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\begin{document}

\title{Sensitization to alpha-gal as a cause of idiopathic anaphylaxis}



\author[1]{Thushali Ranasinghe}%
\author[1]{Inoka Aberathna}%
\author[1]{Jeewantha Jayamali}%
\author[1]{Thashmi Nimasha}%
\author[1]{Harshani Chathurangika}%
\author[1]{Deneshan  Peranantharajah }%
\author[1]{Hashini Colambage}%
\author[1]{Gathsaurie Neelika Malavige}%
\author[1]{Chandima Jeewandara}%
\affil[1]{University of Sri Jayewardenepura}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} The cause for anaphylaxis cannot be identified
after extensive evaluation in a large proportion of patients, who are
classified as having `idiopathic anaphylaxis' (IA). As food consumption
patterns, genetic background, and environmental factors can lead to
differences in allergen sensitization patterns in different regions, we
sought to identify the aetiology of IA in cohort of Sri Lankan patients.
\textbf{Methods:} Of the patients referred to our clinic following
anaphylaxis, 65 were recruited as a cause could not be identified. The
events that led to the episode of anaphylaxis, the triggers, the
severity of symptoms and treatment received were recorded and skin prick
test, ISAC ImmunoCAP test and serum tryptase was carried out.
\textbf{Results:} Of the 65 patients, 42/65 (64.6\%) were females and
49/65 (75.38\%) were adults. 46/65 (70.8\%) had grade II anaphylaxis and
34/65 (52.3\%) were found to have specific IgE to alpha-gal, with
symptoms occurring 0.5 to 6 hours since ingestion of food. Of those who
had specific IgE to alpha-gal, 12 (35.3\%) had consumed red meat and 10
(29.4\%) milk products (3 had consumed fermented buffalo milk), before
the episode of anaphylaxis. Difficulty in breathing, swelling of lips
and syncope was significantly higher in those who were not sensitized to
alpha-gal, while diarrhoea and abdominal pain were more common in those
sensitized to alpha-gal, although this was not significant.
\textbf{Conclusion:} A large proportion of patients presenting with IA
were found to be sensitized to alpha-gal, which was the likely cause of
their anaphylaxis.%
\end{abstract}%



\sloppy


\textbf{Introduction}

The incidence of anaphylaxis has continued to rise globally based on
hospitalised data from Europe, United states, Australia, Brazil and some
Asian countries such as South Korea and Taiwan {[}1, 2{]}. However, the
actual incidence is likely to be several folds higher due to
mis-diagnosis, mis-classification, due to under reporting {[}1{]} and
also because allergies and anaphylaxis being neglected in many
developing countries, due to other disease priorities {[}3{]}. Food
allergy was shown to be the predominant cause of anaphylaxis, followed
by drugs and venom, in many countries {[}1, 2, 4{]}. However, in a large
proportion of cases, even after extensive evaluation, a trigger cannot
be identified, and such cases are classified as `idiopathic
anaphylaxis'{[}5{]}.

Approximately 10\% of children and 30 to 60\% of adults presenting with
anaphylaxis are classified as having idiopathic anaphylaxis (IA), as a
trigger cannot be identified {[}5{]}. Mast cell disorders such as
mastocytosis, mast cell activation syndrome and hereditary
\selectlanguage{greek}α-\selectlanguage{english}tryptasaemia, are some of the conditions that can cause IA, and
screening for these diseases have been suggested in the diagnostic
work-up {[}6{]}. Allergy to Galactose-\selectlanguage{greek}α-\selectlanguage{english}1,3-galactose (\selectlanguage{greek}α-\selectlanguage{english}gal), has shown
to be important cause of anaphylaxis in those in whom a cause cannot be
identified {[}7{]}. Alpha-gal allergy typically occurs 3 to 6 hours
after ingestion of red meat and has shown to occur due to IgE antibodies
specific to the carbohydrate epitope found on mammalian meat {[}8{]}.
Since the identification of \selectlanguage{greek}α-\selectlanguage{english}gal allergy as an important cause of
delayed anaphylaxis, screening for the presence of allergy to \selectlanguage{greek}α-\selectlanguage{english}gal has
been included in the diagnostic workup in a patient, in whom a possible
cause of anaphylaxis cannot be identified {[}7{]}. Other important
causes where IA was shown to be food dependent exercise induced
anaphylaxis (FDEIA), due to presence of IgE to omega-5-gliadin {[}5{]}.
FDIEA, has indeed shown to be an important cause especially in patients
who present at specialised allergy clinics. In one study, 12.2\% of
patients were identified as having FDIEA {[}9{]}.

Although the incidence of anaphylaxis is not reported in many lower
middle-income countries (LMICs), the incidence of asthma and asthma
related mortality has shown to be rising {[}10{]}. Diseases related to
allergies are neglected in many LMICs with adrenalin not used in many
instances, in the management of anaphylaxis and long-term management of
patients with anaphylaxis being sub-optimum due to the non-availability
of adrenalin autoinjectors {[}3, 11{]}. Although there is no data on the
incidence of anaphylaxis and other allergic diseases in Sri Lanka, there
is a high prevalence of asthma and allergen sensitization reported among
Sri Lankan children {[}11, 12{]}. Furthermore, many patients with
anaphylaxis present to specialised allergy clinics in Sri Lanka where
food allergy, FDIEA and allergy to vaccines have been identified as the
predominant causes of anaphylaxis {[}9, 13, 14{]}. As food consumption
patterns, genetic background, and environmental factors can lead to
differences in allergen sensitization patterns in different geographical
regions, we sought to identify the possible triggers of IA in Sri Lankan
patients presenting to specialised allergy clinics in Sri Lanka.

\textbf{Materials and methods}

\textbf{Patients}

This study was approved by the All patients who were referred to our
clinic with a history of anaphylaxis for further management were
recruited to the study following informed written consent. The clinical
features during anaphylaxis, and the treatment received was available
with the patients' clinical records and the diagnosis cards issued by
the hospitals. The patients were evaluated for the possible aetiological
factors, and contributing co-factors for the development of anaphylaxis
and then relevant skin prick tests were carried out to identify the
allergen. Those in whom we could not identify a possible allergen by
skin prick tests were classified as having idiopathic anaphylaxis (IA).
Accordingly, from January to December 2021, 65 patients were considered
to have IA. In all patients the events that led to the episode of
anaphylaxis, the foods that were consumed, the severity of symptoms and
treatment received were recorded.

Severity of anaphylaxis was classified according to the criteria defined
by Brown et al 2004 {[}15{]}. Accordingly, those who developed loss of
consciousness, confusion, collapse, cyanosis or with oxygen saturation
of \textless{}92\% or incontinence were classified has having had severe
anaphylaxis (grade 3).

Ethical approval was obtained from the Ethics Review Committee of the
Faculty of Medical Sciences, University of Sri Jayewardenepura, Sri
Lanka.

\textbf{Skin prick tests (SPT) for suspected allergens}

A qualified health professional performed this test after ensuring that
facilities for resuscitation were available if the need arose. Oral
antihistamines and topical skin corticosteroids were stopped for the
required duration prior to testing. Skin prick testing with the
commercial allergens (Immunotek, Spain) or prick-to-prick testing were
carried out according to the guidelines set by the European Academy of
Allergy and Clinical Immunology by Muraro et al., 2014 {[}16{]}. A
positive and a negative control were included in all instances. The size
of the wheal was recorded at 15 minutes and a test was considered
positive if the wheal size is \textgreater{}3mm of the negative control.

\textbf{ISAC ImmunoCAP}

The Immuno-solid phase allergen chip (ISAC) ImmunoCAP testing was
carried out according to the manufacturers instructions. This enables
testing for specific IgE against 112 allergen components in a multiplex
assay (supplementary data). Results were measured with a biochip scanner
(Capital bio Lux scanner) and evaluated using specialized software (MIA
Array software) as per manufacturers instructions. The results were
reported in ISAC Standardized Units (ISU-E) and interpretation was done
according to international guidelines {[}17{]} as shown below.

\textless{}0.3 ISU-E: Undetectable

0.3 to 0.9 ISU-E: Low

1 to 14.9 ISU-E: Moderate/High

\textgreater{}15 ISU-E: Very High

\textbf{ImmunoCAP tryptase}

The ImmunoCAP tryptase was measured in serum samples according to the
manufacturer's instructions using Thermo-Fisher Phadia 100. The results
were generated using a calibration curve and the threshold for a
positive result was considered to be values \textgreater{} 11\selectlanguage{greek}µ\selectlanguage{english}g/l.

\textbf{Statistical analysis}

Statistical analysis was performed using graph pad prism version 9 and
non-parametric statistical tests were used. The differences in clinical
features between those who had sensitization to alpha-gal compared to
others during the episode of anaphylaxis was expressed as the odds ratio
(OR), which was obtained from standard contingency table analysis by
Haldane's modification of Woolf's method. The Fisher's exact test was
used to determine the p value.

\textbf{Results}

\textbf{Allergen sensitization patterns in those who had idiopathic
anaphylaxis (IA)}

65 patients were classified as having IA, as we could not identify a
cause from the history or by carrying out skin prick tests. Of them 42
(64.6\%) were females and 49/65 (75.38\%) were adults. 8/65 (12.3\%)
patients had grade 1 anaphylaxis, 46 (70.8\%) had grade 2 anaphylaxis
and 11 (16.9\%) patients had grade 3 anaphylaxis. The allergen
sensitization pattern of these 65 patients measured by ISAC Immunocap is
shown in Table 1. 34 (52.3\%) patients were found to have specific IgE
to alpha-gal, while 11 (16.9\%) were sensitized to cow's milk. All 11
patients who were sensitized to cow's milk were also sensitized to
alpha-gal. The other main allergens that these patients were sensitized
to were house dust mite in 20 (30.8\%) patients, and grass pollen in 16
(24.6\%). 7/65 (10.8\%) of patients were found to be sensitized to
tropomyosin and 5/7 (71.43\%) of them were also sensitized to house dust
mite. Although seven were sensitized to tropomyosin, only 4/7 (57.14\%)
of them had developed symptoms following ingestion of shrimp. 3/7
(42.86\%) of those who had specific IgE to tropomyosin also had IgE to
shrimp and only one of them reported a reaction following ingestion of
shrimp.

\textbf{Differences in clinical features in patients who had
sensitization to alpha-gal compared to others}

Of the 34 patients who were found to have specific IgE to alpha-gal, 16
(47.1\%) did not have any detectable IgE to any of the other allergens
included in the ISAC ImmunoCAP. Of the 34 patients 14 (41.2\%) were male
22 (64.7\%) were adults. The clinical features in those with IA,
sensitized to alpha-gal compared to patients sensitized to other
allergens are shown in Table 2. The alpha gal patients reported an
average of 2 episodes of anaphylaxis and the other patients reported an
average of 3 episodes at the time of presentation. Urticaria and itching
were the commonest symptoms in both groups. Difficulty in breathing,
swelling of the lips and syncope was significantly higher in those who
were not sensitized to alpha-gal (Table 2). In contrast, diarrhoea and
abdominal pain were commoner in those who were sensitized to alpha-gal,
compared to others although this was not significant.

Of those who had specific IgE to alpha-gal, 12 (35.3\%) had consumed red
meat before the episode of anaphylaxis, 14 (41.2\%) milk products, 2/34
(5.9\%) products containing gelatine (sweets and gelatine containing
capsules), while ten 10 (29.4\%) did not recall consuming red meat or
any milk products prior to the episode. Of the 14 who had consumed milk
products, 3 (8.8\%) had consumed fermented buffalo milk. 16/34 (47.1\%)
who were sensitized to alpha-gal had never consumed red meat and had not
consumed red meat prior to the reaction.

Of these 34 patients, 14 (41.2\%) had low levels (0.3 -- 0.9 ISU-E) of
specific IgE to alpha-gal, 14 (41.2\%) had moderate/high levels (1 --
14.9 ISU-E) and 6 (17.6\%) had very high levels (\textgreater{}15
ISU-E). The specific IgE levels did not correlate with the severity of
anaphylaxis (Spearmans' r= 0.14, p=0.42). While most individuals had
anaphylaxis between 30 minutes to 6 hours since consumption of food, the
time since consumption of food and development of anaphylaxis varied
from immediate to up to 12 hours. 7/34 (20.6\%) patients developed
anaphylaxis immediately (\textless{}30mins), 12 (35.3\%) from 30 minutes
to two hours after ingestion, 10 (29.4\%) between 2 to 6 hours after
ingestion of food and 5 (14.7\%) after six hours after ingestion of
food.

22/34 (64.7\%) patients had other allergic diseases such as allergic
rhinitis (14, 41.2\%), asthma (10, 29.4\%) and atopic dermatitis (3,
8.8\%). While the majority of patients had only food-associated
allergies, six patients reported an episode(s) of drug allergy, three
patients reported an insect \& insect venom associated allergy and one
patient reported a vaccine-associated allergy resulting in anaphylaxis.

\textbf{Serum tryptase levels in patients with unexplained anaphylaxis}

Serum tryptase levels were done on the patients in whom specific IgE to
any food could not be identified by SPT and were negative for all the
allergens included in ISAC immunocap, due to limited funding.
Accordingly, serum tryptase was done in 11/65 (16.9\%) patients, who all
had levels within the normal range (\textless{}11\selectlanguage{greek}µ\selectlanguage{english}g/l).

\textbf{Discussion}

In this study we have shown that sensitization to alpha-gal was the
predominant cause (52.3\%) of IA in patients presenting to our clinic.
12 (35.3\%) had consumed red meat prior to developing anaphylaxis and
therefore, alpha-gal allergy is likely to be the most likely trigger in
these patients. 16/34 patients who were sensitized had never consumed
any red meat, as red meat consumption is not frequent among many ethnic
groups in Sri Lanka. Therefore, although they did have specific IgE to
alpha-gal possibly following a tick bite, it is not clear if the
presence of alpha-gal specific antibodies played a role in causing
anaphylaxis, in these patients. Interestingly, 14/34 patients who were
found to be sensitized to alpha-gal had consumed milk products and not
red meat prior to the reaction. 3 of these patients had consumed
fermented buffalo milk and not cow's milk. It has been shown that many
individuals who are sensitized to alpha-gal react to different types of
daily products, with 70 to 90\% of individuals with alpha-gal allergy
reacting to milk products in different studies {[}18, 19{]}. It was
shown that although patients with alpha-gal allergy did not react to the
main allergens in cow's milk, they reacted to bovine-\selectlanguage{greek}γ-\selectlanguage{english}globulin,
lactoferrin and lactoperoxidase {[}19{]}. Therefore, it is possible that
in the 14 patients with alpha-gal allergy who developed anaphylaxis
following ingestion of milk, was due to sensitization to these
components in milk.

Two patients developed anaphylaxis following consumption of gelatine
containing products and were also found to have specific antibodies to
alpha-gal. Alpha-gal has been reported in gelatine containing products
previously {[}8{]}, and therefore, the presence of alpha-gal in these
products could have triggered anaphylaxis in these two patients. In
fact, individuals who do not have any specific IgE to gelatine but have
specific IgE to alpha-gal have shown to develop anaphylaxis following
administration of vaccine, which has been shown to be due to the
alpha-gal component in gelatine {[}20-22{]}. Therefore, it is
recommended that gelatine containing vaccines should be administer with
caution or should be avoided if possible in those with alpha-gal allergy
{[}21{]}.

The other causes of anaphylaxis in our cohort could be wheat dependent
exercise induced anaphylaxis, and hidden ingredients or contaminants in
food such as shrimp and cashew. Three of our patients had specific IgE
to omega-5-gliadin and we previously reported that wheat dependent
exercise induced anaphylaxis was a frequent cause in patients referred
to allergy clinicals in Sri Lanka, possibly because of the difficulty in
diagnosis {[}9, 13{]}. Seven of our patients also had specific IgE to
tropomycin, although only 4 of them reported symptoms following
ingestion of shrimps. Although the presence of specific IgE to
tropomyosin is considered to be a good predictor of allergy to shrimp,
tropomyosin in house dust mite, has shown to strongly cross react with
shrimp tropomyosin {[}23, 24{]}. While generation of such cross reactive
IgE in those who have allergy to house dust mite, are shown to sometimes
cause reactions to shrimp, this is not the case in all instances
{[}24{]}.

A large proportion (64.7\%) of patients had other allergic diseases such
as allergic rhinitis (41.2\%), asthma (29.4\%) and atopic dermatitis (3,
8.8\%), suggesting that these individuals had many IgE mediated
diseases. Many (32.3\%) had specific IgE to house dust mite, 24.6\% to
grass pollen and 13.5\% to tree pollens, with some being sensitized to
multiple allergens. Therefore, in addition to the allergens tested by
skin prick tests and ISAC ImmunoCap, they could be sensitized to other
unidentified allergens, which triggered their anaphylaxis. Although it
is recommended that serum tryptase to be done in all individuals
presenting with IA, due to limitations in funding, we only did this test
in those, in whom a trigger could not be identified. All such
individuals, had serum tryptase within the normal range, suggesting that
they are unlikely to have a mast cell disorder.

In summary, a large proportion of patients presenting with IA were found
to be sensitized to alpha-gal, which was the likely cause of their
anaphylaxis. Importantly, 14/34 individuals developed anaphylaxis
following ingestion of milk products and 2/34 after ingestion of
gelatine. As these products are also shown to contain alpha-gal, it
would be important to test for the presence of alpha-gal allergy in
those who present with IA, due to the presence of alpha-gal in these
products.

\textbf{References}

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\textbf{Table 1. Allergen sensitization pattern among patients who
presented with idiopathic anaphylaxis.}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Allergen & Number of patients who had specific IgE to a particular
allergen (\%)\tabularnewline
\midrule
\endhead
\textbf{Alpha-gal} & 34 (52.3\%)\tabularnewline
\textbf{House dust mite} \emph{B.tropicalis}: Mite group 5 (Blo t 5)
\emph{D. farinae} Cysteine protease (Der f 1) NPC2 family (Der f 2)
\emph{D. Pteronyssinus} Cysteine protease (Der p 1) NPC2 family (Der p
2) Peritrophin-like protein domain (Der p 23) & 21 (32.3\%) 11 (16.9\%)
11 (16.9\%) 10 (15.4\%) 4 (6.2\%) 18 (27.7\%) 11 (16.9\%) 7 (10.8\%) 13
(6.2\%)\tabularnewline
\textbf{Grass pollen} Bermuda grass: Grass group 1 (Cyn d 1) Timothy
grass: Berberine bridge enzyme (Phl p 4) Grass group 5 (Phl p 5)
Procalcin (Phl p 7) Profilin (Phl p 12) & 16 (24.6\%) 13 (20\%) 16
(24.6\%) 14 (21.5\%) 1 (1.5\%) 1 (1.5\%) 1 (1.5\%)\tabularnewline
\textbf{Tree pollen} Plane tree: Putative invertase inhibitor (Pla a 1)
Japanese Cedar: Pectate lyase (Cry j 1) Cypress: Pectate lyase (Cup a 1)
Birch: PR-10 Protein (Bet v 1) Olive pollen: Lipid transfer protein
(nsLTP) & 9 (13.8\%) 1 (1.5\%) 6 (9.2\%) 6 (9.2\%) 1 (1.5\%) 1
(1.5\%)\tabularnewline
\textbf{Cow's milk} Transferrin (Bos d lactoferrin) Alpha-lactalbumin
(Bos d 4) Beta-lactoglobulin (Bos d 5) Casein (Bos d 8) Cross-reactive
components: Serum Albumin (Bos d 6) & 11 (16.9\%) 9 (13.8\%) 2 (3.1\%) 2
(3.1\%) 2 (3.1\%) 2 (3.1\%)\tabularnewline
\textbf{Cross-reactive Carbohydrate Determinants (MUXF3)} & 8
(12.3\%)\tabularnewline
\textbf{Tropomyosin} Anisakis (Ani s 3) Cockroach (Bla g 7) D.
Pteronyssinus (Der p 10) Shrimp (Pen m 1) & 7 (10.8\%) 6 (9.2\%) 7
(10.8\%) 6 (9.2\%) 6 (9.2\%)\tabularnewline
\textbf{Animal:} Cat - Fel d 1 (Uteroglobin) & 4 (6.15\%)\tabularnewline
\textbf{Shrimp} Arginine kinase (Pen m 2) Sarcoplasmic calcium binding
protein (Pen m 4) & 3 (4.62\%) 2 (3.1\%) 1 (1.5\%)\tabularnewline
\textbf{Wheat -- \emph{Triticum aestivum}} Omega-5 gliadin (Tri a
19.0101) Lipid transfer protein (nsLTP) Tri a 14 & 3 (4.62\%) 2 (3.1\%)
1 (1.5\%)\tabularnewline
Aspergillus fumigatus Mitogillin family (Asp f 1) Peroxismal protein
(Asp f 3) & 3 (4.62\%) 2 (3.1\%) 1 (1.5\%)\tabularnewline
\textbf{Soybean} Storage protein, Beta-conglycinin (Gly m 5) Storage
protein, Glycinin (Gly m 6) & 2 (3.08\%) 1 (1.5\%) 1
(1.5\%)\tabularnewline
\textbf{Storage mite}: \emph{L. destructor} - NPC2 family (Lep d 2) & 2
(3.08\%)\tabularnewline
\textbf{Cashew-nut:} Storage protein, 11S globulin (Ana o 2) & 1
(1.54\%)\tabularnewline
\textbf{Weed pollen -- Saltwort:} Pectin methylesterase (Sal k 1) & 1
(1.54\%)\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2. Clinical features of those with unexplained anaphylaxis
sensitized to alpha gal compared with patients who had no alpha-gal
specific IgE}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Symptom}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Patients with alpha-gal sensitization} \textbf{N (\%)}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Patients sensitized to other allergens} \textbf{N (\%)}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{P value}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Odds Ratio (95\% CI)}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Anaphylaxis grade 1 2 3\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8 (23.5\%) 19 (55.9\%) 7 (20.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 (0\%) 27 (87.1\%) 4 (2.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.005 0.007 0.51\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Infinity (2.23 to [?]) 0.18 (0.06 to 0.62) 1.750 (0.45 to 5.8)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Urticaria\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
32 (94.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
31 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.49\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 (0 to 2.35)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Abdominal pain\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
15 (44.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
9 (29.0\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.30\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.9 (0.67 to 5.47)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Itching\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
32 (94.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
31 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.49\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 (0 to 2.35)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Vomiting\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 (8.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 (9.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textgreater{}0.99\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.9 (0.2 to 4.13)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Diarrhoea\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
6 (17.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 (9.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.48\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2.0 (0.53 to 7.79)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Swelling of lips\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
19 (55.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
26 (83.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{0.02}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.24 (0.08 to 0.74)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Difficulty in breathing\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
24 (70.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
31 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{0.001}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 (0 to 0.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Syncope\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
14 (41.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
25 (80.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{0.002}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.17 (0.51 to 0.54)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Redness in eyes\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
5 (14.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.05\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Infinity (1.4 to [?])\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Loss of consciousness\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8 (23.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4 (12.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.35\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2.08 (0.59 to 6.7)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Sneezing\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 (8.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.24\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Infinity (0.81 to [?])\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Wheezing\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
21 (61.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
23 (74.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.3\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.56 (0.2 to 1.5)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\selectlanguage{english}
\FloatBarrier
\end{document}

