Congenital Heart Disease Kurobe et alCHD

4. Lindsay EA, Vitelli F, Su H, Morishima M, Huynh T, Pramparo T, et al. Tbx1

haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects

in mice. Nature. 2001;410:97-101.

5. Anderson RH, Cook AC. The anatomy of congenital cardiac malformations. In:

Daiho Yuh D, Vricella LA, Baumgartner W, eds. The Johns Hopkins Manual of

Cardiothoracic Surgery. New York: McGraw-Hill Professional; 2007. 1001.

6. Eysteinsdottir JH, Freysdottir J, Haraldsson A, Stefansdottir J, Skaftadottir I,

Helgason H, et al. The influence of partial or total thymectomy during open heart

surgery in infants on the immune function later in life. Clin Exp Immunol. 2004;

136:349-55.

7. Wells WJ, Parkman R, Smogorzewska E, Barr M. Neonatal thymectomy: does it

affect immune function? J Thorac Cardiovasc Surg. 1998;115:1041-6.

8. Mancebo E, Clemente J, Sanchez J, Ruiz-Contreras J, De Pablos P, Cortezon S,

et al. Longitudinal analysis of immune function in thefirst 3 years of life in thymec-

tomized neonates during cardiac surgery. Clin Exp Immunol. 2008;154:375-83.

9. Prelog M, Wilk C, Keller M, Karall T, Orth D, Geiger R, et al. Diminished

response to tick-borne encephalitis vaccination in thymectomized children. Vac-

cine. 2008;26:595-600.

10. Madhok AB, Chandrasekran A, Parnell V, Gandhi M, Chowdhury D, Pahwa S.

Levels of recent thymic emigrant cells decrease in children undergoing partial

thymectomy during cardiac surgery. Clin Diagn Lab Immunol. 2005;12:563-5.

11. Afifi A, Raja SG, Pennington DJ, Tsang VT. For neonates undergoing cardiac

surgery does thymectomy as opposed to thymic preservation have any adverse im-

munological consequences? Interact Cardiovasc Thorac Surg. 2010;11:287-91.

12. Miller JF. Immunological function of the thymus. Lancet. 1961;2:748-9.

13. Good RA, Dalmasso AP, Martinez C, Archer OK, Pierce JC, Papermaster BW.

The role of the thymus in development of immunologic capacity in rabbits and

mice. J Exp Med. 1962;116:773-96.

14. Sakaguchi S, Takahashi T, Nishizuka Y. Study on cellular events in postthymec-

tomy autoimmune oophoritis in mice. I. Requirement of Lyt-1 effector cells for

oocytes damage after adoptive transfer. J Exp Med. 1982;156:1565-76.

15. Bonomo A, Kehn PJ, Payer E, Rizzo L, Cheever AW, Shevach EM. Pathogenesis

of post-thymectomy autoimmunity. Role of syngeneic MLR-reactive T cells.

J Immunol. 1995;154:6602-11.

16. Halnon NJ, Jamieson B, Plunkett M, Kitchen CM, Pham T, Krogstad P. Thymic

function and impaired maintenance of peripheral T cell populations in children

with congenital heart disease and surgical thymectomy.Pediatr Res. 2005;57:42-8.

17. Barshes NR, Goodpastor SE, Goss JA. Pharmacologic immunosuppression.

Front Biosci. 2004;9:411-20.

18. Oberbeck R. Catecholamines: physiological immunomodulators during health

and illness. Curr Med Chem. 2006;13:1979-89.

19. Hong R. The DiGeorge anomaly. Immunodefic Rev. 1991;3:1-14.

20. Muller W, Peter HH, Wilken M, Juppner H, Kallfelz HC, Krohn HP, et al. The

DiGeorge syndrome. I. Clinical evaluation and course of partial and complete

forms of the syndrome. Eur J Pediatr. 1988;147:496-502.

21. van Gent R, Schadenberg AW, Otto SA, Nievelstein RA, Sieswerda GT, Haas F,

et al. Long-term restoration of the human T-cell compartment after thymectomy

during infancy: a role for thymic regeneration? Blood. 2011;118:627-34.

22. Torfadottir H, Freysdottir J, Skaftadottir I, Haraldsson A, Sigfusson G,

Ogmundsdottir HM. Evidence for extrathymic T cell maturation after thymec-

tomy in infancy. Clin Exp Immunol. 2006;145:407-12.

23. Stocker CF, Shekerdemian LS, Horton SB, Lee KJ, Eyres R, D’Udekem Y, et al.

The influence of bypass temperature on the systemic inflammatory response and

organ injury after pediatric open surgery: a randomized trial. J Thorac Cardio-

vasc Surg. 2011;142:174-80.

24. Cornell TT, Sun L, Hall MW, Gurney JG, Ashbrook MJ, Ohye RG, et al. Clinical

implications and molecular mechanisms of immunoparalysis after cardiopulmo-

nary bypass. J Thorac Cardiovasc Surg. 2012;143:1160-6.e1.

25. MarkertML,DevlinBH,AlexieffMJ,Li J,McCarthyEA,GuptonSE, et al.Review

of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus

transplantation: outcome of 44 consecutive transplants. Blood. 2007;109:4539-47.

DiscussionDr Joren Madsen (Boston, Mass). Excellent presentation and

a well-designed study. What surprises me most about this studyand studies like it is not that there are perturbations in the immune

662 The Journal of Thoracic and Cardiovascular Surg

system after neonatal thymectomy but how minor those perturba-tions really are, because the thymus is an organ of self-tolerance.

I can think of 2 reasons for this. The first is because the humanimmune system and the T-cell repertoire are fairly established atthe time of birth, unlike some other species, such as the mouse,in which neonatal thymectomy results in a DiGeorge-type syn-drome. The other reason is that new data suggest that there areother places than the thymus where T-cell precursors are educatedto distinguish self from nonself.

Compared with other studies that also show a diminution or re-duction in circulating T cells but no increase in infectious compli-cations after thymectomy, your study shows an increase inhospitalizations during the first 3 years of life. What’s differentabout your study that you do see an increase in infectious compli-cations after neonatal thymectomy?

DrKurobe.This difference is related to a broader definition of in-fectioncomplication thanweused in our study,which includedminorinfections such as bronchitis and pneumonia. In our study, therewereno patients withmajor complications such as bacteremia ormeningi-tis, which was in a previous published report. There were no patientsin our study with rubella and major infection during these 3 years.

Dr Madsen. The second question has to do with your in vitroanalysis of the circulating T cells performed using PHAstimulation.That is a crude way to analyze T-cell function, and I’m wonderingif youdid anymore subtle analysis ofT-cell function by, for instance,a mixed lymphocyte reaction using irradiated allogeneic cells.

The reason I ask is because some of these children eventually goon to heart transplantation. If you found that neonatal thymectomygenerates a hole in T-cell repertoire, it might actually help us in tai-loring or minimizing immunosuppression for those patients whogo on to transplantation.

Dr Kurobe. Also, a PHA stimulation test was done, and there isno significant difference between groups P and E. So I think there isnodifference in theT-cell function betweenboth groups. I haveneverdone an analysis of T-cell function except a PHA stimulation test.

Dr Madsen. Third question: Let’s assume that you’re right andneonatal thymectomy does have significant immunologic sequelaeso thatwe need to avoid neonatal thymectomy. But there are some op-erations that cannot be performed safely without removing the wholethymus for exposure.Given this scenario, I see2 options.One is to dis-cern and then treat the immune dysfunction caused by thymectomy.For instance, giving these patients supplemental measles or rubellabooster vaccines to raise their antibody titers. My question is aboutthe potential second option: Is there a surgicalway tomaintain thymicfunction at the same time you perform a neonatal thymectomy?

Dr Kurobe. I think this question is important and difficult to an-swer. As you know, there are some published reports about the trans-plantation in patients with DiGeorge syndrome, and there is alsoa study in which autologous thymic tissuewas implanted into the do-nor heart pig model, thereby creating a composite thymus heart allo-graft transplant. So this thymus implant was performed in the animal,and the study reported success for the reconstitution of thymic func-tion after this transplantation. In the case that complete thymectomycannot be avoided, the autotransplantation of the removed thymusmayoffer a viable option for disturbed immune function after surgery.However, at this time I believe more investigation will be needed toclarify the relationship of the thymic autotransplantation becausethere is no evidence about thymic transplantation in normal children.

ery c March 2013