Mavintramycin A is a promising antibiotic for treating Mycobacterium avium complex infectious disease.

Mycobacterium avium complex (MAC) is a serious disease that is mainly caused by infection with the non-tuberculous mycobacteria (NTM), Mycobacterium avium and Mycobacterium intracellulare. Seven new compounds, designated mavintramycins A-G (1-7), were isolated along with structurally related compounds, including amicetin (9) and plicacetin (10), from the culture broth of Streptomyces sp. OPMA40551 as anti-MAC compounds that were active against M. avium and M. intracellulare. Among them, mavintramycin A showed the most potent and selective inhibition of M. avium and M. intracellulare. Furthermore, mavintramycin A was active against more than 40 clinically isolated M. avium, including multidrug-resistant strains, and inhibited the growth of M. avium in a persistent infection cell model using THP-1 macrophages. Mavintramycin A also exhibited in vivo efficacy in silkworm and mouse infection assays with NTM. An experiment to elucidate its mechanism of action revealed that mavintramycin A inhibits protein synthesis by binding to 23S ribosomal RNA in NTM. Mavintramycin A, with a different chemical structure from those of clinically used agents, is a promising drug candidate for the treatment of MAC infectious disease.

A multicenter phase II trial of the triplet antiemetic therapy with palonosetron, aprepitant, and olanzapine for a cisplatin-containing regimen. - PATROL-I.

Dexamethasone is one of the key antiemetic agents and is widely used even now. However, dexamethasone has been associated with several adverse reactions even after short-term administration. Therefore, developing a steroid-free antiemetic regimen is an important issue to consider. Thus, the purpose of this study was to investigate the efficacy and safety of palonosetron, aprepitant, and olanzapine in a multi-institutional phase II study. Chemotherapy-naive patients scheduled to receive cisplatin were enrolled and evaluated for the occurrence of chemotherapy-induced nausea and vomiting during 120 h after chemotherapy. The primary endpoint of the study was total control (TC) in the overall phase. The key secondary endpoint was complete response (CR), which was assessed in the acute, delayed, and overall phase, respectively. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events. Eighty-five patients were enrolled from 8 centers in Japan, of which 83 were evaluable for analyses. The percentage of patients who achieved TC during the overall phase was 31.3%. CR was achieved in 61.4%, 84.3%, and 65.1% of patients during the overall, acute, and delayed phases, respectively. The most frequently reported adverse event was anorexia. The primary endpoint was below the threshold and we could not find benefit in the dexamethasone-free regimen, but CR during the overall phase was similar to that of the conventional three-drug regimen. This antiemetic regimen without dexamethasone might be an option for patients for whom corticosteroids should not be an active application.

Inactivation of nontuberculous mycobacteria by gaseous ozone treatment.

Nontuberculous mycobacteria (NTM) are environmental bacteria resistant to many common disinfectants and ultraviolet radiation. Inhalation of aerosols generated from NTM-containing water and soil causes NTM lung disease, especially in people with underlying lung diseases and decreased immunity. To prevent healthcare-acquired NTM infections, it is important to eradicate NTM living in hospital environments. Therefore, we evaluated the efficacy of gaseous ozone for the inactivation of NTM, namely Mycobacterium (M.) avium, M. intracellulare, M. kansasii, M. abscessus subsp. abscessus and M.abscessus subsp. massiliense. Gaseous ozone treatment at 1 ppm for 3 h reduced the bacterial number of all strains by more than 97%. Gaseous ozone treatment could be a practical, effective and convenient disinfection method for NTM living in hospital environments.

Longitudinal significance of six-minute walk test in patients with nontuberculous mycobacterial pulmonary disease: an observational study.

BACKGROUND: The long-term exercise tolerance changes in patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) are of great interest because of its chronic course. This study aimed to characterize the associations between changes over time in six-minute walking test (6MWT) parameters and clinical parameters in patients with NTM-PD. METHODS: Overall, 188 patients with NTM-PD, visiting outpatient clinics at Keio University Hospital from April 2012 to March 2020 were included in the study. Data were collected using the St. George's Respiratory Questionnaire (SGRQ), pulmonary function test (PFT), blood tests, and the 6MWT at registration and at least once after that. The association of the anchors and clinical indicators with the 6MWT parameters was assessed. RESULTS: The median age [interquartile range] of the patients was 67 [63-74] years. The median baseline six-minute walk distance (6MWD) and final Borg scale (FBS) were 413 [361-470] m and 1 [0-2], respectively. In the correlation analysis, ΔSGRQ total/year (yr), Δforced vital capacity (FVC, % predicted)/yr, Δforced expiratory volume in 1 s (FEV1, % predicted)/yr, and Δdiffusing capacity for carbon monoxide (DLCO, % predicted)/yr correlated with both Δ6MWD/yr and ΔFBS/yr in the longitudinal analysis (|Rho| > 0.20). When stratified into three quantiles of changes in each anchor, the 6MWT parameters worsened over time in the bottom 25% group by mixed-effects model. Specifically, Δ6MWD was affected by SGRQ activity, SGRQ impacts, PFT (FVC, FEV1, and DLCO), and C-reactive protein (CRP). ΔFBS was affected by all SGRQ components, total score, and PFT. Anchor scores and variables at baseline that worsened Δ6MWD were higher SGRQ scores, lower FVC (% predicted), lower DLCO (% predicted), higher Krebs von den Lungen-6, old age, and undergoing treatment at registration. Similarly, these clinical parameters and elevated CRP, excluding undergoing treatment at registration, worsened ΔFBS. CONCLUSIONS: The decreased walking distance and exacerbation of dyspnea on exertion over time in patients with NTM-PD may reflect a deterioration of health-related quality of life and pulmonary function. Thus, the change in 6MWT over time can be used as an indicator to accurately assess the patient's condition and tailor their healthcare environment.

Osteoporosis in nontuberculous mycobacterial pulmonary disease: a cross-sectional study.

BACKGROUND: Since nontuberculous mycobacterial pulmonary disease (NTM-PD) is common in middle-aged/elderly slender women at risk of osteoporosis, we hypothesized that NTM-PD could be associated with osteoporosis. The study aimed to evaluate the prevalence of osteoporosis in patients with NTM-PD compared with that in the general population and determine the factors associated with osteoporosis in the subjects, including the serum estradiol (E2) and 25-hydroxyvitamin D (25OHD) levels. METHODS: We have recruited 228 consecutive adult patients with NTM-PD from a prospective cohort study at the Keio University Hospital, who had no history of osteoporosis or osteoporosis-associated bone fracture but underwent dual-energy X-ray absorptiometry-based bone mineral density (BMD) evaluation from August 2017-September 2019. The E2 and 25OHD levels were measured in 165 patients with available stored serum samples. We performed multivariable logistic regression analyses for osteopenia and osteoporosis. RESULTS: Osteoporosis (T-score ≤ - 2.5) and osteopenia (T-score - 1 to - 2.5) were diagnosed in 35.1% and 36.8% of patients with NTM-PD, respectively. Compared with the general population, the proportion of osteoporosis was significantly higher in 50-59-, 60-69-, and 70-79-year-old women with NTM-PD. Multivariable analysis revealed that older age (adjusted odds ratio [aOR] for 1-year increase = 1.12; 95% confidence interval [CI] = 1.07-1.18), female sex (aOR = 36.3; 95% CI = 7.57-174), lower BMI (aOR for 1 kg/m2 decrease = 1.37; 95% CI = 1.14-1.65), and chronic Pseudomonas aeruginosa (PA) infection (aOR = 6.70; 95% CI = 1.07-41.8) were independently associated with osteoporosis. Additionally, multivariable analysis in 165 patients whose serum E2 and 25OHD levels were measured showed that both low E2 levels (< 10 pg/mL) and lower 25OHD levels were independently associated with osteoporosis. CONCLUSIONS: Middle-aged/elderly women with NTM-PD have a higher prevalence of osteoporosis than the general population. BMD screening should be considered in NTM-PD, especially in older females with severe diseases such as chronic PA infection and lower BMI, and low serum E2 and 25OHD levels.

Genome-wide association study in patients with pulmonary Mycobacterium avium complex disease.

RATIONALE: Nontuberculous mycobacteria (NTM) are environmental mycobacteria that can cause a chronic progressive lung disease. Although epidemiological data indicate potential genetic predisposition, its nature remains unclear. OBJECTIVES: We aimed to identify host susceptibility loci for Mycobacterium avium complex (MAC), the most common NTM pathogen. METHODS: This genome-wide association study (GWAS) was conducted in Japanese patients with pulmonary MAC and healthy controls, followed by genotyping of candidate single-nucleotide polymorphisms (SNPs) in another Japanese cohort. For verification by Korean and European ancestry, we performed SNP genotyping. RESULTS: The GWAS discovery set included 475 pulmonary MAC cases and 417 controls. Both GWAS and replication analysis of 591 pulmonary MAC cases and 718 controls revealed the strongest association with chromosome 16p21, particularly with rs109592 (p=1.64×10-13, OR 0.54), which is in an intronic region of the calcineurin-like EF-hand protein 2 (CHP2). Expression quantitative trait loci analysis demonstrated an association with lung CHP2 expression. CHP2 was expressed in the lung tissue in pulmonary MAC disease. This SNP was associated with the nodular bronchiectasis subtype. Additionally, this SNP was significantly associated with the disease in patients of Korean (p=2.18×10-12, OR 0.54) and European (p=5.12×10-03, OR 0.63) ancestry. CONCLUSIONS: We identified rs109592 in the CHP2 locus as a susceptibility marker for pulmonary MAC disease.

Serum Krebs von den Lungen-6 level in the disease progression and treatment of Mycobacterium avium complex lung disease.

BACKGROUND AND OBJECTIVE: The lack of useful biomarkers reflecting the disease state limits the management of Mycobacterium avium complex lung disease (MAC-LD). We clarified the associations between serum KL-6 level, disease progression and treatment response. METHODS: Resected lung tissues from MAC-LD patients were immunostained for KL-6. We compared serum KL-6 levels between MAC-LD and healthy control or bronchiectasis patients without nontuberculous mycobacterial lung disease (NTM-LD). Serum KL-6 level was assessed in a prospective observational study at Keio University Hospital between May 2012 and May 2016. We investigated associations between serum KL-6 level and disease progression and treatment response in patients untreated for MAC-LD on registration (n = 187). RESULTS: The KL-6+ alveolar type 2 cell population in the lung and serum KL-6 level were significantly higher in MAC-LD patients than in controls. Serum KL-6 level in bronchiectasis patients without NTM-LD showed no significant increase. Of the 187 patients who did not receive treatment on registration, 53 experienced disease progression requiring treatment. Multivariable Cox analysis revealed that the serum KL-6 level (aHR: 1.18, P = 0.005), positive acid-fast bacilli smear (aHR: 2.64, P = 0.001) and cavitary lesions (aHR: 3.01, P < 0.001) were significantly associated with disease progression. The change in serum KL-6 (ΔKL-6) was significantly higher in the disease progression group; it decreased post-treatment, reflecting the negative sputum culture conversion. CONCLUSION: Serum KL-6 level is associated with disease progression and treatment response. Longitudinal assessment combined with AFB smear status and presence of cavitary lesions may aid MAC-LD management.

Infiltration of tumor-associated macrophages is involved in tumor programmed death-ligand 1 expression in early lung adenocarcinoma.

Programmed death-ligand 1 (PD-L1) is an immune modulator that promotes immunosuppression by binding to programmed death-1 of T-lymphocytes. Although tumor cell PD-L1 expression has been shown to be associated with the clinical response to anti-PD-L1 antibodies, its concise regulatory mechanisms remain elusive. In this study, we evaluated the associations of tumor PD-L1 expression and immune cell infiltrating patterns in 146 cases of early lung adenocarcinoma (AC) to investigate the possible extrinsic regulation of tumor PD-L1 by immune cells. Using immunohistochemistry, cell surface PD-L1 expression in tumor cells was observed in 18.5% of stage 0-IA lung AC patients. Tumor PD-L1 positivity was significantly associated with stromal invasion, which was accompanied by increased tumor-associated macrophages (TAM), CD8+ cytotoxic T cells and FoxP3+ regulatory T cells. Among these immune cells, TAM and CD8+ T cells significantly accumulated in PD-L1-positive carcinoma cell areas, which showed a tumor cell nest-infiltrating pattern. Although CD8+ T cells are known to induce tumor PD-L1 expression via interferon-É£ production, the increased TAM within tumors were also associated with tumor cell PD-L1 positivity, independently of CD8+ T cell infiltration. Our in vitro experiments revealed that PD-L1 expression in lung cancer cell lines was significantly upregulated by co-culture with M2-differentiated macrophages; expression of PD-L1 was reduced to baseline levels following treatment with a transforming growth factor-ß inhibitor. These results demonstrated that tumor-infiltrating TAM are extrinsic regulators of tumor PD-L1 expression, indicating that combination therapy targeting both tumor PD-L1 and stromal TAM might be a possible strategy for effective treatment of lung cancer.

Correction to: Low serum estradiol levels are related to Mycobacterium avium complex lung disease: a cross-sectional study.

After publication of the original article [1], we were notified that units of testosterone in main text and abstract and units of DHEA-S in Fig. 1 and Table 4 are incorrect.

The annual risk of tuberculosis infection in newly hired researchers and healthcare workers using interferon-gamma release assay in Japan.

The tuberculosis (TB) notification rate in Japan is gradually decreasing but has not yet achieved "pre-elimination," defined by the World Health Organization. To effectively tackle, control, and eliminate TB, estimating and monitoring the annual risk of TB infection (ARI) using tuberculin skin testing (TST) to understand the dynamics of TB epidemiology are significantly important. However, studies estimating ARIs using TST are few considering that Bacillus Calmette-Guérin vaccination coverage is high in Japan. This was a single-center, cross-sectional study conducted between January 2011 and December 2018 in Tokyo area where interferon-gamma release assays (IGRAs) were performed in newly hired researchers of Keio University School of Medicine and healthcare workers of Keio University Hospital to determine TB infection. We estimated the prevalence of TB infection and ARI based on their IGRA results. Among the 3908 subjects, 83 (2.124%) had positive IGRA results. Multiple logistic regression analysis revealed that age was a significant risk factor for positive IGRA result (adjusted odds ratio, 1.046). The ARIs were 0.049%-0.156% between 1986 and 2004, midyears of TB infection, but have not significantly decreased over approximately two decades. To decrease the risk of TB infection, advanced strategies to control and eliminate TB in Tokyo area are significantly required.

Showering is associated with Mycobacterium avium complex lung disease: An observational study in Japanese women.

Mycobacterium avium complex refers to a group of environmental bacteria which inhabit water and soil. Although Mycobacterium avium complex is capable of causing refractory lung infections, the risk factors for Mycobacterium avium complex lung disease are still unclear. This study aimed to determine the associations between Mycobacterium avium complex lung disease and soil or water exposure. Using questionnaires along with clinical data, we compared soil exposure, along with bathtub bathing and showering habits between 172 women with Mycobacterium avium complex lung disease and 339 women without Mycobacterium avium complex infection as controls. Showering was found to be independently associated with the presence of Mycobacterium avium complex lung disease (adjusted odds ratio 5.72, 95%, confidence interval 1.99 to 16.46). Although the mean age of the groups was different, an age-matched sub-analysis yielded similar results. These results indicate that showering may be a risk factor for Mycobacterium avium complex lung disease.

Effect of refrigeration of blood samples in lithium-heparin tubes on QuantiFERON TB Gold Plus test result.

The QuantiFERON TB Gold Plus (QFT-Plus) test is a newly approved interferon-gamma releasing assay test for detecting latent tuberculosis. Although blood samples for QFT test can be refrigerated for 48 h in lithium-heparin tubes according to package inserts, no published data are available on the effects of sample refrigeration on the test results. We conducted a clinical study that aimed to elucidate whether sample refrigeration for 48 h affects QFT-Plus test results. We collected 2 blood samples each from 40 participants for QFT-Plus; one sample was refrigerated before incubation for QFT-Plus assay, while the other sample was incubated soon after collection and treated as control. After comparing QFT-Plus test results of refrigerated samples and control samples, the concordance rate and kappa coefficient between them were 95% and 0.90, respectively. Thus, blood samples for QFT-Plus test can be refrigerated for 48 h in lithium-heparin tubes without influencing the test results.

Comorbidities associated with nontuberculous mycobacterial disease in Japanese adults: a claims-data analysis.

BACKGROUND: Nontuberculous mycobacterial (NTM) lung disease is one of a growing number of chronic health problems that is difficult to cure in aging societies. While it is important to be vigilant about associated comorbidities in order to provide better patient care, data on the prevalence of comorbidities stratified by country or region are scarce. We aimed to elucidate the comorbidities associated with NTM disease based on Japanese health insurance claims data. METHODS: Cross-sectional analyses were performed using the claims data for 2014 provided by the Japan Medical Data Center Co., Ltd. Patients aged 20-75 years with ≥3 claims associated with NTM disease were identified and matched to 10 sex-and-age-matched controls that had never made a claim for NTM disease. Thirty-one comorbidities previously suspected to be associated with NTM disease were selected, and the prevalence of these comorbidities compared between cases and controls. RESULT: Overall, 419 NTM patients (134 males and 285 females) and 4190 non-NTM controls were identified from the JMDC database. Aspergillosis, asthma, chronic heart failure, diffuse panbronchiolitis, gastroesophageal reflux, interstitial pneumonia, lung cancer, cancer other than breast, lung, ovary, or prostate cancer, and rheumatoid arthritis were associated with NTM disease in both males and females. Chronic obstructive pulmonary disease was associated with NTM in males while chronic kidney disease, osteoporosis, and Sjögren syndrome were associated with NTM in females. CONCLUSION: NTM disease was associated with multiple comorbidities that should be considered when providing medical care to individuals with NTM disease.

Low serum estradiol levels are related to Mycobacterium avium complex lung disease: a cross-sectional study.

BACKGROUND: The risk factors for Mycobacterium avium complex lung disease (MAC-LD) are not well known. We hypothesized that low serum estradiol (E2) levels are related to MAC-LD as most patients with MAC-LD are postmenopausal women. METHODS: This cross-sectional study compared patients with MAC-LD and healthy controls. Study subjects were postmenopausal women aged 65 years or younger. Serum testosterone, dehydroepiandrosterone sulfate (DHEA-S), and E2 levels were measured and categorized as high or low based on median levels. We performed multivariate analysis, receiver operating characteristic (ROC) curve analysis, and age- and body mass index (BMI)-matched subgroup analysis to evaluate the association between low serum E2 levels and MAC-LD. Additionally, using blood samples obtained for other clinical studies, the levels of sex steroid hormones were compared between age- and BMI-matched MAC-LD and bronchiectasis female patients without non-tuberculosis mycobacterial infections (non-NTM BE). RESULTS: Forty-two patients with MAC-LD and 91 healthy controls were included. The median E2 (2.20 pg/mL vs. 15.0 pg/mL, p < 0.001), testosterone (0.230 ng/L vs. 0.250 ng/L, p = 0.005), and DHEA-S (82.5 µg/dL vs. 114.0 µg/dL, p < 0.001) levels were lower in the MAC-LD group than in the control group. Multivariate analysis revealed that low serum E2 (adjusted odds ratio = 34.62, 95% confidence interval = 6.02-199.14) was independently related to MAC-LD, whereas low DHEA-S and testosterone were not. ROC analysis illustrated a strong relationship between low serum E2 levels and MAC-LD (area under the curve = 0.947, 95% confidence interval = 0.899-0.995). Even the age- and BMI-matched subgroup analysis of 17 MAC-LD patients and 17 healthy controls showed lower serum E2 in MAC-LD patients than in healthy controls. Additionally, serum E2 levels of 20 MAC-LD patients were lower than plasma E2 levels of 11 matched non-NTM BE patients (1.79 pg/mL vs. 11.0 pg/mL, p < 0.001). CONCLUSIONS: Low serum E2 levels were strongly related to MAC-LD in postmenopausal women.

Estimating Latent Tuberculosis Infection Using Interferon-γ Release Assay, Japan.

We estimated the latent tuberculosis infection (LTBI) rate for foreign-born students at Keio University, Tokyo, Japan, using an interferon-γ release assay. The LTBI rate for students from countries with estimated tuberculosis incidence >100 cases/100,000 persons was high (10.0%). Universities should screen for LTBI in students from countries with high tuberculosis incidence.

Natural history of Mycobacterium fortuitum pulmonary infection presenting with migratory infiltrates: a case report with microbiological analysis.

BACKGROUND: Presence of Mycobacterium fortuitum in respiratory tracts usually indicates mere colonization or transient infection, whereas true pulmonary infection occurs in patients with gastroesophageal disease. However, little is known about the diagnostic indications for true M. fortuitum pulmonary infection and the natural history of the disease. CASE PRESENTATION: A 59-year-old man was referred to our hospital for treatment against M. fortuitum pulmonary infection. Fifteen years before the referral, he underwent total gastrectomy, after which he experienced esophageal reflux symptoms. After the referral, the patient was closely monitored without antimicrobial therapy because of mild symptoms and no pathological evidence of M. fortuitum pulmonary infection. During the observation, chest imaging showed migratory infiltrates. Two years after the referral, his lung biopsy specimen revealed foamy macrophages and multinucleated giant cells, indicating lipoid pneumonia. However, he was continually monitored without any treatment because there was no evidence of nontuberculous mycobacterial infection. Four years after the referral, he developed refractory pneumonia despite receiving adequate antibiotic therapy. After confirmation of granulomatous lesions, multiple antimicrobial therapy for M. fortuitum resulted in a remarkable improvement with no exacerbation for over 5 years. Random amplified polymorphic DNA polymerase chain reaction analysis revealed identical M. fortuitum strains in seven isolates from six sputum and one intestinal fluid specimens obtained during the course of the disease. CONCLUSIONS: We have described a patient with M. fortuitum pulmonary infection who presented with migratory infiltrates. The pathological evidence and microbiological analysis suggested that M. fortuitum pulmonary infection was associated with lipoid pneumonia and chronic exposure to gastrointestinal fluid. Therefore, physicians should carefully monitor patients with M. fortuitum detected from lower respiratory tract specimens and consider antimicrobial therapy for M. fortuitum infection when the patient does not respond to adequate antibiotic therapy against common pneumonia pathogens.

Risk of tuberculosis infection among health care workers and nursing students in Japan.

It is important to evaluate the risk of tuberculosis (TB) infection among health care workers (HCWs) and nursing students in Japan to propose the optimal countermeasure against new TB infection for them. To estimate the annual incidence of TB infection in HCWs at a Japanese university hospital without TB wards and in nursing students at a Japanese university using interferon-gamma release assay (IGRA). Serial IGRAs were prospectively conducted on the HCWs between August 2010 and December 2015. For nursing students, two IGRA tests were conducted before commencement of clinical training and at employment as nurses between April 2007 and December 2015. A total of 328 HCWs and 298 nursing students were followed for 670.15 and 1212.80 person-years, respectively. Assuming IGRA-positive conversions were all attributable to true infection, the incidence of TB infection in HCWs and nursing students was 0.149/100 and 0.0825/100 person-years, respectively. At a Japanese university hospital without TB wards and a Japanese university, the annual incidence of TB infection among HCWs and nursing students estimated from serial IGRA results was low, but continued vigilance for the prevention of TB infection is essential.

Association between six-minute walk test parameters and the health-related quality of life in patients with pulmonary Mycobacterium avium complex disease.

BACKGROUND: Pulmonary Mycobacterium avium complex (pMAC) disease is a chronic, slowly progressive disease. The aim of the present study was to determine the association of six-minute walk test (6MWT) parameters with pulmonary function and the health-related quality of life (HRQL) in patients with pMAC disease. METHODS: This cross-sectional study included adult patients with pMAC and was conducted at Keio University Hospital. We investigated the relationship of 6MWT parameters with clinical parameters, including pulmonary function, and HRQL, which was assessed using the 36-Item Short Form Health Survey (SF-36) and St. George's Respiratory Questionnaire (SGRQ). RESULTS: In total, 103 consecutive patients with pMAC participated in 6MWT (median age, 64 years; 80 women) and completed SF-36 and SGRQ. The six-minute walk distance (6MWD) showed significant negative and positive correlations with all SGRQ domain scores [ρ = (- 0.54)-(- 0.32)] and the physical component summary (PCS) score (ρ = 0.39) in SF-36, respectively; the opposite was observed for the final Borg scale (FBS) score (all SGRQ scores, ρ = 0.34-0.58; PCS score, ρ = - 0.50). The distance-saturation product showed significant negative and positive correlations with all SGRQ scores [ρ = (- 0.29)-(- 0.55)] and the PCS score (ρ = 0.40), respectively. Multivariate analysis revealed that 6MWD and the FBS score were significant predictors of HRQL. CONCLUSIONS: Our findings suggest that 6MWD and the FBS score are useful parameters for evaluating HRQL in patients with pMAC. Further studies should investigate the impact of 6WMT parameters on disease progression, treatment responses, and prognosis.

The efficacy, safety, and feasibility of inhaled amikacin for the treatment of difficult-to-treat non-tuberculous mycobacterial lung diseases.

BACKGROUND: In multidrug regimens, including an intravenous aminoglycoside (e.g. amikacin [AMK]) is recommended for difficult-to-treat non-tuberculous mycobacterial (NTM) lung diseases. We aimed to evaluate the efficacy, safety, and feasibility of inhaled AMK therapy in patients with difficult-to-treat NTM lung diseases in a retrospective chart review. METHODS: The study population consisted of patients with NTM lung diseases who received combination therapy, including inhaled AMK therapy, at Keio University Hospital (Tokyo, Japan), from January 2014 through May 2016. A total of 26 cases, consisting of 23 Mycobacterium avium complex (MAC) and three Mycobacterium abscessus complex (MABC) infections cases, were included in this study. The efficacy, safety, and feasibility of inhaled AMK therapy were retrospectively investigated. The Research Ethics Committee of Keio University Hospital approved this study, and informed consent was obtained from all patients. RESULTS: All 26 patients were culture-positive at enrolment. Twenty-three of the 26 patients (88.5%), including 21/23 MAC patients (91.3%) and 2/3 MABC patients (66.7%), were administered inhaled AMK therapy for >3 months. The proportion of patients who had clinical symptoms, including, cough and sputum, declined after inhalation AMK therapy. Ten of the 23 patients (43.5%) who received AMK inhalation, including 8/21 MAC (38.1%) and 2/2 MABC patients (100%), showed sputum conversion, defined as at least three consecutive negative sputum cultures. Seven of the 23 patients, including, 5/21 MAC and 2/2 MABC patients, showed improvements in high-resolution computed tomography imaging of the chest. In addition, the serum AMK trough levels before the second inhalation were <1.2 µg/mL in all 26 patients, with no occurrence of severe adverse events, such as renal toxicity. One patient (3.8%) experienced auditory toxicity, in the form of tinnitus. However, this symptom was reversible, after temporary interruption of AMK, the patient was able to safely resume the therapy. CONCLUSIONS: Inhaled AMK therapy is an effective and feasible therapy for difficult-to-treat NTM lung disease.

hsa-miR-346 is a potential serum biomarker of Mycobacterium avium complex pulmonary disease activity.

MicroRNA (miRNA) has been recently recognized as a biomarker of various diseases; however, there are no known miRNAs associated with Mycobacterium avium complex (MAC) pulmonary disease. In addition, there are no known biomarkers to precisely reflect disease activity after the diagnosis of MAC pulmonary disease. Thus, we sought to identify a miRNA which is a candidate biomarker of MAC pulmonary disease activity. Serum hsa-miR-346 concentrations of 16 patients with M. avium pulmonary disease were significantly higher than those of 16 healthy controls (p = 0.047). The secretion of hsa-miR-346 increased in a multiplicity of infection-dependent manner in M. avium-infected macrophages. Serum hsa-miR-346 levels of 5 patients with bacterial conversion at the end of follow-up were significantly lower than those at the beginning of the follow-up (p = 0.043). In addition, the longitudinal change in serum hsa-miR-346 concentration correlated with bacterial load in 2 patients with M. avium pulmonary disease. Based on our results, it is supposed that MAC-infected macrophages in pulmonary lesions produce hsa-miR-346, which is then secreted into the bloodstream. The magnitude of this process could be quantitatively controlled by the bacterial load, suggesting that serum hsa-miR-346 is a potentially useful biomarker of MAC pulmonary disease activity.