Authors: Luca Allievi1,*, MD; Amedeo
Bongarzoni2, MD; Guido Tassinario2,
MD; Stefano Carugo1, MD.
1Department of Cardiology, Fondazione IRCCS Ca’ Granda
Ospedale Maggiore Policlinico, University of Milan, 20122 Milan, Italy
2Department of Cardiology, ASST Santi Paolo e Carlo,
University of Milan, 20142 Milan, Italy
*Corresponding author: Luca Allievi, MD, Department of Cardiology,
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Sforza
35, University of Milan, 20122 Milan, Italy, Phone: 0039-0255033517,
E-mail:
luca.allievi@unimi.it,
Fax: none.
Word count : Abstract 60 words; Main text 812 words.
Abstract: Nasopharyngeal RT-PCR swab test for COVID-19
diagnosis has a high specificity but also a low sensitivity. The high
false-negative rate and the overconfidence in negative results sometimes
lead to hospital outbreaks. Therefore, we recommend always integrating
the clinical assessment in the diagnostic process, mostly after the
test, to determine what degree of confidence can be attributed to a
negative result.
Keywords : COVID-19; Sars-Cov-2; nasopharyngeal RT-PCR swab;
false-negative; sensitivity; outbreaks.
Every day we face up coronavirus disease 19 (COVID-19) pandemic during
our clinical practice. Despite the attention we pay in trying to detect
severe acute respiratory syndrome-coronavirus-2 (Sars-Cov-2) in the
hospitalized patients, often it is difficult to do, and sometimes
epidemic outbreaks in hospital wards occur.
Nasopharyngeal reverse transcriptase-polymerase chain reaction (RT-PCR)
swab test is a fundamental examination in COVID-19 diagnosis. However,
several studies have shown a suboptimal sensitivity of this test (around
70%1) in detecting Sars-Cov-2; in an infected
patient, the probability of a false-negative result is 67% the day
before the symptom onset, 38% the day of symptom onset, 20% 3 days
later, and then it increases again (to 66% two weeks
later)2. In our experience, a critical patient (then
passed away) with strongly suggestive symptoms for COVID-19 had got 4
consecutive negative RT-PCR swab test results before the positive result
on broncho-alveolar lavage.
This high false-negative rate may be caused by 1) the difficulty to
perform the nasopharyngeal swab correctly (making this examination
operator dependent), 2) a slower rise of the viral load in some
patients3 and 3) the timing of swab tests during the
day. Indeed, RT-PCR test is dependent upon the viral load in detecting
Sars-Cov-2, and the probability of having the highest viral load in
posterior oropharyngeal saliva in early-morning is 61.5%, compared to
23.1% before lunch, 7.7% at 3 p.m. or before dinner, and 0% at
bedtime4; therefore, assuming that this also applies
to nasopharyngeal secretions, performing a swab at another time of the
day could lead to a false-negative result more easily. It is reported
that early-morning saliva may be a better alternative specimen for
detection of Sars-Cov-25. Whatever diagnostic test is
used, it is fundamental to identify Sars-Cov-2 infection early to avoid
in-hospital contagion.
Unfortunately, the RT-PCR swab test is used mostly (and wrongly) for
ruling out Sars-Cov-2 infection in hospital wards: there is often
overconfidence in a negative result, without considering other important
clinical features. As seen previously, some patients with clinical
features suggestive for COVID-19 may have a negative result, but they
may be infected anyway, thus favouring epidemic outbreaks into hospital
wards. Before the positive conversion of the RT-PCR swab test, we often
observed respiratory symptoms (dyspnoea, cough, fever, sore throat),
blood tests (lymphopenia, fibrinogen, lactate dehydrogenase, C-reactive
protein and ferritin above the threshold value) and chest x-ray/computed
tomography (interstitial/ground-glass opacities) suggestive for
Sars-Cov-2 infection. We observed also (but less frequently) elevated
d-dimer and other organ damage proteins (transaminase, troponin,
amylase, lipase, etc.). These findings are confirmed by several studies
on COVID-19 patients and the alteration degree of blood tests is often
related to the severity of the disease.
Therefore, it is fundamental to always integrate the RT-PCR swab test
result with the clinical assessment in the diagnostic process of
COVID-19, to suspect the disease in possibly infected patients with a
negative result and manage them accordingly. The clinical situation
should not be considered only before the RT-PCR test to determine
pre-test probability, but also after the test to determine what degree
of confidence can be attributed to a negative result.
We propose a flowchart for the management of patients who underwent
nasopharyngeal RT-PCR swab test (Fig. 1). If the test result is
positive, immediate transfer to a COVID-19 unit should be performed (red
zone); if negative without clinical features suggestive for Sars-Cov-2
infection (please see below), no further action needs to be performed
(green zone). If the test result is negative but some clinical features
may suggest Sars-Cov-2 infection (i.e. dyspnoea, cough, fever, sore
throat, lymphopenia, fibrinogen, lactate dehydrogenase, C-reactive
protein and ferritin above the threshold value,
interstitial/ground-glass opacities, etc.), the patient should be
isolated, physicians should use personal protective equipment (PPE) as
in front of a COVID-19 patient, daily clinical and laboratory (body
temperature, blood count, C-reactive protein, etc.) monitoring and
serial RT-PCR swab tests should be performed (grey zone). We must admit
that similar findings can be present during other viral infections, but
it is equally true that during this phase we must suspect Sars-Cov-2
primarily, because of the higher danger and spread velocity compared to
other viruses. Weak positive RT-PCR swab tests should be repeated, but
the possible following negative result should be integrated with the
clinical assessment as seen before; we remind that RT-PCR swab test has
low sensitivity but high specificity (95%)1 and,
therefore, a positive result should never be ignored.
In conclusion, COVID-19 should not be ruled out based on RT-PCR swab
test alone, but also the clinical situation should be carefully
assessed2. A cautious approach integrating RT-PCR swab
tests with the clinical assessment may allow to offset the low
sensitivity of swab tests and counteract in-hospital epidemic outbreaks.
New diagnostic tests are necessary to reach the optimal sensitivity in
detecting Sars-Cov-2. We hope that COVID-19 vaccines will help stop the
epidemic outbreaks into the hospital wards, which we still worry about
today.