01. Tuberculosis

López, J., Loader, M., Smith, D., Pastorius, D., Bravard, M., Caviedes, L., Romero, K., Clark, T., Checkley, W., Ticona, E., Friedland, J., Gilman, R.

Am J Trop Med Hyg. 2018 Jun;98(6)

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.

Bonadonna, L., Saunders, M., Zegarra, R., Evans, C., Alegria-Flores, K., Guio, H.

PLoS One. 2017 Sep 25;12(9):e0185018.

Early detection and diagnosis of tuberculosis remain major global priorities for tuberculosis control. Few studies have used a qualitative approach to investigate the social determinants contributing to diagnostic delay and none have compared data collected from individual, community, and health-system levels. We aimed to characterize the social determinants that contribute to diagnostic delay among persons diagnosed with tuberculosis living in resource-constrained settings.

Datta, S., Saunders, M., Tovar, M., and Evans, C.

PLoS Med. 2017 Oct; 14(10): e1002406.

Tuberculosis (TB) is a preventable and curable disease, but it kills more people than any other infection. Many people with TB are never diagnosed, and those who are diagnosed are often ill and contagious for many weeks or months before a diagnosis is made. Barriers to TB diagnosis are well described, often including poverty; stigma; marginalization; indolent, nonspecific symptoms; and poorly performing diagnostic tests. However, despite their central role in TB diagnosis, healthcare providers have been the subject of surprisingly little research [1].

This week in PLOS Medicine, Sylvia and colleagues report findings with important implications for TB elimination [1]. They trained and sent simulated “standardized patients,” also known as “mystery clients,” to healthcare providers at village clinics, township health centers, and county hospitals in China and found that the care provided in 274 consultations differed greatly from TB recommendations. The standardized patients reported classical TB symptoms, but only 15% of the providers mentioned TB, and only 41% of the providers tested or referred patients as recommended for TB. These differences between policy and practice were especially marked in the village clinics where most care was provided, and simulations suggested that a proposed system of managed referral with gatekeeping at the level of the village clinic would further reduce correct management, all of which makes for uncomfortable reading.

Rudgard, W., Evans, C., Sweeney, S., Wingfield, T., Lönnroth, K., Barreira, D., Boccia, D.

PLoS Med. 2017 Nov 7;14(11):e1002418.

Abstract

BACKGROUND:

Illness-related costs for patients with tuberculosis (TB) ≥20% of pre-illness annual household income predict adverse treatment outcomes and have been termed «catastrophic.» Social protection initiatives, including cash transfers, are endorsed to help prevent catastrophic costs. With this aim, cash transfers may either be provided to defray TB-related costs of households with a confirmed TB diagnosis (termed a «TB-specific» approach); or to increase income of households with high TB risk to strengthen their economic resilience (termed a «TB-sensitive» approach). The impact of cash transfers provided with each of these approaches might vary. We undertook an economic modelling study from the patient perspective to compare the potential of these 2 cash transfer approaches to prevent catastrophic costs.

METHODS AND FINDINGS:

Model inputs for 7 low- and middle-income countries (Brazil, Colombia, Ecuador, Ghana, Mexico, Tanzania, and Yemen) were retrieved by literature review and included countries’ mean patient TB-related costs, mean household income, mean cash transfers, and estimated TB-specific and TB-sensitive target populations. Analyses were completed for drug-susceptible (DS) TB-related costs in all 7 out of 7 countries, and additionally for drug-resistant (DR) TB-related costs in 1 of the 7 countries with available data. All cost data were reported in 2013 international dollars ($). The target population for TB-specific cash transfers was poor households with a confirmed TB diagnosis, and for TB-sensitive cash transfers was poor households already targeted by countries’ established poverty-reduction cash transfer programme. Cash transfers offered in countries, unrelated to TB, ranged from $217 to $1,091/year/household. Before cash transfers, DS TB-related costs were catastrophic in 6 out of 7 countries. If cash transfers were provided with a TB-specific approach, alone they would be insufficient to prevent DS TB catastrophic costs in 4 out of 6 countries, and when increased enough to prevent DS TB catastrophic costs would require a budget between $3.8 million (95% CI: $3.8 million-$3.8 million) and $75 million (95% CI: $50 million-$100 million) per country. If instead cash transfers were provided with a TB-sensitive approach, alone they would be insufficient to prevent DS TB-related catastrophic costs in any of the 6 countries, and when increased enough to prevent DS TB catastrophic costs would require a budget between $298 million (95% CI: $219 million-$378 million) and $165,367 million (95% CI: $134,085 million-$196,425 million) per country. DR TB-related costs were catastrophic before and after TB-specific or TB-sensitive cash transfers in 1 out of 1 countries. Sensitivity analyses showed our findings to be robust to imputation of missing TB-related cost components, and use of 10% or 30% instead of 20% as the threshold for measuring catastrophic costs. Key limitations were using national average data and not considering other health and social benefits of cash transfers.

CONCLUSIONS:

A TB-sensitive cash transfer approach to increase all poor households’ income may have broad benefits by reducing poverty, but is unlikely to be as effective or affordable for preventing TB catastrophic costs as a TB-specific cash transfer approach to defray TB-related costs only in poor households with a confirmed TB diagnosis. Preventing DR TB-related catastrophic costs will require considerable additional investment whether a TB-sensitive or a TB-specific cash transfer approach is used.

Datta, S., Shah, L., Gilman, R., Evans, C.

Lancet Glob Health. 2017 Aug;5(8)

Abstract

BACKGROUND:

The performance of laboratory tests to diagnose pulmonary tuberculosis is dependent on the quality of the sputum sample tested. The relative merits of sputum collection methods to improve tuberculosis diagnosis are poorly characterised. We therefore aimed to investigate the effects of sputum collection methods on tuberculosis diagnosis.

METHODS:

We did a systematic review and meta-analysis to investigate whether non-invasive sputum collection methods in people aged at least 12 years improve the diagnostic performance of laboratory testing for pulmonary tuberculosis. We searched PubMed, Google Scholar, ProQuest, Web of Science, CINAHL, and Embase up to April 14, 2017, to identify relevant experimental, case-control, or cohort studies. We analysed data by pairwise meta-analyses with a random-effects model and by network meta-analysis. All diagnostic performance data were calculated at the sputum-sample level, except where authors only reported data at the individual patient-level. Heterogeneity was assessed, with potential causes identified by logistic meta-regression.

FINDINGS:

We identified 23 eligible studies published between 1959 and 2017, involving 8967 participants who provided 19 252 sputum samples. Brief, on-demand spot sputum collection was the main reference standard. Pooled sputum collection increased tuberculosis diagnosis by microscopy (odds ratio [OR] 1·6, 95% CI 1·3-1·9, p<0·0001) or culture (1·7, 1·2-2·4, p=0·01). Providing instructions to the patient before sputum collection, during observed collection, or together with physiotherapy assistance increased diagnostic performance by microscopy (OR 1·6, 95% CI 1·3-2·0, p<0·0001). Collecting early morning sputum did not significantly increase diagnostic performance of microscopy (OR 1·5, 95% CI 0·9-2·6, p=0·2) or culture (1·4, 0·9-2·4, p=0·2). Network meta-analysis confirmed these findings, and revealed that both pooled and instructed spot sputum collections were similarly effective techniques for increasing the diagnostic performance of microscopy.

INTERPRETATION:

Tuberculosis diagnoses were substantially increased by either pooled collection or by providing instruction on how to produce a sputum sample taken at any time of the day. Both interventions had a similar effect to that reported for the introduction of new, expensive laboratory tests, and therefore warrant further exploration in the drive to end the global tuberculosis epidemic.

FUNDING:

Wellcome Trust, Joint Global Health Trials consortium, Innovation For Health and Development, and Bill & Melinda Gates Foundation.

Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Martinez L, Arman A, Haveman N, Lundgren A, Cabrera L, Evans CA, Pelly TF, Saito M, Callacondo D, Oberhelman R, Collazo G, Carnero AM, Gilman RH.

Am J Trop Med Hyg. 2013 Sep;89(3):507-15.

A cross-sectional, community-based study was performed in 2012 with 428 residents of periurban shantytowns in Lima, Peru to study risk factors for and changes in latent tuberculosis infection in age-stratified groups compared with our data from the same region in 1990 (N = 219) and 2005 (N = 103). Tuberculin skin test positivity in these communities was highly prevalent at 52% overall, increased with age (P < 0.01) and was similar to 2005 (53%) and 1990 (48%). From 1990 to 2012, the prevalence of tuberculin positivity decreased in 5-14 and 15-24 year old groups (to 17% and 34%, respectively, both P < 0.05). However, this may be explained by cessation of Bacille Calmette-Guérin revaccination during this period, because Bacille Calmette-Guérin revaccination doubled tuberculin positivity. Over the same 22-year period, tuberculin positivity in the ≥ 25 year old group remained high (71%, P = 0.3), suggesting that prevalent latent tuberculosis infection persists in the adult population despite improving medical care and socioeconomic development in this region.