autopsies – Page 2 – American ME and CFS Society

Long COVID could become a widespread post-pandemic disease? A debate on the organs most affected

Abstract:

Long COVID is an emerging problem in the current health care scenario. It is a syndrome with common symptoms of shortness of breath, fatigue, cognitive dysfunction, and other conditions that have a high impact on daily life. They are fluctuating or relapsing states that occur in patients with a history of SARS-CoV-2 infection for at least 2 months. They are usually conditions that at 3 months after onset cannot be explained by an alternative diagnosis. Currently very little is known about this syndrome.

A thorough review of the literature highlights that the cause is attributable to deposits of tau protein. Massive phosphorylation of tau protein in response to SARS-CoV-2 infection occurred in brain samples from autopsies of people previously affected with COVID-19. The neurological disorders resulting from this clinical condition are termed tauopathies and can give different pathological symptoms depending on the involved anatomical region of the brain.

Peripheral small-fiber neuropathies are also evident among patients with Long COVID leading to fatigue, which is the main symptom of this syndrome. Certainly more research studies could confirm the association between tau protein and Long COVID by defining the main role of tau protein as a biomarker for the diagnosis of this syndrome that is widespread in the post-pandemic period.

Source: Ferrara, F., Zovi, A., Masi, M. et al. Long COVID could become a widespread post-pandemic disease? A debate on the organs most affected. Naunyn-Schmiedeberg’s Arch Pharmacol (2023). https://doi.org/10.1007/s00210-023-02417-5 https://link.springer.com/article/10.1007/s00210-023-02417-5 (Full text)

SARS-CoV-2 infection and persistence in the human body and brain at autopsy

Abstract:

Coronavirus disease 2019 (COVID-19) is known to cause multi-organ dysfunction^1-3 during acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some patients experiencing prolonged symptoms, termed post-acute sequelae of SARS-CoV-2 (refs. ^4,5). However, the burden of infection outside the respiratory tract and time to viral clearance are not well characterized, particularly in the brain^3,6-14.

Here we carried out complete autopsies on 44 patients who died with COVID-19, with extensive sampling of the central nervous system in 11 of these patients, to map and quantify the distribution, replication and cell-type specificity of SARS-CoV-2 across the human body, including the brain, from acute infection to more than seven months following symptom onset.

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. Further, we detected persistent SARS-CoV-2 RNA in multiple anatomic sites, including throughout the brain, as late as 230 days following symptom onset in one case. Despite extensive 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.

Source: Stein SR, Ramelli SC, Grazioli A, Chung JY, Singh M, Yinda CK, Winkler CW, Sun J, Dickey JM, Ylaya K, Ko SH, Platt AP, Burbelo PD, Quezado M, Pittaluga S, Purcell M, Munster VJ, Belinky F, Ramos-Benitez MJ, Boritz EA, Lach IA, Herr DL, Rabin J, Saharia KK, Madathil RJ, Tabatabai A, Soherwardi S, McCurdy MT; NIH COVID-19 Autopsy Consortium; Peterson KE, Cohen JI, de Wit E, Vannella KM, Hewitt SM, Kleiner DE, Chertow DS. SARS-CoV-2 infection and persistence in the human body and brain at autopsy. Nature. 2022 Dec;612(7941):758-763. doi: 10.1038/s41586-022-05542-y. Epub 2022 Dec 14. PMID: 36517603; PMCID: PMC9749650. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9749650/ (Full text)

Persistent SARS-CoV-2 infection in patients seemingly recovered from COVID-19

Abstract:

SARS-CoV-2 infection is clinically heterogeneous, ranging from asymptomatic to deadly. A few patients with COVID-19 appear to recover from acute viral infection but nevertheless progress in their disease and eventually die, despite persistent negativity at molecular tests for SARS-CoV-2 RNA.

Here, we performed post-mortem analyses in 27 consecutive patients who had apparently recovered from COVID-19 but had progressively worsened in their clinical conditions despite repeated viral negativity in nasopharyngeal swabs or bronchioalveolar lavage for 11-300 consecutive days (average: 105.5 days). Three of these patients remained PCR-negative for over 9 months.

Post-mortem analysis revealed evidence of diffuse or focal interstitial pneumonia in 23/27 (81%) patients, accompanied by extensive fibrotic substitution in 13 cases (47%). Despite apparent virological remission, lung pathology was similar to that observed in acute COVID-19 individuals, including micro- and macro-vascular thrombosis (67% of cases), vasculitis (24%), squamous metaplasia of the respiratory epithelium (30%), frequent cytological abnormalities and syncytia (67%), and the presence of dysmorphic features in the bronchial cartilage (44%).

Consistent with molecular test negativity, SARS-CoV-2 antigens were not detected in the respiratory epithelium. In contrast, antibodies against both spike and nucleocapsid revealed the frequent (70%) infection of bronchial cartilage chondrocytes and para-bronchial gland epithelial cells. In a few patients (19%), we also detected positivity in vascular pericytes and endothelial cells. Quantitative RT-PCR amplification in tissue lysates confirmed the presence of viral RNA.

Together, these findings indicate that SARS-CoV-2 infection can persist significantly longer than suggested by standard PCR-negative tests, with specific infection of specific cell types in the lung. Whether these persistently infected cells also play a pathogenic role in long COVID remains to be addressed.

Source: Bussani R, Zentilin L, Correa R, Colliva A, Silvestri F, Zacchigna S, Collesi C, Giacca M. Persistent SARS-CoV-2 infection in patients seemingly recovered from COVID-19. J Pathol. 2023 Jan 18. doi: 10.1002/path.6035. Epub ahead of print. PMID: 36651103. https://onlinelibrary.wiley.com/doi/10.1002/path.6035 (Full text)

Brain autopsies of critically ill COVID-19 patients demonstrate heterogeneous profile of acute vascular injury, inflammation and age-linked chronic brain diseases

Abstract:

Background: This study examined neuropathological findings of patients who died following hospitalization in an intensive care unit with SARS-CoV-2.

Methods: Data originate from 20 decedents who underwent brain autopsy followed by ex-vivo imaging and dissection. Systematic neuropathologic examinations were performed to assess histopathologic changes including cerebrovascular disease and tissue injury, neurodegenerative diseases, and inflammatory response. Cerebrospinal fluid (CSF) and fixed tissues were evaluated for the presence of viral RNA and protein.

Results: The mean age-at-death was 66.2 years (range: 26-97 years) and 14 were male. The patient’s medical history included cardiovascular risk factors or diseases (n = 11, 55%) and dementia (n = 5, 25%). Brain examination revealed a range of acute and chronic pathologies. Acute vascular pathologic changes were common in 16 (80%) subjects and included infarctions (n = 11, 55%) followed by acute hypoxic/ischemic injury (n = 9, 45%) and hemorrhages (n = 7, 35%). These acute pathologic changes were identified in both younger and older groups and those with and without vascular risk factors or diseases. Moderate-to-severe microglial activation were noted in 16 (80%) brains, while moderate-to-severe T lymphocyte accumulation was present in 5 (25%) brains. Encephalitis-like changes included lymphocytic cuffing (n = 6, 30%) and neuronophagia or microglial nodule (most prominent in the brainstem, n = 6, 30%) were also observed. A single brain showed vasculitis-like changes and one other exhibited foci of necrosis with ball-ring hemorrhages reminiscent of acute hemorrhagic leukoencephalopathy changes. Chronic pathologies were identified in only older decedents: 7 brains exhibited neurodegenerative diseases and 8 brains showed vascular disease pathologies. CSF and brain samples did not show evidence of viral RNA or protein.

Conclusions: Acute tissue injuries and microglial activation were the most common abnormalities in COVID-19 brains. Focal evidence of encephalitis-like changes was noted despite the lack of detectable virus. The majority of older subjects showed age-related brain pathologies even in the absence of known neurologic disease. Findings of this study suggest that acute brain injury superimposed on common pre-existing brain disease may put older subjects at higher risk of post-COVID neurologic sequelae.

Source: Agrawal S, Farfel JM, Arfanakis K, Al-Harthi L, Shull T, Teppen TL, Evia AM, Patel MB, Ely EW, Leurgans SE, Bennett DA, Mehta R, Schneider JA. Brain autopsies of critically ill COVID-19 patients demonstrate heterogeneous profile of acute vascular injury, inflammation and age-linked chronic brain diseases. Acta Neuropathol Commun. 2022 Dec 17;10(1):186. doi: 10.1186/s40478-022-01493-7. PMID: 36528671; PMCID: PMC9758667. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9758667/ (Full text)

Neurovascular injury with complement activation and inflammation in COVID-19

Abstract:

The underlying mechanisms by which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to acute and long-term neurological manifestations remains obscure. We aimed to characterize the neuropathological changes in patients with coronavirus disease 2019 and determine the underlying pathophysiological mechanisms. In this autopsy study of the brain, we characterized the vascular pathology, the neuroinflammatory changes and cellular and humoral immune responses by immunohistochemistry.

All patients died during the first wave of the pandemic from March to July 2020. All patients were adults who died after a short duration of the infection, some had died suddenly with minimal respiratory involvement. Infection with SARS-CoV-2 was confirmed on ante-mortem or post-mortem testing. Descriptive analysis of the pathological changes and quantitative analyses of the infiltrates and vascular changes were performed.

All patients had multifocal vascular damage as determined by leakage of serum proteins into the brain parenchyma. This was accompanied by widespread endothelial cell activation. Platelet aggregates and microthrombi were found adherent to the endothelial cells along vascular lumina. Immune complexes with activation of the classical complement pathway were found on the endothelial cells and platelets. Perivascular infiltrates consisted of predominantly macrophages and some CD8+ T cells. Only rare CD4+ T cells and CD20+ B cells were present. Astrogliosis was also prominent in the perivascular regions. Microglial nodules were predominant in the hindbrain, which were associated with focal neuronal loss and neuronophagia.

Antibody-mediated cytotoxicity directed against the endothelial cells is the most likely initiating event that leads to vascular leakage, platelet aggregation, neuroinflammation and neuronal injury. Therapeutic modalities directed against immune complexes should be considered.

Source: Lee MH, Perl DP, Steiner J, Pasternack N, Li W, Maric D, Safavi F, Horkayne-Szakaly I, Jones R, Stram MN, Moncur JT, Hefti M, Folkerth RD, Nath A. Neurovascular injury with complement activation and inflammation in COVID-19. Brain. 2022 Jul 5:awac151. doi: 10.1093/brain/awac151. Epub ahead of print. PMID: 35788639; PMCID: PMC9278212. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9278212/ (Full text)

Microvascular Injury in the Brains of Patients with Covid-19

To the Editor:

We conducted postmortem high-resolution magnetic resonance imaging (magnetic resonance microscopy) of the brains of patients with coronavirus disease 2019 (Covid-19) (median age, 50 years) and histopathological examination that focused on microvascular changes in the olfactory bulb and brain stem. (See the Materials and Methods section in the Supplementary Appendix, available with the full text of this letter at NEJM.org.) Images were obtained from the brains of 13 patients with the use of an 11.7-Tesla scanner at a resolution of 25 μm for the olfactory bulb and at a resolution of 100 μm for the brain. Abnormalities were seen in the brains of 10 patients.

We examined the brains of patients that showed abnormalities by means of multiplex fluorescence imaging (in 5 patients) and by means of chromogenic immunostaining (in 10 patients). We performed conventional histopathological examination of the brains of 18 patients. Fourteen patients had chronic illnesses, including diabetes and hypertension, and 11 had been found dead or had died suddenly and unexpectedly. Of the 16 patients with available medical histories, 1 had delirium, 5 had mild respiratory symptoms, 4 had acute respiratory distress syndrome, 2 had pulmonary embolism, and the symptoms were not known in 3.

Read the rest of this letter HERE.

Source: Lee MH, Perl DP, Nair G, Li W, Maric D, Murray H, Dodd SJ, Koretsky AP, Watts JA, Cheung V, Masliah E, Horkayne-Szakaly I, Jones R, Stram MN, Moncur J, Hefti M, Folkerth RD, Nath A. Microvascular Injury in the Brains of Patients with Covid-19. N Engl J Med. 2021 Feb 4;384(5):481-483. doi: 10.1056/NEJMc2033369. Epub 2020 Dec 30. PMID: 33378608; PMCID: PMC7787217. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787217/ (Full text)

SARS-CoV-2 infection and persistence throughout the human body and brain

Abstract:

COVID-19 is known to cause multi-organ dysfunction^1-3 in acute infection, with prolonged symptoms experienced by some patients, termed Post-Acute Sequelae of SARS-CoV-2 (PASC)^4-5. However, the burden of infection outside the respiratory tract and time to viral clearance is not well characterized, particularly in the brain^3,6-14.

We performed complete autopsies on 44 patients with COVID-19 to map and quantify SARS-CoV-2 distribution, replication, and cell-type specificity across the human body, including brain, from acute infection through over seven months following symptom onset. We show that SARS-CoV-2 is widely distributed, even among patients who died with asymptomatic to mild COVID-19, and that virus replication is present in multiple extrapulmonary tissues early in infection.

Further, we detected SARS-CoV-2 RNA in multiple anatomic sites, including regions throughout the brain, for up to 230 days following symptom onset. Despite extensive distribution of SARS-CoV-2 in the body, we observed a paucity of inflammation or direct viral cytopathology outside of the lungs. Our data prove that SARS-CoV-2 causes systemic infection and can persist in the body for months.

Source: Daniel Chertow, Sydney Stein, Sabrina Ramelli et al. SARS-CoV-2 infection and persistence throughout the human body and brain, 20 December 2021, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-1139035/v1] https://www.researchsquare.com/article/rs-1139035/v1 https://www.nature.com/articles/s41586-022-05542-y (Full text)

CNS findings in chronic fatigue syndrome and a neuropathological case report

Abstract:

Chronic fatigue syndrome (CFS) is characterized as a persistent, debilitating complex disorder of unknown etiology, whereby patients suffer from extreme fatigue, which often presents with symptoms that include chronic pain, depression, weakness, mood disturbances, and neuropsychological impairment. In this mini review and case report, we address central nervous system (CNS) involvement of CFS and present neuropathological autopsy findings from a patient who died with a prior diagnosis of CFS.

Among the most remarkable pathological features of the case are focal areas of white matter loss, neurite beading, and neuritic pathology of axons in the white matter with axonal spheroids. Atypical neurons displaying aberrant sprouting processes in response to injury are observed throughout cortical gray and white matter. Abundant amyloid deposits identical to AD plaques with accompanying intracellular granular structures are observed as well. Neurofibrillary tangles are also present in the white matter of the frontal cortex, thalamus and basal ganglia.

Taken together, these neuropathological findings warrant further studies into CNS disease associated with CFS.

Source: Kimberly Ferrero, Mitchell Silver, Alan Cocchetto, Eliezer Masliah, Dianne Langford. CNS findings in chronic fatigue syndrome and a neuropathological case report. Journal of Investigative Medicine. DOI: 10.1136/jim-2016-000390 Published 6 April 2017. http://jim.bmj.com/content/early/2017/04/06/jim-2016-000390

Epidemic myalgic encephalomyelitis

The letter below, “Epidemic myalgic encephalomyelitis,” was published in the British Medical Journal in 1978. In it, the authors maintain that ME is an organic illness that exists as a distinct clinical entity with recognizable signs and symptoms. The authors propose that the cause may be “a persistent viral infection.”

Epidemic myalgic encephalomyelitis

Outbreaks of the paralytic disease known as epidemic myalgic encephalomyelitis have puzzled doctors all over the world in the past 30 years. One of the best known of these epidemics was that at the Royal Free Hospital in London in 1955, which affected more than 300 people. (1) Most outbreaks tend to occur in the summer, young adults are predominantly affected, and the incidence is higher in women. The evidence suggests that infection is spread by personal contact, and young hospital personnel seem particularly at risk. The features common to every epidemic include headache, unusual muscular pains (which may be severe), lymphadenopathy-often of the posterior cervical lymph nodes-and low-grade fever.(2, 3) In a minority of cases frank neurological signs can be detected by careful clinical examination: there may be nystagmus, diplopia, myoclonus, bulbar weakness, motor weakness, increased or decreased tendon reflexes, disturbances of the sphincters, and extensor plantar responses.(2-7) Fasciculations, cranial nerve lesions, and extrapyramidal signs have also been reported. Most patients complain of paraesthesiae, and sensory loss is common.”(4) One characteristic feature of the disease is exhaustion, any effort producing generalised fatigue. Often there are psychiatric abnormalities, especially emotional lability and lack of concentration.(1- 3, 4) The clinical outcome may take any of three courses: some patients recover completely, some follow a relapsing course, and some are permanently incapacitated.(3)

At a symposium held recently at the Royal Society of Medicine to discuss the disease and plan research there was clear agreement that myalgic encephalomyelitis is a distinct nosological entity. Other terms that have been used to describe the disease were rejected as unsatisfactory for various reasons: the cardinal clinical features show that the disorder is an encephalomyelitis; “Iceland disease” is not specific enough; and “neuromyasthenia” suggests a relation to myasthenia gravis whereas the muscle fatigability is different, as are the electrophysiological findings.(8) Indeed, the exhaustion and tiredness are similar to that described by patients with multiple sclerosis.(9) From the patient’s point of view the designation benign is also misleading, since the illness may be devastating. Originally the term was used because no deaths had been recorded from myalgic encephalomyelitis. Two patients who had had the disease have now been examined post mortem: one was found to have multiple sclerosis. The adjective epidemic is correct, since most cases occur in an epidemic, but the disease may be endemic, and sporadic cases may occur. (10-12)

Some authors have attempted to dismiss this disease as hysterical, (13) but the evidence now makes such a tenet unacceptable. Some purely psychiatric symptoms may well occur, particularly in patients entering the chronic phase. No doubt, too, in an epidemic some hysterical persons will simulate the symptoms of the disease. Nevertheless, the organic basis is clear-from the finding that the putative agent can be transferred to monkeys(14); the detection of an increased urinary output of creatine2 (15); the persistent finding of abnormal lymphocytes in the peripheral blood of some patients (16); the presence of lymphocytes and an increased protein concentration in the cerebrospinal fluid of occasional patients (3); and the neurological findings. At this symposium more evidence was produced to support the organic nature of the disease. Increased serum concentrations of lactic dehydrogenases and transaminases have been found in several patients examined during the acute attack. In a recent outbreak in London immunological studies showed a high incidence of serum anticomplementary activity and the presence of ill-defined aggregates on electron microscopy of acute-phase sera.(17) A perplexing finding, suggesting the possibility of a persistent virus infection, was the ability of lymphocytes from patients to proliferate and survive in vitro for up to 19 weeks. The results of electroencephalographic studies were also stated to be abnormal, confirming other reports. (10)

We still know nothing about the nature and cause of epidemic myalgic encephalomyelitis, but outbreaks are still occurring. Future epidemics should be studied by a collaborative team of neurologists, epidemiologists, virologists, and immunologists. Its findings would be important not only for the study of epidemic myalgic encephalomyelitis but also for other neurological disorders, including multiple sclerosis.

1 British Medical Journal, 1957, 2, 895.

2 White, D N, and Burtch, R B, Neurology, 1954, 4, 506.

3 Acheson, E D, American Journal of Medicine, 1959, 26, 569.

4 Gilliam, A G, Epidemiological Study of an Epidemic, Public Health Bulletin, No 240. US Public Health Service, Washington, 1938.

5 Acheson, E D, Lancet, 1955, 2, 394.

6 Pellew, R A A, Medical Journal of Australia, 1951, 1, 944.

7 Hill, R C J, South African Medical Journal, 1955, 29, 344.

8 Richardson, A T, Annals of Physical Medicine, 1956, 3, 81.

9 McAlpine, D, Compston, N D, and Lumsden, C E, Multiple Sclerosis, chap 5. Edinburgh and London, Livingstone, 1955. ”

10 Ramsay, A M, and O’Sullivan, E, Lancet, 1956, 1, 761.

11 Jelinek, J E, Lancet, 1956, 2, 494.

12 Ramsay, A M, Lancet, 1957, 2, 1196.