key: cord-0891782-i7s5cvyz
authors: Tamimi, Faleh; Altigani, Shiraz; Sanz, Mariano
title: Periodontitis and coronavirus disease 2019
date: 2022-03-04
journal: Periodontol 2000
DOI: 10.1111/prd.12434
sha: 3a72eb15458e398599d17a37638c4e09d34255e2
doc_id: 891782
cord_uid: i7s5cvyz

The coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 is usually a mild condition; however, in some cases it can result in severe sickness and even death. Thus, understanding the reasons behind these grave outcomes is of great importance. Coronavirus disease 2019 and periodontitis share some intriguing characteristics. They can both lead to systemic inflammation and alterations of coagulation pathways, and both share confounding factors, such as diabetes, hypertension, and obesity. Accordingly, a possible association between these conditions has been hypothesized in the literature. The objective of this review was to evaluate the scientific evidence linking these diseases and the possible underlying mechanisms. Evidence has shown that coronavirus disease 2019 presents oral manifestations and can even affect periodontal tissues. Moreover, some studies have shown a possible association between coronavirus disease 2019 severity and the presence of periodontitis. Current evidence suggests that this association could be explained through the direct role of periodontal bacteria in aggravating lung infections, as well as through the indirect effect of periodontitis in inducing systemic inflammation and priming of the immune system to an exacerbated reaction to severe acute respiratory syndrome coronavirus 2 infection. Future research is needed to confirm these observations and explore the possible role that periodontal care might play in the coronavirus disease 2019 pandemic.

Coronavirus disease 2019 (commonly referred to as COVID-19) is caused by a virus from the Coronaviridae family called severe acute respiratory syndrome coronavirus 2, which can infect patients of all ages, mainly through airborne droplets and aerosols. [1] [2] [3] [4] [5] Coronavirus disease 2019 was first identified in the city of Wuhan in China in 2019, and within a very short period it caused the worst global pandemic in recent history with more than 160 million confirmed cases and almost 3.5 million deaths, as of May 25, 2021 (https://coron avirus.jhu.edu/map.html). 3 This public health emergency has threatened the well-being of individuals, ruined economies, and imposed a tremendous burden on health care systems worldwide. 4, 5 Although most coronavirus disease 2019 patients are asymptomatic or only suffer a mild disease, a significant group can present signs and symptoms of severe disease, frequently causing serious complications and even death. Indeed, about 14% of coronavirus disease 2019 cases may require hospitalization and oxygen support, about 5% need admission to intensive care units, and about 1% would end up dying from the disease. 3, 6 Coronavirus disease 2019 symptoms vary depending on the severity of the disease. Most patients present mild symptoms, such as low-grade fever, sore throat, fatigue, dry cough, diarrhea, and other nonspecific symptoms that usually get resolved without any major complication. [7] [8] [9] [10] However, in some cases the disease can progress into a serious and life-threating condition. Severe symptoms include signs of pneumonia, dyspnea at rest, increased respiratory (above 20 breaths per minute) and heart rates (above 100 beats per minute), loss of appetite, confusion, tightness or pressure in the chest, cyanosis, hypoxia (eg, 93%), and high fever (greater than 38°C). [7] [8] [9] [10] [11] Upon entering the body, the virus causes viremia, leading to an early phase of the disease that involves an incubation period of 1-14 days (mostly 3-7 days). [7] [8] [9] [10] [11] Afterwards, the disease may enter a second phase in which the virus spreads to the bloodstream, targeting a wide range of tissues and organs. [8] [9] [10] [11] [12] This results in a deterioration of the patient's condition due to damage to vital organs, such as the lungs, heart, nervous system, gastrointestinal tract, and kidneys, as well as an aberrant inflammatory response termed the "cytokine storm" that contributes to coronavirus disease 2019 mortality. 13, 14 This "cytokine storm" features a hyperactive immune response characterized by increased blood levels of inflammatory mediators such as interferons, interleukins, tumor-necrosis factors, and chemokines, as well as lymphopenia (decrease of cluster of differentiation 3 + , cluster of differentiation 4 + , and cluster of differentiation 8 + T lymphocytes), neutrophilia, alterations of the coagulation cascade (eg, prolonged prothrombin time, thrombocytopenia, elevated D-dimer, low fibrinogen), increased levels of markers for organ damage (aspartate aminotransferase, creatinine, procalcitonin, lactate dehydrogenase, high-sensitivity cardiac troponin), and increased inflammatory markers (eg, erythrocyte sedimentation rate, C-reactive protein, ferritin). 6, [15] [16] [17] [18] The release of inflammatory mediators involved in the innate immune response is usually essential for the clearance of infectious agents; however, at excessively high levels, such as those seen in the "cytokine storm," these mediators can be harmful and cause severe complications. 15 The infectivity of severe acute respiratory syndrome coronavirus 2 is mainly mediated by a protein spike on its surface that is able to bind to the angiotensin-converting enzyme 2, an enzyme found on the membrane of many cells of the human body. [19] [20] [21] Angiotensin-converting enzyme 2 is a counter-regulatory enzyme involved in the breakdown of angiotensin II, thus antagonizing the activation of the classical renin-angiotensin-aldosterone system. [19] [20] [21] Thus, angiotensin-converting enzyme 2 activity is protective against hypertension, diabetes, cardiovascular disease, and damage to the lungs. [19] [20] [21] In fact, angiotensin-converting enzyme 2 is highly expressed in the lower respiratory track, mainly on type II alveolar pneumocytes, which is one of the main reasons why severe acute respiratory syndrome coronavirus 2 infection can harm the lungs and cause an acute respiratory distress syndrome, a highly lethal clinical condition. 19 Type II alveolar pneumocytes act as epithelial immune cells that are able to produce several cytokines such as tumor necrosis factor-alpha, interleukin-6 (IL-6), interleukin-1beta, monocyte chemotactic protein-1, and granulocyte-macrophage colony-stimulating factor. 22 [19] [20] [21] [22] [23] Besides the lungs, angiotensin-converting enzyme 2 activity is also widely expressed in several other tissues including the kidneys, the male testis, the female breast, the liver, and the cardiovascular and gastrointestinal systems. Therefore, severe acute respiratory syndrome coronavirus 2 not only affects the lungs, as it was initially believed, but could also affect multiple organs in the body, thus becoming a multisystemic disease. [24] [25] [26] Several risk factors have been associated with severe coronavirus disease 2019. These include factors such as advanced age and sex (male) and comorbidities such as obesity and the presence of underlying diseases (eg, hypertension, cardiovascular disease, cerebrovascular disease, chronic kidney disease, and diabetes). 7, 14, 19, 27 These predisposing conditions share several standard features that could explain why they are associated with worse disease outcomes. Some of the conditions are known to alter angiotensin-converting enzyme 2 expression in the body, cause endothelial dysfunction, a proinflammatory state, and alterations in the innate immune and inflammatory response. 21, 28, 29 The latter may suggest that a chronic inflammatory condition, such as periodontitis, could play a role in the course of coronavirus disease 2019.

Periodontitis is a chronic multifactorial inflammatory disease associated with dysbiotic dental plaque biofilms, characterized by progressive destruction of the tooth-supporting apparatus. 30 This disease is one of the most common chronic inflammatory noncommunicable diseases and the sixth-most prevalent condition in the world, affecting about 50% of adults. In its more severe form, periodontitis affects about 11% of the population. 30, 31 Owing to its high prevalence and its consequences, periodontitis is a significant public health and socioeconomic problem. Periodontitis not only leads to tooth loss and disability, with the consequent impairment of the patient's quality of life, but it also affects general health. [32] [33] [34] [35] Severe periodontitis has been associated with a range of systemic diseases, including diabetes, cardiovascular diseases, and increased mortality. 34, 35 Owing to this increased systemic risk, various investigations have suggested a possible link between periodontitis and increased severity of coronavirus disease 2019 disease. 1,2 It was, therefore, the main objective of this review to evaluate the scientific evidence studying these links and the possible mechanisms behind this association. 1,2

The oral cavity seems to play an important role in coronavirus disease 2019 pathogenicity. [36] [37] [38] [39] [40] [41] [42] [43] The membrane proteins used by severe acute respiratory syndrome coronavirus 2 to infect cells (angiotensin-converting enzyme 2 and transmembrane protease serine 2) 25 are highly expressed in the oral cavity. [39] [40] [41] [42] [43] They have been found on the epithelial cells of the tongue, oral mucosa, salivary glands, gingiva, and periodontal pockets at levels comparable to those in the lungs and tonsils. In addition, severe acute respiratory syndrome coronavirus 2 can be identified in oral fluids and saliva, and its oral viral load has been associated with disease severity. [37] [38] [39] [40] Some unspecific oral lesions have been associated with coronavirus disease 2019. These include dry mouth, oral vesiculobullous or pustulous lesions, lip necrosis, fissured or depapillated tongue, or erythematous or hemorrhagic mucosal lesions. [39] [40] [41] Such lesions are mostly found among patients with systemic conditions that involve some degree of immunosuppression. 43 

Relevant risk factors associated with coronavirus disease 2019 severity, including smoking, increased age, obesity, diabetes, hypertension, and cardiovascular disease, 26, 27, 29 are also significantly associated with periodontitis. 31, 34 Hence, it is uncertain whether these factors could just behave as comorbidities or whether there are specific mechanisms and pathological pathways linking periodontitis and increased coronavirus disease 2019 severity. 46, 47 A recent case-control study in Qatar on 568 patients investigated the association between coronavirus disease 2019 complications and the presence of periodontitis. 48 The study used dental panoramic radiographs for the assessment of periodontal health.

The results of this study showed that, after adjusting for potential confounders (ie, age, gender, smoking, body-mass index, other chronic diseases, among other factors), moderate to severe periodontitis (stage 2-4) was significantly associated with a higher risk of coronavirus disease 2019 complications, including death (odds ratio 8.81, 95% confidence interval 1.00-77.7), intensive care unit admissions (odds ratio 3.54, 95% confidence interval 1.39-9.05), and need for assisted ventilation (odds ratio 4.57, 95% confidence interval 1. 19-17.4) . 48 Similarly, another study on 137 coronavirus disease 2019 patients (20-65 years) based on oral examination records and panoramic X-rays concluded that patients with signs of oral disease (apical periodontitis, radiographic alveolar bone loss, and dental caries) were significantly more likely to suffer from coronavirus disease 2019 complications, such as positive symptomatology, hospitalizations, and death, than individuals free of oral disease were. 49 However, a positive specific association with periodontitis could not be assessed in this study. 49 Another study used periodontal health data from a telephone survey that was conducted before the pandemic onset and combined it with more recent data on infection and complications caused by coronavirus disease 2019. 50 This study also reported an association between periodontitis and increased coronavirus disease 2019 infection and risk of death. 50 Coronavirus disease 2019-positive participants who had initially reported painful or bleeding gums had a higher risk of mortality from coronavirus disease 2019 (odds ratio 1.71, 95% confidence interval 1.05-2.72), although having loose teeth did not demonstrate a significant association. 50 The association between coronavirus disease 2019 infection and periodontitis has also been investigated in two retrospective studies. One of them used the patient's registry platform of the 

A study on cadaver biopsies from coronavirus disease 2019-positive patients has reported the presence of the severe acute respiratory syndrome coronavirus 2 within their periodontal tissues. 54 This has led to the hypothesis that periodontal pockets may serve as reservoirs for severe acute respiratory syndrome coronavirus 2. 54 It is well established that periodontal pockets present an ideal environment for harboring biofilms rich in bacterial and viral species that may invade the tissues through the frequently ulcerated pocket epithelium. 55, 56 This pathogenic environment could facilitate the entrance of the severe acute respiratory syndrome coronavirus 2, either directly through this damaged epithelia or indirectly by the upregulation in the expression of angiotensin-converting enzyme 2 receptors induced by some periodontal pathogens, such as Fusobacterium nucleatum. 56, 57 Indeed, periodontitis can increase in the oral cavity the expression micro-ribonucleic acids (eg, micro-ribonucleic acids 146a and 155) involved in the regulation of angiotensin-converting enzyme 2, especially among diabetic patients. 57 

Persistent and uncontrolled inflammation is a key manifestation of several diseases, such as periodontitis, cardiovascular diseases, neurodegenerative diseases, diabetes, and coronavirus disease 2019 infection ( Table 1) . [58] [59] [60] [61] [62] Systemic inflammation in periodontitis is characterized by high levels of C-reactive protein and proinflammatory cytokines (interleukin-1 and IL-6) that have been associated with initiating or aggravating diseases, such as diabetes and cardiovascular diseases. 32, 34 Also, periodontitis can prime the immune system toward an exacerbated innate response through the synergistic activation of peripheral polymorphonuclear leukocytes to local and remote inflammatory triggers. 61 Periodontitis has also been impli- patients without periodontitis did. 48 Moreover, blood analyses before patient discharge revealed significantly higher concentrations of neutrophils and higher levels of C-reactive protein than in periodontitis-free patients. 48 Systemic inflammation has also been related to alterations in the sleep-wake cycles of the body (i.e., the circadian rhythm) through the action of the so-called clock genes. These circadian regulatory genes are expressed in most cells and tissues, and their disruption has been associated with inflammatory conditions such as periodontitis and viral infections. For example, the brain and muscle ARNT-like protein-1, an essential circadian regulatory gene, is decreased in periodontitis and viral infections, which suggests common pathogenesis, 

Interleukin-1, 1beta, 1RA, 2, 6, 7, 8, 9, 10, Creactive protein, galectin-3 prostaglandin E2, interferon-gamma inducible protein 10, monocyte chemotactic protein-1, macrophage inflammatory protein-1alpha, fibroblast growth factor-2, granulocytemacrophage colony-stimulating factor, granulocyte colony-stimulating factor, interferon-gamma, tumor necrosis factor-alpha, C3 and C5, and NOD-like receptor family pyrin domain-containing 3 inflammasome, ferritin [6,13,15-18,27,29,36,37,45,4 8,65-67,72] Interleukin-1, 1beta, 1RA, 2, 6, 7, 8, 9, 10, C-reactive protein, galectin-3, prostaglandin E2, interferongamma inducible protein 10, monocyte chemotactic protein-1, macrophage inflammatory protein-1alpha, fibroblast growth factor-2, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon-gamma, tumor necrosis factor-alpha, C3, C5, NOD-like receptor family pyrin domaincontaining 3 inflammasome, ferritin [37, 46, 86] Coagulation biomarkers [46, [88] [89] [90] probably through the nuclear factor-κB pathway. 70 further research would be needed to confirm these hypotheses.

The authors acknowledge support from the Hamad Medical Corporation Business Intelligence Center.

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