key: cord-0917602-foavgrnk
authors: Wu, Qian; Hou, Xinwei; Li, Hongwei; Guo, Jing; Li, Yajie; Yang, Fangfei; Zhang, Yan; Xie, Yi; Li, Li
title: A Follow-Up Study of Respiratory and Physical Functions After Discharge in re-detectable positive SARS-CoV-2 nucleic acid results in Recovered COVID-19 Patients
date: 2021-04-20
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.04.020
sha: 401b15bd45297d3fe92e27d01d82abc226321a29
doc_id: 917602
cord_uid: foavgrnk

Objective This study aimed to evaluate the respiratory and physical functions of patients who retested positive for SARS-CoV-2 RNA during post-COVID-19 rehabilitation. Methods A total of 302 discharged COVID-19 patients were included. Discharged patients were followed up for 14 days to 6 months. The modified Medical Research Council (mMRC) dyspnea scale, Borg rating of perceived exertion, and manual muscle testing (MMT) scores on day 14 and at 6 months after discharge were compared between the re-detectable positive (RP) and non-RP (NRP) groups. Prognoses of respiratory and physical functions were compared between patients who recovered from moderate and severe COVID-19. Results Of the patients, 7.6% were RP. The proportion of patients who used antiviral drugs was significantly lower in the RP group than in the NRP group. There were no differences in the mMRC, Borg, and MMT scores within the RP group and the NRP group. The mMRC, Borg, and MMT scores were worse for severe-type cases than for moderate-type cases at both follow-ups. Conclusion COVID-19 patients who did not take antiviral drugs were more likely to be RP after discharge. However, respiratory and physical function recovery were not related to re-positivity during rehabilitation but to disease severity during hospitalization.

The novel coronavirus disease (COVID-19) pandemic is a major global public health event. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of 4 April 2021, there have been 131,487,572 confirmed cases of COVID-19, including 2,857,702 deaths, reported to WHO [1] . Significant progress has been made in the treatment of COVID-19, and a large number of patients have been cured and discharged. Some recent studies have successively reported that SARS-CoV-2 could be re-detected by RT-PCR during post-COVID-19 rehabilitation [2] [3] [4] [5] . The proportion of re-positive patients ranged from 2.4% to 69.2% [6] , and the re-detectable positive (RP) results lasted from 1 to 38 days after discharge [7] . Most RP patients were asymptomatic or had mild symptoms; however, some patients progressed to a severe condition and died [8] . At present, the characteristics of RP patients are not well understood. Moreover, there is no report on the prognosis of RP patients' respiratory and physical functions. This study aimed to explore the characteristics of respiratory and physical dysfunction in RP patients. 156 imported non-local patients who returned to their home country 6 months after discharge, 12 were lost to follow-up and 2 died. A total of 132 patients were followed up for 6 months. All enrolled patients met the diagnostic criteria, clinical classification, and discharge criteria outlined by the Chinese Clinical Guidance for COVID -19 Pneumonia Diagnosis and Treatment published by the China National Health

Commission [9] . The criteria for diagnostic were as follows: Suspected case with one of the following etiological or serological evidence: 1) Real-time fluorescence RT-PCR detection of novel coronavirus nucleic acid positive; 2) Virus gene sequencing, highly homologous with known novel coronavirus; 3) Serum positive for novel coronavirusspecific IgM and IgG antibodies; Serum clear novel coronavirus specific IgG antibody changed from negative to positive or the recovery period was more than 4 times higher than the acute stage.

All patients met the guidelines for the diagnosis and treatment of novel coronavirus pneumonia issued by China's National Health Commission [9] . The criteria for patient discharge were as follows: 1) body temperature had returned to normal for more than 3 days, 2) respiratory symptoms had been significantly relieved, 3) acute exudative lesions on chest computed tomography (CT) scan had relieved, and 4) two consecutive respiratory specimens (specimens collected at least 24 hours apart) were negative for SARS-CoV-2 RNA by reverse transcription-polymerase chain reaction (RT-PCR). All discharged patients continued to be quarantined and observed for 14 days. The discharged patients were followed up every week. SARS-CoV-2 RNA testing J o u r n a l P r e -p r o o f was performed at each follow-up. Patients who were RP for SARS-CoV-2 RNA were readmitted for further medical observation. Patients were divided into the RP and non-RP (NRP) groups according to their SARS-CoV-2 RNA RT-PCR results during rehabilitation, as well as into moderate-and severe-type groups according to disease severity during hospitalization. Moderate-type disease was defined when symptoms such as fever and respiratory tract symptoms were present and manifestations of pneumonia could be seen on imaging. Patients who met any of the following criteria were classified as having severe-type disease: 1. dyspnea, respiratory rate ≥ 33 bpm; 2.

in resting state, finger oxygen saturation ≤ 93%; 3. arterial blood partial pressure of oxygen/fraction of inspired oxygen ≤ 300 mmHg (1 mmHg = 0.133 kPa); and 4. those whose lung imaging showed that the lesion had progressed significantly, by more than 50% within 24 to 48 hours. The exclusion criteria included patients who (1) died before the follow-up, (2) refused to participate in the follow-up, and (3) left the local area and could not complete the follow-up.

The patient's name, sex, age, comorbidities, use of antiviral drugs, and modified Medical Research Council (mMRC), Borg, and manual muscle test (MMT) scores were collected through a combination of questionnaires and the review of electronic medical records.

J o u r n a l P r e -p r o o f

Nasal, throat, anal, and stool swabs were collected, and SARS-CoV-2 RNA RT-PCR tests were conducted by the Tianjin Center for Disease Control.

Dyspnea was assessed with the modified Medical Research Council (mMRC) Dyspnea Scale in many respiratory diseases [10] .The mMRC scale was used in our study: Grade 0, difficulty breathing only during strenuous exercise; Grade 1, dyspnea when walking fast on flat ground or walking on small slopes; Grade 2, due to dyspnea, the patient was slower than peers or needed to stop and rest when walking on flat ground; Grade 3, the patient needed to stop and rest after walking about 100 meters or a few minutes on flat ground; and Grade 4, the patient could not leave the house due to severe breathing difficulties or had difficulty breathing while getting dressed and undressed.

The Borg scale is a valuable noninvasive test for the prediction of muscle weakness in patients [11] .The Borg rating of perceived exertion was used in our study: 0 points, no dyspnea or fatigue at all; 0.5 points, very slight dyspnea or fatigue, almost imperceptible; 1 point, very slight dyspnea or fatigue; 2 points, mild dyspnea or fatigue; 3 points, moderate dyspnea or fatigue; 4 points, slightly severe dyspnea or fatigue; 5 points, severe dyspnea or fatigue; 6-8 points, very severe dyspnea or fatigue; 9 points, very severe dyspnea or fatigue; and 10 points, extreme dyspnea or fatigue, reaching the limit. Physical function can be assessed readily through manual muscle testing (MMT) [12] .Manual Muscle Testing was used to assess the muscle strength of the upper The patient's condition was evaluated based on fatigue and physical strength.

Committee of Tianjin Haihe Hospital Science and Technology Fund (HHYY-202001).

IBM SPSS Statistics for Windows, version 26.0 (IBM Corp., Armonk, N.Y., USA) was used for statistical analysis. Enumeration data are presented as number of cases (%), and the comparison of rates was performed by the χ 2 test. Measurement data with skewed distribution are presented as medians (25 th percentile-P25, 75 th percentile-P75), and the Mann-Whitney U test was used for comparison between groups. P < 0.05 indicated statistical significance.

In this study, case data of a total of 302 patients with COVID-19 were collected. There were 23 cases in the RP group (19 and 4 cases of the moderate and severe types, respectively) and 279 cases in the NRP group (219 and 60 cases of the moderate and severe types, respectively). In total, 302 and 132 patients completed the mMRC, Borg, J o u r n a l P r e -p r o o f and MMT assessments on the 14 th day and at 6 months, respectively, after discharge ( Figure 1 ).

Among the 23 samples that retested positive, 12 were positive for throat swabs, 5 for nucleic acid in stool samples, 3 for nasal swabs, 2 for anal swabs, and 1 for throat swab and nucleic acid in stool samples at the same time. The average time between the positive retest result and the time of discharge was 11.61 days. The average time for nucleic acid to turn negative again after the positive retest result was 11.48 days (range, 3-37 days) ( Figure 2 ).

There were no significant differences between the two groups of patients in terms of gender, disease type, and comorbidities. The median age in the RP group was 35 (27, 48) years, which was lower than the 41 (27, 54) years in the NRP group (Table 1) . As per the detailed (table 2), the percentage of severe cases within the age group >60 is 26/64, much higher than the age group <60 years (17/238). The proportion of patients using antiviral drugs in the RP group was significantly lower than that in the NRP group (Table 1 ). In the moderate-type group, the proportion of RP patients using antiviral drugs was lower than that of NRP patients. However, in the severe-type group, there was no difference in the proportion of patients using antiviral drugs between the RP and J o u r n a l P r e -p r o o f NRP groups (Table 2 ).

This study showed that on the 14th day after discharge, the mMRC, Borg, and MMT scores of patients in the severe-type group were worse than those for patients in the moderate-type group (Table 3 ). There were no differences in the mMRC, Borg, and MMT scores between the RP and NRP groups (Table 4 ). Further stratified comparison showed no differences in the mMRC, Borg, and MMT scores between patients who had recovered from moderate-and severe-type COVID-19 in the RP group. However, the mMRC, Borg, and MMT scores for the patients who had recovered from severe-type COVID-19 were worse in the NRP group (Table 5 ).

This study conducted a 6-month follow-up of 132 discharged COVID-19 patients, including 23 and 109 in the RP and NRP groups, respectively. A comparison between the two groups showed that the proportion of patients using antiviral therapy was still lower in the RP group (Table 6 ). And there is statistically significant difference between the age group of the RP and NRP group (Table 6 ).

At 6 months after COVID-19 patients were discharged from the hospital, the mMRC, Borg, and MMT scores of patients who had recovered from severe-type COVID-19 were still worse than those for patients who had recovered from moderate-J o u r n a l P r e -p r o o f type COVID-19 (Table 7) . There were no differences in mMRC, Borg, and MMT scores between the RP and NRP groups (Table 8) . Further stratified comparison showed that no differences in the mMRC, Borg, and MMT scores between patients who had recovered from moderate-and severe-type COVID-19 in the RP group. However, the mMRC, Borg, and MMT scores for patients who had recovered from severe-type COVID-19 were worse in the NRP group (Table 9 ).

There were no differences in the mMRC, Borg, and MMT scores of the RP and NRP groups at 14 days and 6 months after discharge (Table 10) .

This study retrospectively analyzed the demographic characteristics and respiratory and physical functions of the RP and NRP groups. A total of 23 RP patients were included, accounting for 7.6% of the patients discharged during the same period.

The study results showed that the proportion of patients using antiviral drugs in the RP group was significantly lower than that in the NRP group. The lack of antiviral treatment may cause incomplete elimination of the virus. When the viral load is insufficient or below the reagent threshold, a false negative result will occur. After the patient is discharged from the hospital, due to lack of treatment, virus proliferation fluctuates, resulting in a positive nucleic acid test again [13] . In this study, patients in J o u r n a l P r e -p r o o f the RP group had recovered from mainly mild and moderate COVID-19. The amount of virus in patients with different disease courses and conditions may vary. When the SARS-CoV-2 load is low, intermittent detoxification will occur during the disease course. This will manifest as negative nucleic acid test results in the intermittent period and positive results during detoxification [14] . This may also be the cause of the positive nucleic acid retest results. Our study showed that at 6 months after the patients were discharged from the hospital, the proportion of moderate patients in the RP group was greater. Previous studies showed that the moderate patients were younger than the severe patients [15] . Our study showed that the age of the RP group was significantly lower than that of the NRP group, this may be related to the higher proportion of moderate patients in the RP group. Therefore, for patients discharged from the hospital, more attention should be paid to nucleic acid testing for young patients who are of moderate type at the initial stage of onset. However, to date, there has been no report of infections in patients exposed to patients who retested positive. A study from South Korea conducted virus culture on 285 COVID-19 cases who retested positive during rehabilitation, and all culture results were negative. This confirmed that there was no active virus in the samples from these patients [16] . Therefore, a positive nucleic acid test result for SARS-CoV-2 can only indicate that the viral nucleic acid has been detected, but not that the virus is reactivated or has caused re-infection [17] . Whether re-infection or re-activation has occurred can be further confirmed by virus whole genome determination and virus culture.

A follow-up study of 383 patients recovering from SARS indicated that 27.3% of J o u r n a l P r e -p r o o f the patients had impaired pulmonary diffusion function at hospital discharge. Forty of these patients were followed up for 1 year, at which time 20 patients (50%) still had abnormal lung function [18] . This shows that the impact of coronaviruses on the lungs is long-lasting. Most reports on abnormal respiratory function of COVID-19 patients have focused on the state of the patients at discharge [19] . Some COVID-19 patients had difficulties in breathing after activities of varying degrees at discharge. Postinflammation pulmonary fibrosis occurred in imaging, and some cases were manifested as varying degrees of usual interstitial pneumonia or non-specific interstitial pneumonia [20] . In addition, there is widespread existence of angiotensin-converting enzyme 2 receptors in the human body, and SARS-CoV-2 causes an inflammatory factor storm. Thus, apart from damage to the lungs, SARS-CoV-2 infection may cause damage to the cardiovascular and renal systems [21, 22] . We retrieved only one cohort study on the prognosis of patients with COVID-19 during the rehabilitation period. The said study suggests that abnormalities in lung diffusion function and imaging are more common in severe-type cases at half a year after discharge [23] . However, the study did not analyze the prognosis of patients who retested positive.

Our study found that the mMRC, Borg, and MMT scores of severe-type cases on the 14th day and at 6 months after discharge were worse than those of the moderatetype cases. There were no differences in respiratory and physical functions between the RP and NRP groups on the 14th day and at 6 months after discharge. In the NRP group, the respiratory and physical function scores of severe-type cases were worse. In the RP group, the respiratory and physical function scores of severe-type cases were not J o u r n a l P r e -p r o o f different from those of moderate-type cases. This may be related to the lower average age and lower proportion of severe-type cases in the RP group of this study. Therefore, we believe that the follow-up of RP patients can be the same as that of NRP patients.

When assessing the prognosis of COVID-19, attention should be paid to disease severity at the time of initial hospitalization, and focus should be on the severe-type cases. Patients with possible abnormal prognoses should be screened out through the assessment form for respiratory and physical functions. Corresponding examinations, assessments, and rehabilitation guidance should then be performed on this population.

This study clarified the populations that deserve close attention after discharge, provided a simple evaluation method, and screened out patients with abnormal recovery through simple evaluation. However, we need to further study the correlation of these abnormal scores with abnormal lung function and chest CT scans. This will require multi-center studies at a larger scale.

Overall, our findings reveal that the prognoses of RP and NRP patients are not different in terms of respiratory and physical function. Respiratory and physical function recovery of COVID-19 patients during rehabilitation had nothing to do with whether the patient retested positive; however, it is related to the patient's condition during hospitalization. It is necessary to strengthen the evaluation and observation of severe-type patients after discharge.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

This study has several limitations. First, this was a single-center retrospective study with a limited sample size and follow-up. Therefore, multi-center studies with a longer follow-up are needed to evaluate the prognosis of patients who retest positive.

Second, dynamic changes in serum specific antibody levels in RP patients can be further studied. That way the continuous protective effect of serum specific antibodies against COVID-19 and the relationship between antibody levels and positive retest results can be evaluated.

The data used to support the findings of this study are available from the corresponding author upon request. 

The authors declare that there are no conflicts of interest regarding the publication of this paper. J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f 

COVID-19) Dashboard

Fujian Medical Team Support Wuhan for COVID-19. Prevalence and outcomes of re-positive nucleic acid tests in discharged COVID-19 patients

South Korea's COVID-19 Infection Status: From the Perspective of Repositive Test Results After Viral Clearance Evidenced by Negative Test Results

Incidence, clinical course and risk factor for recurrent PCR positivity in discharged COVID-19 patients in Guangzhou, China: a prospective cohort study

Fujian Medical Team Support Wuhan for COVID-19. Prevalence and outcomes of re-positive nucleic acid tests in discharged COVID-19 patients

Assessment of patients who tested positive for COVID-19 after recovery

Clinical recurrences of COVID-19 symptoms after recovery: Viral relapse, reinfection or inflammatory rebound?

Recent Advances and Perspectivesof Nucleic Acid Detection for

Pharm Anal

COPD Assessment Test, and Clinical COPD Questionnaire for Symptoms Evaluation Within the New GOLD Staging and Mortality in COPD

The Borg dyspnoea score: a relevant clinical marker of inspiratory in amyotrophic lateral sclerosis

Global muscle strength but not grip strength predicts mortality and length of stay in a general population in a surgical intensive care unit

A perspective on re-detectable positive SARS-CoV-2 nucleic acid results in recovered COVID-19 patients

Factors associated with the duration of viral shedding in adults with COVID-19 outside of Wuhan, China: a retrospective cohort study

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

South Korea's COVID-19 Infection Status: From the Perspective of Repositive Test Results After Viral Clearance Evidenced by Negative Test Results

Positive RTPCR test results in patients recovered from COVID-19

Dynamic changes of serum SARS-coronavirus IgG, pulmonary function and radiography in patients recovering from SARS after hospital discharge

Abnormal pulmonary function in COVID-19 patients at time of hospital discharge

Postinflammatroy pulmonary fibrosis of COVID-19: the current status and perspective. Zhonghua Jie He He Hu Xi Za Zhi

Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China

Association of Cardiac Infection With SARS-CoV-2 in Confirmed COVID-19 Autopsy Cases

6-month consequences of COVID-19 in patients discharged from hospital: a cohort study

We would like to thank Editage (www.editage.com) for our writing support.