Exogenous Reinfection as a Cause of Recurrent Tuberculosis after Curative Treatment
Annelies van Rie, M.D., Robin Warren, Ph.D., Madeleine Richardson, M.Sc., Thomas C. Victor, Ph.D., Robert P. Gie, M.D., Donald A. Enarson, M.D., Nulda Beyers, Ph.D., and Paul D. van Helden, Ph.D.
Background For decades it has been assumed that postprimarytuberculosis is usually caused by reactivation of endogenousinfection rather than by a new, exogenous infection.
Methods We performed DNA fingerprinting with restriction-fragmentlengthpolymorphism analysis on pairs of isolates of Mycobacteriumtuberculosis from 16 compliant patients who had a relapse ofpulmonary tuberculosis after curative treatment of postprimarytuberculosis. The patients lived in areas of South Africa wheretuberculosis is endemic. Medical records were reviewed for clinicaldata.
Results For 12 of the 16 patients, the restriction-fragmentlengthpolymorphism banding patterns for the isolates obtained afterthe relapse were different from those for the isolates fromthe initial tuberculous disease. This finding indicates thatreinfection was the cause of the recurrence of tuberculosisafter curative treatment. Two patients had reinfections witha multidrug-resistant strain. All 15 patients who were testedfor the human immunodeficiency virus were seronegative.
Conclusions Exogenous reinfection appears to be a major causeof postprimary tuberculosis after a previous cure in an areawith a high incidence of this disease. This finding emphasizesthe importance of achieving cures and of preventing anyone withinfectious tuberculosis from exposing others to the disease.
Postprimary tuberculosis, which occurs many years after a primaryinfection, may develop as the result of reactivation of theendogenous, primary infection or as a result of a recent exogenousinfection. Models developed by Sutherland and colleagues1 andmore recently by Vynnycky and Fine,2 based on estimates of theannual risk of infection and the incidence of tuberculosis,have suggested that the relative contribution of exogenous reinfectionincreases in parallel with the incidence of the disease. However,data for use in evaluating these statistical models have beendifficult to obtain. In only a few patients has there been reasonableproof of reinfection by a different organism after known previousinfection.
Before the introduction of antituberculous medication, therewas little recognition of the distinction between endogenousreactivation and exogenous reinfection in patients who had multipleepisodes of tuberculosis, since untreated established tuberculouslesions may be alternately active and dormant.3 Effective treatmentregimens made possible the sterilization of pulmonary lesions,but it was accepted that subsequent episodes of tuberculosiswere almost invariably caused by endogenous reactivation.4 Thecomplete sterilization of a lesion became possible with improvedtreatment regimens, especially with the introduction of rifampin,a drug with a potent sterilizing effect. With short-course combinationtherapy consisting of isoniazid, rifampin, and pyrazinamide,the relapse rate dropped from 21 percent to 1 to 2 percent.5,6,7In this era of effective treatment regimens, the notion thatmultiple episodes of tuberculosis in one patient are almostalways caused by endogenous reactivation may be questioned.It is now possible to characterize the genotype of Mycobacteriumtuberculosis by DNA fingerprinting, which can show whether anew episode of the disease is caused by infection with the samestrain that caused a previous episode or by a different strain.
In this study we used DNA fingerprinting to determine the relativefrequency of endogenous reactivation and exogenous reinfectionin patients with multiple episodes of postprimary tuberculosis.We aimed to determine the importance of this distinction interms of the definition of cure, the efficacy of current treatmentregimens, and the control of tuberculosis.
Methods
All the patients described in this report were treated in twoneighboring suburban communities in metropolitan Cape Town,South Africa. These communities have a geographic area of 2.42km2 and a population of 34,294, of whom 99.7 percent are ofmixed race. The number of reported cases of tuberculosis peryear in these two communities is very high (1000 cases per 100,000population per year).8 The birth rate is 29.3 per 1000 population,and the infant mortality rate is 38 per 1000 live births. Ingeneral, people live in poor socioeconomic conditions, althoughmost live in houses with running water and electricity. Twoprimary care clinics and an adjacent tertiary care hospitalserve the area.
Before 1996, when all the elements of the World Health Organization(WHO) strategy of directly observed short-course treatment (DOTS)were implemented, all patients were treated at one of the primarycare clinics by directly observed therapy with three drugs (patientsneeding treatment for a first episode [new patients]) or fourdrugs (patients needing treatment for a subsequent episode [returningpatients]). Until 1996, there was no systematic surveillancefor treatment failure, although for most patients a sputum samplewas examined (directly and by culture) between the fourth andsixth months. With its implementation in 1996, the WHO DOTSstrategy required an accurate recording of cases in clinic registers,the administration of directly observed therapy (four drugsfor new patients and five drugs for returning patients), andsurveillance for treatment outcome, including treatment failure.Except for multidrug-resistant infections, there was no surveillancefor relapse.
Patients
Patients included in this study had at least two episodes ofpostprimary pulmonary tuberculosis within the study period (betweenSeptember 1992 and May 1998), with cultures from the two mostrecent successive episodes (referred to as first and secondepisodes) available for restriction-fragmentlength polymorphism(RFLP) analysis and with cure as the outcome of the first episode.Extensive clinical histories of the included patients were obtainedand included data on age, sex, medical history, status withregard to infection with the human immunodeficiency virus (HIV),findings on chest radiography, the results of sputum stainingand cultures, drug sensitivities, treatment, and outcome. Accordingto WHO criteria, cure was defined as the completion of a courseof six to eight months of directly observed combination therapy(with isoniazid, rifampin, and pyrazinamide in a single tablet),compliance (attendance for the course of therapy, with at least80 percent of prescribed doses taken), and a sputum culturepositive for M. tuberculosis at diagnosis and at least one negativesputum culture at the end of treatment. All patients who neededtreatment for a subsequent episode but who did not meet thecriteria for previous cure were excluded from the study.
M. tuberculosis Isolates
Sputum samples were stained and cultured at the laboratory thatroutinely served the clinics. Drug-susceptibility testing wasperformed by the indirect-proportion method in accordance withthe guidelines of the South African National Tuberculosis Program.In September 1992, in the Cape Town communities described above,we initiated a prospective study in which all cultures positivefor M. tuberculosis from patients residing in these communitieswere genotyped by RFLP and a data base of the results was established.To evaluate the representativeness of the patients includedin the RFLP data base, they were compared with patients whohad positive cultures in the district tuberculosis registerfor the period from January 1996 through May 1998 with regardto the clinical classification. The percentage of cultures obtainedfor RFLP analysis was calculated for both new and returningpatients. These data were also used to calculate the annualnumber of cases of culture-positive pulmonary tuberculosis per100,000 population.
Isolates of M. tuberculosis were genotyped by RFLP accordingto an internationally standardized method,9 and the resultswere analyzed with GelCompar software (version 4.0, AppliedMaths BVBA, Kortrijk, Belgium). For the RFLP data base, theextent of accumulated laboratory error was calculated by comparingsuccessive DNA fingerprints for serial isolates collected duringthe first two months of treatment, according to the followingformula: laboratory error rate equals the number of isolateswith DNA fingerprints that failed to match the DNA fingerprintsof the subsequent isolate, divided by the total number of serialisolates analyzed. To exclude the possibility of mixed infection,DNA was isolated from the entire culture, and all RFLP patternswere carefully analyzed to identify any background bands reflectingdifferent strains. Analysis of the complete RFLP data base identifiedonly five isolates with background bands. These isolates wereexcluded from further analysis.
The isolates included in this study were analyzed as follows.Genomic DNA was digested with PvuII or HinfI, electrophoreticallyfractionated, and transferred to Hybond-N+ membranes (Amersham,Buckinghamshire, United Kingdom). The PvuII digests were hybridizedwith an IS6110 3' probe (complementary to the IS6110 domainbetween nucleotides 631 and 875) that had been labeled by enhancedchemiluminescence. The HinfI digests were hybridized with a32P-labeled MTB484(1) probe.10 The respective RFLP patternswere visualized by autoradiography. The IS6110 3' DNA fingerprintsfrom each patient's isolates were compared with those in thecomplete RFLP data base (with data gathered from September 1992through May 1998) by means of the clustering formula known asthe "unweighted pair-group method using arithmetic averages"and the Dice coefficient to determine whether the isolates belongedto a cluster (suggesting infection by recent transmission) orwere unique (suggesting reactivation of a latent infection)within the communities studied.
A patient whose isolates of M. tuberculosis from the first andsecond episodes of postprimary tuberculosis were identical onRFLP analysis with each DNA probe was considered to have tuberculosisdue to reactivation of endogenous infection. A patient whoseisolates from the first and second episodes of postprimary tuberculosiswere different was considered to have tuberculosis due to anew, exogenous infection.
Results
The rate of reported cases of culture-positive pulmonary tuberculosisfrom January 1996 through May 1998 was estimated to be veryhigh (225 cases per 100,000 population per year for new casesand 251 per 100,000 per year for all true incident cases) (Table 1).
Table 1. Distribution of Patients with Tuberculosis for Whom Cultures Were Available for Analysis, According to Source of Information.
During the study period (September 1992 through May 1998), DNAfrom cultures of M. tuberculosis was available for at leastone RFLP analysis for 698 patients. For the period from January1996 (when reliable information became available for case notificationas a result of the implementation of the DOTS strategy) throughMay 1998, the average rate of recovery of cultures of M. tuberculosisfor RFLP analysis was estimated to be 82 percent (83 percentfor new patients, 67 percent for patients needing retreatmentafter cure, and 84 percent for other patients needing retreatment)(Table 1). DNA from at least one episode was available for RFLPanalysis for 48 patients considered to have tuberculosis requiringretreatment after cure. However, in only 16 of these 48 patientswere the results of the RFLP analysis for two episodes available,and these 16 patients thus met the requirements for inclusionin the study: two episodes of postprimary pulmonary tuberculosiswithin the study period and cure as the outcome of the firstof those two episodes.
The median age of these 16 patients was 35 years; 9 were womenand 7 were men (Table 2). The median interval between cure andsubsequent diagnosis (isolation of a subsequent culture-positivespecimen) was 25.5 months. Fifteen patients (94 percent) weretested for HIV infection, and all 15 tested negative. None ofthe patients had a medical history of diabetes, end-stage renaldisease, or cancer or had been treated with immunosuppressivedrugs. Chest radiographs revealed evidence of cavitary diseasein 11 patients during the first episode of tuberculosis andin 12 during the second episode of tuberculosis.
Table 2. Epidemiologic and Clinical Characteristics of 16 Patients with Postprimary Pulmonary Tuberculosis after Previous Cure.
For 12 of the 16 patients, the RFLP patterns of the strainsof M. tuberculosis responsible for the disease differed betweenthe two episodes, indicating exogenous reinfection (Table 2and Figure 1). For the other four patients, the RFLP patternsof the M. tuberculosis strains were identical for the two episodes,indicating endogenous reactivation. Of the 16 patients, 4 haddrug-resistant tuberculosis during the second episode (Table 2),which in 2 patients was caused by exogenous reinfectionwith a multidrug-resistant strain and in the other 2 patients(both resistant to only isoniazid) was caused by endogenousreactivation. In one of the latter two patients, drug-susceptibilitytesting performed during the first episode identified a fullydrug-sensitive organism. However, during an episode before thetwo described in this study, resistance to isoniazid had beendiagnosed. During the episode after cure, drug resistance wasproved in only one of five cultures obtained, indicating thatthe resistance to isoniazid was borderline. In the other patient,no drug-susceptibility testing was performed on the isolatefrom the first episode.
Figure 1. Restriction-FragmentLength Polymorphism Patterns of 14 Pairs of Isolates of M. tuberculosis from Patients with Recurrence of Tuberculosis after Cure.
Lanes 1 to 14 show serial isolates from Patients 1 to 14, respectively. Lanes labeled R correspond to control cultures (strain MTB 14323).
Because exogenous reinfection most likely results from closecontact with an adult who has active infection, isolates fromthe 12 patients with reinfection were studied in relation tothe complete RFLP data base for the two communities (coveringSeptember 1992 through May 1998 and including 698 patients).It was found that 11 of the 12 isolates obtained during thesecond episode of tuberculosis from patients who had exogenousreinfection belonged to a cluster of strains present in thecommunities; for the remaining isolate no matching strain wasidentified in the data base.
Of the four patients with tuberculosis due to reactivation,two were older than the median age and two younger. The intervalfrom cure to reactivation was longer than the median intervalin one patient and less than the median in the other three.All four patients were infected with a strain that belongedto a cluster circulating in the community during their respectivedisease-free intervals.
Discussion
Using DNA fingerprinting, we found evidence that exogenous reinfectioncan have a dominant role in the pathogenesis of postprimarytuberculosis in adults in an area with a high incidence of thedisease.1,2,11 To our knowledge, there have been only two otherreports of RFLP analysis of isolates from patients with repeatedepisodes of tuberculosis who were living in a high-incidencearea.12,13 These studies suggested that under conditions ofendemic disease, the rate of endogenous reactivation far exceedsthe rate of exogenous reinfection. However, these reports donot include a definition of cure or detailed information onthe patients' drug regimens, compliance, or immune status. Furthermore,15 patients (34 percent)12 and 40 patients (49 percent)13 wereexcluded because only a single culture was positive and thepossibility of laboratory contamination was raised. If theyhad not been excluded, 90 percent of these patients would havebeen classified as having disease due to exogenous reinfection.Their exclusion might therefore have biased the results towardthe importance of endogenous reactivation.
In our study, the rate of recovery of cultures of M. tuberculosisfor RFLP analysis was lower for patients needing retreatmentafter cure than for other patients. The reason for this differenceis not clear; it was not the result of any deliberate policy.The results of the study must, however, be viewed with cautionbecause of the possibility of some unintentional bias. Nevertheless,there is no reason to suppose that strains from cases due toreinfection would be preferentially recovered as compared withthose from cases due to reactivation, a condition necessaryfor such a bias.
In our study, we did not exclude patients with only a singlepositive culture, for the following reasons. It has been shownthat tuberculous lesions can yield an isolated positive culture.14There was no evidence of false positive cultures: all the patientsreceived a diagnosis of active tuberculosis for both episodeson the basis of positive sputum-test results, the findings onchest radiographs, and the clinical history. The complete RFLPdata base was analyzed to assess the extent of laboratory contamination,and the rate of accumulated error was found to be only 3.4 percent(17 discordant results among 499 serial isolates). On the basisof this error rate, it is possible that results for 1 isolate(3.4 percent of 32 isolates) may have been erroneous. Therefore,we believe that it is unlikely that the classification of diseaseas due to exogenous reinfection reflects extensive laboratoryerror, such as error due to cross-contamination or mixed infectionat the first episode. This argument is further supported bythe observation that in 11 of the 12 cases of exogenous reinfection,the strain responsible for reinfection was identified as oneof a cluster of strains present in the communities. Only oneisolate was retrieved from a patient with reinfection for whomthere was no matching isolate in the entire data base. Thispatient appears to have been reinfected outside the communitiesor by an undetected source within the communities.
All four patients who were found to have disease due to reactivationwere infected with individual strains that belonged to a clustercirculating within the communities during these patients' respectivedisease-free intervals. The molecular definition of exogenousreinfection used in this study excludes the possibility of exogenousreinfection with the same strain. Therefore, it is possiblethat some of the patients considered to have reactivation actuallyhad new, exogenous infection with the same strain. Our resultsmay thus underestimate the extent of exogenous reinfection.
It has generally been believed that reinfection is more difficultto confirm than primary infection, because of the immune responseto M. tuberculosis antigens that develops after primary infection.There are no empirical data on the changes in the level of immunityover time, but it is assumed that in immunocompetent persons,reinfection is rare during the first two to five years aftera first infection.2 In our study, cases of reactivation tendedto occur soon after the previous episode was cured, but manyof the cases due to reinfection also occurred early after aprevious cure. It has been shown in persons infected with HIVthat reinfection can occur not only years after a previous infection(or episode of disease) but even during treatment for activetuberculosis.15 In our study, in which all the patients testedfor HIV infection were negative, reinfection occurred as littleas seven and eight months after a previous cure. These resultssuggest that in immunocompetent persons living in an area wheretuberculosis is endemic, reinfection and progression to activedisease may occur at any time after treatment has been discontinued.
In patients previously treated and cured, a subsequent episodewould be expected to represent endogenous reactivation. We foundthat exogenous reinfection has a predominant role in this populationof patients, who have multiple episodes of active tuberculosis.In areas with a high incidence of tuberculosis, exogenous reinfectionmight also be a cause of the first episode of postprimary tuberculosis,since the immunity that develops after primary infection followedby a period of latency cannot be expected to confer more protectionagainst exogenous reinfection than the immunity that developsafter an episode of active disease.
The controversy with regard to endogenous as opposed to exogenouspathogenesis of tuberculosis is of importance in the planningof clinical trials and national tuberculosis-control programs.If, in areas with a high incidence of the disease, postprimaryepisodes of pulmonary tuberculosis after previous cure resultpredominantly from exogenous reinfection, as indicated by ourresults, the effectiveness of a drug regimen cannot be evaluatedon the basis of the relapse rate without the additional informationprovided by RFLP analysis of bacterial isolates. In the evaluationof national tuberculosis-control programs for areas in whichthe disease is endemic, RFLP analysis can prove the effectivenessof the currently used treatment regimens. "Cure" in a patientwho later has another episode of tuberculosis is not necessarilyan incorrect concept. The more likely possibility is that heor she has a new infection after the cure. The emphasis shouldthus be placed on achieving cure in patients and on prompt casedetection to prevent reexposure to sources of active tuberculosis.
Supported by the Collen Research Foundation, Leuven, Belgium,and the GlaxoWellcome Action TB Initiative.
We are indebted to the technical, secretarial, and nursing staffof the tuberculosis research team; to Gian van der Spuy forassistance with computer analysis; to Dr. I. Toms, Health Services,Tygerberg, South Africa; and to Joske Trappeniers.
Source Information
From the Department of Pediatrics and Child Health (A.V.R., R.P.G., N.B.) and the Medical Research Council Center for Molecular and Cellular Biology and the Department of Medical Biochemistry (R.W., M.R., T.C.V., P.D.V.H.), University of Stellenbosch, Tygerberg, South Africa; the Department of Pediatrics, Catholic University Leuven, Leuven, Belgium (A.V.R.); and the International Union against Tuberculosis and Lung Disease, Paris (D.A.E.).
Address reprint requests to Dr. van Helden at the Department of Medical Biochemistry, University of Stellenbosch, P.O. Box 19063, Tygerberg 7505, South Africa, or at pvh{at}gerga.sun.ac.za.
References
Canetti G, Sutherland I, Svandova E. Endogenous reactivation and exogenous reinfection: their relative importance with regard to the development of non-primary tuberculosis. Bull Int Union Tuberc 1972;47:116-134. [Medline]
Vynnycky E, Fine PEM. The natural history of tuberculosis: the implications of age-dependent risks of disease and the role of reinfection. Epidemiol Infect 1997;119:183-201. [CrossRef][Medline]
Katz HL. Reactivations of tuberculous disease in 250 consecutive surgical resections in 248 cases followed from one to six years. In: Veterans Administration-Armed Forces, National Tuberculosis Association. Transactions of the 17th Conference on the Chemotherapy of Tuberculosis. Washington, D.C.: Government Printing Office, 1958:214-7.
Hong Kong Chest Service/British Medical Research Council. Controlled trial of 4 three-times-weekly regimens and a daily regimen all given for 6 months for pulmonary tuberculosis: second report: the results up to 24 months. Tubercle 1982;63:89-98. [Medline]
British Thoracic Association. A controlled trial of six months chemotherapy in pulmonary tuberculosis: second report: results during the 24 months after the end of chemotherapy. Am Rev Respir Dis 1982;126:460-462. [Medline]
Hong Kong Chest Service/British Medical Research Council. Controlled trial of 6-month and 9-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong: the results up to 30 months. Am Rev Respir Dis 1977;115:727-735. [Medline]
Beyers N, Gie RP, Zietsman L, et al. The use of a geographical information system (GIS) to evaluate the distribution of tuberculosis in a high-incidence community. S Afr Med J 1996;86:40-44. [Medline]
van Embden JDA, Cave MD, Crawford JT, et al. Strain identification of Mycobacterium tuberculosis by DNA fingerprinting: recommendations for a standardized methodology. J Clin Microbiol 1993;31:406-409. [Free Full Text]
Warren R, Richardson M, Sampson S, et al. Genotyping of Mycobacterium tuberculosis with additional markers enhances accuracy in epidemiological studies. J Clin Microbiol 1996;34:2219-2224. [Abstract]
Styblo K. Epidemiology of tuberculosis: selected papers. Proc Tuberc Res Counc 1991;24:62-6.
Sahadevan R, Narayanan S, Paramasivan CN, Prabhakar R, Narayanan PR. Restriction fragment length polymorphism typing of clinical isolates of Mycobacterium tuberculosis from patients with pulmonary tuberculosis in Madras, India, by use of direct-repeat probe. J Clin Microbiol 1995;33:3037-3039. [Abstract]
Das S, Chan SL, Allen BW, Mitchison DA, Lowrie DB. Application of DNA fingerprinting with IS986 to sequential mycobacterial isolates obtained from pulmonary tuberculosis patients in Hong Kong before, during and after short-course chemotherapy. Tuber Lung Dis 1993;74:48-51.
Mitchison DA, Keyes AB, Edwards EA, Ayuma P, Byfield SP, Nunn AJ. Quality control in tuberculosis bacteriology. 2. The origin of isolated positive cultures from the sputum of patients in four studies of short course chemotherapy in Africa. Tubercle 1980;61:135-144. [CrossRef][Medline]
Small PM, Shafer RW, Hopewell PC, et al. Exogenous reinfection with multidrug-resistant Mycobacterium tuberculosis in patients with advanced HIV infection. N Engl J Med 1993;328:1137-1144. [Free Full Text]
Uys, P. W., Warren, R., van Helden, P. D., Murray, M., Victor, T. C.
(2009). Potential of Rapid Diagnosis for Controlling Drug-Susceptible and Drug-Resistant Tuberculosis in Communities Where Mycobacterium tuberculosis Infections Are Highly Prevalent. J. Clin. Microbiol.
47: 1484-1490
[Abstract][Full Text]
Marais, B. J., Parker, S. K., Verver, S., van Rie, A., Warren, R. M.
(2009). Primary and Postprimary or Reactivation Tuberculosis: Time to Revise Confusing Terminology?. Am. J. Roentgenol.
192: W198-W198
[Full Text]
Jeong, Y. J., Koh, W.-J., Lee, K. S.
(2009). Reply. Am. J. Roentgenol.
192: W199-W200
[Full Text]
Bhatt, K., Uzelac, A., Mathur, S., McBride, A., Potian, J., Salgame, P.
(2009). B7 Costimulation Is Critical for Host Control of Chronic Mycobacterium tuberculosis Infection. J. Immunol.
182: 3793-3800
[Abstract][Full Text]
Uys, P. W, van Helden, P. D, Hargrove, J. W
(2009). Tuberculosis reinfection rate as a proportion of total infection rate correlates with the logarithm of the incidence rate: a mathematical model. J R Soc Interface
6: 11-15
[Abstract][Full Text]
Dobler, C. C., Crawford, A. B. H., Jelfs, P. J., Gilbert, G. L., Marks, G. B.
(2009). Recurrence of tuberculosis in a low-incidence setting. Eur Respir J
33: 160-167
[Abstract][Full Text]
Gupta, A., Geetha, N., Mani, J., Upadhyay, P., Katoch, V. M., Natrajan, M., Gupta, U. D., Bhaskar, S.
(2009). Immunogenicity and Protective Efficacy of "Mycobacterium w" against Mycobacterium tuberculosis in Mice Immunized with Live versus Heat-Killed M. w by the Aerosol or Parenteral Route. Infect. Immun.
77: 223-231
[Abstract][Full Text]
Hanekom, M., van der Spuy, G. D., van Pittius, N. C. G., McEvoy, C. R. E., Hoek, K. G. P., Ndabambi, S. L., Jordaan, A. M., Victor, T. C., van Helden, P. D., Warren, R. M.
(2008). Discordance between Mycobacterial Interspersed Repetitive-Unit-Variable-Number Tandem-Repeat Typing and IS6110 Restriction Fragment Length Polymorphism Genotyping for Analysis of Mycobacterium tuberculosis Beijing Strains in a Setting of High Incidence of Tuberculosis . J. Clin. Microbiol.
46: 3338-3345
[Abstract][Full Text]
Rieder, H. L
(2008). Commentary: Reconciling historical epidemiological, bacteriological and immunological observations in tuberculosis. Int J Epidemiol
37: 932-934
[Full Text]
Gallegos, A. M., Pamer, E. G., Glickman, M. S.
(2008). Delayed protection by ESAT-6-specific effector CD4+ T cells after airborne M. tuberculosis infection. JEM
205: 2359-2368
[Abstract][Full Text]
Cacho, J., Perez Meixeira, A., Cano, I., Soria, T., Ramos Martos, A., Sanchez Concheiro, M., Samper, S., Gavin, P., Martin, C.
(2007). Recurrent tuberculosis from 1992 to 2004 in a metropolitan area. Eur Respir J
30: 333-337
[Abstract][Full Text]
Lai, Y.-M., Mohammed, K. A., Nasreen, N., Baumuratov, A., Bellew, B. F., Antony, V. B.
(2007). Induction of cell cycle arrest and apoptosis by BCG infection in cultured human bronchial airway epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol.
293: L393-L401
[Abstract][Full Text]
Nahid, P., Gonzalez, L. C., Rudoy, I., de Jong, B. C., Unger, A., Kawamura, L. M., Osmond, D. H., Hopewell, P. C., Daley, C. L.
(2007). Treatment Outcomes of Patients with HIV and Tuberculosis. Am. J. Respir. Crit. Care Med.
175: 1199-1206
[Abstract][Full Text]
Theus, S. A., Cave, M. D., Eisenach, K., Walrath, J., Lee, H., Mackay, W., Whalen, C., Silver, R. F.
(2006). Differences in the Growth of Paired Ugandan Isolates of Mycobacterium tuberculosis within Human Mononuclear Phagocytes Correlate with Epidemiological Evidence of Strain Virulence. Infect. Immun.
74: 6865-6876
[Abstract][Full Text]
Kamath, A., Woodworth, J. S.M., Behar, S. M.
(2006). Antigen-Specific CD8+ T Cells and the Development of Central Memory during Mycobacterium tuberculosis Infection. J. Immunol.
177: 6361-6369
[Abstract][Full Text]
Mathema, B., Kurepina, N. E., Bifani, P. J., Kreiswirth, B. N.
(2006). Molecular Epidemiology of Tuberculosis: Current Insights. Clin. Microbiol. Rev.
19: 658-685
[Abstract][Full Text]
Cohen, T., Lipsitch, M., Walensky, R. P., Murray, M.
(2006). Beneficial and perverse effects of isoniazid preventive therapy for latent tuberculosis infection in HIV-tuberculosis coinfected populations. Proc. Natl. Acad. Sci. USA
103: 7042-7047
[Abstract][Full Text]
Garcia de Viedma, D., Alonso Rodriguez, N., Andres, S., Ruiz Serrano, M. J., Bouza, E.
(2005). Characterization of Clonal Complexity in Tuberculosis by Mycobacterial Interspersed Repetitive Unit-Variable-Number Tandem Repeat Typing. J. Clin. Microbiol.
43: 5660-5664
[Abstract][Full Text]
(2005). American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Controlling Tuberculosis in the United States. Am. J. Respir. Crit. Care Med.
172: 1169-1227
[Full Text]
Huang, T.-S., Chen, Y.-S., Lee, S. S.-J., Tu, H.-Z., Liu, Y.-C.
(2005). Preservation of Clinical Isolates of Mycobacterium tuberculosis Complex Directly from MGIT Culture Tubes. Annals of Clinical & Laboratory Science
35: 455-458
[Abstract][Full Text]
van Rie, A., Victor, T. C., Richardson, M., Johnson, R., van der Spuy, G. D., Murray, E. J., Beyers, N., van Pittius, N. C. G., van Helden, P. D., Warren, R. M.
(2005). Reinfection and Mixed Infection Cause Changing Mycobacterium tuberculosis Drug-Resistance Patterns. Am. J. Respir. Crit. Care Med.
172: 636-642
[Abstract][Full Text]
Rivas-Santiago, B., Schwander, S. K., Sarabia, C., Diamond, G., Klein-Patel, M. E., Hernandez-Pando, R., Ellner, J. J., Sada, E.
(2005). Human {beta}-Defensin 2 Is Expressed and Associated with Mycobacterium tuberculosis during Infection of Human Alveolar Epithelial Cells. Infect. Immun.
73: 4505-4511
[Abstract][Full Text]
Lienhardt, C, Fielding, K, Sillah, J., Bah, B, Gustafson, P, Warndorff, D, Palayew, M, Lisse, I, Donkor, S, Diallo, S, Manneh, K, Adegbola, R, Aaby, P, Bah-Sow, O, Bennett, S, McAdam, K
(2005). Investigation of the risk factors for tuberculosis: a case-control study in three countries in West Africa. Int J Epidemiol
34: 914-923
[Abstract][Full Text]
Jung, Y.-J., Ryan, L., LaCourse, R., North, R. J.
(2005). Properties and protective value of the secondary versus primary T helper type 1 response to airborne Mycobacterium tuberculosis infection in mice. JEM
201: 1915-1924
[Abstract][Full Text]
Verver, S., Warren, R. M., Beyers, N., Richardson, M., van der Spuy, G. D., Borgdorff, M. W., Enarson, D. A., Behr, M. A., van Helden, P. D.
(2005). Rate of Reinfection Tuberculosis after Successful Treatment Is Higher than Rate of New Tuberculosis. Am. J. Respir. Crit. Care Med.
171: 1430-1435
[Abstract][Full Text]
Keane, J.
(2005). TNF-blocking agents and tuberculosis: new drugs illuminate an old topic. Rheumatology (Oxford)
44: 714-720
[Abstract][Full Text]
Caminero, J. A.
(2005). Management of multidrug-resistant tuberculosis and patients in retreatment. Eur Respir J
25: 928-936
[Abstract][Full Text]
Jasmer, R. M., Bozeman, L., Schwartzman, K., Cave, M. D., Saukkonen, J. J., Metchock, B., Khan, A., Burman, W. J., the Tuberculosis Trials Consortium,
(2004). Recurrent Tuberculosis in the United States and Canada: Relapse or Reinfection?. Am. J. Respir. Crit. Care Med.
170: 1360-1366
[Abstract][Full Text]
Cardona, P-J., Ruiz-Manzano, J.
(2004). On the nature of Mycobacterium tuberculosis-latent bacilli. Eur Respir J
24: 1044-1051
[Abstract][Full Text]
Wherry, E. J., Barber, D. L., Kaech, S. M., Blattman, J. N., Ahmed, R.
(2004). Antigen-independent memory CD8 T cells do not develop during chronic viral infection. Proc. Natl. Acad. Sci. USA
101: 16004-16009
[Abstract][Full Text]
Young, S. K., Taylor, G. M., Jain, S., Suneetha, L. M., Suneetha, S., Lockwood, D. N. J., Young, D. B.
(2004). Microsatellite Mapping of Mycobacterium leprae Populations in Infected Humans. J. Clin. Microbiol.
42: 4931-4936
[Abstract][Full Text]
Hisert, K. B., Kirksey, M. A., Gomez, J. E., Sousa, A. O., Cox, J. S., Jacobs, W. R. Jr., Nathan, C. F., McKinney, J. D.
(2004). Identification of Mycobacterium tuberculosis Counterimmune (cim) Mutants in Immunodeficient Mice by Differential Screening. Infect. Immun.
72: 5315-5321
[Abstract][Full Text]
Garcia de Viedma, D., Marin, M., Ruiz, M. J., Bouza, E.
(2004). Analysis of Clonal Composition of Mycobacterium tuberculosis Isolates in Primary Infections in Children. J. Clin. Microbiol.
42: 3415-3418
[Abstract][Full Text]
Cangelosi, G. A., Freeman, R. J., Lewis, K. N., Livingston-Rosanoff, D., Shah, K. S., Milan, S. J., Goldberg, S. V.
(2004). Evaluation of a High-Throughput Repetitive-Sequence-Based PCR System for DNA Fingerprinting of Mycobacterium tuberculosis and Mycobacterium avium Complex Strains. J. Clin. Microbiol.
42: 2685-2693
[Abstract][Full Text]
Clark, M., Vynnycky, E.
(2004). The use of maximum likelihood methods to estimate the risk of tuberculous infection and disease in a Canadian First Nations population. Int J Epidemiol
33: 477-484
[Abstract][Full Text]
Lauterbach, H., Kerksiek, K. M., Busch, D. H., Berto, E., Bozac, A., Mavromara, P., Manservigi, R., Epstein, A. L., Marconi, P., Brocker, T.
(2004). Protection from Bacterial Infection by a Single Vaccination with Replication-Deficient Mutant Herpes Simplex Virus Type 1. J. Virol.
78: 4020-4028
[Abstract][Full Text]
Verver, S., Warren, R. M, Munch, Z., Vynnycky, E., van Helden, P. D, Richardson, M., van der Spuy, G. D, Enarson, D. A, Borgdorff, M. W, Behr, M. A, Beyers, N.
(2004). Transmission of tuberculosis in a high incidence urban community in South Africa. Int J Epidemiol
33: 351-357
[Abstract][Full Text]
Milan, S. J., Hauge, K. A., Kurepina, N. E., Lofy, K. H., Goldberg, S. V., Narita, M., Nolan, C. M., McElroy, P. D., Kreiswirth, B. N., Cangelosi, G. A.
(2004). Expanded Geographical Distribution of the N Family of Mycobacterium tuberculosis Strains within the United States. J. Clin. Microbiol.
42: 1064-1068
[Abstract][Full Text]
Behr, M. A.
(2004). Tuberculosis due to Multiple Strains: A Concern for the Patient? A Concern for Tuberculosis Control?. Am. J. Respir. Crit. Care Med.
169: 554-555
[Full Text]
Warren, R. M., Victor, T. C., Streicher, E. M., Richardson, M., Beyers, N., van Pittius, N. C. G., van Helden, P. D.
(2004). Patients with Active Tuberculosis often Have Different Strains in the Same Sputum Specimen. Am. J. Respir. Crit. Care Med.
169: 610-614
[Abstract][Full Text]
Seidler, A, Nienhaus, A, Diel, R
(2004). The transmission of tuberculosis in the light of new molecular biological approaches. Occup. Environ. Med.
61: 96-102
[Abstract][Full Text]
Ranjbar, S., Ly, N., Thim, S., Reynes, J.-M., Goldfeld, A. E.
(2004). Mycobacterium tuberculosis Recall Antigens Suppress HIV-1 Replication in Anergic Donor Cells via CD8+ T Cell Expansion and Increased IL-10 Levels. J. Immunol.
172: 1953-1959
[Abstract][Full Text]
Kotlowski, R., Shamputa, I. C., El Aila, N. A., Sajduda, A., Rigouts, L., van Deun, A., Portaels, F.
(2004). PCR-Based Genotyping of Mycobacterium tuberculosis with New GC-Rich Repeated Sequences and IS6110 Inverted Repeats Used as Primers. J. Clin. Microbiol.
42: 372-377
[Abstract][Full Text]
van der Spuy, G. D., Warren, R. M., Richardson, M., Beyers, N., Behr, M. A., van Helden, P. D.
(2003). Use of Genetic Distance as a Measure of Ongoing Transmission of Mycobacterium tuberculosis. J. Clin. Microbiol.
41: 5640-5644
[Abstract][Full Text]
Guwatudde, D., Nakakeeto, M., Jones-Lopez, E. C., Maganda, A., Chiunda, A., Mugerwa, R. D., Ellner, J. J., Bukenya, G., Whalen, C. C.
(2003). Tuberculosis in Household Contacts of Infectious Cases in Kampala, Uganda. Am J Epidemiol
158: 887-898
[Abstract][Full Text]
Barnes, P. F., Cave, M. D.
(2003). Molecular Epidemiology of Tuberculosis. NEJM
349: 1149-1156
[Full Text]
Nguyen, D., Brassard, P., Westley, J., Thibert, L., Proulx, M., Henry, K., Schwartzman, K., Menzies, D., Behr, M. A.
(2003). Widespread Pyrazinamide-Resistant Mycobacterium tuberculosis Family in a Low-Incidence Setting. J. Clin. Microbiol.
41: 2878-2883
[Abstract][Full Text]
Salazar, L., Guerrero, E., Casart, Y., Turcios, L., Bartoli, F.
(2003). Transcription analysis of the dnaA gene and oriC region of the chromosome of Mycobacterium smegmatis and Mycobacterium bovis BCG, and its regulation by the DnaA protein. Microbiology
149: 773-784
[Abstract][Full Text]
(2003). American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of Tuberculosis. Am. J. Respir. Crit. Care Med.
167: 603-662
[Full Text]
Kaufmann, S. H.E., Schaible, U. E.
(2003). A Dangerous Liaison between Two Major Killers: Mycobacterium tuberculosis and HIV Target Dendritic Cells through DC-SIGN. JEM
197: 1-5
[Full Text]
Savine, E., Warren, R. M., van der Spuy, G. D., Beyers, N., van Helden, P. D., Locht, C., Supply, P.
(2002). Stability of Variable-Number Tandem Repeats of Mycobacterial Interspersed Repetitive Units from 12 Loci in Serial Isolates of Mycobacterium tuberculosis. J. Clin. Microbiol.
40: 4561-4566
[Abstract][Full Text]
Warren, R. M., Streicher, E. M., Charalambous, S., Churchyard, G., van der Spuy, G. D., Grant, A. D., van Helden, P. D., Victor, T. C.
(2002). Use of Spoligotyping for Accurate Classification of Recurrent Tuberculosis. J. Clin. Microbiol.
40: 3851-3853
[Abstract][Full Text]
de Viedma, D. G., Marin, M., Hernangomez, S., Diaz, M., Serrano, M. J. R., Alcala, L., Bouza, E.
(2002). Tuberculosis Recurrences: Reinfection Plays a Role in a Population Whose Clinical/Epidemiological Characteristics Do Not Favor Reinfection. Arch Intern Med
162: 1873-1879
[Abstract][Full Text]
Richardson, M., Carroll, N. M., Engelke, E., van der Spuy, G. D., Salker, F., Munch, Z., Gie, R. P., Warren, R. M., Beyers, N., van Helden, P. D.
(2002). Multiple Mycobacterium tuberculosis Strains in Early Cultures from Patients in a High-Incidence Community Setting. J. Clin. Microbiol.
40: 2750-2754
[Abstract][Full Text]
Hernandez-Garduno, E., Kunimoto, D., Wang, L., Rodrigues, M., Elwood, R. K., Black, W., Mak, S., FitzGerald, J. M.
(2002). Predictors of clustering of tuberculosis in Greater Vancouver: a molecular epidemiologic study. CMAJ
167: 349-352
[Abstract][Full Text]
Repique, C. J., Li, A., Collins, F. M., Morris, S. L.
(2002). DNA Immunization in a Mouse Model of Latent Tuberculosis: Effect of DNA Vaccination on Reactivation of Disease and on Reinfection with a Secondary Challenge. Infect. Immun.
70: 3318-3323
[Abstract][Full Text]
Delgado, J. C., Tsai, E. Y., Thim, S., Baena, A., Boussiotis, V. A., Reynes, J.-M., Sath, S., Grosjean, P., Yunis, E. J., Goldfeld, A. E.
(2002). Antigen-specific and persistent tuberculin anergy in a cohort of pulmonary tuberculosis patients from rural Cambodia. Proc. Natl. Acad. Sci. USA
99: 7576-7581
[Abstract][Full Text]
Warren, R. M., van der Spuy, G. D., Richardson, M., Beyers, N., Borgdorff, M. W., Behr, M. A., van Helden, P. D.
(2002). Calculation of the Stability of the IS6110 Banding Pattern in Patients with Persistent Mycobacterium tuberculosis Disease. J. Clin. Microbiol.
40: 1705-1708
[Abstract][Full Text]
van Crevel, R., Ottenhoff, T. H. M., van der Meer, J. W. M.
(2002). Innate Immunity to Mycobacterium tuberculosis. Clin. Microbiol. Rev.
15: 294-309
[Abstract][Full Text]
Warren, R. M., van der Spuy, G. D., Richardson, M., Beyers, N., Booysen, C., Behr, M. A., van Helden, P. D.
(2002). Evolution of the IS6110-Based Restriction Fragment Length Polymorphism Pattern during the Transmission of Mycobacterium tuberculosis. J. Clin. Microbiol.
40: 1277-1282
[Abstract][Full Text]
Murray, M., Alland, D.
(2002). Methodological Problems in the Molecular Epidemiology of Tuberculosis. Am J Epidemiol
155: 565-571
[Abstract][Full Text]
Hoey, J.
(2002). Can you get tuberculosis twice?. CMAJ
166: 478-478
[Full Text]
(2002). Tuberculosis and HIV. AIDS Clin Care
2002: 6-6
[Full Text]
Golub, J. E., Cronin, W. A., Obasanjo, O. O., Coggin, W., Moore, K., Pope, D. S., Thompson, D., Sterling, T. R., Harrington, S., Bishai, W. R., Chaisson, R. E.
(2001). Transmission of Mycobacterium tuberculosis Through Casual Contact With an Infectious Case. Arch Intern Med
161: 2254-2258
[Abstract][Full Text]
CAMINERO, J. A., PENA, M. J., CAMPOS-HERRERO, M. I., RODRIGUEZ, J. C., GARCIA, I., CABRERA, P., LAFOZ, C., SAMPER, S., TAKIFF, H., AFONSO, O., PAVON, J. M., TORRES, M. J., SOOLINGEN, D. V., ENARSON, D. A., MARTIN, C.
(2001). Epidemiological Evidence of the Spread of a Mycobacterium tuberculosis Strain of the Beijing Genotype on Gran Canaria Island. Am. J. Respir. Crit. Care Med.
164: 1165-1170
[Abstract][Full Text]
Small, P. M., Fujiwara, P. I.
(2001). Management of Tuberculosis in the United States. NEJM
345: 189-200
[Full Text]
Bandera, A., Gori, A., Catozzi, L., Esposti, A. D., Marchetti, G., Molteni, C., Ferrario, G., Codecasa, L., Penati, V., Matteelli, A., Franzetti, F.
(2001). Molecular Epidemiology Study of Exogenous Reinfection in an Area with a Low Incidence of Tuberculosis. J. Clin. Microbiol.
39: 2213-2218
[Abstract][Full Text]
Yang, Z. H., Bates, J. H., Eisenach, K. D., Cave, M. D.
(2001). Secondary Typing of Mycobacterium tuberculosis Isolates with Matching IS6110 Fingerprints from Different Geographic Regions of the United States. J. Clin. Microbiol.
39: 1691-1695
[Abstract][Full Text]
Rasolofo-Razanamparany, V., Ramarokoto, H., Aurégan, G., Gicquel, B., Chanteau, S.
(2001). A Combination of Two Genetic Markers Is Sufficient for Restriction Fragment Length Polymorphism Typing of Mycobacterium tuberculosis Complex in Areas with a High Incidence of Tuberculosis. J. Clin. Microbiol.
39: 1530-1535
[Abstract][Full Text]
Rook, G.A.W., Seah, G., Ustianowski, A.
(2001). M. tuberculosis: immunology and vaccination. Eur Respir J
17: 537-557
[Abstract][Full Text]
Lockman, S., Sheppard, J. D., Braden, C. R., Mwasekaga, M. J., Woodley, C. L., Kenyon, T. A., Binkin, N. J., Steinman, M., Montsho, F., Kesupile-Reed, M., Hirschfeldt, C., Notha, M., Moeti, T., Tappero, J. W.
(2001). Molecular and Conventional Epidemiology of Mycobacterium tuberculosis in Botswana: a Population-Based Prospective Study of 301 Pulmonary Tuberculosis Patients. J. Clin. Microbiol.
39: 1042-1047
[Abstract][Full Text]
Bates, J. H.
(2001). Reinfection Tuberculosis . How Important Is It?. Am. J. Respir. Crit. Care Med.
163: 600-601
[Full Text]
CAMINERO, J. A., PENA, M. J., CAMPOS-HERRERO, M. I., RODRIGUEZ, J. C., AFONSO, O., MARTIN, C., PAVON, J. M., TORRES, M. J., BURGOS, M., CABRERA, P., SMALL, P. M., ENARSON, D. A.
(2001). Exogenous Reinfection with Tuberculosis on a European Island with a Moderate Incidence of Disease. Am. J. Respir. Crit. Care Med.
163: 717-720
[Abstract][Full Text]
Van Rie, A., Warren, R., Mshanga, I., Jordaan, A. M, van der Spuy, G. D., Richardson, M., Simpson, J., Gie, R. P., Enarson, D. A., Beyers, N., van Helden, P. D., Victor, T. C.
(2001). Analysis for a Limited Number of Gene Codons Can Predict Drug Resistance of Mycobacterium tuberculosis in a High-Incidence Community. J. Clin. Microbiol.
39: 636-641
[Abstract][Full Text]
Yang, Z. H., Ijaz, K., Bates, J. H., Eisenach, K. D., Cave, M. D.
(2000). Spoligotyping and Polymorphic GC-Rich Repetitive Sequence Fingerprinting of Mycobacterium tuberculosis Strains Having Few Copies of IS6110. J. Clin. Microbiol.
38: 3572-3576
[Abstract][Full Text]
Primm, T. P., Andersen, S. J., Mizrahi, V., Avarbock, D., Rubin, H., Barry, C. E. III
(2000). The Stringent Response of Mycobacterium tuberculosis Is Required for Long-Term Survival. J. Bacteriol.
182: 4889-4898
[Abstract][Full Text]
Stead, W. W., Bates, J. H., de Boer, A. S., van Soolingen, D., Borgdorff, M. W., van Rie, A., Warren, R., van Helden, P. D.
(2000). Recurrent Tuberculosis Due to Exogenous Reinfection. NEJM
342: 1050-1051
[Full Text]
(1999). Reinfection in TB: Exogenous or Endogenous?. JWatch Infect. Diseases
1999: 7-7
[Full Text]
Fine, P. E.M., Small, P. M.
(1999). Exogenous Reinfection in Tuberculosis. NEJM
341: 1226-1227
[Full Text]