Recent transmission of tuberculosis in Madrid: application of capture–recapture analysis to conventional and molecular epidemiology

J Iñigo1, A Arce1, JM Martín-Moreno2,3, R Herruzo3, E Palenque4 and F Chaves4

1 Dirección General de Salud Pública, Consejería de Sanidad de la Comunidad de Madrid, Madrid, Spain.
2 Agencia de Evaluación de Tecnologías Sanitarias, Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo.
3 Departamento de Medicina Preventiva y Salud Pública, Universidad Autónoma de Madrid, Madrid, Spain.
4 Servicio de Microbiología. Hospital Universitario Doce de Octubre, Madrid, Spain.

Dr Jesús Iñigo, Servicio de Epidemiología, Dirección General de Salud Pública, Aduana 29, 28013 Madrid, Spain. E-mail: jesus.inigo{at}madrid.org


    Abstract
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 Abstract
 Methods
 Results
 Discussion
 References
 
Background Population-based studies using a combination of molecular techniques and conventional epidemiological methods have been used to study the dynamics of tuberculosis (TB) transmission but the relative utility of each technique has not yet been established.

Methods A prospective population-based molecular and epidemiological study of patients diagnosed with TB was conducted in three urban districts of Madrid (Spain) during 1997–1999. Analysis was performed using the capture-recapture method including covariates in which conventional epidemiological data and the information on clustered cases obtained by DNA fingerprinting were regarded as independent and complementary procedures.

Results The estimate obtained by molecular analysis alone, that 31.6% of TB cases were due to recent transmission, was revised to 44.8% (95% CI: 31.4–58.2) using the capture-recapture method. The estimated completeness of the combined databases for identification of recent transmission was 59.2%. Underestimation of the true prevalence of recent transmission was higher with conventional epidemiology than molecular analysis, particularly for patients <35 years old and those with a history of imprisonment.

Conclusions In this study, use of the capture-recapture technique allowed us to combine epidemiological information obtained by conventional and molecular methods to quantify the number of cases of recently transmitted TB in the community and identify specific populations at high risk of disease. This information is clearly important because such groups are a prime target for improved TB control measures. In the long term, this combination of techniques may contribute significantly to control the spread of TB.


Keywords Tuberculosis, capture-recapture method, epidemiology, transmission, molecular techniques

Accepted 9 January 2003

After 10–15 years of follow-up of adolescents and young adults between 1950 and 1970, clinical trials of the BCG vaccine and isoniazid chemoprophylaxis showed that 80% of patients who developed active tuberculosis (TB) did so within two years of contact with an infectious case.1–3 In contrast, in the 1980s it was believed that most TB cases in industrialized countries resulted from reactivation of infection that had occurred in the remote past.4 Even at the start of the human immunodeficiency virus (HIV) epidemic it was thought that the increase in the number of TB cases was due to reactivation of old infections rather than recent transmission.5,6 At that time it was believed that recent transmission of TB, defined as progression to disease within two years of infection, did not play an important role in the incidence of the disease.7

By the 1990s, however, population-based studies using a combination of molecular techniques and conventional epidemiological methods to study the dynamics of TB transmission had demonstrated the importance of recent transmission in socioeconomically developed regions. These studies showed that 35–50% of TB cases in urban areas were due to recent transmission of the disease.8–12

Based on clustering statistics in molecular epidemiological studies, it is apparent that there are many diverse factors that can influence the proportion of TB that is attributable to recent transmission. These include the study duration, the genotyping technique used, the age structure of the population and the proportion of TB cases for which DNA typing is performed.13 Statistical models used to predict clustering in different age groups have shown that studies including a high proportion of young patients can underestimate the proportion of disease attributable to recent transmission in this population.14 The magnitude of recent transmission is also likely to be underestimated by failing to take into account patients with unique DNA fingerprint patterns who were infected by contact with cases outside the study population, either because transmission occurred before the study period or because the index cases did not reside in the area in which the study was performed.9

The ability to determine the proportion of TB cases attributable to recent transmission is very important because these cases are potentially preventable through improved TB control measures. Intensified contact investigations and expanded use of directly observed therapy have been associated not only with a decrease in overall TB case rates, but also with a reduction in the incidence of clustered cases.15

In order to estimate the rate of recent TB transmission in Madrid (Spain), we performed a population-based prospective study between 1997 and 1999 in three urban districts located in the south of the city (455 050 inhabitants). Analysis was performed using the capture-recapture method in which conventional epidemiological data and the information on clustered cases obtained by DNA fingerprinting were regarded as independent and complementary data sets.


    Methods
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 Abstract
 Methods
 Results
 Discussion
 References
 
Design and study population
To determine patterns of disease transmission, a prospective population-based molecular and epidemiological study of patients diagnosed with TB was conducted in three urban districts of Madrid (Spain) between 1997 and 1999. These districts have an official population of 455 050 and their largest provider of specialized care is ‘Hospital 12 de Octubre’. The population served is largely middle-class but also includes disadvantaged people living in neighbourhoods with a high incidence of TB and HIV infection. In 1996, 33.3% of notified TB cases in the study area were HIV seropositive, 22.2% were injecting drug users, and 2.8% were foreign born.16

Data sources and characteristics
The Mycobacteriological Database (MB)
Clinical specimens were processed according to standard methods in the Microbiology Department at the Hospital 12 de Octubre in Madrid. DNA fingerprinting was performed as described previously using the insertion sequence IS6110 as a probe.17 Computer-assisted analysis of IS6110 fingerprints was carried out using GelCompar software (Applied Maths, Kortrijk, Belgium). Because strains with few IS6110 copies are difficult to differentiate,18 all strains with fewer than six IS6110 copies were subjected to supplementary spoligotyping.19 Patients were included in clusters if their restriction fragment length polymorphism (RFLP) contained (1) >=6 IS6110 bands in an identical pattern, or (2) <=5 identical IS6110 bands and an identical spoligotyping pattern. Each cluster of n patients was assumed to include an index case (first patient diagnosed) and n-1 secondary cases with recently acquired disease.

To discount the possibility of cross-contamination in the laboratory, we reviewed hospital records to identify all those patients who had only a single culture-positive specimen for which the smear for acid-fast bacilli was negative. These cultures were considered to be false-positive if they were processed in the microbiology laboratory on the same day as a specimen with a positive smear from another patient with the same RFLP pattern.

The Epidemiological Database (ED)
All culture-positive TB patients in the study population were included in the database. For all patients, information was collected using a standardized protocol based on the Regional Registry of Tuberculosis Cases in Madrid. Data were assigned to the following sets of variables: demographic characteristics (age, sex, country of origin, district of residence, employment), clinical characteristics (date of symptom onset, date of diagnosis, site of disease, previous TB), risk factors for TB (homelessness, injecting drug use, presence of HIV infection, previous imprisonment, diabetes, silicosis, gastrectomy, malignant disease), and information from contact investigations. Additional information on HIV-status was obtained by cross-matching the Regional Registry of Tuberculosis with the AIDS Regional Registry.

Epidemiological evidence for active transmission was sought as follows. We examined every case for contact with another TB patient in the two years prior to symptom onset and checked for the inclusion of any contacts in the Regional Registry of Tuberculosis Cases. For clustered patients, medical records were reviewed and general practitioners were questioned in order to obtain supplementary information about previous exposure to other cases of TB, as well as exposure by the patient of other individuals in the community. Interviews with selected patients from clusters were also conducted to record their histories of residence, schooling, work, and attendance at other sites of social congregation. An epidemiological link was defined as sharing of a mutual residence, place of employment, social activity, or family relationship with a case patient.

Statistical analysis
In order to identify risk factors for clustering, univariate analysis was performed using the t-test for continuous variables and the {chi}2 or Fisher’s exact test for categorical variables. Variables which showed a statistically significant association with patients in clusters (P <= 0.05) were then included in a multivariate logistic regression model to determine independent risk factors for clustering.

Capture-recapture method
This analysis consists of cross-matching the information from two databases in order to identify the number of cases common to both lists (‘matched cases’).

Let:

N be the unknown size of a closed population (TB cases with recently acquired disease);

N1 be the number of cases of recent transmission identified by contact tracing (epidemiological database);

N2 be the number of cases of recent transmission identified by RFLP and spoligotyping (molecular database);

n22 be the number of cases omitted by both systems.

The completeness pi of database i is the proportion of all cases found in the database. In our study, the completeness of the epidemiological and molecular databases was defined as the ratio between the number of recently transmitted cases of TB identified in each database and the total number cases of recently transmitted TB that occurred between 1997 and 1999 in the three urban areas of Madrid under study.

Estimates of the total number of recently transmitted cases of TB were calculated using Chapman and Seber unbiased formulae20,21 with the hypothesis that the two data sources were independent and exhibited equal ability to identify cases (i.e. equal catchability). It is important to bear in mind that two sources are considered independent when the probability of notification of an event in one source is not dependent on the probability of notification of that event in the other source. Equal catchability is fulfilled when the probability of notification of one event is not influenced by its characteristics (e.g. age, gender, severity of symptoms, circumstances of the diagnosis) in either source. When the probabilities of capture depend on covariates, one proposed solution is to stratify the data according to covariates and then perform separate capture-recapture analyses for each stratum. In our study, separate analyses were performed on the data stratified by gender, age group, and previous imprisonment. For each analysis, the size of the databases allowed a manual search for matches using the patient’s full name as the identifier.


    Results
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 Methods
 Results
 Discussion
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From 1 January 1997 to 31 December 1999, there were 412 reported cases of TB in the three areas of Madrid under study. Of these, 328 (79.6%) were confirmed by isolation of Mycobacterium tuberculosis. There were 255 cases of pulmonary TB and 73 cases of extrapulmonary disease. The annual incidence of TB per 100 000 of the study population was 31.0, 29.2, and 30.2 cases in 1997, 1998, and 1999 respectively.

DNA fingerprinting analysis of M. tuberculosis isolates and risk factors for clustering
Restriction fragment length polymorphism typing was performed on 212 isolates of M. tuberculosis (64.6%), corresponding to 85 cases diagnosed in 1997, 67 in 1998, and 60 in 1999. An investigation was conducted to determine whether there was bias as to the patients whose isolates were available for molecular typing. Factors examined included age, sex, HIV status, intravenous drug use, and anatomical site from which the organism was isolated. No significant differences were found with the exception that a greater proportion of pulmonary rather than extrapulmonary isolates was available for fingerprinting (84.4% versus 71.6%, P < 0.05).

No isolates with the same RFLP were identified from specimens handled on the same day and consequently the likelihood of laboratory cross-contamination was considered extremely low. Ninety-five of 212 patients (44.8%) shared an RFLP pattern with one or more other cases and could be grouped into clusters on the basis of IS6110 fingerprint patterns. Of the isolates from these patients, eight had fewer than six bands and were grouped into two clusters, one of five isolates with five copies of IS6110 and the other of three isolates with two copies of the insertion element. Spoligotyping confirmed the clustering of these isolates. Overall, the 95 patients were grouped in 28 clusters ranging in size from 2 to 14 people, of which 15 (53.6%) comprised just two patients. Assuming that 1 case per cluster resulted from reactivation of remote infection and that the remainder resulted from recent transmission, 67 (31.6%) of 212 patients were defined as having recently transmitted TB on the basis of molecular analysis.

In an attempt to identify significant differences between the 95 patients in clusters and the 117 patients not in clusters, univariate analysis was performed. Clustered patients were younger (mean age 37.2 years, SD 7.2) than patients with a unique M. tuberculosis RFLP pattern (mean age 48.9 years, SD 19.6) (P < 0.001), were more likely to be intravenous drug users (odds ratio [OR] = 2.1, 95% CI: 1.0–4.6), and to have a history of previous imprisonment (OR = 3.1, 95% CI: 1.4–7.3) (Table 1Go). Adjusted OR showed that age <35 years (OR = 3.8, 95% CI: 2.1–6.9) and previous incarceration in prison (OR = 3.4, 95% CI: 1.3–9.2) remained statistically associated with clustering after adjustment for sex and injecting drug use.


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Table 1 Risk factors for clustering of tuberculosis (TB) cases in Madrid (Spain), 1997–1999
 
A total of 15 patients had received previous treatment for TB, of whom 7 were cases involved in clusters and 8 were individuals with unique isolates (P = 0.9). Twenty-seven of 212 cases (12.7%) had a risk factor for endogenous reactivation of latent TB infection (diabetes, silicosis, malignancy, or gastrectomy). Of these, 23 were patients with a unique M. tuberculosis RFLP pattern (P < 0.05).

Epidemiological and molecular links between TB cases
Among the 328 culture-positive cases of TB in the study population, the conventional epidemiological investigation identified 36 (11.0%) which conformed to the definition of recent transmission used in this study.

Matched cases: Clustered patients with identified epidemiological connections
Molecular techniques confirmed that 16 out of 36 cases with identified epidemiological connections had clinical isolates of M. tuberculosis that shared an identical DNA fingerprint pattern with at least one other case in the study. These 16 patients were grouped in 14 clusters (13 of which comprised 2 people and 1 contained 4 people). In 12 of the 14 clusters (11 with 2 cases and 1 with 4 cases), transmission occurred between households. Of the remaining two clusters, one involved two relatives living in the same apartment building, while the other was the result of nosocomial (hospital) transmission.

Epidemiological evidence of recent transmission not confirmed by molecular methods
In 20 cases, it was not possible to confirm epidemiological evidence of recent transmission by molecular methods. For 13 cases the clinical isolate of M. tuberculosis was not available for RFLP typing. This was because the source case was a household contact with TB who was diagnosed before the study period (six cases); the source case was a household contact who did not have an isolate available for genotyping (four cases); or the source case was a relative living outside the study area (three cases). For the remaining seven cases, other reasons precluded performance of the molecular analysis.

Clustered patients with no epidemiological connections
Among the 95 patients in clusters on the basis of molecular evidence, 16 were matched cases who also had an epidemiological link with another TB patient. The remaining 79 cases who had no epidemiological evidence of contact with another case of TB were grouped in 28 clusters. Assuming that one patient in each cluster acted as an index case for the other patient(s), the number of TB cases with recently acquired disease was 51. Of these, 26 (51%) were in four medium-sized clusters of between 4 and 12 patients.

In order to identify the risk factors associated with recently acquired disease that were not revealed by conventional epidemiological investigation, we compared 29 cases (16 clustered and 13 not clustered) for whom epidemiological evidence of recent transmission was established with 51 clustered cases among whom no epidemiological links with other TB cases were identified (Table 2Go). This analysis showed that patients with no recognised epidemiological connections were significantly younger (mean age 33.3 years, SD 19.3) than patients with established links (mean age 41.1 years, SD 13) (P = 0.04). The number of patients who had epidemiological connections was significantly lower among those who were HIV seropositive or intravenous drug users than among patients not at risk for these factors (P < 0.05).


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Table 2 Risk factors associated with recently acquired tuberculosis (TB) not detected by conventional epidemiology
 
Capture-recapture estimates
According to the definitions used in this study, 87 cases of TB cases were observed due to recently acquired disease. Of these, 36 were identified by epidemiological investigation, 67 were identified using molecular methods and there were 16 matches across the two techniques (Table 3Go). The estimated number of recently acquired cases of TB from the two-source capture-recapture analysis was 147 (95% CI: 103–191) out of a total of 328 culture-positive cases, i.e. 44.8% (95% CI: 31.4–58.2). The estimated completeness for detection of recently transmitted disease using conventional epidemiological methods was 24.5%, while for molecular analysis it was 45.6%, and when both techniques were used in conjunction, it was 59.2%. When stratified by sex and covariables related to capture (age group and previous imprisonment), the estimated completeness of both methods for identification of recent transmission was 47.0% in people <35 years of age and 50.0% for those with a record of previous incarceration (Table 3Go).


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Table 3 Capture-recapture estimates of the number of tuberculosis (TB) cases due to recent transmission and data source completeness
 

    Discussion
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 Abstract
 Methods
 Results
 Discussion
 References
 
To the best of our knowledge, this is the first study to use the capture-recapture method to estimate the true number of recently acquired cases of TB in a community and to examine the sensitivity (i.e. the ability to detect all cases) of conventional epidemiology and molecular RFLP analysis for detection of newly transmitted disease. The estimate obtained by molecular analysis alone that 31.6% of TB cases were due to recent transmission was revised to 44.8% (95% CI: 31.4–58.2) using the capture-recapture method. The estimated completeness of the combined databases for identification of recent transmission was 59.2%. Underestimation of the true prevalence of recent transmission was higher with conventional epidemiology than molecular analysis, particularly for patients <35 years old and those with a history of imprisonment. In these groups, conventional contact tracing identified <=15% of the estimated true number of recently acquired cases of TB.

These results should be considered with caution because the estimates obtained by applying the two-sample capture-recapture method were obtained on the basis of the following assumptions:22,23 (1) the population was closed or at least did not change in composition over the study period, (2) the information available was sufficient to match subjects in the two different databases accurately, (3) the sources of information were independent, and (4) each subject had equal likelihood of capture. Although the first two requirements were fulfilled in this study, there were some limitations regarding the independence of sources and the probability of capture by the two methods of investigation. The probability of a case of TB being reported is higher if the patient is culture-positive, and entry into the RFLP database is dependent on the likelihood of being culture-positive. Furthermore, the probability of transmission of TB to contacts increases with bacillary load as does the likelihood of having culture-positive sputum. Some authors have reported that most data sets used by epidemiologists tend to have a net positive dependence leading to underestimation of the population size (in our case the number of cases of recent transmission of TB).24,25 In spite of these limitations, we believe that the capture-recapture approach can help in understanding the relative importance of the conventional epidemiology and molecular methods in estimating the extent of recent TB transmission.

Other factors are also important in interpreting the results of population-based studies of the molecular epidemiology of TB. In such analyses, inclusion of all cases of TB will never be 100% complete and of those diagnosed and reported to the public health authorities, as mentioned above, only a certain proportion will have cultures available for DNA fingerprinting. In our community, the existence of an active surveillance system for reporting TB and processing of clinical isolates in a centralized clinical mycobacteriology laboratory enabled us to ensure that under-notification of diagnosed cases was minimized. In a population with a predominance of small clusters, the fact that 35.4% of culture-confirmed cases of TB in our study did not have an isolate available for DNA fingerprinting probably led to an underestimation of the true proportion of clustered cases.26

Our findings support the hypothesis that the majority of cases in a typical cluster of TB in our study population were the result of recently acquired disease. The appropriateness of IS6110 typing for detection of recent transmission depends on the rate of change of IS6110 RFLP patterns over time. This has been estimated at 3.2 years, a longer timeframe than the duration of the present and most other population-based studies.27 The relationship between the degree of clustering in a population and the proportion of disease attributable to recent transmission is dependent upon the age of the patients involved. Tuberculosis among younger people is more likely to be the result of recent transmission than disease in the elderly who have had many more opportunities for infection over the course of a lifetime.14 In our study, 57.6% of clustered cases were in individuals below the age of 35, thereby supporting this concept. Molecular epidemiology has successfully identified large outbreaks of TB that were not detected by conventional contact tracing and established possible chains of transmission between patients in suspected clusters.28,29 In Madrid, over half of the clustered patients with no recognised epidemiological connections were grouped into four clusters on the basis of RFLP analysis. Among these, we found that there was an over-representation of risk factors such as injecting drug use, HIV infection, and previous imprisonment, all of which could contribute to a reduction in the efficacy of contact tracing. Furthermore, the most prevalent strains identified in this study were also detected in the prison population in the Madrid area.30 The high prevalence of TB in Spanish prisons, together with a high rate of transmission in these centres31,32 and the possibility of TB dissemination through casual contact with infectious cases severely hampers the confirmation of epidemiological links between patients.33

During the past decade, the application of molecular epidemiology to the field of TB has advanced our understanding of the dynamics of disease transmission. A major goal in population-based studies has been the use of molecular methods to distinguish between reactivation TB and recent transmission. Cases in clusters are considered to be epidemiologically linked chains of recently transmitted disease, while unique isolates are regarded as cases of reactivation disease. In the absence of a ‘gold standard’, the application of capture-recapture analysis can contribute to the refinement of estimates for rates of recent TB transmission. With the widespread use of molecular tools, the criteria for establishing recent transmission have become more strict as each case of recently acquired TB is made to comply with the following requirements: (1) be culture positive; (2) have a fingerprint pattern shared with a previous case of TB (an identical RFLP pattern with IS6110 and, depending on the number of copies of IS6110, sometimes an identical pattern using a complementary molecular method); (3) be epidemiologically linked with the source case (through a person, time or place), and (4) develop TB within two years of contact with an infectious case. In the present study, these criteria were fulfilled in only 16 cases (4.9%), although this is a similar percentage to that obtained in other urban settings.10,34 In order to provide a more accurate assessment of the incidence of recent TB transmission, we propose revising the criteria to include not only those patients in epidemiologically linked clusters, but also those who are grouped in clusters on the basis of molecular analysis alone and those with epidemiological connections to other TB cases that are not included in the study group.


KEY MESSAGES

  • Simple capture-recapture methods applied to conventional and molecular epidemiology can help in understanding transmission of tuberculosis (TB).
  • Using these methods, we estimated that 44.8% of TB cases in Madrid were due to recent transmission.
  • Conventional epidemiology identified 24.5% of recently transmitted cases. This underestimation was higher for patients <35 years old and those with a history of imprisonment.
  • In order to provide a more accurate assessment of recent TB transmission, we propose revising the criteria to consider a recently transmitted case.

 

In this study, the use of the capture-recapture technique allowed us to combine epidemiological information obtained by conventional and molecular methods, quantify the number of cases of recently transmitted TB in the community, and identify specific populations at high risk of disease. This information is clearly important because such groups are a prime target for improved TB control measures. In the long term, we hope that this combination of techniques will significantly contribute to the control of the spread of TB.


    Acknowledgments
 
The authors thank Tobin Hellyer, PhD, for his suggestions and comments. This study was supported by grant 98/1217 from the Fondo de Investigaciones Sanitarias, Spain.


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