key: cord-0693712-hpamkn78
authors: Sharma, Preeti; Malik, Sangeeta; Wadhwan, Vijay; Gotur Palakshappa, Suhasini; Singh, Roli
title: Prevalence of oral manifestations in COVID‐19: A systematic review
date: 2022-03-10
journal: Rev Med Virol
DOI: 10.1002/rmv.2345
sha: a612c6d283244e82476ec44ed7c7247f1891739a
doc_id: 693712
cord_uid: hpamkn78

Coronavirus disease 2019 (COVID‐19) is a novel disease caused by a newly identified virus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) causing diverse systemic manifestations. The oral cavity too is not spared and the symptoms appear either independently, concurrently, or sequentially. In view of the rising documented cases of oral lesions of COVID‐19, this systematic review aims to assess the prevalence of oral manifestations in COVID‐19 confirmed individuals. An extensive literature search was conducted in databases like Scopus, Pubmed/Medline, Livivo, Lilacs and Google Scholar and varied oral signs and symptoms were reported as per the PRISMA guidelines. Studies published in English language literature only were included and were subjected to the risk of bias using the Joana Briggs Institute Appraisal tools for prevalence studies, case series and case reports. In a two‐phase selection, 34 studies were included: 21 observational, 3 case‐series and 10 case reports. These observational studies included approximately 14,003 patients from 10 countries. In this review, we explored the most commonly encountered oral and dental manifestations in COVID‐19 and identified that loss of taste acuity, xerostomia and anosmia were frequently reported. Elevated incidence of opportunistic infections like mucormycosis and aspergillosis were reported during the treatment due to prolonged intake of steroids. Immunosuppression and poor oral hygiene led to secondary manifestations like enanthematous lesions. However, it is not clear that oral signs and symptoms are due to COVID‐19 infection itself or are the result of extensive treatment regimen followed [PROSPERO CRD42021258264].

gastrointestinal tract, liver, central nervous systems, blood vessels, heart and kidneys. [4] [5] [6] Its transmission through respiratory droplets, aerosols, contact and fomites has facilitated the rapid spread worldwide. 5 The most commonly reported manifestations include symptoms common to other viral infections such as fever, cough, sore throat, myalgia, arthralgia, headache, dyspnoea, and excessive sputum production. However, an increasing number of atypical clinical presentations have been reported, such as gastrointestinal symptoms like anorexia, tremors, nausea, vomiting, and diarrhoea, 1 dermatological manifestations, and chemosensory dysfunctions. 2 also causes direct injury to myocardial cells mediated by angiotensin-converting enzyme 2 (ACE2) receptors and additionally by systemic inflammation causing indirect myocyte injury. Thus, myocardial injury, arrhythmias, cardiac arrests, heart failure and coagulation abnormality can manifest as cardiovascular abnormalities in COVID-19 patients, which may cause serious impairment to the patient. 7 There was a positive and moderate correlation between neutrophil lymphocyte ratio values and clinical outcome of acute ischaemic stroke patients with Noteworthily, persistent long COVID symptoms like anxiety, prolonged depression, chest pain, palpitations, dizziness and hair loss as well as prolonged neuromuscular symptoms (fatigue, anosmia, headache, myalgia and joint pain) are a cause of grave concern in COVID-19 patients even after two weeks of recovery. 9, 10 In a systematic review and meta-analysis, the authors explored the association between delirium and poor prognosis in COVID-19 patients and suggested that the delirium in older patients can be an important presenting symptom of COVID-19 implicating poor outcomes and high risk of mortality. 11 Along with these symptoms, this virus can affect other organs including skin, olfactory system and oral cavity. 6 Various manifestations in the oral cavity such as mucosal ulcerative and vesiculobullous lesions, 1 taste changes, gingivitis, 6 inflammation of the papillae of Wharton's duct, plaques on the tongue, 6 xerostomia, halitosis, parotiditis, 5 are reported in the literature. Oral lesions can be an inaugural sign of Covid-19 or a warning sign of peripheral thrombosis. 6 In Covid-19 patients, elevated Interleukin-6 levels and Creactive protein implicate worse clinical outcomes as they cause significant cell damage; thus are a critical factor for shock and multiorgan failure. 12, 13 SARS-CoV-2 invades human cells via the receptor angiotensin converting enzyme II (ACE2). Angiotensin-converting enzyme 2 receptor is highly expressed in the organs at risk, such as lung, heart, oesophagus, kidney, bladder, and ileum, and located specific cell types (i.e., type II alveolar cells (AT2), myocardial cells, proximal tubule cells of the kidney, ileum and oesophagus epithelial cells, and bladder urothelial cells), which are vulnerable to 2019-nCoV infection. 14, 15 Besides high expression of ACE2 receptor on the epithelial cells of the tongue and of the salivary glands, could lead to the development of dysgeusia and oral mucosal ulcerations and necrosis in patients with Though, some of the oral manifestations may be the initial sign of the disease, however, it is still unclear as to whether these oral lesions are due to coronavirus infection or secondary manifestations resulting from local irritants or deterioration of systemic health/ immunosuppression or stress or the side effects of treatment, or a combination of these or just a coexisting finding. 16 

The present systematic review protocol was registered at the Na- 

All narrative reviews, editorial letters and systematic reviews were excluded. Also, the studies where COVID-19 positivity was not confirmed in the study subjects and where COVID-19 patients did not report oral signs and symptoms, were not added for analysis.

Our electronic search included the PubMed, Scopus, Web of Science and Embase databases using various key words alternately like COVID-19, humans, mouth diseases, oral manifestations, prevalence, SARS-CoV-2 on 4, 5 and 6 June 2021 and further updated our research on 1 February 2022 across these databases (Appendix Table 1). A software reference manager (EndNote X7, Thomson Reuters) was used to collect references and remove duplicate articles.

The article selection was completed by two authors in 2 steps. In step 1, two authors (PS and SM) separately screened the titles and abstracts of all the references through Rayyan software. Only those articles which matched the inclusion criteria were tabbed and the remaining publications were rejected. The concluding decision was taken in consultation with the third author (VW). In step 2, we followed the same selection criteria and only those published fulltext articles were selected which described the prevalence of oral manifestations and oral mucosal lesions in COVID-19 patients. The same 2 authors were associated independently in step 2. All selected articles were critically and intensely analysed by 3 authors and the new publications were also chosen for selection analysis. If there was any difference of opinion in either of the steps, it was settled by collective consensus among the 3 authors. Eventually, only full-text articles were preferred and selected for this systematic review.

At the outset, the first (PS) and second (SM) authors extracted the data from the chosen references. An extraction form was developed to list the essential information on the authors, name of the country,

year of study, study design, number of subjects, mean age, gender, severity of COVID-19, clinical features and oral manifestations. This was followed by the third author (VW) verifying the compiled data and affirmed its accuracy/preciseness/authenticity. If there was disagreement on any issue, it was resolved by discussion and mutual agreement among all the authors. However, final decision was taken by first and second authors. In some articles, if the required information was missing, efforts were made to contact the authors of these publications and the necessary data was filled in the excel sheet.

The risk of bias of included studies was assessed by 2 authors (PS and SM) independently using a quality assessment checklist for prevalence studies, case reports and case series adapted by the Joanna Briggs Institute's Critical Appraisal checklist (Munn et al 2015 and Moola et al 2017) . In case of difference of opinion, the third author (VW) was consulted. For each article, scoring was concluded only after consultation with all authors, and a study was specified as a high risk of bias when the 'yes' score was up to 49%, moderate when 50%-69% and low when >70%. 21,22

In the present systematic review, the chief outcome was the preva- neuropathies, taste and smell disturbances, demographic and epidemiological characteristics of patients (age, gender, geographic region, habits).

Initially, 3643 records were recognized from databases. After 

All included studies were assessed for risk of bias following Joana Briggs Institute guidelines and the observations are summarised in Table 1 and Table 2 and details are shown in Appendix Table 3 .

Prevalence studies, case reports and case series were evaluated with the specified checklist for each study design. 21, 22 Most prevalence studies (n = 15; 71.4%) presented low risk of bias overall, however, six studies (28.5%) had moderate risk of bias.

Similarly low risk of bias was observed in almost all case reports (n = 9; 90%) and case series (n = 2; 66.7%) analysed in this systematic review. Olfactory and gustatory disorders were found to be closely associated and were the most commonly reported oral manifestations, followed by xerostomia, anosmia, vesiculobullous lesions and oral ulcers. In concordance with other studies, majority of the prevalence studies included in our systematic review observed taste dysfunction and xerostomia as the most common symptom reported early before the manifestation of other symptoms of Covid-19.

Aphthous 

An observational study carried out on 666 confirmed cases of In the present systematic review, almost all these oral lesions were observed during COVID-19 infection period except the TMD which were the long-lasting symptoms manifesting even after the recovery of the infection. 

Paroxysmal lancinating pain was found in the right VI region that 

In a 51-year old hospitalised female patient, the right lower lip was hyperaemic and showed firm oedema extending towards the jaw, right facial paralysis and fissured tongue, suggestive of Melkersson-Rosenthal syndrome. It was concluded that activated mast cells may play a significant role in the pathogenesis of COVID-19 infection, as they release cytokines in the lungs and may be a probable etiological factor for this presentation. 61

There was a significant increase in the incidence of angio-invasive maxillofacial fungal infections in diabetic patients treated for SARS-CoV-2 with a strong association with corticosteroid administration.

In a retrospective observational study carried out on 18 COVID-19

hospitalised patients, mucormycosis was observed in 16 patients while aspergillosis was found in one patient and another one patient revealed a mixed fungal infection. 62 Oral pseudomembranous candidiasis was the most frequently observed oral presentation, followed by geographic tongue and taste alteration, in 27 COVID-19

positive children in a retrospective study conducted in Italy. 63 SHARMA ET AL. 

Severe, persistent macroglossia was observed following a prolonged course of prone positioning for treatment of a 40 year old COVID-19 patient. 64

Psychological impact of COVID-19 cannot be neglected as it is leading to aggravation TMD, bruxism and anxiety in COVID-19 patients even after recovery. 65 

There are some limitations of this systematic review which must be 

In this systematic review, the most frequently observed oral presentations were taste alterations, followed by xerostomia and vesiculobullous lesions. Though, increasing number of patients are reporting oral manifestations in COVID-19, but, it still remains ambiguous whether they are directly due to the deadly infection or are merely seen as secondary presentation during the treatment. In the current scenario of rapidly changing and new mutated strains of COVID-19 virus, more high-quality prevalence studies are required to be conducted to find a causal relationship between oral symptoms and this highly contagious virus. Noteworthily, dental professionals can play a key role in the early diagnosis of this viral infection.

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None. No funding was received for this study.

The authors declare no conflicts of interest. 

This is a systematic review and data sharing is not applicable to this article as no new data was created in this study. The data for the included studies is presented in Table 1 and Table 2 , while the flow chart for literature search is presented in Figure 1 .

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