Second month sputum smear as a predictor of tuberculosis treatment outcomes in Brazil
Socorro Nantua Evangelista et al.
BMC Res Notes
Second month sputum smear as a predictor of tuberculosis treatment outcomes in Brazil
Maria do Socorro Nantua Evangelista 0 1 2
Rosalia Maia 2
João Paulo Toledo 2
Ricardo Gadelha de Abreu 2
José Uereles Braga 6
Draurio Barreira 5
Anete Trajman 3 4
0 University of Brasilia (UnB) , Federal District, Brasília , Brazil
1 University of Brasilia (UnB) , Federal District, Brasília , Brazil
2 Brazil, Ministry of Health, National Tuberculosis Program , Federal District, Brasília , Brazil
3 McGill University , Montreal, QC , Canada
4 Federal University of Rio de Janeiro (UFRJ) , Rio De Janeiro, RJ , Brazil
5 UNITAID-WHO , Geneva , Switzerland
6 University of the State of Rio de Janeiro (UERJ) , Rio De Janeiro, RJ , Brazil
7 Conj. 10 Casa 8. Lago Sul , Brasília 71675-100 , Brazil
Objective: The value of sputum smear microscopy (SSM) after 2 months of treatment in the management of pulmonary tuberculosis is controversial. We analysed second month-SSM conversion as a predictor of treatment success in Brazil. Results: Overall successful outcome rate was 89.4%. The predictive value of second month-SSM conversion for successful outcomes was 85.2% 72,479/85,118), while the predictive value of non-conversion for unfavourable outcomes was 26.9% (2712/10,071). Unfavourable treatment outcomes were twice more likely among patients who did not convert (adjusted OR = 2.06; 1.97-2.16).
Acid-fast bacilli; Predictive value; Pulmonary tuberculosis; Sputum smear microscopy; Treatment outcomes
Adverse outcomes of tuberculosis (TB) treatment still
hamper the control of the disease worldwide despite the
high efficacy of 6 month-regimen recommended by the
World Health Organization [
]. TB treatment follow-up
usually consists of monthly sputum smear microscopy
(SSM) and an end-of-treatment chest X-ray [
bacillary burden usually decreases steadily during
treatment and by the end of the second month of treatment,
when the intensive phase of treatment is concluded, SSM
is expected to be negative in most cases [
negativation of a previously positive test is known as SSM
conversion. SSM non-conversion after 2 months of treatment
is recognized as a predictor of unfavourable outcomes
], including drug-resistance [
failure is unlikely if SSM during all months of treatment are
7, 12, 13
The Brazilian guidelines  recommend monthly
SSM for smear-positive TB follow-up plus culture with
drug susceptibility test (DST) if SSM conversion is not
observed after 2 months of treatment. However, the
predictive value of SSM conversion for treatment outcomes
has not been carried-out in Brazil [
]. The aim of
this study was to evaluate the positive predictive value of
second month-SSM conversion for successful treatment
outcomes in Brazil as well as of non-conversion for
Study design and population
A retrospective cohort study based on TB data recorded
in the Brazilian National Surveillance System (SINAN)
] was conducted. Data gathered included patients’
sociodemographic characteristics, their SSM results
during follow-up and treatment outcomes up to 9 months
after treatment initiation.
Outcomes were as reported in the notification system.
The following categories exist as outcomes according
to the Brazilian guidelines [
]: (1) cure, defined as an
individual who presents at least two negative SSM of
which one at the end of treatment (5th or 6th month);
(2) treatment completion, defined when there is no
clinical or radiological evidence of failure; (3) death
from TB; (4) death from non-TB causes; (5) loss to
follow up, i.e., a patient who missed a scheduled follow up
visit for at least 30 days; (6) failure, i.e., a positive SSM
result at the end of treatment, SSM with 2+ or 3+ at
the 4th month of treatment or a positive SSM at the 4th
month of treatment after initial conversion; (7) change
of diagnosis and (8) transferred-out.
We further classified these outcomes as successful
(cure or treatment completed) or unfavourable (death
from any cause, loss to follow up or failure) [
New smear-positive pulmonary TB adults (> 14 years)
notified from January 2007 to December 2012 in any
Brazilian municipality were eligible. Patients
transferred-out and those whose diagnosis was changed
were excluded, since true outcomes or diagnosis were
uncertain. For the main analysis, we further excluded
patients whose status of SSM at the second month was
unknown (not done/no results/not informed).
We compared characteristics of initially included
patients according to availability of second month SSM
results, to check for selection bias.
The main analysis consisted of evaluating the positive
predictive value and its exact 95% confidence intervals
(95% CI) of a positive second month-SSM
(non-conversion) for unfavourable treatment outcomes and of a
negative second month-SSM (conversion) for
successful outcomes. This was calculated through the
proportion of patients with a positive second month SSM out
of those who had unfavourable outcomes and the
proportion of those with a negative second month SSM
who had successful outcomes, respectively. Simple and
multiple logistic regression models were used to
calculate the odds ratios (OR) and their 95% CI to
evaluate the independent effect of the second month-SSM
result on unfavourable treatment outcomes, adjusted
for sociodemographic variables. Analyses were
performed using the SPSS® package, version 20.0 (IBM
Inc., Armonk, NY, USA).
A total of 485,290 TB cases were notified from 2007 to
2012, of which 188,585 were not eligible and 201,516 were
excluded. The remaining 95,189 were analysed (Fig. 1).
Sociodemographic characteristics and second
monthSSM results of included versus non-eligible and excluded
patients were similar (Table 1). Most of included patients
(Table 1) presented SSM conversion at the second month
(83.9%), were male (67.2%), aged 15–54 (80.6%), had
mixed race (42.4%) and less than 9 years of study (47.9%).
Overall successful treatment rate was 89.4%. Missing data
were more common among excluded patients and those
with successful treatment.
The positive predictive value of the second month-SSM
non-conversion for unfavourable outcomes was 26.9%
(2712 out of 10,071), while the positive predictive value
for successful outcomes among those who did convert
second month SSM was 85.2% (72,479 out of 85,118).
18,028 entries as relapse
3,542 < 15 years
71,250 SSM-negative pulmonary TB
16,045 retreatment cases
13,450 entries as transfer
1032 changes of diagnosis
14,673 transferred out
35,713 missing outcomes
150,098 missing SSM on 2nd month
485,290 TB cases
reported from 2007 to
Adjusted for sociodemographic characteristics, the
odds for unfavourable outcomes were 2.06 higher (95%
CI = 1.97–2.16) among those that had not converted at
the second month of treatment (Table 2). Other
variables significantly associated with higher odds for
unfavourable outcomes were male gender (aOR = 1.50; 95%
CI = 1.43–1.58); age 25–34 (aOR = 1.41; 95% CI = 1.07–
1.22), age 35–44 (aOR = 1.13; 95% CI = 1.05–1.21), and
age over 65 (aOR = 1.13; 95% CI = 1.04–1.23); black
colour (aOR = 1.15; 95% CI = 1.08–1.23) and illiteracy
(aOR = 1.60; 95% CI = 1.42–1.81). Indigenous
populations (aOR = 0.69; 95% CI = 0.56–0.86) and mixed race
(aOR = 0.91; 95% CI = 0.86–0.95) were inversely
associated with unfavourable outcomes (Table 2).
Discussion and conclusions
In this retrospective analysis of a 5-year cohort of
SSMpositive new TB cases in a high-TB burden country
based on routine programmatic data, overall successful
outcome rate was 89.4%. Having a positive SSM at the
second month of treatment had a low predictive value
(26.9%) for unfavourable outcomes while SSM conversion
at this point had a high predictive value for successful
outcomes (85.2%), although lower than reported in the
10, 13, 18
]. However, the likelihood for
unsuccessful outcomes was twice higher among those who did
not convert the SSM by the second month. The low
predictive value of second month-SSM was due to the high
rates of successful treatment even among those who did
not convert SSM by the second month of treatment.
The SSM non-conversion in the second month as a
predictor of unfavourable outcomes has been a matter of
debate in the literature [
4, 5, 19, 20
]. SSM conversion has
been associated with cure/treatment completion [
]. However, non-conversion does not always indicate
unfavourable outcomes because SSM has low sensitivity
and low specificity to detect failure . Dead bacilli, for
example, are detected by SSM; only culture can
distinguish dead from alive bacilli [
]. True positive
secondmonth SSM results can be associated with comorbidities
], extensive lesions and high bacterial load [
so-called “difficult-to-treat” patients. Most of them will
actually be cured at the end of treatment. However,
irregularity of drug intake in the initial phase of treatment [
] and the presence of resistant bacteria [
] can also be
the reason for non-conversion at the second month and
can result in unfavourable outcomes. Unfortunately, our
study was based on programmatic data and we do not
have, in the database, any information on the extension
of the disease, treatment duration, or sputum culture
results. Information on comorbidities is missing for most
patients. Thus, they were not included in our analyses.
Other variables independently associated with higher
odds for an unfavourable outcome are reported in the
literature and were confirmed in our study: low educational
], male gender [
5, 10, 19, 27
], older age [
] and black/mixed race [
]. Surprisingly, belonging
to indigenous populations was inversely associated with
unfavourable outcomes. Indigenous populations may be
more difficult to reach and follow-up may be hampered
]. However, in Brazil, indigenous ethnicity is a
formal indication for directly observed treatment 
and special health services dedicated to this population
receive special training [
], which may explain this
*Includes true missing data and SSM not performed
a Successful = cure or treatment completion
b Unfavourable = loss to follow up, failure, death from tuberculosis or other causes, relapse of this episode, change of treatment
c Odds are for unfavourable outcomes
The study included a large cohort of patients over
5 years and allowed to extract relevant information
based on programmatic data, based on which decisions
by the Ministry of Health are usually taken. While we
conclude that the second month-SSM is a poor
predictor of unfavourable outcomes, in the absence of a
better predictor, we endorse the current recommendation
to improve surveillance and perform culture and
drugsusceptibility testing for patients with a positive second
month-SSM. Other, more accurate early markers of
poor prognosis are needed in order to trigger an alert
to the treating health team.
This study has a few limitations. First, its retrospective
design based on secondary data is subject to flaws. Missing
data were a main concern. Missing information on
followup smear results in Brazil has been reported previously [
] and can be due both to incomplete data registration
and to non-compliance with National Guidelines  to
perform monthly SSM. Because missing data were not
balanced among patients with different outcomes, our results
should be interpreted with caution, since this can have
resulted in bias. Bias can also have resulted from excluded
patients, although their general characteristics were similar
to the included ones. More missing data were expected in
this group because despite the initial positive SSM, patients
with other diseases either were excluded (such as
nontuberculous mycobacteria disease) or were transferred out
or died from other causes, thus they had no follow-up SSM.
More non-conversion was also expected since they were
initially treated for TB but possibly had other diagnoses or
were relapsed patients, who can have a delayed response to
treatment. Finally, the database did not contain sufficient
comorbidity, treatment duration and culture data.
TB: tuberculosis; SSM: sputum smear microscopy; CI: confidence interval; OR:
odds ratio; DST: drug susceptibility test; SINAN: Brazilian National Surveillance
MSNE, JPT, AT and JUB contributed to study conception, design, and
interpretation of findings, and participated in manuscript preparation and revision.
MSNE, RM, DB and RGA contributed to data analyses and generation of the
simulated data. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Availability of data and materials
The datasets analysed during the current study are available from the
corresponding author on reasonable request.
Consent for publication
Ethics approval and consent to participate
This study was approved by the University of Brasilia Health Sciences College
Ethics Committee (Document 181.344/2012). The patients were not required
to provide consent for participation in this study; access to anonymised
tuberculosis data for this study was provided by the Ministry of Health of Brazil.
No funds were required for this research.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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