**1. Introduction**

Few infectious agents can cause a broad variety of clinical presentations, including scenarios that mimic other infections, systemic inflammatory diseases, and even localized and metastatic cancer. The pathogenic characteristics of *Actinomycosis*, its capability to disseminate and grow in different environments and tissues, and its indolent and resistant presentation, has allowed this organism to confuse the clinician before obtaining a diagnosis and start treatment. Also, the invasiveness of the actinobacteria, many times require complicated procedures to obtain tissue to rule out cancer and to culture and visualize the organism, many times delaying identification. Finally, this organism can cause infection in a variety of hosts, including immunocompetent patients, in which suspicion of infection is not an initial consideration.

Actinomyces is a prokaryotic bacterium that belongs to the family *Actinomyceatacea*. Initially identified as a fungi in the 19th century, this bacteria has unique characteristics that have allowed to be distinguished as a group from other organisms. Unicellular, but elongated that can mimic the physical structure of a fungal hyphae, this bacteria has the capability to live in different organic and inorganic substrates, making this organism unique and fascinating. Actinobacteria can survive using different environmental substrates found in soil and water, and even in the human body. The word "actinomycosis" is derived from the Greek aktino, which refers to the radiating appearance of the sulfur granules produced by the bacteria. The human form was first described in the year 1857, and the first thoracic case was identified approximately 25 years later [1]. In 1891, the *A. israelli,* the most common human infecting specie, was identified [2]. Incidence of the disease is not updated, but the most recent data reports that it affects 1 in 300,000 individuals yearly, and that incidence hast decreased in the last 3 decades [3]. Men are more commonly affected, and several risk factors have been identified as chronic alcohol abuse, diabetes, cancer, temporary immunosuppressive therapy, organ transplant and end stage renal disease [4]. However, immunocompetent patients with poor oral hygiene, and an event of aspiration, have also been documented. The most common form of Actinomycosis is the cervicofacial invasion, but the organism can affect virtually any organ or body site, most commonly the thorax and the abdomen. Delay in diagnosis occurs in many cases as the signs and symptoms are nonspecific, and are often similar to those seen in malignancy and other systemic diseases and infections. There are cases in which the actinomyces infection can coexist with other diseases, as for example lung cancer, as it tends to colonize devitalized tissue, making diagnosis even more challenging [5]. Even in developed countries, the incidence of the disease is underestimate and diagnosis is difficult. It many cases patients are receiving treatment for other conditions and inadvertently been cured for actinomycosis infection. The use of antibiotic therapy has significantly improved the prognosis of patient with actinomycosis. Morbidity and mortality is significatively decreased with appropriate identification and treatment.

## **2. Epidemiology and pathogenesis**

As this organism constitutes part of the human flora, disease manifestation depends on the site of invasion. Several anatomical sites have been identified and include cervicofacial, pulmonary, abdominal, genitourinary, cutaneous, extra facial and joint, central nervous system and disseminated infection. More than 30 species of Actinomycosis have been identified and the most common human pathogen is *Actinomyces Israelli* [6].

Actinomycosis has a worldwide distribution and usually affects middle age individuals. It is two to four times more common in males than in females [1]. The condition is usually considered as infrequent, however the epidemiologic data is very limited and probable underreported [7]. Infection involving the cervicofacial area is the most commonly known, representing 60% of the cases [8]. This occurs after dental or oral procedure, or in a patient with poor dental care. The second most common presentation of actinomycosis is abdominal involvement, constituting 20% of the reported cases [6]. The organism can invade any abdominal tissue, most commonly the bowel, causing appendicitis in 65% of the cases, but also, gastrointestinal perforation and upper and lower bowel obstruction have been reported. The third most common presentation is thoracic actinomycosis (15–20% of the reported cases) [6]. Infection develop after aspiration of the oropharyngeal secretions or perforation of the esophagus. Some cases develop from progression from cervicofacial or abdominal actinomycosis, or after hematogenous spread in disseminated disease [1].

The rarest cases of actinomycosis include musculoskeletal, central nervous system or joint actinomycosis. Central nervous system actinomycosis infection develops from hematogenous spread or extension of a cervicofacial actinomycosis [9]. In one study, the distribution of presentations included brain abscess (67%), meningitis or meningoencephalitis (13%), actinomycoma (7%), subdural empyema (6%), and epidural abscess (6%) [10]. Musculoskeletal actinomycotic infections of hip and knee prostheses have been described, with early presentation suggesting introduction of the organism perioperatively, and late presentation usually indicating hematogenous spread from an extra-articular site [6]. Disseminated Actinomycosis, is a rare presentation, but can be seen after extensive use of antibiotics.

The pathological damage cause by these organisms are secondary to direct tissue invasion and damage by the bacterial population. Also, actinomyces is often found cohabitating with other bacteria as *Eikenella, Enterobacteriaceace*, and species of *Fusobacterium*, *Bacteroides*, *Capnocytophagia*, *Staphylococci*, and *Streptococci*. It has been always a question of how those other organisms contribute to the pathogenesis of actinomycosis. It is believed that the cohabitant bacterias create an ecosystem that facilitates bacterial spread and growth of the actinomyces [11].

## **3. Risks factors**

Actinomycosis is considered an endogenous infection. This organism can affect immunocompromise and immunocompetent hosts. Risk factors associated with the acquisition of actinomycosis include: male sex between 20 and 60 years old, diabetics, poor oral hygiene, implanted foreign bodies as occurs during aspiration, or intrauterine implantable contraceptive device (IUD) [4]. Also, the use of immunosuppressive therapy, as systemic steroids or chemotherapy, has also being identified as possible risk factor for localized and disseminated infection. Other identified factors to acquire the infection include history of HIV, active hematogenous and solid malignancy, organ transplant, alcohol abuse, and accidental or intentional tissue trauma, as tissue radiation or surgery [4].

### **4. Diagnosis**

Diagnosis of Actinomycosis is quite challenging and requires high clinical suspicion. Prolonged time for work up and invasive testing is often part of the diagnostic process in an actinomyces infection. A definitive diagnosis is made from identification of the organism from a collected specimen.

Blood tests are often unspecific, with normochromic anemia and mild leukocytosis with predominance of polymorphonuclear cells as most common finding [4]. Others nonspecific laboratory findings include elevation of alkaline phosphate (ALP) and erythrocyte sedimentation rate (ERS), representing the nonspecific inflammatory nature of the illness. The most common laboratory pattern of the infection is related to the organ and tissue involved.

Imaging studies such as CT scan and MRI are nonspecific and nondiagnostic, specially at the earlier stages of the disease as other inflammatory diseases and neoplastic processes such as lung and intestinal cancer may show similar findings. In cases of thoracic actinomyces infections, the findings are more predominant at the peripheral and lower lobes, reflecting the role of aspiration in the pathogenesis of the disease [3]. Common findings include nodules, masses, cavitations, infected bronchiectasis, segment collapses, tissue calcifications and foreign bodies [3]. All those findings mimicking other infectious or malignant diseases. At latter stages, infiltration to surrounding tissues at different planes and sinus tract formation and fistulas may be identified in radiological images. Mucosal involvement as occurs in the bowel track can mimic cancer and other inflammatory conditions such as Ulcerative Colitis and Chron's disease.

Histopathological findings strongly support the diagnosis of Actinomycosis. The use of Hematoxylin stain (H&E stain) will show the sulfur granules which represent colonies of eosinophilic oval or round basophilic masses, which characterized actinomycosis infection [4]. Giemsa, Gram Stain and Gomori methanamine silver staining are need for identification of Gram-positive filamentous branching organisms. This filamentous organisms can be confused with other bacterias as Nocardia u other branching organisms as fungus. Actinomyces is distinguished from Nocardia as nocardia is acid fast positive and aerobic, and actino is acid fast negative and grow in anaerobic medium.

Identification of the organism from a sterile specimen confirms diagnosis, but failure rates are high due to inhibition of Actinomycosis growth by a coexistent/ contaminant organism, the previous use of antibiotic therapy or inadequate incubation period. Culture growth is slow, with the earliest identification done as a minimum of 5 days, but may take up to 20 days to be identified. Allowing cultures to take at least 10 days is necessary to confirm a negative diagnosis. Actinomycosis culture should be performed on chocolate agar media at 37 degrees Celsius, as well as brain heart infusion broth and Brucella Blood Agar with vitamin K and hemin [4]. Serological assays have a low clinical yield and are still under investigation.

## **5. Systemic clinical features**

Several anatomical areas have been identified where invasion with actinomycosis can led to acute/chronic pathological findings. Most of the presenting symptoms are not specific, making diagnosis challenging. The following presentations will describe the clinical manifestations, diagnosis and general treatment of actinomycosis according to anatomical site.

#### **5.1 Cervicofacial actinomycosis**

Cervicofacial actinomycosis is the most frequent clinical form of actinomycosis. Actinomyces is part of the normal flora of the mouth, which tends to cause infections when the oral mucosa barrier is breach, and poor oral hygiene exists. This clinical presentation usually involves tissues surrounding the upper and lower mandible, cheek, chin, and submaxillary area [6]. Patients may present with a fever and slowly progressive painless indurated mass, in the peri-mandibular region, that can evolve to abscess formation and osteomyelitis. A typical thick yellow exudate can be seen in tissues [4]. This mass lesions usually are misdiagnosed as a malignant lesion, and is some cases as a granulomatous disease [12]. Head and neck lymphadenopathy is usually seen related to the infection. In a retrospective study of 317 patient with cervicofacial actinomycosis, disease progress to bone and muscle leading to bone infection [4]. Diagnosis of the infection is mainly thorough fine needle aspiration of the mass like structure with identification of actinomyces.

## **5.2 Bone and joint actinomycosis**

Extra facial and joint actinomycosis is not as common as cervicofacial actinomycosis. Few data is available on the incidence of the disease. Reported cases are mostly secondary to hematogenous spread. Other causes include polymicrobial bone infection after bone exposition, continuous spread to the spine after pulmonary actinomycosis [6]. Patients who develop extra facial and joint actinomycosis usually present symptoms months after suspected bacteremia, and symptoms are usually insidious and similar to other chronic bone infections or malignancies [6].

### **5.3 Pulmonary actinomycosis**

Pulmonary actinomycosis is a rare and challenging disease to diagnose. It mainly results from aspiration of oropharyngeal or gastrointestinal secretions. Individuals with history of poor oral hygiene, preexisting dental disease, and alcoholism have an increased risk for developing pulmonary actinomycosis. Patients with pulmonary disease like COPD and bronchiectasis are at increased risk of infection [6]. Other risk factors include disease that have high risk of aspirations, such as neurological and psychiatric diseases, drug abuse and severe reflux with hernias. In the 1950s pulmonary actinomycosis presented similar to tuberculosis, as a empyema necessitans, with a sharp chest pain and cutaneous fistulation [3]. In the post antibiotic era, the most common presentation is a focal pulmonary consolidation, mimicking persistent bacterial pneumonia or lung malignancy. It is recommended that in patients with persistent symptoms of cough or hemoptysis refractory to antibiotic therapy, for actinomycosis to become a possible differential diagnosis.

Most cases of pulmonary actinomycoses are misdiagnosed. Differential diagnosis includes other lung pathologies such lung malignancy, pneumonia, mycobacterium infection, aspergillosis and lung abscess. Pulmonary actinomycosis is commonly subdivided depending on the radiological findings, into the airway type including bronchiectasis, the endobronchial, mediastinum and that involving the chest wall [3]. Imaging allows for proper localization and extension of the disease. Patchy air space consolidation, ground glass opacity, cavitation, pleural thickening, atelectasis, pleural effusion, nodular and the appearance of mediastinal and hilar lymphadenopathies may be seen in CT imaging of pulmonary actinomycosis [13]. Parenchymal involvement have an extensive range of presentations from a pulmonary nodule to extensive space consolidation, to the most invasive spreading involving pleural and chest wall invasion with pleural effusions and empyema [13].

Colonization and infection of preexisting bronchial dilations or causing the bronchial changes to develop bronchiectasis, is another presentation. This form may coexist with parenchymal actinomycosis infection. Aspergillus infection can cause similar findings and should also be ruled out. Finally, endobronchial actinomycosis, develops after colonization of broncholiths or foreign bodies in the airway, by actinomyces. These broncholiths are form from eroded and calcified lymph nodes into the airway, which are commonly seen in patient suffering from granulomatous infections such as *Histoplasmosis Capsulatum* or *Mycobacterium Tuberculosis* [14]. On CT imaging, endobronchial nodules with associated obstructive pneumonia, may be observed. Most endobronchial actinomycosis may present as tumor, with irregular thickening or an intrabronchial mass associated to post-obstructive pneumonia, resembling lung cancer and its complications [3]. Some cases of chest wall invasion have been noted, and produce similar findings as those seen in blastomycosis, cryptococcosis, nocardiosis and invasive aspergillosis. Other possible differential diagnosis include lymphoma, malignant mesothelioma and chest wall tumors. Vocal cord can be also involved, and may mimic papilloma, or cancer.

Fiberoptic bronchoscopy help in diagnosis when an endobronchial lesion is biopsied and the organism colonies are identified in the tissue obtained, but it may just represent colonization, so clinical correlation must be done and other diagnosis as malignancy should be rule out.

#### **5.4 Central nervous system**

The central nervous system can also be affected by actinomyces. It is most seen as brain and epidural abscess, meningitis, meningoencephalitis, and as subdural empyema after hematogenous spread most likely from lung or cervicofacial infection or from a penetrating head injury. Its signs and symptoms are non-specific but tend to be similar to other central nervous system infections.

#### **5.5 Cutaneous actinomycosis**

Cutaneous Actinomycosis has been poorly describe in literature. Most cases present as a soft tissue inflammation that develops into an abscess, nodules mass like lesions.

#### **5.6 Abdominal actinomycosis**

Abdominal Actinomycosis usually affects the appendix and ileus [15]. Factors that predispose to infection, include trauma, neoplasia, recent surgery, perforated viscus, as well as the use of intrauterine contraceptive devices [16]. Patient with presents with an indolent course of symptoms such as fever weight loss, fatigue and associated abdominal pain. Physical findings may show a palpable mass, fistula or sinus tract [6]. Laboratory work up often is not specific. Clinical presentation can be similar to clinical Chron's disease, malignancy and extrapulmonary tuberculosis, making diagnosis difficult. The lack of extra intestinal manifestation, as well as the lack of improvement with anti-inflammatory or immunosuppressive drugs may help differentiate form Chron's disease and consider other possible diagnosis, as actinomycosis infection [17].

Radiological findings are nonspecific for the diagnosis of abdominal actinomycosis. Ct Scan may help localized the infection and extension of the disease for tissue diagnosis. Endoscopic evaluation are also nonspecific and remarkable for engrossment and inflammation of mucosa, and bowel wall ulcer formation and nodular and mass like lesions. Definitive diagnosis is obtained with biopsies showing and growing the organism.

#### **5.7 Genitourinary actinomycosis**

After cervicofacial actinomycosis, the genitourinary tract is the system most affected by actinomycosis [6]. It is most seen in women using an intrauterine implantable devices [18]. This is most likely due to disruption of the endothelium of the uterus, facilitating microbial invasion. It is recommended to change the intrauterine device every 5 years as it is mostly seen with prolonged use [19].

Bladder actinomycosis can be confused with bladder carcinoma, and it is important to diagnosed accordingly to avoid unnecessary treatment and procedure thought to be from carcinoma. Findings are usually the identification of a genital mass associated with abdominal pain, and genital infections. Macroscopic hematuria can be seen if bladder wall is invaded by actinomyces. Imaging usually show a mass like lesion with associated lymphadenopathy.An abscess of the tubulo-ovarian structures include actinomycosis in the differential diagnosis [6].

## **5.8 Disseminated actinomycosis**

Hematogenous spread to distant multiple organs is uncommon with Actinomycosis infection, but has been reported. Disseminated actinomycosis have been documented in 15.9% of the reported cases [20]. In many cases, the presenting symptoms do not correlate with the extension of the disease. According to Weese, the diagnosis is properly identified at admission in only 7% of the cases [21]. Disseminated disease may involve any organ, but the most common include lung, skin, brain, liver, bone and muscle.
