Exhaled Nitric Oxide is Not a Biomarker for Pulmonary Tuberculosis.

To reduce transmission of tuberculosis (TB) in resource-limited countries where TB remains a major cause of mortality, novel diagnostic tools are urgently needed. We evaluated the fractional concentration of exhaled nitric oxide (FeNO) as an easily measured, noninvasive potential biomarker for diagnosis and monitoring of treatment response in participants with pulmonary TB including multidrug resistant-TB in Lima, Peru. In a longitudinal study however, we found no differences in baseline median FeNO levels between 38 TB participants and 93 age-matched controls (13 parts per billion [ppb] [interquartile range (IQR) = 8-26] versus 15 ppb [IQR = 12-24]), and there was no change over 60 days of treatment (15 ppb [IQR = 10-19] at day 60). Taking this and previous evidence together, we conclude FeNO is not of value in either the diagnosis of pulmonary TB or as a marker of treatment response.

Cough Frequency During Treatment Associated With Baseline Cavitary Volume and Proximity to the Airway in Pulmonary TB.

BACKGROUND: Cough frequency, and its duration, is a biomarker that can be used in low-resource settings without the need of laboratory culture and has been associated with transmission and treatment response. Radiologic characteristics associated with increased cough frequency may be important in understanding transmission. The relationship between cough frequency and cavitary lung disease has not been studied. METHODS: We analyzed data in 41 adults who were HIV negative and had culture-confirmed, drug-susceptible pulmonary TB throughout treatment. Cough recordings were based on the Cayetano Cough Monitor, and sputum samples were evaluated using microscopic observation drug susceptibility broth culture; among culture-positive samples, bacillary burden was assessed by means of time to positivity. CT scans were analyzed by a US-board-certified radiologist and a computer-automated algorithm. The algorithm evaluated cavity volume and cavitary proximity to the airway. CT scans were obtained within 1 month of treatment initiation. We compared small cavities (≤ 7 mL) and large cavities (> 7 mL) and cavities located closer to (≤ 10 mm) and farther from (> 10 mm) the airway to cough frequency and cough cessation until treatment day 60. RESULTS: Cough frequency during treatment was twofold higher in participants with large cavity volumes (rate ratio [RR], 1.98; P = .01) and cavities located closer to the airway (RR, 2.44; P = .001). Comparably, cough ceased three times faster in participants with smaller cavities (adjusted hazard ratio [HR], 2.89; P = .06) and those farther from the airway (adjusted HR, 3.61;, P = .02). Similar results were found for bacillary burden and culture conversion during treatment. CONCLUSIONS: Cough frequency during treatment is greater and lasts longer in patients with larger cavities, especially those closer to the airway.

Sputum Microscopy With Fluorescein Diacetate Predicts Tuberculosis Infectiousness.

Background: Sputum from patients with tuberculosis contains subpopulations of metabolically active and inactive Mycobacterium tuberculosis with unknown implications for infectiousness. Methods: We assessed sputum microscopy with fluorescein diacetate (FDA, evaluating M. tuberculosis metabolic activity) for predicting infectiousness. Mycobacterium tuberculosis was quantified in pretreatment sputum of patients with pulmonary tuberculosis using FDA microscopy, culture, and acid-fast microscopy. These 35 patients' 209 household contacts were followed with prevalence surveys for tuberculosis disease for 6 years. Results: FDA microscopy was positive for a median of 119 (interquartile range [IQR], 47-386) bacteria/µL sputum, which was 5.1% (IQR, 2.4%-11%) the concentration of acid-fast microscopy-positive bacteria (2069 [IQR, 1358-3734] bacteria/µL). Tuberculosis was diagnosed during follow-up in 6.4% (13/209) of contacts. For patients with lower than median concentration of FDA microscopy-positive M. tuberculosis, 10% of their contacts developed tuberculosis. This was significantly more than 2.7% of the contacts of patients with higher than median FDA microscopy results (crude hazard ratio [HR], 3.8; P = .03). This association maintained statistical significance after adjusting for disease severity, chemoprophylaxis, drug resistance, and social determinants (adjusted HR, 3.9; P = .02). Conclusions: Mycobacterium tuberculosis that was FDA microscopy negative was paradoxically associated with greater infectiousness. FDA microscopy-negative bacteria in these pretreatment samples may be a nonstaining, slowly metabolizing phenotype better adapted to airborne transmission.

Protocol for studying cough frequency in people with pulmonary tuberculosis.

INTRODUCTION: Cough is a key symptom of tuberculosis (TB) as well as the main cause of transmission. However, a recent literature review found that cough frequency (number of coughs per hour) in patients with TB has only been studied once, in 1969. The main aim of this study is to describe cough frequency patterns before and after the start of TB treatment and to determine baseline factors that affect cough frequency in these patients. Secondarily, we will evaluate the correlation between cough frequency and TB microbiological resolution. METHODS: This study will select participants with culture confirmed TB from 2 tertiary hospitals in Lima, Peru. We estimated that a sample size of 107 patients was sufficient to detect clinically significant changes in cough frequency. Participants will initially be evaluated through questionnaires, radiology, microscopic observation drug susceptibility broth TB-culture, auramine smear microscopy and cough recordings. This cohort will be followed for the initial 60 days of anti-TB treatment, and throughout the study several microbiological samples as well as 24 h recordings will be collected. We will describe the variability of cough episodes and determine its association with baseline laboratory parameters of pulmonary TB. In addition, we will analyse the reduction of cough frequency in predicting TB cure, adjusted for potential confounders. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the ethics committees at each participating hospital in Lima, Peru, Asociación Benéfica PRISMA in Lima, Peru, the Universidad Peruana Cayetano Heredia in Lima, Peru and Johns Hopkins University in Baltimore, USA. We aim to publish and disseminate our findings in peer-reviewed journals. We also expect to create and maintain an online repository for TB cough sounds as well as the statistical analysis employed.

Validation of an automated cough detection algorithm for tracking recovery of pulmonary tuberculosis patients.

BACKGROUND: A laboratory-free test for assessing recovery from pulmonary tuberculosis (TB) would be extremely beneficial in regions of the world where laboratory facilities are lacking. Our hypothesis is that analysis of cough sound recordings may provide such a test. In the current paper, we present validation of a cough analysis tool. METHODOLOGY/PRINCIPAL FINDINGS: Cough data was collected from a cohort of TB patients in Lima, Peru and 25.5 hours of recordings were manually annotated by clinical staff. Analysis software was developed and validated by comparison to manual scoring. Because many patients cough in bursts, coughing was characterized in terms of cough epochs. Our software correctly detects 75.5% of cough episodes with a specificity of 99.6% (comparable to past results using the same definition) and a median false positive rate of 4 false positives/hour, due to the noisy, real-world nature of our dataset. We then manually review detected coughs to eliminate false positives, in effect using the algorithm as a pre-screening tool that reduces reviewing time to roughly 5% of the recording length. This cough analysis approach provides a foundation to support larger-scale studies of coughing rates over time for TB patients undergoing treatment.