Two Cases of Mycobacterium shinjukuense Pulmonary Disease With a Long-Term Response to Treatment With Clarithromycin, Rifampicin, and Ethambutol

Mycobacterium shinjukuense is a nontuberculous mycobacterium, and standard treatment for the infection has not been established. We report two cases of M. shinjukuense pulmonary disease in which two patients were treated with clarithromycin (CAM), rifampicin (RFP), and ethambutol (EB). Based on computed tomography (CT) findings, the patients experienced improvement with treatment. Reports of multiple cases of M. shinjukuense pulmonary disease treated with clarithromycin, rifampicin, and ethambutol are valuable, and they suggest that this regimen may be a new treatment option.

Mycobacterium shinjukuense was first isolated in 2004 in the Shinjuku ward, a central location in Tokyo, Japan, and was first reported in 2011 by Saito et al. [1].To date, 23 cases of M. shinjukuense infection have been reported in Japan and Korea [1][2][3][4][5][6][7][8][9][10][11].However, its pathogenicity and prognosis are unknown, and there is no established treatment.The aim of reporting two cases of M. shinjukuense pulmonary disease is to help fill that knowledge gap.

Case Presentation Case 1
A 74-year-old female visited her primary care doctor because of a cough and bloody sputum at the end of June 2018.She had a history of osteoporosis but no history of respiratory diseases or smoking and no episodes of suspected exposure to water or soil.She was prescribed a cough suppressant, levofloxacin, and carbazochrome sodium sulfonate, and her symptoms improved after approximately two weeks.However, a chest radiograph obtained after her symptoms improved showed an enhanced infiltrative shadow in the right lower lung field.Therefore, the patient was referred to our hospital in early July 2018.
At the time of the first visit, her body mass index (BMI) was 19.8, and no abnormalities were observed in her vital signs or physical findings.Blood tests showed no abnormalities in the blood counts or biochemical tests.T-SPOT.TB was positive, but anti-MAC antibody was negative (Table 1).Sputum smear microscopy for acid-fast bacilli, which was performed at the initial visit, was negative.The results of the sputum polymerase chain reaction (PCR) for TB (COBAS TaqMan MTB, Roche, Basel, Switzerland) and MAC (COBAS TaqMan 48, Roche, Basel, Switzerland) were negative (Table 2).Chest radiography revealed an infiltrating shadow with an air bronchogram and bronchiectasis in the right middle and lower lung fields (Figure 1).Chest computed tomography (CT) revealed bronchiectasis mainly in the right middle lobe and a cavity in the right S6 region (Figure 2).As nontuberculous mycobacterial lung disease was suspected on CT, bronchial lavage was performed in the right middle lobe in late July 2018.The smear microscopy of bronchial lavage fluid for acid-fast bacilli was 1+, PCR analyses of bronchial lavage for TB (COBAS TaqMan MTB) and MAC (COBAS TaqMan 48) were both negative.Mycobacterium shinjukuense was isolated from sputum collected at the initial examination and bronchial lavage fluid after six weeks of incubation by mass spectrometry (matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry {MALDI-TOF MS}) (Table 2), resulting in the diagnosis of M. shinjukuense pulmonary disease.
The patient was followed up without treatment after the diagnosis.However, because chest CT showed worsening of the shadows (Figure 3a, 3b), treatment with clarithromycin (CAM), rifampicin (RFP), and ethambutol (EB) was initiated in mid-January 2019.After the initiation of treatment, the shadows on chest CT improved (Figure 3c, 3d), and the respiratory symptoms disappeared.However, treatment was terminated in mid-January 2020, as vision loss appeared with the administration of EB.The patient's visual acuity improved after stopping treatment for M. shinjukuense.After the start of treatment, the amount of sputum decreased, and a sputum examination could not be performed.However, in July 2020, a sputum acid-fast bacilli culture was negative.The CT findings in March 2022 remained stable with no recurrence or progression (Figure 3e, 3f).

Case 2
An 82-year-old female visited her primary care physician in early August 2022 because of a fever.She had no specific medical history and no history of respiratory disease or smoking.She was a floriculturist and had a history of daily exposure to water and soil.She was diagnosed with COVID-19 infection using a COVID-19 antigen test and was referred to our department for close examination and treatment for hypoxemia.
The patient had a fever of 38°C and oxygen saturation of 86% in room air.Her BMI was 17.8, and there were no abnormalities in her physical findings at the time of the first visit.Blood tests showed no abnormalities in blood counts, but biochemical tests showed a mild increase in C-reactive protein.T-SPOT tests were negative for TB and anti-MAC antibodies (Table 3).Sputum smear microscopy for acid-fast bacilli, which was performed at the initial visit, was negative.PCR assays of sputum samples were negative for TB (COBAS TaqMan MTB) and MAC (COBAS TaqMan 48) (Table 4).Chest radiography revealed an infiltrating shadow in the right upper and lower lung fields (Figure 4).Chest CT showed an infiltrative shadow and bronchiectasis in the right upper and middle lobes and lobular central granular shadows in both lower lobes (Figure 5).Chest radiography at the initial visit to our hospital showed an infiltrating shadow in the right upper and lower lung fields.As nontuberculous mycobacterial lung disease was suspected on the basis of CT findings, bronchial lavage was performed in the right middle lobe in late November 2022.The smear microscopy of the bronchial lavage fluid for acid-fast bacilli was negative, and the PCR of the bronchial lavage for TB (COBAS TaqMan MTB) and MAC (COBAS TaqMan 48) was negative.Mycobacterium shinjukuense was isolated from bronchial lavage fluid after eight weeks of incubation by mass spectrometry (MALDI-TOF MS) (Table 4), which resulted in the diagnosis of M. shinjukuense pulmonary disease.

Reference
The patient was followed up without treatment for approximately six months after the diagnosis.However, because the structural destruction of the lungs had already progressed and CT showed no improvement in the shadows (Figure 6a), treatment with CMA, RFP, and EB was initiated in early February 2023.The lobular central granular shadows in both lower lobes have improved since the start of treatment (Figure 6b), and at
Although there have been many reports of M. shinjukuense treated with anti-TB drugs, as mentioned above, five cases of M. shinjukuense that responded to treatment with CAM, RFP, and EB have also been reported [2,4,10,11].The current report adds two more.In Case 1 of our report, the patient completed 12 months of treatment and remained stable without treatment for 26 months.This case has the longest known treatment course for M. shinjukuense lung disease cases reported to date.In most of the reports to date, cases of M. shinjukuense treated with CAM, RFP, and EB have been reported in more detail than cases treated with anti-TB regimen.In many cases, as in Case 1 of the present case, the course of treatment is known for a relatively long time compared with cases treated with anti-TB drugs (Table 5).
The present case report has two limitations.First, we were unable to submit drug susceptibility tests for M. shinjukuense in either case.Although the in vitro drug sensitivity of nontuberculous mycobacteria is not necessarily reflective of in vivo conditions, we believe that it provides important information for determining treatment strategies.Second, nontuberculous mycobacteria may heal spontaneously without treatment, so it may not be possible to conclude that drug treatment was successful.

Conclusions
We report two cases of M. shinjukuense that were treated with CAM, RFP, and EB regimens.Although the standard treatment for M. shinjukuense has not yet been established, our findings suggest that the combination of CAM, RFP, and EB could be an effective approach.Given the rarity of pulmonary infections caused by M. shinjukuense, further investigation through additional case studies is needed.

FIGURE 1 :
FIGURE 1: Chest radiography at the initial visit to our hospital of Case 1.Chest radiography at the initial visit to our hospital showed an infiltrative shadow with an air bronchogram and bronchiectasis in the right middle and lower lung fields.

FIGURE 2 :
FIGURE 2: Chest computed tomography at the initial visit to our hospital of Case 1. Chest computed tomography in early July 2018 (at the initial visit) to our hospital showed a cavity in the right S6 region (a) and bronchiectasis mainly in the right middle lobe (b).

FIGURE 3 :
FIGURE 3: Progress of computed tomography of Case 1. (a and b) Computed tomography (CT) in mid-January 2019 showed an enlarged cavity and worsening infiltrative shadow.(c and d) CT in mid-January 2020 showed a reduction in the cavity and an improvement in the infiltrative shadow.(e and f) CT in mid-March 2022 showed no sign of the re-expansion of the cavity or the reaggravation of the infiltrative shadow.

FIGURE 4 :
FIGURE 4: Chest radiography at the initial visit to our hospital of Case 2.

FIGURE 5 : 2 .
FIGURE 5: Computed tomography at the initial visit to our hospital of Case 2. Computed tomography (CT) showed an infiltrative shadow and bronchiectasis in the right upper (a) and middle lobes and lobular central granular shadows in both lower lobes (b).

FIGURE 6 :
FIGURE 6: Progress of computed tomography of Case 2.

( a )
Computed tomography (CT) in mid-February 2023 showed no improvement of lobular central granular shadows in both lower lobes.(b) CT in early October 2023 showed the improvement of lobular central granular shadows in both lower lobes.

TABLE 5 : Case list and clinical features of M. shinjukuense pulmonary infection.
[13]3][4]6]um shinjukuense has been reported to have good susceptibility to isoniazid (INH), RFP, EB, and CAM in vitro[2][3][4]6].However, in the case of nontuberculous mycobacteria, the results of the drug susceptibility test should be carefully interpreted, as the susceptibility in vitro and in vivo may not be consistent[13].Although the standard chemotherapy for M. shinjukuense has not been established, in the past treated cases (excluding our cases), nine of 15 cases were treated with INH, RFP, and EB (including one case in which the initial regimen was INH+RFP+EB+pyrazinamide {PZA} and changed to CAM+RFP+EB during the course of treatment, one case that changed to erythromycin {EM} during the course of treatment, one case that switched from INH+RFP+EB+PZA, and one case that switched from CAM); five cases were treated with CAM+RFP+EB (including one case that switched from INH+RFP+EB+PZA treatment and two cases that switched from CAM+RFP+EB+kanamycin); and two cases were treated with EM (including one case that switched from INH+RFP+EB to EM and one case in which the initial regimen was INH+RFP+CAM and changed to RFP+CAM+levofloxacin) (Table