In a routine medical check-up, a healthy man in his 20s was found to have an upper left lung abnormality. Subsequent chest CT revealed the cluster sign (CS) and galaxy sign (GS). Although tests such as sputum analysis and interferon-gamma assays reduced the likelihood of tuberculosis, these abnormalities remained unchanged. A lung biopsy indicated non-caseating granuloma unrelated to tuberculosis. Initially suspected of sarcoidosis, the patient later developed fever and malaise. Follow-up CT showed CS progressing to a cavitatory shadow and GS intensification. The detection of Mycobacterium tuberculosis (M. tuberculosis) in a subsequent sputum analysis prompted treatment with antitubercular drugs, leading to symptom relief.
CS and GS are usually associated with sarcoidosis but can also occur in tuberculosis, connected to slower pathogen growth and lower isolation rates. Furthermore, pulmonary tuberculosis may ultimately be present even when biopsies show non-caseating granulomas that are not typical of M. tuberculosis and sputum culture results are negative for M. tuberculosis. Tuberculosis should not be ruled out lightly, and patients should be carefully followed-up.
- TB and other respiratory infections
- Respiratory medicine
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The cluster sign (CS) and galaxy sign (GS) are recognised as typical manifestations within the context of sarcoidosis. GS denotes a substantial pulmonary nodular opacity comprising centrally amalgamated micronodules, a phenomenon detailed in a study conducted by Nakatsu et al.1 In contrast, CS is delineated as a simplistic amalgamation of diminutive nodules, irrespective of central coalescence, as described by Ortega et al.2 Notably, these visual indicators may also manifest in instances of pulmonary tuberculosis.3 4 Here, we report a case of pulmonary tuberculosis that presented with GS and CS and was difficult to diagnose because the biopsy revealed a non-caseating granuloma, which is not typical for tuberculosis, as well asnegative Mycobacterium tuberculosis (M. tuberculosis) sputum culture results.
An asymptomatic Asian man in his 20s underwent a chest X-ray for a medical check-up, which revealed an abnormality in the left upper lung field. No abnormality was noted on his chest X-ray in the previous year. The patient had taken an overseas business trip to several countries 2 years earlier but had not gone abroad since that time. There was no family history of tuberculosis, and his medical background did not feature any distinctive occurrences. He had no previous history of suspected or treated sarcoidosis. He smoked several cigarettes a day for the past 5 years. The patient had an office job and rarely went out except for frequent visits to a sauna as a hobby.
Physical examination revealed no abnormalities of the skin, neurological function or visual field. Electrocardiographic results were normal. Following a span of 2 months from the initial medical check-up, a follow-up thoracic radiograph showed persistent opacities. Therefore, a chest CT scan was performed, which revealed two abnormalities in the left upper lobe, showing CS and GS (figures 1A and 2A). Mediastinal and hilar lymph node enlargement was unremarkable. Acid-fast bacilli (AFB) smear and culture of sputum specimens were all negative. Blood tests showed negative interferon-γ release assay results, negativity for HIV antigen and antibody, an angiotensin I-converting enzyme (ACE) level of 9.6 U/L (normal range: 8.3–21.4 U/L), and a lysozyme level of 5.4 µg/mL (normal range: 5.0–10.2 µg/mL).
Seven months after the initial medical check-up, another CT scan was performed, which showed no changes. Blood tests at that time showed ACE and lysozyme levels of 10.8 U/L and 5.7 µg/mL, respectively. A bronchoscopy test was planned but only performed 10 months after the initial medical check-up for the patient’s convenience. Bronchoalveolar lavage was performed, and the bronchoalveolar lavage fluid (BALF) had a total cell count of 1.35×105 cells/mL, with a slight lymphocyte predominance (lymphocytes 17%, macrophages 70%, eosinophils 0.5%). The CD4/CD8 ratio of lymphocytes in the BALF was 3.16. Brush and transbronchial lung biopsy were performed by endobronchial ultrasonography using a guide sheath technique at a site consistent with the CS and GS. The biopsy revealed a non-caseating granuloma with no evidence of M. tuberculosis. AFB smears, PCR tests, and cultures submitted with brush samples were all negative. Other bacterial and fungal cultures were also negative.
Based on the results of previous tests, the patient believed there was less likelihood of having pulmonary tuberculosis. The pathology results were consistent with sarcoidosis, and a watch-and-wait approach was considered appropriate. We did not list any disease other than tuberculosis or sarcoidosis as differential diagnoses.
Fourteen months after the initial medical check-up, the patient developed fever and malaise that continued for 3 weeks. On chest X-ray, a cavitatory shadow was noted in the left lung field (figures 1B and 2B). Blood tests showed a positive interferon-γ release assay with an ACE level of 7.5 U/L and lysozyme level of 8.7 µg/mL. Sputum examination was smear-positive, PCR detected M. tuberculosis, and subsequent culture identified M. tuberculosis. Therefore, the patient was diagnosed with pulmonary tuberculosis. Regarding the resistance profile, GeneXpert testing could not be performed because it was unavailable at our hospital. Antitubercular medication susceptibility confirmed by culture strains showed no resistance to antimicrobials, including fluoroquinolones and aminoglycosides.
Treatment with four antitubercular medications, rifampicin, isoniazid, ethambutol and pyrazinamide, was initiated, and the symptoms improved within a few days.
Outcome and follow-up
M. tuberculosis was susceptible to all therapeutic agents, and after 2 months, the treatment was changed to rifampicin and isoniazid for a total of 6 months. Chest X-ray at the end of the treatment showed that the cavity had disappeared and improved (figure 1C). The patient has experienced no recurrence since then.
Pulmonary tuberculosis is commonly associated with caseous granulomas and can be diagnosed through the detection of M. tuberculosis by either sputum examination or bronchoscopy. In our case, chest CT revealed the presence of CS and GS, and although a biopsy was performed, pulmonary tuberculosis was not diagnosed. Eventually, due to the progression of the disease, M. tuberculosis was detected by sputum samples.
CS and GS are generally recognised as characteristic features of pulmonary sarcoidosis. Sarcoid GS was first reported by Nakatsu et al, and CT and pathological studies showed numerous coalescent granulomatous lesions, which are denser in the central region.1 The presence of GS has also been shown to be associated with younger age and a low CD4/CD8 ratio in the BALF.5 This is similar to the characteristics of this case and would be consistent if the final diagnosis was sarcoidosis. On the other hand, CS has been shown to correspond to non-caseous, non-coalescing granulomas distributed in lymph vessels.2
CS and GS are not necessarily specific to sarcoidosis, and they can also be found in pulmonary tuberculosis, although less frequently than in sarcoidosis.5 6 However, CS and GS in pulmonary tuberculosis correlate with lower isolation of M. tuberculosis.6 7 It has also been reported that smaller CSs are often non-caseous granulomas.3 Therefore, when a non-caseating granuloma is found on biopsy and the acid-fast staining is negative, as in the present case, distinguishing the case from sarcoidosis is challenging.4 Furthermore, it is known that pulmonary tuberculosis presenting with CS progresses slowly, with a median time of about 6 months, which explains why the images did not initially change for several months in our case.3 As described above, pulmonary tuberculosis presenting with CS and/or GS often presents with atypical findings and should be recognised as a red flag sign to be aware of the possibility of misdiagnosis. At the time bronchoscopy was performed in this case, it was difficult to rule out pulmonary tuberculosis because of the atypical findings and the sensitivity of the tests. However, it is possible to have discomfort with the tentative diagnosis of sarcoidosis. For example, at the time of bronchoscopy in this case, the tissue and microbiological diagnoses were consistent with sarcoidosis, but there was no bilateral hilar lymph enlargement,1 which should be frequently seen on CT, and ACE and lysozyme levels were not elevated. In addition, there were no lesions consistent with sarcoidosis outside of the lungs. Sarcoidosis with these features can exist but is expected to be infrequent. When encountering such a case, the best approach is to follow-up as carefully as possible, inform the patient of the possibility of pulmonary tuberculosis, and educate them to seek medical attention as early as possible at the onset of respiratory symptoms. In fact, 3 weeks had passed since the onset of symptoms in this case, and it is possible that tuberculosis had spread during that time; therefore, early diagnosis is desirable in terms of public health implications. Pulmonary tuberculosis presenting with CS and GS has also been reported in multi-drug-resistant tuberculosis,8 and naturally, it is necessary to aim for accurate diagnosis and appropriate treatment before administering antituberculous agents.
Cluster sign (CS) and galaxy sign (GS) are typically recognised as the characteristic features of pulmonary sarcoidosis; however, they may also be present in pulmonary tuberculosis.
CS and GS in pulmonary tuberculosis are associated with lower pathogen isolation.
Even if a biopsy shows non-caseating granulomas and a sputum culture of Mycobacterium tuberculosis is negative, a diagnosis of pulmonary tuberculosis may ultimately be made.
In these cases, careful follow-up is necessary, and the possibility of pulmonary tuberculosis should not be overlooked.
Patient consent for publication
Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: TN. The following authors gave final approval of the manuscript: NN.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.