Systemic Immune-Inflammatory Index and Other Inflammatory Markers in Odontogenic Cervicofacial Phlegmons

Abstract

Odontogenic cervicofacial phlegmons represent a medical and surgical emergency, being characterized by a high mortality rate. The evolution of the infection toward the superficial and deep cervicofacial spaces is strongly related to the immune status of the individual. These complications are a challenge for the clinician, and a complete assessment of the case is mandatory. By integrating the value of the systemic immune-inflammatory index and other inflammatory markers determined from blood samples, a complete evaluation of the case can be provided from the beginning by assessing the individualized response of the immune system. The systemic immune-inflammatory index has proved its efficiency in assessing the relationship between the host’s inflammatory and immunological condition by integrating the values of the neutrophils, platelets and lymphocytes. Also, the neutrophils-lymphocytes ratio (NLR) can be an important inflammatory marker for revealing the general expansion of the infection. The ongoing treatment and the response are important steps for the outcome of the cases. The quantification of the immune response through these parameters can efficiently guide the initial diagnosis, the treatment options, the continuous monitorization, and, eventually, the prognosis of the patients.

1. Introduction

The odontogenic cervicofacial phlegmons represent an infection with an aggressive evolution toward the nearby anatomical spaces, both superficial and deep ones. Having as a main cause the odontogenic pathogens, their first localization could be in the tooth structures or the periodontium, having the ability to disseminate into the alveolar bone and surrounding soft tissue. Several conditions can influence the progression of oral pathogens, conditions that are represented by the incidence of complications after teeth exodontia, salivary glands pathologies, malignancies that involve the oral hard and soft tissue, and associated health problems of the patient. A concern related to this type of infection is its potential to progress along the facial planes, until, in severe cases, it affects the mediastinum, a situation that requires emergency management of the case, being a life-threatening complication. There are certain complications that the clinician must identify in order to assess the case correctly, and these complications can include internal jugular vein thrombosis, mediastinitis, arterial erosion, pneumonia, empyema, meningitis and sepsis. Special attention must be given to immunocompromised patients, as their immune system cannot manage properly the response to infection, and the delay of the treatment can influence the severity of the case. Normally, the oral cavity is populated with a specific oral flora, known as the oral microbiome, and in a healthy environment, all the pathogens are in symbiosis. Any perturbance in the balance of the oral microflora will determine the increase of specific microorganisms that will influence the occurrence of different pathologies [1, 2, 3].

The evolution of the cervical facial phlegmons is strongly influenced by the response of the immune system, outlining the importance of a prompt evaluation of the case and the existent correlation with existent comorbidities. Among the first evaluations of the patients, the assessment of the inflammatory response is mandatory, being a relevant prognostic value for the case. A helpful approach for these cases would be the permanent monitorization of several inflammation biomarkers identified in the blood, which could offer important information regarding the initial status of the patient, the response of the immune system in relationship with the polymicrobial infection and the evolution of the values of these biomarkers along with the initiation of the surgical treatment and medication.

A complete evaluation of the systemic immune-inflammatory index and other inflammatory markers in correlation with this type of severe infection could be an important step for the initial evaluation of the case, the management and response of the immune system along with the decided treatment option, and for the final evaluation that certifies the absence of the infection present in cervicofacial phlegmons.

Taking into consideration the severe evolution, bad prognosis and high mortality rate associated with these types of infections, the evaluation of the response of the immune system could be the key. Integrating a personalized analysis of these predictive systemic inflammation markers, the management of the clinical cases of odontogenic cervicofacial phlegmons and the survival rate could be improved.

This chapter aims to provide an overview of the odontogenic cervicofacial phlegmons, its causes and aggressive evolution, highlighting the potential that systemic immune-inflammatory index and several inflammatory biomarkers have in the management of the cases.

2. Cervicofacial phlegmons-etiology

2.1 Odontogenic causes

The periodontium, the alveolar bone, and the periosteum are the first oral structures affected by the pathogens and their toxins. Dental pulp gangrene and periodontal diseases are the main bacterial reservoirs capable of initiating odontogenic phlegmons. The route of bacteria dissemination is represented by the tooth crown destruction, dental pulp and tooth apex. After this pattern is followed, the pathogens can migrate into the soft tissues of the head and neck. The shape and anatomical characteristics of the neck and the head region affect the path that the inflammatory processes spread. Through continuity, the presence of blood and lymphatic vessels, as well as through the neurolemma, the infection advances from the oral cavity, face, and neck to the nearby anatomical areas represented by the superficial and deep fascial spaces [1]. The most involved teeth are the inferior molars, but the implication of the frontal teeth is not excluded [2, 3].

2.2 Microbial pathogens

The cervicofacial phlegmons are polymicrobial infections including intraoral indigenous bacteria. Viridans group streptococci and Staphylococcus aureus are the pathogens that are most commonly identified in patients with Ludwig angina, but anaerobes including Bacteroides, Prevotella, Fusobacterium, Peptostreptococci, and peptococci are also frequently implicated. The frequency of anaerobic infection increases with infection severity and dissemination [4, 5]. The infection with Streptococcus anginosus, which is a virulent strain from viridans group streptococci, or infection with gram-negative aerobic infection as well as methicillin-resistant Staphylococcus aureus (MRSA) is correlated with a bad prognosis [3]. In cases of patients with cervicofacial phlegmons and diabetes, the infection with Klebsiella was diagnosed in over half of the patients [6]. Routine aerobic and anaerobic cultures must be performed on samples of drained secretions of the phlegmons from the first presentation of the patient and successive in the case of unfavorable evolution of the cases. The result of the cultures must be correlated with the pharmacological antibiotherapy.

2.3 Nonodontogenic factors

The other factors that can be involved in the etiopathogeneses of the cervicofacial phlegmons are divided into:

• local factors: mandibular fractures, osteomyelitis, soft tissue laceration, sialadenitis, sialolithiasis of the submandibular glands, tumor superinfection, postoperative status, pharyngeal infections and tonsillitis, neoplasms, lingual piercing, foreign bodies, otitis media, peritonsillar abscess, iatrogenic, infectious lesions of the subcutaneous tissue (Staphylococcic infections, suppurated atheroma), superinfected cystic pathology of the thyroglossal tract, general dissemination of the infection, mastoiditis, traumatic penetration of oropharynx, lymphocele [7].

• general factors: systemic illnesses such as diabetes mellitus, mental illness, malnutrition, liver diseases, alcoholism, drug abuse, neutropenia, glomerulonephritis, and a compromised immune system (caused by AIDS, systemic lupus erythematosus, immunosuppression) [3, 8].

2.4 Dissemination routes

Regarding the anatomy of the mandibular alveolar bone, the submandibular space and the roots of the inferior molars that are adjacent, allowing dental infections that develop in the alveolar bone to spread in the submandibular space. The roots are situated below the mylohyoid muscle’s insertion. In fact, this route of transition is the main explanation for the majority of phlegmons.

The spreading of the infection is favored by the natural connection between deep neck spaces. So, the infection can spread directly or in the lymphatic way. Additionally, inflammation spreads in the sublingual region, between the hyoglossus and genioglossus muscles, and involves the mylohyoid muscles area. The inflammation process gains access to the epiglottis in this manner, where it causes edema. The hyoid bone and the mandibular body prevent edema from spreading in other anatomic spaces. The edema and the cellulitis can be transmitted to the deep cervical fascia. The submandibular infection may descend to the mediastinum through the deep cervical fascia. The infection can, albeit less frequently, extend to the carotid, pterygopalatine region or cavernous sinus (Figure 1) [1, 3].

Figure 1.

Odontogenic cervicofacial phlegmons characteristics (personal design and propriety of the authors).

3. Clinical aspects

The classic inflammatory signs are present in the cervicofacial region: rubor, tumor, dolor, calor, function laesa. The first symptoms develop at a high speed and are represented by dental pain, hypersalivation, throat pain and otalgia in the early stages, followed by dysphagia, odynophagia, dysphonia, salivary gland secretion disorders and trismus [9, 10, 11].

3.1 Local examination

The teguments become livid and tense, glossy, few hyperemic areas, with increased consistency and are usually described as “woody”. The area of the neck is firm, edematous, very painful, described as nonfluctuating and without signs of pastiness. Cervical area of the neck is swollen, taking the aspect of” bull neck” and by deformity, the jawline is lost. Double chin aspect is also present as a consequence of the accumulation of the inflammatory exudate in that area. The saliva is drooling, and the patient has difficulty in speaking [12]. Open mouth, mandibular protrusion, and tongue lifted are all symptoms of these patients. Cervicofacial soft tissues may develop subcutaneous emphysema.

The edema is located bilateral and placed above the suprahyoid muscles. The muscle tonus is increased, the area has a nonfluctuating consistency, and the palpation in the affected region is painful. Usually, the patient’s mouth is half open, and the tongue is in an elevated position, in contact with the hard palate, as a consequence of the oral floor edema. The described position of the tongue as superior and posterior can eventually lead to asphyxiation [12, 13].

3.2 General implications

General health status of the patients affected by cervicofacial phlegmons is influenced. In the first stages, the patient can present fever, chills, and general weakness. In a few hours, the symptoms advance in intensity and gravity, with the presence of meningismus, drooling, tachycardia, general agitation, respiratory distress, difficulty breathing, stridor, cyanosis of the teguments and mental alteration status [14]. Patients diagnosed with phlegmon of the oral floor often suffer from dehydration, partially caused by the limitations and pain during dysphagia or as a consequence of the high levels of toxicity in the bloodstream, fact that determines increased sweating and urination, leading to an abnormal general fluid loss [13].

Since hypoxia brought on by obstruction of superior airways is the primary cause of mortality in the first stages of cervicofacial phlegmons, maintaining the permeability of the patient’s airways must be given top attention. The elevation of the oral floor and the posterior positioning of the tongue is a risk of obstruction of the airways. The edema of the epiglottis can also be present and can be a factor that explains the obstruction of the upper airways by blockage.

The edema and the phlegmon pathogens can progress, affecting the parapharyngeal space, and evolving toward the mediastinum, causing severe infections such as mediastinitis, pericarditis, bronchial erosions, and severe heart and pulmonary complications. Strenuous monitoring of the patients is required for any indications of airway blockages, such as stridor and the usage of supplementary breathing muscles. As symptoms worsen, patients may lean forward in the tripoding position in order to maximize the airway diameter. Oxygenation less than 94% associated with clinical signs of airway obstruction are indications for endotracheal intubation, tracheostomy or cricothyroidotomy. The severity of the symptoms requires rapid treatment and admission on ICU [15].

3.3 Complications

General complications can occur at multiple organs, are life-threatening and cand lead to exitus of patients with cervicofacial phlegmons:

• cardiovascular system: endocarditis, pericarditis, abscess of the carotid sheath and jugular thrombophlebitis, hematogenous dissemination to distant organs, coagulation abnormalities ranging from thrombocytopenia to a fulminant state of disseminated intravascular coagulation (DIC)

• respiratory system: pleuropulmonary suppuration, aspiration pneumonia, pneumothorax, descending mediastinitis

• maxillofacial region: necrotizing fasciitis, brain abscess, mandibular or cervical osteomyelitis, cavernous sinus thrombosis, Lemierre’s Syndrome, orbital abcess.

4. Systemic inflammatory response

4.1 Generalities

A systemic inflammatory response from the host is triggered in response to a severe microbial infection of the cervicofacial spaces, as described in the cervicofacial phlegmons. This reaction appears as a response to limit the infection and minimize the general complications. The basic symptoms of this self-defense response that can be observed include fever, tachycardia, tachypnea, and hypotension.

The bacterial activity in the cervicofacial phlegmons leads to significant necrosis of the muscles. Anaerobic organisms are found isolated when the gangrene affects the surrounding soft tissues, as a consequence of the combined action of the hypoxia, released bacterial toxins and the effect of the interstitial pressure. The anaerobic organisms develop even in the soft tissues without gangrene. The tissue is described as being diffuse infiltrated with the presence of neutrophils and dead histiocytes. The presence of leukocytosis is usually described by the involvement of nuclear polymorphic leukocytes [16].

Inflammatory markers evaluated by blood tests are commonly used as objective evaluation parameters both at the admission of the patient, before the surgical and pharmacological treatment and after, in order to assess the gravity of the case and the efficiency of the treatment.

4.2 Immune system cells activity

The immune system, which is a combination of specialized cells that serves as a protective barrier and is made up of an innate system and an acquired system, mediates immunological response. When exposed to an antigen, the innate system launches a general defensive response. On the other hand, the acquired system is an antigen-specific defensive mechanism that has the ability to identify the antigen. As a result, memory cells are developed, and cand recognize and react to an antigen in the event of a new exposure [17].

Leukocytes, which include T, B, and killer lymphocytes, granulocytes, which include neutrophils, basophils, eosinophils, and mast cells; and antigen-presenting cells, which include macrophages, Langerhans cells, and dendritic cells, form the immune system. An immune response to infection is triggered by bacterial invasion. The macrophage is the organism’s initial defense cell. It performs a dual role as an antigen-presenting cell to the neutrophils, who are in charge of bacterial phagocytosis, and as a releaser of chemotactic chemicals that draw them to the site of the lesion. Histamines, bradykinins, cytokines, and prostaglandins are released, which causes vasodilation and the opening of gaps between endothelial cells, enabling plasma to extravagate into the interstitial spaces where it collects and fibrin to develop [18].

Bacterial invasion initiates a series of immunological reactions in order to eradicate the cervicofacial infection. The first fight is a defense process initiated by the macrophage cells. The macrophage has a dual role:

1. releasing chemotactic factors that attract neutrophils to the infection site

2. are an antigen-presenting cell to the neutrophils in order to perform bacterial phagocytosis.

The chemical mediators such as histamines, bradykinins, cytokines and prostaglandins are released. This process causes vasodilatation and widening of spaces between endothelial cells, allowing the plasma extravasation into the interstitial spaces where it accumulates, followed by the development and accumulation of fibrin (Figure 2) [19].

Figure 2.

Steps of the inflammation (personal design and propriety of the authors).

4.3 Systemic inflammatory response syndrome (SIRS)

SIRS is a progressive, pathophysiological process, being the first phase of the systemic host response to odontogenic infections. In the past, the combination of infection and SIRS was defined as sepsis. However, further studies showed that sepsis is not only a pro-inflammatory condition; it may also trigger an early anti-inflammatory reaction in the organism [20].

The reaction of the immune system can be described by two or more of the following conditions:

1. The body temperature under 36.0°C and/or over 38.0°C

2. The heart rate is modified, over 90 beats/minute

3. The respiratory rate is increased, being over 20 breaths/minute or the PaCO2 under 32 mmHg

4. The white blood cell count is over 12,000/cumm, under 4000/cumm, or over 10% immature (band) forms present [21]

5. Inflammatory biomarkers

5.1 Generalities

The commonly used markers for assessing the inflammatory activity of the organisms are the C-reactive protein (CRP), the procalcitonin (PCT), the modified white blood cell count (WBC) and its fractions (neutrophils, lymphocytes and monocytes). However, their values individually cannot determine exactly the severity of the cervicofacial phlegmon cases [22].

5.2 C-reactive protein (CRP)

The C-reactive protein is frequently used as a marker of the presence of inflammation in the organism. Its values are taken into consideration during the diagnosis of head and neck infection detection. However, because it speaks about two days after infection begins, it may not always reflect real-time illness disease [23, 24]. When infection is suspected, CRP is typically evaluated at the time of admission of the patient to the hospital. It can be measured objectively and consistently throughout time. Daily monitoring is more sensitive than body temperature or white blood cell count in the identification of sepsis [25].

Less than 1 mg/L of CRP is considered to be normal. After being stimulated by interleukin-6 (IL-6), its level rises within the first 6 hours and can reach a peak level of around 350–400 mg/L after about 48 hours. Its half-life is between 20 and 24 hours [26].

It is generally accepted that CRP rise in the 10–40 mg/L range is brought on by viral infections and moderate inflammation. CRP levels range from 40 to 200 mg/L when there is active inflammation and bacterial infection. Burns and severe bacterial infections as cervicofacial phlegmons have levels above 200 mg/L.

5.3 Procalcitonin (PCT)

PCT, a precursor of calcitonin, is produced by the thyroid gland’s C-cells. Additionally, PCT is secreted as a result of an immune system response to endotoxins and a mediated response to bacterial infections. For predicting systemic bacterial inflammation, PCT has the best sensitivity and specificity. PCT is considered to have a higher diagnostic value compared to the other traditional tests, among which are the C-reactive protein levels, the white blood cell count, and the levels of interleukin (IL)-6. PCT levels can be used to decide when to start and how long to take antibiotic therapy since they are related to how serious bacterial infections are. In order to swiftly assess a patient’s systemic infection status and begin therapy, PCT analysis may be completed quickly [27].

Serum PCT concentration in healthy individuals is typically <0.1 ng/mL. The absence of bacterial infection is not necessarily indicated by a low or normal PCT content.

This could be the case, notably, during the first stages of bacterial infections or in localized infections. When bacterial infection is present, PCT rises, and the magnitude of the high levels is inversely correlated with the severity of the illness. Patients are more likely to develop a systemic infection if their PCT levels are higher than 0.5 ng/mL. Comparatively to patients with broad sepsis, severe sepsis, and septic shock like patients diagnosed with cervicofacial phlegmons, patients with localized infections have lesser increases in PCT. PCT was confirmed to be a highly accurate test for diagnosing sepsis in patients with maxillofacial infections [20, 27, 28].

5.4 Prepesin (PSEP)

Prepesin represents a specific high-affinity receptor for the lipopolysaccharide (LPS), CD14 being a cell surface antigen cluster marker protein found on neutrophils and monocytes. It is produced by the bone marrow cells and is described as a fragment of CD14. It engages with LPS and then proceeds through a number of signaling pathways and immunological chain reactions. CD14 can be encountered as bound to a membrane CD14 and as a soluble CD14 (sCD14). In case of several pathologies, such as the presence of sepsis, the syndrome of acute respiratory distress, lupus erythematous and the acquired immunodeficiency syndrome, elevated plasmatic concentrations have been reported in case of sCD14 [29].

Although sCD14 functions as a common coreceptor, it is not a specific marker of sepsis on odontogenic infections. Because of this, only the sCD14 subtype, that represents a fragment of CD14 that is released from the bloodstream, with the property of binding to a bacterial pathogen that is related to a specific bacterial infection. It was initially identified during the CD14 reaction, and studies afterward characterized it as a specific marker for the presence of bacterial infections. The epidemiological and molecular aspects of PSEP are still not well understood. The sCD14 subtype levels in the plasma samples were determined using an enzyme immunoassay (EIA), and is known as prepesin [29].

Patients diagnosed with severe cervicofacial phlegmons, the plasma levels of PSEP increase faster than C-reactive protein or procalcitonin levels, the PSEP increased levels can be detected within 4 h of infection. Moreover, the determination time is significantly short (20 min) compared to the other inflammation biomarkers. PSEP can be successfully used for the diagnosis and quantification of the severity of the odontogenic infections and systemic status of the patients. Also, it can be combined with other existing diagnostic approaches for a proper evaluation of the case prognosis.

5.5 White blood cells (WBC)

The white blood cell count (WBC) and its representative fractions (neutrophils, monocytes and lymphocytes) are often used at hospital admission of the patients with cervicofacial phlegmons. However, their determined values alone cannot represent an indicator for the severity of the infection or the prognosis of the odontogenic suppuration cases [30].

6. New prognosis inflammatory indicators

6.1 Systemic immune-inflammation index (SII)

It is a new paraclinical analysis that assesses systemic inflammation and uses the patient’s inflammatory biomarkers. This index is calculated based on the following formula: (N × P)/L (N, P, and L represent neutrophils, platelets, and lymphocytes, respectively)-Figure 3. The SII is a novel inflammatory biomarker that can evaluate the prognosis in a wide range of diseases, including solid malignant tumors, pulmonary embolism, and coronary artery diseases [31]. For SII determination, antecubital venous blood must be collected, and a routine blood examination must be performed immediately after the blood sample is collected. It is a rapid and precise determination, and the results can guide the practician regarding the inflammatory status of the cases.

Figure 3.

SII formula (personal design and propriety of the authors).

The distinctions between the functions of lymphocytes, neutrophils, and platelets throughout the immune response contribute to the usefulness of SII in identifying patients that are more likely to experience severe infections as cervicofacial phlegmons. The only cells in the body that are capable of precisely identifying and detecting various antigens are lymphocytes. They are essential in the majority of chronic inflammatory lesions, particularly in autoimmune disorders and conditions with long-lasting antigens. The most crucial cellular defense against infections is provided by neutrophils, while platelets aid in hemostasis, inflammation, and host defense. With this in mind, SII is able to assess the equilibrium of the host’s inflammatory and immunological condition.

The efficiency of this new index was demonstrated in case of patients diagnosed with cervicofacial phlegmons and other severe odontogenic infections. At the hospital admission of the cases, the calculated SII showed elevated levels that could be correlated with the poor general immune status of the patients. After the surgical treatment of the cervicofacial phlegmons was performed associated with the pharmacological treatment-antibiotherapy, AINS, the SII values decreased significantly [32, 33].

6.2 Neutrophil-Lymphocyte ratio (NLR)

Neutrophil and lymphocyte values are very important for assessing the evolution of cervicofacial phlegmons and for establishing a good prognosis of the cases. A typical reaction to the infectious process of the leucocytes is the increasing values in neutrophils. Compared to other WBC subpopulations, the neutrophil–lymphocyte ratio has a higher sensitivity in detecting the expansion of a systemic infection, being a useful biomarker for sepsis [34].

The NLR formula used for calculation is made by dividing the number of neutrophils by the number of lymphocytes. A normal range of NLR is between 1 and 2. The higher values 3 or smaller than 0.7 in adults are pathological (Figure 4) [35].

Figure 4.

The NLR formula (personal design and propriety of the authors).

The neutrophils involved in the phagocytosis process, which neutralizes the germs involved in the pathogeny of the cervicofacial phlegmons, are activated during the host response to a bacterial infection. Studies show that NLR levels rise in patients with deep neck infections, indicating that it may be a reliable indicator of bacteremia and sepsis.

Assessment of the NLR is a simple, easy, and cost-effective test for the quantification of the inflammatory status and complication risk in the case of neck infections. The NLR values are higher at hospital admission of patients with cervicofacial phlegmons. After a well-conducted surgical treatment of the cervicofacial phlegmons associated with the pharmacological treatment-antibiotherapy, AINS, the NLR values decreased significantly [32].

7. Conclusions

Systemic immune-inflammatory response plays a key role in the cervicofacial phlegmons’ persistence, progression, and aggressiveness. A continuous monitorization of the relevant values of specific blood constituents that are strongly related to the individual response of the host could be the future approach for the management of these types of infections. Calculating and integrating from the beginning the systemic immune-inflammatory index and the presence of other inflammatory biomarkers and their response to the treatment offers a better prognosis for these cases.

Conflict of interest

The authors declare no conflict of interest.