The
n e w e ng l a n d j o u r na l
of
m e dic i n e
c or r e sp ondence
Antimicrobial Prophylaxis for Children with Vesicoureteral Reflux To the Editor: The Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial reported by Hoberman et al. (June 19 issue)1 was similar to our Prevention of Recurrent Urinary Tract Infection in Children with Vesicoureteric Reflux and Normal Renal Tracts (PRIVENT) trial.2 Despite differences in the study populations of the PRIVENT trial and the RIVUR trial, the results were consistent (hazard ratio for the risk of recurrence of urinary tract infection, 0.61; 95% confidence interval [CI], 0.40 to 0.93 vs. 0.5; 95% CI, 0.34 to 0.74). In the RIVUR trial, 80 of 605 participants (13%) were lost to follow-up. This loss was nondifferential, so it was unlikely to bias results, but imputed outcomes based on best or worst scenarios are unusual and their inclusion in the Abstract was surprising. Given that the results of the PRIVENT trial, which were published in 2009, showed that cotrimoxazole prevented urinary tract infection, we wonder how the authors justified continuing the RIVUR trial, exposing some high-risk children to placebo. this week’s letters 1070 Antimicrobial Prophylaxis for Children with Vesicoureteral Reflux 1073 Risk of Celiac Disease According to HLA Haplotype and Country 1074 The Child or Adolescent with Elevated Blood Pressure 1075 Pregnancy and Infection 1077 Medicare Readmission Penalties in Detroit
The rate of kidney damage detected by means of renal scintigraphy with technetium-99m–labeled dimercaptosuccinic acid is low,3 compounding the insufficient power to address this outcome. Only a trial 10 to 100 times larger than RIVUR or PRIVENT could estimate the effect on kidney damage. One subgroup analysis in RIVUR was inconsistent with PRIVENT; the benefit occurred irrespective of whether index urinary tract infections were sensitive to co-trimoxazole. This shows the potential pitfalls of underpowered, nonrandomized subgroup analysis. We hope that with publication of the results of RIVUR, the misleading and methodologically flawed American Academy of Pediatrics (AAP) guidelines on urinary tract infection will be updated and the focus changed from whether antibiotics prevent urinary tract infection to which children would receive a worthwhile benefit from antibiotics. Jonathan C. Craig, M.B., Ch.B., Ph.D. Gabrielle J. Williams, Ph.D., M.P.H. University of Sydney Sydney, NSW, Australia [email protected]
Elisabeth M. Hodson, M.B., B.S. Children’s Hospital at Westmead Sydney, NSW, Australia No potential conflict of interest relevant to this letter was reported. 1. The RIVUR Trial Investigators. Antimicrobial prophylaxis
for children with vesicoureteral reflux. N Engl J Med 2014;370: 2367-76. 2. Craig JC, Simpson JM, Williams GJ, et al. Antibiotic prophylaxis and recurrent urinary tract infection in children. N Engl J Med 2009;361:1748-59. [Erratum, N Engl J Med 2010;362:1250.] 3. Shaikh N, Ewing AL, Bhatnagar S, Hoberman A. Risk of renal scarring in children with a first urinary tract infection: a systematic review. Pediatrics 2010;126:1084-91. DOI: 10.1056/NEJMc1408559
1070
n engl j med 371;11 nejm.org september 11, 2014
The New England Journal of Medicine Downloaded from nejm.org on May 17, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
To the Editor: The RIVUR trial investigators state that the finding of benefit of antimicrobial prophylaxis for children with vesicoureteral reflux “may warrant reconsideration” of the “watchful-waiting approach, without performance of a voiding cystourethrographic study,” which was recommended in the 2011 clinical practice guideline of the AAP.1 My colleagues and I (Drs. Downs, Finnell, Shortliffe, Wald, and Zerin) were authors of the guideline, and we have considered the RIVUR trial findings and the other data available since the guideline was published. We reaffirm the recommendation not to perform voiding cystourethrography routinely in infants 2 to 24 months of age after their first febrile urinary tract infection and normal findings on ultrasonography. The findings in children in the age group of 2 to 24 months (see the Supplementary Appendix, available with the full text of the article by Hoberman et al. at NEJM.org) do not justify subjecting a large number of infants to voiding cystourethrography to identify those with vesicoureteral reflux. Prophylaxis did not reduce the number of infants in whom renal scars developed. In our view, the RIVUR trial does not invalidate the AAP guideline; rather, it supplements it by providing information on the timing and infrequency of recurrences in infants and young children with vesicoureteral reflux. Kenneth B. Roberts, M.D. 3005 Bramblewood Dr. Mebane, NC
for the AAP Subcommittee on Urinary Tract Infection No potential conflict of interest relevant to this letter was reported. 1. Subcommittee on Urinary Tract Infection, Steering Commit-
tee on Quality Improvement and Management. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 2011;128:595-610. DOI: 10.1056/NEJMc1408559
To the Editor: The findings of the RIVUR trial confirm those of recent prospective studies showing that prophylaxis has limited efficacy in preventing urinary tract infections in patients with low grades of vesicoureteral reflux.1 The treatment showed statistical, but not clinical, significance; 16 patient-years of antibiotics were required to prevent one urinary tract infection, and 22 patient-years of antibiotics were required
to prevent one febrile urinary tract infection. Furthermore, the treatment group received in excess of 600 years of prophylaxis without a demonstrable effect on scar formation. One major difference between the RIVUR trial and previous studies was the proportion of boys; 8% of the children in the RIVUR trial were boys, as compared with 33% of the 1660 children who underwent randomization in the previous six studies. An additional concern is the propensity of antibiotics to induce bacterial resistance. As compared with 19% of the children who received placebo, 63% of the children who received antibiotics had Escherichia coli infections that were resistant to trimethoprim–sulfamethoxazole. We believe the data provide support for the current watchful-waiting approach recommended by the most recent guidelines,2-4 without the need to perform voiding cystourethrography after a first uncomplicated febrile urinary tract infection in all young children. Ian Hewitt, M.B., B.S. Princess Margaret Hospital for Children Perth, WA, Australia
Roberto Dall’Amico, M.D., Ph.D. Ospedale di Pordenone Pordenone, Italy
Giovanni Montini, M.D. Azienda Ospedaliero-Universitaria Sant’Orsola-Malpighi Bologna, Italy [email protected] No potential conflict of interest relevant to this letter was reported. 1. Nagler EV, Williams G, Hodson EM, Craig JC. Interventions
for primary vesicoureteric reflux. Cochrane Database Syst Rev 2011;6:CD001532. 2. National Institute for Health and Clinical Excellence. Urinary tract infection in children: diagnosis, treatment and longterm management. 2007 (http://www.nice.org.uk/nicemedia/ pdf/CG54fullguideline.pdf). 3. Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 2011;128:595-610. 4. Ammenti A, Cataldi L, Chimenz R, et al. Febrile urinary tract infections in young children: recommendations for the diagnosis, treatment and follow-up. Acta Paediatr 2012;101:451-7. DOI: 10.1056/NEJMc1408559
To the Editor: Very few boys (8%) were enrolled in the RIVUR trial, so generalizability of the results to boys was limited. Although primary vesicoureteral reflux is more commonly reported in girls, such a huge sex difference has not been shown outside the United States.1-3 This is im-
n engl j med 371;11 nejm.org september 11, 2014
The New England Journal of Medicine Downloaded from nejm.org on May 17, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1071
The
n e w e ng l a n d j o u r na l
portant, because boys did not benefit from prophylaxis in a Swedish trial.3 In the RIVUR trial, some of the subgroup analyses involving a sufficient sample size and event rates are pertinent. The benefit of prophylaxis was insignificant in patients with grade III or IV vesicoureteral reflux and in the absence of bladder and bowel dysfunction. Thus, it appears that prophylaxis benefits a distinct patient population comprising girls with low-grade reflux and bladder and bowel dysfunction, which is consistent with the clinical and genetic heterogeneity of vesicoureteral reflux.4 It appears from this study that prophylaxis would reduce morbidity related to urinary tract infection but not renal scarring and its consequences (hypertension and renal failure), at the cost of increased antimicrobial resistance. A prudent way forward may be to use prophylaxis according to risk stratification rather than according to the mere presence of reflux. Pankaj Hari, M.D. Arvind Bagga, M.D. All India Institute of Medical Sciences Delhi, India [email protected] No potential conflict of interest relevant to this letter was reported. 1. Hannula A, Venhola M, Renko M, Pokka T, Huttunen NP,
Uhari M. Vesicoureteral reflux in children with suspected and proven urinary tract infection. Pediatr Nephrol 2010;25:1463-9. 2. Nakai H, Kakizaki H, Konda R, et al. Clinical characteristics of primary vesicoureteral reflux in infants: multicenter retrospective study in Japan. J Urol 2003;169:309-12. 3. Brandström P, Esbjörner E, Herthelius M, Swerkersson S, Jodal U, Hansson S. The Swedish reflux trial in children: III. Urinary tract infection pattern. J Urol 2010;184:286-91. 4. Williams G, Fletcher JT, Alexander SI, Craig JC. Vesicoureteral reflux. J Am Soc Nephrol 2008;19:847-62. DOI: 10.1056/NEJMc1408559
The Authors Reply: We concur with Craig et al. that the PRIVENT and RIVUR trials unequivocally showed the efficacy of antimicrobial prophylaxis in preventing the recurrence of urinary tract infections. Although the use of imputed results was prespecified in the statistical analysis plan, we emphasized more meaningful nonimputed proportions using Kaplan–Meier analysis. RIVUR was 60% complete when the results of PRIVENT were published; other studies had questioned the role of prophylaxis.1 Scarring, a secondary outcome, would have required 8000 children for adequate power. The editorial by Ingelfinger and Stapleton2 that accompanied our article indicated that the debate regarding the benefit of prophylaxis remains contentious. We agree that 1072
of
m e dic i n e
the focus should shift to which children would benefit from prophylaxis. Roberts reaffirmed the 2011 AAP recommendation not to perform voiding cystourethrography routinely in infants with a first febrile urinary tract infection and normal findings on ultrasonography. Ultrasonography is poor at identifying both high-grade and low-grade reflux3; this was the case in RIVUR at study entry. The PRIVENT and RIVUR trials evaluated a total of 1183 children in a double-blind, placebocontrolled fashion; antimicrobial prophylaxis was superior to placebo in preventing recurrences. All children in RIVUR had a well-characterized urinary tract infection and vesicoureteral reflux at study entry. Scarring never constituted a primary outcome of RIVUR; we remain concerned about the morbidity of recurrent urinary tract infections. Accordingly, we defer conclusions on imaging pending decision analyses and cost-effectiveness analyses that are under way with the use of RIVUR data. Unlike Hewitt et al., we do not consider a hazard ratio of 0.5 to indicate “limited efficacy” in preventing recurrences. Although children with higher grades of vesicoureteral reflux were more likely to have reinfections, a trend was noted for prophylaxis resulting in more protection against recurrences in children with grade I or II reflux than in children with grade III or IV (hazard ratio, 0.32 vs. 0.66; P = 0.08). With regard to resistance, differences on stool colonization were nonsignificant. When children receive antimicrobial prophylaxis, we expect that recurrent pathogens will be resistant to that agent, unless there is nonadherence. Because most practitioners would switch to a third-generation cephalosporin for treatment, this has little impact clinically. RIVUR was not designed to assess the need for voiding cystourethrography after a urinary tract infection — all participants had known vesicoureteral reflux. We agree with Hari and Bagga about the heterogeneity of vesicoureteral reflux. In the current study and in a previous study, we evaluated a U.S. population in which girls predominate.1 The RIVUR trial examined the efficacy of antimicrobial prophylaxis in children 2 months to 6 years of age with vesicoureteral reflux after urinary tract infection. Twice as many children who received placebo had reinfections, and the effect of prophylaxis did not wane over the 2-year study period.
n engl j med 371;11 nejm.org september 11, 2014
The New England Journal of Medicine Downloaded from nejm.org on May 17, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence 1. Hoberman A, Keren R. Antimicrobial prophylaxis for uri-
Alejandro Hoberman, M.D.
Le Bonheur Children’s Hospital Memphis, TN
nary tract infection in children. N Engl J Med 2009;361:1804-6. 2. Ingelfinger JR, Stapleton FB. Antibiotic prophylaxis for vesicoureteral reflux — answers, yet questions. N Engl J Med 2014;370:2440-1. 3. Nelson CP, Johnson EK, Logvinenko T, Chow JS. Ultrasound as a screening test for genitourinary anomalies in children with UTI. Pediatrics 2014;133(3):e394-e403.
for the RIVUR Trial Investigators
DOI: 10.1056/NEJMc1408559
University of Pittsburgh School of Medicine Pittsburgh, PA [email protected]
Russell W. Chesney, M.D.
Since publication of their article, the authors report no further potential conflict of interest.
Risk of Celiac Disease According to HLA Haplotype and Country To the Editor: The Environmental Determinants of Diabetes in the Young (TEDDY) study by Liu et al. (July 3 issue)1 explored the genetic and environmental contributions to the development of celiac disease autoimmunity. However, the authors did not address gut colonization as a cornerstone environmental factor. Important components of initial gut colonization in infants are the method of delivery and diet. Normal colonization occurs when full-term neonates are born by vaginal delivery and are exclusively breast-fed during the first 6 months of life. In contrast, infants who are born by cesarean section or bottle-fed have inadequate initial colonization and mucosal immune dysfunction, leading to an increased risk of allergic and autoimmune diseases.2 There is strong evidence that disruption of the normal colonization process with aberrant probiotic flora can lead to alterations in the symbiotic relationship that is necessary for immune homeostasis and may be involved in the development of autoimmunity (e.g., in celiac disease and type 1 diabetes).3,4 We think that the method of delivery, as well as the method of feeding, should be considered as relevant variables and important environmental risk factors. Hakim Rahmoune, M.D. Nada Boutrid, M.D. Belkacem Bioud, M.D. University Hospital of Sétif Sétif, Algeria
2. Walker WA. Initial intestinal colonization in the human in-
fant and immune homeostasis. Ann Nutr Metab 2013;63:Suppl 2: 8-15. 3. Sánchez E, De Palma G, Capilla A, et al. Influence of environmental and genetic factors linked to celiac disease risk on infant gut colonization by Bacteroides species. Appl Environ Microbiol 2011;77:5316-23. 4. Peng J, Narasimhan S, Marchesi JR, Benson A, Wong FS, Wen L. Long term effect of gut microbiota transfer on diabetes development. J Autoimmun 2014 April 22 (Epub ahead of print). DOI: 10.1056/NEJMc1409252
To the Editor: Liu and colleagues conclude that environmental risk factors, which in their study correlated with Swedish residence, influence the development of celiac disease. One striking result that was not commented on was the role of female sex as a strong risk factor. The literature is inconsistent regarding whether celiac disease is more common in women. Three screening studies from the United States showed that it is equally prevalent among men and women.1-3 However, a Swedish study showed that the prevalence of celiac disease among girls was approximately double that among boys4; this finding was similar to the finding by Liu and colleagues. Since it appears that environmental risk factors may differentially affect the two sexes, it would be of particular interest to know whether the effect of sex on the risk of celiac disease varied among the countries in this study. Benjamin Lebwohl, M.D. Peter Green, M.D. Columbia University New York, NY
[email protected]
[email protected] No potential conflict of interest relevant to this letter was reported. 1. Liu E, Lee HS, Aronsson CA, et al. Risk of pediatric celiac
disease according to HLA haplotype and country. N Engl J Med 2014;371:42-9. [Erratum, N Engl J Med 2014;371:390.]
No potential conflict of interest relevant to this letter was reported. 1. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac
disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med 2003;163:286-92.
n engl j med 371;11 nejm.org september 11, 2014
The New England Journal of Medicine Downloaded from nejm.org on May 17, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1073
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Antimicrobial Prophylaxis for Children with Vesicoureteral Reflux To the Editor: The Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial reported by Hoberman et al. (June 19 issue)1 was similar to our Prevention of Recurrent Urinary Tract Infection in Children with Vesicoureteric Reflux and Normal Renal Tracts (PRIVENT) trial.2 Despite differences in the study populations of the PRIVENT trial and the RIVUR trial, the results were consistent (hazard ratio for the risk of recurrence of urinary tract infection, 0.61; 95% confidence interval [CI], 0.40 to 0.93 vs. 0.5; 95% CI, 0.34 to 0.74). In the RIVUR trial, 80 of 605 participants (13%) were lost to follow-up. This loss was nondifferential, so it was unlikely to bias results, but imputed outcomes based on best or worst scenarios are unusual and their inclusion in the Abstract was surprising. Given that the results of the PRIVENT trial, which were published in 2009, showed that cotrimoxazole prevented urinary tract infection, we wonder how the authors justified continuing the RIVUR trial, exposing some high-risk children to placebo. this week’s letters 1070 Antimicrobial Prophylaxis for Children with Vesicoureteral Reflux 1073 Risk of Celiac Disease According to HLA Haplotype and Country 1074 The Child or Adolescent with Elevated Blood Pressure 1075 Pregnancy and Infection 1077 Medicare Readmission Penalties in Detroit
The rate of kidney damage detected by means of renal scintigraphy with technetium-99m–labeled dimercaptosuccinic acid is low,3 compounding the insufficient power to address this outcome. Only a trial 10 to 100 times larger than RIVUR or PRIVENT could estimate the effect on kidney damage. One subgroup analysis in RIVUR was inconsistent with PRIVENT; the benefit occurred irrespective of whether index urinary tract infections were sensitive to co-trimoxazole. This shows the potential pitfalls of underpowered, nonrandomized subgroup analysis. We hope that with publication of the results of RIVUR, the misleading and methodologically flawed American Academy of Pediatrics (AAP) guidelines on urinary tract infection will be updated and the focus changed from whether antibiotics prevent urinary tract infection to which children would receive a worthwhile benefit from antibiotics. Jonathan C. Craig, M.B., Ch.B., Ph.D. Gabrielle J. Williams, Ph.D., M.P.H. University of Sydney Sydney, NSW, Australia [email protected]
Elisabeth M. Hodson, M.B., B.S. Children’s Hospital at Westmead Sydney, NSW, Australia No potential conflict of interest relevant to this letter was reported. 1. The RIVUR Trial Investigators. Antimicrobial prophylaxis
for children with vesicoureteral reflux. N Engl J Med 2014;370: 2367-76. 2. Craig JC, Simpson JM, Williams GJ, et al. Antibiotic prophylaxis and recurrent urinary tract infection in children. N Engl J Med 2009;361:1748-59. [Erratum, N Engl J Med 2010;362:1250.] 3. Shaikh N, Ewing AL, Bhatnagar S, Hoberman A. Risk of renal scarring in children with a first urinary tract infection: a systematic review. Pediatrics 2010;126:1084-91. DOI: 10.1056/NEJMc1408559
1070
n engl j med 371;11 nejm.org september 11, 2014
The New England Journal of Medicine Downloaded from nejm.org on May 17, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
To the Editor: The RIVUR trial investigators state that the finding of benefit of antimicrobial prophylaxis for children with vesicoureteral reflux “may warrant reconsideration” of the “watchful-waiting approach, without performance of a voiding cystourethrographic study,” which was recommended in the 2011 clinical practice guideline of the AAP.1 My colleagues and I (Drs. Downs, Finnell, Shortliffe, Wald, and Zerin) were authors of the guideline, and we have considered the RIVUR trial findings and the other data available since the guideline was published. We reaffirm the recommendation not to perform voiding cystourethrography routinely in infants 2 to 24 months of age after their first febrile urinary tract infection and normal findings on ultrasonography. The findings in children in the age group of 2 to 24 months (see the Supplementary Appendix, available with the full text of the article by Hoberman et al. at NEJM.org) do not justify subjecting a large number of infants to voiding cystourethrography to identify those with vesicoureteral reflux. Prophylaxis did not reduce the number of infants in whom renal scars developed. In our view, the RIVUR trial does not invalidate the AAP guideline; rather, it supplements it by providing information on the timing and infrequency of recurrences in infants and young children with vesicoureteral reflux. Kenneth B. Roberts, M.D. 3005 Bramblewood Dr. Mebane, NC
for the AAP Subcommittee on Urinary Tract Infection No potential conflict of interest relevant to this letter was reported. 1. Subcommittee on Urinary Tract Infection, Steering Commit-
tee on Quality Improvement and Management. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 2011;128:595-610. DOI: 10.1056/NEJMc1408559
To the Editor: The findings of the RIVUR trial confirm those of recent prospective studies showing that prophylaxis has limited efficacy in preventing urinary tract infections in patients with low grades of vesicoureteral reflux.1 The treatment showed statistical, but not clinical, significance; 16 patient-years of antibiotics were required to prevent one urinary tract infection, and 22 patient-years of antibiotics were required
to prevent one febrile urinary tract infection. Furthermore, the treatment group received in excess of 600 years of prophylaxis without a demonstrable effect on scar formation. One major difference between the RIVUR trial and previous studies was the proportion of boys; 8% of the children in the RIVUR trial were boys, as compared with 33% of the 1660 children who underwent randomization in the previous six studies. An additional concern is the propensity of antibiotics to induce bacterial resistance. As compared with 19% of the children who received placebo, 63% of the children who received antibiotics had Escherichia coli infections that were resistant to trimethoprim–sulfamethoxazole. We believe the data provide support for the current watchful-waiting approach recommended by the most recent guidelines,2-4 without the need to perform voiding cystourethrography after a first uncomplicated febrile urinary tract infection in all young children. Ian Hewitt, M.B., B.S. Princess Margaret Hospital for Children Perth, WA, Australia
Roberto Dall’Amico, M.D., Ph.D. Ospedale di Pordenone Pordenone, Italy
Giovanni Montini, M.D. Azienda Ospedaliero-Universitaria Sant’Orsola-Malpighi Bologna, Italy [email protected] No potential conflict of interest relevant to this letter was reported. 1. Nagler EV, Williams G, Hodson EM, Craig JC. Interventions
for primary vesicoureteric reflux. Cochrane Database Syst Rev 2011;6:CD001532. 2. National Institute for Health and Clinical Excellence. Urinary tract infection in children: diagnosis, treatment and longterm management. 2007 (http://www.nice.org.uk/nicemedia/ pdf/CG54fullguideline.pdf). 3. Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 2011;128:595-610. 4. Ammenti A, Cataldi L, Chimenz R, et al. Febrile urinary tract infections in young children: recommendations for the diagnosis, treatment and follow-up. Acta Paediatr 2012;101:451-7. DOI: 10.1056/NEJMc1408559
To the Editor: Very few boys (8%) were enrolled in the RIVUR trial, so generalizability of the results to boys was limited. Although primary vesicoureteral reflux is more commonly reported in girls, such a huge sex difference has not been shown outside the United States.1-3 This is im-
n engl j med 371;11 nejm.org september 11, 2014
The New England Journal of Medicine Downloaded from nejm.org on May 17, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1071
The
n e w e ng l a n d j o u r na l
portant, because boys did not benefit from prophylaxis in a Swedish trial.3 In the RIVUR trial, some of the subgroup analyses involving a sufficient sample size and event rates are pertinent. The benefit of prophylaxis was insignificant in patients with grade III or IV vesicoureteral reflux and in the absence of bladder and bowel dysfunction. Thus, it appears that prophylaxis benefits a distinct patient population comprising girls with low-grade reflux and bladder and bowel dysfunction, which is consistent with the clinical and genetic heterogeneity of vesicoureteral reflux.4 It appears from this study that prophylaxis would reduce morbidity related to urinary tract infection but not renal scarring and its consequences (hypertension and renal failure), at the cost of increased antimicrobial resistance. A prudent way forward may be to use prophylaxis according to risk stratification rather than according to the mere presence of reflux. Pankaj Hari, M.D. Arvind Bagga, M.D. All India Institute of Medical Sciences Delhi, India [email protected] No potential conflict of interest relevant to this letter was reported. 1. Hannula A, Venhola M, Renko M, Pokka T, Huttunen NP,
Uhari M. Vesicoureteral reflux in children with suspected and proven urinary tract infection. Pediatr Nephrol 2010;25:1463-9. 2. Nakai H, Kakizaki H, Konda R, et al. Clinical characteristics of primary vesicoureteral reflux in infants: multicenter retrospective study in Japan. J Urol 2003;169:309-12. 3. Brandström P, Esbjörner E, Herthelius M, Swerkersson S, Jodal U, Hansson S. The Swedish reflux trial in children: III. Urinary tract infection pattern. J Urol 2010;184:286-91. 4. Williams G, Fletcher JT, Alexander SI, Craig JC. Vesicoureteral reflux. J Am Soc Nephrol 2008;19:847-62. DOI: 10.1056/NEJMc1408559
The Authors Reply: We concur with Craig et al. that the PRIVENT and RIVUR trials unequivocally showed the efficacy of antimicrobial prophylaxis in preventing the recurrence of urinary tract infections. Although the use of imputed results was prespecified in the statistical analysis plan, we emphasized more meaningful nonimputed proportions using Kaplan–Meier analysis. RIVUR was 60% complete when the results of PRIVENT were published; other studies had questioned the role of prophylaxis.1 Scarring, a secondary outcome, would have required 8000 children for adequate power. The editorial by Ingelfinger and Stapleton2 that accompanied our article indicated that the debate regarding the benefit of prophylaxis remains contentious. We agree that 1072
of
m e dic i n e
the focus should shift to which children would benefit from prophylaxis. Roberts reaffirmed the 2011 AAP recommendation not to perform voiding cystourethrography routinely in infants with a first febrile urinary tract infection and normal findings on ultrasonography. Ultrasonography is poor at identifying both high-grade and low-grade reflux3; this was the case in RIVUR at study entry. The PRIVENT and RIVUR trials evaluated a total of 1183 children in a double-blind, placebocontrolled fashion; antimicrobial prophylaxis was superior to placebo in preventing recurrences. All children in RIVUR had a well-characterized urinary tract infection and vesicoureteral reflux at study entry. Scarring never constituted a primary outcome of RIVUR; we remain concerned about the morbidity of recurrent urinary tract infections. Accordingly, we defer conclusions on imaging pending decision analyses and cost-effectiveness analyses that are under way with the use of RIVUR data. Unlike Hewitt et al., we do not consider a hazard ratio of 0.5 to indicate “limited efficacy” in preventing recurrences. Although children with higher grades of vesicoureteral reflux were more likely to have reinfections, a trend was noted for prophylaxis resulting in more protection against recurrences in children with grade I or II reflux than in children with grade III or IV (hazard ratio, 0.32 vs. 0.66; P = 0.08). With regard to resistance, differences on stool colonization were nonsignificant. When children receive antimicrobial prophylaxis, we expect that recurrent pathogens will be resistant to that agent, unless there is nonadherence. Because most practitioners would switch to a third-generation cephalosporin for treatment, this has little impact clinically. RIVUR was not designed to assess the need for voiding cystourethrography after a urinary tract infection — all participants had known vesicoureteral reflux. We agree with Hari and Bagga about the heterogeneity of vesicoureteral reflux. In the current study and in a previous study, we evaluated a U.S. population in which girls predominate.1 The RIVUR trial examined the efficacy of antimicrobial prophylaxis in children 2 months to 6 years of age with vesicoureteral reflux after urinary tract infection. Twice as many children who received placebo had reinfections, and the effect of prophylaxis did not wane over the 2-year study period.
n engl j med 371;11 nejm.org september 11, 2014
The New England Journal of Medicine Downloaded from nejm.org on May 17, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence 1. Hoberman A, Keren R. Antimicrobial prophylaxis for uri-
Alejandro Hoberman, M.D.
Le Bonheur Children’s Hospital Memphis, TN
nary tract infection in children. N Engl J Med 2009;361:1804-6. 2. Ingelfinger JR, Stapleton FB. Antibiotic prophylaxis for vesicoureteral reflux — answers, yet questions. N Engl J Med 2014;370:2440-1. 3. Nelson CP, Johnson EK, Logvinenko T, Chow JS. Ultrasound as a screening test for genitourinary anomalies in children with UTI. Pediatrics 2014;133(3):e394-e403.
for the RIVUR Trial Investigators
DOI: 10.1056/NEJMc1408559
University of Pittsburgh School of Medicine Pittsburgh, PA [email protected]
Russell W. Chesney, M.D.
Since publication of their article, the authors report no further potential conflict of interest.
Risk of Celiac Disease According to HLA Haplotype and Country To the Editor: The Environmental Determinants of Diabetes in the Young (TEDDY) study by Liu et al. (July 3 issue)1 explored the genetic and environmental contributions to the development of celiac disease autoimmunity. However, the authors did not address gut colonization as a cornerstone environmental factor. Important components of initial gut colonization in infants are the method of delivery and diet. Normal colonization occurs when full-term neonates are born by vaginal delivery and are exclusively breast-fed during the first 6 months of life. In contrast, infants who are born by cesarean section or bottle-fed have inadequate initial colonization and mucosal immune dysfunction, leading to an increased risk of allergic and autoimmune diseases.2 There is strong evidence that disruption of the normal colonization process with aberrant probiotic flora can lead to alterations in the symbiotic relationship that is necessary for immune homeostasis and may be involved in the development of autoimmunity (e.g., in celiac disease and type 1 diabetes).3,4 We think that the method of delivery, as well as the method of feeding, should be considered as relevant variables and important environmental risk factors. Hakim Rahmoune, M.D. Nada Boutrid, M.D. Belkacem Bioud, M.D. University Hospital of Sétif Sétif, Algeria
2. Walker WA. Initial intestinal colonization in the human in-
fant and immune homeostasis. Ann Nutr Metab 2013;63:Suppl 2: 8-15. 3. Sánchez E, De Palma G, Capilla A, et al. Influence of environmental and genetic factors linked to celiac disease risk on infant gut colonization by Bacteroides species. Appl Environ Microbiol 2011;77:5316-23. 4. Peng J, Narasimhan S, Marchesi JR, Benson A, Wong FS, Wen L. Long term effect of gut microbiota transfer on diabetes development. J Autoimmun 2014 April 22 (Epub ahead of print). DOI: 10.1056/NEJMc1409252
To the Editor: Liu and colleagues conclude that environmental risk factors, which in their study correlated with Swedish residence, influence the development of celiac disease. One striking result that was not commented on was the role of female sex as a strong risk factor. The literature is inconsistent regarding whether celiac disease is more common in women. Three screening studies from the United States showed that it is equally prevalent among men and women.1-3 However, a Swedish study showed that the prevalence of celiac disease among girls was approximately double that among boys4; this finding was similar to the finding by Liu and colleagues. Since it appears that environmental risk factors may differentially affect the two sexes, it would be of particular interest to know whether the effect of sex on the risk of celiac disease varied among the countries in this study. Benjamin Lebwohl, M.D. Peter Green, M.D. Columbia University New York, NY
[email protected]
[email protected] No potential conflict of interest relevant to this letter was reported. 1. Liu E, Lee HS, Aronsson CA, et al. Risk of pediatric celiac
disease according to HLA haplotype and country. N Engl J Med 2014;371:42-9. [Erratum, N Engl J Med 2014;371:390.]
No potential conflict of interest relevant to this letter was reported. 1. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac
disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med 2003;163:286-92.
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