April 11, 2022

expert reaction to post mortem study looking at COVID-19 and olfactory damage in the brain

A study published in JAMA Neurology looks at the olfactory pathology associated with COVID-19 infection.

Dr Payam Rezaie, Reader in Neuropathology, The Open University, said:

“Viral infection of the upper respiratory tract can lead to disturbances in sensory olfaction (sense of smell). Total or partial loss of smell, experienced by a proportion of individuals who have contracted COVID-19 (infected with SARS-CoV-2) is recognised as a cardinal symptom, occurring early in the course of illness, does not appear to be directly associated with viral load, and in most instances resolves spontaneously within a few weeks. In a subset of individuals, olfactory disturbances may persist and the reasons for this have remained unknown although severe damage to the olfactory system has been suspected. Whether the virus directly infects and injures olfactory neurons or causes indirect damage through secondary inflammation has remained unclear.

“In this neuropathological (post-mortem) study, the authors describe severe axonal pathology, loss of axons accompanied by microvascular pathology (injury to vascular endothelium) within olfactory tissues obtained from a relatively small cohort of 23 patients who passed away from COVID-19 (16 of whom had active SARS-CoV-2 virus at the time of death) compared to matched controls without infection. 9/23 had previously reported either a loss or diminished sense of smell. SARS-CoV-2 was detected in olfactory tissue by PCR and/or immunofluorescence in 3/23 COVID-19 cases (only one of whom had previously reported loss of smell). Damage assessed from histopathological and ultrastructural examination appeared to be more severe in those who had reported disturbances in their sense of smell. Axonal injury/loss is also recognised to occur with increasing age. The authors took account of this in their results and confirmed that the association of COVID-19 with axon and vascular pathology was independent of age.

“The fact that SARS-CoV-2 virus could not be routinely detected in olfactory tissue (it was only detected in 3/23 COVID-19 cases) and pathology was not associated with clinical severity led the authors to conclude that damage to olfactory tissue did not result from direct viral injury, but may instead be associated with local inflammation. Although this may be in keeping with previous hypotheses, the conclusion that ‘damage is secondary to inflammation’ would need to be supported by independent data examining profiles of cytokines and inflammatory markers, particularly as the authors found “no obvious increase in lymphocytic infiltrates, microglia, or reactive astrocytes in COVID-19 olfactory tissue”. Likewise, while the study demonstrated ‘mild to moderate findings’ in 9/23 cases with COVID-19 who had previously reported either a loss or diminished sense of smell, the authors’ conclusion that “the severity of pathology in some COVID-19 cases indicates that the olfactory system damage and dysfunction can be permanent” remains speculative without further supporting evidence.”

Note concerning ethical review: Although under ‘Setting’ it is made clear that the autopsies (from April 7, 2020 to September 11, 2021 at the University of Maryland Medical Center, Maryland Office of the Chief Medical Examiner or Orlando health’) were performed with consent from next of kin, it is somewhat surprising that the authors state in the Methods section that “This postmortem study was not considered human subjects research and therefore was exempt from institutional review boards review at University of Maryland Baltimore”, given that postmortem studies which involve collection of tissue for research purposes remain of ethical concern – the process not only involves obtaining informed consent from grieving family members, but must also consider important elements including data protection (e.g. anonymising clinical and research data; storage and retention of data), respectful storage, retention and disposal of human remains and other relevant aspects of research governance that would warrant formal ethical review.”

Prof Tara Spires-Jones, Deputy Director of the Centre for Discovery Brain Sciences, University of Edinburgh, said:

“This paper by Ho and team shows that a part of the brain important for smell – the olfactory bulb – is damaged in people who died with COVID-19.  The study was well conducted and convincing, but the number of people studied was relatively small (14 people without COVID, 10 people with COVID and disrupted sense of smell, and 13 people with COVID who did not have known disruption of smell).  It is also important to note that the olfactory bulb can sometimes recover from damage. It is not clear from this study of people who died whether people with similar levels of damage would eventually recover normal smell.”

‘Postmortem Assessment of Olfactory Tissue Degeneration and Microvasculopathy in Patients With COVID-19’ by Cheng-Ying Ho et al. was published in JAMA Neurology at 16:00 UK time on Monday 11 April.

DOI: doi:10.1001/jamaneurol.2022.0154

Declared interests

Dr Payam Rezaie: “No conflicts of interest.”

Prof Tara Spires-Jones: “No conflicts of interest.”