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Ruthenium(II) piano stool coordination compounds with aminomethylphosphanes: Synthesis, characterisation and preliminary biological study in vitro.
TYPE Original Research
PUBLISHED 11 July 2023
DOI 10.3389/fphar.2023.1180685
OPEN ACCESS
EDITED BY
Kenneth Hartigan-Go,
Ateneo de Manila University, Philippines
REVIEWED BY
Weimin Zhong,
Xiamen Fifth Hospital, China
Xiangyi Kong,
Chinese Academy of Medical Sciences
and Peking Union Medical College, China
Jia-Jie Mo,
Capital Medical University, China
*CORRESPONDENCE
Anchang Liu,
acleu@126.com
Active surveillance and clinical
analysis of anaphylaxis based on
the China Hospital
Pharmacovigilance System
Chengcheng Wang 1, Zejing Li 2, Yingying Yu 1, Maoyan Feng 1 and
Anchang Liu 1*
1
Department of Pharmacy, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University,
Qingdao, China, 2Department of Otolaryngology Head and Neck Surgery, Qilu Hospital (Qingdao),
Cheeloo College of Medicine, Shandong University, Qingdao, China
RECEIVED 06 March 2023
ACCEPTED 27 June 2023
PUBLISHED 11 July 2023
CITATION
Wang C, Li Z, Yu Y, Feng M and Liu A
(2023), Active surveillance and clinical
analysis of anaphylaxis based on the
China Hospital
Pharmacovigilance System.
Front. Pharmacol. 14:1180685.
doi: 10.3389/fphar.2023.1180685
COPYRIGHT
© 2023 Wang, Li, Yu, Feng and Liu. This is
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author(s) and the copyright owner(s) are
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which does not comply with these terms.
Objective: This study aimed to develop active surveillance programs (ASPs) for
anaphylaxis using the China Hospital Pharmacovigilance System (CHPS) and
analyze the characteristics, allergens, and management strategies for
anaphylaxis within a tertiary hospital setting in China.
Methods: We retrospectively analyzed the anaphylaxis cases reported to the
National Adverse Drug Reaction Monitoring System in our hospital from
2014 to 2021. Characteristic medical orders, progress notes, and diagnoses in
these cases were recorded to identify initial anaphylaxis trigger entries. Based on
these initial entries, the questionnaire was developed, and the Delphi method was
used to establish consensus entries for anaphylaxis triggers. The CHPS was used to
program these trigger entries and construct ASPs, which were then tested on the
238,194 discharged patients to evaluate their performance and analyze the related
clinical data.
Results: Ten anaphylaxis triggers and three ASPs were ultimately identified. The
ASPs captured 309 cases, out of which 94 cases were confirmed as anaphylaxis
following manual screening. After removing duplicates, we noted 76 patients who
experienced anaphylaxis 79 times. The positive rate of triggers and the positive
predictive value of the programs were 0.13% and 30.42%, respectively. The
incidence of anaphylaxis in our study was 0.03%, and the number of
anaphylaxis cases detected by the ASPs was 5.64 times higher than those
detected by the spontaneous reporting system. Anaphylaxis was more
common among female patients. Antibacterial drugs, antineoplastic drugs, and
contrast media were the most prevalent allergens in clinical practice. Anaphylaxis
to antineoplastic drugs had the highest incidence (0.6%) when compared with
patients admitted during the same period. Our study revealed a significant
underuse of epinephrine and overuse of second-line therapy (glucocorticoids
and antihistamines) in the management of anaphylaxis. Furthermore, we found the
use and dosage of epinephrine to be inappropriate.
Conclusion: The CHPS can effectively utilize both structured and unstructured
data to construct anaphylaxis ASPs, and this could counteract the under-reporting
by the spontaneous reporting system, the primary adverse reaction monitoring
method in China. The treatment and management of anaphylaxis are currently
inadequate and require improvement to reduce mortality risk.
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KEYWORDS
active surveillance, anaphylaxis, China Hospital Pharmacovigilance System, epinephrine,
Delphi method
1 Introduction
data on anaphylaxis. Additionally, studies showed gaps in the initial
treatment of anaphylaxis between China and international
guidelines (Jiang et al., 2020).
The China Hospital Pharmacovigilance System (CHPS),
launched and promoted by the China National Center for ADR
Monitoring since 2016, possesses the capability to automatically
collect and analyze data extracted from electronic hospital
information systems (HISs) in sentinel hospitals (Figure 1) (Li
et al., 2018). These data include a myriad of information,
spanning diagnoses, medical orders, progress notes, test and
examination results, and other information. The connection to
the HIS makes it possible to simply, actively, and
comprehensively obtain real-world drug safety data. At present,
the CHPS encompasses more than 400 hospitals across China and is
utilized in drug safety research owing to its high operability and
accessibility (Li et al., 2018; Sun et al., 2020). Sun et al. (2020) utilized
the CHPS to conduct a retrospective analysis of ADRs among
217 COVID-19 patients in China. The study underscored the
CHPS’s critical role in actively monitoring and detecting ADR
signals that reflect real-world ADRs during COVID-19 treatment,
thereby providing valuable insights for ensuring safe medication in
clinical settings.
This study aims to develop anaphylaxis triggers using the Delphi
method and construct ASPs based on the CHPS. These ASPs are
Anaphylaxis is a severe, potentially fatal, systemic allergic
reaction that occurs suddenly after contact with an allergycausing substance (Sampson et al., 2006), and it can lead to
serious consequences if there is a delayed diagnosis and
inappropriate treatments. Drugs are generally considered to be
the main cause of anaphylaxis (Tejedor-Alonso MA et al., 2015),
and despite its relative rarity as an adverse drug reaction (ADR),
drug-induced anaphylaxis remains a leading cause of allergy-related
deaths in adults (Lee and Vadas, 2011; Jerschow et al., 2014). In
addition, with the introduction of new medications such as
biologics, small-molecule drugs, and chemotherapeutic drugs, the
incidence of hospitalization caused by drug-induced anaphylaxis
continues to increase (Cardona et al., 2020; Muraro et al., 2022).
During the past decade, there has been an advanced understanding
of the diagnosis, pathogenesis, and treatment management of
anaphylaxis (Dribin and Castells, 2022; Weiler et al., 2023), but
significant data and knowledge gaps remain in key clinical care and
research domains, such as population science, validated clinical or
biomarker-based models that predict disease outcome, and acute
management (Dribin and Castells, 2022; Dribin et al., 2022). These
shortcomings are especially acute in China (Li et al., 2019), where
there is a dearth of active surveillance studies and epidemiological
FIGURE 1
Data acquisition structure diagram of the CHPS.
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TABLE 1 Diagnostic criteria for anaphylaxis.
Anaphylaxis is highly likely when any one of the following three criteria is fulfilled
1. Acute onset of illness (minutes to several hours), with involvement of the skin, mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, and swollen lips, tongue, or
uvula)
AND AT LEAST ONE OF THE FOLLOWING: a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow (PEF), and hypoxemia)
b. Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], syncope, and incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours): a. Involvement of the skin-mucosal tissue (e.g.,
generalized hives, itch-flush, and swollen lips, tongue, or uvula)
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, and hypoxemia)
c. Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, and incontinence)
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain and vomiting)
3. Reduced BP after exposure to a known allergen for that patient (minutes to several hours): a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in
systolic BP
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s baseline
All panelists were selected based on their extensive experience in
the diagnosis and treatment of anaphylaxis.
then applied to a cohort of 238,194 discharged patients, thereby
facilitating an evaluation of their effectiveness and a detailed analysis
of anaphylaxis characteristics, implicated allergens, and associated
management practices within the Chinese population.
2.3 Employing the Delphi method for trigger
entries
2 Materials and methods
All experts were asked to rate the importance and familiarity of
each item on a 5-point Likert scale (with 1 meaning strongly
disagree, 2 meaning agree, 3 meaning neutral, 4 meaning agree,
and 5 indicating strongly agree). The basis of judgment was classified
into four categories: theoretical analysis, practice, informed by
domestic and foreign peers, and intuition. A gradation from
0.1 to 0.5 points was allocated in accordance with the degree of
impact on expert judgment, with the highest score of 0.5 being
awarded when practice considerably influenced expert opinion.
Furthermore, panel members were encouraged to submit freetext comments to clarify their responses to every question,
suggest additional questions, or recommend modifications to the
existing queries. The indicators of the Delphi method include the
experts’ positive coefficient, the degree of expert authority, the
concentration of expert opinions, and the degree coordination
among expert opinions (Huan-huana et al., 2017). The positivity
coefficient of experts was represented as the recovery rate of the
questionnaire. The authority coefficient of experts, denoted as Cr,
was dictated by the judgment basis of the entries (Ca) and the degree
of familiarity with the consultation content (Cs), wherein Cr was
given by the equation Cr (Ca + Cs)/2, and Cr values of 0.7 or
higher were generally considered to carry a high degree of credibility.
The concentration of expert opinion was depicted by the mean value
of the importance score (Mj) and full score frequency (Kj) of the
trigger entries. The cut-off value of Mj and Kj = mean-standard
deviation, and those with scores higher than the cut-off value were
included. The degree of expert opinion coordination was expressed
as the coefficient of variation (Vj). The cut-off values of Vj = mean +
standard deviation and those with scores lower than the cut-off value
were included. Entries that failed to satisfy any of the three criteria
were subsequently eliminated (Zeng, 1996).
2.1 Retrospective analysis of ADR reports
ADR reports from our hospital, spanning from January 2014 to
December 2021, were retrieved from the National Adverse Drug
Reaction Monitoring System. These reports were then
retrospectively reviewed by both a pharmacist (CCW) and an
allergist (ZJL). In reference to the diagnostic criteria for
anaphylaxis (Sampson et al., 2006) (Table 1) and the Technical
Specifications and Evaluation Criteria for Common Serious Adverse
Drug Reactions issued by the National Center for ADR, China, the
reviewers identified anaphylaxis cases and filled in the electronic
case report forms. These forms included various details, such as
diagnoses, departments, characteristic medical orders, and progress
notes. After analyzing the relevant data, we formulated initial trigger
entries for anaphylaxis.
2.2 Designing the expert consultation
questionnaire
An expert consultation questionnaire was conceived, taking into
account the initial entries. The questionnaire was structured in two
sections; the first collected fundamental information about the
experts, encompassing their field of specialization, educational
background, years of professional experience, and academic title.
The second section sought expert evaluation on the importance,
familiarity, and judgment basis of trigger entries. A multidisciplinary
panel of experts, each representing the fields of allergology,
dermatology, emergency medicine, cardiology, intensive care,
respiratory medicine, neurology, and pharmacy, was assembled.
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FIGURE 2
Website of the CHPS drug evaluation system.
2.4 Construction of ASPs
comprehensive database for patients suffering from anaphylaxis.
Furthermore, we calculated the count of anaphylaxis cases identified
by ASPs to assess the performance of our system. The positive
predictive value (PPV) of the ASPs was computed by dividing the
number of anaphylaxis cases identified by the ASPs by the number
of cases with positive triggers. The incidence of anaphylaxis was
determined by dividing the number of anaphylaxis cases identified
by ASPs by the total number of discharged patients. To quantify the
efficiency of the ASPs relative to the spontaneous reporting system,
we devised a ratio of the anaphylaxis cases detected by the ASPs to
the anaphylaxis reports lodged within the spontaneous reporting
system over an identical time frame.
The CHPS Drug Evaluation System (Figure 2), a subsystem of the
CHPS, procures seven dimensions of clinical data from the HIS. These
dimensions include patient information retrieval (basic information
about patients), test retrieval (test items and test values), medical
order retrieval (drug ID), medical record retrieval (admission records
and progress notes), diagnosis retrieval, physical sign retrieval, and
examination retrieval, and these seven dimensions can be easily
connected with each other by Boolean logic operators. In this study,
we utilized Boolean logic programming to formulate retrieval rules for
triggers within medical orders, diagnoses, and progress notes. To
augment the positive rate, triggers embedded in the progress notes
and medical orders were conjoined by an “AND”operator.
These retrieval rules were then applied to discharged patients to
obtain trigger-positive patient cases. Two reviewers, a pharmacist
(CCW) and an allergist (ZJL), independently examined the results of
the automated screening and jointly decided whether the cases were
anaphylaxis. Cases were categorized as false positive if both
reviewers considered them to be non-anaphylaxis. In the event of
disagreement, a third more sophisticated reviewer with more
experience (MYF) was consulted to make the final decision.
Thereafter, the cases of false positives were analyzed, and
exclusion rules were established to enhance the performance of
the triggers. Ultimately, ASPs were constructed by integrating
retrieval rules and exclusion rules (Figure 3).
2.6 Analysis of clinical data
We created additional electronic case report forms to extract
various patient information, including patient ID, gender, age, the
department of hospitalization, the time of anaphylaxis occurrence,
descriptions of anaphylaxis processes in progress notes, suspected
drugs, and the types and usage of therapeutic drugs. Furthermore,
the suspected drugs were classified according to their
pharmacological effects, and patients in the anaphylaxis database
were categorized based on whether they experienced anaphylactic
shock.
2.7 Statistic analysis
2.5 Performance evaluation of ASPs
Categorical data were described by frequency counts and
percentages. Continuous variables were depicted as means with
standard deviation. Numerical differences between groups were
Upon running the ASPs, we manually reviewed the positivetriggered cases one by one, consequently establishing a
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FIGURE 3
Flow chart of active surveillance for anaphylaxis.
We distributed a 28-question online questionnaire to experts,
and all eight questionnaires were effectively recovered, with a
questionnaire recovery rate of 100%. Questionnaire data analysis
yielded an expert authority coefficient of 0.92 ± 0.10, demonstrating
high expert authority. The Mj, Kj, and Vj of the triggered entries are
shown in Table 2. Finally, 10 trigger entries were developed by the
Delphi method (Table 2).
assessed by the Chi-square test for categorical variables. The
threshold for statistical significance was defined as p < 0.05. All
statistical analyses were conducted using SPSS, Version 25.0 (SPSS
Inc., Chicago, IL, United States)
3 Results
3.1 Trigger entries of anaphylaxis
3.2 ASPs and performance
From 2014 to 2021, our hospital reported 1827 ADR cases to the
National Adverse Drug Reaction Monitoring System, and 22 cases were
identified as anaphylaxis. We designed initial triggers using diagnoses,
medical orders, and descriptions of progress notes. To refine trigger
performance, we formulated exclusion rules. These included (1) the
exclusion of descriptions of progress notes containing “anaphylactic
shock” in informed consent prior to invasive procedures (such as
anesthesia, bronchoscopy, and hematopoietic stem cells) and records
aimed at preventing allergies, conducting allergy tests, and documenting
allergy history; (2) the exclusion of the long-term medical order type for
rescue drugs or when the interval between different rescue drug usage
exceeded a day.
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After using Boolean logic programming to integrate the trigger
entries and optimizing the rules, the final surveillance programs were
obtained (Table 3). The programs ran for approximately 3 min,
automatically monitoring 238,194 medical records of discharge
patients from 2018 to 2021, and 309 cases were positive for triggers,
with a positive rate of 0.13%. After the manual screening, 94 cases of
anaphylaxis were obtained, and the PPV was 30.42%. In total, 76 patients
with 79 cases of anaphylaxis were finally obtained after removing the
duplicates, including 37 cases of anaphylactic shock and 42 cases of no
anaphylaxis shock. The incidence of anaphylaxis detected by the ASPs
was 0.03%. During the same period, 14 cases of anaphylaxis were
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TABLE 2 Trigger entries and scores for anaphylaxis.
Trigger entries
Mj (Cutoff = 3.90)
Kj (Cutoff = 0.36)
Vj (Cutoff = 0.37)
Diagnosis contains “anaphylactic shock”
5.00
1.00
0.00
Medical orders contain “epinephrine”
4.88
0.88
0.07
Medical orders contain “glucocorticoids (dexamethasone or methylprednisolone) combined with
promethazine”
4.13
0.50
0.31
Progress notes contain “anaphylactic shock”
4.88
0.88
0.07
Progress notes contain “allergy”
4.38
0.63
0.17
Progress notes contain “cutaneous adverse reactions” (e.g., rash, flushing, pruritus)
4.38
0.63
0.20
Progress notes contain “respiratory system adverse reactions” (e.g., chest tightness, dyspnea,
suffocation)
4.88
0.88
0.07
Progress notes contain “nervous system adverse reactions” (e.g., dizziness, irritability,
unconsciousness, confusion)
3.80
0.50
0.63
Progress notes contain “digestive system adverse reactions” (e.g., nausea, vomiting, diarrhea)
3.50
0.13
0.22
Progress notes contain “circulatory system adverse reactions " (e.g., reduced BP, palpitation,
precordial discomfort)
4.25
0.38
0.13
TABLE 3 Active surveillance programs for anaphylaxis and its performance.
Items in surveillance programs
Positive frequency of
triggers
Frequency of
anaphylaxis
PPV
(%)
Diagnosis contains “anaphylactic shock”
31
30
96.78
Progress notes contain “anaphylactic shock" and medical orders contain “epinephrine or
glucocorticoids combined with promethazine”
19
11
57.89
Progress notes contain “allergy" and “adverse skin or respiratory or nervous system or digestive
or circulatory system reactions,” and medical orders contain “epinephrine or glucocorticoids
combined with promethazine”
259
53
20.46
Total
309
94
30.42
with unidentified allergens, three cases were animal-induced (insect and
shrimp allergens), and two cases were caused by absolute alcohol and
irritating odors. Antibacterial drugs were the most common class of
allergenic drugs, with cephalosporins being the most frequent, followed
by antineoplastic drugs and contrast media. The drug with the highest
individual frequency identified by the ASPs was oxaliplatin (5 cases,
7.58%), followed by carboplatin (4 cases, 6.06%). Additionally,
traditional Chinese medicine injections, a class of drugs under
special management in China due to safety concerns, were also
commonly associated with anaphylaxis.
reported to the National Adverse Drug Reaction Monitoring System in
our hospital. The number of anaphylaxis cases detected by the ASPs was
5.64 times higher than that detected by the spontaneous reporting
system, and the under-reporting rate of the spontaneous reporting
system was 83.72%.
3.3 Characteristics of anaphylaxis
Among the detected cases (Table 4), 25 (31.65%) were males and
54 (68.35%) females, with a mean age of 55.78 years (range:
4–79 years). The highest incidence of anaphylaxis occurred in the
emergency department (19 cases, 24.05%), succeeded by the
oncology (12 cases, 15.19%) and gynecology departments
(8 cases, 10.13%). It should be noted that all anaphylaxis in the
gynecology department was caused by antineoplastic drugs.
3.5 Treatment regimen
Glucocorticoids (66 cases, 83.54%) were the most commonly
used therapeutic drugs for patients with anaphylaxis, followed by
promethazine (46 cases, 58.23%) and epinephrine (35 cases,
44.30%). Other drugs, including vitamin C injection (18 cases,
22.78%) and calcium gluconate (16 cases, 20.25%), were also
utilized in the treatment of anaphylaxis (Table 6).
A total of 35 anaphylaxis cases treated with epinephrine were
analyzed, and there was a statistically significant difference in the
3.4 Anaphylaxis allergens
Out of the 79 anaphylaxis cases, 66 were drug-induced, constituting
83.54% of all anaphylaxis cases (Table 5). Others included eight cases
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epinephrine usage rate between patients with anaphylactic shock
and those with non-anaphylactic shock (p < 0.01) (Table 7). The
main route of epinephrine administration was intramuscular
injection (45.71%), with subcutaneous injection (28.57%), bolus
(25.71%), and other routes, but the epinephrine dose varied
widely (Table 8).
TABLE 4 Demographic characteristics of anaphylaxis.
Demographic characteristics
Numbers
Age
55.78 ± 17.56
Gender
Male
25 (31.65%)
Female
54 (68.35%)
4 Discussion
Department(n ≥ 2)
Emergency department
19 (24.05%)
Oncology department
12 (15.19%)
Gynecology department
8 (10.13%)
Cardiology department
5 (6.33%)
Neurology department
4 (5.06%)
Hepatology department
4 (5.06%)
Critical care medicine
3 (3.80%)
Neurosurgery department
3 (3.80%)
Respiratory department
3 (3.80%)
Hematology department
2 (2.53%)
Gastroenterology department
2 (2.53%)
Bone tumor department
2 (2.53%)
Pediatrics department
2 (2.53%)
Obstetrics department
2 (2.53%)
Anorectal department
2 (2.53%)
Anaphylaxis constitutes an acute, potentially fatal systemic
allergic reaction. Measuring and evaluating epidemiological data
related to anaphylaxis is an important way to identify disease
burden trends and risk factors. At present, epidemiological data
sources for anaphylaxis encompass the purchase of epinephrine
auto-injectors, national databases, primary care databases,
representative sample surveys from the general population,
hospital admissions, and emergency department visits
(Tejedor Alonso et al., 2015; Tejedor-Alonso MA et al., 2015;
Tanno et al., 2018), and hospital admission datasets were deemed
the largest and most robust data available to understand trends in
anaphylaxis (Turner et al., 2020). Research grounded on
hospitalizations typically employs structured data such as the
International Classification of Diseases (ICD)-9 and ICD-10 to
identify patients with anaphylaxis (Mulla et al., 2011).
Nonetheless, such studies are prone to drawbacks like
misdiagnosis and misclassification (Tanno et al., 2018), which
subsequently lead to an underestimation of anaphylaxis
incidence. For example, Klein and Yocum (1995) undertook a
retrospective analysis of patient records from the emergency
department, uncovering 17 cases of anaphylaxis. However,
TABLE 5 Drugs that induced anaphylaxis.
Drug classification
Drug
Number
Antibacterial drugs
11 cephalosporins (four unspecified cephalosporins, three
cefoperazone–sulbactam, three cefotiam, and one cefuroxime), three
piperacillin–tazobactam, two amoxicillin, one metronidazole, and one
levofloxacin
18
Antineoplastic drugs
Five oxaliplatin, four carboplatin, three doxorubicin liposome, two cetuximab,
one nedaplatin, and one infliximab
16
Three iodixanol, three iopromide, and one iodine contrast agent with
unknown details
7
Two Shenmai injections and one Xingnaojing injection
3
Glucocorticoid
Two dexamethasone and one methylprednisolone
3
Blood products
Two plasma and one platelet
3
Other drugs
One potassium sodium dehydroandroandrographolide succinate for injection,
one extract of Ginkgo biloba leaf injection and citicoline, one reduced
glutathione, one combined with compound paracetamol and amantadine
hydrochloride, Qingre Sanjie capsule, Ganmao Qingre granule, one muscle
relaxant, one lansoprazole, one epinastine and pantoprazole, one lidocaine, one
domperidone, one iron sucrose, two transcatheter artery chemoembolization
related drugs, one radionuclide, and one Zhenggu Zijin Wan
14
Unclear drugs
2
2
Contrast media
Traditional Chinese medicine injections
Total
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“allergy,” also had a “prevention” note, which accounts for their
exclusion from ASP monitoring. Hence, it is crucial to standardize
the management of anaphylaxis and medical record
documentation to enhance the sensitivity of the detection method.
Regarding demographic characteristics, our study
demonstrated that the incidence of anaphylaxis was
significantly higher in females than in males. Taking into
account the gender composition of patients during the same
period, the ratio of male-to-female anaphylaxis incidence was 1:
2.1. Banerji et al. (2014) reported a similar gender disparity, with
71% of 716 anaphylaxis patients being female. Studies have
indicated that anaphylaxis in females is less frequent than in
males before puberty but increases rapidly and surpasses male
incidence with age, although the exact mechanism is yet to be
deciphered (Simons et al., 2002; Sheikh et al., 2008).
Death rates from drug-induced anaphylaxis have risen 300%
over the last decade (Tejedor Alonso et al., 2015), and drugs
associated with anaphylaxis vary based on different populations,
time, geographic regions, drug usage patterns, genetic factors,
anaphylaxis definitions, case registries, and study designs
(Giavina-Bianchi et al., 2018). In our study, drugs were
responsible for a significant 83.54% of all anaphylaxis cases,
and the leading drug classes linked with anaphylaxis were
antibacterial drugs, antineoplastic drugs, and contrast media.
When compared with the number of patients treated at our
hospital during the same period, we observed that anaphylaxis
triggered by antineoplastic drugs had the highest proportion
(0.06%), trailed by antibacterial drugs (0.02%) and contrast
media (0.02%). Among the antineoplastic drugs, oxaliplatin
emerged as the most common trigger, a finding consistent
with results from the Korean population (Park et al., 2017).
Indeed, hypersensitivity reactions induced by oxaliplatin have
garnered substantial attention (Aroldi et al., 2015; Otani et al.,
2017; Rogers et al., 2019), leading the China National Medical
Products Administration to revise the package insert in August
2021 (Administration and N.M.P, 2021). This revision included a
black-box warning about potential severe allergic reactions, even
death, associated with oxaliplatin. Antibacterial drugs,
particularly beta-lactams, are recognized as the primary causes
of anaphylaxis, with previous studies suggesting a lower
incidence of anaphylaxis with cephalosporins than penicillins
(Park et al., 2017; Giavina-Bianchi et al., 2018), and drugs
containing amoxicillin have been reported as the most
frequent anaphylaxis triggers to the FDA (Yu et al., 2021).
However, our study observed that cephalosporins were the
most frequently implicated drugs, likely due to prescription
practices in our hospital. As routine skin tests are not
advocated prior to the administration of cephalosporins,
future research should focus on devising prediction methods
for allergic reactions with heightened sensitivity and specificity.
TABLE 6 Drugs for the treatment of anaphylaxis.
Treatment drugs
Case
numbers (%)
Glucocorticoids (dexamethasone, methylprednisolone, and
betamethasone
66 (83.54%)
Promethazine
46 (58.23%)
Epinephrine
35 (44.30%)
Vitamin C
18 (22.78%)
Calcium gluconate
16 (20.25%)
Others (dopamine, norepinephrine, etc.)
17 (21.52%)
only four of these 17 patients received an anaphylaxis diagnosis
identifiable by ICD-9.
In this study, we devised trigger entries for anaphylaxis
encompassing both structured (e.g., medical orders and
diagnostic data) and unstructured (e.g., progress notes). This
incorporation of unstructured data led to a two-fold rise in the
anaphylaxis detection rate compared to the reliance solely on
diagnosis-based
structured
data,
thereby
substantially
augmenting the performance of the programs. Concurrently,
when compared with the spontaneous reporting system of our
hospital during the same period, it was evident that 83.72% of
anaphylaxis cases were under-reported. This finding underscores
the significant potential of ASPs to rectify the deficiencies of the
spontaneous reporting system, the primary monitoring method for
adverse reactions in China. The study by Panesar et al. (2013)
illustrated that the incidence rates for anaphylaxis in Europe
fluctuated between 1.5 and 7.9 per 100,000 person-years. Our
research found the incidence of anaphylaxis in the Chinese
population to be 8.29 episodes per 100,000 person-years, a
figure surpassing other studies (Bann et al., 2021; Nunes et al.,
2022) reliant on electronic medical records, which signals the
efficacy of the ASPs. However, the sensitivity of our programs
remained suboptimal. We analyzed 4,874 medical records of
discharged patients from our hospital from 1 December to
31 December 2020 and recorded all suspected ADRs (based on
the progress notes and diagnoses). Out of these, three cases were
identified as anaphylaxis, and only one case could be effectively
tracked by the ASPs. Analysis of undetected anaphylaxis in the
aforementioned discharged patients and the spontaneous
reporting system (see Supplementary Table S1) revealed that all
eight patients were not diagnosed with anaphylactic shock. Among
these, five cases either received only dexamethasone treatment or
did not receive any pharmacological intervention postanaphylaxis. Furthermore, two cases lacked progress notes
indicating an “allergy,” and one case, although marked as
TABLE 7 Epinephrine use in patients with anaphylaxis.
With epinephrine
Without epinephrine
p-value
Anaphylactic shock
29
8
<0.01
Non-anaphylactic shock
6
36
Patient classification
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Wang et al.
10.3389/fphar.2023.1180685
anaphylaxis management and treatment by medical
professionals to reduce mortality from this severe allergic reaction.
Our study does possess several limitations. Primarily, as a singlecenter study, the formulation of triggers in medical orders was based
on the prescribing habits of doctors in our hospital; this contextspecific design may compromise its external validity. Thus, when
attempting to apply these triggers to other hospitals, certain
elements may require modification. Additionally, our ASPs may
not have captured all anaphylaxis cases due to certain inherent
limitations, which could potentially affect the thoroughness of our
results. This factor may have subtly influenced the outcomes of our
research.
TABLE 8 Dosage and administration of epinephrine.
Dosage and administration of
epinephrine
Intramuscular injection
Number (%)
0.5 mg
10 (28.57%)
0.3 mg
3 (8.57%)
4 mg
1 (2.86%)
1 mg
1 (2.86%)
0.4 mg
1 (2.86%)
0.5 mg
4 (11.43%)
0.3 mg
3 (8.57%)
1 mg
2 (5.71%)
0.15 mg
1 (2.86%)
1 mg
2 (5.71%)
0.02 mg
2 (5.71%)
0.25 mg
1 (2.86%)
0.2 mg
1 (2.86%)
0.1 mg
1 (2.86%)
0.03 mg
1 (2.86%)
Unknown
1 (2.86%)
Subcutaneous injection
Data availability statement
The original contributions presented in the study are included in
the article/Supplementary Material; further inquiries can be directed
to the corresponding author.
Bolus
Ethics statement
Ethical review and approval was not required for the study on
human participants in accordance with the local legislation and
institutional requirements. Written informed consent from the
patients was not required to participate in this study in
accordance with the national legislation and the institutional
requirements.
Administering an immediate intramuscular injection of
epinephrine into the mid-thigh area is the primary treatment
strategy for anaphylaxis, regardless of the presence of shock, as
outlined in multiple guidelines (Cardona et al., 2020; Muraro et al.,
2022). For adults, the recommended dosage is 0.01 mg/kg of body
weight, not exceeding a total dose of 0.5 mg. Importantly,
subcutaneous injection is not recommended for emergency
intervention because of its slower onset of action (Li et al.,
2019). Furthermore, although glucocorticosteroids and
antihistamines are frequently employed in managing
anaphylaxis, they are only recommended as secondary
treatment options per guidelines, and their routine usage
remains a contentious issue. Current evidence suggests that
glucocorticosteroids may not provide any benefit or might even
be detrimental in the acute management of anaphylaxis (Cardona
et al., 2020). In our study, we noted that the use of
glucocorticosteroids and antihistamines significantly outpaced
that of epinephrine in anaphylaxis management (83.54% vs.
44.30%, 58.23% vs. 44.30%, p < 0.01). Notably, the employment
of epinephrine was significantly less common in non-shock cases
compared to shock incidents. Moreover, the application and
dosage of epinephrine were not rational, reflected by a high
percentage of subcutaneous epinephrine injections and
considerable dosage inconsistency. Jiang et al. (2020) similarly
underscored the significant underutilization, inappropriate usage,
and dosage of epinephrine and the unreasonably high employment
of glucocorticoids in China. Hence, it is crucial to improve
Frontiers in Pharmacology
Author contributions
CW, ZL, and AL contributed to the conception and design of
the study. CW, ZL, and MF reviewed the ADR reports and
formulated the initial triggers. CW and YY performed the
statistical analysis. CW wrote the first draft of the manuscript.
All authors contributed to the article and approved the submitted
version.
Funding
This work was supported by the Clinical Pharmacy Research
of Shandong Medical Association (YXH2021ZX017) and Open
Project of the Key Laboratory of Pharmacovigilance Technology
Research and Evaluation of National Medical Products
Administration.
Acknowledgments
The authors thank Zheng He, Fangfang Bu, Xi Guo, Wenjing Lu,
Jinxiang Wang, and Chenglong Lu for their contribution to the
questionnaires.
09
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Wang et al.
10.3389/fphar.2023.1180685
Conflict of interest
organizations, or those of the publisher, the editors, and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher.
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Supplementary material
Publisher’s note
The Supplementary Material for this article can be found online
at: https://www.frontiersin.org/articles/10.3389/fphar.2023.1180685/
full#supplementary-material
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated
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