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INT J TUBERC LUNG DIS 14(1):34–39

© 2010 The Union

Multidrug-resistant pulmonary tuberculosis in Los Altos,


Selva and Norte regions, Chiapas, Mexico

H. J. Sánchez-Pérez,*† A. Díaz-Vázquez,* J. C. Nájera-Ortiz,* S. Balandrano,‡ M. Martín-Mateo§


* Área Académica de Sociedad, Cultura y Salud, El Colegio de la Frontera Sur, San Cristóbal de Las Casas, Chiapas,
† Grupos de Investigación en Salud para América y África Latinas, Ecosur, México, ‡ Departamento de Micobacterias,

Instituto de Diagnóstico y Referencia Epidemiológicos, México DF, México; § Unidad de Bioestadística, Facultad de
Medicina, GRAAL, Universidad Autónoma de Barcelona, Barcelona, Spain

SUMMARY

OBJECTIVES: To analyse the proportion of multidrug- 4.6% (2 of 43), that of secondary MDR-TB was 29.2%
resistant tuberculosis (MDR-TB) in cultures performed (7/24), while among those whose history of treatment
during the period 2000–2002 in Los Altos, Selva and was unknown the proportion was 14.3% (3/21). Accord-
Norte regions, Chiapas, Mexico, and to analyse MDR- ing to the logistic regression model, the variables most
TB in terms of clinical and sociodemographic indicators. highly associated with MDR-TB were as follows: having
M E T H O D S : Cross-sectional study of patients with pul- received anti-tuberculosis treatment previously, cough
monary tuberculosis (PTB) from the above regions. Drug of >3 years’ duration and not being indigenous.
susceptibility testing results from two research projects C O N C L U S I O N S : The high proportion of MDR cases
were analysed, as were those of routine sputum samples found in the regions studied shows that it is necessary
sent in by health personnel for processing (n = 114). to significantly improve the control and surveillance of
MDR-TB was analysed in terms of the various variables PTB.
of interest using bivariate tests of association and logis- K E Y W O R D S : indigenous population; Mexico; tubercu-
tic regression. losis; multidrug-resistant; pulmonary
R E S U LT S : The proportion of primary MDR-TB was

ALARMINGLY HIGH LEVELS of tuberculosis (TB) tuberculosis treatment. The WHO estimates that over
continue to be observed worldwide. The World 400 000 cases occur annually.1 While treatment of a
Health Organization (WHO) estimated an incidence ‘normal’ TB case costs under US$150, that of a MDR-
of 9.27 million cases globally for 2007, a prevalence TB case can cost as much as US$16 400, with no
of 13.7 million cases and 1.8 million deaths associ- guarantee of cure.8,9 From an economic point of view,
ated with this disease.1 In 2007, there were an esti- patient deaths and morbidity are much more costly
mated 0.5 million cases of multidrug-resistant TB for a country than anti-tuberculosis treatment.
(MDR-TB, defined as resistance to both isoniazid In Mexico, published data on MDR-TB have only
[INH] and rifampicin [RMP]).1 been available since 1997: in three states of a total
In Mexico, Chiapas is one of the states with the of 32, rates of primary and secondary (or acquired)
highest incidence rates of pulmonary tuberculosis MDR-TB were estimated at respectively 2.4% and
(PTB). According to official 2006 figures, the registered 22.4%.10 According to WHO estimates for the coun-
incidence rate was 16.1 per 100 000 population in try as a whole, the prevalence of MDR-TB is 1–3% in
Chiapas, while it was 12.9 for the country as a whole.2 primary cases.11 For Chiapas, the only reference found
While the registered death rate due to PTB in 2005 corresponds to six PTB cases in 2000, two of which
was 4.4/100 000 in Chiapas, for the country as a whole were MDR-TB.12
it was 2.1.3 There is evidence that sub-notification and We analysed the MDR-TB results obtained from
underdiagnosis of TB (of both cases and deaths) are two studies carried out in the regions of Los Altos,
very high in Chiapas.4–6 Selva and Norte of Chiapas,4,13 as well as from all
One of the greatest problems for TB control which sputum samples sent in by health personnel from
is also on the increase is MDR-TB.7 Generally, MDR- these three regions to El Colegio de la Frontera Sur
TB occurs as a consequence of inappropriate anti- (Ecosur) for TB diagnosis by culture during the years

Correspondence to: Héctor Javier Sánchez Pérez, El Colegio de la Frontera Sur, Carretera Panamericana y Periférico Sur S/N
29290, San Cristóbal de Las Casas, Chiapas, México. Tel: (+52) 967 674 9000, extn 1510. Fax: (+52) 967 674 9021.
e-mail: hsanchez@ecosur.mx
Article submitted 5 March 2009. Final version accepted 2 August 2009.
MDR-TB in Chiapas 35

2000–2002. The main objective was to calculate the Drug susceptibility testing (DST) was carried out
proportion of MDR-TB, and to analyse MDR-TB in by the Institute of Epidemiological Diagnosis and Ref-
terms of clinical and socio-demographic indicators. erence (InDRE) using the BACTEC radiometric tech-
nique.14 InDRE, located in Mexico City, is responsible
STUDY POPULATIONS AND METHODS for conducting all DST in Mexico.
Study area Statistical analysis
The Los Altos, Selva and Norte regions of Chiapas MDR-TB rates were obtained by dividing the MDR
are zones with very high levels of poverty; the major- cases by the total number of culture-tested patients.
ity of the populations are indigenous Mayan people. MDR-TB status was analysed in terms of the various
These regions have been most badly affected by the variables of interest using bivariate tests of associa-
armed conflict begun in 1994 by the Zapatista Na- tion and calculation of crude odds ratios (ORs). The
tional Liberation Army.4 variables analysed were demographic factors (sex,
age, ethnic origin, Spanish-speaking or not [only in-
Study design and population
digenous subjects]), socio-economic factors (occu-
This was a cross-sectional study conducted based on pation, schooling, social security, religion, housing
the results obtained in two studies,4,13 as well as on characteristics [type of floor, electricity, type of cook-
routine sputum samples sent in to Ecosur for analysis: ing facilities, overcrowding], area of residence [urban
1 The project ‘Pulmonary tuberculosis in Los Altos vs. rural]), clinical factors (duration of cough, pres-
region of Chiapas: advances or recessions in its ence of haemoptysis, fever, weight loss), health ser-
control?’ (PTBA),13 was an active case-finding vice utilisation and accessibility indicators (health
study, conducted between March 2000 and March agent consulted, history of anti-tuberculosis treat-
2002, of coughers aged ⩾15 among patients who ment, treatment default), and family history of PTB.
visited the Ministry of Health General Hospital in Logistic regression was used to model MDR-TB
San Cristobal de Las Casas, the reference hospital status in terms of those variables found to be signifi-
for 90% of the population of the Los Altos region, cantly associated in bivariate analyses. Logistic regres-
for any reason. There were 487 productive cough- sion analysis was restricted to data from the PTBA
ers with at least one sputum sample; of 375 cul- and P&H studies, as the only details provided on pa-
tures performed, 79.5% were negative, 3.7% were tients for whom routine samples were tested were
contaminated and 16.8% (n = 63) were PTB. age, sex and place of residence. All statistical analyses
2 Project ‘Health and Peace’ (H&P)4 was an active were performed using SPSS version 11.0. (Statistical
case-finding study of coughers aged ⩾15 years Package for the Social Sciences, Chicago, IL, USA).
from a population-based study conducted between
October 2000 and December 2001 in regions most Ethical issues
affected by the armed conflict in Chiapas. There In the PTBA and P&H studies and for the routine
were 603 productive coughers with at least one samples, the Helsinki Declaration guidelines were fol-
sputum sample. Of 429 cultures performed, 92.3% lowed.16 All patients were directly informed of their
were negative, 2.8% were contaminated and 4.9% results, which were also delivered to the National Tu-
(n = 21) were PTB. berculosis Programme (NTP) authorities for treat-
3 Sputum samples sent in for processing (routine sam- ment management. The H&P study was approved
ples) were included as a separate group. Between by the authorities and people of the communities
March 2000 and March 2002, health personnel studied, as well as by a committee of Physicians for
in the main governmental and non-governmental Human Rights.4
health institutions in the three regions under study
sent sputum samples of 221 coughers for culture RESULTS
analysis. Of 163 cultures, 78.5% were negative,
3.1% were contaminated and 18.4% (n = 30) Overall, for all three groups, sputum was available
were PTB. for 1311 individuals, for whom culture analysis was
possible for 967 (73.8%). The remainder could not be
Laboratory testing processed due to poor quality (23% of PTBA, 29.5%
In the PTBA and H&P studies, coughers were asked of P&H and 34.4% of the routine samples). Of these
to provide three sputum samples. Patients were in- 967 cultures, 114 (11.8%) were PTB-positive: DST
structed in the correct method to obtain and preserve results were available for 88 (77.2%), and 26 (22.3%)
the samples.14 The samples were transported in dry were contaminated.
ice to the laboratory at Ecosur, where smear testing With regard to the demographic, socio-economic
using the Ziehl-Neelsen technique and culture analysis and respiratory symptom indicators analysed by type
using Löwenstein-Jensen media were conducted.14,15 of study, with the exception of sex, age and place of
The routine samples sent to Ecosur were processed residence, we had no data on the patients for the
immediately on arrival using the same procedure. group of routine samples. Among the PTB-positive
36 The International Journal of Tuberculosis and Lung Disease

Table 1 Demographic, socio-economic and respiratory symptom indicators among PTB


culture-positive patients in Los Altos, Norte and Selva regions, Chiapas, Mexico, 2000–2002
Routine
PTBA H&P samples Total
(n = 63) (n = 21) (n = 30) (N = 114)
% % % % P value*
Demographic
Male 58.7 52.4 80.0 63.2 0.073
Median age, years 38.0 42.0 36.5 38.0 0.124
Average rank, years† 58.6 65.5 49.5 57.9 0.217
Indigenous language speaker 88.9 85.7 NA 88.1 0.697
Spanish language speaker‡ 57.1 44.4 NA 54.1 0.347
Region of residence
Los Altos 95.2 23.8 73.3 76.3
Selva 1.6 33.3 23.3 13.2
Norte 3.2 42.9 3.3 10.5 <0.001
Socio-economic factors
Employed in agriculture 33.3 42.9 NA 35.7 0.430
No social security 98.4 100.0 NA 98.8 0.561
Third (primary) grade schooling or less 80.3 76.2 NA 79.3 0.687
Residing in a rural community§ 65.1 100.0 80.0 75.4 0.004
Earth floor in dwelling 68.3 61.9 NA 66.7 0.593
No electricity in dwelling 17.7 4.8 NA 14.5 0.144
Cook with wood or charcoal 83.6 95.2 NA 86.6 0.177
Overcrowding¶ 60.3 76.2 NA 64.3 0.189
Catholic 63.6 64.7 NA 63.9 0.936
Respiratory symptoms
Duration of cough, years, median 1.0 3.0 NA 1.1 0.702
Haemoptysis# 48.4 42.9 NA 47.0 0.661
Fever** 75.4 42.9 NA 67.1 0.006
Weight loss†† 80.0 61.9 NA 75.0 0.103
Family history of PTB 29.5 14.3 NA 25.6 0.168

* Among the three groups analysed, unless otherwise specified.


† Kruskal-Wallis test.
‡ Only among indigenous subjects.
§ <2500 inhabitants.
¶ ⩾3 persons per bedroom.
# At the time of the study.

** In the 15 days before the study.


†† Since coughing began.

PTB = pulmonary tuberculosis; PTBA = ‘Pulmonary tuberculosis in Los Altos region of Chiapas: advances or reces-
sions in its control’ project13; H&P = ‘Health and Peace’ project4; NA = not available.

patients in the other two studies, statistically signifi- were previous anti-tuberculosis treatment, cough of
cant differences were found only for region of resi- >3 years’ duration and not being indigenous (Table 4).
dence, living in a rural community and presence of
fever (Table 1).
DISCUSSION
Rate of MDR The observed rates of primary and secondary MDR
Of the 88 cultures analysed, 57 (64.8%) were suscep- suggest that in the regions studied, MDR is a public
tible, 19 (21.6%) were resistant and 12 (13.6%) were health problem of alarming proportions, mainly for
MDR (Table 2); 43 had no history of previous anti- the following reasons.
tuberculosis treatment, of which two (4.6%) were The MDR rates obtained exceeded those calcu-
MDR (primary MDR); 24 had a history of treatment, lated for the country as a whole (by 1–3% for pri-
of which seven (29.2%) were MDR (secondary or ac- mary and 20% for secondary MDR-TB).11,17 In Bo-
quired MDR); for a further 21, history information gota, Colombia, Hernández et al.,found a rate of
was not available, although three (14.3%) were MDR. 2.9% for the period 1995–2006,18 and in California,
Granich et al.,reported a rate of 1.4% for the period
MDR in relation to the indicators analysed 1994–2003.10 In Turkey, Surucuoglu et al. reported
According to the bivariate analyses, the variables as- primary and secondary rates of respectively 4.4%
sociated with MDR were non-indigenous status, no and 22.4%, for the period 1997–2003.19
electricity in the home, duration of cough >3 years Another major reason is deficiencies in the NTP.
and previous history of anti-tuberculosis treatment Although the cultures analysed correspond to the
(Table 3). years 2000–2002, there are no signs to suggest that
Logistic regression modelling showed that the the TB situation in these regions has improved. Vari-
variables most likely to be associated with MDR-TB ous studies, as well as the official statistics themselves,
MDR-TB in Chiapas 37

Table 2 DST results among PTB culture-positive patients Table 3 Variables associated with multidrug resistance*
in Los Altos, Norte and Selva regions, Chiapas, Mexico, in Los Altos, Norte and Selva regions of Chiapas, Mexico,
2000–2002 2000–2002
Routine MDR
PTBA H&P samples Total % OR (95%CI)
n (%) n (%) n (%) n (%)
Demographic factor
Culture-positive patients Indigenous language speaker
with DST performed 63 21 30 114 No (n = 8) 37.5 5.5 (1.1–29.0)
DST results Yes (n = 61) 9.8
Susceptible to 5 drugs 41 (65.1) 5 (23.8) 11 (36.7) 57 (50.0) Socio-economic factor
Resistant* 12 (19.0) 2 (9.5) 5 (16.6) 19 (16.7) Electricity in dwelling
Multidrug-resistant 7 (11.1) 2 (9.5) 3 (10.0) 12 (10.5) No (n = 10) 40.0 7.1 (1.5–33.7)
No result due to sample Yes (n = 58) 8.6
contamination 3 (4.8) 12 (57.2) 11 (36.7) 26 (22.8) Clinical symptoms
DST results, not including Duration of cough
contaminated cases 60 9 19 88 >3 years (n = 12) 41.7 9.1 (2.0–42.2)
Susceptible 41 (68.3) 5 (55.6) 11 (57.9) 57 (64.8) ⩽3 years (n = 55) 7.3
Resistant 12 (20.0) 2 (22.2) 5 (26.3) 19 (21.6) History of anti-tuberculosis treatment
Multidrug-resistant 7 (11.7) 2 (22.2) 3 (15.8) 12 (13.6) Yes (n = 24) 29.2 8.4 (1.6–44.9)
Type of multidrug No (n = 43) 4.7
resistance 7 2 3 12
Primary 1 1 0 2 * No association with MDR found for the following variables: demographic
factors: sex, age (15–44 years vs. ⩾45 years), whether Spanish spoken or not
Secondary 6 1 0 7
(only indigenous subjects); socio-economic factors: occupation (agriculture,
Unknown 0 0 3 3 other), social security (yes/no), schooling (0–3 years, ⩾4 years), area of resi-
dence (urban, rural), religion (Catholic, other); household-related: type of floor
* 13 resistant to INH, 2 to INH+EMB; 1 to INH+PZA; 2 to SM; 1 to (bare, covered), fuel for cooking (gas, other), overcrowding (<3, ⩾3 per-
SM+EMB. sons per bedroom); clinical symptoms: haemoptisis (yes/no), fever (yes/no),
DST = drug susceptibility testing; PTB = pulmonary tuberculosis; PTBA = weight loss (yes/no), health agent consulted (institutional services, other),
‘Pulmonary tuberculosis in Los Altos region of Chiapas: advances or reces- anti-tuberculosis treatment abandoned (yes/no), family history of PTB (yes/
sions in its control’ project13; H&P = ‘Health and Peace’ project4; INH = iso- no); type of study: (PTBA, H&P, sample sent in).
niazid; EMB = ethambutol; PZA = pyrazinamide; SM = streptomycin. MDR = multidrug resistance; OR = odds ratio; CI = confidence interval; PTB =
pulmonary tuberculosis; PTBA = ‘Pulmonary tuberculosis in Los Altos region
of Chiapas: advances or recessions in its control’ project13; H&P = ‘Health
and Peace’ project4.
demonstrate that in these areas the health system fails
to diagnose cases appropriately and that application
of the DOTS strategy is deficient.20 It is therefore the health services, this would not be the case. Health
likely that many patients remain undiagnosed,4 while service personnel cannot spend so much time locat-
others are not properly followed up, resulting in low ing patients and their corresponding samples; it is
cure rates (<60%), high mortality21 and the emer- therefore very likely that the number of poor quality
gence of considerable numbers of MDR-TB cases. samples would be much higher. The main obstacles to
Thus, whereas in Chiapas the recorded incidence rate obtaining acceptable sputum samples result from bar-
of PTB was 16.1/100 000 in 2006, different studies riers in communication with the indigenous people,
have found prevalence rates of PTB of 161.8/100 0004 who have different cultural conceptions about the
and 276.9/100 000 persons aged ⩾15 years.22 An- health-disease process, and many do not speak Span-
other recent study in the Los Altos region observed a ish, among other aspects. This situation leads to prob-
high rate of mortality due to PTB.21 lems where patients have to be instructed about ex-
In the regions studied, it is extremely difficult to per- actly what kind of sputum samples are required.4–6,13,21
form culture analysis, and even more difficult to con- In addition, the distance of the communities from the
duct DST in those cases that require it. In the present centres where samples are processed, the unsuitable
study the percentage of contaminated cultures was transport conditions and the risk of exposure to sun-
high (22%) due to poor quality sputum samples. It is light or lack of refrigeration, makes preserving and
important to stress that, in the case of the two projects, transporting sputum samples difficult, particularly
considerable effort was dedicated to obtaining those when samples need to be sent for DST to InDRE, in
samples. Under the ‘normal’ operating conditions of Mexico City, from the remote Chiapas communities.

Table 4 Variables associated with multidrug resistance according to logistic regression model,
Los Altos, Norte and Selva regions of Chiapas, Mexico, 2000–2002
95%CI for
Variable β ET Wald Sig Exp (β) Exp (β)
Not being indigenous 2.455 1.200 4.188 0.041 11.644 1.1–122.2
Duration of cough >3 years 2.993 1.071 7.809 0.005 19.942 2.4–162.7
With history of anti-tuberculosis
treatment 2.285 1.003 5.185 0.023 9.826 1.4–70.2
Constant −4.486 1.080 17.237 0.000 0.011
CI = confidence interval.
38 The International Journal of Tuberculosis and Lung Disease

The quantity of poor quality samples affected this ondary resistance, as did all seven patients with a his-
study in two ways: the confidence intervals for statis- tory of anti-tuberculosis treatment.
tical analysis were wider, and it reduced the possibility
Limitations of the study
of analysing MDR as a function of other variables of
interest. As a result, we cannot say whether the quan- The main limitations of this study are the lack of de-
tity of contaminated cultures resulted in an under- or tail about patients whose sputum samples were anal-
overestimation of the proportion of MDR-TB found. ysed for TB, as this limited proper analysis of MDR-
Finally, the geographical, economic and cultural TB in terms of other variables of interest; a possible
barriers to be overcome in accessing the health ser- selection bias among patients studied by the PTBA
vices,4,22 as well as the highly rural and widely dis- Project and in routine samples; the high proportion
persed nature of the communities (the vast majority of samples for which culture analysis was not possi-
have fewer than 1000 inhabitants), leads to low rates ble (around 23–39%); and the proportion (3%) of
of diagnosis and follow-up of cases. cultures not analysed due to contamination. These
With regard to MDR as a function of the demo- deficiencies are reflected in the wide confidence inter-
graphic indicators analysed, it is notable that non- vals obtained in the logistic regression. However, we
indigenous patients had higher MDR rates than in- believe that the main contribution of the study lies in
digenous patients. In the six cases identified among the fact that it documents the failure of a TB preven-
indigenous patients, two had primary and four sec- tion and control programme. The proportion of MDR
ondary MDR, whereas all three non-indigenous pa- cases found alone indicates that the NTP is failing
tients were secondary. Although very few of the cases its patients.
analysed were non-indigenous patients, it is possible
that their higher MDR rate was due to more frequent CONCLUSIONS
contact with the health services. Given the deficient Given the high proportion of MDR cases found in
quality of care in the regions studied, this in itself the studied regions, it is necessary to significantly im-
represents a risk factor for MDR, and suggests that prove TB control and surveillance.
there are more undiagnosed TB cases among the in-
digenous population (due to lack of access to health
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16 World Medical Association. Declaration of Helsinki: ethical SIDA de México. Mexico DF, Mexico: CENAVE, 2004. http://
principles for medical research involving human subjects. Ed- www.cenave.gob.mx/tuberculosis/eventos/omstbsida.htm Ac-
inburgh, Scotland: WMA, 2002. cessed July 2009.
17 Muñoz-Mendoza W A, Téllez-Medina H A, Baeza-Peña B. Tuber-

RÉSUMÉ

OBJECTIFS : Analyser la proportion de tuberculoses à d’intérêt en utilisant des tests bivariés d’association ainsi
germes multirésistants (TB-MDR) dans les cultures réali- que la régression logistique.
sées pendant la période 2000–2002 dans les régions de R É S U LTAT S : La proportion des TB-MDR primaires est
Los Altos, Selva et Norte de Chiapas, Méxique, et ana- de 4,6% (2/43) et celle des TB-MDR secondaires de
lyser les TB-MDR en termes d’indicateurs cliniques et 29,2% ; elle est de 14,3% (3/21) chez ceux dont les anté-
socio-démographiques. cédents de traitement sont inconnus. Selon le modèle de
M É T H O D E S : Etude transversale de patients atteints de régression logistique construit, les variables qui expri-
tuberculose pulmonaire (TBP) provenant des régions ment le mieux le statut de MDR sont les suivantes : un
mentionnées ci-dessus. Les résultats des tests de sensibi- traitement antituberculeux antérieur, toux depuis plus
lité aux médicaments provenant de deux projets de re- de 3 années et ne pas être indigène.
cherche ont été analysés, de même que ceux obtenus à C O N C L U S I O N : Vu la proportion élevée de cas de MDR
partir d’échantillons de crachats envoyés par le person- décelés dans les régions étudiées, il est nécessaire
nel de santé en vue d’un traitement (n = 114). On a d’améliorer de façon significative la lutte et la surveil-
analysé les TB-MDR en termes de diverses variables lance de la TBP.

RESUMEN

OBJETIVOS: Analizar la proporción de tuberculosis R E S U LTA D O S : La proporción de TB-MDR primaria


multidrogorresistente (TB-MDR) en cultivos efectuados hallada fue de 4,6% (2/43), la de TB-MDR secundaria
durante el período 2000–2002 en las regiones de los Al- de 29,2% (7/24) y, en aquellos pacientes en los que se
tos, Selva y Norte de Chiapas, México, y analizar la TB- desconocieron antecedentes de tratamiento antitubercu-
MDR según indicadores clínicos y sociodemográficos. losis, de 14,3% (3/21). Según el modelo de regresión
M É T O D O : Estudio transversal de pacientes con tubercu- logística construido, las variables que mejor explicaron
losis pulmonar (TBP) de las regiones mencionadas. Se la condición de TB-MDR fueron tratamiento antituber-
analizaron los resultados de fármaco-sensibilidad de dos culosis previo, tos de >3 años de duración y no ser
proyectos, así como de muestras enviadas por el perso- indígena.
nal de salud para su procesamiento (n = 114). La TB- C O N C L U S I O N E S : Dada la alta proporción de casos de
MDR fue analizada en términos de variables de interés, TB-MDR encontrada en las regiones estudiadas, es nece-
mediante análisis bivariado (pruebas de asociación) y sario mejorar significativamente el control y la vigilan-
regresión logística. cia de la TBP.

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