Objective. To evaluate the immune function in HIV-exposed uninfected (HIV-EU) infants fed human donor milk. Methods. Ultrasound-obtained thymic index (Ti), T-lymphocyte subsets, and the number of infections were examined from birth to 18 months of age in 18 HIV-EU infants. The infants were compared to a cohort of 47 term, HIV-unexposed breastfed or formula-fed infants. Results. The thymic size at 12 months of age was not significantly different between the HIV-EU group and the control infants ( ). At 4 months of age, the HIV-EU infants had significantly fewer infections than the control infants ( ). Furthermore, in the control group, the infants exclusively breastfed at 4 months of age had significantly fewer infections at 8 months when compared to age-matched formula-fed infants ( ). Conclusion. HIV-EU infants fed human donor milk have normal growth of thymus and contract fewer infections than other healthy infants. This finding along with fewer infections in exclusively breastfed infants compared to formula-fed infants supports the beneficial effect of human milk on the immune system. We suggest, when breastfeeding is not possible, that providing human donor milk to vulnerable groups of infants will be beneficial for their maturing immune system. 1. Introduction Vertical transmission of HIV from HIV-positive mothers to their infants is, in industrialised countries, reduced to less than 1-2% [1–3]. Consequently, the number of HIV-exposed uninfected (HIV-EU) infants in the world is growing. Despite HIV-EU infants remaining uninfected, there have been reports of impaired immune function and reduced CD4 counts in HIV-EU newborns [4–8]. However, reports on the long-term impact of HIV exposure on the immune system have been conflicting and there have been very few studies of whether the infection burden in HIV-EU infants is higher than in HIV-unexposed infants [9, 10]. The thymus plays a key role in the development of a functional immune system, providing the environment for T-lymphocyte maturation and being a central organ for the development and maintenance of cell-mediated immunity. The thymus is also known to be a target organ in HIV-infection [11]. The transition of T-cell progenitors in the thymus has been extensively evaluated, but the significance of the size or alterations in the size of the thymus in infancy is still unclear [12–15]. The positive correlation between thymic size and weight and length at birth and during the first months of life is well known and infections are reported to result in decreasing thymic size [16–20]. We have also
References
[1]
C. N. Mnyani and J. A. McIntyre, “Preventing mother-to-child transmission of HIV,” International Journal of Obstetrics and Gynaecology, vol. 116, pp. 71–76, 2009.
[2]
C. Thorne, “Mother-to-child transmission of HIV infection in the era of highly active antiretroviral therapy,” Clinical Infectious Diseases, vol. 40, no. 3, pp. 458–465, 2005.
[3]
C. Kind, C. Rudin, C. A. Siegrist et al., “Prevention of vertical HIV transmission: additive protective effect of elective Cesarean section and zidovudine prophylaxis,” AIDS, vol. 12, no. 2, pp. 205–210, 1998.
[4]
M. Clerici, M. Saresella, F. Colombo et al., “T-lymphocyte maturation abnormalities in uninfected newborns and children with vertical exposure to HIV,” Blood, vol. 96, no. 12, pp. 3866–3871, 2000.
[5]
S. D. Nielsen, D. L. Jeppesen, L. Kolte et al., “Impaired progenitor cell function in HIV-negative infants of HIV-positive mothers results in decreased thymic output and low CD4 counts,” Blood, vol. 98, no. 2, pp. 398–404, 2001.
[6]
E. Ono, A. M. Nunes dos Santos, R. C. de Menezes Succi et al., “Imbalance of naive and memory T lymphocytes with sustained high cellular activation during the first year of life from uninfected children born to HIV-1-infected mothers on HAART,” Brazilian Journal of Medical and Biological Research, vol. 41, no. 8, pp. 700–708, 2008.
[7]
C. Feiterna-Sperling, K. Weizsaecker, C. Bührer et al., “Hematologic effects of maternal antiretroviral therapy and transmission prophylaxis in HIV-1-exposed uninfected newborn infants,” Journal of Acquired Immune Deficiency Syndromes, vol. 45, no. 1, pp. 43–51, 2007.
[8]
J. Le Chenadec, M. J. Mayaux, C. Guihenneuc-Jouyaux, and S. Blanche, “Perinatal antiretroviral treatment and hematopoiesis in HIV-uninfected infants,” AIDS, vol. 17, no. 14, pp. 2053–2061, 2003.
[9]
A. Slogrove, B. Reikie, S. Naidoo, C. De Beer, K. Ho, M. Cotton, et al., “HIV-exposed uninfected infants are at increased risk for severe infections in the first year of life,” Journal of Tropical Pediatrics, 2012.
[10]
L. Kolte, V. Rosenfeldt, L. Vang et al., “Reduced thymic size but no evidence of impaired thymic function in uninfected children born to human immunodeficiency virus-infected mothers,” Pediatric Infectious Disease Journal, vol. 30, no. 4, pp. 325–330, 2011.
[11]
T. Rozmyslowicz, S. L. Murphy, D. O. Conover, and G. N. Gaulton, “HIV-1 infection inhibits cytokine production in human thymic macrophages,” Experimental Hematology, vol. 38, no. 12, pp. 1157–1166, 2010.
[12]
P. Res, B. Blom, T. Hori, K. Weijer, and H. Spits, “Downregulation of CD1 marks acquisition of functional maturation of human thymocytes and defines a control point in late stages of human T cell development,” Journal of Experimental Medicine, vol. 185, no. 1, pp. 141–151, 1997.
[13]
D. Ribatti, E. Crivellato, and A. Vacca, “Miller's seminal studies on the role of thymus in immunity,” Clinical and Experimental Immunology, vol. 144, no. 3, pp. 371–375, 2006.
[14]
G. Awong, E. Herer, C. D. Surh, J. E. Dick, R. N. La Motte-Mohs, and J. C. Zú?iga-Pflücker, “Characterization in vitro and engraftment potential in vivo of human progenitor T cells generated from hematopoietic stem cells,” Blood, vol. 114, no. 5, pp. 972–982, 2009.
[15]
B. C. Beaudette-Zlatanovaa, K. L. Knighta, S. Zhang, P. J. Stiff, J. C. Zuniga-Pflücker, and P. T. Le, “A human thymic epithelial cell culture system for the promotion of lymphopoiesis from hematopoietic stem cells,” Experimental Hematology, vol. 39, pp. 570–659, 2011.
[16]
H. Hasselbalch, D. L. Jeppesen, A. K. Ersb?ll, M. D. M. Engelmann, and M. B. Nielsen, “Thymus size evaluated by sonography: a longitudinal study on infants during the first year of life,” Acta Radiologica, vol. 38, no. 2, pp. 222–227, 1997.
[17]
H. Hasselbalch, A. K. Ersb?ll, D. L. Jeppesen, and M. B. Nielsen, “Thymus size in infants from birth until 24 months of age evaluated by ultrasound: a longitudinal prediction model for the thymic index,” Acta Radiologica, vol. 40, no. 1, pp. 41–44, 1999.
[18]
I. Varga, A. Uhrinova, F. Toth, and J. Mistinova, “Assessment of the thymic morphometry using ultrasound in full-term newborns,” Surgical and Radiologic Anatomy, vol. 33, pp. 689–695, 2011.
[19]
J. van Baarlen, H. J. Schuurman, and J. Huber, “Acute thymus involution in infancy and childhood: a reliable marker for duration of acute illness,” Human Pathology, vol. 19, no. 10, pp. 1155–1160, 1988.
[20]
D. L. Jeppesen, A. K. Ersb?ll, S. D. Nielsen, T. U. Hoppe, and N. H. Valerius, “Low thymic size in preterm infants in the neonatal intensive care unit, a possible marker of infection? A prospective study form birth to 1 year of age,” Acta Paediatrica, vol. 100, pp. 1319–1325, 2011.
[21]
H. Hasselbalch, D. L. Jeppesen, M. D. M. Engelmann, K. F. Michaelsen, and M. B. Nielsen, “Decreased thymus size in formula-fed infants compared with breastfed infants,” Acta Paediatrica, vol. 85, no. 9, pp. 1029–1032, 1996.
[22]
H. Hasselbalch, M. D. M. Engelmann, K. Fleischer-Michaelsen, A. K. Ersb?ll, and D. L. Jeppesen, “Breast-feeding influences thymic size in late infancy,” European Journal of Pediatrics, vol. 158, no. 12, pp. 964–967, 1999.
[23]
D. Jeppesen, H. Hasselbalch, A. K. Ersb?ll, C. Heilmann, and N. H. Valerius, “Thymic size in uninfected infants born to HIV-positive mothers and fed with pasteurized human milk,” Acta Paediatrica, vol. 92, no. 6, pp. 679–683, 2003.
[24]
A. Vigano, S. Vella, N. Principi et al., “Thymus volume correlates with the progression of vertical HIV infection,” AIDS, vol. 13, no. 5, pp. F29–F34, 1999.
[25]
P. Chevalier, S. Diagbouga, Y. Traore, A. M. Cassel-Beraud, and P. Van de Perre, “Thymic size and muscle mass of HIV-infected asymptomatic children from Burkina Faso,” Journal of Acquired Immune Deficiency Syndromes, vol. 29, no. 4, pp. 427–428, 2002.
[26]
M. L. Garly, S. L. Trautner, C. Marx et al., “Thymus size at 6 months of age and subsequent child mortality,” Journal of Pediatrics, vol. 153, no. 5, pp. 683–688, 2008.
[27]
D. L. Jeppesen, H. Hasselbalch, I. M. Lisse, A. K. Ersb?ll, and M. D. M. Engelmann, “T-lymphocyte subsets, thymic size and breastfeeding in infancy,” Pediatric Allergy and Immunology, vol. 15, no. 2, pp. 127–132, 2004.
[28]
A. Afifi, S. G. Raja, D. J. Pennington, and V. T. Tsang, “For neonates undergoing cardiac surgery does thymectomy as opposed to thymic preservation have any adverse immunological consequences?” Interactive Cardiovascular and Thoracic Surgery, vol. 11, no. 3, pp. 287–291, 2010.
[29]
L. D. Arnold, “Donor milk banking in Scandinavia,” Journal of Human Lactation, vol. 15, no. 1, pp. 55–59, 1999.
[30]
P. Aaby, C. Marx, S. Trautner et al., “Thymus size at birth is associated with infant mortality: a community study from Guinea-Bissau,” Acta Paediatrica, vol. 91, no. 6, pp. 698–703, 2002.
[31]
R. Savilahti, J. Uitti, and T. Husman, “Validity and recall of information from questionnaires concerning respiratory infections among schoolchildren,” Central European Journal of Public Health, vol. 13, no. 2, pp. 74–77, 2005.
[32]
N. H. Vissing, S. M. Jensen, and H. Bisgaard, “Validity of information on atopic disease and other illness in young children reported by parents in a prospective birth cohort study,” BMC Medical Research Methodology, vol. 12, pp. 160–166, 2012.
[33]
P. Aaby, H. Jensen, B. Samb et al., “Differences in female-male mortality after high-titre measles vaccine and association with subsequent vaccination with diphtheria-tetanus-pertussis and inactivated poliovirus: reanalysis of West African studies,” The Lancet, vol. 361, no. 9376, pp. 2183–2188, 2003.