Pulmonary actinomycosis is a rare but important and challenging diagnosis to make. Even when the clinical suspicion is high, the disease is commonly confused with other chronic suppurative lung diseases and with malignancy.
An early, accurate diagnosis will prevent the considerable psychological and physical morbidity, including unwarranted surgery, associated with delayed diagnosis.
The clinical, radiological and therapeutic characteristics of the infection are reviewed here.
Respiratory physicians should be aware of this important differential when investigating patients for persistent pulmonary shadowing. This will expedite the diagnosis of an otherwise highly treatable condition with an excellent prognosis if picked up early.
Actinomyces spp. are higher prokaryotic bacteria belonging to the family Actinomyceataceae. When they were first described in the early 19th Century, they were misclassified as fungi 1. The name A. bovis was given to a ray-like organism found in purulent material obtained from cattle mandibles; the word “actinomycosis” was derived from the Greek terms aktino, which refers to the radiating appearance of a sulphur granule, and mykos, which labels the condition a mycotic disease. The first published clinical description of the human form of the disease appeared in 1857 2. The thoracic form was described 25 yrs later, but it was not until 1891 that A. israelii, the main species responsible for the human disease, was isolated 3. The classic clinical picture of the disease actinomycosis is that of its commonest form, the cervicofacial type, in which a middle-aged male patient presents with a large mass on the jaw, not too dissimilar to the lumpy disease originally described in cattle. In fact, the infection can involve virtually every organ or body site (table 1⇓).
Pulmonary actinomycosis is a difficult condition to diagnose. Even among experienced physicians, sometimes despite pointers to the disease, delayed diagnosis or misdiagnosis as tuberculosis, lung abscess or lung cancer is common 12. The epidemiological, clinical, diagnostic and therapeutic characteristics of the disease are reviewed here. An increased awareness of the infection may expedite diagnosis and prevent undesirable complications, including unwarranted surgery, in patients under investigation for persistent pulmonary shadowing.
Actinomycosis has been reported around the world. Although there is little accurate prevalence data in the literature, the incidence of all forms of actinomycosis appears to have declined markedly in the last three to four decades 12. The pulmonary form of actinomycosis constitutes ∼15% of the total burden of disease, although estimates of up to 50% have been reported 12–15. It is now a rare infection, particularly in the developed world. In the current authors' 1,100-bed teaching hospital (Nottingham City Hospital, Nottingham, UK), serving a large metropolitan area in the UK and acting as a regional centre for thoracic surgery, pulmonary actinomycosis was diagnosed histologically in only four cases over a 15-yr period (I. Soomro, Dept of Histopathology, City Hospital, Nottingham, UK, personal communication). Table 2⇓ summarises all series of pulmonary actinomycosis with more than five cases reported in the adult English language literature in the last two decades.
The presentation of pulmonary actinomycosis has also changed. It now appears less aggressive in nature compared with the pre-antibiotic era 12. These changes in both the disease's presentation and its incidence may be the result of improvements in oral hygiene, in the ready availability of antibiotics and in the early initiation of treatment when pulmonary infection is suspected. Actinomyces spp. are sensitive to several antibiotics in common use 27. In the developing world, where healthcare resources are limited, it is possible that the incidence of the disease may be higher, but accurate data are lacking. Even in the developed world, the disease's incidence may be an underestimation; the diagnosis is quite difficult to make in the first place and it is possible some early cases are being inadvertently treated and cured when antibiotics are given for other reasons 28. Somewhat surprisingly, socioeconomical class per se does not appear to correlate with disease incidence in the developed world 29.
Pulmonary actinomycosis occurs at all ages, although it is very unusual in children. A bimodal age distribution with an earlier peak at ages 11–20 has been described, but most series describe a clear peak incidence in the 4th and 5th decades 2, 30. Bates and Cruickshank 31 reported finding only 27% of all forms of actinomycosis infections occurring in individuals >20 yrs of age. The incidence of infection is two to four times greater in males compared with females 2. This disparity has been partly attributed to poorer oral hygiene and/or a higher incidence of facial trauma in males resulting in dental and facial disease. These may also be risk factors for the thoracic form 28. A higher incidence of pulmonary actinomycosis has also been reported in patients with underlying respiratory disorders, such as emphysema, chronic bronchitis and bronchiectasis, and in alcoholics, but the series were small 8, 30. Despite references to the contrary, Actinomyces spp. have been demonstrated in nature outside of an animal or human host 32. However, no person-to-person transmission or racial, seasonal or occupational predilection has been demonstrated 12, 33.
Microbiology: organisms involved
Members of the genus Actinomyces are Gram-positive, nonspore-forming, predominantly anaerobic prokaryotic bacteria belonging to the family Actinomyceataceae. They are bacteria rather than fungi for a variety of reasons: they replicate through bacterial fission rather than by budding, they lack sterols in their cell walls, they are resistant to polyene antifungal agents and they are sensitive to standard antibacterial agents such as penicillin 2. Actinomyces spp. are commensals of the human oropharnynx, gastrointestinal tract and female genitalia, and are often routinely cultured from these mucosa-lined orifices. Fourteen species have been clearly characterised to date 28. Six of these are thought to be pathogenic in humans, including A. israelii, A. naeslundi, A. odontolyticus, A. viscosus, A. meyeri and A. gerencseriae. A. israelli is the organism most commonly incriminated in human disease. In contrast to other species, A. meyeri may have a greater tendency for affecting the lung and haematogenous dissemination. This propensity for dissemination is difficult to explain; A. meyeri is no different from the other species in its microbiological characteristics 34. In addition to these traditional actinomycotic forms, some coryneform anaerobic bacteria have also recently been assigned to the genus Actinomyces by the Centres for Disease Control (CDC) in the USA 35, 36. Their pathogenic role in humans remains unclear 37. A. bovis, the causative agent in bovine infections, is generally not considered to be a human pathogen. Arachnia propionica, from the related genus Arachnia, is also a well-established cause of actinomycosis.
Depending on the site of infection, most cases of actinomycosis yield a variety of other microorganisms on culture, in addition to Actinomyces spp.
Acinobacillus actinomycetesmcomitans, Eikenella corrodens, Enterobacteriaceace, and species of Fusobacterium, Bacteroides, Capnocytophagia, Staphylococci, and Streptococci have all been isolated with Actinomyces spp. in various combinations 38. An average of two to four and sometimes up to 10 of these concomitant species are usually found in association with the causative actinomycete. Their contribution to the pathogenesis in actinomycosis is unclear. While they are generally regarded as nonpathogenic in the context of actinomycosis, the possibility remains that the disease actinomycosis may be caused by a polymicrobial infection in which Actinomyces spp. predominate 8, 39. It is possible that these other organisms enhance the pathogenicity of actinomycetes by creating an anaerobic millenuea in which Actinomyces thrives. This may be due to the reduction of oxygen tension in tissues and through anaerobiosis-induced inhibition of phagocytes 12. Implications of this for treatment will be discussed later.
Culture and staining characteristics
Actinomyces are fastidious bacteria that are difficult to culture. Bacterial confirmation of a clinico-pathological diagnosis is usually obtained in <50% of cases due to inadequate culturing technique, previous antibiotic therapy and bacterial overgrowth, even when the clinical suspicion is high 2. Actinomyces are sensitive to most of the antibiotics used in everyday practice; even a single dose of an antibiotic before culture may inhibit the organism's growth 27. Correct techniques for collecting and delivering tissue specimens for anaerobic culture are vital, as is communication between the clinician and the microbiologist. Culture requires brain/heart-enriched agar and the organisms grow best at a temperature of 37°C in an atmosphere of 6–10% ambient carbon dioxide. A. viscosus is unique because it grows under microaerophilic or aerobic conditions. A few strains of A. israelii are also microaeropholic. Characteristically, colonies of Actinomyces appear as “molar-tooth” or “bread-crumb” colonies in broth media after 3–7 days of incubation. For adequate growth, however, cultures should be observed for up to 21 days. Differentiation of the species is difficult, requiring assessment of several metabolic capabilities. Fluoroscein-conjugated antibody typing is now available for species differentiation in some centres 28.
Actinomyces stain in tissue with Gomori methenamine silver and the Brown and Brenn modification of the Gram stain 8. Most of the literature classifies the tissue response as granulomatous or “granulomatoid-like”, although giant cells and granulomata are rarely seen 39. Sulphur granules are the pathological hallmark of the disease. These are round or oval basophilic masses with a radiating arrangement of eosinophilic clubs on the surface; they sometimes can be seen even with a magnifying glass. The name “sulphur granule” has its origin in the small nodules resembling elemental sulphur that were commonly used in pharmaceuticals in the 19th century 4. Although they are usually highly suggestive of actinomycosis, they are not diagnostic on their own; they are also seen in nocardiosis, chromomycosis, eumycetoma and botryomycosis, albeit very rarely 39.
A vital step in the development of actinomycosis is the disruption of the mucosal barrier, allowing the organisms to invade. For cervicofacial and abdominal actinomycosis, such a break may result from dental sepsis, appendicitis, diverticulitis, trauma or surgery 4. For pelvic disease it may result from the use of intra-uterine or intravaginal devices 5. Pulmonary actinomycosis probably results from aspiration of oropharyngeal or gastrointestinal secretions into the respiratory tract 2. Poor oral hygiene and associated dental disease may increase the risk 12. Support for aspiration as a risk factor comes from reports of a higher prevalence of alcoholism in patients with the pulmonary form of the disease and from the basilar predominance of the disease radiologically 10. In the pre-antibiotic era, transdiaphragmatic spread of infection from the abdomen was an important route in thoracic actinomycosis, but this is probably no longer so 2, 12. Infection as a result of distant haematogenous seeding, lymphatic spread or spread from the neck through the mediastinum is also now very rare 10. The haematogenous route of dissemination may be a more important source in paediatric thoracic actinomycosis, where the disease has been noted to occur in apparently healthy children with “good” dental health 14, 15.
Pulmonary actinomycosis probably starts when saliva, or other material laden with Actinomyces spp., is aspirated into a minor bronchus, causing atelectasis and a pneumonitis. Once established, the initial acute inflammation is followed by the characteristic chronic, indolent phase that generates local necrosis and fibrosis and commonly cavitates 39. It progresses slowly with little regard for anatomic boundaries, crossing interlobar fissures. It is not clear how much of this propensity to spread is related to the bacteria's proteolytic enzymes, some reports having shown a relative paucity of these 30. If unchecked, the disease invades the pleura, chest wall, soft tissues and bony structures; sinus tracts may form, opening and closing spontaneously.
It is important to make a diagnosis of pulmonary actinomycosis. Although it is now a rare disease with a very low mortality rate 12, early accurate diagnosis will prevent the considerable morbidity, both psychological and physical, associated with either delayed or missed diagnosis. Misdiagnosis, particularly for a malignancy, is distressing for the patient who may end up with a thoracotomy and lung resection for essentially a benign and curable disease. Yet the diagnosis can be quite a challenge. In one series, the diagnosis was suspected on admission in <7% of patients who later turned out to have the infection 29. The average duration of illness before definitive diagnosis was ∼6 months, a consistent figure in most series 29. Even when the clinical suspicion is high, microbiological confirmation can still be difficult, as has been already alluded to. The disease shares many similar clinical features with chronic suppurative lung infections, such as tuberculosis, fungal infections and lung abscesses, and also lung malignancy with which it is commonly confused. Up to a quarter of cases of thoracic actinomycosis are initially diagnosed as malignancy. To confound matters, the disease can coexist with lung-cancer, as Actinomyces spp. have a tendency to colonise devitalised tissue, which commonly occurs within necrotic neoplasms 40. Finding Actinomycetes filaments in sputum alone, particularly without the characteristic sulphur granules, may therefore represent simple colonisation. Thus, short of exploratory thoracotomy, differentiation from lung carcinoma may sometimes be impossible. The diagnosis therefore requires a combination of several factors, including a positive culture and demonstration of sulphur granules in purulent matter from infected tissue, correlation with the clinical and radiological features, and the response to antibiotic treatment.
In 1957, Bates and Cruickshank 31 described a fairly dramatic presentation of pulmonary actinomycosis with prominent chest pain and cutaneous fistulas discharging sulphur granules. This mode of presentation has changed with time in line with the decrease in the disease's prevalence 40, 41. The commonest presentation is probably now as a shadow on a chest radiograph, similar to that caused by bronchial carcinoma. In a previous review of thoracic actinomycosis in five health regions in the UK, the current authors found the three commonest complaints to be cough, sputum and chest pain (table 3⇓). While chest pain was a prominent symptom and may act as a pointer to actinomycosis, the disease's symptoms are still quite nonspecific and similar to those of other chronic suppurative chest diseases and malignancy. In a patient known to have pulmonary actinomycocis, marked weight loss, malaise and high fever may be more suggestive of disseminated disease 10, 11. Physical signs are equally nonspecific, except in advanced, untreated disease, when sinuses and fistulae may then give the diagnosis away. The findings are occasionally those of the associated complications, such as pleural effusion or empyema.
Immunosuppression and pulmonary actinomycosis
Considering the impairments in both cellular and humoral immunity that accompany the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) infection, it is somewhat surprising that the reported incidence of actinomycosis in this group of patients has remained low 42. This fact was recognised early in the course of the epidemic and has subsequently been borne out in more recent studies. While a plethora of other rare granulomatous opportunistic infections have been associated with the AIDS pandemic, there were only 17 reported cases of all forms of actinomycosis in the English literature between 1996 and December 1999 42. Only three of these were pulmonary and even then there was no clear correlation with degree of immunosuppression 43–45. The reason for this is not clear. It is possible the disease is under-diagnosed in this group of patients. Actinomycosis is an infection that is difficult to diagnose even in immunocompetent patients; it may be even more difficult to diagnose in the setting of HIV/AIDS where there are a myriad of other infections with similar indolent and nonspecific presentations. It may also be a reflection of the widespread use of antibiotics in this population, leading to resolution of undiagnosed actinomycotic infection. Younger people also tend to have better dental hygiene and so it is possible that this risk factor is smaller in the predominantly younger group affected by HIV/AIDS, but there is no objective evidence for this. When the disease does occur in HIV/AIDS, its clinical presentation appears similar in pattern to that in immunocompetent people and it appears to respond to the conventional treatment regimens 42. Pulmonary actinomycosis has also not been convincingly shown to have an increased prevalence among other immunocompromised hosts, such as those on chronic steroid therapy, cancer chemotherapy or immunosuppressive therapy postorgan transplant 2, 12. As already alluded to, anecdotal reports have suggested an increased prevalence of the disease in patients with underlying lung disease and alcoholism 8, 30.
Basic tests reflect the nonspecific inflammatory nature of the illness. There is usually a mild leukocytosis, predominantly polymorphonuclear, and, depending on the duration of the illness, a normochromic anaemia. The erythrocyte sedimentation rate and the C‐reactive protein may be moderately raised as with any chronic disease and these probably do not confer any diagnostic advantage.
Radiological pulmonary actinomycosis can resemble a spectrum of lung pathologies ranging from benign infection to metastatic tumour. The main problem is distinguishing the disease from a neoplasm 46. Although, in experienced hands, some forms of imaging may show features more suggestive of actinomycosis, or at least an inflammatory process, than a neoplasm 47, imaging modalities on their own are not diagnostic. Definitive diagnosis is still based on histological or microbiological conformation. Imaging is useful in evaluating the exact location and extent of disease to help direct accurate biopsy and to monitor response to treatment. Irrespective of the imaging modality, a few general principles apply. First, the radiological findings depend on the duration of the infection; in the early stages of the infection, the findings are usually indistinguishable from those of any other pneumonic process. Secondly, the disease usually shows a peripheral and lower lobe predominance, probably reflecting the role of aspiration in its pathogenesis 19. Finally, the disease usually shows some diminution in size within 4 weeks of starting treatment 40.
Plain chest radiograph findings in actinomycosis are nonspecific. A nonsegmental pneumonia, usually in the lower zones, tends to occur peripherally crossing fissures. However, the spectrum of changes is wide, ranging from a few pulmonary infiltrates to cavitating mass lesions involving the pleura, chest wall or even vertebral spine 48, 49.
Computerised tomography and magnetic resonance imaging
There is limited information on both computed tomography (CT) and magnetic resonance imaging (MRI) findings in pulmonary actinomycosis 48, 50. Most of the published series are small retrospective studies. The CT is probably more helpful than the plain radiograph, particularly if performed with a bone window display, which gives a better delineation of minimal bony change, such as early rib erosion and osteomyelitis. These may be easily missed by plain chest radiography. A range of findings have been described on CT in pulmonary actinomycosis, including patchy air-space consolidation, multifocal nodular appearances, cavitation, pleural thickening, pleural effusions and hilar, and/or mediastinal lymphadenopathy 48, 49, 51. Mediastinal lymphadenopathy may be more common than previously thought 19. Consolidation with involvement of adjacent pleura and chest wall, and pulmonary infiltrates with air bronchograms or so-called “air sign”, may be more suggestive of thoracic actinomycosis 30, 47, 49. Associated pleural effusions tend to be small to moderate in size rather than massive 15. Very occasionally, pericardial effusion results from pericardial involvement or pericarditis 52, 53.
Although there is considerable data on the use of MRI in other forms of actinomycosis, such as in the central nervous system, there is little data for its use in the thoracic form 50. Part of the reason may be the attendant problems associated with imaging the chest using MRI.
Fibreoptic bronchoscopy is usually not diagnostic in pulmonary actinomycosis unless there is clear endobronchial disease on which biopsy can be performed 17. Simple culture of the bacteria in bronchoalveolar secretions alone, as with sputum, is inadequate for the diagnosis as it may represent mere colonisation 56. Bronchoscopy is still a useful investigation however, particularly in excluding lung malignancy. Endobronchial actinomycosis may manifest as irregular granular thickening and partial occlusion of bronchi, which resembles submucosal tumour, yet may only demonstrate nonspecific chronic inflammation histologically. It may also be florid disease, showing an exophytic mass with a purulent exudates and characteristic histology with sulphur granules 44. The method of obtaining a bronchial sample is important. The sample should be procured anaerobically with a protected specimen brush 28. Ordinary bronchoalveolar lavage culture, which is not obtained routinely under anaerobic conditions, may be falsely negative if exposed to air for more than 20 min. Transbronchial biopsies have not been successful in providing diagnostic material for thoracic actinomycosis 18, 57.
Some form of lung biopsy is usually necessary to obtain uncontaminated samples for histological and microbiological conformation of pulmonary actinomyocosis 2. The challenge for the clinician is to obtain this in the least invasive fashion. Traditionally, excisional biopsy was the definitive diagnostic procedure 40. In general, an attempt at establishing diagnosis by percutaneous biopsy with fine needle aspiration or core biopsy is now made before “blind” thoracotomy 58. When guided by ultrasound or CT, this has proven a simple, safe and effective diagnostic technique and reduced the number of unnecessary resections 59–61. Sometimes reassurance that the patient does not have a malignancy can only be provided by open resection. In these few patients, if the diagnosis is suspected pre-operatively, the aim should be to conserve as much of the lung as possible. Since the gross appearance of the pulmonary actinomycosis intra-operatively is indistinguishable from that of carcinoma, a frozen section, on a wedge resection or surgical trucut biopsy, may help in deciding the extent of the resection 59, 60. It is still important to alert the pathologist of the suspected diagnosis, as special stains may have to be used to look for the organism 59.
Sulphonamides were the real first breakthrough rationale drug therapy in actinomycosis in the late 1930s, until they were superseded by penicillin, which has remained the drug of choice over the last 50 yrs. Before that, a whole variety of unproven remedies had been tried, including potassium iodide (KI), radiation treatment and thymol and copper. KI was used because of an early misconception that the Actinobacillus in cattle, which is sensitive to KI, was the causative agent in humans. Actinomyces is insensitive to KI 62. Thymol and copper were popularised for their astringent properties before the availability and acceptance of antibiotics. When the disease is diagnosed early, pulmonary actinomycosis is a relatively easy disease to treat with an excellent prognosis. The duration of treatment is less clear.
The rationale for the use of penicillin in actinomycosis is based more on extensive successful clinical experience over the last 50 yrs than on randomised control trials 12. The main principle of treatment is the use of high-dose intravenous penicillin for a long duration of treatment. Although treatment has to be tailored to the individual, generally 18–24 million units of penicillin per day are given for 2–6 weeks followed by oral therapy with penicillin V (or amoxicillin) for 6–12 months. In general, the thoracic form appears to require longer treatment courses compared to the other commoner forms 40. Tetracyclines are the alternative especially for penicillin-allergic patients. In pregnant, penicillin-sensitive patients, erythromycin is a safe alternative. Other alternatives, which are probably effective, but for which there is less extensive clinical experience, are shown in table 4⇓.
Presumably, the avascularity and induration of infected areas account for the need for prolonged treatment and undoubtedly longer courses minimise the risk of relapses, a clinical hallmark of the infection. Response to treatment should be monitored radiologically with plain radiographs and/or CT. Diminution in the shadowing on a chest radiograph is expected within 4 weeks. Coexistent bronchial carcinoma should be suspected in case of medical treatment failure 22. Evidence shows that this standard treatment approach applies to people who are immunocompromised for one reason or another 42. Several newer antimicrobial agents have been tried with an emphasis on shorter courses of treatment (table 4⇓). Although there are anecdotal reports of success with this approach, there is limited clinical experience and only randomised trials, which are probably impractical, would resolve this question.
The question of whether to treat the co-pathogens usually associated with Actinomycetes is not completely resolved. Some have advocated designing initial antibiotic regimens to specifically target these organisms as well. Interestingly, although most of these organisms are not sensitive to penicillin in vitro, they are usually eradicated (clinical cure) when the antibiotic is administered 29. It is probably not necessary to use additional antibiotics.
Even with extensive pulmonary disease, medical cure should still be attempted. Nevertheless, surgery remains an important therapeutic adjunct. It is particularly useful if there are complications, such as well-defined abscesses and empyemas, or where discharging fistulas and sinuses may need to be opened up 68, or, in very rare instances, to control life threatening haemoptysis that can occur with the infection 69, 70. When surgery has been the initial treatment, even if histology suggests complete resection, it still needs to be followed by prolonged antibiotic therapy, as surgery alone is usually not curative 71, 72. Inadequate antibiotic therapy postoperatively may result in complications such as broncho-pleural fistulas and empyema.
The prognosis of the pulmonary form of actinomycosis may be less favourable compared with the other commoner forms, such as cervicofacial and abdominal disease 10. This may be related to the greater incidence of disseminated disease in the thoracic form and may also be a reflection of late diagnosis in this condition. However, when the infection is recognised early and proper treatment is given the condition has an excellent prognosis with a very low mortality 29. Every respiratory physician should be familiar with this important differential in any patient with long-standing pulmonary infiltrates to prevent unnecessary morbidity or even unwarranted surgery.
↵Previous articles in this series: No. 1: Tärnvik A, Berglund L. Tularaemia. Eur Respir J 2003; 21: 361–373.
- Received September 29, 2002.
- Accepted October 25, 2002.
- © ERS Journals Ltd