**1. Introduction**

Human actinomycosis is an unusual but insidiously chronic granulomatous bacterial infection caused by Actinomyces genera. These pathogens are filamentous gram-positive anaerobic bacteria from the Actinomycetaceae family [1]. Due to its insidious chronicity and rarity, human actinomycosis is often misdiagnosed for other more common conditions such as tuberculosis and even malignancy [2]. Once astutely identified in a timely manner, it is however treatable with good prognostic outcomes.

Actinomycosis in humans was first described in 1878 by Israel and Wolfe [3, 4]. In early reports of infections caused by filamentous gram-positive organisms, no distinction was made between diseases caused by actinomyces and nocardia's. As more taxonomy was developing, Kruse in 1896 described these organisms as streptothrix Israeli [5]. It was not until 1943 that the genera were clearly differentiated by Waksman and Henrici, enabling separation of the diseases they caused [6]. Today, *Actinomycosis Israeli* is a well-known pathogen that can cause human disease.

It must be noted that the human beings remain the natural reservoirs of these organisms. Given that the *Actinomyces Israeli* is found in abundance within the oral cavity, gastro-intestinal tract and female genital tract, as part of normal flora, it is of no surprise that this organism is commonly aetiologic to the infections affecting these anatomical regions. In rare cases, other species of the actinomyces family such as *Actinomyces odontolyticus, A. viscosus*, *Actinomyces naeslundii*, *Actinomyces radingae*, *Actinomyces turicensis*, and *A. meyeri* have also been aetiologically implicated. For actinomyces to cause disease, these organisms appear to require a synergistic

relation with other accompanying bacteria, both from within and outside the genera [7–10].

In clinical practice, the diagnosis of actinomycosis requires a physician to be highly suspicious of the disease. Other confounders include the irrational use of penicillin containing antimicrobials leading to delayed diagnosis of the actinomycosis. The penicillin's are generally used for any suspected upper and lower aerodigestive tract infections particularly in low income countries. Actinomycosis commonly affect the structures of the head and neck region though it can affect virtually any organ of the body. The central nervous system, pelvic, abdominal, and thoracic involvements are generally very rare, with cervicofacial actinomycosis representing the most common (more than 50% cases) clinical form of actinomycosis disease manifestation [11, 12].

Cervicofacial actinomycosis is a chronic suppurative disease that results in typical formation of fistulae, sinus tracts, and fibrosis of the affected tissue. The characteristic spread of the disease tends to evade fascial planes thereby forming the typical sinuses, fistulae and tracts. In the physicians clinic, one of the most challenging aspects in the diagnosis of cervicofacial actinomycosis is the variation in phenotypical presentation of the disease. It is in accordance with the authors that the diagnosis often rests in the physicians highest index of suspicion. Once such a suspicion is raised, then necessary investigations should be undertaken. A tissue sample is always necessary for the diagnosis that almost always depends on a combination of clinical and characteristic histopathological features. If a physician becomes mistaken to think that the patient has odontogenic abscess, the empiric treatment is by means of broad spectrum penicillin based antibiotics. In this case, there exists a serious dilemma in the diagnosis because the genus actinomyces generally respond to broad spectrum antimicrobial (albeit prolonged courses) that are often used in treatment for odontogenic abscesses. Also, to isolate the genus actinomyces, prolonged anaerobic cultures are required. However, the recurrence and progression of the disease in this case should sensitise the treating clinician into thinking of the possibility of cervicofacial actinomycosis. Actinomycosis treatment typically require prolonged (6-12 months) penicillin containing antimicrobial agents as compared to short course (7–14 days) therapies typically used in odontogenic abscesses [8].

Herein we describe the 4 main clinical forms recognised, namely, cervicofacial (typically known as a lumpy jaw), primary cutaneous, thoracic, and abdominopelvic actinomycosis. In this chapter, we will give a detailed account on various clinical forms of forms of presentation, their investigations and management principle from a clinical point of view. There shall also be an account on synopsis regarding the classes of antibiotic that may be used to successfully treat actinomycosis in general from a physician's point of view guided by the scientific literature. Whilst other anatomical classifications include musculoskeletal and disseminated clinical forms exist, we have elected to focus our brief discussion on the aforementioned four clinical forms and elaborate on extended manifestations therein. The other forms of actinomycosis is pretty rare.

#### **2. Clinical phenotypes**

#### **2.1 Cervicofacial actinomycosis**

This clinical variant of human actinomycosis is the commonest form encountered owing to its typical clinical presentation, it is often referred to as a 'lumpy jaw" [7, 10]. See **Figures 1**–**3**. Generally, the disease can present acutely or chronically to the physician's clinic.

*Diagnosis of Actinomycosis in the Physician's Clinic DOI: http://dx.doi.org/10.5772/intechopen.104878*

#### **Figure 1.**

*Massive induration on the left side of the face extending into the scalp. Small nodules visible in the preauricular region.*

It typically presents with a slow growing non-tender firm lump located around the neck, cheek and/or jaw, depending on primary site of inoculation. Clinical signs within the jaw region may be trismus as well as facial asymmetry, as a result of muscles of mastication undergoing spasms and fibrosis. With further chronicity, the infection may extend to adjacent anatomical structures such as lymph nodes, tongue, bones, oropharynx and rarely meninges of brain and spinal cord. The acute disease process is rare and typically can present with pain, trismus and rapid progression towards abscess formation on the affected site.

#### **Figure 3.**

*Early lesion of cervicofacial actinomycosis represented by an ulcerated plaque on the left cheek.*

Risk factors for cervicofacial actinomycosis


### **2.2 Primary cutaneous actinomycosis**

Primary cutaneous disease may result from direct inoculation of skin by actinomyces organisms. Although very rare, this type of clinical manifestation can be seen following trauma to the site of inoculation (**Figures 4** and **5**). The anatomical sites that can be involved are variable and include the hands, feet, and head and neck region (ears and nose). Clinical examination may reveal, localised non-healing ulcers, suppurative discharging abscesses, and sinuses. It cannot be overemphasised that disseminated cutaneous manifestation of this disease is of extreme rarity especially when the patient does not have any concomitant systemic infections [8, 9].

*Diagnosis of Actinomycosis in the Physician's Clinic DOI: http://dx.doi.org/10.5772/intechopen.104878*

#### **Figure 4.**

*Cutaneous actinomycosis presenting as crusted and indurated multiple plaques on lumbo-sacral region.*

#### **Figure 5.**

*Primary cutaneous actinomycosis of the hand. This represents an area of primary inoculation.*

#### **2.3 Thoracic actinomycosis**

Accounting for 15–20% of anatomically classified actinomycosis clinical patterns [20], thoracic actinomycosis requires a particularly high index of suspicion to successfully diagnose and manage.

#### *2.3.1 Pathogenesis*

The anatomical location and construct of the thoracic cavity makes it inherently vulnerable to being infected. Located between the Head-and-Neck region and abdominal cavity, it may succumb to direct regional extension of cervicofacial infection (above), Oesophageal breach (within), and abdominopelvic infection (below). Other routes of infection may involve, *inter alia*, inhalation of contaminated aerosol particles, aspiration of gastric content or oropharyngeal secretions, and hematogenous dissemination [15]. Risk factors for thoracic actinomycosis would thus include, but limited to, dental caries, swallowing problems for aspiration, immunosuppression, and previous surgery with resultant clean-contaminated wound.

#### *2.3.2 Clinical manifestation*

There are no clear demographic predilections for thoracic actinomycosis. Though several studies have noted a 2–4 times greater prevalence in males aged 30 to 50 years [21, 22], still others have reported cases in children as young as 14 years old and as the elderly over 70 years [23]. This follows also for both sex and gender.

Patients may present symptomatic or asymptomatic. Naturally, structures within the thoracic cavity that may be affected include the lungs, pleura, mediastinum, or chest wall [15]. Depending on the anatomical structure affected, so will the clinical manifestations results.

The most affected structures are the lungs and pleura (either primarily or secondary to a chronic lung foci contiguously manifesting as empyema). Therefore, it is no surprise why the most common symptoms are haemoptysis, cough, sputum production, chest pain, fever, and weight loss [23, 24]. This makes the diagnosis of particular difficulty as these symptoms are equally common in most thoracic pathologies, tuberculosis and malignancy being the more prevalent. Suffice to say, Actinomycosis can also co-exist with the aforementioned diseases, making diagnosis and further management even more challenging.

Patients may also present asymptomatically, with vicinal destruction of ribs or sternum, sinus tracts extending to the skin (**Figure 6**), or incidental finding of an endobronchial mass [15]. Endo-, myo-, and pericardial disease are not uncommon, often resulting from haematogenous spread or direct extension of mediastinal disease – These patients commonly present with pericarditis related signs and

#### **Figure 6.**

*Pulmonary actinomycosis with infiltration into the chest wall. Multiple fibrotic sinus tracts and ulcerated, indurated plaques and nodules are evident mostly on left upper posterior chest.*

symptoms [25]. Investigations such as chest radiographs, CT-scan, cardiac echograms, bronchoscopy with biopsies, may be equivocal even with findings of sulphur granules in sputum or sinus tract discharge. It would thus follow that Actinomycosis remains a diagnosis of exclusion, after eliminating the more common and even aggressive diagnosis of malignancy.

### *2.3.3 Abdominopelvic actinomycosis*

Abdominopelvic disease accounts for 20% of human actinomycosis [26], 65% of which is as a result of acute appendicitis [25]. Abdominopelvic actinomycosis may be the most difficult to diagnose due to its indolence and latency, often presenting months to years after the initial insult [15].

#### *2.3.4 Pathogenesis*

Already established as being mainly an endogenous infection, in that the pathogenic *Actinomyces* species are commensals and normal inhabitants of the oropharynx, gastrointestinal tract, and female genital tracts in humans. It thus follows that pathogenicity in the abdominopelvic region would involve a breach in intestinal or internal genital mucosal lining [15], thus affecting the local structures and organs. Causes would therefore include penetrating trauma, gastrointestinal or gynaecological surgery, neoplasia, and foreign bodies in the gastrointestinal tract or genitourinary tract, with or without erosion through the mucosal barrier [25].

In the abdomen the disease may be localised, often with a strong predilection for the ileocecal region as a result of acute appendicitis. However, the vast array of more common pathologies within this region such as tuberculosis, carcinoid, typhlitis, ameboma, regional enteritis, chronic appendicitis, or malignancy, makes diagnosis extremely challenging. The disease may also spread extensively with very little respect for fascial and connective tissue planes. This represents one of the ways in which pelvic actinomycosis may develop- direct extension from the abdomen.

Primary involvement of pelvic structures may also occur and is predominantly associated with intrauterine contraceptive devices (IUDs) as a result of colonisation and/or infection [27]. Other primary causes may include septic abortions and retained sutures from previous surgery [15].

#### *2.3.5 Clinical manifestation*

As with thoracic actinomycosis, there is no clear demographic predilections for abdominopelvic actinomycosis. Risk factors generally remain the same, that being males (except for pelvic actinomycosis, where woman are mainly affected), age 20–60 years, immunosuppression (with diabetes mellitus ranking highest) [14, 26–28]. However, caution must be exercised, as many patients seldom present with any of the mentioned risk factors.

With a predilection for the ileocecal region, patients may present with localised symptoms of right iliac fossa pain. Other symptoms may be nonspecific such as fever, weight loss, and generalised abdominal pain. Clinical examination may only elicit tenderness and or an abdominal mass (of which less than 10% are diagnosed preoperatively [14], or a completely normal abdominal thus making the diagnosis difficult of abdominal actinomycosis extremely challenging. It is no surprise that less than 10% are diagnosed preoperatively.

Anorectal disease is not uncommon, with a clinical picture as vast as rectal strictures, draining sinuses and fistulas, and perirectal or ischiorectal abscesses [15].

The diagnosis of Pelvic Actinomycosis is of equal perplexity, with patients often presenting with nonspecific symptoms (lower abdominal or suprapubic pain, weight loss, vaginal discharge, and low-grade fever if at all). These symptoms may persist from months to years [28]. The biggest clue in these patients is a prolonged use of an intrauterine contraceptive devices (IUDs), as it is the predominant cause.

## **3. Overarching mechanism of disease and diagnosis**

Actinomyces spp. reside on their respective mucosal surfaces of the anatomical sites that they inhabit. A gain into deeper adjacent tissues require a disruption of the mucosal surface usually following some mechanical factor such as trauma or surgery [29, 30].

The gold standard diagnostic method is through a tissue sample plus clinical correlation in some cases. Tissue biopsy must be performed usually with two separate specimens. One specimen should be sent for microbiological microscopy, culture and sensitivity for confirmation, or to exclude other possible infections that could mimic the actinomycosis. The second specimen is then sent for histopathological sectioning and assessment.

Microbiological assessment of the tissue specimens is often braised with challenges. It is generally difficult to obtain bacteriological identification of Actinomyces as a result of various factors. The heterogenicity of the actinomyces, frequent presence of other micro-organisms, short incubation period, as well as recent antibiotic therapy of the patient, all contribute to the negative microbiological tests in majority of cases. The sulphur granules, although strongly suggestive, are also not diagnostic as these may also be found in other bacteria, mainly nocardia spp. [29–31].

Histopathological sections of affected tissue may depict abscesses and sinuses in the midst of mixed inflammatory cell infiltrate and fibrotic changes. The bacterial colonies and their sulphur granules may also be seen in the centre of the lesions reminiscent of the concept of Splendore-hoeppli phenomenon. Radiological examination is important for extra-cutaneous disease. X-rays and computed tomography scans are useful in delineating lesions affecting the soft tissue and bony structures [7, 8].

### **4. The differential diagnosis**

In clinical practice, it is always crucial to rule out most mimickers of actinomycosis. These disorders range from chronic inflammatory, infectious, to malignant diseases. The authors find it useful to categorise the differential diagnosis (which is by no means exhaustive) according to the site of involvement. Therefore, for abdominal and pelvic disease, the following differential diagnosis must be considered:


*Diagnosis of Actinomycosis in the Physician's Clinic DOI: http://dx.doi.org/10.5772/intechopen.104878*


And for the thoracic disease, the clinician ought to rule out the following:


For cutaneous disease, a clinician ought to exclude the following differential diagnosis by means of tissue sample for culture, microscopy, and where necessary polymerase chain reaction tests:


Finally, the cervical, facial and central nervous system involvement can also mimic a wide variety of diseases that are of interest in terms of differential diagnosis. These are:


#### **5. Management**

The management of human actinomycosis is comprised of antimicrobial agents as well as surgery as indicated. The choice to use combination treatment is necessitated by the severity and clinical condition of the patient. Fortunately, antimicrobial resistance are generally not considered an issue when it comes to actinomyces spp. The organisms are favourably sensitive to penicillin based antibiotic therapy as they do not produce beta lactamase. Amoxycillin or penicillin G are considered as the drugs of choice for treating actinomycosis [7, 10]. Macrolides and clindamycin have all been used with good efficacy. Cloxacillin, oxacillin, doxycycline ciprofloxacin, metronidazole, cephalexin are not considered effective in treating human actinomycosis.

Although Piperacillin plus tazobactam, carbapenems such as meropenem and imipenem, are also effective, they should not be used to avoid acquisition of resistant normal flora to these agents. Notably, *Actinomyces graevenitzii* and *A. europaeus* have been particularly reported to be resistant to third generation cephalosporins suggesting that there is limitations regarding the use of this group of antimicrobials [14–16, 32].

#### **6. Conclusion**

Human infection with actinomyces spp. remains rare however an important clinical entity for physicians to recognise and treat promptly. The cervicofacial disease has a predilection towards tropical countries, farm workers, and those with poor dental hygiene. Other risk factors include post-surgery of the anatomic site where actinomyces spp. are a part of normal flora as well as the prolonged use of intrauterine contraceptive device in female patients.

Early disease can be treated successfully, albeit for a long time (6-12 months) with antimicrobial agents such as penicillin's, tetracyclines and macrolides.

Advanced disease often requires a combination of antimicrobial agents as well as surgical intervention.

Primary prevention seems to be of great value in management of the human actinomycosis. Measures such as maintaining good oral health, reduction of alcohol abuse, may limit occurrence of extra-cutaneous actinomycosis.

*Diagnosis of Actinomycosis in the Physician's Clinic DOI: http://dx.doi.org/10.5772/intechopen.104878*

Women should also consider frequent changing of the intrauterine contraceptive devices according to the manufacturers' stipulation in order to circumvent the occurrence of pelvic actinomycosis.

It is the authors view that actinomycosis remains a diagnosis of exclusion, therefore this calls for a high index of clinical suspicion, and an astute physician for the successful diagnosis and management therein.
