Discussion
Using our population-wide data, CEDAR was able to generate a registry of
comprising of more than 7,337,778 individuals. To our knowledge, this is
the largest population-wide drug epidemiology study to date; allowing
detailed characterisation of the absolute-prevalence and -incidence,
individual drug culprits, as well as the age of incident drug allergies
of our entire population.
Our study is also the first to investigate the longitudinal incidence of
drug allergy labelling on a population-wide basis. CEDAR revealed that
the annual incidence of reported drug allergy Hong Kong remained
relatively stable over the 5-year study period (331-352 per 100,000
population), until a significant 16.3% drop in 2020. This was likely
due to the COVID-19 pandemic resulting in a population-wide reduction in
medical visits, drug prescriptions, or allergy
reporting.21 It would be interesting to see if the
incidence of drug allergy will rebound back to pre-COVID figures
following relaxation of social distancing restrictions. Our study also
confirmed that about 1 in 18 (5.61%) of Hong Kong’s population have
physician-reported drug allergies, which differs quite substantially
with other regions (especially in Western cohorts), as well as our own
previous hospital-based studies.8,22-26 Although drug
allergy prevalence varies across time and region (likely due to
combination of differing prescribing practices and biological
differences) we postulate discrepancies may also arise due to previous
type I errors from inadequate sampling, which would be minimised from
this population-wide study. This needs to be confirmed by collaborative
inter-regional and -ethnic big data studies in the future.
Interestingly, our unified physician-reported drug allergy system
revealed that most drug allergies were reported among middle-aged
individuals, with disproportionately higher incidence among those above
40. This is contrary to the traditional dogma reflected from the
previous experience from Western cohorts, suggesting the majority of
individuals acquire drug allergy labels during childhood and carry them
into adulthood.27 We postulate this stark difference
may be due to either genuine inter-population differences, or a paradigm
shift that has remained unnoticed due to the paucity of prior systematic
or large population-based drug allergy studies. This emphasises the
importance of region-specific big data studies, which can discover
unique features and trends of drug allergy labelling among different
populations. Furthermore, identifying target subpopulations would inform
the best strategy for allergy education and proactive delabelling at a
population level. For example, there are significantly fewer adult
allergists than paediatric allergists in Hong Kong (1:2,800,000 vs
1:540,000 per population), which is disproportionate to the incidence
and burden of drug allergy in our locality.28 Hence,
we advocate for more active drug allergy delabelling initiatives among
adults, further resources and positions for training of adult
allergists, as well as strengthening the ability of frontline healthcare
professionals to discern symptoms of genuine allergy – especially among
adult patients.
This study also confirms the severity of a penicillin-dominated drug
allergy landscape in Hong Kong. Within anti-infectives, beta-lactams
constituted the majority of all reported drug allergy, with penicillins
contributing to almost 82.9% of all beta-lactam labels. Penicillins
were among the most commonly reported culprits of drug-induced
anaphylaxis and Steven-Johnson syndrome. However, our previous studies
revealed that only 10-13.8% of reported penicillin allergy are found to
be correct after evaluation.1,10 Incorrect labels lead
to unnecessary penicillin avoidance, posing immense challenges in
antimicrobial stewardship. This is especially relevant in Hong Kong,
where there has been an upsurge of various multi-drug resistant
organisms.29,30 Penicilin allergy labels have also
shown to affect geriatric and immunocompromised patients, associated
with a multitude of adverse clinical outcomes, including increased
healthcare costs, more frequent and longer hospital stays, and even
death.22,31-33 Despite the severe lack of allergists
in the Asia-Pacific region, previous multi-disciplinary initiatives have
shown much promise in tackling drug
allergies.10,34,35For example, a nurse-led penicillin allergy delabelling initiative
demonstrated superior outcomes compared to traditional allergist
evaluation in Hong Kong and similar strategies employing trained
pharmacists are underway.10 Further research on wider
applications of similar multidisciplinary drug allergy initiatives is
warranted.
Given the direct and indirect consequences of genuine or perceived
excipient allergy – from rare cases of excipient-associated anaphylaxis
to inappropriate fear of excipient allergy leading to vaccine hesitancy
– the ability to accurately disprove excipient allergy is of paramount
importance.13-17 However, diagnosis of excipient
allergy is near impossible when excipient information is not available.
This is a common problem for many regions where no pharmaceutical
legislations exist to mandate excipient disclosure in registered
medications. Despite our best efforts to construct a excipient registry,
we were unable to obtain excipient information from the vast majority of
drug formulations. Using PEG as an example, we were able to confirm its
presence or absence among only 724 of 2,070 formulations investigated,
only representing a mere 36% included in the registry. This made it
impossible to exclude or confirm presence of PEG in all formulations of
any of the top 50 reported drug allergy culprits in Hong Kong. Lack of
transparent drug information impedes in comprehensive evaluations in
drug allergy, and undermines the safety and public confidence of
population-wide vaccination programmes. Despite past efforts to advocate
for regulartory improvements, ingredient disclosure remains to be a
persistent issue in our locality and legislative changes have yet to
materialise.16,17
Given its observational nature, this study has several limitations.
First, only limited patient data was available, and more detailed
clinical data such as comorbidities, medication use or hospitalisation
records were not available for further subgroup analysis. Second, we did
not include reported drug allergies which were entered as ‘free text’
into the patient’s electronic health record that could not be manually
converted into structured item (often due to incomplete information).
Third, drug allergy labels in Hong Kong were physician-reported, and
albeit more preferred than patient-reported adverse reactions, may still
be inaccurate and do not reflect only genuine and confirmed drug
allergy. This highlights the importance of dedicated and interventional
studies in the future.
In conclusion, population-specific drug allergy research is needed to
inform the directions of appropriate public health initiatives in an
evidence-based manner. The use of big data can unlock new dimensions of
drug allergy research - such as drug allergy incidence and comparative
age distribution of reported drug allergies. Using our population-based
data, we were able to report the longitudinal incidence of reported drug
allergy, specific allergy culprits as well as identifying
disproportionate drug allergy labelling among middle-aged patients.
Future inter-regional and -ethnic big data studies will be required to
confirm external validity of our findings to other populations. Lastly,
excipient registries remain ineffective and proper allergy evaluation
cannot be conducted in countries where excipient information are
unavailable. International and collaborative efforts should be united to
advocate for universal recommendations toward ingredient disclosure for
all registered medications.