Screening Strategies for Tuberculosis in Children With Kidney Disease: What Is Cost-Effective?

Abstract

Related Article, p. 22 Related Article, p. 22 Tuberculosis (TB) is an infection that occurs at a higher frequency and with greater virulence in immunosuppressed patients. Infection may occur from reactivation of latent disease or from de novo infection, and in the particular case of transplant recipients, de novo infection may be donor derived. Compared with nonimmunosuppressed individuals, rates of TB infection are 20-74 times more common in solid-organ transplant recipients,1Singh N. Paterson D.L. Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management.Clin Infect Dis. 1998; 27: 1266-1277Crossref PubMed Scopus (482) Google Scholar, 2Subramanian A. Dorman S. Mycobacterium tuberculosis in solid organ transplant recipients.Am J Transplant. 2009; 9: S57-S62Crossref PubMed Scopus (92) Google Scholar 2 times more common in hematopoietic stem cell transplant recipients,3Roy V. Weisdorf D. Mycobacterial infections following bone marrow transplantation: a 20 year retrospective review.Bone Marrow Transplant. 1997; 19: 467-470Crossref PubMed Scopus (125) Google Scholar and 50-90 times more common in patients with rheumatoid arthritis taking infliximab.4Gomez-Reino J.J. Carmona L. Valverde V.R. Mola E.M. Montero M.D. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report.Arthritis Rheum. 2003; 48: 2122-2127Crossref PubMed Scopus (906) Google Scholar Mortality rates as high as 31% in solid-organ transplant recipients5Aguado J.M. Herrero J.A. Gavalda J. et al.Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain Spanish Transplantation Infection Study Group, GESITRA.Transplantation. 1997; 63: 1278-1286Crossref PubMed Scopus (279) Google Scholar and 50% in hematopoietic stem cell transplant recipients6Russo R.L. Dulley F.L. Suganuma L. Franca I.L. Yasuda M.A. Costa S.F. Tuberculosis in hematopoietic stem cell transplant patients: case report and review of the literature.Int J Infect Dis. 2010; 14: e187-e191Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar have been reported. Unfortunately, immunosuppressants such as prednisone can yield false-negative results in latent TB screening.7Bovornkitti S. Kangsadal P. Sathirapat P. Oonsombatti P. Reversion and reconversion rate of tuberculin skin reactions in correction with the use of prednisone.Dis Chest. 1960; 38: 51-55Crossref PubMed Google Scholar, 8Belard E. Semb S. Ruhwald M. et al.Prednisolone treatment affects the performance of the QuantiFERON Gold In-Tube test and the tuberculin skin test in patients with autoimmune disorders screened for latent tuberculosis infection.Inflamm Bowel Dis. 2011; 17: 2340-2349Crossref PubMed Scopus (111) Google Scholar This sobering situation emphasizes the importance of screening for latent TB infection before initiating immunosuppressive therapy.9Bumbacea D. Arend S.M. Eyuboglu F. et al.The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement.Eur Respir J. 2012; 40: 990-1013Crossref PubMed Scopus (159) Google Scholar In this issue of AJKD, Laskin et al10Laskin B.L. Goebel J. Starke J.R. Schauer D.P. Eckman M.H. Cost-effectiveness of latent tuberculosis screening before steroid therapy for idiopathic nephrotic syndrome in children.Am J Kidney Dis. 2013; 61: 22-32Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar examine cost-effective approaches to TB screening by modeling several strategies to detect latent TB prior to administering steroids to children with newly diagnosed idiopathic nephrotic syndrome. The study is unique in being the first to our knowledge to examine the cost-effectiveness of screening strategies for latent TB prior to immunosuppression. Until 2001, the only TB screening option was a delayed skin reaction to the intradermal injection of species-nonspecific proteins, otherwise known as the purified protein derivative (PPD) or Mantoux test. The Mantoux test has several disadvantages. Given antigen nonspecificity, false-positive Mantoux test results after BCG vaccination is common, although this usually happens only in the first 1-2 decades after administration. In addition, Mantoux testing requires 2 patient visits to obtain results, raising concerns about health care costs and loss to follow-up. Finally, in patients with kidney failure treated with dialysis, false-negative Mantoux test results may be secondary to anergic responses to intradermal antigens.11Woeltje K.F. Mathew A. Rothstein M. Seiler S. Fraser V.J. Tuberculosis infection and anergy in hemodialysis patients.Am J Kidney Dis. 1998; 31: 848-852Abstract Full Text PDF PubMed Scopus (102) Google Scholar, 12Poduval R.D. Hammes M.D. Tuberculosis screening in dialysis patients—is the tuberculin test effective?.Clin Nephrol. 2003; 59: 436-440Crossref PubMed Scopus (43) Google Scholar, 13Smirnoff M. Patt C. Seckler B. Adler J.J. Tuberculin and anergy skin testing of patients receiving long-term hemodialysis.Chest. 1998; 113: 25-27Crossref PubMed Scopus (98) Google Scholar Booster Mantoux testing in dialysis patients variably decreases the rate of false-negative results in countries where tuberculosis is endemic.14Dogan E. Erkoc R. Sayarlioglu H. Uzun K. Tuberculin skin test results and the booster phenomenon in two-step tuberculin skin testing in hemodialysis patients.Ren Fail. 2005; 27: 425-428PubMed Google Scholar, 15Akcay A. Erdem Y. Altun B. et al.The booster phenomenon in 2-step tuberculin skin testing of patients receiving long-term hemodialysis.Am J Infect Control. 2003; 31: 371-374Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 16Sagheb M.M. Goodarzi M. Roozbeh J. The booster phenomenon of tuberculin skin testing in patients receiving hemodialysis.Iran J Immunol. 2008; 5: 212-216PubMed Google Scholar, 17Shankar M.S. Aravindan A.N. Sohal P.M. et al.The prevalence of tuberculin sensitivity and anergy in chronic renal failure in an endemic area: tuberculin test and the risk of post-transplant tuberculosis.Nephrol Dial Transplant. 2005; 20: 2720-2724Crossref PubMed Scopus (62) Google Scholar Anergy and differential response to booster Mantoux testing have been attributed to differences in nutritional status as well as defects in cell-mediated immunity under uremic conditions.16Sagheb M.M. Goodarzi M. Roozbeh J. The booster phenomenon of tuberculin skin testing in patients receiving hemodialysis.Iran J Immunol. 2008; 5: 212-216PubMed Google Scholar, 17Shankar M.S. Aravindan A.N. Sohal P.M. et al.The prevalence of tuberculin sensitivity and anergy in chronic renal failure in an endemic area: tuberculin test and the risk of post-transplant tuberculosis.Nephrol Dial Transplant. 2005; 20: 2720-2724Crossref PubMed Scopus (62) Google Scholar The disease that Laskin et al10Laskin B.L. Goebel J. Starke J.R. Schauer D.P. Eckman M.H. Cost-effectiveness of latent tuberculosis screening before steroid therapy for idiopathic nephrotic syndrome in children.Am J Kidney Dis. 2013; 61: 22-32Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar used in their model, idiopathic nephrotic syndrome, also is associated with defective cell-mediated immunity and impaired quantitative immunoglobulin production.18Taube D. Brown Z. Williams D.G. Impaired lymphocyte and suppressor cell function in minimal change nephropathy, membranous nephropathy and focal glomerulosclerosis.Clin Nephrol. 1984; 22: 176-182PubMed Google Scholar, 19Yokoyama H. Kida H. Abe T. Koshino Y. Yoshimura M. Hattori N. Impaired immunoglobulin G production in minimal change nephrotic syndrome in adults.Clin Exp Immunol. 1987; 70: 110-115PubMed Google Scholar One might expect similar anergic responses to Mantoux testing. However, this has not been studied and the authors do not account for potential anergic responses in their model. Interferon γ release assays (IGRAs) are the newest diagnostic modality to assess for latent TB exposure.20Perez-Velez C.M. Marais B.J. Tuberculosis in children.N Engl J Med. 2012; 367: 348-361Crossref PubMed Scopus (358) Google Scholar IGRAs capture the amount of cytokine (interferon γ) elaborated upon T-cell stimulation by TB species–specific peptide. Two of these assays are in commercial use: the QuantiFERON-TB test, which examines interferon γ levels in whole blood, and the T-SPOT.TB test, which quantifies interferon γ–producing T cells after antigen stimulation. IGRAs may produce indeterminate results when the positive control produces little interferon γ from T cells or high levels of background interferon γ in serum cause the negative control to fail.21Pai M. Lewinsohn D.M. Interferon-gamma assays for tuberculosis: is anergy the Achilles' heel?.Am J Respir Crit Care Med. 2005; 172: 519-521Crossref PubMed Scopus (67) Google Scholar There are several advantages to IGRA testing in general and in the population of dialysis and immunosuppressed patients in particular. It has been shown that interferon γ levels are unaffected by dialysis, although low-flux hemodialysis may alter IGRA results.22Hoogewerf M. Boland G.J. Hoepelman A.I. Boer W.H. Mudrikova T. No influence of haemodialysis on interferon production in the QuantiFERON-TB Gold-In-Tube test.J Nephrol. 2011; 24: 625-630Crossref PubMed Scopus (6) Google Scholar, 23Hursitoglu M. Cikrikcioglu M.A. Tukek T. et al.Acute effect of low-flux hemodialysis process on the results of the interferon-gamma-based QuantiFERON-TB Gold In-Tube test in end-stage renal disease patients.Transpl Infect Dis. 2009; 11: 28-32Crossref PubMed Scopus (20) Google Scholar IGRA testing requires only one health care visit. The specificity of stimulating peptide in IGRA testing eliminates false-positive test results due to BCG vaccinate exposure.24Diel R. Goletti D. Ferrara G. et al.Interferon-gamma release assays for the diagnosis of latent Mycobacterium tuberculosis infection: a systematic review and meta-analysis.Eur Respir J. 2011; 37: 88-99Crossref PubMed Scopus (440) Google Scholar Multiple comparisons of IGRA and Mantoux testing have been performed in dialysis patients. Positive IGRA test results appear to correlate better with recent TB contact than Mantoux testing in this population.25Winthrop K.L. Nyendak M. Calvet H. et al.Interferon-gamma release assays for diagnosing Mycobacterium tuberculosis infection in renal dialysis patients.Clin J Am Soc Nephrol. 2008; 3: 1357-1363Crossref PubMed Scopus (75) Google Scholar, 26Seyhan E.C. Sokucu S. Altin S. et al.Comparison of the QuantiFERON-TB Gold In-Tube test with the tuberculin skin test for detecting latent tuberculosis infection in hemodialysis patients.Transpl Infect Dis. 2010; 12: 98-105Crossref PubMed Scopus (44) Google Scholar A prospective study performed in Taiwan compared QuantiFERON-TB, T-SPOT.TB, and Mantoux testing in dialysis patients with that in age-matched controls and followed up these patients for 2 years to identify cases of active TB. The authors identified numerous cases of latent TB in the dialysis patients and concluded that QuantiFERON-TB was the superior testing modality.27Lee S.S. Chou K.J. Su I.J. et al.High prevalence of latent tuberculosis infection in patients in end-stage renal disease on hemodialysis: comparison of QuantiFERON-TB GOLD, ELISPOT, and tuberculin skin test.Infection. 2009; 37: 96-102Crossref PubMed Scopus (87) Google Scholar IGRA screening has been shown to be at least equivalent and occasionally superior to Mantoux testing in identifying latent TB infection in prospective kidney transplant recipients.28Kim S.H. Lee S.O. Park J.B. et al.A prospective longitudinal study evaluating the usefulness of a T-cell-based assay for latent tuberculosis infection in kidney transplant recipients.Am J Transplant. 2011; 11: 1927-1935Crossref PubMed Scopus (66) Google Scholar, 29Kim S.H. Lee S.O. Park I.A. et al.Diagnostic usefulness of a T cell-based assay for latent tuberculosis infection in kidney transplant candidates before transplantation.Transpl Infect Dis. 2010; 12: 113-119Crossref PubMed Scopus (34) Google Scholar, 30Theodoropoulos N. Lanternier F. Rassiwala J. et al.Use of the QuantiFERON-TB Gold interferon-gamma release assay for screening transplant candidates: a single-center retrospective study.Transpl Infect Dis. 2012; 14: 1-8Crossref PubMed Scopus (30) Google Scholar Significantly, 4 Korean kidney transplant recipients who developed TB posttransplantation had negative Mantoux test results but positive IGRA test results beforehand.28Kim S.H. Lee S.O. Park J.B. et al.A prospective longitudinal study evaluating the usefulness of a T-cell-based assay for latent tuberculosis infection in kidney transplant recipients.Am J Transplant. 2011; 11: 1927-1935Crossref PubMed Scopus (66) Google Scholar IGRA testing also may be superior in patients with depressed cell-mediated immunity, by either disease process (HIV [human immunodeficiency virus]) or medication (tumor necrosis factor α inhibitors).31Richeldi L. Losi M. D'Amico R. et al.Performance of tests for latent tuberculosis in different groups of immunocompromised patients.Chest. 2009; 136: 198-204Crossref PubMed Scopus (130) Google Scholar, 32Jones S. de Gijsel D. Wallach F.R. Gurtman A.C. Shi Q. Sacks H. Utility of QuantiFERON-TB Gold In-Tube testing for latent TB infection in HIV-infected individuals.Int J Tuberc Lung Dis. 2007; 11: 1190-1195PubMed Google Scholar, 33Park J.H. Seo G.Y. Lee J.S. Kim T.H. Yoo D.H. Positive conversion of tuberculin skin test and performance of interferon release assay to detect hidden tuberculosis infection during anti-tumor necrosis factor agent trial.J Rheumatol. 2009; 36: 2158-2163Crossref PubMed Scopus (45) Google Scholar, 34Ringrose J.S. Sanche S.E. Taylor-Gjevre R.M. Detecting latent tuberculosis infection during anti-tumor necrosis factor therapy.Clin Exp Rheumatol. 2011; 29: 790-794PubMed Google Scholar Laskin et al10Laskin B.L. Goebel J. Starke J.R. Schauer D.P. Eckman M.H. Cost-effectiveness of latent tuberculosis screening before steroid therapy for idiopathic nephrotic syndrome in children.Am J Kidney Dis. 2013; 61: 22-32Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar model IGRA testing in a population of 5-year-old children. The authors note that IGRA testing is not yet approved by the US Food and Drug Administration in children and that the utility of IGRA testing in this population is unclear. A recent cross-sectional study performed in Greece concluded that indeterminate QuantiFERON-TB results were more common in children than in adolescents.35Critselis E. Amanatidou V. Syridou G. et al.The effect of age on whole blood interferon-gamma release assay response among children investigated for latent tuberculosis infection.J Pediatr. 2012; 161: 632-638Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Infants were found to have higher background levels of interferon γ.35Critselis E. Amanatidou V. Syridou G. et al.The effect of age on whole blood interferon-gamma release assay response among children investigated for latent tuberculosis infection.J Pediatr. 2012; 161: 632-638Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Pooled analysis from the Pediatric Tuberculosis Network European Trials Group also showed an increase in indeterminate T-SPOT.TB test results in children younger than 5 years.36Basu Roy R. Sotgiu G. Altet-Gomez N. et al.Identifying predictors of interferon-gamma release assay results in pediatric latent tuberculosis: a protective role of BCG?.Am J Respir Crit Care Med. 2012; 186: 378-384Crossref PubMed Scopus (82) Google Scholar The literature shows rates of indeterminate IGRA test results in children to be from 0%-35%.37Chiappini E. Bonsignori F. Accetta G. et al.Interferon-gamma release assays for the diagnosis of Mycobacterium tuberculosis infection in children: a literature review.Int J Immunopathol Pharmacol. 2012; 25: 335-343PubMed Google Scholar In endemic areas of TB, infection, childhood malnutrition, and intestinal parasite infection may contribute to more frequent indeterminate results for IGRAs in children.38Thomas T.A. Mondal D. Noor Z. et al.Malnutrition and helminth infection affect performance of an interferon gamma-release assay.Pediatrics. 2010; 126: e1522-e1529Crossref PubMed Scopus (66) Google Scholar By analyzing children at the age of 5 years, Laskin et al10Laskin B.L. Goebel J. Starke J.R. Schauer D.P. Eckman M.H. Cost-effectiveness of latent tuberculosis screening before steroid therapy for idiopathic nephrotic syndrome in children.Am J Kidney Dis. 2013; 61: 22-32Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar circumvent the subset of children most likely to have indeterminate IGRA results. A recent cost-effectiveness analysis of latent TB management in child contacts of index TB cases used IGRA test parameters specific to children aged 0-5 years and found that clinical history alone without IGRA or Mantoux screen is cost-effective.39Mandalakas AM, Hesseling AC, Gie RP, Schaaf HS, Marais BJ, Sinanovic E. Modelling the cost-effectiveness of strategies to prevent tuberculosis in child contacts in a high-burden setting [published online ahead of print June 20, 2012]. Thorax. doi:10.1136/thoraxjnl-2011-200933.Google Scholar The crux of cost-effective latent TB screening as defined by Laskin et al10Laskin B.L. Goebel J. Starke J.R. Schauer D.P. Eckman M.H. Cost-effectiveness of latent tuberculosis screening before steroid therapy for idiopathic nephrotic syndrome in children.Am J Kidney Dis. 2013; 61: 22-32Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar is the judicious deployment of screening tests (Mantoux or IGRA) according to pretest probability of disease. Laskin et al10Laskin B.L. Goebel J. Starke J.R. Schauer D.P. Eckman M.H. Cost-effectiveness of latent tuberculosis screening before steroid therapy for idiopathic nephrotic syndrome in children.Am J Kidney Dis. 2013; 61: 22-32Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar show that only in areas where TB affects almost one-fifth of the population does it become cost-effective to perform universal Mantoux screening in children with idiopathic nephrotic syndrome before beginning steroid therapy. In scenarios in which TB is less prevalent, a gateway survey for TB risk factors with subsequent IGRA testing in at-risk children is shown to be cost-effective. The authors assume that the burden of TB disease in the endemic population does not impact on IGRA and TST test parameters. However, in patients at high risk of latent TB, Mantoux and IGRA testing may have improved positive and negative predictive values, which underlies the importance of risk stratification for latent TB management.40Diel R. Loddenkemper R. Nienhaus A. Predictive value of interferon-gamma release assays and tuberculin skin testing for predicting progression from latent TB infection to disease state: a meta-analysis.Chest. 2012; 142: 63-75Crossref PubMed Scopus (207) Google Scholar The article by Laskin et al10Laskin B.L. Goebel J. Starke J.R. Schauer D.P. Eckman M.H. Cost-effectiveness of latent tuberculosis screening before steroid therapy for idiopathic nephrotic syndrome in children.Am J Kidney Dis. 2013; 61: 22-32Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar reinforces a time-honored tenet of medicine, namely that sophisticated tests do not replace the importance of taking a comprehensive history in rational economic health care. Financial Disclosure: Dr Kotton is an unpaid scientific consultant to Cellestis, which markets the QuantiFERON-TB assay. Dr Nellore declares that she has no relevant financial interests. Cost-Effectiveness of Latent Tuberculosis Screening Before Steroid Therapy for Idiopathic Nephrotic Syndrome in ChildrenAmerican Journal of Kidney DiseasesVol. 61Issue 1PreviewGuidelines differ on screening recommendations for latent tuberculosis infection (LTBI) prior to immunosuppressive therapy. We aimed to determine the most cost-effective LTBI screening strategy before long-term steroid therapy in a child with new-onset idiopathic nephrotic syndrome. Full-Text PDF