Matthew Strand

Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients

Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis.

Body Mass and Glucocorticoid Response in Asthma

RATIONALE Obesity may alter glucocorticoid response in asthma. OBJECTIVES To evaluate the relationship between body mass index (BMI, kg/m(2)) and glucocorticoid response in subjects with and without asthma. METHODS Nonsmoking adult subjects underwent characterization of lung function, BMI, and spirometric response to prednisone. Dexamethasone (DEX, 10(-6) M)-induced mitogen-activated protein kinase phosphatase-1 (MKP-1) and baseline tumor necrosis factor (TNF)-alpha expression were evaluated by polymerase chain reaction in peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage cells. The relationship between BMI and expression of MKP-1 and TNF-alpha was analyzed. MEASUREMENTS AND MAIN RESULTS A total of 45 nonsmoking adults, 33 with asthma (mean [SD] FEV(1)% of 70.7 [9.8]%) and 12 without asthma were enrolled. DEX-induced PBMC MKP-1 expression was reduced in overweight/obese versus lean patients with asthma, with mean (+/- SEM) fold-induction of 3.11 (+/-0.46) versus 5.27 (+/-0.66), respectively (P = 0.01). In patients with asthma, regression analysis revealed a -0.16 (+/-0.08)-fold decrease in DEX-induced MKP-1 per unit BMI increase (P = 0.04). PBMC TNF-alpha expression increased as BMI increased in subjects with asthma, with a 0.27 unit increase in log (TNF-alpha [ng/ml]) per unit BMI increase (P = 0.01). The ratio of PBMC log (TNF-alpha):DEX-induced MKP-1 also increased as BMI increased in patients with asthma (+0.09 +/- 0.02; P = 0.004). In bronchoalveolar lavage cells, DEX-induced MKP-1 expression was also reduced in overweight/obese versus lean patients with asthma (1.36 +/- 0.09-fold vs. 1.76 +/- 0.15-fold induction; P = 0.05). Similar findings were not observed in control subjects without asthma. CONCLUSIONS Elevated BMI is associated with blunted in vitro response to dexamethasone in overweight and obese patients with asthma.

Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis

The broadest pattern of tuberculosis drug resistance for which a consensus definition exists is extensively drug-resistant tuberculosis (XDR-TB). It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR-alone and three non-mutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) capreomycin and kanamycin/amikacin (XDR+2sli); XDR plus resistance to second-line injectables and to ≥1 Group 4 drug, i.e. : ethionamide/prothionamide, cycloserine/terizidone or PAS (XDR+sliG4); and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR-alone; 68 XDR+2sli; 48 XDR+sliG4; and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted Odds Ratio (aOR): 0.4; 95% Confidence Interval: 0.2–0.8) compared to XDR-alone, while odds of failure+death were higher in all XDR patients with additional resistance (aOR range: 2.6–2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current DST methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.The broadest pattern of tuberculosis (TB) drug resistance for which a consensus definition exists is extensively drug-resistant (XDR)-TB. It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance in order to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR alone and three nonmutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) and capreomycin and kanamycin/amikacin (XDR+2sli) XDR plus resistance to second-line injectables and to more than one group 4 drug, i.e. ethionamide/protionamide, cycloserine/terizidone or para-aminosalicylic acid (XDR+sliG4) and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR alone, 68 XDR+2sli, 48 XDR+sliG4 and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted OR 0.4, 95% CI 0.2–0.8) compared to XDR alone, while odds of failure and death were higher in all XDR patients with additional resistance (adjusted OR 2.6–2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current drug susceptibility testing methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.

Patients with Nontuberculous Mycobacterial Lung Disease Exhibit Unique Body and Immune Phenotypes

RATIONALE Among patients with nontuberculous mycobacterial lung disease is a subset of previously healthy women with a slender body morphotype, often with scoliosis and/or pectus excavatum. We hypothesize that unidentified factors predispose these individuals to pulmonary nontuberculous mycobacterial disease. OBJECTIVES To compare body morphotype, serum adipokine levels, and whole-blood cytokine responses of patients with pulmonary nontuberculous mycobacteria (pNTM) with contemporary control subjects who are well matched demographically. METHODS We enrolled 103 patients with pNTM and 101 uninfected control subjects of similar demographics. Body mass index and body fat were quantified. All patients with pNTM and a subset of control subjects were evaluated for scoliosis and pectus excavatum. Serum leptin and adiponectin were measured. Specific cytokines important to host-defense against mycobacteria were measured in whole blood before and after stimulation. MEASUREMENTS AND MAIN RESULTS Patients with pNTM and control subjects were well matched for age, gender, and race. Patients with pNTM had significantly lower body mass index and body fat and were significantly taller than control subjects. Scoliosis and pectus excavatum were significantly more prevalent in patients with pNTM. The normal relationships between the adipokines and body fat were lost in the patients with pNTM, a novel finding. IFN-γ and IL-10 levels were significantly suppressed in stimulated whole blood of patients with pNTM. CONCLUSIONS This is the first study to comprehensively compare body morphotype, adipokines, and cytokine responses between patients with NTM lung disease and demographically matched controls. Our findings suggest a novel, predisposing immunophenotype that should be mechanistically defined.

Association between Functional Small Airway Disease and FEV1 Decline in Chronic Obstructive Pulmonary Disease.

RATIONALE The small conducting airways are the major site of airflow obstruction in chronic obstructive pulmonary disease and may precede emphysema development. OBJECTIVES We hypothesized a novel computed tomography (CT) biomarker of small airway disease predicts FEV1 decline. METHODS We analyzed 1,508 current and former smokers from COPDGene with linear regression to assess predictors of change in FEV1 (ml/yr) over 5 years. Separate models for subjects without and with airflow obstruction were generated using baseline clinical and physiologic predictors in addition to two novel CT metrics created by parametric response mapping (PRM), a technique pairing inspiratory and expiratory CT images to define emphysema (PRM(emph)) and functional small airways disease (PRM(fSAD)), a measure of nonemphysematous air trapping. MEASUREMENTS AND MAIN RESULTS Mean (SD) rate of FEV1 decline in ml/yr for GOLD (Global Initiative for Chronic Obstructive Lung Disease) 0-4 was as follows: 41.8 (47.7), 53.8 (57.1), 45.6 (61.1), 31.6 (43.6), and 5.1 (35.8), respectively (trend test for grades 1-4; P < 0.001). In multivariable linear regression, for participants without airflow obstruction, PRM(fSAD) but not PRM(emph) was associated with FEV1 decline (P < 0.001). In GOLD 1-4 participants, both PRM(fSAD) and PRM(emph) were associated with FEV1 decline (P < 0.001 and P = 0.001, respectively). Based on the model, the proportional contribution of the two CT metrics to FEV1 decline, relative to each other, was 87% versus 13% and 68% versus 32% for PRM(fSAD) and PRM(emph) in GOLD 1/2 and 3/4, respectively. CONCLUSIONS CT-assessed functional small airway disease and emphysema are associated with FEV1 decline, but the association with functional small airway disease has greatest importance in mild-to-moderate stage chronic obstructive pulmonary disease where the rate of FEV1 decline is the greatest. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

Alpha-1-antitrypsin (AAT) anomalies are associated with lung disease due to rapidly growing mycobacteria and AAT inhibits Mycobacterium abscessus infection of macrophages

Rapidly growing mycobacteria (RGM) are ubiquitous in the environment but cause lung disease in only a fraction of exposed individuals. This variable susceptibility to disease implies vulnerability to RGM infection due to weakness in host defense. Since most persons who contract RGM lung disease have no known host defense defect, it is likely that uncharacterized host deficiencies exist that predispose to RGM infection. Alpha-1-antitrypsin (AAT) is a host factor that may protect individuals from respiratory infections. Therefore, we assessed AAT protein anomalies as a risk factor for RGM lung disease. In a cohort of 100 patients with RGM lung disease, Mycobacterium (M.) abscessus was the most prevalent organism, isolated in 64 (64%) subjects. Anomalous AAT proteins were present in 27% of the cohort, which is 1.6 times the estimated prevalence of anomalous AAT proteins in the United States population (p =0.008). In in vitro studies, both AAT and a synthetic inhibitor of serine proteases suppressed M. abscessus infection of monocyte-derived macrophages by up to 65% (p<0.01). AAT may be an anti-RGM host-defense factor, and anomalous AAT phenotypes or AAT deficiency may constitute risk factors for pulmonary disease due to RGM.

Risk analysis of early childhood eczema.

BACKGROUND The increasing prevalence of eczema suggests the role of environmental factors triggering a genetic predisposition. OBJECTIVE To analyze the effect of environmental exposures in early life and genetic predisposition on the development of eczema before age 3 years. METHODS The Copenhagen Study on Asthma in Childhood is a prospective clinical study of a birth cohort of 411 children born of mothers with asthma. Eczema was diagnosed, treated, and monitored at the clinical research unit, and complete follow-up for the first 3 years of life was available for 356 children. Risk assessments included filaggrin loss-of-function mutation; parents atopic disease; sex; social status; previous deliveries; third trimester complications and exposures; anthropometrics at birth; month of birth; duration solely breast-fed; introduction of egg, cows milk, and fish; time spent in day care; cat and dog at home; feather pillow; nicotine in infants hair; and temperature and humidity in bedroom. RESULTS Eczema developed in 43.5% of the infants. Filaggrin mutation (odds ratio [OR], 3.20; 95% CI, 1.46-7.02; P = .004), mothers eczema (OR, 2.80; 95% CI, 1.70-4.63; P < .0001), and fathers allergic rhinitis (OR, 1.91; 95% CI, 1.09-3.33; P = .02) were directly associated with risk of eczema. Risk of eczema was significantly reduced by birth length (OR per cm increase, 0.87; 95% CI, 0.78-0.97; P = .02), increased bedroom temperature (probably inverse causality; OR, 0.80; 95% CI, 0.66-0.97; P = .02), and dog living in the home (OR, 0.44; 95% CI, 0.23-0.87; P = .02). CONCLUSIONS Dog exposure reduced the risk of eczema, whereas short length at birth, filaggrin mutation, and parental atopy increased the risk of eczema by age 3 years.

Treatment Outcomes in Extensively Resistant Tuberculosis

The authors retrospectively analyzed 205 cases of multidrug-resistant tuberculosis to determine what percentage met the definition of extensively drug-resistant tuberculosis and compared the treatment outcomes. Odds ratios for treatment success in the group of patients who had multidrug-resistant tuberculosis, as compared with those who had extensively drug-resistant tuberculosis, were 23.4 for the initial outcome and 21.1 for the long-term outcome.

The effect of aspirin desensitization on novel biomarkers in aspirin-exacerbated respiratory diseases

BACKGROUND Patients with aspirin-exacerbated respiratory disease have been shown to benefit clinically from aspirin desensitization followed by chronic high-dose aspirin therapy. However, the mechanism of this phenomenon is still unclear. OBJECTIVE The aim of this study was to characterize the airway inflammatory response to aspirin desensitization and after treatment with high-dose aspirin for 6 months. METHODS Twenty-one adult patients with asthma, chronic polypoid sinusitis, and a convincing history of acute respiratory reaction to the ingestion of aspirin or nonsteroidal anti-inflammatory drugs were selected. These patients underwent an oral desensitization to aspirin over a 2-day period, followed by daily ingestion of aspirin 650 mg twice daily. Induced sputum samples and exhaled nitric oxide measurements were taken before the procedure, during the second day of the procedure, and after 6 months of treatment. RESULTS There was a significant elevation in both the exhaled nitric oxide level (P = .03) and sputum tryptase level (P = .05) during the desensitization process. After 6 months of aspirin treatment, sputum IL-4 (P = .0007) and matrix metalloproteinase 9 (MMP-9; P = .05) decreased significantly compared with baseline. Predesensitization to postdesensitization changes in MMP-9 and tissue inhibitors of metalloproteinases 1 were highly correlated (r = 0.79; P = .0003). Immediately after the desensitization, MMP-9 and tryptase were correlated (r = 0.82; P = .001), whereas IL-4 was inversely related with FMS-like tyrosine kinase 3 ligand (FLT3-L) (r = -0.79; P = .0008). There was a significant decrease in the average symptom score at 6 months. CONCLUSION Consistent with previous reports, acute aspirin desensitization in patients with aspirin-exacerbated respiratory disease involves mast cell degranulation. In contrast, long-term treatment with aspirin involves suppression of IL-4 as well as downregulation of proinflammatory MMP-9 while T(H)1 marker FLT3-L increases.

The Response of Children with Asthma to Ambient Particulate Is Modified by Tobacco Smoke Exposure

RATIONALE Ambient particulate matter concentrations have been positively associated with urinary leukotriene E(4) (LTE(4)) levels and albuterol usage in children with asthma but interactions with environmental tobacco smoke (ETS) exposure have not been demonstrated despite obvious exposure to both pollutants in an urban setting. OBJECTIVES To assess the health effects of concurrent ETS and ambient particulate matter exposure in children with asthma. METHODS Albuterol usage and LTE(4) levels were monitored in 82 urban schoolchildren with asthma over three consecutive fall to spring school periods. Concentrations of morning maximum ambient particulate matter <2.5 μm in aerodynamic diameter (mmPM(2.5)) and urine cotinine levels were also measured daily. MEASUREMENTS AND MAIN RESULTS Albuterol usage and LTE(4) were related to mmPM(2.5) concentrations on days when urine cotinine levels were low (<10 ng/ml/mg creatinine); on these days, mean albuterol usage and LTE(4) increased up to 5 or 6% per 10 μg/m(3) increase in mmPM(2.5). In contrast, no significant relationship was observed when cotinine was high, although mean albuterol usage and LTE(4) levels were greater in this case. Model fits for LTE(4) levels as a function of mmPM(2.5) concentrations were improved when mmPM(2.5) concentrations were logged, suggesting a nonlinear dose-response relationship between particulate matter exposure concentrations and airway mediators of asthma, for which the relationship tends to flatten at higher concentrations. CONCLUSIONS This study suggests that ETS modifies the acute effects of low-level ambient PM(2.5) exposure on childhood asthma. This negative interaction, the smaller effect of particulate matter exposure in children exposed to higher ETS, may be related to a nonlinear dose-response relationship between asthma mediators and particulate exposures.