Neurological disorders throughout acute SARS-CoV2 infection: a comparative study between vaccinated and non-vaccinated patients

doi:10.21203/rs.3.rs-2087859/v1

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Neurological disorders throughout acute SARS-CoV2 infection: a comparative study between vaccinated and non-vaccinated patients

https://doi.org/10.21203/rs.3.rs-2087859/v1

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Background

The role of vaccination on Covid-19 severity in neurological patients is still unknown. We aim at describing clinical characteristics and outcomes of breakthrough and unvaccinated Covid-19 patients hospitalized for neurological disorders.

Methods

Two hundred thirty-two Covid-19 patients were admitted to a neuro-Covid Unit form March 2021 to February 2022. Out of the total sample, 74 (32%) were full vaccinated. The prevalence, clinical characteristics and final outcomes of neurological syndromes were compared between vaccinated and unvaccinated cases.

Results

Breakthrough vaccinated cases were older (years 72.4+16.3 vs 67.0+18.9 years, p=0.029), showed higher pre-admission comorbidity score and Clinical Frailty scale score (4.46+1.6 vs 3.75+2.0, p=0.008) with no differences in terms of disease progression or mortality rate (16.2% vs 15.2%), compared to full-dose vaccinated patients.

Cox-regression analysis showed age and NEWS2 score as the variables with a significant relation to mortality between the two groups, independently from pre-morbid conditions and inflammatory response.

Conclusion

This study on breakthrough COVID-19 infection could help identify vulnerable neurological patients with higher risk of poor outcomes.

COVID-19

neurological disease

vaccine

mortality

Since the introduction of COVID-19 vaccination in January 2021, its increasing rates were expected to reduce transmission of SARS-CoV-2 infection worldwide and thereby the burden of COVID-19 disease, in terms of lives lost, hospitalization rates, social and economic impact.

Despite compelling evidence of vaccination effectiveness (1), breakthrough cases have been emerging (2), likely due to continued occurrence of new SARS-CoV-2 variants. In the current shifting landscape of severe viral infection requiring hospitalization, most breakthrough COVID-19 cases have been reported mild or moderate in severity (3).

Several neurological complications, ranging from mild symptoms to severe conditions, have been extensively described in patients with SARS-CoV2 infection, often associated with increased risk of mortality and poor outcome (4,5).

To date, there is no comprehensive survey aimed to document differences of neurological manifestations and severity in vaccinated patients compared to unvaccinated subjects who developed COVID-19.

This study examined the association between prior vaccination and hospitalization for neurologic diseases, as well as the differences in terms of disease severity and progression among COVID-19 patients admitted at neuro-COVID unit in a single Italian hub.

This cohort study included 232 adult neurological inpatients (≥18 years old) with SARS-CoV-2 infection consecutively admitted at the Neuro-COVID Unit of the ASST Spedali Civili Hospital, Brescia from January 2021 to February 2022. Out of the total sample, 74 subjects (32%) were breakthrough cases, defined as a percentage of fully vaccinated persons who still got SARS-CoV2 infection.

The Hospital was a designated hub for acute cerebrovascular diseases and CNS manifestations during the COVID-19 outbreak, in a metropolitan area of more than 1,200,000 people (Neuro-COVID unit). SARS-CoV-2 infection was confirmed by RT-PCR in nasopharyngeal/oropharyngeal swabs or bronchoalveolar lavage.

Epidemiological, demographical, clinical, laboratory, treatment, and outcome data were extracted

from both printed and electronic medical records using standardized anonymized data collection

forms. During hospitalization, National Early Warning Score (NEWS) 2, based on a simple aggregate scoring system of physiological measurements, was used to standardize the assessment and response to acute illness (6), whereas respiratory COVID-19 severity was expressed by the Brescia-COVID Respiratory Severity Scale (BCRSS) as previously reported (7).

Continuous and categorical variables are reported as mean values ± standard deviation and n (%) respectively. Differences between patients with and without SARS-CoV-2 vaccinations were compared by t-test, x² test or Fisher’s exact test where appropriate.

Cox regression model was implemented in order to investigate the combined effect of predictors of mortality, namely age, pre-admission comorbidity severity index, inflammatory and physiological parameters, on vaccinated and non-vaccinated neurological patients. A two-sided p-value <0.05 was considered significant; analyses were carried out using SPSS software (version 21.0).

Two hundred thirty-two COVID-19 patients were hospitalized in the Neuro-COVID Unit of the ASST Spedali Civili of Brescia Hospital, from January 2021 to February 2022.

Demographic, clinical and laboratory characteristics of included patients are reported in Table 1.

Table 1. Demographic, clinical, laboratory characteristics of neurological Covid-19 patients unvaccinated and vaccinated (at list 2 doses) from January 2021. *p values were calculated by t-test or Fisher’s exact test, as appropriate.

	Unvaccinated	Vaccinated	*p Value
	(n=158)	(n=74)
Clinical and demographics features
Age, years	67.0+18.9	72.4+16.3	0.029
Sex, female	76 (48.1%)	33 (44.6%)	0.618
CFS pre-admission	3.75+2.0	4.46+1.6	0.008
CIRS pre-admission	1.38+0.3	1.59+0.3	<0.001
BCRSS, mean	1.50+1.5	1.72+1.5	0.310
NEWS2	3.19+2.7	2.13+2.2	0.005
Lymphocytes	1.89+2.6	1.99+2.6	0.811
C-reactive protein (mg/L)	43.3+52.9	65.3+66.9	0.019
D-dimer (mg/L)	1898.7+3650.4	1219.9+1099.0	0.040
Admission Diagnosis
Ischemic Stroke	20 (12.7%)	3 (4.1%)	0.057
TIA	11 (7.0%)	7 (9.5%)	0.599
ICH	3 (1.9%)	1 (1.4%)	0.760
Encephalitis	6 (3.8%)	0 (0.0%)	0.181
Encephalopathy	9 (5.7%)	5 (6.8%)	0.772
Delirium	50 (31.6%)	23 (31.1%)	0.931
Cerebral tumor	6 (3.8%)	2 (2.7%)	0.670
Seizures	18 (11.4%)	0 (0.0%)	0.001
Headache	17 (10.8%)	11 (14.9%)	0.392
Vertigo	7 (4.4%)	5 (6.8%)	0.528
GBS	3 (1.9%)	0 (0.0%)	0.553
Other diagnosis	24 (15.2%)	23 (31.1%)	0.005
Therapy:
Oxygen therapy, n (%)	92 (58.2%)	49 (66.2%)	0.253
Non-invasive/invasive Ventilation	30 (19.0%)	11 (14.9%)	0.580
Outcomes measures
In Hospital mortality, n (%)	24 (15.2%)	12 (16.2%)	0.841

Abbreviations: BCRSS, Brescia-COVID Respiratory Severity Scale; CFS, Clinical Frailty Scale; CIRS, Cumulative Illness Rating Scale; GBS, Guillain-Barrè syndrome; ICH, Intracerebral hemorrhage; NEWS2, National Early Warning Score 2; TIA, Transient Ischemic Attack.

Out of the total sample, 74 subjects (32%) were full dose vaccinated with mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech) vaccine; they were older (years 72.4+16.3 vs 67.0+18.9, p=0.029), exhibited a higher pre-morbid Cumulative Illness Rating Scale (CIRS) severity index (1.59+0.3 vs. 1.38+0.3, p<0.001) and Clinical Frailty Scale (CFS) score (4.46+1.6 vs. 3.75+2.0, p=0.008) compared to non-vaccinated subjects.

We observed a significant decrease in seizures among breakthrough COVID-19 cases (n=0, 0.0% vs n=18, 11.4%), with a similar distribution as regards the other neurological diagnosis. Of note, the number of ischemic strokes was lower in the vaccinated group, with a borderline statistical significance (n= 3, 4.1% vs n=20, 12.7%, p=0.057) and a lower d-dimer level (1219.9+1099.0 vs 1898.7+3650.4, p=0.040) compared to unvaccinated patients.

The 31.1% of full vaccinated patients exhibited other neurologic diagnosis, namely Bell’s palsy, syncope, myalgia.

Laboratory analysis showed an increased C-reactive protein (65.3+66.9 vs 43.3+52.9, p=0.019) among the breakthrough cases, whereas physiological parameters severity, as expressed by NEWS2 score, were worse (3.19+2.7 vs 2.13+2.2, p=0.005) in the unvaccinated group. Notably, no differences were observed in terms of intensive care treatments, namely invasive/non-invasive ventilation (19.0% vs 14.9%, p=0.580) and mortality rate (15.2% vs 16.2%, p=0.841) between the two groups.

Cox-regression analysis showed that age (p=0.011) and physiological parameters severity (p=0.031) were the two variables related to mortality odds, independently from pre-admission comorbidity score and inflammatory parameters, between vaccinated and un-vaccinated patients (Figure 1).

This retrospective cohort study identified several differences between Covid-19 hospitalized neurological patients who received a full-dose vaccine compared to unvaccinated subjects. The percentage of neurological hospitalized COVID-19 with previous vaccination was 32%; breakthrough cases were older, showed higher comorbidity severity index and clinical frailty scale score, and greater inflammatory blood parameters compared to unvaccinated patients, consistently with a previous UK study (8).

Admission diagnosis showed a lower number of seizures in the group who received SARS-CoV2 vaccine (n=0, 0.0% vs n=18, 11.4%, p=0.001) and we did not find any case of encephalitis or GBS among vaccinated subjects. Furthermore, there were a lower number of ischemic strokes in the breakthrough cases, albeit without reaching statistical significance (n=3, 4.1% vs n=20, 12.7%, p=0.057). Interestingly, D-dimer levels was higher in the un-vaccinated group (1898.7+3650.4 vs 1219.9+1099.0, p=0.040), even in presence of lower inflammatory profile assessed by C-reactive protein. This suggests that the claimed association between stroke and COVID-19 could be driven alterations in coagulopathy instead of peripheral inflammatory response (9). Vaccination might decrease the risk of coagulopathy complications even in presence of high systemic response. The higher NEWS2 score we found in unvaccinated patients (with lower PCR) indicates that COVID-19 severity was higher in this group, independently from general inflammatory response. Of interest, vaccinated and un-vaccinated patients showed no differences in terms of respiratory worsening or mortality rate.

Notably, we found that age and physiological parameters severity were the two variables significatively related to mortality in the two groups, independently from pre-admission comorbidity score and inflammatory parameters. These findings thus suggest that age and systemic conditions, due to both neurological and pneumological diseases, play a major role in modulating the odds of mortality in the two groups.

Older adults are at particular risk of transmitting respiratory illness and may have an altered immune function (immunosenescence) (10), with a consequent poor response to the SARS-CoV2 vaccine. Furthermore, frailty in post-vaccinated cases could also explain the severe outcome of Covid-19 patients, especially among patients with high comorbidity severity index and worse systemic response, who are overrepresented in inpatient settings compared with the general population (11).

To the best of our knowledge, previous works showed that patients hospitalized for COVID-19 during the breakthrough were mostly older people, had elevated comorbidity and a high mortality rate (12). Furthermore, growing evidence points to the multi-organ involvement of COVID-19, particularly the nervous system, which increases morbidity and mortality (13,14,5).

We acknowledge that this work entails some limitations. First, the lack of IgG title data for immunized patients with breakthrough SARS-CoV2 infection establishing the individual immune response, and secondly the different SARS-CoV2 genotypes included, leading to variable respiratory involvement. Nevertheless, this is the first comprehensive comparative study comparing vaccinated and unvaccinated patients, affected by SARS-CoV2 infection and hospitalized for neurological disorders.

Although vaccines are very effective at preventing severe cases of COVID-19, our study showed that full-vaccinated Covid-19 patients hospitalized for neurological disorders still represent the 30% of Covid-19 neurological admissions; breakthrough cases exhibited older age, higher comorbidity and inflammatory parameters compared to unvaccinated patient; nevertheless, we did not find differences in terms of pneumological severity or mortality rates between the two groups.

Larger studies are warranted to confirm and extend these findings in order to identify breakthrough patients affected by neurological disease, with extreme vulnerability and a higher risk of poor outcomes.

Ethics approval and consent to participate

This study received approval from the ethical standards committee on human experimentation (local ethics committee of the ASST Spedali Civili Hospital, Brescia: NP 4067, approved in this last version on the 16.12.2021). The requirement for informed consent was waived by the ethics commission for patients who were not longer alive or reachable at the time of approval, while full written informed consent was required for all other participants. All methods were carried out in accordance with relevant guidelines and regulations (Declaration of Helsinki)

Consent for publication

Non Applicable

Availability of data and material

All study data, including raw and analyzed data, and materials will be available from the corresponding author, A.P., upon reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

No targeted funding reported.

Authors’ Contributions

V.C., A.P. and A.P. conceptualized study and had a major role in the acquisition of data, analyzed the data and drafted the manuscript for intellectual content; S.C.P., I.L., M.G., M.L. had an important role in the acquisition of data; all the authors reviewed the manuscript

Acknowledgments

We would like to express our gratitude to the nurses, auxiliary staff, technicians and all the

colleagues who collaborated for the management of patients during the COVID-19 outbreaks.

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No competing interests reported.

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Neurological disorders throughout acute SARS-CoV2 infection: a comparative study between vaccinated and non-vaccinated patients

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Introduction

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