There are more and more reports of “fuyang” after discharge from hospital, but the clinical characteristics, significance and potential causes of Fuyang patients are still elusive. The latest clinical research shows that “Fuyang” of the new crown patients and “no fuyang” of the new crown patients, relatively small age, before the disease is often lighter, faster improvement. In addition, although “Fuyang” patients may carry the new coronavirus, but in this study, “Fuyang” patients in close contact with no one infected.
The above research from Shenzhen Third People’s Hospital, the National Center for Clinical Medicine for Infectious Diseases, Tsinghua University, The Massachusetts Institute of Technology, the Southern University of Science and Technology and other units, the communication author is the third people’s hospital in Shenzhen, Liu Lei, shenzhen Third People’s Hospital Director Professor Zhang Zheng. The paper is entitled “Clinical naturals of the recovered COVID-19 patients with re-detectable positive RNA test”, It was recently published on the medical preprint website medRxiv.
A total of 262 COVID-19 patients were selected from January 23 to February 25, 2020, and grouped to analyze their clinical parameters. Patients with Fuyang (RP) and non-Fuyang (NRP) were grouped according to the severity of the disease during hospitalization and analyzed the clinical characteristics of readmission. The researchers used a high sensitivity test to detect levels of neo-coronavirus RNA and plasma antibodies.
As of March 10, 2020, the researchers found 38 patients (14.5%) of the 262 new coronapatients who had been followed up for at least 14 days. Compared with non-fuyang patients, fuyang patients are characterized by: younger age, a higher proportion of adolescents under 14 years of age, mild and moderate disease. It is worth noting that there were no patients with reyang during hospitalization with severe symptoms.
A review found that patients with complexsunic disease showed fewer symptoms, more long-lasting CT imaging remission and earlier RNA transfemininity during hospitalization than non-fuyang patients, but plasma antibody levels were similar to those in non-complexyang patients. After readmission, these patients showed no significant clinical symptoms or disease progression, normal CT imaging and normal inflammatory cytokine levels. All 21 close contacts in Fuyang patients tested negative for nucleic acid and did not report suspected clinical symptoms.
Notably, the team then re-used ultra-sensitive methods in 24 RNA-negative samples detected in commercial kits , from 15 patients with fuyang, and found 18 RNA positives. They believe this suggests that there may be a viral carrier status in the current new coronary rehabilitation patients.
The results of the study showed that young, mild COVID-19 patients appeared to be more likely to develop resuscitation after discharge. In addition, there were no significant clinical symptoms and disease progression after re-admission to the hospital. More sensitive RNA detection methods are needed to monitor these patients during follow-up. The authors believe that the results of this study provide empirical information and evidence for the effective management of the recovery period of COVID-19 patients.
At a marching news conference, Zhong Nanshan also talked about whether close contacts with Fuyang patients would be infected. He also said, “So far, the information I have gathered, as if not seen, we have to see the facts.” “
Attached: Research Methods
Typically, COVID-19 is less severe and fatal than SARS, but some patients, especially those with comorbidities, are prone to more severe symptoms and require urgent medical intervention. Many literatures review the clinical characteristics of patients with neo-coronavirus infection. Recently, more and more COVID-19 patients have been discharged from hospital and received regular follow-up and observation. In some recovering patients, the new coronavirus RNA test is reported to re-test positive (RP). The treatment of Patients in Fuyang has attracted wide attention.
However, the number of patients reported in the literature is very small, follow-up time is short. In addition, the lack of clinical characteristics, the potential impact and significance of patients with fuyang is still unknown, which makes it difficult to provide empirical information and evidence support for the treatment of COVID-19 patients during recovery.
The study retrospectively analyzed the clinical characteristics of 38 patients with complex sun and 224 non-reyang (NRP) patients in COVID-19 rehabilitation discharge. The study found that patients with fuyang were characterized by younger age and a milder condition. They had mild symptoms, more continuous remission of CT imaging during hospitalization, earlier RNA-negative conversion, but similar plasma antibody levels. When the patient was admitted to hospital again, there was no significant progressocity or infectiousness. Ultra-sensitive detection methods identify new coronavirus RNA molecules from most samples tested negative with commercial kits, indicating the presence of carriers of the virus in recovered COVID-19 patients. These findings provide key information for effective treatment in patients with COVID-19 during rehabilitation.
Research design and participants
The study included 262 confirmed COVID-19 patients discharged from the Third People’s Hospital of Shenzhen from 23 January 2020 to 25 February 2020. All discharged COVID-19 patients continued to be isolated and observed for 14 days, once a week, and timely detection of neo-coronavirus RNA. Among them, Fuyang patients were again sent to the hospital for further medical observation, and close follow-up. The remaining recovered non-fuyang patients were followed closely outside the hospital.
According to the new diagnostic guidelines for coronavirus infection issued by the National Health and Reform Commission (6th edition), all the first cases of COVID-19 were diagnosed through a positive respiratory RT-PCR test. The discharge criteria for recovering patients include: a return to normal temperature for more than 3 days, a marked improvement in respiratory symptoms, a significant absorption of lung lesions from chest CT imaging, and a continuous 2month negative RNA test results separated from each other for at least 24 hours. Patients with fuyang have been confirmed by digestive (anal swab) and respiratory positive RT-PCR tests. From February 22, 2020, shenzhen Third People’s Hospital on the swab negative assessment to supplement the discharge standard.
The study reviewed the medical records of 262 patients with new coronary rehabilitation, including 38 patients with complex sun. The study collected, summarized and analyzed patient epidemiology, demographics, clinical, and laboratory data.
Based on the first chest CT imaging after admission, the researchers classified the degree of inflammation in the lungs into mild, moderate, and severe, based on lesions involving monolith, double lung, polyleaves, and double lung whole leaves. The remission of the lesions was assessed based on chest CT within 7 days of admission. An increase in lesions indicates temporary deterioration, while a steady or absorption or decrease in the lesions indicates sustained remission.
During hospitalization, the researchers collected patient’s nasopharynx and samples and sent cases of viral transport to the laboratory for qRT-PCR (reverse transcription polymerase chain reaction) analysis. The researchers extracted nucleic acids from samples using the QIAamp RNA Virus Kit (Qiagen, Heiden, Germany) and quantified RT-PCR (GeneoDX) using commercial kits approved by the State Food and Drug Administration (CFDA) for new coronavirus testing Co., Ltd., Shanghai, China) or Sherlock kit provided by MIT’s Zhang Feng Lab. The researchers also performed ELISA assays on IgG and IgM antibodies of the patient’s new coronavirus. In statistical analysis, the researchers used SPSS for statistical analysis. All statistical tests are bidirectional and significant differences are taken into account at p.lt;0.05. Evaluate continuous variables using median and quartile spacing (IQR) values. The card-side test or Fisher precision test is used to compare the proportions of categorical variables.
Demographic, epidemiological and clinical characteristics of patients
Between January 23, 2020 and February 25, 2020, 262 patients were discharged from the hospital, and the researchers followed them for at least 14 days. Of these, 11.4% (30), 81.0% (212) and 7.6 % (20) were mild, moderate and severe, respectively. As of 10 March, 14.5 per cent of recovered patients (38 people) had sun-drenuated during the follow-up period. There are no severely ill people with re-yang.
The results showed that the vast majority of patients with fuyang (97.4%, 37 people) were under 60 years of age. Among them, patients under 14 years of age were more common than those between the ages of 14 and 60 (35.0% vs. 16.0%, p.lt;0.01). In addition, 36.7% (11/38) of patients with fuyang were found to have mild symptoms. This percentage is significantly higher than in non-sunpatients (12.7%, 19/204, p?lt;0.01). There were no significant differences in gender distribution.
It is worth noting that the initial symptoms of mild reyang patients are mild compared to mild non-reyang patients (p?lt;0.01). At the same time, 45.5% of mildly reyang patients showed only upper respiratory symptoms at first admission, while mild non-reyang patients usually showed lower respiratory symptoms at first admission. There was no difference in the degree of lesions in the first chest CT imaging in moderate stage patients with and non-fuyang. However, compared to non-fuyang patients, the study found that the incidence of fuyang (85.2%) was particularly associated with continuous remission of chest CT imaging. Among non-fuyang patients, 36.2% showed temporary deterioration during their first hospitalization.
There was no significant difference in the use of steroids and antiviral therapy during the first hospitalization of patients with and non-fuyang. In addition, compared with non-Fuyang patients, Fuyang patients in Hubei Province travel and life history is no difference.
RNA dynamic differences between patients with and from non-fuyang patients
There was no difference in the number of days used in patients with and non-reyang patients since the onset of disease and hospitalization to the last RNA trans-yin. Importantly, 63.6% of mild lysing patients developed RNA toyin within 2-3 weeks of onset, and 22.2% of patients with moderate reyang within 1-2 weeks of the onset of the disease. In contrast, after onset, more non-reactive patients showed RNA transfeminineence after 3 weeks, both mild and moderate. These data suggest that patients with fuyang are characterized by relatively fast RNA negatives in early stages, rather than in patients with complexsund diseases that take a relatively long time to remove the virus.
CHANGES IN COVID-19 RECOVERY OF SERUM ANTI-NEW CORONAVIRUS IGG AND IGM ANTIBODIES IN PATIENTS
To assess the effect of serum-specific antibody levels on the occurrence of fuyang, the team analyzed differences in the levels of neo-coronavirus IgG antibodies and IgM antibodies when patients with complex and non-fuyang were discharged from the hospital. More than half of patients with reyang and non-sunication showed moderate levels of IgG and IgM antibody levels, regardless of the severity of the disease. However, there was no difference in antibody levels between the two groups. The researchers also assessed the dynamics of IgG and IgM antibody levels when patients were discharged and readmitted to hospital. IgG and IgM levels remained stable for 14 days in these patients.
Negative results of supplemental swabs test upon discharge from hospital did not reduce the recurrence of COVID-19 patients
The researchers compared the cases of re-yang before And After February 22 ndein, adding swab tests to the patient’s discharge criteria. The results showed no statistical difference in the incidence of reyang patients before 22 February and after 22 February (14.5% vs. 14.3%, p . . . 0.77). These data show that supplemental swabs do not reduce the risk of re-yang in patients.
There are no obvious clinical symptoms and disease progression in patients with fuyang
All 38 patients with Fuyang were readmitted to hospital for further medical observation. Analysis showed that none of these patients had a fever. A small number of patients reported mild coughing and chest tightness, which did not worsen.
All mild lysing patients subsequently recovered, with 37.0% of the patients in moderate patients with normal chest CT imaging with no signs of inflammation, and 63.0% (n s 17) of chest CT imaging showing signs of inflammation. All patients with complexsunion were admitted to the hospital with lymphocytes counted, and plasma IL-6 and CRP levels were within the normal range. After admission, only one patient received short-term alpha interferon inhalation treatment, and four patients received low-flow oxygen inhalation and traditional Chinese medicine treatment.
In addition, since all recovering patients in the study needed to be isolated or strengthened at home, only 21 close contacts were produced. As of March 10, 2020, all 21 close contacts of the new coronavirus RNA were tested negative and no suspected clinical symptoms were found.
Ultra-sensitive detection methods may improve patient detection
To study whether low-sensitivity commercial RNA testing kits were the cause of false negatives, the team used a highly sensitive laboratory method to test various types of samples from these and non-reyang patients. Five to seven days after readmission, the researchers took 24 samples from 15 patients with fuyang, using hypersensitivity to detect 75 percent of spike genes and 41.6 percent of ORF-based positives, while commercial test kits tested only 12.5 percent positive N-positive and 4.2 percent RF-positive. The use of hypersensitivity kits confirms that 8 of the 15 patients with complex sun are POSITIVE for RNA, while only 1 person can be confirmed using a commercial kit. In contrast, eight samples of non-fuyang patients were negative in both methods. These data suggest that hypersensitivity may improve RNA positive testing in samples of patients with fuyang, excluding false negatives.
Previous studies have shown the presence of patients with complex sun, but their clinical characteristics are not yet clear. The study retrospectively analyzed clinical and follow-up data for the cohorts of reyang and non-fuyang patients during the same discharge.
As of March 10, 2020, there were 38 cases of Fuyang patients, accounting for 14.5% of the follow-up patients discharged during the same period. These patients showed several important characteristics, including younger age and only mild or moderate symptoms during hospitalization, as previously reported. Mild reyang patients are usually less than 14 years old, and moderate reyang patients are less than 60 years old. In contrast, severe new crown patients were not found to be sun-positive after discharge.
In addition, more patients with complexsunos showed smaller symptoms during hospitalization, and had fewer comorbidities and fevers, with the above respiratory symptoms being the most common. Compared with non-fuyang patients, the patients showed more relief in CT imaging. These data show that patients with fuyang are characterized by youthful and mild symptoms during hospitalization.
Virus load is generally thought to be related to disease outcomes. This study shows that RNA transfemininity usually occurs within 2-3 weeks of the onset of moderate reyang, while in patients with moderate non-reyang for more than 3 weeks. Significant reduction in RNA transgenic time may affect the persistence of high levels of adaptive immunity. Our recent studies have shown that higher antibody titer in plasma in patients with COVID-19 is independently associated with disease severity. However, the levels of IgG and IgM antibodies in the plasma of patients with complex and non-fuyang were similar. Future studies should investigate the host’s immune responses, which can usually determine the patient’s clinical outcomes.
When Fuyang patients were admitted to hospital again, the team also took a comprehensive record of their clinical symptoms. In these patients, no clinical evidence of significant disease progression or recurrence was found, including CT and laboratory examinations. These patients do not need to use antibiotics, steroids, antivirals and continuous oxygen supplementation, and the inflammatory response is significantly reduced. These data show that even if they are tested positive, the disease in the patient of Fuyang does not develop into a more serious state.
What’s more, these patients were discharged from the hospital without causing new infections. Long-term follow-up to close contacts with patients with Fuyang patients will ensure an assessment of the possible risk of Fuyang.
The potential mechanism for the occurrence of Fuyang is not clear. Many experts believe that the possible causes are related to virology, immunology and sampling methodology. In virology, false negatives, viral residues, intermittent virus release and viral distribution are often considered major factors. Their data support the view that false negatives using commercial kits may partly explain fuyang, as the kit’s positive rate is only 30%-50%. Using a commercial kit to re-test 24 samples of fuyang patients in the next few days of admission, the N gene and the ORF1b gene were both negative RNA, possibly because of the relatively high detection limit (500 copies/ml). However, using the Sherlock kit at the more sensitive Zhang Feng laboratory, which tested at a lower test limit of 100 copies/ml, tested 75 percent of the samples positive for the S gene and 41.6 percent positive for the ORF gene. This led to half of the positive subjects in the complex were found to be negative during their stay in hospital for testing using commercial kits. In contrast, none of the eight samples used by Sherlock or commercial kits were positive in eight samples of non-complexyang patients. Therefore, future studies should simultaneously increase the sensitivity and specificity of the test kit to accurately identify clinical samples.
Another virological factor is the long-term residual virus in the intestines and other tissues, similar to SARS. A recent study showed that neo-viral nucleic acids can be preserved in the digestive tract and feces for nearly 50 days. Therefore, it is necessary to extend the testing time after the discharge of COVID-19 patients. However, the results of such studies show that adding swab RNA testing as a discharge standard negative does not significantly reduce the occurrence of reyang patients. Therefore, Fuyang may also be related to other factors, but the researchers cannot rule out sampling factors, including differential sampling and operation methods, sample quality, and the technical staff’s professional level. They also cannot rule out immune factors including low mucosal immune responses (e.g. low IgA levels). These factors may pose some uncertain risks that can lead to the occurrence of sun-dwelling. Future studies should reduce the occurrence of sun-dwelling by using ultra-specific ultra-sensitive detection kits and simultaneously detecting multiple samples with more immune markers.
The study has several limitations. First, this study is a single-center retrospective study that takes a short follow-up period and requires more clinical observation to assess the potential risk of new coronary recurrence and infection. Second, the dynamics of RNA of the new coronavirus in patients with the sun need to be monitored and evaluated in PATIENTs with COVID-19. Third, other studies should measure the dynamic changes in serum-specific antibody levels in patients with complex sun and evaluate the continuous protective effect of serum-specific antibodies on COVID-19 patients. Finally, there should be a distinction between patients with fuyang and other patients, for which two different prevention and control strategies will be adopted.
Overall, the authors say the study reveals the clinical characteristics of patients who did not exhibit recurrence of clinical symptoms and abnormal laboratory examination. However, ultra-sensitive detection methods indicate the presence of RNA from the new coronavirus in samples of patients tested negative for the use of a market-able kit. Therefore, it is necessary to make more accurate quantitative assessments of the RNA dynamics of viruses and other detoxification standards to help doctors make decisions. This study provides valuable empirical information and clinical evidence support for the effective management of patients with COVID-19 during rehabilitation. Further research should assess the potential clinical significance and risk of transmission in patients with fuyang.
(Journalist He Liping)
(Original title: Latest New Coronary Fuyang Study: Relatively Young but Not Infected, or Need to Improve Kit)