\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[T2A]{fontenc}
\usepackage[ngerman,greek,polish,english]{babel}



\usepackage{float}








\begin{document}

\title{Higher basal tryptase, asthma and loss of consciousness in anaphylaxis
are associated with biphasic reactions}



\author[1]{Terence Langlois}%
\author[2]{Pascale Nicaise}%
\author[1]{Camille Taillé}%
\author[1]{Patrick Natta}%
\author[1]{Bruno Crestani}%
\author[2]{Sylvie Chollet-Martin}%
\author[2]{Luc de Chaisemartin}%
\author[1]{Catherine Neukirch}%
\affil[1]{Hopital Bichat - Claude-Bernard Service Pneumologie A}%
\affil[2]{Hopital Bichat - Claude-Bernard}%


\vspace{-1em}



  
  \date{May 18, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
\textbf{Background:} Anaphylaxis is the more severe form of immediate
hypersensitivity. It can be life-threatening and therefore requires fast
and appropriate medical management. After a first hypersensitivity
phase, a recurrence of symptoms without an elicitor re-exposure may
occur, called a biphasic reaction. The aim of this study was to identify
biological and clinical predictors of biphasic reactions in patients
with anaphylaxis. \textbf{Methods:} We retrospectively compared patients
with monophasic anaphylaxis to those with biphasic anaphylaxis from an
allergology day hospital in a French university hospital between January
2017 and May 2020. \textbf{Results:} Among the 237 patients, the rate of
biphasic reactions was 5.5\% (n = 13). The odds of a biphasic reaction
was increased with asthma (p = 0.021; odds ratio = 4 {[}95\% confidence
interval 1.05-14.81{]}) and loss of consciousness during anaphylaxis (p
= 0.008) as compared with monophasic anaphylaxis. Basal tryptase levels
were significantly higher with biphasic than monophasic anaphylaxis (p =
0.009). \textbf{Conclusions:} Asthma and unconsciousness during the
first phase of anaphylaxis could be associated with a biphasic reaction
\textbf{.} Elevated basal tryptase was linked to biphasic reactions,
which should be further explored.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Anaphylaxis is a serious systemic hypersensitivity reaction that is
usually rapid in onset and may cause death in its more severe form (1).
Therefore, it requires fast and appropriate medical management (1).
Individual risk factors and cofactors that affect the severity of
anaphylaxis have been described (2, 3).

In the classical form, anaphylaxis is triggered by mediators released by
activated mast cells after cross-binding of surface-bound immunoglobulin
E (IgE) by an allergen, but it can also be activated by other
immunologic and non-immunologic elicitors. This activation leads to a
release of mast cell tryptase in the blood, which can be measured and
used as a diagnostic tool.

Low levels of tryptase are secreted permanently even in the absence of
mast cell activation and reflect total body mast cell burden. Therefore,
baseline tryptase levels are elevated in systemic mastocytosis (4) but
also slightly increased in older people and in males versus females (5,
6, 7). A high baseline tryptase level is known to be associated with
severe anaphylaxis (8, 9, 10, 11).

The acute phase of anaphylaxis typically occurs within minutes after
contact with the allergen and then symptoms regress within 4 hr (12).
However, anaphylaxis can also be biphasic, which means that after
initial symptoms completely resolve, a new onset of symptoms occurs
without re-exposure to an elicitor (13). The reported incidence of
biphasic anaphylaxis ranges from 0.4\% to 23.3\%, but more recent data
indicate 4\% to 5\% (14, 15, 16, 17, 18). The mechanism in biphasic
anaphylaxis in humans is known to be a prolonged expression of the
initial IgE-mediated reaction rather than an additional mechanism (19,
20).

A biphasic reaction usually occurs at 1 to 48 hr after the initial
reaction (14, 17, 21, 22) and in rare instances up to 72 hr (23, 24).
Symptoms of this second-phase reaction can be less than, as much as, or
more severe than the first reaction. (25). Biphasic hypersensitivity
reactions are globally more severe than are monophasic reactions (26).
Therefore, close monitoring is recommended for 1 to 6 hr after an
anaphylactic reaction, depending on the clinical severity, and
potentially up to 12 hr in some cases (27, 28). A previous history of
anaphylaxis (26), severe anaphylaxis (29), greater number of doses of
adrenaline during medical care (30), delay in initiation of medical care
or administration of epinephrine (17, 31), cardiovascular disease (32),
history of drug anaphylaxis (33, 34), an unknown elicitor (14, 26), an
oral allergen elicitor (35) and age 6 to 9 years (36) have been
described as risk factors for a biphasic reaction.

Here we analysed the clinical parameters of biphasic reactions. Because
the occurrence of a biphasic reaction has been associated with the
severity of anaphylaxis (26, 37, 38, 39) and elevated basal tryptase is
associated with anaphylaxis severity (40, 41, 42), we also compared
plasma tryptase levels in patients with monophasic and biphasic
reactions.

\textbf{Methods}

\emph{Patients}

This was a retrospective, observational and monocentric study. We
examined the medical files of patients [?] 15 years old who were referred
to the allergology day hospital in one university hospital in Paris for
exploring a suspected immediate hypersensitivity event between January
2017 and May 2020. We included patients with basal tryptase level
measurement.

We extracted from the medical records the patient's history and
anaphylaxis characterization (1) and also severity of the reaction
according to the Ring and Messmer classification (43), allergic status,
medical antecedents and current treatments.

Patients with asthma were all diagnosed and followed up by a
pulmonologist or a general practitioner.

All investigations such as basal tryptase measurement were performed at
least 4 weeks after the hypersensitivity reaction. Plasma basal tryptase
level was measured by the UniCAP-Tryptase fluoroimmunoassay method
(Phadia, Thermo Fisher Scientific, Uppsala, Sweden) following the
manufacturer's instructions. Patients with basal tryptase level
\textgreater{} 11 \selectlanguage{greek}µ\selectlanguage{english}g/L and/or REMA score [?]2 for Hymenoptera
venom-elicited anaphylaxis (44) were suspected to have mast
cell--related disorder and referred to hematology consultation for
additional exploration. Allergy tests performed in the day hospital
included skin tests (prick tests and intradermal tests), specific IgE
measurements, and challenge tests for allergen reintroduction if
necessary (drugs or foods).

We excluded patients if they had a diagnosis of mast cell disease or if
their reaction did not meet the anaphylaxis criteria of the 2020 World
Allergy Organization (1).

\emph{Statistics}

Statistical analysis involved using Matlab 2018b. Because tryptase
values do not follow a normal distribution, we compared them between
monophasic and biphasic anaphylaxis patients by unpaired signed-rank
Wilcoxon test (45, 46) Comparison of the clinical parameters involved
the non-parametric Fisher exact test. P\textless{}0.05 was considered
statistically significant.

\emph{Ethical Considerations}

The included patients had been informed beforehand in their letters of
consultation or hospitalization that unless they expressed an objection,
their medical data could be used in an anonymous form for medical
research purposes. No objections were expressed by any of the included
patients.

\textbf{Results}

\emph{Description of biphasic patients}

During the study period, 237 patients with available tryptase
measurements and a suspected anaphylaxis event consulted at our allergy
center (Figure 1); 13 (5.5\%) had a biphasic reaction. Detailed
characteristics of these patients are in Table 1.

Six of the 13 patients (46\%) presented a severe secondary reaction
(Ring and Messmer grade III-IV), whereas 7 patients (64\%) had a mild or
moderate reaction (Ring and Messmer grade I-II). The mean delay between
the first and second reaction was 8 hr (range 1-48). As compared with
the first reaction, the second was less severe for 5 (38.5\%) patients,
as severe for 7 (53.8\%) patients and more severe for only one (7.7\%)
patient. Nine patients required a transfer to an intensive care unit for
the biphasic reaction, and 2 were already hospitalized when the biphasic
reaction occurred. The identified allergens were Hymenoptera venom for 6
patients, neuro-muscular blocking agents (NMBAs) for 4 patients,
antibiotics for 2 patients, and seafood for one patient.

\emph{Comparison of biphasic and monophasic anaphylaxis}

Patients with monophasic anaphylaxis (n = 224) and biphasic anaphylaxis
(n = 13), did not differ by sex, mean age or age distribution
(Supplemental Figure), cardiovascular disease, diabetes, dysthyroidism,
chronic urticaria, renal failure, beta-blocker treatment, inhaled
corticosteroids use, proton pump inhibitor use or smoking habits (Table
2). However, asthma was more frequent with biphasic than monophasic
anaphylaxis (n=6/13, 46.1\%; vs 38/224, 16.9\%; odds ratio = 4 {[}95\%
confidence interval 1.05-14.81{]}, p = 0.02). In the monophasic group,
19 patients had mild asthma, 16 moderate asthma and 3 severe asthma. In
the biphasic group, 4 patients had mild asthma and 2 moderate asthma.
The proportion of patients with atopic disease was similar in both
groups (34/38, 89\%; and 5/6, 83\%). The two groups did not differ in
the use of inhaled corticosteroids (n=19/38, 50\%; and 2/6, 33\%, odds
ratio= 0.341 {[}95\% confidence interval 0.03-2.23{]}, p = 0.26).

The two groups did not differ in history of allergic
rhino-conjunctivitis, atopic dermatitis, contact eczema, history of
Hymenoptera venom allergy, food allergy or drug hypersensitivity (Table
2) or severity grade of anaphylaxis, skin involvement, respiratory
symptoms, digestive symptoms and use of epinephrine (Table 3). However,
loss of consciousness during the first phase was more frequent with
biphasic than monophasic anaphylaxis (100\% of biphasic patients vs
58.9\% of monophasic patients, p= 0.008) (Table 3). The distribution of
culprit allergens was similar in both groups, with Hymenoptera venom and
NMBAs the most frequently reported in our allergy center (Table 4).

Basal tryptase levels were significantly higher with biphasic than
monophasic anaphylaxis (median: 6.1 \selectlanguage{greek}µ\selectlanguage{english}g/l, n = 13 vs 4.2 \selectlanguage{greek}µ\selectlanguage{english}g/l, n = 224,
p=0.009) (Figure 2). For asthma patients, basal tryptase level was
significantly higher for those with biphasic than monophasic anaphylaxis
(median: 5.3 \selectlanguage{greek}µ\selectlanguage{english}g/l, n = 6 vs 3.7 \selectlanguage{greek}µ\selectlanguage{english}g/l, n = 38, p=0.015). Of note,
although with Hymenoptera venom allergy, basal tryptase level was
similar with biphasic and monophasic anaphylaxis (median 4.9 vs 4.5
\selectlanguage{greek}µ\selectlanguage{english}g/l, p=0.46), for drug allergy, the level was significantly higher with
biphasic than monophasic anaphylaxis (median 11.2 vs 4.2 \selectlanguage{greek}µ\selectlanguage{english}g/L,
p=0.0004).

\textbf{Discussion}

In this monocentric retrospective study, 13/237 (5.5\%) patients with an
anaphylaxis event had a biphasic reaction. The mean time of onset for
the biphasic reaction was 8 hr. This observed prevalence, time of onset
and range are in line with the current literature (14, 15, 16, 17, 18).
However, our results differ from the literature in the distribution of
the severity grade according to the Ring and Messmer classification
(25), which is described in equal proportions for mild, moderate and
severe reactions (47).

Patients with biphasic and monophasic anaphylaxis did not differ in
clinical and allergological features, except for loss of consciousness
during anaphylaxis and asthma, both more frequent with biphasic than
monophasic anaphylaxis. Furthermore, basal tryptase levels were
significantly more elevated with biphasic than monophasic reactions.

That we found more loss of consciousness with biphasic than monophasic
reactions suggests a more severe reaction with the former. However, the
Ring and Messmer classification did not significantly differ between the
groups. The association between severe anaphylaxis and biphasic
reactions was recently investigated in a large cohort (42):
gastrointestinal, skin symptoms, respiratory arrest, cardiac symptoms,
and chronic urticaria were associated with the occurrence of biphasic
reaction. Such a difference with our results can be explained by the
limited number of biphasic patients in our study.

There are no reports of a link between asthma comorbidity and biphasic
anaphylaxis (48, 49), which could be explained by recruitment bias
because our hospital service also includes an asthma center. However,
none of the asthmatic patients with a biphasic reaction were followed by
fellow pulmonologists. Moreover, the proportion of asthmatic patients we
found is lower than in the literature (18.5\% of 237 patients vs 22.5\%
in a large anaphylaxis registry (3)).

Although asthma was more frequent with biphasic than monophasic
anaphylaxis, the former group exhibited no severe asthma, and
respiratory symptoms during anaphylaxis were similar in both groups.
Asthma is known to increase the severity of anaphylaxis (48, 50, 51),
and severe asthma is also associated with a predominance of mast cells
positive for tryptase and chymase in the airway submucosa and epithelium
(52). Furthermore, severe asthma was recently found associated with
elevated basal tryptase level (even independently of type 2
inflammation) (53). We cannot conclude a potential link with asthma
treatment because only two patients used inhaled corticosteroids in the
biphasic group.

In our study, basal tryptase level was higher with biphasic than
monophasic anaphylaxis. To our knowledge, this has never been reported.
A potential explanation could be the more frequent history of asthma in
the biphasic than monophasic group because basal tryptase level was
higher with biphasic than monophasic anaphylaxis for asthmatic patients.
Older age and renal failure increase tryptase levels and could be
confounding factors, so we examined the distribution of age between our
two groups and it was similar. Additionally, none of our biphasic
patients had renal failure. Kraft et al (42) found no significant
difference in mean basal tryptase level between monophasic (n = 4786)
and biphasic anaphylaxis (n = 237). However, the authors included
patients with systemic mastocytosis in their analysis, which could
perhaps mask a difference in basal tryptase level and explain the
discrepancy with our results. Other factors regulating the activation of
mast cells, such as the cytokine environmental network or genetic
regulation of tryptase production could be involved (54).

We found no significant difference in culprit allergens between
monophasic and biphasic anaphylaxis. The most common allergens in our
study were drugs and Hymenoptera venom, which agrees with the literature
on epidemiological prevalence for the cause of anaphylaxis in adults
(51, 55) and could explain the few patients with a food elicitor in our
study. In addition, the basal tryptase level in biphasic and monophasic
groups with an allergy to Hymenoptera venom was similar but was higher
in biphasic patients with drug allergy. This has not been reported
before and warrants confirmation in further studies.

The main strength of this study is the detailed information on patient
characteristics. Furthermore, symptoms and medical management of
biphasic phases were well documented. All patients with an anaphylaxis
reaction had documented basal tryptase level, allergy test results and a
complementary interview in our center.

The retrospective monocentric design of the study is its main
limitation. The lack of power due to a small number of participants with
biphasic reactions did not allow for applying a multivariate analysis of
risk factors.

In conclusion, we show for the first time that elevated basal tryptase
is linked to biphasic reactions. The role of basal tryptase level as a
risk factor for biphasic reaction requires further investigations.
Additionally, asthma and unconsciousness during the first phase of
anaphylaxis could be associated with a biphasic reaction. These findings
advocate for prolonged monitoring of these patients during their care.

\textbf{Conflict of interest}

The authors declare that they do not have conflict of interests related
to the contents of this article.

\textbf{ORCID}

Terence Langlois\emph{https://orcid.org/0000-0002-6814-2983}

Bruno Crestani\emph{https://orcid.org/0000-0002-2961-3455}

Sylvie Chollet-Martin\emph{https://orcid.org/0000-0003-1434-4114}

Luc de Chaisemartin\emph{https://orcid.org/0000-0001-8973-1536}

Catherine Neukirch\emph{https://orcid.org/0000-0002-0778-4165}

\textbf{References}

1. Cardona V, Ansotegui IJ, Ebisawa M, El-Gamal Y, Fernandez Rivas M,
Fineman S, et al. World allergy organization anaphylaxis guidance 2020.
World Allergy Organ J. 2020;13(10):100472.

2. Bil\selectlanguage{ngerman}ò MB, Martini M, Tontini C, Corsi A, Antonicelli L. Anaphylaxis.
Eur Ann Allergy Clin Immunol. 2021;53(1):4\selectlanguage{english}-17.

3. Poziomkowska-G\selectlanguage{polish}ę\selectlanguage{english}sicka I, Kostrzewska M, Kurek M. Comorbidities and
Cofactors of Anaphylaxis in Patients with Moderate to Severe
Anaphylaxis. Analysis of Data from the Anaphylaxis Registry for West
Pomerania Province, Poland. Int J Environ Res Public Health.
2021;18(1):E333.

4. Caughey GH. Mast cell proteases as pharmacological targets. Eur J
Pharmacol. 2016;778:44-55.

5. Gonzalez-Quintela A, Vizcaino L, Gude F, Rey J, Meijide L,
Fernandez-Merino C, et al. Factors influencing serum total tryptase
concentrations in a general adult population. Clin Chem Lab Med.
2010;48(5):701-6.

6. Fenger RV, Linneberg A, Vidal C, Vizcaino L, Husemoen LL, Aadahl M,
et al. Determinants of serum tryptase in a general population: the
relationship of serum tryptase to obesity and asthma. Int Arch Allergy
Immunol. 2012;157(2):151-8.

7. Sperr WR, El-Samahi A, Kundi M, Girschikofsky M, Winkler S, Lutz D,
et al. Elevated tryptase levels selectively cluster in myeloid
neoplasms: a novel diagnostic approach and screen marker in clinical
haematology. Eur J Clin Invest. 2009;39(10):914-23.

8. Aniceto V, Dias MM, Melo JML, Trevisan-Neto O, Aragon DC, Maia LSM,
et al. Serum Baseline Tryptase Level as a Marker for the Severity of
Anaphylaxis. Int Arch Allergy Immunol. 2019;179(3):201-8.

9. Sahiner UM, Yavuz ST, Buyuktiryaki B, Cavkaytar O, Yilmaz EA, Tuncer
A, et al. Serum basal tryptase may be a good marker for predicting the
risk of anaphylaxis in children with food allergy. Allergy.
2014;69(2):265-8.

10. Francuzik W, Ru\selectlanguage{ngerman}ëff F, Bauer A, Bilò MB, Cardona V, Christoff G, et
al. Phenotype and risk factors of venom-induced anaphylaxis:
A~case-control study of the European Anaphylaxis Registry. J Allergy
Clin Immunol. 2021;147(2):653-662.e9.

11. Fellinger C, Hemmer W, Wöhrl S, Sesztak-Greinecker G, Jarisch R,
Wantke F. Clinical characteristics and risk profile of patients with
elevated baseline serum tryptase. Allergol Immunopathol (Madr).
2014;42(6):544\selectlanguage{english}-52.

12. Dribin TE, Schnadower D, Wang J, Camargo CA, Michelson KA, Shaker M,
et al. Anaphylaxis knowledge gaps and future research priorities:
A~consensus report. J Allergy Clin Immunol. 2021;S0091-6749(21)01209-4.

13. Nomura T, Sekii H, Sugita M, Nakahara S. Association between
biphasic reactions and the systems of symptoms and treatment in patients
with anaphylaxis hospitalized from the emergency department. Acute Med
Surg. dec 2020;7(1):e599.

14. Lee S, Bellolio MF, Hess EP, Erwin P, Murad MH, Campbell RL. Time of
Onset and Predictors of Biphasic Anaphylactic Reactions: A Systematic
Review and Meta-analysis. J Allergy Clin Immunol Pract.
2015;3(3):408-416.e1-2.

15. Lee S, Peterson A, Lohse CM, Hess EP, Campbell RL. Further
Evaluation of Factors That May Predict Biphasic Reactions in Emergency
Department Anaphylaxis Patients. J Allergy Clin Immunol Pract.
2017;5(5):1295\selectlanguage{english}-301.

16. Grunau BE, Li J, Yi TW, Stenstrom R, Grafstein E, Wiens MO, et al.
Incidence of clinically important biphasic reactions in emergency
department patients with allergic reactions or anaphylaxis. Ann Emerg
Med. 2014;63(6):736-744.e2.

17. Pourmand A, Robinson C, Syed W, Mazer-Amirshahi M. Biphasic
anaphylaxis: A review of the literature and implications for emergency
management. Am J Emerg Med. 2018;36(8):1480\selectlanguage{english}-5.

18. Rohacek M, Edenhofer H, Bircher A, Bingisser R. Biphasic
anaphylactic reactions: occurrence and mortality. Allergy.
2014;69(6):791\selectlanguage{english}-7.

19. Allergy Clin Immunol., editeur. Late cutaneous allergic responses in
IgE-dependent reactions. In 1973. p. 52: 38-46.

20. Solley GO, Gleich GJ, Jordon RE, Schroeter AL. The late phase of the
immediate wheal and flare skin reaction. Its dependence upon IgE
antibodies. J Clin Invest. 1976;58(2):408\selectlanguage{english}-20.

21. Dribin TE, Schnadower D, Wang J, Camargo CA, Michelson KA, Shaker M,
et al. Anaphylaxis knowledge gaps and future research priorities:
A~consensus report. J Allergy Clin Immunol. 2021;S0091-6749(21)01209-4.

22. Brazil E, MacNamara AF. <<~Not so immediate~>> hypersensitivity--the
danger of biphasic anaphylactic reactions. J Accid Emerg Med.
1998;15(4):252\selectlanguage{english}-3.

23. Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma
Immunol Off Publ Am Coll Allergy Asthma Immunol. 2005;95(3):217\selectlanguage{english}-26; quiz
226, 258.

24. Douglas DM, Sukenick E, Andrade WP, Brown JS. Biphasic systemic
anaphylaxis: an inpatient and outpatient study. J Allergy Clin Immunol.
1994;93(6):977\selectlanguage{english}-85.

25. Ellis A. Biphasic anaphylaxis: a prospective evaluation of
incidence, characteristics, and predictors. In Kingston; 2002.

26. Lee S, Bellolio MF, Hess EP, Campbell RL. Predictors of biphasic
reactions in the emergency department for patients with anaphylaxis. J
Allergy Clin Immunol Pract. 2014;2(3):281\selectlanguage{english}-7.

27. Shaker MS, Wallace DV, Golden DBK, Oppenheimer J, Bernstein JA,
Campbell RL, et al. Anaphylaxis-a 2020 practice parameter update,
systematic review, and Grading of Recommendations, Assessment,
Development and Evaluation (GRADE) analysis. J Allergy Clin Immunol.
2020;145(4):1082\selectlanguage{english}-123.

28. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA,
Branum A, et al. Second symposium on the definition and management of
anaphylaxis: Summary report - Second National Institute of Allergy and
Infectious Disease/Food Allergy and Anaphylaxis Network Symposium. Ann
Emerg Med. 2006;47(4):373\selectlanguage{english}-80.

29. Simard D, Bouchard V, Plourde A, Lefebvre S, Herman-Lemelin A,
Lapointe S, et al. Factors influencing emergency department observation
time following anaphylaxis: a systematic review. CJEM.
2021;23(4):480\selectlanguage{english}-93.

30. Lee S, Sadosty AT, Campbell RL. Update on biphasic anaphylaxis. Curr
Opin Allergy Clin Immunol. 2016;16(4):346\selectlanguage{english}-51.

31. Liu X, Lee S, Lohse CM, Hardy CT, Campbell RL. Biphasic Reactions in
Emergency Department Anaphylaxis Patients: A Prospective Cohort Study. J
Allergy Clin Immunol Pract. 2020;8(4):1230\selectlanguage{english}-8.

32. Brady WJ, Luber S, Joyce TP. Multiphasic anaphylaxis: report of a
case with prehospital and emergency department considerations. J Emerg
Med. 1997;15(4):477\selectlanguage{english}-81.

33. Lee S, Bellolio MF, Hess EP, Erwin P, Murad MH, Campbell RL. Time of
Onset and Predictors of Biphasic Anaphylactic Reactions: A Systematic
Review and Meta-analysis. J Allergy Clin Immunol Pract.
2015;3(3):408-416.e1-2.

34. Ko BS, Kim WY, Ryoo SM, Ahn S, Sohn CH, Seo D-W, et al. Biphasic
reactions in patients with anaphylaxis treated with~corticosteroids. Ann
Allergy Asthma Immunol Off Publ Am Coll Allergy Asthma Immunol.
2015;115(4):312\selectlanguage{english}-6.

35. Stark BJ, Sullivan TJ. Biphasic and protracted anaphylaxis. J
Allergy Clin Immunol. 1986;78(1 Pt 1):76\selectlanguage{english}-83.

36. Alqurashi W, Stiell I, Chan K, Neto G, Alsadoon A, Wells G.
Epidemiology and clinical predictors of biphasic reactions in children
with anaphylaxis. Ann Allergy Asthma Immunol Off Publ Am Coll Allergy
Asthma Immunol. 2015;115(3):217-223.e2.

37. Scranton SE, Gonzalez EG, Waibel KH. Incidence and characteristics
of biphasic reactions after allergen immunotherapy. J Allergy Clin
Immunol. 2009;123(2):493\selectlanguage{english}-8.

38. Confino-Cohen R, Goldberg A. Allergen immunotherapy-induced biphasic
systemic reactions: incidence, characteristics, and outcome: a
prospective study. Ann Allergy Asthma Immunol Off Publ Am Coll Allergy
Asthma Immunol. 2010;104(1):73\selectlanguage{english}-8.

39. Brady WJ, Luber S, Joyce TP. Multiphasic anaphylaxis: report of a
case with prehospital and emergency department considerations. J Emerg
Med. 1997;15(4):477\selectlanguage{english}-81.

40. Gulen T, Ljung C, Nilsson G, Akin C. Risk Factor Analysis of
Anaphylactic Reactions in Patients With Systemic Mastocytosis. J Allergy
Clin Immunol Pract. 2017;5(5):1248\selectlanguage{english}-55.

41. Bonadonna P, Zanotti R, Muller U. Mastocytosis and insect venom
allergy. Curr Opin Allergy Clin Immunol. 2010;10(4):347\selectlanguage{english}-53.

42. Kraft M, Scherer Hofmeier K, Rueff F, Pfohler C, Renaudin J-M, Bilo
MB, et al. Risk Factors and Characteristics of Biphasic Anaphylaxis. J
Allergy Clin Immunol Pract. 2020;8(10):3388-3395.e6.

43. Ring J, Messmer K. Incidence and severity of anaphylactoid reactions
to colloid volume substitutes. Lancet Lond Engl. 1977;1(8009):466\selectlanguage{english}-9.

44. Alvarez-Twose I, Gonzalez de Olano D, Sanchez-Munoz L, Matito A,
Esteban-Lopez MI, Vega A, et al. Clinical, biological, and molecular
characteristics of clonal mast cell disorders presenting with systemic
mast cell activation symptoms. J Allergy Clin Immunol.
2010;125(6):1269-1278.e2.

45. Rakotomalala R. Comparaison de populations. 2008;109.

46. Borovkov A. Mathematical Statistics. MIR. Moscow; 1987.

47. Ellis A. Biphasic anaphylaxis: a prospective evaluation of
incidence, characteristics, and predictors.~In Kingston; 2002.

48. Simons FER, Ardusso LR, Bilo MB, Cardona V, Ebisawa M, El-Gamal YM,
et al. International consensus on (ICON) anaphylaxis. World Allergy
Organ J. 2014;7(1):9.

49. Gonzalez-Perez A, Aponte Z, Vidaurre CF, Rodriguez LAG. Anaphylaxis
epidemiology in patients with and patients without asthma: a United
Kingdom database review. J Allergy Clin Immunol.
2010;125(5):1098-1104.e1.

50. Cardona V, Ansotegui IJ, Ebisawa M, El-Gamal Y, Fernandez Rivas M,
Fineman S, et al. World allergy organization anaphylaxis guidance 2020.
World Allergy Organ J. 2020;13(10):100472.

51. Turner PJ, Campbell DE, Motosue MS, Campbell RL. Global Trends in
Anaphylaxis Epidemiology and Clinical Implications. J Allergy Clin
Immunol Pract. 2020;8(4):1169\selectlanguage{english}-76.

52. Balzar S, Fajt ML, Comhair SAA, Erzurum SC, Bleecker E, Busse WW, et
al. Mast cell phenotype, location, and activation in severe asthma. Data
from the Severe Asthma Research Program. Am J Respir Crit Care Med.
2011;183(3):299\selectlanguage{english}-309.

53. Maun HR, Jackman JK, Choy DF, Loyet KM, Staton TL, Jia G, et al. An
Allosteric Anti-tryptase Antibody for the Treatment of Mast
Cell-Mediated Severe Asthma. Cell. 2019;179(2):417-431.e19.

54. Sprinzl B, Greiner G, Uyanik G, Arock M, Haferlach T, Sperr WR, et
al. Genetic Regulation of Tryptase Production and Clinical Impact:
Hereditary Alpha Tryptasemia, Mastocytosis and Beyond. Int J Mol Sci.
2021;22(5):2458.

55. Turner PJ, Gowland MH, Sharma V, Ierodiakonou D, Harper N, Garcez T,
et al. Increase in anaphylaxis-related hospitalizations but no increase
in fatalities: an analysis of United Kingdom national anaphylaxis data,
1992-2012. J Allergy Clin Immunol. 2015;135(4):956-963.e1.

\textbf{Table 1.} Profile of biphasic reactions\selectlanguage{english}
\begin{longtable}[]{@{}lllllllllllll@{}}
\toprule
\begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Age/sex\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Allergen\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Basal tryptase level (\selectlanguage{greek}µ\selectlanguage{english}g/L)\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Severity of first reaction\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Treatment of first reaction\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Severity of second reaction\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Time to second phase (hr)\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Biphasic manifestations\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Management location\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Asthma\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Cardiovascular\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Cardiovascular\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Atopy\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
41/F\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
ATB\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
10.8\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
III\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
EPI, AH, CS\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
III\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Cutaneous, cardiovascular\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
ED\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
23/M\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
ATB\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
5.4\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
II\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
AH, CS\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
I\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
14\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Cutaneous\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Outpatient\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
59/M\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NMBAs\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
12.4\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
III\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
EPI, AH, CS\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
II\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Cutaneous, respiratory\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Hospital\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
38/F\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NMBAs\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
22.2\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
II\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
EPI. AH\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
I\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Cutaneous\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Hospital\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
29/F\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NMBAs\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
5.2\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
II\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
EPI, AH, CS\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
III\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Cutaneous, cardiovascular\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
ICU\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
26/M\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NMBAs\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
11.6\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
III\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
EPI, AH, CS\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
III\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Cutaneous respiratory, cardiovascular\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
ICU\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
76/F\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Hymen.\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
8.5\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
III\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
EPI, AH, CS\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
III\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
8\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Cardiovascular, cutaneous, respiratory\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
ICU\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
62/M\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Hymen.\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
6.5\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
III\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
EPI, AH, CS\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
III\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
1.5\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Cutaneous, cardiovascular\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
ED\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
56/M\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Hymen.\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
3.9\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
III\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
EPI. AH\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
II\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
12\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Cutaneous, respiratory\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
ED\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
47/F\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Hymen.\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
1.7\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
III\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
EPI, AH, CS\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
III\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Cutaneous, cardiovascular\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
ICU\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
53/F\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Hymen.\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
3.2\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
II\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
AH, CS\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
I\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
48\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Cutaneous\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Outpatient\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
71/F\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Hymen.\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
6.1\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
II\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
AH, CS\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
II\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Cutaneous, cardiovascular\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
ED\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
67/F\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Food\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
4.6\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
II\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
AH\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
II\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
1.5\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Cardiovascular, digestive\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
ED\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Yes\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: ATB: antibiotic; NMBAs: neuromuscular blocking agents;
ED: emergency department; ICU: intensive care unit; EPI: epinephrine;
AH: antihistamine; CS: corticosteroids; Hymen. Hymenoptera venom

\textbf{Table 2} . Clinical characteristics\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Monophasic anaphylaxis n=224\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Biphasic anaphylaxis n=13\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
P-value\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Men\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
87 (38.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5 (38.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Age, mean (SD)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
49.2 (16.7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
49.8 (17.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Asthma\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
38 (16.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6 (46.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{p = 0.021*}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Inhaled steroids\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
19 (8.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2 (15.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 0.34\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Atopic dermatitis\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
16 (7.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1 (7.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Contact eczema\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
41 (18.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3 (23.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 0.72\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Chronic urticaria\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5 (2.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Allergic rhino-conjunctivitis\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
77 (34.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7 (53.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 0.24\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
History of Hymenoptera venom hypersensitivity\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4 (1.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
History of drug hypersensitivity\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
13 (5.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
History of food hypersensitivity\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
34 (15.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3 (23.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 0.44\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Cardiovascular disease\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
73 (32.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4 (30.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Diabetes\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
14 (6.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1 (7.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 0.58\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Dysthyroidism\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
18 (8.0\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1 (7.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Renal failure\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1 (0.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
PPI treatment\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
44 (19.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2 (15.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Beta-blocker treatment\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
26 (11.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 0.37\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Smoking\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
85 (37.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7 (53.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 0.26\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

PPI, proton pump inhibitor

\textbf{*} OR = 4, confidence interval {[}1.05--14.81{]}

\textbf{Table 3} . Clinical features

* OR=Inf {[}CI95{]}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Monophasic anaphylaxis n=224\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Biphasic anaphylaxis n=13\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
P-value\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Severity grade II III + IV\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
112 (50\%) 112 (50\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6 (46.1\%) 7 (53.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 1 p = 1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Skin signs\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
182 (81.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
11 (84.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Respiratory signs\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
118 (52.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7 (53.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 0.98\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Digestive signs\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
39 (17.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5 (38.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 0.14\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Loss of consciousness\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
132 (58.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
13 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{p = 0.008}*\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Epinephrine treatment engaged\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
99 (44.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
9 (69.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 0.39\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 4.} Elicitors for monophasic and biphasic anaphylaxis\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Elicitors\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Monophasic anaphylaxis N=224\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Biphasic anaphylaxis n=13\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
p-value\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
ATB\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
34 (15.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2 (15.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NMBAs\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
57 (25.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4 (30.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
P = 0.745\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
ICM\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
11 (4.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Hymenoptera venom\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
50 (22.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6 (46.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 0.39\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NSAIDs/aspirin\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
15 (6.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Food\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3 (1.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1 (7.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 0.22\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Paracetamol\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1 (0.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Other\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1 (0.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Non-IgE mediated/ idiopathic\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
52 (23.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p = 0.08\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

ATB: antibiotic; NMBAs: neuromuscular blocking agents; ICM: iodinated
contrast media; NSAIDs: nonsteroidal anti-inflammatory drugs; IgE,
immunoglobulin E



\emph{Figure legends}

\textbf{Figure 1.} Flowchart of the study

\textbf{Figure 2.} Basal tryptase concentrations

Box plot according to monophasic anaphylaxis and biphasic anaphylaxis;
horizontal bars are median, box edges are interquartile range and
whiskers are range.

Monophasic (\selectlanguage{greek}µ\selectlanguage{english}g/L): median (range) = 4.2 (1--19.5); SD = 3.1 (n=224)

Biphasic (\selectlanguage{greek}µ\selectlanguage{english}g/L): median (range) = 6.1 (1.7--22.2); SD = 5.4 (n=13)

*p = 0.009 (after unpaired signed-rank Wilcoxon test)

\emph{}

\emph{Appendices}

\textbf{Hosted file}

\verb`image1.emf`  available at \url{https://authorea.com/users/464306/articles/713455-higher-basal-tryptase-asthma-and-loss-of-consciousness-in-anaphylaxis-are-associated-with-biphasic-reactions}

\par\null

\textbf{Supplemental figure:} Age distribution at anaphylaxis onset with
monophasic and biphasic anaphylaxis. y, years

\textbf{Hosted file}

\verb`Original figures.docx`  available at \url{https://authorea.com/users/464306/articles/713455-higher-basal-tryptase-asthma-and-loss-of-consciousness-in-anaphylaxis-are-associated-with-biphasic-reactions}

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

