INTRODUCTION:

Periodontal disease (PD) represents a broad category that includes a spectrum of inflammatory disorders, like gingivitis and periodontitis, commonly found in adults and not uncommon in children. PD is a comprehensive designation for various inflammatory ailments affecting the periodontium, encompassing the gingiva, cementum, periodontal ligament, and alveolar bone. The initiation of PD typically arises from an uncontrolled inflammatory response to the gradual colonization of bacteria on the tooth surface and soft gingival tissues, leading to gingivitis. However, the host's inflammatory reaction to this microbial intrusion ultimately culminates in the degradation of the periodontium, referred to as Periodontitis. In instances of periodontitis, pathogens prompt the leukocytes of the innate immune system to secrete pro-inflammatory mediators such as cytokines, which play a pivotal role in the advancement of chronic periodontitis (CP)^1,2.

The outbreak of Coronavirus Disease 2019 (COVID-19) is a current respiratory illness caused by the coronavirus, which is recognized for its ability to induce severe acute respiratory syndrome (SARS-CoV-2)³. Periodontitis not only increases the susceptibility to complications related to COVID-19 but also exerts an indirect influence on the outcomes of COVID-19 by affecting systemic complications^4-6. This review endeavors to initially delineate the analogous immunopathogenesis and signal pathways that are mutually shared by periodontitis and COVID-19. Subsequently, it offers immunological evidence that buttresses a correlation between the two conditions. Ultimately, the review delves into scrutinizing the association between periodontitis and COVID-19. On one hand, this comprehensive review provides readers with a succinct overview of the disease characteristics and current research status about periodontitis and COVID-19. On the other hand, it assists researchers in pinpointing potential links between the two conditions, thereby paving the way for further investigations in subsequent phases. Furthermore, the review extensively elucidates the immunological correlation between these maladies, which carries significant implications for drug selection and clinical interventions.

Figure 1: Schematic relation factors between COVID-19 and Periodontal

The humeral and cellular immune system's role in periodontitis:

Microbial dysbiosis, or a disturbance in the microbiota homeostasis brought on by an imbalance in the functional makeup and metabolic activities of the microbial species, is the root cause of the molecular and physiological alterations that result in Parkinson's disease (PD) in the oral cavities⁷. Periodontitis is associated with immunopathological processes that include both innate and adaptive immune responses. An intricate web of interactions between the complement system, neutrophils, antigen-presenting cells, T lymphocytes, and B lymphocytes contributes to the inflammatory and immunological responses in the periodontal tissues⁸.

The disorder of cell-cell interactions caused by neutrophil-associated chemokines and protease activity allows for tissular inflammation. Neutrophils are recognized as the primary line of defense for the host against pathogens. The presence of oral bacteria and their byproducts can trigger the activation of innate immune cells, leading to their recruitment into the inflamed periodontal tissues via the bloodstream⁹. Abnormalities in neutrophil count, function, or activity can exacerbate the progression of periodontitis. Individuals with inherited neutrophil disorders, like congenital neutropenia, often exhibit severe periodontal disease in its early stages. The proliferation of keystone pathogens is facilitated by their ability to evade immune surveillance. Periodontitis disrupts the regulation of neutrophils, resulting in their excessive recruitment, hyperactivity, or impaired function^9,10. Proteases—in particular, matrix metalloproteinases, or MMPs—are essential for causing tissue damage and pathological inflammation. Excessive MMPs can damage basement membranes and extracellular matrix elements, which exacerbates the deterioration of periodontal tissues. Patients with periodontal disease frequently have elevated levels of MMP-8 and MMP-9, which might be used as biomarkers to test for and diagnose periodontitis. NETs are structures made of chromatin and other proteins that are secreted by neutrophils to entangle and kill bacteria^11,12.

Cytokines and chemokines are essential in the commencement and development of periodontitis. The formation of a cytokine network, which triggers inflammatory processes, is an intermediary mechanism that exists between bacterial stimulation and tissue damage, as was discussed in the preceding sections¹³. Periodontal tissue degradation may result from dysregulated immune responses, which are defined by the incorrect release of certain pro- and anti-inflammatory cytokines. Moreover, these locally generated cytokines can disperse and enter the systemic circulation, maintaining a widespread inflammatory state. These cytokines consist of acquired immune cytokines, innate immune cytokines, and chemokines¹⁴. Certain T lymphocyte subsets (naive CD4+ T cells) are intimately associated with certain cytokines. These subsets are stimulated by inflammatory cytokines to develop into Th1, Th2, Th17, Tfh (follicular helper T cells), and Treg cells. Of these, pleiotropic and anti-inflammatory effects in periodontitis have been linked to Th1 (IL-12, IFN-γ) and Treg (IL-2 and TGF-β, IL-10 family); pleiotropic effects have also been linked to Th17 (IL-17 and IL-23) and Th2 (IL-4, IL-5, IL-13). In chronic periodontitis, Th2 cells have been linked to a damaging B cell response. Th17 cells have been linked to the etiology of several immune-mediated inflammatory illnesses and have been demonstrated to be strong inducers of tissue inflammation^15,16.

SARS-CoV-2 Immunological Aspects:

SARS-CoV-2 interactions with hosts result in COVID-19. Local or systemic harm is caused by the virus itself, by immunological abnormalities brought on by the infection, and by unchecked inflammatory reactions. According to current theories, COVID-19 may have an immune etiology that includes cytokine storm (CS), diminished or delayed type I interferon (IFN-I) response, dysregulation of monocytes and macrophages, lymphopenia, and neutrophilia¹⁷. Current hypotheses suggest that in infected cells, SARS-CoV-2 can inhibit and delay the induction of IFN I or inhibit the IFN I response. Through suppression of transcription and translation in host cells, SARS-CoV-2 can evade IFN I inducibility. Moreover, it can precisely target and control the production of IFN I host proteins¹⁸.

Th17 cell responses are additionally implicated in the immunopathogenesis of COVID-19, primarily through the release of diverse cytokines, such as IL-17, granulocyte-macrophage colony-stimulating factor, IL-21, and IL-22. The involvement of IL-1b and TNFα, as inducers of human Th17 cell differentiation, in promoting vascular permeability and leakage is also noteworthy. It has been demonstrated, however, that individuals with severe COVID-19 exhibit heightened levels of CCR+ Th17 cells. This observation potentially indicates the participation of Th17 cells and their cytokines in the cytokine storm^19,20.

One important pro-inflammatory factor that can worsen tissue damage in both acute and chronic inflammatory diseases is IL-1β. In reaction to PAMPs or DAMPs, immune cells like monocytes or macrophages mostly release it. In vitro and in vivo, IL-1β plays a pivotal role in several important pathophysiological processes such as inflammation, immunological response, hematologic response, metabolism, and physiologic response^21,22. Excessive levels of IL-1β can exacerbate autoimmune disorders and inflammatory reactions. Severe COVID-19 individuals exhibited a positive connection with IL-1β and other cytokines associated with CRS. Increased vascular permeability, vascular leakage, and coagulation are caused by IL-1β and TNF, and in severe COVID-19 individuals, these outcomes lead to pulmonary edema, disseminated intravascular coagulation, and hemorrhage²³. There is a strong clinical correlation between the incidence of different ailments and IL-6. Many disorders can be brought on by or made worse by the dysregulation of IL-6 expression. COVID-19 and periodontitis are two conditions in which IL-6 is significant. It has been demonstrated that salivary IL-6 is a good indicator of gingival health. Saliva and serum IL-6 levels were significantly greater in patients with periodontitis. Salivary IL-6 levels rose dramatically in correlation with tooth loss and the severity of periodontitis²⁴.

Connection between COVID-19 and periodontitis:

One possible outcome of COVID-19 infection is a variety of oral clinical symptoms, including necrotic periodontal disease. However, long-term inflammation from diseases like periodontitis might make a patient more vulnerable to COVID-19, which will make the virus worse and lead to systemic inflammation. The connection between COVID-19 and periodontitis is the main topic of this section. Male sex is the most common risk factor for periodontal disease, which significantly increases the risk of the condition. Based on information gathered from the National Health and Nutrition Examination Survey (NHANES) 2009–2014, 42.2% of adult US citizens aged 30 and over had periodontitis, with 7.8% of cases classified as severe (SP) and 34.4% as non-severe (NSP)^4,25.

Male gender was observed to be related with increased COVID-19 severity and overall COVID-19 mortality. Gender variations in risk factors included smoking, changes in ACE2 and TMPRSS2 expression levels, and hormonal variances in inflammatory processes. On the other hand, female patients appear to be more susceptible to COVID-19's long-term effects, including post-COVID syndrome, decreased resilience, and decreased exercise tolerance. There are more male patients (50.2%) than female patients (34.6%) with complete periodontitis. Males were more likely than females to have NSP and SP^26,27. The pathophysiology of COVID-19 may include the oral cavity and periodontal tissues, according to a recent study. The tongue, salivary glands, and oral mucosa all contain ACE2, which indicates that these tissues may serve as focal sites for SARS-CoV-2 infection. Further evidence that periodontal pockets may aid in the spread of the virus and the advancement of the illness comes from the discovery that ACE2 is present in periodontal ligament cells and gingival epithelium²⁸.

In Riyadh, Saudi Arabia, the first retrospective cohort research evaluated the relationship between periodontitis and the severity of COVID-19. It showed a statistical relationship between the severity of COVID-19 and periodontitis. Patients with periodontitis had a threefold increased risk of COVID-19 problems. Patients with diabetes and hypertension had a 3.5-fold increased risk of COVID-19 problems.Gaining insight into the possible connection between systemic inflammation and COVID-19-related periodontitis might pave the road for high-quality medical treatmen^t29. According to Gupta and Sahni (2020), the pathophysiology of both COVID-19 and periodontal disease involves the development of neutrophil extracellular traps. These speculative hypotheses might provide a means of investigating the correlation found between COVID-19 and periodontal disease, namely, the finding that the illness's incidence has gone higher throughout the pandemic³⁰.

Takahashi et al. (2020) suggest that the aspiration of periodontopathic bacteria in saliva may lead to the overexpression of ACE2 and proinflammatory cytokines in the lower respiratory tract, thereby exacerbating COVID-19 symptoms. Additionally, it has been suggested that by breaking down the S glycoproteins of SARS-CoV-2, periodontopathic bacteria increase the virulence of the virus³¹.

The close association of the virus with periodontal tissues due to elevated levels of ACEII and CD147, as well as the potential excessive production of several cytokines, referred to as the COVID-19 "cytokine storm," which includes elevated levels of interleukins like IL-1 beta, IL-2, IL-6, IL-10, IL-17, IL-8, and IL-9, as well as other significant cytokines like GM-CSF, GCSF, IFN-gamma, TNF alpha, and MCP1, are the two potential mechanisms that could explain the relationship between periodontitis and COVID-19²⁰. In general, the role of Interleukin-6 (IL-6) is primarily characterized as a dependable biomarker utilized for the prompt identification and advancement monitoring of COVID-19 ³².

Biomarkers in conjunction with diagnostics in Periodontal diseases:

Various enzymes present in the gingival crevicular fluid (GCF) are derived from stromal, epithelial, bacterial, and inflammatory cells. Enzymes like AST (aspartate aminotransferase), ALT (alanine aminotransferase), peroxidase, GGT (gamma-glutamyl transferase), lysozyme, ALP (alkaline phosphatase), and ACP (acidic phosphatase) have shown associations with the severity of periodontal diseases^33,34. Immunoglobulins (Ig) present in saliva, particularly IgA, IgM, and IgG, serve as specific defense factors that impede bacterial adherence and impact the oral microbiota. Numerous studies have established a positive relationship between immunoglobulin levels, periodontal inflammation severity, and salivary IgA concentrations³⁵.

Several pro-inflammatory cytokines, including interleukins (IL)-1α, IL-1β, IL-6, Tumor Necrosis Factor-α (TNF-α), Prostaglandin E2 (PGE2), Transforming Growth Factor-β (TGF-β), and Macrophage inflammatory protein-1 alpha (MIP-1α/CCL3), have been utilized in the diagnosis of periodontal diseases due to their representation of inflammatory cell cascades, such as leukocytes and lysozymes, which contribute to tissue degradation³⁶. IL-1β, produced by activated macrophages, lymphocytes, and fibroblasts, triggers PGE2 secretion, leading to bone loss. These cells also release MMPs, influencing connective tissue breakdown³⁷. The pro-inflammatory cytokines such as IL-1β and IL-6 have been implicated in the induction of severe inflammation and tissue degradation in periodontitis. These indicators have the potential to serve as a valuable tool for early detection and diagnosis of periodontitis. IL-1β has proven to be a highly sensitive marker for evaluating periodontal health, with 90% sensitivity and 76% specificity. Studies by Ebersole have highlighted the discriminatory potential of IL-1β, IL-6, and MMP-8 in distinguishing periodontitis patients from healthy individuals³⁸. Macrophage inflammatory protein-1 alpha (MIP-1α) has recently been identified as abundantly secreted at sites of periodontal inflammation and bone resorption³⁹. C-reactive protein, induced by circulating cytokines like TNF α and interleukin-1, is synthesized in the liver and reaches saliva through GCF or salivary glands. Elevated levels of C-reactive protein have been linked to chronic and aggressive periodontal diseases, along with other inflammatory biomarkers⁴⁰. The stimulation of osteoclast precursors' proliferation and differentiation, along with its impact on mature osteoclasts by activating them, is observed with the presence of TNF factor, which signifies the existence of chronic generalized periodontitis. An escalation in its levels is noted during periodontal inflammation, as it is generated by macrophages that play a crucial role in the formation of nitric oxide radicals and phagocytosis⁴¹.

Increased circulating levels of inflammatory cytokines, such as IL6 and IL10, have been linked to the severity and mortality of COVID-19, according to a recent systematic review and meta-analysis. While it was proposed that IL8, IL10, and TNF only correlate with the severity of SARS-Cov-2 infection, another study also showed a high level of circulating IL6 related to the severity of infection by human coronavirus strains, including SARS and MERS. Additionally, recent research linked severe and fatal COVID-19 patients to elevated levels of IL6, CRP, procalcitonin, D-dimer, ferritin, neutrophils, and leucocytes. It showed that individuals with severe COVID-19 had greater levels of IL6 than patients with less severe illness, indicating that IL6 inhibition might be a new target for COVID-19^42,43.

CRP levels have been highlighted as an initial biomarker for assessing the severity of COVID-19 infections. Research has shown a correlation between poorer periodontal health outcomes and elevated CRP levels in COVID-19 patients. This association between increased CRP levels and compromised periodontal health is well-documented in the literature preceding the current pandemic⁴⁴.

According to published data, site-specific tests and mouth rinses containing active matrix metalloproteinase (aMMP-8) were shown to be able to correctly identify periodontal disease in 38.1% and 33.3% of patients, respectively. However, in 21.1% (mouth rinse kit) and 13.9% (site-specific kit) of periodontally healthy people, both kits had beneficial outcomes. Because of elevated levels of aMMP-8 in the oral cavity—possibly brought on by the COVID-19-related cytokine storm—the kits revealed a greater percentage of false positives. The reported results might have been caused by an increase in aMMP-8 expression and degranulation brought on by this storm⁴⁵.

The integration of microbial and molecular-level biomarkers could significantly improve the management of periodontal diseases. Ebersole validated this hypothesis by studying the expression of IL-6 and MMP-8, while Gursoy found that a combination of IL-6, MMP8, and IL-1β demonstrated a predictive value of 100%, suggesting its reliability in diagnosing periodontitis^46,47. To assess COVID-19 results, the observational trial included two groups: one with periodontitis and the other without. Adult participants who had seen a dentist at least once and had been hospitalized or isolated as a result of a COVID-19 consequence (such as an in-ward, ICU, or fatality) were selected according to the inclusion criteria. The findings showed that COVID-19 patients with periodontal disease had substantially higher blood levels of HbA1c, WBC, and CRP than did those without periodontal disease²⁹.

Handling Periodontal Patients During the COVID-19 Pandemic

Despite being a relatively new and extremely infectious illness, little is known about how COVID-19 spreads in dental settings. In addition, several infectious illnesses are emerging and reemerging globally throughout this eco-epidemiology age. Maintaining physical distance is one of the basics of virus prevention that cannot be achieved in dentistry practices. Furthermore, proximity, the production of spit and aerosols, cramped quarters, a deficiency of personal protective equipment (PPE), and inadequate ventilation—all contribute to the transmission of viruses in most dental clinics⁴⁸. The majority of current infection control recommendations are predicated on broad ideas. It will need more laboratory and clinical research to reduce or completely eradicate the spread of microorganisms during dental procedures. In periodontal practice, it should be standard procedure to apply four-handed dentistry with an ergonomic clinic design to facilitate the handling of saliva ejectors and High Volume Evacuation (HVE). Keeping in mind that no one method of infection management can avoid cross-transmission, necessary personal protective equipment (PPE), surface cleaning, effective ventilation and air purification, and sterilization should be carefully used to limit microbial transmission. Ocular, oral, and other regions surrounding the dental chair can get infected even while using HVE. Consequently, during periodontal treatments, all equipment required for infection prevention should be used. In the post-COVID age, tight infection control procedures in dental clinics and academic periodontal environments, public health education, and the integration of cutting-edge technology should be the top goals⁴⁹.

Both locally and systemically, the microbial load and the levels of inflammatory cytokines are decreased by treating periodontitis. A case-control study (N = 13253) reported how periodontal therapies can affect COVID-19 problems. Patients with untreated periodontitis had a significantly higher risk of needing mechanical ventilation compared to those with a healthy periodontium ⁵⁰. Based on these results, it appears that among the five potential pathways including the inflammatoryhypothesis,oral‑vascular‑pulmonary route, hypercoagulable state, microbiological hypothesis, and geneticsthat have been suggested to link COVID-19 and periodontitis, the function of inflammation and coagulopathy appears to have stronger support at this time.

CONCLUSION:

Periodontal health education should be integrated with other health education methods. Virtual periodontal clinics can reduce interview duration. A simple, less invasive examination is recommended. Single-visit NSPT is preferred for periodontitis treatment. Pre-procedural antiviral mouthwash/rinse should be used before procedures. Manual periodontal instrumentation and polishing should be used. Sterile gauze should be used instead of irrigation. Saliva ejectors and HVE should be used regularly. PPE such as N95 respirators and face shields should be worn. Surface decontamination and air ventilation protocols should be established. Regular maintenance of dental unit waterlines is necessary. Multi-unit clinics should be redesigned for equal isolation and ventilation.

Periodontitis and COVID-19 demonstrate an intricate interaction, where systemic inflammation plays a pivotal role in worsening existing periodontal conditions. Elevated levels of inflammatory markers such as IL-6, MMP8, and IL-1β are correlated with periodontitis, underscoring their potential as diagnostic tools for the condition. The severity of COVID-19 and mortality rates are associated with male gender and the presence of severe or non-severe forms of periodontitis, underscoring the significance of considering these variables in disease management. Biomarkers like CRP, D-dimer, and NLR act as indicators of systemic inflammation and disease severity, offering valuable insights into the pathophysiology of COVID-19 and periodontitis.

FUTURE RESEARCH DIRECTIONS:

1) Conduct systematic reviews following PROBE guidelines to evaluate the predictability and reliability of novel salivary biomarkers for diagnosing periodontal diseases, potentially enhancing diagnostic accuracy.

2) Explore the integration of microbial and molecular-level biomarkers to improve the management of periodontal diseases, aiming to develop more effective diagnostic and treatment strategies.

3) Investigate infection control measures in dental settings to minimize microbial transmission during procedures, emphasizing the importance of implementing standard protocols like four-handed dentistry and using personal protective equipment to prevent cross-transmission.

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Received on 20.05.2024 Revised on 14.09.2024

Accepted on 05.11.2024 Published on 27.03.2025

Available online from March 27, 2025

Research J. Pharmacy and Technology. 2025;18(3):1439-1445.

DOI: 10.52711/0974-360X.2025.00207

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