DISCUSSION
Discrepancies in preoperative reverse transcriptase polymerase chain
reaction (RT-PCR) screening for SARS-CoV-2 can create major concerns
with regards to proceeding with otolaryngologic surgeries that are
medically urgent yet risky for SARS-CoV-2 transmission. Justified fear
for the safety of the patient and the healthcare providers involved in
the patient’s care can cause significant changes to the course of care.
Lei et al. (2020) have reported that operating during the prodrome of
COVID-19 can lead to life-threatening complications. False negative
results are widely known to occur and are well-documented in the medical
literature, however nothing has been published about false positive
results.21 Therefore, when faced with patients with
suspected false positive results, our department and institution as a
whole were left with little guidance on how to proceed in these
circumstances. It would have been dangerous to providers to simply
assume the single positive result was spurious; likewise, delaying
urgent surgery for three weeks for what might be a spurious positive
result carried significant implications for the patient.
We turned to the expertise of several colleagues, including pathology,
radiology, and infectious disease, as well as internal departmental
experts who were part of the Surgical Review Committee. It seemed
reasonable that if repeat testing, multiple times in some instances, was
negative, we could declare patients as falsely positive and safely
proceed with surgery. Chest imaging, particularly computed tomography,
and subsequent clinical course also supported the determination that
these were false positives. These false positives tests were seen in a
clinically significant 7.1% of our patients. As part of the decision
process, pathologists were able to re-review tests to report the titer
levels. Rather than accepting the results reported simply as
“detected” or “not detected” in the electronic medical record, we
discussed suspicious cases to determine if titers were borderline
positive or strongly positive. We sparked conversation with infectious
disease physicians, pulmonologists, and particularly infectious disease
specialists who were now specializing in the care of COVID-19 positive
patients to seek expert opinions.
To our knowledge, there are no papers reporting false positive
SARS-CoV-2 RT-PCR tests. Tahamtan and Ardebili (2020) discuss possible
factors causing false negative results of SARS-CoV-2 RT-PCR, namely
mismatches between the testing primers and viral genome or low viral
loads in samples due to timing of disease or location of
collection.22 False positive RT-PCR for the diagnosis
of norovirus and dengue virus have been discussed, and indicate higher
rates of false positives for certain viral
targets.23-25 This supports repeat testing of patients
using a different testing platform with a different viral target for
more accurate testing when the result is questioned.
We hypothesize that mechanisms for generation of false positive results
for SARS-CoV-2 may include the following:
1) pure technical artifacts where fluorescence signal is generated due
to non-specific nuclease degradation of the probe probably associated
with off-target probe binding. In short, a technical artifact. This is
most likely associated with a weak positive signal.
2) detection of another non-SARS-CoV-2 virus/microorganism that has not
yet been accounted for in the global databases used to design the
primers/probes in these assays. Recall that all of these assays are new.
3) technical cross-contamination at any point along the sample chain of
testing. If a manual pipetting step is involved, it could a technologist
who accidentally made an error. In some instrument configurations, it
could be a sample carryover contamination event. We tend to trust robots
and instruments, but they are not infallible.
Otolaryngology patients are unique in that the patient often has disease
involving the mucosa in the upper aerodigestive where the SARS-CoV-2
virus resides, and from which our nasopharyngeal swabs are obtained.
Changing the location in which the sample is obtained could be
considered. One of our patients, who was heavily irradiated in the area
swabbed, had a tracheostomy, and thus, a bronchioalveolar lavage would
have been easy to obtain. However, this was not performed. There has
been no previous discussion in the literature regarding whether local
mucosal cancer, infection, or inflammation can affect RT-PCR testing for
this disease. Individual history of radiation to the head and neck can
affect saliva production which may theoretically alter the ability of
nasopharyngeal swab to collect specimen. While there was no difference
seen in our groups regarding mucosal pathology, cancer diagnosis, or
history of radiation, our sample size is quite small and further
investigation is warranted. In any case, it would seem logical that
mucosal abnormalities would lead to false negatives more often than
false positives due to inadequate sampling.
Chest computed tomography (CT) has never been described as a tool for
screening asymptomatic preoperative patients with no history of COVID-19
exposure. It has, however, been discussed for its utility as both a sole
diagnostic test and as an adjunct along with RT-PCR. Findings of
COVID-19 have been reported as ground-glass opacities with segmental
consolidations; these overlap with many other pulmonary disease and
therefore on meta-analysis, pooled specificity and positive-predictive
value is low, 37% and 1.5-30.7% respectively.26,27Sensitivity of CT chest alone is 94-97%, with a negative predictive
value of 95.4 to 99.8% in reports out of China with high
prevalance.26,28 Ai et al. (2020) showed 75% of
patients with symptoms concerning for COVID-19 and a negative RT-PCR but
positive CT chest later converted to positive
RT-PCR.28 Individual case reports have similarly shown
the utility of chest CT as adjunct with RT-PCR to diagnose COVID-19 in
patients with negative RT-PCR.27,29
There are reports of asymptomatic positive patients with classic CT
chest findings for COVID-19, however these patients were known to have
exposure to SARS-CoV-2.30,31 Between 70-100% of
patients were found to have CT findings consistent with COVID-19, and
between one-fifth and one-fourth of patients later developed symptoms of
the disease. Our preoperative patients were asymptomatic with no known
history of direct COVID-19 exposure; their only risk factor was living
in a city during the ascending portion of the COVID-19 pandemic.
Regardless, these reports provide evidence for CT chest changes in
pre-symptomatic patients. It therefore seems reasonable that CT chest
can serve as an adjunct test to help providers determine if subclinical
infection could be present. This may assist with determining which of
the two results is false. A negative CT chest can help reassure
providers that the positive RT-PCR test is spurious and allow the
surgery to proceed as scheduled.
Among our four patients with discrepant results: five additional RT-PCR
tests were performed, two patients had surgery delayed 3 or 4 days each,
two patients were sent to COVID-19 designated units, and one patient
left against medical advice without surgery for an orbital abscess. As
the weeks progressed, we became familiar with the possibility of false
positive findings and had raised suspicions for when positive results
might indeed reflect false positives. In the most recent patient with
positive preoperative testing without symptoms (Patient #3),
pathologists recommended immediate re-testing based on the borderline
titers in her test results rather than delaying surgery for weeks for a
potential COVID-19 infection. We were therefore able to move swiftly and
continue with the surgery, rather than delay for weeks anticipating a
clinical COVID-19 infection, which a more strongly positive test might
have required.
Prolonged inpatient stays pose risks for all patients at all times;
however, in the midst of the pandemic there are heightened risks.
Particularly for Patient #2, who falls into a highly at-risk group due
both to age and underlying pulmonary disease, the importance of a
prolonged stay should not be minimized. Fortunately, we were familiar
with the possibility of false positives by the time that this patient’s
positive test occurred, and we were able to keep her out of the COVID
unit until additional testing was performed and negative on three
further repeat tests. Placement in COVID-19 designated units, as seen
with the earlier cases of Patient #1 and #4, creates safety concerns
for both patients and providers. While COVID-specific units are
appropriate and necessary for the safe treatment of COVID-positive
patients, the misplacement of false positive patients in these units
exposes the patients to SARS-CoV-2 at an unnecessarily high rate.
Providers from the surgical team, who in ordinary circumstances would
not be in these high-risk units, are also placed in an environment with
increased risk of disease contraction for themselves and risk of
transmission to other patients. Moreover, our young and healthy patient
was so concerned about his placement in this high-risk ward that he left
against medical advice despite the risk of progressive vision loss. The
psychological effects of these wards on our surgical patients should not
be dismissed.
At this point in time, there is no “gold standard” test to which the
results of the RT-PCR can be compared, which limits the statistical
validity in the reporting a specificity. We therefore favor reporting a
probable false positive rate of 7.1% in lieu of specificity, until such
a time that a more accurate test is available. However, if we are to use
chest imaging, close clinical follow up, and expert opinion as a gold
standard in the absence of a true gold standard, the specificity would
be 0.97. Classic statistical teaching is that a positive result in a
highly specific test, such as in this case, should rule in the disease.
However, we believe these test results must be considered as part of the
broader clinical picture.
Little data exists about the use of RT-PCR tests to screen preoperative
patients without symptoms of COVID-19. In the preoperative setting, the
use of a screening test such as RT-PCR for SARS-CoV-2 is faulty in that
screening tests have a higher accepted false positive rate, and the
pre-test probability of a positive test in these patients is already
low. Ideally there should be a confirmation test for positive results
with higher accuracy, and perhaps, once validated, testing for
immunoglobulins against SARS-CoV-2 can fill this role in the future. As
the prevalence of the disease continues to increase, concern over false
positives will increase as many providers become hesitant to consider a
test falsely positive. Unlike false positive tests in the general
population for whom this result would cause self-quarantine, unrealized
false positive tests in preoperative patients can have significant
clinical implications and interfere with urgent cancer surgery or other
emergency surgery.