Amikacin liposome inhalation suspension for Mycobacterium avium complex pulmonary disease: A subgroup analysis of Japanese patients in the randomized, phase 3, CONVERT study.

BACKGROUND: CONVERT, a randomized, active-controlled, global, Phase 3 trial demonstrated that patients with treatment-refractory Mycobacterium avium complex (MAC) pulmonary disease were more likely to achieve culture conversion with amikacin liposome inhalation suspension (ALIS) plus guideline-based therapy (GBT) versus those continuing on GBT alone. This subgroup analysis reports the efficacy and safety of ALIS in Japanese patients enrolled in CONVERT. METHODS: Japanese patients aged ≥20 years with treatment-refractory MAC pulmonary disease from Japanese sites were included. Patients were randomized to receive once-daily 590 mg ALIS + GBT or GBT alone; patients converting by Month 6 remained in the study to complete 12-month treatment followed by a 12-month off-treatment period. Nonconverters exited the study at Month 8. The primary endpoint was the proportion of patients achieving culture conversion by Month 6. RESULTS: Of the 59 Japanese patients screened, 48 were randomized to receive ALIS + GBT (n = 34) or GBT alone (n = 14), and 41/48 (85.4 %) were women. The mean (standard deviation) age of patients was 64.5 (8.6) years, and 83.3 % of patients had bronchiectasis at baseline. By Month 6, sputum culture conversion was cumulatively achieved in 9/34 (26.5 %) patients receiving ALIS + GBT versus none receiving GBT alone. Treatment-emergent adverse events were reported in 94.1 % and 100.0 % of patients receiving ALIS + GBT and GBT alone, respectively. No deaths were reported. CONCLUSIONS: The efficacy observed in the Japanese subpopulation was largely consistent with that in the overall CONVERT study population, with more patients achieving culture conversion with ALIS + GBT versus GBT alone. Safety profiles were similar between the overall population and the Japanese subpopulation. CLINICAL TRIAL REGISTRATION: NCT02344004.

Risk factors for clinical progression in patients with pulmonary Mycobacterium avium complex disease without culture-positive sputum: a single-center, retrospective study.

OBJECTIVES: Limited data are available on the progression of pulmonary Mycobacterium avium complex (MAC) disease without culture-positive sputum. The aim of this study was to identify the risk factors associated with clinical progression of pulmonary MAC disease diagnosed by bronchoscopy. METHODS: A single-center, retrospective, observational study was conducted. Pulmonary MAC patients diagnosed by bronchoscopy without culture-positive sputum from January 1, 2013, to December 31, 2017 were analyzed. Clinical progression after diagnosis was defined as having culture-positive sputum at least once or initiation of guideline-based therapy. Then, clinical characteristics were compared between clinically progressed patients and stable patients. RESULTS: Ninety-three pulmonary MAC patients diagnosed by bronchoscopy were included in the analysis. During the 4-year period after diagnosis, 38 patients (40.9%) started treatment, and 35 patients (37.6%) had new culture-positive sputum. Consequently, 52 patients (55.9%) were classified into the progressed group, and 41 patients (44.1%) were classified into the stable group. There were no significant differences between the progressed and the stable groups in age, body mass index, smoking status, comorbidities, symptoms, or species isolated from bronchoscopy. On multivariate analysis, male sex, monocyte to lymphocyte ratio (MLR) ≥ 0.17, and the presence of combined lesions in the middle (lingula) and lower lobes were risk factors for clinical progression. CONCLUSIONS: Some patients with pulmonary MAC disease without culture-positive sputum progress within 4 years. Therefore, pulmonary MAC patients, especially male patients, having higher MLR or lesions in the middle (lingula) and lower lobes might need careful follow-up for a longer time.

Pathophysiology of pulmonary nontuberculous mycobacterial (NTM) disease.

In recent years, the incidence and prevalence of pulmonary nontuberculous mycobacterial (NTM) disease have increased worldwide. Although the reasons for this increase are unclear, dealing with this disease is essential. Pulmonary NTM disease is a chronic pulmonary infection caused by NTM bacteria, which are ubiquitous in various environments. In Japan, Mycobacterium avium-intracellulare complex (MAC) accounts for approximately 90% of the causative organisms of pulmonary NTM disease, which is also called pulmonary MAC disease or pulmonary MAI disease. It is important to elucidate the pathophysiology of this disease, which occurs frequently in postmenopausal women despite the absence of obvious immunodeficiency. The pathophysiology of this disease has not been fully elucidated; however, it can largely be divided into bacterial (environmental) and host-side problems. The host factors can be further divided into immune and airway problems. The authors suggest that the triangular relationship between bacteria, immunity, and the airway is important in the pathophysiology of this disease. The latest findings on the pathophysiology of pulmonary NTM disease are reviewed.

Impact of sleep-related hypoventilation in patients with pleuroparenchymal fibroelastosis.

BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) is a rare fibrosing lung disease with a predilection for the upper lobe and its progression causes hypoventilation, resulting in hypercapnia. Even though the association between sleep-related hypoventilation (SRH) and chronic obstructive pulmonary disease was well documented, its impact in patients with PPFE was not evaluated. The aim of this study is to clarify the impact of SRH on prognosis in PPFE. METHODS: A retrospective review of the medical records of 52 patients with PPFE who underwent transcutaneous carbon dioxide monitoring during sleep was done. Patients were stratified into SRH (n = 28) and non-SRH (n = 24) groups based on American Academy of Sleep Medicine criteria. The impact of SRH on the prognosis of PPFE, as well as the clinical factors and comorbidities of PPFE associated with SRH, were evaluated. RESULTS: Forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), total lung capacity (TLC), and carbon monoxide diffusing capacity (DLco) in the SRH group were significantly lower than the non-SRH group (P < .01). Chronic pulmonary aspergillosis (CPA) was found at a higher rate in the SRH group (P = .02). The median survival time for SRH patients was 330 days, whereas roughly 80% of non-SRH patients were alive during the 3-year observation period (P < .01). Body mass index was a significant prognostic factor in PPFE patients with SRH (HR .78; 95% CI; .64-.94; P < .01). Home oxygen therapy (HOT) during the day and noninvasive positive pressure ventilation (NPPV) at night while sleeping tended to improve prognosis in the SRH group, as indicated by HR of .25 (P = .07). CONCLUSIONS: SRH may be a poor prognostic factor for PPFE. Additionally, SRH may modify susceptibility to Aspergillosis in patients with PPFE. HOT plus NPPV may improve the disease outcomes in patients with SRH.

A case of primary multidrug-resistant pulmonary tuberculosis with high minimum inhibitory concentration value for bedaquiline.

Bedaquiline is a new ATP synthesis inhibitor developed as an anti-tuberculosis agent. It has resistance-associated variants (RAV), regardless of preceding bedaquiline exposure. Herein, we describe the case of a patient with multidrug-resistant tuberculosis (MDR-TB) who had no history of bedaquiline therapy but presented a relatively high minimum inhibitory concentration (MIC) of bedaquiline (1 µg/mL). Whole genome sequencing revealed a mutation in the resistance-associated gene Rv0678. The patient was first treated with a five-drug regimen (bedaquiline, delamanid, levofloxacin, cycloserine, and amikacin), which induced negative sputum culture conversion. Despite the successful treatment outcome, several questions remain regarding the efficacy of bedaquiline in this patient. Bedaquiline is an indispensable drug for MDR-TB treatment, but its clinical efficiency in the presence of Rv0678 mutations remains unclear. Therefore, evaluating the MIC of bedaquiline even in patients without a history of bedaquiline use is important for therapeutic regimen selection and may emphasize the importance of therapeutic drug monitoring in cases of bedaquiline RAV.

The Role of NRF2 in Mycobacterial Infection.

The incidence of pulmonary nontuberculous mycobacterial (NTM) infection is increasing worldwide, and its clinical outcomes with current chemotherapies are unsatisfactory. The incidence of tuberculosis (TB) is still high in Africa, and the existence of drug-resistant tuberculosis is also an important issue for treatment. To discover and develop new efficacious anti-mycobacterial treatments, it is important to understand the host-defense mechanisms against mycobacterial infection. Nuclear erythroid 2 p45-related factor-2 (NRF2) is known to be a major regulator of various antioxidant response element (ARE)-driven cytoprotective gene expressions, and its protective role has been demonstrated in infections. However, there are not many papers or reviews regarding the role of NRF2 in mycobacterial infectious disease. Therefore, this review focuses on the role of NRF2 in the pathogenesis of Mycobacterium tuberculosis and Mycobacterium avium infection.

Usual interstitial pneumonia progressing to nonspecific interstitial pneumonia-like pattern on high-resolution CT with histologic confirmation.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease. Although high-resolution computed tomography (HRCT) is important for the diagnosis of IPF, the changes in the HRCT findings in IPF are not fully understood. The patient was a 66-year-old man. His HRCT findings had atypically developed from a probable usual interstitial pneumonia pattern to a nonspecific interstitial pneumonia (NSIP) like pattern over 6 years. On the basis of the histologic examination and multidisciplinary discussion, IPF was diagnosed, and nintedanib, administered. This case can be useful for the differential diagnosis of IPF and NSIP.

Negative-pressure pulmonary Hemorrhaging Due to Severe Obstructive Sleep Apnea.

A 24-year-old man with a history of bloody sputum for 6 months was referred to our hospital with suspected alveolar hemorrhaging due to vasculitis. Chest computed tomography showed ground-glass opacities in both lungs, and an examination of his bronchoalveolar lavage fluid showed alveolar hemorrhaging. However, no evidence of vasculitis was found, and subsequent polysomnographic testing confirmed that he had severe obstructive sleep apnea (OSA). Since the alveolar hemorrhaging improved after the initiation of continuous positive airway pressure treatment, the diagnosis was negative-pressure alveolar hemorrhaging due to severe OSA.

A case of Marfan syndrome with massive haemoptysis from collaterals of the lateral thoracic artery.

BACKGROUND: Marfan Syndrome (MFS) is a heritable connective tissue disorder with a high degree of clinical variability including respiratory diseases; a rare case of MFS with massive intrathoracic bleeding has been reported recently. CASE PRESENTATION: A 32-year-old man who had been diagnosed with MFS underwent a Bentall operation with artificial valve replacement for aortic dissection and regurgitation of an aortic valve in 2012. Warfarin was started postoperatively, and the dosage was gradually increased until 2017, when the patient was transported to our hospital due to sudden massive haemoptysis. Computed tomography (CT) with a maximum intensity projection (MIP) revealed several giant pulmonary cysts with fluid levels in the apex of the right lung with an abnormal vessel from the right subclavian artery. Transcatheter arterial embolization was performed with angiography and haemostasis was achieved, which suggested that the bleeding vessel was the lateral thoracic artery (LTA) branch. CT taken before the incident indicated thickening of the cystic wall adjacent to the thorax; therefore, it was postulated that the bleeding originated from fragile anastomoses between the LTA and pulmonary or bronchial arteries. It appears that the vessels exhibited inflammation that began postoperatively, which extended to the cysts. CONCLUSION: We experienced a case of MFS with massive haemoptysis from the right LTA. We have to be aware of the possibility that massive haemoptysis could be induced in MFS with inflamed pulmonary cysts.

A Case of Pulmonary Metastasis of Breast Cancer 23 Years after Surgery Accompanied with Non-Tuberculous Mycobacterium Infection.

Recurrence of oestrogen receptor (ER)-positive breast cancer rarely occurs postoperatively after a long period. Breast cancer cells survive and settle in distant organs in a dormant state, a phenomenon known as "tumour dormancy." Here, we present a 66-year-old woman with recurrence of ER-positive breast cancer in the left lung 23 years after surgery accompanied with non-tuberculous mycobacterium infection (NTM). At the age of 43 years, the patient underwent a right mastectomy and adjuvant hormonotherapy to completely cure breast cancer. Twenty-three years after the operation, when the patient was 66 years old, computed tomography presented nodular shadows in the lower lobes bilaterally with bronchiectasis and ill-defined satellite tree-in-bud nodules. Mycobacterium intracellulare was detected in cultured bronchoalveolar lavage fluid obtained from the left lower lobe by bronchoscopy. Rifampicin, ethambutol, and clarithromycin were started, which resulted in shrinkage of the nodule in the right lower lobe and satellite nodules; however, the nodule in the left lower lobe increased in size gradually. Wedge resection of the left lower lobe containing the nodule by video-assisted thoracoscopic surgery was performed, which demonstrated that the nodule was adenocarcinoma in intraoperative pathological diagnosis; therefore, a left lower lobectomy and mediastinal lymph node dissection were performed. The tumour was revealed to be consistent with recurrence of previous breast cancer according to its morphology and immunohistochemical staining. Furthermore, caseous epithelioid cell granulomas existed in the periphery of the tumour. It is reported that inflammatory cytokines induce reawakening of dormant oestrogen-dependent breast cancer and, in our case, NTM infection might have stimulated the dormant tumour cells in the lower lobe.

Borderline pulmonary hypertension is associated with exercise intolerance and increased risk for acute exacerbation in patients with interstitial lung disease.

BACKGROUND: Pulmonary hypertension (PH) is traditionally defined as a resting mean pulmonary artery pressure (mPAP) of ≥25 mmHg, while mPAP in the range of 21 to 24 mmHg is recognized as "borderline PH." Interstitial lung disease (ILD) is complicated by the development of PH, which is known to be linked with exercise intolerance and a poor prognosis. Even though it has recently been recommended that PH is redefined as a mPAP of > 20 mmHg, little is known about the clinical significance of borderline PH in ILD. We evaluated whether borderline PH has an impact on the exercise capacity, risk of acute exacerbation (AE), and mortality in patients with ILD. METHODS: A total of 80 patients with ILD who underwent right heart catheterization (RHC) between November 2013 and October 2016 were included. The patients were divided into 3 groups according to the mPAP values: mPAP ≤20 mmHg (No-PH group; n = 56), 20 < mPAP < 25 mmHg (Bo-PH group; n = 18), and mPAP ≥25 mmHg (PH group; n = 6). The demographic, hemodynamic, spirometric, and 6-min walk test (6MWT) data of the patients were collected. In addition, the 1-year incidence of AEs and 1-year survival of the patients after the initial RHC were also evaluated. RESULTS: There were no significant differences among the 3 groups in the mean age, pulmonary function parameters or the PaO2, however, 6-min walk distance was significantly lower in both the Bo-PH and PH groups (p < 0.001 for both) as compared to the No-PH group. The results of the Kaplan-Meier analysis revealed that while there was no significant difference in the 1-year survival rate among the three groups, the 1-year incidence of AEs was significantly higher in both the Bo-PH and PH groups (p < 0.001, p = 0.023, respectively) as compared to the No-PH group. CONCLUSIONS: The current study suggested that borderline PH may be associated with poorer exercise tolerance and an increased risk of AEs in patients with ILD. Therefore, the physicians should pay close attention to the presence of even mild elevation of the mPAP at the initial evaluation in patients with ILD.

A case of airway aluminosis with likely secondary pleuroparenchymal fibroelastosis.

BACKGROUND: Excessive inhalation of aluminium powder occasionally results in upper lobe predominant lung fibrosis, which is similar to idiopathic pleuroparenchymal fibroelastosis (IPPFE) and has been suggested to be secondary PPFE. CASE PRESENTATION: A 67-year-old man who had worked in an aluminum-processing factory for 50 years visited our hospital complaining of exertional dyspnea. Chest computed tomography (CT) showed bilateral dense sub-pleural consolidation in the upper and middle lung fields, which was consistent with IPPFE; however, the possibility of secondary PPFE associated with aluminosis was not ruled out. Considering the patient's critical condition, trans-bronchial lung biopsy (TBLB) rather than surgical lung biopsy was performed, with elemental analysis of the biopsied specimen. Unfortunately, the specimen obtained by TBLB did not contain alveolar tissue; therefore, pathological diagnosis of PPFE was not possible. However, radiographic findings were highly suggestive of PPFE. On elemental analysis, excessive amounts of aluminum were detected in the bronchiolar walls, establishing a diagnosis of airway aluminosis with likely secondary PPFE resulting from aluminium exposure. CONCLUSIONS: TBLB with elemental analysis might be useful in differentiating idiopathic PPFE from secondary causes in dust inhalation related disease, such as aluminosis. This case indicated that inhalation of aluminium might cause secondary PPFE, with attention needing to be paid to avoid further exposure.

Methimazole-induced ANCA-associated vasculitis with diffuse alveolar haemorrhage.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) caused by methimazole (MMI) is known to be relatively rare; therefore, the optimal therapeutic approach for these cases remains to be established. A 59-year-old man who was treated with MMI for a diagnosis of Graves' disease was referred to our hospital because of progressive haemoptysis. The patient was diagnosed with diffuse alveolar haemorrhage (DAH) secondary to AAV based on increased inflammatory reactions with positive myeloperoxidase-ANCA in the serum and the results of bronchoalveolar lavage fluid. MMI was suspected as the cause of the AAV; therefore, the administration of MMI was discontinued. Thereafter, the patient's symptoms as well as chest radiographic abnormalities completely resolved, in conjunction with normalization of the serum ANCA level. Our experience with this case suggests that DAH secondary to AAV caused by MMI may improve with discontinuation of the offending drug alone, with no other treatment.