Current Infections of the Orofacial Region: Treatment, Diagnosis, and Epidemiology

Undoubtedly, diagnosing and managing infections is one of the most challenging issues for orofacial clinicians. As a result of the diversity of symptoms, complicated behavior, and sometimes confusing nature of these conditions, it has become increasingly difficult to diagnose and treat them. It also highlights the need to gain a deeper insight into the orofacial microbiome as we try to improve our understanding of it. In addition to changes in patients’ lifestyles, such as changes in diet, smoking habits, sexual practices, immunosuppressive conditions, and occupational exposures, there have been changes in patients’ lifestyles that complicate the issue. Recent years have seen the development of new infection treatments due to the increased knowledge about the biology and physiology of infections. This review aimed to provide a comprehensive overview of the types of infections in the mouth, including the types that viruses, fungi, or bacteria may cause. It is important to note that we searched the published literature in the Scopus, Medline, Google Scholar, and Cochran databases from 2010 to 2021 using the following keywords: “Orofacial/Oral Infections,” “Viral/Fungal/Bacterial Infections”, “Oral Microbiota” And “Oral Microflora” without limiting our search to languages and study designs. According to the evidence, the most common infections in the clinic include herpes simplex virus, human papillomavirus, Candida albicans, Aspergillus, Actinomycosis, and Streptococcus mutans. The purpose of this study is to review the new findings on characteristics, epidemiology, risk factors, clinical manifestations, diagnosis, and new treatment for these types of infectious diseases.


Introduction
The natural flora of the mouth is very diverse. After the large intestine, it has the second highest complexity in terms of microorganisms, including more than 700 microorganisms [1]. The tongue is the primary source of microbes in saliva and the major oral

Herpes Simplex Virus
Herpes simplex virus [16] is one of 200 species of the Herpesviridae family and belongs to the subfamily Alphaherpesvirinae, the genus Simplexvirus. Despite differences in host and morphology, this family is thought to be originated from a common ancestor with tailed bacteriophages [17]. These viruses are about 120 to 200 nanometers in diameter. Structurally, they include a circled DNA containing a unique long (UL) segment and a unique short (US) segment (opposite repeats) [17,18]. In addition, they have an icosahedral symmetric capsid, protein coating, and a lipid bilayer cell-like envelope. Genome transcription and replication and the formation of new capsids occur in the host cell's nucleus [18]. These viruses' short reproductive cycle helps them rapidly destroy the host cells [17]. During the infection procedure, the envelope releases the capsid into the host cell's cytoplasm after fusion with its plasma membrane. HSV can attack nerve tissue and multiply there (neuro-virulence). Eighty-three percent identical nucleotides and fifty percent homology in the sequence display a strong association between the two types of herpes virus: HSV-1 and 2 [17].
HSV is also recognized for its latency ability in trigeminal and sacral ganglion nuclei of the ganglia structures [17,19]. HSV fuses to the axon termini to establish latency and moves retrogradely along the sensory fibers ( Figure 1) [17]. Then, it generates latencyassociated transcripts (LATs) that enhance axon regeneration, reduce viral gene expression, and prevent nerve cell apoptosis [20].

Epidemiology
HSV is most commonly transmitted through asymptomatic shedding from an infected person's mouth or genitals. It is mainly transmitted through proximity to an infected person in immunocompromised and immunocompetent individuals [21]. Recurrent HSV infections occur in one-third of the world's population. HSV-1 and 2 usually infect the mucocutaneous of the mouth and genitals, respectively. The incidence of HSV is 40-95% worldwide, depending on the socio-economic status of the studied population, with higher rates in lower socio-economic populations. Sixty percent of adults with HSV-2 have orolabial herpes [21]. Generally, the seroprevalence of HSV increases with age and shows some correlations to the country's income. Sixty percent higher seroprevalence in people over the age of 40 than in those under 20 suggests an increased risk of exposure that should be observed by health beneficiaries [22].

Clinical Presentation
The disease has no clinical signs at the initial acquisition or during periods of reactivation. However, symptoms occur in the active periods of the disease, following asymptomatic periods, on a rotating basis [23]. Clinical symptoms of the first episode of the disease include headache, fever, muscle aches, and inflammation of the lymph nodes [23]. Then, classic lesions are created that include fluid-filled vesicles that become purulent and dry. Genital herpes includes small blisters resulting in benign ulcers, whereas, in cold sores, several small blisters are aggregated [23]. Other vital clinical signs of common gingivitis include bleeding gums with edema and friable erythematosus. In addition, sores on the buccal mucosa and gums may be yellow based on a red halo. These oral lesions are Figure 1. The latent infection of HSV-1 leads to permanent arrest in an G0/G1-like state in the sensory ganglia that will never reenter mitosis 1 . During reactivation, virus genes are expressed in cells in the most permissive state 2 . Then, reactivated virions travels in axons 3 to termini on the epidermis 4 , and then transmitted to the spinosum and granulosum strata layers of the epidermis 5 [17].

Epidemiology
HSV is most commonly transmitted through asymptomatic shedding from an infected person's mouth or genitals. It is mainly transmitted through proximity to an infected person in immunocompromised and immunocompetent individuals [21]. Recurrent HSV infections occur in one-third of the world's population. HSV-1 and 2 usually infect the mucocutaneous of the mouth and genitals, respectively. The incidence of HSV is 40-95% worldwide, depending on the socio-economic status of the studied population, with higher rates in lower socio-economic populations. Sixty percent of adults with HSV-2 have orolabial herpes [21]. Generally, the seroprevalence of HSV increases with age and shows some correlations to the country's income. Sixty percent higher seroprevalence in people over the age of 40 than in those under 20 suggests an increased risk of exposure that should be observed by health beneficiaries [22].

Clinical Presentation
The disease has no clinical signs at the initial acquisition or during periods of reactivation. However, symptoms occur in the active periods of the disease, following asymptomatic periods, on a rotating basis [23]. Clinical symptoms of the first episode of the disease include headache, fever, muscle aches, and inflammation of the lymph nodes [23]. Then, classic lesions are created that include fluid-filled vesicles that become purulent and dry. Genital herpes includes small blisters resulting in benign ulcers, whereas, in cold sores, several small blisters are aggregated [23]. Other vital clinical signs of common gingivitis include bleeding gums with edema and friable erythematosus. In addition, sores on the buccal mucosa and gums may be yellow based on a red halo. These oral lesions are often associated with anorexia. Symptoms in young children can include drooling, halitosis, and dehydration [23]. Herpetic vitiligo is another manifestation, which is painful, erythematous, and swollen lesions often occur in the distal phalanx of the hand, caused by HSV-1 or HSV-2. This lesion mainly affects the fingers (thumb) and rarely the palm [23]. HSV-1 eczema herpeticum of Kaposi varicelliform eruption is caused by poor immunity due to atopic dermatitis, burns, or topical immunosuppressants. The disease includes vesicular skin lesions [24]. HSV eye keratitis and HSV encephalitis are other complications caused by this virus. Eye involvement can lead to sensitive retinal necrosis, conjunctivitis, blepharitis, or chorioretinitis. Reaching this viral infection to the brain parenchyma leads to extensive hemorrhagic necrosis and vascular occlusion. Encephalitis is the worst outcome that can occur in a healthy person following this infection [24,25]. Patients with good immunity have milder symptoms in the recurrence period than in the early symptoms. In general, patients with HSV-1 usually have lesions around the lips and mouth. Several studies have reported a local burning prodrome with roughness or itching before the vesicles erupt. The lymph nodes in the affected area can become sensitive and enlarged without systemic symptoms and fever. Studies have shown that HSV-1 and Epstein-Barr virus (EBV) is associated with invasive periodontal disease caused by bacteria [26].

Diagnosis
Because most people with HSV-2 do not have the classic clinical symptoms, genital herpes is more challenging to diagnose than oral herpes and can be confused with related diseases such as fungal infections, lichen planus, atopic dermatitis, and urinary tract diseases. Diagnosis is confirmed by laboratory tests, including polymerase chain reaction (PCR), skin biopsy, immunofluorescence, and virus culture polymerase chain reaction (PCR). Blood and urine cultures determine previous and ongoing infections, respectively. PCR is more sensitive and accurate for diagnosing HSV in mucosal surfaces than vesicular fluid culture. In patients with a history of genital ulcers lacking active lesions, serological diagnostic tests are conducted [27].

Treatment
Although antiviral drugs, including acyclovir, valaciclovir, famciclovir, and penciclovir, reduce the disease's incidence, duration, and severity, no way exists to remove the virus from the body. Painkillers and topical anesthetic treatments can relieve pain/fever and itching, respectively; however, their efficiency has been controversial [28]. In addition, intravenous infusion of acyclovir is recommended for eczema herpeticum to be limited and prevented from spreading to the eye [25]. Seizure control, fluids management, and intracranial pressure control will improve results in HSV-based eye keratitis [24,25]. Suppressive therapy, such as corticosteroids, is commonly used to improve pain and tenderness at the onset of symptoms. Oral acyclovir has a positive therapeutic effect on primary and recurrent HSV genital infections [25]. Some studies have discussed the antiviral activity of some essential oils on the HSV spp. (even acyclovir-resistant strains) through different mechanisms, such as inhibiting cell attachment. These studies also imply that the synergistic activity of the extracts and, thus, essential oils minimize the development of resistant virus strains [29,30]. A recent development in treating HSV is presented in Table 1. Accelerated fractionation radiotherapy and standard-fractionation radiotherapy Over 6o percent of patients were HPV-positive and showed better overall survival in 3 years compared to HPV-negative tumors.
The following-up prescription showed insufficiency in prohibiting recurrent meningitis. [ Valacyclovir showed no effect on the viral infection. HSV-1 infection co-occurred with a more severe form of schizophrenia.
[49] 2019 HSV-1 and 2 Patients receiving mechanical ventilation for over 4 days Intravenous acyclovir 5 mg/kg Acyclovir did not decrease the duration of mechanical ventilation and did not increase the number of ventilator-free days in patients with HSV oropharyngeal reactivation.
[50] 2019 HPV Patients with anogenital warts Podophyllotoxin cream 0.15% or imiquimod cream 5% with vaccination Imiquimod and podophyllotoxin creams could similarly clear the wart, but the vaccine benefit was not observed.

Human Papilloma Viruses
Papillomaviruses have a wide genetic diversity. Human papillomavirus (HPV) viruses use human cellular proteins to reproduce and survive [52]. The virus genome consists of open reading frames [53] and long control regions (LCR) to regulate the replication and transcription of primary genes [54]. The main reservoir of HPV is inflamed gums, salivary gland epithelium, and cryptal epithelium of tonsils, oral border, and oropharynx. The most clinically important genus of HPV is the alpha genus of human papillomavirus [52]. In high-risk HPV, placing the virus genome in the host genome breaks the virus genome at the E1 and E2 sites, and losing E2, in turn, causes E6 and E7 to lose control that, inhibits the regular function of p53 and pRb, respectively, and interfere with the cell cycle [55].

Epidemiology
Owing to effective screening strategies, the incidence of HPV-caused cervical cancer has decreased; however, the oropharyngeal squamous cell carcinoma (OPSCC) cases have kept rising. In addition, the prevalence of HPV DNA has increased by between 24-45 percent from 1990 to 2005 [56]. In a study in the US, oral HPV rates in men were around 60 percent higher than in women. Additionally, their study evidenced the HPV is the leading cause of oropharyngeal carcinoma (OPC) in men, whereas smoking is the predominant cause in women [57].

Clinical Presentation
HPV infection can be transmitted from the mother's cervix (sexual and non-sexual fomite transmission) and produces clinical or subclinical lesions. Oral HPV lesions include a range of benign oral lesions, lichen planus, fibroma, hyperplastic, papillomatous, verrucous, and carcinoma lesions. Generally, flat, exophytic, or wart-like white lesions in the oral mucosa, exophytic, wart-like, or papillary proliferations can be considered clinical manifestations of HPV [58]. Oral sex is the main transmission root in these diseases, and soft-circumscribed sessile nodular lesions and koilocytosis are some of their pathological and cellular manifestations [59]. The latent location of HPV in the mouth is usually in the gingival pocket because it is the only place where basal cells are in direct contact with the environment [60]. In about one-fourth of patients with periodontal disease in a clinical survey, the gingival samples have been associated with HPV [60]. Additionally, alveolar bone loss has been related to tumor-positive HPV [60,61].

Risk Factors
Risk factors for HPV infection include unsafe sexual behavior, smoking, periodontitis, and inflammation. These factors affect HPV infection by altering the oral environment. Cigarettes stimulate and suppress immune mechanisms in the mouth through the chemicals in tobacco. In women with oral HPV, the prevalence of HPV-infected cervixes is also higher, which may be a factor in increasing the risk of oral HPV [62].

Diagnosis
There are several diagnostic methods for HPV. Immunohistochemical analysis-specific antibodies (e.g., p16INK4A and p16 IHC) and HPV mRNA/DNA-detecting PCR are the sensitive and cost-effective diagnostic methods for HNSCC tumor specimens. However, studies have shown that mRNA tests are the best approach for confirming the diagnosis [63]. Serological biomarker tests cannot be used for detecting HPV infection in the oral cavity. Their examination in oral fluids is useful for identifying and examining the incidence and course of the disease as they are low-cost, non-invasive, and local-specific [64].

Treatment
Syrjänen discusses that HPV particles only get inactivated at temperatures 75-80 • C [62]. Preventive approaches such as vaccination and routine screening of HPV antibodies in the saliva are among the most effective ways to prevent HPV-associated head and neck diseases.
Cold therapy, electrosurgery, surgical resection, laser therapy, and trichloroacetic acid are the usual treatments for papillomas/condyloma, verocroas, and FEH occurred by HPV [52]. The therapeutic developments in treating HPV infection are summarized in Table 1.

Candida albicans
More than 200 species of the genus Candida are usually non-pathogenic in humans. However, in immunocompromised individuals, Candida is the most frequent cause of oral mucosal infections, commonly due to antibiotics and the consequent change in the bacterial microbiota. In addition, suppressing the local or systemic immune system prepares the environment for infection. This group's most common pathogen species is C. albicans, which accounts for more than 90% of oral lesions [65]. Morphological control between yeast and hyphae by C. albicans is involved in its pathogenesis. C. albicans co-adhesion with oral bacteria such as S. mutans helps it to colonize, persist, and grow by receiving a carbon supply. Vice versa, Candida reduces the bacteria's oxygen stress, promotes better bacteria adhesion, and prepares stimulatory growth factors [66,67].

Epidemiology
The general prevalence of C. albicans is 20-75%, with 95% incidence in HIV patients, 90% in patients undergoing chemotherapy and acute leukemia, 88-65% in patients at longterm caring centers, 50-65% in people with detachable dentures, 45-30% in healthy adults, 65-45% in healthy children, and 45% in infants. In immunocompromised individuals, severe systemic exposure to Candida species increases mortality [68]. Oropharyngeal Candida is an opportunistic and recurrent fungal infection in more than 90% of patients with HIV [69]. The mortality rate of Candida bloodstream infection (candidemias) is more than 30% [68].

Clinical Presentation
Pseudomembranous, erythema, hyperplasticity, mucosal irritation, and edema are the symptoms of primary oral candidiasis [70,71]. In more severe cases, hemodynamic instability, positive blood cultures, fever, shock, and tachycardia may occur [70]. Pseudomembranous Candidiasis (thrush) is found on the white plaques, buccal mucosa, oropharynx, and junction of the hard and soft palate and is the most common form of candidiasis. Although some patients may experience a sour taste, burning sensation, and bleeding in the affected areas, most patients are asymptomatic [71]. Candidiasis may be hyperplastic or atrophic and occurs in either chronic or acute forms [70,72]. Different types of candidiasis can be asymptomatic or ulcerous [70]. Hyperplastic candidiasis resembles leukoplakia and may involve the labial commissures and become malignant [72]. Its chronic form is challenging to diagnose since the hyphae may hide in any rough surface in the oral cavity, such as papilloma, epithelial dysplasia, and squamous cell carcinoma [72]. Acute atrophic candidiasis is usually iatrogenic (such as antibiotic consumption) and especially common in HIV patients, whereas chronic atrophic candidiasis is iatrogenic mainly due to orthodontic retainers or dentures that do not adequately fit in place [70]. Chronic atrophic candidiasis and inflammatory papillary hyperplasia [73] may also accompany due to iatrogenic candidiasis because of taking biopsies from median rhomboid glossitis, smoking, and inhaled steroids, for instance [70]. Symptoms of esophageal candidiasis include ulceration, obstruction, narrowing of the esophagus, chest pain, nausea, and vomiting [70]. C. albicans, S. aureus, and β-hemolytic Streptococcus species are among the microorganisms present in angular cheilitis. The anterior region of the nostrils to the corners of the mouth is the source of staphylococci. Iron deficiency anemia, and vitamin B12 deficiency are among the etiological factors [74].

Risk Factors
IgA, mucins, and antifungal agents (e.g., histatin 5 and calprotectin) protect the oral environment from Candida infection. However, factors such as age, organ transplants, HIV, chemotherapy, poor oral hygiene, smoking, inhaled steroids, and radiotherapy increases its risk [75]. Then, in all patients with daily dental care, treatment of xerostomia, control of diabetes, restriction of corticosteroids and topical or systemic antibiotics, and elimination of underlying predisposing factors are very important [76]. The oral amount of Candida in HIV patients relates to their salivary flow [77]. The overgrowth of Candida species has no significant association with oral bacterial dysfunction [75].

Diagnosis
Candidiasis suspicion is based on examining mucosal changes, stained smears with Schiff's reagent or KOH, and histopathological biopsies, searching for the hyphae or epithelial parakeratosis with polymorphonuclear leukocytes [78]. Transcribed internal distance sequencing [40] can be used to identify emerging candidate species and the historical course of candidiasis. For the rapid diagnosis of invasive candidiasis, serological biomarkers, including antibodies against mycelium, β-d-glucan (BDG), mannan antigen (Mannan-Ag), and mannan antibodies, are evaluated [79]. Endoscopy is also necessary for esophageal candidiasis suspicion patients [70].

Treatment
Polyenes and azoles are two types of antifungal drugs [80,81]. Polyenes (with conjugated double bonds) bind to sterols (mainly ergosterols) and change the cell membrane transfer temperature. Then, the leakage of monovalent ions (K + , Na + , H + , and Cl2) and small organic molecules lead to cell death [80]. On the other hand, azole stores α-methylase enosterol to prevent the lanosterol to ergosterol conversion. These topical drugs have no pharmacological systemic side effects since they have no systemic absorption. In cases where topical drugs do not respond, systemic drugs are used [81]. Studies have shown that probiotics may affect the toxicity of C. albicans. For example, Lactobacillus spp. and S. salivarius prevent the differentiation of C. albicans into hyphae or biofilm structure and decrease the salivary yeast level. Probiotics also increase the level of anti-Candida IgA and, consequently, the yeast level [82]. Recent developments for candida infection are shown in Table 2.

Aspergillus
Aspergillosis genus is the second most common opportunistic fungal infection in humans. Aspergillus fumigatus is an air-borne fungal pathogen causing many diseases [108,109]. This pathogen has a saprotrophic mycelial with an efficient spread through asexual spores and a life mostly on decaying organic matter secreting a wide range of enzymes (e.g., amylases, xylanases, pectinases, and elastase) [108]. However, some studies have evidence of heterothallism and a periodical sexual mating procedure [110]. All isolates of A. fumigatus are highly hydrophobic and fast-growing, but their virulence can vary based on indefinite factors such as the growth rate of isolates [109].
The main virulence factors of A. fumigatus are its cell wall containing polysaccharides (90%) and proteins and the glutotoxin from the epipolythiodioxopiperazines family [108]. Through the pathogenesis of Aspergilloma (noninvasive chronic pulmonary Aspergillosis), A. fumigatus hyphae form a biofilm in the extracellular matrix (ECM) with a different cell wall composition and structure [110].

Epidemiology
The epidemiological studies report that the prevalence of Aspergillus varies in a geographical-, regional-, seasonal-, and occupational-dependent manner [111]. Aspergillus spp. has been isolated from the respiratory tract of asymptomatic patients, and its DNA has been found in 37% of healthy individuals [112]. Its prevalence has been 30% in patients with chronic obstructive pulmonary disease (COPD), and 53% of patients with Aspergillus positive culture were conflicted with invasive Aspergillosis (IA) [112]. Distallateral subungual onychomycosis (DLSO) is an onychomycosis condition due to Aspergillus spp., with a prevalence of up to 35% on average and 71% in the diabetic population. It also accounts for 18-50% of all nail diseases and 30% of fungal skin infections [111].

Clinical Presentation
Aspergillus colonization function damages the epithelial cells and upregulation of ECM proteins by disrupting the expression of the ZNF77 transcription factor in bronchial epithelium and causing conidial adhesion. The immune system-survived and metabolically activated conidia grow, germinate, form hyphae, spread by attacking blood vessels, and invade the lung tissue [113]. Aspergillosis is divided into three categories: invasive (nonfulminant and fulminant), noninvasive, and noninvasive destructive. The nonfulminant invasive types are slowly progressive, and the fulminant invasive types are very aggressive. The non-invasive type can be locally destructive but has no tissue invasion and includes Aspergilloma, fungal ball, and Mycetoma [78,114]. Headache, fever, nasal congestion, swelling of the face, purulent or bloody nasal discharge, nasal pain, and epitaxy are the clinical symptoms of A. rhinosinusitis. This diagnosis should be considered in people with regular sinusitis or who are resistant to antibiotics. Oral lesions associated with Aspergillosis and other systemic mycoses can be considered dispersed diseases of the lungs. Irregular oral lesions may indicate the spread of an adjacent structure, such as the maxillary sinus, or a significant infection of the oral mucosa [115]. In the first stage of Aspergillosis, marginal growth areas appear to contain degraded epithelium and infiltrate fungal hyphae in the connective tissue. In the next stage, the previous lesions change to necrotic gray lesions and spread by attachment to the gums by ulceration and pseudomembrane. Invasion of the arteries is found at the base of these wounds. In the last stage, progressive damage to the alveolar bone and muscles is characterized by histopathological evidence of the penetration of fungal hyphae around the face [116]. Poor outcomes were associated with cases of older age, bone marrow transplantation, high sequential organ failure assessment (SOFA) score, and mechanical ventilation [112].

Diagnosis
To diagnose Aspergilloma, chest radiographs are still a suitable imaging technique that shows a round solid body enclosed in a radiolucent crescent in the upper part of the lung (bilateral and multiple). Thin-section chest computed tomography (MDCT), multiple incision (MSCT), spiral computed tomography (CT), and high-resolution CT at the optimal dose are suitable methods for patients at risk of IA. In the early stages of IA analysis, CT lung angiography can show vascular occlusion at the level of a suspected fungal lesion [117]. Additionally, microscopic examination and culture should be performed in patients at risk for IA. Culture is not a specific and appropriate diagnostic marker, while sputum culture is positive for Aspergillus in half of the patients with Aspergilloma. In the microscopic examination, it is essential to prove tissue attack by hyphae. The sensitivity of microscopic examination for IA is about 50% [118]. Evaluation of anti-Aspergillus antibodies by immunoblots and enzyme-linked immunosorbent assay (ELISA) methods is available as a robust and inexpensive method which is the reference method for serological diagnosis of chronic pulmonary Aspergillosis (CPA) [119].

Treatment
The standard doses of anti-fungi drugs recommended for treating IA may not be safe or effective for all patients. Then, high doses of drugs are commonly required in severe infectious diseases, treatment of difficult places, and infections caused by Aspergillus spp. with increased MIC. Patients with hematological malignancy at risk for IA are also managed by receiving initial prophylaxis or controlling biomarkers without receiving prophylaxis [120]. Oral-delivered Raziol treats CPA. All treatment instructions for the invasive Aspergillosis include using azoles, Amphotericin B (AmB), or echinocandin at appropriate doses with therapeutic evidence. However, in some regions, high rates of triazole resistance have been observed in A. fumigatus. In patients without previous exposure to antifungal therapies, a worrying resistance rate of 6% has been reported [108]. Recent developments in treating Aspergillosis are presented in Table 2.

Actinomyces
The genus Actinomyces spp. belongs to the typical human flora that can be found in the oropharynx, gastrointestinal tract, and urinary tract. It is one of the leading oral bacteria usually identifiable in healthy dental mucosa, dental plaque biofilm, periodontal lesions, and root rot. Actinomycosis resembles malignancy, tuberculosis, or nocardiosis in terms of its continuous and gradual spread [121]. The most common species in clinical conflicts is Actinomyces israelii. Actinomycosis infections can be associated with companion microbes inhibiting the host defense or reducing oxygen stress. The onset of Actinomycosis is likely to be multifactorial, and its association with mucosal cleavage is unpredictable. For example, minor trauma to the mucosa caused Actinomycosis in one patient, while no significant actinomycosis was observed in the large ruptures of the mouth [122].

Epidemiology
In 60% of all patients, Lmpy jaw syndrome (or action) is associated with odontogenic infection. The most common clinical form is cervicofacial Actinomycosis, and the most prevalent species are A. israeli and A. gerencseriae, A. naeslundii, A. viscosus, P. propionicum, A. gerencseriae, and A. odontolyticus [122]. Actinomycosis is more common in rural areas, men, and middle-aged people (50-30 years). The mortality rate is between 0 and 28% [123].

Risk Factors
Actinomycosis is associated with dental procedures. Diabetic patients are more likely to get infections because they have structural changes in their tissues and have impaired wound healing. Tumors, surgery, and radiation may also cause local tissue damage to spread into this infection [124].

Clinical Presentation
Complete vascularization of mucosal tissues and their replacement by weakly irritated tissue in actinomycetes supports its growth and provides adequate oxygen pressure. In necrotic foci, filamentous "sulfur" granules spread as a "sunburst radiation". The ends of these granules can form extensions or rosettes due to the adhesion of neutrophils [123]. Cervicofacial clinical symptoms, which may last from 4 days to 1 year before diagnosis, include irregularly painful soft-tissue swelling of the submandibular or perimandibular area and emptying of the sinus ducts with sulfur granules, chewing problems, and recurrent and chronic infection [123]. In about 10% of patients, the bone is involved. Chronic infection can lead to osteomyelitis of the jawbone. Osteomyelitis due to cervicofacial Actinomycosis can spread to the lungs, gastrointestinal tract, tongue, sinuses, middle ear, larynx, ciliary tract, and thyroid gland [125].

Diagnosis
The best diagnoses are histological examination and bacterial culture of abscesses or suspected tissue. Staining sulfur granules with hematoxylin-eosin turns them into round basophil masses containing eosinophilic terminal clubs. Prescribing antimicrobial drugs leading to false negative culture results may cause anemia, mild leucocytosis, increased erythrocyte sedimentation rate, and increased C-reactive rutin value. Increased alkaline phosphatase concentrations may be seen in patients with hepatic Actinomycosis [126]. The blood test is a nonspecific diagnostic method for this disease. Imaging features are nonspecific and non-diagnostic in the early stages and may even be related to other inflammatory processes or neoplasms. Although cross-sectional imaging with CT or magnetic resonance imaging (MRI) does not provide accurate or diagnostic information, it can provide accurate anatomical information for sampling. Regional lymphadenopathy is rare in these patients. In later stages, infiltration of the surrounding tissues may be observed that is not diagnostic again. An aspiration biopsy should be performed in oscillating abscesses to examine the pus in the sulfur granules [127].

Treatment
Depending on the infection course, the course of antibiotics determines the clinical manifestations and response in Actinomycosis. The treatment is experimental because no similar success has been achieved with any antibiotic. The use of high doses of intravenous antibiotics for 2-6 weeks or 6-12 months orally is the primary treatment [128]. Acute lesions are often treated with tooth extractions, abscess drainage, and antibiotics for 2-3 weeks (penicillin). The penetration of antibiotics into the lesion may be delayed by weak vessels and solid capsules. Surgical interventions such as bone necrosis removal are performed for subacute or chronic voluminous lesions [129]. The recent treatments for Actinomycosis are summarized in Table 3. The non-smokers showed the lowest proportions of the orange complex and a meaningful increase in the proportions of Actinomyces species.
[132] 2013 S. mutans Children with decayed, missing, or filled teeth Propolis and xylitol chewing gums Both gums reduced the bacterial saliva load suggesting them an anti-cariogenic agent.

Healthy adult subjects
Beverages containing apple fiber and polyphenols from boysenberry The apple-boysenberry beverage exerted the most reduction on the colonization and biofilm adhesion.  There were similarities in the effects of MicroR and PomeGr; however, the effectiveness of the two, given separately or in combination, varied based on which microbial agent was being treated.

Streptococcus mutans
S. mutans lives in the mouth, specifically on dental plaque. Its importance is for involvement in the etiology of dental caries and its possible association with subacute infective endocarditis. Studies have shown that S. mutans is a major cause of tooth decay because of its ability to make large amounts of organic acids and activity at low pH compared to other species [154][155][156]. Through pathogenesis, S. mutans develop a biofilm starting by attachment of the initial pioneer species followed by colonization, co-adhesion, and co-aggregation of other species. Then, the bacteria produce extracellular polysaccharides, separate from the biofilm surface, and spread in the oral cavity environment [157]. S. mutans produces a sticky glucan by the action of glucosyltransferases (GTF) on sucrose that helps bacteria tight binding to the tooth surface. This binding allows bacteria to withstand rapid and frequent environmental fluctuations such as nutrient access, aerobic to anaerobic transfer, and pH changes. S. mutans also produces other virulence factors, including glucan-binding (Gbp) proteins and antigenic cell surface protein (PAc). PAc is in contact with salivary glands and plays an essential role in bacterial adhesion to tooth surfaces [158].

Epidemiology
Permanent tooth decay did not change according to age standards between 1990 and 2010 and peaked between 25 and 70, respectively. No significant differences were observed in terms of gender. Untreated tooth decay is the most common health condition worldwide. Studies have shown that the prevalence of early childhood caries is worrying in various regions worldwide [159].

Clinical Presentation
Tooth decay, the leading cause of tooth loss, is a multifactorial, infectious, and transmissible disease [160]. According to plaque-specific plaque (SPH) hypotheses, certain Gram-positive acidogenic and aciduric bacteria, including S. mutans and S. obrinus are typical infective dental plaques causing tooth decay as a biofilm-mediated disease in humans [161]. Environmental conditions such as regular daily sugar intake or salivary dysfunction increase the aciduric/acidogenic oral microbiome. As the lesions spread, the physiological balance between the tooth mineral and the biofilm fluid is disturbed, moving toward demineralization [162].

Diagnosis
Caries is diagnosed by visual and tactile dental examination. Alternative methods, including illumination-based methods such as optical coherence tomography [71], nearinfrared [116], and fiber-optic technology, are also available [163]. In addition, the quantitative fluorescence light (QLF) devices, categorized by red, blue, and green labels based on the various wavelengths they generate, can be used in the early stages of caries [164]. Another method is an electronic caries monitor (ECM) that measures the bulk resistance of dental tissue. Material properties such as porosity, contact area, tissue thickness, enamel hydration, and ionic content of tooth fluids determine its electrical conductivity. Visual and radiographic assessments are used alongside other methods such as Diagnodent, ECM, or QLF. However, it is unclear whether such methods can be used as a standard tool in diagnosing tooth decay [165].

Treatment
First, biofilm management should be considered before tissue removal [166]. Patients are advised to consume less fermentable carbohydrates to correct the environmental pressures responsible for plaque biofilm dysbiosis [167]. Recent therapeutic advances are shown in Table 3.

Streptococcus sanguinis
S. sanguinis is a member of the Streptococcus family and a Gram-positive and facultative anaerobe. Similar to other streptococci, S. sanguinis divides along a single axis. According to reports, S.sanguinis is nonmotile. S.sanguinis use several carbohydrate sources to sustain itself. During the eruption of the first teeth of toddlers, S. sanguinis colonizes the oral cavity. Streptococcus species, however, have been reported to form biofilm during the first four to eight hours following biofilm formation. Their colonization of enamel is pioneering, particularly that of the mitis. As a result of refraining from using a toothbrush for some time, Streptococcus spp. colonizes the enamel more quickly, which could contribute to its cariogenic nature. S. sanguinis may colonize a mature biofilm at different rates, resulting in different cariogenic traits [168].

Epidemiology
Commensal bacteria such as S. sanguinis are common in the mouth. In human saliva, it can be found on tooth surfaces and the surface of the oral mucosa. In both supragingival and subgingival plaque, S. sanguinis thrives as an anaerobic species. Despite similar plaque mass, S. sanguinis biomass can differ substantially at different tooth locations. Teeth with lower incisors/canines have a high proportion of it, but upper molars with low proportions. Various dental implant surfaces have also been shown to form biofilms due to S. sanguinis [169].

Mechanism of Action
In general, S. sanguinis and S. gordonii are less acid-tolerant than S. mutans, but they contain arginine deiminases, which produce ammonia and provide ATP when exposed to acidic conditions. This system improves the survival and persistence of these organisms. Researchers have found that bacterial uptake and catabolism of specific carbohydrates can affect H 2 O 2 and AD production by these commensals [170].

Clinical Importance
Dental caries has previously been shown to be prevented by S. sanguinis. For many years, S. mutans and humans have been antagonistic. There is a significant correlation between early S. sanguinis colonization and later S. mutans colonization. S. sanguinis levels decrease after S. mutans colonization. The inhibiting ability of S. sanguinis strains against Prevotella intermedia BS6 was found in at least one-third of the strains tested. As a result of hydrogen peroxide production by S. sanguinis, A. actinomycetemcomitans cannot grow in vitro [171]. Microbial and HSP epitope mimicry and microbial and HSP colonization of the oral mucosa have been proposed to elicit immunity and autoreactive T-cell clones. HSP stimulates adaptive and natural immune responses. Several autoimmune diseases, such as Behcet's disease, have been linked to oral bacteria, including S. sanguinis [172].

Diagnosis
It has been primarily physiological and biochemical characteristics used to identify S. sanguinis in the past. Nevertheless, phenotypic identification methods and investigators differed in reliability and reproducibility. Previously, genotypic and phenotypic methods did not accurately identify clinical S. sanguinis isolates. To identify S. sanguinis and other oral bacteria, other methods, such as PCR with nucleic acid probes, are being investigated. [173].

Conclusions
Today, protecting and adequately repairing the tooth structure is the most critical approach to caries management. Successful clinical management of dental caries requires a good biological understanding of the disease process and the associated microbiome. Current approaches are based on the International Caries Consensus Collaboration (ICCC) recommendations, which state that tooth decay is a biofilm disease. In this regard, the literature states that biofilm management should be focused on before tissue removal to prevent the formation of new lesions and control the previous lesions [166]. Then, an understanding of microbiology, anatomy, pharmacology, wound healing, and oral surgery is required to manage acute dental infections. Today, the natural balance of the oral microbiome can be altered by lifestyle. The clinical goal in these patients is to establish this balance.
Despite treatment according to protocols, severe infections can be life-threatening. Therefore, using the idea of oral microbiome balance is essential for patients and healthcare professionals. The first approach is to maintain health rather than disease management. In preventing and diagnosing oral infections, healthcare providers can be very effective with activities such as controlling infections according to new protocols, educating patients, raising awareness about proper nutrition and uncontrolled sexual relationships, and motivating regular checkups. Early detection of infection and pathogens helps reduce oral or general infection. Identifying all aspects that cause antimicrobial resistance, immune system volatility profiles, potential mutations, and genotype differences should be examined in managing these infections. Timely management prevents complications in the patient and prevents the spread of the disease to others. In addition to their skills in treating these infections, clinicians need evidence-based knowledge about the pros and cons of any treatment.

Future Directions
It is suggested to study the mechanisms controlling the fate and function of infected tissues. Meta-analysis studies and robust trials with long follow-up periods should be performed, considering individual differences and other clinical limitations. Using the results of these studies, develop new treatments and approaches for tooth decay or damage to teeth and orofacial tissues. Several strategies have been used to prevent and manage oral infections in some not-yet-published current clinical trials. Genetics is also suggested as an important underlying factor that can affect the spread of infection and the immune response. Today, with the advancement of modern imaging systems and rigorous laboratory experiments, researchers can examine their treatment methods and disagreements in a shorter time.