<div>ABBREVIATIONS</div><div>CA cannabis allergy</div><div>CCDs cross-reactive carbohydrate determinants</div><div>CI confidence interval</div><div>CSA cannabis sativa allergic patients</div><div>nsLTP s nonspecific lipid transfer proteins</div><div>P+LTP- controls sensitized to pollen without nsLTP sensitization</div><div>P+LTP+ controls sensitized to pollen and nsLTPs</div><div>(r) recombinant</div><div>sIgE specific immunoglobulin E</div><div>ST skin tests</div><div>tIgE total immunoglobulin E</div><div>KEYWORDS</div><div>Cannabis allergy, sIgE, total IgE, allergy diagnosis, sIgE-to-total IgE
ratio</div><div>To the Editor,</div><div>The most important “diagnostic test” for CA is a detailed history.
However, a positive history is no absolute proof of CA, mainly because
of physiological effects of cannabis i.e. (rhino)conjunctivitis presence
and possibly because of incorrect interpretation or recollection of
symptoms by the patients under the drug’s influence. Consequently,
clinical suspicion of CA requires confirmatory testing. A cannabis
challenge, being excluded for obvious ethical/legal reasons,
documentation of CA generally starts with skin testing (ST) or specific
IgE-quantification. However, in the absence of a standardized extract
for ST, many will use prick-prick tests (e.g., with buds, leaves, seeds)<sup>1 2</sup>. Crude plant parts or extracts thereof, can
contain both genuine and cross-reactive allergenic components.
Consequently, positive results of crude extract ST and sIgE should
always be interpreted cautiously, as it might merely reflect (cross-)
sensitization instead of allergy.</div><div>Here, we sought to investigate whether serological diagnosis of CA could
benefit from an adjustment for tIgE. For this purpose, sIgE-to-tIgE
ratios were calculated for sIgE hemp (FEIA, ImmunoCAP ThermoFisher
Scientific), sIgE to recombinant (r) Can s 3 and rCan s 5 (Cytometric
Bead Assay) as detailed elsewhere <sup>3</sup>. A sIgE rCan s
3-to-rPru p 3 and sIgE rCan s 5-to-rBet v 1 ratio was also calculated.
Negative sIgE values were excluded, as these cannot benefit from such an
adjustment. Patients were selected from our previously published data<sup>3 4</sup>; cannabis sativa allergic patients (CSA), controls
with a pollen but no nsLTP sensitization (P+LTP-) and controls with both
pollen and nsLTP sensitizations (P+LTP+) were enrolled.</div><div>Detailed demographic information is shown in table 1 of our previously
published article<sup>3</sup>. As shown in figure 1, the
distribution of the sIgE hemp-to-tIgE ratio and sIgE rCan s 5-to-tIgE
differed significantly between controls and CSA.
Using a cut-off of 0.02 for sIgE hemp-to-tIgE, it was shown that a
specificity of 93% (95% confidence interval (CI), 85-98%) could be
reached (table 1). A second, lower cut-off (0.005) can benefit most of
the CSA population (sensitivity 77% (95% CI 67-85%)) and retains a
relatively good specificity 79% (95% CI 68-87%).</div><div>For sIgE rCan s 5-to-tIgE, a cut-off of 0.01 could possibly be
beneficial. However, small group numbers make it difficult to estimate
its true value. The ratio of sIgE rCan s 3-to-tIgE did not show added
value (p=0.86).</div><div>Comparing CSA patients with and without anaphylaxis; no added value was
found to identify (a risk of) cannabis related anaphylaxis for any of
the explored sIgE-to-tIgE ratios (sIgE
hemp-to-tIgE-&gt;p=0.104; sIgE rCan s
3-to-tIgE-&gt;p=0.416; sIgE rCan s
5-to-tIgE-&gt;p=0.84, data not shown).</div><div>Finally, ratios of similar protein families i.e. sIgE rCan s 3-to-sIgE
rPru p 3 and sIgE rCan s 5-to-sIgE rBet v 1 were explored, showing no
additional diagnostic value (see figure E1 in the online repository).</div><div>These results indicate that sIgE-to-tIgE ratios might have a place in
the diagnostic approach of CA. In the case of a definite history of
cannabis related symptoms we recommend (figure E2) a sIgE hemp assay
(sensitivity 82% (95% CI 74-89%) and specificity 32% (95% CI
20-45%)) <sup>3</sup>. A negative result significantly reduces
the chance of IgE-mediated CA. A positive result should be followed by a
sIgE hemp-to-tIgE ratio as it notably increases test specificity. Where
available, it is worthwhile using cannabis component resolved
diagnostics as it was shown that over two-thirds of CSA who experienced
anaphylaxis are Can s 3 sensitized <sup>3</sup>. This study is
bound by certain limitations; group numbers vary between the different
analyses because of insufficient patients’ sera. Additionally, we could
not explore sIgE rCan s 2-to-tIgE, sIgE rCan s 4-to-tIgE and sIgE rCan s
4-to-sIgE rBet v 2, because of insufficient group numbers. Finally,
there is no guarantee that these results can be extrapolated to other
CSA populations or different geographical regions. The results of these
study are of a preliminary nature. Repetition of our methods in other,
ideally larger populations are feasible to see whether these results can
be confirmed and remain intact in different CA populations.</div><div>FIGURES &amp; TABLES</div><div>FIGURE 1</div>