American Journal of Transplantation 2013; 13: 3230–3235 Wiley Periodicals Inc.
C
Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.12470
Brief Communication
Results of Implementation of Preventive Recommendations for Tuberculosis After Renal Transplantation in an Endemic Area A. S. de Lemos1,2, M. A. M. S. Vieira3, M. Halpern1,2, R. G. Quaresma1,2, A. C. Borchardt1,2, M. A. A. R. Santos4, R. T. Gonc¸alves4 and G. Santoro-Lopes1,2,* 1 Infectious Diseases Clinic, Hospital Universita´rio Clementino Fraga Filho, Rio de Janeiro, Brazil 2 Department of Preventive Medicine, School of Medicine, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil 3 Tuberculosis Control Program, Hospital Universita´rio Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil 4 Nephrology Clinic, Hospital Universita´rio Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil Corresponding author: Guilherme Santoro-Lopes,
[email protected]
This retrospective cohort study assessed the results of the implementation of preventive recommendations for tuberculosis (TB) among renal transplant recipients in an endemic area (Rio de Janeiro, Brazil). Subjects were defined as at high risk for TB if they had latent tuberculosis infection (LTBI), reported recent close contact with individuals with TB or received a graft from a donor with LTBI. A 6-month course of isoniazid preventive therapy (IPT) was targeted to high-risk subjects. The study end point was TB confirmed by culture. Altogether, 535 patients were included. Median follow-up was 59 months. The overall cumulative incidence of TB was 2.1% while among the 274 patients in whom the preventive protocol was fully implemented, the incidence was only 0.7%. The incidence of TB among 75 high-risk recipients not treated with isoniazid (7%) was significantly higher than that observed in 209 untreated low-risk patients (1%, p ¼ 0.006) and in 65 high-risk subjects that received IPT (no case, p ¼ 0.03). In conclusion, the implementation of preventive recommendations for TB in an endemic area allowed the appropriate discrimination between high- and low-risk renal transplant recipients and was associated with long-term reduction in the incidence of this complication among high-risk subjects. Keywords: Isoniazid, prevention, renal transplantation, tuberculosis 3230
Abbreviations: ALA, antilymphocyte antibodies; CI, confidence interval; CT, computerized tomography; HLA, human leukocyte antigens; HR, hazard ratio; IGRA, interferon-gamma release assays; IPT, isoniazid preventive therapy; LTBI, latent tuberculosis infection; TB, tuberculosis; TST, tuberculin skin test Received 5 March 2013, revised 29 July 2013 and accepted for publication 5 August 2013
Introduction The incidence of tuberculosis (TB) is much higher among solid organ transplant recipients than in the general population, with a mortality rate of up to 30% (1–4). About two-thirds of TB cases in transplant recipients occur within the first year after transplantation (3). It is thought that, in most cases, the disease occurs by reactivation of old foci of latent infection (2,5). Therefore, targeted isoniazid preventive therapy (IPT) has been recommended for transplant candidates and recipients who have a diagnosis of latent tuberculosis infection (LTBI), who were exposed to cases of active TB or who received an organ from a donor with untreated LTBI (5–12). A few trials (13,14), carried out in countries with high TB burden, and a meta-analysis (15) have shown that universal IPT given to unselected renal transplant candidates and recipients effectively reduces the risk of active TB. However, there are scarce data on the impact that the recommended approach of targeting IPT to high-risk subjects has on the overall incidence of this disease among transplant recipients. Different factors may lower the effectiveness of this preventive strategy. The most important is the limited accuracy of the tuberculin skin test (TST) (16) and chest radiograph (17), the most commonly used methods to detect LTBI. In addition, de novo acquisition of the TB infection in the community after the end of IPT might reduce the long-term effectiveness of IPT among transplant recipients living in countries with intermediate or high TB incidence rates. Brazil is included among the countries with high TB burden (18). The incidence of TB varies widely across the country. In the city of Rio de Janeiro, where this study was performed, the TB incidence rate has ranged from 115 to 95 cases/100 000 patient-years between 2001 and 2010 (19,20). In our center, a preventive protocol based
Tuberculosis Prevention After Transplantation
on IPT targeted to high-risk transplant recipients has been in place since 1998. In this study, we assessed the results associated with its implementation.
Methods Study design and patients This was a retrospective cohort study that included patients who were consecutively submitted to kidney transplantation between March 1998 and December 2004 and followed until July 2010. The study was approved by the Institutional Committee on Research Ethics (protocol 036/05).
Data collection Medical charts were reviewed to gather data on baseline and follow-up variables. Baseline variables included sex, age, transplant date, type of donor, donor–recipient human leukocyte antigens (HLA) match, total cold ischemia time, previous renal transplantation, time spent on dialysis, the presence of diabetes mellitus, pretransplant history of TB in the recipient or in a living donor, use of corticosteroids preoperatively, household or nosocomial contact with a smear positive case of TB within 2 years, results of TST and chest radiograph (or computerized tomography [CT] scan) in the recipient and in living donors and pretransplant treatment for latent or active TB. Follow-up variables included the occurrence of acute rejection, posttransplant treatment for LTBI and the adverse events associated with it, and the occurrence of active TB.
Tuberculosis prevention protocol Recipients and living donors were screened preoperatively or at the time of transplantation for epidemiological, clinical and radiological evidence of LTBI. Patients defined to be at high risk for TB were treated with isoniazid 300 mg/ day for 6 months. Active TB was ruled out before the start of the preventive therapy by symptom review, chest radiography and, in patients with respiratory symptoms, smear examination and culture of an induced sputum specimen.
Whitney test was used to compare the distribution of numeric variables. The chi-square and Fisher’s exact tests were used to compare the distribution of categorical variables. TB incidence rates are described by the estimated number of cases per 100 000 patient-years. Cox models were used to compare the risk of TB between groups of patients. In these analyses, an intention-to-treat approach was used to assess the effect of isoniazid therapy. The assumption of proportionality of hazards was checked by inspection of log(log(survival)) curves. The results are described by the estimated hazard ratios (HR) and their 95% confidence intervals (95% CI). The score test was used to calculate p-values. All p-values are two-tailed. Statistical analyses were performed with SPSS for Windows 18.0 (SPSS Inc., Chicago, IL).
Results During the study period, 572 patients underwent renal transplantation. Thirty-seven were excluded from the study. The reasons for exclusion were the presence of TB at the time of transplantation (four cases), the use of isoniazid by patients without a diagnosis of LTBI (two cases) and follow-up time shorter than 30 days (31 cases). The demographic and clinical characteristics of the 535 patients included in the analysis are shown in Table 1. Figure 1 describes patients’ distribution according to the implementation of the preventive protocol and risk stratification. Only 349 patients (65%) completed screening and 140 (26%) of them were defined as at high risk for TB. Seventy-five of these high-risk patients were not treated for LTBI. Thus, TB preventive recommendations were fully implemented in 274 (51%) patients. Of these, 65 were subjects with a diagnosis of LTBI who were treated with isoniazid, while the other 209 were patients who were
Definitions High-risk patients were defined as: (1) recipients with a diagnosis of LTBI who were not preoperatively treated with isoniazid; (2) patients who received a graft from a living donor with a diagnosis of LTBI; and (3) those who had household, workplace or nosocomial exposure to individuals with active TB in the previous 2 years. LTBI diagnosis was defined by one of the following criteria: (1) chest radiograph or CT scan with lesions compatible with old healed TB in asymptomatic patients who had never been treated; (2) history of past TB without complete treatment; or (3) a positive TST defined as an induration of 5 mm in a transplant recipient/candidate or 10 mm in a living-donor 48–72 h after intradermal administration of 2 U of the RT-23 strain, equivalent to 5 tuberculin units of purified protein derivative of tuberculin. The full implementation of the preventive protocol was defined by completion of screening for LTBI and treatment of high-risk patients with isoniazid.
Outcome The occurrence of active TB confirmed by culture.
Statistical analysis Numerical data are described by median and interquartile range (IQR). Categorical data are presented as absolute counts and percents. The Mann–
American Journal of Transplantation 2013; 13: 3230–3235
Table 1: Demographic and clinical characteristics of the cohort Variable Sex Male Female Age (years) Previous time on dialysis (months) Donor Related living donor Unrelated living donor Deceased HLA match Retransplantation Tuberculosis before transplantation Corticosteroids use before transplantation Diabetes mellitus Pretransplantion Posttransplantation Use of antilymphocyte antibodiesb Acute rejection
n (%) 292 243 40 34
(55) (45) (32–48)a (14–90)a
297 32 206 2 15 17 21
(56) (6) (38) (0–4) (3) (3) (4)
42 50 36 177
(8) (9) (7) (33)
HLA, human leukocyte antigens. Median (interquartile interval). b OKT3 or antithymocyte globulin. a
3231
de Lemos et al 535 patients included
349 (65%) completed screening
209 defined as at low risk for TB
Protocol fully implemented n=274 (51%)
65 at high risk treated for LTBI
186 did not complete screening
140 (26%) defined as at high risk for TB
75 at highrisk not treated for LTBI
Figure 1: Distribution of the patients included in the study according to the implementation of the diagnostic and therapeutic components of the preventive protocol.
defined as at low risk for TB after screening and, thus, did not receive IPT. Patients in whom the protocol was not fully implemented included the subgroup of 75 high-risk subjects who did not start IPT and the remaining 186 recipients who lacked a preoperative TST. Table 2 shows the distribution of variables according to the compliance with the preventive recommendations. Their full implementation was significantly more frequent among women (p ¼ 0.046) and among patients treated for acute rejection (p < 0.001).
Patients were followed for a total 2522.7 patient-years. The median follow-up per patient was 4.9 years (59 months). Thirty-five subjects (6.5%) were lost to follow-up. There was no association between losses to follow-up and implementation of the preventive intervention (Table 2). During follow-up, active TB occurred in 11 patients (2.1%). The overall incidence rate of TB was 436 cases/100 000 patient-years. The median time to the diagnosis of TB after transplantation was 6 months (IQR: 3–41 months). The clinical presentation was pulmonary in seven cases (64%), extra-pulmonary in two (18%) and disseminated in the remaining two (18%) patients. TB was significantly less frequent among patients in whom the preventive recommendations were fully implemented (HR: 0.21, 95% CI: 0.05–0.98, p ¼ 0.03). There were only two cases (0.7%) of TB among these patients (incidence rate: 158/100 000 patient-years), while nine cases occurred in the remaining 261 recipients (3.5%, incidence rate: 719/ 100 000 patient-years). Similar results were obtained in models adjusted for sex (HR ¼ 0.22; 95% CI: 0.22–1.00) and treatment for acute rejection (HR ¼ 0.21, 95% CI: 0.05– 1.00). Subsequently, the incidence of TB was separately calculated for the 186 patients who did not complete screening for LTBI and the 75 high-risk patients not treated with isoniazid. These results were then compared with those observed in the 274 in whom the preventive protocol was fully implemented (Table 3). The latter group of patients had a significantly lower incidence of TB as compared with highrisk subjects who did not receive IPT (HR: 0.11, p ¼ 0.008). Full compliance with the preventive protocol was also associated with a lower risk of TB in the comparison with
Table 2: Distribution of baseline and follow-up variables according to implementation of the preventive protocol n (%) Variable Female sex Age (years) White race Previous time on dialysis (months) Deceased donor HLA match Retransplantation Previous episode of TB Corticosteroids before transplantation DM (pretransplant) DM (posttransplant) Use of ALA Acute rejection High-risk for TB Follow-up (months) Lost to follow-up Deaths
Full implementation (n ¼ 274) 136 40 98 26 99 2 5 7 10 18 27 19 112 65 58.7 17 42
(50) (32–47)a (36) (13–85)a (36) (0–3)a (2) (3) (4) (7) (10) (7) (41) (24%) (26.5–82.3)a (6) (15)
No or partial implementation (n ¼ 261) 107 39 102 40 107 1 10 10 11 24 23 17 68 75 57.8 18 48
(41) (31–48)a (39) (14–94)a (41) (1–3)a (4) (4) (4) (9) (9) (7) (26) (29%) (21.3–88.1)a (7) (18)
p 0.046 0.77 0.37 0.28 0.25 0.41 0.20 0.47 0.83 0.27 0.77 0.87
