key: cord-0715226-heasez5j
authors: Halepas, Steven; Lee, Kevin C.; Myers, Aaron; Yoon, Richard K.; Chung, Wendy; Peters, Scott M.
title: Oral manifestations of COVID-19 related multi-system inflammatory syndrome in children: a review of 47 pediatric patients
date: 2020-12-09
journal: J Am Dent Assoc
DOI: 10.1016/j.adaj.2020.11.014
sha: 6d1d9ebf8a2213daf869b56f74519a0edec99370
doc_id: 715226
cord_uid: heasez5j

Background Although much is still unknown about the full effects of COVID-19, recent literature supports a post-viral immunological reaction resulting in a multisystem inflammatory syndrome in children (MIS-C). The purpose of this study was to report the rates of documented oral and oropharyngeal manifestations among these patients and to determine the association of these findings with other MIS-C symptoms. Methods This was a retrospective review of COVID-19 positive pediatric patients admitted to the Morgan Stanley Children’s Hospital of NewYork-Presbyterian (MSCHONY). Patients fulfilling the Centers for Disease Control and Prevention (CDC) criteria for MIS-C were included in this study. The documented signs, symptoms, and laboratory values were collected and compared against the presence of oral or oropharyngeal findings. Results The mean age of MIS-C patients was 9.0 ± 5.0 (1.3-20 years), and there was no obvious sex difference (51.1% male, 48.9% female). With respect to oral findings, 23 patients (48.9%) presented with red and/or swollen lips while only 5 (10.6%) were noted to have a strawberry tongue. Oral or oropharyngeal findings were significantly associated with the presence of systemic rash (p=0.04) and conjunctivitis (p=0.02). Conclusions The presence of oral or oropharyngeal changes may be early indicators of MIS-C and should prompt suspicion for MIS-C in the setting of COVID-19 infection.

Coronaviruses are enveloped, non-segmented, positive sense, RNA viruses belonging to the Coronaviridae family 1-3 . While most cause mild cold or flu-like symptoms, two betacoronaviruses, severe acute respiratory syndrome (SARS-CoV-1) and Middle East respiratory syndrome (MERS-CoV), resulted in more serious illnesses in recent years 4, 5 1, 2 .

Since December 2019, the novel strain SARS-CoV-2, the virus responsible for Coronavirus disease (COVID-19), has caused a global pandemic [6] [7] [8] . While older adults and immunocompromised patients have suffered substantially from this infection, children and adolescents with COVID-19 generally are asymptomatic and experience only mild respiratory symptoms [9] [10] [11] [12] [13] [14] . Despite this observation, an alarming new trend in pediatric COVID-19 infections has been reported. A growing body of literature supports the association between COVID-19 and a post-viral immunological reaction resulting in a multisystem inflammatory syndrome in children (MIS-C) [15] [16] [17] [18] [19] [20] .

MIS-C has been defined by the Centers for Disease Control and Prevention (CDC) as an individual less than 21 years of age presenting with fever, laboratory evidence of inflammation, and clinical evidence of severe illness necessitating hospitalization, including involvement of at least two or more organ systems 21 . These patients are also required to be positive for SARS-CoV-2 infection, confirmed either via reverse transcription polymerase chain reaction (RT-PCR), serology, or antigen testing, and to be without any other plausible cause for their symptoms 21 .

A fever is defined as a recorded temperature of 38.0 C or greater lasting for at least 24 hours.

Laboratory evidence of inflammation includes measurements such as elevated c-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and D-dimer elevation. While not all J o u r n a l P r e -p r o o f patients with MIS-C are expected to have the same signs and symptoms, clinical features may include fatigue, rash, oropharyngeal erythema, cardiac abnormalities, and dilation of conjunctival blood vessels 22 . There have been noted similarities between the defining clinical and laboratory features of MIS-C and Kawasaki Disease (KD), although the two are considered distinct entities 22, 23 .

KD is the most common primary vasculitis in childhood [24] [25] [26] . Although the exact etiology is unknown, recent studies suggest that it may be a virally induced illness [27] [28] [29] . Diagnosis of KD requires the presence of fever lasting for more than 5 days with at least 4 of the 5 physical exam findings: conjunctival injection, oral mucous membrane changes (including erythema of the lip vermilion and labial mucosa, erythema of the oral and oropharyngeal mucosa, and strawberry tongue), peripheral extremity changes (erythema or edema), polymorphous rash, and/or cervical lymphadenopathy 30 . Although laboratory results are non-specific, patients with KD will also usually have elevated c-reactive proteins (CRP), erythrocyte sedimentation rates (ESR), and D-dimers 26 . KD is considered a diagnosis of exclusion 25, 31, 32 .

MIS-C appears to share many similarities with KD, but currently it is considered a distinct diagnosis 33 . Oral findings are a prominent feature of KD, and from recently published reports oral mucous membrane changes also appear to be an important finding in MIS-C 16, 34 . One of the more frequently reported oral manifestations of KD is the presence of strawberry tongue 28, 35 . Strawberry tongue describes a hyperplastic appearance of the fungiform papilla set against either a white (white strawberry tongue) or erythematous (red strawberry tongue) background.

This presentation alone is not diagnostic for KD, and may also be seen in patients with food or medication allergies or in other infectious conditions such as scarlet fever 36, 37 .

Unlike KD, in MIS-C the precise incidence of oral findings and their clinical and prognostic significance is unknown. While dentists and other oral healthcare professionals are accustomed to documenting oral mucosal pathologies, frontline providers may experience difficulty detecting these subtle but potentially important changes. The purpose of this study was to review the incidence and clinical significance of oral and oropharyngeal findings among pediatric patients with MIS-C. Our aims were to report the rates of documented oral and oropharyngeal findings in these patients and to determine the association of these findings with other MIS-C symptoms.

This was a cross-sectional study of all COVID-19 positive patients with MIS-C hospitalized at Morgan Stanley Children's Hospital of NewYork-Presbyterian (MSCHONY) in New York, NY between March 15 th and June 1 st 2020. In this study, MIS-C was defined using the CDC criteria statistics were conducted to determine the overall prevalence of various subjective and objective findings within this patient sample. Comparisons were conducted between oral and oropharyngeal findings and all other study variables in order to reveal any descriptive associations. Univariate comparisons were conducted using chi-square and independent sample t-tests. A p<0.05 was considered statistically significant. This study was conducted with the approval and compliance of the Columbia University Irving Medical Center's Institutional Review Board (protocol no. AAAT0723). (Table 1) . Overall, oral or oropharyngeal findings were identified in over half (55.3%) of patients with MIS-C. These findings were significantly associated with the presence of a systemic rash (p=0.04), conjunctivitis (p=0.02), and absence of a cough (p=0.02) ( Table 2 ). The presence of oral and oropharyngeal changes was not associated with co-existing cardiac conditions such as myocarditis (p=0.33) or pericardial effusions (p=0.55).

The association between MIS-C and COVID-19 was first described anecdotally but has been reported more extensively in the global literature [17] [18] [19] 38 The purpose of our study was to report the incidence of oral and oropharyngeal findings in MIS-C and to determine the clinical significance of these changes. In our cohort of 47 patients, approximately half (23) had documented swelling, redness, or cracking of the labial mucosa on examination. A much smaller number (5) were reported to have strawberry tongue.

While it is unclear whether this represents a true negative finding or an error of omission, the lack of documented strawberry tongue in our patient cohort was noted significantly more frequently than other extraoral diagnostic criteria for MIS-C, such as fever (47 patients), systemic rash (32 patients), and conjunctivitis (27 patients). In two of the five cases of confirmed strawberry tongue, intraoral photographs were taken. The findings are more subtle when the hyperplastic papilla appear against an erythematous background (red strawberry tongue, Figure 1A ) as opposed to when they present in a patient with white strawberry tongue ( Figure 1B) . A cursory examination in a small child could easily result in these changes going undetected. Furthermore, the discordance between documented labial findings (48.9%) and strawberry tongue (10.6%) may suggest that the healthcare providers who are performing these evaluations experience difficulty detecting intraoral lesions. If this is the case, it reinforces the value of a dental provider in the workup and management of MIS-C patients. Of note, none of the patients in our sample were assessed by a dentist or dental specialist during their inpatient course at MSCHONY for evaluation of oral manifestations of MIS-C.

In addition to labial mucosal alterations and strawberry tongue, seven patients in our cohort also had other oral changes noted on clinical examination, which we categorized as J o u r n a l P r e -p r o o f "other oral manifestations." Three patients had reported blisters or sores in their mouths, however neither the site, size, nor clinical appearance was recorded in any of the three cases.

The lack of additional information makes it difficult to assess whether these lesions were viral or traumatic in etiology. One patient had a lesion noted on the inner lip and one had reported complaints of "mouth pain." Specific mention of posterior oropharyngeal erythema was made for one patient. There was one documented case of "smile asymmetry and tongue deviation."

This was presumed to be caused by cranial nerve palsy, which is another potential characteristic of MIS-C. Cranial nerve palsy was documented in six patients in our study, four of whom had reported oral or oropharyngeal findings.

The documented mean age of diagnosis of 9 years in our patient cohort is consistent with other studies reporting a higher average age of diagnosis in MIS-C when compared to KD, which is traditionally diagnosed in children under the age of 5 years with a peak incidence around 10 months of age 16, 22 . The relationship between MIS-C and KD is unclear, and there is undoubtedly overlap between the two with regard to clinical and laboratory findings. To this end, some have questioned whether MIS-C and KD may in fact be the same entity, with some cases of MIS-C being categorized as either incomplete or complete manifestations of KD [41] [42] [43] [44] . While it is beyond the scope of this paper to speculate on the uniqueness of these two entities, it is noteworthy to mention that oral manifestations were more commonly associated with the other diagnostic criteria for both MIS-C and KD including systemic rash (p=0.04) and conjunctivitis (p=0.02). Strawberry tongue, which is a characteristic albeit non-specific oral manifestation of KD, was only reported in five of the 47 patients with MIS-C. As previously stated, it is unclear whether this means that strawberry tongue is not strongly associated with 

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