Facial Nerve Paralysis and COVID‐19: A Systematic Review

Authors: Amirpouyan Namavarian, MD, 1 Anas Eid, BMSc, 2 Hedyeh Ziai, MD, 1 Emily YiQin Cheng, BSc, 3 and Danny Enepekides, MD, MSc, FRCSC Laryngoscope. 2022 Aug 8 : 10.1002/lary.30333. doi: 10.1002/lary.30333

Abstract

Objective

Several cases of facial nerve paralysis (FNP) post‐COVID‐19 infection have been reported with varying presentations and management. This study aims to identify FNP clinical characteristics and recovery outcomes among patients acutely infected with COVID‐19. We hypothesize that FNP is a potentially unique sequalae associated with COVID‐19 infections.

Methods

A systematic review of PubMed‐Medline, OVID Embase, and Web of Science databases from inception to November 2021 was conducted following the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines.

Results

This search identified 630 studies with 53 meeting inclusion criteria. This resulted in 72 patients, of which 30 (42%) were diagnosed with Guillain‐Barré Syndrome (GBS). Non‐GBS patients were on average younger (36 vs. 53 years) and more likely to present with unilateral FNP (88%) compared to GBS patients who presented predominantly with bilateral FNP (74%). Among non‐GBS patients, majority (70%) of FNP presented a median of 8 [IQR 10] days after the onset of initial COVID‐19 symptom(s). Treatment for non‐GBS patients consisted of steroids (60%), antivirals (29%), antibiotics (21%), and no treatment (21%). Complete FNP recovery in non‐GBS patients was achieved in 67% patients within a median of 11 [IQR 24] days.

Conclusion

FNP is a possible presentation post COVID‐19 infections, associated with both GBS and non‐GBS patients. Although no causation can be assumed, the clinical course of isolated FNP associated with COVID‐19 raises the possibility of a unique presentation differing from Bell’s palsy, seen with higher proportion of patients developing bilateral FNP and a shorter duration to complete recovery. Laryngoscope, 2022

Keywords: Bell’s palsy, COVID‐19, facial nerve, paralysis

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Abstract

Several cases of facial nerve paralysis (FNP) post‐COVID‐19 infection have been reported. This study aims to identify FNP clinical characteristics and recovery outcomes among patients acutely infected with COVID‐19. A systematic review of databases was performed resulting in 53 included studies and a total of 72 patients, of which 30 (42%) were diagnosed with Guillain‐Barré Syndrome (GBS). Among non‐GBS patients, 70% of FNP presented a median of 8 days after the onset of initial COVID‐19 symptom(s). Complete FNP recovery in non‐GBS patients was achieved in 67% patients within a median of 11 days. Although no causation can be assumed, the clinical course of isolated FNP associated with COVID‐19 raises the possibility of a unique presentation differing from Bell’s palsy, seen with higher proportion of patients developing bilateral FNP and a shorter duration to complete recovery.

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INTRODUCTION

Facial nerve paralysis/palsy (FNP) is a debilitating condition with significant morbidity associated with functional and psychological implications. 1 Although the etiology of FNP is broad, viral‐associated Bell’s palsy is thought to be the most prevalent contributor. 2 Herpes simplex virus (HSV) and Varicella zoster virus (VZV) are known contributors in the development of Bell’s Palsy in the pediatric and adult population. 3 Since the onset of the COVID‐19 pandemic, FNP incidence has increased and there has been a suggested association with COVID‐19 infections. 5 8

Many neurological symptoms have been reported in patients infected with COVID‐19 including anosmia, ageusia, myalgia, paraplegias, and facial palsy among others. 9 10 FNP has been described by numerous studies as an outcome of COVID‐19, either as an isolated symptom in patients who have otherwise been asymptomatic or in combination with other COVID‐19 symptoms. 6 11 Guillain‐Barré Syndrome (GBS), an autoimmune polyneuropathy, is linked to viral infections including Epstein–Barr virus (EBV), VZV, human immunodeficiency virus, and influenza among others. 12 GBS has also been described by numerous case reports as a sequelae of COVID‐19 infections, with many reported cases of FNP. 13 The mechanism of GBS is believed to involve an aberrant immune response resulting in nerve trauma secondary to inappropriate complement activation and inflammatory mediators. 14

The current literature highlights facial paralysis in COVID‐19 infected patients including both adult and pediatric cohorts. Although many case reports have described the presence of acute facial paralysis in COVID‐19 patients, to date, there is no comprehensive systematic review on these patients. The objective of this study is to identify FNP clinical characteristics and recovery outcomes among patients acutely infected with COVID‐19 (confirmed by a positive reverse transcription polymerase chain reaction [RT‐PCR]). We hypothesize that FNP is a potentially unique sequalae associated with COVID‐19 infections. In this systematic review, we summarize the current literature on the presentations of facial nerve paralysis in COVID‐19 patients and describe the management of these patients with the aim of providing guidance for future practitioners on these patients’ clinical diagnosis and management.

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METHODS

Search Strategy

This systematic review was completed using the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines (Fig. 1). The search strategy was conducted using Ovid Embase, PubMed‐Medline, CINAHL and Web of Science databases from inception to November 2021. The database search was done by two reviewers (a.e./a.n.). Keywords and medical subject headings (MeSH) included facial, facial nerve, peripheral facial nerve, paralysis, paresis, palsy, droop, impair*, Bell’s palsy, weakness, disease, movement, COVID‐19, coronavirus, covid, and SARS‐CoV‐2. The exact search details used for all databases are found in Table S1.

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Fig. 1

PRISMA flow diagram. aTwo studies were included after a screen of the citations from the papers during the eligibility phase. RT‐PCR = reverse transcription polymerase chain reaction. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]

Inclusion and Exclusion Criteria

Inclusion criteria consisted of studies reporting FNP in adult and/or pediatric patients actively infected with COVID‐19. This was defined as a positive COVID‐19 RT‐PCR result. There was no comparator and the outcomes recorded included study design, patient demographic, and FNP clinical characteristics and recovery outcome. Published original studies including case reports, randomized controlled trials, prospective, or retrospective observational studies, cross‐sectional and case–control trials since journal inception were included. Patients with non‐active COVID‐19 infections (i.e., negative RT‐PCR results) despite positive serology (positive immunoglobulin G) were excluded. Furthermore, papers published in a non‐English language or non‐peer reviewed publications (abstracts, conference posters, reviews, letters to editors, and editorials) were also excluded.

Data Extraction and Analysis

The search titles and abstracts were independently screened by two reviewers (a.e./a.n.) based on the inclusion and exclusion criteria. Complete manuscripts were retrieved and independently reviewed by the same two reviewers. If there were any disagreements in article selection between the two reviewers, these were resolved by consensus. If a disagreement persisted, a third reviewer was consulted (h.z.). All titles, abstracts, and full texts screening were completed using Covidence (version 1501). Cross‐checking of the included articles and relevant reviews, as well as a manual web search was conducted for unidentified articles. Extracted data included study design, study population demographics, and clinical characteristics. Information regarding FNP onset, laterality, House‐Brackmann (HB) score, associated symptoms, investigations, treatments, and outcomes was extracted. Patients in studies that did not report HB score were assigned a score by the reviewers based on the described clinical presentation and HB scale by the reviewers when possible. 15 Similarly, if there was any disagreement between the two reviewers, a third reviewer was consulted.

Risk of Bias Assessment

The Joanna Briggs Institute critical appraisal checklist for case reports and case series assessment tools were used to appraise the quality of the studies. This was independently assessed by two authors (a.e. and e.c.). Discrepancies were resolved by consensus or by involving a third author (a.n.). The quality of the studies was quantified according to the assessment tools and a final quality rating of “Good,” “Fair,” or “Poor” was given (Table S2A and B). For case reports, “Good” was defined as at least 6 out of 8 criteria met, “Fair” as 4 or 5 criteria met, and “Poor” as 3 or less criteria met. For case series, “Good” was defined as at least 7 out of 10 criteria met, “Fair” as 5 or 6 criteria met, and “Poor” as 4 or less criteria met.

Statistical Analysis

Descriptive statistics were computed for all variables. Categorical variables were reported as unweighted frequencies and percentages. Continuous variables were reported as medians and interquartile range (IQR). Subgroup analysis was performed based on GBS status. IBM SPSS Statistics for Windows, Version 27.0 was used for all statistical analyses.

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RESULTS

Study Selection

Our search identified 1064 studies. After duplicates were removed, a total of 630 studies were reviewed for initial screening. Fifty‐two studies met our inclusion, and two studies were found during our screen of citations listed in our included papers. A total of 54 studies were included (Fig. 1), resulting in 73 patients. 5 10 11 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 The characteristics of each study can be found in Table S3.

Clinical Features: Non‐GBS Versus GBS Patients

The clinical presentations are summarized in Table I. Forty‐two percent of patients presented with FNP in the context of GBS. Patients without GBS were younger than those with GBS (36 vs. 54 years, respectively). Additionally, more non‐GBS patients presented with unilateral FNP compared to those with GBS (88% vs. 26%, respectively). Furthermore, non‐GBS patients had a shorter delay to FNP onset (median [IQR]; 8 [10] days) from the onset of initial COVID‐19 symptoms compared to GBS patients (16 [11] days).

TABLE I

Overall Study Demographics and FNP Clinical Presentations.

Non‐GBS (n = 42)GBS (n = 30)
Patients (%)5842
Age (years), median [IQR]36 [22]54 [23]
Male, n (%)19 (49)21 (70)
Onset of FNP relative to COVID‐19 symptoms, n (%)
Only FNP4 (11)0
Before or concurrent7 (19)2 (6.8)
After26 (70)27 (93.1)
Days from initial symptoms to onset of FNP, median [IQR]8 [10]16 [11]
Unilateral FNP, n (%)37 (88)7 (25.9)
Degree of FNP, median [IQR]3 [2]4.5 [3]
Complete recovery of FNP achieved, n (%)20 (67)4 (13.3)
Days to complete recovery of FNP, median11 [24]30

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FNP = facial nerve paralysis; GBS = Guillain‐Barré Syndrome; IQR = interquartile range.

Thirty‐two studies reported the severity of the FNP using the House‐Brackmann scale, the median grade was 3 [IQR 2] and 4.5 [3] for non‐GBS and GBS patients, respectively.

Of the COVID‐19 symptoms, the most reported were fever (36% and 60% in non‐GBS and GBS patients, respectively) and cough (32% and 63% in non‐GBS and GBS patients, respectively). When considering neurological symptoms in patients with COVID‐19 other than FNP, impairments in taste function (e.g., ageusia, hypogeusia or dysgeusia) were most reported (10% in non‐GBS vs. 37% in GBS) followed by impairments in olfaction (8% and 23% in non‐GBS and GBS patients, respectively). The detailed distribution of symptoms associated with COVID‐19 is found in Table II.

TABLE II

Patient Symptoms.

SymptomNon‐GBS (n = 42), n (%)GBS (n = 30), n (%)
Non‐neurologic
Fever10 (36)18 (60)
Cough9 (32)19 (63.3)
Myalgia8 (29)5 (16.7)
Dyspnea5 (18)7 (23.3)
Fatigue3 (11)5 (16.7)
Neurologic
Anosmia or hyposmia3 (8)7 (23.3)
Ageusia, hypogeusia, dysgeusia4 (10)11 (36.7)
Dysarthria04 (13.3)
Dysphagia04 (13.3)
Odynophagia1 (3)1 (3.3)
Diplopia1 (3)3 (10)

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GBS = Guillain‐Barré Syndrome.

When considering the distribution of non‐neurological COVID‐19 symptoms based on patient GBS status, more GBS patients presented with a cough compared to non‐GBS patients (63% vs. 32%, respectively) (Table II). More GBS presented with taste dysfunction (37% vs. 10%), dysarthria (13% vs. 0%), and dysphagia (13% vs. 0%) compared with non‐GBS patients.

Imaging

The distribution of utilized imaging investigations is shown in Table S3. Magnetic resonance imaging was performed in 36 patients, all of which reported no structural pathology contributing to their FNP (i.e., retro cochlear or middle ear pathology).

Treatment

A summary of the management is shown in Table III. The non‐GBS patients were most frequently treated with steroids (n = 25, 60%), followed by antivirals (n = 12, 29%), antibiotics (n = 9, 21%), symptom management/no treatment (n = 9, 21%), intravenous immunoglobulins (IVIG) (n = 4, 10%), hydroxychloroquine (n = 4, 10%), and physiotherapy (n = 2, 5%). On the other hand, patients with GBS were most treated with IVIG (n = 24, 80%), followed by hydroxychloroquine (n = 12, 43%), plasmapheresis (n = 8, 27%), steroids (n = 7, 23%), antivirals (n = 6, 21%), antibiotics (n = 6, 21%), and physiotherapy (n = 1, 3%).

TABLE III

Patient Management.

TreatmentNon‐GBS (%)GBS (%)
Steroids25 (60)7 (23.3)
Antivirals12 (29)6 (21.4)
Antibiotics9 (21)6 (21.4)
Hydroxychloroquine4 (10)12 (42.9)
IVIG4 (10)24 (80)
Plasmapheresis08 (26.7)
Physiotherapy2 (5)1 (3.3)
No treatment9 (21)0

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GBS = Guillain‐Barré Syndrome; IVIG = intravenous immunoglobulins.

Recovery Outcomes: Non‐GBS Versus GBS

More patients presenting without GBS had complete recovery of their FNP symptoms compared to those with GBS (67% vs. 13% respectively; Table I). Among those with complete recovery in the non‐GBS group, the majority (80%) did not have any additional neurological symptoms, whereas a minority (20%) had further cranial nerve involvement. Fifty‐three percent (n = 8) of those 15 patients treated with steroids in the non‐GBS group completely recovered within 60 days. In contrast, only 15% (n = 2/13) of the GBS patients treated with IVIG achieved complete FNP recovery within 44 days. There was insufficient data on steroid therapy among GBS patients to compare outcomes to non‐GBS patients.

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DISCUSSION

This systematic review summarizes FNP in the context of COVID‐19 infections highlighting patients with systemic autoimmune pathology of GBS and isolated FNP (non‐GBS). Most patients had moderate FNP as graded on the HB scale. Of the reported non‐neurological COVID‐19 symptoms, the most common were fever and cough. Patients with and without GBS during COVID‐19 infections presented and progressed with FNP differently, with GBS patients typically presenting with a delayed onset, more severe FNP, and worse facial nerve outcomes. Additionally, the clinical course of isolated FNP associated with COVID‐19 appears to differ from typical Bell’s palsy. Non‐GBS FNP patients had a shorter duration to complete recovery and a higher proportion of bilateral FNP compared to Bell’s palsy patients. This suggests that we may be observing an etiology different than Bell’s palsy patients with differing presentation and prognosis.

Patients diagnosed with GBS were on average older than non‐GBS patients and the duration from the onset of COVID‐19 symptoms to the manifestation of FNP differed considerably between the GBS and non‐GBS diagnosed subgroups. The most common treatments for non‐GBS patients consisted of steroids, antivirals, and antibiotics. Complete recovery of FNP in non‐GBS patients was achieved in over two thirds of patients within an average of under 3 weeks. In contrast, only 17% of GBS patients achieved complete recovery of FNP within an average of over a month.

Clinical Presentation

The initial COVID‐19 symptoms including cough, fever, and dyspnea can be challenging to interpret as they are similar to common upper respiratory tract infections. With the advent of COVID‐19, clinical suspicion of these symptoms has become increasingly recognized and should also be considered when taking a history from a patient presenting with acute FNP. In the context of known viral etiologies related to FNP, COVID‐19 infected patients presented differently. For example, when evaluating the non‐GBS patient category, most patients with FNP after COVID‐19 infection (70%) presented on average 9 days (1–20 days) after the onset of initial COVID‐19 symptom(s). In comparison, FNP secondary to Ramsay Hunt syndrome typically presents either before or concurrently with the typical manifestations including VZV blisters. 64 65

In terms of laterality, bilateral FNP is an extremely rare clinical manifestation of Bell’s palsy, accounting for only up to 2% of these patients. 66 67 68 69 In comparison, a larger proportion (12%) of the isolated FNP patients in this review presented with bilateral FNP. This may be explained by the potentially greater inflammatory impact of the COVID‐19 virus on the facial nerve that has been previously hypothesized. 6 In our study, approximately 75% of the GBS patients presented with bilateral FNP which was higher than non‐GBS patients. Unlike Bell’s palsy, GBS has systemic involvement, more severe symptoms, and highly variable clinical course and outcome. 70

Lastly, a small minority (11%) of the non‐GBS patients presented with FNP as either their presenting or sole symptom of COVID‐19 during an active infection. These findings highlight the importance of considering COVID‐19 infection in the differential diagnosis when evaluating patients with isolated FNP symptoms who may otherwise be asymptomatic. An RT‐PCR for COVID‐19 may be considered in an infectious work‐up of patients presenting with isolated FNP.

Treatments and Outcomes

The most common treatment for non‐GBS patients consisted of steroids, antivirals, and/or antibiotics. Twenty percent of patients had no treatment. According to the American Academy of Neurology (AAN) and the American Academy of Otolaryngology‐Head and Neck Surgery Foundation (AAO‐HNSF), the treatment of Bell’s palsy primarily focuses on the use of corticosteroids and advises against the routine use of antiviral therapy. 71 72 73 However, previous studies have shown that treatment of FNP from Bell’s palsy and RHS with acyclovir and prednisone leads to better outcomes. 74 75 Half of those treated with steroids and half of patients treated with antiviral therapy had complete recovery within 60 days. Among our non‐GBS patients, there were no differences in outcomes between prednisone monotherapy and the combination therapy with antivirals.

Our findings suggest that patients with GBS who develop FNP were more likely to develop severe presentations and were more prone to worse clinical outcomes. Patients presenting with FNP in the context of GBS were most treated with IVIG, followed by hydroxychloroquine, plasmapheresis, and/or steroids. The first line treatments for GBS are plasma exchange or IVIG therapy which should be initiated within 7 and 14 days of symptom onset, respectively, to hasten recovery. 76 In contrast, corticosteroids are not recommended for the treatment of GBS, as several clinical trials have shown no benefit in recovery outcomes compared to placebo. 77 This could explain why steroids were much less commonly used in our GBS patients compared to plasmapheresis and IVIG. Importantly, patients presenting with GBS and FNP were over three times less likely to have complete recovery of FNP compared to non‐GBS patients. This can be explained by the systemic involvement of GBS with more severe symptoms, and highly variable clinical course and outcome. 70

When comparing patients with Bell’s palsy, FNP associated with COVID‐19 infection appeared to have a shorter time to complete recovery. Complete recovery of FNP in non‐GBS patients was achieved in over two thirds of patients within almost 20 days with and without treatments. Previous studies on the natural history of Bell’s palsy have suggested that approximately 85% of patients begin to experience some recovery of their FNP within the first 3 weeks. 71 However, complete recovery of Bell’s palsy with steroid treatment is typically seen in 3–9 months and our study was limited in terms of follow up duration. 78 In our non‐GBS cohort, complete recovery was achieved in the majority (62%) within the first 2 months.

Although our study did not identify any significant predictors of FNP outcomes related to treatment for COVID‐19 patients, this is likely due to the limited sample size, and is an area for future research.

Etiology

Infectious etiology of FNP has a broad differential. Presumed culprits include HSV, VZV, EBV, and Borrelia burgdorferi. With the advent of COVID‐19, our results suggest that the etiology of FNP in non‐GBS COVID‐19 patients is potentially novel.

COVID‐19 has been hypothesized to cause neurologic damage by two distinct mechanisms: (1) dissemination to the central nervous system by hematogenous spread or trans‐neuronally via cranial nerves causing direct neuronal damage due to viral neurotropism and (2) neuronal damage secondary to an abnormal immune‐mediated response. 6 79 The first is thought to be responsible for cranial nerve manifestations (e.g., hypogeusia, hyposmia, headache, and vertigo), whereas the latter mechanism is believed to result in severe complications and contribute to the development of dysimmune neuropathies like GBS. 13 80

Our findings indicate that among the non‐GBS patients, a suggestion can be made of an association between COVID‐19 and a clinical manifestation of FNP, although no causation can be assumed. Although the acute onset and age distribution of the non‐GBS patients present similarly to Bell’s palsy, the differences in clinical presentations and outcomes should be considered. The non‐GBS subgroup had a relatively shorter duration to complete recovery and a higher proportion of bilateral FNP compared to Bell’s palsy patients. 69 78

This study is not without limitations. Firstly, a full infectious work‐up to rule out other potential infectious causes of FNP was done in only 41% patients, although it was non‐contributory except for one patient who also had an active concurrent EBV infection. Secondly, there was variability in the length of follow‐up with the majority being 60 days or less and thus long‐term outcomes data are limited. Since the full recovery of Bell’s palsy typically occurs within a year, this limitation may be underestimating the recovery in our patients. Furthermore, we did not discuss treatment specific outcomes as we were unable to control for multiple patient specific variables and concurrent treatments. Another important limitation is that case reports and case series are more likely to report severe manifestations of COVID‐19. Therefore, the patients included in our study may not represent the complete spectrum of FNP associated COVID‐19, and instead could underestimate the true prevalence of mild, undifferentiated, or undiagnosed cases. Additionally, the onset of FNP was determined relative to patient awareness of related COVID‐19 symptom(s) which may have been non‐specific and may not have been accurately reported. Finally, since the completion of our literature search in November 2021, subsequent omicron and delta variants may not have been adequately represented in our results. Despite these limitations, this study is the first systematic review on patients with COVID‐19 and FNP and may help advance knowledge and guide management of these patients.

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CONCLUSION

Although COVID‐19 symptoms are predominantly respiratory, emerging evidence has highlighted various neurologic manifestations associated with COVID‐19 infections. Our study highlights and delineates the presentations of FNP in the context of COVID‐19 for systemic conditions such as GBS as well as an isolated FNP. Systemic and isolated cases of FNP during COVID‐19 infections present and progress differently. Additionally, the clinical course of isolated FNP associated with COVID‐19 appears to differ from typical Bell’s palsy presentation and prognosis. This suggests that patients with COVID‐19 may have an atypical presentation of Bell’s palsy with a more severe initial presentation and a relatively better prognosis with higher propensity for complete recovery. This review suggests COVID‐19 infection may be associated with the development of a unique clinical manifestation of FNP. There is some literature associating FNP with COVID‐19, although a causal association cannot be definitively assumed. Our study may help future practitioners in identifying FNP as a possible sequela of COVID‐19 infection that may aid in the management of these patients.

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Supporting information

Table S1. Database Search Algorithm.

Table S2A. Case Reports Risk of Bias Assessment.

Table S2B. Case Series Risk of Bias Assessment.

Table S3. Study Demographics

Click here for additional data file.(93K, docx)

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Impact of Systemic Diseases on Olfactory Function in COVID-19 Infected Patients

Authors: Ayat A Awwad,1 Osama MM Abd Elhay,2 Moustafa M Rabie,3 Eman A Awad,4 Fatma M Kotb,4 Hend M Maghraby,4 Rmadan H Eldamarawy,4 Yahia MA Dawood,1 Mostafa IEI Balat,1 Ahmed IM Hasan,5 Ahmed H Elsheshiny,6 Said SMM El Sayed,2 Albayoumi AB Fouda,2 Ahmad MF Alkot2 DovPress November 7, 2022

1Otorhinolaryngology department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt; 2Medical Physiology Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt; 3Public Health and Community Medicine Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt; 4Internal medicine department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt; 5Pediatric Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt; 6Neurology department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt

Correspondence: Ayat A Awwad, Otorhinolaryngology department, Faculty of Medicine, Al-Azhar University, Al Zhraa University Hhospital, Alabasia, Cairo, 11517, Egypt, Email ayatnasr7419@yahoo.com; dr.ayat@azhar.edu.eg Osama MM Abd Elhay, Medical Physiology Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt, Email osama.m.m.abdelhay@gmail.com; osamaabdelhay@domazhermedicine.edu.eg

Background: COVID-19 (SARS-CoV-2/2019-nCoV) is now a major public health threat to the world. Olfactory dysfunctions (ODs) are considered potential indicating symptoms and early case identification triaging for coronavirus disease 2019 (COVID-19). The most common reported comorbidities are diabetes mellitus, chronic lung disease, and cardiovascular disease. The objective of this study was to evaluate prevalence of different types of smell disorders in patients with laboratory-confirmed COVID-19 infection and impact of involved systemic diseases.
Methodology: A cross-sectional retrospective study has been done for patients with laboratory-confirmed COVID-19 infection (mild-to-moderate). The data collected from patient’s files and developed online electronic questionnaire (WhatsApp) based on the patients most common and recurrent reported data including: a) symptoms of olfactory dysfunction and associated covid19 symptoms fever and headache, cough, sore throat, pneumonia, nausea, vomiting and diarrhea, arthralgia and myalgia and taste dysfunction. b) Associated systemic diseases including: diabetes, hypertension, asthma, chronic renal disease, chorionic liver disease and hypothyroidism.
Results: Of 308 patients confirmed with Covid-19 infection, (72.4%) developed OD distributed as follows; complete anosmia (57.8%), troposmia (8.4%), hyposmia (2.9%), partial anosmia (2.6%) and euosmia (0.6%). Significantly increased prevalence of diabetes, hypertension asthma in the group with olfactory dysfunction (p < 0.001), chronic liver disease (p = 0.005), and hypothyroidism (p = 0.03).
Conclusion: The development of ODs after Covid-19 infection was associated with mild disease form and lower hospitalization. In addition, it showed significant relationship with preexisting systemic diseases. Anosmia is the common modality of ODs.

Keywords: COVID-19, anosmia, olfactory dysfunction

Introduction

World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) to be pandemic after it quickly spread all over the world.1 The involved cause is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).2 Human-to-human transmission is extremely rapid.3 Coronavirus is contagious with an incubation period ranging from 2 to 14 days. Through this period, patients can transmit infection even if asymptomatic.4

Asia reported that the most prevalent symptoms as: fever, myalgia, arthralgia cough, dyspnea, headache, diarrhea, rhinorrhea, and sore throat.5 Also, respiratory complications as pneumonia, lung fibrosis, and even death have been reported.6 Later, atypical presentation of the disease is widely observed including olfactory and gustatory malfunction but without rhinorrhea or nasal obstruction which are usually associated to other respiratory viral infections.7

WHO considers smell disorders as key symptoms of COVID-19.8 The American Academy of Otolaryngology–Head and Neck Surgery Foundation, 20209 together with Ear, Nose, and Throat Society of the United Kingdom (ENTUK) recommended self-isolation for patients presenting with these clinical features. Many countries reported the association smell disorder and taste with COVID-1910–12, but evidence remains controversial. In addition, none of them was concerned the incidence of different types of dysfunction.

COVID-19 virus appears to be more severe in severe older people and people with systemic conditions (such as diabetes, hypertension and asthma).13

The previous studies confirmed on olfactory dysfunction alone, neither its types nor impact of chronic diseases on OD so the aim of this study is to evaluate prevalence of different types of smell disorders in patients with laboratory-confirmed COVID-19 infection and impact of involved systemic diseases on ODs.

Methodology

The study was approved from Ethical Committee of the Faculty of medicine of Al-Azhar University (IRP) which complies with the Declaration of Helsinki. A cross-sectional retrospective study to patients with laboratory-confirmed COVID-19 infection (mild-to-moderate) who admitted in Al – Azhar University hospitals, fever hospitals, in addition to some of our patient’s clinics in Cairo, Egypt between the period from June 2020 to December 2020. The patients were divided into asymptomatic and symptomatic. The severity of the symptomatic diseases was classified into mild, moderate and severe.14

Informed consent was obtained from all patients (or a parent or legal guardian of patients under 18 years of age). The data collected from patient’s files and developed online electronic questionnaire (WhatsApp). Electronic questionnaire was designed by Professional otorhinolaryngologist, so that each participant could complete the survey. Questionnaire was based the patients most common and recurrent reported data including:

  • 4 items for assessment of ODs including: presence of smell dysfunction (yes or no), types of smell dysfunction (anosmia, hyposmia, partial anosmia, euosmia and troposmia).
  • 8 items for symptoms associated with covid-19 including: fever, headache, cough, sore throat, pneumonia, nausea, vomiting, diarrhea, arthralgia, myalgia and taste dysfunction (yes/no)
  • 6 items for associated systemic diseases including: diabetes, hypertension, asthma, chronic renal disease, chorionic liver disease and hypothyroidism (yes or no)

Inclusion criteria were: (> 12 years old of both genders); laboratory-confirmed COVID-19 infection (reverse transcription polymerase chain reaction, RT-PCR); native speaker patients, and patients clinically able to fulfill the questionnaire.

Patients with history of smell disorders, and not confirmed COVID-19, were unable to fulfill the questionnaire in addition to patients admitted to intensive care were also excluded from the study.

The data were collected, tabulated, and analyzed by Statistical Package for Social Sciences (version 21; SPSS Inc., Chicago, IL, USA). Two types of statistics were done:

  • Descriptive statistics [eg percentage (%), mean (x) and standard deviation (SD)],
  • Analytic statistics: which include the following:
    1. Chi-square test (χ2): was used to indicate presence or absence of a statistically significant difference between two qualitative variables.
    2. P-value of <0.05 was considered statistically significant.

Results

Demographic characteristics, comorbidities, and symptoms at the onset were reported in all patients confirmed with COVID-19 as shown in Table 1.

Table 1 Characteristics of Study Participants (N = 308)

The prevalence of ODs were 72% (223) with anosmia being the most common presented type (57.8%) while euosmia was the least presented type being only in (0.6%) as shown in Table 2 and Figure 1.

Table 2 Prevalence of Different Types of Olfactory Dysfunction Among COVID-19 Infected Patients (N = 308)

Figure 1 Prevalence of olfactory dysfunction types among cases who suffers from this dysfunction.

The frequency of ODs were significantly high with increasing in age (P value =0.000). But there was no significant difference between genders (P value =0.167) as reported in Table 3. Significant increases in different types of ODs with increasing in age (P value =0.000) while, there was no significant difference regarding gender (P value = 0.564) as shown in Table 4. Anosmia was the commonest presenting type of smell dysfunction in both genders (Figure 2).

Table 3 Frequency Distribution of Olfactory Dysfunction Occurrence According to Age and Sex

Table 4 Frequency Distribution of Olfactory Dysfunction Types in Relation to Age and Sex

Figure 2 Percent distribution of olfactory dysfunction types according to sex.

Regarding to other symptoms, the frequency of ODs were significantly associated to fever and headache, arthralgia, myalgia, taste dysfunction (P value =0.000), cough (P value =0.001), sore throat (P value =0.037), diarrhea, nausea and vomiting (P value =0.002). But it was not significantly associated with Pneumonia (P value =0.077) as shown in Table 5. ODs were the only presenting symptoms in 59.7% of patients Figure 3.

Table 5 Frequency Distribution of Olfactory Dysfunction Occurrence According to the Other Symptoms Experienced

Figure 3 Percent distribution of olfactory dysfunction as the only presenting symptom.

The frequency of ODs were significantly associated with diabetes, hypertension, asthma (P value=0.000), chronic liver disease, hypothyroidism (P value =0.003) and chronic renal disease (P value =0.005) as reported in Table 6. The different types of smell dysfunction showed significant association with asthma, chronic renal disease (P value =0.000), diabetes (P value =0.003), and hypertension (P value =0.002) while, there was no significant association with chronic liver disease and hypothyroidism (P value =0.158 and 0.524 respectively). Anosmia was the most common type of OD in association with diabetes, hypertension, asthma and chronic liver disease while, troposmia was the most common type of OD associated with chronic renal disease. The only case presented with euosmia was reported in chronic liver disease Table 7.

Table 6 Frequency Distribution of Olfactory Dysfunction Occurrence According to the Different Comorbidities

Table 7 Frequency Distribution of Olfactory Dysfunction Types in Relation to the Comorbidities

Discussion

The CDC (Center for Disease Control and Prevention) has highlighted the loss of smell as a significant symptom of COVID-19. In addition, recent research has indicated that OD may serve as an early clinical manifestation of this contagious.15–17

The current study was conducted to study the prevalence of different types of olfactory disorders in patients with laboratory-confirmed COVID-19 infection and its relationship with preexisting systemic comorbidities. Handling the effects of systemic comorbidities on olfactory manifestations in Covid-19 patients is poorly discussed in the literature. This poses a strong point in favor of our study.

We included a total of 308 patients confirmed with Covid-19 infection, 223 patients from them developed olfactory dysfunction (72.4%). When analyzing OD encountered in our research, it was distributed as follows; complete anosmia (57.8%), troposmia (8.4%), hyposmia (2.9%), partial anosmia (2.6%) and euosmia (0.6%). This is in line with multiple previous studies which reported that smell alternations are frequent manifestations of Covid-19 infection, with a prevalence ranging from 19.4% to 88%.3,12,13

This prevalence appears to be widely different between different studies. Mao et al reported lower prevalence (5%) in China18 and Marzano et al (18%) in Italy.19 Others reported much higher prevalence, reaching up to 98% in the study of Moein et al20 and 100% in the study of Heidari et al21 in Iran. This great heterogenicity could be explained by different sample sizes, patient characteristics, and methods of evaluating OD. In addition, Meng et al22 reported the difference of incidence in different countries as COVID-19 has three central variants A, B and C. Variants A and C which affect the nasal cavity causing OD were prevalent in Europe and America. Beside, human species affects significantly the susceptibility for infection.

Brann et al23 suggested that OD associated with Covid-19 infection is due to viral invasion of olfactory epithelial cells and vascular pericytes, which will negatively impact olfactory neuronal function. Additionally, nasal inflammation, congestion, and swelling may prevent olfactory molecules from reaching the olfactory cleft. Therefore, this conductive malfunction may play a role in developing OD.24

Lechien et al25 study handling the same perspective, the encountered OD was distributed as follows; anosmia (79.6%), while the remaining cases had hyposmia (20.4%). In another study, Vaira et al26 reported that among the Covid patients diagnosed with olfactory dysfunction, mild, moderate, and severe hyposmia was detected in 76, 59, and 45 patients, respectively. In addition, the remaining 61 cases had anosmia. It is expected to find some differences between different studies regarding the type of olfactory function diagnosed, according to the sample population included and criteria used to define each type.

In the current study, a significant difference was noted between patients with and without OD regarding patient age (p < 0.001), which tended to be significantly younger in the OD group. On the contrary a previous meta-analysis by Desiato et al17 has against this relationship. Several mechanisms could explain this association between advancing age and declining olfactory function including, nasal epithelial atrophy, olfactory bulb shrinkage, cribriform plate changes, in addition to age-associated cortical degeneration.27–29,30

However, another study by Mercante et al31 reported that the severity of OD was significantly increased in younger individuals, while older ones expressed mild or no symptoms. This confirms our findings.

Our findings showed no significant impact of gender on the development of this complication (p = 0.167). Thakur et al25 confirmed the previous findings regarding the insignificant association between gender and OD (p = 0.59). On the other hand, a recent meta-analysis by Saniasiaya et al32 had shown that the female gender is a risk factor for this manifestation, as it showed higher predominance compared to men. Researchers attributed that finding to the sex-related difference in the inflammatory process.33 Additionally, female patients were more sensitive than males to detect small alternations.32

Our findings showed a significant association between OD and fever, which is more prevalent in patients with this complication. In accordance with the previous results, Lechien et al25 reported a significant positive association between OD and fever (p < 0.001).

In the current study, the headache was significantly more prevalent in patients with OD (p < 0.001). This coincides with multiple previous studies which confirmed the association between headache and olfactory disturbances.34,35 This association was explained by either CNS involvement by the virus itself or hypoxic headache, which results from nasal congestion, which is associated with a decrease in olfactory function.36,37

In our study, taste dysfunction was significantly more encountered in patients with olfactory disturbances. This was confirmed before; as Lechien et al26 reported a significant positive association between both olfactory and gustatory functions (p < 0.001). Also Speth et al38 confirmed the previous findings.

In the current study, one could notice the significantly higher prevalence of other clinical findings (including sore throat, cough, diarrhea, nausea, vomiting, arthralgia, and myalgia) in association with OD.

Likewise, Talavera et al39 also reported the significant relationship between anosmia, myalgia, and cough in patients with Covid disease (p = 0.006). Nevertheless, other manifestations did not express a significant association with olfactory disturbances (p > 0.05).

Conversely, Yan et al12 reported that olfactory dysfunction was associated with a mild disease form. Moreover, another study Izquierdo-Domínguez et al40 reported that the same dysfunction was associated with lower C-reactive protein levels and a lower need for hospitalization.

Our findings showed significantly increased diabetes prevalence in the group with OD (p < 0.001). Although there is a paucity of studies handling the link between diabetes and OD in Covid-19 patients, the association between diabetes and the development of such dysfunction is well documented in a recent meta-analysis by Kim et al.41

Multiple mechanisms could induce this, including olfactory neurodegeneration and diabetes-associated microvascular disease.22,42,43 Of course, with the presence of these diabetes-associated factors, catching Covid-19 infection will increase the chance of having that dysfunction, especially in diabetic personnel. It was previously reported that the diabetic population is at high risk of having OD compared to healthy controls (OR = 1.58).41 In contrast to the previous findings, Talavera et al39 noted no significant impact of diabetes on the development of anosmia (p = 0.448). It was present in 17.1% and 20.5% of patients with and without anosmia, respectively.

Our findings showed that olfactory disturbances were significantly associated with hypertension (p < 0.001). Hypertension was present in 23.3% and 3.5% of patients with and without this dysfunction. We are the first researchers to report that finding in Covid-19 patients to the best of our knowledge. Our finding is supported by the accumulating evidence supporting the association between OD and cardiovascular disease.44,45 Several theories could explain this association; cardiovascular disease is common in the elderly, which is associated with degenerative neuronal changes, as discussed before. Also, the proinflammatory cytokines present with atherosclerosis could decrease olfactory function. Furthermore, some cardiovascular medications have a negative impact on hearing.46,47,48

In a recent study conducted in 2021, hypertensive patients expressed a lower prevalence of OD (p < 0.001), which was present in 74.9% and 88% of patients without and with hypertension, respectively.3 This is in contrast with our findings. In fact, the role of hypertension and the potential intake of angiotensin-converting enzyme inhibitors in the development of OD need to be well discussed in the upcoming studies.

In the current study, the prevalence of asthma showed a significant increase in patients with OD (p < 0.001). Asthma and olfactory impairment have never been linked, according to a recent report published in 2021 by Rhyou et al.48 However, the presence of allergic rhinitis or sinusitis in association with asthma surely decreases the olfactory sensation.29,49

Another study negated any significant difference between the anosmia and non-anosmia groups regarding the prevalence of respiratory diseases, which was present in 19.9% and 27% of patients in the same groups, respectively (p = 0.109).39

Our findings showed a higher prevalence of chronic liver disease in association with anosmia (p = 0.003). Previously, Heiser et al50 reported that olfactory deficits are frequently encountered in patients with cirrhosis. This functional decline is the result of calorie, protein, and micronutrient deficiency in such patients.51 This evidence was supported by the improvement of this function after liver transplantation, as reported by Bloomfield et al.52

In the current study, the prevalence of chronic kidney disease was significantly higher in association with OD (p = 0.005). In fact, patients with such comorbidities often complain of olfactory impairment, which could be the consequence of malnutrition and decreased fluid intake.53,54 Uremia itself could induce neuropathy and decreased smell sensation.54

Our findings showed that hypothyroidism was significantly more common in the OD group (p = 0.03). In line with the previous findings, Tsivgoulis et al55 have reported that hypothyroidism is associated with more prolonged Covid-19 induced anosmia. Sorrily, there is no clear data about whether hypothyroidism can induce OD in adult humans.56

Our study has some limitations; we should have evaluated the impact of OD on patient outcome and long-term nasal function. In addition to this retrospective study may together have some bias to mention. This study did not perform an objective olfactory test on the patients but was based on an electronic questionnaire, which may affect the accuracy of the survey.

All in all, based on our findings, complete anosmia was the most presented modality of OD. Fever, headache, taste dysfunction, sore throat, cough, diarrhea, nausea, vomiting, arthralgia, and myalgia were common symptoms associated with OD. Mild disease form, low C-reactive protein and lower need for hospitalization were common association with OD. Significant increases in incidence of OD in diabetes mellitus, hypertension, bronchial asthma, chronic liver disease, chronic kidney disease and hypothyroidism. Lower incidence of respiratory symptoms in anosmia compared to non-anosmia group.

References

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20. Moein ST, Hashemian SM, Mansourafshar B, Khorram-Tousi A, Tabarsi P, Doty RL. Smell dysfunction: a biomarker for COVID-19. Int Forum Allergy Rhinol. 2020;10(8):944–950. doi:10.1002/alr.22587

21. Heidari F, Karimi E, Firouzifar M, et al. Anosmia as a prominent symptom of COVID-19 infection. Rhinology. 2020;58(3):302–303. doi:10.4193/Rhin20.140

22. Meng X, Deng Y, Dai Z, Meng Z. COVID-19 and anosmia: a review based on up-to-date knowledge. Am J Otolaryngol. 2020;41(5):102581. doi:10.1016/j.amjoto.2020.102581

23. Brann DH, Tsukahara T, Weinreb C, et al. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. Sci Adv. 2020;6(31). doi:10.1126/sciadv.abc5801

24. Thakur K, Sagayaraj A, Prasad KC, Gupta A. Olfactory dysfunction in COVID-19 patients: findings from a tertiary rural centre. Indian J Otolaryngol Head Neck Surg. 2021;1–7. doi:10.1007/s12070-021-02364-8

25. Lechien JR, Chiesa-Estomba CM, De Siati DR, et al. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur Arch Otorhinolaryngol. 2020;277(8):2251–2261. doi:10.1007/s00405-020-05965-1

26. Vaira LA, Hopkins C, Salzano G, et al. Olfactory and gustatory function impairment in COVID-19 patients: Italian objective multicenter-study. Head Neck. 2020;42(7):1560–1569. doi:10.1002/hed.26269

27. Kalmey JK, Thewissen JG, Dluzen DE. Age-related size reduction of foramina in the cribriform plate. Anat Rec. 1998;251(3):326–329. doi:10.1002/(SICI)1097-0185(199807)251:3<326::AID-AR7>3.0.CO;2-T

28. Sama Ul H, Tahir M, Lone KP. Age and gender-related differences in mitral cells of olfactory bulb. J Coll Physicians Surg Pak. 2008;18(11):669–673.

29. Segura B, Baggio HC, Solana E, et al. Neuroanatomical correlates of olfactory loss in normal aged subjects. Behav Brain Res. 2013;246:148–153. doi:10.1016/j.bbr.2013.02.025

30. Doty RL, Kamath V. The influences of age on olfaction: a review. Front Psychol. 2014;5:20. doi:10.3389/fpsyg.2014.00020

31. Mercante G, Ferreli F, De Virgilio A, et al. Prevalence of taste and smell dysfunction in coronavirus disease 2019. JAMA Otolaryngol Head Neck Surg. 2020;146(8):723–728. doi:10.1001/jamaoto.2020.1155

32. Saniasiaya J, Islam MA, Abdullah B. Prevalence of olfactory dysfunction in coronavirus disease 2019 (COVID-19): a meta-analysis of 27,492 patients. Laryngoscope. 2021;131(4):865–878. doi:10.1002/lary.29286

33. Lefèvre N, Corazza F, Valsamis J, et al. The number of X chromosomes influences inflammatory cytokine production following toll-like receptor stimulation. Front Immunol. 2019;10:1052. doi:10.3389/fimmu.2019.01052

34. Sedaghat AR, Gengler I, Speth MM. Olfactory dysfunction: a highly prevalent symptom of COVID-19 with public health significance. Otolaryngol Head Neck Surg. 2020;163(1):12–15. doi:10.1177/0194599820926464

35. Wu Y, Xu X, Chen Z, et al. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain Behav Immun. 2020;87:18–22. doi:10.1016/j.bbi.2020.03.031

36. Hatton CF, Duncan CJA. Microglia are essential to protective antiviral immunity: lessons from mouse models of viral encephalitis. Front Immunol. 2019;10:2656. doi:10.3389/fimmu.2019.02656

37. Ralli M, Di Stadio A, Greco A, de Vincentiis M, Polimeni A. Defining the burden of olfactory dysfunction in COVID-19 patients. Eur Rev Med Pharmacol Sci. 2020;24(7):3440–3441. doi:10.26355/eurrev_202004_20797

38. Speth MM, Singer-Cornelius T, Oberle M, Gengler I, Brockmeier SJ, Sedaghat AR. Olfactory dysfunction and sinonasal symptomatology in COVID-19: prevalence, severity, timing, and associated characteristics. Otolaryngol Head Neck Surg. 2020;163(1):114–120. doi:10.1177/0194599820929185

39. Talavera B, García-Azorín D, Martínez-Pías E, et al. Anosmia is associated with lower in-hospital mortality in COVID-19. J Neurol Sci. 2020;419:117163. doi:10.1016/j.jns.2020.117163

40. Izquierdo-Domínguez A, Rojas-Lechuga MJ, Chiesa-Estomba C, et al. Smell and taste dysfunction in COVID-19 is associated with younger age in ambulatory settings: a multicenter cross-sectional study. J Investig Allergol Clin Immunol. 2020;30(5):346–357. doi:10.18176/jiaci.0595

41. Kim SJ, Windon MJ, Lin SY. The association between diabetes and olfactory impairment in adults: a systematic review and meta-analysis. Laryngoscope Investig Otolaryngol. 2019;4(5):465–475. doi:10.1002/lio2.291

42. Brady S, Lalli P, Midha N, et al. The presence of neuropathic pain may explain poor performances on olfactory testing in diabetes mellitus patients. Chem Senses. 2013;38(6):497–507. doi:10.1093/chemse/bjt013

43. Gouveri E, Katotomichelakis M, Gouveris H, Danielides V, Maltezos E, Papanas N. Olfactory dysfunction in type 2 diabetes mellitus: an additional manifestation of microvascular disease? Angiology. 2014;65(10):869–876. doi:10.1177/0003319714520956

44. Liu B, Luo Z, Pinto JM, et al. Relationship between poor olfaction and mortality among community-dwelling older adults: a cohort study. Ann Intern Med. 2019;170(10):673–681. doi:10.7326/M18-0775

45. Siegel JK, Wroblewski KE, McClintock MK, Pinto JM. Olfactory dysfunction persists after smoking cessation and signals increased cardiovascular risk. Int Forum Allergy Rhinol. 2019;9(9):977–985. doi:10.1002/alr.22357

46. Thiebaud N, Johnson MC, Butler JL, et al. Hyperlipidemic diet causes loss of olfactory sensory neurons, reduces olfactory discrimination, and disrupts odor-reversal learning. J Neurosci. 2014;34(20):6970–6984. doi:10.1523/JNEUROSCI.3366-13.2014

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49. Jung AY, Kim YH. Reversal of olfactory disturbance in allergic rhinitis related to omp suppression by intranasal budesonide treatment. Allergy Asthma Immunol Res. 2020;12(1):110–124. doi:10.4168/aair.2020.12.1.110

50. Heiser C, Haller B, Sohn M, et al. Olfactory function is affected in patients with cirrhosis depending on the severity of hepatic encephalopathy. Ann Hepatol. 2018;17(5):822–829. doi:10.5604/01.3001.0012.3143

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56. Günbey E, Karlı R, Gökosmanoğlu F, et al. Evaluation of olfactory function in adults with primary hypothyroidism. Int Forum Allergy Rhinol. 2015;5(10):919–922. doi:10.1002/alr.21565

Mild or Moderate Covid-19

Authors. Rajesh T. Gandhi, M.D.,  John B. Lynch, M.D., M.P.H.,  nd Carlos del Rio, M.D. NEJM 10/29/2022

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors’ clinical recommendations.

A 73-year-old man with hypertension and chronic obstructive pulmonary disease reports that he has had fever, cough, and shortness of breath for 2 days. His medications include losartan and inhaled glucocorticoids. He lives alone. How should he be evaluated? If he has coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), then how should he be treated?

The Clinical Problem

Coronaviruses typically cause common cold symptoms, but two betacoronaviruses — SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) — can cause pneumonia, respiratory failure, and death. In late 2019, infection with a novel betacoronavirus, subsequently named SARS-CoV-2, was reported in people who had been exposed to a market in Wuhan, China, where live animals were sold. Since then, there has been rapid spread of the virus, leading to a global pandemic of Covid-19. Here, we discuss the presentation and management of Covid-19 in patients with mild or moderate illness, as well as prevention and control of the infection. Discussion of Covid-19 that occurs in children and during pregnancy and of severe disease is beyond the scope of this article.

KEY CLINICAL POINTS

Mild or Moderate Covid-19

  • Covid-19 has a range of clinical manifestations, including cough, fever, myalgias, gastrointestinal symptoms, and anosmia.
  • Diagnosis of Covid-19 is commonly made through detection of SARS-CoV-2 RNA by PCR testing of a nasopharyngeal swab or other specimens, including saliva. Antigen tests are generally less sensitive than PCR tests but are less expensive and can be used at the point of care with rapid results.
  • Evaluation and management of Covid-19 depend on the severity of the disease. Patients with mild disease usually recover at home, whereas patients with moderate disease should be monitored closely and sometimes hospitalized.
  • Remdesivir and dexamethasone have demonstrated benefits in hospitalized patients with severe Covid-19, but in patients with moderate disease, dexamethasone is not efficacious (and may be harmful) and data are insufficient to recommend for or against routine use of remdesivir.
  • Infection control efforts center on personal protective equipment for health care workers, social distancing, and testing.

Strategies and Evidence

Coronaviruses are RNA viruses that are divided into four genera; alphacoronaviruses and betacoronaviruses are known to infect humans.1 SARS-CoV-2 is related to bat coronaviruses and to SARS-CoV, the virus that causes SARS.2 Similar to SARS-CoV, SARS-CoV-2 enters human cells through the angiotensin-converting–enzyme 2 (ACE2) receptor.3 SARS-CoV-2 has RNA-dependent RNA polymerase and proteases, which are targets of drugs under investigation.

TRANSMISSION

SARS-CoV-2 is primarily spread from person to person through respiratory particles, probably of varying sizes, which are released when an infected person coughs, sneezes, or speaks.4 Because both smaller particles (aerosols) and larger particles (droplets) are concentrated within a few meters, the likelihood of transmission decreases with physical distancing and increased ventilation. Most SARS-CoV-2 infections are spread by respiratory-particle transmission within a short distance (when a person is <2 m from an infected person).5,6 Aerosols can be generated during certain procedures (e.g., intubation or the use of nebulizers) but also occur with other activities and under special circumstances, such as talking, singing, or shouting indoors in poorly ventilated environments7-10; in these situations, transmission over longer distances may occur.5,6 Because respiratory transmission is so prominent, masking and physical distancing markedly decrease the chance of transmission.11 SARS-CoV-2 RNA has been detected in blood and stool, although fecal–oral spread has not been documented. An environmental and epidemiologic study of a small cluster of cases suggested the possibility of fecal aerosol–associated airborne transmission after toilet flushing, but this is likely to be rare.12 Under laboratory conditions, SARS-CoV-2 may persist on cardboard, plastic, and stainless steel for days.8,13 Contamination of inanimate surfaces has been proposed to play a role in transmission,9 but its contribution is uncertain and may be relatively small.

A major challenge to containing the spread of SARS-CoV-2 is that asymptomatic and presymptomatic people are infectious.14 Patients may be infectious 1 to 3 days before symptom onset, and up to 40 to 50% of cases may be attributable to transmission from asymptomatic or presymptomatic people.7,15 Just before and soon after symptom onset, patients have high nasopharyngeal viral levels, which then fall over a period of 1 to 2 weeks.16 Patients may have detectable SARS-CoV-2 RNA on polymerase-chain-reaction (PCR) tests for weeks to months, but studies that detect viable virus and contact-tracing assessments suggest that the duration of infectivity is much shorter; current expert recommendations support lifting isolation in most patients 10 days after symptom onset if fever has been absent for at least 24 hours (without the use of antipyretic agents) and other symptoms have decreased.17-19

CLINICAL MANIFESTATIONS

The clinical spectrum of SARS-CoV-2 infection ranges from asymptomatic infection to critical illness. Among patients who are symptomatic, the median incubation period is approximately 4 to 5 days, and 97.5% have symptoms within 11.5 days after infection.20 Symptoms may include fever, cough, sore throat, malaise, and myalgias. Some patients have gastrointestinal symptoms, including anorexia, nausea, and diarrhea.21,22 Anosmia and ageusia have been reported in up to 68% of patients and are more common in women than in men.23 In some series of hospitalized patients, shortness of breath developed a median of 5 to 8 days after initial symptom onset21,24; its occurrence is suggestive of worsening disease.Table 1.Risk Factors for Severe Covid-19.

Risk factors for complications of Covid-19 include older age, cardiovascular disease, chronic lung disease, diabetes, and obesity (Table 1).24,26-29 It is unclear whether other conditions (e.g., uncontrolled human immunodeficiency virus infection or use of immunosuppressive medications) confer an increased risk of complications, but because these conditions may be associated with worse outcomes after infection with other respiratory pathogens, close monitoring of patients with Covid-19 who have these conditions is warranted.

Laboratory findings in hospitalized patients may include lymphopenia and elevated levels of d-dimer, lactate dehydrogenase, C-reactive protein, and ferritin. At presentation, the procalcitonin level is typically normal. Findings associated with poor outcomes include an increasing white-cell count with lymphopenia, prolonged prothrombin time, and elevated levels of liver enzymes, lactate dehydrogenase, d-dimer, interleukin-6, C-reactive protein, and procalcitonin.21,27,30-32 When abnormalities are present on imaging, typical findings are ground-glass opacifications or consolidation.33

DIAGNOSIS

Diagnostic testing to identify persons currently infected with SARS-CoV-2 usually involves the detection of SARS-CoV-2 nucleic acid by means of PCR assay. Just before and soon after symptom onset, the sensitivity of PCR testing of nasopharyngeal swabs is high.34 If testing is negative in a person who is suspected to have Covid-19, then repeat testing is recommended.35 The specificity of most SARS-CoV-2 PCR assays is nearly 100% as long as no cross-contamination occurs during specimen processing.

The Food and Drug Administration (FDA) has issued emergency use authorizations (EUAs) for commercial PCR assays validated for use with multiple specimen types, including nasopharyngeal, oropharyngeal, and mid-turbinate and anterior nares (nasal) swabs, as well as the most recently validated specimen type, saliva.36 (A video demonstrating how to obtain a nasopharyngeal swab specimen is available at NEJM.org.) The FDA EUA allows patient collection of an anterior nares specimen with observation by a health care worker,37 which can reduce exposures for health care workers. Patient collection at home with shipment to a laboratory has been shown to be safe and effective, but access is limited in the United States.38 Testing of lower respiratory tract specimens may have higher sensitivity than testing of nasopharyngeal swabs.16

The FDA has also granted EUAs for rapid antigen testing to identify SARS-CoV-2 in a nasopharyngeal or nasal swab. Antigen tests are generally less sensitive than reverse-transcriptase–PCR tests but are less expensive and can be used at the point of care with results in 15 minutes. They may be particularly useful when rapid turnaround is critical, such as in high-risk congregate settings.39

In addition, EUAs have been issued for several serologic tests for SARS-CoV-2. The tests measure different immunoglobulins and detect antibodies against various viral antigens with the use of different analytic methods, so direct comparison of the tests is challenging. Anti–SARS-CoV-2 antibodies are detectable in the majority of patients 14 days or more after the development of symptoms.40 Their use in diagnosis is generally reserved for people who are suspected to have Covid-19 but have negative PCR testing and in whom symptoms began at least 14 days earlier. Antibody testing after 2 weeks also may be considered when there is a clinical or epidemiologic reason for detecting past infection, such as serosurveillance. Because antibody levels may decrease over time and the correlates of immunity are not yet known, serologic test results cannot currently inform whether a person is protected against reinfection.40

EVALUATION

Figure 1.Characteristics, Diagnosis, and Management of Covid-19 According to Disease Stage or Severity.

Evaluation of Covid-19 is guided by the severity of illness (Figure 1). According to data from China, 81% of people with Covid-19 had mild or moderate disease (including people without pneumonia and people with mild pneumonia), 14% had severe disease, and 5% had critical illness.42

Patients who have mild signs and symptoms generally do not need additional evaluation. However, some patients who have mild symptoms initially will subsequently have precipitous clinical deterioration that occurs approximately 1 week after symptom onset.24,26 In patients who have risk factors for severe disease (Table 1), close monitoring for clinical progression is warranted, with a low threshold for additional evaluation.

If new or worsening symptoms (e.g., dyspnea) develop in patients with initially mild illness, additional evaluation is warranted. Physical examination should be performed to assess for tachypnea, hypoxemia, and abnormal lung findings. In addition, testing for other pathogens (e.g., influenza virus, depending on the season, and other respiratory viruses) should be performed, if available, and chest imaging should be done.

Hallmarks of moderate disease are the presence of clinical or radiographic evidence of lower respiratory tract disease but with a blood oxygen saturation of 94% or higher while the patient is breathing ambient air. Indicators of severe disease are marked tachypnea (respiratory rate, ≥30 breaths per minute), hypoxemia (oxygen saturation, ≤93%; ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, <300), and lung infiltrates (>50% of the lung field involved within 24 to 48 hours).42

Laboratory testing in hospitalized patients should include a complete blood count and a comprehensive metabolic panel. In most instances, and especially if a medication that affects the corrected QT (QTc) interval is considered, a baseline electrocardiogram should be obtained.

Chest radiography is usually the initial imaging method. Some centers also use lung ultrasonography. The American College of Radiology recommends against the use of computed tomography as a screening or initial imaging study to diagnose Covid-19, urging that it should be used “sparingly” and only in hospitalized patients when there are specific indications.43

Additional tests that are sometimes performed include coagulation studies (e.g., d-dimer measurement) and tests for inflammatory markers (e.g., C-reactive protein and ferritin), lactate dehydrogenase, creatine kinase, and procalcitonin.

MANAGEMENT OF COVID-19

Patients who have mild illness usually recover at home, with supportive care and isolation. It may be useful for people who are at high risk for complications to have a pulse oximeter to self-monitor the oxygen saturation.

Patients who have moderate disease should be monitored closely and sometimes hospitalized; those with severe disease should be hospitalized. If there is clinical evidence of bacterial pneumonia, empirical antibacterial therapy is reasonable but should be stopped as soon as possible. Empirical treatment for influenza may be considered when seasonal influenza transmission is occurring until results of specific testing are known.

Treatment of Covid-19 depends on the stage and severity of disease (Figure 1).41 Because SARS-CoV-2 replication is greatest just before or soon after symptom onset, antiviral medications (e.g., remdesivir and antibody-based treatments) are likely to be most effective when used early. Later in the disease, a hyperinflammatory state and coagulopathy are thought to lead to clinical complications; in this stage, antiinflammatory medications, immunomodulators, anticoagulants, or a combination of these treatments may be more effective than antiviral agents. There are no approved treatments for Covid-19 but some medications have been shown to be beneficial.

Hydroxychloroquine and Chloroquine with or without Azithromycin

Chloroquine and hydroxychloroquine have in vitro activity against SARS-CoV-2, perhaps by blocking endosomal transport.44 Results from single-group observational studies and small randomized trials led to initial interest in hydroxychloroquine for the treatment of Covid-19, but subsequent randomized trials did not show a benefit. The Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial showed that, as compared with standard care, hydroxychloroquine did not decrease mortality among hospitalized patients.45 In another randomized trial involving hospitalized patients with mild-to-moderate Covid-19, hydroxychloroquine with or without azithromycin did not improve clinical outcomes.46 Moreover, no benefit was observed with hydroxychloroquine in randomized trials involving outpatients with Covid-1947,48 or patients who had recent exposure to SARS-CoV-2 (with hydroxychloroquine used as postexposure prophylaxis).49,50 Current guidelines recommend that hydroxychloroquine not be used outside clinical trials for the treatment of patients with Covid-19.51,52

Remdesivir

Remdesivir, an inhibitor of RNA-dependent RNA polymerase, has activity against SARS-CoV-2 in vitro53 and in animals.54 In the final report of the Adaptive Covid-19 Treatment Trial 1 (ACTT-1),55 which involved hospitalized patients with evidence of lower respiratory tract infection, those randomly assigned to receive 10 days of intravenous remdesivir recovered more rapidly than those assigned to receive placebo (median recovery time, 10 vs. 15 days); mortality estimates by day 29 were 11.4% and 15.2%, respectively (hazard ratio, 0.73; 95% confidence interval, 0.52 to 1.03). In another trial, clinical outcomes with 5 days of remdesivir were similar to those with 10 days of remdesivir.56 In an open-label, randomized trial involving hospitalized patients with moderate Covid-19 (with pulmonary infiltrates and an oxygen saturation of ≥94%), clinical status was better with 5 days of remdesivir (but not with 10 days of remdesivir) than with standard care, but the benefit was small and of uncertain clinical importance.57 The FDA has issued an EUA for remdesivir for hospitalized patients with Covid-19.58 Guidelines recommend remdesivir for the treatment of hospitalized patients with severe Covid-19 but consider data to be insufficient to recommend for or against the routine use of this drug for moderate disease.51,52 Decisions about the use of remdesivir in hospitalized patients with moderate disease should be individualized and based on judgment regarding the risk of clinical deterioration.

Convalescent Plasma and Monoclonal Antibodies

Small randomized trials of convalescent plasma obtained from people who have recovered from Covid-19 have not shown a clear benefit.59 Data from patients with Covid-19 who were enrolled in a large expanded-access program for convalescent plasma in the United States suggested that mortality might be lower with receipt of plasma with a high titer of antibody than with receipt of plasma with a low titer of antibody; the data also suggested that mortality might be lower when plasma is given within 3 days after diagnosis than when plasma is given more than 3 days after diagnosis.60,61 Interpretation of these data is complicated by the lack of an untreated control group and the possibility of confounding or a deleterious effect of receiving plasma with a low titer of antibody. The National Institutes of Health Covid-19 Treatment Guidelines Panel51 and the FDA, which issued an EUA for convalescent plasma in August 2020,60 emphasize that convalescent plasma is not the standard of care for the treatment of Covid-19. Ongoing randomized trials must be completed to determine the role of convalescent plasma.

Monoclonal antibodies directed against the SARS-CoV-2 spike protein are being evaluated in randomized trials as treatment for people with mild or moderate Covid-19 and as prophylaxis for household contacts of persons with Covid-19. Published data are not yet available to inform clinical practice.

Glucocorticoids

Because of concerns that a hyperinflammatory state may drive severe manifestations of Covid-19, immunomodulating therapies have been or are being investigated. In the RECOVERY trial, dexamethasone reduced mortality among hospitalized patients with Covid-19, but the benefit was limited to patients who received supplemental oxygen and was greatest among patients who underwent mechanical ventilation.62 Dexamethasone did not improve outcomes, and may have caused harm, among patients who did not receive supplemental oxygen, and thus it is not recommended for the treatment of mild or moderate Covid-19.

USE OF CONCOMITANT MEDICATIONS IN PEOPLE WITH COVID-19

Because SARS-CoV-2 enters human cells through the ACE2 receptor,3 questions were raised regarding whether the use of ACE inhibitors or angiotensin-receptor blockers (ARBs) — which may increase ACE2 levels — might affect the course of Covid-19.63 However, large observational studies have not shown an association with increased risk,64 and patients who are receiving ACE inhibitors or ARBs for another indication should not stop taking these agents, even if they have Covid-19.63,65 In addition, several authoritative organizations have noted the absence of clinical data to support a potential concern about the use of nonsteroidal antiinflammatory drugs (NSAIDs) in patients with Covid-19,66 and results from a cohort study were reassuring.67

INFECTION CONTROL AND PREVENTION

Table 2.SARS-CoV-2 Transmission According to Stage of Infection.

Health care workers must be protected from acquiring SARS-CoV-2 when they are providing clinical care (Table 2). Using telehealth when possible, reducing the number of health care workers who interact with infected patients, ensuring appropriate ventilation, and performing assiduous environmental cleaning are critical. Personal protective equipment (PPE) used while caring for patients with known or suspected Covid-19 should include, at a minimum, an isolation gown, gloves, a face mask, and eye protection (goggles or a face shield). The use of these droplet and contact precautions for the routine care of patients with Covid-19 appears to be effective5,68 and is consistent with guidelines from the World Health Organization (WHO)69; however, the Centers for Disease Control and Prevention (CDC) prefers the use of a respirator (usually an N95 filtering facepiece respirator, a powered air-purifying respirator [PAPR] unit, or a contained air-purifying respirator [CAPR] unit) instead of a face mask70 but considers face masks to be acceptable where there are supply shortages. The CDC and WHO recommend the use of enhanced protection for aerosol-generating procedures, including the use of a respirator and an airborne infection isolation room. At sites where enhanced protection is not available, the use of nebulizers and other aerosol-generating procedures should be avoided, when possible. In the context of the ongoing pandemic, the possibility of transmission in the absence of symptoms supports the universal use of masks and eye protection for all patient encounters.7,71

Strategies to facilitate infection prevention and control are needed for people with unstable housing or people who live in crowded facilities or congregate settings, where physical distancing is inconsistent or impossible (e.g., dormitories, jails, prisons, detention centers, long-term care facilities, and behavioral health facilities).

Areas of Uncertainty

Many uncertainties remain in our understanding of the spread of Covid-19 and its management. More data are needed to establish the standard of care for patients with mild or moderate disease and to evaluate potential strategies to reduce the risk of infection in exposed persons; numerous clinical trials are registered and ongoing. Studies are under way to develop an effective vaccine; several candidates have been shown to boost immune responses, and large trials are under way to assess their safety and efficacy in preventing Covid-19. It is unknown whether infection confers immunity (and, if so, for how long) and whether results of serologic testing can be used to inform when health care workers and others can safely return to work.

Guidelines in a Rapidly Changing Pandemic

Many professional organizations have developed guidelines for the management and prevention of Covid-19 (see the Supplementary Appendix, available with the full text of this article at NEJM.org).

Conclusions and Recommendations

The patient in the vignette is at high risk for having Covid-19 with potential complications. Given his dyspnea and risk factors for severe illness, we would refer him for SARS-CoV-2 PCR testing of a nasopharyngeal swab, along with an examination and chest radiography. At a health care facility, he should wear a surgical mask and be promptly escorted to an examination room. He should be assessed for hypoxemia, which, if present, would prompt admission and specific therapies. We would continue his treatment with an ARB and inhaled glucocorticoids. In accordance with current guidelines, we would advise that he remain isolated for 10 days after symptom onset and until he has had resolution of fever for at least 24 hours (without the use of antipyretics) and alleviation of other symptoms.

How Covid-19 damages lungs explained

Authors: mINT oCTOBER 31, 2022

sYNOPSIS

SARS-CoV-2 is the third novel coronavirus to cause human outbreaks in the 21st century, following SARS-CoV in 2003 and MERS-CoV in 2012.

Covid-19: The virus attacks mitochondria, continuing an ancient battle that began in the primordial soup

Kingston (Canada), (The Conversation): Viruses and bacteria have a very long history. Because viruses can’t reproduce without a host, they’ve been attacking bacteria for millions of years. Some of those bacteria eventually became mitochondria, synergistically adapting to life within eukaryotic cells (cells that have a nucleus containing chromosomes).

Ultimately, mitochondria became the powerhouses within all human cells.

Fast-forward to the rise of novel coronaviruses like SARS-CoV-2, and the global spread of COVID-19. Approximately five per cent of people infected with SARS-CoV-2 suffer respiratory failure (low blood oxygen) requiring hospitalization. In Canada about 1.1 per cent of infected patients (almost 46,000 people) have died.

This is the story of how a team, assembled during the pandemic, recognized the mechanism by which these viruses were causing lung injury and lowering oxygen levels in patients: It is a throwback to the primitive war between viruses and bacteria — more specifically, between this novel virus and the evolutionary offspring of bacteria, our mitochondria.

SARS-CoV-2 is the third novel coronavirus to cause human outbreaks in the 21st century, following SARS-CoV in 2003 and MERS-CoV in 2012. We need to better understand how coronaviruses cause lung injury to prepare for the next pandemic.

How COVID-19 affects lungs

People with severe COVID-19 pneumonia often arrive at the hospital with unusually low oxygen levels. They have two unusual features distinct from patients with other types of pneumonia:

First, they suffer widespread injury to their lower airway (the alveoli, which is where oxygen is taken up).

Second, they shunt blood to unventilated areas of the lung, which is called ventilation-perfusion mismatch. This means blood is going to parts of the lung where it won’t get sufficiently oxygenated.

Together, these abnormalities lower blood oxygen. However, the cause of these abnormalities was unknown. In 2020, our team of 20 researchers at three Canadian universities set about to unravel this mystery. We proposed that SARS-CoV-2 worsened COVID-19 pneumonia by targeting mitochondria in airway epithelial cells (the cells that line the airways) and pulmonary artery smooth muscle cells.

We already knew that mitochondria are not just the powerhouse of the cell, but also its main consumers and sensors of oxygen. Mitochondria control the process of programmed cell death (called apoptosis), and they regulate the distribution of blood flow in the lung by a mechanism called hypoxic pulmonary vasoconstriction.

This mechanism has an important function. It directs blood away from areas of pneumonia to better ventilated lobes of the lung, which optimizes oxygen-uptake. By damaging the mitochondria in the smooth muscle cells of the pulmonary artery, the virus allows blood flow to continue into areas of pneumonia, which also lowers oxygen levels.

It appeared plausible that SARS-CoV-2 was damaging mitochondria. The results of this damage — an increase in apoptosis in airway epithelial cells, and loss of hypoxic pulmonary vasoconstriction — were making lung injury and hypoxemia (low blood oxygen) worse.

Our discovery, published in Redox Biology, explains how SARS-CoV-2, the coronavirus that causes COVID-19 pneumonia, reduces blood oxygen levels.

We show that SARS-CoV-2 kills airway epithelial cells by damaging their mitochondria. This results in fluid accumulation in the lower airways, interfering with oxygen uptake. We also show that SARS-CoV-2 damages mitochondria in the pulmonary artery smooth muscle cells, which inhibits hypoxic pulmonary vasoconstriction and lowers oxygen levels.

Attacking mitochondria

Coronaviruses damage mitochondria in two ways: by regulating mitochondria-related gene expression, and by direct protein-protein interactions. When SARS-CoV-2 infects a cell, it hijacks the host’s protein synthesis machinery to make new virus copies. However, these viral proteins also target host proteins, causing them to malfunction. We soon learned that many of the host cellular proteins targeted by SARS-CoV-2 were in the mitochondria.

Viral proteins fragment the mitochondria, depriving cells of energy and interfering with their oxygen-sensing capability. The viral attack on mitochondria starts within hours of infection, turning on genes that break the mitochondria into pieces (called mitochondrial fission) and make their membranes leaky (an early step in apoptosis called mitochondrial depolarization).

In our experiments, we didn’t need to use a replicating virus to damage the mitochondria — simply introducing single SARS-CoV-2 proteins was enough to cause these adverse effects. This mitochondrial damage also occurred with other coronaviruses that we studied.

We are now developing drugs that may one day counteract COVID-19 by blocking mitochondrial fission and apoptosis, or by preserving hypoxic pulmonary vasoconstriction. Our drug discovery efforts have already enabled us to identify a promising mitochondrial fission inhibitor, called Drpitor1a.

Our team’s infectious diseases expert, Gerald Evans, notes that this discovery also has the potential to help us understand Long COVID. “The predominant features of that condition — fatigue and neurologic dysfunction — could be due to the lingering effects of mitochondrial damage caused by SARS-CoV-2 infection,” he explains.

The ongoing evolutionary battle

This research also has an interesting evolutionary angle. Considering that mitochondria were once bacteria, before being adopted by cells back in the primordial soup, our findings reveal an Alien versus Predator scenario in which viruses are attacking “bacteria.”

Bacteria are regularly attacked by viruses, called bacteriophages, that need a host to replicate in. The bacteria in turn fight back, using an ancient form of immune system called the CRISPR-cas system, that chops up the viruses’ genetic material. Humans have recently exploited this CRISPR-cas system for a Nobel Prize-winning gene editing discovery.

The ongoing competition between bacteria and viruses is a very old one; and recall that our mitochondria were once bacteria. So perhaps it’s not surprising at all that SARS-CoV-2 attacks our mitochondria as part of the COVID-19 syndrome.

Pandemic pivot

The original team members on this project are heart and lung researchers with expertise in mitochondrial biology. In early 2020 we pivoted to apply that in another field — virology — in an effort to make a small contribution to the COVID-19 puzzle.

The diverse team we put together also brought expertise in mitochondrial biology, cardiopulmonary physiology, SARS-CoV-2, transcriptomics, synthetic chemistry, molecular imaging and infectious diseases.

Our discovery owes a lot to our virology collaborators. Early in the pandemic, University of Toronto virologist Gary Levy offered us a mouse coronavirus (MHV-1) to work with, which we used to make a model of COVID-19 pneumonia. Che Colpitts, a virologist at Queen’s University, helped us study the mitochondrial injury caused by another human beta coronavirus, HCoV-OC43.

Finally, Arinjay Banerjee and his expert SARS-CoV-2 virology team at Vaccine and Infectious Disease Organization (VIDO) in Saskatoon performed key studies of human SARS-CoV-2 in airway epithelial cells. VIDO is one of the few Canadian centres equipped to handle the highly infectious SARS-CoV-2 virus.

Our team’s super-resolution microscopy expert, Jeff Mewburn, notes the specific challenges the team had to contend with.

“Having to follow numerous and extensive COVID-19 protocols, they were still able to exhibit incredible flexibility to retool and refocus our laboratory specifically on the study of coronavirus infection and its effects on cellular/mitochondrial functions, so very relevant to our global situation,” he said.

Our discovery will hopefully be translated into new medicines to counter future pandemics.

What Is COVID Tongue, and What Does It Mean?

Authors: Medically reviewed by Elizabeth Thottacherry, MD — By S. Behring — Updated on January 20, 2022 HealthLine

In March 2020, the World Health Organization (WHO) declared a pandemic in response to the spread of the COVID-19 infection.

Since then, more than 50 million casesTrusted Source occurred in the United States alone. Medical professionals gathered data to determine the symptoms of COVID-19. The early symptoms observed included fatigue, shortness of breath, and fever.

But as COVID-19 cases continue, new symptoms are documented, including a rare symptom known as COVID tongue. People with COVID tongue have swollen tongues that might develop bumps, ulcers, and white patches. Read on to learn more about this unusual COVID-19 symptom.

What is COVID tongue?

Along with the more well-known symptoms of COVID-19, some people experience bumps, ulcers, swelling, and inflammation of the tongue. This is known as “COVID tongue.”

People with COVID tongue might notice that the top of their tongue looks white and patchy, or that their tongue looks red and feels swollen. They sometimes find bumps or open areas called ulcers on their tongue. Additionally, many people with COVID tongue report experiencing a loss of taste and a burning sensation in their mouth.

2021 study documented COVID tongue as a possible COVID-19 symptom. But just like many things about COVID-19, there’s a lot we don’t know right now about COVID tongue.

What’s happening inside your body to cause COVID tongue?

Another reason there are many questions about COVID tongue is that there are several possible causes. It’s common for illnesses and infections to cause changes to your tongue.

What looks like COVID tongue could easily be a symptom of a different viral or bacterial infection. Even when the bumps and swelling are clearly connected to COVID, there are many possible reasons. COVID tongue might be caused by:

  • A high number of ACE receptors in your tongue. ACE receptors are proteins found on cells in your body. When the virus that causes COVID-19, SARS-CoV-2, attaches to ACE receptors, it can get into your cells. You have many ACE receptors in your tongue, which could lead to swellingTrusted Source when you have a COVID-19 infection.
  • Your immune system fighting COVID-19. When your immune system is fighting a bacterial or viral infection, it can cause swelling throughout your body. This could include the tongue swelling associated with COVID tongue.
  • COVID-causing oral thrush. Oral thrush is a fungus in your mouth that can be caused by a number of infections. This might include COVID-19. Plus, oral thrush is a side effect of some medications used to treat COVID-19.
  • Changes to the surface of your tongue. Infections sometimes lead to changes on the surface of your tongue, such as mouth ulcers and other symptoms. It’s possible COVID-19 can lead to this sort of change as well.
  • Dry mouth. COVID-19 can affect your salivary glands and cause them to secrete less saliva. This could lead to dry mouth. Research shows that dry mouth can lead to multiple other oral health concerns.
  • COVID-activating oral herpes. The inflammation caused by COVID-19 can activate other viruses in your body. This might include the herpes simplex virus, which lays dormant in your body even when you don’t have symptoms. COVID-19 could causeTrusted Source the herpes virus to activate and cause mouth ulcers.

COVID tongue could be caused by any one of these factors or by a combination of them. There’s also a chance that COVID tongue is sometimes caused by breathing tubes and other COVID treatments that could irritate your mouth and lead to a swollen tongue.

Until we know more about COVID-19, we won’t know the exact cause of COVID tongue.

How many people get COVID tongue?

Currently, scientists don’t know how rare COVID tongue is. In one small study, up to 11 percent of people hospitalized with COVID-19 had COVID tongue, but such studies are too small to make a conclusion.

As more data from hospitals around the world come in, we might get a better idea of how common COVID tongue is.

Many people with COVID-19 have mild or moderate symptoms and can recover at home. But right now, even less is known about how many people in this group develop COVID tongue. Often they recover without contacting a doctor at all, so their symptoms are never recorded.

Even when people with mild or moderate COVID-19 do seek treatment, they often wear masks or use telehealth for a video appointment. That makes it difficult for medical professionals to see their tongues and document any abnormalities.

What is the treatment for COVID tongue?

There is currently no single set treatment for COVID tongue. You might not need treatment targeted to COVID tongue. In some cases, the treatments you already receive for COVID will be enough to resolve COVID tongue.

When COVID tongue is more severe and doesn’t respond to overall treatment, you might receive specialized treatment. This could include:

  • corticosteroids or other anti-inflammatory medications to bring down tongue swelling
  • antibacterial, antiviral, or antifungal mouth rinses to treat bumps, patches, and ulcers
  • artificial saliva mouth rinses to help combat dry mouth and promote overall tongue healing
  • low level laser therapy to treat ulcers

Treatment for swollen tongue

COVID-19 may cause the tongue to swell. Tongue swelling can quickly become a medical emergency if your airway becomes blocked. If you think your tongue is swelling, seek medical attention immediately.

The treatment for a swollen tongue is designed to reduce the swelling and relieve pain and discomfort.

Treatment options for swollen tongue include:

  • over-the-counter medications such as ibuprofen (Advil)
  • prescription anti-inflammatory medications
  • medications to treat the underlying condition causing your tongue to swell

What to do if your tongue swells

Call 911 if your tongue swells and you feel like it’s harder to breathe. Do not drive yourself to the ER because your condition could worsen on the way. For many people, calling 911 means help will reach you faster than going to an ER.

  • Have someone stay with you until help arrives.
  • Contact your healthcare professional immediately if you notice that your tongue swells.
  • If you have mild tongue swelling that gets worse, contact your doctor or healthcare professional immediately for an examination.

What’s the outlook for people with COVID tongue?

It’s currently unclear whether COVID tongue is an early symptom of COVID-19, or a symptom that develops as the condition progresses.

No matter when it develops, you might also have other, more-common COVID-19 symptoms:

  • fever
  • cough
  • shortness of breath
  • fatigue
  • nausea
  • pain

Studies are being done to see if COVID tongue is an early or warning symptom.

Mild to moderate COVID-19

People with mild and moderate cases of COVID-19 usually recover at home without medical intervention. Rates of recovery are also improving for people hospitalized with COVID-19 as doctors learn how to best treat the infection.

But since COVID-19 is still a relatively new illness, we don’t know for sure right now what the long-term effects for people will be. Some symptoms of COVID-19 might linger for weeks or even months.

Geographic tongue

While research on COVID tongue is limited now, we do know that viral infections can sometimes lead to a condition called geographic tongue.

This condition causes smooth red patches with white borders to appear on your tongue and can last for months — or even years. Geographic tongue doesn’t generally cause pain or other health concerns, but flare-ups can make it difficult to eat spicy foods.

It’s currently unclear whether COVID tongue is related to geographic tongue, or whether COVID-19 can lead to geographic tongue. As more people recover from COVID-19 and more data become available, doctors will have a better understanding of COVID tongue and any possible long-term effects.

If you have COVID-19 and are experiencing any mouth or tongue health concerns, talk with your doctor.

The bottom line

Some people with COVID-19 develop bumps, white patches, and swelling on their tongues. This is known as COVID tongue and it’s still being studied.

Right now, there are a lot of unanswered questions about COVID tongue. We currently don’t know how many people get COVID tongue or what causes it. More information about COVID tongue will be available as doctors learn more about COVID tongue and more research occurs.

COVID-19 “Long-Haulers:” The Emergence of Auditory/Vestibular Problems After Medical Intervention

Authors: Robert M. DiSogra Audiology Today American Academy of Audiology

Johns Hopkins University’s Center for Systems Science and Engineering (CSSE) in the United States reported over seven million documented cases of COVID-19 and over 212,000 deaths since the virus was first identified in this country in January 2020 (2020).

Early in the pandemic, the medical profession, the Centers for Disease Control and Prevention (CDC), the National Institute of Health (NIH), and both federal and state governments worked 24/7 to develop testing protocols and intervention strategies (pharmacological management and vaccines).

Until a scientifically proven intervention strategy is identified along with a vaccine, the public continues to be advised by the CDC to wear face masks, socially distance from each other, wash their hands regularly, and avoid crowds/indoor events. This major change in our lifestyle/behavior and the associated economic impact is still with us today.

As a novel virus, no assumptions can be made about treatment or management strategies or prediction of late onset of new symptoms. Within a few months after the pandemic was declared, a variety of pharmacological interventions were proposed by the federal government—all without scientific evidence. The most popular unproven intervention strategy in the United States was the combined use of two known ototoxic drugs: hydroxychloroquine and azithromycin (Bortoli and Santiago, 2007; FDA, 2017; Prayuenyong. et al, 2020).

DiSogra (2020a) provides a detailed review of this strategy from an audiologist’s perspective. In Europe, hydroxychloroquine and chloroquine were prescribed for almost 12 percent of COVID-19 patients (Lechien et al, 2020).

Researchers attempted to determine if other FDA-approved drugs could be repurposed as an intervention strategy. A summary of several FDA-approved drugs that were being repurposed for COVID-19 patients appears in DiSogra (2020b).

Vaccines for COVID-19 are still undergoing clinical trials. The U.S. National Library of Medicine’s Clinical Trials website is monitoring over 80 COVID-19 vaccine-related clinical trials (in various phases of development) worldwide as of September 24, 2020.

COVID-19 Recovery

A self-organized group of COVID-19 “long-haul” patients, who are researchers in relevant fields (e.g., participatory design, neuroscience, public policy, data collection and analysis, human-centered design, health activism) and have intimate knowledge of COVID-19, have been working on patient-led research around the COVID experience and prolonged recoveries (Assaf et al, 2020).

To capture and share the experiences of patients suffering from prolonged or long-haul COVID-19 symptoms, survivor/researchers used a data-driven participatory-type survey and patient-centric analysis. With 640 survey respondents, many participants experienced fluctuations in the type (70 percent reporting) and intensity (89 percent reporting) of symptoms over the course of being symptomatic.

For approximately 10 percent who had recovered, the average length of time of being symptomatic was 27 days. Unrecovered respondents experienced symptoms for an average of 40 days, with a large proportion experiencing symptoms for five to seven weeks. The chance of full recovery by day 50 was smaller than 20 percent.

Most common auditory/vestibular symptoms were earaches and vertigo lasting up to eight weeks after the diagnosis. Sixty percent of the respondents reported balance issues that peaked by second week and subsided over the next four weeks. Earaches (~32 percent) and vertigo/motion sickness (~25 percent) persisted over six weeks. One patient reported hearing loss that recovered after three weeks. Subjects listed tinnitus as the second highest complaint on a write-in list of symptoms.

All patients experienced a full recovery after 90 days except for patients with pre-existing asthma. The majority of survey respondents were not hospitalized; however, a large number of participants (37.5 percent) had visited the emergency rooms or urgent care but were not admitted for further testing or overnight observation.

Auditory Symptoms After COVID-19 Treatment

For this manuscript, “auditory symptoms” is defined as hearing loss (any degree/type), earache, subjective tinnitus, or vertigo/balance problems.

Sensorineural Hearing Loss

Almufarrij et al (2020) conducted a rapid systematic review investigated audio-vestibular symptoms associated with coronavirus. They found five case reports and two cross-sectional studies that met the inclusion criteria (N=2300). No records of audio-vestibular symptoms were reported with the earlier types of coronavirus (i.e., severe-acute respiratory syndrome [SARS] and Middle East respiratory syndrome [MERS]).

Reports of hearing loss, tinnitus, and vertigo were rarely reported in individuals who tested positive for the SARS-CoV-2. They opined that reports of audio-vestibular symptoms in confirmed COVID-19 cases are few “with mostly minor symptoms, and the studies are of poor quality.”

Munro et al (2020) concluded that it was unclear which cases of hearing loss [and tinnitus] can be directly attributed to SARS-CoV-2 or perhaps related to the many possible causes of hearing loss associated with critical care including ototoxic mediations (Ciorba et al. 2020), local, or systematic infections, vascular disorders and auto-immune disease.

Elbiol (2020) reported only one case (N=121) of sudden hearing loss (0.6 percent). A case report of sudden hearing loss that occurred one week after hospitalization was also published by Koumpa et al (2020).

Conductive Hearing Loss

Fiden (2020) reported one COVID-19 patient with a unilateral otitis media. The conductive hearing loss was mild to moderate.

Tinnitus

Tinnitus was reported in four studies in 2020 (N = 8 patients; Cui et al, Fidan, Lechien et al, and Sun et al). The characteristics of the tinnitus and the impact on the individual were not reported.

Munro, et al (2020) followed 121 COVID-19 patients eight weeks after discharge. Sixteen (13.2 percent) patients reported a change in hearing and/or tinnitus after diagnosis of COVID-19. However, there was no pattern for the duration of the recovery.

Some patients showed no changes in tinnitus while one patient reported no tinnitus after eight weeks. There was self-reported tinnitus in eight cases with three reporting a pre-existing hearing loss. Another patient reported that their tinnitus resolved. Elibol (2020) noted that tinnitus is rarely seen in COVID-19 patients.

Liang et al (2020) attempted to identify and describe neurosensory dysfunctions (including tinnitus) of COVID-19 patients. A total of 86 patients were screened but only three (3.5 percent) were identified as having tinnitus. The average interval from onset of tinnitus was one day; while the average interval from onset of tinnitus to admission was 6 ± 5.29 days; the average duration of tinnitus was 5 ± 0 days. Finally, a non-organic component of the tinnitus (i.e., anxiety) cannot be ruled out (Xia et al, 2020). Although the current studies indicate a low incidence of tinnitus in these patients, development of tinnitus management protocol may be beneficial.

Vertigo

The Munro study (2020) identified one patient with hearing loss that also reported vertigo, which the authors concluded may have been vestibular in origin. TABLE 1 summarizes the earliest case reports and cross-sectional study designs that identified auditory/vestibular problems.

AUTHORTYPE OF STUDYNAUDITORY/VESTIBULAR SYMPTOMS
Asaaf et al, 2020Survey640Earaches (32 %)
Vertigo (60%)
Hearing Loss (0.15%)
Ciu et al, 2020Case Report20Tinnitus (N=1)
Otitis media (N=1)
Fiden, 2020Case Report1Tinnitus
Otitis media
Han et al, 2019Case Report1Vertigo
Lechien et al, 2019Cross Sectional1420Ear pain (N=358 or 25%)
Rotary vertigo (N=6 or 0.4%)
Tinnitus (N=5 or 0.3%)
Mustafa, 2020Cross Sectional20Sensorineural HL
Sriwijitalai and Wiwanitkit, 2020Case Report82Sensorineural HL (N=1 or 1.2%)
Sun et al, 2020Case Report1Sensorineural HL

TABLE 1. Summary of published case reports and cross-sectional research that identified some type of auditory/vestibular problems (adapted from Almufarrij et al, 2020).

The Mustafa study (2020) compared two groups of patients (asymptomatic SARS-CoV-2 vs. control), and the results found that the asymptomatic SARS-CoV-2 group had significantly poorer hearing thresholds at 4-8 kHz and lower amplitude transient evoked otoacoustic emissions (Mustafa, 2020). Almufarrij et al (2020) concluded that high-quality studies are required in different age groups to investigate the acute effects of coronavirus. These studies include temporary effects from medications as well as studies on long-term risks on the audio-vestibular system.

Some Intervention Strategies

Aside for re-purposed pharmaceuticals, dietary supplements are proposed as a treatment option (DiSogra, 2020c). In the Aasaf study (2020), Tylenol® (followed by an inhaler) were the top medications taken by respondents in their survey to treat symptoms. Supplements, such as vitamin C, vitamin D, zinc and electrolytes, were taken by many of the respondents over several weeks. Hot liquids were also very popular with the respondents.

Other popular entries for medications, supplements and treatments reported by participants included Mucinex®, prednisone, steroids, ginger, magnesium, steam, probiotics, oregano oil/supplements, Flonase®, and other nasal sprays.

The majority of respondents never consumed any of the following substances: smoke/vape nicotine, edible or liquid cannabis, smoke/vape recreational cannabis, consume or smoke cannabidiol-only products or consume recreational drugs. Many of the respondents said they occasionally or frequently consumed alcoholic beverages.

Conclusion

The auditory-vestibular side effects of any illness, or from a pharmaceutical, nutraceutical, noise, or trauma, as well as any psychogenic component, will always be a concern for audiologists. With COVID-19, it is still too early to predict auditory-vestibular side effects, although several studies have attempted to do so or at least guide us in our short and long-term management.

If these “long-hauler” patients can be followed more closely, a body of knowledge should emerge that will help audiologists better manage COVID-19 survivors when their auditory/vestibular symptoms result in a referral for testing. It would appear that conductive and sensorineural hearing loss, tinnitus (including its non-organic origin) and vertigo can be expected but with no predictable pattern.

Protocols for management will need to be developed; however, in the interim, an ototoxic drug monitoring protocol can serve as a reference (American Academy of Audiology, 2009). The duration of these symptoms (after the diagnosis) can last from one day to eight weeks but, again, it is still too early in the life of this pandemic to state definitively if these symptoms are temporary or permanent. Although no formal protocols have been developed, audiologists must keep in mind that the more severe, life-threatening side effects of COVID-19 will continue to get researcher’s attention.

This article is a part of the September/October 2020 Audiology Today issue.

References

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American Academy of Audiology. (2009) Position statement and clinical practice guidelines – ototoxicity monitoring. Accessed at https://audiology-web.s3.amazonaws.com/migrated/OtoMonGuidelines.pdf_539974c40999c1.58842217.pdf.

Assaf G, Davis, H, McCorkell L, Wei H, Brooke O, Akrami A, Low R, Mercier J, Adetutu A. (2020) Report: What does COVID-19 recovery actually look like? Patient Led Res.  Accessed at https://patientresearchcovid19.com/research/report-1/#Recovery_Timecourse. Accessed online September 26, 2020.

Bortoli R, Santiago M. (2007) Chloroquine ototoxicity. Clin Rheumatol 26 (11):1809–1810 

Ciorba A, Corazzi V, Skarzynski PH, Skarzynska MB, Bianchini C, Pelucchi S, Hatzopoulos S. (2020) Don’t forget ototoxicity during the SARS-CoV-2 (Covid-19) pandemic. Int J Immunopath Pharmacol 34:1–3. 

Cui C, Yao Q, Zhang D, Zhao Y, Zhang K, Nisenbaum E, Liu X, Cao P, Zhao K, Huang X, Leng D,Liu C, Li N, Luo Y, Chen B, Casiano R,Weed D, Sargi Z, Telischi F, Lu H, Denneny III JC, Shu Y,  Liu X. (2020) Approaching otolaryngology patients during the COVID-19 pandemic. Otolaryngol Head Neck Surg 163(1):121–131

DiSogra RM. (2020a) Audiological management of COVID-19 survivors treated with hydroxychloroquine and azithromycin. Accessed September 24, 2020, at www.audiology.org/audiology-today-mayjune-2020/online-feature-audiological-management-covid-19-survivors-treated

DiSogra RM. (2020b) Ototoxicity of FDA-approved drugs being re-purposed for COVID-19 treatment. Accessed on September 24, 2020, at www.audiology.org/audiology-today-mayjune-2020/online-feature-ototoxicity-fda-approved-drugs-being-re-purposed-covid.

DiSogra RM. (2020c) Dietary supplements used for COVID-19 treatment. Accessed on September 24, 2020, at www.audiology.org/audiology-today-mayjune-2020/online-feature-dietary-supplements-used-covid-19-treatment. Accessed online 9/24/2020

Elibol E. (2020) Otolaryngological symptoms in COVID-19. Eur Arch Otorhinolaryngol 1:1–4. Accessed online ahead of print September 24, 2020.

Fidan, V. (2020) New type of corona virus induced acute otitis media in adult. Amer J Otolaryngol 41:3 Article in Press. Accessed online September 24, 2020.

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Koumpa FS, Forde CT, Manjaly JG. (2020) Sudden irreversible hearing loss post COVID-19. BMJ Case Reports 13(11):e238419.

Lechien JR, Chiesa-Estomba CM, Place S, Van Laethem Y, Cabaraux P, Mat Q, Saussez S. (2019) Clinical and epidemiological characteristics of 1,420 European patients with mild-to-moderate coronavirus disease. J Intern Med 288:3, 1–10

Liang Y, Xu J, Chu M, Mai J, Lai N, Tang W, Yang T, Zhang S, Guan C, Zhong F, Yang L, Liao G. (2020) Neurosensory dysfunction: A diagnostic marker of early COVID-19. Int J Infect Dis. 98:347–352.

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Auditory Disturbances and SARS-CoV-2 Infection: Brain Inflammation or Cochlear Affection? Systematic Review and Discussion of Potential Pathogenesis

Pietro De Luca1Alfonso Scarpa1Massimo Ralli2Domenico Tassone3Matteo Simone3Luca De Campora3Claudia Cassandro4† and Arianna Di Stadio Frontiers in Medicine

Patients affected by COVID-19 present a series of different symptoms; despite some of these are common, other less likely appear. Auditory symptoms seem to be less frequent, maybe because rarer or, alternatively, because they are underestimated during the clinical investigation. The hearing impairment might be related to the central or peripheral involvement of the auditory pathways; in particular, the likelihood of thrombosis might be one of the causes. To date, the prevalence of auditory symptoms such as sudden or progressive sensorineural hearing loss and tinnitus is unclear in COVID-19 patients. However, their presence might be an early sign of thrombosis or spread of the infection into the brain. In this systematic review of the literature we investigated the presence of auditory symptoms in COVID-19 patients and discussed their potential origin and causal relationship with SARS-CoV-2. Results showed that, despite rarely, auditory impairment can appear in patients with COVID-19 and should always be investigated for an early treatment and potential indicator of involvement of the central nervous system.

Introduction

Coronavirus Disease 19 (COVID-19) has spread worldwide, negatively impacting the healthcare systems and institutions (1). COVID-19 presents several symptoms, that generally arise 2-14 days after the start of the infection. Common symptoms include fever, cough, shortness of breath, respiratory distress; furthermore, olfactory and gustatory alterations have been widely reported (23). The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is responsible of different neurological manifestations and systemic complication (4).

Despite rarely, several viral infections that determine inflammation of the cochlea can cause auditory deficits (5); the pathogenetic mechanisms of these symptoms have been widely explained and confirmed by the literature (67). Researchers have attributed their onset to the peripheral damage affecting the cochlea (6) or to the involvement of the central auditory pathways (8).

Several studies have described the presence of brain lesions as responsible of auditory impairment (911), supporting the hypothesis that SARS-CoV-2, which has neuro-invasive characteristics, might determine a central hearing loss in COVID-19 patients both in the active phase and during recovery (12). It has been shown that the virus can spread from neuroepithelium to the olfactory bulb to the brain (1315), causing loss of smell (16), persistent cough after pneumonia resolution (17), memory deficit (18), and neurocognitive problems (19).

Although the central hypothesis seems to be the most plausible, the peripheral involvement of the cochlea cannot be totally excluded.

The presence of auditory symptoms in COVID-19 might be underestimated because they are not a primary symptom of the disease, while they might be a sign of the spread of the virus in the superior auditory pathways, or of a thrombosis.

The aim of this paper is to assess the incidence of sudden sensorineural hearing loss (SSNHL) and hearing deterioration in COVID-19 patients and discuss their possible causes.

Methods

This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) checklist and statement recommendations (Figure 1). The nature of this review did not require Institutional Review Board approval.

Figure 1

FIGURE 1. Prisma diagram to illustrate the method used to select the articles.

Search Strategy

A comprehensive search strategy, developed in partnership with a medical librarian, was performed on PubMed, Scopus and Google Scholar without time restrictions. The keywords used were: “hearing loss,” “hearing impairment” “tinnitus” “audio and vestibular symptom” “sudden hearing loss,” “SARS-CoV-2” and “COVID-19”. Only articles in the English language were considered for the analysis.

Two independent investigators reviewed the articles extracted from the literature review. Duplicates were removed, then each reviewer singularly filled in an Excel data sheet (Microsoft Corporation, USA) including information extracted from the articles. Files were then compared and disagreements on the inclusion/exclusion papers were debated until complete agreement of both researchers. Only papers that received full consensus were considered.

PRISMA guidelines were followed to conduct the systematic review and the full list of references was screened for potentially relevant articles.

Study Selection Criteria

We included articles with the following characteristics: patients (0-99 years) affected by sudden sensorineural hearing loss or hearing deterioration after SARS-CoV-2 infection, written in English language, with full-text available. There were no restrictions in terms of diagnostic tools used to detect SARS-CoV-2. Suspected/unconfirmed COVID-19 patients were excluded. Selected articles were read in full to assess the study objectives and the level of evidence.

Data Extraction

A spreadsheet was filled using the data extracted from the articles read in full by the researchers. The following information were included: name of the author, year of publication, type of study, country where the study was conducted, number of subjects analyzed, patients’ characteristics, auditory results, treatment, outcome, presence or absence of the comparison group, characteristics of control groups.

Risk of Bias Assessment

The National Institutes of Health’s (NIH) quality assessment tools were used to assess the risk-of-bias checklists due to the different study designs (20). The rating of each study was categorized as: poor, fair or good (i.e., unbiased and fully described). The two authors independently gave a score to each article and any disagreement was resolved by direct comparison among the researchers.

Results

Study Selection

One-hundred seventeen records were identified (Figure 1 and Table 1). After removal of duplicates and abstract evaluation, 93 articles were excluded. Twenty-four full-text articles matched the inclusion/exclusion criteria. Five full-text articles were excluded because at high-risk of bias and the remaining 19 were included in the systematic review. The articles identified an association between SARS-CoV-2 and hearing impairment/sudden sensorineural hearing loss. All studies were published over a period of 2 years, between 2019 and 2021.

Table 1

TABLE 1. Summary of studies included in the systematic review.

Study Characteristics

Sudden Sensorineural Hearing Loss in Patients With SARS-CoV-2 Infection

Twelve full-text articles were identified (72131) (Table 2); we identified 11 case reports and 1 case series. Two studies were conducted in Turkey, two in France, two in the United Kingdom, and one in each of the following countries: Thailand, Germany, Brazil, Australia, Egypt, and United States of America. Sixteen patients (10 men and 6 women; age range 18-84 years) evaluated in these studies tested positive for COVID-19. All patients suffered from SSNHL; tinnitus was reported by four patients. Two patients suffered from vertigo, two had nausea or vomiting, and one was affected by ear fullness. Four subjects had bilateral impairment. Five patients had right SSNHL and five left SSNHL; in two studies the side of the affection was not specified. The hearing function was always (100%) assessed by pure tone audiometry (PTA); tympanometry was performed in three studies, speech audiometry and otoacoustic emissions in one, respectively. Two studies did not report the audiological assessment.

Table 2

TABLE 2. Characteristics of studies exploring sudden sensorineural hearing loss (SSNHL) in patients with COVID-19 and included in the systematic review.

Nine patients were exclusively treated by oral steroids, one subject with intratympanic steroid only; three patients were treated by combining oral steroid and intratympanic corticosteroids. In one case the treatment was not described. One patient, who did not recover, needed cochlear implant and only one patient recovered spontaneously.

Three patients completely recovered the auditory function (only one spontaneously) and five had a partial improvement; two studies did not mention the hearing outcome.

Hearing Loss in Patients With SARS-CoV-2 Infection

Seven full-text articles were identified (27323638) (Table 3). They included four prospective studies, one retrospective study, one case series, and one case report. The studies were conducted in Italy, Portugal, Iran, United Kingdom, Turkey, Egypt, and Qatar. A total of one 188 patients were evaluated. Ninety-three patients were males, 95 were females; age ranged from 0 to 82 years. Only one study did not report details about age and gender of the patients. Hearing ability was assessed by PTA by four authors, speech audiometry in one study, otoacoustic emissions in three and tympanometry in two articles. Only one author reported hearing capacity as “self-reported hearing loss” without objective assessment.

Table 3

TABLE 3. Characteristics of studies exploring hearing loss (HL) in patients with COVID-19 included in the systematic review.

Discussion

The results of our systematic review showed that, despite uncommon, the hearing function might be affected by SARS-CoV-2 infection. Because of wide differences among the studies and the lack of clinical trials, we were not able to perform a meta-analysis to clarify the real prevalence of this symptom.

Gallus et al. (32) performed a retrospective study investigating the audiological and vestibular characteristics of 48 non-hospitalized patients affected by COVID-19; after two consecutive negative RT-PCR on nasopharyngeal swabs, the doctors analyzed patients’ auditory and vestibular functions. All subjects were investigated by pure-tone audiometry, tympanometry, and cochleo-stapedius reflex. Four (8.3%) of them reported self-perception of hearing loss, in presence of normal hearing threshold at the time of testing.

Alves de Sousa et al. (33) in a prospective study showed that patients with light forms of COVID-19 had worse auditory thresholds at 1,000, 2,000, 4,000, and 8,000 Hz compared to healthy subjects, and the severity of hearing loss worsened in patients with moderate-severe forms of the disease. The results observed by Karimi-Galougahi et al. (34) and the report from Chirakkal et al. (38) confirmed the association between hearing deterioration and SARS-CoV-2 infection in a sample of five patients.

Celik et al. tested the auditory function on newborns from mothers who suffered from COVID-19 during pregnancy; 37 infants were studied by transient evoked otoacoustic emission (TEOAEs), distortion product otoacoustic emission (DPOAE), and contralateral suppression of otoacoustic emission (CLS OAE). The results were compared to healthy controls. The authors found statistically significant differences between TEOAEs (3,000 and 4,000 Hz) of infants exposed to COVID-19 infection during pregnancy compared to the ones of non-exposed newborns. Analyzing the results of CLS OAE, the authors observed similar significant statistical differences in all auditory frequencies (more significant at high frequencies) (35). Mustafa et al. used TEOAE to evaluate the hearing function in a cohort of asymptomatic COVID-19 patients; their results were compared to those of non-infected subjects. The authors identified that TEOAE amplitude was significant worse in SARS-CoV-2 positive subjects compared to the control (36). Munro et al. investigated the hearing functions of 138 adult patients with confirmed SARS-CoV-2 infection using a questionnaire; 16 (13.2%) patients referred changes in their hearing status after COVID-19 diagnosis; unfortunately, no audiological evaluation was performed to objectively assess the hearing in this cohort (37).

Sriwijtalaia and Wiwanitkit were the first to describe a correlation between COVID-19 and hearing loss (21); unfortunately, detailed data about patients’ characteristic were missing. Similarly, Degen et al. (22) described a 60-year-old man with profound SSNHL and COVID-19, but they did not report the outcome after treatment. Lang et al. (23) described a 30-year-old woman with severe unilateral SSNHL treated with oral steroids without significative improvement of the symptom. Furthermore, Lamounier et al. (24) and Koumpa et al. (25) showed that patients (one case for each author) could obtain partial recovery of their hearing function combining oral and intratympanic steroids. Guigou et al. described a 29-year-old man with bilateral SSNHL and positive to SARS-CoV-2, who obtained complete recovery of the hearing after treatment with oral corticosteroids (26). Notably, in this patient the SSNHL was the presenting symptom of COVID-19.

Chern et al. showed a case of bilateral intralabyrinthine hemorrhage in an adult woman affected by COVID-19; the patient suffered from bilateral SSNHL, aural fullness and vertigo. The magnetic resonance imaging (MRI) showed bilateral intralabyrinthine hemorrhage, which was identified as the cause of the hearing symptoms. The patient partially recovered hearing function after treatment with high-dose oral prednisone and left intratympanic dexamethasone injection (31).

Perret et al. described a case of acute labyrinthitis and SSNHL (29); the patient was treated with oral prednisone and showed progressive recovery. The oral steroid treatment was effective also for treating the hearing impairment in a patient on peritoneal dialysis program who showed SSNHL as presenting symptom of SARS-CoV-2 infection (29). An improvement of the hearing capacity was also reported by Abdel Rhman and Abdel Wahid (30); in this case the patient was treated with intratympanic steroids.

Kilic et al., speculating that hearing loss could be a presenting symptom of COVID-19, performed a real-time polymerase chain reaction (RT-PCR) in five consecutive male patients presenting with unilateral SSNHL. Only one of these subjects was positive for SARS-CoV-2, and SSNHL positively responded to COVID-19-specific treatment in the SARS-CoV-2 (739).

Finally, Jacob et al. observed a complete and spontaneous recovery of hearing in a 61-year-old woman with SSNHL and SARS-CoV-2 infection (27).

Etiopathology of Hearing Impairment in COVID-19

In patients affected by COVID-19, hearing loss and hearing disturbances might be related to a central and/or peripheral involvement of the auditory pathways. The cause can be indirectly (e.g., thrombosis) or directly (e.g., viral spread) related to SARS-CoV2.

SARS-CoV-2 infection increases the risk of systemic thrombosis (40), a condition that may determine neurological symptoms (41). Thrombosis is more common in the mild/moderate forms of the disease (42) rather than in severe ones, probably because in the latter anti-coagulant therapy is promptly administered (4243). An alteration of coagulation rate (44) could cause a macro and/or micro thrombosis, with consequent transitory ischemia and hypoxia in the auditory pathways determining the onset of hearing alterations. The thrombus, which can occlude the cochlear-vestibular artery or one of its afferent vessels (Figure 2), could determine transitory SSNHL or, in case of extremely rapid resolution, a slight hearing impairment or tinnitus. However, despite rapid resolution, transitory hypoxia into the cochlea could stress the inner ear cells and increase the concentration of reactive oxygen species (ROS), that could be responsible of additional damage of the hair cells. On the other hand, a thrombus in one of the vessels of the superior auditory pathways (Figure 2) can determine central hearing loss (45).

Figure 2

FIGURE 2. Direct Virus Effect. The image clearly shows the contiguity between the olfactory and the auditory areas. The virus can easy spread from the olfactory bulb to the olfactory area, reach the auditory area and once there inducing neuroinflammation responsible of the onset of the auditory symptoms.

Another hypothesis is that central auditory pathways—especially the auditory cortex (Figure 3)—might undergo the same inflammatory process observed in the olfactory area (16), directly caused by SARS-CoV-2. Recently, it has been confirmed that SARS-CoV2 spreads up to the olfactory bulb passing through the olfactory epithelium and lamina cribrosa (13); we speculate that the virus might, for contingency among the olfactory and auditory areas (Figure 3), determine transitory neuro-inflammation and consequent hearing symptoms. This hypothesis, although only speculative, could be supported by the clinical evidence of symptoms’ resolution using steroids.

Figure 3

FIGURE 3. Indirect Virus Effect. The images illustrates the different position of a potential trombosis, which can determine the onset of the audio-vestibular disorders because it stops the blood flow in the audiovestibular artery.

Moreover, the presence of vertigo/dizziness (4647) in patients with COVID-19 could have the same etiopathogenesis; in fact, a thrombosis in the audio-vestibular artery may alter the blood flow both in the cochlea and the vestibule explaining the presence of these symptoms (47). However, because of vestibular compensative mechanism, equilibrium disorders may be less perceived by the patients than hearing disturbances.

Vestibular disorders arising from central origin have been already confirmed in other diseases (4849); it is reasonable that SARS-CoV-2 spreading in the vestibular pathways may be responsible of equilibrium disorders observed in COVID-19 patients.

Limits of the Study

This study presents several limitations. First, the sample size (204 patients) is small. Second, the quality rating of the studies is not always satisfactory; in fact, there are several case reports and the cross-sectional studies have uncontrolled designs or provide insufficient details on the control groups. Third, in some studies the hearing deterioration could be already present before SARS-CoV-2 infection. Lastly, some of these studies described “self-reported symptoms” without an objective assessment of the hearing.

Conclusions

Hearing loss, despite rarely, might be present in COVID-19 patients. Auditory evaluation, although with all preventive measures to prevent contagion for healthcare providers, should be performed, especially if hearing disturbance are self-reported. The early recognition of these non-specific symptoms, which might be an early sign of brain inflammation, could help in preventing the spread of the infection to other areas of the brain.

Optic Neuropathy after COVID-19

Authors: Alicia ChenAndrew Go Lee, MDNagham Al-Zubidi, MDNoor LaylaniPamela Davila-Siliezar American Academy of Ophthalmology

the process is ischemic optic neuropathy (ION) and both anterior ION and posterior ION have been reported with COVID19. Clinicians should be aware of the possibility of ION in COVID19.

Contents

Background

Ischemic optic neuropathy (ION) is a sudden, painless loss of vision due to an interruption of blood supply to the optic nerve[1]. ION can be classified as anterior with disc edema (AION) or posterior without disc edema (PION). AION is typically divided into arteritic (A-AION) and non-arteritic (NA-AION) etiologies[1].

Recently, cases of optic neuropathy have been reported following infection with the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus that causes the Corona Virus Disease-19 (COVID19)[2] [3][4][5][6][7][8][9]. Proposed mechanisms of how SARS-CoV-2 might cause ION (AION or PION) include inducing a severe inflammatory response, endothelial damage, hypercoagulable state, and hypoxemia, which leads to hypoperfusion and subsequent ischemia of the optic nerve[3] [10][11][12][13].

Typical non-COVID19 related NA-AION is associated with risk factors: (1) structural factors which make the optic nerve head susceptible to ischemic events (e.g., small cup to disc ratio or “disc at risk”) and (2) vascular factors which predispose to acute hypoperfusion of the optic nerve head (e.g., diabetes mellitus, systemic hypertension, nocturnal arterial hypotension, ischemic heart disease, anemia)[1]. Non-arteritic posterior ischemic optic neuropathy (NA-PION) is thought to have similar vascular risk factors as NA-AION, but no structural risk has been found[14]. Typical AION is the common presentation, while PION is rare[14].

Pathophysiology of COVID19-related ION

The coronavirus has been reported to cause activation of inflammatory cells (e.g. neutrophils and monocytes) and endothelial cells leading to high levels of circulating inflammatory cytokines (e.g., CRP, ferritin, IL-2, TNF-α) and excess production of pro-coagulants (e.g., tissue factor and von Willebrand factor)[3] [11]. Extensive complement involvement and membrane attack complex-mediated microvascular endothelial cell injury have also been reported to lead to COVID19-associated coagulopathy, which can include venous, arterial, and microvascular thrombosis[12][13]. COVID19 has also been reported to cause clinically significant hypoxemia[14].

In ION, it has been hypothesized that these factors in COVID19 (inflammatory response, hypercoagulable state, and hypoxemia) may lead to thrombosis of the blood vessels (e.g., ciliary vessels) supplying the optic nerve and subsequent ischemia of the optic nerve[2][3][4][5][7][8][9]. However, there have been no studies to confirm this pathogenesis.

Savastano et al. reported the impact of SARS-CoV-2 infection on the microvascular network of optic nerve head in patients who recovered from COVID19. The study reported that in the patients who recovered from COVID19, there was an impairment in the blood supply to the peripapillary retinal nerve fiber layer, characterized by a reduction of radial peripapillary capillary plexus (RPCP) density. RPCP density has been previously correlated to visual acuity and visual field loss in NAION patients[15].

Case Reports of Presumed ION after COVID19 Infection

CaseSexAgePast Medical HistoryOphthalmic SymptomsPhysical ExamLabsDiagnosis
1[2]F50HTN, HLDAcute, painless vision loss OD; 1 week after testing positive for COVID20/70 OD. Temporal and inferior nasal field loss OD.No RAPD. Normal fundoscopic exam with no optic disc edema.Normal CBC, BMP, ESR. CRP 7 and d dimer 206 ng/ml.PION
2[3]M52NoneAcute, painless vision loss and floater OD; 2 weeks after COVID hospitalizationHand motion perception OD. RAPD OD. Central and nasal field loss OD.Pale optic disc without swelling OD, small optic disc OS.ESR 42 (high), CRP 39 (high). Lymphopenia (WBC 6800/ul; lymphocyte: 11.5%)NAION
3[4]M43DM, HLDAcute, painless vision loss OD; 4 weeks after COVID symptoms and testing positive20/30 OD. RAPD OD. Inferior hemifield defect OD. Temporal pallor of optic nerve OD.Normal CBC, ESR, BMP.NAION
4[5]M45DM, HTNAcute, blurry vision OD followed by blurry vision OS 2 weeks later; started 1 month after COVID-19 infection6/6 OD, 6/24 OS. RAPD OS. Inferior field defect OS. Superior and inferior field defects OS. Hyperemic optic disc with blurred margins (OD), pale edematous disc (OS).Normal CBC, ESR, BMP.Bilateral sequential NAION
5[6]F67CAD s/p PCI 7 years ago, HTNDecreased vision OS preceded by 2-day headache; tested positive for Sars-CoV-2 2 days later20/800 OS (with dense posterior subcapsular cataract). No RAPD. Superior visual field loss OS.Normal labsNAION
6[7]F69DM, HTNVision loss OS with severe headaches near eyes and occiput, and scalp tenderness; 2.5 weeks after positive SARS-CoV-2 testLight perception from nasal and superior side OS. No direct response and slow indirect response to light OS. Blurring of optic margins with flame hemorrhages OS.Elevated ESR (63 mm/h; range, 3-15 mm/h). Ultrasound of temporal arteries revealed wall thickening and a “halo.”GCA/AAION
7[8]M72DM, HTN, smokingAcute, painless, blurred vision OD; 13 days after COVID-19 symptoms0.3 OD. No RAPD. Inferior visual field loss OD. Optic disc swelling OD.Normal labsNAION
8[9]M64NoneVision loss OD; 5 weeks after COVID-19 symptoms and hospitalization20/20 OD. RAPD OD. Inferior visual field loss OD. Pale optic disc with sectorial papillary edema ODNormal labsNAION

Prognosis

About 40% of patients with non-COVID19 related NAION will spontaneously recover some vision[16].

Treatment

While there are no definite treatments for NAION, the underlying cause should be treated to prevent further complications. Risk factors for atherosclerosis should be controlled, including blood pressure and diabetes[16]. Most of the recommended treatments are intended to prevent thrombosis (e.g., aspirin) or reduce the edema of the optic disc [6]. While corticosteroids can lead to improvement in systemic symptoms and prevention of blindness in arteritic ION/giant cell arteritis (GCA), corticosteroids are not suggested for NAION[17]. In the context of COVID19, the benefits of steroids have not been explored[6].

Summary

Optic neuropathy has been reported in COVID19 and the mechanisms remain ill defined although several hypotheses have been proposed including inflammatory cytokines and a transient hypercoagulable state. Many authors believe that the process is ION and both AION and PION have been reported with COVID19. Further work is necessary to confirm if the optic neuropathy is truly ischemic in origin and what potential treatments might be considered. In typical AION the major diagnostic dilemma is differentiating arteritic (i.e., giant cell arteritis) from non-arteritic AION (NAION). In the setting of COVID19 infection, the acute phase reactants (e.g., ESR, CRP, platelet count) might be elevated and mistaken for signs of GCA. Evaluation for A-AION and GCA in elderly patients including temporal artery biopsy might still be necessary however and some of the cases of AION and COVID19 in the literature may have been coincidental (GCA) and not causal. Clinicians should be aware of the possibility of ION in COVID19.

References

  1. ↑ Jump up to:1.0 1.1 1.2 Hayreh S. S. (2011). Management of ischemic optic neuropathies. Indian journal of ophthalmology59(2), 123–136. https://doi.org/10.4103/0301-4738.77024
  2. ↑ Jump up to:2.0 2.1 2.2 Selvaraj V, Sacchetti D, Finn A, Dapaah-Afriyie K. (2020). Acute Vision Loss in a Patient with COVID-19. Rhode Island Medical Journal, 103(6), 37-38.
  3. ↑ Jump up to:3.0 3.1 3.2 3.3 3.4 Golabchi, K., Rezaee, A., Aghadoost, D., & Hashemipour, M. (2021). Anterior ischemic optic neuropathy as a rare manifestation of COVID-19: a case report. Future virology, 10.2217/fvl-2021-0068. https://doi.org/10.2217/fvl-2021-0068
  4. ↑ Jump up to:4.0 4.1 4.2 Rho, J., Dryden, S. C., McGuffey, C. D., Fowler, B. T., & Fleming, J. (2020). A Case of Non-Arteritic Anterior Ischemic Optic Neuropathy with COVID-19. Cureus12(12), e11950. https://doi.org/10.7759/cureus.11950
  5. ↑ Jump up to:5.0 5.1 5.2 Sanoria, A., Jain, P., Arora, R., & Bharti, N. (2022). Bilateral sequential non-arteritic optic neuropathy post-COVID-19. Indian journal of ophthalmology70(2), 676–679. https://doi.org/10.4103/ijo.IJO_2365_21
  6. ↑ Jump up to:6.0 6.1 6.2 6.3 Babazadeh, A., Barary, M., Ebrahimpour, S., Sio, T. T., & Mohseni Afshar, Z. (2022). Non-arteritic anterior ischemic optic neuropathy as an atypical feature of COVID-19: A case report. Journal francais d’ophtalmologie45(4), e171–e173. https://doi.org/10.1016/j.jfo.2021.12.001
  7. ↑ Jump up to:7.0 7.1 7.2 Szydełko-Paśko, U., Przeździecka-Dołyk, J., Kręcicka, J., Małecki, R., Misiuk-Hojło, M., & Turno-Kręcicka, A. (2022). Arteritic Anterior Ischemic Optic Neuropathy in the Course of Giant Cell Arteritis After COVID-19. The American journal of case reports23, e933471.
  8. ↑ Jump up to:8.0 8.1 8.2 Yüksel, B., Bıçak, F., Gümüş, F., & Küsbeci, T. (2021). Non-Arteritic Anterior Ischaemic Optic Neuropathy with Progressive Macular Ganglion Cell Atrophy due to COVID-19. Neuro-ophthalmology (Aeolus Press)46(2), 104–108.
  9. ↑ Jump up to:9.0 9.1 9.2 Moschetta, L., Fasolino, G., & Kuijpers, R. W. (2021). Non-arteritic anterior ischaemic optic neuropathy sequential to SARS-CoV-2 virus pneumonia: preventable by endothelial protection?. BMJ case reports14(7), e240542. https://doi.org/10.1136/bcr-2020-240542
  10.  Kaur, S., Bansal, R., Kollimuttathuillam, S., Gowda, A. M., Singh, B., Mehta, D., & Maroules, M. (2021). The looming storm: Blood and cytokines in COVID-19. Blood reviews46, 100743. https://doi.org/10.1016/j.blre.2020.100743
  11. ↑ Jump up to:11.0 11.1 Magro, C., Mulvey, J. J., Berlin, D., Nuovo, G., Salvatore, S., Harp, J., Baxter-Stoltzfus, A., & Laurence, J. (2020). Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Translational research : the journal of laboratory and clinical medicine, 220, 1–13. https://doi.org/10.1016/j.trsl.2020.04.007
  12. ↑ Jump up to:12.0 12.1 Goshua, G., Pine, A. B., Meizlish, M. L., Chang, C. H., Zhang, H., Bahel, P., Baluha, A., Bar, N., Bona, R. D., Burns, A. J., Dela Cruz, C. S., Dumont, A., Halene, S., Hwa, J., Koff, J., Menninger, H., Neparidze, N., Price, C., Siner, J. M., Tormey, C., … Lee, A. I. (2020). Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. The Lancet. Haematology7(8), e575–e582. https://doi.org/10.1016/S2352-3026(20)30216-7
  13. ↑ Jump up to:13.0 13.1 Tobin, M. J., Laghi, F., & Jubran, A. (2020). Why COVID-19 Silent Hypoxemia Is Baffling to Physicians. American journal of respiratory and critical care medicine202(3), 356–360. https://doi.org/10.1164/rccm.202006-2157CP
  14. ↑ Jump up to:14.0 14.1 14.2 Sadda SR, Nee M, Miller NR, Biousse V, Newman NJ, Kouzis A. (2001). Clinical spectrum of posterior ischemic optic neuropathy. American Journal of Ophthalmology, 132(5):743-750.
  15.  Savastano, A., Crincoli, E., Savastano, M. C., Younis, S., Gambini, G., De Vico, U., Cozzupoli, G. M., Culiersi, C., Rizzo, S., & Gemelli Against Covid-Post-Acute Care Study Group (2020). Peripapillary Retinal Vascular Involvement in Early Post-COVID-19 Patients. Journal of clinical medicine9(9), 2895. https://doi.org/10.3390/jcm9092895
  16. ↑ Jump up to:16.0 16.1 Garrity, J. (2021). Ischemic Optic Neuropathy. Merck Manual. https://www.merckmanuals.com/home/eye-disorders/optic-nerve-disorders/ischemic-optic-neuropathy
  17.  Aiello, P. D., Trautmann, J. C., McPhee, T. J., Kunselman, A. R., & Hunder, G. G. (1993). Visual prognosis in giant cell arteritis. Ophthalmology100(4), 550–555. https://doi.org/10.1016/s0161-6420(93)31608-8

COVID-19-associated optic neuritis – A case series and review of literature

Authors: Jossy, Ajax; Jacob, Ninan; Sarkar, Sandip; Gokhale, Tanmay; Kaliaperumal, Subashini; Deb, Amit K IJO Ophthalmology

Abstract

Neuroophthalmic manifestations are very rare in corona virus disease-19 (COVID-19) infection. Only few reports have been published till date describing COVID-19-associated neuroophthalmic manifestations. We, hereby, present a series of three cases who developed optic neuritis during the recovery period from COVID-19 infection. Among the three patients, demyelinating lesions were identified in two cases, while another case was associated with serum antibodies against myelin oligodendrocyte glycoprotein. All three patients received intravenous methylprednisolone followed by oral steroids according to the Optic Neuritis Treatment Trail ptotocol. Vision recovery was noted in all three patients, which was maintained at 2 months of the last follow up visit.

COVID-19 infection predo minantly causes a respiratory illness, but it can have a myriad of symptoms, affecting almost all organs of the body.[1] Varied ocular manifestations including conjunctivitis, episcleritis, vascular occlusions, dacryoadenitis, mucormycosis, etc., have been reported in COVID-19 infection.[2] Neuroophthalmic manifestations in COVID-19 infection are uncommon, but they can seldom develop either during the active course or the recovery period.[3] Neuroophthalmic manifestations of COVID-19 infection includes optic neuritis, acute transverse myelitis, viral encephalitis, toxic encephalopathy, leukoencephalopathy, acute disseminated encephalomyelitis, diffuse corticospinal tract signs, etc.[4] Only a handful reports of optic neuritis associated with COVID-19 infection with or without demyelinating lesions have been published. Few of them are associated with serum antibodies against myelin oligodendrocyte glycoprotein (MOG).[567891011121314151617181920] In this report, we describe the clinical profile and treatment outcome of three patients who developed optic neuritis during recovery from COVID-19 infection.

Case Reports

Case 1

A 16-year-old boy presented with sudden gross diminution of vision in the left eye (LE) for 3 days with headache and eyepain on extraocular movements. His past history was unremarkable. The patient had tested positive for COVID-19 infection with reverse transcription polymerase chain reaction (RT-PCR) 2 weeks prior to the incident. He was advised home isolation without any supplemental oxygen or steroids. Systemic and neurological examinations were unremarkable. On ocular examination, best-corrected visual acuity (BCVA) was 20/20 in the right eye (RE) and perception of light (PL+) in the LE, with a grade 2 relative afferent pupillary defect in the LE. Fundus examination revealed normal optic discs in both eyes with no evidence of disc edema or hyperemia [Fig. 1a and 1b]. A diagnosis of LE retrobulbar neuritis was made. Laboratory investigations, imaging, treatment received, and disease course are provided in Table 1.

F1
Figure 1: Fundus images of both eyes at presentation showing normal disc and macula (a and b), magnetic resonance imaging of the orbits at presentation (c) showing hyperintense lesion in the left optic nerve (red arrow), and pattern visual evoked potential at 1 week (d) showing increased latency and decreased amplitudes in the left eye
T1
Table 1: Investigation and treatment details of all cases

Case 2

A 35-year-old male presented with sudden vision loss in LE with pain on extraocular movements for 1 week. His past history was unremarkable. He was tested positive for COVID-19 infection with RT-PCR 6 months prior to the vision loss. He was advised home isolation and did not require oxygen or steroids for COVID-19. On ocular examination, BCVA was 20/20 in RE and 20/600 in LE, with grade I RAPD in LE. Fundus examination of the LE revealed edematous disc with blurred margins and peripapillary edema, which was confirmed on optical coherence tomography, while the RE fundus was normal [Fig. 2a and 2b]. A diagnosis of LE papillitis was made. Laboratory investigations, imaging, treatment, and disease course are described in Table 1.

F2
Figure 2: Fundus image of RE (a) showing normal disc and macula and LE (b) showing an edematous disc with blurred margins and peripapillary edema, magnetic resonance imaging of the orbits (c) showing normal findings; visual evoked potential performed 2 weeks after presentation (d) showed minimally increased latency with decreased amplitude in the left eye

Case 3

A 38-year-old male presented with sudden gross diminution of vision and pain on extraocular movements in the LE for 5 days. The patient had a similar complaint in the LE 1 month ago. He was treated elsewhere for the same with intravenous methylprednisolone and oral prednisolone. There was symptomatic improvement in the vision within a week following the initiation of treatment. However, he noticed another similar episode of decreased vision in the LE 3 weeks later, when he presented to us. He was tested positive for COVID-19 infection with RT-PCR one-and-half month prior to the current episode. He was advised home isolation, and he also did not require oxygen or steroids for COVID-19 infection. Systemic examination was unremarkable. On ocular examination, BCVA was RE 20/20 and LE hand movements (HM+), with grade III RAPD in the LE. Fundus examination showed normal discs in both eyes [Fig. 3a and 3b]. A diagnosis of LE retrobulbar neuritis was made. Laboratory investigations, imaging findings, treatment, and disease course are described in Table 1.

F3
Figure 3: Fundus image of both eyes (a) & (b) showing normal disc and macula, magnetic resonance imaging of the orbits (c) showing hyperintense lesion in the optic nerves of both eyes (red arrows), and flash VEP (d) showed normal N2-P2 latency with decreased amplitudes in both the eyes

Discussion

Optic neuritis is an inflammatory demyelinating optic neuropathy causing acute uniocular or binocular loss of vision.[21] Optic neuritis is mainly a clinical diagnosis based on history and examination findings. Investigations like magnetic resonance imaging, lumbar puncture, and antibodies against AQP4 and MOG help in finding the association and cause of vision loss.[21] Once the diagnosis is established, treatment is done based on optic neuritis treatment trial (ONTT) protocol.[22]

Neurotropism of the virus was postulated as one of the mechanisms for neuroophthalmic manifestations.[2] Another mechanism involves molecular mimicry where the viral antigens trigger host immune response directed toward the CNS myelin proteins.[46] All the three cases reported by us had viral prodromes and positive COVID-19 infection. It is interesting to note that all three cases had mild COVID-19 infections with no oxygen requirement or steroid use, and their recoveries were uneventful. Vision loss in all the three cases happened during the recovery period of the infections and dramatic response to steroids points toward an inflammatory disorder triggered by the viral antigen. In the third case, the patient had two similar episodes of vision loss in 2 months after the COVID-19 infection. He was tested positive for MOG antibody. MOG antibody-associated optic neuritis usually has good visual recovery with good response to steroids but shows bilaterality and recurrence. Our case also showed initial good response to systemic steroids with recurrence within 2 weeks of discontinuation of steroids. MOG antibody-associated optic neuritis in COVID-19 infection has been reported by Zhou et al.,[6] Zoric et al.,[10] Kugure et al.,[12] Sawalha et al.,[5] de Ruijter et al.,[14] Rojas-Correa et al.[19]. Table 2 describes the details of all cases of COVID-19-associated optic neuritis. Due to the ongoing COVID-19 pandemic, we can expect more similar cases in future. So, prospective studies are warranted to establish the relationship between the viral antigen, severity of COVID-19 infection, and associated optic neuritis.

T2
Table 2: Summary of all the published studies

Conclusion

Neuro-ophthalmic manifestations are rare in COVID-19 infection, and can be seen either during the active disease phase or the recovery phase.[3] Optic neuritis is one such rare manifestation. The three cases of optic neuritis being reported by us had mild COVID-19 infection. Two cases developed ocular symptoms and signs within the first six weeks of recovery while another case developed ocular manifestations six months after recovery from COVID-19. All the three cases showed good response to systemic steroids with significant visual recovery. Keeping the ongoing pandemic in perspective, we should, therefore, be vigilant in identifying the neuro-ophthalmic features of COVID-19 infection to prevent irreversible vision loss.

Coronavirus and the Nervous System

Authors: NIH What is SARS-CoV-2 and COVID-19?

What is SARS-CoV-2 and COVID-19?

Coronaviruses are common causes of usually mild to moderate upper respiratory tract illnesses like the common cold, with symptoms that may include runny nose, fever, sore throat, cough, or a general feeling of being ill. However, a new coronavirus called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) emerged and spread to cause the COVID-19 pandemic.

COVID-19, which means Coronavirus disease 2019, is an infectious disease that can affect people of all ages in many ways. It is most dangerous when the virus spreads from the upper respiratory tract into the lungs to cause viral pneumonia and lung damage leading to Acute Respiratory Distress Syndrome (ARDS). When severe, this impairs the body’s ability to maintain critical levels of oxygen in the blood stream—which can cause multiple body systems to fail and can be fatal.

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What do we know about the effects of SARS-CoV-2 and COVID-19 on the nervous system?

Much of the research to date has focused on the acute infection and saving lives. These strategies have included preventing infection with vaccines, treating COVID-19 symptoms with medicines or antibodies, and reducing complications in infected individuals.

Research shows the many neurological symptoms of COVID-19 are likely a result of the body’s widespread immune response to infection rather than the virus directly infecting the brain or nervous system. In some people, the SARS-CoV-2 infection causes an overreactive response of the immune system which can also damage body systems. Changes in the immune system have been seen in studies of the cerebrospinal fluid, which bathes the brain, in people who have been infected by SARS-CoV-2. This includes the presence of antibodies—proteins made by the immune system to fight the virus—that may also react with the nervous system. Although still under intense investigation, there is no evidence of widespread viral infection in the brain. Scientists are still learning how the virus affects the brain and other organs in the long-term. Research is just beginning to focus on the role of autoimmune reactions and other changes that cause the set of symptoms that some people experience after their initial recovery. It is unknown if injury to the nervous system or other body organs cause lingering effects that will resolve over time, or whether COVID-19 infection sets up a more persistent or even chronic disorder.

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What are the immediate (acute) effects of SARS-CoV-2 and COVID-19 on the brain?

Most people infected with SARS-CoV-2 virus will have no or mild to moderate symptoms associated with the brain or nervous system. However, most individuals hospitalized due to the virus do have symptoms related to the brain or nervous system, most commonly including muscle aches, headaches, dizziness, and altered taste and smell. Some people with COVID-19 either initially have, or develop in the hospital, a dramatic state of confusion called delirium. Although rare, COVID-19 can cause seizures or major strokes. Muscular weakness, nerve injury, and pain syndromes are common in people who require intensive care during infections. There are also very rare reports of conditions that develop after SARS-CoV-2 infection, as they sometimes do with other types of infections. These disorders of inflammation in the nervous system include Guillain-Barré syndrome (which affects nerves), transverse myelitis (which affects the spinal cord), and acute necrotizing leukoencephalopathy (which affects the brain).

Bleeding in the brain, weakened blood vessels, and blood clots in acute infection

The SARS-CoV-2 virus attaches to a specific molecule (called a receptor) on the surface of cells in the body. This molecule is concentrated in the lung cells but is also present on certain cells that line blood vessels in the body. The infection causes some arteries and veins—including those in the brain—to  become thin, weaken, and leak. Breaks in small blood vessels have caused bleeding in the brain (so-called microbleeds) in some people with COVID-19 infection. Studies in people who have died due to COVID-19 infection show leaky blood vessels in different areas of the brain that allow water and a host of other molecules as well as blood cells that are normally excluded from the brain to move from the blood stream into the brain. This leak, as well as the resulting inflammation around blood vessels, can cause multiple small areas of damage. COVID-19 also causes blood cells to clump and form clots in arteries and veins throughout the body. These blockages reduce or block the flow of blood, oxygen, and nutrients that cells need to function and can lead to a stroke or heart attack.

stroke is a sudden interruption of continuous blood flow to the brain. A stroke occurs either when a blood vessel in the brain becomes blocked or narrowed or when a blood vessel bursts and spills blood into the brain. Strokes can damage brain cells and cause permanent disability. The blood clots and vascular (relating to the veins, capillaries, and arteries in the body) damage from COVID-19 can cause strokes even in young healthy adults who do not have the common risk factors for stroke.

COVID-19 can cause blood clots in other parts of the body, too. A blood clot in or near the heart can cause a heart attack. A heart attack or Inflammation in the heart, called myocarditis, can cause heart failure, and reduce the flow of blood to other parts of the body. A blood clot in the lungs can impair breathing and cause pain. Blood clots also can damage the kidneys and other organs.

Low levels of oxygen in the body (called hypoxia) can permanently damage the brain and other vital organs in the body. Some hospitalized individuals require artificial ventilation on respirators. To avoid chest movements that oppose use of the ventilator it may be necessary to temporarily “paralyze” the person and use anesthetic drugs to put the individual to sleep. Some individuals with severe hypoxia require artificial means of bringing oxygen into their blood stream, a technique called extra corporeal membrane oxygenation (ECMO). Hypoxia combined with these intensive care unit measure generally cause cognitive disorders that show slow recovery.

Diagnostic imaging of some people who have had COVID-19 show changes in the brain’s white matter that contains the long nerve fibers, or “wires,” over which information flows from one brain region to another. These changes may be due to a lack of oxygen in the brain, the inflammatory immune system response to the virus, injury to blood vessels, or leaky blood vessels. This “diffuse white matter disease” might contribute to cognitive difficulties in people with COVID-19. Diffuse white matter disease is not uncommon in individuals requiring intensive hospital care but it not clear if it also occurs in those with mild to moderate severity of COVID-19 illness.

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What is the typical recovery from COVID-19?

Fortunately, people who have mild to moderate symptoms typically recover in a few days or weeks. However, some  people who have had only mild or moderate symptoms of COVID-19 continue to experience dysfunction of body systems—particularly in the lungs but also possibly affecting the liver, kidneys, heart, skin, and brain and nervous system—months after their infection. In rare cases, some individuals may develop new symptoms (called sequelae) that stem from but were not present at the time of initial infection. People who require intensive care for Acute Respiratory Distress Syndrome, regardless of the cause, usually have a long period of recovery. Individuals with long-term effects, whether following mild or more severe COVID-19, have in some cases self-identified as having “long COVID” or “long haul COVID.” These long-term symptoms are included in the scientific term, Post Acute Sequelae of SARS-CoV-2 Infection (PASC).

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What are possible long-term neurological complications of COVID-19?

Researchers are following some known acute effects of the virus to determine their relationship to the post-acute complications of COVID-19 infection. These post-acute effects usually include fatigue in combination with a series of other symptoms. These may include trouble with concentration and memory, sleep disorders, fluctuating heart rate and alternating sense of feeling hot or cold, cough, shortness of breath, problems with sleep, inability to exercise to previous normal levels, feeling sick for a day or two after exercising (post-exertional malaise), and pain in muscle, joints, and chest. It is not yet known how the infection leads to these persistent symptoms and why in some individuals and not others.

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Nerve damage, including peripheral neuropathy

Fatigue and post-exertional malaise

Cognitive impairment/altered mental state

Muscle, joint, and chest pain

Prolonged/lingering loss of smell (anosmia) or taste

Persistent fevers and chills

Prolonged respiratory effects and lung damage

Headaches

Sleep disturbances

Anxiety, depression, and stress post-COVID

 How do the long-term effects of SARS-CoV-2 infection/COVID-19 relate to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)?

Some of the symptom clusters reported by people still suffering months after their COVID-19 infection overlap with symptoms described by individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). People with a diagnosis of ME/CFS have wide-ranging and debilitating effects including fatigue, PEM, unrefreshing sleep, cognitive difficulties, postural orthostatic tachycardia, and joint and muscle pain. Unfortunately, many people with ME/CFS do not return to pre-disease levels of activity. The cause of ME/CFS is unknown but many people report its onset after an infectious-like illness. Rest, conserving energy, and pacing activities are important to feeling better but don’t cure the disease. Although the long-term symptoms of COVID-19 may share features with it, ME/CFS is defined by symptom-based criteria and there are no tests that confirm an ME/CFS diagnosis.

ME/CFS is not diagnosed until the key features, especially severe fatigue, post-exertional malaise, and unrefreshing sleep, are present for greater than six months. It is now becoming more apparent that following infection with SARS-CoV-2/COVID-19, some individuals may continue to exhibit these symptoms beyond six months and qualify for an ME/CFS diagnosis. It is unknown how many people will develop ME/CFS after SARS-CoV-2 infection. It is possible that many individuals with ME/CFS, and other disorders impacting the nervous system, may benefit greatly if research on the long-term effects of COVID-19 uncovers the cause of debilitating symptoms including intense fatigue, problems with memory and concentration, and pain.

Am I at a higher risk if I currently have a neurological disorder?

Much is still unknown about the coronavirus but people having one of several underlying medical conditions may have an increased risk of illness. However, not everyone with an underlying condition will be at risk of developing severe illness. People who have a neurological disorder may want to discuss their concerns with their doctors.

Because COVID-19 is a new virus, there is little information on the risk of getting the infection in people who have a neurological disorder. People with any of these conditions might be at increased risk of severe illness from COVID-19:

  • Cerebrovascular disease
  • Stroke
  • Obesity
  • Dementia
  • Diabetes
  • High blood pressure

There is evidence that COVID-19 seems to disproportionately affect some racial and ethnic populations, perhaps because of higher rates of pre-existing conditions such as heart disease, diabetes, and lung disease. Social determinants of health (such as access to health care, poverty, education, ability to remain socially distant, and where people live and work) also contribute to increased health risk and outcomes.

Can COVID-19 cause other neurological disorders?

In some people, response to the coronavirus has been shown to increase the risk of stroke, dementia, muscle and nerve damage, encephalitis, and vascular disorders. Some researchers think the unbalanced immune system caused by reacting to the coronavirus may lead to autoimmune diseases, but it’s too early to tell.

Anecdotal reports of other diseases and conditions that may be triggered by the immune system response to COVID-19 include para-infectious conditions that occur within days to a few weeks after infection:

  • Multi-system infammatory syndrome – which causes inflammation in the body’s blood vessels
  • Transverse myelitis – an inflammation of the spinal cord
  • Guillain-Barré sydrome (sometimes known as acute polyradiculoneuritis) – a rare neurological disorder which can range from brief weakness to nearly devastating paralysis, leaving the person unable to breathe independently
  • Dysautonomia – dysfunction of the autonomic nerve system, which is involved with functions such a breathing, heart rate, and temperature control
  • Acute disseminating encephalomyelitis (ADEM) – an attack on the protective myelin covering of nerve fibers in the brain and spinal cord
  • Acute necrotizing hemorrhagic encephalopathy – a rare type of brain disease that causes lesions in certain parts of the brain and bleeding (hemorrhage) that can cause tissue death (necrosis)
  • Facial nerve palsies (lack of function of a facial nerve) such as Bell’s Palsy
  • Parkinson’s disease-like symptoms have been reported in a few individuals who had no family history or early signs of the disease

Does the COVID-19 vaccine cause neurological problems?

Almost everyone should get the COVID-19 vaccination. It will help protect you from getting COVID-19. The vaccines are safe and effective and cannot give you the disease. Most side effects of the vaccine may feel like flu and are temporary and go away within a day or two. The U.S. Food and Drug Administration (FDA) continues to investigate any report of adverse consequences of the vaccine. Consult your primary care doctor or specialist if you have concerns regarding any pre-existing known allergic or other severe reactions and vaccine safety.

A recent study from the United Kingdom demonstrated an increase in Guillain-Barré Syndrome related to the Astra Zeneca COVID-19 vaccine (virally delivered) but not the Moderna (messenger RNA vaccine). Guillain-Barré syndrome (a rare neurological disorder in which the body’s immune system damages nerve cells, causing muscle weakness and sometimes paralysis) has also occurred in some people who have received the Janssen COVID-19 Vaccine (also virally delivered). In most of these people, symptoms began within weeks following receipt of the vaccine. The chance of having this occur after these  vaccines is very low, 5 per million vaccinated persons in the UK study. The chance of developing Guillain-Barré Syndrome was much higher if one develops COVID-19 infection (i.e., has a positive COVID test) than after receiving the Astra Zeneca vaccine. The general sense is that there are COVID-19 vaccines that are safe in individuals whose Guillain-Barré syndrome was not associated with a previous vaccination and that actual infection is the greater risk for developing Guillain-Barré Syndrome. 

The U.S. Centers for Disease Control and Prevention (CDC) site offers information on vaccine resources. The National Institutes of Health (NIH) has information on vaccines for the coronavirus. The CDC  has make public its report on the association of Guillain-Barré Syndrome with the Janssen COVID-19 Vaccine and no increased incidence occurred after vaccination with the Moderna or Pfizer vaccines.

More information about Guillain-Barré Syndrome here.

There have been reports of  neurological complications from other SARS-CoV-2 vaccinations. Visit the FDA COVID-19 Vaccines webpage for information about coronavirus vaccines and fact sheets for recipients and caregivers that outline possible neurological and other risks.