Drug-induced anaphylaxis in China: a 10 year retrospective analysis of the Beijing Pharmacovigilance Database
Drug‑induced anaphylaxis in China: a 10 year retrospective analysis of the Beijing Pharmacovigilance Database
Ying Zhao 0 1 2 4
Shusen Sun 0 1 2 4
Xiaotong Li 0 1 2 4
Xiang Ma 0 1 2 4
Huilin Tang 0 1 2 4
Lulu Sun 0 1 2 4
Suodi Zhai 0 1 2 4
Tiansheng Wang 0 1 2 4
0 Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University-Purdue University Indianapolis , Indianapolis, IN , USA
1 Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University , Beijing , China
2 Department of Pharmacy, Beijing Shijitan Hospital , Beijing , China
3 Tiansheng Wang
4 Department of Epidemiology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina , USA
Background Few studies on the causes of drug-induced anaphylaxis (DIA) in the hospital setting are available. Objective We aimed to use the Beijing Pharmacovigilance Database (BPD) to identify the causes of DIA in Beijing, China. Setting Anaphylactic case reports from the BPD provided by the Beijing Center for Adverse Drug Reaction Monitoring. Method DIA cases collected by the BPD from January 2004 to December 2014 were adjudicated. Cases were analyzed for demographics, causative drugs and route of administration, and clinical signs and outcomes. Main outcome measure Drugs implicated in DIAs were identified and the signs and symptoms of the DIA cases were analyzed. Results A total of 1189 DIA cases were analyzed. The mean age was 47.6 years, and 732 (61.6%) were aged from 18 to 59 years. A total of 627 patients (52.7%) were females. There was a predominance of cardiovascular (83.8%) followed by respiratory (55.4%), central nervous (50.1%), mucocutaneous (47.4%), and gastrointestinal symptoms (31.3%). A total of 249 different drugs were involved. DIAs were mainly caused by antibiotics (39.3%), traditional Chinese medicines (TCM) (11.9%), radiocontrast agents (11.9%), and antineoplastic agents (10.3%). Cephalosporins accounted for majority (34.5%) of antibiotic-induced anaphylaxis, followed by fluoroquinolones (29.6%), betalactam/beta-lactamase inhibitors (15.4%) and penicillins (7.9%). Blood products and biological agents (3.1%), and plasma substitutes (2.1%) were also important contributors to DIAs. Conclusion A variety of drug classes were implicated in DIAs. Patients should be closely monitored for signs and symptoms of anaphylaxis when medications are administered especially with antibiotics, TCM, radiocontrast and antineoplastic agents.
China; Clinical features; Drug category; Drug-induced anaphylaxis; Pharmacovigilance
Ying Zhao and Shusen Sun have contributed equally to this
Department of Pharmacy, Peking University Third Hospital,
College of Pharmacy and Health Sciences, Western New
England University, Springfield, Massachusetts, USA
Impacts on practice
• Drug-induced anaphylaxis accounts for at least 12% of
adverse drug event reports in Chinese hospitals collected
by the Beijing Pharmacovigilance Database between
2004 to 2014, and the associated mortality rate is 3.3%.
• The top four drug categories implicated in drug
induced anaphylaxis cases in China are antibiotics,
traditional Chinese medicines, radiocontrast media
and antineoplastic agents.
• Dr ug induced anaphylaxis most often presents
with cardiovascular system symptoms, followed by
mucocutaneous, respiratory and central nervous
Anaphylaxis is a severe, life-threatening, systemic allergic
reaction that occurs rapidly after contact with an inducing
substance. Common triggers of anaphylaxis include food,
insect stings, drugs and latex [
]. Susceptibility (or
incidence) of anaphylaxis varies with age, allergen
exposure, and predisposing genetic factors [
of anaphylaxis may progress rapidly and involve multiple
target organ systems including the integumentary,
respiratory, gastrointestinal, and cardiovascular systems [
Of the most common triggers of anaphylaxis [
drugs are considered to be the primary triggers in adults
]. Administration of any drug by any route can
potentially cause anaphylaxis [
]. According to a
retrospective U.S. epidemiology study, medications were the most
common cause (58.8%) of 2458 anaphylaxis-related
deaths from 1999 to 2010 . Furthermore, a multicenter
retrospective study from Korea, drug-induced
anaphylaxis (DIA) accounted for 46.5% of all 1806 anaphylaxis
cases, becoming the most common trigger of anaphylaxis
in Korea [
Although the epidemiological data of DIA have been
reported in western countries [
6, 8, 9
], data is limited in
Asian population. Most published studies are case reports
or case series focused on specific drugs such as
antibiotics or special clinical situations for instance during
perioperative procedures. Studies are needed to confirm the
previous findings and to add new knowledge to this area
in Asian population. Our previous study assessed the use
of epinephrine in managing patients with DIA through
the analysis of the Beijing Pharmacovigilance Database
], and the present study is an extension of this
project to provide a detailed analysis of the reported DIA
Aim of the study
The objective of this study was to contribute to a better
understanding of DIAs in Beijing, China, based on
anaphylaxis case reports by the BPD over a decade period. The
following information was extracted and analyzed: causative
drugs, clinical features and severities of DIA cases.
This study was considered to be exempt from further review
by the Institutional Review Board, Peking University Third
Hospital. Patient informed consent was not required because
this was a retrospective study using only de-identified data.
Using a structured database inquiry, extraction, and case
adjudication methodology as reported in our previous study
], we performed a detailed analysis on DIA cases. The
cases were reported to the BPD from January 1, 2004 to
December 31, 2014.
In contrast with our previous study [
anaphylaxisinducing drugs were classified into various
pharmacotherapeutic groups according to the Martindale—The Complete
Drug Reference (37th edition) [
], World Health
Organization (WHO) Model Formulary (2008) [
], and Chinese
Pharmacopoeia (ChP) [
]. Within each group there were
several subgroups. Previously, cases in which more than one
drug was suspected were defined as “Associations” [
this study, we further classified drugs under the
“Associations” according to the original judgments of physicians
when information is available. For example, a case was
reported in which two drugs were administered to a
patientAmbroxol injection and Lomefloxacin injection. Clinicians
filing the report deemed that Lomefloxacin injection was
more likely to induce anaphylaxis. Accordingly, we
classified this case into “Antibiotics” instead of “Associations”.
For each DIA case, we assessed the case severity into three
grades: grade 1 category was patients with only cutaneous
involvement, grade 2 included patients with
mild-to-moderate manifestations of anaphylaxis, and those with grade
3 reactions had severe presentations with cutaneous,
gastrointestinal, and potentially life-threatening respiratory or
cardiovascular signs and symptoms [
The statistical analysis was performed using the SPSS
version 22 (SPSS Inc., IL, USA). Continuous variables
were subjected to normality tests using the single sample
Kolmogorov–Smirnov test, where data in accordance with
normal distribution was expressed as mean ± standard
deviation, while those in accordance with the non-normal
distribution was expressed as median (min, max), and
the dichotomous variables were described as frequency
Demographic and clinical characteristics
A total of 9425 patients with drug-induced hypersensitivity
reactions were identified from the BPD. After initial
screening and adjudication, 1189 patients were ultimately included
in our analysis [
]. Of these patients, the mean age was
47.6 years, 732 (61.6%) were aged from 18 to 59 years. A
total of 627 (52.7%) were female patients (Table 1).
The majority of patients (83.8%) experienced
cardiovascular anaphylactic symptoms; the percentage of patients who
developed mucocutaneous compromise, respiratory
compromise, central nervous symptoms were 47.4, 55.4, and
50.1%, respectively. Gastrointestinal anaphylactic symptoms
occurred in 31.3% of the cases. Overall, 73 (6.1%) of the
patients were admitted to intensive care units (ICU), and 39
A total of 249 individual drugs were involved in the
anaphylactic cases analyzed, classified into 23
pharmacotherapeutic groups and 53 subgroups. A total of 1145 (96.3%)
cases were attributed to single drugs, and 44 (3.7%) were
attributed to “Associations” (Table 2). While various drug
triggers were reported, the main four general categories for
DIAs were antibiotics (39.3%), traditional Chinese
medicines (TCM, 11.9%), radiocontrast agents (11.9%) and
antineoplastic agents (10.3%).
Antibiotics held the leading trigger medications of
druginduced anaphylaxis (467/1189, 39.3%). Among the
antibiotics, the top three sub-groups included beta-lactams
(275/467, 58.9%), fluoroquinolones (138/467, 29.6%), and
macrolides (28/467, 6.0%) (Table 3). Within the beta
lactams in particular, cephalosporins (161/275, 58.5%) were
identified the most followed by beta-lactam/beta-lactamase
inhibitors (72/275, 26.2%) and penicillins (37/275, 13.5%)
There were 141 DIA cases (11.9%) induced by TCMs,
most cases involving TCM injections (135/141, 95.7%), with
the remaining cases including oral or topical TCM
formulations. A total of 36 different TCM injections were identified.
These injections were mainly used for the treatment of
cardiovascular and cerebrovascular disease, digestive system
disease, respiratory system disease, and cancer. Ciwujia was the
leading cause followed by Qingkailing, Houttuynia cordata,
Shuxuening, Shuanghuanglian, Chuanhuning, Safflower and
Yinxingdamo (Tables 2, 4). Other TCM injections (53 cases)
were listed in Appendix 1 in the electronic supplementary
Radiocontrast agents were reported 141 times, and the top
three were contrast media used in X-ray (113/141, 80.1%),
magnetic resonance imaging (12/141, 8.5%) and ophthalmic
procedures (10/141, 7.1%) (Tables 2, 4).
Among the DIA cases caused by antineoplastic drugs
(122/1189, 10.3%), paclitaxel (68/122, 55.7%) and
platinumbased antineoplastics (40/122, 32.8%) were important
contributors (Tables 2, 4). The remaining identified DIA cases
(274) were listed in Table 2.
There were 149 anaphylaxis cases occurred during
perioperative procedures, and the top three drug groups involved
were antibiotics (43.0%), radiocontrast agents (14.8%) and
plasma substitutes (9.4%) (Appendix 2).
Most causative drugs were administered by the
intravenous route (86.4%), oral route (5.4%), intramuscular route
(3.0%), subcutaneous route (1.6%), and intra-arterial route
(1.4%). There were 12 cases of anaphylactic reactions
occurred during intradermal tests.
TCM traditional Chinese medicine, NSAIDs non-steroidal anti-inflammatory drugs, MRI magnetic
resonance imaging, NMBAs neuromuscular blocking agents, ACEI angiotensin converting enzyme inhibitor; BB
beta-blocker, PPI proton pump inhibitor
aOther antibiotics included aminoglycosides, clindamycin, vancomycin, and metronidazole
bOther radiocontrast agent was indocyanine green injection
cAssociations were defined as those cases in which more than one medication was suspected to cause the
anaphylaxis. Details of anaphylaxis induced by associations were listed in Appendix 3
d“Others” category included monosialotetrahexosylganglioside sodium for injection, sodium
deoxyribonucleotide injection, cerebroprotein hydrolysate for injection, and coenzyme A for injection
Of the 44 DIA cases caused by the association of two or
more drugs, 14 (31.8%) anaphylaxis cases involved one or
more TCM combined with one or more other non-TCM, 12
(27.3%) occurred during general anesthesia, and 21 (47.7%)
included antibiotics (Appendix 3).
Severity and anaphylaxis‑related deaths
Among the 1189 DIA cases, 1029 (86.5%) were considered
as severe (grade 3) and 39 (3.3%) were fatal. Mortality was
due mainly to the following top four medication groups:
antibiotics (13/39, 33.3%), radiocontrast agents (12/39,
30.8%), antineoplastic agents (4/39, 10.3%), TCM injections
(3/39, 7.7%). The detailed information was listed in Table 5.
To our knowledge, this is the first analysis of drug-induced
anaphylaxis in the hospital setting in China. Using the
Beijing Pharmacovigilance Database, our study shows that there
were 1189 DIA cases in clinical settings over a decade in
Beijing, China, accounting for 12.6% of all ADE reports
collected by the BPD. The percentage of DIA in Beijing, China
is higher than the percentage of DIA in Portugal (5–7%)
spanning over a decade [
]. Patients aged between 18 and
59 years (61.6%) had the highest frequency of DIA among
all three age groups, which is consistent with a recent study
in China by Jiang et al. [
]. Similar to most studies [
], females had a higher frequency of anaphylaxis
compared to males in our analysis. A high proportion of patients
(n = 467) Value,
(n = 467) Value,
ATC anatomical therapeutic chemical, NA not available
developed cardiovascular symptoms (83.8%), and the
mortality rate of 3.3% is comparable to previous studies [
Of all DIAs reported in BPD and included within our
analysis, antibiotics attributed to the most common cause of DIA
(39.3%), comparable to the incidence of antibiotic-induced
anaphylaxis within the U.S. (40.5%) [
antibiotic-induced anaphylaxis occurred more frequently than
reports from Korea (10.5%) [
] and Portugal (16.7%) [
agreement with previous reports, anaphylaxis from β-lactam
antibiotics (58.9%) were reported more frequently than
nonβ-lactam antibiotics [
]. Cephalosporins accounted for the
majority of β-lactam antibiotic-related anaphylaxis followed
by beta-lactam/beta-lactamase inhibitors and penicillins.
This may be explained partly by the greater use of
cephalosporins in Chinese hospitals [
]. The likelihood of
anaphylaxis from penicillins can be assessed by skin tests [
However, routine intradermal skin testing of a cephalosporin
may not be useful for predicting an immediate
hypersensitivity because of the extremely low test sensitivity, which
was confirmed by a recent retrospective study conducted by
Yoon et al. [
]. Fluoroquinolone antibiotics also accounted
for a high proportion of all 1189 anaphylaxis cases (11.6%),
which is consistent with the frequency (11.7%) found by
Faria et al. [
]. The high frequency of anaphylaxis from
fluoroquinolones maybe due to the overuse of
fluoroquinolone antibiotics in China [
], and the hypersensitivity to
quinolones is less likely to be determined from skin testing
Given that antibiotics are the most common trigger
for anaphylaxis, the importance of inquiring and
documenting patient’s medication allergic history cannot be
TCM traditional Chinese medicine, ATC anatomical therapeutic chemical, NA not available
aOnly the top 8 common TCMs were listed; detailed information on the Others category was presented in
Appendix 1 in the electronic supplementary materials
underestimated. This is the area pharmacists could
contribute to patient safety. Clinical symptoms and signs related to
anaphylaxis should be closely monitored when antibiotics,
especially cephalosporins and fluoroquinolones, are
administered to patients in the hospital setting.
The use of TCM was the second most common drug trigger
in our analysis, and almost all (95.7%) TCM-related
anaphylactic cases were from injectable TCM formulations.
The result is similar to a study reported by Jiang et al. [
TCM is unique to the Chinese population and therefore the
DIAs associated with TCM is unique to that population as
a result. Along with extensive indications for TCM, there is
greater use of TCM injections compared to other countries.
In our review, 36 different TCM injections were identified
(n = 39) value,
resulting in 11.4% of the anaphylaxis cases, among which
three cases were fatal. The four most common triggers were
injections of Ciwujia, Qingkailing, Houttuynia cordata and
Shuxuening. The results were similar to those of Jiang et al.,
who found the most common triggers were injections of
Qingkailing, Shuanghuanglian and Houttuynia cordata [
TCM injection is extracted from Chinese herbs, which
may contain one or several active ingredients. The high
frequency of anaphylactic cases related to TCM injections may
be explained as follows: (1) the components of a TCM
injection are relatively complex and most formulations have not
been thoroughly analyzed and identified; (2) a TCM
injection also contains various additives, such as pigment,
tannin, starch and protein, and these additives may trigger the
body’s immune system and cause anaphylaxis [
quality control of TCM injections is relatively difficult due to the
formulation complexity, and impurities may cause
anaphylaxis as well; and (4) drug interactions between TCM
injections and other medications should also be considered. Of
the 135 patients who suffered anaphylaxis induced by TCM
injections, patients’ age ranged from 4 to 90 years:
children under 18 years (5%), adults between 18 and 59 years
(58.6%), and adults over 60 years (36.4%). This is consistent
with a previous study reporting that patient of any age can
suffer anaphylaxis induced by TCM injections [
Therefore, caution should be exercised before considering the use
of TCM and all patients regardless of age should be closely
monitored during TCM administration.
Our study found that radiocontrast agents were the third
most common cause (11.9%) of DIA, coinciding with the
frequency of previous studies in Korea (12.0%) [
However DIA through radiocontrast agents was reported less
frequently than that in the United States (30.4%) [
these radiocontrast-induced anaphylaxis cases, the
majority (80.1%) were caused by iodine-based contrast agents.
The number of anaphylaxis cases induced by iopromide
(36.9%) were greater than any other non-ionic
iodinated contrast agents, which is similar to the results from
a previous study [
]. A recent retrospective study from
Korea indicated that among the anaphylactic patients,
iopromide was associated with more severe anaphylaxis
with hypotension [
Patients with allergies, asthma, renal insufficiency,
anxiety, significant cardiac disease and other miscellaneous risk
factors may be at an increased risk for anaphylactoid contrast
]. Patient’s medical history should be collected
and the risk of contrast media induced anaphylactic
reactions should be assessment before contrast media
administration. More importantly, appropriate resuscitative equipment
should be available to treat anaphylactic reactions promptly.
Premedications such as corticosteroids should also be used
for pretreatment of “at-risk” patients who require a
contrastenhanced examination [
Antineoplastic agents were another frequent cause of
DIA in the current study, consistent with those reported
in literature [
]. This may be related to the increasing
chemotherapy use with ever increasing cancer prevalence
in Beijing, China . Paclitaxel accounted for 55.7% of
antineoplastics-induced anaphylaxis, and the high
frequency may be related to the solubilizer, polyoxyethylene
castor oil, which can induce anaphylaxis [
]. We also
found that platinum-based agents accounted for 32.8%
of all antineoplastics-induced anaphylaxis cases. Among
these agents, oxaliplatin was a major trigger accounting for
1.5% of all 1189 DIA cases, and this finding is consistent
with a published study [
Although a recent study from Nonna et al. found that for
patients with carboplatin induced hypersensitivity reaction,
the use of oxaliplatin maybe a safer alternative [
should be carefully monitored for signs and symptoms of
anaphylaxis with any platinum-based chemotherapeutic
Our retrospective analysis was based on self-reported cases
by health care professionals from the BPD, and therefore
our study has the following limitations: (1) lack of the
frequency of causative drug use as we could not obtain
either prescription or reimbursement data; (2) we could
not assess the prevalence of DIA in the region studied as
we do not have the information of the total patient base;
(3) potential reporting bias may exist: majority of reported
cases were hospitalized patients in the non-ED setting, and
only severe anaphylactic cases may have been reported;
(4) we may not have included all DIA cases in the BPD:
cases missed if clinicians did not report using the terms
related to allergy or anaphylaxis or hypersensitivity (e.g. a
patient with wheeze, vomiting, bronchospasm but was not
described as “allergy” by clinicians when reporting to the
BPD). In addition, some reported cases were not included
due to insufficient information. Despite these limitations,
the method we have taken should be robust against a range
of potential biases: rigorous inclusion/exclusion criteria
were utilized and all potential anaphylaxis cases were
adjudicated by trained physician/allergists; and only patients
with confirmed anaphylaxis and complete data record were
included in the analysis.
This first detailed analysis of DIA case reports from 2004 to
2014 in Chinese patients provides valuable information to
clinicians. Antibiotics, TCM, radiocontrast media and
antineoplastic agents are the most common causes of DIA cases.
The majority of DIA cases are considered to be severe with
a high mortality rate of 3.3%. Pharmacists should be
working closely with prescribers to assess each patient’s risks of
developing anaphylaxis when drug therapy is involved, and
to provide prompt treatment and resuscitations to reduce the
morbidity and mortality when anaphylaxis occurs.
Acknowledgements The authors would like to thank the Beijing
Pharmacovigilance Database for providing data.
Funding This research is partially supported by the Research Grant
892FY60221022 from School of Pharmaceutical Sciences, Peking
Conflicts of interest The authors have no conflicts of interest to
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