás E, Sastre J. Chicken serum albumin (Gal d 5) is a
partially heat-labile inhalant and food allergen implicated in
the bird-egg syndrome. Allergy. 2001; 56:754-62.
6. Nevot Falcó S, Casas Ramisa R, Lleonart Bellll R. Bird-egg
syndrome in children. Allergol Immunopathol. 2003;3(3):161-
5.
7. R García, Urra JM, Feo JF, Galindo PA, Borja J, Gómez E, Lara
and Guerra F. Oral rush desensitization to egg: efcacy and
safety. Clin Exl allergy. 2011 (41) 1289-96.
8. Liacouras CA, Furuta GT, Hirano I, Atkins D, Attwood SE, Bonis
PA, Burks AW, Chehade M, Collins MH, Dellon ES, Dohil R,
Falk GW, Gonsalves N, Gupta SK, Katzka DA, Lucendo AJ,
Markowitz JE, Noel RJ, Odze RD, Putnam PE, Richter JE,
Romero Y, Ruchelli E, Sampson HA, Schoepfer A, Shaheen NJ,
Sicherer SH, Spechler S, Spergel JM, Straumann A, Wershil BK,
Rothenberg ME, Aceves SS. Eosinophilic esophagitis: Updated
consensus recommendations for children and adults. Clinical
reviews in allergy and immunology. J Allergy Clin Immunol.
2011 Jul; 128(1): 3-20.
9. Lucendo AJ, Arias Á, González-Cervera J, Yagüe-Compadre
JL, Guagnozzi D, Angueira T, Jiménez-Contreras S, González-
Castillo S, Rodríguez-Domíngez B, De Rezende LC, Tenias
JM. Empiric 6-food elimination diet induced and maintained
prolonged remission in patients with adult eosinophilic
esophagitis: A prospective study on the food cause of the
disease. J Allergy Clin Immunol. 2013, 131(3):797-804.
Manuscript received December 20, 2013; accepted for
publication, March 11, 2014.
Elisa Gómez Torrijos
Sección de Alergología
Hospital General Universitario de Ciudad Real.
C/ Obispo Rafael Torija s.n.
13005-Ciudad Real, Spain
E-mail: egomezt.cr@gmail.com
10. Dominguez Ortega J, Pérez-Bedmar J, Rodriguez Jimenez B,
Butrón M, Kindelan C, Ledesma A. Eosinophilic esophagitis
due to prolin allergy. J Invest Allergol Clin Immunol. 2009;
19:338-9.
62

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82© 2015 Esmon Publicidad
In a study of patients with ACEI abdominal visceral
angioedema, CT findings included ascites and small-
bowel wall thickening, dilatation without obstruction,
and straightening [4]. While ACEI-induced small-bowel
angioedema is included in the differential diagnosis of
abdominal pain in the setting of current ACEI use, this case
report underscores the need to consider intestinal angioedema
as a cause of abdominal pain in patients on ARB therapy who
present with abdominal complaints.
While the mechanism of ARB-induced angioedema is
unknown, mechanisms studied in ACEI-induced angioedema
include elevations of bradykinin, substance P, and the bradykinin
metabolite, des–Arg9–BK [5]. An accurate medication history
will help to differentiate ACEI-induced visceral angioedema
from other causes of angioedema. In patients with a history
of ACEI-induced angioedema who relapsed following
discontinuation of ACEI, the majority (88%) relapsed within a
month of stopping ACEI [6]. There have been 28 reported cases
of ACEI-induced visceral angioedema in the literature [7].
Given our patient’s previous reaction to the ACEI (lisinopril)
and persistent abdominal pain for an additional year after
discontinuation of lisinopril, losartan was suspected as the
causative agent of her current symptoms. The CT scan ndings
and resolution of symptoms with prompt ARB discontinuation
conrmed our clinical suspicion of ABR-induced visceral
angioedema.
In conclusion, visceral angioedema of the intestine due
to ARBs should be considered in the differential diagnosis of
abdominal pain. While there is no denitive diagnostic test for
ACEI- or ARB-induced visceral angioedema, the combination
of appropriate clinical and medication history, radiologic
imaging, and relief of symptoms with discontinuation of
the offending medication are helpful in making the correct
diagnosis and preventing future morbidity and mortality for
these patients.
Funding
The authors declare that no funding was received for
this study.
Angiotensin Receptor Blocker–Induced Visceral
Angioedema
Thalanayar Muthukrishnan P1*, Fajt ML2*, Birnie KM3, Ghobrial
II1, Petrov AA2
1Department of Internal Medicine, University of Pittsburgh
Medical Center, McKeesport, Pennsylvania, USA
2Division of Pulmonary, Allergy, and Critical Care Medicine;
Department of Medicine, University of Pittsburgh School of
Medicine, Pittsburgh, Pennsylvania, USA
3Greater Washington Radiology, Washington, Pennsylvania, USA
*These authors contributed equally to the work and are both
rst authors
Key words: Visceral angioedema. Angiotensin receptor blocker.
Palabras clave: Angioedema visceral. Bloqueador del receptor de la
angiotensina.
Angioedema is a rare complication of angiotensin converting
enzyme inhibitor (ACEI) and angiotensin receptor blocker
(ARB) therapy. In a large study of more than 2 million patients
on antihypertensive therapy, the cumulative incidences per 1000
persons were 1.79 cases for ACEIs and 0.62 cases for ARBs [1].
The risk of recurrent angioedema with ARBs for patients with
previous ACEI-associated angioedema is 6.6% [2,3]. Isolated
visceral angioedema has not been previously reported with ARB
treatment after discontinuation of ACEI.
A 31-year-old African-American woman with a history of
chronic abdominal pain, hemodialysis-dependent end-stage
renal disease, and hypertension presented to the emergency
department with a recurrent bout of severe abdominal
pain, nausea, vomiting, and diarrhea. The patient’s current
medications included nifedipine, losartan, and clonidine.
Physical exam revealed tenderness in the epigastrium and right
lower quadrant, and hypoactive bowel sounds, without guarding
or rigidity. Complete blood count, a comprehensive metabolic
panel, and lipase were normal. Previous noncontrast abdominal
computed tomography (CT) scans were remarkable only for
perihepatic uid. In the emergency department, an abdominal
CT scan with contrast was performed and revealed perihepatic
uid, as well as small-bowel wall edema and a target sign
(stratied appearance of the bowel wall) (Figure). C1-esterase
inhibitor (quantity and function) and C4 levels were normal.
Review of the patient’s medical records showed that the
onset of abdominal pain 6 years earlier had coincided with
the introduction of lisinopril. One year ago, the patient also
developed a cough which led to discontinuation of lisinopril
treatment. She was started on losartan, with resolution of cough
but persistence of abdominal pain. Given her current clinical
and radiographic ndings drug-induced visceral angioedema
was suspected. Losartan was discontinued and the patient’s
abdominal symptoms resolved. At the 12-month follow up,
she remained symptom-free off losartan (and all other ARBs
and ACEIs), which supported the diagnosis of ACEI and ARB-
induced visceral angioedema.
Figure. Computed tomography scan with intravenous contrast of the
abdomen and pelvis. Small bowel target sign due to mural stratication
and prominent circumferential edema of the bowel wall.
63

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82 © 2015 Esmon Publicidad
Conicts of Interest
The authors declare that they have no conicts of interest.
References
1. Toh S, Reichman ME, Houstoun M, Ross Southworth M, Ding
X, Hernandez AF, Levenson M, Li L, McCloskey C, Shoaibi A, Wu
E, Zornberg G, Hennessy S. Comparative risk for angioedema
associated with the use of drugs that target the renin-
angiotensin-aldosterone system. Arch Intern Med. 2012 Nov
12;172(20):1582-9. doi: 10.1001/2013.jamainternmed.34.
PMID: 23147456
2. Haymore BR, DeZee KJ. Use of angiotensin receptor blockers
after angioedema with an angiotensin-converting enzyme
inhibitor. Ann Allergy Asthma Immunol. 2009 Jul;103(1):83-4.
doi: 10.1016/S1081-1206(10)60151-2. PMID: 19663135
3. Haymore BR, Yoon J, Mikita CP, Klote MM, DeZee KJ. Risk of
angioedema with angiotensin receptor blockers in patients
with prior angioedema associated with angiotensin-
converting enzyme inhibitors: a meta-analysis. Ann Allergy
Asthma Immunol. 2008 Nov; 101(5):495-9.
4. Scheirey CD, Scholz FJ, Shortsleeve MJ, Katz DS. Angiotensin-
converting enzyme inhibitor-induced small-bowel
angioedema: clinical and imaging ndings in 20 patients.
AJR Am J Roentgenol. 2011 Aug;197(2):393-8. doi: 10.2214/
AJR.10.4451.PMID:21785085
5. Hoover T, Lippmann M, Grouzmann E, Marceau F, Herscu P.
Angiotensin converting enzyme inhibitor induced angio-
oedema: a review of the pathophysiology and risk factors.
Clin Exp Allergy. 2010 Jan;40(1):50-61. doi: 10.1111/j.1365-
2222.2009.03323.x. PMID:19659669
6. Beltrami L, Zanichelli A, Zingale L, Vacchini R, Carugo S, Cicardi
M. Long-term follow-up of 111 patients with angiotensin-
converting enzyme inhibitor-related angioedema. J Hypertens.
2011; 29(11): 2273-7.
7. Korniyenko A, Alviar CL, Cordova JP, Messerli FH. Visceral
angioedema due to angiotensin-converting enzyme inhibitor
therapy. Cleve Clin J Med 2011; 78(5): 297-304
Manuscript received January 16, 2014; accepted for publication,
March 11, 2014.
Andrej Petrov
UPMC Montefiore Hospital
NW628, 3459 Fifth Ave
Pittsburgh, Pennsylvania 15213
USA
E-mail: petrovaa@upmc.edu
Occupational Asthma and Dermatitis Induced by
Eugenol in a Cleaner
López-Sáez MP1, Carrillo P1, Huertas AJ2, Fernández-Nieto M3,
López JD1
1Servicio de Alergología, Hospital Clínico Universitario Virgen
de la Arrixaca, Murcia, Spain
2Servicio de Alergología, Complejo Hospitalario Universitario
de Cartagena, Murcia, Spain
3Servicio de Alergología, Fundación Jiménez Díaz, Madrid, Spain
Key words: Eugenol. Occupational asthma. Dermatitis. Cleaner.
Palabras clave: Eugenol. Asma profesional. Dermatitis. Limpiadora.
Eugenol, 4 allyl-2-methoxy phenol C10H12O2, is a member
of the allylbenzene class of chemical compounds. It is a pale
yellow oily liquid extracted from certain essential oils, and
clove oil in particular. It is used in perfumes, avorings,
essential oils, and in medicine as a local antiseptic, anesthetic,
and ingredient in temporary llings.
Several adverse reactions have been described for eugenol.
Most of these have been allergic contact dermatitis [1], but
a small number of urticaria cases have been described [2,3].
There has also been a report of occupational asthma and rhinitis
in a hairdresser [4].
We report the case of 34-year-old woman who was
working for a cleaning company 2 hours a day from Monday
to Saturday. She used a mop spray containing several chemical
products including eugenol. One month after starting to use
this spray, she developed maculopapular erythema on areas
exposed to the spray in addition to cough and dyspnea. After
successive exposures, her respiratory and cutaneous symptoms
became more intense and immediate, and the skin lesions
became more generalized. The symptoms resolved in 1 to
2 hours with the use of antihistamines and bronchodilators
and disappeared completely when the patient was off work
or on holidays.
In the work-up, general biochemistry, complete blood
count, coagulation prole, thyroid function, protein levels,
serum immunoglobulins (IgG, IgA, IgM, and IgD),
complement levels, and nonorgan-specic antibodies were
normal. Total serum IgE was 592.8 IU/L and the baseline
serum tryptase level was 6.08 µg/L.
Patch testing with the European standard series and
fragrance series was negative. Skin prick testing with a series
of common airborne allergens, latex, eugenol 2%, clove, and
cinnamon showed positive results for Artemisia vulgaris
pollen only.
The chest x-ray and forced spirometry were normal and
the fractional exhaled nitric oxide test result was negative
(6 ppb). A methacholine challenge was positive (dose required
to cause a 20% fall in forced expiratory volume in the rst
second [FEV1], 0.76 mg/dL).
A specic inhalation challenge with eugenol was performed
in a 7-m3 challenge chamber with 2-minute nebulization of
64

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82© 2015 Esmon Publicidad
eugenol at the corresponding dilution [4,5]. A bronchial
challenge test was negative at a concentration of 1:10000,
with no signicant differences observed in FEV1. However,
the same challenge with a concentration of 1:1000 led to a
17% decrease in FEV1 8 hours later accompanied by dyspnea
and cough. Skin lesions consisting of isolated and occasionally
conuent erythematous maculopapules measuring 2 to 3 cm
appeared on the face, chest, back, and arms 12 hours later.
The late decrease in FEV1 of above 15% accompanied by
respiratory symptoms was considered positive in the bronchial
challenge [6], and the patient was diagnosed with occupational
asthma and dermatitis due to eugenol and removed from her
work.
Despite continuous treatment with antihistamines,
bronchodilators, and inhaled corticosteroids, the patient
progressed poorly and experienced almost daily wheezing,
dyspnea, cough, and skin lesions due to small, continuous
environmental exposures (perfumes, fresheners, cleaning
products, etc.). The patient required many visits to the
emergency room and her symptoms were only brought under
control with the addition of 6 mg of deazacort every 48 hours.
The association between exposure to cleaning products
and fragrances and the risk of bronchial asthma has been
reported [7]. Cleaners are exposed to a large number of
products, most of which have an irritating effect on the skin
and mucous membranes that can produce worsening of asthma.
Other products such as quaternary ammonium and amine
compounds can produce asthma by specic sensitization [8].
Exposure to high concentrations of fragrances is associated
with the risk of contact dermatitis without disruption of
pulmonary function in certain individuals [9]. Most adverse
reactions due to eugenol exposure are contact dermatitis, seen
mainly in dental personnel [2], hairdressers, and drugstore
workers.
In the current case, the spirometric response and
appearance of skin lesions after eugenol exposure strongly
suggest that eugenol was the cause of the patient’s respiratory
and cutaneous symptoms, although the pathogenic mechanism
is unknown. This condition can be considered an occupational
disease because eugenol is a mop spray component whose use
is mandatory at work.
This case highlights the fact that eugenol is a potentially
serious problem for patients with hypersensitivity to this
substance because it is a widespread agent forming part of
fresheners, perfumes, and many other products that can be
difcult to avoid.
Funding
The authors declare that no funding was received for the
present study.
Conicts of Interest
The authors declare that they have no conicts of interest.
References
1. Johansen JD, Rastogi SC, Menné T. Contact allergy to popular
perfumes assessed by patch test, use test and chemical
analysis. Br J Dermatol. 1996; 135: 419-22.
2. Bhalla M, Thami GP. Acute urticaria due to dental eugenol.
Allergy. 2003 58: 158.
3. Grade AC, Martens BPM. Chronic urticaria due to eugenol.
Dermatologica. 1989; 178: 217-20.
4. Quirce S, Fernández-Nieto M, del Pozo V, Sastre B, Sastre J.
Occupational asthma and rhinitis caused by eugenol in a
hairdresser. Allergy. 2008 Jan; 63: 137-8.
5. Quirce S, Baeza ML, Tornero P, Blasco A, Barranco R, Sastre J.
Occupational asthma caused by exposure to cyanoacrylate.
Allergy. 2001; 56: 446-9.
6. Joaquin Sastre Domínguez. Métodos de diagnóstico en asma.
In: de Zubiría Consuegra E, de Zubiría Salgado E, de Zubiría
Salgado A. Asma bronquial. Editorial Médica Panamericana;
2004. p. 285-414.
7. Zock JP, Vizcaya D, Le Moual N. Update on asthma and
cleaners. Curr Opin Allergy Clin Immunol. 2010; 10: 114-20.
8. Quirce S, Barranco P. Cleaning agents and asthma. J Investig
Allergol Clin Immunol. 2010, 20: 542-50.
9. Schnuch A, Oppel E, Oppel T, Römmelt H, Kramer M, Riu E,
Darsow U, Przybilla B, Nowak D, Jörres RA. Experimental
inhalation of fragrance allergens in predisposed subjects:
effects on skin and airways. Br J Dermatol. 2010; 162: 598-
606.
Manuscript received January 21, 2014; accepted for publication,
March 11, 2014.
Maria Pilar López Sáez
H.C.U. Virgen de la Arrixaca
Ctra. Madrid-Cartagena, s/n, 30120
El Palmar, Murcia, Spain
E-mail: mpilarlopezsaez@yahoo.es
65

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82 © 2015 Esmon Publicidad
Allergic Contact Dermatitis From Ethylhexyl
Salicylate
Miralles JC, Escudero AI, Carbonell A, Martínez A, Fernández E,
Cardona P
Allergy Section, Hospital General Universitario Reina Sofía,
Murcia, Spain
Key words: Ethylhexyl salicylate. Salicylates. Allergic contact dermatitis.
Palabras clave: Etilhexil salicilato. Salicilatos. Dermatitis alérgica de
contacto.
Ethylhexyl salicylate, also known as octyl salicylate,
octisalate, 2-ethylhexyl salicylate (CAS 118-60-5) is a
cosmetic ingredient used as both a UV lter and a fragrance
compound. Allergic contact dermatitis from salicylates is
uncommon. To date, there have been only 3 reports of allergic
contact dermatitis due to ethylhexyl salicylate [1-3] and 1 of
cheilitis [4], and none of these were in Spain.
We present the case of a 40-year-old woman with a history
of rhinitis and intrinsic bronchial asthma under treatment
with nasal budesonide 100 mcg/d, uticasone propionate
spray 250 mcg/d, and salbutamol. Over several summers,
the patient had developed erythematous micropapules
progressing to microvesicles and vesicles on her back, chest,
and abdomen (Figure). The lesions appeared only in the
summer months, lasted about 14 days, and needed treatment
with antihistamines and corticosteroids. These clinical
manifestations seemed to be related to the use of sunscreens.
The patient reported having used Isdin extrem cream and
Isdin transparent spray in the past year. A skin biopsy of the
lesions revealed a dermal hypersensitivity reaction consistent
with contact dermatitis.
Patch testing was negative for Isdin extrem cream
and positive for Isdin transparent spray. We performed
epicutaneous tests with the components of Isdin transparent
spray (supplied by the manufacturer). The whole list of
substances was denaturalized alcohol, octocrylene, butyl
methoxydibenzoylmethane, ethylhexyl salicylate, C12 -15 alkyl
benzoate, dibutyladipate, aqua (water), cyclopentasiloxane,
4-methylbenzylidene camphor, diethylhexyl butamido
triazone, cyclohexasiloxane, acrylates/ethylhexylacrylamide
copolymer, parfum (fragrance), BHT, tocopheryl acetate, and
linalool. The results were positive for ethylhexyl salicylate,
but negative for the other components tested. Patch tests with
a standard patch test series (T.R.U.E TEST, Martitor) gave
a positive result for cobalt chloride and a negative result for
the rest of contactants included. Patch tests carried out with
other salicylates (methyl salicylate, phenyl salicylate, benzyl
salicylate, sodium salicylate, salicylic acid, and acetyl salicylic
acid, and salicilaldehyde) also showed negative results. Finally,
we performed photopatch tests with ethylhexyl salicylate and
the other salicylates. The results were positive for ethylhexyl
salicylate, with the same intensity as without sun exposure
(+++), and negative in all other cases.
Ethylhexyl salicylate has an absorption spectrum ranging
from 280 to 320 nm (UV-B). Salicylates are weak UV
absorbers, but they are highly water insoluble and therefore
suitable for use as sunscreens during bathing. Allergy to
sunscreens in the general population is estimated to be
less than 2%, but contact dermatitis from salicylates is
infrequent, especially considering their extensive use. Thus
they represent one of the safest sunscreens, even at high
concentrations.
It is noteworthy that the results for other salicylates tested
in our patient, including acetyl salicylic acid, were negative.
The degree of cross-reactivity between salicylates is currently
unknown. In a case of ethylhexyl salicylate allergy reported
by Shaw [3], this substance showed cross-reactivity with
cis-3-hexenyl salicylate, which has a very similar chemical
structure. In another case reported by Mortz et al [1], the patient
only showed positive results for ethylhexyl salicylate, despite
testing with an extensive series of salicylates. In general, few
patients with allergy to a particular salicylate have been patch
tested with other salicylates.
Furthermore, there has been a report of contact dermatitis
due to methyl salicylate [5] in which oral intake of acetyl
salicylic acid produced a recurrence of dermatitis at the site of
previous lesions due to methyl salicylate. Our patient tolerated
oral acetyl salicylic acid without adverse effects.
In summary, we have reported the rst case of contact
dermatitis from ethylhexyl salicylate in Spain. Although
cross-reactivity between salicylates is unknown, our patient
had negative patch tests with other salicylates.
Funding
The authors declare that no funding was received for this
study.
Conicts of Interest
The authors have no conicts of interest to declare.
Figure. Skin lesions: papules, microvesicles and vesicles.
66

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82© 2015 Esmon Publicidad
References
1. Mortz CG, Thormann H, Goossens A, Andersen KE. Allergic
contact dermatitis from ethylhexyl salicylate and other
salicylates. Dermatitis. 2010 Mar-Apr;21(2):E7-10.
2. Singh M, Beck MH. Octyl salicylate: a new contact sensitivity.
Contact Dermatitis. 2007 Jan;56(1):48.
3. Shaw DW. Allergic contact dermatitis from octisalate and cis-
3-hexenyl salicylate. Dermatitis. 2006 Sep;17(3):152-5.
4. Strauss RM, Orton DI. Allergic contact cheilitis in the United
Kingdom: a retrospective study. Am J Contact Dermat. 2003;
14: 75-7.
5. Hindson C. Contact eczema from methyl salicylate reproduced
by oral aspirin (acetyl salicylic acid). Contact Dermatitis. 1977;
3: 348-9.
Manuscript received January 7, 2014; accepted for publication,
March 13, 2014.
Juan Carlos Miralles López
Plaza Juan XXIII nº 3 – 7º E
30008 Murcia, Spain
E-mail: juanc.miralles@carm.es
Airborne Contact Dermatitis From Dittrichia viscosa
Galindo-Bonilla PA1, Alfaya-Arias T1, Bartolomé-Zavala B2, De
la Roca-Pinzón F1, García-Rodríguez C1, Feo-Brito F1
1Allergy Section, Hospital General Universitario, Ciudad Real, Spain
2Research & Development Department, Bial-Arístegui, Bilbao, Spain
Key words: Airborne. Contact dermatitis. Compositae.
Dittrichia viscosa
.
Palabras clave: Aerotransportada. Dermatitis de contacto. Compuestas.
Dittrichia viscosa
.
Dittrichia viscosa, previously known as Inula viscosa, is
an aromatic Mediterranean weed belonging to the Compositae
(Asteraceae) family. It grows along roads and pathways and
in uncultivated elds, and its lanceolate leaves and stems are
covered with ne glandular hairs (trichomes) [1]. D viscosa
has occasionally been reported as a cause of allergic contact
dermatitis [1-3].
A 76-year-old man had experienced a pruriginous
erythemato-squamous eruption on his ankles, hands, forearms,
and face over the previous 2 years. Sometimes the dermatitis
was widespread. The patient related the eruption to trips to
the countryside, and in particular to an area where a certain
plant grew. The dermatitis appeared exclusively in the months
of May to September. The suspicious plant, collected by the
patient, was identied by a botanist as D viscosa.
Complete blood count, erythrocyte sedimentation rate,
and biochemistry were normal. Total IgE was within the
normal range (39.7 kU/L). We carried out patch tests with
the Spanish standard series (GEIDC), standard commercial
pollens, Chrysanthemum frutescens, laurel, chamomile, and
fresh D viscosa plants. Readings were performed on D2 and
D4 according to the guidelines of the International Contact
Dermatitis Research Group (ICDRG). The only positive result
obtained was for D viscosa (++ on D2 and D4).
Ethereal extracts from D viscosa stems, leaves, and owers
were prepared and used to carry out patch tests at 0.4%, 2%,
and 4% in petrolatum (pet). Positive results (++ on D2 and D4)
were obtained for all extracts. The same tests were negative
in 20 controls.
The main allergens of D viscosa are sesquiterpene lactones
contained in the leaves and glandular trichomes. The trichomes
are released on contact or fall off as the plant withers, leading to
an airborne pattern of dermatitis from dry windborne fragments
of the plant [1].
Spanish authors Pinedo et al [2] reported the rst case
of contact dermatitis due to I viscosa Aiton in a patient who
used the plant in an infusion to treat hemorrhoids. Patch tests
were positive with ethereal extracts of I viscosa and with 2
sesquiterpene lactones; patch tests with the ICDRG standard
series were negative.
Other cases of allergic contact dermatitis to D viscosa have
subsequently been reported in Portugal [1,3] and there has also
been a case caused by Dittrichia graveolens [4]. Gonçalo and
Gonçalo [1] reported 9 cases of contact dermatitis to D viscosa,
67

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82 © 2015 Esmon Publicidad
mainly with an airborne pattern. All the patients reacted to the
fresh leaves and ethereal extracts (1% and 0.5% pet); positive
reactions to Frullania dilatata, Laurus nobilis, other members
of the Compositae family, and sesquiterpene lactones were also
observed, suggesting sesquiterpene lactone–induced allergic
contact dermatitis. Estrela et al [3] reported the case of a
patient who experienced dermatitis with an airborne pattern
from August to October; patch tests were positive with fresh
owers and leaves, D viscosa at 0.5% pet, and alantolactone.
Supporting previous reports, an airborne pattern was
also seen in our case. Patch tests were positive with ethereal
extracts at 0.4%, 2% and 4% pet and with the unaltered fresh
plant. Patch tests with the GEIDC standard series (containing
sesquiterpene-lactones) were negative, as in the case reported
by Pinedo et al [2], although these authors did observe positive
patch tests with lantolactone and isoalantolactone. We did
not test lactones other than those included in the GEIDC
series (sesquiterpene lactone mix 0.1% pet), but the fact that
our patient did not react to other Asteraceae plants suggests
that the offending allergen is specic to Dittrichia and not a
sesquiterpene lactone.
Funding
The authors declare that no funding was received for the
current study.
Conicts of Interest
The authors declare that they have no conicts of interest.
References
1. Gonçalo M, Gonçalo S. Allergic contact dermatitis from
Dittrichia viscosa (L.) Greuter. Contact Dermatitis. 1991;24:40-
4.
2. Pinedo JM, Gonzalez de Canales F, Hinojosa JL, Llamas P,
Hausen M. Contact dermatitis to sequisterpene lactones in
Inula viscose Aiton. Contact Dermatitis. 1987;17:322-3.
3. Estrela F, Tapadinhas C, Pereira F. Allergic contact dermatitis
from Dittrichia viscosa (L.) Greuter. Contact Dermatitis.
1995;32:108-9.
4. Thong HY, Yokota M, Kardassakis D, Maibach HI. Allergic
contact dermatitis from Dittrichia gravolens (L.) Greuter
(stinkwort). Contact Dermatitis. 2008;58:51-3.
Manuscript received March 3, 2014; accepted for publication,
March 17, 2014.
Pedro Angel Galindo Bonilla
Sección de Alergología
Hospital General Universitario de Ciudad Real
C/ Obispo Rafael Torija s.n.
13005 Ciudad Real, Spain
E-mail: pagalindobonilla@gmail.com
Aspirin Does Not Preferentially Potentiate IgE-
Dependent Basophil CD63 Upregulation in Patients
With Food-Dependent Exercise-Induced Anaphylaxis
Medrala W1, Barg W2, Radlinska A1, Skotny A1, Siwak E1,3,
Zbrojewicz E1, Nadobna G1, Nittner-Marszalska M1, Wolanczyk-
Medrala A1
1Department of Internal Diseases, Geriatrics and Allergology,
Wroclaw Medical University, Wroclaw, Poland
2Department of Physiology, Wroclaw Medical University,
Wroclaw, Poland
3Department of Medical Biochemistry, Wroclaw Medical
University, Wroclaw, Poland
Key words: Food allergy. Aspirin. Food-dependent exercise-induced
anaphylaxis (FDEIA).
Palabras clave: Alergia alimentaria. Aspirina. Analaxia inducida por
ejercicio dependiente de alimento.
Food-dependent exercise-induced anaphylaxis (FDEIA) is
a rare syndrome that was rst described in 1979 by Maultiz
et al [1], who reported the case of a patient with anaphylactic
symptoms after exercise preceded by ingestion of shellsh.
Strenuous exercise or ingestion of the causative food alone was
well tolerated [1]. In 1983, Kidd et al [2] described 4 patients
with similar symptoms and proposed the term FDEIA [2].
In patients with FDEIA for whom challenges with food and
exercise are negative, addition of aspirin (as a third potential
trigger) or even ingestion of aspirin instead of exercise
makes challenge results positive [3,4]. Therefore, aspirin,
rather than exercise, is the trigger of anaphylaxis. Aspirin
can also stimulate basophils in patients with hypersensitivity
to nonsteroidal anti-inammatory drugs (NSAIDs), although
similar results can also be observed in healthy individuals [5].
Since the allergen and aspirin act simultaneously in a patient
with FDEIA, it seems interesting to examine the inuence of
aspirin on IgE-dependent basophil activation.
The study population comprised 7 patients (3 men) aged 26
to 36 years (mean, 29 years) with FDEIA, 17 patients (11 men)
aged 31 to 61 years (mean, 42 years) with hypersensitivity
to NSAIDs, 17 patients (9 men) aged 21 to 57 years (mean,
32 years) with allergic rhinitis and/or asthma, and 15 healthy
persons (8 men) aged 21 to 56 years (mean, 31 years) with
no symptoms of allergy and negative skin prick test results
(controls). Five of the 7 FDEIA patients had allergic rhinitis
and/or asthma; the other 2 had no atopic comorbidities. The
number of FDEIA episodes ranged from 1 to more than 10.
Symptoms of FDEIA varied from patient to patient and ranged
from anaphylactic shock requiring adrenaline to urticaria and
itching. Culprit food allergens differed between the patients
and comprised celery, carrot, apple, banana, hazelnut, tomato
sauce, natural yoghurt, egg, canned ham, and chicken. The
intensity of the exercise that triggered the episode was classed
as high in 5 patients and mild in 2. Hypersensitivity to aspirin
was excluded in healthy persons and patients with allergic
68

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82© 2015 Esmon Publicidad
A B
100
80
60
40
20
0
500
400
300
200
100
0
Concentration of Aspirin, mM Concentration of Aspirin, mM
FDEIA FDEIAAP APNHG NHGHC HC
CD63+ Basophils, %
CD63+ Basophils, %
0
0.100
0.386
1.130
1.574
0
0.100
0.386
1.130
1.574
0
0.100
0.386
1.130
1.574
0
0.100
0.386
1.130
1.574
0
0.100
0.386
1.130
1.574
Figure. Effect of aspirin on IgE-dependent basophil CD63 upregulation in patients with food-dependent exercise-induced anaphylaxis (FDEIA), atopic
patients (AP), patients with hypersensitivity reaction to nonsteroidal anti-inammatory drugs (NHG), and healthy controls (HC). A, IgE-dependent CD63
basophil upregulation (shown as percentages of CD63+ cells). B, Increased IgE-dependent basophil CD63 upregulation with increasing aspirin concentrations
(shown as the percentage of results obtained without aspirin).
rhinitis and/or asthma. The basophil CD63 upregulation
test was performed using the Flow Cast kit (Bühlmann
Laboratories AG). Five 50-μL samples of whole blood from
each participant were incubated for 20 minutes at 37°C with
50 μL of polyclonal rabbit antihuman IgE (Dako Denmark A/S)
at a concentration of 1 μg/mL without aspirin and after adding
50 μL of aspirin (Lys-Aspirin, Bühlmann Laboratories AG) at
concentrations of 1.574, 1.13, 0.386, and 0.1 mM, respectively.
The aspirin concentrations used in our study were similar to
those used in a study by Matsuo et al [6]. After taking 600 mg
of aspirin, the plasma concentration yielded peak plasma
levels of 28 µM to 56 µM and peak salicylic acid (the main
metabolite of aspirin) levels of 72 µM to 290 µM [7]. However,
their local concentration in the intestinal tract might be much
higher. The activity of IgE-dependent basophils was presented
as a percentage of activated basophils after subtracting the
patient’s background value (spontaneous activity, ie, negative
control value). The study design was approved by the Ethics
Committee of Wroclaw Medical University, and informed
consent was obtained from all the participants.
Aspirin boosted IgE-dependent basophil activation in
all the groups, although the increase was not statistically
signicant (P>.05). We noticed various effects depending
on the concentration of aspirin. The effect of aspirin on IgE-
dependent basophil CD63 upregulation varied from person to
person and was not always dose-dependent. Some individuals
presented increased CD63 upregulation at lower aspirin
concentrations, whereas others did so at higher concentrations,
irrespective of the group. Therefore, our results are very
disperse, a common nding in nonselected groups.
Our results do not support the observations of Matsuo
et al [6], who demonstrated a preferential increase in anti-IgE
basophil histamine release in patients with FDEIA or urticaria
in comparison with healthy persons. Our ndings are more
consistent with those of Fukunaga et al [8], who found that
ingestion of aspirin by persons with FDEIA changed neither
basophil activation nor the results of skin prick tests. In our
opinion, the effect of aspirin on IgE-dependent basophil
activation in vitro is a rather common feature, and patients
with FDEIA do not differ from other individuals in this respect.
However, the proposed role of NSAIDs as a nonspecic
agent that enhances mast cell and basophil activation by food
allergens in the pathogenesis of FDEIA is coherent with current
knowledge [6] and seems very likely.
Funding
The authors declare that no funding was received for the
present study.
Conicts of Interest
The authors declare that they have no conicts of interest.
References
1. Maulitz RM, Pratt DS, Schocket AL. Exercise-induced
anaphylactic reaction to shellsh. J Allergy Clin Immunol.
1979;63:433-4.
2. Kidd JM 3rd, Cohen SH, Sosman AJ, Fink JN. Food-dependent
exercise-induced anaphylaxis. J Allergy Clin Immunol.
1983;71:407-11.
3. Harada S, Horikawa T, Ashida M, Kamo T, Nishioka E, Ichihashi
M. Aspirin enhances the induction of type I allergic symptoms
when combined with food and exercise in patients with
food-dependent exercise-induced anaphylaxis. Br J Dermatol.
2001;145:336-9.
4. Kohno K, Matsuo H, Takahashi H, Niihara H, Chinuki Y, Kaneko
S, Honjoh T, Horikawa T, Mihara S, Morita E. Serum gliadin
monitoring extracts patients with false negative results
in challenge tests for the diagnosis of wheat-dependent
exercise-induced anaphylaxis. Allergol Int. 2013;62:229-38.
5. De Weck AL, Sanz ML, Gamboa PM, Jermann JM, Kowalski
M, Medrala W, Sainte-Laudy J, Schneider MS, Weber JM,
Wolanczyk-Medrala A. Nonsteroidal anti-inammatory drug
hypersensitivity syndrome: a multicenter study. II. Basophil
69

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82 © 2015 Esmon Publicidad
Manuscript received December 4, 2013; accepted for publication
April 11, 2014.
Wojciech Medrala
Department of Internal Diseases,
Geriatrics and Allergology
Wroclaw University of Medicine
Sklodowskiej-Curie 66
50-369 Wroclaw, Poland
E-mail: wojmed@wp.pl
activation by nonsteroidal anti-inammatory drugs and its
impact on pathogenesis. J Investig Allergol Clin Immunol.
2010;20:39-57.
6. Matsuo H, Yokooji T, Morita H, Ooi M, Urata K, Ishii K, Takahagi
S, Yanase Y, Hiragun T, Mihara S, Hide M. Aspirin augments IgE-
mediated histamine release from human peripheral basophils
via Syk kinase activation. Allergol Int. 2013;62:503-11.
7. Siebert DJ, Bochner F, Imhoff DM, Watts S, Lloyd JV, Field J,
Gabb BW. Aspirin kinetics and platelet aggregation in man.
Clin Pharmacol Ther. 1983;33:367-74.
8. Fukunaga A, Shimizu H, Tanaka M, Kikuzawa A, Tsujimoto
M, Sekimukai A, Yamashita J, Horikawa T, Nishigori C.
Limited inuence of aspirin intake on mast cell activation in
patients with food-dependent exercise-induced anaphylaxis:
comparison using skin prick and histamine release tests. Acta
Derm Venereol. 2012;92:480-3.
Marihuana Allergy: Beyond the Joint
Faber M1, Van Gasse A1, Sabato V1, Hagendorens MM1,2, Bridts
CH1, De Clerck LS1, Ebo DG1
1Department of Immunology-Allergology-Rheumatology, Faculty
of Medicine and Health Sciences, University of Antwerp, Antwerp,
Belgium and Immunology-Allergology-Rheumatology, Antwerp
University Hospital, Antwerp, Belgium
2Pediatrics, Antwerp University Hospital, Antwerp, Belgium
Key words: Basophil activation test.
Cannabis sativa
allergy. Food allergy.
Nonspecic lipid transfer proteins. Tobacco allergy.
Palabras clave: Test de activación de basólos. Alergia a
Cannabis sativa
.
Alergia alimentaria. Proteínas de transferencia de lípidos no especícas.
Alergia a tabaco.
Plant food allergy is a major health problem. It can be
acquired through direct sensitization in the gastrointestinal
tract or it can be secondary to a sensitization to cross-reactive
pollen or Hevea latex [1].
Plant food allergy has distinct geographic and age-
related phenotypes. In Belgium, plant food allergy results
most frequently from cross-reactivity with birch pollen
and is generally characterized by oral allergy syndrome.
In the Mediterranean Basin, plant food allergy originates
mainly from sensitization to nonspecic lipid transfer
proteins (ns-LTPs).
ns-LTPs are panallergens and have been identied as
clinically relevant allergenic components in fruits, vegetables,
nuts, cereals, pollens, Hevea latex, and Cannabis sativa [2].
ns-LTPs can show signicant IgE cross-reactivity which
might lead to various fruit and vegetable allergies, the
so-called ns-LTP syndrome [3]. In southern Europe, the ns-
LTP of peach (Prunus persica) is thought to be an important
sensitizing molecule and is frequently used as a marker
molecule for ns-LTP allergy. In Belgium, we demonstrated that
C sativa constitutes a potential source of sensitization towards
ns-LTPs and can consequently trigger food allergies [2]. We
recently observed an increasing number of marihuana-allergic
patients with cross-reactive allergies extending beyond allergy
to fruit and vegetables but also involving cereals, Hevea latex,
tobacco, wine, and beer.
We present our index patient and describe our diagnostic
approach with respect to marihuana allergy. A 24-year-old
woman attended our clinic in mid-2012 with generalized
urticaria, angioedema, and dyspnea after eating cherries,
hazelnuts, walnuts, peanuts, nectarines, and apples. Her history
disclosed no pollen or latex allergy but revealed that the prior
allergic symptoms occurred while smoking marihuana.
In 2013, she consulted because of localized urticaria after
using latex gloves and episodes of angioedema and dyspnea
after smoking tobacco. She also reported generalized urticaria
after eating tomatoes, pineapple, cucumber, raspberries, and
fennel and after drinking wine and gastrointestinal symptoms
after eating wheat-containing products.
70

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82© 2015 Esmon Publicidad
protein of cannabis unlikely [4]. The results of sIgE testing
for molds and fungi remained negative.
In 2013, determination of sIgE revealed seroconversion to
native Hevea latex extract, whereas sIgE to rHev b 1, rHev b 3,
rHev b 5, rHev b 6.01, rHev b 6.02, rHev b 8, rHev b 9, and
rHev b 11 remained negative. The patient also had a positive
sIgE result to tobacco and to the ns-LTP of wheat (rTri a 14).
The Figure shows upregulation of the activation marker
CD63 for the ns-LTPs of C sativa and peach. In 2013, the
result of a basophil activation test (BAT) became positive
for the ns-LTPs of tobacco and crude latex extract (data not
shown). However, although the patient had no history of
kiwifruit allergy and determination of sIgE revealed a positive
sIgE to kiwifruit (5.47 kUA/L) with negative sIgE to various
kiwifruit components, BAT with kiwifruit ns-LTP revealed a
dose-response shift compared with the other ns-LTP extracts.
We report the case of a 24-year-old woman with an IgE-
mediated allergy to marihuana who subsequently developed
extensive cross-reactivity to vegetables, fruit, wheat, tobacco,
latex, and wine. Diagnosis of cannabis allergy was conrmed
by BAT, SPT, and sIgE to industrial hemp, as described
elsewhere [2]. Extensive CRD showed these allergies to be
part of an “ns-LTP syndrome”, with primary sensitization to
In 2012, we performed skin prick tests (SPTs) as described
elsewhere [2], and the result was positive for C sativa extract.
SPTs with inhalant allergens including fungi and latex
disclosed only sensitization to weed pollen. Prick-prick tests
with food extracts revealed skin reactivity to apple, peanut,
and hazelnut.
SPTs were repeated in 2013 and revealed de novo
sensitization to latex and to birch pollen. The result of a prick-
prick test with tobacco was also positive.
In 2012, sIgE reactivity was observed to peanut, hazelnut,
peach, and tomato, as well as to birch, grass, and weed pollen
extracts, but not to latex. Component-resolved diagnosis
(CRD) revealed no sIgE to the recombinant components of
the pollen allergens, suggesting that the plant food allergy was
not caused by pollen or latex. CRD disclosed that the patient
was sensitized to cross-reactive carbohydrate determinants
and to the recombinant ns-LTP of peanut (rAra h 9), hazelnut
(rCor a 8), peach (rPru p 3), and apple (rMal d 3) and to the
native ns-LTP of mugwort (nArt v 3).
Determination of sIgE revealed that the patient produced
antibodies to the industrial hemp variety of C sativa but not
to the thaumatin-like protein of kiwifruit (Actinidia deliciosa,
nAct d 2), thus making sensitization to the thaumatin-like
Cannabis sativa
Tobacco
Peach
Kiwifruit
100
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
0
CD63+ Basophils, %CD63+ Basophils, %
0.01
0.01
0.01
0.01
0.1
0.1
0.1
0.1
1
1
1
1
10
10
10
10
µg/mL
µg/mL
µg/mL
µg/mL
Figure. Percentages of CD63+of the patient’s basophils after stimulation with 4 different concentrations of ns-LTP extract from
Cannabis sativa
, peach,
tobacco, and kiwifruit (black lines). Median (minimum-maximum) of 3 patients sensitized to the major component of birch pollen, Bet v 1 (long dashes),
and 3 healthy individuals who served as controls (short dashes).
71

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82 © 2015 Esmon Publicidad
Manuscript received February 11, 2014; accepted for publication
April 25, 2014.
DG Ebo
University of Antwerp
Faculty of Medicine and Health Sciences
Immunology – Allergology - Rheumatology
Campus Drie Eiken T5.95
Universiteitsplein 1
2610 Antwerpen
Belgium
E-mail: immuno@uantwerpen.be
Can s 3 from C sativa. It has been speculated that Can s 3 is
the major allergen of C sativa and a potential primary source
of sensitization to cross-reactive ns-LTP [5]. Our case-control
study revealed that most patients with cannabis allergy are
sensitized to ns-LTPs from several sources [2]. Comparison
of our data with ndings from Spanish surveys [4,5] and
US surveys [6] reveals that marihuana allergy and related
allergies might differ depending on the geographic region.
In the Spanish series, in addition to sensitization to Can s 3,
a thaumatin-like protein was found to be another cause of
cross-reactivity with food. In contrast to European patients, US
patients are rarely sensitized to Can s 3 and do not demonstrate
overt food allergy. These distinct sensitization proles could
also be associated with differences in allergen composition,
drug manufacturing, and/or sensitization route(s).
In the present case report, different eliciting plant foods are
mentioned and many of them have been reported to contain
clinically relevant ns-LTPs. However, the potential clinical
relevance of tobacco ns-LTP [7] and Hev b 12 from Hevea
latex [8,9] is unclear.
IgE-mediated reactions to tobacco have been reported,
although no association with ns-LTPs has ever been suggested.
Stockli and Bircher [7] described a patient who was sensitized
to tobacco and cannabis; however, they assumed that the
allergic symptoms observed were due to cosensitization.
In conclusion, we report the case of a patient with genuine
marihuana allergy and extensive cross-allergies. These cross-
allergies are rapidly evolving and have extended beyond fruit
and vegetables to involve wheat, tobacco, and Hevea latex. As
this cross-reactivity appears to be associated with sensitization
to an ns-LTP from cannabis, the term marihuana connection
is proposed.
Funding
The authors declare that no funding was received for the
present study.
Conicts of Interest
Vito Sabato is a Clinical Researcher at Research
Foundation Flanders (FWO: 1700614N). Didier G Ebo is a
Senior Clinical Researcher at Research Foundation Flanders
(FWO: 1800614N). The remaining authors declare that they
have no conicts of interest.
References
1. Ballmer-Weber BK, Hoffmann-Sommergruber K. Molecular
diagnosis of fruit and vegetable allergy. Curr Opin Allergy Clin
Immunol. 2011;11(3):229-35.
2. Ebo DG, Swerts S, Sabato V, Hagendorens MM, Bridts CH,
Jorens PG, De Clerck LS. New food allergies in a European
non-Mediterranean region: is Cannabis sativa to blame? Int
Arch Allergy Immunol. 2013;161(3):220-8.
3. Pascal M, Munoz-Cano R, Reina Z, Palacin A, Vilella R, Picado
C, Juan M, Sanchez-Lopez J, Rueda M, Salcedo G, Valero A,
Yague J, Bartra J. Lipid transfer protein syndrome: clinical
pattern, cofactor effect and prole of molecular sensitization to
plant-foods and pollens. Clin Exp Allergy. 2012;42(10):1529-
39.
4. Larramendi CH, Lopez-Matas MA, Ferrer A, Huertas AJ,
Pagan JA, Navarro LA, Garcia-Abujeta JL, Andreu C, Carnes J.
Prevalence of sensitization to Cannabis sativa. Lipid-transfer
and thaumatin-like proteins are relevant allergens. Int Arch
Allergy Immunol. 2013;162(2):115-22.
5. Gamboa P, Sanchez-Monge R, Sanz ML, Palacin A, Salcedo G,
Diaz-Perales A. Sensitization to Cannabis sativa caused by a
novel allergenic lipid transfer protein, Can s 3. J Allergy Clin
Immunol. 2007;120(6):1459-60.
6. Nayak AP, Green BJ, Sussman G, Berlin N, Lata H, Chandra
S, ElSohly MA, Hettick JM, Beezhold DH. Characterization
of Cannabis sativa allergens. Ann Allergy Asthma Immunol.
2013;111(1):32-7.
7. Stockli SS, Bircher AJ. Generalized pruritus in a patient
sensitized to tobacco and cannabis. J Dtsch Dermatol Ges.
2007;5(4):303-4.
8. Pamies R, Oliver F, Raulf-Heimsoth M, Rihs HP, Barber D.
No rHev b 12-specic IgE-response in children sensitized to
natural rubber latex. Allergy. 2005;60(5):709-10.
9. Rihs HP, Rueff F, Lundberg M, Rozynek P, Barber D, Scheurer
S, Cistero-Bahima A, Bruning T, Raulf-Heimsoth M. Relevance
of the recombinant lipid transfer protein of Hevea brasiliensis:
IgE-binding reactivity in fruit-allergic adults. Ann Allergy
Asthma Immunol. 2006;97(5):643-9.
72

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82© 2015 Esmon Publicidad
Prevalence of Asthma and Related Symptoms in
Adolescents: Findings From 3 Surveys
Solé D1, Rosário Filho N2, Sarinho EC3, Silva AR3, Britto M4,
Riedi C3, Cardozo C2, Camelo-Nunes IC1, de Andrade D1, Mallol J5
1Division of Allergy, Clinical Immunology and Rheumatology,
Department of Pediatrics – Escola Paulista de Medicina-Federal
University of São Paulo (EPM-UNIFESP), São Paulo, Brazil
2Department of Pediatrics, Federal University of Paraná, Paraná,
Brazil
3Department of Pediatrics, Federal University of Pernambuco,
Pernambuco, Brazil
4Mother and Child Institute of Pernambuco, Pernambuco, Brazil
5Division of Pediatric Pneumology, University of Santiago,
Santiago, Chile
Key words: Asthma. Adolescents. Prevalence. Severe asthma. ISAAC.
Palabras clave: Asma. Adolescentes. Prevalencia. Asma severa. ISAAC.
The prevalence of asthma has increased signicantly
since the publication of the International Study of Asthma
and Allergies in Childhood (ISAAC) [1]. This standardized
and universally validated instrument can be used throughout
the world to compare rates between centers within the same
country and within the same center on different occasions [1].
Before the advent of ISAAC, few studies had assessed
temporal trends in the prevalence of asthma in children.
Hansen et al [2] observed that the prevalence of asthma and
allergic diseases in Norwegian children (7-14 years) increased
over a period of 23 years (1985-2008) [2]. Malik et al [3]
studied children (9-12 years) in Aberdeen (United Kingdom)
over a longer period (1964-2009) and found a signicant
increase in prevalence from 24.3% in 1999 to 28.4% in 2004,
followed by a decrease to 22.1% in 2009 [3].
In Brazil, the only data available on the sequential
prevalence of asthma are those obtained from the ISAAC
protocol in adolescents (13-14 years) in phases 1 (ISF1, 1994)
and 3 (ISF3, 2003) in 5 centers (Porto Alegre, Curitiba, São
Paulo, Salvador, and Recife). In this rst reassessment (ISF3), a
downward trend in the mean prevalence of current asthma was
documented (wheezing in the last year, 27.7% vs. 19.9%), with
no change in the prevalence of physician-diagnosed asthma
or severe asthma (speech disturbance due to wheezing) [4].
Nine years after completion of ISF3, we thought it would
be interesting to determine the prevalence of current asthma
among adolescents living in those centers that participated in
both ISF1 and ISF3. To answer this question, and following
the recommendations of the ISAAC protocol [1], we collected
new data in Recife, São Paulo, and Curitiba in 2012 with the
approval of the local Institutional Review Boards. The data
obtained during ISF1 and ISF3 were analyzed and approved by
the ISAAC International Data Center, and the 3 centers were
recognized as ofcial. Data were collected at each time point in
the same schools as in ISF1 and ISF3. We used the chi-square
test for trends, and statistical signicance was set at P<.05.
The prevalence of active asthma remained stable in Curitiba
and Recife, but decreased signicantly in São Paulo (Table).
However, there was a signicant increase in the prevalence of
physician-diagnosed asthma. The frequency of episodes tended
to decrease in 2003, although it rose signicantly in 2012 in all
centers. Wheezing associated with exercise remained stable in
Curitiba and Recife and decreased signicantly in São Paulo.
A higher prevalence of nocturnal symptoms was documented
in all centers. In general, the prevalence of current asthma
remained stable with a tendency to decrease, meaning that it
had possibly reached a plateau. The prevalence of physician-
diagnosed asthma increased at all centers, as did that of atypical
symptoms of asthma (nocturnal cough).
Table. Prevalence of Positive Responses to Questions From the Asthma Core Written Questionnaire of the International Study of Asthma and Allergies
in Childhood (ISAAC)a
Question Curitiba São Paulo Recife
1994/5 2003 2012 P 1994/5 2003 2012 P 1994/5 2003 2012 P
N=3008 N=3628 N=3530 Valueb N=3008 N=3161 N=2433 Valueb N=3086 N=2865 N=1149 Valueb
Wheezing ever 40.4 40.7 39.8 NS 45.4 44.6 43.7 NS 39.0 37.8 32.9c <.05
Wheezing last year 18.4 18.9 17.6 NS 23.3 18.7 21.3c <.05 19.7 19.1 19.6 NS
Speech disorder 4.6 3.1 4.5c <.05 5.7 2.9 4.4c <.05 4.8 4.1 7.0d <.05
Physician-diagnosed
asthma 8.6 9.2 13.1d <.05 10.0 10.4 13.6d <.05 21.0 18.0 22.5¥ <.05
Wheezing with
exercise 19.8 19.1 19.9 NS 20.5 17.0 12.1c <.05 20.8 23.0 22.5 NS
Nocturnal cough 30.1 34.7 42.4d <.05 33.0 33.3 45.4d <.05 31.0 37.3 41.0d <.05
Abbreviation: NS, nonsignicant or stable.
aQuestionnaire completed by adolescents from ofcial ISAAC centers that participated in Phase 1 (1994/5), Phase 3 (2003), and in 2012.
bChi-squared.
cDecrease.
dIncrease.
73

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82 © 2015 Esmon Publicidad
Manuscript received April 6, 2014; accepted for publication
April 25, 2014.
Dirceu Solé
Rua dos Otonis 725, Vila Clementino
CEP: 04025-002
E-mail: dirceu.sole@unifesp.br
During the 18 years since ISF1, we found that the Human
Development Index (HDI) in Brazil had increased from 0.724
in 1993-4 to 0.807 [5] in 2012. The HDI included all 3 cities.
The data are supported by the change observed in gross
national income per capita, which increased from US$3040 in
1994 to US$11 630 in 2012 [6]. Although the economic status
of Brazil has improved, no association can be established with
the changes in prevalence rates observed in the 3 cities.
In the year 2000, asthma began to receive more
attention from the health authorities, which extended free
medication for severe asthma to patients with mild or
moderate asthma [7] from 2005 onward. The creation of care
programs for patients with asthma and continuing medical
education might explain the increase in medical diagnosis.
It is possible that accessibility to specic treatment enabled
better control of the disease, as seen in the reduced frequency
of severe exacerbations and nonspecic symptoms in some
adolescents. With the introduction of guidelines and consensus
statements on asthma, knowledge about the disease is more
widespread; therefore, the term asthma is increasingly used
by physicians and patients to replace euphemisms such as
bronchitis and tracheobronchitis. Another consequence was the
standardization of asthma management, although this was not
always based on national or international guidelines. Finally,
air pollution and climate changes may have played a role in
the reduced prevalence of the disease. Of the 3 participating
centers, the monitoring systems in Curitiba and São Paulo
detected a signicant improvement in air quality [8,9,10].
In conclusion, the prevalence of current asthma throughout
the 18-year period reached its peak and then leveled off.
Meanwhile, the prevalence of more severe and atypical forms
has increased. The explanations for these ndings remain
unknown, but the results of the present study indicate that
the therapeutic approach to patients with asthma should be as
comprehensive as possible and focus primarily on reducing
severity and morbidity.
Funding
This study was partially funded by PP-SUS and FAPESP
proc.# 2009-53303-5, São Paulo, Brazil.
Conicts of Interest
The authors declare that they have no conicts of interest.
References
1. Asher MI, Keil U, Anderson HR, Beasley R, Crane J, Martinez
F, Mitchell EA, Pearce N, Sibbald B, Stewart AW, Strachan D,
Weiland SK, Williams HC. International Study of Asthma and
Allergies in Childhood (ISAAC): rationale and methods. Eur
Respir J. 1995;8:483-91.
2. Hansen TE, Evjenth B, Holt J. Increasing prevalence of asthma,
allergic rhinoconjunctivitis and eczema among schoolchildren:
three surveys during the period 1985-2008. Acta Paediatr.
2013;102:47-52.
3. Malik G, Tagiyeva N, Aucott L, McNeill G, Turner SW. Changing
trends in asthma in 9-12 year olds between 1964 and 2009.
Arch Dis Child. 2011;96:227-31.
4. Solé D, Melo KC, Camelo-Nunes IC, Freitas LS, Britto M,
Rosário NA, Jones M, Fischer GB, Naspitz CK. Changes in the
prevalence of asthma and allergic diseases among Brazilian
schoolchildren (13–14 years old): comparison between ISAAC
Phases One and Three. J Trop Pediatr. 2007;53:13-21.
5. PNUD – Programa das Nações Unidas para o Desenvolvimento
– Ranking IDHM Municípios 2010 Mozilla Firefox in
http://www.pnud.org.br/atlas/ranking/Ranking-IDHM-
Municipios-2010.aspx Last accessed January 10, 2014 .
6. U.S. Census Bureau, Statistical Abstract of the United States:
2011; GNI per capita, Atlas method (current US$) in http://
data.worldbank.org/indicator/NY.GNP.PCAP.CD Last accessed
January 16, 2014
7. Rizzo JA. Disponibilidade dos medicamentos para asma
e os direitos dos asmáticos. Rev Bras Alerg Imunopatol.
2006;29:142-3.
8. Comportamento sazonal da poluição do ar em São Paulo -
Análise de 14 anos de dados da RMSP e Cubatão - 1981 a
1994 in http://www.cetesb.sp.gov.br/ar/qualidade-do-ar/31-
publicacoes-e-relatorios Last accessed December 20, 2013
9. Qualidade do ar no estado de São Paulo 2012 / CETESB,
São Paulo: CETESB, 2013. In http://www.cetesb.sp.gov.br/ar/
qualidade-do-ar/31-publicacoes-e-relatorios. Last accessed
December 20,2013 .
10. Relatório qualidade do ar na região metropolitana de
Curitiba – Ano de 2003 em Monitoramento da qualidade
do ar – Secretaria do meio ambiente e recursos hídricos
in http://www.iap.pr.gov.br/modules/conteudo/conteudo.
php?conteudo= 639 Last accessed December 20, 2013.
74

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82© 2015 Esmon Publicidad
An 18-year-old girl (patient 1) and her 48-year-old father
(patient 2) attended our outpatient clinic because of possible
hypersensitivity reactions within 15-30 minutes after ingestion
of homemade apple beignets and coffee. Patient 1 experienced
dyspnea, generalized pruritus, and eyelid angioedema. Patient
2 presented similar—albeit more severe—symptoms and had
generalized urticaria. Both were successfully treated with
antihistamines and short-acting β2-agonists. The clinical history
revealed that both patients had an atopic background with
rhinoconjunctivitis and mild asthma due to monosensitization
to house dust mite. On 1 occasion, patient 2 experienced an
identical reaction after ingestion of pancakes made from the
same packet of beignet our, which was stored open at room
temperature in a kitchen cupboard. Interestingly, the mother
and another daughter, neither of whom was sensitized to house
dust mite, had eaten the apple beignets without incident. The
table summarizes the laboratory and skin test ndings that
demonstrate sensitization to house dust mite and various storage
mites in both patients. In contrast, no sensitization was observed
with wheat, buckwheat, lupine, a-amylase, uncontaminated
beignet our, and yeast. Although the suspected beignet our
was thrown away and therefore unavailable for further testing,
we believe these 2 simultaneous case histories and the absence
of symptoms in 2 relatives are highly indicative of OMA
caused by mite-contaminated beignet our. Moreover, since
the diagnosis of OMA was conrmed, both patients have eaten
beignets made from uncontaminated beignet our such as that
applied in the skin tests.
Although the aeroallergens house dust mite and storage
mite are well-recognized causes of respiratory allergies
such as rhinoconjunctivitis and asthma, their potential as
food allergens remains less clear. OMA is a relatively new
syndrome, which was rst described by Erben et al [1] in 1993.
It affects patients of all ages and both sexes and manifests with
symptoms that vary depending on the site and extent of mast
cell/basophil degranulation, which generally occurs within
15-60 minutes of ingestion. Although the clinical course may
be self-limiting, most reactions are severe, with angioedema
(also of the oropharynx with stridor) and involvement of
the upper and lower respiratory tracts (eg, rhinorrhea, nasal
itching and/or congestion, dyspnea, wheezing, and chest
tightness). Gastrointestinal symptoms frequently complete
the clinical picture. Cardiovascular reactions and death are
not excluded [2-6]. To date, OMA has not been observed
to present as isolated oral allergy syndrome. An association
has been proposed between OMA and hypersensitivity to
nonsteroidal anti-inflammatory drugs [2,7] or exercise;
however, this association was absent in the cases we report
and elsewhere [6]. The latter has been designated dust mite
ingestion–associated exercise-induced anaphylaxis [8]. OMA
has also been described after inhaling cooking vapors from a
commercial pancake mix contaminated with the house dust
mite Dermatophagoides farinae [9].
Although most cases have been reported in tropical and
subtropical countries, where climatological conditions are
favorable for mite growth (high temperature and relative
humidity), the ndings presented here and in other case
reports [9,10] indicate that OMA can also occur in countries
with a temperate climate. In these cases, mite infestation
should be sought in inappropriate storage conditions at ambient
Simultaneous Oral Mite Anaphylaxis (Pancake
syndrome) in a Father and Daughter and a Review of
the Literature
Mangodt EA, Van Gasse AL, Bridts CH, Sabato V, Ebo DG
Faculty of Medicine and Health Science, Department of
Immunology–Allergology–Rheumatology, University of Antwerp,
Antwerp University Hospital, Antwerp, Belgium
Key words: Pancake syndrome. Oral mite anaphylaxis. Food allergy.
House dust mite.
Palabras clave: Síndrome del pancake. Analaxia oral por ácaros. Alergia
alimentaria. Ácaros del polvo de casa.
Oral mite anaphylaxis (OMA), also known as pancake
syndrome, is a condition characterized by (severe) allergic
reactions after ingestion of food containing mite-contaminated
our. We report for the rst time a case of OMA occurring
simultaneously in a father and daughter that was probably
caused by mite-contaminated beignet our.
Table. Laboratory and Skin Test Results
Parameter Patient 1 Patient 2 Normal Value
Total and Specic IgE
Total IgE 361.7 235.6 <120 kU/L
Dermatophagoides
pteronyssinus 76 24.00 <0.35 kUA/L
Der p 1 49.90 6.62 <0.35 kUA/L
Der p 2 41.20 11.80 <0.35 kUA/L
Der p 10 <0.35 <0.35 <0.35 kUA/L
Dermatophagoides farinae 56.40 12.80 <0.35 kUA/L
Acarus siroa 3.57 0.52 <0.35 kUA/L
Glycyphagus domesticusa 3.40 1.28 <0.35 kUA/L
Tyrophagus putrescentiaea 12.00 1.56 <0.35 kUA/L
Wheat <0.35 <0.35 <0.35 kUA/L
Buckwheat <0.35 <0.35 <0.35 kUA/L
a-Amylase <0.35 <0.35 <0.35 kUA/L
Lupine <0.35 <0.35 <0.35 kUA/L
Saccharomyces cerevisiae <0.35 <0.35 <0.35 kUA/L
Skin Prick Testsb
House dust mite 7/22 5/12 <3/3 mm
Wheat 0/0 0/0 <3/3 mm
Beignet our (new packet,
uncontaminated) 0/0 0/0 <3/3 mm
aStorage mites
bSkin test results are expressed as wheal/are reactions in mm.
75

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82 © 2015 Esmon Publicidad
temperature, as we report here. In fact, packets of opened
our should be stored in sealed containers in the refrigerator
or freezer, where conditions are hostile to mite infestation.
The foods predominantly involved in OMA are pancakes
(most common), beignets, sponge cakes, pizza, pasta,
wheat bread, white sauce, and meat or fish dusted with
wheat our. In Japan, the food most commonly involved
in OMA is okonomiyaki mix, whose ingredients contain
wheat our. Takoyaki mix, which is similar to okonomiyaki
mix, is the second most prevalent cause of OMA in
Japan [6]. The mite species involved are Dermatophagoides
pteronyssinus, D farinae, Blomia tropicalis, and the storage
mites Lepidoglyphus destructor, Tyrophagus putrescentiae,
Thyreophagus entomophagus, Blomia freemani, Suidasia
medanensis, and Aleuroglyphus ovatus. All of these species
can live indoors if the conditions are favorable. To date, the
allergen(s) responsible for OMA remains elusive. As cooked
and baked foods are able to trigger symptoms, it has been
suggested that heat-stable components such as Der p 2 are
involved in the pathogenesis of OMA [2]. The patients reported
here are sensitized to both Der p 1 and Der p 2, but not to house
dust mite tropomyosin (Der p 10).
The criteria for the diagnosis of OMA are the following:
compatible symptoms occurring after ingestion of food
prepared with contaminated our; previous history of rhinitis,
asthma, atopic dermatitis, and/or food allergy; demonstration
of IgE-mediated sensitization to mite allergens in vivo or in
vitro; positive skin test result with the suspect our; negative
skin test result to wheat and to uncontaminated our; clinical
tolerance to food made with uncontaminated wheat our;
and identication of mites or mite allergens in the suspect
our. However, as reported here and elsewhere [6], the culprit
food/our might not always be available for skin testing or
microscopic evaluation. The main differential diagnoses are
with genuine wheat allergy and wheat-dependent exercise-
induced anaphylaxis.
No cure has been found for OMA. Patients who are
sensitized to mites should avoid ingestion of mite-infested
food. To our knowledge, there are no data on the effects of
mite immunotherapy on OMA.
In conclusion, OMA is easily overlooked and may be
responsible for anaphylaxis where no obvious cause is
identiable (idiopathic anaphylaxis). Therefore, mites should
be considered in patients presenting with mite sensitization
and food-induced allergic reactions with no apparent allergy
to the ingredients.
Funding
The authors declare that no funding was received for the
present study.
Conicts of Interest
The authors declare that they have no conicts of interest.
References
1. Erben AM, Rodriguez JL, McCullough J, Ownby DR.
Anaphylaxis after ingestion of beignets contaminated
with Dermatophagoides farinae. J Allergy Clin Immunol.
1993;92:846-9.
2. Blanco C, Quiralte J, Castillo R, Delgado J, Arteaga C,
Barber D, Carrillo T. Anaphylaxis after ingestion of wheat
our contaminated with mites. J Allergy Clin Immunol.
1997;99:308-13.
3. Sanchez-Borges M, Capriles-Hulett A, Fernandez-Caldas
E, Suarez-Chacon R, Caballero F, Castillo S, Sotillo E. Mite-
contaminated foods as a cause of anaphylaxis. J Allergy Clin
Immunol. 1997;99:738-43.
4. Edston E, van Hage-Hamsten M. Death in anaphylaxis in a man
with house dust mite allergy. Int J Legal Med. 2003;117:299-
301.
5. Sanchez-Borges M, Suarez CR, Capriles-Hulett A, Caballero-
Fonseca F, Fernandez-Caldas E. Anaphylaxis from ingestion
of mites: pancake anaphylaxis. J Allergy Clin Immunol.
2013;131:31-5.
6. Takahashi K, Taniguchi M, Fukutomi Y, Sekiya K, Watai K,
Mitsui C, Tanimoto H, Oshikata C, Tsuburai T, Tsurikisawa N,
Minoguchi K, Nakajima H, Akiyama K. Oral mite anaphylaxis
caused by mite-contaminated okonomiyaki/ pancake-mix
in Japan: 8 case reports and a review of 28 reported cases.
Allergol Int. 2014;63:51-6.
7. Sanchez-Borges M, Capriles-Hulett A, Capriles-Behrens E,
Fernandez-Caldas E. A new triad: sensitivity to aspirin, allergic
rhinitis, and severe allergic reaction to ingested aeroallergens.
Cutis. 1997;59:311-4.
8. Sanchez-Borges M, Iraola V, Fernandez-Caldas E, Capriles-
Hulett A, Caballero-Fonseca F. Dust mite ingestion-associated,
exercise-induced anaphylaxis. J Allergy Clin Immunol.
2007;120:714-6.
9. Hannaway PJ, Miller JD. The pancake syndrome (oral mite
anaphylaxis) by ingestion and inhalation in a 52-year-old
woman in the northeastern United States. Ann Allergy Asthma
Immunol. 2008;100:397-8.
10. Posthumus J, Borish L. A 71-year-old man with anaphylaxis
after eating grits. Allergy Asthma Proc. 2012;33(1):110-3.
Manuscript received July 17, 2014; accepted for publication
October 20, 2014.
DG Ebo
University of Antwerp
Faculty of Medicine and Health Science
Department of Immunology, Allergology, Rheumatology
Campus Drie Eiken T.595
Universiteitsplein 1
2610 Antwerpen, Belgium
E-mail: immuno@uantwerpen.be
76

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82© 2015 Esmon Publicidad
Oral Tolerance Induction With Wheat: A Valid
Therapeutic Option in Allergic Patients
Vila L, García V
Pediatric Allergy Unit, Hospital Teresa Herrera, La Coruña, Spain
Key words: Wheat allergy. Gluten. Oral tolerance induction. Liver
transplant. Food allergy.
Palabras clave: Alergia a trigo. Gluten. Inducción de tolerancia oral.
Trasplante hepático. Alergia alimentaria.
Wheat is the most widely consumed cereal in the world.
In Europe, the prevalence of wheat allergy in infancy has been
estimated to be 0.1% [1].
In the last few years, an increasing number of studies have
investigated achievement of tolerance by repeated exposure
to a food allergen (especially cow’s milk, egg, and peanut),
and the results have been encouraging [2].
We report 3 cases of children with persistent wheat allergy
who underwent successful oral tolerance induction (OTI).
Patient 1 was an 8-year-old girl who developed generalized
urticaria at 17 months of age immediately after ingestion of
baby food containing wheat, oats, barley, rye, rice, and corn.
She was diagnosed with gluten allergy based on skin prick
testing (SPT) and serum specic IgE determination. Since
then, she has followed a gluten-free diet.
At 7 years of age, the results of SPT were still positive to
gluten (25 mm), w-5-gliadin (10 mm), wheat (10 mm), oats
(5 mm), barley (15 mm), and rye (16 mm), as were those for
serum IgE (ImmunoCAP, Phadia) to wheat (>100 kUA/L),
gluten (>100 kUA/L), rye (>100 kUA/L), barley (>100 kUA/L),
oats (17.4 kUA/L), and w-5-gliadin (1.54 kUA/L).
At this time, OTI with gluten-containing cereals was
started. Baby food (Nutriben, Alter Farmacia) containing
5 cereals (wheat, oats, rye, corn, and rice) was initially
administered as shown in the Table. The initial dose was 0.3 g
of baby food diluted in water. Doses were increased every
week. When 14 g was reached, the baby food was substituted
with wheat Marie biscuits (Artiach) to maintain palatability.
The induction phase was nished once 100 g of biscuit was
tolerated, and a daily intake of at least 100 g of wheat was
recommended.
During this phase, the patient complained of occasional,
mild abdominal pain.
One year later, she developed generalized urticaria induced
by exercise 2 hours after eating a sandwich. She was advised
to avoid exercise for 4 hours after ingestion of wheat, and she
has not presented further reactions.
Tolerance to rye was conrmed by open food challenge
9 months after OTI.
Patient 2 was a 7-year-old boy who experienced vomiting,
diarrhea, and eyelid angioedema immediately after eating
baby food containing gluten when he was 1 year old. He was
diagnosed with allergy to wheat, barley, and rye based on
SPT and serum specic IgE determination. Since then, he has
followed a gluten-free diet.
He was also allergic to egg and cow’s milk.
He had outgrown the egg allergy by 4 years of age. When he
was 5 years old, he underwent successful OTI with cow’s milk.
At 6 years of age, serum specic IgE was determined to
wheat (4.3 kUA/L), barley (2.3 kUA/L), oats (<0.35 kUA/L), and
rTri a 19 (<0.35 kUA/L). The results of SPT were positive to
wheat (10 mm), barley (3 mm), and rye (3 mm) and negative
for oats and w-5-gliadin. Open food challenge with oats was
then performed with no adverse reactions. Before OTI, the
patient underwent open food challenge with wheat. A few
minutes after ingestion of 15 g of Marie biscuit, he began to
vomit and developed and perioral urticaria.
OTI with wheat was performed as described above (Table).
The patient did not present adverse reactions during the
induction phase and has been on maintenance therapy for 10
months with no reported reactions.
Tolerance to rye was conrmed by open food challenge
9 months after OTI.
Patient 3 was a 14-year-old girl who underwent liver
transplant when she was 1 year old because of biliary atresia.
Since then, she has been taking daily oral tacrolimus and
cotrimoxazole 3 times a week. Two years after transplant, she
developed multiple food allergies to milk, egg, kiwi, banana,
gluten-containing cereals, sh, and tree nuts.
At 13 years of age, the patient underwent an open food
challenge with wheat Marie biscuits. After ingesting 2 g (0.13 g
of protein), she developed dysphagia and oral pruritus. The
results of SPT at that time were positive for gluten (11×10 mm),
wheat (15×7 mm), barley (5×5 mm), and rye (5×5 mm) and
negative for oats. Serum gluten IgE was 8.67 kUA/L.
We followed the protocol described above, but the patient
eventually rejected the biscuits, so they were substituted with
an equivalent amount of wheat bread. During the induction
phase she complained of occasional mild abdominal pain and,
after 10 weeks, could tolerate 100 g of bread. She has been on
maintenance therapy for 4 months with no further reactions.
Table. Oral Tolerance Induction With Wheat: Induction Phase
Week Cereal-Containing Fooda Dose
1 Cereal baby food 300 mg
2 Cereal baby food 600 mg
3 Cereal baby food 1.2 g
4 Cereal baby food 3.2 g
5 Cereal baby food 7 g
6 Cereal baby food 14 g
7 Marie biscuit 10 g
8 Marie biscuit 20 g
9 Marie biscuit 40 g
10 Marie biscuit 60 g
11 Marie biscuit 80 g
12 Marie biscuit 100 g
aCereal baby food contained 5.5 g of protein/100 g; Marie biscuit
contained 6.5 g of protein/100 g.
77

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82 © 2015 Esmon Publicidad
Tolerance to rye was confirmed by open food challenge
3 months after OTI.
Although patients tend to tolerate wheat allergy, most outgrow
it by late childhood or adolescence [3,4]. During this time, an
exclusion diet was the only possible therapeutic approach besides
medication for accidental exposure. Few reports on OTI with
wheat have been published [5-7]. Recently, Rodríguez del Río
et al [7] described a short protocol followed by 6 wheat-allergic
children with a favorable outcome in 5 cases. This is the most
extended report on wheat OTI published up to date.
Gluten, specically Tri a 19 (a ω-5-gliadin) [8] and Tri a 36
(a low-molecular-weight glutenin) [9], has been identied as a
major allergen in immediate wheat allergy in children. Gluten
is also present in barley and rye. Oats are gluten-free, although
they can be a source of gluten, since many oat products are
contaminated with wheat and barley during harvesting and
milling processes.
Interestingly, Rodríguez del Río et al [7] could not
demonstrate specic IgE to ω-5-gliadin and glutenin in most
of the children included in their study, although they did nd a
high prevalence of sensitization to 3 members of the α-amylase
inhibitor family, thus supporting the role of these inhibitors
as major allergens. This prole seems likely for patient 2,
who did not have specic IgE to gluten or ω-5-gliadin, unlike
patients 1 and 3.
Multiple food allergy is a major problem in children after
liver transplantation. Oral tacrolimus and young age at the
time of the transplant have been described as risk factors for
the development of food allergy, which seems to be persistent
over time [10]. This is the rst report on successful OTI in a
liver transplant recipient.
We believe that OTI with wheat is a valid alternative to an
exclusion diet in wheat-allergic patients.
Acknowledgments
We are grateful to our nurse, Ofelia Alba Lago, for her
work.
Funding
The authors declare that no funding was received for the
present study.
Conicts of Interest
The authors declare that they have no conicts of interest.
References
1. Nwaru BI, Hickstein L, Panesar SS, Roberts G, Muraro A, Sheikh
A. The EAACI Food Allergy and Anaphylaxis Guidelines Group.
Prevalence of common food allergies in Europe: a systematic
review and meta-analysis. Allergy. 2014;69(8):992-07.
2. Calvani M, Giorgio V, Miceli Sopo S. Specic oral tolerance
induction for food. A systematic review. Eur Ann Allergy Clin
Immunol. 2010;42:11-9.
3. Keet CA1, Matsui EC, Dhillon G, Lenehan P, Paterakis M, Wood
RA. The natural history of wheat allergy. Ann Allergy Asthma
Immunol. 2009;102(5):410-5.
Manuscript received September 17, 2014; accepted for
publication October 20, 2014.
Leticia Vila
Pediatric Allergy Unit
Children’s Hospital Teresa Herrera
Xubias de Abaixo, s/n
15006 La Coruña, Spain
E-mail: leticia.vila.sexto@sergas.es
4. Czaja-Bulsa G, Bulsa M. The natural history of IgE mediated
wheat allergy in children with dominant gastrointestinal
symptoms. Allergy Asthma Clin Immunol. 2014;10(1):12.
5. Nucera E, Pollastrini E, De Pasquale T, Buonomo A, Roncallo C,
Lombardo C, Sabato V, Gasbarrini G, Schiavino D, Patriarca G.
New Protocol for Desensitization to Wheat Allergy in a Single
Case. Dig Dis Sci. 2005;50(9):1708-9.
6. Fujino A, Kurihara K. Two cases of rush specic oral tolerance
induction for wheat allergy. Aerugi. 2010;59(11):1580-4.
7. Rodriguez del Río P, Díaz-Perales A, Sanchez-García S,
Escudero C, dos Santos P, Catarino M, Ibañez MD. Oral
immunotherapy in children with IgE-mediated wheat allergy:
outcome and molecular changes. J Investig Allergol Clin
Immunol. 2014;24(4):240-8.
8. Palosuo K, Varjonen E, Kekki OM, Klemola T, Kalkkinen N,
Alenius H, Reunala T. Wheat omega-5 gliadin is a major
allergen in children with immediate allergy to ingested wheat.
J Allergy Clin Immunol. 2001;108:634-8.
9. Baar A, Pahr S, Constantin C, Scheiblhofer S, Thalhamer J,
Giavi S, Papadopoulos NG, Ebner C, Mari A, Vrtala S, Valenta
R. Molecular and immunological characterization of Tri a 36, a
low molecular weight glutenin, as a novel major wheat food
allergen. J Immunol. 2012;189:3018-25.
10. De Bruyne R, Dullaers M, Van Biervliet S, Vande Velde S,
Raes A, Gevaert P, Van Winckel M. Post-transplant food
allergy in children is associated with liver and not with renal
transplantation: a monocentric comparative study. Eur J
Pediatr. 2013;172(8):1069-75.
78

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82© 2015 Esmon Publicidad
IgE-Mediated Anaphylaxis to Ketoprofen: A Case
Report
De Pasquale T1, Buonomo A2, Illuminati I1, D’Alò S1, Pucci S1
1Department of Allergy, Ospedale Generale, Civitanova Marche,
Italy
2Department of Allergy, Università Cattolica del Sacro Cuore,
Rome, Italy
Key words: Anaphylaxis. IgE-mediated ketoprofen allergy. Tryptase.
Palabras clave: Analaxia. Alergia a ketoprofeno mediada por IgE.
Triptasa.
The propionic acid derivative ketoprofen is a nonsteroidal
anti-inammatory drug (NSAID) that is used both topically and
systemically because of its analgesic and anti-inammatory
properties.
It is frequently responsible for contact and photocontact
allergic reactions when used topically, with severe and costly
adverse reactions [1]. Nonallergic hypersensitivity reactions
are also frequent. These have a wide spectrum of clinical
presentations and severity, ranging from cutaneous symptoms
such as urticaria and/or angioedema to anaphylaxis [2].
Selective immediate hypersensitivity reactions to a single
NSAID are less frequent, and an IgE-mediated mechanism is
often hypothesized but rarely demonstrated [3]. Nine cases
of anaphylaxis to diclofenac were recently reported. Seven
patients underwent allergy testing, and 4 had positive skin
test results. In 2, a positive result was also obtained with the
basophil activation test [4].
We report the case of a 42-year-old woman with chronic
spontaneous urticaria treated with cetirizine 10 mg/d. The
patient experienced an anaphylactic reaction characterized by
generalized urticaria, labial angioedema, vomiting, diarrhea,
and hypotension 2 hours after oral administration of ketoprofen
80 mg. She went to the emergency department, where her
blood pressure (BP) was 90/70, and was treated immediately
with intravenous (IV) chlorphenamine 10 mg, IV ranitidine
50 mg, and IV methylprednisolone 40 mg. A blood sample was
taken to detect serum tryptase (ImmunoCAP, Thermo Fisher
Scientic). Cutaneous symptoms receded in about 2 hours, and
the patient was discharged with a BP of 130/80.
Six weeks later, the patient was referred to the allergy
department of the local hospital. She underwent skin prick
and intradermal tests with injectable ketoprofen at a maximum
concentration of 3 mg/mL (dilution 1:10), and another
blood sample was taken to measure baseline serum tryptase
(ImmunoCAP). Histamine (10 mg/mL) and saline were used
as positive and negative controls, respectively. Intradermal
tests with ketoprofen were also performed in 10 healthy
controls, who gave their written informed consent. Skin tests
were performed and read according to the indications of the
European Academy of Allergy and Clinical Immunology [5].
Skin prick tests yielded negative results but the intradermal
test with ketoprofen was strongly positive at a concentration
of 0.03 mg/mL (mean wheal diameter, 6.5 mm; surrounding
are, 21 mm) while all the controls had negative results.
Serum tryptase was 30.30 μg/L during the reaction, although
the baseline value was within the normal range (3.61 μg/L).
These data are consistent with a true anaphylactic reaction
caused by an IgE-mediated allergy to ketoprofen.
The tests were followed by an oral challenge test with
acetaminophen, in which the patient tolerated a cumulative
dose of 500 mg.
NSAID hypersensitivity reactions are very common in
clinical practice and are often characterized by respiratory or
cutaneous symptoms [2]. Anaphylaxis is less frequent, although
it has been reported with diclofenac [4], ibuprofen [6], and
naproxen [7]. IgE-mediated reactions are rare and are mostly
induced by pyrazolones [3].
We report the rst case of an IgE-mediated allergy to
ketoprofen conrmed by skin tests. In previous reports of
anaphylaxis to ibuprofen [6] and naproxen [8], an IgE-
mediated reaction was conrmed by skin prick test only for
ibuprofen, whereas skin tests with naproxen were negative.
We think the possibility of an IgE-mediated reaction to an
NSAID should always be taken into consideration in patients
with severe reactions and no clinical history of other NSAID
reactions. Therefore, skin testing with the culprit drug should
be performed in all single reactions to conrm or rule out an
immune-mediated hypersensitivity reaction. Further studies
are needed to establish the concentrations for skin tests to
ketoprofen (and other NSAIDs) in order to guarantee adequate
specicity.
A possible explanation for the 2-hour interval between
ingestion and the reaction is that the patient was under treatment
with an antihistamine that could have delayed the reaction.
Serum tryptase is a useful marker for conrming the
clinical diagnosis of anaphylaxis and should be applied in all
emergency departments.
Our findings are limited by the fact that we did not
analyze cross-reactivity with other propionic acid derivatives
(eg, naproxen and ibuprofen). Moreover, we did not perform
challenge tests with nonselective NSAIDs such as salicylic
acid derivatives and acetic acid derivatives, because they could
have exacerbated the patient’s chronic spontaneous urticaria.
Although no standardized protocols have been designed
to date, we recommend considering the possibility of IgE-
mediated reactions to NSAIDs and performing skin tests to
conrm or rule out allergy.
Funding
The authors declare that no funding was received for the
present study.
Conicts of Interest
The authors declare that they have no conicts of interest.
References
1. Noize P, Bénard-Laribière A, Aulois-Griot M, Moore N,
Miremont-Salamé G, Haramburu F. Cutaneous adverse effects
79

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82 © 2015 Esmon Publicidad
of ketoprofen for topical use: clinical patterns and costs. Am J
Clin Dermatol. 2010;11:131-6.
2. Kowalski ML, Asero R, Bavbek S, Blanca M, Blanca-Lopez
N, Bochenek G, Brockow K, Campo P, Celik G, Cernadas J,
Cortellini G, Gomes E, Niżankowska-Mogilnicka E, Romano
A, Szczeklik A, Testi S, Torres MJ, Wöhrl S, Makowska J.
Classication and practical approach to the diagnosis
and management of hypersensitivity to nonsteroidal anti-
inammatory drugs. Allergy. 2013;68:1219-32.
3. Canto MG, Andreu I, Fernandez J, Blanca M. Selective
immediate hypersensitivity reactions to NSAIDs. Curr Opin
Allergy Clin Immunol. 2009;9:293-7.
4. Picaud J, Beaudouin E, Renaudin JM, Pirson F, Metz-Favre
C, Dron-Gonsalvez M, Moneret-Vautrin DA. Anaphylaxis
to diclofenac: nine cases reported to the Allergy Vigilance
Network in France. Allergy. 2014;69:1420-23.
5. Brockow K, Garvey LH, Aberer W, Atanaskovic-Markovic M,
Barbaud A, Bilo MB, Bircher A, Blanca M, Bonadonna B, Campi
P, Castro E, Cernadas JR, Chiriac AM, Demoly P, Grosber M,
Gooi J, Lombardo C, Mertes PM, Mosbech H, Nasser S, Pagani
M, Ring J, Romano A, Scherer K, Schnyder B, Testi S, Torres M,
Trautmann A, Terreehorst I; ENDA/EAACI Drug Allergy Interest
Group. Skin test concentrations for systemically administered
drugs -- an ENDA/EAACI Drug Allergy Interest Group position
paper. Allergy. 2013;68:702-12.
6. Takahama K, Kubota Y, Mizoguchi M. A case of anaphylaxis
due to ibuprofen. J Dermatol. 2000;27:337-40.
7. van Puijenbroek EP, Egberts A, Meyboom R, Leufkens
H. Different risks for NSAID-induced anaphylaxis. Ann
Pharmacother. 2002;36:24-9.
8. Klote MM, Smith LJ. A case of anaphylaxis to naproxen.
Allergy. 2005;60:260-1.
Manuscript received September 18, 2014; accepted for
publication October 28, 2014.
Alessandro Buonomo
Department of Allergy
Università Cattolica del Sacro Cuore
Largo Gemelli, 8
00168 Rome
Italy
E-mail: alessandrobuonomo@hotmail.com
Two Cases of Cytarabine Syndrome Successfully
Resolved by Desensitization
Lim KH, Kim JY, Kang MG, Park HK, Kang HR
Department of Internal Medicine, Seoul National University
College of Medicine, Seoul, Korea
Key words: Cytarabine. Infusion reaction. Desensitization.
Palabras clave: Citarabina. Reacción infusional. Desensibilización.
The chemotherapeutic agent cytarabine is effective in
the treatment of acute leukemia and lymphoma. Common
adverse effects of cytarabine include myelosuppression,
gastrointestinal disturbances, neurotoxicity, and an infusion
reaction known as cytarabine syndrome. Cytarabine syndrome
commonly presents as fever, diaphoresis, myalgia, skin
eruptions [1], and, less frequently, hypotension [2]. While its
mechanism is unclear, proinammatory cytokines are believed
to mediate in this u-like syndrome [3]. The clinical signs
and symptoms of cytarabine syndrome are similar to those
of allergic reactions. Unlike allergic reactions, the symptoms
of cytarabine syndrome can occur even on the rst exposure
to the drug and are mainly associated with the concentration
and infusion rate. Slower infusion rates and premedication
with corticosteroids, antihistamines, and acetaminophen
can prevent most infusion reactions. However, in some
patients, severe infusion reactions occur despite intensive
premedication, and measures such as desensitization are
necessary before treatment can be continued. Desensitization
protocols to prevent non–IgE-mediated infusion reactions have
been reported in the literature [4,5], but they are relatively
uncommon. Here, we report 2 cases of cytarabine syndrome
that resolved successfully after desensitization.
A 45-year-old woman diagnosed with precursor B
acute lymphoblastic leukemia underwent bone marrow
transplantation but experienced a relapse. She took reinduction
chemotherapy including high-dose methotrexate and
cytarabine (intravenous methotrexate 1.0 g/m2 on day 1,
followed by cytarabine 3.0 g/m2 twice daily on days 2 and 3).
On the second day, 30 minutes after the rst cytarabine
infusion, she developed fever (38.3ºC), which rose to 40.3ºC
despite treatment with acetaminophen 650 mg, and her blood
pressure dropped from 113/74 mmHg to 79/46 mmHg. Her
vital signs normalized with normal saline and norepinephrine.
However, she experienced shivering, headache, chest
tightness, shortness of breath, and hypotension within
2 minutes of restarting the infusion. Her symptoms subsided
with discontinuation of cytarabine. On day 3, cytarabine was
resumed at a slower rate with premedication (acetaminophen
650 mg, chlorpheniramine 4 mg, and hydrocortisone 100 mg).
However, dyspnea, chest tightness, headache, and hypotension
reappeared, and the infusion was stopped. After a thorough
review of the patient’s medications, intravenous uids, and
signs and symptoms, it was decided that the most likely
diagnosis was cytarabine-induced infusion reaction. In order
80

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82© 2015 Esmon Publicidad
to continue administering of therapy with cytarabine, we
developed a desensitization protocol. Our 11-step protocol
consisted of 4 solutions starting with a 1:1000 dilution of the
full concentration. Chlorpheniramine 4 mg and hydrocortisone
100 mg were administered 30 minutes before initiation of
desensitization (Table). The patient completed the protocol
without adverse events and received the full planned dose of
cytarabine.
The second patient was a 66-year-old woman who received
induction chemotherapy with udarabine, cytarabine, and
idarubicin for acute myeloid leukemia. She experienced
fever, chills, and shivering within 1 hour of the cytarabine
infusion, although the chemotherapy cycle was completed with
occasional acetaminophen and symptomatic treatment. Since
her disease had not remitted after the rst course of induction
chemotherapy, reinduction chemotherapy was administered
with the same regimen. However, she presented fever, chills,
shivering, and hypotension after 30 minutes of the cytarabine
infusion, and it was decided to administer cytarabine through
desensitization. The desensitization protocol used was the same
as in the rst case, and a full therapeutic dose of cytarabine
was administered without breakthrough reactions.
Many antineoplastic drugs, including cytarabine, are
frequently associated with infusion reactions. Patients who
experience severe reactions require prompt assessment and
aggressive management because the reactions sometimes lead
to serious complications and discontinuation of therapy. The
distinction between infusion reactions and hypersensitivity
reactions is often obscure. Most infusion reactions are
associated with cytokine release rather an allergic component.
However, the mechanisms underlying these reactions remain
unclear. Cytarabine syndrome has previously been reported
in both children [6] and adults [1]. Ek et al [7] reported that
pretreatment with corticosteroids decreased the incidence of
fever in pediatric patients receiving high-dose cytarabine,
and Metz et al [8] suggested a premedication protocol in a
patient with cytarabine syndrome. In the cases we report,
premedication was ineffective, and safe administration
of the planned dose of cytarabine was attained using the
desensitization protocol.
Although desensitization is usually indicated in type I
hypersensitivity reactions, it can be applied in severe infusion
reactions that persist despite premedication and slower
infusion rates, such as vancomycin-induced infusion reactions
(red man syndrome) [4]. Severe taxane-induced infusion
reactions are also candidates for desensitization, and it has
been reported that patients experiencing such reactions can
be successfully desensitized with the standard 3-solution,
12-step protocol [5]. Although this protocol is widely used,
the infusion rate of the initial step of each solution is too
slow to guarantee delivery of a sufcient dose for successful
desensitization. Priming intravenous lines with a nondrug
solution to reduce exposure to hazardous agents also interferes
with infusion of small volumes [9]. To complement this
limitation, we modied the protocol reported by Castells
et al [10] to design a new 4-solution (1:1000, 1:100, 1:10,
and 1:1), 11-step desensitization protocol. As the patients
developed severe reactions involving hypotension and oxygen
Table. Eleven-Step Desensitization Protocol Used in the First Patient
Solution Dextrose Water (DW) Concentration, mg/mL Total Dose in Mixing Procedure
Each Solution, mg
A 200 mL 0.0087 1.788 Solution B 22 mL in DW 200 mL
B 200 mL 0.0878 17.88 Solution C 22 mL in DW 200 mL
C 200 mL 0.886 178.8 Solution D 22 mL in DW 200 mL
D 500 mL 8.94 4470 Cytarabine 4470 mg in DW 500 mL
Step Solution Rate, mL/h Time, mina Dose Administered, mg Cumulative Dose Infused, mg
1 A 100 20 0.290 0.290
2 A 250 15 0.544 0.834
3 A 500 14.9 1.080 1.914
4 B 100 20 2.927 4.841
5 B 250 15 5.487 10.328
6 B 500 12.5 9.145 19.473
7 C 100 20 29.532 49.005
8 C 250 15 55.372 104.377
9 C 500 12.5 92.286 196.663
10 D 100 20 298.000 494.663
11 D 250 106.7 3975.320 4469.983
aTotal time required for desensitization was 271.6 minutes.
81

Practitioner's Corner
J Investig Allergol Clin Immunol 2015; Vol. 25(1): 55-82 © 2015 Esmon Publicidad
Manuscript received August 17, 2014; accepted for publication
November 6, 2014.
Hye-Ryun Kang
Department of Internal Medicine
Seoul National University Hospital
101 Daehak-ro Jongno-Gu, Seoul, 110-744, Korea
E-mail: helenmed@snu.ac.kr
desaturation, we initiated the desensitization protocol with the
bag containing the 1:1000 dilution of the full concentration.
Every solution in this protocol is administered at 100 mL/h
over 20 minutes to overcome the problem of insufcient dose
in the initial steps. In the 2 cases we report, the protocol was
successfully administered without breakthrough reactions.
Desensitization not only prevents discomfort, but also gives
patients an opportunity to continue therapy with a clinically
useful chemotherapeutic agent. In patients for whom
alternatives are less effective or not available, desensitization
can be judiciously applied in patients who are intolerant to
chemotherapeutic agents such as cytarabine.
Funding
This research was supported by a grant from the Ministry
of Food and Drug Safety for the operation of the regional
pharmacovigilance center in 2014.
Conicts of Interest
The authors declare that they have no conicts of interest.
References
1. Manoharan A. The cytarabine syndrome in adults. Aust N Z J
Med. 1985;15(4):451-2.
2. Williams SF, Larson RA. Hypersensitivity reaction to high-dose
cytarabine. Br J Haematol. 1989;73(2):274-5.
3. Ek T, Jarfelt M, Mellander L, Abrahamsson J. Proinammatory
cytokines mediate the systemic inammatory response
associated with high-dose cytarabine treatment in children.
Med Pediatr Oncol. 2001;37(5):459-64.
4. Lin RY. Desensitization in the management of vancomycin
hypersensitivity. Arch Intern Med. 1990;150(10):2197-8.
5. Feldweg AM, Lee CW, Matulonis UA, Castells M. Rapid
desensitization for hypersensitivity reactions to paclitaxel and
docetaxel: a new standard protocol used in 77 successful
treatments. Gynecol Oncol. 2005;96(3):824-9.
6. Castleberry RP, Crist WM, Holbrook T, Malluh A, Gaddy D. The
cytosine arabinoside (Ara-C) syndrome. Med Pediatr Oncol.
1981;9(3):257-64.
7. Ek T, Pinkava M, Abrahamsson J. Ara-C fever and infections
after high-dose ara-C treatment in pediatric lymphoid
malignancies. J Pediatr Hematol Oncol. 2005;27(7):364-9.
8. Metz KA, Johnson T, Hershey GK, Lierl MB, Seidu L, Burns
K, Assa'ad A. Successful administration of cytarabine in
a 16-month-old girl with acute myelogenous leukemia
and cytarabine syndrome. Ann Allergy Asthma Immunol.
2009;102(2):173-4.
9. Madrigal-Burgaleta R, Berges-Gimeno MP, Angel-Pereira
D, Ferreiro-Monteagudo R, Guillen-Ponce C, Pueyo C,
Gomez de Salazar E, Alvarez-Cuesta E. Hypersensitivity and
desensitization to antineoplastic agents: outcomes of 189
procedures with a new short protocol and novel diagnostic
tools assessment. Allergy. 2013;68(7):853-61.
10. Castells M. Rapid desensitization for hypersensitivity reactions
to chemotherapy agents. Curr Opin Allergy Clin Immunol.
2006;6(4):271-7.
82