Mareli M. Claassens

Breath analysis as a potential diagnostic tool for tuberculosis

SETTING Cape Town, South Africa. OBJECTIVES We investigated the potential of breath analysis by gas chromatography-mass spectrometry (GC-MS) to discriminate between samples collected prospectively from patients with suspected tuberculosis (TB). DESIGN Samples were obtained in a TB-endemic setting in South Africa, where 28% of culture-proven TB patients had Ziehl-Neelsen (ZN) negative sputum smear. A training set of breath samples from 50 sputum culture-proven TB patients and 50 culture-negative non-TB patients was analysed using GC-MS. We used support vector machine analysis for classification of the patient samples into TB and non-TB. RESULTS A classification model with seven compounds had a sensitivity of 72%, a specificity of 86% and an accuracy of 79% compared with culture. The classification model was validated with breath samples from a different set of 21 TB and 50 non-TB patients from the same area, giving a sensitivity of 62%, a specificity of 84% and an accuracy of 77%. CONCLUSION This study shows that GC-MS breath analysis is able to differentiate between TB and non-TB breath samples even among patients with a negative ZN sputum smear but a positive culture for Mycobacterium tuberculosis. We conclude that breath analysis by GC-MS merits further research.

Tuberculosis In Healthcare Workers And Infection Control Measures At Primary Healthcare Facilities In South Africa

Background Challenges exist regarding TB infection control and TB in hospital-based healthcare workers in South Africa. However, few studies report on TB in non-hospital based healthcare workers such as primary or community healthcare workers. Our objectives were to investigate the implementation of TB infection control measures at primary healthcare facilities, the smear positive TB incidence rate amongst primary healthcare workers and the association between TB infection control measures and all types of TB in healthcare workers. Methods One hundred and thirty three primary healthcare facilities were visited in five provinces of South Africa in 2009. At each facility, a TB infection control audit and facility questionnaire were completed. The number of healthcare workers who had had TB during the past three years was obtained. Results The standardised incidence ratio of smear positive TB in primary healthcare workers indicated an incidence rate of more than double that of the general population. In a univariable logistic regression, the infection control audit score was significantly associated with reported cases of TB in healthcare workers (OR=1.04, 95%CI 1.01-1.08, p=0.02) as was the number of staff (OR=3.78, 95%CI 1.77-8.08). In the multivariable analysis, the number of staff remained significantly associated with TB in healthcare workers (OR=3.33, 95%CI 1.37-8.08). Conclusion The high rate of TB in healthcare workers suggests a substantial nosocomial transmission risk, but the infection control audit tool which was used did not perform adequately as a measure of this risk. Infection control measures should be monitored by validated tools developed and tested locally. Different strategies, such as routine surveillance systems, could be used to evaluate the burden of TB in healthcare workers in order to calculate TB incidence, monitor trends and implement interventions to decrease occupational TB.

High prevalence of Tuberculosis and insufficient case detection in two communities in the Western Cape, South Africa

Background In South Africa the estimated incidence of all forms of tuberculosis (TB) for 2008 was 960/100000. It was reported that all South Africans lived in districts with Directly Observed Therapy, Short-course. However, the 2011 WHO report indicated South Africa as the only country in the world where the TB incidence is still rising. Aims To report the results of a TB prevalence survey and to determine the speed of TB case detection in the study communities. Methods In 2005 a TB prevalence survey was done to inform the sample size calculation for the ZAMSTAR (Zambia South Africa TB and AIDS Reduction) trial. It was a cluster survey with clustering by enumeration area; all households were visited within enumeration areas and informed consent obtained from eligible adults. A questionnaire was completed and a sputum sample collected from each adult. Samples were inoculated on both liquid mycobacterium growth indicator tube (MGIT) and Löwenstein-Jensen media. A follow-up HIV prevalence survey was done in 2007. Results In Community A, the adjusted prevalence of culture positive TB was 32/1000 (95%CI 25–41/1000) and of smear positive TB 8/1000 (95%CI 5–13/1000). In Community B, the adjusted prevalence of culture positive TB was 24/1000 (95%CI 17–32/1000) and of smear positive TB 9/1000 (95%CI 6–15/1000). In Community A the patient diagnostic rate was 0.38/person-year while in community B it was 0.30/person-year. In both communities the adjusted HIV prevalence was 25% (19–30%). Discussion In both communities a higher TB prevalence than national estimates and a low patient diagnostic rate was calculated, suggesting that cases are not detected at a sufficient rate to interrupt transmission. These findings may contribute to the rising TB incidence in South Africa. The TB epidemic should therefore be addressed rapidly and effectively, especially in the presence of the concurrently high HIV prevalence.

Tuberculosis Patients In Primary Care Do Not Start Treatment. What Role Do Health System Delays Play

SETTING Primary health care facilities in five provinces of South Africa. OBJECTIVE To investigate the association between the proportion of sputum results with a prolonged smear turnaround time and the proportion of smear-positive tuberculosis (TB) cases initially lost to follow-up. DESIGN The unit of investigation was a primary health care facility and the outcome was the initial loss to follow-up rate per facility, which was calculated by comparing the sputum register with the TB treatment register. A prolonged turnaround time was defined as more than 48 h from when the sputum sample was documented in the sputum register to receipt of the result at the facility. RESULTS The mean initial loss to follow-up rate was 25% (95%CI 22-28). Smear turnaround time overall was inversely associated with initial loss to follow-up (P = 0.008), when comparing Category 2 (33-66% turnaround time within 48 h) with Category 1 (0-32%) (OR 0.73, 95%CI 0.48-1.13, P = 0.163) and when comparing Category 3 (67-100%) with Category 1 (OR 0.62, 95%CI 0.39-0.99, P = 0.045). The population preventable fraction of initial loss to follow-up (when turnaround time was <48 h in ≥67% of smear results) was 21%. CONCLUSION Initial loss to follow-up should be reported as part of the TB programme to ensure that patients are initiated on treatment to prevent transmission within communities.

Tuberculosis cases missed in primary health care facilities: should we redefine case finding?

SETTING This study was conducted in Cape Town in two primary health care facilities in a sub-district with a high prevalence of bacteriologically confirmed pulmonary tuberculosis (TB). OBJECTIVE To determine the proportion of adults with respiratory symptoms who attend health care facilities but are not examined for nor diagnosed with TB in facilities where routine TB diagnosis depends on passive case finding. DESIGN A total of 423 adults with respiratory symptoms exiting primary health care services were consecutively enrolled during April-July 2011. RESULTS Twenty-one (5%) participants were diagnosed with culture-positive TB. None had sought care at the facility for their respiratory symptoms, none were asked about respiratory symptoms during their visit and none were asked to produce a sputum sample. Nine cases had attended the facility for reasons regarding their own health, while 12 cases were accompanying someone else attending the facility, or for another reason. CONCLUSION Patients with infectious TB attend primary health care facilities, but are not recognised and diagnosed as cases. Health care staff should search actively within facilities for cases who attend the health care services to ensure that cases are not missed. Intensified case finding should start within the facility, and should not be limited to patients who report respiratory symptoms or who are human immunodeficiency virus positive.

Validation of biomarkers for distinguishing Mycobacterium tuberculosis from non-tuberculous mycobacteria using gas chromatography-mass spectrometry and chemometrics.

Tuberculosis (TB) remains a major international health problem. Rapid differentiation of Mycobacterium tuberculosis complex (MTB) from non-tuberculous mycobacteria (NTM) is critical for decisions regarding patient management and choice of therapeutic regimen. Recently we developed a 20-compound model to distinguish between MTB and NTM. It is based on thermally assisted hydrolysis and methylation gas chromatography-mass spectrometry and partial least square discriminant analysis. Here we report the validation of this model with two independent sample sets, one consisting of 39 MTB and 17 NTM isolates from the Netherlands, the other comprising 103 isolates (91 MTB and 12 NTM) from Stellenbosch, Cape Town, South Africa. All the MTB strains in the 56 Dutch samples were correctly identified and the model had a sensitivity of 100% and a specificity of 94%. For the South African samples the model had a sensitivity of 88% and specificity of 100%. Based on our model, we have developed a new decision-tree that allows the differentiation of MTB from NTM with 100% accuracy. Encouraged by these findings we will proceed with the development of a simple, rapid, affordable, high-throughput test to identify MTB directly in sputum.

Health care workers' gender bias in testing could contribute to missed tuberculosis among women in South Africa.

SETTING Eight communities with high tuberculosis (TB) prevalence, Western Cape, South Africa. OBJECTIVE To identify sex differences in TB health-seeking behaviour and diagnosis in primary health care facilities and how this influences TB diagnosis. DESIGN We used data from a prevalence survey among 30,017 adults conducted in 2010 as part of the Zambia, South Africa Tuberculosis and AIDS Reduction (ZAMSTAR) trial. RESULTS A total of 1670 (5.4%) adults indicated they had a cough of ⩾2 weeks, 950 (56.9%) of whom were women. Women were less likely to report a cough of ⩾2 weeks (5.1% vs. 6.4%, P < 0.001), but were more likely to seek care for their cough (32.6% vs. 26.9%, P = 0.012). Of all adults who sought care, 403 (80.0%) sought care for their cough at a primary health care (PHC) facility (79.0% women vs. 81.4% men, P = 0.511). Women were less likely to be asked for a sputum sample at the PHC facility (63.3% vs. 77.2%, P = 0.003) and less likely to have a positive sputum result (12.6% vs. 20.7%, P = 0.023). CONCLUSION The attainment of sex equity in the provision of TB health services requires adherence to testing protocols. Everyone, irrespective of sex, who seeks care for a cough of ⩾2 weeks should be tested.

It’s complicated : why do tuberculosis patients not initiate or stay adherent to treatment? a qualitative study from South Africa

BackgroundIndividuals who test positive for active tuberculosis (TB) but do not initiate treatment present a challenge to TB programmes because they contribute to ongoing transmission within communities. To better understand why individuals do not initiate treatment, or are adherent after initiating treatment, South African respondents were approached to obtain insights as to which factors enabled and inhibited the treatment process.MethodsThis qualitative work was nested in a larger study investigating initial loss to follow-up (LTFU) amongst new smear positive TB patients across five provinces of South Africa. In-depth interviews were done with 41 adherent and initial LTFU respondents.ResultsKey issues contributing to initial LTFU appeared to be a poor knowledge, or low awareness of TB treatment; stigma around TB including its connection to HIV; immediate problems in the respondents’ lives particularly poverty, lack of access to transport and the need to continue working; and problems in the healthcare facilities including under resourced facilities, poor functioning health systems and negative staff attitudes. In contrast the reasons given for being adherent related to the level of illness, support received at home and healthcare facilities, a belief in the health system and positive experiences in the health service including positive attitudes from staff.ConclusionsKey changes need to be made to the healthcare system to enable patients to initiate treatment and remain adherent, but the six month regimen of daily observed treatment presents real practical and personal challenges to patients. Alternative strategies to DOTS at facility level should be investigated to bring services closer to communities to encourage patients to access care, initiate and adhere to treatment.

Symptom screening rules to identify active pulmonary tuberculosis : findings from the Zambian South African Tuberculosis and HIV/ AIDS Reduction (ZAMSTAR) trial prevalence surveys

Background High tuberculosis (TB) burden countries should consider systematic screening among adults in the general population. We identified symptom screening rules to be used in addition to cough ≥2 weeks, in a context where X-ray screening is not feasible, aiming to increase the sensitivity of screening while achieving a specificity of ≥85%. Methods We used 2010 Zambia South Africa Tuberculosis and HIV/AIDS Reduction (ZAMSTAR) survey data: a South African (SA) training dataset, a SA testing dataset for internal validation and a Zambian dataset for external validation. Regression analyses investigated relationships between symptoms or combinations of symptoms and active disease. Sensitivity and specificity were calculated for candidate rules. Results Among all participants, the sensitivity of using only cough ≥2 weeks as a screening rule was less than 25% in both SA and Zambia. The addition of any three of six TB symptoms (cough <2 weeks, night sweats, weight loss, fever, chest pain, shortness of breath), or 2 or more of cough <2 weeks, night sweats, and weight loss, increased the sensitivity to ~38%, while reducing specificity from ~95% to ~85% in SA and ~97% to ~92% in Zambia. Among HIV-negative adults, findings were similar in SA, whereas in Zambia the increase in sensitivity was relatively small (15% to 22%). Conclusion High TB burden countries should investigate cost-effective strategies for systematic screening: one such strategy could be to use our rule in addition to cough ≥2 weeks.

Scanty smears associated with initial loss to follow-up in South African tuberculosis patients.

BACKGROUND Smear-positive patients should be started on anti-tuberculosis treatment promptly. However, studies show that up to 38% of diagnosed patients are initial loss to follow-up (LTFU), meaning they do not start treatment after diagnosis. We investigated determinants of initial LTFU at primary health care facilities. DESIGN In a facility-matched case-control study, health care facilities were visited from October 2010 to September 2012. After identification from registers, patients were traced and invited to complete a questionnaire. RESULTS Of 973 participants, 233 (24%) were cases and 740 (74%) controls. Initial LTFU was associated with smear grade (pooled adjusted odds ratio [aOR] 0.73, 95% confidence interval [CI] 0.64-0.90, scanty at baseline) for participants identified at facilities, but not with age (overall P = 0.80) or sex (aOR 0.83, 95%CI 0.58-1.20). Of the 233 cases, 197 (85%) were traced in the community, of whom 58 (29%) were found. Among the group found, initial LTFU was associated with age (aOR 3.38, 95%CI 1.15-9.95) and smear grade (aOR 0.08, 95%CI 0.02-0.34, scanty at baseline). CONCLUSION Scanty smear positivity was associated with initial LTFU. Tuberculosis programmes should start scanty smear-positive patients on treatment early and develop alternative community tracing strategies. Health care worker training could address the first aspect, and the use of technology to improve treatment initiation, such as mobile phone applications, the second.