Oral Manifestations of COVID-19 in Hospitalized Patients: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Giulia Orilisi.

The oral cavity represents a target of SARS-CoV-2, and oral lesions are observed in both non-hospitalized and hospitalized patients. Oral ulcers, cheilitis, and tongue lesions were more common in patients before hospitalization, while perioral pressure ulcers, macroglossia, blisters, and oral candidiasis were more recurrent in patients during hospitalization.  An accurate oral examination during the hospital admission of all confirmed COVID-19 cases is encouraged to recognize oral early manifestations and to apply appropriate treatments.

  • SARS-CoV-2
  • COVID-19
  • oral lesions
  • hospitalized patients
  • oral ulcers
  • tongue lesions

1. Introduction

The outbreak of novel coronavirus SARS-CoV-2 has created a global crisis and challenged healthcare systems across the world [1]. It was first identified in Wuhan, China, on 31 December 2019, in association with a severe human respiratory disease (COVID-19). On 30 January 2020, the World Health Organization (WHO) declared the COVID-19 infection as a Public Health Emergency of International Concern.
SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus with multiple spikes on the surface and a genome size of approximately 26–32 kilobases. Fever, dyspnea, body aches, and dry cough are the most common symptoms [2], but severe cases can develop pneumonia, severe acute respiratory syndrome, and kidney failure, representing a life-threatening condition [3,4][3][4]. Most patients display moderate symptoms (80%), while 20% of them may develop a severe disease and 5% may become critically ill, developing pneumonia or acute respiratory distress syndrome, which requires mechanical ventilation and intensive care unit hospitalization [5]. SARS-CoV-2 mainly spreads through respiratory droplets, aerosols, contact, and fomites [6,7,8,9][6][7][8][9].
A recent study has shown that coronavirus invades human cells via the receptor angiotensin-converting enzyme 2 (ACE2), using the spike-like protein [10]. The ACE2 receptors are located in many organs and tissues, such as skin, olfactory system, and oral cavity; therefore, these cells may host the virus, triggering the inflammatory response [11,12][11][12].
Oral manifestations have been reported in several literature studies [13,14,15,16][13][14][15][16]. The main symptoms, displayed during the pre-symptomatic stage, are ageusia (loss of taste), non-specific anosmia (loss of smell), and hyposalivation [17,18][17][18]. Moreover, the most frequently reported oral signs include ulcerative lesions, vesiculobullous/macular lesions, desquamative gingivitis, petechiae, and coinfections such as candidiasis [15,19][15][19]. Palate and tongue represent the most involved oral subsites, followed by gingiva and lips [15].
The morphological spectrum of mucocutaneous diseases is still uncertain, as is its relationship with the clinical pattern and course of affected patients. However, many hypotheses have been proposed regarding the etiology of these diseases: direct SARS-CoV-2 infection, a coinfection, a consequence of the impaired immune system, and an adverse reaction to medical treatments and devices [20,21,22][20][21][22]. According to Sarode et al., oral manifestations seen in COVID-19 could be related to SARS-CoV-2 induced anemia [23]. Indeed, ACE2, CD147, and CD26 receptors located on the erythrocytes are potential targets for SARS-CoV-2 attachment, which can lead to hemolysis [24]. On the other hand, some authors have suggested that mucosal ulcers could be considered, not as a primary manifestation of COVID-19, but as a secondary signs related to bacterial and viral coinfections [25]. According to Hocková et al., oral mucocutaneous complications could be caused by the prolonged prone position and mechanical ventilation devices of the intensive care unit (ICU) setting [21]. Most of these studies were case reports and case series; therefore, it is still unclear whether the reported cases were directly due to the COVID-19 infection or indirectly related to stress, anxiety, comorbidities, and medical treatments.

2. Oral Manifestations of COVID-19 in Hospitalized Patients

2.1. Tongue Lesions

Tongue lesions appearing before hospital admission were reported in 14 studies [37,38[26][27][28][29][30][31][32][33][34][35][36][37][38][39],43,51,61,63,65,70,71,74,81,87,88,89], while 14 articles showed that tongue manifestations occurred during hospitalization [21,34,36,39,48,54,59,60,66,69,70,82,84][21][40][41][42][43][44][45][46][47][48][33][49][50]. The sample consisted of 172 males (age: 57.0 ± 15.1) and 155 females (age: 46.1 ± 22.1). Moreover, 135 patients with no specified sex and mean age were included.
Before hospitalization, white tongue, necrosis of the dorsal tongue, glossitis, geographic and fissured tongue, strawberry tongue, and depapillation of the tongue were the most common lesions diagnosed, directly related to SARS-CoV-2. One patient with a complex medical history showed a 1.5 × 1.5 cm ulcer in the right border of the tongue, while another patient reported a mucopurulent membrane in the anterior dorsal tongue [37][26]. Only three studies that reported tongue lesions referred to Kawasaki-like disease, potentially associated with COVID-19 [38,51,65][27][29][32].
During hospital admission, the main SARS-CoV-2 related lesions were tongue ulcers, especially in ICU patients [21]. Moreover, white plaque on tongue dorsum, geographic tongue, tongue redness, fissured tongue, and macroglossia were reported [35,54,66][51][44][47]. Macroglossia was reported in two patients who experienced prolonged pronation cycles for several days. Andrews et al. suggested 10 days of methylprednisolone in addition to a bite block to prevent this complication [35][51]; on the contrary, according to Mascitti et al., macroglossia could be referred to acute lymphatic and vascular obstruction due to COVID-19-related inflammatory response [54][44].

2.2. Ulcerative and Erosive Lesions

Ulcerative and erosive lesions were frequently present in COVID-19 patients, both before and during hospital admission. In particular, 14 studies reported that lesions appeared during hospitalization [21[21][40][41][26][52][53][54][43][55][56][57][48][33][49],34,36,37,42,45,47,48,52,57,64,69,70,82], while 6 articles referred to lesions that emerged before hospitalization [36,37,38,41,61,70][41][26][27][58][30][33]. The sample consisted of 111 males (age: 56.7 ± 15.3) and 90 females (age: 53.2 ± 22.4). Moreover, 123 patients with no specified sex and age were included.
Before and during hospitalization, ulcerative and erosive lesions were the most common orofacial manifestations of COVID-19. The ulcers emerged after a latency time of 4 to 7 days after the onset of COVID-19 symptoms, and most of them were diagnosed upon hospital admission. Only in one case did small oral ulcers appear 40 days after a COVID-19 positive test [42][52]. Some patients displayed painful herpetic and hemorrhagic ulcers with irregular margins, which were variable in size and number. Ulcers that appeared before hospital admission were located on the hard palate and lips, while the lesions that occurred during hospitalization mainly affected the tongue dorsum, lips, and buccal mucosa.
Some authors suggested different factors involved in the development of ulcerative and erosive lesions [12,41,60,61,91][12][58][46][30][59]. Ulcers could be related directly to SARS-CoV-2 infection or could be caused by drugs, vasculitis, or thrombotic vasculopathy secondary to COVID-19 [34,41][40][58]. Oral ulcerative lesions and erosive plaques appeared a few days after the onset of respiratory symptoms and worsened during hospitalization, due to persistent immunological impairment, and lesions did not heal after SARS-CoV-2 eradication [47][54]. In four ICU patients, the authors suggested that oral ulcers could be caused by medical devices during the prone positioning phases [21,57][21][56]. A wide range of therapies has been used for oral ulcers, including drugs (e.g., dexamethasone, tetracycline) and photobiomodulation therapies [37,57,64][26][56][57].

2.3. Aphthous-like Lesions

Aphthous-like lesions were reported in four studies, affecting six minors and three adults (>50 years). Moreover, aphthous-like lesions were showed in 78 cases with various oral signs and symptoms associated with COVID-19 [88][38]. Lesions were mainly related to COVID-19, probably due to the distribution of the ACE2 receptor on the oral mucosae [11[11][60],86], although one patient with minor aphthous ulcers was diagnosed with Sweet syndrome related to COVID-19 [62][61]. Stress and immunosuppression secondary to COVID-19 infection could be other possible reasons of these lesions [92][62].

2.4. Vesiculobullous Lesions

Vesiculobullous lesions, including herpetiform lesions, angina bullosa-like lesions, and oral blisters, were described in three studies [26,46,53,70][63][64][65][33]. Carreras-Presas et al. presented a 65-year-old female with lip blisters and desquamative gingivitis, occurring 22 days after viral infection. These lesions seem to be caused by COVID-19 through mechanisms shared with others virus, such as Herpes Simplex Virus-1 (HSV-1)-related gingivostomatitis [26][63].
Favia et al. detected oral blisters in 19 hospitalized patients (15.4%) that appeared during the first week after the onset of general symptoms and were mainly located on the tongue and palate [70][33]. According to the authors, lesions could be related to SARS-CoV-2, medical treatments, and/or poor oral hygiene.
Orolabial recurrent herpes simplex were observed in eight patients [46][64]. This manifestation was found in at HSV-1-positive patients, suggesting a possible superinfection of herpetic virus with COVID-19.

2.5. Lip Lesions

Lip lesions included fissured lip, angular cheilitis, and perioral pressure ulcers. Fissured lips have been detected mainly in young patients, who were diagnosed with Kawasaki-like disease related to COVID-19 [39,40,51,54,65,71,72][42][66][29][44][32][34][67]. Mazzotta et al. described a 9-year-old male with Down syndrome and alopecia areata universalis, presenting glossitis and cheilitis, probably due to the excessive and persistent inflammation that occurred during the interstitial pneumonia with acute respiratory failure [74][35]. Angular cheilitis, due to stress and immunosuppression, was observed in a 53-year-old man a few days after hospital discharge; after the treatment, this lesion completely disappeared [43][28].
Prolonged prone position and endotracheal intubation were the most common risk factors for perioral and lip pressure ulcers, interfering with mechanical ventilation equipment in the critical care setting [21,49,56,58,59,66,73,77,78,90][21][68][69][70][45][47][71][72][73][74]. Most cases were treated with antimicrobial dressing, debridement of necrotic tissue, and paraffin gauze dressing. Finally, some articles reported lip lesions directly related to COVID-19, which appeared as a mucopurulent membrane with superficial necrosis or swollen lips and disappeared after 10–12 days of treatment [37,63,71][26][31][34].

2.6. Functional Disorders

Functional disorders included xerostomia, viscous saliva, ageusia and dysgeusia, halitosis, burning mouth, masticatory muscle weakness, salivary gland ectasia, temporo-mandibular article abnormalities, and facial tingling. These disorders were reported by several studies referred to hospitalized patients affected by COVD-19 [3,34,43,76,82,88][3][40][28][75][49][38]. The authors suggested these alterations could be directly related to SARS-CoV-2 and could be considered as an early manifestation of COVID-19 infection. Indeed, ACE2 receptors have been found in the taste buds and glandular epithelium, leading to salivary gland dysfunction and salivary flow impairment [93][76].
Masticatory muscle weakness, salivary gland ectasia, temporo-mandibular article abnormalities, and facial tingling were reported by Gherlone et al. [48][43]. The authors suggested that salivary gland ectasia reflected the hyperinflammatory response to SARS-CoV-2, as demonstrated by the significant relationship with C-reactive protein and lactate dehydrogenase levels at hospital admission, and antibiotics use during acute disease.

2.7. Candidiasis

Candidiasis appeared as white plaques on the dorsum of tongue, gingiva, and palate [43,44,66,70,75,80,81][28][77][47][33][78][79][36]. The authors suggested it could be related to the long-lasting antibiotic therapy, the deterioration of general status, and poor oral hygiene [80][79]. Salehi et al. isolated 65 species of Candida spp. (70.7% C. albicans) in a cohort of COVID-19 patients with oropharyngeal candidiasis [75][78]. Interestingly, Dima et al. reported oral candidiasis with diaper erythema in three newborns positive with COVID-19 [44][77]. The oral candidiasis in young patients was also reported by Bardellini et al. [81][36], describing two cases of oral pseudomembranous candidiasis diagnosed at the hospitalization.

2.8. Nonspecific Lesions (Mucositis)

Petechiae, macules, erythema, stomatitis, brown pigmentation, mucositis, enanthema, and desquamative gingivitis were reported in many hospitalized patients [26][63]. Vascular disorders could cause mucositis in the affected patients. Indeed, Cruz-Tapia et al. described a 51-year-old female with diffuse vascular-like purple macule on the left palate and a papule-plaque on the right palate [68][80]. Riad et al. described 13 patients affected by mucositis; enanthema of the buccal mucosa, palate, and gingiva; and depapillation of the tongue, at hospitalization. These lesions disappeared after 7–14 days of “Magic mouthwash” and paracetamol and could be related directly to COVID-19 infection [6,89][6][39]. Only one study described a patient affected by oral lichenoid reaction and a case with oral enanthema, directly due to COVID-19 [54][44]. Marouf et al. suggested that periodontitis was significantly associated with a higher risk of COVID-19 complications, such as ICU admission, assisted ventilation, and the increased markers levels of COVID-19 worse outcome [55][81].

3. Summary

A broad spectrum of signs and symptoms were reported in association with COVID-19; however, only a few studies highlighted oral clinical manifestations observed in hospitalized patients. The pathogenesis remains unclear, but some hypotheses have been formulated. Xu et al. showed a higher expression of ACE2 in the oral mucosa, especially on the tongue and in the salivary glands [11]. Thus, the oral cavity might be an anatomical site susceptible to SARS-CoV-2 infection [94][82]. Consequently, the interaction between SARS-CoV-2 and ACE2 might dysregulate the oral keratinocytes’ function, leading to painful oral ulcers [37][26]. This mechanism could also be the basis of early manifestations of COVID-19, such as taste alteration and xerostomia [95][83]. The immune response to infection could activate Langerhans cells and lymphocytes, leading to vasculitis and thrombocytopenia, causing oral lesions related to vascular disorders (e.g., petechiae) [19,41,92,96][19][58][62][84].
It is still unclear whether oral lesions reflect a direct viral cytopathic effect or represent a consequence of stress, poor oral hygiene, systemic infections, medical treatments, or medical devices used during hospital admission [97][85]. However, to the best of our knowledge, no attempt has been made to review the available literature regarding oral lesions in hospitalized COVID-19 patients. Therefore, this systematic review is the first to characterizs the patterns of oral lesions that occurred in hospitalized patients affected by COVID-19. As intraoral examination has not yet been considered in the screening of the disease, literature still lacks evidence to better understand the onset of oral manifestations. In this review, the most common oral lesions seen in patients before hospital admission are painful ulcers, cheilitis, and tongue lesions. According to several authors, these lesions are related directly to COVID-19 [36,37,88,89][41][26][38][39]. Conversely, the most common oral lesions displayed by patients during hospitalization are perioral pressure ulcers, macroglossia, blisters, and oral candidiasis. These lesions may be due to the long-lasting prone position of ICU patients [21[21][74],90], increased pressure of the endotracheal tubes [59][45], prolonged inpatient care [52][55], persistent immunological impairment [43[28][54],47], and medical treatments [80][79].
Although the evidence derived from case series and case reports is very low, a strong recommendation for oral lesions of hospitalized patients, affected by COVID-19, can be provide. Moreover, GRADE literature describes five paradigmatic situations in which a strong recommendation can be made based on low quality evidence, such as a condition of life threatening [99][86].
It could be suggest that: (1) painful oral ulcers, cheilitis, and tongue lesions are more frequent in patients before hospital admission; (2) perioral pressure ulcers, macroglossia, blisters, and oral candidiasis are more evident in patients during hospitalization; (3) lesions that appeared before hospital admission are mainly related directly to COVID-19; (4) lesions that appeared during hospitalization are mainly associated with medical devices and treatments, prone position, and immunological impairment; (5) all clinicians, during the hospital admission, should be encouraged to perform an accurate oral examination of all confirmed COVID-19 cases to recognize the disease’s possible early manifestations; (6) further studies are necessary to establish the pathological significance of oral manifestations during COVID-19.

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