Abstract: Letter to the Editor
doi: 10.1111/joim.13183
Use of proton pump inhibitors and risk of adverse clinical
outcomes from COVID-19: a meta-analysis
Dear Editor,
We read with interest the study by Luxenburger
et al. [1] which reported that patients with coronavirus disease 2019 (COVID-19) receiving proton
pump inhibitors (PPIs) were at increased risk for
the development of secondary infection and acute
respiratory distress syndrome. Understandably,
the use of PPIs may lead to excessive suppression
of gastric acid, and thus leading to impaired
eradication of ingested pathogens, which results
in the increased risk of secondary infection
reported in the study. However, the association
between the use of PPIs and adverse clinical
outcomes such as acute respiratory syndrome in
patients with COVID-19 is not expected, since
previous in vitro study has demonstrated the ability
for PPIs to inhibit the production of pro-inflammatory cytokines, which is suggestive of their potential to dampen cytokine storm associated with
COVID-19 [2]. Since there have been few studies
addressing the same issue, we aimed to perform a
meta-analysis to summarize the overall effect of PPI
on the COVID-19 associated adverse clinical outcomes.
We performed literature searches in PubMed,
Google Scholar and medRxiv (preprint repository)
databases, up to 5 September 2020, for studies
evaluating the risk of adverse clinical outcomes
among COVID-19 patients with PPI use compared
to nonuse of PPI, with the following keywords and
their MeSH terms: ‘COVID-19’, ‘proton pump
inhibitor’ and ‘PPI’ without language restrictions.
The inclusion criteria were studies that investigated the use of PPIs on the risk of adverse clinical
outcomes in patients with COVID-19 with reported
adjusted measures of association. Each included
article was independently evaluated by two authors
(CSK and SSH) who extracted the study characteristics and measures of effect. The quality of
included studies was evaluated with the Newcastle-Ottawa Scale [3]. The outcome of interest
was the development of any COVID-19 associated
adverse clinical outcomes. Adjusted odds ratios
(ORs) and adjusted relative risks and their
corresponding 95% confidence intervals (CIs) from
each study were pooled in a random-effects model
of meta-analysis using Meta XL, version 5.3
(EpiGear International, Queensland, Australia).
The I2 statistic was performed to estimate the
heterogeneity.
Five studies that corresponded to inclusion criteria
with a total of 37 372 patients were included for
our meta-analysis [1,4-6]. Study characteristics
are depicted in Table 1. All studies included are
deemed good quality with a Newcastle-Ottawa
Scale of 8. There was nonuniformity in the definition of the adverse clinical outcomes utilized across
the five included studies. In the study by McKeigue
et al. [5], the adverse clinical outcome was defined
as an entry to critical care, death within 28 days,
or a death certificate with COVID-19 as an underlying cause. In the study by Ramachandran et al.
[6], the adverse clinical outcome was defined as inhospital mortality or the requirement for mechanical ventilation. In the study by Lee et al. [4], we
utilized the composite endpoint of requirement of
oxygen therapy, intensive care unit admission,
administration of invasive ventilation, or death to
define the adverse clinical outcome. In both the
studies by Luxenburger et al. [1] and by Li et al. [7],
the adverse clinical outcome was defined as..
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