Association between bronchiectasis exacerbations and longitudinal changes in FEV1 in patients from the US bronchiectasis and NTM research registry.

BACKGROUND: This study aimed to evaluate the association between the number of non-cystic fibrosis bronchiectasis (bronchiectasis) exacerbations during baseline and follow-up (objective 1) and to identify longitudinal changes in FEV1 associated with exacerbation frequency (objective 2). METHODS: This was a retrospective cohort study of adult patients enrolled in the US Bronchiectasis and Nontuberculous Mycobacteria Research Registry September 2008 to March 2020. Objective 1 outcome was association between exacerbations during baseline (24 months) and 0-to-24 month and 24-to-48 month follow-up windows. Objective 2 outcomes were change in FEV1 and FEV1 % predicted over 24 months stratified by baseline exacerbation frequency. RESULTS: Objective 1 cohort (N = 520) baseline frequency of any exacerbations was 59.2%. Overall, 71.4% and 75.0% of patients with ≥1 baseline exacerbations had ≥1 exacerbations during the 0-to-24 and 24-to-48 month follow-ups. Having ≥1 exacerbation during baseline was significantly associated with ≥1 exacerbation during the 0-to-24 month (P = 0.0085) and 24-to-48 month follow-ups (P=<0.0001). Objective 2 cohort (N = 431) baseline FEV1 was significantly lower in patients who had more exacerbations; however, decline in FEV1 from baseline was not significantly different between patients with 0, 1, and ≥2 exacerbations. In patients with more baseline exacerbations, FEV1 % predicted was significantly lower at baseline (P < 0.0001) and at 12 (P = 0.0002) and 24 month follow-ups (P < 0.0001). CONCLUSIONS: Patients with frequent bronchiectasis exacerbations may be more likely than those with less frequent exacerbations to experience disease progression based on future exacerbation frequency and lower FEV1 at baseline, although FEV1 decline may not differ by baseline exacerbation frequency.

CLINICAL CHARACTERISTICS AND VISUAL OUTCOMES IN ENDOPHTHALMITIS AFTER KERATOPROSTHESIS IMPLANTATION.

PURPOSE: To describe the presentation, microbiology, management, and prognosis of eyes with endophthalmitis after Boston keratoprosthesis implantation. METHODS: Retrospective case series with history, diagnostics, management, and outcomes data in endophthalmitis after keratoprosthesis implantation presenting to a tertiary center between 2009 and 2020. RESULTS: Of 137 keratoprosthesis-implanted eyes, 7 eyes of 7 patients (5%) developed endophthalmitis. On presentation, 6 (86%) reported decreased visual acuity, and only 1 (14%) reported pain. Peripheral corneal ulcers were present in 2 eyes (29%). Seidel testing was negative in all cases. Six eyes (86%) had retroprosthetic membranes. One (14%) underwent initial pars plana vitrectomy with mechanical vitreous biopsy, whereas 6 (86%) received a needle vitreous tap-half of which were dry. Organisms were isolated after vitreous tap in two eyes: Streptococcus intermedius and Mycobacterium abscessus. The mean visual acuity preendophthalmitis, at presentation, and at 6 months were 20/267, 20/5,944, and 20/734, respectively. The visual acuity improved 9.08 ± 11.78 Early Treatment Diabetic Retinopathy Study lines from presentation to 6 months. Six-month visual acuity was correlated with preendophthalmitis visual acuity (r = 0.92, P = 0.003) but not presenting visual acuity (P = 0.838). CONCLUSION: Visual acuity at 6 months is correlated with preendophthalmitis visual acuity, not presenting visual acuity. Endophthalmitis should be considered in the differential diagnosis of painless intraocular inflammation any time after keratoprosthesis implantation, even if Seidel negative.

Pulmonary Manifestations of GATA2 Deficiency.

BACKGROUND: GATA2 deficiency is a genetic disorder of hematopoiesis, lymphatics, and immunity caused by autosomal dominant or sporadic mutations in GATA2. The disease has a broad phenotype encompassing immunodeficiency, myelodysplasia, leukemia, and vascular or lymphatic dysfunction as well as prominent pulmonary manifestations. RESEARCH QUESTION: What are the pulmonary manifestations of GATA2 deficiency? STUDY DESIGN AND METHODS: A retrospective review was conducted of clinical medical records, diagnostic imaging, pulmonary pathologic specimens, and tests of pulmonary function. RESULTS: Of 124 patients (95 probands and 29 ascertained), the lung was affected in 56%. In addition to chronic infections, pulmonary alveolar proteinosis (11 probands) and pulmonary arterial hypertension (nine probands) were present. Thoracic CT imaging found small nodules in 54% (54 probands and 12 relatives), reticular infiltrates in 40% (45 probands and four relatives), paraseptal emphysema in 25% (30 probands and one relative), ground-glass opacities in 35% (41 probands and two relatives), consolidation in 21% (23 probands and two relatives), and a typical crazy-paving pattern in 7% (eight probands and no relatives). Nontuberculous mycobacteria were the most frequent organisms associated with chronic infection. Allogeneic hematopoietic stem cell transplantation successfully reversed myelodysplasia and immune deficiency and also improved pulmonary hypertension and pulmonary alveolar proteinosis in most patients. INTERPRETATION: GATA2 deficiency has prominent pulmonary manifestations. These clinical observations confirm the essential role of hematopoietic cells in many aspects of pulmonary function, including infections, alveolar proteinosis, and pulmonary hypertension, many of which precede the formal diagnosis, and many of which respond to stem cell transplantation.

Mycobacterial fatty acid catabolism is repressed by FdmR to sustain lipogenesis and virulence.

Host-derived fatty acids are an important carbon source for pathogenic mycobacteria during infection. How mycobacterial cells regulate the catabolism of fatty acids to serve the pathogenicity, however, remains unknown. Here, we identified a TetR-family transcriptional factor, FdmR, as the key regulator of fatty acid catabolism in the pathogen Mycobacterium marinum by combining use of transcriptomics, chromatin immunoprecipitation followed by sequencing, dynamic 13C-based flux analysis, metabolomics, and lipidomics. An M. marinum mutant deficient in FdmR was severely attenuated in zebrafish larvae and adult zebrafish. The mutant showed defective growth but high substrate consumption on fatty acids. FdmR was identified as a long-chain acyl-coenzyme A (acyl-CoA)-responsive repressor of genes involved in fatty acid degradation and modification. We demonstrated that FdmR functions as a valve to direct the flux of exogenously derived fatty acids away from ß-oxidation toward lipid biosynthesis, thereby avoiding the overactive catabolism and accumulation of biologically toxic intermediates. Moreover, we found that FdmR suppresses degradation of long-chain acyl-CoAs endogenously synthesized through the type I fatty acid synthase. By modulating the supply of long-chain acyl-CoAs for lipogenesis, FdmR controls the abundance and chain length of virulence-associated lipids and mycolates and plays an important role in the impermeability of the cell envelope. These results reveal that despite the fact that host-derived fatty acids are used as an important carbon source, overactive catabolism of fatty acids is detrimental to mycobacterial cell growth and pathogenicity. This study thus presents FdmR as a potentially attractive target for chemotherapy.

Outcome according to subspecies following lung transplantation in cystic fibrosis pediatric patients infected with Mycobacterium abscessus.

BACKGROUND: Mycobacterium abscessus infection has been associated with variable outcomes following lung transplantation. M abscessus comprises three subspecies (M abscessus subsp abscessus, M abscessus subsp massiliense, and M abscessus subsp bolletii). We investigated whether lung transplantation outcome in cystic fibrosis (CF) patients in a single center was related to the M abscessus subspecies and genetic cluster. METHODS: CF patients with chronic M abscessus infection transplanted at Great Ormond Street Hospital between 2004 and 2017 were retrospectively examined. All M abscessus isolates were identified to subspecies level by polymerase chain reaction and sequencing. Genetic cluster was determined by variable number tandem repeat profiling and whole-genome sequencing (WGS), and sequence type inferred from WGS. RESULTS: Thirteen patients with chronic M abscessus infection underwent heart/lung or lung transplantation. Subspecies identification showed n = 1 with M abscessus bolletii, n = 5 with M abscessus massiliense, and n = 7 with M abscessus abscessus infection. Eight (62%) patients (one with M abscessus massiliense and seven with M abscessus abscessus) died post-lung transplant. The patient with M abscessus bolletii and three patients with M abscessus massiliense did well post-transplant. One patient with M abscessus massiliense is receiving ongoing treatment. CONCLUSIONS: Dramatically worse outcomes are observed in patients infected with M abscessus subspecies abscessus, the majority of whom were infected with ST-1 and ST-26 strains. Patients infected with other M abcsessus strains can have acceptable outcomes.

Incremental Shuttle Walk Distance as an Indicator for Functional Exercise Capacity of Pre-Surgical Patients with Nontuberculous Mycobacterial Lung Disease.

The incidence of nontuberculous mycobacterial lung disease (NTMLD) is increasing worldwide, the number of lung surgeries is increasing accordingly. The disease is progressive and is characterized by exertional intolerance, respiratory dysfunctions, and impaired health-related quality of life (HRQOL). Treatment comprises multidrug antibiotic treatment combined with lung resection. The incremental shuttle walk distance (ISWD) is a standard tool for assessing the patients' tolerance to lung resection. The exertional tolerance, physical functions and HRQOL among pre-surgical patients with NTMLD are clinically important, but not fully studied yet from the viewpoint of physiotherapy. The purpose of this study was to explore the clinical significance of ISWD for assessing the exercise capacity of pre-surgical patients with NTMLD. For peripheral muscle evaluation, the strength of the quadriceps femoris muscle was measured. HRQOL was evaluated using scores of the St. George's Respiratory Questionnaire (SGRQ). Thirty-three patients (mean age 54.9 ± 13 years) were enrolled. The mean ISWD was 505 ± 134 m, shorter than the reference values (ISWD %predicted: 96 ± 27%). Regression analysis showed significant associations between ISWD and percent-predicted vital capacity (r = 0.38, p = 0.03) and percent quadriceps force/body weight (r = 0.54, p = 0.001). HRQOL assessed by SGRQ scores was correlated with ISWD (r < -0.4, p < 0.05). Multiple regression analysis showed that ISWD was significantly associated with leg muscle strength and with HRQOL. In conclusion, ISWD is useful to evaluate the exercise capacity among pre-surgical patients with NTMLD.

Pilot study to test inhaled nitric oxide in cystic fibrosis patients with refractory Mycobacterium abscessus lung infection.

BACKGROUND: Airways of Cystic Fibrosis (CF) patients are Nitric Oxide (NO) deficient which may contribute to impaired lung function and infection clearance. Mycobacterium abscessus (M. abscessus) infection prevalence is increasing in CF patients and is associated with increased morbidity and mortality. Here, we assess the safety and efficacy of intermittent inhaled NO (iNO) as adjuvant therapy in CF patients with refractory M. abscessus lung infection. METHODS: A prospective, open-label pilot study of iNO (160 ppm) administered five times/day during hospitalization (14 days), and three times/day during ambulatory treatment (7 days) was conducted. The primary outcome was safety measured by NO-related adverse events (AEs). Secondary outcomes were six-minute walk distance (6MWD), forced expiratory volume in 1 s (FEV1), and M. abscessus burden in airways. RESULTS: Nine subjects were recruited. INO at 160 ppm was well-tolerated and no iNO-related SAEs were observed during the study. Mean FEV1 and 6WMD were increased relative to baseline during NO treatment. M. abscessus culture conversion was not achieved, but 3/9 patients experienced at least one negative culture during the study. Mean time to positivity in M. abscessus culture, and qPCR analysis showed reductions in sputum bacterial load. The study was not powered to achieve statistical significance in FEV1, 6WMD, and bacterial load. CONCLUSIONS: Intermittent iNO at 160 ppm is well tolerated and safe and led to increases in mean 6MWD and FEV1. INO exhibited potential antibacterial activity against M. abscessus. Further evaluation of secondary endpoints in a larger cohort of CF patients is warranted to demonstrate statistical significance.

Pulmonary Densitovolumetry Using Computed Tomography in Patients with Nontuberculous Mycobacteria: Correlation with Pulmonary Function Tests.

BACKGROUND: Since nontuberculous mycobacterial pulmonary disease (NTM-PD) is a condition with increasing morbidity, a more detailed knowledge of radiological aspects and pulmonary function plays a relevant role in the diagnosis and appropriate therapeutic management of these patients. OBJECTIVES: The purpose of this study was to evaluate changes in lung parenchyma through computed tomography (CT) densitometry and, secondarily, to analyze its correlation with pulmonary function testing (PFT) in patients with NTM-PD. METHODS: This is a cross-sectional study in which 31 patients with NTM-PD and 27 controls matched by sex, age, and body mass index underwent CT pulmonary densitovolumetry and pulmonary function tests including spirometry and body plethysmograph. RESULTS: Based on the total lung volume (TLV) and total lung mass (TLM) measurements, the cumulative mass ratios were calculated for 3% (M3), 15% (M15), 85% (M85), and 97% (M97) of the TLV. We also calculated the complement, which is represented by TLM (100%) minus the mass of 15% (C85) or 3% (C97) of the TLV. Patients with NTM-PD presented lower values of M3 and M15 than controls, with greater significant differences in the apical third and middle third measurements. Compared to controls, patients with NTM-PD showed higher values of C85 and C97, although significant differences were observed only in the basal third measurements. There were negative correlations of total lung capacity with M3 and M15 in the middle third and apical third measurements. There were positive correlations of residual volume and airway resistance with M3 at the apical third measurement. CONCLUSIONS: Patients with NTM-PD show reduced lung mass and increased lung mass in the apical and basal regions of the lungs, respectively. Furthermore, there is a relationship between lung mass measurements and pulmonary function parameters.

Influence of intersegmental plane size and segment division methods on preserved lung volume and function after pulmonary segmentectomy.

OBJECTIVES: We previously reported that the use of a stapler to divide intersegmental planes did not decrease preserved pulmonary volume or function relative to electrocautery. However, preservation of pulmonary volume or function can be compromised when a stapler is used with larger intersegmental planes. Here, we assessed the correlations between preserved lung volume and pulmonary function after segmentectomy and the size of the intersegmental planes, based on the division method. METHODS: Intersegmental plane sizes in 56 patients were semi-automatically calculated using image analysis software on computed tomography images. The ratios of the remnant segment and ipsilateral lung volumes to their preoperative values (R-seg and R-ips) and the ratio of the postoperative pulmonary function relative to the predicted value were calculated based on three-dimensional volumetry. Correlations between preserved lung volume and pulmonary function and the intersegmental plane sizes were analyzed according to the division method. RESULTS: Intersegmental planes were divided by either electrocautery or with a stapler (EC/Mixed) in 21 patients and by stapler alone (ST) in 35 patients. There was no difference in the average size of the intersegmental planes between the two groups. The intersegmental plane size negatively correlated with R-seg in the ST group. CONCLUSIONS: Using the stapler method, as the size of the intersegmental planes increased, the preserved remnant segmental volume decreased; however, relation between the plane size and preserved pulmonary function was unclear. These findings indicate that stapler use is acceptable even for large intersegmental planes.

Surgical Site Infections due to Non-Tuberculous Mycobacteria.

INTRODUCTION: Non-tuberculous Mycobacteria are increasingly recognized, nowadays as an important pathogen in delayed surgical site infection in post operative cases. We here in describe cases of surgical site infection caused by Non-tuberculous Mycobacteria, seen in two centers in Jhapa. The aim of the study was to increase awareness of this atypical mycobacterial infection, prompt diagnosis, and treatment that may ultimately provide better care to patients. METHODS: Forty four patients underwent different kinds of operations in two different private hospitals in Jhapa district of Nepal. All patients were presented with painful, draining subcutaneous nodules at the infection sites. Repeated aspiration of abscess, incision and drainage of the wound were done and specimen was sent for microbiological and histopathological examination. All patients were treated with repeated wound debridement and tab. Clarithromycin and inj. Tobramycin for 45days. RESULTS: Mycobacterium Chelone were isolated from the purulent drainage obtained from wounds by routine microbiological techniques. Of the forty four cases, thirty of them had acid fast bacilli stain positive, two had acid fast bacilli culture positive. All the patients except two cases were treated with injection Tobramycin and Clarithromycin for six weeks. CONCLUSIONS: There should be high level of clinical suspicion for patients presenting with delayed post- operative wound infections for the diagnosis of non-tubercular mycobacreria as causative agents. These infections not only cause physical but also emotional distress that affects both the patients and the surgeon. Emphasis should be given on good sterilization technique to avoid such infections.

A cluster of nontuberculous mycobacterial endophthalmitis (NTME) cases after cataract surgery: clinical features and treatment outcomes.

PURPOSE: To report the clinical features and treatment outcomes in a cluster of patients with endophthalmitis after cataract surgery caused by nontuberculous mycobacterium. PATIENTS AND METHODS: Retrospective chart review and noncomparative, consecutive case series. Nine consecutive cases of endophthalmitis, after cataract surgery in a local clinic, were referred to our hospital. The treatment outcomes and analysis of risk factors for infection are reported. RESULTS: The major symptoms at presentation were pain, redness, and decreased vision. Best-corrected visual acuity at presentation ranged from hand motion in two cases (22%), counting fingers at 30 cm in three cases (33%), 20/100 in two cases (20%), 20/63 in one case (11%), to 20/50 in one (11%) case. The mean duration between cataract surgery to presentation at our hospital was 16.7 days. Prompt intravitreal injections (IVI) of amikacin (0.4 mg/0.1 mL) and vancomycin (1 mg/0.1 mL), with topical moxifloxacin were administered initially. Pars plana vitrectomy with amikacin (10 mg/L) and vancomycin (20 mg/L) intravitreal irrigation, and intraocular lens removal were performed for all patients. Systemic antibiotics including amikacin and tigecycline were prescribed for 10 days, and clarithromycin was prescribed for at least 3 months. In all the nine cases, the culture results from either aqueous tapping or vitrectomy sample were positive for nontuberculous Mycobacterium: Mycobacterium abscessus/chelonae, which was compatible with iatrogenic clustered infection. At the last follow-up, three cases (33.3%) had best-corrected visual acuity of counting fingers at 30 cm, while the other six cases had no light perception. Two cases (22%) were enucleated and one case (11%) had phthisis bulbi. CONCLUSION: Nontuberculous mycobacterium endophthalmitis (NTME) often induces chronic recurrent or persistent intraocular inflammation. Very poor outcomes despite aggressive antibiotic treatment and repeated surgical interventions are suggestive of the virulent nature of the organisms. Autoclave sterilization and perioperative disinfection may help in reducing iatrogenic clustered infection.

Mycobacterium marinum infection in fish and man: epidemiology, pathophysiology and management; a review.

Mycobacterium marinum is an opportunistic pathogen inducing infection in fresh and marine water fish. This pathogen causes necrotizing granuloma like tuberculosis, morbidity and mortality in fish. The cell wall-associated lipid phthiocerol dimycocerosates, phenolic glycolipids and ESAT-6 secretion system 1 (ESX-1) are the conserved virulence determinant of the organism. Human infections with Mycobacterium marinum hypothetically are classified into four clinical categories (type I-type IV) and have been associated with the exposure of damaged skin to polluted water from fish pools or contacting objects contaminated with infected fish. Fish mycobacteriosis is clinically manifested and characterized in man by purple painless nodules, liable to develop into superficial crusting ulceration with scar formation. Early laboratory diagnosis of M. marinum including histopathology, culture and PCR is essential and critical as the clinical response to antibiotics requires months to be attained. The pathogenicity and virulence determinants of M. marinum need to be thoroughly and comprehensively investigated and understood. In spite of accumulating information on this pathogen, the different relevant data should be compared, connected and globally compiled. This article is reviewing the epidemiology, virulence factors, diagnosis and disease management in fish while casting light on the potential associated public health hazards.

Mycobacterium xenopi Genotype Associated with Clinical Phenotype in Lung Disease.

Mycobacterium xenopi is responsible for pulmonary disease (PD) in Europe and Canada. Despite its high prevalence and increasing clinical importance, little is known about the genetic diversity of M. xenopi. Through a prospective study for M. xenopi strain type and the relation to clinical phenotype, 39 patients with M. xenopi PD were analyzed. Our study demonstrated that sequence type (ST) 5 was dominant in Ontario among 15 distinct STs and caused PD in people even without underlying lung disease, whereas disease due to non-ST5 was found almost exclusively in patients with underlying lung disease.