European Review for Medical and Pharmacological Sciences 2010; 14: 1085-1095 Oral inflammatory process and general health Part 1: The focal infection and the oral inflammatory lesion

F. SOMMA*, R. CASTAGNOLA*, D. BOLLINO*, L. MARIGO**

*Section of and **Section of Clinic and Pathology; Department of Odontostomatological Discipline, Catholic University of the Sacred Heart Rome (Italy)

Abstract. – A focal infection is a localized Much researche, sometimes contrasting, has or generalized infection caused by the dissemi- evaluated periodontal pathogens in atheroma- nation of microorganisms or toxic products tous plaques isolated from patients with chronic from a focus of infection in various organic dis- periodontitis. Oral inflammatory lesions have tricts, including the oral district. In the Part 1 of been shown unequivocally to contribute to ele- this two-part review article, after historical vated systemic inflammatory responses. In signs, the Authors describe the current patho- some researches intensive periodontal therapy genic concepts like the “immuno-allergic theo- showed a significant reduction of ry” and the formation of auto- in hu- formula, of CRP levels, of interleukin-6 (IL-6) man body, contributing to the genesis of au- and of LDL cholesterol after two months. toimmune illnesses sustained by individual re- activity linked to eredo-constitutionality. Some Key Words: theories suppose a focal origin even for general Bacteremia, , Focal infection. pathology such as cancer, sarcoidosis, multiple sclerosis, amyotrophic lateral sclerosis, autism, Guillain-Barré syndrome, Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS), Tourette’s syndrome, myasthenia gravis, polycystic kidney Introduction disease, obesity, Alzheimer’s disease and dia- betes mellitus. Laboratory analyses (leucocytic 1 formula, protein electrophoresis, C-reactive pro- In accordance with Easlick , a focus of infec- tein, REUMA test VES, TAS, etc.) are suggestive tion is a confined area that: (1) contains patho- of the presence of an inflammatory process or genic microorganisms, (2) can occur anywhere in of the presence of an aspecific answer to an in- the body and (3) usually causes no clinical mani- flammatory situation. The DNA-Polymerase festations. A focal infection is a localized or gen- Chain Reaction method (PCR) is fundamental for the diagnosis of bacterial and viral infec- eralized infection caused by the dissemination of tions, particularly for those that have non-cul- microorganisms or toxic products from a focus of turable microorganisms or in cases where are infection. present but in extremely small number in the sample to be analyzed. A positive result con- firms the diagnosis, but negative result is not Historical Signs indicator of the absence of illness. Even for oral inflammatory lesions, different basic mecha- nisms concerning the possible association with The first “report” of focal infection has been systemic diseases exist. They concern local ascribed to who attributed the cure spread, metastatic spread or immunologic of a case of arthritis to a tooth extraction. In the cross-reactivity. In this case we assume that early 1800s, Benjamin Rush, an American most of the ailments come from dental or peri- and signer of the Declaration of Inde- odontal foci, as in the bacterial endocarditis, but pendence, also related arthritis cure to tooth ex- instead of considering them as possible patho- 2 genetic mechanism of an immune nature, we traction . consider them as originated by the body’s re- In 1890, the dentist and physician, WD Miller, sponse to the presence of bacterial published his treatise: “The Micro-Organisms of through the formation of specific antibodies. the Human : The Local and General Dis-

Corresponding Author: Luca Marigo, DDS; e-mail: [email protected] 1085 F. Somma, R. Castagnola, D. Bollino, L. Marigo eases Which are Caused By Them” and a year and consequently, the theory of focal infection later in Dental Cosmos first used the term: “focal was vigorously taught, citing infected teeth or infection”. their surrounding structures as being responsible In 1900, the English physician, William Hunter, for a wide range of diseases14. reported in the British Medical Journal on “ Since 1930 researchers began to question the as a Cause of Disease” listing poor oral health and evidence supporting the , the expanding use of ‘conservative dentistry’ (the despite review articles upholding its claims15. preservation of the dentition by dental treatment) Some Authors16,17 started to closely analyze as a cause of the multitude of diseases attributed to heart disease, considerate the only apparent iden- focal infection: he theorized that the microorgan- tifiable form of a focal infection and elective lo- isms presented in the oral cavity were able to dif- calization from dental origin. fuse throughout the whole organism, with conse- Reimann and Havens18 concluded that “the re- quent possible systemic illness. moval of local infections in the hope of influenc- From 1910 to 1940, the medical and dental lit- ing remote or general symptoms and disease erature contained several references to re- must still be regarded as an experimental proce- searcher’s focal infections of dental origin and of dure not devoid of hazard”. the idea that efforts were instrumental in gaining Similarly while Slocumb et al19, even if they the medical profession’s broad acceptance a lo- continued to support the concept of focal infec- calized, low grade chronic infection could pro- tion, particularly in relation to specific clinical duce disease elsewhere in the body. entities including heart disease, chronic infec- Other published articles3,4 claimed a clearly tious arthritis and glomerulonephritis, they defined link between infective rheumatoid arthri- thought accepted that a more logical and scientif- tis and foci of infection, with oral sepsis cited as ic approach to focal infection should be adopted. a main contributing origin. Billings4 declared Lazansky et al20 recorde large variations in the “when the focal infection, wheresoever it may be frequency of bacteremia following dental extrac- located, seems to be related to the systemic dis- tions, ranging from 34 to 100%, depending on ease, radical measures should be instituted to re- the different techniques employed at the time of move it”. extraction. Mayo5 concluded that “root and pus In a critical appraisal reviewing the relation- pockets connecting with them are often the ship between focal infection and rheumatoid dis- source of acute and chronic rheumatism”. ease, Freyberg21 postulated that removal of foci Afterwards, other researches6-8 supported the of infection should only be part of a broad spec- hypothesis that systemic diffusion of microor- trum of treatment and in chronic cases removal ganisms and their toxins from a focus infection of these foci would be of little benefit. in a determinate tissue, was able to originate or In the sixties, the critical review of focal infec- to increase a general illness and/or damage a dis- tion continued thanks to Easlick1 and Mitchell tant tissue. and Helman22 who brought into question the pre- Initially, only a few expressed some cise connection between dental foci and systemic doubts9. diseases. Several Authors10,11 regarded all pulpless teeth All this scientific diatribes created doubts as probable foci of infection and conciuded that among researchers and motivated them to im- the extraction of teeth in several individuals im- prove the quality of the research about this issue, proved their various medical conditions or centralizing the attention on the relationship be- pathologies as . tween bacteremia and endodontic procedures. According to this point of view, a research of Kennedy et al23 showed that bacteremia could oc- Shandalow12 revealed that the primary infective cur in monkeys after the introduction of Strepto- agent in rheumatoid sufferers was apparently the coccus haemolyticus into the root canal. Other organism which was prevalent in oral activities were also demonstrated to produce the oral tissues. Rhein et al13 suggested that the a bacteremia, including chewing24, periodontal extraction of healthy teeth was justifiable in the scaling25,26, tooth brushing27, oral prophylaxis28, prevention of focal infection. dental flossing29 and the removal of osteosynthe- These early papers promoted the ritual of sis plates30. In reguard to possible problems with wholesale dental extractions and the laboratory methodologies technics used in as the complete cure for many systemic ailments, scientific study Rogosa et al31 pointed out the

1086 Oral inflammatory process and general health, Part 1 sole use of aerobic culturing techniques was an apical granuloma, tonsillar and , inadequate environment for the growth of all mi- sensitize the predisposed organism and provoke al- croorganisms originating within the oral cavity lergic-hiperergic reactions in secondary organs and that in order to detect a broader range of mi- during successive insertion in the blood stream. croorganisms, better anaerobic techniques would “Neurotrophic theory” of Speransky: dental have to be employed. foci are starting point of neurotoxic stimuli More recently there has been a renewed inter- which irritate the neurovegetative system and est on the influence that the focus of infection provoke neurodystrofic alterations of organs far has on the general health. A current thesis sug- from dental apparatus. When secondary dystrofic gests a possible relationship between dental stimulus is activated, it becomes independent health and cardiovascular illness, while many from the initial provoking stimulus and does not published case reports have pointed to an indi- regress when the original focus is removed. vidual’s dental sources as the causes of many The above-mentioned theories can coexist and systemic illnesses32. complete among themselves: a toxic-infective According to the recent WHO Oral Health Re- genesis indeed can integrate with allergic aware- port33, caries, despite of all efforts and measures ness that can have an impact on an altered ex- undertaken to control the disease, is still identifi- citability of the neurovegetative system. able as a continuing global health care problem. The focal disease is due to an immune patho- The consequence of caries are not limited to the genic mechanism according to a new theory for- destruction of tooth substance that results in mulated during recent decades. needs for dental restoratives, crown and bridge- works as well as implants in case of tooth loss. Caries, if left untreated, also causes inflammato- Current Pathogenic Concepts ry conditions and infectious processes of the den- tal pulp and the tissues surrounding the involved The immuno-allergic theory supporting focus tooth. The sequel to infectious pulpitis, namely explains auto antibodies formation in human body, apical periodontitis, must be regarded the more contributing to the genesis of autoimmune illness- severe disease condition from a general health es sustained by individual reactivity linked to ere- care perspective34. do-constitutionality (biological substratum geneti- cally predisposed). A series of antigens that are unrecognized by the orgamism as it’s own are re- Pathogenesis leased in the affected zone wich leads to the for- mation of antibodies. The antibodies react with the In accordance with traditionalist medicine, an antigens, and form a series of - organ is able to develop a focal role when it is af- complexes; the complexes precipitate in some tar- flicted with an inflammatory chronic process on get organs determining the activation of the com- infectious base. plement and an inflammatory chronic process and the consequent damage to those organs. Previous Pathogenetic Conceptions The focal disease can therefore been consid- The “toxic-infective theory” of Rosenow, the ered as a pathological autoimmune process, that “allergic theory” of Berger and the “neurotrophic causes the alteration of an organ that is defined theory” of Speransky have to be mentioned the “target”. The alteration is caused by the un- among several formulated theories. balance of another organ that is defined as the “Toxic-infective theory” of Rosenow: focal “focal organ”. The most common centers of fo- pathology is due to the passage of germs and tox- cus of infection have been considered to be ton- ins from the focus to the blood stream and to sils, adenoids, sinuses and oral cavity, with the their elective localization in some organs (articu- less common foci have been considered to be lation, eyes, kidneys, heart, skin) through an prostate, appendix, gallbladder and kidney35. organotropism process or an “anacoresis” phe- The most important chronic infective dental nomenon for which septic inactive foci can cap- and periodontal foci are apical granuloma, peri- ture circulating germs from the blood and so be- odontal affections (pockets and deep bone le- come acute or active. sions), chronic apical osteitis, pulpal necrosis and “Allergic theory” of Berger: bacterial toxins, , incomplete canal therapy on devital- coming from chronic inflammated areas, such as ized teeth and radicular cysts.

1087 F. Somma, R. Castagnola, D. Bollino, L. Marigo

The systems and the organic apparatuses in- Ig blood. The diagnosis of suspicious pathology volved as target organs are manifold: we remem- from focal stimuluses make use of a series of ber the locomotor system (rheumatoid arthritis, clinical examinations. It is essential to do in- myositis, myalgia), the nervous system (neural- spections of specific lesions in the oral cavity gias, neuritides), the cardiovascular system (my- such as gengivitis, periodontitis, alveolar ab- ocarditis, endocarditis, pericarditis, throm- scess and fistulas. Thermal tests are performed bophlebitis), the excretory system (nephritis, ure- for the evaluation of the pulpal vitality of the thritis, cystitis), the ocular system (uveitis, con- teeth and percussion and mastication tests can be junctivitis, keratitis, ulcer of the cornea, optic iri- indicative of the passage of pathogenic germs tis, choroiditis, neuritis), the dermatologic system and bacterial toxins from the periapical region to (knotty erythema), the hematic system (primitive the systemic circulation, causing the exacerba- and secondary anaemias) and the digestive sys- tions of the secondary clinical manifestations tem (subacute and chronic , peptic gastric (diagnosis ex adiuvantibus). Moreover radiolog- ulcer, duodenal ulcer, appendicitis and gallblad- ical investigations (ortopantomography and en- der). A focal origin is hypothesized even for gen- doral periapical radiography) are used for the eral pathology as cancer36,37, sarcoidosis, multiple evaluation of endo-perio-apical anatomical le- sclerosis, amyotrophic lateral sclerosis, autism, sions and for previous endodontic therapies (in- the Guillain-Barré syndrome, Pediatric Autoim- complete therapies, fragments of tools or diffu- mune Neuropsychiatric Disorders Associated sion over apex of materials of closing). with Streptococcal infections (PANDAS), the Tourette’s syndrome, myasthenia gravis, polycys- tic kidney disease, obesity, Alzheimer’s disease Laboratory Examinations and mellitus diabetes38. In clinical medicine these disorders are often found to occur contemporane- Laboratory examinations have a fundamental ously with septic focuses of the oral cavity such role in diagnosis. as chronic infections of the pulp and the peri- The hemochrome examination is usefull in or- odontium, chronic osteitis and of der to appraise the leucocytic formula. The ab- the maxillary, cysts and granulomas understood solute number and the percentage of all of five as pathogenic noxae. types of specific cells: neutrophils, eosinophils, basophils, and monocytes are a pa- rameters of specific interest. Neutrophils that de- Diagnosis fend the organism from the infection caused by bacteria, contain different chemical proteins and The issue of metafocal pathology is controver- substances that irreversibly damage the mem- sial, because the clinic observations indicate long branes of the pathogenic microorganisms. oral infections are accompanied rarely by sec- Eosinophils have the principal function of de- ondary diseases of other distant organs and be- fending the organism to several kind of parasites cause in several secondary infections with sus- and their number also increases in the allergic ill- pect focal origin, the careful removal of all po- nesses and they are accountable for some typical tential foci is not followed by the healing of the symptoms of these illnesses. The function of the infection. basophils is not well known, although their num- The diagnostic criteria are all based on ele- ber increase in the allergies. They contain hista- ments of presumption, which may be of clinical mine that, when released in excess in the blood nature, bacteriological or immunological. Typi- and in tissues, provokes itching or the appearance cally, the clinician is suspicious when recog- of cutaneous rash. Lymphocytes are appraised nized tipical features, such as a tendency to be- generically to be one class, but include different come chronic, easy to relapse, insensitivity to subtypes, mainly B and T lymphocytes. The B specific therapies, a secondary aggravation of lymphocytes are responsible for humoral immu- the disease in distant organs during an inflam- nity and they produce immunoglobulins (anti- matory re-ignition of outbreaks of oro-dental (ex bodies), while the T lymphocytes are responsible nocentibus criterion) as well as the disappear- for the immune cellular-mediated overall re- ance or improvement of focal disease after the sponse against viral infections. Lymphocytes are removal of the targeted or accidental focus (ex basically able to recognize extraneous or not-self adiuvantibus criterion) and, finally, high titers of cells as in case of rejection of the transplants. Fi-

1088 Oral inflammatory process and general health, Part 1 nally, monocytes (M), are phagocytary cells. the presence of substances during the infections They are important in the defence of the organ- from β-haemolytic streptococcus of the A, C ism against many types of bacteria and they help and G group. The antistaphylolysinic titer (AS- the neutrophils. TAT) indicates the staphylococcic lysines, solu- Protein electrophoresis evaluate the proteins ble substances produced by pathogenic logs content in the serum. The liver produces the (the most important are the lysines a and b). greatest part of these proteins, which are re- The antistreptohyaluronidasic title (AH) indi- leased in the blood to cells of the immune sys- cates the titer hyaluronidase, an enzyme secret- tem. Their presence constitutes a sure index in ed by any types of β-haemolytic streptococcus an elevated number of pathology and during of A, B, C, G group and that is important to the electrophoresis they are categorized by per cent diffusion of the microorganism in the tissues. age and divided in to their subtypes: albumins, The gammaglutamiltranspeptidase (Gamma- α1-globulins, α2-globulins, β-globulins and γ- GT) are enzymes localized in many organs such globulins. During the acute phase, aptoglobulin as kidney, pancreas, , heart and, above (n.v. 30-160 mg/100 ml) (α2-globulin), cerulo- all, liver and learned bilious. Although in renal plasmin (n.v. 30-40 mg/100 ml) (α2-globulin) tubular cells they are contained twelve times and C factor (β2-globulin) have been found. more than in the liver, the clinical application During inflammation their counts increase. of their dosing is almost exclusively limited to The separation of plasmatic proteins in to the liver, bilious tree and cardiac illnesses. It the counts of immunoglobulins, idendifies the has usually been considered a very important proteins that possess antibody activity. These indicator of cholestasis (with the alkaline phos- are separated in to antigenic subgroups, indi- phatase) to control hepatopathy (acute hepati- cated as immunoglobulins of types G, A, M, D tis), or the heart attack (in the 50% of the cases and E. IgG are usually present in the plasma the increase of its value begins on the four or and they direct their antibody activity mainly fifth day). toward soluble antigens as bacterial toxins. During particular therapies (such as barbitu- IgA are present primarily in the secretions of rates), or after alcohol use or abuse, lactic-de- apparatuses and act against the infectious hydrogenase (LDH) catalyzes the oxidation of agents of respiratory apparatus. IgM are pre- the lactic acid to pyruvic acid. Its anomalous sent primarily in the plasma and inactivate ex- presence does not discriminate pathology of a traneous substances to the organism and cor- specific tissue, being representative of a class puscular antigens. IgD are represented in small of five isoenzymes, but constitutes a marker of number and we don’t know their functions. IgE cellular suffering. The reuma test or factor act in all allergic manifestations. rheumatism (FR) indicates the presence in the The C-reactive protein is a glycoprotein. Its serum of M type immunoglobulins versus hu- count increases in all cases of inflammatory man G type immunoglobulins. It is not a specif- problems. It is not modified by the state of preg- ic test for the diagnosis of rheumatoid arthritis nancy, by anemia or altered eritrocitary values and is often in association with the Waleer (hyperglobulinemias). It is more sensitive than Rose, a reaction of emoagglutination to indi- the erythrosedimentation rate (ESR), but above cate the rheumatoid factors. The system of all it is more specific. It is found in autoimmune complement consist of proteins of the immune pathology, bacterial and infections, tissutal system, it is activated after bacterial infections necrosis and neoplasias. or inflammations. Its fundamental is to protect All these data are undoubtedly useful, but the organism purpose by removing of patho- have limits because some conditions cause an genic agents (bacteria and ), facilitating increase in the levels of the proteins of the acute their elimination or their control trough biolog- phase (false positiveness). The ESR increases in ical systems like serum or the cellular system. the infectious illnesses. The antistreptolysinic The C3 fraction of complement is activated titre (AST) indicates antistreptolysin presence when the organism recognizes the presence of in circle. It usually constitutes a consequence of bacterial cells or immunocomplex. The pharyn- a β-haemolytic streptococcus of A group infec- geal tampon and the cultivation examination of tion: its presence is an indicator of an antigenic the urines for the confirmation or the exclusion stimulus and of a persistence of bacterial focali- of other active sites complete the aforemen- ty. The antistreptokinasic titer (ASKT) indicates tioned tests.

1089 F. Somma, R. Castagnola, D. Bollino, L. Marigo

The DNA-Polymerase Chain Reaction (PCR) Metastatic Spread is a process through which a specific sequence of One of the facets of microbial metastasis that nucleic acid can be amplified exponentially in is often unappreciated is that microorganisms ex- vitro. This amplification pratically replaces the pend much of their time and energy locating, de- biological one obtained with traditional culture veloping and defending biological niches in methods. There are several applications of this which they can prosper. Microbes require very technique such as the clinical diagnosis of dis- specific growth nutrients, favorable local envi- eases caused by mutations, the determination of ronments (i.e. pH) and safety from their enemies: chromosomal translocations associated with on- other bacteria and and natural host de- set of cancer and the study of resistance. It is fenses. This is the reason for biofilms. To survive fundamental for the diagnosis of bacterial and vi- and thrive, microbes have learned to avoid hostile ral infections, particularly for those associated regions of the body. with non-culturable microorganisms or in case Even the most ubiquitous of human pathogens where the microorganism are present, but in ex- (streptococci and staphylococci) may only be tremely small numbers, in the sample to be anal- such because they possess elaborate adhesive ized. With PCR method is possible amplify the properties that allow them to attach to the body nucleic acid to produce a sufficient quantity to surface (skin and mucosa). Streptococcus pneu- detect and identify the type of organism present. moniae is abundant in the , sinuses and Much researches, sometimes contrasting, have lower respiratory tract but has never been isolat- evaluated periodontal pathogens in atheromatous ed from an oral cavity only inches away. For plaques isolated from patients with chronic peri- some reason the oral environment is very inhos- odontitis. Dental plaque was taken from pockets, pitable to the pneumococcus. bacteria were isolated, placed in culture and ana- The periodontal pathogens, Prevotella and lyzed by the PCR method and the same proce- Porphyromonas, are only located in the oral cavi- dure was done for carotid atheromatous39,40. ty and the genitourinary tract. Laboratory analyses are suggestive of the pres- Actinobacillus actinomycetemcomitans has on- ence of an inflammatory process or of the pres- ly one biological niche: the oral cavity. ence of aspecific response to an inflammatory It is also imperative to distinguish between situation. A positive result confirms the diagno- metastatic infections that merely reflect the typi- sis, but a negative result is not indicator of the cal pathology produced by the microorganism absence of the illness. but in a different place (a streptococcal-induced According to Idikó et al34 there are different liver ) and non-typical pathology as seen basic mechanisms that can account for a possible with cancer and various autoimmune disorders association between oral inflammatory lesions resulting from antigenic mimicry: microbical and systemic diseases. antigens similar to the host antigens induces an immune reaction, that damages the same host tis- Local Spread of Oral Inflammatory Lesions sue42. The acute infection of the oral cavity, includ- ing periapical lesions, may result in complica- Metastatic Infection I tions characterized by per continuitatem exten- Hematogenous spread of oral microbes to tis- sion of the local infection towards adjacent tis- sue surfaces of remote organs. sues and organs. Purulent discharge may pene- Transient bacteremia is a well-known conse- trate the oral mucous membranes and the skin re- quence of invasive professional dental treat- sulting in sinus tract or fistula formation. The ments, including endodontic instrumentation ap- progression of bacterial infection may take a proaching beyond the tooth apex and periapical more generalized form involving the paranasal surgery43,44, but there is a wide variation in re- sinuses, the bones of the skull, the eye, the brain, ported frequencies of bacteremia in patients re- the preformed soft tissue planes and spaces sulting from dental procedures: tooth extraction around the pharynx and the mediastinum. Severe, (10-100%), periodontal surgery (36-88%), scal- even life-threatening diseases, such as orofacial ing and root planing (8-80%), teeth cleaning (up abscesses, cellulitis, deep cervical infections, me- to 40%), rubber dam matrix/wedge placement (9- diastinitis41, cavernous sinus thrombosis, acute 32%) and endodontic procedures (up to 20%)45. osteomyelitis, requiring immediate surgical inter- Transient bacteremia also occurs frequently dur- ventions and therapy may develop. ing routine daily activities unrelated to a dental

1090 Oral inflammatory process and general health, Part 1 procedure: tooth brushing and flossing (20-68%), ganisms present within the associated bacter- use of wooden toothpicks (20-40%), use of water aemia were anaerobes55, (2) using SDS-PAGE irrigation devices (7-50%) and chewing food (7- electrophoresis they established that the organ- 51%)46. isms in an endodontic-related bacteraemia were The extent and the duration of bacteremia are identical to those arising from within the root related to the aggressivity and duration of the in- canal44, (3) the same results were repeated with tervention, as well as to the number of bacteria ribotyping using a DNA hybridization method56 inhabiting the area of the procedure. and then using both phenotype and genetic meth- In particular the magnitude of bacteremia re- ods57. An other paper, where there was an inten- sulting from a dental procedure is relatively low, tional instrumentation through the apex, reports is similar to that resulting from routine daily ac- that bacteremias occurred with an incidence of tivities47,48 and is less then that used to cause ex- 31 to 54% and biochemical tests and antibi- perimental (i.e. in animals) effects. Although the ograms revealed that the bacterials isolated from infective dose required to cause i.e. in humans is the root canal and from blood had identical pro- unknown, the number of microorganisms in files within the patients, strongly suggesting that blood after a dental procedure or associated with the microorganisms isolated from the blood had daily activities is low. the root canal as their source58. The role of duration of bacteremia on the risk In conclusion all these studies, although they of acquisition of focal infection is uncertain. were based on a small sample group, showed far More recent studies support these data, but report greater bacteraemias resulting from root canal a small percentage of positive blood cultures treatment procedures then data produced in the from 30 to 60 minutes after tooth extraction48-50. past, as a result of the more sensitive culturing Intuitively, it seems logical to assume that the and identification techniques applied. Since it longer the duration of bacteremia, the greater the may not be technically determined if instrumen- risk of focal infection, but no published studies tation has occurred beyond the apex, an antibiot- support this assumption. Few results exist that ic prophylaxis for the prevention of the endo- show the incidence or magnitude of “sponta- carditis is recommended, especially for patients neous bacteremias” from infected root canals at risk59. with chronic periradicular lesions or with acute However, the colonization of the endocardial periodontal abscesses46 and of “provokes bac- layer and destruction of heart tissues, such as teremias”. In their studies Baumgartner et al51,52 valves, by oral bacteria is a rare complication demonstrated that nonsurgical root canal treat- that occurs only in a selected group of patients at ment resulted in a much lower bacteraemia inci- risk, carriers of previous cardiac valvular lesions, dence (3.3%: as a result of over-instrumentation), congenital or acquired. These lesions make pos- than surgical flap reflection (83.3%), periradicu- sible the settlement and colonization by bacteria lar curettage (33.3%) or tooth extraction (100%). in circulation, thus giving rise to a process of Bender et al53 have developed a study to measure bacterial or infective endocarditis. Other cate- bacteraemia subsequent . The gories of people at risk of this serious disease Authors found a misure of 0% (if the instrumen- that is still characterized by a high mortality rate tation remained within the canal) and 15% inci- despite the remarkable success of antibiotic ther- dence of bacteremia (if it extended beyond the apy, are patients with immunodifensive cellular apex). The postoperative bacteraemia following and humoral mechanisms, those being treated endodontic procedures was shown to last no with steroids, cytostatics or immunosuppressive longer than 10 min54, the microorganisms within drugs, as well as those who have undergone re- the circulation being cleared by ini- cent cardiac surgery. tially and then by the reticuloendothelial system. Debelian et al43 in 1992 published further evi- Metastatic infection II dence that a bacteraemia occurred if root canal Intracellular invasion. Repeated identifica- instrumentation was carried beyond the apex, and tion of Chlamydia pneumoniae, Helicobacter the most likely bacteria involved were anaerobic pylori and human Cytomegalovirus (CMV) in types. In other following works same Authors, atheromatous lesions, as well as demonstration besides, showed that (1) a bacteraemia could oc- of elevated antibody titers to these microorgan- cur even if instrumentation was maintained with- isms suggest that a direct infection of endothelial in the root canal and that the most common or- cells may be responsible for the genesis of ather-

1091 F. Somma, R. Castagnola, D. Bollino, L. Marigo osclerotic lesions in some patients60. Moreover, response in remote organs induced by oral infec- DNA of periodontopathic/endodontopathic bac- tions. In the context of , we al- teria were repeatedly recovered from atheroscle- so consider the case of bacterial proteins mole- rotic lesions61. cules with sequence homology of human regula- tory molecules. A heptamer amino acid sequence Metastatic Infection III of an outer membrane-associated protein of the Airways may be inoculated by pathogenic oral pathogen Streptococcus sanguis was shown bacteria originating from the oral cavity. Bacteria to be identical to the platelet-interactive domain recovered from patients with aspiration pneumo- of type I and III collagens equipping the microbe nia were shown to be either part of the indige- with a potential for inducing platelet aggregation, nous oral microflora or nosocomially acquired an event that has been shown to contribute to pathogens62. DNA genomic analysis demonstrat- vascular plaque development65. ed that an identical microbial strain was isolated from oropharyngeal or gastric samples and bronchial samples of the majority of patients63. Soluble Immune-Inflammatory Mediators Soluble immune-inflammatory mediators may elicit systemic effects. Immunity Oral inflammatory lesions, elicited by patho- genic microorganisms, are connected with the Molecular Mimicry production and release of soluble regulatory Immunologic cross-reactivity. Pathological compounds amplifying the consequences of lo- immunoreactions and inflammatory processes cal cell-to-cell interactions, and mediating in- play a fundamental role in the pathogenesis of flammatory reactions to remote tissues and or- metafocal diseases. In this case, we assume most gans. Detection of biochemical markers of a of the ailments do not have a direct dependence chronic low-grade inflammation has repeatedly from dental or periodontal foci, but rather are been reported in patients with cardiovascular pathogenetic mechanisms of an immune nature. diseases66. Moreover, C-reactive protein (CRP), They originate as a lively body’s response to the as a sensitive marker of inflammation has been presence of bacterial antigens through the forma- shown to predict future risk of cardiovascular tion of specific antibodies. The continued pro- diseases in initially healthy individuals67. Oral duction of antigens by the chronic outbreak leads inflammatory lesions have been shown unequiv- to the synthesis of immune complexes, i.e. anti- ocally to contribute to elevated systemic inflam- gen-antibody complexes, both locally and within matory responses68. D’Aiuto et al69 reported da- the general circulation. These immune complex- ta on the effect of periodontal standard therapy es can settle anywhere in the organs with vascu- vs aggressive therapy after six months. The in- lar structures in the filter, such as, for example, tensive therapy group showed a significant re- the synovial joint, the choroid of the eye, the kid- duction of lymphocyte count, of CRP levels, of ney glomerulus, the skin tissues, etc. We do not interleukin-6 (IL-6) and of LDL cholesterol af- excluded, as part of this mechanism, a massive ter two months. cell-mediated immunity, i.e. immunoreactions delayed hypersensitivity of type IV, these are Soluble Mediators I considered responsible for the direct cytotoxic Bacterial toxins. The anaerobic Gram-nega- effects (cytotoxic T lymphocytes), the release of tive bacteria constitute the majority of the mi- a series of numbers of lymphokines, and finally croflora present in polymicrobial oral infec- the attraction and activation of mononuclear cells tions, especially in the contents of septic necrot- (macrophages). -mediated injury of cardiac ic root canals and periodontal pockets. They myocytes in Chlamydia infections was proven to contain bacterial endotoxins, which are chemi- be initiated through antigenic mimicry between cally defined as lipopolysaccharide (LPS). the bacterial 60 kDa cystein-rich outer membrane Among the soluble factors, these are probably protein and M7Aα, the dominant autoaggressive the most powerful and most studied components epitope of the cardiac-specific α myosin heavy involved in the systemic inflammatory response. chain molecule64. Experimental observations sug- The LPS, present in dental plaque and infected gested that a similar mechanism may explain root canal, can penetrate the gingiva and the pe- host tissue damage or an inflammatory type of riapical area in high concentration70. These par-

1092 Oral inflammatory process and general health, Part 1 ticular toxic substances are considered to be re- 4) BILLINGS F. Chronic focal infection as a causative sponsible for systemic diseases, trigeminal neu- factor in chronic arthritis. JAMA 1913; 61: 819- ralgia and atypical facial neuralgia. They are a 822. potent vasodilator and also possess an action 5) MAYO CH. Mouth infection as a source of systemic detrimental to the PMN, preventing chemotactic disease. JAMA 1914; 63: 2025-2026. activity and phagocytosis. Biological activity is 6) DAVIS DJ. Bacteriological and experimental obser- explained by the production of an array of vations on focal infections. Arch Intern Med 1912; proinflammatory and chemotactic cytokines in- 9: 505-514. cluding granulocyte-macrophage colony-stimu- 7) DALAND J. Focal sepsis. New York Med J 1916; lating factor (GM-CSF), interferon (IFN)-γ, in- 103: 1159-1160. α β terleukin (IL)-1 and - , IL-6, -8, monocyte 8) ROSENOW EC. The relation of dental infection to chemoattractant protein-1 (MCP-1) and tumor systemic disease. Dental Cosmos 1917; 59: 485- necrosis factor (TNF)-α71. 491.

The proinflammatory and procoagulant state, 9) HOWE PR. To what degree are oral pathological as well as the endothelial dysfunction elicited by conditions responsible for systemic disease? LPS may contribute to atherogenesis. CMV and Dental Cosmos 1919; 61: 33-40. Epstein–Barr virus (EBV) infections, which have 10) RHOADS PS, DICK GF. Roentgenographically nega- recently been implicated in the development of tive pulpless teeth as foci of infection: results of root canal and periapical lesions, also can induce quantitative cultures. J Am Dent Assoc 1923; 157: inflammatory and chemotactic cytokines72. The 1884-1893. deleterious effects of CMV and EBV on the vas- 11) CECIL RL, ANGEVINE MD. Clinical and experimental cular endothelium adds to that produced from the observations on focal infection with an analysis of LPS73,74. 200 cases of rheumatoid arthritis. Ann Intern Med 1938; 12: 577-584.

Soluble Mediators II 12) SHANDALOW SL. Oral focal sepsis in relation to Host compounds. The most studied chain of systemic disease. Dental Cosmos 1928; 70: events is represented by the oral inflammatory 609-618. lesion → (LPS) → IL-1/IL-6/TNF-α → liv- 13) RHEIN ML, KRASNOW F, G IES W. A prolonged study of er positive acute phase proteins/coagulation fac- the electrical treatment of dental focal infections a tors target organ axis. Positive acute phase pro- preliminary report. Dental Cosmos 1926; 68: 971- teins, including certain coagulation factors, such 981. as fibrinogen, are synthesized by hepatocytes in 14) HOLMAN WL. Focal infection and elective localiza- response to IL-1, -6, and TNF-α75. tion. Arch Pathol and Lab Med 1928; 5: 68-136. 15) VALENTINE E, VAN METER M. The localization of Common Etiopathogenic Factors streptococci in the tissues of rabbits. J Infect Dis There are well-defined patient-related and en- 1930; 47: 56-82. vironmental risk factors, such as age, smoking, 16) JONES NW, NEWSOM SJ. Experimentally produced diabetes, socio-economic status and lifestyle that focal infection in relation to cardiac structure. Arch are common in certain oral inflammatory dis- Pathol 1931; 13: 392-414. eases and systemic diseases. 17) ABRAHAMSON L. Subacute bacterial endocarditis following removal of septic foci. Br Med J 1931; 2: 8-9.

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