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The impact of oral health status on COVID-19 severity, recovery period and C-reactive protein values Amany Hany Mohamed Kamel,*1 Ahmed Basuoni,2 Zeinab A. Salem3,4 and Nermeen AbuBakr1

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for coronavirus disease 2019 (COVID-19).1 The World Health Organisation (WHO) declared a global pandemic on 11 March 2020.2 By 17 November 2020, there were over 54 million confirmed cases of COVID-19 with 1,324,249 deaths globally. In Egypt, by this date, there were over 111,009 confirmed cases and 6,465 deaths.3

COVID-19  can manifest with a range of symptoms, from mild flu-like symptoms of fever,

dry cough, fatigue, muscle pain and diarrhoea, to more serious presentations characterised by severe pneumonia progressing to adult respiratory distress syndrome (ARDS). Not all affected persons will display symptoms.4 The mortality rate of COVID-19 ARDS can approach 40–50%.5 Other cases can be deteriorated to aggressive counteracting of the immune system, known as ‘cytokine storm syndrome’, in which the levels of released cytokines – tumour necrosis factor (TNF), interleukin-6 (IL-6) and interleukin-1β (IL-1β) – are injurious to host cells. This may expose patients to an expanded hazard of vascular permeability which can cause damage to many organs, such as the kidneys and heart.5 Moreover, vascular complications have also been reported in severe cases.6

C-reactive protein (CRP) is a marker of hyper-inflammation. Patients with high levels of CRP have been shown to have a worse prognosis with COVID-19. Recent studies have revealed that the increased CRP levels were likely due to acute inflammatory pathogenesis identified with COVID-19, during which various cytokines

were released and their amount was associated with disease severity.7,8

Several risk factors for COVID-19 infection have been recognised by the WHO and the Centers for Disease Control and Prevention (CDC), including ageing, diabetes, hypertension, immunodeficiency and cardiovascular diseases.9 These comorbidities are associated with increased severity of COVID-19; however, there are various other risk factors that could also be involved in affecting disease outcomes.

Recent studies have demonstrated the association between oral health status and systemic diseases, including systemic infections, cardiovascular disease, pregnancy outcomes and respiratory diseases.10,11 Moreover, the impact of good oral care on risk reduction of viral acute respiratory diseases has been reported in numerous studies.12,13

The oral cavity is well known as a potential reservoir for respiratory pathogens. It houses more than 700 bacterial species or phylotypes.14 Viral respiratory infections predispose patients to bacterial super-infections. It was

Oral health status could have a potential impact on the severity of COVID-19.

Poor oral health was correlated to increased values of C-reactive protein.

Delayed recovery period was observed in patients with poor oral health.

Key points

Abstract Objectives The oral cavity is a potential reservoir for respiratory pathogens which can predispose patients to bacterial super-infection. Several trials have correlated poor oral hygiene with hyper-inflammation. Similarly, COVID-19 severity has been linked to hyper-inflammatory responses. Hence, in this study, we assumed that increased COVID-19 severity may be linked to poor oral health status. This was achieved through assessing oral health status, severity of COVID-19 symptoms, C-reactive protein (CRP) levels and duration of recovery.

Methods Cross-sectional study based on a questionnaire; 308 Egyptian patients with confirmed positive polymerase chain reaction (PCR) tests were included in the study after exclusion criteria. The questionnaire was designed with two sections: the first section for oral health evaluation and the second section for COVID-19 severity evaluation. Assessment of the effect of oral health on COVID-19 severity was performed using an oral health score. The effect of oral health on CRP and recovery period were evaluated as secondary endpoints. Data of CRP levels and COVID-19 PCR tests were collected via the questionnaire and confirmed by reviewing medical records.

Results The correlation between oral health and COVID-19 severity showed a significant inverse correlation (p <0.001, r = -0.512). Moreover, the correlation between oral health with recovery period and CRP values also revealed a significant inverse correlation (p <0.001, -0.449 and p <0.001, -0.190, respectively), showing that poor oral health was correlated to increased values of CRP and delayed recovery period.

Conclusions Our study provided some evidence that oral health could have a potential impact on the severity of COVID-19. However, the correlation is limited by the study design. A more substantial research project is required to address this relation.

1Lecturer, Oral Biology Department, Faculty of Dentistry, Cairo University, Cairo, Egypt; 2MD in Cardiology, Faculty of Medicine, Cairo University, Cairo, Egypt; 3Assistant Professor, Oral Biology Department, Faculty of Dentistry, Cairo University, Cairo, Egypt. 4Assistant Professor, Faculty of Oral and Dental Medicine, Ahram Canadian University, Cairo, Egypt *Correspondence to: Amany Hany Mohamed Kamel Email address: [email protected]

Refereed Paper. Accepted 14 January 2021 https://doi.org/10.1038/s41415-021-2656-1

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found that severe COVID-19 cases were significantly associated with secondary bacterial infections.15 Moreover, several trials have linked COVID-19 severity to high SARS- CoV-2 viral load in the nasal and oral cavity.16,17

The latest survey conducted by the Egyptian Ministry of Public Health in collaboration with the WHO on the status of oral health among Egyptians noted that 40% of subjects have encountered dental problems at the time of examination. Visiting behaviours of subjects showed that almost 20% had not visited a dentist for more than two years, plus another 20% had never been to a dentist.18

The aim of this study was to investigate the potential effect of oral health on COVID-19 illness severity in recovered patients.

Methods

Sample size The sample size was 464 recovered COVID- 19 Egyptian patients. The sample size was calculated from the targeted population (recovered COVID-19 patients) – in Egypt, by the date the study was performed, there were around 20,000. On estimating the sample size, it was 377, with 95% confidence level and 5% confidence interval.

Study design The study design was a cross-sectional trial based on a questionnaire survey (Fig. 1). The included patients were recruited from COVID- 19 dashboard records of the Egyptian Ministry of Health from 1 April 2020 to 1 July 2020. All patients were tested positive for the COVID- 19 polymerase chain reaction (PCR) test. The questionnaire contained demographic data regarding patient gender, age, weight, height, level of education and general health condition (online Supplementary Material 1). The questionnaire was divided into two sections: the first section for oral health evaluation assessed by a group of dentists (online Supplementary Material 2) and the second section for COVID- 19 severity assessed by a group of physicians (online Supplementary Material 3). This was done via phone call interviews and/or a link on Google Drive sent to each patient via WhatsApp message. The analysis of the answers to both sections was blinded to the other.

Inclusion criteria This included patients aged 19–55 years old, of both genders and with confirmed positive COVID-19 PCR test result.

Exclusion criteria This included smokers, alcoholics, severe obesity (body mass index ≥35), pregnancy and patients with comorbidities (diabetes mellitus, hypertension, cardiovascular diseases, chronic kidney disease, chronic lung diseases and patients who had immunosuppressive conditions or were on immunosuppressive medications). This also included patients who failed to complete the questionnaire or refused to provide consent.

Ethical approval This questionnaire and methodology were approved by the Ethics Committee of Faculty of Dentistry, Cairo University, Cairo, Egypt (approval number: 21/6/20).  All participants gave their informed consent to the interviewer verbally, using the telephone interview as a format for data collection. In

addition, a link to the consent form was sent electronically.

Questionnaire tool The questionnaire was reviewed by an expert committee consisting of dental clinicians, physicians and professors at Cairo University. The questionnaire design of the oral health section was guided by a study conducted by Levin et al. (2013)  who reported that their questionnaire provided an accurate screening tool for caries risk assessment as reflected by clinical and radiographic examinations,19 in addition to Prado et al.’s (2017) questionnaire which was regarded as a reliable and valid tool for evaluating oral health status.20 All the questions regarding oral health status in both questionnaires were included in the current questionnaire design and a similar scoring system was utilised.

Cross sectional double blinded study

464 Egyptian recovered COVID-19 patients

308 included in the study

Questionnaire survey

Statistical analysis and correlation

Impact of oral health on COVID-19

Impact of oral health on C-reactive protein values

Impact of oral health on recovery period

Oral health status evaluation

Oral health score 0-37

Poor Fair Good

COVID-19 severity assessment

Severe Mild

First section Second section

After exclusion criteria

Fig. 1 A schematic diagram showing the design and methodology of the study

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Assessment of the effect of oral health on COVID-19 severity as a primary endpoint Oral health interpretation Interpretation was carried out according to the scores mentioned in online Supplementary Material 2. The questionnaire consisted of 18 questions; each answer denoted a given score of points. The total score ranged from 0–37 with a higher score denoting good oral health status. The participants were categorised according to their answers into three groups: poor, fair and good oral health, with a threshold of 0–14, 15–23 and 24–37, respectively.

COVID-19 severity interpretation Scoring and interpretation were done via the questionnaire. Patients were classified into mild and severe cases. Severe COVID- 19 illness was characterised by the following criteria: high respiratory rate (>30 breaths per minute); heart rate >100 beats/minute; severe dyspnoea or chest pain; oxygen saturation <93%; and high-grade fever (>39 °C). Additionally, all hospitalised patients who required oxygen or intensive care unit admission were considered as severe cases. Patients who were not hospitalised due to a shortage of available hospital beds were considered as severe cases if they fulfilled the aforementioned criteria.21,22,23,24

Assessment of CRP values CRP values for each patient during the first week of illness were obtained retrospectively from laboratory test results supplied to the questionnaire, confirmed by reviewing medical records (online Supplementary Material 3). The inflammatory marker level was then correlated to the COVID-19 severity and oral health status of each patient.

Assessment of recovery period Patients were categorised according to their recovery period (complete absence of symptoms) into: fast recovery (two weeks or less); intermediate recovery (four weeks); and delayed recovery (six weeks). Data obtained were then correlated to the COVID-19 severity and oral health status of each participant. This data was obtained from the questionnaire.

Statistical analysis Data were coded and entered using the statistical package SPSS version 22 (IBM Corp., Armonk, USA). Categorical variables were summarised as frequency and percentage. Quantitative variables were summarised as

means  ±  standard deviation. Comparisons between groups were carried out using the chi-squared test when comparing for the incidence of studied parameters and an unpaired t-test was used when comparing variables between the two groups. Receiver operating characteristic (ROC) curve analysis was done to detect the prediction value of oral health score. Spearman’s correlation was used for correlation between studied variables. A p value <0.05 was considered significant.

Results

Survey respondents Responses were received from 464 participants, but only 308 respondents were included in the study as 156 respondents were excluded according to exclusion criteria – 4 patients were <19 years old, 18 were >55 years old, 30 were smokers, 34 were severely obese, 3 were pregnant, 63 had comorbidities and 4 failed to complete the questionnaire or refused to provide consent. See online Supplementary Material 4 for demographic data and online Supplementary Material 5 for descriptive statistics.

Effect of oral health on COVID-19 severity (primary endpoint) The incidence of severe COVID-19 illness was significantly observed in participants with poor oral health status (p <0.001). Participants with good oral health status had a significantly reduced incidence of severe COVID-19 illness (p <0.001, r  =  -0.512) (Tables 1 and 2; Fig. 2a).

Subgroup analysis of serious COVID-19 cases Subgroup analysis of severe COVID-19 cases according to deterioration timing showed 23.75% and 76.25% of serious cases deteriorated during the first and second weeks of illness, respectively. The incidence of poor oral health status in those who experienced first-week deterioration (63.1%) was significantly higher than that of good oral health status (10.6%) (p <0.001). Similarly, the incidence of poor oral health status in those who experienced second-week deterioration (65.6%) was significantly higher than that of good oral health status (9.8%) (p <0.001) (Table 3).

Oral health status COVID-19 severity

P value Severe Mild

Poor oral health N 52 12

<0.001

% 65.0% 5.3%

Fair oral health N 20 146

% 25.0% 64.0%

Good oral health N 8 70

% 10.0% 30.7%

Table 1 Assessment of the effect of oral health of the included participants on COVID-19 severity (primary endpoint) with a significant difference as p value <0.001

Variable Oral health status COVID-19 severity Recovery period CRP

Oral health status

R 1.000 -0.512** -0.449** -0.190*

P value . 0.000 0.000 0.018

N 308 308 308 308

COVID-19 severity

R -0.512** 1.000 -0.575** -0.369**

P value 0.000 . 0.000 0.000

N 308 308 308 308

Key: * = P value <0.05 ** = P value <0.01, indicates more significance

Table 2 Correlations between oral health and COVID-19 severity, recovery period and CRP values

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Secondary endpoints Effect of COVID-19 severity on the recovery period The incidence of the delayed recovery period (six weeks) was significantly higher in severe COVID-19 patients (45.0%) compared to that in mild cases (6.1%) (p <0.001). Conversely, a fast recovery period (two weeks) was significantly observed in mild COVID-19 cases (70.2%) compared to that in severe cases (10%) (p <0.001, r = -0.575) (Tables 2 and 4).

Effect of oral health on the recovery period The incidence of the delayed recovery period (six weeks) was significantly higher in those with poor oral health status (40.6%) (p <0.001) and a fast recovery period (two weeks) was significantly observed in those with good oral

health status (82.1%) (p <0.001, r = -0.449) (Tables 2 and 4; Fig. 2b).

Effect of COVID-19 severity on CRP values The incidence of elevated values of CRP (>18 mg/L) significantly occurred in severe COVID-19 participants (75.0%) (p <0.001) and lower CRP values (<18 mg/L) were significantly observed in mild COVID-19 participants (81.6%) (p <0.001, r = -0.369) (Tables 2 and 4).

Effect of oral health on CRP values The incidence of elevated values of CRP (>18 mg/L) significantly occurred in those with poor oral health status (65.6%) (p <0.001). Significantly, lower CRP values (<18 mg/L) were observed in those with good oral health

status (74.4%) (p <0.001, r = -0.190) (Tables 2 and 4; Fig. 2c).

ROC curve analysis Oral health score (ROC) curve analysis showed p <0.001; at a cut-off value of 18 for health score with a 71% sensitivity (true positive cases) and 80% specificity (true negative cases), positive predictive value (PPV) 77%, negative predictive value (NPV) 75% (Fig. 2d).

Discussion

We aimed to investigate the effect of oral health on the severity of COVID-19 illness in recovered patients via a detailed questionnaire, as well as previous access to health data through a nationwide database and blood investigation

0 Good Fair Poor Good Fair Poor Good Fair Poor Good Fair Poor Good Fair Poor

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Fig. 2 a) A graph showing the impact of oral health status on COVID-19 severity. b) A graph showing the impact of oral health status on the recovery period of COVID-19 patients. c) A graph showing the impact of oral health status on CRP values during the first week of COVID-19 illness. d) ROC curve assessing oral health score as an indicator for COVID-19 severity in the studied population. The area under the curve was found to be 0.828 (95% confidence interval was between 0.745 and 0.911)

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results through corresponding participant health records. The analysis of the dental section of the questionnaire was performed by a group of dentists blinded to the results of the COVID-19 severity section (which was analysed by a group of physicians); therefore, proactive efforts to mitigate the risk of bias were made.

Participants with known risk factors and comorbidities that could affect COVID-19 severity other than the investigated parameter (oral health) were excluded. In addition, subjects above 55 years of age were excluded as they are considered to be more prone to experiencing severe COVID-19.25

Assessment of the severity of COVID- 19 patients has been somewhat unclear, but guidelines from different disease centres, such as the CDC, WHO, NHS and National Institute for Health and Care Excellence (NICE), used the same criteria as in this study to classify and assess COVID-19 severity.9,23,26 However, all available scores which classified pneumonia or COVID-19 severity were dependent on face- to-face consultations and examination, which were not applicable in the COVID-19  era, and some examination tools have also been prohibited. Some trials showed good results in

assessing patients using phone calls, video calls or filling hospital forms. Therefore, using the questionnaire tool to assess COVID-19 severity can be beneficial.27,28,29

In the current study, it was observed that the severity of COVID-19 symptoms significantly increased in patients with poor oral health status. Moreover, symptoms of severity significantly decreased in those with good oral health status (p <0.001). These findings highlighted the potential impact of oral health status on COVID-19 severity. This is in agreement with several studies that demonstrated the role of oral health in secondary respiratory infections, either bacterial or viral.12,13

In patients with poor oral health status, the bacterial count colonising teeth was proven to be raised twofold to tenfold, thus introducing more bacteria into the bloodstream, resulting in bacteraemia.30 It was reported that, when a soluble antigen enters the bloodstream, it may interact with a specific circulating antibody and produce an immunocomplex. These macromolecular complexes stimulate various chronic and acute inflammatory reactions.31

Moreover, the pro-inflammatory cytokines, such as gamma interferon, interleukins,

prostaglandin E2 and TNF, attain increased tissue concentrations in periodontitis. These mediators fight against various microorganisms, but when the immunologic response becomes hyperactive, it can damage various tissues. The periodontium therefore acts as a

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