Csoma, Zsanett

Kemény, Lajos

Oláh, Judit Magdolna

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T h e  n e w  e ng l a nd  j o u r na l  o f  m e dic i n en engl j med 358;23 www.nejm.org june 5, 20082522sequence of immunosuppression, which has impli-cations for all so-called nonpersistent pathogens. Previously, we observed prolonged and possibly chronic shedding of human metapneumovirus in two patients with cancer who were immunosup-pressed because they were receiving chemother-apy.2 Furthermore, it was recently reported that immunosuppression induced by lactate dehydro-genase–elevating virus led to increases in the se-verity and duration of the acute phase of friend virus infection in mice, most likely because of diminished CD8− responses.3 Such observations may provide support for earlier assumptions that if the CD4+ defense is insufficient because of im-munosuppression, the CD8− response is unlikely to eliminate infection.4 The study by Kamar et al. revealed significantly reduced CD4− counts in pa-tients with chronic HEV infection. Under these specific circumstances, so-called nonpersistent viruses may cause chronic colonization and re-current infection. Hence, reducing drug-induced immunosuppression during acute HEV infection might be a strategy to prevent the progression to chronic hepatitis.Oliver Schildgen, Ph.D. Andreas Müller, M.D. Arne Simon, M.D.University of Bonn 53105 Bonn, Germany schildgen@virology-bonn.deKamar N, Selves J, Mansuy J-M, et al. Hepatitis E virus and chronic hepatitis in organ-transplant recipients. N Engl J Med 2008;358:811-7.Wilkesmann A, Schildgen O, Eis-Hübinger AM, et al. Hu-man metapneumovirus infections cause similar symptoms and clinical severity as respiratory syncytial virus infections. Eur J Pe-diatr 2006;165:467-75.Robertson SJ, Ammann CG, Messer RJ, et al. Suppression of acute anti-friend virus CD8+ T-cell responses by coinfection with lactate dehydrogenase-elevating virus. J Virol 2008;82:408-18.Wherry EJ, Ha SJ, Kaech SM, et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immu-nity 2007;27:670-84. [Erratum, Immunity 2007;27:824.]1.2.3.4.The Authors Reply: With regard to the com-ments by Schildgen et al., prolonged acute hepa-titis A virus and HEV infections have been report-ed previously in both immunocompromised and nonimmunocompromised patients.1,2 Our report indicated that HEV infection may evolve to chron-ic hepatitis in organ-transplant recipients. In ad-dition, a unique case of HEV-related cirrhosis has recently been reported.3 Schildgen et al. suggest that the evolution of HEV infection to chronic hepatitis is related to marked immunosuppres-sion. They base their assumption on two studies of viral infections that appear to be unrelated to those that have been observed in organ-transplant recipients. We agree that the evolution of HEV in-fection to chronic hepatitis in the setting of marked immunosuppression may be a mechanism, since we have found a lower CD4+ cell count in patients in whom chronic hepatitis evolved than in patients who were clear of the virus. Hence, in HEV-infected transplant recipients, we suggest reducing immu-nosuppressive therapies that target T cells (i.e., mainly calcineurin inhibitors) in order to allow clearance of the virus.Nassim Kamar, M.D., Ph.D. Jacques Izopet, Pharm.D., Ph.D. Lionel Rostaing, M.D., Ph.D.Toulouse University Hospital 31059 Toulouse, France kamar.n@chu-toulouse.frCosta-Mattioli M, Allavena C, Poirier AS, Billaudel S, Raffi F, Ferré V. Prolonged hepatitis A infection in an HIV-1 seropositive patient. J Med Virol 2002;68:7-11.Tamura A, Shimizu YK, Tanaka T, et al. Persistent infection of hepatitis E virus transmitted by blood transfusion in a patient with T-cell lymphoma. Hepatol Res 2007;37:113-20.Gérolami R, Moal V, Colson P. Chronic hepatitis E with cir-rhosis in a kidney-transplant recipient. N Engl J Med 2008;358: 859-60.1.2.3.Phototherapy for Neonatal JaundiceTo the Editor: In their Clinical Therapeutics ar-ticle on phototherapy for neonatal jaundice, Maisels and McDonagh (Feb. 28 issue)1 describe various mechanisms for maximizing the efficacy of pho-totherapy. They state, “The dose and efficacy of phototherapy are also affected by the infant’s dis-tance from the light (the nearer the light source, the greater the irradiance).” However, this state-ment must be applied with great care. Indeed, guidelines from the American Academy of Pedi-atrics Subcommittee on Hyperbilirubinemia spe-cifically urge caution when halogen lamps, which Copyright © 2008 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org by LAJOS KEMENY MD on July 24, 2008 . correspondencen engl j med 358;23 www.nejm.org june 5, 2008 2523can generate significant amounts of heat, are used.2 Placing these lamps as close as possible increases the risk of burns. Thus, physicians should be aware of this untoward side effect when positioning a halogen light to obtain maximum irradiance of a newborn with jaundice.Roger Kapoor, M.D., M.B.A.Stanford University Palo Alto, CA 94305 rkapoor1@stanford.eduMaisels MJ, McDonagh AF. Phototherapy for neonatal jaun-dice. N Engl J Med 2008;358:920-8.American Academy of Pediatrics Subcommittee on Hyper-bilirubinemia. Management of hyperbilirubinemia in the new-born infant 35 or more weeks of gestation. Pediatrics 2004;114: 297-316. [Erratum, Pediatrics 2004;114:1138.]To the Editor: In their review of phototherapy for neonatal jaundice, Maisels and McDonagh cite our work, suggesting that this form of therapy may influence the development of dysplastic nevi.1,2 We have now investigated the prevalence of me-lanocytic nevi among 11 monozygotic twin pairs 1.2.in which one twin received phototherapy for neo-natal jaundice and the other did not. Neonatal blue-light phototherapy was associated with a consid-erably higher number of common and clinically atypical nevi (Table 1). The increased number of nevi on persons receiving phototherapy might well be due to the effects of light on neonatal skin. Ultraviolet A light has profound immunosuppres-sive effects and is sufficient to induce melanoma and melanoma precursors in animal models.3 Moreover, visible light has also been shown to ex-ert indirect DNA damage through the generation of reactive oxygen species.4 In view of the imma-turity of the skin and immune system in newborns, intensive neonatal phototherapy could markedly influence melanocytes and nevus development.Zsanett Csoma, M.D., Ph.D. Lajos Kemeny, M.D., Ph.D. Judit Olah, M.D., Ph.D.University of Szeged 6720 Szeged, Hungary csomazs@mail.derma.szote.u-szeged.huTable 1. Prevalence of Common and Clinically Atypical Melanocytic Nevi in 11 Monozygotic Twin Pairs in Which One Twin Received Neonatal Blue-Light Phototherapy (BLP) and the Other Twin Did Not.*Twin Pair No. Sex AgeNo. of Common  Melanocytic NeviNo. of Clinically Atypical Melanocytic NeviTotal No. of  Melanocytic NeviNo BLP BLP No BLP BLP No BLP BLPyr1 M 6 0 3 0 0 0 32 F 8 1 4 0 0 1 43 M 11 4 17 1 3 5 204 F 14 26 28 0 5 26 335 M 14 12 27 2 4 14 316 M 18 3 3 0 1 3 47 M 20 11 12 0 1 11 138 F 23 21 15 1 3 22 189 M 24 8 9 0 1 8 1010 F 24 9 27 0 3 9 3011 M 30 3 12 3 13 6 25P value 0.03 0.008 0.02* Differences in the prevalence of common and clinically atypical melanocytic nevi between the exposed and nonex-posed subjects were analyzed by means of a two-sided Wilcoxon signed-rank test (SPSS software, version 15.0). P val-ues of less than 0.05 were considered to indicate statistical significance. Data concerning the neonatal history of the subjects were based on the official neonatal medical charts. A detailed standardized questionnaire was used to assess data concerning constitutional factors, sun exposure, and other variables; these factors proved to be very consistent in the examined twin pairs.Copyright © 2008 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org by LAJOS KEMENY MD on July 24, 2008 . T h e  n e w  e ng l a nd  j o u r na l  o f  m e dic i n en engl j med 358;23 www.nejm.org june 5, 20082524Csoma Z, Hencz P, Orvos H, et al. Neonatal blue-light pho-totherapy could increase the risk of dysplastic nevus develop-ment. Pediatrics 2007;119:1036-7.Idem. Neonatal blue-light phototherapy could increase the risk of dysplastic nevus development. Pediatrics 2007;119:1269.Wang SQ, Setlow R, Berwick M, et al. Ultraviolet A and mel-anoma: a review. J Am Acad Dermatol 2001;44:837-46.Mahmoud BH, Hexsel CL, Hamzavi IH, Lim HW. Effects of visible light on the skin. Photochem Photobiol 2008;84:450-62.To the Editor: The article by Maisels and Mc-Donagh succinctly summarizes the mechanisms and application of phototherapy for jaundiced new-borns. The authors promote the guidelines for using phototherapy that were published in 2004 by the American Academy of Pediatrics,1 which are based primarily on total serum bilirubin levels. They admit that these guidelines are not evidence-based, but rely primarily on expert opinion, and that “many infants are treated [2 to 3% of term or near-term infants and 150,000 to 250,000 pre-mature infants each year] whose levels of total se-rum bilirubin would not have reached the thresh-old for exchange transfusion had phototherapy been withheld.”The authors fail, however, to mention that theo-retical considerations,2 substantial experimental data,3,4 and increasing evidence in human new-borns5 all indicate that total serum bilirubin is a poor predictor of bilirubin-induced neurologic damage, whereas unbound (“free”) bilirubin lev-els correlate well with neurotoxicity. Establishing evidence-based guidelines for phototherapy (and exchange transfusion), with the use of unbound (free) bilirubin measurements, could significantly improve selection and reduce the number of in-fants requiring these treatments, as well as de-crease hospital readmissions and the associated health care costs.J. Donald Ostrow, M.D. Richard P. Wennberg, M.D., Ph.D.University of Washington School of Medicine Seattle, WA 98195-6424 jdostrow@medicine.washington.eduClaudio Tiribelli, M.D., Ph.D.University of Trieste 34012 Trieste, ItalyAmerican Academy of Pediatrics Subcommittee on Hyper-bilirubinemia. Management of hyperbilirubinemia in the new-born infant 35 or more weeks of gestation. Pediatrics 2004;114: 297-316. [Erratum, Pediatrics 2004;114:1138.]Ostrow JD, Pascolo L, Brites D, Tiribelli C. Molecular basis of bilirubin-induced neurotoxicity. Trends Mol Med 2004;10: 65-70.Calligaris SD, Bellarosa C, Giraudi P, Wennberg RP, Ostrow 1.2.3.4.1.2.3.JD, Tiribelli C. Cytotoxicity is predicted by unbound and not to-tal bilirubin concentration. Pediatr Res 2007;62:576-80.Ahlfors CE, Shapiro SM. Auditory brainstem response and unbound bilirubin in jaundiced (jj) Gunn rat pups. Biol Neonate 2001;80:158-62.Wennberg RP, Ahlfors CE, Bhutani VK, Johnson LH, Shapiro SM. Toward understanding kernicterus: a challenge to improve the management of jaundiced newborns. Pediatrics 2006;117: 474-85. [Erratum, Pediatrics 2006;117:1467.]The authors reply: Kapoor draws attention to an important issue. Halogen and tungsten lights should not be placed closer to the baby than rec-ommended by the manufacturer because of the danger of a burn. We noted this in our article (Fig. 3 legend), and it is also a recommendation of the American Academy of Pediatrics guidelines.1As noted by Csoma et al., the development of dysplastic nevi is a concern requiring further inves-tigation. It is difficult to evaluate their findings because of a lack of information about the spec-tral emission of the phototherapy lights, partic-ularly their ultraviolet output; the distribution of the nevi; and the patients’ skin types. Properly shielded fluorescent lamps emit little radiation (<400 nm),2 and blue light-emitting-diode (LED) lights none at all. Although the findings in twin pairs might appear to be persuasive, the untreat-ed twin is not an adequate control for the effects of phototherapy light on the treated twin. Proper sibling controls would need to be treated identi-cally to their twins but not exposed to blue light or, alternatively, exposed to the same fixtures con-taining lamps with only long-wavelength visible emission. In the absence of proper controls, the results reported could equally well be attributed, for example, to effects of electromagnetic-field radiation from the light-fixture ballasts as to ef-fects of the phototherapy light. Reassuringly, to our knowledge, there are no reports of increased nevus formation in patients with the Crigler–Naj-jar syndrome who have received daily photother-apy since birth.It is well known that the total bilirubin con-centration alone is a poor predictor of kernicterus. Nevertheless, the risk of bilirubin encephalopathy increases with the bilirubin concentration at high bilirubin levels. Kernicterus in term and late-pre-term infants is almost always associated with bilirubin concentrations higher than 25 mg per deciliter (428 μmol per liter) and rarely occurs at lower concentrations. Therefore, the total biliru-bin concentration, which is readily measured, is 4.5.Copyright © 2008 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org by LAJOS KEMENY MD on July 24, 2008 . correspondencen engl j med 358;23 www.nejm.org june 5, 2008 2525not to be ignored. The idea that unbound (“free”) bilirubin levels are useful in improving the selec-tion of infants requiring treatment is a long-stand-ing hypothesis that requires validation. Currently, such measurements are not offered by clinical laboratories in the United States, and there is con-cern that bilirubin photoisomers may complicate their interpretation.3 Alternatives are the biliru-bin:albumin molar ratio and the reserve bilirubin-binding capacity of albumin in serum,4,5 which are more easily measured and might also facilitate identification of infants at greatest risk. Currently, attempts are being made to refine the American Academy of Pediatrics guidelines and reduce un-necessary treatment.M. Jeffrey Maisels, M.B., B.Ch.William Beaumont Hospital Royal Oak, MI 48073 jmaisels@beaumont.eduAntony F. McDonagh, Ph.D.University of California at San Francisco San Francisco, CA 94143American Academy of Pediatrics Subcommittee on Hyper-bilirubinemia. Management of hyperbilirubinemia in the new-born infant 35 or more weeks of gestation. Pediatrics 2004;114: 297-316. [Erratum, Pediatrics 2004;114:1138.]Gies HP, Roy CR. Bilirubin phototherapy and potential UVR hazards. Health Phys 1990;58:313-20.McDonagh AF, Wong RJ, Vreman HJ. Photoisomers — ob-fuscating factors in clinical peroxidase measurements of un-bound bilirubin. Pediatrics (in press).Brown AK, Eisinger J, Blumberg WE, Flores J, Boyle G, La-mola AA. A rapid fluorometric method for determining biliru-bin levels and binding in the blood of neonates: comparisons with a diazo method and with 2-(4’-hydroxybenzene) azoben-zoic acid dye binding. Pediatrics 1980;65:767-76.Ash KO, Hentschel WM, Chan GM, Wu JT. Reserve bilirubin binding capacity assessed by difference spectroscopy: assay sta-tistics and results on newborn sera. Clin Chim Acta 1980;104:309-18.Correspondence Copyright © 2008 Massachusetts Medical Society.1.2.3.4.5.instructions for letters to the editorLetters to the Editor are considered for publication, subject to editing and abridgment, provided they do not contain material that has been submitted or published elsewhere. Please note the following: •Letters in reference to a Journal article must not exceed 175 words (excluding references) and must be received within 3 weeks after publication of the article. Letters not related to a Journal article must not exceed 400 words. All letters must be submitted over the Internet at http://authors.nejm.org. •A letter can have no more than five references and one figure or table. •A letter can be signed by no more than three authors. •Financial associations or other possible conflicts of interest must be disclosed. (Such disclosures will be published with the letters. For authors of Journal articles who are responding to letters, this information appears in the published articles.) •Include your full mailing address, telephone number, fax number, and e-mail address with your letter.  Our Web site: http://authors.nejm.orgWe cannot acknowledge receipt of your letter, but we will notify you when we have made a decision about publication. Letters that do not adhere to these instructions will not be considered. Rejected letters and figures will not be returned. We are unable to provide prepublication proofs. Submission of a letter constitutes permission for the Massachusetts Medical Society, its licensees, and its assignees to use it in the Journal’s various print and electronic publications and in collections, revisions, and any other form or medium.Copyright © 2008 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org by LAJOS KEMENY MD on July 24, 2008 . 

Phototherapy for neonatal jaundice

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