Drastically progressive lung cavity lesion caused by Actinomyces odontolyticus in a patient undergoing chemoradiotherapy: A case report and literature review.

Pulmonary actinomycosis reportedly forms 15% of all cases of actinomycosis, and pulmonary Actinomyces odontolyticus is particularly rare. A 60-year-old man with a hoarse voice was referred to our hospital. Lung squamous cell carcinoma was diagnosed at the clinical tumor-node-metastasis stage of cT2N2M0, and concurrent chemoradiotherapy was initiated. Further, a small cavity was also detected in the left upper lobe, but it was observed. During chemoradiotherapy, the small cavity lesion rapidly increased accompanying infiltration, and administration of short-term antibiotics did not improve the patient's condition. Bronchoscopy did not show any diagnostic results. Although a rapidly progressive malignant lesion could not be excluded and surgical management was considered, resection could not be performed because of the tight adhesion of the mass. Therefore, bronchoscopy was performed again, and the bronchial lavage culture showed a positive smear for the Actinomyces species. Further, using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), the bacteria was identified as A. odontolyticus. After long-term administration of amoxicillin, the lung cavity with infiltration gradually improved. To the best of our knowledge, there have been nine cases of pulmonary A. odontolyticus (excluding those with only empyema or pleural mass without lung lesions), which can occur in immunocompetent patients with persistent lung shadow. None of the cases showed drastic deterioration; therefore, the present case is the first to highlight that A. odontolyticus possibly produce drastically progressive lung cavity lesion. Further, repeated bronchoscopy and MALDI-TOF MS could help to diagnose pulmonary actinomycosis.

Introduction

Actinomyces species are anaerobic gram-positive rods. Actinomycosis has been reported worldwide. Recently, the incidence of all types of actinomycosis has markedly declined. Total 15% of all cases of actinomycosis are of pulmonary actinomycosis [1]. Pulmonary actinomycosis is rare, mainly owing to A. israelii and A. odontolyticus being particularly rare [[1], [2], [3]]. A. odontolyticus was first isolated from dental caries in 1958 and is a commensal organism found in the mouth [4]. Actinomycosis is difficult to diagnose using bronchoscopy or sputum culture [1], and in many patients, surgery is required for diagnosis [5]. In addition, usually, pulmonary actinomycosis gradually grows with air-space consolidation, adjacent pleural thickening, or cavitation in the lung field [6]; hence, pulmonary actinomycosis is not likely to be a disease with a rapidly progressive clinical course. Therefore, patients with progressive pulmonary disease can be misdiagnosed and consequently treated inappropriately. Here we report a case of drastically progressive lung cavity lesion caused by A. odontolyticus in a patient undergoing chemoradiotherapy and present a literature review.

Case report

A 60-year-old man with a hoarse voice was referred to our hospital. He did not have any medical history but had been smoking for 40 pack-years. His physical examination revealed no apparent abnormalities except for hoarse voice. Left vocal cord paralysis was discovered, and chest X-ray revealed a mass in the left hilum (Fig. 1a).

Fig. 1

(a) Chest X-ray at the time of the patient's referral showing a mass in the left hilum. (b) The first bronchoscopy showing a mass with distended vessels in the left main bronchus that was identified as lung squamous cell carcinoma. (c, d) Positron emission tomography showing high uptake of fluorodeoxyglucose with mediastinal lymphadenopathy in the mass in the left main bronchus [maximum standardized uptake value (SUVmax) = 11.5]; however, minor uptake was observed in a small cavity in the left upper lobe (SUVmax = 1.9).

Computed tomography (CT) revealed a mass with mediastinal lymphadenopathy in the left main bronchus and a small cavity in the left upper lobe. Bronchoscopy revealed a mass with distended vessels in the left main bronchus (Fig. 1b), and the mass was revealed to be lung squamous cell carcinoma. Positron emission tomography revealed high uptake of fluorodeoxyglucose in the mass in the left main bronchus [maximum standardized uptake value (SUVmax) = 11.5]; however, minor uptake was observed in the lung cavity (SUVmax = 1.9) (Fig. 1c and d). The patient was diagnosed with lung squamous cell carcinoma at the clinical tumor-node-metastasis stage of cT2N2M0 (stage 3A). Concurrent chemoradiotherapy, i.e., chemotherapy comprising weekly carboplatin and paclitaxel combined with radiation therapy (60 Gy; 30 fractions), was initiated. A small cavity located in the left upper lobe was not included in the radiation field.

During chemoradiotherapy, the small cavity lesion steadily increased (Fig. 2).

Fig. 2

Clinical and radiological course.

The small cavity in the left upper field rapidly increased and gradually improved after long-term administration of antibiotics. Continuous arrows represent the points considered for CXR and dashed arrows represent those for CT shown below.

ABPC, ampicillin; ABPC/SBT, ampicillin/sulbactam; AMPC, amoxicillin; wCBDCA, weekly carboplatin; CT, computed tomography; CXR, chest X-ray; FBS, fiberoptic bronchoscopy; GRNX, garenoxacin; MEPM, meropenem; wPTX, weekly paclitaxel.

Two weeks after chemoradiotherapy was initiated, CT revealed increased cavity wall thickness and new infiltration. Although the patient had no fever or purulent sputum, bacterial infection was assumed, and administration of antibiotics (ampicillin/sulbactam, 1.5 g every 6 h) was initiated. All sputum cultures for bacteria, including acid-fast bacteria, were negative, and chest X-ray obtained 5 days later revealed enlargement of the cavity under the administration of antibiotics.

Physical examination revealed no apparent abnormality, even in the oral cavity, and the following observations were noted: heart rate, 88 beats/min and regular; blood pressure level, 102/72 mmHg; oxygen saturation level, 97% on room air; and body temperature, 36.5 °C. Laboratory testing revealed a white blood cell count of 4800/mm3 with a neutrophil percentage of 70.9% and C-reactive protein level of 2.66 mg/dL. Procalcitonin level, interferon-gamma release assay findings, Mycobacterium avium complex-specific glycopeptidolipid core antigen antibody level, Aspergillus galactomannan antigen level, and β-d-glucan level were all within normal ranges. The second bronchoscopy was performed for diagnosis; although the mass in the left main bronchus identified as lung squamous cell carcinoma was diminished, there were no apparent findings indicating bacterial infection. However, garenoxacin, 400mg once daily, was administered owing to the rapid progression of the disease and the consideration of bacterial infection. The bronchial lavage culture was negative for bacteria, and the bronchial tissue showed no evidence of malignancy. Further, Mycobacterium szulgai was cultured; however, considering the clinical course, as described later, the organism was not considered to be the causative organism.

Although the administration of garenoxacin was continued, the lung cavity with infiltration drastically increased (Fig. 2). Because the presence of a rapidly progressive malignant lesion could not be excluded, surgical management was considered for the diagnostic therapy. However, resection could not be performed because of the tight adhesion of the mass. Therefore, the third bronchoscopy was performed. The bronchial lavage culture showed a positive smear for the Actinomyces species, and using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS; MALDI Biotyper; BRUKER, Billerica, MA, USA), the bacteria was identified to be A. odontolyticus.

Based on the antimicrobial susceptibility test results (minimum inhibitory concentration <0.125 μg/ml for ampicillin), ampicillin, 2 g every 6 h, was injected for 2 weeks followed by oral administration of amoxicillin, 500 mg t.i.d. The patient continued to receive treatment in the outpatient department. After chemoradiotherapy, the lung squamous cell carcinoma was treated using durvalumab. Continuous administration of durvalumab and amoxicillin for 4 months suppressed the lung squamous cell carcinoma and gradually improved the lung cavity with infiltration (Fig. 2).

Discussion

We reported a drastically progressive lung cavity lesion caused by A. odontolyticus in a patient undergoing chemoradiotherapy. In this case, diagnosis of drastically progressive lung cavity lesion and its distinction from the diagnosis of rapidly progressive malignant tumor were difficult; however, repeated bronchoscopy and MALDI-TOF MS identified A. odontolyticus, which contributed to the appropriate treatment.

Oral insanitation, diabetes, and frequent alcohol consumption are reportedly the risk factors of pulmonary actinomycosis; however, no baseline diseases are found in 30% of them [7]. Of note, immunosuppression, such as that caused by acquired immune deficiency syndrome, cancer chemotherapy, or chronic steroid therapy, has not been reported as the risk factor for pulmonary actinomycosis [8,9]; however, underlying lung disease reportedly increases the prevalence of pulmonary actinomycosis [10]. Emphysema is reported to be associated with increased activity of proteolytic enzymes, which are activated because of inflammation and oxidative stress occurring in chronic obstructive pulmonary disease (COPD) [11]. Also, inflammation and chronic colonization of Haemophilus influenzae in sputum of patients with COPD were reported to be associated with the degree of emphysema and bronchiectasis on CT [12]. Therefore, in the present case, having emphysematous lesions might have predisposed the patients to bacterial infections, and these lesions possibly contributed to the infection by A. odontolyticus. Although the lung cavity lesion was not included in the radiation field, local immunosuppression might have affected the course of pulmonary actinomycosis because of the presence of lung squamous cell carcinoma and the administration of chemoradiotherapy.

Pulmonary actinomycosis is reportedly difficult to culture owing to the lack of culturing techniques, prevalence of previous antibiotic therapy in the patient, and bacterial overgrowth even when clinical suspicion is high, thereby resulting in a culture rate of <50% [1,9]. First, A. odontolyticus is part of the normal oropharyngeal flora, and positive sputum culture cannot establish the diagnosis of pulmonary actinomycosis [3]. Generally speaking, it is difficult to prevent the cross contamination of oral bacteria during bronchoscopy, and in this case, it was impossible to rule out coinfection by other bacteria in addition to A. odontolyticus. However, incubation of the bronchial lavage led to a significant number of A. odontolyticus colonies, and long-term administration of antibiotics was effective for treating the lung cavity lesion. Therefore, we believe that A. odontolyticus was the causative organism in this case. Pulmonary actinomycosis is most commonly misdiagnosed as a malignant disease or tuberculosis [13]; moreover, nocardiosis, histoplasmosis, blastomycosis, mixed anaerobic infections, bronchogenic carcinoma, lymphoma, mesothelioma, and pulmonary infarction are among the entities confused with pulmonary actinomycosis [14]. A quarter of cases were misdiagnosed as malignancy, and surgery was performed [1]. In the present case, although surgical resection was difficult, repeated bronchoscopy yielded the specimen. In addition, MALDI-TOF MS was effective in detecting the causative organism. Thus, MALDI-TOF MS would be a new tool for the diagnosis of this infectious disease [5,15].

In the present case, short-term administration of antibiotics could not improve the patient's condition; however, this does not necessarily indicate that the bacteria were resistant to the antibiotics. Infection caused by Actinomyces species is usually recommended to be treated using penicillin injection for 2–6 weeks followed by oral penicillin for 6–12 months [1,13]. In fact, in the present case, long-term administration of antibiotics improved the radiological findings.

To the best of our knowledge, there have been nine patients with pulmonary A. odontolyticus (excluding those with only empyema or pleural mass without lung lesions) [2,3,[16], [17], [18], [19], [20], [21], [22]]. A summary of the reported cases is presented in Table 1.

Table 1

Summary of pulmonary Actinomyces odontolyticus (excluding those with only empyema or pleural mass without lung lesions).

Authors	Age (y), sex	Presentation	Comorbidities or immunocompromised factors	Diagnostic method	Antibiotics for long-term administration	Outcome
Takiguchi et al. [3]	64, female	Lung abscess	Periodontal disease	Percutaneous needle aspiration	Sultamicillin tosilate	Recovery
Baron et al. [16]	61, female	Lung abscess	Rheumatoid arthritis with prednisone therapy	Transthoracic aspiration	Penicillin	Recovery
Dontfraid F et al. [17]	52, female	Pneumonia with soft-tissue abscesses	Alcoholism and periodontal disease	Cutaneous drainage	Amoxicillin	Recovery
Bassiri et al. [2]	61, male	Pneumonia	Lung transplantation with prednisone, cyclosporine, and azathioprine	Bronchoscopy	Penicillin	Recovery
Iancu et al. [18]	37, female	Lung abscess	B cell lymphoma with prednisone therapy	Thoracotomy	Penicillin and metronidazole	Deceased
Verrot et al. [19]	52, female	Pneumonia	Bronchiectasis	Surgery	Imipenem and minocycline	Recovery
Susaki et al. [20]	51, male	Pneumonia	Dental caries	Sputum	Penicillin	Recovery
Gray et al. [21]	11, female	Pneumonia	Bronchiectasis	Bronchoscopy	Penicillin	Recovery
Erro Iribarren et al. [22]	43, male	Pneumonia	Bronchial asthma with omalizumab	Bronchoscopy	Amoxicillin-clavulanic acid	Recovery
Present case	60, male	Pneumonia	Lung squamous cell carcinoma undergoing chemoradiotherapy	Bronchoscopy	Amoxicillin	Recovery

Considering the reported cases, an immunocompetent patient can also suffer from pulmonary A. odontolyticus. Aspiration of oropharyngeal or gastrointestinal secretions into the respiratory tract, or in rare cases, hematogenous dissemination due to disruption of the gastrointestinal tract mucosal barrier caused by periodontal disease, dental procedure, bacterial suppuration, surgery, or trauma is considered to cause pulmonary actinomycosis [1,13]. Although there was no apparent periodontal disease, dental caries, or Actinomyces bacteremia in the present case, similar cases have previously been reported [19,21]. Although one patient died likely due to lymphoma, pulmonary A. odontolyticus usually has a good prognosis. None of the cases, including immunocompromised ones, showed drastic deterioration. Therefore, the clinical course of the disease in our patient was rare; however, our case suggests that we should be aware that pulmonary A. odontolyticus could rapidly become exacerbated.

In conclusion, pulmonary A. odontolyticus is rare but can occur in immunocompetent patients with persistent lung shadow. Further, it should be noted that A. odontolyticus may produce drastically progressive lung cavity lesion. Repeated bronchoscopy and MALDI-TOF MS could help to diagnose pulmonary actinomycosis.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Patient consent for publication

Consent for publication has been obtained.

Declaration of competing interest

The authors have no conflict of interest.