Summary Coronavirus disease 2019 (COVID-19) is known to cause multiple organ dysfunction during acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and some patients experience prolonged symptoms, termed post-acute sequelae of SARS-CoV. -2. However, the infection burden outside the respiratory tract and the time of viral clearance are not well characterized, particularly in the brain. Here we performed full autopsies on 44 patients who died with COVID-19, with extensive central nervous system sampling in 11 of these patients, to map and quantify the distribution, replication, and cell type specificity of SARS-CoV-2 across of the human body, including the brain, from acute infection to more than seven months after the onset of symptoms. We show that SARS-CoV-2 is widely distributed, predominantly among patients who died with severe COVID-19, and that virus replication is present in multiple respiratory and non-respiratory tissues, including the brain, early in infection. Additionally, we detected persistent SARS-CoV-2 RNA in multiple anatomical sites, including throughout the brain, up to 230 days after symptom onset in one case. Despite the wide distribution of SARS-CoV-2 RNA throughout the body, we observed little evidence of inflammation or direct viral cytopathology outside the respiratory tract. Our data indicate that, in some patients, SARS-CoV-2 can cause systemic infection and persist in the body for months. |
Figure: Heat map shows the highest mean quantification of SARS-CoV-2 RNA (N) via ddPCR present in autopsy tissues from 11 patients who died with COVID-19 and underwent brain and brain sampling. whole body. Patients are aligned from shortest to longest duration of illness (DOI) before death, listed at the bottom of the figure, and grouped into early (≤14 days), middle (15–30 days), and late duration. (≥31 days) of illness. disease. The tissues are organized by tissue groups starting with the respiratory tissues at the top and the CNS at the bottom. Viral RNA levels range from 0.002 to 500,000 N gene copies per nanogram of RNA input, represented as a gradient from dark blue at the lowest level to dark red at the highest level. Tissues that also tested positive for subgenomic RNA (sgRNA+) via real-time RT-qPCR are shaded with black vertical bars. oh, another; PNS, peripheral nervous system; SM, skeletal muscle.
Discussion
Here we provide, to our knowledge, the most comprehensive analysis to date of cellular tropism, quantification, and persistence of SARS-CoV-2 throughout the human body, including the brain. We show that SARS-CoV-2 disseminates early in infection in some patients, with a significantly higher viral load in respiratory than non-respiratory tissues. We demonstrated virus replication at multiple non-respiratory sites during the first two weeks after symptom onset and detected subgenomic RNA in at least one tissue in 14 of 27 cases beyond D14, indicating that viral replication may occur in non-respiratory tissues for several months.
While others have proposed that the detection of SARS-CoV-2 in non-respiratory tissues could be due to residual blood within the tissues or cross-contamination of the lungs during tissue collection, our data indicate otherwise . Specifically, only 12 of our cases had detectable SARS-CoV-2 RNA in a perimortem plasma sample , only 2 cases had SARS-CoV-2 subgenomic RNA detected in plasma, and negligible, if any, RNA was detected. , in stored peripheral blood mononuclear samples from representative cases.
Our results show that, although the highest load of SARS-CoV-2 is found in respiratory tissues, the virus can spread throughout the body.
Comments
In the most comprehensive autopsy tissue study to date, researchers found traces of the SARS-CoV-2 virus throughout the body, from the brain and heart to the eyes. The findings indicate that the virus can cause persistent infections in many parts of the body, months after an initial illness, and support the case for more research into antiviral drugs as a possible treatment for long COVID.
It’s been three years since the emergence of the new coronavirus SARS-CoV-2, and scientists are still working to understand exactly how this virus interacts with the human body. An ongoing mystery is how widely SARS-CoV-2 infects different organs, beyond the respiratory system.
Several studies, for example, have reached different conclusions about whether the neurological effects of COVID are due to the virus directly infecting brain tissue. More recently, a team at Stanford School of Medicine closely analyzed postmortem brain tissue samples from several COVID patients and could not find any trace of viral RNA.
That research, on the other hand, detected significant inflammatory biomarkers, leading to the hypothesis that short- and long-term neurological symptoms could be due to persistent activity of the immune system. This hypothesis has been supported by subsequent autopsy studies that found neuroinflammation in COVID patients.
This new research, led by scientists at the National Institutes of Health in partnership with the University of Maryland, performed autopsies on 44 patients who died from or with COVID-19. The study focused on collecting tissue shortly after death from a variety of different locations in the body.
"Our focus on short postmortem intervals , a comprehensive standardized approach to tissue collection, brain dissection before fixation, subsequent tissue preservation in RNA, and flash freezing of fresh tissue allowed us to detect and quantify levels of SARS-CoV-2 RNA with high sensitivity using ddPCR [polymerase chain reaction] and ISH [ in situ hybridization ], as well as isolating viruses in cell cultures from multiple non-respiratory tissues, including the brain, which are notable differences in compared to other studies," the researchers write in the new study.
The findings revealed that SARS-CoV-2 RNA could be detected in 84 different locations in the body. The highest load of viral RNA was found in the respiratory tract and lung tissue; However, the virus was also detected in the brain, intestine, heart, kidneys, eyes, adrenal glands, and lymph nodes.
The tissue analyzed came from patients at several different stages of infection, from the earliest stages (less than 14 days after symptom onset) to nine months after acute illness. As expected, the highest viral load was found in those patients in the early stages of an infection, but 14 of 27 patients beyond two weeks still showed the presence of the virus in at least one non-respiratory tissue analyzed.
While the study’s findings are certainly surprising, what they mean is still unclear. All patients included in the research were elderly, unvaccinated, autopsied during the first year of the pandemic and suffered from many comorbidities. Therefore, it is unknown whether new virus variants spread through similarly vaccinated younger people.
However, what this study clearly illustrates is the potential for SARS-CoV-2 to spread through tissues throughout the body, including the brain. And researchers are now wondering if this could play a role in patients experiencing long COVID.
The next step for the research team is to collect post-mortem tissue from deceased long COVID patients to understand whether the virus can be found months after an acute illness. This is part of a larger project called RECOVER (COVID Research to Improve Recovery).
Alongside the tissue pathology work, the RECOVER project is conducting a clinical trial to test the effectiveness of the antiviral Paxlovid in treating long-COVID patients. The hypothesis is that if long COVID symptoms are caused by persistent SARS-CoV-2 infections in certain parts of the body, then trying to eliminate the virus with antivirals should improve those symptoms.
Paxlovid’s long COVID trial is scheduled to begin this year and the RECOVER project is scheduled to last up to four years.
Source: Large COVID autopsy study finds SARS-CoV-2 all over the human body. By Rich Haridy. New Atlas .
