COVID-19 severity impacts on long-term neurological manifestation after hospitalisation

Background: Preclinical and clinical investigations have argued for nervous system

Alberto Raggi has no financial conflicts to disclose.
Antonio Canale has no financial conflicts to disclose.
Stefano Gipponi has no financial conflicts to disclose.
Ilenia Libri has no financial conflicts to disclose.
Martina Frigerio has no financial conflicts to disclose.
Michela Bezzi has no financial conflicts to disclose.
Matilde Leonardi has no financial conflicts to disclose.
Alessandro Padovani is consultant and served on the scientific advisory board of GE Healthcare, Eli-Lilly and Actelion Ltd Pharmaceuticals, received speaker honoraria from Nutricia, PIAM, Lansgstone Technology, GE Healthcare, Lilly, UCB Pharma and Chiesi Pharmaceuticals.He is founded by Grant of Ministry of University (MURST).

ABSTRACT
Background: Preclinical and clinical investigations have argued for nervous system involvement in SARS-CoV-2 infection and for long term sequalae including neurological manifestations Methods: a sample of 208 previously hospitalized COVID-19 patients, 165 patients were reassessed at 6 months according to a structured standardized clinical protocol.Premorbid comorbidities and clinical status, severity of COVID-19 disease, complications during and after hospitalization were recorded.
Results At 6-month follow-up after hospitalisation due to COVID-19 disease, patients displayed a wide array of neurological symptoms, being fatigue (34%), memory/attention (31%), and sleep disorders (30%) the most frequent.Subjects reporting neurological symptoms were affected by more severe respiratory SARS-CoV-2 infection parameters during hospitalisation.At neurological examination, 37.4% of patients exhibited neurological abnormalities, being cognitive deficits (17.5%), hyposmia (15.7%) and postural tremor (13.8%) the most common.Patients with cognitive deficits at follow-up were comparable for age, sex and pre-admission comorbidities but experienced worse respiratory SARS-CoV-2 infection disease and longer hospitalisation.

INTRODUCTION
After the first cases of the novel coronavirus disease 2019 (COVID-19) were reported in Wuhan, China, in December 2019, the spread rapidly became a pandemic, involving millions of cases worldwide.With the increasing number of confirmed cases and the accumulating clinical data, it is now well established that, in addition to the predominant respiratory symptoms, a significant proportion of COVID-19 patients experience neurological symptoms and syndromes [1][2][3] .
Clinical findings on previously hospitalised and non-hospitalised patients with COVID19 reported the persistence of multiple symptoms, particularly fatigue and dyspnoea 4 .Accordingly, some authors have suggested the so called, but not yet defined, "post-COVID-19 syndrome" based on symptoms reported after three months of SARS-CoV-2 infection 5 .Few follow up studies, however, have investigated patients discharged from hospital after recovery from COVID-19 and no data about persistent neurological manifestations are available yet.
In this study, subjects previously hospitalised for COVID-19 disease entered a longitudinal study in order to evaluate neurological manifestations after 6 months of follow-up and their potential relationship with pre-morbid conditions and severity of SARS-CoV-2 infection.

METHODS
All COVID-19 survived patients without pre-morbid neurological disease discharged between February and April 2020 from a COVID-19 Unit of the ASST Spedali Civili Hospital were asked to participate to a follow-up study including a standardised medical and neurological symptoms checklist and a neurological examination at 6 months.Premorbid conditions were recorded at admission using the Cumulative Illness rating scale 6 (CIRS).Hospitalisation data included the severity of COVID-19 disease, classified according to the Brescia-COVID Respiratory Severity Scale (BCRSS 7 ), assigning one point to i) dyspnoea ii) respiratory rate > 22 iii) PaO2<65 mmHg or SpO2 <90% iv) worsening of interstitial pneumonia at X-ray and the risk of deterioration with the quick Sequential Organ Failure Assessment (qSOFA) score 8 .
At follow-up, data were collected using a neurological checklist including symptoms related to central, peripheral, myopathic and cognitive manifestations, whereas the neurological examination assessed cranial nerves, motor, sensory, cerebellar, basal ganglia-related function, deep tendon reflexes, pyramidal signs and global cognitive function using the Montreal Cognitive Assessment (MoCA).The study was approved by the local ethics committee of ASST "Spedali Civili di Brescia" Hospital and the requirement for informed consent was waived by the Ethics Commission (NP 4166).

Statistical analysis
Differences between patients according to COVID-19 respiratory severity (BCRSS) and the association with neurological complaints were evaluated by Fisher's exact test or ANOVA with Bonferroni correction for dichotomic and continuous variables, respectively.Logistic regression analyses were performed in order to evaluate demographics and clinical predictors (including age, sex, CIRS, days of hospitalisation, O2 treatment and BCRSS) of the presence of i) neurological complaints or ii) neurological features at examination (separately for the most common symptoms and features reported).
The data that support the findings of this study are available from the corresponding author upon reasonable request.

RESULTS
From a sample of 208 consecutively hospitalized patients for COVID-19 disease, 33 deceased during hospitalisation.Survivors were younger (p=0.001;65.7+12.6vs 78.6+8.6) and exhibited less comorbidities (p=0.004,mean CIRS 1.36+0.51vs 1.51+0.4) in front of similar COVID-19 severity compared to deceased patients.Out of 175 survivors, five patients died after discharge, three had a previous diagnosis of dementia and two refused to participate, resulting in a final sample of 165 patients included (supplementary Figure 1).Patients stratified according to COVID-19 severity (BCRSS) differ for number of days of hospitalisation, O2 treatment and qSOFA but not for age or premorbid total and severity comorbidity index (Table 1).
Severity of COVID-19 disease and duration of hospitalisation (p=0.002 for both) were the best predictors of abnormal MoCA after adjusting for age, sex and premorbid comorbidities in logistic regression analyses.

DISCUSSION
Findings showed that previously hospitalized COVID-19 patients reported a wide array of neurological symptoms six months after SARS-CoV-2 infection, predicted by combination of age, premorbid conditions and severity of disease.These findings extend recent studies which have argued for a high prevalence of Post-COVID clinical manifestation and claimed that long term consequences of COVID-19 involve both central and peripheral nervous systems 1,2,10,11 .In particular, Goertz and coauthors 5 reported common persistent symptoms about 3 months after COVID-19 onset in a large survey of previously hospitalised and non-hospitalised patients.Similarly, Carfi and co-authors 4 found that in patients hospitalized for COVID-19 disease, 87% reported persistence of at least one symptom, particularly fatigue and dyspnoea -about 60 days after discharge.
In the present cohort of patients with six months of follow-up, the most prevalent symptoms reported were fatigue, memory complaints, sleep disorders and myalgias followed by depression/anxiety, visual disturbances, paraesthesias and hyposmia.Long-term neurological complaints showed different distributions according to COVID-19 severity, whereas age and oxygen treatment were the best predictors in logistic regression analyses.The neurological examination revealed hyposmia, cognitive impairment and postural tremor as the most prevalent features.Longer hospitalization and premorbid conditions were the strongest predictors of neurological abnormalities at examination, whereas cognitive impairment was specifically associated with severity of COVID-19 independently from age and pre-morbid conditions.On one hand, this suggest that hospitalization and severity of COVID-19 have a large impact in subjects with increased multimorbidity, in line with other infectious diseases, such as community-acquired pneumonia 12 .On the other, the persistence of observed cognitive deficits needs to be addressed in COVID-19 follow-up programs in order to specifically evaluate their impact and progression overtime and disentangle their potential relationship with psychosocial and psychiatric disturbances [13][14] .
Several limitations should also be acknowledged.First, pre-morbid conditions were based on medical records and assessment during hospitalisation thus not allowing an extensive neurological and psychiatric screening at the baseline.Second, in this study patients with neurological diseases developed during the acute phase of SARS-CoV-2 infection were not considered, thus potentially underestimate the global neurological burden due to COVID-19.Furthermore, this is a single-center study with a relatively small sample size and large studies including non-hospitalized patients are warranted to confirm the present data.
Limitations notwithstanding, our findings indicate that several neurological features are a relevant component of long-term manifestations of COVID-19 disease even in less severe patients, thus suggesting the importance of long-term follow-up programs to properly care patients and to be able to evaluate the real impact of SARS-CoV-2 infection on brain health status that is still uncertain 15 .

Conclusions:
long term neurological manifestations after hospitalization due to COVID-19 infection affects one third of survivors.Multiple neurological abnormalities including mild cognitive impairment are associated with severity of respiratory SARS-CoV-2 infection.

FIGURE LEGEND Figure 1
FIGURE LEGEND

Table 1
Demographic and clinical characteristics of the sample according to COVID-19 severity.In bold significant results after Bonferroni correction * significant for the comparison between BCRSS1 vs BCRSS2 groups #: significant for the comparison between BCRSS2 vs BCRSS3 groups ¶: significant for the comparison between BCRSS1 vs BCRSS3 groups Abbreviations: BCRSS, Brescia-COVID Respiratory Severity Scale; CIRS, Cumulative Illness rating scale; qSOFA, quick Sequential Organ Failure Assessment.