![Overview of clinical and in vitro parameters. Color variations represent increasing frequencies of positive results for the shown variable. For example, frequency of asthmatics (specific IgE [sIgE] measurements are shown as percentage "sensitized/not sensitized"). *Measured by BAT or sIgE rCan s 3.BAT, Basophil activation test; CA-A, likely-anaphylaxis to cannabis; CA-C, cutaneous symptoms to cannabis; CA-R, respiratory symptoms to cannabis; CA-RC, localized respiratory and cutaneous symptoms to cannabis; LTP, lipid transfer protein; OAS, oral allergy syndrome defined as localized and mild oropharyngeal symptoms without generalization; PþLTPÀ, pollensensitized controls without an nsLTP sensitization; PþLTPþ, pollen and nsLTP-sensitized controls; SR, systemic reaction defined by generalized and severe symptoms in at least 1 organ system 14 ; TOL, tolerant.](https://www.researchgate.net/profile/Didier-Ebo/publication/327958405/figure/fig2/AS:719232933318656@1548489902236/Overview-of-clinical-and-in-vitro-parameters-Color-variations-represent-increasing_Q320.jpg)
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Original Article
Exploring the Diagnosis and Profile of Cannabis
Allergy
Ine Ilona Decuyper, MD
a,b
, Athina Ludovica Van Gasse, MD
a
, Margaretha A. Faber, MD, PhD
a
, Jessy Elst, MSc
a
,
Christel Mertens, MLT
a
, Hans-Peter Rihs, PhD
c
, Margo M. Hagendorens, MD, PhD
a,b
, Vito Sabato, MD, PhD
a
,
Hilde Lapeere, MD, PhD
d
, Chris H. Bridts, MLT
a
, Luc S. De Clerck, MD, PhD
a
, and Didier Gaston Ebo, MD, PhD
a
Antwerp, Ghent, Belgium; and Bochum, Germany
What is already known about this topic? Cannabis allergy, although rare, can manifest with severe and generalized
symptoms and has been linked to Can s 3, the nonspecific lipid transfer protein present in Cannabis sativa.
What does this article add to our knowledge? This article compares the performance of multiple cannabis diagnostic
methods and explores clinical and in vitro characteristics of cannabis allergy in one of the largest cannabis allergic
populations described up until now.
How does this study impact current management guidelines? There are no guidelines available on cannabis allergy
diagnosis or management. This article’s perspective on diagnostic performances could aid in accurately approximating
post-test probabilities and gives insight into the profile of Western European cannabis allergic patients.
BACKGROUND: Cannabis allergy (CA) has mainly been
attributed to Can s 3, the nonspecific lipid transfer protein
(nsLTP) of Cannabis sativa. Nevertheless, standardized
diagnostic tests are lacking and research on CA is scarce.
OBJECTIVE: To explore the performance of 5 cannabis
diagnostic tests and the phenotypic profile of CA.
METHODS: A total of 120 patients with CA were included and
stratified according to the nature of their cannabis-related
symptoms; 62 healthy and 189 atopic controls were included.
Specific IgE (sIgE) hemp, sIgE and basophil activation test
(BAT) with a recombinant Can s 3 protein from Cannabis sativa
(rCan s 3), BAT with a crude cannabis extract, and a skin prick
test (SPT) with an nCan s 3-rich cannabis extract were
performed. Clinical information was based on patient history
and a standardized questionnaire.
RESULTS: First, up to 72% of CA reporting likely-anaphylaxis
(CA-A) are Can s 3 sensitized. Actually, the Can s 3-based
diagnostic tests show the best combination of positive and
negative predictive values, 80% and 60%, respectively. sIgE
hemp displays 82% sensitivity but only 32% specificity.
Secondly, Can s 3DCA reported significantly more cofactor-
mediated reactions and displayed significantly more sensitiza-
tions to other nsLTPs than Can s 3-CA. Finally, the highest
prevalence of systemic reactions to plant-derived foods was seen
in CA-A, namely 72%.
CONCLUSIONS: The most effective and practical tests to
confirm CA are the SPT with an nCan s 3-rich extract and the
sIgE rCan s 3. Can s 3 sensitization entails a risk of systemic
reactions to plant-derived foods and cofactor-mediated reactions.
However, as Can s 3 sensitization is not absolute, other cannabis
allergens probably play a role. Ó2018 Published by Elsevier
Inc. on behalf of the American Academy of Allergy, Asthma &
Immunology (J Allergy Clin Immunol Pract 2018;-:---)
Key words: Cannabis allergy; Diagnosis; BAT; Specific IgE; Skin
prick test; Can s 3; nsLTP; Cofactor; Basophil; Anaphylaxis;
Hemp
Cannabis is one of the most consumed drugs worldwide.
1
Despite its widespread use, reports on cannabis allergy (CA)
remain rare and generally deal with relatively small numbers of
cases.
2-6
Nevertheless, from these reports evidence is accumu-
lating that CA can manifest with severe and generalized
a
Department of Immunology-Allergology-Rheumatology, University Hospital of
Antwerp, University of Antwerp, Antwerp, Belgium
b
Department of Pediatrics, University Hospital of Antwerp, University of Antwerp,
Antwerp, Belgium
c
IPA—Institute for Prevention and Occupational Medicine, German Social Accident
Insurance, Ruhr-University Bochum, Bochum, Germany
d
Ghent University Hospital, University of Ghent, Ghent, Belgium
This work was supported by the Agency for Innovation by Science and Technology
(grant number 140185). Furthermore, V. Sabato is a senior clinical researcher of
the Research Foundation Flanders/Fonds Wetenschappelijk Onderzoek (FWO:
1804518N). D. G. Ebo is a senior clinical researcher of the Research Foundation
Flanders/Fonds Wetenschappelijk Onderzoek (FWO: 1800614N). A. L. Van
Gasse is a fellow of the Research Foundation Flanders/Fonds Wetenschappelijk
Onderzoek (FWO: 1113617N).
Conflicts of interest: The authors declare that they have no relevant conflicts of
interest.
Received for publication July 17, 2018; revised August 17, 2018; accepted for
publication September 15, 2018.
Available online --
Correspondence author: Didier Gaston Ebo, MD, PhD, Department of Immunology,
Allergology, Rheumatology, Faculty of Medicine and Health Science, University
of Antwerp, Campus Drie Eiken T5.95, Universiteitsplein 1, 2610 Antwerp,
Belgium. E-mail: immuno@uantwerpen.be.
2213-2198
Ó2018 Published by Elsevier Inc. on behalf of the American Academy of Allergy,
Asthma & Immunology
https://doi.org/10.1016/j.jaip.2018.09.017
1
Abbreviations used
BAT- Basophil activation test
CA- Cannabis allergy
CA-A- Likely-anaphylaxis to cannabis
CA-C- Cutaneous symptoms to cannabis
CA-R- Respiratory symptoms to cannabis
CA-RC- Localized respiratory and cutaneous symptoms to
cannabis
CBA- Cytometric bead array
CS- Cannabis sativa
HC- Healthy controls
NPV- Negative predictive value
nsLTP- Nonspecific lipid transfer protein
PþLTP- Atopic pollen-sensitized participants without an nsLTP
sensitization
PþLTPþ- Atopic pollen and nsLTP-sensitized participants
PPV- Positive predictive value
rCan s 3- Recombinant Can s 3 protein from CS
sIgE- Specific IgE
SPT- Skin prick test
symptoms and a variety of cross-reactive plant-derived food
allergies, mainly attributed to a Can s 3 sensitization, the
nonspecific lipid transfer protein (nsLTP) from Cannabis sativa
(CS). As a matter of fact, in some European surveys, Can s 3 has
been demonstrated to be a major allergen.
7-9
NsLTPs are heat
stable allergens widely distributed throughout the plant kingdom
and showing extensive in vitro and in vivo cross-reactivity.
10
Both
the severe phenotype and the extensive cross-reactivity associated
with CA can be attributed to the physiochemical properties of
Can s 3. Other putative cannabis allergens are ribulose-1,5-
bisphosphate carboxylase/oxygenase, oxygen-evolving enhancer
protein 2, and a thaumatin-like protein.
2,4
However, unlike Can
s3,
3
these allergens have not yet been successfully isolated nor
expressed as a recombinant protein and are currently unavailable
for diagnosis.
So far, in the majority of studies on CA, diagnosis is docu-
mented by prick-prick tests with buds or leaves
4-6,9
and therefore
are difficult to standardize, because of the heterogeneous
composition of the different source materials. The clinical
severity and cross-reactivity of CA together with the unpredict-
ability of the source materials used for skin testing constitute
strong incentives for more reliable cannabis diagnostic tests,
in vitro or in vivo.
In 2 preliminary studies, we have standardized and presented
initial performance results using 4 different cannabis diagnostic
tests, namely, a basophil activation test (BAT) with recombinant
Can s 3 protein from CS (rCan s 3), a BAT with a crude CS
extract, a skin prick test (SPT) with an nCan s 3-rich extract, and
finally, a specific IgE (sIgE) rCan s 3 assay using a cytometric
bead array (CBA) technique. These diagnostic tests were
compared with sIgE industrial hemp by fluorescence enzyme
immunoassay (FEIA) ImmunoCAP. All 4 of our diagnostic tests
have been found reliable in diagnosing CA
7,8
and revealed Can s
3 sensitization in up to 75% of patients with CA with an
anaphylaxis-like phenotype. Alternatively, the sIgE hemp assay,
albeit displaying an excellent sensitivity, was shown to be poorly
reliable because of an important proportion of clinically irrele-
vant positive results in cannabis-tolerant individuals sensitized to
pollen and/or nsLTPs.
Importantly, for robust validation purposes, our recent study
8
was restricted to patients with an anaphylaxis-like phenotype on
cannabis exposure. However, in general practice, physicians
might frequently encounter patients with less compelling
histories such as isolated respiratory symptoms and in whom Can
s 3 sensitization seems less predominant.
3
Therefore, this study
investigates the diagnostic test performances and intertest
differences between these 5 diagnostic tests in a larger study
population expressing distinct clinical phenotypes on cannabis
exposure. Secondly, this study explores the clinical and molecular
characteristics of CA; the sensitization profiles, the severity of
cross-reactivities with other plant-derived foods, and the signifi-
cance of cofactors, as patients presenting with nsLTP-related
allergies have frequently been reported to necessitate a cofactor
to become symptomatic.
11,12
METHODS
Inclusion
Patients and controls were included through the outpatients’
clinic of Allergology at the Antwerp University Hospital and the
Dermatology department of the Ghent University Hospital,
Belgium. The local ethics committees of both hospitals approved this
study (B300201524055), and patients or their representatives signed
an informed consent in accordance with the Declaration of Helsinki.
Patients with respiratory, gastrointestinal, cardiovascular, and/or
cutaneous symptoms on exposure to cannabis were included.
Exposure to cannabis was defined as active smoking, ingestion, and/
or direct cutaneous contact with cannabis. Patients with generalized
symptoms in 2 or more organ systems were categorized as likely-
anaphylactic according to the criteria defined by Sampson et al.
13
Furthermore, 2 distinct control groups were included: first,
healthy controls (HC) without pollen or nsLTP sensitization;
secondly, a so-called atopic control group comprising patients with a
documented pollen allergy with (PþLTPþ) or without nsLTP
(PþLTP) sensitization. Controls were further stratified according
to exposure and tolerance to cannabis, that is, uneventful exposure.
Definitions of pollen and nsLTP sensitizations are shown in this
article’s Online Repository at www.jaci-inpractice.org.
Information on CA, cofactor-associated reactions (reported plant-
derived food allergies with a history of overt or more severe/gener-
alized reactions in the presence of nonsteroidal anti-inflammatory
drugs, alcohol, or physical exercise than when the reaction
occurred in the absence thereof), and severity of plant-derived food-
associated reactions was gathered by history taking and a standard-
ized questionnaire. Three cofactors were defined in this study: the
use of alcoholic beverages, nonsteroidal anti-inflammatory drugs,
and/or the performance of exercise within 3 hours preceding
occurrence of an allergic reaction. A systemic reaction was defined as
grade 1 or higher as defined by the World Allergy Organization
criteria of systemic allergic reactions.
14
Patients with chronic
spontaneous urticaria, uncontrolled asthma, eosinophilic esophagi-
tis/colitis, or systemic mastocytosis were excluded.
Diagnostic tests
Basophil activation test. BAT with rCan s 3 and a crude CS
extract were performed, as detailed in this article’s Online Repository
at www.jaci-inpractice.org and previously validated as described in
detail elsewhere.
8
Results were expressed as net percentages of
CD63
þ
basophils, calculated by subtraction of the spontaneous
expression from the allergen-induced CD63 expression. A result
J ALLERGY CLIN IMMUNOL PRACT
MONTH 2018
2DECUYPER ET AL
>5% CD63
þ
basophils was considered positive as defined by
previous validation.
8
Total and specific IgE. Total and sIgE to industrial hemp,
rBet v 1 and rBet v 2 from birch (Betula verrucosa), rPhl p 1 and rPhl
p 5b from timothy grass (Phleum pratense), nArt v 1 and nArt v 3
from mugwort (Artemisia vulgaris), rAra h 9 from peanut (Arachis
hypogeae), rCor a 8 from hazelnut (Corylus avellana), rMal d 3 from
apple (Malus domesticus), rJug r 3 from walnut (Juglans regia), rPru
p 3 from peach (Prunus persica), rPar j 2 from wall pellitory (Pari-
etaria judaica), and nAna 2 c from bromelain (Ananas comosus), as a
marker for sensitization to cross-reactive carbohydrate determinants,
were quantified by the FEIA ImmunoCAP technique (Thermo-
Fisher Scientific, Uppsala, Sweden) according to the manufacturer’s
instructions. All sIgE assays are readily available, except for industrial
hemp, which is available for research use only and was kindly pro-
vided by ThermoFisher Scientific. Specific IgE to rCan s 3 was
quantified using a flow CBA technique (BD Biosciences, Franklin
Lakes, NJ). The method was validated as previously described.
8
Results 0.10 kU
A
/L were considered positive.
Skin prick tests. SPT implied an nCan s 3-rich CS extract that
was prepared as described elsewhere.
7
SPT responses were read after
15 minutes and considered positive when the wheal exceeded 3 mm
(largest diameter). A positive control with histamine (10 mg/mL)
and a negative saline control without allergen (ALK-Abello Ltd,
Berkshire, United Kingdom) were performed to rule out non-
responsiveness or dermographism of the skin, respectively.
Statistical analysis
IBM SPSS version 24.0 (IBM, Chicago, Ill) software was used for
data analysis. Data are expressed as medians and interquartile ranges.
Nonparametric tests and
c
2
analysis were used where appropriate.
Test performances were compared by using McNemar’s test. Where
needed, missing values were imputed by using a multiple-imputation
model with 5 imputations based on all available information that
were subsequently pooled in SPSS. Significance levels for the pooled
imputed data were calculated according to the method described by
Schafer et al.
15
APvalue of <.05 was regarded as statistically
significant.
RESULTS
Demographics
As shown in Figure 1, a total of 371 individuals were
included; 120 patients with symptoms on cannabis exposure
(CA) of which 21% (n ¼25) were classified as likely-
anaphylactic (CA-A), 19% (n ¼23) presented with mild and
localized respiratory and cutaneous symptoms (CA-RC), 51%
reported isolated respiratory symptoms (CA-R), and 9% report
isolated cutaneous symptoms (CA-C). The remaining 251 par-
ticipants were control individuals, either HC or atopics with a
pollen sensitization (PþLTPþ), with or without nsLTP sensi-
tizations (PþLTP). As displayed in Figure 1, 50% to 60% of
each control group reported the regular use of cannabis in the
past 12 months without any symptoms apart from the known
psychoactive effects; the other half reported no previous contact
with cannabis. All patients with CA displayed symptoms during
active smoking, except for 3 patients denying any previous direct
contact with cannabis (no active smoking, ingestion, or cuta-
neous contact) but who had experienced symptoms on passive
exposure to cannabis smoke. Furthermore, in total 34 patients
with CA reported respiratory and/or cutaneous symptoms on
n = 371
CA
n = 120
likely-
anaphylaxis
n = 25
respiratory
symptoms
n = 61
cutaneous
symptoms
n = 11
localized
respiratory and
cutaneous symptoms
n = 23
HC
n = 62
CS exposed
n = 37
not CS exposed
n = 25
P+
n = 90
CS exposed
n = 47
not CS exposed
n = 43
P+LTP+
n = 99
CS exposed
n = 49
not CS exposed
n = 50
FIGURE 1. Inclusion overview. CA, Cannabis allergic patients; CS,Cannabis sativa;HC, healthy controls; PþLTP, pollen-sensitized
controls without an nsLTP sensitization; PþLTPþ, pollen and nsLTP-sensitized controls.
J ALLERGY CLIN IMMUNOL PRACT
VOLUME -, NUMBER -
DECUYPER ET AL 3
isolated passive exposure to cannabis smoke apart from symp-
toms on active smoking. Finally, 4 patients also reported
symptoms on ingestion of cannabis processed as space cake,
cannabis seeds or oil, resulting in anaphylaxis in 2 of the cases.
The individual symptoms reported by CA-A are shown in
Table E1 in this article’s Online Repository at www.jaci-
inpractice.org. In summary, 23 of 25 reported respiratory
symptoms and/or cutaneous symptoms, 4 patients also
mentioned cardiovascular symptoms comprising palpitations
and/or hypotension, and finally, 5 patients additionally reported
gastrointestinal symptoms comprising abdominal pain, nausea,
and vomiting.
Table I displays demographic data of the different study
groups revealing similar age, sex ratios, and asthma prevalence in
all groups. In contrast, atopic dermatitis and elevated total IgE
values were significantly more prevalent in the PþLTPþgroup
than in the CA group and in the PþLTPgroup. Total IgE was
also significantly higher in the PþLTPgroup compared with
the CA group. Finally, importantly, 84% of patients with CA
showed a pollen sensitization and 72% an nsLTP sensitization.
It is important to note that pollen sensitization was predomi-
nated by Bet v 1; 72% of CA sensitized) and 79% of PþLTPþ
exhibited a Bet v 1 sensitization.
Performance of cannabis diagnostic tests
Figure 2 shows the individual results of 5 different cannabis
diagnostic tests: the sIgE industrial hemp, sIgE rCan s 3 CBA,
SPT with an nCan s 3-rich extract, and the BAT with both rCan
TABLE I. Demographic data
HC [62 CA [120 PDLTPL[90 PDLTPD[99
Age (y), median (Q
25
-Q
75
) 28.3 (24.8-36.1) 29.2 (25.1-35.2) 28.8 (22.9-37.7) 29.9 (20.1-37.1)
Sex
(% male) 42% 48% 37% 49%
Eczema*0% 37% 37% 54%
Asthma†5% 30% 28% 39%
Total IgE (kU/L), median (Q
25
-Q
75
) 16.7 (6.0-46.5) 247.4 (83.0-495.0) 126.0 (65.0-314.0) 424.5 (147.0-1054.0)
Pollen sensitizationz0% 84% 100% 100%
NsLTP sensitizationx0% 72% 0% 100%
CA, Cannabis allergy; CS,Cannabis sativa;HC, healthy controls; PþLTPþ, pollen and nsLTP-sensitized controls; PþLTP, pollen-sensitized controls without an nsLTP
sensitization; nsLTP, nonspecific lipid transfer protein.
*According to patient recollection and recent use of topical CS.
†According to patient recollection.
zAt least one of the following sIgEs 0.1 kU
A
/L: rBet v 1, rBet v 2, nArt v 1, rPhl p 1, rPhl 5b.
xAt least one of the following sIgEs 0.1 kU
A
/L: rPru p 3, rMal d 3, rJug r 3, rAra h 9, rCor a 8, nArt v 3, rPar j 2, rTri a 14.
FIGURE 2. Individual test results. A, Dot plots showing healthy controls (HC), pollen and nsLTP-sensitized controls (PþLT P þ), pollen-
sensitized controls without an nsLTP sensitization (PþLT P ), and cannabis allergy (CA). B, Dot plots for the different CA groups:
CA-A, CA-RC, CA-R, and CA-C. Percentages reflect the proportion of positive results and horizontal lines represent group mean.
Dindicates patients with <15% response to anti-IgE stimulation (nonresponders). Of 371, 55 (15%) were classified as nonresponders:
15 HC, 12 PþLT P ,14PþLT P þ, and 14 CA. BAT, Basophil activation test; CA-A, likely-anaphylaxis to cannabis; CA-C, cutaneous
symptoms to cannabis; CA-R, respiratory symptoms to cannabis; CA-RC, localized respiratory and cutaneous symptoms to cannabis;
sIgE, specific IgE; SPT, skin prick test.
J ALLERGY CLIN IMMUNOL PRACT
MONTH 2018
4DECUYPER ET AL
s 3 and a crude cannabis extract. Table II compares the test
performances. For more details on the difference in test perfor-
mance for sIgE rCan s 3 and sIgE hemp (considering 0.10 or
0.35 kU
A
/L cutoff), the reader is referred to Figure E1 and
Table E2 in this article’s Online Repository at www.jaci-
inpractice.org.
First of all, test performances showed important variances
between the different clinical CA groups. The 3 Can s 3-based
diagnostic methods (BAT, sIgE, and SPT) displayed a similar
sensitivity, 63% to 72% in CA-A (45% to 58% in the total CA
group), and a similar specificity (81% to 87% in the total CA
group). However, up to 37% (n ¼34) of PþLTPþshowed
clinically irrelevant Can s 3 sensitizations (measured by BAT,
sIgE, or SPT): 20 of 34 reported tolerance to active cannabis use
and 14 of 34 reported no previous cannabis contact. In com-
parison, the sIgE rCan s 3 and BAT rCan s 3 showed no clini-
cally irrelevant positive results in pollen-sensitized individuals
without nsLTP sensitizations (PþLTP).
Secondly, the sIgE industrial hemp displayed a significantly
higher sensitivity, up to 82% (P<.01) in the total CA group
compared with the Can s 3-based diagnostic tests (45% to 58%).
However, sIgE hemp also demonstrated a significantly higher
number of clinically irrelevant positive results in PþLTPand
PþLTPþ, that is, 51% to 82% respectively compared with 0%
to 25% for the Can s 3 diagnostic tests (all P<.01). Interest-
ingly, an increase in sensitivity as seen in the sIgE hemp was not
found in the BAT with a crude cannabis extract. The latter
reached an overall sensitivity of 49% in the total CA group that
was not superior to the Can s 3-based assays. In addition, the
BAT with the crude extract was not superior to the Can s 3
diagnostic tests in terms of specificity either, showing 19% to
38% of clinically irrelevant positive results in PþLTPand
PþLTPþ. Collectively, for all diagnostic techniques, the
majority of clinically irrelevant results were seen in the PþLTPþ
group.
In summary, when all different clinical CA groups are
considered (analysis B in Table II), it appears that the 3 Can s
3-based diagnostic tests did not significantly differ in perfor-
mance and had the best combined positive predictive value
(PPV) and negative predictive value (NPV) of around 80% and
60%, respectively. The sIgE industrial hemp lacked specificity,
whereas the BAT crude CS extract showed no advantage over the
Can s 3-based diagnostic tests.
The clinical and molecular characteristics of
CA. Figure 3 compares different clinical and in vitro charac-
teristics for the different CA profiles and the control groups. The
most prominent differences were found between CA-A and
CA-R with significantly higher numbers of Pru p 3, Mal d 3, Cor
a 8, Jug r 3, Tri a 14, Art v 3 sensitizations (all P<.01) in CA-A
than in CA-R. Furthermore, CA-A showed a higher prevalence
of systemic reactions to plant-derived foods (72% compared with
40%, P¼.02) and cofactor-mediated allergic reactions (50%
compared with 18%, P¼.01) compared with CA-R. In addi-
tion, CA-C and CA-RC showed a single difference from CA-A,
namely a considerably lower prevalence of systemic reactions to
plant-derived foods (71% in CA-A compared with 43% in
CA-RC [P<.01] and 18% in CA-C [P¼.08]). It appears that
none of the clinical nor in vitro parameters displayed significant
differences between CA-R, CA-C, and CA-RC.
Regarding the comparison of Can s 3-sensitized and non-
sensitized CA (as demonstrated in Table E3 in this article’s
Online Repository at www.jaci-inpractice.org), it became clear
that Can s 3þCA had a significantly higher prevalence of other
nsLTP sensitizations (92%) than Can s 3-CA (39%) with higher
frequencies of all measured nsLTPs (all P<.01), except for Par j
2. Also, Can s 3þCA displayed higher frequencies of pollen
sensitizations than Can s 3-CA (92% compared with 74%) with
significantly more Bet v 1 sensitizations in the Can s 3-sensitized
population. In addition, Can s 3þCA showed a considerably
higher prevalence of cofactor-mediated allergic reactions when
compared with Can s 3-CA (41% vs 12%; P<.01).
In a further analysis, the complete CA group was compared
with the PþLTPþgroup (as demonstrated in Table E4 in this
TABLE II. Test performance
sIgE hemp sIgE rCan s 3 BAT rCan s 3 BAT crude CS extract SPT nCan s 3-rich extract
A
Sensitivity 86% (66-97) 63% (41-81) 71% (48-89) 63% (38-84) 72% (51-89)
Specificity 32% (20-45) 87% (78-93) 85% (76-92) 67% (55-78) 81% (71-88)
PPV 33% (28-38) 56% (40-70) 54% (39-67) 35% (25-47) 51% (39-63)
NPV 86% (66-95) 90% (84-94) 93% (86-96) 87% (78-92) 91% (84-95)
LHRþ1.3 (1.0-1.6) 4.7 (2.6-8.7) 4.8 (2.7-8.6) 1.9 (1.2-3.1) 3.7 (2.3-6.0)
LHR0.4 (0.1-1.3) 0.40 (0.3-0.7) 0.3 (0.2-0.7) 0.6 (0.3-1.0) 0.4 (0.2-0.7)
B
Sensitivity 82% (74-89) 47% (38-56) 45% (35-55) 49% (37-60) 58% (49-67)
Specificity 32% (20-45) 87% (78-93) 85% (76-92) 67% (55-78) 81% (71-88)
PPV 70% (66-74) 82% (72-89) 78% (67-86) 64% (54-73) 80% (72-86)
NPV 47% (34-61) 56% (51-60) 57% (52-62) 52% (46-59) 58% (53-64)
LHRþ1.2 (1.0-1.5) 3.5 (2.0-6.2) 3.0 (1.8-5.2) 1.5 (1.0-2.2) 3.0 (1.9-4.7)
LHR0.6 (0.3-1.0) 0.60 (0.5-0.7) 0.7 (0.5-0.8) 0.8 (0.6-1.0) 0.5 (0.4-0.7)
A: calculations based on CA-A group vs cannabis-tolerant PþLTPand PþLTPþ.
B: calculations based on the whole CA group (respiratory and/or cutaneous symptoms) vs cannabis-tolerant PþLTPand PþLTPþ. Test performance for both BATs was
calculated by considering both responders and nonresponders to anti-IgE.
BAT, Basophil activation test; CA-A, likely-anaphylaxis to cannabis; CS,Cannabis sativa;NPV, negative predictive value; PPV, positive predictive value; LHRþ, positive
likelihood ratio; LHR, negative likelihood ratio; PþLTPþ, pollen and nsLTP-sensitized controls; PþLTP, pollen-sensitized controls without an nsLTP sensitization; sIgE,
specific IgE; SPT, skin prick test.
J ALLERGY CLIN IMMUNOL PRACT
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DECUYPER ET AL 5
article’s Online Repository at www.jaci-inpractice.org). This
exploration revealed a significantly (P<.01) higher prevalence of
Can s 3 sensitizations in CA (63%) compared with PþLTPþ
(35%). Furthermore, a significantly lower prevalence of Pru p 3,
Mal d 3, Jug r 3, Par j 2 (all P<.01) but also bromelain (P¼
.02) and Phl p 1 (P<.01) sensitizations was seen in the CA
group compared with PþLTPþ. Finally, as already mentioned in
the demographic paragraph, significantly (P<.01) more eczema
was reported in the PþLTPþgroup than the CA group and
subsequently total IgE values were also significantly higher in
PþLTPþthan in the CA group (P<.01). Although there was
no significant difference between CA and PþLTPþconcerning
the frequency of systemic reactions to plant-derived foods (P¼
.11), CA-A did show double the frequency of systemic reactions
to plant-derived foods than PþLTPþ(71% vs 35%, P<.01).
DISCUSSION
To the best of our knowledge, this is the largest survey
exploring diagnostic performances in different clinical pheno-
types of CS allergy. Along with the observation that the diag-
nostic utilities of our tests depend on the clinical presentation, it
appears that the CA profile in this study population has the
following peculiarities.
Primarily, in terms of practicality, efficiency, and standardi-
zation, the SPT with an nCans 3-rich extract and the sIgE rCan s
3 are the easiest and fastest tests to confirm a clinical suspicion of
CA, both equally reliable. However, because of unavailability, in
clinical practice, physicians will need to rely on other tests to
screen patients with a convincing history. As a matter of fact,
according to our data, it seems that the sIgE hemp assay (avail-
able on request from ThermoFisher) could serve as a suitable
diagnostic in central Europe to exclude CA, because a negative
test result reduces the risk of CA considerably (only 18% of CA
have negative sIgE hemp results). Alternatively, patients with a
convincing history together with a positive sIgE hemp should
undergo additional testing to elucidate the clinical significance of
the hemp solid phase assay. In addition, exploration of different
cutoffs for the sIgE rCan s 3 and hemp shows that, when
considering the 0.35 kUa/L cutoff, sensitivity of both tests de-
creases by around 10% in the total CA population. Nevertheless,
sensitivity to detect CA-A remains the same for both. Even
though the specificity of sIgE hemp almost doubles, it still only
reaches a maximum of 60%, which is not ideal.
However, none of our diagnostic tests appear absolutely pre-
dictive for the clinical outcome. Nevertheless, for the time being,
on the basis of our findings, we propose to perform the SPT with
an nCan s 3-rich extract or quantify sIgE rCan s 3 keeping in
mind that Can s 3 does not cover the entire IgE sensitization
profile, particularly in patients with a less severe/pronounced
phenotype. In addition, it could be questioned whether Can s 3-
negative patients, especially if reporting only milder symptoms to
cannabis, should effectively be categorized as CA, because their
symptoms could result from nonspecific skin or airway irritation.
Furthermore, because of ethical and legal limitations, it is
impossible to confirm CA by an oral or respiratory challenge.
Considering this hypothesis, it follows that the actual test per-
formances are possibly underestimated in this study and that Can s
3 might even play a more prominent role than already suspected.
Furthermore, it is likely that performances of a Can s 3 assay
display regional differences due to geographic differences in IgE
reactivity profiles. The reason(s) why Can s 3 negative CA pa-
tients go undetected in the BAT with the full CS extract re-
main(s) elusive but could relate to a sensitization to allergens that
are poorly present in our crude extract or do not resist our
current extraction procedure. Moreover, the low presence and
the physicochemical properties of the constituent allergens might
also explain the different sensitization profiles in the distinct
phenotypes, namely, the lower prevalence of nsLTP sensitiza-
tions in CA-R compared with CA-A.
Eczema
Asthma
Cofactor
SR to plant-foods
Pollen sensitization
Bet v 1
Bet v 2
Phl p 1
Phl p 5b
Art v 1
LTP sensitization
Pru p 3
Mal d 3
Cor a 8
Ara h 9
Jug r 3
Tri a 14
Art v 3
Par j 2
Can s 3*
Bromelain
P+LTP-
P+LTP+
CA total
CA-A
CA-R
CA-RC
CA-C
SCALE
0% 0%
10% 10%
20% 20%
30% 30%
40% 40%
50% 50%
60% 60%
70% 70%
80% 80%
90% 90%
100% 100%
FIGURE 3. Overview of clinical and in vitro parameters. Color variations represent increasing frequencies of positive results for the shown
variable. For example, frequency of asthmatics (specific IgE [sIgE] measurements are shown as percentage “sensitized/not sensitized”).
*Measured by BAT or sIgE rCan s 3.BAT, Basophil activation test; CA-A, likely-anaphylaxis to cannabis; CA-C, cutaneous symptoms to
cannabis; CA-R, respiratory symptoms to cannabis; CA-RC, localized respiratory and cutaneous symptoms to cannabis; LTP, lipid transfer
protein; OAS, oral allergy syndrome defined as localized and mild oropharyngeal symptoms without generalization; PþLTP, pollen-
sensitized controls without an nsLTP sensitization; PþLTPþ, pollen and nsLTP-sensitized controls; SR, systemic reaction defined by
generalized and severe symptoms in at least 1 organ system
14
;TOL, tolerant.
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6DECUYPER ET AL
Secondly, although historically sensitization to nsLTP has
mainly been recognized to occur in the Mediterranean region,
characterized by severe reactions and governed by peach,
10,16
more
recent data have accumulated showing that sensitization to nsLTP
might also occur in other European regions and frequently remain
asymptomatic with uncertainties about the route(s) of sensitiza-
tion.
17-19
In this survey, we confirm that nsLTP sensitization
occurs frequently in CA and Can s 3 is a major allergen in patients
with CA-A, but CA also implies a risk of systemic reactions to
plant-derived foods and cofactor-mediated reactions. Furthermore,
Can s 3 sensitization can occur as a result of in vitro cross-reactivity
to nsLTPs from taxonomically related or more distant sources
such as pollen and/or plant-derived foods as suggested by the Can
s 3 positive PþLTPþpatients without any previous cannabis
contact. On the other hand, it seems that a Can s 3 sensitization in
patients with CA might also mirror a primary sensitization instead
of only in vitro cross-reactivity as indicated by the significantly
higher prevalence of Can 3 and lower prevalence of Pru p 3, Mal
d 3, Jug r 3, and Par j 2 sensitizations in CA compared with
PþLTPþ.
Another important fact to highlight is that, because of the lack
of data on the true prevalence of CA, it is likely that the number
of patients per study group in this survey do not necessarily
reflect the true prevalence of CA. Therefore, the test perfor-
mances would differ depending on the characteristics of the
tested population and the geographic prevalence of CA itself.
Finally, this study was not designed to explore the different
individual types of plant-derived food allergies, as symptoms to
different plant-derived foods were only assessed by a standardized
questionnaire complemented with a history taking without sys-
tematic confirmatory testing. However, it would be interesting to
further explore the actual differences in individual plant-derived
food allergies within CA such as the differences in symptom
severity with and without peel, the types of plant-derived foods
eliciting allergic symptoms but also the comparison of these
factors between CA and other nsLTP-sensitized individuals.
In conclusion, this study is the largest study exploring diagnostic
test performance, clinical phenotypes, and biological profiles of
CA. It shows that the most effective and practical tests to confirm a
clinical suspicion of CA are the SPT with an nCan s 3-rich extract
and sIgE rCan s 3. Both tests display a PPV and NPV of approx-
imately 80% and 60%, respectively. However, because of current
unavailability, screening with sIgE hemp could be a suitable tool in
symptomatic cannabis users, because a negative result considerably
reduces the likelihood of CA. Alternatively, we dissuade the general
use of sIgE hemp to diagnose CA, mainly because of its limited
PPV. Furthermore, we show that Can s 3 is a major allergen in
patients with a history of likely-anaphylaxis on cannabis exposure
and, like other nsLTP-associated allergies, CA might indicate a risk
of systemic reactions to plant-derived foods and cofactor-mediated
reactions. Because around 30% of CA-A and even higher pro-
portions in other, milder CA groups are not sensitized to Can s 3, it
is likely that other cannabis allergens might play a role in CA.
Further studies are thus warranted to identify and express other CA
allergens that could then be applied to spike natural extracts or to
compose mixtures of allergens. Lastly, additional research should
further explore the nature of plant-derived food allergies in CA as
this study was not designed to evaluate specific plant-derived food
allergies in CA.
Acknowledgments
We thank B. Van Camp, head of the Unit “drug production,”
Central Drug Department, Directorate of organized crime,
Belgian Federal Judicial police for his help with providing the
necessary plant materials. We would also like to thank Mrs. K.
Vandebos and N. Maes, our study nurses, for their help in the
performance of the skin prick tests and blood sampling. Finally,
our gratitude goes out to Mrs. K Wouters, for her help and
statistical advice.
REFERENCES
1. United Nations Office on Drugs and Crime. World Drug Report 2017. Available
from: www.unodc.org/wdr2017. Accessed June 7, 2018.
2. Nayak AP, Green BJ, Sussman G, Berlin N, Lata H, Chandra S, et al. Char-
acterization of Cannabis sativa allergens. Ann Allergy Asthma Immunol 2013;
111:32-7.
3. Rihs HP, Armentia A, Sander I, Bruning T, Raulf M, Varga R. IgE-binding
properties of a recombinant lipid transfer protein from Cannabis sativa. Ann
Allergy Asthma Immunol 2014;113:233-4.
4. Larramendi CH, López-Matas M, Ferrer A, Huertas AJ, Pagán JA, Navarro LÁ,
et al. Prevalence of sensitization to Cannabis sativa. Lipid-transfer and
thaumatin-like proteins are relevant allergens. Int Arch Allergy Immunol 2013;
162:115-22.
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Cannabis allergy: a diagnostic challenge. Allergy 2018;73:1911-4.
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Quesada J. Molecular diagnosis in cannabis allergy. J Allergy Clin Immunol
Pract 2014;2:351-2.
10. Pastorello EA, Robino AM. Clinical role of lipid transfer proteins in food
allergy. Mol Nutr Food Res 2004;48:356-62.
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transfer protein syndrome: clinical pattern, cofactor effect and profile of molecular
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12. González-Mancebo E, González-de-Olano D, Trujillo MJ, Santos S, Gandolfo-
Cano M, Meléndez A, et al. Prevalence of sensitization to lipid transfer proteins
and profilins in a population of 430 patients in the south of Madrid. J Investig
Allergol Clin Immunol 2011;21:278-82.
13. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA,
Branum A, et al. Second symposium on the definition and management of
anaphylaxis: summary report—second National Institute of Allergy and Infec-
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14. Cox LS, Sanchez-Borges M, Lockey RF. World Allergy Organization systemic
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15. Schafer JL. Analysis of Incomplete Multivariate Data. London: Chapman &
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16. Fernandez-Rivas M. Fruit and vegetable allergy. Chemical Immunol Allergy
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17. Pascal M, Vazquez-Ortiz M, Folque MM, Jimenez-Feijoo R, Lozano J,
Dominguez O, et al. Asymptomatic LTP sensitisation is common in plant-food
allergic children from the Northeast of Spain. Allergol Immunopathol (Madr)
2016;44:351-8.
18. Faber MA, Van Gasse AL, Decuyper II, Uyttebroek A, Sabato V,
Hagendorens MM, et al. IgE-reactivity profiles to nonspecific lipid transfer
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Immunol 2016;169:181-8.
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ONLINE REPOSITORY
METHODS
Patient stratification. Pollen sensitization was defined by at
least 1 positive specific IgE (sIgE) result to the following re-
combinant (r) or native (n) allergens: rBet v 1 and rBet v 2 from
birch (Betula verrucosa), rPhl p 1 and rPhl p 5b from timothy
grass (Phleum pratense), and/or nArt v 1 of mugwort (Artemisia
vulgaris). Nonspecific lipid transfer protein (nsLTP) sensitization
was documented by at least 1 positive sIgE result to the following
nsLTP allergens: rAra h 9 from peanut (Arachis hypogeae), rCor a
8 from hazelnut (Corylus avellana), rMal d 3 from apple (Malus
domesticus), rJug r 3 from walnut (Juglans regia), rPru p 3 from
peach (Prunus persica), nArt v 3 from mugwort (Artemisia vul-
garis), and rPar j 2 from wall pellitory (Parietaria judaica).
Diagnostic methods. Briefly, prewarmed heparinized blood
samples were stimulated with rCan s 3 (expressed in Escherichia
coli
E1
) and a crude Cannabis sativa extract (extraction method as
described elsewhere,
E2
obtained by solvent precipitation in the
presence of enzyme inhibitors). Antihuman IgE served as a
positive control (10
m
g/mL, clone G7-18, BD Biosciences,
Erembodegem, Belgium) and stimulation buffer was used to
measure spontaneous CD63 expression by quiescent cells.
Basophil activation test was performed using side scatter, anti-
IgE, and anti-CD203c (clone NP4D6, BD Biosciences) to
characterize the basophils. Subsequently, within this gate, baso-
phil activation was quantified as the percentage
CD203cþþCD63þexpressing basophils using anti-CD63
(clone H5C6, BD Biosciences). Results were expressed as net
percentages of CD63
þ
basophils, calculated by subtraction of the
spontaneous expression from the allergen-induced CD63
expression.
Results
Cannabis allergyerelated symptoms
Performance of cannabis diagnostic tests. As shown
in Figure E1 and Table E2, sIgE rCan s 3’s specificity does not
change when the cutoff is increased from 0.10 to 0.35 kU
A
/L.
Specificity of sIgE hemp rises almost 2-fold (32% to 60%)
when a cutoff of 0.35 kU
A
/L is considered.
When only considering CA reporting likely-anaphylaxis (CA-
A), there is no difference in sensitivity between a cutoff of 0.10 vs
0.35 kU
A
/L for either sIgE rCan s 3 or sIgE hemp. In other
words, all sensitized CA-A have an sIgE result 0.35 kU
A
/L for
both tests. When the complete CA group is considered, sensi-
tivity decreases around 10% for both tests: sIgE hemp (82% to
72%; P<.001), sIgE rCan s 3 (47% to 38%; P¼.002).
J ALLERGY CLIN IMMUNOL PRACT
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7.e1 DECUYPER ET AL
FIGURE E1. sIgE results for sIgE hemp and sIgE rCan s 3 showing both cutoff 0.10 kU
A
/L and 0.35 10 kU
A
/L. CA-A, CA reporting likely-
anaphylaxis; CA-C, cutaneous symptoms to cannabis; CA-R, respiratory symptoms to cannabis; CA-RC, localized respiratory and
cutaneous symptoms to cannabis; HC, healthy controls; PþLTP, pollen-sensitized controls without an nsLTP sensitization; PþLTPþ,
pollen and nsLTP-sensitized controls; sIgE, specific IgE.
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TABLE E1. Symptoms reported on cannabis exposure by CA-A
Patient Symptoms on cannabis exposure
PT1 AE, D, RC
PT2 AE, AP, C, U, W
PT3 AE, D, P
PT4 D, P, RC, U
PT5 AE, D, RC, U
PT6 AD, D, P, RC, U
PT7 AE, D, P, U, W
PT8 AE, C, D, RC
PT9 BP, OAS, RC, U
PT10 D, RC, U
PT11 AE, D, N, V
PT12 D, RC, U
PT13 D, RC, U
PT14 D, OAS, RC, U
PT15 D, RC, U
PT16 AE, D, P, PL, U
PT17 AE, D, OAS
PT18 AE, D, U
PT19 D, RC, U
PT20 OAS, V, U
PT21 D, N, PL, W
PT22 D, P, RC, U
PT23 N, U, V
PT24 AE, D, P, PL, RC, U
PT25 D, RC, P, U
AD, Atopic dermatitis flair; AE, angioedema; AP, abdominal pain; BP, blood pres-
sure drop; C, cough; CA-A, CA reporting likely-anaphylaxis; D, dyspnea; N, nausea;
OAS, oral allergy syndrome; P, pruritus; PL, palpitations; RC, rhinoconjunctivitis; U,
urticaria; V, vomiting; W, wheezing.
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7.e3 DECUYPER ET AL
TABLE E2. Differences in sIgE results between 0.1 and 0.35 kU
A
/L cutoffs
Cutoff
sIgE hemp
Pvalue
sIgE rCan s 3
Pvalue0.10 kU
A
/L 0.35 kU
A
/L 0.10 kU
A
/L 0.35 kU
A
/L
Sensitivity*CA-A 86 (66-97) 77 (55-92) .5 63 (41-81) 63 (41-81) 1
Sensitivity CA†82 (74-89) 72 (63-80) .001 47 (38-56) 38 (29-48) .002
Specificityz32 (20-45) 60 (49-70) <.001 87 (78-93) 89 (83-93) 1
CA, Cannabis allergy; CA-A, CA reporting likely-anaphylaxis; PþLTP, pollen-sensitized controls without an nsLTP sensitization; PþLTP þ, pollen and nsLTP-sensitized
controls; sIgE, specific IgE.
*Calculations based on the CA-A group vs cannabis-tolerant PþLTPand PþLTPþ.
†Calculations based on the whole CA group (respiratory and/or cutaneous symptoms) vs cannabis-tolerant PþLTPand PþLTPþ.
zCalculations based on the PþLTPand PþLTPþgroups. Pvalues calculated by McNemar analyses.
TABLE E3. Comparison of Can s 3-sensitized and nonsensitized
CA patients
Can s 3DCA Can s 3LCA Pvalue
Eczema 31% 47% .08
Asthma 30% 35% .42
Cofactor*42% 15% <.01
Systemic reaction to plant foods†52% 35% .14
Pollen-sensitized individuals*92% 74% .03
Bet v 1*82% 56% <.01
Bet v 2 14% 20% .46
Phl p 1 54% 62% .45
Phl p 5b 43% 43% 1
Art v 1 17% 8% .15
nsLTP-sensitized individuals*92% 39% <.01
Pru p 3*86% 35% <.01
Mal d 3*87% 30% <.01
Cor a 8*80% 16% <.01
Ara h 9*76% 18% <.01
Jug r 3*80% 28% <.01
Tri a 14*55% 19% <.01
Art v 3*70% 10% <.01
Par j 2 9% 20% .11
Bromelain 37% 20% .07
CA, Cannabis allergy; nsLTP, nonspecific lipid transfer protein; WAO, World
Allergy Organization.
*Significant differences as measured by P<.05.
†Defined as grade 1 or higher as described by the WAO criteria of systemic allergic
reactions.
E3
TABLE E4. Comparison of CA and PþLT P þpatients
CA PDLTPDPvalue
Eczema*37% 54% .01
Asthma 30% 39% .14
Cofactor*31% 19% .05
Systemic reaction to plant foods†45% 33% .11
Total IgE (mean)*247.4 424.5 <.01
Pollen-sensitized individuals*84% 100% <.01
Bet v 1 72% 79% .27
Bet v 2 16% 23% .17
Phl p 1*57% 79% <.01
Phl p 5b 43% 54% .09
Art v 1 14% 19% .32
nsLTP-sensitized individuals*72% 100% <.01
Pru p 3*66% 88% <.01
Mal d 3*65% 82% <.01
Cor a 8 56% 61% .50
Ara h 9 54% 62% .23
Jug r 3*60% 79% <.01
Tri a 14 41% 45% .54
Art v 3 47% 42% .45
Par j 2*14% 38% <.01
Can s 3*z63% 35% <.01
Bromelain*30% 45% .02
BAT, Basophil activation test; CA, cannabis allergy; nsLTP, nonspecific lipid transfer
protein; PþLTPþ, pollen and nsLTP-sensitized controls; sIgE, specific IgE; SPT,
skin prick test; WAO, World Allergy Organization.
*Significant differences as measured by P<.05.
†Defined as grade 1 or higher as described by the WAO criteria of systemic allergic
reactions.
E3
zMeasured by sIgE, BAT, or SPT.
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REFERENCES
E1. Rihs HP, Armentia A, Sander I, Bruning T, Raulf M, Varga R. IgE-binding
properties of a recombinant lipid transfer protein from Cannabis sativa. Ann
Allergy Asthma Immunol 2014;113:233-4.
E2. Decuyper II, Faber MA, Lapeere H, Mertens C, Rihs HP, Van Gasse AL, et al.
Cannabis allergy: a diagnostic challenge. Allergy 2018;73:1911-4.
E3. González-Mancebo E, González-de-Olano D, Trujillo MJ, Santos S, Gandolfo-
Cano M, Meléndez A, et al. Prevalence of sensitization to lipid transfer proteins
and profilins in a population of 430 patients in the south of Madrid. J Investig
Allergol Clin Immunol 2011;21:278-82.
J ALLERGY CLIN IMMUNOL PRACT
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7.e5 DECUYPER ET AL
