Coronavirus disease (COVID-19) is a severe acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged in Wuhan, Hubei, China, with subsequent global spread.1, 2 Although the disease results in mild symptoms in most cases, it progresses to severe pneumonia and multi-organ failure, leading to mortality, in some cases, depending on patient age and the presence of comorbidities.3–5 Although risk factors, such as age, sex, and comorbidities, which increase the risk of complications and mortality, have been highlighted, there is still a large proportion of patients with no identified risk factors who suffer from severe COVID-19-related adverse effects and complications.6
Periodontitis is a chronic, multifactorial, inflammatory disease, associated with plaque biofilms and characterized by the progressive destruction of the tooth-supporting structures.7 Periodontitis increases the systemic inflammatory burden, as the inflamed periodontal tissues release host-derived proinflammatory cytokines and tissue destruction mediators into the circulatory system, which can activate an acute-phase response in the liver and can amplify systemic inflammation.8 The inflammatory reaction in periodontitis results in increased levels of inflammatory mediators, such as tumor necrosis factor-α, interferon-γ, prostaglandin E2, interleukin (IL)-1β, IL-4, IL-6, IL-10, ferritin, and C-reactive protein.9, 10 Periodontopathic bacteria are involved in the pathogenesis of respiratory diseases, such as pneumonia and chronic obstructive pulmonary disease (COPD), as well as in that of systemic diseases, including diabetes and cardiovascular disease.11 Periodontopathic bacteria were detected in the bronchoalveolar lavage fluid of patients with COVID-19.12, 13 There are similarities between the cytokine storm in severe COVID-19 infections and the cytokine expression profile in periodontitis, suggesting a possible link between periodontitis and COVID-19 and its associated complications.14, 15 The increased expression level of angiotensin-converting enzyme 2 (ACE2) in the oral cavity, promoted by periodontopathic bacteria, may increase the SARS-CoV-2 infection rate.16 An elevated IL-6 level is associated with excess inflammation, which contributes to increased mortality in patients with COVID-19.17
Periodontal diseases can increase the inflammatory response in patients, which might exacerbate the systemic symptoms and clinical course of COVID-19. The potential association of periodontitis and COVID-19 severity can be explained by the alteration in the expression of cellular receptors enhancing the virulence of SARS-CoV-2 and by periodontal pockets acting as viral reservoirs.16, 18 Very few studies have been conducted to identify the association between periodontitis and COVID-19. A study based on radiographic assessment concluded that periodontitis is significantly associated with higher risks of COVID-19 complications and higher blood marker levels.19 Currently, no clinical data are available regarding the association between COVID-19 and periodontitis. Therefore, the present study was undertaken with the aim of determining whether periodontitis and poor oral hygiene are associated with COVID-19.
2 MATERIALS AND METHODS
The present study was conducted as a case-control study at the Department of Dentistry, ESIC Medical College, Hyderabad, India, during the period from August 2020 to February 2021. Patients visiting the dedicated COVID Outpatient Department (OPD) of the institution who had undergone real-time reverse transcription polymerase chain reaction (rRT-PCR) for the diagnosis of COVID-19 were recruited for the study. The patient’s contact details were collected from the Medical Records Section of the Institution and were communicated through telephone by the author PJ regarding their willingness for participation in the study. Only the author PJ had knowledge regarding the results of the reverse transcription polymerase chain reaction (rRT-PCR) for COVID-19 diagnosis of the individual patients. Periodontal examination was performed by the author PSA who was blind to the results of rRT-PCR test. Subsequently, prior to data analysis, the patients for whom complete set of data were available were categorized as either case or control depending on the results of rRT-PCR test by the author PJ. Patients who had positive rRT-PCR results were included in the case group, and patients with negative results were included in the control group. Individuals aged 18 and above who had at least 20 teeth in the oral cavity were included in the study.
Patients in the control group were scheduled for an oral examination after the negative rRT-PCR, and patients who were positive for the virus (case group) were scheduled for an oral examination after the completion of treatment when they were determined to be disease free through a negative rRT-PCR. The following study variables were recorded: age, sex, presence, or absence of symptoms on visiting the COVID OPD, presence or absence of any systemic diseases, tobacco consumption status (smoking and smokeless; categorized as current user, former user, or never user), and oral hygiene habits (types of oral hygiene aids and frequency of daily oral hygiene practice). This was followed by a complete periodontal examination during which the dentition status was recorded, followed by the recording of plaque scores, calculus scores, tooth mobility, gingival bleeding, probing depth (PD), recession (REC), and clinical attachment level (CAL). All the permanent teeth apart from the third molars were examined for the purpose of the study.
As the dentition status, the numbers of present teeth, carious teeth, and missing teeth were recorded. A tooth was recorded as missing either if it was absent or if it was indicated for extraction because of periodontal disease, dental caries, or wasting diseases, such as abrasion and attrition. A tooth was considered to be indicated for extraction because of periodontal disease either if it was non-functional or if it exhibited considerable mobility. A tooth was considered to be indicated for extraction because of dental caries or tooth wear if it was deemed non-restorable. Plaque and calculus scores were recorded in all the teeth per the plaque index criteria of Silness and Loe20 and the calculus component of the simplified oral hygiene index of Greene and Vermillion,21 respectively. Gingival bleeding was recorded as either present or absent22 in all the teeth, and the percentage of bleeding sites was computed. Further, PD, REC, and CAL were recorded at six sites per tooth in all the teeth using a periodontal probe* . The mean values of PD, REC, and CAL, and mean percentage of inter-proximal sites with various thresholds for periodontal disease (PD ≥ 4 mm, PD ≥ 5 mm, CAL ≥ 3 mm, CAL ≥ 4 mm, CAL ≥ 6 mm) were compared between the two groups.
All the periodontal examinations were performed by a single trained examiner (PSA) who was blind to the categorization of the study participants. For calibration purposes, examiner reliability was determined by re-examination of a randomly selected quadrant among 10 patients who were not part of the study. The patients involved in the calibration exercise were probed twice during the same visit, and intra-class correlation coefficients were determined. The intra-class correlation coefficients for PD and CAL were 0.92 and 0.90, respectively.
The study protocol was approved by the Human Ethics Committee of the institution, and the study was conducted in accordance with the Helsinki Declaration as revised in 2013. Written informed consent in a language suitable for the participants was obtained from all the prospective study participants.
2.1 Statistical analysis
A sample size calculation with CAL as the reference variable revealed that a sample size of 64 patients in each arm would yield a power of 80% for a standardized difference of 0.5 at a significance level of 0.05.23 All data were entered onto a personal computer and were analyzed using software for statistical analysis† . All categorical variables were analyzed using the chi-square test, and continuous variables were expressed as mean and standard deviation and were analyzed using Student’s t-test. Mean percentages of inter-proximal sites with various thresholds for periodontal disease were computed and analyzed using Student’s t-test after arcsine transformation. The proportions of individuals with (a) a mean plaque score ≥ 1, (b) gingivitis (≥ 20% of sites with gingival bleeding), (c) mean CAL ≥ 2 mm, and (d) severe periodontitis24 were compared between the two groups using the chi-square test. The associations of COVID-19 with poor oral hygiene, gingival bleeding, and periodontal disease were determined using a logistic regression model adjusted for variables that were found to be significant in the univariate analysis.
Of a total of 196 patients who were provided with an explanation regarding the purpose of the study, 167 agreed to participate in the study. Nine patients were excluded as they had fewer than 20 teeth, whereas eight participants opted out because of discomfort during the periodontal examination. Among the 150 participants who had complete sets of data, 79 were categorized as cases and 71 as controls. The age, sex distribution, medical history, oral hygiene practices, and tobacco-related habits between the two groups are presented in Table 1. Although the age of the participants with COVID-19 was significantly higher than that of the controls, the two groups did not differ significantly in terms of sex distribution, medical history, and tobacco-related habits. None of the study participants reported a history of cardiovascular or renal diseases. A significantly larger number of participants were in the habit of practicing oral hygiene twice daily in the control group compared to in the case group.
|Variable||Case group (n = 79)||Control group (n = 71)||P|
|Age (mean ± SD)||43.34 ± 10.16||38.24 ± 10.72||0.003b|
|Sex (No./Percentage)||Males||50 (63.3)||35 (49.3)||0.084a|
|Females||29 (36.7)||36 (50.7)|
|Smoking status (No./Percentage)||Current smoker||6 (7.6)||7 (9.9)||0.484a|
|Former smoker||7 (8.9)||3 (4.2)|
|Never smoker||66 (83.5)||61 (85.9)|
|Smokeless tobacco use (No./Percentage)||Current user||2 (2.5)||3 (4.2)||0.822a|
|Former user||7 (8.9)||7 (9.9)|
|Never user||70 (88.6)||61 (85.9)|
|Diabetes (No./Percentage)||Yes||8 (10.1)||8 (11.3)||0.821a|
|No||71 (89.9)||63 (88.7)|
|Hypertension (No./Percentage)||Yes||16 (20.3)||8 (11.3)||0.134a|
|No||63 (79.7)||63 (88.7)|
|Neoplasia (No./Percentage)||Yes||2 (2.5)||0||0.177a|
|Oral hygiene practice (No./Percentage)||Once daily||68 (86.1)||40 (56.3)||< 0.001a|
|Twice daily||11 (13.9)||31 (43.7)|
- Abbreviation: SD, standard deviation.
- a Student’s t-test.
- b Chi-square test.
Table 2 presents the dental and periodontal variables between the two groups. Although there were no significant differences between the two groups in terms of missing teeth, carious teeth, and calculus scores, the 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.
|Variable (Mean ± SD)||Case group (n = 79)||Control group (n = 71)||P *|
|Missing teeth||0.81 ± 1.14||0.69 ± 1.13||0.520|
|Carious teeth||1.76 ± 1.59||1.79 ± 1.60||0.911|
|Plaque scores||0.77 ± 0.50||0.29 ± 0.30||< 0.001|
|Calculus scores||1.26 ± 0.80||1.01 ± 5.07||0.643|
|Mobile teeth||2.95 ± 2.26||1.35 ± 1.81||< 0.001|
|Gingival bleeding||0.62 ± 0.24||0.29 ± 0.20||< 0.001|
|PD||2.09 ± 0.48||1.48 ± 0.36||< 0.001|
|REC||0.20 ± 0.25||0.05 ± 0.10||< 0.001|
|CAL||2.28 ± 0.56||1.51 ± 0.42||< 0.001|
|Proportion of interproximal sites with various thresholds of disease|
|PD ≥ 4 mm||13.20 ± 10.67||1.79 ± 4.07||< 0.001|
|PD ≥ 5 mm||5.89 ± 6.86||0.59 ± 1.72||< 0.001|
|CAL ≥ 3 mm||39.71 ± 21.85||11.26 ± 15.07||< 0.001|
|CAL ≥ 4 mm||16.48 ± 12.18||2.43 ± 5.21||< 0.001|
|CAL ≥ 6 mm||2.52 ± 33.18||0.27 ± 0.83||< 0.001|
- Abbreviations: CAL, clinical attachment level; PD, probing depth; REC, recession; SD, standard deviation.
- * Student’s t-test.
The proportions of individuals with a mean plaque score ≥ 1, gingivitis, mean CAL ≥ 2 mm, and severe periodontitis were significantly larger in the case group than in the control group (Table 3). The results of the logistic regression analysis are shown in Table 4. This analysis showed significant associations of COVID-19 with mean plaque scores ≥ 1 (odds ratio (OR), 7.01; 95% confidence interval (CI), 1.83 to 26.94), gingivitis (OR, 17.65; 95% CI, 5.95 to 52.37), mean CAL ≥ 2 mm (OR, 8.46; 95% CI, 3.47 to 20.63), and severe periodontitis (OR, 11.75; 95% CI, 3.89 to 35.49) after adjusting for age and the frequency of oral hygiene practices.
|Variable (No./Percentage)||Case group (n = 79)||Control group (n = 71)||P *|
|Plaque score ≥ 1||19 (24.1)||3 (4.2)||0.001|
|Gingivitis||74 (93.7)||36 (50.7)||< 0.001|
|Mean CAL ≥ 2 mm||51 (64.6)||15 (21.1)||< 0.001|
|Severe periodontitis||39 (49.4)||7 (9.9)||< 0.001|
- Abbreviation: CAL, clinical attachment level.
- * Chi-square test.
|Plaque score ≥ 1||7.01||0.005||1.83-26.94|
|Mean CAL ≥ 2 mm||8.46||< 0.001||3.47-20.63|
|Severe periodontitis||11.75||< 0.001||3.89-35.49|
- Abbreviations: CAL, clinical attachment level; CI, confidence interval; OR, odds ratio.
The findings of our study revealed that periodontitis is significantly associated with COVID-19. Periodontitis is a multifactorial disease leading to the destruction of the supporting structures of the teeth, and its association with systemic conditions has been widely studied.11, 25 COVID-19 has been shown to be more severe among patients with comorbidities, such as diabetes, cardiovascular diseases, and renal diseases.5 Oral dysbiosis resulting from increased dental plaque in periodontitis may provide an environment for the oral carriage of respiratory pathogens, thereby causing COVID-19-related complications. In a systematic review, Scannapieco et al.25 concluded that there was a significant association between poor oral hygiene and nosocomial pneumonia. Periodontitis has been linked with both COPD and pneumonia either by the direct aspiration of oral pathogens into the lungs or by the alteration of mucous surfaces in the respiratory tract, promoting adhesion, and the invasion of pathogens.26–28 This may also aid in explaining the association between periodontal disease and COVID-19 observed in the present study.
Periodontopathic bacteria induce the release of proinflammatory cytokines in the lower respiratory tract, and these cytokines may play a role in COVID-19.16 It has also been suggested that periodontitis and periodontopathic bacteria can increase oral colonization by SARS-CoV-2, and thus, the oral cavity may serve as a reservoir for the virus.16, 29, 30 The presence of viruses in periodontal lesions has been previously demonstrated,31 and it has been shown that periodontal pockets and dental plaque can harbor pathogens, such as Helicobacter Pylori, and may thus serve as reservoirs for infection.32, 33 It has also been shown that periodontitis,34 gingival bleeding,35 the presence of dental plaque,36 and the presence of respiratory pathogens in the oral cavity34, 37 can increase the risk of the development of pneumonia among hospitalized patients.38 In the present study also, dental plaque and gingival bleeding were found to be associated with COVID-19.
Studies showing the association between periodontitis and COVID-19 are limited. A study by Marouf et al.19 reported that patients with severe periodontitis are more likely to develop complications associated with COVID-19 than patients with milder forms of periodontitis. They diagnosed periodontal disease from archived patient radiographs. To the best of our knowledge, the present study is the first to clinically compare the periodontal status of individuals with COVID-19. A clinical periodontal examination requires a close interaction with the patient, and therefore, the periodontal examination for all the participants was scheduled after ensuring a negative rRT-PCR result in order to minimize the risk of the transmission of the virus to the investigators.
Smoking is considered a risk factor for both COVID-1939, 40 and periodontitis.41, 42 However, in the present study, there was no significant difference between the groups in terms of tobacco-related habits. This could also be related to the small number of smokers. The presence of systemic diseases that were considered risk factors for COVID-19 or of periodontal disease was also not significantly different between the groups. Gingival bleeding and plaque scores were found to be significantly high among the COVID-19 patients. An earlier study found a higher risk of mortality in individuals with COVID-19 who had bleeding gums and concluded that the mortality risk was higher in patients with periodontal disease.43 Larvin et al.43 concluded that it is essential to assess the oral health status of patients with COVID-19 in order to prevent adverse outcomes. The study group was recruited after the recovery from COVID-19; the stress associated with the disease and its treatment might have had an effect on the oral hygiene practice as well as on the periodontal condition of these patients.44 Stress elevates salivary cortisol levels, which in turn reduces immune responses and upregulates various inflammatory markers, leading to gingival inflammation and periodontal tissue destruction.45
This is a pioneer study that was undertaken to evaluate all possible periodontal parameters and oral hygiene levels by directly examining patients with COVID-19. There are some limitations associated with this case-control study. Because of the serious transmission risk, the patients could not be examined during the course of the active phase of the disease. Nevertheless, as periodontal destruction is a slow process,46 it may be assumed that the participants in the case group were suffering from periodontitis prior to developing the SARS-CoV-2 infection. As patients were not examined during the course of the disease, only patients who were willing to revisit the institution for the purpose of the study were available for data collection. During this process, valuable data from patients with severe forms of the infection may have been lost. However, as this was an initial study, the data that were generated may be used for directing future research with improved methodology and with a larger sample size in order to better understand the association between periodontitis and SARS-CoV-2 infection.
Within the limitations of this case-control study, it can be concluded that there is an association between periodontitis and COVID-19. The increased prevalence and severity of periodontitis and associated poor oral hygiene might contribute to the aggravation of SARS-CoV-2 infection. Gingival bleeding and dental plaque accumulation were also found to be more frequent among the COVID-19 patients. Hence, it is essential to maintain periodontal health and good oral hygiene as an important measure for the prevention and management of COVID-19 and its complications. Further clinical trials assessing the periodontal status in patients with COVID-19 are needed to more firmly establish the links between SARS-CoV-2 infection and periodontal disease.
The study was approved by the Institutional Ethics Committee of the ESIC Medical College & Hospital, Sanathnagar, Hyderabad, with the reference number F0188/05/2020.
CONFLICTS OF INTEREST
The authors declare no conflicts of interest.
Pradeep S. Anand, Kavitha P. Kamath, and Sukumaran Anil contributed to the design of the study, interpretation of results, and drafting of the manuscript and revising it critically. Pradeep S. Anand did the clinical examination. Pradeep S. Anand, Pranavi Jadhav, Salavadi Revanth Kumar, and Sandapola Vijayalaxmi contributed to data collection. Pradeep S. Anand and Kavitha P. Kamath contributed to data analysis. All authors have approved the final manuscript for submission.
- 1, , , et al. A novel coronavirus from patients with pneumonia in China, 2019. New Engl J Med. 2020; 382: 727– 733.
- 2, , , et al. Identification of a novel coronavirus causing severe pneumonia in human: a descriptive study. Chin Med J. 2020; 133: 1015– 1024.
- 3, , . Why do people with diabetes have a high risk for severe COVID-19 Disease?-A dental hypothesis and possible prevention strategy. J Diabetes Sci Technol. 2020; 14: 769– 771.
- 4, , , , . The cytokine storm in COVID-19: an overview of the involvement of the chemokine/chemokine-receptor system. Cytokine Growth Factor Rev. 2020; 53: 25– 32.
- 5, , , et al. A systematic review and meta-analysis of geographic differences in comorbidities and associated severity and mortality among individuals with COVID-19. Scientif Rep. 2021; 11:8562.
- 6, , , . Co-infections: potentially lethal and unexplored in COVID-19. Lancet Microbe. 2020; 1:e11.
- 7, , , et al. Periodontitis: consensus report of workgroup 2 of the 2017 world workshop on the classification of periodontal and peri-implant diseases and conditions. J Clin Periodontol. 2018; 45(Suppl 20): S162– S170.
- 8. Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol. 2015; 15: 30– 44.
- 9. Cytokines that promote periodontal tissue destruction. J Periodontol 2008; 79: 1585– 1591.
- 10, . The contribution of interleukin-1 and tumor necrosis factor to periodontal tissue destruction. J Periodontol. 2003; 74: 391– 401.
- 11, , . Periodontal diseases. Nat Rev Dis Prim. 2017; 3:17038.
- 12, , , et al. Genomic diversity of severe acute respiratory syndrome-coronavirus 2 in patients with Coronavirus disease 2019. Clin Infect Diseases. 2020; 71: 713– 720.
- 13, , , et al. Significance of anaerobes and oral bacteria in community-acquired pneumonia. Plos One. 2013; 8:e63103.
- 14, . COVID-19 and Periodontitis: the cytokine connection. Med Hypothes. 2020; 144:109908.
- 15, , , et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med. 2020; 26: 1636– 1643.
- 16, , , , , . Aspiration of periodontopathic bacteria due to poor oral hygiene potentially contributes to the aggravation of COVID-19. J Oral Sci. 2020; 63: 1– 3.
- 17, , , et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020; 395: 1033– 1034.
- 18, , , et al. Periodontal tissues are targets for Sars-Cov-2: a post-mortem study. J Oral Microbiol. 2020; 13:1848135.
- 19, , , et al. Association between periodontitis and severity of COVID-19 infection: a case-control study. J Clin Periodontol. 2021; 48: 483– 491.
- 20, . Periodontal disease in pregnancy. II. Correlation between oral hygiene and periodontal condtion. Acta Odontologica Scandinavica. 1964; 22: 121– 135.
- 21, . The simplified oral hygiene index. J Am Dent Assoc. 1964; 68: 7– 13.
- 22, , . Clinical dimensions of the supraosseous gingivae in healthy periodontium. J Periodontol. 2008; 79: 2267– 2272.
- 23, , . An introduction to power and sample size estimation. Emerge Med J. 2003; 20: 453– 458.
- 24, , , et al. Update on prevalence of periodontitis in adults in the United States: nHANES 2009 to 2012. J Periodontol. 2015; 86: 611– 622.
- 25, , . Associations between periodontal disease and risk for nosocomial bacterial pneumonia and chronic obstructive pulmonary disease. A systematic review. Ann Periodontol. 2003; 8: 54– 69.
- 26, , , , . A systematic review of the preventive effect of oral hygiene on pneumonia and respiratory tract infection in elderly people in hospitals and nursing homes: effect estimates and methodological quality of randomized controlled trials. J Am Geriatr Soc. 2008; 56: 2124– 2130.
- 27, , , et al. The periodontopathic bacterium Fusobacterium nucleatum induced proinflammatory cytokine production by human respiratory epithelial cell lines and in the lower respiratory organs in mice. Cell Physiol Biochem. 2019; 53: 49– 61.
- 28. Role of oral bacteria in respiratory infection. J Periodontoly. 1999; 70: 793– 802.
- 29Madapusi Balaji T, , , et al. Oral cancer and periodontal disease increase the risk of COVID 19? A mechanism mediated through furin and cathepsin overexpression. Med Hypothes. 2020; 144:109936.
- 30, , , , . Periodontal pockets: a potential reservoir for SARS-CoV-2?. Med Hypothes. 2020; 143:109907.
- 31, . Herpesviruses in human periodontal disease. J Periodont Res. 2000; 35: 3– 16.
- 32, , . Are dental plaque, poor oral hygiene, and periodontal disease associated with Helicobacter pylori infection?. J Periodontol. 2006; 77: 692– 698.
- 33, , . Role of dental plaque, saliva and periodontal disease in Helicobacter pylori infection. World J Gastroenterol: Wjg. 2014; 20: 5639– 5653.
- 34, , , et al. Role of pathogenic oral flora in postoperative pneumonia following brain surgery. BMC Infect Dis. 2009; 9:104.
- 35, , , et al. Analysis of oral risk factors for ventilator-associated pneumonia in critically ill patients. Clin Oral Investigat. 2021; 25: 1217– 1222.
- 36, , , Jr., , . Hummel RS, 3rd. Oral health status and development of ventilator-associated pneumonia: a descriptive study. Am J Critic Care. 2006; 15: 453– 460.
- 37, , , et al. Colonization of dental plaques: a reservoir of respiratory pathogens for hospital-acquired pneumonia in institutionalized elders. Chest. 2004; 126: 1575– 1582.
- 38, . Systematic review of the association between respiratory diseases and oral health. J Periodontol. 2006; 77: 1465– 1482.
- 39, , , et al. Current smoking and COVID-19 risk: results from a population symptom app in over 2.4 million people. Thorax. 2021; 76: 714– 722.
- 40, , , , . The Effect of smoking on COVID-19 symptom severity: systematic review and meta-analysis. Pulm Med. 2020; 2020:7590207.
- 41, . Relationship of cigarette smoking to attachment level profiles. J Clin Periodontol. 2001; 28: 283– 295.
- 42, . Smoking-attributable periodontitis in the United States: findings from NHANES III. national health and nutrition examination survey. J Periodontol. 2000; 71: 743– 751.
- 43, , , . The impact of periodontal disease on hospital admission and mortality during COVID-19 pandemic. Front Med (Lausanne). 2020; 7:604980.
- 44, , , et al. Prevalence of stress, anxiety, depression among the general population during the COVID-19 pandemic: a systematic review and meta-analysis. Global Health. 2020; 16:57.
- 45, , , . Stress, depression, cortisol, and periodontal disease. J Periodontol. 2009; 80: 260– 266.
- 46, , , . Natural history of periodontal disease in man. Rapid, moderate and no loss of attachment in Sri Lankan laborers 14 to 46 years of age. J Clin Periodontol. 1986; 13: 431– 445.
Discussion about this post