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Human Tuberculosis due to Mycobacterium bovis in the United States, 1995-2005

  1. Michele C. Hlavsa1,2,
  2. Patrick K. Moonan2,
  3. Lauren S. Cowan2,
  4. Thomas R. Navin2,
  5. J. Steve Kammerer2,3,
  6. Glenn P. Morlock2,
  7. Jack T. Crawford2, and
  8. Philip A. LoBue2
  1. 1Epidemic Intelligence Service, Office of Workforce and Career Development, Atlanta, Georgia
  2. 2Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, Sexually Transmitted Diseases, and Tuberculosis Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
  3. 3Northrup Grumman, Atlanta, Georgia
  1. Reprints or correspondence: Michele Hlavsa, Div. of Parasitic Diseases, Centers for Disease Control and Prevention, 4770 Buford Hwy., MS F-22, Atlanta, GA 30341-3724 (acz3{at}cdc.gov).
 
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Abstract

Background. Understanding the epidemiology of human Mycobacterium bovis tuberculosis (TB) in the United States is imperative; this disease can be foodborne or airborne, and current US control strategies are focused on TB due to Mycobacterium tuberculosis and airborne transmission. The National TB Genotyping Service's work has allowed systematic identification of M. tuberculosis-complex isolates and enabled the first US-wide study of M. bovis TB.

Methods. Results of spacer oligonucleotide and mycobacterial interspersed repetitive units typing were linked to corresponding national surveillance data for TB cases reported for the period 2004–2005 and select cases for the period 1995–2003.We also used National TB Genotyping Service data to evaluate the traditional antituberculous drug resistance-based case definition of M. bovis TB.

Results. Isolates from 165 (1.4%) of 11,860 linked cases were identified as M. bovis. Patients who were not born in the United States, Hispanic patients, patients <15 years of age, patients reported to be HIV infected, and patients with extrapulmonary disease each had increased adjusted odds of having M. bovis versus M. tuberculosis TB. Most US-born, Hispanic patients with TB due to M. bovis (29 [90.6%] of 32) had extrapulmonary disease, and their overall median age was 9.5 years. The National TB Genotyping Service's data indicated that the pyrazinamide- based case definition's sensitivity was 82.5% (95% confidence interval; 75.3%–87.9%) and that data identified 14 errors in pyrazinamide-susceptibility testing or reporting.

Conclusions. The prevalence of extrapulmonary disease in the young, US-born Hispanic population suggests recent transmission of M. bovis, possibly related to foodborne exposure. Because of its significantly different epidemiologic profile, compared with that of M. tuberculosis TB, we recommend routine surveillance of M. bovis TB. Routine surveillance and an improved understanding of M. bovis TB transmission dynamics would help direct the development of additional control measures.

Tuberculosis (TB) due to Mycobacterium bovis is a zoonosis that affects humans around the world [1, 2]. Although it has a wide range of hosts, M. bovis primarily infects cattle, which can transmit the agent to humans through the consumption of unpasteurized, contaminated dairy products [3]. Like Mycobacterium tuberculosis, M. bovis can also be transmitted between persons through the inhalation of infectious droplet nuclei, particularly among HIV-infected persons [4, 5].

In developed countries, like the United States, the pasteurization of milk and the testing and culling of infected cattle have resulted in steep decreases in the incidence of M. bovis TB [6, 7]. M. bovis caused as much as 25% of cases of human TB in developed countries in the late 19th and early 20th centuries. Today, only 1%–2% of human TB cases in developed countries are caused by M. bovis [7], which usually affects persons who acquired the infection locally before the implementation of control measures or in developing countries where control measures have not been implemented. This is in contrast with the findings of a New York City investigation of 35 genotypically confirmed cases of M. bovis TB during the period 2001–2004 [3]. Investigators concluded that recent foodborne transmission within the United States had occurred, because there was a lack of evidence of airborne, person-to-person transmission, and because none of the patients <5 years of age (1 of whom died because of peritoneal TB) had a history of international travel.

Because M. tuberculosis is the predominant cause of human TB, current standard US TB-control strategies focus on preventing airborne, person-to-person transmission. These strategies do not prevent the foodborne transmission of M. bovis. Although human TB caused by any of the M. tuberculosis complex species is reportable in all US jurisdictions [8], the national TB surveillance system does not capture data on which species caused a particular case. Consequently, previous analyses of national data were unable to differentiate between TB cases caused by M. bovis, those caused by M. tuberculosis, and those caused by the other 5 species of the M. tuberculosis complex. Determining which TB cases are caused by M. bovis is an essential first step to elucidating the epidemiology of M. bovis TB, which in turn would support the development and implementation of appropriate prevention strategies.

TB caused by M. bovis and TB caused by M. tuberculosis cannot be distinguished clinically, radiographically, or pathologically in individual patients [9]; thus, the identification of these causative agents requires laboratory testing. Pyrazinamide susceptibility testing can be used to screen for M. bovis, because of its inherent resistance to this antituberculous drug [10]. Other biochemical methods can then be used as confirmatory tests [11]. However, US laboratories do not uniformly test pyrazinamide susceptibility or generally perform the other biochemical tests; they generally only determine whether or not a pathogen belongs to the M. tuberculosis complex.

Methods to examine the genetic makeup of M. tuberculosis complex isolates, such as sequencing of the pncA gene (a marker for pyrazinamide resistance), began to emerge in the early 1990s. In 2004, the US Centers for Disease Control and Prevention launched the National TB Genotyping Service (NTGS), with the aim of genotyping 1 M. tuberculosis complex isolate from each current patient in the United States with cultureconfirmed TB [12]. Select isolates (e.g., isolates from patients suspected to be part of a cluster) collected prior to 2004 can also be submitted to NTGS. Notably, not all reporting US jurisdictions participated in NTGS until 2006.

Designed primarily as a tool to detect the possible transmission of M. tuberculosis, NTGS mainly uses 2 rapid and standardized genotyping methods, spacer oligonucleotide typing (spoligotyping) and mycobacterial interspersed repetitive units (MIRU) typing [13]. An added benefit of this molecular characterization mechanism is that it allows the systematic identification of specific M. tuberculosis complex agents [14]. Thus, we used linked national TB genotype and surveillance data to conduct this first nationwide US epidemiologic study of human M. bovis TB with the following objectives: to determine the proportion of human TB cases caused by M. bovis in the United States; to determine, among TB patients, the risk factors associated with M. bovis TB; and to compare the sensitivity, specificity, and predictive values of a pyrazinamide resistance-based case definition with a genotype-based case definition.

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METHODS

Genotype and surveillance records were linked by the reporting jurisdiction and the unique identifier that the reporting jurisdiction assigned to each case. Notably, the NTGS database includes genotype results for prospectively submitted isolates from culture-confirmed TB cases reported for the period 2004–2005 and retrospectively submitted isolates of select cases reported for the period 1995–2003. Conversely, the US national TB surveillance database includes all TB cases reported for the period 1993–2005.

Genotype-based case definition. M. tuberculosis complex isolates were classified as M. bovis on the basis of spoligotyping results; spoligotyping is a tool for differentiating M. bovis from M. tuberculosis that is more powerful than traditional methods [15]. This spoligotyping-based definition required either (1) the absence of spacers 3, 9, 16, and 39–43; the presence of at least 1 of the spacers 29–32; and the presence of at least 1 of the spacers 33–36; or (2) the absence of spacers 3, 9, 16, and 39–43 and ⩾2 copies of the repeated sequence at MIRU locus 24 [16]. Bacille Calmette-Guérin strains of M. bovis were defined as those meeting the above criteria and having MIRU patterns 2x2324253322, 2y2324253322, or 2z2324253322. Genotype results for Bacille Calmette-Guérin strains were excluded from analysis. Disease caused by Bacille Calmette-Guérin strains, which are used in the TB vaccine and cancer immunotherapy, is considered to be health care-associated and not to be communicable. It does not meet the US case definition for reportable TB. Spoligotyping and MIRU typing were also used to identify M. tuberculosis isolates [13] and the isolates of other species of the M. tuberculosis complex (e.g., Mycobacterium africanum [16]). Cases in which the isolate's genotype results were not identified as indicating either M. bovis or M. tuberculosis were also excluded from analysis.

All analyses were conducted using SAS, version 9.1 (SAS Institute), and for all statistical tests, results were considered to be significant if P < .05.We compared the patient and disease characteristics between M. bovis and M. tuberculosis TB cases and between M. bovis TB cases in US-born and non-US-born persons. The χ2 test and Fisher's exact test were used to detect differences in proportions of individuals. Additionally, we used the 1-sided Wilcoxon 2-sample rank-sum test to compare median values. Patient and disease factors that were statistically significant (P < .05) according to bivariate analysis were entered into a multivariate logistic regression model to determine whether any were independently associated with M. bovis versus M. tuberculosis TB. We excluded drug resistance from the multivariate logistic regression model, because the data were incomplete. To better assess the possible routes of transmission, we restricted our multivariate analysis to either extrapulmonary or pulmonary disease only, on the basis of the assumption that extrapulmonary TB signifies foodborne transmission, whereas pulmonary TB signifies airborne transmission. We used variance inflation factors and the -2 log likelihood test to assess the model for collinearity and interaction, respectively, and then we used backward elimination to formulate the final model, keeping only statistically significant predictors (P < .05).

Evaluation of a pyrazinamide resistance-based case definition. The pyrazinamide resistance-based case definition of M. bovis TB required that patients have an isolate with test results indicating resistance to pyrazinamide and susceptibility to both isoniazid and rifampin. Pyrazinamide monoresistance is a characteristic of M. bovis, but rare instances of pyrazinamide monoresistance in M. tuberculosis isolates have been reported [17]. The sensitivity, specificity, and positive and negative predictive values of the pyrazinamide resistance-based case definition were calculated using the genotype-based case definition as the gold standard. If a case met the genotype-based case definition for M. bovis TB but its isolate was reported to be susceptible to all 3 antituberculous drugs, the appropriate jurisdiction was contacted to confirm the initially reported pyrazinamide susceptibility test results and asked to submit a DNA sample from the previously tested isolate. These samples were then studied using deletion analysis (another genotyping method that allows identification of specific M. tuberculosis complex agents [18]) and pncA gene sequencing [19].

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RESULTS

Genotype-based case definition. We excluded genotype data for 2297 (16.2%) of the 14,157 M. tuberculosis complex isolates submitted to the NTGS as of 30 June 2006. Genotype data were excluded because the reporting jurisdiction did not submit the isolate with the unique case identifier used to link genotype and corresponding surveillance data (1396 [60.8%] of 2297 cases); because multiple isolates were submitted for a given patient (764 [33.3%]); because the isolate could not be genotyped (78 [3.4%]); because the isolate was M. africanum (37 [1.6%]); because the isolate was a reference strain, indicating a false-positive result (12 [0.5%]); or because the isolate was a Bacille Calmette-Guérin strain of M. bovis (10 [0.4%]). Spoligotyping and MIRU typing results for 11,860 M. tuberculosis complex isolates were linked to corresponding surveillance data reported by 41 US states. Of the 11,860 cases, 10,319 (87.0%) were reported for the period 2004–2005 (the first 2 years of prospective genotyping); this represents 46.4% of the 22,262 culture-confirmed TB cases reported for the 2-year period. HIV status was reported for 7363 (62.1%) of the 11,860 cases. A total of 165 M. bovis TB cases were identified (table 1). Most patients were Hispanic (147 [89.1%] of 165 patients with TB due to M. bovis); of the 164 who reported a country of birth, 117 (71.3%) were born outside the United States, mainly in Mexico (102 [87.2%] of 117 patients). None of the patients with TB due to M. bovis were <1 year of age. Of the 155 M. bovis TB cases with reported pyrazinamide susceptibility results, 138 (89.0%) involved isolates that were reported to be pyrazinamide resistant.

Table 1.
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Table 1.

Characteristics of Mycobacterium bovis and Mycobacterium tuberculosis cases with a genotyped isolate, United States, 1995–2005.

In bivariate analysis, M. bovis and M. tuberculosis TB cases differed significantly with regard to patient characteristics and disease site (table 1). However, M. bovis and M. tuberculosis TB cases of pulmonary disease did not differ significantly with respect to the presence of a cavity on chest radiography or acidfast bacilli results on sputum smear, 2 factors that are associated with an increased likelihood of airborne transmission of M. tuberculosis. Neither collinearity nor significant interactions were detected in the logistic regression model that included all factors that were significant in bivariate analysis, except drug resistance. Country of birth, race/ethnicity, age, reported HIV status, and disease site were each independently associated with the outcome; thus, none of them were eliminated. Patients born outside of the United States, Hispanic patients, patients aged <15 years, patients reported to be HIV infected, and patients who had extrapulmonary disease each had increased adjusted odds of having M. bovis versus M. tuberculosis TB (table 2).

Table 2.
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Table 2.

Multivariate analysis of risk factors associated with Mycobacterium bovis versus Mycobacterium tuberculosis tuberculosis, United States, 1995–2005.

Table 3.
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Table 3.

Characteristics of Mycobacterium bovis tuberculosis cases with a genotyped isolate, by origin, United States, 1995–2005.

Although US-born and non-US-born patients with TB due to M. bovis also significantly differed with respect to some patient characteristics and disease site in bivariate analysis (table 3), low case counts precluded multivariate analysis. Among USborn patients with TB due to M. bovis who had either extrapulmonary or pulmonary disease, 29 (90.6%) of 32 Hispanic patients and 3 (50.0%) of 6 white, non-Hispanic patients had the former, a difference that was statistically significant (P = .04, by Fisher's exact test ). US-born Hispanic patients (median age, 9.5 years; range, 1–82 years) were also significantly younger than the US-born white, non-Hispanic patients (median age, 66.5 years; range, 29–87 years; P = .001).

Evaluation of a pyrazinamide resistance-based case definition. The sensitivity of the pyrazinamide resistance- based case definition with respect to the genotype-based case definition was 82.5% (95% CI, 75.3%–87.9%); 127 of 154 genotypically confirmed M. bovis isolates with reported drug susceptibility results were classified as M. bovis. Conversely, its specificity was 99.2% (95% CI, 99.0%-99.4%), because 9664 of 9738 genotypically confirmed M. tuberculosis isolates with reported drug susceptibility results were not classified as M. bovis. Finally, the positive and negative predictive values were 63.2% (95% CI, 56.1%–69.8%) and 99.7% (95% CI, 99.6%–99.8%), respectively. Twenty-seven TB cases met the genotypebased case definition but not the pyrazinamide resistance-based case definition. Ten of these cases involved isolates that were reported to be resistant to pyrazinamide and isoniazid and/or rifampin. The remaining 17 cases involved isolates that were reported to be susceptible to all 3 antituberculous drugs. Deletion analysis identified 16 (94.1%) of these 17 isolates as M. bovis and indicated that 2 cases involved mixed M. bovis and M. tuberculosis infection. Deletion analysis identified the 17th isolate as Mycobacterium caprae, another member of the M. tuberculosis complex. PncA gene sequencing indicated that all 16 isolates that were identified as M. bovis by deletion analysis were resistant to pyrazinamide; thus, at least 14 errors in pyrazinamide susceptibility testing or reporting occurred.

One US state further investigated its 6 M. bovis TB cases that met the genotype-based case definition but failed to meet the pyrazinamide resistance-based case definition, because the respective isolates were reported to be susceptible to all 3 antituberculous drugs. The state uncovered 5 reporting errors (i.e., the isolates tested resistant to pyrazinamide but were reported to be susceptible) and 1 possible testing error (i.e., the isolate had previously tested susceptible to pyrazinamide but then was found to be pyrazinamide resistant upon retesting).

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DISCUSSION

This report summarizes the findings of the first nationwide US epidemiologic study of human M. bovis TB. We found that M. bovis caused 1.4% of reported TB cases by analysis of linked national genotype and surveillance data. This percentage is consistent with what has been reported for other industrialized countries [20–23] that, like the United States, implemented control measures for M. bovis TB in the past century. We also found that patients born outside the United States, Hispanic patients, patients aged <15 years, patients reported to be HIV infected, and patients who had extrapulmonary disease were each more likely to have M. bovis TB than to have M. tuberculosis TB.

Among the US-born patients with TB due to M. bovis, white, non-Hispanic patients and Hispanic patients significantly differed with respect to disease site and age. These differences could represent 2 distinct routes of transmission of M. bovis in the United States. The pulmonary disease in white, non-Hispanic patients and the higher median age of this group (66.5 years) might indicate airborne transmission of M. bovis earlier in life—perhaps prior to the implementation of measures to control M. bovis transmission—followed by recent progression to disease. In contrast, the preponderance of extrapulmonary disease in younger, US-born Hispanic patients suggests recent transmission, and disease might be the result of foodborne exposure.

Several reports suggest that M. bovis might be transmitted to US-born Hispanic individuals via unpasteurized, contaminated dairy products from Mexico. First, M. bovis TB continues to be prevalent in dairy herds in some parts of Mexico [24], although this disease has been nearly eradicated in cattle in the United States and Canada [25]. Second, some studies suggest more specifically that unpasteurized, contaminated Mexican cheese might be the vehicle for M. bovis transmission. In 2005, the US Department of Agriculture isolated M. bovis from cheese produced in Mexico as part of its sampling program along the US-Mexican border [26]. Additionally, the epidemiologic investigation of M. bovis TB cases in New York City revealed that 19 (82.6%) of 23 patients reported eating cheese produced in Mexico while living in the United States [3]. Lastly, over twothirds of all patients with TB due to M. bovis in this study were born in Mexico. Perhaps M. bovis infection is transmitted to US-born Hispanic children who share foods (including unpasteurized, contaminated Mexican cheese) with their Mexican- born parents, who maintain the food traditions of their native country.

The generalizability of this study's findings might be limited, because NTGS coverage is incomplete; only 80% of reported TB cases are culture-confirmed [8], and not all isolates are submitted to NTGS with the reporting jurisdiction's unique case identifier used to link national genotype and surveillance data. HIV infection status was reported for ∼60% of all cases, which limited the number of cases included in the model. Moreover, culture confirmation of TB is age dependent, because obtaining sputum specimens from children aged <10 years is difficult [27]. We also were not able to study exposure to unpasteurized dairy products, travel history, or the nativity of the parents of pediatric patients with TB, because the national TB surveillance system does not collect data on these possible risk factors. However, all M. bovis isolates genotyped by NTGS were included in this study, and despite the possible limitations, the findings are consistent with those of local US studies [3,28].

A considerable number of genotypically confirmed M. bovis isolates were reported to be susceptible to pyrazinamide. Because of the natural resistance of M. bovis to pyrazinamide, we expected the percentage reported as susceptible to be close to 0%. Fourteen cases met the genotype-based case definition but failed to meet the pyrazinamide resistance-based case definition, because the isolates obtained in these cases were reported to be susceptible to pyrazinamide. Deletion analysis and pncA gene sequencing confirmed the spoligotyping and MIRU typing results that indicated that these isolates were misclassified by the pyrazinamide resistance-based case definition because of errors in pyrazinamide susceptibility testing or reporting. In addition to identifying instances of disease caused by Bacille Calmette-Guérin strains that were incorrectly reported as TB, these findings demonstrate NTGS's potential to assess the quality of national TB surveillance data. Moreover, identifying the factors that lead to errors in testing and reporting drug susceptibilities and addressing these issues are imperative because of the emerging public health threat of extensively drug-resistant TB and its drug resistance-based case definition.

Because the epidemiologic profiles of M. bovis and M. tuberculosis TB differ significantly, and because the NTGS appears to provide a systematic mechanism to identify M. bovis TB and potentially assess the quality of national TB surveillance data, we recommend conducting routine surveillance for M. bovis TB using linked national TB genotype and surveillance data. As the NTGS matures, it will become possible to validly estimate the incidence of M. bovis TB and describe its geographic distribution. Finally, additional studies are needed to establish the current US transmission dynamics of M. bovis, which, in turn, would direct the development and implementation of new and appropriate strategies to control its transmission.

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Acknowledgement

Genotyping was conducted at the California Department of Public Health and the Michigan Department of Community Health and was funded by the US Centers for Disease Control and Prevention. We thank Drs. John Jereb and Alexandre Macedo de Oliveira for their careful review and insightful comments on the manuscript.

Potential conflicts of interest. All authors: no conflicts.

  • Received January 9, 2008.
  • Accepted March 5, 2008.
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