Współudział cytotoksycznych limfocytów T w anosmii w przebiegu COVID-19

Introduction

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 is a novel virus that comes under the same family as SARS-CoV and MERS. Due to failure in its containment, it has spread globally since its emergence in 2019, which subsequently led the World Health Organization (WHO) to declare a pandemic. SARS-CoV-2 causes the coronavirus disease of 2019 (COVID-19), presenting with symptoms akin to flu, which are potentially serious in cases of high-risk individuals [1]. Not unlike other coronaviruses, SARS-CoV-2 predominantly causes flu-like symptoms, i.e., cough, fever, and asthaenia [2]. Severe lung injury has been reported irrespective of patients’ age, but the elderly and those suffering from multimorbidities are more likely to develop interstitial pneumonia, ARDS, and multiorgan failure causing severe acute respiratory failure and a high mortality rate. Even though these viruses most often affect the respiratory system, their potential neurotropism has been noted in experimental studies and case reports. In SARS-CoV-2 cases there have been reports of patients developing nausea, myalgia, headaches and faintness [3], impaired consciousness, hyposmia, and hypogeusia [4], all of which account for nervous system involvement.
SARS-CoV-2 has a spike protein surface unit 1 that has a high binding affinity to the human receptor angiotensin-converting enzyme 2 (ACE2) [3]. Increased ACE2 expression of lower respiratory tract epithelial cells promotes entry by means of fusion with the cell membrane [5, 6]. ACE2 expression is a likely explanation behind the involvement of the medullary structures, but it does not reach this extent in the case of temporo-limbic involvement. ACE2 is strongly expressed in areas playing a significant role in respiratory cycle regulation, i.e., ventrolateral medulla and the nucleus of the tractus solitarius [7]. However, the virus’s affinity for the olfactory bulb is believed to be mediated by another mechanism, the nature of which remains unidentified. In the case of rodents, transnasal exposure led to quick detection in areas with direct neuronal link to the olfactory bulb, i.e., the piriform and infralimbic cortex, basal ganglia, and the midbrain [8]. Prior studies have demonstrated that SARS-CoV and MERS, probably through inflammatory response or autophagy, lead to the upregulation of interleukin-1 (IL-1), IL-6, and tumor necrosis factor- (TNF-) cytokine response, resulting in direct neuronal death in the respiratory centre in the medulla [8]. Further studies are necessary to determine whether such observations are applicable to the SARS-CoV virus.

Aim

The aim of the case description is to show spotty inflammatory lesions in the olfactory bulb, which could lead to passing anosmia.

Case report

A 62-year-old female patient was admitted to hospital in bad general condition showing severe dyspnoea and cyanosis. Real-time polymerase chain reaction (RT PCR) and 15-minute cassette tests were performed, and both results were SARS-CoV-19 positive. The chest computed tomography (CT) scan showed typical interstitial pneumonia with honeycomb pattern. According to the patient’s family the patient complained of weakness and anosmia for the preceding week. Unfortunately, intense therapy proved ineffective, and the patient died during her first day after admission. The autopsy report revealed severe pulmonary injury, such as diffuse alveolar damage (DAD) with severe hyaline membrane syndrome, pneumocytes II hypertrophy, and intra-alveolar haemorrhage.

Neuropathological findings in central nervous system

Routine tissue samples taken from the cortex, basal ganglia, hippocampus, midbrain, and cerebellum showed moderate to severe oedema and significant pericellular ‘halo’ around oligodendrocytes, typical for severe central nervous system (CNS) ischaemia. There was no sign of encephalitis or neurodegeneration. Our attention was focused on the olfactory bulb nerve sample, in which we noted microglia proliferation with the formation of small microglia nodules (Figure 1). We applied double chromogen (RED, DAB Ventana Roche Diagnostics) immunohistochemistry to detect lymphocyte CD4+ and CD8+ fractions. We observed a spotty perivascular cytotoxic T (CD8+) lymphocyte infiltration with lesser contribution of CD4+ lymphocytes (Figure 2). Interestingly, neuropil abnormalities with peculiar myelin figures were observed. Pericellular myeline loops and pericellular myeline cap features were described as forming a ‘chicken wire-like’ pattern (Figures 3, 4).

Discussion

Clinical data from 214 COVID-19 patients demonstrated neurological symptoms in 36.4% of cases. These symptoms included headaches, impaired consciousness, ataxia, acute cerebrovascular disease, seizures, hyposmia, hypogeusia, and neuralgias. The data suggests that patients with more severe systemic presentations were more likely to have neurological symptoms than those with milder forms of infection: acute cerebrovascular diseases (5.7% vs. 0.8%), impaired consciousness (14.8% vs. 2.4%), and skeletal muscle injury (19.3% vs. 4.8%) [4]. Neuromuscular symptoms caused by COVID-19 include developed weakness, sensorimotor peripheral nerve symptoms, and decreased deep tendon reflexes (DTRs), usually present after the third week of initial SARS onset [9]. The most common complaints were of hypogeusia and hyposmia [10]. It is still unclear how neurotransmission is changed by Covid-19. Last year provided an explosion of papers concerning Coronavirus biology, but information about neurodegeneration is still scarce [11–13]. The lethal case reported herein presents a typical respiratory tract injury complicated by severe ARDS and severe hypoxia. The antiviral cellular response we observed would be a causative factor for inhibition of neuron signal transduction. Being aware only of a singular case, we would like to report our findings, which need to be enhanced in additional cohort studies.

Conclusions

Cytotoxic T response might be a causative factor in respiratory tract injury, but it is also involved in the neural system. The myelin figures are unclear. It would be a specific pattern of neurodegeneration and postmortem artifact as well, so it requires further studies.

Conflict of interest

The authors declare no conflict of interest.

References