Actinomyces species are Gram-positive bacteria with anaerobic and facultative microaerophilic metabolism that typically colonize the oropharynx, urogenital tract, or gastrointestinal system (1, 2). Actinomycosis is generally considered an endogenous infection. Although the bacteria are initially colonized on the surface of the mucosa, they can reach the deeper tissues through any disruption of the mucosal barrier caused by procedures such as trauma, surgical intervention, or foreign bodies (2–4). Actinomycosis is a rare and granulomatous disease that progresses slowly and creates sinus tract fistulae in a chronic form with a slow progression that creates sinus tract fistulae in a chronic form. It has been known for more than 150 years, and the most common causative agent is Actinomyces israelii (5, 6). In recent years, the frequency of all forms of actinomycosis has decreased, possibly as a result of the enhancement of oral hygiene and antibiotic therapy upon infection suspicion (1). However, there is no solid proof to support the effectiveness of such actions in reducing the incidence of colonization and mild periodontal infection with Actinomyces species (4, 6).

The common forms of actinomycosis are cervicofacial, abdominal, pelvic, and pulmonary. Moreover, on rare occasions, the spread of local infection through hematogenous dissemination may lead to the development of actinomycotic lesions in the lungs. Despite anatomic barriers, Actinomyces can spread and eventually invade the pleura, resulting in empyema formation.

With the improvement of oral hygiene and the availability of effective antibiotics, the severity of PA manifestation has become less severe. Furthermore, if diagnosis and treatment are not performed correctly, it can spread into the chest wall and create a pleuro-cutaneous fistula and destruction of vertebrae and ribs (1, 2, 7, 8). The diagnosis of pulmonary actinomycosis (PA) is quite challenging, and the delay in diagnosis can last for 6 months. PA usually results in the formation of nodules, consolidation, or mass that can often be mistaken for lung cancer. Therefore, PA could be misdiagnosed as lung cancer, lung abscess, or tuberculosis (9, 10). Due to non-specific laboratory and clinical features, it is usually challenging to differentiate PA from lung malignancy. Moreover, the most common initial diagnosis of PA among physicians is lung cancer (10–14). The common signs and symptoms of PA are fever, chest pain, hemoptysis, shortness of breath, and a productive cough (15, 16). Furthermore, the severity of PA manifestations has become less severe with the enhancement of oral hygiene and the availability of effective antibiotics.

Dealing with PA can be challenging due to its difficult diagnosis. However, if more people are aware of this infection, it could lead to an easier diagnosis and prevent undesired complications such as unnecessary surgeries and treatment with the wrong medication. To study this, we conducted a scoping review that explored the clinical, epidemiological, diagnostic, and therapeutic features of PA cases that were initially suspected of lung cancer.

PA is a rare actinomycosis disease with a slow-progressing form of pulmonary infection, with a prevalence of 15% in all actinomycosis cases. This infection is often associated with the aspiration of oropharyngeal or gastrointestinal secretions (31, 48). It can involve both sexes and any age, but our findings showed that most of the infected patients were men and that 75% of patients were over 50 years of age. This is in correlation with other studies declaring that PA was more common in male patients and that the peak incidence of infection reached in the fourth to fifth decades of age (12, 24, 48). The high incidence of PA in male patients could be partly related to poorer oral hygiene and the occurrence of more facial trauma (9, 48).

The findings of a chest computed tomography scan (CT scan) of actinomycosis are non-specific and resemble necrotic lung malignancy. This condition is characterized by chronic segmental airspace consolidation with low-attenuation areas that have peripheral enhancement (7, 10, 49). Additionally, cavitations, shadowing, and pleural effusion with cavitary lesions are also typical features of PA that can be misdiagnosed as tuberculosis (28). Similarly, our results revealed that in most of the cases, CT scans were useful for diagnosis, but not always conclusive. The scan showed air space consolidation, mass in the middle lobes that could be misinterpreted as malignancy, pleural empyema, and opacity in the lobes, which could mimic pulmonary metastases. Moreover, positron emission tomography-computed tomography (PET-CT) is a helpful imaging technique to differentiate benign lesions from malignant ones, but there is limited information on PET-CT findings about PA (10, 50).

This technique was used in five cases and showed lesions and masses in lung lobes. Nevertheless, there is minimal information about PET-CT findings on PA. This diagnostic method has also encountered some issues. According to Choi et al., PET-CT is not an ideal tool for the differentiation of PA from lung cancer because of its high fluorodeoxyglucose (FDG) uptake. Consequently, physicians may mistake the high FDG uptake in favor of lung malignancy over PA. Therefore, clinicians must carefully evaluate the need for lung resection surgery when PA is suspected (17, 41, 51).

Some pulmonary infections, such as tuberculosis, aspergilloma, and histoplasmosis, can create false positive results due to their high metabolic uptake. Furthermore, FDG uptake has been observed in actinomycosis, leading to a mimicry of pulmonary malignancies (10, 24, 45, 52).

Although the diagnosis of PA could be delayed, our results showed that the mortality rate was only 6.25% and the overall outcome was acceptable. Similarly, a recent study in China showed that 75.9% of patients fully recovered, while another study in Korea reported a 98% recovery rate among 94 patients with PA (12). Therefore, PA seemed to have a good prognosis with a low rate of mortality because of antibiotic treatment and surgical intervention.

Actinomycosis might coexist with lung cancer, making the diagnosis even harder (9). Among the patients we studied, six had a history of cancer, and two had lung cancer. Although actinomycosis is unusual in immunosuppressed patients, immune system abnormalities may be a facilitating factor for the development of infection. However, the exact relationship between the two conditions is not yet fully understood (53). Interestingly, we found three cases in our research where PA involvement was diagnosed after cancer treatment (54–56). In one of the cases, the patient has been treated with bevacizumab for advanced non-small-cell lung cancer. After 36 months of bevacizumab maintenance, the patient was diagnosed with actinomycosis in the right lung. Bevacizumab was discontinued, and the patient was treated with amoxicillin–clavulanic acid. Unfortunately, the patient passed away after 3 months (54). The diagnostic method was culture in only 12% of the cases. Currently, positive culture in PA is rare due to the challenges of culturing anaerobic bacteria. Previous antibiotic treatments and bacterial overgrowth can also complicate matters. In addition, the evidence suggests that using normal saline, which is usually used for bronchoalveolar lavage, can prevent Actinomyces growth (9, 45, 57, 58). On the other hand, isolating Actinomyces may be crucial to distinguishing nocardiosis or botryomycosis from actinomycosis, which is usually difficult to differentiate morphologically. As a result, the direct culture of biopsy material in both aerobic and anaerobic blood culture media can improve culture sensitivity (59). The accurate diagnosis of PA depends on HE, as radiologic imaging and culture may not be conclusive. Without histological or microbiological confirmation, misdiagnosis can be fairly common (48, 60). However, sulfur granules in biopsy can be essential and suggestive, but not specific. On the other hand, when a small amount of tissue is biopsied, sulfur granules can be missed (60, 61). Nevertheless, granulomas and multinucleated giant cells can be observed in some cases. These morphological shapes are not specific, and other pathogens such as Nocardia spp. and some fungal and parasitic infections can cause similar observations. Furthermore, Grocott methenamine silver staining can identify the branching microorganism that is specific for the existence of actinomycosis infection (6, 62, 63).

Furthermore, surgical intervention may be necessary for diagnosis and treatment if lung cancer cannot be ruled out (31, 47). Endo et al. declared that a conclusive differential diagnosis between PA and necrotic lung cancer might be possible only when the surgical restriction specimen is sent for HE (47).

Furthermore, it has been shown that surgery can be avoided in most cases of thoracic actinomycosis, and long-term intravenous penicillin therapy leads to a good prognosis. However, early surgical intervention may lead to equally good or better outcomes by shortening the antibiotic therapy period (13, 64).

Our results showed that in 75% of the cases diagnosed with HE, and similarly, in 94 cases in Korea, all PA patients were diagnosed with HE (12). Altogether, HE is an essential method for the correct diagnosis of PA (17). Moreover, the new approach of using molecular methods in diagnosis can be helpful in the detection of PA, as in one case, HE and 16SrRNA sequencing were used together for diagnosis. This was a complicated case, and the patient had a co-infection with PA and tuberculosis. The molecular method also led to the identification of a bacterial species, which was A. odontolyticus.

Moreover, 16SrRNA sequencing helped the diagnosis of A. meyeri in a complicated case of PA involvement with a brain abscess. In another case, the diagnosis made by 16SrDNA demonstrated that A. meyeri was a causative agent of PA. Furthermore, 16SrRNA is a component of the 30S ribosomal subunit in prokaryotic cells, and it is transcribed as a single-stranded ribosomal RNA molecule. On the other hand, the 16SrDNA is the gene that encodes the 16SrRNA, and it consists of double-stranded chromosomal DNA. 16SrRNA sequencing is used to detect and identify bacterial pathogens in clinical specimens from patients with a suspicion of infection. 16SrDNA is applied to identify microorganisms and determine microbial communities.

Recently, molecular techniques, including 16SrRNA sequencing, have been used to reach fast and precise results in reference or research laboratories, and such methods are now recommended in challenging conditions such as PA infection.

Furthermore, our results showed that beta-lactam antibiotics were used in the majority of cases (91%) as a selective drug, with intravenous and oral penicillin being used in half of the cases, followed by amoxicillin, amoxicillin–clavulanic acid, and ampicillin. This result is predictable, as antibiotic resistance is not considered a problem in actinomycosis.

Usually, Actinomyces spp. are susceptible to beta-lactams, and in particular, penicillin G and amoxicillin are considered the desirable drugs for actinomycosis treatment. Since Actinomyces spp. do not produce beta-lactamases, combining amoxicillin with beta-lactam inhibitors such as clavulanic acid is not usually necessary unless there are co-pathogens such as Enterobacteriaceae presumed in the infection (3, 65, 66).

Furthermore, in a retrospective analysis from China, 46% of the cases were treated with penicillin G (60). A recent study was conducted in Turkey on 37 PA patients, and it was reported that most cases (73%) were treated with penicillin G and ampicillin-sulbactam, 13% with cefuroxime and ceftriaxone, and 5.4% with clarithromycin, levofloxacin, and moxifloxacin (1). Contrastingly, ampicillin/sulbactam was used only in one case. Cefuroxime, erythromycin, and clarithromycin were used in one case. Additionally, macrolides are considered useful alternatives (65).

Furthermore, the presence of A. actinomycetemcomitans, Prevotella spp., P. acnes, F. nucleatum, Peptostreptococcus spp., and Fusobacterium spp. alongside Actinomyces spp. was reported in some cases. It seems that treatment with beta-lactam agents can effectively lead to the successful treatment of PA. However, it is important to note that metronidazole has no in vitro activity against Actinomyces (65). Therefore, combination therapy with penicillin G was observed in one case of PA, where P. acnes and F. nucleatum were grown simultaneously. Hoca et al. reported the combination of metronidazole with other antibiotics in four cases of PA with co-infection (1).

Treatment with piperacillin–tazobactam was observed in only one case and could be related to the fact that although piperacillin–tazobactam, meropenem, and imipenem are considered active against Actinomyces spp., their use should be limited to prevent the acquisition of resistant flora, as they have broad-spectrum effects (65). Interestingly, feneticilline, which is not approved, was used in one case from the Netherlands after initial treatment with penicillin G. Finally, antibiotic therapy is administered for a prolonged duration because of the chance of recurrence in PA. Patients with no surgical intervention and a shorter period of 3 months of antibiotic therapy are at a higher risk of recurrence (13, 58, 67). Furthermore, no study currently suggests the period for follow-up of recurrent infection, although some studies suggested 3 months, 6 months, and 1-year follow-ups (9, 60, 67, 68). In summary, the treatment duration should be implemented in each case based on the main factors, such as severity and possible changes in the follow-up imaging.

PA is a rare form of infection that is challenging to diagnose due to its non-specific symptoms, failure to detect pathogens, and resemblance to lung cancer. Although it can show similar imagining results as malignancy, which should be differentiated by the presence of nodules, in the sinus tract on the chest wall. Radiological techniques can be helpful in diagnosing PA but have their limitations. The limited available information about PA means that it can be easily confused with other diseases, leading to unnecessary surgeries.

Therefore, clinicians should be aware of the overlapping of signs and symptoms between PA and lung cancer. As antibiotic therapy may be adequate to treat this lung infection, biopsy specimen and histopathological examination should be considered before any surgical operation (i.e., lobectomy).

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

AK: Writing – original draft, Writing – review & editing. NA: Writing – review & editing. SM: Writing – review & editing.