By Alexander E. Merkler, MD

Assistant Professor of Neurology and Neuroscience, Weill Cornell Medical College, and Assistant Attending Neurologist, New York-Presbyterian Hospital

SYNOPSIS: SARS-CoV-2 may gain access to the brain via the olfactory epithelium. The olfactory epithelium and bulbs may serve as an entry point for SARS-CoV-2 infection into the central nervous system.

SOURCES: Matschke J, Lutgehetmann M, Hagel C, et al. Neuropathology of patients with COVID-19 in Germany: A post-mortem case series. Lancet Neurol 2020;19:919-929.

Chiesa-Estomba CM, Lechien JR, Radulesco T, et al. Patterns of smell recovery in 751 patients affected by the COVID-19 outbreak. Eur J Neurol 2020;27:2318-2321.

The COVID-19 worldwide pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neurological involvement in COVID-19 is common, occurring in approximately one-third of patients hospitalized with COVID-19.1 Both the central and peripheral nervous system can be affected. One major area of uncertainty is the route that SARS-CoV-2 uses to gain access to the central nervous system (CNS).

In the current study, Matschke et al evaluated the neuropathological features in the brains of patients with COVID-19 who died in Hamburg, Germany.2 Forty-three patients were included in the analysis. The median age was 76 years and 37% were women; the cause of death was attributed to respiratory illness in the majority of individuals. SARS-CoV-2 was detected via polymerase chain reaction (PCR) in 21 (53%) of the 40 patients with adequate samples.

In addition, there was evidence for an inflammatory response in all examined brains, with prominent involvement of the brainstem. Interestingly, the neuropathological evidence of SARS-CoV-2 was not associated with the severity of the neuroinflammatory response. Finally, evidence of acute cerebral infarction was found in 14% of the patients, consistent with prior reports suggesting that COVID-19 is associated with a heightened risk of stroke.3 Whether SARS-CoV-2 causes direct neurological injury, or whether SARS-CoV-2 leads to a neuroinflammatory response remains to be determined and requires further study.

How does SARS-CoV-2 gain access to the CNS? Whether SARS-CoV-2 gains entry via neurotropism and direct invasion or, rather, indirectly through systemic SARS-CoV-2 infection remains uncertain. In data from Wuhan, China, olfactory and gustatory dysfunction was reported in 5% of hospitalized patients with COVID-19.1 Since then, other reports have found that olfactory and gustatory dysfunction is common in non-severe cases of patients infected with SARS-CoV-2 and can be the initial or only symptom of COVID-19 disease.4 The current study by Chiesa-Estomba et al enrolled ambulatory and hospitalized patients with confirmed SARS-CoV-2 via nasal PCR or serum immunoglobulin G/immunoglobulin M.5 Data regarding olfactory dysfunction was acquired via completion of survey responses. Overall, among the 751 participants with COVID-19 who completed the study, olfactory dysfunction was reported in 83%. After a mean follow up of 48 ± 7 days, 37% reported persistent subjective loss of smell, 14% reported partial recovery, and 49% reported complete recovery. The mean duration of olfactory dysfunction was 10 ± 6 days among the participants with complete olfactory recovery.

COMMENTARY

Given the frequency of olfactory dysfunction in COVID-19, the olfactory epithelium has been suggested to represent a gateway to the CNS for SARS-CoV-2. Cells of the olfactory epithelium express angiotensin converting enzyme 2 (ACE2) receptor, which may allow for access of SARS-CoV-2 into the olfactory bulbs and, subsequently, the CNS.6 Given the density of SARS-CoV-2 in the nares (via inhalation of the virus), this may explain why olfactory dysfunction is so prevalent in patients with COVID-19. 

REFERENCES

  1. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol 2020;77:683-690.
  2. Matschke J, Lutgehetmann M, Hagel C, et al. Neuropathology of patients with COVID-19 in Germany: A post-mortem case series. Lancet Neurol 2020;19:919-929.
  3. Merkler AE, Parikh NS, Mir S, et al. Risk of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) vs patients with influenza. JAMA Neurol 2020;77:1-7.
  4. Lechien JR, Chiesa-Estomba CM, De Siati DR, et al. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): A multicenter European study. Eur Arch Otorhinolaryngol 2020;277:2251-2261.
  5. Chiesa-Estomba CM, Lechien JR, Radulesco T, et al. Patterns of smell recovery in 751 patients affected by the COVID-19 outbreak. Eur J Neurol 2020;11:2318-2321.
  6. Bilinska K, Jakubowska P, Von Bartheld CS, Butowt R. Expression of the SARS-CoV-2 entry proteins, ACE2 and TMPRSS2, in cells of the olfactory epithelium: Identification of cell types and trends with age. ACS Chem Neurosci 2020;11:1555-1562.