Non-tuberculous mycobacterial pulmonary disease.

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is a challenging infection which is becoming increasingly prevalent, particularly in the elderly, for reasons which are unknown. While underlying lung disease is a well-established risk factor for NTM-PD, it may also occur in apparently healthy individuals. No single common genetic or immunological defect has been identified in this group, and it is likely that multiple pathways contribute towards host susceptibility to NTM-PD which further interact with environmental and microbiological factors leading to the development of disease.The diagnosis of NTM-PD relies on the integration of clinical, radiological and microbiological results. The clinical course of NTM-PD is heterogeneous, with some patients remaining stable without the need for treatment and others developing refractory disease associated with considerable mortality and morbidity. Treatment regimens are based on the identity of the isolated species, drug sensitivity testing (for some agents) and the severity of disease. Multiple antibiotics are typically required for prolonged periods of time and treatment is frequently poorly tolerated. Surgery may be beneficial in selected cases. In some circumstances cure may not be attainable and there is a pressing need for better regimens to treat refractory and drug-resistant NTM-PD.This review summarises current knowledge on the epidemiology, aetiology and diagnosis of NTM-PD and discusses the treatment of two of the most clinically significant species, the M. avium and M. abscessus complexes, with a focus on refractory disease and novel therapies.

Whole-Blood Gene Expression in Pulmonary Nontuberculous Mycobacterial Infection.

The factors predisposing toward the development of pulmonary nontuberculous mycobacterial (pNTM) disease and influencing disease progression remain unclear. Impaired immune responses have been reported in individuals with pNTM disease, but data are limited and inconsistent. In this study, we sought to use gene expression profiling to examine the host response to pNTM disease. Microarray analysis of whole-blood gene expression was performed on 25 subjects with pNTM disease and 27 uninfected control subjects with respiratory disease. Gene expression results were compared with phenotypic variables and survival data. Compared with uninfected control subjects, pNTM disease was associated with downregulation of 213 transcripts enriched for terms related to T cell signaling, including IFNG. Reduced IFNG expression was associated with more severe computed tomography changes and impaired lung function. Mortality was associated with the expression of transcripts related to the innate immune response and inflammation, whereas transcripts related to T and B cell function were associated with improved survival. These findings suggest that pNTM disease is associated with an aberrant immune response, which may reflect an underlying propensity to infection or result from NTM infection itself. There were important differences in the immune response associated with survival and mortality in pNTM disease.

Metal worker's lung: spatial association with Mycobacterium avium.

BACKGROUND: Outbreaks of hypersensitivity pneumonitis (HP) are not uncommon in workplaces where metal working fluid (MWF) is used to facilitate metal turning. Inhalation of microbe-contaminated MWF has been assumed to be the cause, but previous investigations have failed to establish a spatial relationship between a contaminated source and an outbreak. OBJECTIVES: After an outbreak of five cases of HP in a UK factory, we carried out blinded, molecular-based microbiological investigation of MWF samples in order to identify potential links between specific microbial taxa and machines in the outbreak zone. METHODS: Custom-quantitative PCR assays, microscopy and phylogenetic analyses were performed on blinded MWF samples to quantify microbial burden and identify potential aetiological agents of HP in metal workers. MEASUREMENTS AND MAIN RESULTS: MWF from machines fed by a central sump, but not those with an isolated supply, was contaminated by mycobacteria. The factory sump and a single linked machine at the centre of the outbreak zone, known to be the workstation of the index cases, had very high levels of detectable organisms. Phylogenetic placement of mycobacterial taxonomic marker genes generated from these samples indicated that the contaminating organisms were closely related to Mycobacterium avium. CONCLUSIONS: We describe, for the first time, a close spatial relationship between the abundance of a mycobacterium-like organism, most probably M. avium, and a localised outbreak of MWF-associated HP. The further development of sequence-based analytic techniques should assist in the prevention of this important occupational disease.

Diagnosis of Nontuberculous Mycobacteria Lung Disease.

The diagnosis of pulmonary nontuberculous mycobacteria (NTM) disease may be challenging, as their presence alone does not necessarily indicate disease and diagnosis requires the integration of clinical, radiological, and microbiological findings. The first step is to suspect NTM disease; however, clinical manifestations of NTM are nonspecific and it may not be possible to separate them from those caused by underlying respiratory disease. The radiological appearance generally falls into two patterns, fibrocavitary disease and nodular-bronchiectatic disease; consolidation, infiltrates, and solitary nodules are also described. The isolation of NTM from clinical samples is fundamental to the diagnosis and they may be cultured from sputum, bronchoalveolar lavage fluid, or tissue specimens. If sputum is used, more than one isolate is required for diagnosis due to the propensity of NTM to contaminate clinical samples. The correct identification of NTM is vital, as their clinical relevance varies widely between species, and treatment is dictated by the identity of the isolated organism. This review covers the clinical presentation of NTM disease, the interpretation of radiological findings, and issues surrounding the isolation and identification of mycobacteria.

Host-Microbial Interactions in Idiopathic Pulmonary Fibrosis.

RATIONALE: Changes in the respiratory microbiome are associated with disease progression in idiopathic pulmonary fibrosis (IPF). The role of the host response to the respiratory microbiome remains unknown. OBJECTIVES: To explore the host-microbial interactions in IPF. METHODS: Sixty patients diagnosed with IPF were prospectively enrolled together with 20 matched control subjects. Subjects underwent bronchoalveolar lavage (BAL), and peripheral whole blood was collected into PAXgene tubes for all subjects at baseline. For subjects with IPF, additional samples were taken at 1, 3, and 6 months and (if alive) 1 year. Gene expression profiles were generated using Affymetrix Human Gene 1.1 ST arrays. MEASUREMENTS AND MAIN RESULTS: By network analysis of gene expression data, we identified two gene modules that strongly associated with a diagnosis of IPF, BAL bacterial burden (determined by 16S quantitative polymerase chain reaction), and specific microbial operational taxonomic units, as well as with lavage and peripheral blood neutrophilia. Genes within these modules that are involved in the host defense response include NLRC4, PGLYRP1, MMP9, and DEFA4. The modules also contain two genes encoding specific antimicrobial peptides (SLPI and CAMP). Many of these particular transcripts were associated with survival and showed longitudinal overexpression in subjects experiencing disease progression, further strengthening the relationship of the transcripts with disease. CONCLUSIONS: Integrated analysis of the host transcriptome and microbial signatures demonstrated an apparent host response to the presence of an altered or more abundant microbiome. These responses remained elevated in longitudinal follow-up, suggesting that the bacterial communities of the lower airways may act as persistent stimuli for repetitive alveolar injury in IPF.

Latent class analysis to define radiological subgroups in pulmonary nontuberculous mycobacterial disease.

BACKGROUND: Nontuberculous mycobacterial (NTM) pulmonary disease has conventionally been classified on the basis of radiology into fibrocavitary and nodular-bronchiectatic disease. Whilst being of great clinical utility, this may not capture the full spectrum of radiological appearances present. The aim of this study was to use latent class analysis (LCA) as an unbiased method of grouping subjects with NTM-pulmonary disease based on their CT features and to compare the clinical characteristics of these groups. METHODS: Individuals with NTM-pulmonary disease were recruited and a contemporaneous CT scan obtained. This was scored using an NTM-specific scoring system. LCA was used to identify groups with common radiological characteristics. The analysis was then repeated in an independent cohort. RESULTS: Three classes were identified in the initial cohort of 85 subjects. Group 1 was characterised by severe bronchiectasis, cavitation and aspergillomas, Group 2 by relatively minor radiological changes, and Group 3 by predominantly bronchiectasis only. These findings were reproduced in an independent cohort of 62 subjects. Subjects in Group 1 had a lower BMI and serum albumin, higher serum CRP, and a higher mortality. CONCLUSIONS: These findings suggest that NTM-pulmonary may be divided into three radiological subgroups, and that important clinical and survival differences exist between these groups.

Predicting mortality in bronchiectasis using bronchiectasis severity index and FACED scores: a 19-year cohort study.

The clinical course of bronchiectasis is unpredictable, posing a challenge both in clinical practice and in research. Two mortality prediction scores, the bronchiectasis severity index (BSI) and FACED scores, have recently been developed. The aim of this study was to assess the ability of these scores to predict long-term mortality and to compare the two scores.The study was a single-centre retrospective cohort analysis consisting of 91 subjects originally recruited in 1994. BSI and FACED scores were calculated at the time of enrolment and long-term mortality ascertained. Data was available for 74 patients with a median of 18.8 years of follow-up.Both scoring systems had similar predictive power for 5-year mortality (area under receiver operator characteristic curve (AUC) 0.79 for BSI and 0.8 for FACED). Both scores were able to predict 15-year mortality with the FACED score showing slightly superior predictive power (AUC 0.82 versus 0.69, p=0.0495).This study provides further validation of the FACED and BSI scores for the prediction of mortality in bronchiectasis and demonstrates their utility over a longer period than originally described. Whilst both scores had excellent predictive power, the FACED score was superior for 15-year mortality.

Profiling mycobacterial communities in pulmonary nontuberculous mycobacterial disease.

The diagnosis of pulmonary non-tuberculous mycobacterial disease (pNTM) is dependent on the isolation of NTM in culture, which is prone to overgrowth and contamination and may not capture the diversity of mycobacteria present, including rare or unidentified species. This study aimed to develop a culture independent method of detecting and identifying mycobacteria from sputum samples using partial sequencing of the hsp65 gene. DNA was extracted from sputum samples from subjects with pNTM and disease controls. Multiplexed partial sequencing of the hsp65 gene was performed using the Illumina MiSeq and custom primers. A reference database of hsp65 sequences was created for taxonomy assignment. Sequencing results were obtained from 42 subjects (31 cases, 11 controls). Mycobacterial sequences were identified in all subjects. In 90.5% of samples more than one species was found (median 5.5). The species isolated in culture was detected by sequencing in 81% of subjects and was the most abundant species in 62%. The sequencing of NTM from clinical samples reveals a far greater diversity than conventional culture and suggests NTM are present as communities rather than a single species. NTM were found to be present even in the absence of isolation in culture or clinical disease.

Superior vena cava stent migration into the pulmonary artery causing fatal pulmonary infarction.

Migration of superior vena cava (SVC) stents is a well-recognised complication of their deployment, and numerous strategies exist for their retrieval. To our knowledge, only three cases of migration of an SVC stent to the pulmonary vasculature have previously been reported. None of these patients developed complications that resulted in death. We report a case of SVC stent migration to the pulmonary vasculature with delayed pulmonary artery thrombosis and death from pulmonary infarction. We conclude that early retrieval of migrated stents should be performed to decrease the risk of serious complications.