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\begin{document}

\title{An Overview of COVID-19 Testing and Implications for
Otolaryngologists}



\author[1]{Xiao Zhao, MD, PhD}%
\affil[1]{The University of Texas MD Anderson Cancer Center}%


\vspace{-1em}



  
  \date{May 19, 2024}


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\begin{abstract}
Background :~Testing for SARS-CoV-2 is important for decision making
prior to surgery in otolaryngology. An understanding of current and
developing testing methods is important for interpreting test results.

Methods :~We performed a literature review of current evidence
surrounding SARS-CoV-2 diagnostic testing highlighting its utility,
limitations, and implications for otolaryngologists.

Results :~The currently accepted RT-PCR test for SARS-CoV-2 has varying
sensitivity according to which subsite of the aerodigestive tract is
sampled. Nasal swab sensitivities appear to be about 70\%. Chest CT
imaging for screening purposes is not currently recommended.

Conclusion :~Due to the current sensitivity of RT-PCR based testing for
SARS-CoV-2, a negative test cannot rule out COVID-19.~ Full PPE should
be worn during high risk procedures such as aerosol generating
procedures even if testing is negative. Patients who test positive
during screening should have their surgeries postponed if possible until
asymptomatic and have tested negative for~SARS-CoV-2.%
\end{abstract}%



\sloppy


\subsection*{Daniel B Vinh MD 1 , Xiao Zhao MD PhD*,2, Kimberley L Kiong
MBBS 2 , Theresa Guo MD 2 , Yelda Jozaghi MD 2 , Chris Yao MD 2 , James
M Kelley MD PhD 3 , Ehab Hanna MD
2}

{\label{358704}}

1 Department of Otolaryngology -- Head and Neck Surgery, Baylor College
of Medicine, Houston, TX, USA 2 Department of Head and Neck Surgery, MD
Anderson Cancer Center, Houston, TX, USA 3 Department of Laboratory
Medicine, Division of Pathology and Laboratory Medicine, MD Anderson
Cancer Center, Houston, TX, USA

* Corresponding author. E-mail:
\href{mailto:XZhao6@mdanderson.org}{\nolinkurl{XZhao6@mdanderson.org}}

\par\null

Key words: COVID-19, PCR, sensitivity, SARS-CoV-2, testing

\emph{} \textbf{Abstract}

\emph{Background} :~Testing for SARS-CoV-2 is important for decision
making prior to surgery in otolaryngology. An understanding of current
and developing testing methods is important for interpreting test
results.

\emph{Methods} :~We performed a literature review of current evidence
surrounding SARS-CoV-2 diagnostic testing highlighting its utility,
limitations, and implications for otolaryngologists.

\emph{Results} :~The currently accepted RT-PCR test for SARS-CoV-2 has
varying sensitivity according to which subsite of the aerodigestive
tract is sampled. Nasal swab sensitivities appear to be about 70\%.
Chest CT imaging for screening purposes is not currently recommended.

\emph{Conclusion} :~Due to the current sensitivity of RT-PCR based
testing for SARS-CoV-2, a negative test cannot rule out COVID-19.~ Full
PPE should be worn during high risk procedures such as aerosol
generating procedures even if testing is negative. Patients who test
positive during screening should have their surgeries postponed if
possible until asymptomatic and have tested negative for~SARS-CoV-2.

\emph{Introduction}

In December of 2019, an outbreak of patients with severe pneumonia was
reported in Wuhan, China. A novel Coronavirus was isolated as the
causative agent. It has been named by the World Health Organization
(WHO) as the severe acute respiratory distress syndrome coronavirus 2
(SARS-CoV-2) which causes the coronavirus disease 2019 (COVID-19). The
genome of this novel coronavirus is a single-stranded positive-sense RNA
(+ssRNA). It belongs to the family \emph{Coronaviridae} containing
strains responsible for the SARS outbreak in 2003 as well as the Middle
East respiratory syndrome (MERS) outbreak in 2012. SARS-CoV-2 has spread
rapidly across the world and by March 11\textsuperscript{th}, 2020, the
WHO officially declared the outbreak a pandemic.\textsuperscript{4} This
pandemic has resulted in unprecedented challenges to the healthcare
system and to society as a whole.

Among the healthcare workforce, otolaryngologists are at particular risk
for acquiring the disease due to performance of exams and procedures
involving a potentially infected upper aerodigestive tract. Routine
endoscopic examinations including nasal endoscopy, flexible laryngoscopy
as well as the use of energy devices during surgery are considered
aerosol generating procedures (AGPs) with high risk for
transmission.\textsuperscript{5} An analysis of 138 patients
hospitalized with COVID-19 in Wuhan, China found that 40 (29\%) were
healthcare workers.\textsuperscript{6} In fact, the first reported
physician death associated with the disease was that of an
otolaryngologist in Wuhan.\textsuperscript{7} In recognition of these
risks and to conserve limited resources, the American Academy of
Otolaryngology-Head and Neck Surgery has recommended only performing
procedures or surgeries that are time sensitive or
emergent.\textsuperscript{8} Similar recommendations have been made by
the American College of Surgeons as well as the Centers for Medicare and
Medicaid Services (CMS).\textsuperscript{9,10} In an effort to reduce
risk, many professional societies have recommended screening for
COVID-19 prior to high risk procedures as emerging data suggests that
patients can be asymptomatic carriers.\textsuperscript{5,11}

In this article, we will review the current testing standards for
COVID-19 and discuss their strengths and limitations. Of note, new
information on the COVID-19 pandemic is being published at a fast rate.
The data presented here rely primarily on early studies with confounders
that can influence interpretation. As there is no current gold standard
for SARS-CoV-2 testing, careful re-evaluation of the published evidence
over time will be imperative.

\emph{Presenting symptoms and lab values}

The first report of 41 patients confirmed to have COVID-19 in Wuhan,
China found that initial symptoms included fever (98\%), cough (76\%),
myalgia or fatigue (44\%), sputum production (28\%), headache (8\%),
hemoptysis (5\%), and diarrhea (3\%). Dyspnea developed in 55\% of
patients with progression to ARDS in 29\% of patients. A total of 13
(32\%) patients were admitted to the ICU and 6 patients (15\%)
died.\textsuperscript{12} A subsequent report of 138 patients, also from
Wuhan, found that 98.6\% of patients had fever, 69.6\% had fatigue, and
59.4\% dry cough. In that cohort, 36 patients (26\%) required ICU care,
and 6 patients (4.3\%) died.\textsuperscript{6} A larger,
multi-institutional characterization of 1099 patients with laboratory
confirmed COVID-19 throughout China found that 88.7\% of patients
developed fever during their hospital admission. The second most common
symptom was cough (67.8\%). Less frequent were nausea or vomiting (5\%)
and diarrhea (3.8\%). Upper respiratory type symptoms were relatively
infrequent with only 13.9\% presenting with sore throat and 4.8\% of
patients with nasal congestion. Of those patients, 5\% were admitted to
the ICU, 2.3\% required mechanical ventilation, and 1.4\%
died.\textsuperscript{13} While not initially reported, multiple recent
studies have found chemosensory dysfunctions associated with
COVID-19,\textsuperscript{14,15} with one study finding up to 85.6\% and
88\% showing olfactory and gustatory dysfunction
respectively.\textsuperscript{16} Notably, emerging data has found the
asymptomatic carrier rate to be in the range of
17.9-21.7\%.\textsuperscript{17,18} The most common laboratory
abnormalities included lymphocytopenia (83.2\%), thrombocytopenia
(36.2\%), and leukopenia (33.7\%).\textsuperscript{13}

\emph{Current Testing Standards}

The current test for the diagnosis of COVID-19, as recommended by the
United States Centers for Disease Control and Prevention (CDC), is a
qualitative real time RT-PCR nasopharyngeal swab which detects the
presence of specific segments of the SARS-CoV-2 genome. The current CDC
test detects and amplifies two regions of the nucleoside coding genome,
N1 and N2. A positive test is found when both segments are detected. An
inconclusive test occurs when only 1 segment is detected, and a negative
test occurs when both segments are not detected. RNA primers for
amplification and detection of these genetic segments are available
publicly on the CDC website.\textsuperscript{19} Internal testing by the
CDC comparing these primers and probes for N1 and N2 against public
domain nucleotide sequences found no significant homologies with the
human genome, other coronaviruses, or human microflora that would lead
to a potential false positive.\textsuperscript{20} Limits of detection
by RT-PCR were also tested internally by the CDC. While detection
thresholds varied according to different commercially available master
mixes of enzyme, all assays were able to reliably detect concentrations
of 10 copies/uL.\textsuperscript{20} Multiple laboratories within the
United States including reference laboratories and private hospital
groups have implemented this testing, made allowable by the FDA under an
Emergency Use Authorization (EUA). The FDA has also approved an EUA for
multiple other commercial entities and academic medical centers to offer
molecular testing either modified from the CDC protocol or developed
with unique primers.\textsuperscript{21} RT-PCR testing by other
countries has targeted other sequences of the SARS-CoV-2
genome.\textsuperscript{22}

\emph{Sensitivity of PCR Assay}

Currently the CDC states that a negative result does not exclude
SARS-CoV-2 infection. Sources of false negative testing include patient
misidentification, collection of inappropriate or inadequate material,
improper specimen transportation, low viral density in pre-symptomatic
patients, and lab errors. In addition to these factors, the location of
testing in the aerodigestive tract plays a large role in the sensitivity
to detect SARS-CoV-2. As was shown by Zou et
al.,\textsuperscript{3}viral loads in the upper respiratory tract of 18
patients varied according to sub-site, with about 64 fold higher viral
loads detected in the nasal cavity than in the pharynx. In a study of
213 patients with confirmed COVID-19, the authors found that sputum
samples showed the highest positive rate in both severe (88.9\%) and
mild (82.2\%) cases, followed by nasal swabs (73.3\%, 72.1\%), and then
throat swabs (60.0\%, 61.3\%).\textsuperscript{2} In a similar study
consisting of 205 patients, Wang et al. found that bronchoalveolar
lavage had the highest positive rates (93\%), followed by sputum (72\%),
nasal swabs (63\%), bronchoscope brushings (46\%), pharyngeal swabs
(32\%), feces (29\%), and blood (1\%).\textsuperscript{1} From these
studies, it appears that the highest positive detection rate is from
lower respiratory tract specimens. A plausible explanation is that
SARS-CoV-2 binds to human angiotensin-converting enzyme 2 (ACE2), found
predominantly in the lower respiratory tract.\textsuperscript{23}
However a potential confounder is that invasive lower respiratory tract
sampling would be primarily performed on patients that have been
intubated, which suggests that these patients overall may have higher
viral load. Finally, to add further complexity to diagnosis, there may
be variable viral load and shedding over time, even when the patient is
asymptomatic. There currently is no consensus on when PCR testing should
be performed, and this is an area that needs further study.

\emph{Imaging}

Chest CT imaging of COVID-19 patients typically demonstrate ground-glass
opacities, multifocal patchy consolidation, and/or interstitial changes
with a peripheral distribution.\textsuperscript{24} In one study, the
authors found that Chest CT scans had higher sensitivity for diagnosis
of COVID-19 (88\%) as opposed to initial RT-PCR using throat swabs
(59\%).\textsuperscript{25} Another study assessed radiologists' ability
to distinguish COVID-19 pneumonia from non-COVID-19 pneumonia. It found
sensitivities among radiologists to be between 73-93\% and specificities
to be between 93-100\%.\textsuperscript{26} At this time, however, the
majority of radiology societies do not recommend routine screening for
COVID-19 with chest CT.\textsuperscript{27}

\emph{Serologic Testing}

Testing of IgM and IgG specific antibodies to SARS-CoV-2 is done readily
by obtaining blood samples and does not require specialized PCR
equipment. An initial study on the kinetics of antibody formation found
that of 535 patients, the total seroconversion rate for total Ab, IgM,
and IgG was 93.1\%, 82.7\%, and 64.7\%, with median seroconversion time
of 11, 12, and 14 days.\textsuperscript{28} The same authors reported
that combining RT-PCR and antibody detection can improve the sensitivity
for diagnosis of COVID-19.\textsuperscript{28}

A patient with a positive serologic test, however, only means that they
have been exposed to SARS-CoV-2. Whether the resulting antibodies confer
immunity to the virus requires further study. As such, the presence of
antibodies does not necessarily reflect a person's potential to transmit
the disease. There are reports showing that patients who developed
COVID-19 and then resolved with negative serial PCR testing later again
became positive on PCR assay.\textsuperscript{29} This could potentially
represent a false positive result, or a viral carrier state despite a
measured serologic conversion. As such, while serologic testing is
important in the setting of confirming SARS-CoV-2 infection, this test
does not indicate whether the patient is or is not actively infectious
and shedding the virus. Until further research is done, the WHO does not
currently recommend utilizing serologic testing to guide decision
making.\textsuperscript{30}

\emph{How Testing Impacts Management}

For patients who are being screened prior to potential head and neck
surgery, a nasopharyngeal swab should be performed by a healthcare
provider, preferably 24 hours prior to surgery.\textsuperscript{31} In
an effort to broaden access to testing, the CDC has now allowed
self-collection of nasal swabs.\textsuperscript{32} While there are no
data on the sensitivity of these self-administrated tests, there is
potentially lower sensitivity due to inadequate sampling. Until more
data is available, self-administered testing has not been established as
an adequate alternative to testing performed by a health care provider.

Given the above sensitivity limitations of PCR-based assays, it is not
clear whether a negative COVID-19 test should impact practice patterns
in a high-risk specialty such as Otolaryngology-Head and Neck Surgery.
Current sensitivities are considered to be acceptable for the general
population and for patients who do not undergo high-risk procedures.
However, for patients who undergo AGPs, the impact of a false negative
result has serious implications to healthcare providers and other
patients in the hospital. As such, many institutions have recommended
that all personnel at risk for exposure to aerosolization of SARS-CoV-2
wear full personal protective equipment. This would include N95 or
powered air purifying respirator (PAPR), even for asymptomatic patients
with negative testing during this pandemic.\textsuperscript{7}

For patients who test positive for COVID-19, the CDC has recommended
that these patients be quarantined for at least 7 days and be
asymptomatic with two negative PCR results done 24 hours apart to
confirm clearance of SARS-CoV-2.\textsuperscript{33} New evidence has
emerged suggesting that performing elective surgery on patients with
COVID-19 carries high risk of patient morbidity. Of 34 patients who
underwent elective surgeries and subsequently became positive for
COVID-19, 44\% required admission to the ICU and the mortality rate was
20.5\%.\textsuperscript{34} As such, all patients with confirmed
COVID-19 should be discussed within a multi-disciplinary team and
surgery deferred, if possible, until proof of virus clearance is
obtained and the patient is asymptomatic.

\emph{Conclusion}

Currently, there is no gold standard for the diagnosis of SARS-CoV-2.
Early evidence suggests that the current standard for the diagnosis of
SARS-CoV-2 using RT-PCR has variations in sensitivity dependent on the
sub-site tested. Nasal swab specimens appear to have high viral loads,
but even then sensitivities are in the range of
60-70\%.\textsuperscript{1-3} Furthermore, while clinical history, CT
imaging, and laboratory tests may support the diagnosis of COVID-19,
none of these tests alone or in combination with RT-PCR have been proven
to have optimal sensitivity to rule out SARS-CoV-2 infection, especially
for high risk AGPs. As such even for patients tested negative for
COVID19, many institutions suggest that the highest level of PPE
available should be worn that protects against potential transmission of
aerosolized SARS-CoV-2 for procedures of the upper aerodigestive tract.
Moreover, the emerging data demonstrating high morbidity and mortality
for patients who develop COVID-19 after elective surgeries would suggest
that elective surgery should be postponed in this patient population.
Finally, it is imperative to point out once again the evidence on the
COVID-19 pandemic is rapidly evolving. We will need to constantly
re-evaluate the nature of testing and result interpretation, especially
as the prevalence of SARS-CoV-2 continues to change and new testing
methodologies become available.

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