Periodontal disease and COVID-19: a systematic review and meta-analysis of observational studies

doi:10.21203/rs.3.rs-2614191/v1

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Periodontal disease and COVID-19: a systematic review and meta-analysis of observational studies

https://doi.org/10.21203/rs.3.rs-2614191/v1

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Background: A larger proportion of people with severe cases of Coronavirus Disease 2019 (COVID-19) appears to have comorbidities compared to the general population. However, evidence regarding the roles of periodontal disease(PD), in context of Coronavirus Disease 2019(COVID-19), is limited. Thus, to explore the association between PD and COVID-19, this systematic review and meta analysis was conducted.

Methods: 7 online databases were searched by January 31, 2023. Heterogeneity was tested by I² index. OR and 95% CI were pooled through either random-effect or fixed-effect models. Subgroup analyses, sensitivity analyses, and publication bias assessments were also conducted.

Results: Of the 823 articles identified and reviewed, 11 articles with 16,708 subjects met inclusion criteria and were included. PD was found to be associated with a statistically significant increase in risk of progression to severe diseases for COVID-19 patients(OR=2.20, 95% CI=1.38-3.49). Further analysis suggested that PD was associated with assisted ventilation(OR=5.01, 95% CI:2.61-9.63), ICU admission(OR=1.61, 95% CI:1.24-2.09), pneumonia(OR=5.19, 95% CI:1.17-23.00), and death(OR=2.25, 95% CI:1.55-3.28) for COVID-19 cases.

Conclusions: Our results show that individuals with PD have an increased risk for ICU admission, assisted mechanical ventilation therapy, and a significantly increased risk of pneumonia and death. This suggests, to some extent, that the oral cavity is the gateway to COVID-19 infection; in other words, periodontitis is a risk factor for COVID-19 severity.

Periodontal Disease

COVID-19

Meta-analysis

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was detected in Wuhan, China, in December 2019. During a World Health Organization (WHO) press conference on 12 March 2020, the WHO announced that Coronavirus pandemic 2019 (COVID-19) has been declared around the world.¹ Despite widely applied public health measures, such as vaccinations and mask-wearing, cumulative number of confirmed cases of COVID-19 worldwide exceeds 756 million and cumulative number of deaths exceeds 6 million as of February 13, 2023.²

Clinical symptoms of COVID-19 vary, with most patients presenting with mild symptoms such as fever, cough, loss of smell and/or taste, hearing loss and fatigue. However, about one in five patients present with more severe symptoms such as acute respiratory distress syndrome (ARDS), multi-organ failure with sepsis, and even death.³ It has been proved that SARS-CoV-2 invades cells mainly by recognizing angiotensin-converting enzyme II (ACE-2), which is similar to severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) in its mechanism of action. It has been reported that the oral mucosa could be another path for SARS-CoV-2 invasion to human body due to the higher expression of ACE-2 in oral epithelial cells.⁴

In almost every country, periodontal disease, also known as gingivitis and periodontitis, is prevalent.^5,6 Studies suggest that people with periodontitis may be more prone to systemic disease, including cardiopulmonary disease, hypertension, respiratory disease, diabetes, and cancer.^7,8 COVID-19 and PD share some common features, such as risk factors including diabetes, obesity and hypertension, and they both have the potential to induce systemic inflammation.^9,10

There was a case-control study that reported periodontitis was associated with adverse outcomes like death, hospitalization, and requiring assisted ventilation in COVID-19 patients.¹¹ Another study with more than 13,000 participants in the United Kingdom found that patients with painful or bleeding gums or loosened teeth had a higher risk of COVID-19 death, although the risks of COVID-19 infection or COVID-19 related hospital admission were not increased. In addition, self-reported tooth loss was not associated with an increased risk of hospital admission or death in COVID-19.¹²

Given these controversial findings, this meta-analysis was conducted to address the discrepancy in outcomes with the aim to assess the relationship between outcomes of COVID-19 infection and PD.

PRISMA guidelines were followed in this study. In addition, the study protocol is prospectively registered on PROSPERO.¹³ The study protocol was prospectively registered in PROSPERO (http://www.crd.york.ac.uk/PROSPERO; registration number: CRD42022306216).

2.1. Search strategy

A comprehensive and systematic literature search through online databases was completed to select relevant available articles up to January 31, 2023. (1) MEDLINE; (2) Web of Science; (3) EMBASE; (4) China National Knowledge Infrastructure (CNKI); (5) Wanfang Data Knowledge Service Platform; (6) China Biology Medicine (CBM); and (7) China Science and Technology Journal VIP Database. There were no language restrictions. The search strategy was as following: (COVID OR coronavirus) AND (periodontal disease OR gingivitis OR paradontopathy OR alveolar bone loss OR gum disease OR paradontosis).

2.2. Inclusion criteria

(1)The type of study was observational study, including cross-sectional, case-control, prospective studies; (2)The primary outcome was the relationship between PD and and COVID-19 severity, including hospital admission, assisted ventilation, admission to intensive care unit(ICU), death and/or pneumonia in COVID-19 patients; (3) studies reporting the relationship between PD and COVID-19, and providing effect size (relative risk [RR], hazard ratio [HR], or odds ratio [OR]) and its 95% confidence interval (CI); (4) or studies providing raw data to calculate RR or OR.

2.3. Exclusion criteria

(1) Studies that did not meet the inclusion criteria; (2) studies that used in vitro experiments; (3) studies that were reviews or meta-analyses; (4) duplicate studies; (5) studies that were not human studies.

2.3. Data extraction and quality assessment.

2.3.1 Data extraction (selection and coding)

It was undertaken independently by three reviewers(YW, JG and GJ) to conduct the literature search, select the studies, and extract the data. Disagreements were resolved through discussion with a third investigator (CS). For the purpose of data extraction, patients with PD were considered as the case group, while patients without PD were defined as the control group. Outcome is defined as the presence of severe diseases. The following data were extracted from the included studies: first author, year of publication, location, type of study design, sample size, age, exposure, outcome indicators and adjusting factors.

2.3.2 Risk of bias (quality) assessment

Modified versions of the Newcastle-Ottawa Scale (NOS) was used at the discretion of each of the three authors(YW, JG and GJ) to assess the quality of the included studies. NOS assessed the quality of non-randomized studies based on three categories: selection of study groups, their compatibility and the determination of outcomes. Studies scoring 0–3, 4–6 and 7–9 were identified as low, medium or high quality, respectively.¹⁴ Based on an 11-item checklist recommended by the Agency for Healthcare Research and Quality (AHRQ), the methodological quality of the included cross-sectional studies was assessed. Article quality was assessed as follows: low quality = 0–3; moderate quality = 4–7; high quality = 8-11.¹⁵

2.4. Statistical analysis

All statistical analyses were performed using STATA 16.0. The main results were displayed as forest plots. A pooled OR estimate for PD and COVID-19 outcomes was calculated using the raw data extracted and its 95% CI. RR and OR were considered to be identical.¹⁶ Heterogeneity between included studies was measured by using Cochran’s Q test and the I² statistic.¹⁷ There was low, moderate, and high heterogeneity represented by I² values of 25%, 50%, and 75%. If I² was less than 50%, a fixed effects model would be used for analysis, while a random effects model would be used if I² was greater than or equal to 50%.¹⁸ A sensitivity analysis was conducted to compare the results with and without the exclusion of one study at a time to determine the stability of the results.¹⁹ Publication bias was assessed quantitatively by Egger’s test and Begg’s test.^20,21 P values less than 0.05 were considered statistically significant. meta regression was adopted to explore sources of heterogeneity.

3.1. Study Selection and Study Characteristics

After a comprehensive search, 823 studies were screened, and 72 underwent full-text review(Fig. 1). After applying rigorous inclusion and exclusion criteria, 11 published articles. with 16,708 participants were included. These included six case-control studies^{11,12,22−25}, three cohort studies^26–28 and two cross-sectional studies.^5,29 The NOS scores of the Seven studies were ≧ 5, and the scores of the 11 checklist recommend by AHRQ were ≧ 8, which suggested moderate or high quality for the included studies. The basic characteristics of the included literature are shown in Table 1.

Table 1

Characteristics of eligible studies included in this meta-analysis
study(year)	study location	Study type	Sample size	Age	Exposure	Outcome	Effect size (RR^a, HR^b, OR^c)	Adjustment	score
Nadya Marouf(2021)	Qatar	Case control	568	> 18	periodontitis	death, ICU^d admissions or need of assisted ventilation for COVID-19	total: OR = 3.67,95%CI:1.46–9.27 death: OR = 8.81,95%CI:1.00-77.7 ICU: OR = 3.54,95%CI:1.39–9.05 assisted ventilation : OR = 4.57,95%CI:1.19–17.4	age, sex, smoking, BMI^e, diabetes and comorbidities	8
Shipra Gupta(2021)	India	Cross sectional	82	> 18	gingivitis and stage I–IV periodontitis	pneumonia, Death, Hospital admission, and need of assisted ventilation for COVID-19	assisted ventilation: OR = 7.45,95%CI:2.71–20.45 hospital admission: OR = 36.52,95%CI:4.62-288.64 death: OR = 14.58,95%CI:1.69-125.33 pneumonia: OR = 4.42,95%CI:1.57–12.45	age, sex, smoking habits and other COVID- 19-related comorbidities/risk factors	8
Supriya Mishra(2022)	India	Cross sectional	294	NA^f	periodontitis	severe COVID-19 Pneumonia	OR = 2.8133,95%CI:0.4077–19.7523	age,sex,	8
Camila Alves Costa(2022)	Brazil	cohort study	128	20–97	periodontitis	ICU admission, critical symptoms, death for COVID-19	ICU admission IRR = 1.44,95%CI:1.07–1.95, critical symptoms IRR = 2.56,95%CI:1.44–4.55, death IRR = 2.05 ,95%CI:1.12–3.76	age and comorbidities	6
Nora, Alnomay(2022)	Saudi Arabia	cohort study	188	≥ 19	periodontitis	covid-19 complications (ward admission, ICU admission, and death.)	OR = 3.063,95%CI:1.150–8.157	NA	6
Donders et al.(2022)	Netherlands	cohort study	92	NA	Alveolar bone loss > 1/3 root length in ≥ 2 nonadjacent teeth	Hospital admission, ICU admissions or death for COVID-19	Hospitalized OR = 1.51,95%CI:0.37–6.10 ICU/death OR = 3.33,95%CI: 0.39–28.15	Age,male sex, diabetes mellitus, cardiovascular diseases, chronic Kidney disease, and smoking status	8
Harriet Larvin(2020)	United Kindom	Case control	13,253	40–69	loose teeth	Hospital admission and mortality for COVID-19	Infection:OR = 1.15, 95% CI: 0.84–1.59 death: OR = 1.85,95%CI:0.92–2.72 hospital admission: OR = 1.55,95%CI:0.87–2.77	age at test, sex, ethnicity, average total household income, BMI, systolic and diastolic blood pressure, smoking, cancer, hypertension, angina, cardiac arrest, diabetes, myocardial infarction, stroke, peripheral artery disease, atrial fibrillation, and respiratory disease	6
S. Wadhwa(2022)	united states	Case control	387	NA	Missing teeth	Hospital admission for COVID-19	OR = 1.113,95%CI: 1.034–1.197	Age, Sex, race, ethnicity, HTN, diabetes, smoking	7
Khalid N Said(2022)	Qatar	Case control	1325	≥ 18	periodontal bone loss	Deceased ICU admission Ventilation Any complications for COVID-19	Deceased OR = 3.56,95%CI:0.60-21.28 ICU admission OR = 1.76,95%CI:0.89–3.46 Ventilation OR = 3.32,95%CI:1.10-10.08 Any complications OR = 1.81,95%CI:0.94–3.48	sex, age, diabetes, smoking habits, BMI and other co-morbidities	8
Guardado Luevanos(2022)	Mexico	Case control	369	20–75	The self-reported periodontitis	COVID-19 infection	OR = 3.3,95%CI:1.8–6.0	NA	5
Dnyaneshwari Gujar(2022)	NA	Case control	150	≥ 18	Severe periodontitis	COVID-19 infection	OR = 11.75,95%CI:3.89–35.49	age and frequency of oral hygiene	6
RR^a: relative risk;
HR^b: hazard risk;
OR^c: odds ratio;
ICU ^d: intensive care unit;
BMI ^e: body mass index;
NA^f: not available

Main outcome

Heterogeneity was observed in the risk of progression to severe diseases (I² = 75.5%, P _{Heterogeneity}<0.001), and random effect model was applied. The pooled OR was 2.20 (95% CI = 1.38–3.49, P = 0.001), suggesting a significant association between PD and an increased risk of COVID-19 severity. (Fig. 2)

Subgroup Analyses

To explore the sources of heterogeneity, a series of subgroup analyses were performed. When subgroup analyses were performed based on study outcomes, we found that those with PD had significantly higher risk of ICU admissions(OR = 1.61, 95%CI = 1.24–2.09, P < 0.001), the presence of pneumonia complications(OR = 5.19, 95%CI = 1.17-23.00, P = 0.03), need for assisted ventilation therapy(OR = 5.01, 95%CI = 2.61–9.63, P < 0.001) and a higher risk of death(OR = 2.55, 95%CI = 1.55–3.28, P < 0.001) when infected with COVID-19 compared to those without PD, whereas a marginally significant association was in COVID infection(OR = 3.21, 95%CI = 0.99–10.34, P = 0.051). However, no association between PD and hospital admission was observed(OR = 1.82, 95%CI = 0.88–3.76, P = 0.107). Subgroup analysis based on study design shows a significant association between PD and increased risk of severe disease following COVID-19 infection in case control studies(OR = 1.6, 95%CI = 1.02–2.52, P = 0.042) and cohort studies(OR = 2.51, 95%CI = 1.58–4.01, P < 0.001), whereas not discovered in cross-sectional studies(OR = 9.88, 95%CI = 0.80-121.74, P = 0.074). When subgroup analysis was performed according to study region, we found that PD was significantly associated with an increased risk of severe disease after COVID-19 infection in Asia(OR = 2.80, 95%CI = 1.79–4.36, P < 0.001), but not significantly in Europe(OR = 1.54, 95%CI = 0.9–2.64, P = 0.033) and other regions(OR = 1.60, 95%CI = 0.71–3.61, P = 0.253). A subgroup analysis of COVID-19 symptomatic disease was also performed on the basis of the qualities scores, the results showed statistical significance whether the score was greater than or equal to 7(OR = 2.34, 95%CI = 1.16–4.69, P = 0.017) or less than 7(OR = 2.13, 95%CI = 1.46–3.10, P < 0.001).

Sensitivity Analyses and Publication bias

Sensitivity analyses were conducted by omitting the included studies one by one, the pooled ORs suggested that the results of this study were stable and reliable (Fig. 3) The Egger's test (t = 4.96, P = 0.002) and Begg's test (z = 0.52, P = 0.602) indicated publication bias for the main outcome. Egger's test and Begg's test were conducted for the subgroup analyses meanwhile (Table 2). Meta-regression analysis also indicated that the association between PD and increased risk of severe illness for COVID-19 cases was influenced by outcome (P = 0.021), study design (P = 0.033), but not by study quality score (P = 0.058) and location (P = 0.269).

Table 2

Association Between PD and increased risk of COVID-19 patients
Subgroups	Number of studies	OR(95%CI)	I square, %	P for Begg’s test	p for Egger’s test
Outcome
Infection	3	3.21(0.99–10.34)	91.00	0.296	0.077
Hospital admission	3	1.82(0.88–3.76)	75.60	0.462	0.067
ICU admission	4	1.61(1.24–2.09)	20.20	0.308	0.155
Assisted ventilation	3	5.01(2.61–9.63)	0.00	1.000	0.695
Death	6	2.25(1.55–3.28)	7.10	0.060	0.017
Pneumonia	3	5.19(1.17-23.00)	66.10	0.296	0.490
Study design
Case control	4	1.60(1.02–2.52)	68.50	0.089	0.051
Cross-sectional	2	9.88(0.80-121.74)	68.20	/	/
Cohort	3	2.51(1.58–4.01)	0.00	1.000	0.650
Location
Asia	5	2.80(1.79–4.36)	50.00	0.462	0.125
European	2	1.54(0.9–2.64)	0.00	1.000	0.273
Other	2	1.60(0.71–3.61)	87.40	/	/
Quality score
≥ 7	7	2.34(1.16–4.69)	75.30	0.260	0.031
< 7	3	2.13(1.46–3.10)	3.80	1.000	0.638

This meta-analysis reveals association between PD and increased risk of severe disease following COVID-19 infection, which is consistent with previous studies reported individuals with PD tend to be more negatively affected by COVID-19³⁰. It is noteworthy that results of the current meta-analysis regarding risk of severe disease should be interpreted with caution because different outcomes of included studies were pooled for the main outcome of severe disease. In addition, our analysis included studies with relatively small sample sizes. Thus, a significant heterogeneity was observed. Studies have shown that ACE-2 is the main receptor for SARS-CoV-2 to enter human cells. ACE-2 mainly exists in lung, nasopharyngeal mucosa, salivary gland and oral mucosa.^4,31 Flynase, a protease in the oral cavity that is elevated in chronic periodontitis, can prefragment the coronavirus spike protein (S protein) into two subunits (S1 and S2), and the S1 receptor binding domain (RBD) can attach itself to ACE-2. Finally, upon binding of the S1 subunit to the ACE-2, the virus passes through the host cell to fuse and form a nucleus, resulting in the closure of the cell membrane of the virus and the host and leading to cell fusion and infection.³² Therefore, it can be hypothesized that increased protease levels in periodontitis may increase the risk of oral mucosa-mediated SARS-CoV-2 infection, and even contribute to worsening COVID-19 infection. In addition, people with PD may have an increased risk for subsequent systemic diseases, including cardiovascular disease, hypertension, respiratory disease, and diabetes.^33–37 This might contribute to development of poor outcomes if PD patients are infected with SARS-CoV-2. Besides, it has been claimed that cytokines produced during periodontitis can promote adhesion of respiratory pathogens to the lung epithelium and colonisation of the lungs, and inhaled periodontal bacteria may induce cytokine secretion in the lower respiratory tract, exacerbating the symptoms of COVID-19.^38,39

There was no increase in hospital admission among COVID-19 patients with PD compared to those with healthy periodontal condition, which contradicted conclusions of Gupta et al.⁵ This may be related to the fact that the included studies had different diagnostic criteria for exposure, e.g. Larvin et al.¹² used self-diagnosed periodontal disease while other studies used rigorous examination methods. Compared with COVID-19 cases without PD, those with PD had a 0.61-fold increased risk of ICU admission, a 1.25-fold increased risk of death, and a 4.01- and 4.19-fold increased risk of mechanical ventilation and pneumonia, respectively. Periodontitis has long been thought to have its pathophysiological roots in cytokine responses.⁴⁰ In addition, the adverse outcomes of the COVID-19 infection have been reported to be associated with cytokine storms. These adverse outcomes also share some similar cytokine expression profiles to periodontitis.⁴¹ Several studies also demonstrated that, in patients with gingivitis, the number of cytokine and chemokine producing cells in gingival tissues and cytokine level in serum increased significantly comparing to healthy controls.⁴² Two studies have shown that patients requiring assisted ventilation presented higher CRP and D-dimer blood levels.^5,10 This is consistent with previous studies reporting elevated inflammatory markers in patients with COVID-19 who passed away.⁴³ CRP levels are considered to be an early biomarker of the severity of COVID-19 infection, and elevated D-dimer has been reported as a prognostic marker associated with a worsening prognosis in patients with COVID-19.^44,45

Subgroup analyses based on study type were performed, and statistical associations of PD with COVID-19 severe disease were found in case-control study and cohort study but not in cross-sectional study. In the subgroup analysis based on study location, this study found a statistically significant association in the Asia, whereas not in European and other location. Differences in COVID-19 administration policy, vaccination schedule, and prevalent strains may also have contributed to this variability. In this study, a subgroup analysis was performed based on the original study quality assessment scores. Both groups of studies showed that PD was associated with the development of COVID-19 to severe disease. Meta-regression was used to explore the sources of heterogeneity, and the results concluded that both COVID-19 outcomes and study design type had an effect on heterogeneity, whereas region and study quality were unlikely to be sources of heterogeneity.

Notably, to our knowledge, this is not the first meta-analysis to examine the relationship between PD and COVID-19. In contrast to the previously published study by Baima et al,⁴⁶ we chose observational studies for the meta-analysis and included a larger number of studies. In addition, there were some differences between our findings and the results of the former meta-analysis, the results of the previous meta-analysis found that periodontitis was associated with increased odds of hospitalization, however, this association was not found in our study. Furthermore, in a subgroup analysis of COVID-19 outcomes, we added the outcome of pneumonia complications and found a significant association. Finally, we conducted more detailed subgroup analyses based on study type, study region, and quality assessment scores to further explore sources of heterogeneity.

There are several inherent limitations to our study. Firstly, this meta-analysis included studies with relatively small sample size, and in terms of COVID-19 patient outcomes, two studies included only pneumonia, one study only analyzed death, and one study only explored the risk of assisted ventilation, therefore the results may be biased. Secondly, there was a high degree of heterogeneity in the overall analysis, which may have been due to variations in types of studies included. During the pandemic, some COVID-19 patients may not be able to receive periodontal examinations, and self-reported periodontal bleeding and pain may be associated with other dental conditions such as dental caries. Third, the lack of raw data on gender, age, comorbidities, and vaccination status prevented appropriate subgroup analyses to explore these possible sources of heterogeneity. Last but not least, Publication bias was detected in our study. Despite these limitations, the present study shows the following strengths. This is the first meta-analysis of observational studies describing the relationship between PD and COVID-19 with a larger number of subjects, and the vast majority of the studies we included adjusted for the same confounders such as gender, age. Therefore, the results were more reasonable, stable, and convincing. Secondly, different effect models are used according to the level of heterogeneity and the study results are more rigorous and credible. Thirdly, the sensitivity analysis found a robust result, prompting our results to be credible.

After the liberalization of the epidemic policy, many novel variants of COVID-19 have emerged, the risk of infection in the population has increased, knowledge about the sequelae of infection is still insufficient, and the outcome of recurrent infections is still unknown. Our results show that individuals with periodontal disease have an increased risk for ICU admission, assisted mechanical ventilation therapy, and a significantly increased risk of pneumonia and death. This suggests that the oral cavity is the gateway to COVID-19 infection; in other words, periodontitis is a risk factor for COVID-19 severity and maintaining oral hygiene is crucial. However, only limited number of original studies are available. Therefore, more original studies with larger sample size, longer follow-up time, and adjustments for confounding factors are needed to further clarify the roles of PD in COVID-19.

COVID-19 Coronavirus Disease 2019

PD periodontal disease

SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2

WHO World Health Organization

ARDS acute respiratory distress syndrome

ACE-2 angiotensin-converting enzyme II

SARS-CoV-1 severe acute respiratory syndrome coronavirus 1

CNKI China National Knowledge Infrastructure

CBM China Biology Medicine

ICU intensive care unit

RR relative risk

HR hazard ratio

OR odds ratio

NOS Newcastle-Ottawa Scale

AHRQ Agency for Healthcare Research and Quality

RBD receptor binding domain

S protein spike protein

CRP C-reactive protein

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and materials

All data generated or analysed during this study are included in this published article.

Competing interests

The authors declare that they have no competing interests

Funding

Not applicable

Authors' contributions

Yuyan Wu, Juan Gao and Guangju Ji: Conceptualization, Methodology, Formal analysis, Writing - original draft, Writing - review & editing.

Linya Feng: Investigation, Software, Writing - review & editing.

Vicky Yau: Resources, Data curation, Writing - review & editing.

Yaru Li: Software, Writing - review & editing.

John Patrick Nanola: Visualization, Writing - review & editing.

Chenyu Sun: Conceptualization, Resources, Formal analysis, Supervision, Writing - review & editing.

Acknowledgements

Not applicable

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Periodontal disease and COVID-19: a systematic review and meta-analysis of observational studies

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Methods

2.4. Statistical analysis

Results

Main outcome

Subgroup Analyses

Sensitivity Analyses and Publication bias

Discussion

Conclusion

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