key: cord-318909-h5b7mncf
authors: Liguori, Claudio; Pierantozzi, Mariangela; Spanetta, Matteo; Sarmati, Loredana; Cesta, Novella; Iannetta, Marco; Ora, Josuel; Genga Mina, Grazia; Puxeddu, Ermanno; Balbi, Ottavia; Pezzuto, Gabriella; Magrini, Andrea; Rogliani, Paola; Andreoni, Massimo; Biagio Mercuri, Nicola
title: Subjective neurological symptoms frequently occur in patients with SARS-CoV2 infection
date: 2020-05-19
journal: Brain Behav Immun
DOI: 10.1016/j.bbi.2020.05.037
sha: 
doc_id: 318909
cord_uid: h5b7mncf

OBJECTIVE: Coronavirus disease 2019 (COVID-19) represents a novel pneumonia leading to severe acute respiratory syndrome (SARS). Recent studies documented that SARS-Coronavirus2 (SARS-CoV2), responsible for COVID-19, can affect the nervous system. The aim of the present observational study was to prospectively assess subjective neurological symptoms (sNS) in patients with SARS-CoV2 infection. METHODS: We included patients hospitalized at the University Hospital of Rome Tor Vergata, medical center dedicated to the treatment of patients with COVID-19 diagnosis, who underwent an anamnestic interview about sNS consisting of 13 items, each related to a specific symptom, requiring a dichotomized answer. RESULTS: We included 103 patients with SARS-CoV2 infection. Ninety-four patients (91.3%) reported at least one sNS. Sleep impairment was the most frequent symptom, followed by dysgeusia, headache, hyposmia, and depression. Women more frequently complained hyposmia, dysgeusia, dizziness, numbeness/paresthesias, daytime sleepiness, and muscle ache. Moreover, muscle ache and daytime sleepiness were more frequent in the first 2 days after admission. Conversely, sleep impairment was more frequent in patients with more than 7 days of hospitalization. In these patients we also documented higher white blood cells and lower C-reactive protein levels. These laboratory findings correlated with the occurrence of hyposmia, dysgeusia, headache, daytime sleepiness, and depression. CONCLUSIONS: Patients with SARS-CoV2 infection frequently present with sNS. These symptoms were present from the early phases of the disease. The possibly intrinsic neurotropic properties of SARS-CoV2 may justify the very high frequency of sNS. Further studies targeted at investigating the consequences of SARS-CoV2 infection on the CNS should be planned.

Coronavirus disease 2019 (COVID-19) is a novel pathology due to severe acute respiratory syndrome (SARS) -coronavirus-2 (CoV2) infection, currently representing a great global public health concern causing a SARS with a mortality higher than other acute pneumonia. 1 However, the majority of patients with infection develop mild to moderate respiratory illness, whose clinical manifestations are fever and cough. 2 A part the respiratory illness, an increasing number of reports pointed out that SARS-CoV2 can also affect the nervous system, since neurological manifestations may occur quite frequently in hospitalized patients. 3-4 COVID-19 has been associated with various neurological complications, such as acute cerebrovascular disease and seizures, as well as with several neurological symptoms, including myalgia, headache, confusion, and dizziness. [5] [6] [7] Moreover, hyposmia and dysgeusia have been reported as early manifestations of SARS-CoV2 infection. 7 A large retrospective analysis carried out in China on 214 patients affected by SARS-CoV2 infection confirmed that hospitalized patients complained of subjective neurological symptoms (sNS) in a 36 .4% of cases, including headache, disturbed consciousness, and paresthesia as the most frequent. 4 However, it is not well-defined whether neurological manifestations are consequences of hypoxia and prolonged hospitalization or rather they are related to the neurotropic properties of SARS-CoV2.

Therefore, it has been proposed that the virus may infiltrate the central nervous system (CNS) by possibly passing the blood-brain barrier (BBB) or gathering the olfactory bulb and vagus nerve. 8 In order to carefully explore the presence of sNS during COVID-19, we conducted an observational study aimed at identifying and quantifying the occurrence of sNS by an anamnestic interview in hospitalized patients with SARS-CoV2 infection.

The study was designed as an observational data collection carried out in patients affected by COVID-19. All patients were hospitalized at the University Hospital of Rome "Tor Vergata", representing a medical center dedicated to the treatment of patients with a confirmed diagnosis of COVID-19.

Eligible patients had to meet the following inclusion criteria: be over 18-year-old, conscious, cognitively and mentally conserved, and linguistically competent to respond to the anamnestic interview; diagnosis of COVID-19 based on clinical suspicion and confirmed by viral RNA detection at oropharyngeal and nasopharyngeal swabs; be affected by non-severe respiratory form of COVID-19, as defined using the American Thoracic Society guidelines for community-acquired pneumonia. 9 Additionally, the access to patients' demographic and clinical data, including their corporeal temperature (CT) and their ongoing pharmacological treatments, was mandatory for inclusion.

Exclusion Criteria were: previous diagnosis of neurologic and psychiatric disorders; CT >38° C.

At the time of admission or during hospitalization, patients with COVID-19 fulfilling the entry criteria for the study underwent an anamnestic interview to investigate the presence of sNS. The interview consisted of 13 items, each related to a specific symptom, requiring a dichotomized answer (YES/NO): 1) hyposmia, 2) dysgeusia, 3) auditory dysfunction, 4) headache, 5) confusion, 6) dizziness, 7) numbness/paresthesia, 8) fatigue, 9) daytime sleepiness, 10) sleep impairment, 11) muscle ache, 12) depression, 13) anxiety.

All anamnestic interviews were collected by clinicians from the care units where patients were hospitalized, and reviewed and confirmed by two trained neurologists (CL and MP).

For the purpose of this observational study, we collected the following patients' data: age, sex, CT, laboratory test, duration of hospitalization and sNS recorded at the time of anamnestic interview.

Laboratory testing was performed at the time of anamnestic interview and the following serum markers were included in the analysis: white blood cell (WBC) count, neutrophil total cell count and percentage of WBC, lymphocyte total cell count and percentage of WBC, C-reactive protein (CRP).

Quantitative measurements of WBC and serum CRP were analyzed by an immunonephelometric method, performed on a Dimension System Vista (Siemens Healthcare Diagnostics).

All participants gave written informed consent after receiving an extensive disclosure of study purposes. The local ethics committee at University Hospital of Rome Tor Vergata approved the procedures (protocol no. 48.20, version 2020).

Statistical Package for the Social Sciences for Windows (SPSS version 22,0; IBM Corp, Armonk, NY, USA) was used to perform the statistical analyses.

Categorical data were expressed as absolute frequencies and percentages where appropriate. The parametric data are presented using descriptive statistics (mean ± standard deviation). Proportions for categorical variables were compared using the χ 2 test or ANOVA with post-hoc analysis, when appropriate. The significance threshold was set at a 2-sided P value less than .05.

103 patients with a confirmed SARS-CoV2 infection were included in the analysis following the inclusion and exclusion criteria for the study within the time interval between 30 th March and 24 th April 2020. Fifty-nine patients were men and 44 patients were women. Thirty-three patients underwent the anamnestic interview to assess the sNS on the 1 st and 2 nd day after admission, 31 patients responded to the interview between the 3 rd and 7 th day of hospitalization, and the remaining 39 patients after the 7 th day of hospitalization. Demographic and clinical characteristics are shown in Table 1 and Table 2 . 37.86%). Moreover, we performed a sex-based analysis comparing the occurrence of sNS between men and women and documented that hyposmia, dysgeusia, headache, dizziness, numbness/paresthesia, daytime sleepiness, and muscle ache were more frequent in women than men ( (Table 3) .

When comparing the data achieved by the anamnestic interview during the period of hospitalization, we documented that sNS were more frequent in the first 2 days after admission and after the 7 th day of hospitalization than in the period in between ( Table 2) . Muscle ache and daytime sleepiness were more frequent in patients evaluated on the first 2 days and in the period between the 3 rd and 7 th day after admission compared to patients with a hospitalization long more than 7 days; moreover, sleep impairment was more frequent after the 7 th day of hospitalization than the other analyzed periods (Table 2) .

Considering the sex-based distribution of patients, we documented higher WBC and CRP in man than women (Table 1 ). In patients evaluated after the 7 th day of hospitalization, we documented higher WBC and lower CRP levels than the other two groups of patients (Table 2 ). Considering the subgroups of patients distributed based on the sNS, we did not find differences among the three groups ( 

This observational study, carried out in 103 patients affected by SARS-CoV2 infection, documented the high prevalence of sNS during the course of the disease, even immediately after admission to the Hospital.

Although the involvement of nervous system during SARS-CoV2 infection has been extensively proposed, [10] [11] [12] few studies focused the investigation on neurological symptoms in patients with 7 The largest study examining the neurological manifestations of hospitalized patients with COVID-19 was a retrospective analysis achieved by reviewing patients' clinical charts. 4 The authors documented a neurological manifestation in 36.4% of cases, reporting that patients with severe COVID-19 showed more nervous system symptoms than patients with the non-severe form of the infection. 4 Moreover, other reports, not centered on the neurological manifestations of COVID-19, reported the presence of few neurological symptoms in patients with SARS-CoV2 infection. [5] [6] [13] [14] However, since all these studies have a retrospective design and data were achieved by the extraction from electronic medical records, detection of slight neurological manifestations, such as sleep and wake impairment, headache, dysgeusia, hyposmia, and dizziness, could be limited. 15 In the present study, we performed a prospective observation in patients with non-severe respiratory form of SARS-CoV2 by using an anamnestic interview designed to better determinate the occurrence and type of sNS over the course of the disease. Based on the prospective design of this examination, we documented a very high number of patients complaining sNS. Consistently, only 9 out of 103 patients (less than 10%) did not report sNS and more than 65% of the whole sample described three or more sNS at the interview. Namely, in the total group of patients, sleep impairment, dysgeusia, headache and hyposmia were the most frequent complained sNS. Notably, the frequency of sNS was elevated from the early phases of the disease, immediately after the admission to the hospital, remaining high also after a prolonged hospitalization. Considering the different timing of administration of the anamnestic interview in the patients included, we documented that muscle ache and daytime sleepiness were more frequent in the first two days after admission, whereas sleep impairment appeared more frequently after the 7 th day of hospitalization.

Taking all the findings of this study into account, it appeared evident that patients with SARS-CoV2 frequently experienced sNS. Accordingly, during the infection, sNS seem to be present from the very early stages of the disease and in some cases prior to the hospitalization, as previously reported. 7, 16 We documented that patients may complain more than one sNS during the prolonged hospitalization and sleep impairment was the main complain in patients interviewed after the 7 th day from admission.

It has been already explained that hospitalization may significantly disrupt sleep, thus clinically producing insomnia symptoms. 17 The mechanisms at the basis of the high frequency of neurologic complaints in patients with SARS-CoV2 infection are not completely understood and thus they are still hypothetical. 8, [18] [19] The autoptic studies performed in patients with COVID-19 documented hyperemia, oedema, and neuronal degeneration reflecting nervous system damage. 3 Therefore, the intrinsic properties of this novel coronavirus may represent possible mechanisms for affecting the nervous system. SARS-CoV2 may enter the nervous system through hematogenous or non-hematogenous routes. No study demonstrated the ability of the novel coronavirus to pass the BBB, but only singular case reports documented encephalitis due to SARS-CoV2 possibly passing the BBB by increasing its permeability through the production of cytokines or by the action of concomitant bacteria destroying it. Therefore, the nonhematogenous route of infection has been mostly hypothesized. 8, [20] [21] [22] Considering this latter route of infection, neuronal pathway represents the most suitable mechanism of infection, since it is considered an important vehicle for neurotropic viruses to enter the CNS. In the hypothetical model of CNS invasion, virus can migrate by infecting nerve endings and achieving retrograde or anterograde neuronal transport through the motor proteins, dynein and kinesins. 23 The main gate of CNS infection by neurotropic viruses is the olfactory pathway. 24 As a consequence, SARS-CoV2, as the other coronaviruses affecting the nasal mucosa, can enter the brain through the olfactory tract from the early stages of infection. 8, [25] [26] Moreover, coronaviruses can migrate from the olfactory bulb to cortex, basal ganglia, and midbrain, which are affected during their spreading. 27 This hypothesis has been confirmed in animal models by the removal of the olfactory bulb, which resulted in a restricted invasion of coronaviruses into CNS. 28 Taken together, the potential neuroinvasive propensity of SARS-CoV2 may justify the sNS complained by patients. Further possible mechanism explaining the involvement of nervous system during COVID-19 is related to ACE2 that represents the functional receptor of SARS-CoV2 and is widely expressed in multiple tissues, including the nervous system. [29] [30] Finally, the nervous system can by indirectly affected by SARS-CoV2 due to the mediated effects generated by the immune system. 31 Accordingly, this neurotropic virus can trigger the development of a systemic inflammatory response syndrome (SIRS). SIRS can be localized also in the nervous system and is mediated by activated glial cells inducing a pro-inflammatory state during the SARS-CoV2 infection. 32 As a consequence, activated glial cells release several inflammatory factors, such as interleukin (IL)-6, which is an important member of the cytokine storm. 28, 33 This inflammatory response may be responsible for sNS in patients with COVID-19.

Consistently, IL-6, IL-1, and tumor necrosis factor (TNF)-α have been reported to induce symptoms such as impaired mood, anxiety, cognitive disturbances, fatigue, hyperalgesia. [34] [35] [36] We also included in the analysis the main laboratory findings used for quantifying the immune and inflammatory response, such as WBC and CRP, in order to investigate the relationship between these immune parameters and the occurrence of sNS. Significantly, the increment of CRP was evident in the first days after admission, while WBC count was higher in patients evaluated after a prolonged hospitalization. This finding may reflect the initial inflammatory response and possibly subsequent bacterial co-infection in patients with SARS-CoV2 infection. 37 In patients with more than 3 sNS the CRP tended to be higher, but the distribution of patients in the three groups cannot allow achieving the statistical significance. This point needs to be further analyzed in studies focused on the relationship between the inflammatory response and the occurrence of sNS in patients with SARS-CoV2 infection.

The sex-based distribution of patients demonstrated that female patients reported more frequently sNS than men. In particular, hyposmia, dysgeusia, headache, dizziness, numbness/paresthesia, daytime sleepiness, and muscle ache were more frequent in women than men. This sex-based difference can be attributed to the humoral and innate immune responses to viral infections more marked in women than men. [38] [39] [40] However, we documented higher CRP, WBC, and neutrophil cell count in men than women, which can reflect an higher immune response in men possibly driven by the occurrence of a concomitant bacterial infection leading to a more severe infection. 37, 41 In this study we documented the high frequency of neurological symptoms in patients with SARS-CoV2 infection. In particular, sNS were present in patients not admitted to intensive care units and without severe pneumonia. Hence, it is conceivable that the infection per se, more than the severity of pneumonia, prolonged hospitalization, or adverse effects of the anti-COVID treatments, may affect the CNS and thus cause the neurological symptoms in patients with COVID-19. 42 To check this hypothesis, we documented the relationship between the occurrence of sNS and the alteration of the main laboratory findings reflecting the immune and inflammatory responses (CRP and WBC); however, this very preliminary impression needs to be further investigated in larger studies evaluating different infection-related biomarkers, inflammatory cytokines, and WBC subsets.

We are aware that this study presents some limitations. We included patients admitted to a single hospital recognized by the Government for treating patients with SARS-CoV2 infection; more information about patients confined to home isolation can be useful to mitigate the possibly negative effects of hospitalization. We performed an observational, but cross-sectional analysis, in patients at different time points during their hospitalization and a longitudinal evaluation of patients during the course of the disease can give more information about the progression of the sNS. However, the strength of this study is the homogeneous sample of patients prospectively evaluated by using an anamnestic interview centered on sNS, which were categorized for better analyzing their prevalence.

This study showed that neurological symptoms may be frequently complained in patients with COVID-19. Moreover, they may contribute to hospitalization, and increase the distress due to SARS-CoV2 infection also in patients without severe forms of the disease. As a consequence, it is particularly required to make clinicians aware of the impact of SARS-CoV2 infection on the nervous system, also in patients without severe respiratory infection. 

Epidemiological Characteristics of COVID-19: A Systemic Review and Meta-Analysis

Epidemiology and Transmission of COVID-19 in Shenzhen China: Analysis of 391 cases and 1,286 of their close contacts

National Health Commission of the People's Republic of China. Diagnosis and treatment of the novel coronavirus pneumonia

Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study

Nervous system involvement after infection with COVID-19 and other coronaviruses

Diagnosis and Treatment of Adults with Communityacquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America

Looking ahead: The risk of neurologic complications due to COVID-19

Neurologic complications of coronavirus infections

The Spectrum of Neurologic Disease in the Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic Infection: Neurologists Move to the Frontlines

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet

Understanding of COVID-19 based on current evidence

Acute-onset smell and taste disorders in the context of Covid-19: a pilot multicenter PCR-based case-control study

Sleep in hospitalized medical patients, part 1: factors affecting sleep

Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms

The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients

A first case of meningitis/encephalitis associated with SARS-Coronavirus-2

COVID-19-associated Acute Hemorrhagic Necrotizing Encephalopathy: CT and MRI Features

Encephalitis as a clinical manifestation of COVID-19

Viral diseases of the central nervous system

Virus infections in the nervous system

Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System? Viruses

Transolfactory neuroinvasion by viruses threatens the human brain. cta Virol

Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2

Neurologic Alterations Due to Respiratory Virus Infections

Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

Infectious immunity in the central nervous system and brain function

Coronavirus neurovirulence correlates with the ability of the virus to induce proinflammatory cytokine signals from astrocytes and microglia

Characteristics of lymphocyte subsets and cytokines inperipheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)

Biological basis of the behavior of sick animals

Sickness behavior as a new target for drug development

Men and women differ in inflammatory and neuroendocrine responses to endotoxin but not in the severity of sickness symptoms

Dysregulation of immune response in patients with COVID-19 in Wuhan, China

Gender differences in human sepsis

Sex differences in autoimmune disease

Alterations in Smell or Taste in Mildly Symptomatic Outpatients With SARS-CoV-2 Infection

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Neurological manifestations of the coronavirus (SARS-CoV-2) pandemic 2019-2020

We would thank all the patients who answered at the anamnestic interview during their disease and who understand the importance of reporting their symptoms in order to improve the management of SARS-SoV2 infection. 

 COVID-19 is a novel pathology due to SARS-CoV2 infection  Nervous system manifestations of SARS-CoV2 infection has been reported  Neurological symptoms occur in more than 90% of patients with SARS-CoV2 infection  Women more frequently present subjective neurological symptoms than men