Daniel S. Chertow, a Principal Investigator and Head of the Emerging Pathogens Section at the National Institutes of Health (NIH) Clinical Center, known as “America’s Research Hospital,” and a team of colleagues known as the NIH COVID-19 Autopsy Consortium recently concluded and shared a study investigating unanswered questions about COVID-19. While SARS-CoV-2, the virus behind COVID-19 triggers a myriad of pulmonary and extrapulmonary (outside the lungs) symptoms as well as potentially long COVID (ongoing symptoms from the disease involving cardiovascular, pulmonary, and neurological manifestations), this research collaborative understood that, to date, while autopsy investigations of the COVID-19 deceased verify SARS-CoV-2’s ability to infect multiple organs, data from organs outside of the lungs lack evidence of both virally-mediated injury or inflammation. A key quandary driving this investigational unit: “The paradox of extra-pulmonary infection without injury or inflammation” led to direct study topics for this investigation, including inquiring as to the nature and level of burden of SARS-CoV-2 infection within versus outside of the respiratory tract. As SARS-CoV-2 infects other parts of the body (other organs associated tissue) what cell types are affected and is this part of the infection and replication process? Does SARS-CoV-2 persist even in the absence of cellular injury and inflammation in the tissues outside of the lungs? Finally, is this pathogen called SARS-CoV-2 evolving as it spreads and persists in various areas of the body? Unfortunately, they offer proof that this novel coronavirus not only widely distributes among the study subject samples—even among those who were asymptomatic or mildly ill, but also makes its way to multiple anatomic sites, including the brain for up to 230 days or 7.5 months. Yet outside of the lungs, there is little to no inflammation. The NIH-led mission, according to the study authors, offers proof that SARS-CoV-2 can persist in the human body for up to 82 months.
The group known as the COVID-19 Autopsy Consortium designed a protocol including an evaluation of tissues based on comprehensive autopsies on a diverse population of 44 persons who died due to COVID-19 up to 230 days past initial symptom onset. Their findings, yet to be peer-reviewed, were uploaded to Research Square. The study was made possible by financial and other contributions from the following:
Intramural Research Program—National Institutes of Health
Other support came from the following:
NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, Genentech, the American Association for Dental Research, and the Colgate-Palmolive Company
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The Study Methods
To facilitate a more sensitive detection and quantification of SARS-CoV-2 gene targets in all tissue samples collected, the study team employed the use of droplet digital polymerase chain reaction (ddPCR) in a bid to reveal SARS-CoV-2 cell-type specificity while validating the ddPCR findings.
This included an “in situ hybridization (ISH) (a laboratory technique) broadly across sampled tissues.” Furthermore, the team employed the use of immunohistochemistry (IHC) in the hopes of validating cell-type specificity in the region of the human brain. Scientists are not fully aligned on the regional distribution of SARS-CoV-2 in the brain; nor on the cellular tropism of the infection—that is, how cells and tissues of the various organs and tissue (e.g., the brain) support growth and replication of SARS-CoV-2.
The study protocol delineated a series of pathways. For example, using the ddPCR as the team detected COVID-19 RNA in the tissue samples, they then undertook qRT-PCR to identify and measure subgenomic (sg) RNA, a test to suggest viral replication. In six of the deceased subjects, the team used high-throughput, single-genome amplification, and sequencing, known as HT-SGS to quantify not only the variety but also the “anatomic distribution of intra-individual SARS-CoV-2 variants (e.g., Beta, Delta, Omicron).
The study team categorized the various autopsy-based case of COVID-19 by “Early” (N=17), “mid” (n=13), or “late” (n=14) by illness day (D) at the time of death measured as
Autopsy CategoryN#Illness Day time of deathEarly17≤D14Mid13D15-D30Late14≥D31, 117
The team segmented the results of this study analysis by the following categories:
Respiratory tract
Cardiovascular
Lymphoid
Gastrointestinal
Renal
Endocrine
Reproductive
Muscle
Skin
Adipose
Peripheral nerves
Brain
After performing 72 complete autopsies on 44 deceased COVID-19 patients the study team mapped and quantified the pathogen’s distribution, replication, and cell-type specificity across the decedent’s body including the brain due to acute infection for at least seven months from symptom onset.
What did they find?
The study team confirmed the widespread impact of COVID-19 on the human body. They report in their yet-to-be peer-reviewed findings published in Research Square that they detected the pathogen even in those decedents who only had asymptomatic to mild COVID-19. Moreover, and unfortunately, the NIH-led study team determined that SARS-CoV-2 will replicate in multiple lung-related and other tissues early in the viral infection.
Additionally, this novel coronavirus RNA manifests in multiple anatomic sites, including the brain for up to 230 days after the initial onset of COVID-19-associated symptoms. Noteworthy findings, as SARS-CoV-2 distributes or replicates across the body tissues, the scientists involved in the study report “a paucity of inflammation or direct viral cytopathology (study of disease at the cellular level) outside of the lungs.” The authors declare they offer proof of the pathogen’s ability to infect and persist for up to 82 months.
The study team declares this investigation produces proof that COVID-19 causes not only systemic infection but that it may persist in the individual for many months.
Lead Research/Investigator
Daniel S. Chertow, MD, MPH a Principal Investigator and Head of the Emerging Pathogens Section at the National Institutes of Health. Chertow also works with the Laboratory of Immunoregulation at the National Institute of Allergy and Infectious Diseases; Corresponding Author
Note dozens of co-investigators from not only the NIH and various affiliated institutes but also several prominent academic medical centers and health organizations.