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\begin{document}

\title{Glucocorticoids and rates of biphasic reactions in patients with
adrenaline-treated anaphylaxis}



\author[1]{Shimpei Nagata}%
\author[1]{Hiroyuki Ohbe}%
\author[1]{Taisuke Jo}%
\author[1]{Hiroki Matsui}%
\author[2]{Kiyohide Fushimi}%
\author[1]{Hideo Yasunaga}%
\affil[1]{The University of Tokyo}%
\affil[2]{Tokyo Medical and Dental University Graduate School of Medicine}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: The effectiveness of glucocorticoids in preventing biphasic
reactions in patients with anaphylaxis is still controversial. We
evaluated the effects of glucocorticoids on rates of biphasic reactions
in patients with anaphylaxis treated with adrenaline. Methods: In this
retrospective observational study using a national inpatient database in
Japan, we identified 31,570 patients with anaphylaxis treated with
adrenaline on the day of admission. We divided them into two groups:
those who were treated with adrenaline plus glucocorticoids and those
who received adrenaline only on the day of admission. We performed a
one-to-four propensity score matching analysis between the two groups.
The primary outcome was occurrence of a biphasic reaction and the
secondary outcome was 7-day all-cause mortality. Results: Of the 31,570
eligible patients, 28,145 (89.2\%) were treated with glucocorticoids.
After propensity score matching, there were no significant differences
in rates of biphasic reactions (odds ratio, 1.03; 95\% confidence
interval, 0.86--1.24; p=0.14) or 7-day all-cause mortality (odds ratio,
0.68; 95\% confidence interval, 0.40--1.17; p=0.16) between patients
with anaphylaxis treated with and without glucocorticoids. Conclusion:
Our findings do not support the use of glucocorticoids to prevent
biphasic reactions in patients with severe anaphylaxis requiring
adrenaline.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Anaphylaxis, a form of hypersensitive reaction, can be life-threatening
at any age and in either sex. A biphasic reaction is defined as the
recurrence of anaphylactic symptoms without re-exposure to the allergen
within 72 hours of resolution of the initial
reaction.\textsuperscript{1} Biphasic reactions reportedly occur in
4.6\% of patients with anaphylaxis.\textsuperscript{1}Current
anaphylaxis guidelines therefore recommend continuous observation for
several hours or longer after resolution of the initial
reaction.\textsuperscript{2--5} In these guidelines, intramuscular
injection of adrenaline is the recommended first-line treatment,
glucocorticoids, histamine-1 receptor blockers, and beta 2-adrenergic
receptor stimulants being second-line treatments.\textsuperscript{2--5}
However, there is limited available evidence for the effects of
second-line treatments on symptoms and rates of biphasic reactions in
patients with anaphylaxis.

Glucocorticoids inhibit inflammatory responses by suppressing the
function of mast cells and are thought to prevent biphasic reactions in
patients with anaphylaxis.\textsuperscript{6} Recent retrospective
cohort studies have failed to show any preventive effects of
glucocorticoids on biphasic reactions.\textsuperscript{7,8}However, the
cohorts of these studies included patients with various types of
allergy, including mild to moderate anaphylaxis. Given that
glucocorticoids can ameliorate allergic inflammatory responses, it is
possible that they prevent biphasic reactions, especially in patients
with severe anaphylaxis.

Therefore, in this retrospective observational study using a national
inpatient database in Japan, we aimed to examine the effect of
glucocorticoids on rates of biphasic reactions in patients with severe
anaphylaxis treated with adrenaline.

\textbf{Methods}

Data source

In this nationwide retrospective cohort study, we used data from the
Japanese Diagnosis Procedure Combination database, the details of which
have been described elsewhere.\textsuperscript{9} Briefly, this database
includes data of approximately 7 million inpatients per year, which
represent more than half of all inpatient admissions to acute care
hospitals in Japan. The database includes the following characteristics
for each patient: age, sex, body height, weight, Japan Coma Scale score,
smoking status, diagnoses, pre-admission comorbidities, post-admission
complications, medications, and discharge status. Diagnoses are recorded
using the International Classification of Disease 10th revision (ICD-10)
codes. The Institutional Review Board of The University of Tokyo
approved this study (Approval Number, 3501-3; 25 December 2017). Because
the data were anonymized, the requirement for informed consent was
waived.

Patients, intervention, and outcomes

Using data from July 2010 to March 2018, we identified patients who were
diagnosed with anaphylaxis and treated with intramuscular adrenaline on
the day of admission. Patients with anaphylaxis were identified on the
basis of the following ICD-10 codes: T78.0 (Anaphylactic shock due to
adverse food reaction), T78.2 (Anaphylactic shock, unspecified), and
T88.6 (Anaphylactic shock due to adverse effect of correct drug or
medicament properly administered). We only assessed the initial
hospitalization for patients who were hospitalized twice or more during
the study period. We defined the glucocorticoids group as patients who
received oral or intravenous glucocorticoids on the day of admission,
the remaining patients comprising the control group.

The primary outcome was a biphasic reaction within 7 days of admission.
We defined biphasic reaction as adrenaline re-use within 7 days from the
date of admission. The secondary outcome was 7-day all-cause mortality.

Statistical analyses

We conducted propensity score matching analysis to compare outcomes
between the two groups. A multivariable logistic regression model with
the following variables as covariates was used to estimate propensity
scores for receiving glucocorticoids on the day of admission: age, sex;
body mass index category, Japan Coma Scale score (alert, drowsy,
somnolent, and comatose)\textsuperscript{10}; smoking status (never,
past and current smoker, and missing); diagnoses (T78.0, T78.2, T88.6);
Charlson Comorbidity Index score (0, 1, 2, and [?]3); history of asthma,
atopic dermatitis, and atopic rhinitis; use of histamine 1 blockers,
histamine 2 blockers and beta 2-adrenergic receptor stimulants; hospital
volume (very low, low, high, and very high); and teaching hospital. We
performed one-to-four nearest-neighbor matching with replacement for
estimated propensity scores, using a caliper width set at one fifth of
the standard deviation of the estimated propensity scores. To assess the
accuracy of the matching, we compared the covariates before and after
propensity-score matching using absolute standardized differences,
absolute standardized differences [?] 10\% being considered to denote
negligible imbalances between the two groups.\textsuperscript{11} After
propensity score matching, we assessed the outcomes through generalized
linear models, accompanied by cluster-robust standard errors with
hospitals as the clusters. We calculated odds ratios and their 95\%
confidence intervals (CIs) with generalized linear models using the
logit link function.

Sensitivity analyses

We used the following statistical methods to conduct sensitivity
analyses to check the robustness of our findings. First, we performed
traditional multivariable regression analysis using a generalized linear
model. In this analysis, we created a generalized linear model using
outcomes as dependent variable and glucocorticoids on the day of
admission and all covariates as independent variables. Second, we
performed a propensity score adjustment analysis. In this analysis, we
created a generalized linear model using outcomes as dependent variables
and estimated propensity score in the main analysis as independent
variables. Third, we conducted an inverse probability of treatment
weighting analysis.\textsuperscript{12} For this, we used a weighted
generalized linear model with stabilized average treatment effect weight
calculated from the estimated propensity scores in the main analysis.

Continuous variables are presented as mean and standard deviation (SD),
and categorical variables as number and percentage. p\textless{}0.05 was
defined as denoting statistical significance. We used Stata version 16.0
(StataCorp, College Station, TX, USA) to perform all statistical
analyses.

\textbf{Results}

We identified 31,570 eligible patients during the study period. Of
these, 28,145 (89.2\%) were treated with glucocorticoids on the day of
admission (Fig. 1).

Table 1 shows the patients' baseline characteristics before and after
propensity score matching. Before propensity score matching,
significantly higher proportions of patients were using histamine-1
receptor blockers, histamine-2 receptor blockers, and beta 2-adrenergic
receptor stimulants in the glucocorticoids group than in the control
group.

The overall percentage of biphasic reactions within 7 days of admission
was 11.2\% and 7-day all-cause mortality was 0.4\% (Table 2). The
percentages of biphasic reactions that occurred on days 1, 2, and 3--7
of the initial reaction were 88.8\%, 9.1\%, and 2.1\%, respectively.

One-to-four propensity-score matching created matched cohorts of 3,425
patients in the control group and 13,700 patients in the glucocorticoid
group. After propensity score matching, the distribution of patient
characteristics was well-balanced between the matched groups and there
were no statistically significant differences in rates of biphasic
reactions (odds ratio 1.03; 95\% CI 0.86--1.24; p=0.14) or 7-day
all-cause mortality (odds ratio 0.68; 95\% CI 0.40--1.17; p=0.16)
between the two groups (Table 2).

The results of three sensitivity analyses of traditional multivariable
regression analyses, propensity score adjustment, and inverse
probability of treatment weighting were similar to those using
propensity score matching for biphasic reactions (Table 3).

\textbf{Discussion}

In this study, about 90\% of the 31,570 patients with anaphylaxis
treated with adrenaline were also treated with glucocorticoids. The
overall proportion of biphasic reactions was 11.2\%. There were no
significant differences in rates of biphasic reactions or 7-day
all-cause mortality between those treated with and without
glucocorticoids.

Previous studies have failed to show that glucocorticoids reduce the
rate of biphasic reactions in patients with anaphylaxis of varying
severity.\textsuperscript{7,8} In the present study, which included only
patients with severe anaphylaxis, we also found no evidence that
glucocorticoids reduce the rate of biphasic reactions.

Biphasic reactions occurred on the day of the initial anaphylactic
reaction in about 90\% of the patients in our study. A previous study
reported a median time between initial symptom resolution and onset of
biphasic reaction of 11 hours (range 0.2--72
hours.\textsuperscript{1}The anti-allergic effects of glucocorticoids,
which are thought to be responsible for any effect on biphasic
reactions, occur within 4 to 6 hours.\textsuperscript{6} Therefore, the
failure of glucocorticoids to reduce the rate of biphasic reactions may
be attributable to the difference between the time required for
glucocorticoids to take effect and the time of onset of biphasic
reactions.

Long-term steroid administration is associated with adverse effects,
including infection, osteoporosis, hypertension, mood disorder, peptic
ulcer, and adrenal insufficiency. Even short-term administration may
result in avascular necrosis.\textsuperscript{13,14} Short-term steroid
use can also be associated with development of hyperglycemia within a
few hours.\textsuperscript{15} Given that this study showed no
significant association between glucocorticoid use and rate of biphasic
reaction, routine use of glucocorticoids to prevent biphasic reaction
may not be indicated, not even in patients with severe anaphylaxis
requiring intramuscular adrenaline.

This study has several limitations. First, it was a retrospective
observational study. Although we used propensity score matching to
adjust for confounding factors, our results may have been affected by
unmeasured confounding factors, including symptoms of anaphylaxis, time
from onset of anaphylaxis to treatment, use of epinephrine
autoinjectors, and the results of laboratory tests. Future research is
expected to be prospective or to use registries that include detailed
clinical data. Second, in this study, severe anaphylaxis was defined as
anaphylaxis requiring admission to hospital and treatment with
adrenaline. However, some patients without severe clinical symptoms
receive adrenaline, potentially resulting in misclassification and
underestimation of the effects of glucocorticoids.

\textbf{Conclusion}

Our nationwide database study of patients with severe anaphylaxis showed
no significant reduction in rates of biphasic reactions by
glucocorticoids. Our findings do not justify routine administration of
glucocorticoids to prevent biphasic reaction in patients with severe
anaphylaxis.

\textbf{References}

\begin{enumerate}
\item
  Lee S, Bellolio MF, Hess EP, Erwin P, Murad MH, Campbell RL. Time of
  onset and predictors of biphasic anaphylactic reactions: A systematic
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  2015;3(3):408-416.
\item
  Japanese Society of Allergology. Anaphylaxis guideline
  2014.\emph{https://anaphylaxis-guideline.jp/pdf/anaphylaxis\_guideline}.
  pdf Accessed March 11, 2021
\item
  Shaker MS, Wallace DV, Golden DBK, et al. Anaphylaxis--a 2020 practice
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  Assessment, Development and Evaluation (GRADE) analysis. J Allergy
  Clin Immunol 2020;145(4):1082-1123.
\item
  Simons FE, Ebisawa M, Sanchez-Borges M, et al. 2015 update of the
  evidence base: World Allergy Organization anaphylaxis guidelines.
  World Allergy Organ J 2015 Oct 28;8(1):32.
\item
  Muraro A, Roberts G, Worm M, et al. Anaphylaxis: guidelines from the
  European Academy of Allergy and Clinical Immunology. Allergy
  2014;69(8):1026-1045.
\item
  Liyanage CK, Galappatthy P, Seneviratne SL. Corticosteroids in
  management of anaphylaxis; a systematic review of evidence. Eur Ann
  Allergy Clin Immunol 2017;49(5):196-207.
\item
  Grunau BE, Wiens MO, Rowe BH, et al. Emergency department
  corticosteroid use for allergy or anaphylaxis is not associated with
  decreased relapses. Ann Emerg Med 2015;66(4):381-389.
\item
  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):281-287.
\item
  Yasunaga H. Real World Data in Japan: Chapter II The Diagnosis
  Procedure Combination Database. Ann Clin Epidemiol 2019;1(3):76-79.
\item
  Ono K, Wada K, Takahara T, Shirotani T. Indications for computed
  tomography in patients with mild head injury. Neurol Med Chir (Tokyo).
  2007;47(7):291-297.
\item
  Austin PC. Balance diagnostics for comparing the distribution of
  baseline covariates between treatment groups in propensity-score
  matched samples. Stat Med 2009;28(25):3083-3107.
\item
  Cole SR, Hern\selectlanguage{ngerman}án MA. Constructing inverse probability weights for
  marginal structural models. Am J Epidemiol 2008;168(6):656-664.
\item
  Dilisio MF. Osteonecrosis following short-term, low-dose oral
  corticosteroids: a population-based study of 24 million patients.
  Orthopedics 2014;37(7):e631-636.
\item
  Kennedy P, Bassiouni A, Psaltis A, Antisdel J, Brunworth J. Avascular
  necrosis after oral corticosteroids in otolaryngology: Case report and
  review of the literature. Allergy Rhinol (Providence) 2016;7(1):50-54.
\item
  Roberts A, James J, Dhatariya K; Joint British Diabetes Societies
  (JBDS) for Inpatient Care. Management of hyperglycaemia and steroid
  (glucocorticoid) therapy: a guideline from the Joint British Diabetes
  Societies (JBDS) for Inpatient Care group. Diabet Med
  2018;35(8):1011-1017.
\item
\end{enumerate}

\textbf{Table 1} . Baseline characteristics of patients treated with and
without glucocorticoids according to unmatched and propensity
score-matched groups\selectlanguage{english}
\begin{longtable}[]{@{}llllllll@{}}
\toprule
& & Unmatched & Unmatched & Unmatched & After 1:4 matching & After 1:4
matching & After 1:4 matching\tabularnewline
\midrule
\endhead
Characteristics & & Control (n=3425) & Glucocorticoids (n=28145) & ASD
(\%) & Control (n=3425) & Glucocorticoids (n=13700) & ASD
(\%)\tabularnewline
Age, mean (SD) (y) & & 37.1 (27.4) & 38.6 (26.5) & 5.4 & 37.1 (27.4) &
36.0 (27.1) & 0.4\tabularnewline
Male & & 1829 (53.4) & 15125 (53.7) & 0.7 & 1829 (53.4) & 7423 (54.2) &
1.6\tabularnewline
Body Mass Index (kg/m\textsuperscript{2}) & Body Mass Index
(kg/m\textsuperscript{2}) & & & & & &\tabularnewline
& \textless{}18.5 & 861 (25.1) & 6291 (22.4) & 6.6 & 861 (25.1) & 3594
(26.2) & 2.5\tabularnewline
& 18.5\textless{}= \textless{}25.0 & 1379 (40.3) & 11765 (41.8) & 3.1 &
1379 (40.3) & 5417 (39.5) & 1.5\tabularnewline
& 25.0\textless{}= \textless{}30.0 & 443 (12.9) & 3973 (14.1) & 3.5 &
443 (12.9) & 1746 (12.7) & 0.6\tabularnewline
& \textgreater{}=30.0 & 132 (3.9) & 1064 (3.8) & 0.4 & 132 (3.9) & 476
(3.5) & 0.2\tabularnewline
& missing & 610 (17.8) & 5052 (17.9) & 0.4 & 610 (17.8) & 2467 (18.0) &
0.0\tabularnewline
Japan Coma Scale & Japan Coma Scale & & & & & &\tabularnewline
& Alert & 2941 (85.9) & 24175 (85.9) & 0.1 & 2941 (85.9) & 11952 (87.2)
& 4.0\tabularnewline
& Drowsy & 332 (9.7) & 2750 (9.8) & 0.3 & 332 (9.7) & 1228 (9.0) &
2.5\tabularnewline
& Somnolence & 104 (3.0) & 852 (3.0) & 0.1 & 104 (3.0) & 336 (2.5) &
3.6\tabularnewline
& Coma & 48 (1.4) & 368 (1.3) & 0.8 & 48 (1.4) & 184 (1.3) &
0.5\tabularnewline
Smoking status & Smoking status & & & & & &\tabularnewline
& never & 2341 (68.4) & 18605 (66.1) & 4.8 & 2341 (68.4) & 9600 (70.1) &
3.7\tabularnewline
& past and current & 717 (20.9) & 6262 (22.2) & 3.2 & 717 (20.9) & 2700
(19.7) & 3.0\tabularnewline
& missing & 367 (10.7) & 3278 (11.6) & 3.0 & 367 (10.7) & 1400 (10.2) &
1.6\tabularnewline
Diagnosis & Diagnosis & & & & & &\tabularnewline
& T78.0\textsuperscript{+} & 730 (21.3) & 5284 (18.8) & 6.3 & 730 (21.3)
& 2901 (21.2) & 0.3\tabularnewline
& T78.2\textsuperscript{++} & 2343 (68.4) & 20039 (71.2) & 6.1 & 2343
(68.4) & 9512 (69.4) & 2.2\tabularnewline
& T88.6\selectlanguage{ngerman}\textsuperscript{§} & 352 (10.3) & 2822 (10.0) & 0.8 & 352 (10.3)
& 1287 (9.4) & 3.0\tabularnewline
Charlson Comorbidity Index & Charlson Comorbidity Index & & & & &
&\tabularnewline
& 0 & 2771 (80.9) & 21834 (77.6) & 8.2 & 2771 (80.9) & 11231 (82.0) &
2.8\tabularnewline
& 1 & 441 (12.9) & 4160 (14.8) & 5.5 & 441 (12.9) & 1673 (12.2) &
2.0\tabularnewline
& 2 & 135 (3.9) & 1288 (4.6) & 3.1 & 135 (3.9) & 519 (3.8) &
0.8\tabularnewline
& [?]3 & 78 (2.3) & 863 (3.1) & 4.9 & 78 (2.3) & 277 (2.0) &
1.8\tabularnewline
Medical history & Medical history & & & & & &\tabularnewline
& Asthma & 197 (5.8) & 2139 (7.6) & 7.4 & 197 (5.8) & 712 (5.2) &
2.4\tabularnewline
& Atopic dermatitis & 80 (2.3) & 634 (2.3) & 0.6 & 80 (2.3) & 316 (2.3)
& 0.0\tabularnewline
& Atopic rhinitis & 50 (1.5) & 686 (2.4) & 7.1 & 50 (1.5) & 205 (1.5) &
0.0\tabularnewline
Use of drugs & Use of drugs & & & & & &\tabularnewline
& H1 blocker & 2385 (69.6) & 24227 (86.1) & 40.4 & 2385 (69.6) & 9549
(69.7) & 0.1\tabularnewline
& H2 blocker & 1398 (40.8) & 15167 (53.9) & 26.4 & 1398 (40.8) & 5665
(41.4) & 1.1\tabularnewline
& \selectlanguage{greek}β\selectlanguage{english}2 agonist & 392 (11.4) & 4531 (16.1) & 13.5 & 392 (11.4) & 1619
(11.8) & 1.2\tabularnewline
Hospital volume & Hospital volume & & & & & &\tabularnewline
& Very low & 756 (22.1) & 7268 (25.8) & 8.8 & 756 (22.1) & 2897 (21.1) &
2.3\tabularnewline
& Low & 868 (25.3) & 7014 (24.9) & 1.0 & 868 (25.3) & 3639 (26.6) &
2.8\tabularnewline
& High & 852 (24.9) & 6982 (24.8) & 0.2 & 852 (24.9) & 3372 (24.6) &
0.0\tabularnewline
& Very high & 949 (27.7) & 6881 (24.4) & 7.4 & 949 (27.7) & 3792 (27.7)
& 0.0\tabularnewline
Clinical training hospital & Clinical training hospital & 3167 (92.5) &
26027 (92.5) & 0.0 & 3167 (92.5) & 12730 (92.9) & 1.7\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: ASD, absolute standardized difference; H1 blocker,
histamine-1 receptor blockers; H2 blocker, histamine-2 receptor
blockers; SD, standardized difference; \selectlanguage{greek}β\selectlanguage{english}2 agonist, beta 2-adrenergic
receptor stimulants.

+: T78.0, Anaphylactic shock due to adverse food reaction

++: T78.2, Anaphylactic shock, unspecified

\selectlanguage{ngerman}§: T88.6, Anaphylactic shock due to adverse effect of correct drug or
medicament properly administered

\textbf{Table 2} . Proportions of biphasic reactions and 7-days
all-cause mortality in unmatched and propensity score-matched groups\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
& Unmatched & Unmatched & Unmatched & After 1:4 matching & After 1:4
matching & After 1:4 matching & After 1:4 matching & After 1:4
matching\tabularnewline
\midrule
\endhead
& Control (n=3425) & Glucocorticoids (n=28145) & Total (n=31570) &
Control (n=3425) & Glucocorticoids (n=13700) & Odds Ratio & 95\%
Confidence Interval & P-value\tabularnewline
Biphasic reaction & 358 (10.5) & 3172 (11.3) & 3530 (11.2) & 358 (10.5)
& 1474 (10.8) & 1.03 & 0.86-1.24 & 0.14\tabularnewline
Death & 19 (0.6) & 93 (0.3) & 112 (0.4) & 19 (0.6) & 52 (0.4) & 0.68 &
0.40-1.17 & 0.16\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 3} . Results using other analytic methods\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
& Biphasic reaction & Biphasic reaction & Death & Death\tabularnewline
\midrule
\endhead
& Odds Ratio (95\% Confidence Interval) & P-value & Odds Ratio (95\%
Confidence Interval) & P-value\tabularnewline
Traditional multivariable regression analyses & 1.07 (0.95-1.21) & 0.25
& 0.72 (0.41-1.29) & 0.28\tabularnewline
Propensity score adjustment & 1.07 (0.95-1.20) & 0.26 & 0.76 (0.45-1.26)
& 0.28\tabularnewline
Inverse probability of treatment weighting & 1.11 (0.98-1.26) & 0.10 &
0.94 (0.53-1.66) & 0.83\tabularnewline
\bottomrule
\end{longtable}

\textbf{Figure legend}

Figure 1. Flowchart showing the stratification and selection of patients
with severe anaphylaxis.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure1-210321/Figure1-210321}

\end{center}
\end{figure}

\selectlanguage{english}
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