Brian W. Allwood

Do adjunct tuberculosis tests, when combined with Xpert MTB/RIF, improve accuracy and the cost of diagnosis in a resource-poor setting?

Information regarding the utility of adjunct diagnostic tests in combination with Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) is limited. We hypothesised adjunct tests could enhance accuracy and/or reduce the cost of tuberculosis (TB) diagnosis prior to MTB/RIF testing, and rule-in or rule-out TB in MTB/RIF-negative individuals. We assessed the accuracy and/or laboratory-associated cost of diagnosis of smear microscopy, chest radiography (CXR) and interferon-&ggr; release assays (IGRAs; T-SPOT-TB (Oxford Immunotec, Oxford, UK) and QuantiFERON-TB Gold In-Tube (Cellestis, Chadstone, Australia)) combined with MTB/RIF for TB in 480 patients in South Africa. When conducted prior to MTB/RIF: 1) smear microscopy followed by MTB/RIF (if smear negative) had the lowest cost of diagnosis of any strategy investigated; 2) a combination of smear microscopy, CXR (if smear negative) and MTB/RIF (if imaging compatible with active TB) did not further reduce the cost per TB case diagnosed; and 3) a normal CXR ruled out TB in 18% of patients (57 out of 324; negative predictive value (NPV) 100%). When downstream adjunct tests were applied to MTB/RIF-negative individuals, radiology ruled out TB in 24% (56 out of 234; NPV 100%), smear microscopy ruled in TB in 21% (seven out of 24) of culture-positive individuals and IGRAs were not useful in either context. In resource-poor settings, smear microscopy combined with MTB/RIF had the highest accuracy and lowest cost of diagnosis compared to either technique alone. In MTB/RIF-negative individuals, CXR has poor rule-in value but can reliably rule out TB in approximately one in four cases. These data inform upon the programmatic utility of MTB/RIF in high-burden settings.

Are interferon-γ release assays useful for diagnosing active tuberculosis in a high-burden setting?

Although interferon-&ggr; release assays (IGRAs) are intended for diagnosing latent tuberculosis (TB), we hypothesised that in a high-burden setting: 1) the magnitude of the response when using IGRAs can distinguish active TB from other diagnoses; 2) IGRAs may aid in the diagnosis of smear-negative TB; and 3) IGRAs could be useful as rule-out tests for active TB. We evaluated the accuracy of two IGRAs (QuantiFERON®-TB Gold In-tube (QFT-GIT) and T-SPOT®.TB) in 395 patients (27% HIV-infected) with suspected TB in Cape Town, South Africa. IGRA sensitivity and specificity (95% CI) were 76% (68–83%) and 42% (36–49%) for QFT-GIT and 84% (77–90%) and 47% (40–53%) for T-SPOT®.TB, respectively. Although interferon-&ggr; responses were significantly higher in the TB versus non-TB groups (p<0.0001), varying the cut-offs did not improve discriminatory ability. In culture-negative patients, depending on whether those with clinically diagnosed TB were included or excluded from the analysis, the negative predictive value (NPV) of QFT-GIT, T-SPOT®.TB and chest radiograph in smear-negative patients varied between 85 and 89, 87 and 92, and 98% (for chest radiograph), respectively. Overall accuracy was independent of HIV status and CD4 count. In a high-burden setting, IGRAs alone do not have value as rule-in or -out tests for active TB. In smear-negative patients, chest radiography had better NPV even in HIV-infected patients.

Accuracy and impact of Xpert MTB/RIF for the diagnosis of smear-negative or sputum-scarce tuberculosis using bronchoalveolar lavage fluid

Rationale The accuracy and impact of new tuberculosis (TB) tests, such as Xpert MTB/RIF, when performed on bronchoalveolar lavage fluid (BALF) obtained from patients with sputum-scarce or smear-negative TB is unclear. Methods South African patients with suspected pulmonary TB (n=160) who were sputum-scarce or smear-negative underwent bronchoscopy. MTB/RIF was performed on uncentrifuged BALF (1 ml) and/or a resuspended pellet of centrifuged BALF (∼10 ml). Time to TB detection and anti-TB treatment initiation were compared between phase one, when MTB/RIF was performed as a research tool, and phase two, when it was used for patient management. Results 27 of 154 patients with complete data had culture-confirmed TB. Of these, a significantly lower proportion were detected by smear microscopy compared with MTB/RIF (58%, 95% CI 39% to 75% versus 93%, 77% to 98%; p<0.001). Of the 127 patients who were culture negative, 96% (91% to 98%) were MTB/RIF negative. When phase two was compared with phase one, MTB/RIF reduced the median days to TB detection (29 (18–41) to 0 (0–0); p<0.001). However, more patients initiated empirical therapy (absence of a positive test in those commencing treatment) in phase one versus phase two (79% (11/14) versus 28% (10/25); p=0.026). Consequently, there was no detectable difference in the overall proportion of patients initiating treatment (26% (17/67; 17% to 37%) versus 36% (26/73; 26% to 47%); p=0.196) or the days to treatment initiation (10 (1–49) versus 7 (0–21); p=0.330). BALF centrifugation, HIV coinfection and a second MTB/RIF did not result in detectable changes in accuracy. Conclusions MTB/RIF detected TB cases more accurately and more rapidly than smear microscopy and significantly reduced the rate of empirical treatment.

A systematic review of the association between pulmonary tuberculosis and the development of chronic airflow obstruction in adults.

Background: Chronic obstructive pulmonary disease (COPD) is a major public health concern, accounting for 3 million deaths annually, 90% of which occur in low- and middle-income countries. Pulmonary tuberculosis (PTB) as a contributory factor in the aetiology of COPD is under debate, with most epidemiologic evidence suggesting a positive association. Objectives: To compile a systematic review of evidence for an association between PTB and the development of chronic airflow obstruction (CAO). Methods: We performed a systematic review of original English-language, peer-reviewed literature using the PubMed/MEDLINE database. CAO was defined by spirometry [FEV₁:FVC ratio <0.70 or <LLN (lower limit of normal) for age]. Results: Nineteen studies (1 case series, 3 case-control studies, 4 cohort studies, 8 single-centre cross-sectional studies and 3 multi-centre cross-sectional studies) met the eligibility criteria. All but 2 reported a positive association between PTB and CAO. Three of 4 large population-based surveys (n = 4,291-8,066) confirmed a significant association between PTB and CAO (OR 1.37 - 2.94). A formal meta-analysis was not possible owing to marked heterogeneity between studies. Conclusions: This systematic review confirms evidence for a positive association between a past history of tuberculosis and the presence of CAO. The association is independent of cigarette smoking. Causality is likely but cannot be assumed.

Comparison of same day diagnostic tools including Gene Xpert and unstimulated IFN-γ for the evaluation of pleural tuberculosis: a prospective cohort study

BackgroundThe accuracy of currently available same-day diagnostic tools (smear microscopy and conventional nucleic acid amplification tests) for pleural tuberculosis (TB) is sub-optimal. Newer technologies may offer improved detection.MethodsSmear-microscopy, adenosine deaminase (ADA), interferon gamma (IFN-γ), and Xpert MTB/RIF [using an unprocessed (1 ml) and centrifuged (~20 ml) sample] test accuracy was evaluated in pleural fluid from 103 consecutive patients with suspected pleural TB. Culture for M.tuberculosis and/or histopathology (pleural biopsy) served as the reference standard. Patients were followed prospectively to determine their diagnostic categorisation.ResultsOf 93 evaluable participants, 40 had definite-TB (reference positive), 5 probable-TB (not definite but treated for TB) and 48 non-TB (culture and histology negative, and not treated for TB). Xpert MTB/RIF sensitivity and specificity (95% CI) was 22.5% (12.4 - 37.6) and 98% (89.2 - 99.7), respectively, and centrifugation did not improve sensitivity (23.7%). The Xpert MTB/RIF internal positive control showed no evidence of inhibition. Biomarker specific sensitivity, specificity, PPV, and NPVs were: ADA (48.85 IU/L; rule-in cut-point) 55.3% (39.8 - 69.9), 95.2% (83.9 - 98.7), 91.4 (73.4 - 95.4), 69.7% (56.7 - 80.1); ADA (30 IU/L; clinically used cut-point) 79% (63.7 - 89), 92.7% (80.6 - 97.5), 91.0 (73.4 - 95.4), 82.7% (69.3 - 90.1); and IFN-γ (107.7 pg/ml; rule-in cut-point) 92.5% (80.2 - 97.5), 95.9% (86.1 - 98.9), 94.9% (83.2 - 98.6), 93.9% (83.5 - 97.9), respectively (IFN-γ sensitivity and NPV better than Xpert [p < 0.05] and rule-in ADA [p < 0.05]).ConclusionThe usefulness of Xpert MTB/RIF to diagnose pleural TB is limited by its poor sensitivity. IFN-γ is an excellent rule-in test and, compared to ADA, has significantly better sensitivity and rule-out value in a TB-endemic setting.

Tuberculous pleural effusions: advances and controversies

On a global scale, tuberculosis (TB) remains one of the most frequent causes of pleural effusions. Our understanding of the pathogenesis of the disease has evolved and what was once thought to be an effusion as a result of a pure delayed hypersensitivity reaction is now believed to be the consequence of direct infection of the pleural space with a cascade of events including an immunological response. Pulmonary involvement is more common than previously believed and induced sputum, which is grossly underutilised, can be diagnostic in approximately 50%. The gold standard for the diagnosis of tuberculous pleuritis remains the detection of Mycobacterium tuberculosis in pleural fluid, or pleural biopsy specimens, either by microscopy and/or culture, or the histological demonstration of caseating granulomas in the pleura along with acid fast bacilli (AFB). In high burden settings, however, the diagnosis is frequently inferred in patients who present with a lymphocytic predominant exudate and a high adenosine deaminase (ADA) level, which is a valuable adjunct in the diagnostic evaluation. ADA is generally readily accessible, and together with lymphocyte predominance justifies treatment initiation in patients with a high pre-test probability. Still, false-negative and false-positive results remain an issue. When adding closed pleural biopsy to ADA and lymphocyte count, diagnostic accuracy approaches that of thoracoscopy. The role of other biomarkers is less well described. Early pleural drainage may have a role in selected cases, but more research is required to validate its use and to define the subpopulation that may benefit from such interventions.

Time for the Global Rollout of Endoscopic Lung Volume Reduction

Chronic obstructive pulmonary disease remains one of the most common causes of morbidity and mortality globally. The disease is generally managed with pharmacotherapy, as well as guidance about smoking cessation and pulmonary rehabilitation. Endoscopic lung volume reduction (ELVR) has been proposed for the treatment of advanced emphysema, with the aim of obtaining the same clinical and functional advantages of surgical lung volume reduction whilst potentially reducing risks and costs. There is a growing body of evidence that certain well-defined sub-groups of patients with advanced emphysema may benefit from ELVR, provided the selection criteria are met and a systematic approach is followed. ELVR devices, particularly unidirectional valves and coils, are currently being rolled out to many countries outside of the USA and Europe, although very few centres currently have the capacity to correctly evaluate and provide ELVR to prospective candidates. The high cost of these interventions underpins the need for careful patient selection to best identify those who may or may not benefit from ELVR-related procedures. The aim of this review is to provide the practicing pulmonologist with an overview of the practical aspects and current evidence for the use of the various techniques available, and to suggest an evidence-based approach for the appropriate use of these devices, particularly in emerging markets, where there should be a drive to develop and equip key specialised ELVR units.

Endobronchial Valve Used as Salvage Therapy in a Mechanically Ventilated Patient with Intractable Life-Threatening Haemoptysis

Treatment options for intractable life-threatening haemoptysis in mechanically ventilated patients with structural lung disease who do not respond to bronchial artery embolisation (BAE) and who are deemed unfit for surgery are limited. A 26-year-old HIV-positive male with a poorly preserved CD4 count and active pulmonary tuberculosis was intubated and mechanically ventilated for persistent life-threatening haemoptysis. Two attempts at BAE failed, and life-threatening haemoptysis recurred daily for 14 days despite antituberculous therapy. He was deemed unfit for surgery during that period. We proceeded to identify the source of bleeding endoscopically and implanted an endobronchial valve in the left upper lobe bronchus. Following the collapse of the affected lobe, haemoptysis ceased and the patient was promptly liberated from mechanical ventilation. He remained haemoptysis free for the duration of his hospitalisation. Endobronchial valves, therefore, may be a viable option in patients mechanically ventilated with persistent life-threatening haemoptysis in whom all other conventional measures fail and who are considered unfit for surgery.

Electronic cigarettes: The potential benefits outweigh the risks

Electronic cigarettes (e-cigarettes) are relatively new in South Africa and their popularity is increasing. Their appearance coincides with intensifying attempts by government and society to reduce tobacco smoking through stricter limitation on its sale, advertising and use. Debate has been triggered on their use regarding the potential risks of increasing nicotine addiction and encouraging people to start smoking, or whether e-cigarettes might serve rather as an efficient means of treating addiction, thus assisting smokers to quit. Opinions among doctors regarding e-cigarettes vary, some seeing potential for good, others condemning them outright. Several professional medical societies have taken the stand that, whatever their potential as a smoking-cessation method, they cannot be encouraged since they are produced and promoted by the tobacco industry. Also, that research supported by the manufacturers of e-cigarettes may not be presented at their meetings or in their medical journals. We present the following arguments for the potential benefit and harms of e-cigarettes, based on the currently available evidence.

Obstructive pulmonary disease in patients with previous tuberculosis : pathophysiology of a community-based cohort

BACKGROUND An association between chronic airflow limitation (CAL) and a history of pulmonary tuberculosis (PTB) has been confirmed in epidemiological studies, but the mechanisms responsible for this association are unclear. It is debated whether CAL in this context should be viewed as chronic obstructive pulmonary disease (COPD) or a separate phenotype. OBJECTIVE To compare lung physiology and high-resolution computed tomography (HRCT) findings in subjects with CAL and evidence of previous (healed) PTB with those in subjects with smoking-related COPD without evidence of previous PTB. METHODS Subjects with CAL identified during a Burden of Obstructive Lung Disease (BOLD) study performed in South Africa were studied. Investigations included questionnaires, lung physiology (spirometry, body plethysmography and diffusing capacity) and quantitative HRCT scans to assess bronchial anatomy and the presence of emphysema (<-950 HU), gas trapping (<-860 HU) and fibrosis (>-200 HU). Findings in subjects with a past history and/or HRCT evidence of PTB were compared with those in subjects without these features. RESULTS One hundred and seven of 196 eligible subjects (54.6%) were enrolled, 104 performed physiology tests and 94 had an HRCT scan. Based on history and HRCT findings, subjects were categorised as no previous PTB (NPTB, n=31), probable previous PTB (n=33) or definite previous PTB (DPTB, n=39). Subjects with DPTB had a lower diffusing capacity (Δ=-17.7%; p=0.001) and inspiratory capacity (Δ=-21.5%; p=0.001) than NPTB subjects, and higher gas-trapping and fibrosis but not emphysema scores (Δ=+6.2% (p=0.021), +0.36% (p=0.017) and +3.5% (p=0.098), respectively). CONCLUSIONS The mechanisms of CAL associated with previous PTB appear to differ from those in the more common smoking-related COPD and warrant further study.