key: cord-0761167-ahdfbrxx
authors: Manganotti, Paolo; Bellavita, Giulia; Tommasini, Valentina; D′Acunto, Laura; Fabris, Martina; Cecotti, Laura; Furlanis, Giovanni; Sartori, Arianna; Bonzi, Lucia; Buoite Stella, Alex; Pesavento, Valentina
title: Cerebrospinal fluid and serum interleukins 6 and 8 during the acute and recovery phase in COVID‐19 neuropathy patients
date: 2021-06-06
journal: J Med Virol
DOI: 10.1002/jmv.27061
sha: 4b029310ecc673f185e4247eada552cf539da626
doc_id: 761167
cord_uid: ahdfbrxx

This case series describes three patients affected by severe acute respiratory syndrome coronavirus 2, who developed polyradiculoneuritis as a probable neurological complication of coronavirus disease 2019 (COVID‐19). A diagnosis of Guillain Barré syndrome was made on the basis of clinical symptoms, cerebrospinal fluid analysis, and electroneurography. In all of them, the therapeutic approach included the administration of intravenous immunoglobulin (0.4 gr/kg for 5 days), which resulted in the improvement of neurological symptoms. Clinical neurophysiology revealed the presence of conduction block, absence of F waves, and in two cases, a significant decrease in amplitude of compound motor action potential cMAP. Due to the potential role of inflammation on symptoms development and prognosis, interleukin‐6 (IL‐6) and IL−8 levels were measured in serum and cerebrospinal fluid during the acute phase, while only serum was tested after recovery. Both IL‐6 and IL‐8 were found increased during the acute phase, both in the serum and cerebrospinal fluid, whereas 4 months after admission (at complete recovery), only IL‐8 remained elevated in the serum. These results confirm the inflammatory response that might be linked to peripheral nervous system complications and encourage the use of IL‐6 and IL‐8 as prognostic biomarkers in COVID‐19.

nervous system manifestations, the most frequently observed are hyposmia, hypogeusia, and Guillain-Barré syndrome (GBS). 5, [8] [9] [10] GBS is a heterogeneous condition with several variant forms: the most common presentation is the progressively ascending tetraparesis (acute inflammatory demyelinating polyneuropathy), but other localized clinical variants are also recognized. About 60% of the abovementioned autoimmune syndromes can be infection-related by humoral and cellular cross-reactivity, 11, 12 most frequently gastrointestinal (Campylobacter jejuni) or respiratory tract infections, including flu syndrome and pneumonia. 13, 14 In coronavirus disease 2019 (COVID-19), a trigger for autoimmune reactions could be the release of a large amount of proinflammatory cytokines in an event known as "cytokine storm." Indeed, COVID-19 infection is accompanied by an aggressive inflammatory response the host immune response to the SARS-CoV-2 virus is hyperactive resulting in an excessive inflammatory reaction. 15 Reports describing the immunological profile of critically ill patients with COVID-19 have suggested hyperactivation of the humoral immune pathway-including interleukin (IL)−6 and 8. IL-6, a chemokine, is an important biomarker of inflammation and has been shown in studies as an important predictor of severe COVID-19. 16 IL-6 is responsible for elevation of acute-phase reactants, such as C-reactive protein, serum amyloid A, fibrinogen, and hepcidin, and inhibition of albumin synthesis. The dysregulated production of IL-6 has been attributed to autoimmunity and chronic inflammation. 17 IL-8, a proinflammatory cytokine produced by blood cells and many types of tissue, might be increased in COVID-19, although its diagnostic and predictive role is still debated. 18 This report describes a case series of three patients affected by COVID-19 who developed a spectrum of autoimmune polyneuropathies during hospitalization. The patients were monitored throughout the hospitalization, and the follow-up lasted 4 months after the first admission, until full recovery from neurological symptoms. Intriguingly, serum and cerebrospinal fluid (CSF) analyses, including interleukins measurements, revealed a characteristic pattern well aligned with the transition from the acute to the recovery phase.

This case series describes three patients admitted to the hospital affected by bilateral pneumonia due to SARS-CoV-2 infection from March to April 2020. Symptoms on admission were fever and cough, and in these three patients, significant impairment of taste and smell was also reported ( were also performed, including analysis for SARS-CoV-2. Additionally, both CSF and serum samples were used in the acute and, only serum, in the post-acute phase, to assess IL-6 and IL-8 levels. suggested. 23 Interleukin-6 levels suggest that neuroinflammation might play a critical role in the development of pathological pain. 24 Indeed, nerve injury induced the elevation of IL-6 in close Dorsal

Root Ganglia (DRG), but also in remote DRG, suggesting a general neuro-inflammatory reaction of the nervous system to local nerve injury. 25 One limitation of the present report is the impossibility to compare CSF cytokines levels between COVID-19 neuropathies patients and non-COVID-19 neuropathies patients; indeed, due to the small sample, the authors feel that it might be incautious to propose differences between the different clinical conditions.

Nevertheless, future studies are encouraged to assess these potential differences in larger samples of neuropathies with or without COVID-19, and whether IL-8 represents a prognostic marker of the disease.

Despite the exact mechanisms linking SARS-CoV-2 infection to neurological symptoms needing further investigation, it may be imprudent to exclude a direct penetration of the virus in the peripheral and central nervous system. 26, 27 Nevertheless, the pathogenic link between GBS and COVID-19 is still a matter of debate, 28,29 with a possible influence of critical illness on neurological signs development. 30 The neurophysiological examination was useful to detect subclinical findings and define the diagnosis of polyradiculonevritis, to start therapy with IVIG in the appropriate time useful to detect subclinical findings, better defining the diagnosis, and encouraging the start of the appropriate therapy with IVIG. 17, 31 Indeed, the clinical improvement after IVIG was successful in all the patients, although one of them showed only a partial rapid recovery of weakness which might be explained by the prolonged bed rest and intubation. [32] [33] [34] In addition to the already recognized use of anti-IL-6

drugs (e.g., tocilizumab), new therapeutic approaches are considering the development and use of anti-IL-8 drugs (BMS-986253) to improve the health condition of individuals infected with COVID-19. 35 In conclusion, this study reports the elevation and progressive changes of IL-6 and IL-8 in serum and CSF of patients with COVID-19 and peripheral nervous system complications, showing a specific pattern in relation to the clinical recovery, and encouraging the use of these biomarkers for a better prognosis of these patients.

The authors would like to thank all the staff of the COVID-19 ward and the neurophysiology and lab technicians.

The authors declare that there are no conflicts of interest. 

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Cerebrospinal fluid and serum interleukins 6 and 8 during the acute and recovery phase in COVID-19 neuropathy patients