Cervicofacial actinomycosis

INTRODUCTION — Cervicofacial actinomycosis is a chronic disease characterized by abscess formation, draining sinus tracts, fistulae, and tissue fibrosis. It can mimic a number of other conditions, particularly malignancy and granulomatous disease, and should be included in the differential diagnosis of any soft tissue swelling in the head and neck. Cervicofacial involvement is the most common manifestation of actinomycosis, accounting for 50 percent of all cases, while central nervous system, thoracic, abdominal, and pelvic actinomycosis occur less frequently [1,2].

Cervicofacial actinomycosis will be reviewed here. Ileocecal actinomycosis and actinomycosis related to intrauterine devices are discussed separately. (See "Abdominal actinomycosis" and "Intrauterine contraception: Candidates and device selection".)

MICROBIOLOGY — Cervicofacial actinomycosis is caused by branching gram-positive bacteria belonging to the order Actinomycetales, family Actinomycetaceae, genus Actinomyces [3]. Of note, both Mycobacteria and Nocardia species also belong to the same order, and infections caused by these microbes may at times be difficult to distinguish from Actinomyces [3]. Actinomycosis was originally described in 1878 by Israel [4] and later by Wolfe [5], who isolated the causative organism and defined its anaerobic nature [6].

Actinomyces are non-spore-forming, strict or facultative anaerobes with a variable cellular morphology, ranging from diphtheroidal to coccoid filaments (picture 1). They are normal constituents of the oral flora within gingival crevices and tonsillar crypts and are particularly prevalent in periodontal pockets, dental plaques, and on carious teeth [3]. (See "Deep neck space infections in adults".)

Distinguishing features from fungi — The name actinomycosis literally translates as "ray fungus" and reflects its filamentous, fungal-like characteristic appearance in infected tissues. However, Actinomyces are true bacteria with filaments much narrower than fungal hyphae. While actinomycotic filaments readily fragment into bacillary forms, tubular hyphae of molds never fragment and exhibit distinct branching patterns. Another distinguishing feature between actinomyces and fungi is the method of reproduction, which occurs by binary fission in Actinomyces and not by spore formation or budding as in fungi [3].

Growth characteristics — Actinomyces are fastidious organisms that require an enriched medium (such as brain-heart infusion broth) for growth. Incubation at 37ºC with 6 to 10 percent carbon dioxide provides for optimal growth conditions. Given their slow-growing nature, cultures should be observed for at least 14 to 21 days to allow adequate detection [6]; this should be specifically requested of the clinical microbiology laboratory if Actinomyces are suspected.

Infecting species — Human actinomycosis is primarily caused by Actinomyces israelii. With improved microbiologic detection methods including molecular techniques, several novel species including Actinomyces neuii and Actinomyces meyeri are increasingly recognized in human infections [2]. At least 49 different Actinomyces species have been described [7], of which more than 26 have been associated with disease in humans, including A. odontolyticus, A. naeslundii, A. meyeri, A. viscosus, A. funkei, A. gerencseriae, A. pyogenes, A. urogenitalis, A. georgiae, and A. graevenitzii [6,8-11]. Other implicated species include Propionibacterium propionicus (formerly Arachnia propionicus) as well as the coryneform bacteria, Actinomyces neuii, A. radingae, and A. turicensis [6,12]. Actinomyces bovis causes the disease known as "lumpy jaw" in cattle but does not cause disease in humans [13].

Coinfecting organisms — Actinomyces are almost invariably isolated as part of a polymicrobial flora. In one study of more than 650 cases of actinomycosis, Actinomyces were not isolated in pure culture in a single case [14]. Aggregatibacter (Actinobacillus) actinomycetemcomitans and Haemophilus aphrophilus were the most common co-isolates in this study. Other bacteria frequently isolated along with Actinomyces include Eikenella corrodens, Fusobacterium, Bacteroides, Capnocytophaga, Staphylococcus, Streptococcus, and Enterococcus [6,15]. However, the significance of these coexisting bacteria in the pathogenesis of actinomycosis remains unclear [16].

Sulfur granules — Actinomyces are noted for forming characteristic sulfur granules in infected tissue but not in vitro. The term "sulfur granule" is a misnomer, reflecting only the yellow color of the granule in pus, since they are not composed of any sulfur at all. The granules are actually discrete macroscopic grains of hard consistency, 100 to 1000 mcm in diameter, often visible to the naked eye or by microscopy with low magnification (10x) (picture 2). They are composed of an internal tangle of mycelial fragments and a rosette of peripheral clubs.

The granule is stabilized by a protein-polysaccharide complex and mineralized by host calcium phosphate [3]. Some authors suggest that the protein-polysaccharide complex provides a mechanism of resistance to host phagocytic activity. Filaments within a granule are often seen by Gram or silver methenamine stain, though more calcified granules may be difficult to identify [17,18].

Similar granules may be formed by other microorganisms, notably Nocardia brasiliensis and Streptomyces madurae (both can cause mycetoma), as well as Staphylococcus aureus (a cause of botryomycosis). These other granules are best distinguished by an absence of peripheral clubs, which appear to be specific to Actinomyces species. However, not all Actinomyces species form sulfur granules (eg, A. odontolyticus), and a peripheral fringe of clubs may be absent in certain instances, such as in a tonsillar crypt infection in which there is a minimal surrounding tissue reaction [2,3].

PATHOGENESIS — While not typically considered as opportunistic pathogens, Actinomyces species capitalize on tissue injury or mucosal breach to invade adjacent structures in the head and neck regions. As a result, dental infections and oromaxillofacial trauma are common antecedent events [13]. Disease occurs almost exclusively by direct invasion and rarely by hematogenous spread. A hallmark of cervicofacial actinomycosis is the tendency to spread without regard for anatomical barriers, including fascial planes or lymphatic drainage, and the development of multiple sinus tracts.

EPIDEMIOLOGY — Actinomyces are not found in the environment, and humans are the only natural reservoir for the species that cause cervicofacial disease [6]. Cervicofacial actinomycosis is a relatively rare condition but has a worldwide distribution with no predilection for age, race, season, or occupation [13,14]. However, there is a male to female predominance of 1.5 to 3:1 reported in many series [1].

Predisposing conditions — Predisposing factors include [19]:

●Dental caries and extractions

●Dental implants

●Gingivitis and gingival trauma

●Infection in erupting secondary teeth

Adult males with poor oral hygiene appear to be at greatest risk. Other predisposing conditions include:

●Diabetes mellitus

●Immunosuppression including human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) [20,21]

●Malnutrition

●Local tissue damage caused by neoplastic disease or irradiation

●Bisphosphate related osteonecrosis of the jaws [22]

The diagnosis of actinomycosis in children should arouse suspicion of an underlying immunodeficiency state, particularly chronic granulomatous disease [14].

CLINICAL MANIFESTATIONS — Cervicofacial actinomycosis can present with variable signs and symptoms, but it usually evolves in one of two distinct patterns. Typically, the infection presents as a chronic, slowly progressive, nontender, indurated mass, which evolves into multiple abscesses, fistulae, and draining sinus tracts. Less commonly, it may present as an acute suppurative infection with rapid progression to abscess formation. At this stage, pain and trismus may arise, which appear disproportionate to the local (visible) inflammation. With perimandibular space infections, inflammation of the muscles of mastication may also elicit significant pain and trismus. Fistulization from the perimandibular region is the most easily recognized manifestation of cervicofacial actinomycosis [3].

Pain is generally an uncommon feature, particularly in chronic cases, although it may be prominent as a result of compression of adjacent structures in the ororespiratory tract such as the tongue [13,23]. Dyspnea and dysphagia may occur but are distinctly uncommon. Fever and constitutional symptoms, including fatigue and malaise, are occasionally noted in the acute, pyogenic form of the disease. Because actinomycosis spreads by direct extension without regard for normal tissue planes, regional lymphadenopathy is rare until quite late in the disease course [24].

Characteristic lesions usually develop slowly, over weeks to months, with adherence to overlying skin giving it a bluish or reddish appearance. This is often mistaken for cellulitis but, in fact, more likely represents venous congestion. Over time, sinus tracts invariably form on the skin surface or oral mucosa, eventually erupting to express a thick yellow or serous exudate, which yields the characteristic sulfur granules [3]. An inflammatory cicatricial scarring is one of the more noticeable long-term sequelae [19].

Cervicofacial actinomycosis may involve almost any tissue or structure surrounding the upper or lower mandible. However, the mandible itself is consistently the most commonly identified site of infection [3]. In one study of 317 patients reported from Cologne between 1952 and 1975, the presenting sites were identified as [25]:

●Mandible – 53.6 percent

●Cheek – 16.4 percent

●Chin – 13.3 percent

●Submaxillary ramus and angle – 10.7 percent

●Upper jaw – 5.7 percent

●Mandibular joint – 0.3 percent

While direct bony invasion is decidedly uncommon, periostitis and posttraumatic osteomyelitis occurred in 11.7 percent of cases in this study [25]. Rarely, actinomycosis may also present as a case of severe periodontitis [26]. More recently, Actinomyces spp have been implicated in the pathogenesis of two clinical conditions: peri-implantitis associated with dental implant failure [27,28] and bisphosphonate-related osteonecrosis of the jaw [29]. In both entities, Actinomyces colonies could be identified by histopathology in a high percentage of cases. Although most cases of cervicofacial actinomycosis are of odontogenic origin, primary infections have been reported in various other structures within the head and neck, often quite remote from any potential periodontal source. In particular, actinomycosis involving the scalp, tongue, maxillary sinus, ethmoid sinus, larynx, thyroid gland, thyroidectomy incision site, and lungs have all been reported [23,30-33].

DIAGNOSIS — Cervicofacial actinomycosis has been dubbed "the great masquerader of head and neck disease" [34]. This serves to highlight not only its elusive nature but also the lack of familiarity to most clinicians. As a consequence, appropriate steps to obtain an adequate specimen for histopathologic examination and culture are often neglected.

Pitfalls in the diagnosis — Cervicofacial actinomycosis often responds, at least temporarily, to short courses of broad-spectrum antibiotics given in the mistaken belief that the patient has a bacterial odontogenic infection. (See "Complications, diagnosis, and treatment of odontogenic infections".)

This approach leads to two key problems [35]:

●Isolation of the causative organisms from patients who have received antibiotics within 7 to 10 days is extremely rare.

●As the diagnosis is delayed, chronicity of the disease course and fibrosis is further encouraged. The enhanced fibrosis also hinders the identification of typical sulphur granules by histologic examination.

As the disease progresses with repeated courses of antibiotic therapy, the fibrotic and "woody" induration often comes to resemble a malignant process. Occasionally, the granulomatous appearance of a biopsy specimen is mistaken for tuberculous disease. Perhaps even more commonly, granules are misidentified by staining or biopsy as an indication of nocardiosis. However, these pitfalls can be avoided by bearing in mind that malignant lesions should not respond at all to antimicrobial therapy, and that both Nocardia and mycobacterial species are typically acid fast, while Actinomyces are not. (See "Treatment of nocardiosis".)

Definitive diagnosis — Actinomycosis is usually diagnosed by culturing the organism, although the specimens must be handled properly and, as noted above, cultures held for at least 14 days.

Culture — Confirmation of the diagnosis requires the recovery of Actinomyces species from an appropriately cultured specimen, typically by needle aspiration of an abscess, fistula, or sinus tract or from a large biopsy specimen. Care needs to be taken to avoid contamination by other commensal flora from the oral cavity. Incubation of specimens under strict anaerobic or at least microaerophilic conditions for a minimum of 14 days is recommended [3].

Histology — Multiple sections of a biopsy specimen from different tissue levels are suggested to improve histologic diagnosis [3,36]. In one retrospective study of biopsy samples from 68 patients with suspected cervicofacial actinomycosis but negative cultures for anaerobic/microaerophilic microorganisms, 22 (32 percent) were found to contain Actinomyces colonies by histopathologic examination [36]. Sections of biopsy material typically reveal acute or chronic inflammatory granulation tissue with infiltration by neutrophils, foamy macrophages, plasma cells and lymphocytes, and a surrounding dense fibrosis. Healing lesions tend to demonstrate profound fibrosis, even avascular in nature, often in proximity to areas of acute suppuration [3]. Sulfur granules may comprise no more than 1 percent of total tissue in a given lesion, and hence are easily missed by routine tissue staining. Often, a series of biopsies is required to confirm a pathologic diagnosis [24]. Furthermore, filaments of Nocardia and Actinomyces species are next to impossible to differentiate by conventional methods such as Grocott-Gomori-methenamine stain and hematoxylin-eosin [3,6]. Other methods, including p-aminosalicylic acid, MacCallen-Goodpasture, and Brown-Brenn stains do not appear to offer additional sensitivity.

Monoclonal antibody staining — In contrast, specific staining using fluorescent-conjugated monoclonal antibody (FA) has been shown to improve the identification of various Actinomyces species, even in mixed infections and after fixation in formalin [6]. An additional advantage is the ability to define single filaments in granulation tissue.

Molecular techniques — The diagnosis of cervicofacial actinomycosis has been greatly improved with the advent of molecular techniques such as detection by polymerase chain reaction with 16S ribosomal ribonucleic acid (rRNA) gene probes from clinical specimens [37] and accurate identification using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) [38]. MALDI-TOF MS was found to be both accurate and rapid in identifying Actinomyces spp from clinical specimens, comparable with 16S rRNA gene sequencing [39].

Serology — Serology does not appear to be a practical or reliable diagnostic tool. While agglutinins and complement-fixing antibodies appear in the serum of some patients with cervicofacial actinomycosis, they may represent cross-reactive antibodies due to other disease processes, particularly tuberculosis [40]. Rapid serodiagnosis by the detection of specific antibodies using immunoelectrophoresis or monospecific antigens is under development, but they are not widely available for clinical use [40].

TREATMENT — We recommend high-dose penicillin as the treatment of choice for actinomycosis [6,41]. Alternative agents include amoxicillin or amoxicillin-clavulanate or doxycycline [42]. Management of cervicofacial actinomycosis often requires prolonged courses of antibiotics. Surgical intervention may also be necessary in more complicated cases. In severe periapical actinomycosis resistant to conventional therapy, root-end surgery with bone grafting may be required [43]. Treatment of actinomycosis is discussed in detail elsewhere. (See "Treatment of actinomycosis".)

PREVENTION — There are no defined measures for preventing cervicofacial actinomycosis. However, maintenance of good oral hygiene and appropriate dental plaque removal can limit the tendency of Actinomyces to establish dense colonization and subclinical periodontal infection, an important precipitating event for more extensive disease [6].

SUMMARY AND RECOMMENDATIONS

●Cervicofacial actinomycosis is a chronic disease characterized by abscess formation, draining sinus tracts, fistulae, and tissue fibrosis. It can mimic a number of other conditions, particularly malignancy and granulomatous disease. (See 'Introduction' above.)

●Cervicofacial actinomycosis is caused by branching gram-positive bacteria with a variable cellular morphology, ranging from diphtheroidal to coccoid filaments (picture 1) belonging to the genus Actinomyces. (See 'Microbiology' above.)

●Actinomyces are noted for forming characteristic sulfur granules in infected tissue but not in vitro (picture 2). (See 'Sulfur granules' above.)

●A hallmark of cervicofacial actinomycosis is the tendency to spread without regard for anatomical barriers, including fascial planes or lymphatic drainage, and the development of multiple sinus tracts. Actinomyces species capitalize on tissue injury or mucosal breach to invade adjacent structures; dental infections and oromaxillofacial trauma are common antecedent events. (See 'Pathogenesis' above.)

●Predisposing factors include (see 'Predisposing conditions' above):

•Dental caries and extractions

•Dental implants

•Gingivitis and gingival trauma

•Infection in erupting secondary teeth

•Diabetes mellitus

•Immunosuppression including HIV/AIDS

•Malnutrition

•Local tissue damage caused by neoplastic disease or irradiation

•Bisphosphate related osteonecrosis of the jaws

●Actinomycosis typically presents as a chronic, slowly progressive, nontender, indurated mass, which evolves into multiple abscesses, fistulae, and draining sinus tracts. Less commonly, it may present as an acute suppurative infection with a rapidly progressive, fluctuant, and pyogenic mass. (See 'Clinical manifestations' above.)

●Confirmation of the diagnosis of actinomycosis requires the recovery of Actinomyces species from an appropriately cultured specimen, typically by needle aspiration of an abscess, fistula or sinus tract, or from a large biopsy specimen. Due to the slow-growing nature of the organism, cultures should be held for at least 14 days. (See 'Definitive diagnosis' above.)

●Management of actinomycosis generally involves prolonged courses of antibiotics; surgical intervention may be warranted in complicated cases. The treatment of actinomycosis is discussed in detail elsewhere. (See "Treatment of actinomycosis", section on 'Antimicrobial therapy'.)