Pathologists at The Mount Sinai Hospital, at the epicenter of the COVID-19 global pandemic, have prepared one of the largest, most comprehensive analysis of autopsies of COVID-19 victims to date, revealing many complex new details about the disease.
The analysis was released on the preprint server MedRxiv.
“An essential contribution of pathology is the understanding of the biology of the disease and the range of organ damage, and for this reason, we decided to uncompromisingly perform as many autopsies as possible,” said Carlos Cordon-Cardo, MD, Ph.D., Irene Heinz Given and John LaPorte Given Professor and Chair of the Lillian and Henry M. Stratton-Hans Popper Department of Pathology, Molecular and Cell-Based Medicine, and co-author of the study.
“Post-mortem examinations (autopsies) are the gold standard for the elucidation of the underlying pathophysiology of disease. Despite a rapidly growing body of literature focusing on the clinical impact and molecular microbiology of SARS-CoV-2, autopsy studies have comparatively been few and far between,” said Mary Fowkes, MD, Ph.D., Director of the Autopsy Service, and senior author of the paper. SARS-CoV-2 is the virus that causes COVID-19.
To date, the team has performed more than 90 autopsies on deceased COVID-19 patients at The Mount Sinai Hospital.
The published work analyzes the first 67. Gross anatomical findings were combined with the clinical history and laboratory data for all 67 patients. Microscopic examinations were carried out by the team, using special stains, immunochemistry, electron microscopy, and molecular pathology assays.
COVID-19 was initially conceptualized as a primarily respiratory illness, but the Mount Sinai analysis laid out in detail that it also causes damage to the thin layer of cells that line blood vessels (endothelium), which underlies the clotting abnormalities and hypoxia observed in severely ill patients who develop multi-organ failure that leads to death in some patients.
“The physical evidence we ascertained through our postmortem analyses helps elucidate the mechanisms behind some of the clinical symptoms observed by physicians treating COVID-19 patients, including thromboembolisms and neuropsychiatric disorders,” says Clare Bryce, MBChB, Associate Professor of Pathology, Molecular and Cell Based Medicine, and, first author of the study.
The lungs in nearly all cases showed diffuse damage to the alveoli, the small sacs where oxygen and carbon dioxide are exchanged with the blood. This damage is the typical microscopic evidence of clinical acute respiratory distress syndrome (ARDS), with most cases showing fibrin (a fibrous, non-globular protein involved in the clotting of blood) and/or platelet thrombi, or clots, to varying extents.
This same pathology is found in most cases of ARDS, including those related to other coronoaviruses. However, the totality of findings in the autopsy series as a whole, with blood clots in multiple other organ systems – most notably the brain, kidney, and liver – reflects endothelial damage as an underlying process, which would also correlate with the activation of the coagulation cascade and persistent elevation of blood markers of inflammation.
The examined brains showed a surprising scarcity of inflammation, with only a few cases showing small foci of chronic inflammation. However, a surprising number of cases showed microthrombi with small and patchy evidence of tissue death caused by blockage of blood vessels in both peripheral and deep parts of the brain.
These small microinfarcts may explain some of the psychological changes seen in some COVID-19 positive patients.
This study brings new light into the pathophysiology of COVID-19, offering justification for novel treatment plans, including the anticoagulation strategies being put into effect by clinical leaders including Valentin Fuster, MD, Ph.D., Director of Mount Sinai Heart and Physician-in-Chief at The Mount Sinai Hospital.
The first confirmed case of SARS-CoV-2 infection in the United States was reported on January 20, 2020. Since that time, the virus has spread across the country, with several cities within the United States becoming epicenters of the pandemic.
As of March 31, 2020 the Louisiana Department of Health reported a total of 5,237 COVID-19 cases with 1,355 hospitalizations, and 239 COVID-19 related deaths statewide. A total of 1,834 of the 5,239 COVID-19 cases and 101 of the 239 deaths have occurred in the city of New Orleans – the highest rate of death per capita in the United States.
University Medical Center in New Orleans, built following Hurricane Katrina, is equipped with an autopsy suite meeting the modern standards recommended by the CDC for performance of autopsy on COVID-19 positive patients. We report here on the cardiopulmonary findings of the first four autopsies of a series of twelve performed on patients within the United States, with relevant implications for the treatment of severe cases.
Brief Clinical Summary:
The four decedents included male and female patients, ages 44-76. All were African American, and had a history of obesity class 2-3, and hypertension controlled by medication. Three of the patients had insulin-dependent type II diabetes, two had known chronic kidney disease (stages 2 and 3), and one was taking methotrexate.
In all cases the clinical course consisted of approximately three days of mild cough and fever to 101- 102° F., with sudden respiratory decompensation just prior to arrival in the emergency department.
Chest radiographs revealed bilateral ground-glass opacities, consistent with acute respiratory distress syndrome (ARDS) which worsened over the hospital course. The patients were intubated and brought to the ICU.
Treatment in the ICU included vancomycin, azithromycin, and aefepime for all patients, with one patient receiving dexamethasone. All of the patients tested positive for SARS-CoV-2 (by 2019 Novel Coronavirus Real Time RT-PCR).
Notable laboratory findings were the development of elevated ferritin, fibrinogen, PT, and within 24 hours of death, an increased neutrophil count with relative lymphopenia. Glucose and AST became slightly elevated above normal, and creatinine increased above baseline for all patients.
D-dimers drawn near the time of death in two patients were markedly elevated (1200-2900 ng/mL). (A detailed description of ante-mortem laboratory findings can be found in Table S1 in the Supplementary Appendix).
When the patients continued to deteriorate despite support, the families elected to withdraw care. In each case, consent for autopsy was given, and non- restricted by the next of kin. Studies performed outside of routine autopsy were determined to be exempt by the IRB at Tulane University.
Gross examination of the lungs at the time of autopsy revealed the tracheae to be of normal caliber and mildly erythematous. All of the lungs were heavy, the left ranging from 680g to 1030g , normal (583 +/-216); right ranging from 800g to 1050g, normal (663+/-239). They contained the usual lobes and fissures, with exception to one decedent with prior partial lobectomy on the right
side. The pulmonary arteries at the hilum of each of the lungs were free of thromboemboli. The bronchi revealed thick, white mucous in the lungs of one patient, and pink froth in the airways of the other three. Mild to moderate serosanguinous pericardial and pleural effusions were also present.
The parenchyma of each of the lungs was diffusely edematous and firm, consistent with the clinical diagnosis of ARDS. Notably, regions of dark-colored hemorrhage with focal demarcation could be identified throughout the peripheral parenchyma in the lungs of all but one of the decedents (Figure 1A).
On cut sections, the areas identified as hemorrhagic on the external surface showed frank hemorrhage. After fixation, the cut surfaces of the lung tissue showed alternating areas of tan-grey consolidation with patchy areas of hemorrhage that ranged from 3-6 cm in maximal diameter.
In some cases, small, firm thrombi were present in sections of the peripheral parenchyma (Figure 1C). Only in the case of the patient on immunosuppression was there focal consolidation – the remainder of the lungs showed no evidence of lobar infiltrate, abscess, or definitive gross inflammatory process.
Examination of the heart was performed in three cases, with the hearts ranging in size from 430g to 550g (normal: 365g +/-71).
The most significant gross findings were cardiomegaly, and right ventricular dilatation. In one case, massive dilatation could be seen, in which the right ventricular cavity measured 3.6cm in diameter, while the left ventricle measured 3.4cm in greatest diameter (Figure 1B).
The cut surface of the myocardium was firm, red-brown, and free of significant lesions in all cases, and the coronary arteries showed no significant stenosis or acute thrombus formation.
Pulmonary. The lungs were extensively sampled across central and peripheral regions of each lobe bilaterally. Histologic examination of the lungs showed bilateral diffuse alveolar damage with a comparatively mild-to-moderate lymphocytic infiltrate, composed of a mixture of CD4+ and CD8+ lymphocytes (Figure 2), located predominantly in the interstitial spaces and around larger bronchioles. CD4+ lymphocytes could be seen in aggregates around small vessels, some of which appeared to contain platelets and small thrombi.
In all but one case, foci of hemorrhage were present. Desquamated type 2-pneumocytes with apparent viral cytopathic effect consisting of cytomegaly, and enlarged nuclei with bright, eosinophilic nucleoli, were present within alveolar spaces (Figure 3).
The largest of these cells frequently contained an eccentric clearing of the cytoplasm with small vesicles discernible at higher power, likely representing viral inclusions. Scattered hyaline membranes could be seen, as well as fibrin deposition, highlighted by trichrome stains (Figure 2), consistent with diffuse alveolar damage.
The alveolar capillaries were notably thickened, with surrounding edema, and fibrin thrombi were present within the capillaries and small vessels. A notable finding was the presence of CD61+ megakaryocytes (Figure 2), possibly representing resident pulmonary megakaryocytes, with significant nuclear hyperchromasia and atypia.
These cells were located within alveolar capillaries, and could be seen in association with, and actively producing platelets (Figure 2). The fibrin and platelets present within small vessels also appeared to aggregate inflammatory cells, with entrapment of numerous neutrophils. Only in the case of the patient on immunosuppression was there evidence of a focal acute inflammatory infiltrate possibly consistent with secondary infection.
The neutrophils in this case, however, were partially degenerated and entrapped in fibers, possibly representing neutrophil extracellular traps (Figure 3),1,2 and were present in association with clusters of CD4+ mononuclear cells. No significant neutrophilic infiltrate was identified within airways or the interstitium to suggest secondary infection in other cases.
Cardiac. The sections of myocardium did not show any large or confluent areas of myocyte necrosis.
The cardiac histopathology was remarkable, however, for scattered individual cell myocyte necrosis in each heart examined. In rare areas, lymphocytes were adjacent to, but not surrounding degenerating myocytes.
Whether this may represent an early manifestation of a viral myocarditis is not certain, but there was no significant brisk lymphocytic inflammatory infiltrate consistent with the typical pattern of viral myocarditis.
This may be consistent with a recent paper by Chen et al. that hypothesizes that pericytes may be infected by the SARS-CoV-2 virus and cause capillary endothelial cell/microvascular dysfunction which may cause individual cell necrosis.3
There was no obvious viral cytopathic effect by light microscopy, but direct viral infection of myocytes cannot be entirely ruled out in this limited examination.
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More information: Clare Bryce et al. Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience, (2020). DOI: 10.1101/2020.05.18.20099960