Discussion
Our study prospectively evaluated the utility of FebriDx to rapidly
identify suspected cases of COVID-19 disease in a hospital / ED setting
in an effort to improve isolation and cohorting procedures. Forty-nine
patients were enrolled, and one patient was excluded after enrollment
due to the inability to obtain enough blood for FebriDx testing after
the first attempt. Due to the patient’s advanced age and unstable
clinical state at the time of testing, FebriDx testing was not repeated
and thus this patient was excluded from the analyses. Therefore, 48
patients were included in the analyses of the for the primary and
secondary endpoints. After using PHE screening criteria for suspected
COVID-19 signs/symptoms, FebriDx correctly identified all patients
(35/35) who met the Case Definition30,31 for COVID-19
(Figure 3). FebriDx also correctly identified all patients that had a
bacterial infection by case definition (8/8) which resulted in a
diagnostic sensitivity of 100%. FebriDx had three false positives for
bacterial infection in two non-infectious patients and one clinically
indeterminate patient demonstrating a specificity for bacterial
infection of 92.5% (37/40) (Table 2). T he mortality rate for
COVID-19 related deaths was 33.3% our cohort. This is in keeping with
COVID-19 related mortality rates for hospitalised patients within our
health system as well as the national mortality figures for hospitalised
patients.35 Standalone conventional CRP was elevated
in both COVID-19 viral cases and bacterial cases in our study (median
[IQR] 76 mg/L [50.3-115.5]; 94 mg/L [59.5.0-152.0],
respectively). Brendish et al., also found CRP to be elevated in both
COVID and Non-COVID-19 cases (median (range) 83 mg/L (32-136 mg/L); 33
(9-114 mg/L) respectively p<0.0001).36Although Brendish et al. found the difference to be statistically
significant, the considerable overlap of quantitative CRP may make it
difficult to differentiate viral from bacterial infection as a
standalone test.36 The same appears to apply to
procalcitonin and leukocyte count in our study (Table 1). MxA confers
the diagnostic sensitivity and specificity needed to differentiate
elevated CRP associated with viral vs. bacterial infection and may help
to avoid mixing non-COVID-19 with COVID-19 whilst awaiting the results
of rRT-PCR that can take up to 48 hours in the hospital/ED settings. In
our study 7 patients, who in the end were not diagnosed with COVID-19,
were inadvertently exposed to COVID-19 due to the unintended mixed
cohorting that occurred whilst awaiting swab rRT-PCR results. As our
study was intended to evaluate diagnostic accuracy of FebriDx as part of
an initial triage strategy, the FebriDx test results were not used to
make decisions regarding cohorting until after the study was concluded
and the results were analysed. Based on the high NPV of FebriDx in our
setting, it is possible that the unintended exposure of non-COVID-19
patients could have been avoided if FebriDx was utilised part of the
initial triage of ARI patients with suspected COVID-19. Utilising
FebriDx for enabling cohorting decisions could have avoided exposure in
these cases.
A recent study by Brendish and colleagues from University Hospital
Southampton, Southampton, England, also evaluated the diagnostic
accuracy of FebriDx in 248 hospitalised adults who presented with
suspected COVID-19 regardless of duration of symptom onset (inclusive of
the PHE Case Definition for Possible Infection).36,37Of the 248 patients who underwent FebriDx and SARS-CoV-2 rRT-PCR, 118
had SARS-CoV-2 detected (prevalence 48%). Diagnostic sensitivity,
specificity, NPV and PPV were 93%, 86%, 86% and 93%, respectively.
Despite some methodological differences their results were comparable to
our study.
Based on the diagnostic performance characteristics of FebriDx
demonstrated in our study as well as Brendish et
al.36, we propose that in the current SARS-CoV-2
pandemic situation, patients presenting with signs and symptoms of ARI
and suspected of COVID-19 infection should be tested with FebriDx test
as part of the initial diagnostic triage process. Those testing ‘viral
positive’ (+MxA), should be treated as ‘positive COVID-19’ and cohorted
with other COVID-19 positive patients. This would help avoid unnecessary
exposure to other suspected patients who may turn out to be negative on
confirmatory rRT-PCR testing. If FebriDx result is ‘viral negative’ an
alternative diagnosis such as bacterial infection or non-infectious
conditions such as bacterial pneumonia or LRTI, should be considered at
the outset. It should be noted however, that patient enrollment took
place at the peak of the COVID-19 outbreak in our region and pre-test
probability of recruiting COVID-19 positive patients was relatively
high. This strategy allowed us to obtain a maximum number of potential
COVID-19 infections to evaluate FebriDx-based identification of
SARS-CoV-2 infection. Therefore, the prevalence of COVID-19 infection
was 73.2% in our setting and this may have increased the chance of
obtaining a high PPV.
Future viral outbreaks and seasonal infections could be managed,
ideally, by optimizing all available diagnostic tools (e.g. clinical
assessment, host response, molecular testing, antibody testing
etc.).13 Pulia et al. proposed ‘Multi-tiered Screening
and Diagnostic Strategy’ that incorporates a comprehensive approach that
could be used in the SARS-CoV-2 pandemic and potentially as a general
strategy in future pandemics.13 The strategy proposes
that after initial screening (e.g. clinical signs/symptoms of the
suspected infection), such as the initial screening performed in our
study, patients could be (i) be quickly tested for a viral, bacterial or
absent immune response to an infection, followed by (ii) rapid
confirmatory pathogen-specific testing; and (iii) rapid antibody testing
could be performed in patients that present with greater than 7 days of
symptom onset to confirm a recent or past infection. Although FebriDx
should not be used as a surrogate for pathogen-detection tests, it can
be applied to rapidly categorise patients as having bacterial or viral
infections or non-infectious conditions as part of the diagnostic triage
process.36 This would allow bacterial
infections/non-infectious conditions to be cohorted separately from
suspected viral infections. Those with viral infections would go on to
have confirmatory testing to improve cohorting within the viral
category, whereas antibiotics could be considered for patients positive
for bacterial infection. Repeat rRT-PCR testing could be considered in
high risk patients who test viral positive on FebriDx but have a
negative initial SARS-CoV-2 PCR.
Our study is not without limitations. Based on the urgent need to
improve testing turnaround times and patient isolation strategies at our
hospital, it was not possible to design and perform a multi-centre trial
that included a control group. Antibody testing was not available for
all patients enrolled nor is antibody testing required by PHE, ECDC nor
CDC for confirmation of COVID-19 infection. That said, antibody
confirmation would be ideal for determining definitive COVID-19
infection after 14 days of symptom onset, especially in cases that have
a high clinical suspicion but were SARS-CoV-2 is not detected by rRT-PCR
testing. Due to the lack of a gold standard test for COVID-19 infection,
the current assessment of the performance characteristics of rRT-PCR may
suffer from an incorporation bias. We attempted to mitigate this by
including clinical, radiological, and epidemiological criteria for final
diagnosis of COVID-19 infection as is consistent with the ECDC and CDC
Case Definitions. Finally, patients presenting in our hospital with
COVID-19 symptoms were generally adults. Therefore, additional studies
would be required to assess this strategy in children.
At the moment, in our clinical setting, and according to overwhelming
data reports by the PHE, CDC and ECDC, the predominant virus causing
hospitalisation amongst adults at present, seems to be
SARS-CoV-2.28 Based on our study findings, we provide
evidence that FebriDx could be deployed as part of the initial
diagnostic triage process for early identification of symptomatic
COVID-19 patients presenting in a hospital setting.
Disclosures
Authors declare that they have no conflicts of interest.