Discussion
Spurious BLA labels are dangerous to patients and pose a public health
emergency in terms of health care costs and driving ABR. In what we
believe to be the first publication on the epidemiology of reported BLA
in Africa, we found that the prevalence of reported BLA in hospitalised
patients was only 3.3%, a rate considerably lower than HIC rates. The
self reported BLA rates were lower in government-funded hospitals than
in the privately-funded hospitals. Sadly, very few participants in our
study with a BLA label returned for allergy de-labeling.
The lowest rate of self-reported BLA from a HIC inpatient settings is
9.9% of 1738 patients enrolled over a one-year period in Montreal,
Canada (9). Our study reports a rate less than half of this low-end
rate. Furthermore, more than 80% of our small number of self-reported
cases of BLA were considered low risk for true BLA, meaning that the
prevalence of confirmed beta-lactam hypersensitivity may in fact be even
lower in our South African population. There are several possible
contributing factors that may explain both a lower rate of BLA label as
well as a possible lower rate of true beta-lactam hypersensitivity in
our population. Antibiotic prescribing patterns differ across the world,
and involve a complex interplay of social, patient, provider, and
economic factors(18). The majority of BLA labels are the result of viral
or drug-related exanthems in childhood (2). But difficulties in
accessing healthcare in South Africa (particularly in rural areas)
resulting in less antibiotics being given(18), may limit the childhood
exposure to BLA allergens and so contribute to less identification of
true BLA in our setting.
Drug-related (and viral) exanthems, considered to be the predominant
driver of incorrect BLA labels, are predominantly T-cell mediated, the
majority of which are HLA-restricted. A recent genome-wide association
study (GWAS) linked HLAB55:01 with penicillin allergy label.
Interestingly, this allele has relatively low frequencies in Black
African populations. This contrasts with another recent GWAS amongst
confirmed cases of immediate hypersensitivity to beta-lactams, that
identify HLA-DRB1*10:01 as a risk allele. HLA-DRB1*10:01 is carried
twice as frequently in those of African ancestry (19). Other genetic
studies in European populations with confirmed beta-lactam
hypersensitivity have linked polymorphisms in cytokine genes (TNFA,
IL-13, IL-4, IL4R)(20), which are also likely to be population-specific.
Thus, it is possible that genetically African populations may have
similar or higher risk for true immediate beta-lactam hypersensitivity,
but less likelihood of mild delayed reactions, the major drivers of
incorrect BLA labeling in childhood. Finally, skin colour may impact the
detection of maculopapular exanthems in those with Fitzpatrick skin type
IV, V and VI (Lehloenya North American clinics accepted for
publication), as erythema and fine rashes are harder to detect in
pigmented skin. Taken together, there may be several genetic, and
biological factors that explain self reported BLA prevalence in in
African populations.
BLA labels were significantly more common in patients attending private
compared to (government funded) hospitals. South Africa is the most
inequitable country in Africa with a GINI coefficient of 0.63 in 2015,
an inequality reflected in its public versus private healthcare. Race
and socioeconomic status are a major factor(21-23). The population
utilizing privately funded health care sector in South Africa more
closely resembles that of a HIC in that the predominant racial group is
white (European ancestry)(22) with a higher income. The population that
accesses government-funded health care has a high percentage of black
African, Indian, or mixed race patients. Thus, the difference in BLA
rates between government and private hospital inpatients may reflect
both differences in access to healthcare in childhood with different
levels of antibiotic exposure, as well as genetic and skin pigment
biological factors related to populations of origin. Further qualitative
and basic science research is required to understand these differences.
Using the PEN-FAST tool, most patients with BLA label in our study were
considered low risk for true type 1 hypersensitivity to beta-lactams.
However, despite several attempts to contact and assist patients to
attend our tertiary allergy clinic at GSH, only 1 patient could complete
direct oral challenge for de-labeling. Multiple factors play into this
failure, including: patient-perceived lack of importance of carrying a
BLA label, fear of the testing and procedures or the time involved,
changes in contact details and a mobile patient population, or even lack
of resources to return for clinic visits (18, 22, 24). This inability to
have patients return and attend allergy clinics or elective procedures
has been highlighted, even in HICs, and undoubtedly aggravated across
the world by the COVID-19 pandemic (25). In paediatric patients
recommendations now exclude the use of SPT as a possible barrier to care
and with concerns regarding increased false positive test rates(26).
This data supports that the only viable option for BLA de-labeling in
LMICs will be direct de-labelling or challenges in low-risk patients by
non-allergists at the bedside. The development, validation and
implementation of risk-stratification tools will be critical to this
effort. A comprehensive framework for incorporation of BLA de-labeling
in LMIC/LIC has been recently outlined (4).
The inclusion of several hospitals across different levels of the health
system, and inclusion of private and government-funded hospitals,
improved the generalizability of this data. However, the fact that the
study was only performed in one city of SA is a limitation. The COVID-19
pandemic meant that there was a several month gap between the initial
survey at GSH in April 2019 and the other surveys in the study, as well
as limiting bed occupancy at the time of surveys in several hospitals,
which may have impacted results. The lack of reported BLA in patients
under 18 years is likely due to the low bed occupancy rates the high
percentage of paediatric patients under the age of one year in the
cohort, likely limits the generalisability of paediatric data.
In conclusion, this study provides the first data on the epidemiology of
BLA in Africa and demonstrates that the overall prevalence of BLA is
much lower than that reported in HICs. Furthermore, there is disparity
of our results across health sectors, which highlights several of the
complex social and biological determinants of both true and incorrectly
labeled BLA. The inability to confirm BLA in the majority of cases
through skin testing and direct oral challenge in the allergy clinic
highlights the challenges of incorporating BLA de-labeling strategies in
antibiotic stewardship programs in LMICs, and demands a different
solution than HICs, by shifting the site of testing to the bedside.
Epidemiology data from other LMIC is required to confirm our findings
and help LMIC policy makers decide on the importance of targeting BLA
de-labeling in local antibiotic stewardship efforts. Affordable
strategies for direct de-labeling or inpatient challenge are supported
by this data.