Causal inference with multiple concurrent medications: A comparison of methods and an application in multidrug-resistant tuberculosis.

This paper investigates different approaches for causal estimation under multiple concurrent medications. Our parameter of interest is the marginal mean counterfactual outcome under different combinations of medications. We explore parametric and non-parametric methods to estimate the generalized propensity score. We then apply three causal estimation approaches (inverse probability of treatment weighting, propensity score adjustment, and targeted maximum likelihood estimation) to estimate the causal parameter of interest. Focusing on the estimation of the expected outcome under the most prevalent regimens, we compare the results obtained using these methods in a simulation study with four potentially concurrent medications. We perform a second simulation study in which some combinations of medications may occur rarely or not occur at all in the dataset. Finally, we apply the methods explored to contrast the probability of patient treatment success for the most prevalent regimens of antimicrobial agents for patients with multidrug-resistant pulmonary tuberculosis.

Scaling up interventions to achieve global tuberculosis control: progress and new developments.

Tuberculosis is still one of the most important causes of death worldwide. The 2010 Lancet tuberculosis series provided a comprehensive overview of global control efforts and challenges. In this update we review recent progress. With improved control efforts, the world and most regions are on track to achieve the Millennium Development Goal of decreasing tuberculosis incidence by 2015, and the Stop TB Partnership target of halving 1990 mortality rates by 2015; the exception is Africa. Despite these advances, full scale-up of tuberculosis and HIV collaborative activities remains challenging and emerging drug-resistant tuberculosis is a major threat. Recognition of the effect that non-communicable diseases--such as smoking-related lung disease, diet-related diabetes mellitus, and alcohol and drug misuse--have on individual vulnerability, as well as the contribution of poor living conditions to community vulnerability, shows the need for multidisciplinary approaches. Several new diagnostic tests are being introduced in endemic countries and for the first time in 40 years a coordinated portfolio of promising new tuberculosis drugs exists. However, none of these advances offer easy solutions. Achievement of international tuberculosis control targets and maintenance of these gains needs optimum national health policies and services, with ongoing investment into new approaches and strategies. Despite growing funding in recent years, a serious shortfall persists. International and national financial uncertainty places gains at serious risk. Perseverance and renewed commitment are needed to achieve global control of tuberculosis, and ultimately, its elimination.

Bronchoalveolar lavage enzyme-linked immunospot for a rapid diagnosis of tuberculosis: a Tuberculosis Network European Trialsgroup study.

RATIONALE: The rapid diagnosis of pulmonary tuberculosis (TB) is difficult when acid fast bacilli (AFB) cannot be detected in sputum smears. OBJECTIVES: Following a proof of principle study, we examined in routine clinical practice whether individuals with sputum AFB smear-negative TB can be discriminated from those with latent TB infection by local immunodiagnosis with a Mycobacterium tuberculosis-specific enzyme-linked immunospot (ELISpot) assay. METHODS: Subjects suspected of having active TB who were unable to produce sputum or with AFB-negative sputum smears were prospectively enrolled at Tuberculosis Network European Trialsgroup centers in Europe. ELISpot with early-secretory-antigenic-target-6 and culture-filtrate-protein-10 peptides was performed on peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage mononuclear cells (BALMCs). M. tuberculosis-specific nucleic acid amplification (NAAT) was performed on bronchoalveolar lavage fluid. MEASUREMENTS AND MAIN RESULTS: Seventy-one of 347 (20.4%) patients had active TB. Out of 276 patients who had an alternative diagnosis, 127 (46.0%) were considered to be latently infected with M. tuberculosis by a positive PBMC ELISpot result. The sensitivity and specificity of BALMC ELISpot for the diagnosis of active pulmonary TB were 91 and 80%, respectively. The BALMC ELISpot (diagnostic odds ratio [OR], 40.4) was superior to PBMC ELISpot (OR, 10.0), tuberculin skin test (OR, 7.8), and M. tuberculosis specific NAAT (OR, 12.4) to diagnose sputum AFB smear-negative TB. In contrast to PBMC ELISpot and tuberculin skin test, the BALMC ELISpot was not influenced by previous history of TB. CONCLUSIONS: Bronchoalveolar lavage ELISpot is an important advancement to rapidly distinguish sputum AFB smear-negative TB from latent TB infection in routine clinical practice.

Validity and reproducibility of morphologic analysis of nasal secretions obtained using ultrasonic nebulization of hypertonic solution.

BACKGROUND: Collection of nasal secretions is important for the evaluation of upper airways inflammation in many nasal disorders. OBJECTIVE: To study the validity and reproducibility of nasal secretion cellularity induced by nebulization of hypertonic solution in patients with allergic rhinitis (AR), patients with nonallergic rhinitis with eosinophilia syndrome (NARES), and control subjects. METHODS: Sixty-eight individuals (29 with AR [mean +/- SD age, 33.3 +/- 16.9 years], 23 with NARES [mean +/- SD age, 46.4 +/- 16.6 years], and 16 controls [mean +/- SD age, 42.1 +/- 15.1 years]) underwent ultrasonic nebulization of hypertonic (4.5%) saline solution on 2 different occasions to study the validity and reproducibility of total and differential cell counts of nasal secretions. RESULTS: The mean +/- SD percentage of eosinophils was significantly higher in samples from patients with AR (20.8% +/- 23.1%) and NARES (18.7% +/- 22.8%) than in samples from controls (0.6% +/- 0.6%; P < .001 for both). There was a significant correlation between 2 samples of nasal secretions obtained on 2 different occasions for percentages of macrophages, neutrophils, eosinophils, and epithelial cells. CONCLUSIONS: The analysis of nasal secretions obtained using ultrasonic nebulization of hypertonic solution can distinguish patients with AR and NARES from controls. The reproducibility of this technique is good for macrophages, neutrophils, eosinophils, and epithelial cells. This method could be used to detect nasal airway inflammation in clinical settings.

Changes in sputum composition during 15 min of sputum induction in healthy subjects and patients with asthma and chronic obstructive pulmonary disease.

INTRODUCTION: The use of sputum induction by inhalation of hypertonic saline to study the cellular and biochemical composition of the airways allows noninvasive sampling of the airways content and identification of markers of airways inflammation. OBJECTIVE: The present study aimed to identify possible changes in the cellular composition of induced sputum between samples obtained sequentially (three periods of 5 min each) during one sputum induction. Moreover, difference between these samples and the mixed one (mixture of samples obtained after 5, 10 and 15 min of induction) was investigated. METHODS: Forty-six subjects (10 healthy volunteers, 12 patients with chronic obstructive pulmonary disease (COPD) and 24 patients with asthma) (mean age 53.0+/-14.0 yr, forced expiratory volume in one second (FEV(1)) 71.8+/-19.0% pred) produced sputum after three consecutive 5 min periods of hypertonic (4.5%) saline inhalation. Stained cytospins from the three periods separately and from the mixed sample were produced and analyzed. RESULTS: The mean percentage of neutrophils, eosinophils, lymphocytes and epithelial cells did not change significantly in samples obtained consecutively after 5, 10 and 15 min of the induction procedure. There was no significant difference in the cellular composition of samples obtained after 5, 10 and 15 min of induction and the cellular composition of the mixed sample (P=0.06). CONCLUSION: The separate analysis of induced sputum from three consecutive sampling and the mixed sample did not demonstrate significant changes in their cellular composition. Fifteen minutes induction procedure with the fixed concentration of hypertonic saline and processing of the mixed sample can be recommended for clinical settings and clinical trials.