A multi-country non-inferiority cluster randomized trial of frontloaded smear microscopy for the diagnosis of pulmonary tuberculosis

Luis Eduardo Cuevas; Mohammed Ahmed Yassin; Najla Al-Sonboli; Lovett Lawson; Isabel Arbide; Nasher Al-Aghbari; Jeevan Bahadur Sherchand; Amin Al-Absi; Emmanuel Nnamdi Emenyonu; Yared Merid; Mosis Ifenyi Okobi; Juliana Olubunmi Onuoha; Melkamsew Aschalew; Abraham Aseffa; Greg Harper; Rachel Mary Anderson de Cuevas; Kristin Kremer; Dick van Soolingen; Carl-Michael Nathanson; Jean Joly; Brian Faragher; Stephen Bertel Squire; Andrew Ramsay

doi:10.1371/journal.pmed.1000443

A multi-country non-inferiority cluster randomized trial of frontloaded smear microscopy for the diagnosis of pulmonary tuberculosis

Luis Eduardo Cuevas
, Mohammed Ahmed Yassin
, Najla Al-Sonboli
, Lovett Lawson
, Isabel Arbide
, Nasher Al-Aghbari
, Jeevan Bahadur Sherchand
, Amin Al-Absi
, Emmanuel Nnamdi Emenyonu
, Yared Merid
, Mosis Ifenyi Okobi
, Juliana Olubunmi Onuoha
, Melkamsew Aschalew
, Abraham Aseffa
, Greg Harper
, Rachel Mary Anderson de Cuevas
, Kristin Kremer
, Dick van Soolingen
, Carl-Michael Nathanson
, Jean Joly

Brian Faragher, Stephen Bertel Squire, Andrew Ramsay

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: More than 50 million people around the world are investigated for tuberculosis using sputum smear microscopy annually. This process requires repeated visits and patients often drop out.

METHODS AND FINDINGS: This clinical trial of adults with cough ≥2 wk duration (in Ethiopia, Nepal, Nigeria, and Yemen) compared the sensitivity/specificity of two sputum samples collected "on the spot" during the first visit plus one sputum sample collected the following morning (spot-spot-morning [SSM]) versus the standard spot-morning-spot (SMS) scheme. Analyses were per protocol analysis (PPA) and intention to treat (ITT). A sub-analysis compared just the first two smears of each scheme, spot-spot and spot-morning. In total, 6,627 patients (3,052 SSM/3,575 SMS) were enrolled; 6,466 had culture and 1,526 were culture-positive. The sensitivity of SSM (ITT, 70.2%, 95% CI 66.5%-73.9%) was non-inferior to the sensitivity of SMS (PPA, 65.9%, 95% CI 62.3%-69.5%). Similarly, the specificity of SSM (ITT, 96.9%, 95% CI 93.2%-99.9%) was non-inferior to the specificity of SMS (ITT, 97.6%, 95% CI 94.0%-99.9%). The sensitivity of spot-spot (ITT, 63.6%, 95% CI 59.7%-67.5%) was also non-inferior to spot-morning (ITT, 64.8%, 95% CI 61.3%-68.3%), as the difference was within the selected -5% non-inferiority limit (difference ITT = 1.4%, 95% CI -3.7% to 6.6%). Patients screened using the SSM scheme were more likely to provide the first two specimens than patients screened with the SMS scheme (98% versus 94.2%, p<0.01). The PPA and ITT analysis resulted in similar results.

CONCLUSIONS: The sensitivity and specificity of SSM are non-inferior to those of SMS, with a higher proportion of patients submitting specimens. The scheme identifies most smear-positive patients on the first day of consultation.

TRIAL REGISTRATION: Current Controlled Trials ISRCTN53339491. Please see later in the article for the Editors' Summary.

Original language	English
Pages (from-to)	e1000443
Journal	PLoS Medicine
Volume	8
Issue number	7
DOIs	https://doi.org/10.1371/journal.pmed.1000443
Publication status	Published - Jul 2011

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Adult
Cluster Analysis
Cough/etiology
Female
Humans
Intention to Treat Analysis
Male
Mass Screening/methods
Microscopy/methods
Middle Aged
Mycobacterium tuberculosis/isolation & purification
Patient Compliance
Sensitivity and Specificity
Specimen Handling/methods
Sputum/microbiology
Tuberculosis, Pulmonary/complications
Young Adult

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Cuevas, L. E., Yassin, M. A., Al-Sonboli, N., Lawson, L., Arbide, I., Al-Aghbari, N., Sherchand, J. B., Al-Absi, A., Emenyonu, E. N., Merid, Y., Okobi, M. I., Onuoha, J. O., Aschalew, M., Aseffa, A., Harper, G., de Cuevas, R. M. A., Kremer, K., van Soolingen, D., Nathanson, C.-M., ... Ramsay, A. (2011). A multi-country non-inferiority cluster randomized trial of frontloaded smear microscopy for the diagnosis of pulmonary tuberculosis. PLoS Medicine, 8(7), e1000443. https://doi.org/10.1371/journal.pmed.1000443

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title = "A multi-country non-inferiority cluster randomized trial of frontloaded smear microscopy for the diagnosis of pulmonary tuberculosis",

abstract = "BACKGROUND: More than 50 million people around the world are investigated for tuberculosis using sputum smear microscopy annually. This process requires repeated visits and patients often drop out.METHODS AND FINDINGS: This clinical trial of adults with cough ≥2 wk duration (in Ethiopia, Nepal, Nigeria, and Yemen) compared the sensitivity/specificity of two sputum samples collected {"}on the spot{"} during the first visit plus one sputum sample collected the following morning (spot-spot-morning [SSM]) versus the standard spot-morning-spot (SMS) scheme. Analyses were per protocol analysis (PPA) and intention to treat (ITT). A sub-analysis compared just the first two smears of each scheme, spot-spot and spot-morning. In total, 6,627 patients (3,052 SSM/3,575 SMS) were enrolled; 6,466 had culture and 1,526 were culture-positive. The sensitivity of SSM (ITT, 70.2\%, 95\% CI 66.5\%-73.9\%) was non-inferior to the sensitivity of SMS (PPA, 65.9\%, 95\% CI 62.3\%-69.5\%). Similarly, the specificity of SSM (ITT, 96.9\%, 95\% CI 93.2\%-99.9\%) was non-inferior to the specificity of SMS (ITT, 97.6\%, 95\% CI 94.0\%-99.9\%). The sensitivity of spot-spot (ITT, 63.6\%, 95\% CI 59.7\%-67.5\%) was also non-inferior to spot-morning (ITT, 64.8\%, 95\% CI 61.3\%-68.3\%), as the difference was within the selected -5\% non-inferiority limit (difference ITT = 1.4\%, 95\% CI -3.7\% to 6.6\%). Patients screened using the SSM scheme were more likely to provide the first two specimens than patients screened with the SMS scheme (98\% versus 94.2\%, p<0.01). The PPA and ITT analysis resulted in similar results.CONCLUSIONS: The sensitivity and specificity of SSM are non-inferior to those of SMS, with a higher proportion of patients submitting specimens. The scheme identifies most smear-positive patients on the first day of consultation.TRIAL REGISTRATION: Current Controlled Trials ISRCTN53339491. Please see later in the article for the Editors' Summary.",

keywords = "Adult, Cluster Analysis, Cough/etiology, Female, Humans, Intention to Treat Analysis, Male, Mass Screening/methods, Microscopy/methods, Middle Aged, Mycobacterium tuberculosis/isolation \& purification, Patient Compliance, Sensitivity and Specificity, Specimen Handling/methods, Sputum/microbiology, Tuberculosis, Pulmonary/complications, Young Adult",

author = "Cuevas, \{Luis Eduardo\} and Yassin, \{Mohammed Ahmed\} and Najla Al-Sonboli and Lovett Lawson and Isabel Arbide and Nasher Al-Aghbari and Sherchand, \{Jeevan Bahadur\} and Amin Al-Absi and Emenyonu, \{Emmanuel Nnamdi\} and Yared Merid and Okobi, \{Mosis Ifenyi\} and Onuoha, \{Juliana Olubunmi\} and Melkamsew Aschalew and Abraham Aseffa and Greg Harper and \{de Cuevas\}, \{Rachel Mary Anderson\} and Kristin Kremer and \{van Soolingen\}, Dick and Carl-Michael Nathanson and Jean Joly and Brian Faragher and Squire, \{Stephen Bertel\} and Andrew Ramsay",

year = "2011",

month = jul,

doi = "10.1371/journal.pmed.1000443",

language = "English",

volume = "8",

pages = "e1000443",

journal = "PLoS Medicine",

issn = "1549-1277",

publisher = "Public Library of Science",

number = "7",

}

Cuevas, LE, Yassin, MA, Al-Sonboli, N, Lawson, L, Arbide, I, Al-Aghbari, N, Sherchand, JB, Al-Absi, A, Emenyonu, EN, Merid, Y, Okobi, MI, Onuoha, JO, Aschalew, M, Aseffa, A, Harper, G, de Cuevas, RMA, Kremer, K, van Soolingen, D, Nathanson, C-M, Joly, J, Faragher, B, Squire, SB & Ramsay, A 2011, 'A multi-country non-inferiority cluster randomized trial of frontloaded smear microscopy for the diagnosis of pulmonary tuberculosis', PLoS Medicine, vol. 8, no. 7, pp. e1000443. https://doi.org/10.1371/journal.pmed.1000443

TY - JOUR

T1 - A multi-country non-inferiority cluster randomized trial of frontloaded smear microscopy for the diagnosis of pulmonary tuberculosis

AU - Cuevas, Luis Eduardo

AU - Yassin, Mohammed Ahmed

AU - Al-Sonboli, Najla

AU - Lawson, Lovett

AU - Arbide, Isabel

AU - Al-Aghbari, Nasher

AU - Sherchand, Jeevan Bahadur

AU - Al-Absi, Amin

AU - Emenyonu, Emmanuel Nnamdi

AU - Merid, Yared

AU - Okobi, Mosis Ifenyi

AU - Onuoha, Juliana Olubunmi

AU - Aschalew, Melkamsew

AU - Aseffa, Abraham

AU - Harper, Greg

AU - de Cuevas, Rachel Mary Anderson

AU - Kremer, Kristin

AU - van Soolingen, Dick

AU - Nathanson, Carl-Michael

AU - Joly, Jean

AU - Faragher, Brian

AU - Squire, Stephen Bertel

AU - Ramsay, Andrew

PY - 2011/7

Y1 - 2011/7

N2 - BACKGROUND: More than 50 million people around the world are investigated for tuberculosis using sputum smear microscopy annually. This process requires repeated visits and patients often drop out.METHODS AND FINDINGS: This clinical trial of adults with cough ≥2 wk duration (in Ethiopia, Nepal, Nigeria, and Yemen) compared the sensitivity/specificity of two sputum samples collected "on the spot" during the first visit plus one sputum sample collected the following morning (spot-spot-morning [SSM]) versus the standard spot-morning-spot (SMS) scheme. Analyses were per protocol analysis (PPA) and intention to treat (ITT). A sub-analysis compared just the first two smears of each scheme, spot-spot and spot-morning. In total, 6,627 patients (3,052 SSM/3,575 SMS) were enrolled; 6,466 had culture and 1,526 were culture-positive. The sensitivity of SSM (ITT, 70.2%, 95% CI 66.5%-73.9%) was non-inferior to the sensitivity of SMS (PPA, 65.9%, 95% CI 62.3%-69.5%). Similarly, the specificity of SSM (ITT, 96.9%, 95% CI 93.2%-99.9%) was non-inferior to the specificity of SMS (ITT, 97.6%, 95% CI 94.0%-99.9%). The sensitivity of spot-spot (ITT, 63.6%, 95% CI 59.7%-67.5%) was also non-inferior to spot-morning (ITT, 64.8%, 95% CI 61.3%-68.3%), as the difference was within the selected -5% non-inferiority limit (difference ITT = 1.4%, 95% CI -3.7% to 6.6%). Patients screened using the SSM scheme were more likely to provide the first two specimens than patients screened with the SMS scheme (98% versus 94.2%, p<0.01). The PPA and ITT analysis resulted in similar results.CONCLUSIONS: The sensitivity and specificity of SSM are non-inferior to those of SMS, with a higher proportion of patients submitting specimens. The scheme identifies most smear-positive patients on the first day of consultation.TRIAL REGISTRATION: Current Controlled Trials ISRCTN53339491. Please see later in the article for the Editors' Summary.

AB - BACKGROUND: More than 50 million people around the world are investigated for tuberculosis using sputum smear microscopy annually. This process requires repeated visits and patients often drop out.METHODS AND FINDINGS: This clinical trial of adults with cough ≥2 wk duration (in Ethiopia, Nepal, Nigeria, and Yemen) compared the sensitivity/specificity of two sputum samples collected "on the spot" during the first visit plus one sputum sample collected the following morning (spot-spot-morning [SSM]) versus the standard spot-morning-spot (SMS) scheme. Analyses were per protocol analysis (PPA) and intention to treat (ITT). A sub-analysis compared just the first two smears of each scheme, spot-spot and spot-morning. In total, 6,627 patients (3,052 SSM/3,575 SMS) were enrolled; 6,466 had culture and 1,526 were culture-positive. The sensitivity of SSM (ITT, 70.2%, 95% CI 66.5%-73.9%) was non-inferior to the sensitivity of SMS (PPA, 65.9%, 95% CI 62.3%-69.5%). Similarly, the specificity of SSM (ITT, 96.9%, 95% CI 93.2%-99.9%) was non-inferior to the specificity of SMS (ITT, 97.6%, 95% CI 94.0%-99.9%). The sensitivity of spot-spot (ITT, 63.6%, 95% CI 59.7%-67.5%) was also non-inferior to spot-morning (ITT, 64.8%, 95% CI 61.3%-68.3%), as the difference was within the selected -5% non-inferiority limit (difference ITT = 1.4%, 95% CI -3.7% to 6.6%). Patients screened using the SSM scheme were more likely to provide the first two specimens than patients screened with the SMS scheme (98% versus 94.2%, p<0.01). The PPA and ITT analysis resulted in similar results.CONCLUSIONS: The sensitivity and specificity of SSM are non-inferior to those of SMS, with a higher proportion of patients submitting specimens. The scheme identifies most smear-positive patients on the first day of consultation.TRIAL REGISTRATION: Current Controlled Trials ISRCTN53339491. Please see later in the article for the Editors' Summary.

KW - Adult

KW - Cluster Analysis

KW - Cough/etiology

KW - Female

KW - Humans

KW - Intention to Treat Analysis

KW - Male

KW - Mass Screening/methods

KW - Microscopy/methods

KW - Middle Aged

KW - Mycobacterium tuberculosis/isolation & purification

KW - Patient Compliance

KW - Sensitivity and Specificity

KW - Specimen Handling/methods

KW - Sputum/microbiology

KW - Tuberculosis, Pulmonary/complications

KW - Young Adult

U2 - 10.1371/journal.pmed.1000443

DO - 10.1371/journal.pmed.1000443

M3 - Article

C2 - 21765808

SN - 1549-1277

VL - 8

SP - e1000443

JO - PLoS Medicine

JF - PLoS Medicine

IS - 7

ER -

A multi-country non-inferiority cluster randomized trial of frontloaded smear microscopy for the diagnosis of pulmonary tuberculosis

Abstract

UN SDGs

Keywords

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