Recurrence, Reactivation, or Inflammatory Rebound of SARS-CoV-2 Infection With Acute Vestibular Symptoms: A Case Report and Revision of Literature

A case of recurrent coronavirus disease 2019 (COVID-19) with neurovestibular symptoms was reported. In March 2020, a physician working in an Italian pediatric hospital had flu-like symptoms with anosmia and dysgeusia, and following a reverse transcription PCR (RT/PCR) test with a nasopharyngeal swab tested positive for SARS-CoV-2. After home quarantine, 21 days from the beginning of the symptoms, the patient tested negative in two subsequent swabs and was declared healed and readmitted to work. Serological testing showed a low level of immunoglobulin G (IgG) antibody title and absence of immunoglobulin M (IgM). However, 2 weeks later, before resuming work, the patient complained of acute vestibular syndrome, and the RT/PCR test with mucosal swab turned positive. On the basis of the literature examined and reviewed for recurrence cases and vestibular symptoms during COVID-19, to our knowledge this case is the first case of recurrence with vestibular impairment as a neurological symptom, and we defined it as probably a viral reactivation. The PCR retest positivity cannot differentiate re-infectivity, relapse, and dead-viral RNA detection. Serological antibody testing and viral genome sequencing could be always performed in recurrence cases.


INTRODUCTION
In China, in December 2019, the epidemic caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) rapidly diffused all over the world leading to a pandemic. While the coronavirus disease 2019  typically presents as a self-limiting respiratory disease, and in hospitalized patients, the clinical picture is dominated by respiratory distress (Del Sole et al., 2020), progression to severe illness with multiorgan involvement, including the blood vessels, heart, gut, kidneys, testicles, and brain has been reported (Asadi-Pooya and Simani, 2020;Ibrahim, 2020;Leonardi et al., 2020;Nepal et al., 2020). Patients suffering from COVID-19 can develop acute or long-term neurological sequelae (Ellul et al., 2020). The prevalence of neuro-COVID varies considerably between individual studies ranging from 4.1%  to 57.4% (Romero-Sánchez et al., 2020) and even 84% in COVID-19 with acute respiratory distress syndrome (Helms et al., 2020). The onset of nervous system damage can be asynchronous with systemic manifestations and the typically salient severe respiratory disease (Vavougios, 2020).
In our pediatric hospital, between March and May 2020, there were 25 cases of COVID-19 among healthcare workers (HCWs), equal to 1.1% of the total staff. Two of them had at least one symptom, namely, headache, anosmia, and dysgeusia or all the three symptoms at the same time. These neurological symptoms indicate that the virus, like other respiratory viruses (Bohmwald et al., 2018), enters the central nervous system (CNS) through the olfactory bulb causing inflammation. Furthermore, SARS-CoV-2 viruses can spread from the mechano-and chemo-receptors in the lungs and lower respiratory airways to the medullary cardiorespiratory center via a synapse-connected route .
In this study, we report a case of recurrent SARS-CoV-2 infection with neurovestibular involvement, review literature cases with vestibular involvement, and discuss the neurotropism of this virus based on literature data.

Case Description
A 48-year-old female physician in a pediatric hospital presented cough, slight dyspnea, severe myalgia, asthenia, and headache on March, 2020, followed by anosmia and dysgeusia over the following few days (Figure 1) without fever. When symptoms appeared the worker self-isolated at home. The allergic rhinitis the patient suffers from led to a short delay in diagnosis; however, a swab carried out 8 days from the beginning of the symptoms tested positive for SARS-CoV-2 (Allplex TM 2019-nCoV Assay). In subsequent days, the patient felt better and became asymptomatic. On days 23 and 27 the patient was retested and was negative both times. On day 37, serology was performed by ELISA and a low level of immunoglobulin G (IgG) against SARS-CoV-2 was detected. Immunoglobulin M (IgM) search was negative. She was feeling well and was declared fit to work by the occupational physician of the hospital. However, before returning to work, on day 39 the patient woke up experiencing intensive dizziness, described as subjective vertigo, associated with vomiting and bilateral aural fullness (Figure 1). The dizziness quickly got worse as the patient lied supine on the right side. She was transported by ambulance to the emergency room of a hospital where dizzying syndrome was diagnosed and treated with metoclopramide. Physical examination revealed normal vital signs, while the patient was breathing ambient air. Some relevant auxiliary examinations such as blood routine, coagulation function, liver and renal function, electrolytes, and inflammation indicators were completed, and the results were normal. After 3 h and the improvement of the symptoms, she was discharged home, cared by health public service, and treated with betahistine dihydrochloride for 1 week. The day after, on day 40, a nasal swab was obtained, which tested positive.
In the following days, the dizziness disappeared and only a mild postural instability persisted, whereas aural fullness was unchanged. The only pathology that she suffered from was allergic rhinitis. She had never suffered from dizziness in the past.
An ear, nose, and throat (ENT) visit took place on day 44. Otoscopy was negative. Romberg, Unterberger (March-inplace), and finger-to-nose tests were negative. Neither bedside vestibular examination with Frenzel glasses showed spontaneous nystagmus, nor was nystagmus evoked by supine position, Dix-Hallpike maneuver, lateral head rotation, and Rose position. The head-shaking test was negative. The only relevant finding of the vestibular examination was the patient complaining about slight dizziness during the Dix-Hallpike maneuver on the right side (supine position with the head hyperextended and tilted to the right side). The patient did not develop fever both in the first and in the second phase of the symptoms related to COVID-19. Despite fever being one of the most common symptoms of COVID-19, it may be absent in some individuals. Finally, the patient was completely healed without any deficit and was able to return to work.

DISCUSSION
The case reported presents numerous points of interest. First, the recurring nature of the symptoms must be emphasized along with the neurological origin of the symptoms themselves. Second, the neurotropism and neuroinvasive potential of the virus into recurrence mode should be considered. Finally, the observation that the presence of anti-spike IgG has been followed by a positive PCR test; this feature is rather infrequent, having been found in 0.13 per 10,000 days at risk in HCWs, whereas the probability of having a positive PCR test in the anti-spike-seronegative HCWs is significantly higher (1.09 per 10,000 days at risk) (Lumley et al., 2020).
The presence of at least two consecutive negative RT-PCR tests in respiratory samples (with samples taken at least 24 h apart) and the appearance of specific IgG at serological test, according to the discharge criteria of the European Centre for Disease Prevention and Control (Yahav et al., 2021), permits to classify the case exposed as recurrent COVID-19 with multiple district neurological symptoms (vestibular symptoms, previously anosmia and dysgeusia). Indeed reinfection should be considered during the first 90 days if clinical symptoms of the first episode resolve and two PCR tests were negative before the new episode (Yahav et al., 2021).
Currently, there are numerous reports that a number of patients tested positive again after two consecutive negative PCR tests or after clinical recovery ( Table 1) (Falahi and Kenarkoohi, 2020). Nasopharyngeal swabs tend to have a higher sensitivity than the other samples and are the most common method for diagnosis of COVID-19 recurrence, regardless of the clinical disease manifestation. With the progression of SARS-CoV-2 infection, the virus could migrate from the upper respiratory tract to the lower respiratory tract and lungs, resulting in insufficient viral load in the upper respiratory tract, which may explain the negative result of the nasopharyngeal swab test. The detection rate and sensitivity have been improved by multisite specimen collection and serological assays ( Table 1). The prevalence of disease recurrence among COVID-19 recovered patients was approximately 14.8%, ranging from 7.35 to 21.4% (Azam et al., 2020;Hoang, 2020). The interval duration from the last negative PCR tests to recurrent positive results ranged from 1 to 123 days (min average 16.16 ± 20.93 ds, max average 25.39 ± 23.00 ds) for 1,038 cases in a selected population of 13,565 patients ( Table 1). The case described experienced at the onset two of the three typical symptoms in the first phase of infection, namely, cough (68%) and shortness of breath (66%) without fever (69%). About 92% of the patients experienced at least one of these, less frequently in women (66, 64, 66 respectively; 90% at least one of these; vs. men 70, 67, 71; 93%, each p < 0.001) (ISARIC Clinical Characterisation Group, 2021). She presented symptoms of recurrence 17 days from the last negative PCR tests, in accordance with the literature. True reinfection has criteria that must be considered, including isolation of the complete genome of the virus (and not just genomic fragments) in the second episode (Falahi and Kenarkoohi, 2020), but we did not have this data. In our patient, we could suspect a viral reactivation due to low level of IgG against SARS-CoV-2 detected, even without lymphopenia. It is also possible that the immune responses can suppress, but not completely eradicate, SARS-CoV-2, which may have led to the false-negative results due to lower viral loads . Once the virus starts replicating again, the RT-PCR results reverted to positive and expressed as a new neuroinvasion in the vestibular system. NeuroCovid is now well-known (Whittaker et al., 2020), but recurrence of positive RT-PCR with neurological symptoms is very rare and no further instances of vestibular symptoms are described as recurrence ( Table 1). To our knowledge, this is the first case of vestibular symptoms as recurrence of positive RT-PCR SARS-CoV-2. This case shows the neuroinvasive potentials of SARS-CoV-2 and the possibility of disease reactivation after clinical and analytic recovery. SARS-CoV-2 might be latent in some neurons to hide from immune surveillance (Brandt and Dieterich, 2017;Zhang M. et al., 2020). For reasons unclear, after an apparent remission the virus reactivated and was again identifiable in the respiratory tract. At the same time, the multiplication in the nervous system caused recurrence with intense neurological disturbance, clinically highlighted by dizziness associated with slight dyspnea.
The clinical picture and subsequent ENT are compatible with a diagnosis of the spontaneous acute vestibular syndrome. The most common cause is an acute peripheral vestibulopathy known as vestibular neuritis, affecting the vestibular nerve or "pseudoneuritis" if the acute lesions affect the root entry zone of the eighth nerve or the vestibular nucleus .
A relapse of the disease with the involvement of the nervous system may indicate that the virus can be neurotropic since the beginning of the disease or in its recurrence form.
The virus may reach the central nervous system via the olfactory nerve. Olfactory and gustatory dysfunctions without rhinorrhea or nasal obstruction are distinctive of patients with mild-to-moderate COVID-19 infection (Baig, 2020;Cooper et al., 2020;Magnavita et al., 2020;Paniz-Mondolfi et al., 2020;, leading to speculation regarding the olfactory nerve as a possible route of the central nervous system entry. Dizziness is a common onset symptom of COVID-19 ( Table 2). This symptom is often considered a non-specific neurological manifestation and is not actively researched or        Table 2). Vertigo should be investigated in SARS-CoV-2 patients and considered along with neurological signs induced by the invasion of the vestibular pathway from the nerve to the vestibular nuclei complex. It is plausible to hypothesize that if the SARS-CoV-2 can also reach the brain from the lungs through the vagus nerve, the virus will invade the brainstem starting with the vagal nucleus and surrounding sites, including the respiratory control center and more, which can lead to more respiratory dysfunction that further exacerbates the damage caused by the primary infection in the lungs or others neurological symptoms (Lukiw et al., 2020;Yachou et al., 2020), such as vestibular impairment. This hypothesis is supported by the evidence of the presence of a consistent angiotensin-converting enzyme (ACE2) expression across the cerebral cortex. The highest ACE2 expression was found in the pons and the medulla oblongata (Guan et al., 2020). Indeed, SARS-CoV-2 appears to bind exclusively to the ACE2 protein, a single-pass type 1 transmembrane receptor with its enzymatically active domain exposed on the surface of multiple cell types, such as type II alveolar cells of the respiratory system, enterocytes and intestinal epithelial cells, endothelial cells, epithelial cells of the conjunctival epithelium, kidney cells (renal tubules), and certain immune cells, such as the alveolar monocytes/macrophages and certain cells of the CNS including those of the cerebral cortex, especially the brainstem (Zubair et al., 2019;Chigr et al., 2020;Kabbani and Olds, 2020;Li M. et al., 2020;Panupattanapong and Brooks, 2020;154). The highest levels of ACE2-expression in the brain were found in the pons and medulla oblongata, the breathing centers of the brain, which may in part explain the unusually strong ability of SARS-CoV-2 to disrupt normal respiration and pulmonary manifestations including shortness of breath, impaired breathing, and severe respiratory distress. Significant neuroinvasion involving SARS-CoV-2 has been reported from both patients and experimental animals, where the brainstem was heavily infected from apparent spreading via a synapseconnected route to the medullary cardiorespiratory centers (Panupattanapong and Brooks, 2020). A limitation of this case consists of the absence of magnetic resonance documentation of vestibular impairment and the genetic characterization of the viruses at the onset and recurrence of COVID-19. The rapid resolution of clinical symptoms within a few days and the trend of not submitting the non-hospitalized patient to neuroimaging exam above all in patients with low suspicions of CNS disease and plan for outpatient ENT visit in the pandemic period, prompted the emergency physician not to proceed. Several causes for repositive tests for SARS-CoV-2 in COVID-19 patients during the recovery period have been described. They include false RT-PCR results or positive due to traces of the RNA genome, intermittent virus shedding, viral reactivation in people with low antibody levels or immunity, reinfection with another SARS-CoV-2 strain, an acute severe systemic inflammatory response known as cytokine release syndrome (CRS), or exposure to a contaminated environmental surface after discharge Dao et al., 2021). Various molecular diagnostic assays have been developed and used worldwide, but the differences in their diagnostic performances remain poorly understood (Matsumura et al., 2020;Liotti et al., 2021;Wang M. et al., 2021). Most of the articles do not report the commercial kit used for RT-PCR, and, where reported, the sensitivity and specificity data for the kit is not often available in the literature ( Table 1). All the assays exhibited a specificity of 100%, while sensitivity varied ( Table 1). The RT-PCR test cannot distinguish between live and dead viruses, but most recurrence of positive RT-PCR is expressed in an asymptomatic way; therefore likely due to dead viruses. We did not perform a genetic characterization of the viruses in order to distinguish between reinfection and reactivation of SARS-CoV-2 in our repositive patient.

CONCLUSIONS
This case is suggestive of colonization of the nervous system that can also result in clinical manifestations in cases of recurrence witnessing the diffusion or permanence of SARS-CoV-2 in the nervous system. It also suggests the neurotrophic hypothesis with the possibility of brainstem invasion (pons and medulla oblongata) and the possibility of recurrence with a SARS-CoV-2 positive RT-PCR test and of clinical recurrence with specific neurological symptoms.
Neurological symptoms should be sought and typified in each SARS-CoV-2 patient.
With the outbreak of COVID-19, to better manage the current phase of the pandemic, we should be vigilant for the presence of any neurological symptoms, both as an onset and as a recurrence of infection.
On the basis of the literature examined and reviewed, for recurrence cases and vestibular symptoms during COVID-19, to our knowledge, this is the first case of recurrence with vestibular impairment as neurological symptom, and we suspect it is likely due to viral reactivation. The PCR retest positivity cannot differentiate between reinfectivity and relapse, and dead-viral RNA detection, serological antibody testing, and viral genome sequencing could be always performed in recurrence cases.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

ETHICS STATEMENT
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

AUTHOR CONTRIBUTIONS
All authors equally contributed to the conception and design of the study. All the authors agreed on the previous version of the manuscript, read, and approved the final manuscript.