Discussion
We found that the
repositive
rate of SARS-CoV-2 was over 20% (157/745, 21.1%) among discharged
patients affected by COVID-19 at a follow-up visit after at least 6
weeks. They reported positive RT-PCR testing results with median days
8.0 to 14.0 after discharge. Over 4 in 10 children and adolescents were
found to be positive again; in contrast, the repositivity rate of
SARS-CoV-2 in middle-aged and elderly individuals was 16%. Moreover,
patients with more clinically severe disease were less likely to have
redetectable positive test results
than those with mild severity; asymptomatic patients were most likely to
have redetectable positive test results. Manifestation of certain
symptoms at first admission, such as fever, was also associated with a
lower risk for repositivity. Based on the Chinese guidelines for
discharged patients (National_Health_Commission_of_China, 2020),
positive retest patients were required to quarantine for a second time.
No other positive patients emerged within their families and close
contacts.
Several studies, mainly
case
reports, have been performed to investigate the percentage of retested
positivity and the clinical characteristics of discharged
patients(Habibzadeh et al., 2020; Lan et al., 2020; Tao et al., 2020).
Previous studies reported that the repositivity rate ranged from 6.9%
to 69.0% for discharged patients(Habibzadeh et al., 2020; Landi et al.,
2020; Tao et al., 2020). However, the studies were limited to a small
number of patients with mild or moderate infection. In our study, we
evaluated the overall prognosis of patients with COVID-19 after meeting
the criteria for discharge in Guangzhou, China. After screening 745
discharged patients, up to September 21, 2020, the repositivity rate was
over 20% (157/745), which was higher than that in other cities of China
(20/182, 11.0%)(Yuan et al., 2020) and Italy (16.7%)(Landi et al.,
2020), and this may be due to the longer follow-up time, more stringent
monitoring and higher frequency of RT-PCR testing in Guangzhou. Our
study has lasted more than 7 months since the start of the outbreak,
which was far longer than other study (most lasted for one or two
months)(Lu et al., 2020; Tao et al., 2020; Yuan et al., 2020; Zheng et
al., 2020) and to some extent represented the overall prognosis of the
disease.
According to the Chinese clinical guidance for
COVID-19(National_Health_Commission_of_China, 2020 ), all positive
retest patients should test negative for nasopharyngeal and anal swabs
for two successive tests before discharge. Then, all discharged patients
were continuously quarantined in designated health care facilities with
strict interventions on disease transmission. Thus, the identification
of another positive SARS-CoV-2 test during the quarantine period likely
excludes the possibility that positive retest patients are caused by
secondary viral infection. A recent study also experimentally confirmed
that the virus was involved in the initial infection instead of a
secondary infection(F. Hu et al., 2020). Abnormal CT and lymphopenia are
common and correlate with poor clinical outcomes in patients with
COVID-19(Cheng et al., 2020).
Most
positive retest patients at the second admission showed increased
lymphocyte cell counts, and CT examination showed abnormal but obvious
improvements (Table 2 ), suggesting that positive retest
patients have no obvious disease progression but are still asymptomatic
carriers of the virus.
Our results showed that the observation of positive retest patients was
not random and was mainly observed in young patients without severe
clinical symptoms, which was consistent with previous studies(F. Hu et
al., 2020; Lu et al., 2020). At present, it has been reported that
negative conversion of viral RNA generally takes 2 to 3 weeks or
longer(X. Hu et al., 2020; Hung et al., 2020; To et al., 2020; L. Zou et
al., 2020), and one study showed that SARS-CoV-2 nucleic acid existed in
fecal samples for 47 days after the first symptom onset(Wu et al.,
2020). In our study, the days of first hospitalization were shorter in
positive retest patients than in negative retest patients (Table
1 ), suggesting that the SARS-CoV-2 virus may not be completely
eliminated due to the lighter symptoms and the faster attainment of the
discharge standard. In addition, one study reported that recurrently
positive RT-PCR testing results in patients with three consecutive
negative results were significantly decreased compared with those in
patients with two consecutive negative results(Y. Zou et al., 2020),
suggesting that a prolonged quarantine phase is necessary.
Among positive retest patients in our study, no families or close
contacts of positive retest patients tested positive, which was
consistent with current studies(Chandrashekar et al., 2020; Lu et al.,
2020). All positive retest patients had observed social distancing
measures and worn face masks. Regarding these observations, it is very
difficult to affirm whether these patients were truly contagious. RT-PCR
testing does not discriminate between an infectious virus and
noninfectious RNA(Atkinson & Petersen, 2020; Quick et al., 2017).
Therefore, positive testing may not necessarily imply an active
infection or ability to transmit infection. However, whether discharged
patients have infectivity is an issue of concern around the world at
present. One recent study reported that no infectious strain could be
obtained by culture, and no full-length viral genomes could be sequenced
using samples of positive retest patients(Lu et al., 2020). However,
other studies found that active SARS-CoV-2 viral replication was
observed(Gousseff et al., 2020) and managed to obtain a nearly
full-length viral genome sequence in positive retest patients by
detecting intracellular SARS-CoV-2 subgenomic messenger RNA (sgmRNA)(F.
Hu et al., 2020), and the presence of SARS-CoV-2
sgmRNA
was widely accepted as direct evidence of active viral replication and
production(Kim et al., 2020; Wölfel et al., 2020). Furthermore, a recent
study found that SARS-CoV-2 viral particles remained in the lungs of
patients in the hospital whose nasopharyngeal swab sample testing
results were negative at three consecutive times(Yao et al., 2020).
Therefore, careful consideration should be given to the potential for
patients who are positive retest patients to become chronic virus
carriers.
Our study has some limitations. First, as our data were based on the
public health response to COVID-19, sample collection did not follow a
stringent study design. Therefore, some of the patients, especially in
the early stage, had missing fecal samples. Second, nasopharyngeal swab
samples cannot differentiate whether the virus comes from the
nasopharynx or from secretions from the lower respiratory tract; thus,
virus elimination in the lower respiratory tract cannot be confirmed. In
contrast, the positive rate of RT‐PCR testing through alveolar lavage
fluid may be higher. However, this method is invasive and cannot be
widely performed in clinical practice. In our opinion, both qualities of
respiratory samples and the variability of technique sensitivity can be
attributed to the influencing factors of repositivity. Third,
as
the discharge patients were usually placed under centralized quarantine
and medical observation, the infectivity of the positive retest patients
might be underestimated.
In summary, we found that the repositivity rate of discharged patients
was relatively high (21.1%), and they tested positive with a median of
8.0 to 14.0 days after discharge. The observation of positive retest
patients was not random and was mainly observed in young patients
without severe clinical symptoms. We suspected that SARS-CoV-2 may not
be completely eliminated in positive retest patients due to the lighter
symptoms and the faster attainment of the discharge standard. Meanwhile,
as the discharge patients were usually put under centralized quarantine,
it is difficult to affirm whether these patients were truly contagious.
These findings suggest that a significant proportion of patients could
carry viral fragments for a long time, and effective management, such as
a prolonged quarantine phase for discharged patients, is necessary.
Acknowledgements. We acknowledge all staffs involved in the
prevention and control of COVID-19 at the Guangzhou Centers for Disease
Control and Prevention. We thank all patients involved in the study.
Conflicts of interest.All
authors report no potential conflicts.
Author Contribution. D.L. contributed to the statistical
analyses and drafted the manuscript. C.M., L.L., D.L., Z.H.L., Z.H.W.,
P.D.Z, X.R.Z., Y.J.Z., W.F.Z. and W.Q.S. revised the final manuscript.
Z.B.Z., C.J.X., Z.Q.C., W.T.Z., P.Y. and Q.M.H. collected the
epidemiological and clinical data. H.W. and D.L. are responsible for
summarizing all epidemiological and clinical data, and contributed to
the data cleaning. All authors critically reviewed the manuscript for
important intellectual content.
Data Availability Statement. The data that support the findings
of this study are available from the corresponding author upon
reasonable request.
Financial support. This work was supported by the Guangdong
Province Higher Vocational Colleges and Schools Pearl River Scholar
Funded Scheme (2019), the Construction of High-level University of
Guangdong (G820332010, G618339167 and G618339164), Young Elite
Scientists Sponsorship Program by CAST (2019QNRC001), the National
Natural Science Foundation of China (82041030), the Zhejiang University
special scientific research fund for COVID-19 prevention and control
(K920330111).