What We’ve Learned About Coronavirus Pathophysiology
To tell the evolving story of what havoc the novel coronavirus wreaks in people who die from it, NIH’s Covid-19 scientific interest group lecture series recently tapped a tag team. Dr. David Kleiner and Dr. Stefania Pittaluga, both senior research physicians in NCI’s Laboratory of Pathology, presented “Covid-19 Autopsy Findings: A Joint Effort Between NYU-Winthrop Hospital and NCI—What Have We Learned So Far.”
Chief scientific officer at the Clinical Center Dr. John Gallin introduced the lecture by summarizing NIH’s covid case census.
“I wanted to make sure you’re all aware not only of the outstanding care we’re giving to patients with Covid-19—about 11 people have been treated at the Clinical Center—but also you may not be aware that currently there are 40 clinical protocols in the Intramural Research Program and 29 of them are housed in the Clinical Center, often in partnership with other institutions,” he said.
Kleiner, who heads histopathology and autopsy pathology in the Laboratory of Pathology, led off by describing several challenges unique to performing autopsies on covid patients.
First, he said, it’s hard to obtain the proper personal protective equipment and necessary negative-pressure suite where the remains of extremely contagious patients can be safely handled. Then there is overcoming the understandable reluctance of personnel to participate in covid-related autopsies as well as difficulty securing appropriate disinfection procedures afterward.
“These challenges are sufficient to prevent most hospitals from even performing these autopsies at all and no medical examiner that I know of is performing autopsies on patients with covid infection,” Kleiner said.
Additional problems include arranging transportation for patients with SARS-CoV-2 to autopsy and obtaining permission from next of kin.
“Families are not present at the bedside when the patient dies and this leads to issues trying to reach family members to give consent for autopsies.”
Finally, Kleiner noted difficulties getting quality tissue—covid patient remains are often hypoxic or obese. And there are challenges interpreting the findings—distinguishing pathology caused by the virus from pathology due to complications after infection or underlying disease.
The lecture covered 18 cases—11 men and 7 women, ranging in age from 44 to 85, with an average age of 65. Thirteen had hypertension, 8 had diabetes and 10 were obese. Other comorbidities in the group included COPD, coronary artery disease, cirrhosis, kidney transplantation and cancer. Morbid obesity evidenced by dense fatty tissue in the lower abdomen was identified at autopsy in 17 of the cases. Two of the patients in the study group technically had never been hospitalized; they died in the emergency room before actual admission.
Kleiner pointed out that the main post-mortem finding—a medical observation that has been widely reported throughout pandemic media coverage—was severely impaired lungs or diffuse alveolar damage (DAD) that is commonly associated with acute respiratory distress syndrome.
“[DAD] results in lungs that are completely solid,” he explained. “When you hold them, they are heavy…You don’t feel the air crackling underneath your fingertips as it moves through the alveoli. They’re full of fluid and cells.”
Most of the patients also showed peribronchial inflammation. Kleiner noted that once people exhibit the extent of fibrosis resulting from DAD, their condition rarely improves. Typically, he said, the patient’s lungs further deteriorate and they develop pneumonia in addition to DAD.
Investigators also observed microthrombi, or platelet clumps, which obstruct blood flow within the lungs, in a number of the patient samples.
The pathology team, seeing that thrombosis may be indicated in early Covid-19 disease progression, quickly published those findings in the Lancet’s EClinicalMedicine July edition.
In her half of the lecture, Pittaluga focused on several special studies on tissue localization of viral particles and gave an overview of some initial cytokine/chemokine evidence identified in the autopsy samples. She and her team pursued clinical residue of possible responses to SARS-CoV-2 by the immune system and other major organ systems.
Research partners at NYU performed the dissection and electron microscopy of the tissues. Samples were collected from patients’ lungs, heart, kidney, bone marrow, liver and skeletal muscle. SARS-CoV-2 particles were identified in the kidney and bone marrow, Pittaluga reported.
In addition to immunohistochemical staining, NIH scientists used another method to examine the tissues.
“In situ hybridization is a powerful technique that may allow us to characterize the spatial and temporal nature of host-viral interactions in Covid-19,” said Pittaluga, a member of NIH distinguished investigator Dr. Elaine Jaffe’s hematopathology section in NCI and an expert on in situ hybridization.
Researchers at NIH were able to detect the virus only in lung tissue samples and in just 5 out of 16 cases, with greater viral loads found in untreated patients early in the course of their infection.
NIH investigators went looking for and found evidence of IL-6 production in the patient samples, Pittaluga said. Since the pandemic’s start, scientists have wondered whether the presence of large quantities of IL-6, which the body often produces in response to inflammation, could indicate which Covid-19 patients are in the poorest condition. High levels of IL-6 in the serum has been linked with poor outcome in several large studies, she pointed out.
Pittaluga said her group found IL-6 in 13 of the 16 samples, but could not definitively correlate the amounts of IL-6 to the amounts of coronavirus detected.
“We did not [see] a correlation between the level of expression of IL-6 in the serum and the amount present in the tissues,” she explained. “Of course this is a very small study and not a prospective one, so we have the serum level at the time of hospitalization and not at the time of death.
“We will continue to investigate pro-inflammatory mediators in lung and other tissues of SARS-CoV-2 patients,” she concluded.