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.

Efficacy of an oscillating positive expiratory pressure device in patients with Mycobacterium avium complex pulmonary disease.

Patients with Mycobacterium avium complex pulmonary disease (MAC-PD) often suffer from chronic symptoms such as sputum production, which reduces quality of life. Oscillatory positive expiratory pressure (OPEP) devices are used in physiotherapy to promote the clearance of respiratory secretions. We report two cases of improved lung function and improved scores on the Leicester Cough Questionnaire (LCQ) and the Breathlessness, Cough and Sputum Scale (BCSS) after the use of OPEP in patients with MAC-PD where treatment with guideline-based therapy, including amikacin liposome inhalation suspension, had proved ineffective for symptoms. Use of OPEP might maximize the efficacy of therapy and thereby improves outcomes in patients with MAC-PD. It is important to use both guideline-based therapy and OPEP, especially in patients whose health-related quality of life is affected by sputum symptoms. Further prospective studies are warranted to assess the benefit of adding OPEP to guidelines concerning therapy for patients with MAC-PD and sputum symptoms.

A Case of Lymphangioleiomyomatosis Showing the Development of Mycobacterium abscessus subsp. massiliense Infection During Sirolimus Therapy.

Among nontuberculous mycobacterial pulmonary diseases (NTM-PDs), Mycobacterium abscessus species pulmonary disease (MABS-PD) is one of the most severe and intractable infections. We herein report a 45-year-old woman with advanced lymphangioleiomyomatosis (LAM) who developed MABS-PD while undergoing sirolimus therapy. MABS-PD was immediately controlled using antibiotic therapy, although the patient's lung transplant registration was significantly delayed. To our knowledge, this is the first case report on the development of NTM-PD in a patient with LAM before lung transplantation. This case suggests that the early diagnosis and optimal treatment of NTM-PD are crucial in patients with advanced LAM.

COVID-19 in Patients with Pre-Existing Interstitial Lung Disease: Potential Value of a Steroid-Based Treatment Strategy.

The prognosis of patients with coronavirus disease 2019 (COVID-19) and pre-existing interstitial lung disease (preILD) is poor, and no effective treatment strategy has been determined. The aim of this study was to assess the effectiveness of a steroid-based treatment strategy for patients with COVID-19 and preILD. We retrospectively reviewed the medical records of 610 consecutive patients with COVID-19 treated at our institution between 1 March 2020 and 30 October 2021 and identified 7 patients with preILD, all of whom were treated with corticosteroids and remdesivir. All the patients were men with a median age of 63 years. Three of four patients with severe disease required invasive positive-pressure ventilation (n = 2) or nasal high-flow therapy (n = 1). All three patients could be weaned from respiratory support; however, one died in hospital. The remaining patient with severe COVID-19 had a do-not-resuscitate order in place and died while hospitalized. All three patients with moderate COVID-19 were discharged. The 30-day mortality was 0%, and the mortality rate during the entire observation period was 28.5%. The prognosis of our patients with COVID-19 and preILD has been better than in previous reports. Our management strategy using corticosteroids may have improved these patients' prognosis.

Cases of severe Mycobacterium avium lung disease occurred in a married couple caused by identical strain.

Bacteria of the Mycobacterium avium complex, which are environmental organisms found in soil and water, have been found to cause human lung diseases. Although infection is reported to occur in cohabiting patients, the incidence of infection from the single clone remains rarely documented. Herein, we report a case of M. avium lung disease caused by specimens with the same clone strains in a married couple. The wife, a 67-year-old female, had severe M. avium lung disease despite receiving multidrug chemotherapy for eleven years. The husband, a 68-year-old male, died of acute lung injury complicated by M. avium pleurisy. The result of the variable-number tandem-repeat analysis of isolates from serial sputum specimens of both patients indicated that the severe M. avium lung disease in a married couple was caused by the isolates with identical pattern. This case were considered to have acquired clarithromycin resistance during each clinical course, revealing the possibility of infection with a strain that may induce severe pulmonary condition.

Increased lactate dehydrogenase reflects the progression of COVID-19 pneumonia on chest computed tomography and predicts subsequent severe disease.

Chest computed tomography (CT) is effective for assessing the severity of coronavirus disease 2019 (COVID-19). However, the clinical factors reflecting the disease progression of COVID-19 pneumonia on chest CT and predicting a subsequent exacerbation remain controversial. We conducted a retrospective cohort study of 450 COVID-19 patients. We used an automated image processing tool to quantify the COVID-19 pneumonia lesion extent on chest CT at admission. The factors associated with the lesion extent were estimated by a multiple regression analysis. After adjusting for background factors by propensity score matching, we conducted a multivariate Cox proportional hazards analysis to identify factors associated with severe disease after admission. The multiple regression analysis identified, body-mass index (BMI), lactate dehydrogenase (LDH), C-reactive protein (CRP), and albumin as continuous variables associated with the lesion extent on chest CT. The standardized partial regression coefficients for them were 1.76, 2.42, 1.54, and 0.71. The multivariate Cox proportional hazards analysis identified LDH (hazard ratio, 1.003; 95% confidence interval, 1.001-1.005) as a factor independently associated with the development of severe COVID-19 pneumonia. Increased serum LDH at admission may be useful in real-world clinical practice for the simple screening of COVID-19 patients at high risk of developing subsequent severe disease.

Mycobacterium avium Pleurisy with Bronchopleural Fistula Resulting in Rapidly Progressive Respiratory Failure Diagnosed by Transbronchial Autopsy.

Nontuberculous mycobacterial lung disease usually manifests as a chronic pulmonary infection. We herein report a fatal case of Mycobacterium avium pleurisy in a man with a refractory bronchopleural fistula that led to rapidly progressive pneumonia. A post-mortem transbronchial biopsy was performed. Histopathology revealed an acute lung injury pattern and epithelioid granulomas. Variable number tandem repeat analyses and drug susceptibility testing revealed Mycobacterium avium had acquired macrolide resistance during chemotherapy with rifampicin, ethambutol, and clarithromycin. Clinicians should be aware that Mycobacterium avium pleurisy with bronchopleural fistula can lead to fatal pneumonia, especially in patients with persistently positive cultures despite multidrug treatment.

Effect of sputum quality on Mycobacterium avium-intracellulare complex lung disease diagnosis and treatment initiation according to disease type.

We evaluated sputum quality to establish a diagnostic and treatment strategy for Mycobacterium avium-intracellulare complex lung disease (MAC-LD). Of all 905 MAC-LD patients, 564 (62.3%) had nonpurulent sputum. Furthermore, 88 treated patients were associated with purulent sputum. Therefore, sputum quality may be useful for diagnosing MAC-LD and deciding treatment initiation.

Delirium in Patients with COVID-19 in Japan.

Objective The incidence and clinical importance of delirium in coronavirus disease 2019 (COVID-19) have not yet been fully investigated. The present study reported the prevalence of delirium in patients with COVID-19 and identified the factors associated with delirium and mortality. Methods We performed an observational, retrospective study of patients diagnosed with COVID-19 at the Kinki-Chuo Chest Medical Center. Univariate and multivariate logistic regression analyses were used to explore delirium risk factors. Patients All consecutive patients diagnosed with COVID-19 at the Kinki-Chuo Chest Medical Center. Results We identified 600 patients [median age: 61.0 (interquartile range: 49.0-77.0) years old], of whom 61 (10.2%) developed delirium during their stay. Compared with patients without delirium, these patients were older (median age 84.0 vs. 56.0 years old, p<0.01) and had more comorbidities. Based on a multivariate analysis, age, dementia, severe disease, and lactate dehydrogenase (LDH) levels were independent risk factors for developing delirium. For every 1-year increase in age and 10-IU/L increase in LDH, the delirium risk increased by 10.8-12.0% and 4.6-5.7%, respectively. There were 15 (24.6%) in-hospital deaths in the group with delirium and 8 (1.6%) in the group without delirium (p<0.01). Delirium was associated with an increased mortality. Conclusion Delirium in patients with COVID-19 is prevalent and associated with poor clinical outcomes in Japan. Despite difficulties with COVID-19 patient care during the pandemic, physicians should be aware of the risk of delirium and be trained in its optimal management.

The feasibility of rifampicin Re-administration in patients with tuberculosis and Clostridioides difficile infection.

BACKGROUND: The effects of a rifampicin (RIF) on the evolution of Clostridioides difficile infection (CDI) have not previously been investigated and there is currently no consensus on whether RIF re-administration is feasible. METHODS: This retrospective observational study included consecutive tuberculosis (TB) patients diagnosed with comorbid RIF-associated CDI (RA-CDI) using strict diagnostic criteria. We investigated the association between RA-CDI and clinical outcomes, and also examined the feasibility of re-administering RIF. RESULTS: Out of the 11,230 patients were admitted to TB ward at our hospital, 156 TB patients (1.4%) were diagnosed with CDI and the overall incidence of CDI was calculated as 2.1 cases per 10,000 patient-days. Of 156 patients with CDI, 86 were diagnosed with RA-CDI, of whom 28 (32.6%) were re-administered with RIF. In the re-administration group, time to initial sputum smear conversion was significantly shorter than for patients who were not re-administered with RIF (42 days [interquartile range, IQR: 35-65] vs. 55 days [IQR: 44-70], p = 0.041). Further, RIF re-administration significantly reduced length of hospital stay (69 days [IQR: 66-82] vs. 81 days [IQR: 72-89], p = 0.014). Ten patients (35.7%) had recurrent CDI after RIF re-administration. On the other hand, 15 patients (53.6%) were able to continue their TB treatment, including the RIF regimen. CONCLUSIONS: The present study strengthens the argument for including RIF in the list of antibiotics that can induce CDI, particularly in elderly men suffering from underlying conditions. Although careful attention must be paid to the possibility of CDI recurrence, a strategy of re-administration of RIF is feasible.

Clinical characteristics of COVID-19 in Osaka, Japan: Comparison of the first-third waves with the fourth wave.

BACKGROUND: The fourth wave of COVID-19 in Osaka Prefecture, Japan, caused a medical crisis. Here, we aim to identify the risk factors for COVID-19 severity and compare patients between the first-third waves and the fourth wave. METHODS: We performed an observational retrospective study of COVID-19 cases at the National Hospital Organization Kinki-Chuo Chest Medical Center. RESULTS: We identified 404 patients (median age: 71.0 years [interquartile range: 56.0-80.0]), of whom 199 (49.1%) had mild disease, 142 (35.2%) had moderate disease, and 63 (15.6%) had severe disease. The overall mortality rate was 5.4% (22/404). Based on multivariate logistic regression analysis, cardiovascular disease, fever, dyspnea, and several inflammatory biomarkers were independent risk factors for moderate to severe disease. For every 1 mg/dL increase in C-reactive protein, 10 IU/L increase in lactate dehydrogenase, and 100 ng/mL increase in ferritin, the risk for moderate to severe disease increased by 18.3%, 12.9%, and 8.9%, respectively. Overall disease severity in the fourth wave was higher than in the first-third waves. However, there was no significant difference in mortality. Because of a shortage of beds, four of the 28 severe patients (14.3%) in the fourth wave could not be transferred to the advanced hospital. CONCLUSIONS: Cardiovascular disease, fever, dyspnea, and several inflammatory biomarkers were risk factors for moderate to severe COVID-19 in our cohort. During the fourth wave, COVID-19 severity worsened, increasing the number of patients who could not be transferred to beds for severe cases, resulting in a medical crisis in Osaka.

Molecular Epidemiology of Drug-Resistant Mycobacterium Tuberculosis in Japan.

Clinical isolates of drug-resistant (isoniazid and/or rifampicin-resistant) Mycobacterium tuberculosis were obtained from 254 patients diagnosed with drug-resistant tuberculosis in Japan from April 2015 to March 2017 in National Hospital Organization hospitals. The 254 patients were approximately 32% of all 795 patients who were diagnosed with culture-confirmed drug-resistant tuberculosis from 2015 to 2016 nationwide in Japan. The whole-genome sequences of all the isolates from the 254 patients and the lineages of these isolates were determined, and phylogenetic trees were constructed based on single nucleotide polymorphism concatemers. Of these patients, 202 (79.5%) were born in Japan and 52 (20.5%) were born elsewhere. Of the 254 drug-resistant isolates, 54 (21.3%) were multidrug resistant, being resistant to both isoniazid and rifampicin. The percentages of multidrug-resistant isolates were significantly higher in foreign-born (38.5% [20/52]) than Japanese-born patients (16.8% [34/202]). Of the 54 multidrug-resistant isolates, nine were extensively drug resistant, which were all obtained from Japanese-born patients. Five extensively drug-resistant isolates were obtained from patients with incipient tuberculosis. A significant number of multidrug-resistant M. tuberculosis strains were isolated from foreign-born patients from Asian countries that have a high tuberculosis burden. Foreign-derived isolates affect the nationwide genetic diversity of drug-resistant M. tuberculosis in Japan. Extensively drug-resistant M. tuberculosis isolates were transmitted among the Japanese population. IMPORTANCE The incidence rate of tuberculosis (TB) in Japan was 11.5 per 100,000 of the population in 2019. Of TB patients in Japan, 61.1% were aged >70 years, and 10.7% were born outside Japan, mostly in Asian countries with a high burden of tuberculosis. Of the tuberculosis patients in the present study, 5.4% and 1.0% showed resistance to isoniazid and rifampicin, respectively, and 0.7% were multidrug resistant. The objective of this study was to clarify the molecular epidemiological properties of drug-resistant tuberculosis in Japan. Molecular epidemiology provides several clues to inform potential measures to control drug-resistant tuberculosis in Japan.

Comparison of drug-susceptibility patterns and gene sequences associated with clarithromycin and azithromycin resistance in Mycobacterium abscessus complex isolates and evaluation of the accumulation of intrinsic macrolide resistance.

Introduction. Mycobacterium abscessus complex (MABC) is an infectious agent associated with macrolide resistance and treatment failure.Hypothesis/Gap Statement. Despite drug-susceptibility testing for MABC isolates including clarithromycin (CAM), long-term treatment with azithromycin (AZM) for MABC disease is recommended.Aim. We compared phenotypic and genotypic resistance to AZM and CAM in clinical isolates and evaluated the accumulation of intrinsic macrolide resistance (AIM) and morphological changes by macrolides exposure.Methodology. Forty-nine isolates were characterized regarding erm(41) sequevars. Sequencing data were compared to the nucleotide sequence of rrl and whiB7. The AIM MIC was performed in three reference strains and 15 isolates were randomized [each set of five isolates with M. abscessus subsp. abscessus (MAA) T28, MAA C28 and subsp. massiliense (MAM)].Results. The 49 isolates were distributed as 24 MAA T28, 5 MAA C28 and 20 MAM. The MIC50 values to CAM at day 3 in MAA T28, C28 and MAM were 1, 0.12 and 0.12 µg ml-1, while those at day 14 were 32, 0.5 and 0.12 µg ml-1, respectively. The AZM-MIC50 values at day 3 of the above isolates were 4, 0.25 and 0.5 µg ml-1, while those at day 14 were >64, 0.5 and 0.5 µg ml-1, respectively. Neither mutations in rrl of MAA T28 with acquired resistance nor deletions in whiB7 of MAA T28 without inducible resistance were observed . For AIM MIC, MAA T28 showed that the time-to-detection of AZM resistance was significantly faster over that of CAM (P<0.05). Morphological changes were not determined in all isolates.Conclusion. Our findings did not support the suggestion for the preferential use of AZM for, at least, MAA T28 disease due to the high-level MIC value and the increased AIM. The long duration of AZM-based treatment eventually may favour the emergence of isolates with a high-level of intrinsic resistance.

Resumption/efficacy and safety of an azithromycin-containing regimen against Mycobacterium avium complex lung disease in patients who experienced adverse effects with a clarithromycin-containing regimen.

BACKGROUND: Antibiotic therapy, including clarithromycin (CLR), has been widely used for the management of Mycobacterium avium complex (MAC) lung disease in clinical settings. When patients develop adverse events (AEs) during CLR-based treatment, the treatment regimen is modified or chemotherapy itself is discontinued. The need for alternative macrolide treatment strategies is emphasized due to the high rate of AEs possibly caused by CLR. Thus, the current study aimed to examine the efficacy and safety of azithromycin (AZM) in patients with MAC lung disease whose treatment was switched from CLR to AZM. METHODS: We performed a retrospective study of patients with MAC lung disease. The inclusion criteria were as follows: (1) patients who experienced AEs during treatment with antibiotics, including CLR, between December 2012 and November 2017, and (2) those who had antimicrobial therapy that was switched from CLR to AZM. The efficacy and safety of AZM during the clinical course of the disease after switching the regimen from CLR to AZM were investigated. RESULTS: Antibiotic therapy was switched in 31 patients who presented with AEs including drug-induced fever, rash, dysgeusia, liver dysfunction, and neutropenia during treatment with CLR-containing regimens. After switching to AZM, the median duration of treatment was 1286 (364-4615) days. During follow-up, 13 patients had a negative conversion of sputum culture. CONCLUSIONS: AZM may be safe and effective for patients with MAC lung disease who have difficulty tolerating CLR. In patients who experienced AEs possibly caused by CLR, switching from CLR to AZM might be an appropriate strategy.

Risk factors for hemoptysis in Mycobacterium avium complex lung disease.

BACKGROUND: Hemoptysis is a frequent and sometimes fatal complication of non-tuberculous mycobacterial (NTM) lung disease. The risk factors for hemoptysis are not well understood. In the current study, potential risk factors for hemoptysis were investigated in patients with Mycobacterium avium complex (MAC) lung disease, which is the most common NTM in Japan. METHODS: Medical records from the Kinki-Chuo Chest Medical Center were reviewed. Consecutive patients with MAC lung disease diagnosed in 2014 and followed up for more than 1 year in the hospital were included in the study. Hemoptysis was confirmed between 2014 and 2016. The characteristics of patients with hemoptysis and non-hemoptysis at the time of the initial diagnosis of MAC lung disease were obtained from the medical records, and the two groups were compared. The radiological findings assessed included nodules, infiltration shadows, cavities, and bronchiectasis. Each was classified and scored individually in six lung fields, and these data were used to generate radiological scores. RESULTS: The study included 82 patients with MAC lung disease, 18 with hemoptysis and 64 without. Higher total radiological severity score at the time of the initial diagnosis of MAC was associated with an increased risk of hemoptysis. Among the radiological scores, infiltration and cavities were marginally associated with the risk of hemoptysis. CONCLUSIONS: The radiological severity score at the time of initial diagnosis of MAC lung disease was associated with hemoptysis.

Two New Cases of Pulmonary Infection by Mycobacterium shigaense, Japan.

We report 2 case-patients in Japan with Mycobacterium shigaense pulmonary infections. One patient was given aggressive treatment and the other conservative treatment, according to distinctive radiologic evidence. A close phylogenetic relationship based on whole-genome sequencing was found between strain from the conservatively treated patient and a reference strain of cutaneous origin.

Serum immunoglobulin a antibodies to glycopeptidolipid core antigen for Mycobacteroides abscessus complex lung disease.

Background: Mycobacteroides abscessus complex (MABC) exhibits smooth morphotypes, expressing glycopeptidolipid (GPL), and rough morphotypes, expressing diminished GPL, on the MABC cell wall. Few reports have focused on the relationship between anti-GPL-core immunoglobulin A (IgA) antibody and colony morphology in MABC lung disease. Methods: This study aimed to test GPL core antigen in patients with MABC lung disease to investigate the relationship between coinfection/contamination in other nontuberculous mycobacteria species and colony morphology variant in MABC isolates. Patients with MABC lung disease and contamination diagnosed between 2012 and 2017 at our hospital were enrolled retrospectively. Results: Of the assessed patients, 43 patients with MABC lung disease and 13 with MABC contamination were included. There was a significant difference in anti-GPL-core IgA antibody levels between them (P = 0.02). Forty-three patients with MABC lung disease were divided into two groups as positive and negative antibodies groups. A significant increase in the positive anti-GPL-core IgA antibody was observed in coexistence with both Mycobacterium avium complex (MAC) (P = 0.02) and the isolate of the smooth variant (P = 0.03) in MABC. Conclusions: Anti-GPL-core IgA antibodies in patients with MABC are greatly influenced by MAC coexistence, and colony morphology variant of the MABC isolate.