The impact of periodontal disease on the clinical outcomes of COVID-19: A systematic review and meta-analysis

Background A possible relationship between periodontitis (PD) and COVID-19 and its adverse outcomes has been suggested. Hence, the present systematic review and meta-analysis aimed to investigate the available evidence regarding the potential association between periodontitis (PD) and COVID-19 and its adverse outcomes. Materials and methods PubMed, Scopus, Web of Science, and Google Scholar were searched for relevant studies published up to April 15th, 2023. Studies that evaluated the association between PD and COVID-19 were included. Risk of bias was evaluated by two reviewers, and meta-analyses were performed using RevMan 5.3 software. Results A total of 22 studies involving 92,535 patients from USA, Europe, Asia, the Middle East and South America were included; of these, 12 were pooled into the meta-analysis. Most of the studies (19 studies) reported a significant association between PD and COVID-19. The pooled data found a significant association between PD and COVID-19 outcomes: more severe symptoms (OR = 6.95, P = 0.0008), ICU admissions (OR = 3.15, P = 0.0001), and mortality (OR = 1.92, P = 0.21). Additionally, compared to mild PD, severe PD was significantly associated with higher risks of severe COVID-19 outcomes: severe symptoms (P = 0.02); ICU admission (P = 0.0001); and higher mortality rates (P = 0.0001). The results also revealed 58% higher risk for COVID-19 infection in patients with PD (P = 0.00001). Conclusions The present findings suggest a possible association between poor periodontal health and the risk of poor COVID-19 outcomes. However, owing to the observed methodological heterogeneity across the included studies, further prospective cohort studies with standardized methodologies are warranted to further unravel the potential association between periodontal disease and COVID-19 and its adverse outcomes. Supplementary Information The online version contains supplementary material available at 10.1186/s12903-023-03378-0.


Background
The Corona virus disease of 2019 (COVID-19) caused by the SARS-CoV-2 virus has resulted in an enormous impact on the global health and economy [1][2][3].Despite the fact that most COVID-19 patients recover without major complications, few patients still suffer severe complications including multiple organ failure and death [4,5].Such complications are driven by serious conditions triggered by the infection such severe acute respiratory distress, systemic inflammatory reactions, and coagulopathies [6,7].It became obvious that several comorbidities such as obesity, hypertension, diabetes and advanced age are associated with severe COVID-19 [4][5][6]8].A considerable fraction of apparently healthy and young patients, with no clear identifiable risk factors, however, still develops severe complications.
Periodontitis (PD), the most common form of periodontal diseases, is a chronic disease involving the inflammation and subsequent damage of the tissues surrounding the teeth [9].If not treated properly, PD leads to the destruction of the bone surrounding the teeth and ultimately loss of the teeth themselves [10].Beyond such local consequences, PD can also have detrimental effects on systemic health [10].Growing evidence links PD to several systemic diseases including diabetes mellitus, cardiovascular diseases, pneumonia, metabolic syndrome, and cancers [9,[11][12][13][14][15][16][17].Such systemic effects of PD might be ascribed to the bacterial products and inflammatory mediators in the periodontal infected tissues that can reach the blood stream and increase the systemic inflammatory burden [18].Worth to mention that periodontal pathogens can reach the respiratory tract, aggravating, and/or even initiating respiratory infections [17].
Given that PD shares with COVID-19 many features including comorbidities and increased blood levels of inflammation and coagulation biomarkers, [19,20] several researchers have hypothesized that PD could be associated with a higher risk of COVID-19, and the development of its adverse outcomes [20,21].Marouf et al. reported a higher risk of COVID-19 complications including death (OR = 8.81), intensive care unit (ICU) admission (OR = 3.54), and the need for assisted ventilation (OR = 4.57) in patients with periodontitis [22].Gupta et al. reported that the likelihood of requiring assisted ventilation, hospital admission, death, and getting COVID-19-related pneumonia were 7.45, 36.52,14.58, and 4.42 folds, respectively, in COVID-19 patients with PD compared to COVID-19 patients without PD [23].Additionally, 2022 case-control study among US COVID-19 patients reported significantly greater missing teeth and alveolar loss tooth in Covid-19 positive patients and in those with severe complications [24].Interestingly, a 2022 case-control study by Said et al. reported a significant association between history of periodontal therapy and favorable COVID-19 outcomes, indicating a positive role of periodontal therapy on Covid-19 complications [25].Using a two-sample Mendelian randomization, Wang et al. revealed that PD was significantly associated with higher risk for COVID-19 infection and severe complications [26].Conversely, two studies with a large sample size from UK Biobank cohorts did not support any significant association between PD and the risk and outcomes of COVID-19 [27,28].Similarly, a retrospective cross-sectional Dutch study did not find a significant association between alveolar bone loss and complications of COVID-19 [29].One systematic review of two studies reported a significant association between PD and COVID-19 [30].A more recent systematic review and meta-analysis by Baima et al., [31] investigating the potential link between PD and Covid-19, reported a significant association between PD and Covid-19 susceptibility and poor outcomes [31].Nevertheless, the latter review included only very limited studies (n = 8; studies published up till Feb. 2022), and since then numerous relevant studies were published with interesting findings.Additionally, the latter two systematic reviews did not in-depth assess the correlation between severity of PD and severity of Covid-19 symptoms.Therefore, this systematic review and meta-analysis sought to comprehensively analyze and summarize the available evidence on the association between PD and COVID-19.The focused question was: Does periodontal health status have an impact on COVID-19 risk and clinical outcomes?

Materials and methods
The present systematic review and meta-analysis adhered strictly to the PRISMA 2020 guidelines and followed utterly PECO principles.This systematic review was registered in Open Science Framework (OSF) registries (https:// doi.org/ 10. 17605/ OSF.IO/ KW7TC).The PECO research question was: Is periodontal disease a risk factor for COVID-19 and its poor outcomes?

Eligibility criteria
All studies (cohort, case-control, and cross-sectional and interventional studies) that assessed the association of periodontal diseases with COVID-19 outcomes in humans were eligible.
Outcome: COVID-19 infection and/or its associated adverse outcomes.
Case reports, post-mortem studies, animal and experimental studies, review articles, commentaries, and studies with unclear exposures/outcomes were excluded.

Search strategy and information sources
An extensive search of online databases (PubMed, Scopus, and Web of Science) and Google Scholar search engine, supplemented with manual search was conducted independently by two reviewers (SA and MA) on April 16 th , 2023 for all relevant studies published from December 2019 up to April 15 th , 2023.The following Mesh terms and free keywords were used: ("Periodontal Diseases"[Mesh] OR "Oral Health"[Mesh] OR "Periodontal disease" OR periodontitis" OR Periodont* OR periodontal pathogen*) AND ("SARS-CoV-2″[Mesh] OR COVID -19).Detailed information about the search strategies is presented in Supplementary Table 1.

Screening and selection process
All retrieved studies were exported to the EndNote program, which eased removal of duplicates.Then, the titles and abstracts of all articles were screened independently by two reviewers (SA and FT), and irrelevant articles were excluded.The full-texts of all potentially eligible articles were independently evaluated by the two reviewers for inclusions, and irrelevant articles were eliminated.

Data extraction
All relevant data were independently extracted by two investigators (SA, MA) using customized forms.The extracted data included the following: first author name, country of the study, study design, sample size, age and gender of the participants, periodontal variables (exposure) and COVID-19 variables (the main outcomes).

Quality assessment
Two reviewers (SA and MA) assessed independently the quality of all included studies using the Newcastle Ottawa Scale (NOS) for assessing the quality of nonrandomized studies [32].Disagreements, if any, were resolved by discussion.The overall quality of each study was rated as either: high quality, 7-9 stars; moderate quality, 4-6 stars; or poor quality, 0-3 stars [32].

Statistical analysis
The Review Manager (RevMan) Version 5.3 software was used for data analysis.The pooled odds ratios (ORs) along with 95% confidence intervals (CIs) were used to calculate the risk of COVID-19 and associated outcomes in patients with PD and periodontium healthy patients.Heterogeneity was evaluated using the Chi-square test and the I 2 statistics.A Fixedeffects model was used for low/moderate heterogeneity (I 2 ≤ 50%), while a random effect model was applied for significant heterogeneity (I 2 > 50%).
Se nsitivity tests: due to the limited number of analyzed studies, no sensitivity tests were done.

Study selection
Figure 1 presents the search strategy of the present study.The initial online searches yielded 3002 articles, of which 2050 duplicate records were excluded.The titles and abstracts of 952 articles were screened for eligibility, and 895 were found irrelevant and thus excluded.The full-texts of the remaining 57 articles were assessed for eligibility, and 35 were excluded for various reasons (Supplementary Table 2).Eventually, 22 studies were included in the present systematic review, and 12 were pooled into the meta-analysis.

Outcome measures
Most of the studies reported on adverse outcomes of Covid-19.Ascertainment of the adverse outcomes of COVID-19 included one or more of the following: severity of symptoms, ICU admission, hospital admission, and mortality (Table 1).Nine studies [24, 26-28, 34, 37-39, 46] also reported on the risk of covid-19 in periodontitis patients.

Larvin et al 2020 [29]
There was no any association between painful/bleeding gum and the risk of COVID-19 (OR = 1.10, 95% CI = 0.72-1.69)or risk of hospital admission (OR = 0.90, 95% CI = 0.59-1.37).However, there was a significant association between PD and the mortality rate; participants with painful/bleeding gum had twofold higher mortality rate than those with healthy gum (OR = 1.71, 95% CI = 1.05-2.72).There was no a significant association between loose teeth with COVID- The results showed a significant increase in the risk of COVID-19 in PD subjects (OR: 1.20).However, after controlling all potential confounding factors, no significant association was observed between the two conditions.
Larvin et al 2021 [30] The risk for COVID-19 infection was not associated with periodontal disease across the 3 BMI categories: normal weight (OR, 0.97; 95% CI, 0.88 to 1.07), overweight (OR, 1.06; 95% CI, 0.98 to 1.15), and obese (OR, 1.08; 95% CI, 0.99 to 1.17).The risk of hospital admission for people with periodontal disease was 38% higher in participants who were overweight (HR, 1.38;95% CI, 1.02 to 1.87) and 124% higher in those who were obese (HR, 2.24; 95% CI, 1.66 to 3.03) compared to those of normal weigh.In addition, for participants with obesity, the mortality rate was much higher (hazard ratio, 3.11; 95% CI, 1.91 to 5.06) in participants with periodontal disease than those with healthy periodontium.Kaur et al 2022 [42] The risk of severe periodontal disease was 6.32 times higher in COVID-19 patients with severe symptoms (P= 0.024) as compared to mild COVID cases.

Kamel et al. 2021 [24]
There was a significant association between poor oral health and the severity of COVID-19.Additionally, poor oral health was significantly associated with delayed recovery time and higher CRP values.
Sirin & Ozcelik 2021 [47] There was a significant association between dental disease including alveolar bone loss and severity of COVID-19 complications.Individuals with severe dental diseases (including alveolar bone loss) had more severe COVID-19 symptoms and higher mortality rate than those with no/mild dental diseases.

Sari et al., 2023 [46]
A higher prevalence of periodontitis compared with gingivitis and periodontal health was detected in the test group (p=0.003).In line with this, all clinical periodontal parameters related to periodontal disease severity were higher in the test group than in the control group.In particular, GI, BOP (%), PD, CAL, and the number of missing teeth were statistically significantly higher in the test group than in the control group (p < 0.05), except PI, which did not reach statistical significance (p = 0.052).

Said et al., 2023 [27]
Risk analysis of COVID-19 complications revealed that while periodontitis stage 2-4 (regardless of treatment) was associated with higher risk of complications (i.e.need for mechanical ventilation [AOR = 3.32, 95% CI 1.10-10.08,p = 0.034]), subjects with treated periodontitis had a lower risk than the non-treated ones.Adjusted OR analysis comparing treated and non-treated periodontitis (stages 2-4) revealed that treated patients were at lower risk of complications; however, this was not statistically significant.
Guardado-Luevanos et al., 2022 [38] A statistically significant difference (p value < 0.001) was observed, showing that positive self-RPD (n = 95, 85.1%) was often higher in SARS-CoV-2-positive individuals than in the controls (n = 66, 56.4%), with an OR of 3.3 (1.8-6.0) for SARS-CoV-2 infection in people with self-reported periodontal disease.Participants with COVID-19 had significantly higher mean values of plaque scores, number of mobile teeth, gingival bleeding scores, PD, REC, and CAL compared to the controls.The mean percentages of inter-proximal sites with PD ≥ 4 mm, PD ≥ 5 mm, CAL ≥ 3 mm, CAL ≥ 4 mm, and CAL ≥ 6 mm were also significantly higher in the case group than in the control group.
Wadhwa et al. 2022 [26] Covid-19 infected patients had significantly greater alveolar bone loss and missing teeth than controls.Additionally, missing teeth and bone loss were associated with more hospitalization.
Poyato-Borrego et al., 2023 [45] A significant association has been found between the severity of COVID-19 and the periodontal disease (p= 0.04).

Kalsi et al., 2023 [41]
The percentage of patients suffering from severe COVID disease was least (8.3%) in stage 1 of periodontitis and was highest (62.5%) in stage 4 of periodontitis.Whereas out of eight patients tested positive in stage 1 of periodontitis, 7 had only mild disease.Out of total of 8 patients with stage 4 category of periodontitis, two remain uninfected, five developed severe form of COVID, and only one patient had moderate COVID disease.
Bemquerer et al., 2023 [36] In the COVID-19 group, plaque index was worse in patients with periodontitis than in patients without periodontitis (p < 0.001).Among individuals with COVID-19, periodontitis was associated with more hospitalization (p = 0.009), more days in the ICU (p = 0.042), admission to the SICU (p = 0.047), and higher need for oxygen therapy (p = 0.042).However, there was no difference in total hospitalization length, need for ICU, need for mechanical ventilation, or death between individuals with and without periodontitis in the COVID-19 group.Individuals with periodontitis were 1.13 times more likely to be hospitalized than individuals without periodontitis (CI = 1.01-1.26;p = 0.028).

Publication bias
The funnel plots for publication bias of the include studies for all categories are presented in the Supplementary file 2.
Generally, there was not a noticeable publication bias among the studies, except Fig. 1 in the Supplementary file 2 which showed slight publication bias for the association between periodontal disease (PD) and severe COVID-19 symptoms.

Quality assessment
The results of the quality assessment-based on NOS-are presented in Table 3. Overall, the included studies revealed relatively good quality ranging from five to nine stars.Fourteen studies [22-25, 27-29, 34, 36-38, 40, 43-45] were of high quality, while seven studies were of moderate quality [33,35,39,41,42,46,47].The most frequent methodological shortcomings were related to the self-report ascertainment of the exposure and bias in selection of cases/controls (Table 3).

Discussion
Medical literature has linked PD to the risk and severity of COVID-19.Hence, the present systematic review and meta-analysis sought to answer the following focused question: Does PD influence the risk and severity of COVID-19?Qualitatively, most of the included studies reported significant association between PD and COVID-19 severity.However, three studies [27][28][29] failed to replicate these results.Quantitatively the pooled data found a significant positive association between PD and the risk and adverse outcomes of COVID-19 such as severe symptoms, ICU admission.Additionally, severe PD was significantly associated with higher risk of severe COVID-19 symptoms (P = 0.02), ICU admission (P = 0.0001), and mortality rate (P = 0.00001) compared to mild PD.Indeed, the results revealed that patients with PD have significantly 54% higher risk to getting COVID-19 infection.However, these findings should be interpreted with caution owing to the heterogeneity among the included studies as well as some methodological limitations, discussed in the following sections.
The findings of the present systematic review support the results of previous systematic reviews [30,31].Nevertheless, although the results of the current study are interesting, the mechanism(s) by which periodontitis aggravate(s) COVID-19 adverse outcomes still unclear so far.However, many theories have been suggested, and deserve discussion.With regard to one of the key findings of the current study: association of PD and COVID-19 adverse outcomes, one possible explanation is related to the expression of angiotensin converting enzyme 2 (the well-known receptor for SARS-CoV-2) by the inspired periopathogenes.This subsequently leads to production of inflammatory cytokines such as IL-6 and IL-8 in the lower respiratory tract, thus aggravating the response [48].Further, periopathogenes have been reported to enhance the virulence of SARS-CoV-2 by cleaving its S glycoproteins, a matter that exacerbates COVID-19 complications [49].Of utmost important, the chronic inflammatory nature of periodontitis may play a role through triggering systemic inflammation, which aggravates the inflammatory response in context of many disease processes, and COVID-19 wouldn't be an exception.A recent study reported existence of periopathogenes in the metagenome of patients severely infected with SARS-CoV-2: Mainly high reads for Prevotella (493 reads), Staphylococcus (1,659 reads) and Fusobacterium (463 reads) were discovered [50].Indeed, the potential role of PD in pulmonary infections (and diseases) has long been investigated and well documented in the literature [16,[51][52][53].Mounting evidence from systematic reviews and meta-analyses found a significant association between PD and exacerbation of respiratory conditions, mainly pneumonia and COPD [14,17].
The significant association between PD and the risk of COVID-19 is another key and pivotal finding of the current study: patients with PD were 54% at higher risk of COVID-19 acquisition than people with healthy periodontium.Essentially, the oral cavity, including gingival pocket epithelium, has been reported to be potentially high risk for SARS-CoV-2 infectious susceptibility, mediated by expression of angiotensin converting enzyme 2 [54,55].These results might be explained by the role of periopathogenic bacteria in initiating the expression of angiotensin converting enzyme, as already discussed above.A very recent evidence suggests that periodontal pockets and decayed teeth serve as reservoirs for SARS-CoV-2, making people more prone to COVID-19 [56].In addition to being hiding areas, where the antibacterial action of the saliva and mouth rinses is not effective, the periodontally involved pockets have higher surface area than that of normal gingival sulcus, providing more opportunities for SARS-CoV-2 to bind and eventually infect more enzyme-expressing cells, in addition to acting as reservoirs for continuing infection, or recurring, or complicating the current infection leading to a more severe disease.However, these are still hypotheses and more research are required to elucidate these phenomena.
Worthy to note that the positive association of PD with the outcomes of COVID-19 was supported by all of the included studies except two studies by Larvin et al., which failed to do so [27,28].It must be acknowledged that these two studies involved relatively large sample sizes of COVID-19 patients.However, the exposure (periodontal status) was self-reported, a matter which raises a lot of doubts and reduces reliability of these two studies.Obviously, it is a clear shortcoming, and therefore the results might have not accurately reflected the periodontal status of the participants, and thus might have biased the results.Apart from the fact that the number of present and/or the missing teeth can be self-reported to a large extent of reliability, the other periodontal health outcomes and parameters cannot be reported by the patients precisely [57] .This, in turn, may explain the different results obtained by these two studies, a matter that must be acknowledged too.By contrast, except for Kamel et al. study, all other studies, which reported positive association of PD with the outcomes of COVID-19 ascertained the periodontal parameters objectively, either clinically or using radiographs.
Undoubtedly, the quality of the individual studies is a very determining factor that influences the quality of the overall evidence of any meta-analysis [58].For this purpose, two reviewers evaluated independently the quality of all included studies using NOS, a very valid risk assessment tool.The results revealed relatively good quality of the included studies.Selection bias and self-reporting of the exposure (periodontal parameters) were the most frequently shortcomings, which cause biased results: recapitulating and reminding Larvin et al. studies mentioned above.
The present systematic review has many points that add to its strength and should be recognized.First, the study included a good number of studies with a relatively large sample size.Second, the studies were conducted in different geographical areas representing the world and thus substantiating its external validity.However, there are few limitations that should be highlighted.The main limitation is the heterogeneity among the included studies in many respects including: study design, the assessed periodontal parameters (exposure), COVID-19 parameters (outcome), setting of the included patients (hospitalized vs non-hospitalized patients), age of the participants, and many other confounders.The differences in methods of measurements of periodontal parameters represent a marked heterogeneity, being self-reported in a few studies, using radiographs in some studies, and clinical examination in the other studies.In particular, the self-reporting of periodontal status is an evident drawback of the present study that might have caused bias in the results.Furthermore, missing of some of the numerical data was an obvious obstacle that hindered including all studies in the quantitative analysis.

Conclusion
In conclusion, the present systematic review and metaanalysis suggests a significant association between poor periodontal health and poor COVID-19 outcomes.However, the results should be interpreted with caution given the marked heterogeneity across the included studies along with some methodological limitations in some of these studies.Hence, further large-scale prospective cohort studies with standardized methodologies are highly required to further elucidate the potential association between periodontal diseases and the risk of poor COVID-19 outcomes.

Fig. 8
Fig. 8 Meta-analysis of COVID-19 risk in relation to periodontal health status (PD vs. healthy)

Table 1
General characteristics of the included studies

Table 2
Summary of the main outcomes

Table 3
NOS-based quality analysis of the included studies