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The number of confirmed infections with the new coronavirus (SARS-CoV-2) has exceeded 600 million
worldwide.
After the infected person recovers, the virus nucleic acid detected again in the body has always attracted much attention
.
According to the source, concentration and transmission risk of the virus, the re-detection of viral nucleic acid in people who have recovered from the new crown can be divided into three categories: viral nucleic acid re-positive, viral rebound and virus reinfection
.
Viral nucleic acid re-positive refers to the situation
in which an infected person is tested positive for viral nucleic acid again after discharge, under the premise of excluding reinfection.
Viral rebound mainly refers to the phenomenon
of viral titer rebounding after a full medication cycle observed in the clinical application of direct-acting antivirals (DAAs, such as Paxlovid and Molnupiravir).
Viral reinfection is due to loss or weakening of virus-specific immunity, and some recovered people are subject to secondary or multiple infections different from the first virus
.
In the early stage, the team of Tang Xiaoping/Li Feng of the Eighth Affiliated Hospital of Guangzhou Medical University conducted a large-sample analysis of the Delta variant infected with viral nucleic acid Fuyang, and found that although the incidence of viral nucleic acid re-positive was high, Fuyang patients had low viral load, negative virus culture, and basically non-infectious (National Science Review, Volume 9, Issue 10, October 2022, nwac141, https://doi.
org/10.
1093/nsr/nwac141）
。 However, the re-positive rate of the new variant and the effect of host immunity on the occurrence of viral nucleic acid re-positive are still unclear
.
Based on this research, the team published a journal in the Journal of Medical Virology titled "High titers of neutralizing antibodies in the blood fail to eliminate SARS-CoV-2 viral RNA in the upper respiratory.
" tract" article
.
The study compared the viral nucleic acid re-positive rates of different variants; The effects of
vaccination and neutralizing antibody (BRII-196/198) treatment on the viral nucleic acid re-positive rate after recovery were analyzed.
It was found that in patients with viral nucleic acid re-positive, despite the presence of high concentrations of virus-specific antibodies in the blood, it could not effectively remove viral nucleic acid
that had been present in the upper respiratory tract for a long time.
First, the study compared the nucleic acid re-positive of
different variants of the virus.
In 2020, the nucleic acid re-positive rate of SARS-CoV-2 infection with wild strain was 7.
27% (21/289).
However, the viral nucleic acid re-positive rate infected with Delta and Omicron variants increased significantly to 61.
41% (514/837) and 39.
53% (119/301),
respectively.
Unlike wild strains SARS-CoV-2 infected with viral nucleic acid re-positive (15/21, 71.
40%), Delta strains mostly occur in upper respiratory tract viral nucleic acid re-positive
.
It is worth noting that the peak titers of nasopharyngeal swab virus infected with Delta and Omicron variants were significantly higher than those of wild strains (Figure 1C), and high viral titers in the upper respiratory tract may be one of the influencing factors of
viral nucleic acid re-positive.
Fig.
1 Nucleic acid re-positive of different variants of virus (from J Med Virol.
2022 Oct 13.
doi: 10.
1002/jmv.
28219) In addition, can the effective immune response of the host inhibit the viral nucleic acid re-positive? This paper analyzes the effects of
vaccination and neutralizing antibody therapy on viral nucleic acid re-positive.
Vaccination is an effective part of preventing new coronary pneumonia and can reduce the rate of severe disease and mortality
.
However, the authors observed that rapidly elevated RBD-IgG antibodies were detectable in the blood of infected people with breakthrough vaccines, and levels were significantly higher than in unvaccinated infected people
.
However, even in the presence of high concentrations of virus-specific antibodies, the viral nucleic acid re-positive rate of Delta breakthrough infected patients is still high (65.
52%, 266/406, Figure 2A).
There were no significant differences in RBD-IgG levels, hospital stays, and transcriptome levels of PBMCs in the Fuyang and non-Fuyang populations (Figures 2C, D, E).
Fig.
2 Effect of vaccination on viral nucleic acid re-positive (extracted from J Med Virol.
2022 Oct 13.
doi: 10.
1002/jmv.
28219) In addition, the researchers also evaluated the effect
of neutralizing antibody (BRII-196/198) treatment on the control of Delta variant infection in unvaccinated infected patients 。 Immediately after intravenous infusion of therapeutic neutralizing antibodies, RBD-IgG levels in the patient's blood rise to high levels and can persist for up
to 100 days.
However, the viral nucleic acid re-positive rate of patients receiving treatment did not decrease (67.
27%, 37/55), and the number of hospital days was not shortened (Figures 3C and D).
Fig.
3 Effect of neutralizing antibody therapy on Delta nucleic acid re-positive (extracted from J Med Virol.
2022 Oct 13.
doi: 10.
1002/JMV.
28219) In the presence of high concentrations of virus neutralizing antibodies in the blood of infected patients, it still cannot effectively remove the long-term viral nucleic acid in the upper respiratory tract, which poses a big problem
for the clinical treatment of the new crown 。 The results of this study suggest that systemic immunity can not completely clear the upper respiratory tract virus nucleic acid, and insufficient local antiviral mucosal immunity of the upper respiratory tract may be the main reason for
the long-term retention of viral nucleic acid.
Based on the theme of the resurgence of the new coronavirus, the Tang Xiaoping/Li Feng team published a report entitled "The compartmentalized upper respiratory mucosa needs time to rally a sufficient immune" in the journal Cellular & Molecular Immunology force for SARS-CoV-2 clearance", focusing on the characteristics of the two phenomena of new coronavirus nucleic acid re-positive and virus rebound, emphasizing that the mucosal immunity of the upper respiratory tract against the new coronavirus is relatively independent and lags behind the systemic antiviral immune response, and believes that the local antiviral mucosal immune response of the upper respiratory tract needs a certain period of time to mature, and the strong antiviral mucosal immunity after maturity is the effective removal of the virus in the upper respiratory tract.
and maintain the main force
of long-term control.
The characteristics of the rebound of the new coronavirus are different
from the revival of the virus nucleic acid.
In the initial stage of viral infection, the levels of viral titers were comparable
.
Among the patients with viral nucleic acid re-positive, the viral nucleic acid load in the re-positive stage was 100,000 times lower than that in the early stage of infection.
Nucleic acid re-positive is sporadic, irregular, and unpredictable, and can occur intermittently for up to several months (Figure 4C); failure to culture live virus; Epidemiological tracking also did not reveal community transmission
.
However, in viral rebound, the viral nucleic acid load of the rebound can rise to a level comparable to the initial infection; The dynamic change law of viral nucleic acid was similar to that of the initial acute infection period (Figure 4D).
The rebound phase can culture live virus
.
Fig.
4 Dynamic changes of RNA load and antibody levels of novel coronavirus in different viral recurrent types (extracted from Cell Mol Immunol.
2022 Oct 11; 1-4.
doi: 10.
1038/S41423-022-00931-9.
) In the viral nucleic acid re-positive stage, most cases have no clinical symptoms, and their lung inflammation also shows an improvement trend
.
Only 4% of patients have occasional cough and fatigue, but no further treatment
is required.
In contrast, almost all people who rebound from the virus still develop symptoms associated with severe disease outcomes, and about one in six of them require further treatment
.
Viral rebound is more likely to occur in patients
with comorbidities, organ transplantation, and immunosuppressants.
It shows that when the virus rebounds, it should be contained
in time.
These viral resurgence phenomena have prompted researchers to conduct in-depth analysis
of their underlying mechanisms.
(1) Where do these Fuyang viruses or viral nucleic acids exist? (2) Why can't the host immune system completely clear the viral nucleic acid? (3) What measures can promote the clearance of new coronavirus nucleic acid? The virus-specific immune response in peripheral blood is effective in protecting the lungs from SARS-CoV-2 attack, but has limited
effect on clearing residual viral nucleic acid from the upper respiratory tract.
The authors propose that the frequent occurrence of new coronavirus relapse may be related to the virus characteristics of the upper and lower respiratory tractsHeterosexual mucosal reactions are separated (or delayed) related (Figure 5E).
The rich blood circulation in the lungs can provide a large number of immune cells, antibodies, cytokines and antiviral drugs, forming a strong barrier and inhibiting the replication
of the virus.
In contrast, the mucosa of the upper respiratory tract is a unique anatomical site responsible for capturing small extraneous particles and moist inhaled air
.
In order to avoid frequent inflammation, the immunity of the nasal mucosa has a high level
of tolerance to external stimuli.
When the nasopharyngeal mucosa of the upper respiratory tract fails to establish a strong antiviral immunity, the virus may persist in some specific cells and occasionally be detected, showing a nucleic acid re-positive phenomenon (Figure 5F).
Compared with antibodies and cytokines, small molecule DAAs penetrate better from the blood into the nasal mucosa and accumulate to sufficient concentrations to inhibit SARS-CoV-2 replication
.
Typically, DAAs therapy with the host's own virus-specific mucosal immune response is sufficient to clear all viruses
.
After stopping the medication, the virus-specific mucosal immunity formed in time begins to play a role and control the rebound
of the virus.
However, in immunocompromised individuals (e.
g.
, comorbidities, organ transplantation, or immunosuppressants), residual virus can be revived once DAAs are stopped prematurely when the effective upper respiratory mucosa has not yet developed immune control (Figure 4D
).
Theoretically, appropriately extending the treatment time of DAAs to the natural infection cycle of the virus will be conducive to the full maturity of virus-specific mucosal immunity, thereby avoiding viral rebound
.
Fig.
5 Comparison of upper and lower respiratory tract SARS-CoV-2 infection (extracted from Cell Mol Immunol .
2022 Oct 11; 1-4.
doi: 10.
1038/S41423-022-00931-9.
) As can be seen from the above, strengthening virus-specific mucosal immunity of the upper respiratory tract appears to be essential
to eliminate SARS-CoV-2 and avoid viral rebound.
At present, eligible people have been vaccinated with the new crown vaccine, and on this basis, vaccines that can improve the immune response of the upper respiratory tract mucosa need to be encouraged
.
At the same time, direct delivery of antiviral drugs and neutralizing antibodies to the mucosa of the upper respiratory tract should also be considered, and the course of treatment should be extended to achieve complete clearance of viral nucleic acid
.
Professor Tang Xiaoping, researcher Hu Fengyu and researcher Li Feng of the Eighth Affiliated Hospital of Guangzhou Medical University are the corresponding authors
of the article.
Li Lu, postdoctoral fellow of the Eighth Affiliated Hospital of Guangzhou Medical University, and Cui Jianping and Tang Jingyan, master's students, presented the paper "High titers of neutralizing antibodies in the blood fail to eliminate SARS-CoV-2 viral RNA in the upper respiratory tract" Co-first author
.
Zheng Xiaowen, an infectious disease physician at the Eighth Affiliated Hospital of Guangzhou Medical University, is the first author of the article "The compartmentalized upper respiratory mucosa needs time to rally a sufficient immune force for SARS-CoV-2 clearance
。 The research was supported
by the Guangzhou Laboratory and the Guangdong Provincial Department of Science and Technology.
Original link:
worldwide.
After the infected person recovers, the virus nucleic acid detected again in the body has always attracted much attention
.
According to the source, concentration and transmission risk of the virus, the re-detection of viral nucleic acid in people who have recovered from the new crown can be divided into three categories: viral nucleic acid re-positive, viral rebound and virus reinfection
.
Viral nucleic acid re-positive refers to the situation
in which an infected person is tested positive for viral nucleic acid again after discharge, under the premise of excluding reinfection.
Viral rebound mainly refers to the phenomenon
of viral titer rebounding after a full medication cycle observed in the clinical application of direct-acting antivirals (DAAs, such as Paxlovid and Molnupiravir).
Viral reinfection is due to loss or weakening of virus-specific immunity, and some recovered people are subject to secondary or multiple infections different from the first virus
.
In the early stage, the team of Tang Xiaoping/Li Feng of the Eighth Affiliated Hospital of Guangzhou Medical University conducted a large-sample analysis of the Delta variant infected with viral nucleic acid Fuyang, and found that although the incidence of viral nucleic acid re-positive was high, Fuyang patients had low viral load, negative virus culture, and basically non-infectious (National Science Review, Volume 9, Issue 10, October 2022, nwac141, https://doi.
org/10.
1093/nsr/nwac141）
。 However, the re-positive rate of the new variant and the effect of host immunity on the occurrence of viral nucleic acid re-positive are still unclear
.
Based on this research, the team published a journal in the Journal of Medical Virology titled "High titers of neutralizing antibodies in the blood fail to eliminate SARS-CoV-2 viral RNA in the upper respiratory.
" tract" article
.
The study compared the viral nucleic acid re-positive rates of different variants; The effects of
vaccination and neutralizing antibody (BRII-196/198) treatment on the viral nucleic acid re-positive rate after recovery were analyzed.
It was found that in patients with viral nucleic acid re-positive, despite the presence of high concentrations of virus-specific antibodies in the blood, it could not effectively remove viral nucleic acid
that had been present in the upper respiratory tract for a long time.
First, the study compared the nucleic acid re-positive of
different variants of the virus.
In 2020, the nucleic acid re-positive rate of SARS-CoV-2 infection with wild strain was 7.
27% (21/289).
However, the viral nucleic acid re-positive rate infected with Delta and Omicron variants increased significantly to 61.
41% (514/837) and 39.
53% (119/301),
respectively.
Unlike wild strains SARS-CoV-2 infected with viral nucleic acid re-positive (15/21, 71.
40%), Delta strains mostly occur in upper respiratory tract viral nucleic acid re-positive
.
It is worth noting that the peak titers of nasopharyngeal swab virus infected with Delta and Omicron variants were significantly higher than those of wild strains (Figure 1C), and high viral titers in the upper respiratory tract may be one of the influencing factors of
viral nucleic acid re-positive.
Fig.
1 Nucleic acid re-positive of different variants of virus (from J Med Virol.
2022 Oct 13.
doi: 10.
1002/jmv.
28219) In addition, can the effective immune response of the host inhibit the viral nucleic acid re-positive? This paper analyzes the effects of
vaccination and neutralizing antibody therapy on viral nucleic acid re-positive.
Vaccination is an effective part of preventing new coronary pneumonia and can reduce the rate of severe disease and mortality
.
However, the authors observed that rapidly elevated RBD-IgG antibodies were detectable in the blood of infected people with breakthrough vaccines, and levels were significantly higher than in unvaccinated infected people
.
However, even in the presence of high concentrations of virus-specific antibodies, the viral nucleic acid re-positive rate of Delta breakthrough infected patients is still high (65.
52%, 266/406, Figure 2A).
There were no significant differences in RBD-IgG levels, hospital stays, and transcriptome levels of PBMCs in the Fuyang and non-Fuyang populations (Figures 2C, D, E).
Fig.
2 Effect of vaccination on viral nucleic acid re-positive (extracted from J Med Virol.
2022 Oct 13.
doi: 10.
1002/jmv.
28219) In addition, the researchers also evaluated the effect
of neutralizing antibody (BRII-196/198) treatment on the control of Delta variant infection in unvaccinated infected patients 。 Immediately after intravenous infusion of therapeutic neutralizing antibodies, RBD-IgG levels in the patient's blood rise to high levels and can persist for up
to 100 days.
However, the viral nucleic acid re-positive rate of patients receiving treatment did not decrease (67.
27%, 37/55), and the number of hospital days was not shortened (Figures 3C and D).
Fig.
3 Effect of neutralizing antibody therapy on Delta nucleic acid re-positive (extracted from J Med Virol.
2022 Oct 13.
doi: 10.
1002/JMV.
28219) In the presence of high concentrations of virus neutralizing antibodies in the blood of infected patients, it still cannot effectively remove the long-term viral nucleic acid in the upper respiratory tract, which poses a big problem
for the clinical treatment of the new crown 。 The results of this study suggest that systemic immunity can not completely clear the upper respiratory tract virus nucleic acid, and insufficient local antiviral mucosal immunity of the upper respiratory tract may be the main reason for
the long-term retention of viral nucleic acid.
Based on the theme of the resurgence of the new coronavirus, the Tang Xiaoping/Li Feng team published a report entitled "The compartmentalized upper respiratory mucosa needs time to rally a sufficient immune" in the journal Cellular & Molecular Immunology force for SARS-CoV-2 clearance", focusing on the characteristics of the two phenomena of new coronavirus nucleic acid re-positive and virus rebound, emphasizing that the mucosal immunity of the upper respiratory tract against the new coronavirus is relatively independent and lags behind the systemic antiviral immune response, and believes that the local antiviral mucosal immune response of the upper respiratory tract needs a certain period of time to mature, and the strong antiviral mucosal immunity after maturity is the effective removal of the virus in the upper respiratory tract.
and maintain the main force
of long-term control.
The characteristics of the rebound of the new coronavirus are different
from the revival of the virus nucleic acid.
In the initial stage of viral infection, the levels of viral titers were comparable
.
Among the patients with viral nucleic acid re-positive, the viral nucleic acid load in the re-positive stage was 100,000 times lower than that in the early stage of infection.
Nucleic acid re-positive is sporadic, irregular, and unpredictable, and can occur intermittently for up to several months (Figure 4C); failure to culture live virus; Epidemiological tracking also did not reveal community transmission
.
However, in viral rebound, the viral nucleic acid load of the rebound can rise to a level comparable to the initial infection; The dynamic change law of viral nucleic acid was similar to that of the initial acute infection period (Figure 4D).
The rebound phase can culture live virus
.
Fig.
4 Dynamic changes of RNA load and antibody levels of novel coronavirus in different viral recurrent types (extracted from Cell Mol Immunol.
2022 Oct 11; 1-4.
doi: 10.
1038/S41423-022-00931-9.
) In the viral nucleic acid re-positive stage, most cases have no clinical symptoms, and their lung inflammation also shows an improvement trend
.
Only 4% of patients have occasional cough and fatigue, but no further treatment
is required.
In contrast, almost all people who rebound from the virus still develop symptoms associated with severe disease outcomes, and about one in six of them require further treatment
.
Viral rebound is more likely to occur in patients
with comorbidities, organ transplantation, and immunosuppressants.
It shows that when the virus rebounds, it should be contained
in time.
These viral resurgence phenomena have prompted researchers to conduct in-depth analysis
of their underlying mechanisms.
(1) Where do these Fuyang viruses or viral nucleic acids exist? (2) Why can't the host immune system completely clear the viral nucleic acid? (3) What measures can promote the clearance of new coronavirus nucleic acid? The virus-specific immune response in peripheral blood is effective in protecting the lungs from SARS-CoV-2 attack, but has limited
effect on clearing residual viral nucleic acid from the upper respiratory tract.
The authors propose that the frequent occurrence of new coronavirus relapse may be related to the virus characteristics of the upper and lower respiratory tractsHeterosexual mucosal reactions are separated (or delayed) related (Figure 5E).
The rich blood circulation in the lungs can provide a large number of immune cells, antibodies, cytokines and antiviral drugs, forming a strong barrier and inhibiting the replication
of the virus.
In contrast, the mucosa of the upper respiratory tract is a unique anatomical site responsible for capturing small extraneous particles and moist inhaled air
.
In order to avoid frequent inflammation, the immunity of the nasal mucosa has a high level
of tolerance to external stimuli.
When the nasopharyngeal mucosa of the upper respiratory tract fails to establish a strong antiviral immunity, the virus may persist in some specific cells and occasionally be detected, showing a nucleic acid re-positive phenomenon (Figure 5F).
Compared with antibodies and cytokines, small molecule DAAs penetrate better from the blood into the nasal mucosa and accumulate to sufficient concentrations to inhibit SARS-CoV-2 replication
.
Typically, DAAs therapy with the host's own virus-specific mucosal immune response is sufficient to clear all viruses
.
After stopping the medication, the virus-specific mucosal immunity formed in time begins to play a role and control the rebound
of the virus.
However, in immunocompromised individuals (e.
g.
, comorbidities, organ transplantation, or immunosuppressants), residual virus can be revived once DAAs are stopped prematurely when the effective upper respiratory mucosa has not yet developed immune control (Figure 4D
).
Theoretically, appropriately extending the treatment time of DAAs to the natural infection cycle of the virus will be conducive to the full maturity of virus-specific mucosal immunity, thereby avoiding viral rebound
.
Fig.
5 Comparison of upper and lower respiratory tract SARS-CoV-2 infection (extracted from Cell Mol Immunol .
2022 Oct 11; 1-4.
doi: 10.
1038/S41423-022-00931-9.
) As can be seen from the above, strengthening virus-specific mucosal immunity of the upper respiratory tract appears to be essential
to eliminate SARS-CoV-2 and avoid viral rebound.
At present, eligible people have been vaccinated with the new crown vaccine, and on this basis, vaccines that can improve the immune response of the upper respiratory tract mucosa need to be encouraged
.
At the same time, direct delivery of antiviral drugs and neutralizing antibodies to the mucosa of the upper respiratory tract should also be considered, and the course of treatment should be extended to achieve complete clearance of viral nucleic acid
.
Professor Tang Xiaoping, researcher Hu Fengyu and researcher Li Feng of the Eighth Affiliated Hospital of Guangzhou Medical University are the corresponding authors
of the article.
Li Lu, postdoctoral fellow of the Eighth Affiliated Hospital of Guangzhou Medical University, and Cui Jianping and Tang Jingyan, master's students, presented the paper "High titers of neutralizing antibodies in the blood fail to eliminate SARS-CoV-2 viral RNA in the upper respiratory tract" Co-first author
.
Zheng Xiaowen, an infectious disease physician at the Eighth Affiliated Hospital of Guangzhou Medical University, is the first author of the article "The compartmentalized upper respiratory mucosa needs time to rally a sufficient immune force for SARS-CoV-2 clearance
。 The research was supported
by the Guangzhou Laboratory and the Guangdong Provincial Department of Science and Technology.
Original link:
- J Med Virol.
https://onlinelibrary.
wiley.
com/doi/10.
1002/jmv.
28219 - Cell Mol Immunol.
style="margin-right: auto;margin-left: auto;outline: 0px;width: 30px;display: inline-block;">—END—The content is iNature
