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Sep 14, 2004 - Martien W. Borgdorff, Donald A. Enarson, Marcel A. Behr, and Paul D. van ... Desmond Tutu TB Center, Department of Pediatrics and Child ...
Rate of Reinfection Tuberculosis after Successful Treatment Is Higher than Rate of New Tuberculosis Suzanne Verver, Robin M. Warren, Nulda Beyers, Madalene Richardson,† Gian D. van der Spuy, Martien W. Borgdorff, Donald A. Enarson, Marcel A. Behr, and Paul D. van Helden Desmond Tutu TB Center, Department of Pediatrics and Child Health, and MRC Center for Molecular and Cellular Biology, Department of Medical Biochemistry, Stellenbosch University, Cape Town, South Africa; KNCV Tuberculosis Foundation, The Hague; Department of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, Amsterdam, The Netherlands; International Union against Tuberculosis and Lung Disease (IUATLD), Paris, France; and Division of Infectious Diseases, Department of Medicine, McGill University Health Center, Montreal, Quebec, Canada

Rationale: In a high–tuberculosis (TB) incidence area of Cape Town, South Africa, there is a very high rate of unexplained recurrent TB. The incidence of new bacteriologically confirmed disease in the area is 313 per 100,000 individuals. Objective: To estimate the rate of recurrent TB attributable to reinfection after successful treatment. Methods: All patients with reported TB in the area between 1993 and 1998 were followed up to 2001 for disease needing retreatment (recurrences). Patients who were multi-drug–resistant or who had treatment failure, were transferred, or died during treatment were excluded. Analysis was restricted to patients for whom DNA fingerprinting of their Mycobacterium tuberculosis isolates was obtained. Reinfection TB was defined as a recurrent TB episode in which the strains of the separate episodes differed by more than four bands. Measurements and Main Results: 612 of 897 (68%) patients had a DNA fingerprint available at enrollment. Median duration of followup was 5.2 years. Recurrent TB occurred in 108 of 612 (18%) patients, of whom 61 of 447 (14%) experienced recurrence after successful treatment, and 47 of 165 (28%) experience recurrence after default. Of the 108 patients with recurrent TB, 68 (63%) had a DNA fingerprint in the second episode. Among these patients, 24 of 31 (77%) recurrences after successful treatment and 4 of 37 (11%) recurrences after default were attributable to reinfection. The reinfection disease rate after successful treatment was estimated at 2.2 per 100 person-years. Conclusions: The age-adjusted incidence rate of TB attributable to reinfection after successful treatment was four times that of new TB. People who had TB once are at a strongly increased risk of developing TB when reinfected. Keywords: incidence; molecular epidemiology; Mycobacterium tuberculosis; recurrence; survival analysis

Of patients with tuberculosis (TB) who are cured after shortcourse treatment in trial conditions, up to 7% have recurrent disease needing retreatment within 1 to 2 years (1). With the help of DNA fingerprinting of Mycobacterium tuberculosis, it has been shown that some of these recurrences are not treatment failures but rather represent reinfection with a different strain

(2–4). It is unclear what proportion of recurrent cases is caused by reinfection, because published studies each have fewer than 40 cases with DNA fingerprint in two disease episodes, and methods differ widely (3). In studies with at least eight cases, the proportion of reinfection cases among recurrent cases was reported to be from 0 to 33% in low-incidence areas (5–10), 12 to 75% in medium-incidence areas (11–12), and 23 to 75% in high-incidence areas (4, 13–17). Disease attributable to reinfection is more common in people who are HIV-positive (9, 14, 16–18). It is hypothesized that TB with one strain will protect, at least partially, against subsequent reinfection disease with another strain (18–20). If true, one could expect that the disease rate attributable to reinfection among cured patients would be lower than the incidence rate of new TB in a given population. Only one study reported the rate of reinfection disease after cure, which was 0.35 per 100 person-years (PYRS) in non-HIV infected individuals and 11 of 100 PYRS in patients with HIV (16, 21). However, this study took place in an unusual workplace setting (South African goldmines) with an exceptionally high incidence rate of TB and a high prevalence of silicosis as well as HIV. The objective of our study was to determine the incidence rate of TB attributable to reinfection among successfully treated patients in an epidemiologic fieldsite in Cape Town, South Africa, with a long duration of follow-up (median, 5 years). A high proportion of reinfections among recurrent cases was previously reported from this setting (4). We have now followed up largely the same and all other patients in the area for 3 additional years, using bacterial DNA fingerprinting to estimate the incidence of reinfection disease. This study has been presented at conferences in Paris (2003) (22), Prague (2003) (23), Geneva (2004) (24), and Amsterdam (25), and has been reported in the form of abstracts.

METHODS Setting

(Received in original form September 14, 2004; accepted in final form April 6, 2005) Supported by the GlaxoSmithKline Action TB Program, the DST/NRF Centre of Excellence for Biomedical TB Research (P.D.v.H.), and Aeras Global Tuberculosis Vaccine Foundation (S.V., M.W.B., and M.A.B.). The sponsors of the study had no role in study design, data collection, and data analysis. † We dedicate this paper to the memory of Madalene Richardson, who sadly passed away while this manuscript was under review. Correspondence and requests for reprints should be addressed to Suzanne Verver, M.Sc., Ph.D., KNCV Tuberculosis Foundation, P.O. Box 146, 2501 CC The Hague, The Netherlands. E-mail: [email protected] This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org Am J Respir Crit Care Med Vol 171. pp 1430–1435, 2005 Originally Published in Press as DOI: 10.1164/rccm.200409-1200OC on April 14, 2005 Internet address: www.atsjournals.org

The epidemiologic fieldsite of Ravensmead/Uitsig, two adjacent urban communities of Cape Town, has been extensively described (see online supplement) (4, 26–28). The incidence of new smear- and/or culturepositive disease was on average 313 per 100,000 population per year (1993–1998). Unfortunately, the HIV status of most patients is unknown. The HIV seroprevalence among women attending antenatal clinics increased from 1.2 to 5.2% between 1994 and 1998. In the study area, the prevalence of HIV infection among new patients with smearpositive TB was 11% in 1999–2000.

Study Population All bacteriologically confirmed (by smear or culture) patients with TB who were resident in and reported to the clinics in the fieldsite between 1993 and 1998 were eligible for this retrospective analysis (see online supplement). We included patients with pulmonary TB as well as extrapulmonary TB. We included new patients and patients who had been treated before (retreatment patients). Patients with multidrug resistance

Verver, Warren, Beyers, et al.: Rate of Reinfection Tuberculosis

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in any disease episode were excluded, as well as those who, while on treatment, remained or became smear-positive 5 months or more after starting treatment (treatment failure) and those who were transferred out or died during treatment.

M. tuberculosis Isolates Isolates of M. tuberculosis were obtained from the majority of patients diagnosed between 1993 and 1998. DNA fingerprinting was determined by IS6110-based restriction fragment length polymorphism (see online supplement for definitions) (29). Strains harboring fewer than five copies of IS6110 copies were also subjected to subtyping with MTB484 (29). The laboratory error rate was 3.4%, as reported previously (4).

Follow-up Period Patients who had at least one DNA fingerprint were enrolled at the time of the disease episode of their first fingerprint. Patients were followed up until their first bacteriologically confirmed recurrent episode, or until the end of the study period (December 2001). Consequently, the follow-up period varies from 3 to 8.5 years. Recurrent episodes of TB were diagnosed through passive case finding, because there was no active surveillance during the follow-up period. Recurrence and reinfection rates are underestimates because we could not determine mortality or emigration (see online supplement).

Definitions World Health Organization definitions were used to determine treatment outcome (see online supplement) (30). We defined recurrent disease as a bacteriologically confirmed disease episode needing retreatment after a patient was successfully treated or defaulted during a previous disease episode. Disease attributable to reinfection was defined as a recurrent disease episode with an M. tuberculosis strain different than that found in the disease episode at enrollment, unlikely to be from evolution. To be conservative, we assumed that recurrences with the same strain or a strain with fewer than five bands’ difference were attributable to relapse.

Figure 1. Selection of patients.

rates in patients with and without DNA fingerprint were similar (Table 1).

Rates

Recurrences

The calculation of recurrence rates, confirmed reinfection rates, and likely reinfection rates is described in the online supplement. We calculated the representativeness of enrolled patients (those with one DNA fingerprint) for all patients, and used only patients with DNA fingerprints to calculate reinfection rates. To guard against the possibility that some cases of recurrence represented laboratory error, the proportions of recurrent TB attributable to reinfection were recalculated more strictly (i.e., restricted to patients for whom the second episode was associated with two or more sputum samples positive by culture or smear microscopy) (3, 16). The Kaplan-Meier method was used to construct survival curves, with survival defined as being free of active TB. Cox regression was used to assess if age, sex, smear, location of TB (pulmonary TB or extrapulmonary TB), and outcome were risk factors for relapse and reinfection in successfully treated patients with at least one DNA fingerprint (31).

The median duration of follow-up was 5.2 years in the enrolled patients. During follow-up, 108 of 612 (18%) of these patients had a recurrence, 61 of 447 (14%) after successful treatment and 47 of 165 (28%) after default. The recurrence rate after successful treatment (2.7/100 PYRS) was lower than that after default (6.5/100 PYRS; hazard ratio, 2.1; 95% confidence interval, 1.5–2.9). There was no significant difference between the recurrence rates after cure and after treatment completion. The recurrence rate was not significantly different between retreatment (3.4/100 PYRS) and new patients after successful treatment (2.4/100 PYRS; hazard ratio, 0.72; 95% confidence interval, 0.46–1.13), but it was higher in retreatment than in new patients after default (8.5 vs. 4.6/100 PYRS; hazard ratio, 1.71; 95% confidence interval, 1.01–2.89).

RESULTS Description of Patients

A total of 1,093 bacteriologically confirmed patients were diagnosed between 1993 and 1998, of whom 86 had multidrug resistance in any disease episode during this study and were excluded. Of the remaining 1,007 patients, 11 were excluded because of treatment failure, 38 were excluded because they died during treatment, and 61 were excluded because they were transferred during treatment (Figure 1). Of the remaining 897 patients, 836 (93%) had a positive culture; of these patients, 612 (73%) had a DNA fingerprint. These 612 patients were enrolled. Compared with patients without DNA fingerprint data, patients with a DNA fingerprint were less often children younger than 15 years, patients with extrapulmonary TB, and patients who completed treatment without confirmation of cure (Table 1). Recurrence

Reinfections

Of the 108 patients with a recurrence, 68 (63%) had a DNA fingerprint available from their first and second episodes. These 68 were representative of all recurrences with respect to year of diagnosis, age, sex, patient category, and sputum smear (Table 2). However, patients with disease recurrence after default were more likely to have a second DNA fingerprint than patients with a recurrence after successful treatment (Table 2). Among the 68 patients with a DNA fingerprint in their second episode, reinfection occurred in 24 of 31 (77%) of those successfully treated, and in 3 of 37 (8%) of defaulters using IS6110-based typing. Ten of 68 patients showed a strain with five or fewer copies of IS6110 (low copy numbers) in both episodes. These were all among defaulters. Subtyping strains from these 10 patients with MTB484 showed one reinfection, increasing the number of reinfections among defaulters to 4 of 37 (11%; Table 3).

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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 171 2005 TABLE 1. REPRESENTATIVENESS OF ENROLLED PATIENTS (THOSE WITH AT LEAST ONE DNA FINGERPRINT) FOR ALL PATIENTS

Year of diagnosis 1993 1994 1995 1996 1997 1998 Age, yr ⬍ 15 15–24 25–34 35–44 45–54 ⭓ 55 Unknown Sex Female Male Unknown Patient category New Retreatment Unknown Smear Positive Negative Unknown Location of TB PTB EPTB Unknown Outcome Cure* Treatment completed* Default Recurrence No Yes Total

No. Patients

No. Enrolled Patients

%

OR

152 185 154 140 120 146

101 145 86 92 79 109

66 78 56 66 66 75

1 1.83 0.64 0.97 0.97 1.49

52 149 294 212 113 74 3

22 100 212 148 77 51 2

42 67 72 70 68 69

0.28 0.79 1 0.89 0.83 0.86

389 504 4

259 351 2

67 70

1 1.15

0.87–1.53

625 242 30

413 174 25

66 72 83

1 1.31

0.95–1.82

634 222 41

435 156 21

69 70 51

1 1.08

0.78–1.51

857 28 12

593 13 6

69 46 50

1 0.39

0.18–0.82†

505 161 231

358 89 165

71 55 71

1 0.51 1.03

0.35–0.73† 0.73–1.45

747 150 897

504 108 612

67 72 68

1 1.24

0.84–1.83

95% CI Trend NS

0.15–0.50† 0.52–1.21 0.61–1.32 0.52–1.32 0.49–1.49

Definition of abbreviations: CI ⫽ confidence interval; EPTB ⫽ extrapulmonary tuberculosis; NS ⫽ not significant; OR ⫽ odds ratio; PTB ⫽ pulmonary tuberculosis; TB ⫽ tuberculosis. * Successful treatment versus default; OR, 0.82 (0.59–1.13). † p ⬍ 0.05.

Six of 68 patients had a low IS6110 band copy number isolate in one of their episodes, but a strain with more than five bands in the other episode. These were all among the successfully treated patients. The rates of TB attributable to confirmed and likely reinfection after successful treatment were 1.1 and 2.2 per 100 PYRS, respectively (Table 3). Rates of confirmed reinfection disease were the same in cured patients and in those with treatment completion (hazard ratio, 1.01; 95% confidence interval, 0.38– 2.69). The rate of reinfection disease (2.2/100 PYRS) was approximately seven times the crude incidence rate (313/100,000) and approximately four times the age-adjusted incidence rate of new TB (515/100,000). The disease rate attributable to confirmed reinfection seemed to remain constant for at least 7 years after the end of treatment (Figure 2). There was no significant difference in rates of confirmed reinfection between those who had previously defaulted and those who had been successfully treated (hazard ratio, 0.54; 95% confidence interval, 0.19–1.57; Figure 2). To exclude the possibility that patients with a single positive culture might represent laboratory error, we repeated the analy-

sis limited to patients with two or more positive samples in the second episode. In this restricted analysis, the proportion of recurrences attributable to reinfection remained unchanged: 17 of 21 (81%) after successful treatment and 3 of 23 (13%) after default. Using this subset of cases, confirmed and likely reinfection disease rates after successful treatment hardly changed: they were still 0.8 and 2.2 per 100 PYRS, respectively. Risk Factors for Reinfection

Age, sex, smear positivity, and being a new or retreatment patient at enrollment were not found to be risk factors for reinfection disease. Among patients successfully treated, no risk factors for recurrence were identified.

DISCUSSION This study shows that in a high-incidence area the risk of TB attributable to reinfection after successful treatment was approximately 2% per annum. The rate of reinfection disease was approximately seven times the crude incidence rate and approximately four times the age-adjusted incidence rate of new TB.

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TABLE 2. REPRESENTATIVENESS OF RECURRENCES WITH DNA FINGERPRINT FOR ALL RECURRENCES AFTER ENROLLMENT No. Enrolled Patients

Recurrences in Enrolled Patients

DNA Fingerprint in Recurrence

%

OR

101 145 86 92 79 109

26 35 11 14 6 16

18 21 8 9 4 8

69 60 73 64 67 50

1 0.67 1.19 0.80 0.89 0.44

22 100 212 148 77 51 2

2 18 43 30 10 5 0

2 13 26 19 8 0

100 72 60 63 80 0

1.70 1 1.13 2.62

0.43–2.96 0.49–13.83

259 351 2

40 68 0

25 43

63 63

1 1.03

0.46–2.31

413 174 25

65 40 3

38 29 1

59 73 33

1 1.87

0.80–4.39

435 156 21

77 30 1

49 19 0

64 63

1 0.99

0.41–2.37

593 13 6

107 1 0

67 1

63 100

358 89 165 612

48 13 47 108

21 10 37 68

44 77 79 63

1 4.29 4.76

1.05–17.6† 1.93–11.72†

Year of diagnosis 1993 1994 1995 1996 1997 1998 Age, yr ⬍ 15 15–24 25–34 35–44 45–54 ⭓ 55 Unknown Sex Female Male Unknown Patient category New Retreatment Unknown Smear Positive Negative Unknown Location of TB PTB EPTB Unknown Outcome Cure* Treatment completed* Default Total

95% CI Trend NS

0.51–5.64

For definition of abbreviations, see Table 1. * Successful treatment versus default; OR, 3.59; 95% CI, 1.51–8.46. † p ⬍ 0.05.

This suggests that individuals who have been successfully treated for TB are at an increased risk of developing TB again, rather than being protected against subsequent episodes after reinfection. Moreover, the disease rate attributable to confirmed reinfection seemed to remain constant for at least 7 years after the end of treatment, consistent with a susceptibility to development of new disease in the face of ongoing risk of reinfection (Figure 2). These results represent an extension of those reported in earlier studies and demonstrate that most TB in this area results from recent infection or reinfection (26). Of considerable con-

cern is the observation that most of this transmission takes place outside the household (27). The estimated rate of reinfection disease is a minimum estimate, because it is not known how many people have died or moved during the follow-up period. We expect that during a follow-up period of 5 years, approximately 10 to 20% have moved. The reinfection disease rates could also be somewhat underestimated because of reinfection with the same strain, but this effect is not expected to be large because strain diversity in this community is high (28). Because the HIV prevalence is

TABLE 3. PROPORTION AND RATE OF RECURRENCES AND REINFECTION DISEASE IN ENROLLED PATIENTS BY OUTCOME OF FIRST DISEASE EPISODE Outcome of First Episode with DNA FP Cure* TC* Default

No. Patients

PYRS Follow-up

No. Recurrences

Recurrence Rate/ 100 PYRS

No. DNA FP in Second Episode

No. Confirmed Reinfections (% )

Confirmed Reinfection Disease Rate/100 PYRS (95% CI)

Likely Reinfection Disease Rate/100 PYRS† (95% CI)

358 89 165

1,794 466 725

48 13 47

2.7 2.8 6.5

21 10 37

19 (90) 5 (50) 4 (11)

1.1 (0.7–1.7) 1.1 (0.3–2.5) 0.6 (0.2–1.4)

2.4 (1.4–3.8) 1.4 (0.5–3.3) 0.7 (0.2–1.6)

Definition of abbreviations: CI ⫽ confidence interval; FP ⫽ fingerprint; PYRS ⫽ person-years; TC ⫽ treatment completed. * For successful treatment (either cure or TC) confirmed reinfections are 24 of 31 (77%), confirmed reinfection disease rate is 1.1 (0.7–1.6) per 100 PYRS, and likely reinfection disease rate is 2.2 (1.6–2.9) per 100 PYRS. † The likely reinfection disease rate is the recurrence rate multiplied with the proportion confirmed reinfections among recurrences with a DNA FP available.

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Figure 2. Kaplan-Meier curve showing risk of confirmed reinfection in 447 patients successfully treated and 165 defaulters.

relatively low, we believe that most reinfections cannot be explained by HIV status. Of note, the rate that we estimate lies between what has been observed for HIV-negative and HIVpositive populations in trials of short-course chemotherapy (32, 33). Our relapse rate may be somewhat higher if compliance is lower in the community than in the conditions applied for clinical trials. Conversely, our reinfection rate is likely higher because of a greater annual risk of TB infection in our study area. If laboratory cross-contamination or administrative errors occur, this would lead to an overestimate of the proportion of recurrences attributed to reinfection. In our study, we believe that these errors did not play a major role for two reasons. First, the proportion of reinfections among recurrences was much higher after successful treatment (77%) than after default (11%). There is no reason why recurrences after successful treatment would be more often involved in laboratory or administrative errors than recurrences after default. Second, laboratory crosscontamination and administrative errors are most likely to explain reinfection based on isolated positive cultures. However, when excluding episodes with isolated positive cultures from the analysis, the proportion of recurrences attributed to reinfection remained similar. Furthermore, the rate of reinfection TB after successful treatment was still twice the incidence rate of new TB. The main limitation of this study was the low percentage of enrolled patients who had DNA fingerprints available: 68% of all bacteriologically confirmed patients and 63% of patients during the recurrence. This missing data cause a twofold difference between confirmed and likely reinfection disease rate. However, we do not believe this missing data could have biased our results because the patients with DNA fingerprints were representative for those without, except for patients with lower bacterial load (⬍ 15 years of age and patients with extrapulmonary TB). Patients after default were more likely to have a DNA fingerprint at recurrence than patients after successful treatment, perhaps because of more intensive follow-up by the health system. This should not affect the proportion of recurrences that are attributable to reinfection because the availability of a DNA fingerprint

did not depend on whether disease was attributable to reinfection or relapse. However, some patients may have had a dual infection with M. tuberculosis, of which one strain was cultured during the first disease episode and the other during the recurrent episode (34, 35). By DNA fingerprinting, it is impossible to distinguish between reinfection with a new strain and dual infection followed by reactivation of that same strain. A possible bias in our study is that patients reporting for their first episode may be more likely to report for their second, thus leading to an overestimate of rate ratio of reinfection disease and new disease. Furthermore, because case detection is passive, microcommunities with undiagnosed disease may be missed. However, to explain a rate ratio of four, this would require that all recurrent patients are diagnosed and only 25% of new patients are diagnosed. The fieldsite has two clinics in an area of less than 4 km2, and the case detection rate is estimated at over 50%. Therefore, we do not consider selection bias a sufficient explanation for our results. We conclude that people who have been treated successfully for TB are at higher risk of developing TB from reinfection than the general population. This suggests that a subgroup of individuals is intrinsically vulnerable to TB. Further study is needed to find out whether the high risk of reinfection disease is attributable to a high risk of reinfection or a high risk of breakdown to disease. This is currently difficult because there is no test that differentiates between an old infection (e.g., after healed disease) and a recent infection. Possible risk factors for progression to disease should be studied in ex-patients. These may include socioeconomic factors, genetic risk factors (36, 37), lung damage caused by the previous episode, and perhaps smoking and drug abuse. Regardless, this result challenges the hypothesis that, in immunocompetent persons, infection with one strain of M. tuberculosis protects against disease attributable to subsequent reinfection with another strain (18–20). The failure of natural disease to protect against reinfection disease at a later point may partially explain the relative ineffectiveness of vaccination with bacillus Calmette-Gue´rin (19). For national TB control programs in areas with a high infection risk, patients who have been successfully treated for TB should be made aware of their high risk of recurrent disease, and contact tracing should get more attention. Conflict of Interest Statement : S.V. is sponsored by the Sequella Global Tuberculosis Foundation, currently called Aeras Global TB Vaccine Foundation; R.M.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; N.B. received £111,150 in 2000 and £150,000 per year for 2001–2003 and £85,000 in 2004 from the GlaxoSmithKline (GSK) Action TB Program as research grants for developing and maintaining an epidemiologic fieldsite and for doing studies aimed at identifying surrogate markers for response to treatment in patients with TB. She also received £500 for speaking at a conference where one session was sponsored by GSK; M.R. has been employed by GSK, with a monthly salary, from January 1994. During this period of employment, the techniques, methodology, and background knowledge used for contribution to this article were developed, but these do not have a direct financial benefit to herself or her institution. She has received sponsorship from GSK as well as from the International Union against Tuberculosis and Lung Disease and Centers for Disease Control to attend conferences where aspects of the research projects in which she is involved were presented, again without specific gain to herself or her institution; G.D.v.d.S. does not have a financial relationship with a commercial entity that has in an interest in the subject of this manuscript; M.W.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; D.A.E. has participated in an Advisory Board workshop for GSK concerning Drugs for Diseases of the Developing World, held in England on December 12, 2003, and received no remuneration for this participation. He has been a member of the Advisory Board of Aventis Nelson Mandela Project in South Africa since September 2003 and received no remuneration for this activity; M.A.B. has one patent (US 6,291,190) that is related to bacillus Calmette-Gue´rin vaccines and is unrelated to this manuscript; P.D.v.H. has received a research grant from GSK for searching for surrogate markers for antibiotic response during TB therapy. Acknowledgment : The authors thank the nurses and patients of the Ravensmead and Uitsig clinics and Dr. I. Toms, Director City Health, Cape Town. They thank

Verver, Warren, Beyers, et al.: Rate of Reinfection Tuberculosis Dr. R. Gie for dedicated reading of all chest x-rays and Ms. V. Chihota and Mr. S. Ndabambi and the TB research team for their valuable assistance.

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