The Role of Breast-Feeding in Cytomegalovirus Transmission and Hematopoietic Stem Cell Transplant Outcomes in Infants with Severe Combined Immunodeficiency.

Clinical Implications•Data from a large single-center cohort from 1997 to 2016 suggest a 5% rate of breast milk transmission of cytomegalovirus to infants with severe combined immunodeficiency. •Data from a large single-center cohort from 1997 to 2016 suggest a 5% rate of breast milk transmission of cytomegalovirus to infants with severe combined immunodeficiency. Severe combined immunodeficiency (SCID) is characterized by severe T lymphopenia1Dorsey M.J. Dvorak C.C. Cowan M.J. Puck J.M. Treatment of infants identified as having severe combined immunodeficiency by means of newborn screening.J Allergy Clin Immunol. 2017; 139: 733Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar Five-year survival rate is 94% for patients with SCID 3.5 months or older at the time of hematopoietic stem cell transplant (HSCT).2Pai S.Y. Logan B.R. Griffith L.M. Buckley R.H. Parrott R.E. Dvorak C.C. et al.Transplantation outcomes for severe combined immunodeficiency, 2000–2009.N Engl J Med. 2014; 371: 434-446Crossref PubMed Scopus (495) Google Scholar History of treated infection has a substantial negative effect on the 5-year survival post-HSCT. Patients older than 3.5 months with a history of treated infection before HSCT have an 82% 5-year survival rate compared with 50% in patients with an active infection.2Pai S.Y. Logan B.R. Griffith L.M. Buckley R.H. Parrott R.E. Dvorak C.C. et al.Transplantation outcomes for severe combined immunodeficiency, 2000–2009.N Engl J Med. 2014; 371: 434-446Crossref PubMed Scopus (495) Google Scholar Active infections are commonly associated with graft failure. Repeat transplantation is necessary when donor stem cells fail to engraft.2Pai S.Y. Logan B.R. Griffith L.M. Buckley R.H. Parrott R.E. Dvorak C.C. et al.Transplantation outcomes for severe combined immunodeficiency, 2000–2009.N Engl J Med. 2014; 371: 434-446Crossref PubMed Scopus (495) Google Scholar Cytomegalovirus (CMV) can be contracted during the postnatal period through vaginal secretions, breast-feeding, or blood transfusions, though it is most commonly thought that it is mainly transmitted to newborns via breast-feeding.3Schliess M.R. Role of breast milk in acquisition of cytomegalovirus: recent advances.Curr Opin Pediatr. 2006; 18: 48-52PubMed Google Scholar Viral culture and PCR analyses show that 93% of CMV-seropositive mothers shed CMV into their breast milk.3Schliess M.R. Role of breast milk in acquisition of cytomegalovirus: recent advances.Curr Opin Pediatr. 2006; 18: 48-52PubMed Google Scholar On average, CMV is detectable in breast milk 5 days after birth,4Hamprecht K. Maschmann J. Vochem M. Dietz K. Speer C. Gerhard J. Epidemiology of transmission of cytomegalovirus from mother to preterm infant by breastfeeding.Lancet. 2001; 357: 513-518Abstract Full Text Full Text PDF PubMed Scopus (366) Google Scholar, 5Chiavarini M. Bragetti P. Sensini A. Cenci E. Castronari R. Rossi M.J. et al.Breastfeeding and transmission of cytomegalovirus to preterm infants: case report and kinetic of CMV-DNA in breast milk.Ital J Pediatr. 2011; 37Crossref PubMed Scopus (32) Google Scholar and this can result in 40% of infants contracting CMV from mother's breast milk.4Hamprecht K. Maschmann J. Vochem M. Dietz K. Speer C. Gerhard J. Epidemiology of transmission of cytomegalovirus from mother to preterm infant by breastfeeding.Lancet. 2001; 357: 513-518Abstract Full Text Full Text PDF PubMed Scopus (366) Google Scholar For infants with SCID, CMV can be a life-threatening illness, before and after HSCT.6Heimall J. Logan B.R. Cowan M.J. Notarangelo L.D. Griffith L.M. Puck J.M. et al.Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: a PIDTC natural history study.Blood. 2017; 130: 2718-2727Crossref PubMed Scopus (149) Google Scholar CMV infection is associated with an increase in post-HSCT morbidity and mortality in adequately treated leukemia patients,7Fries B.C. Riddell S.R. Kim H.W. Corey L. Dahlgren C. Woolfrey A. et al.Cytomegalovirus disease before hematopoietic cell transplantation as a risk for complications after transplantation.Biol Blood Marrow Transplant. 2005; 11: 135-148Abstract Full Text Full Text PDF Scopus (31) Google Scholar but it is unknown whether this increased morbidity can be extrapolated to CMV-infected patients with SCID. There is little published data on the risk of breast milk transmission of CMV to infants with SCID. Because of the risk of infection and potential compromise of the HSCT treatment, the current recommendation of most SCID experts is to withhold breast-feeding on diagnosis of SCID until the mother's CMV serostatus is determined.8Thaker M.S. Hintermeyer M.K. Gries M.G. Routes J.M. Verbsky J.W. A practical approach to newborn screening for severe combined immunodeficiency using the T cell receptor excision circle assay.Front Immunol. 2017; 8: 1470Crossref PubMed Scopus (31) Google Scholar Mothers of infants with SCID who are confirmed to be CMV seropositive are advised not to restart breast-feeding. The purpose of this study was to provide case-based evidence regarding the risk of breast milk transmission of CMV to infants with SCID and HSCT treatment outcomes. This was a retrospective, cross-sectional study of patients with SCID and their biological mothers with HSCT from January 1, 1997, to December 31, 2016, at Texas Children's Hospital. Data regarding feeding practices, transplantation outcomes, and maternal/child CMV status were gathered via telephone interview with an institutional review board–approved questionnaire (see Figure E1 in this article's Online Repository at www.jaci-inpractice.org) and retrospective chart review of electronic medical record databases. Mothers who breast-fed for any duration were considered positive for breast-feeding. Statistical analysis was performed by SPSS software (version 22, IBM Corporation, Armonk, NY, 2013) using Fisher exact tests. This study was approved by the Institutional Review Board of Baylor College of Medicine. Data regarding CMV status and breast-feeding habits were available for infant-mother pairs of 43 of 51 children born with SCID from 1997 to 2015. Thirty-one mothers of the 43 had a documented positive CMV status. Nineteen of the 31 CMV-positive mothers reported breast-feeding. One of 19 breast-fed infants and 1 of 12 non–breast-fed infants contracted CMV (Table I) before the HSCT. There was no significant difference in CMV infection in breast-fed and non–breast-fed infants. Data regarding clinical outcomes including incidence of graft versus host disease and 1-year and 5-year survival are presented in Table II. One of the 2 children with CMV developed graft versus host disease. Both CMV-positive children had successful engraftment after 1 transplant and both are alive today, surviving 4.5 and 10 years posttransplantation. Diagnostic information, lymphocyte profile, and proliferative assays of the CMV-positive infants can be found in Table III, Table IV, Table V. Data regarding clinical outcomes for patients with any pre-HSCT infection can be found in Table E1 in this article's Online Repository at www.jaci-inpractice.org.Table ICMV Transmission in infants with or without breast-feeding (N = 31)CMV statusNot breast-fedBreast-fedNegative CMV PCR, n (%)11 (92)18 (95)Positive CMV PCR, n (%)1 (8)1 (5) Open table in a new tab Table IICMV Infection status in infants with or without breast-feeding,∗Breast-feeding data were unavailable for 10 of 51 infants. incidence of GvHD,†GvHD data were not available for 6 of 51 infants, 2 negative for infection and 4 positive for infection. 1-y and 5-y post-HSCT survival, with and without pre-HSCT CMV infection∗Breast-feeding data were unavailable for 10 of 51 infants.Infant characteristicsNegative for CMV infectionPositive for CMV infectionP valueTotal patients (n = 51)492Breast-fed patients (n = 27)2611.0Non–breast-fed patients (n = 14)131GvHD, n (%) Total9 of 45 (20%)1 of 2 (50%).384 Breast-fed6 of 24 (25%)1 of 1 (100%).28 Non–breast-fed‡No breast-feeding data for 4 infants negative for infection and 4 infants positive for infection.3 of 11 (27%)0 of 1 (0%)1.0One-year survival, n (%)§Breast-feeding data were unavailable for 10 of 51 patients. Total47 of 51 (92%)2 of 2 (100%)1.0 Breast-fed26 of 26 (100%)1 of 1 (100%)1.0 Non–breast-fed11 of 13 (84%)1 of 1 (100%)1.0Five-year survival, n (%)‖Five-year survival, n (%): 13 of 51 infants surviving and <60 mo post- HSCT. Total33 of 37 (89%)1 of 1 (100%)1.0 Breast-fed15 of 15 (100%)1 of 1 (100%)1.0 Non–breast-fed8 of 10 (80%)NAGvHD, Graft versus host disease; NA, not applicable/available.∗ Breast-feeding data were unavailable for 10 of 51 infants.† GvHD data were not available for 6 of 51 infants, 2 negative for infection and 4 positive for infection.‡ No breast-feeding data for 4 infants negative for infection and 4 infants positive for infection.§ Breast-feeding data were unavailable for 10 of 51 patients.‖ Five-year survival, n (%): 13 of 51 infants surviving and <60 mo post- HSCT. Open table in a new tab Table IIIClinical profile of CMV-infected infantsProfileBreast-fed patient with CMVNon–breast-fed patient with CMVAge at CMV diagnosis7 mo1 moSpecific diseaseMHC Class II deficiencyX-Linked, IL2RG mutationMutationNA, no genetic testing performedc317_320delTATT mutation in IL2RG geneNo. of transplants11Posttransplant days to engraftment1318CMV viral load at time of transplant800 IU/mLUndetectableYears of survival posttransplantation104.5NA, Not applicable. Open table in a new tab Table IVLymphocyte profile for CMV-infected infantsProfileBreast-fed CMV patient 1Non–breast–fed patient 2Healthy control ranges%Count (#/mm3)%Count (#/mm3)%Count (#/mm3)CD3−, CD56, CD16+4.61243173–16116–783CD255.214971670–93884–2800Average CD354.514770056–841920–4991CD3+, CD4+13.33600041–661546–3673CD3+, CD8+39.110600010–28359–1489CD1939.21062965426–28542CD2039.21062955373–2559–457All C56+3.7101166–23137–478HLA-DR+0.37995599–36177–692CD45RA+4.1110003–33134–969CD45RO+7.62050016–42301–919CD4/CD8 ratio0.3NA0NA1.7–4.8NANA, Not applicable/available. Open table in a new tab Table VProliferative assays for CMV-infected infantsAssayBreast-fed CMV patient 1Non–breast-fed CMV patient 2Normal rangeMitogen stimulation (CPM) PHA 10 μg/mL424,177232163,507–415,087 PHA 1.0 μg/mL139,72161135,494–225,107 ConA 50 μg/mL242,7391,75680,718–286,866 ConA 5.0 μg/mL92,6601,69728,998–108,585 PWM 100 ng/mL117,67317337,006–157,955 PWM 10 ng/mL75,81012824,369–94,311 Unstimulated1,28045215–1,161Con A, Concanavalin A; PMW, pokeweed mitogen. Open table in a new tab GvHD, Graft versus host disease; NA, not applicable/available. NA, Not applicable. NA, Not applicable/available. Con A, Concanavalin A; PMW, pokeweed mitogen. This retrospective pilot study representing a single-center large cohort of 43 patients with SCID assessed the prevalence of CMV in breast-fed and non–breast-fed infants with SCID and the impact of infection on clinical outcomes. Although the results of this study were not powered for statistical significance, the finding that 18 of 19 (95%) SCID HSCT recipient infants breast-fed by CMV-positive mothers did not contract CMV merits further investigation. The results demonstrated similar incidences of CMV infection in the non–breast-fed infant group compared with the breast-fed group. Another recent study shows a similarly low rate of transmission, with 2 of 32 (6%) infants with CMV-seropositive mothers contracting CMV, with breast milk as the only identifiable source.1Dorsey M.J. Dvorak C.C. Cowan M.J. Puck J.M. Treatment of infants identified as having severe combined immunodeficiency by means of newborn screening.J Allergy Clin Immunol. 2017; 139: 733Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar With the addition of data from other pediatric hospitals around the country in the future, it may be possible to draw conclusions regarding CMV transmission via breast-feeding in the patient population with SCID and HSCT outcomes for breast-fed and non–breast-fed children. Numerous studies have examined the prevalence and symptomatic manifestations of CMV in infants. The benefits of breast-feeding outweigh the risks of CMV transmission in most term, healthy, nonimmunodeficient infants.9The American Academy of PediatricsPolicy statement: breastfeeding and the use of human milk.Pediatrics. 2012; 129: e827-e841Crossref PubMed Scopus (3445) Google Scholar Premature infants have a relatively immunodeficient state and are more likely to develop symptoms following CMV infection.7Fries B.C. Riddell S.R. Kim H.W. Corey L. Dahlgren C. Woolfrey A. et al.Cytomegalovirus disease before hematopoietic cell transplantation as a risk for complications after transplantation.Biol Blood Marrow Transplant. 2005; 11: 135-148Abstract Full Text Full Text PDF Scopus (31) Google Scholar However, no long-term neurodevelopmental abnormalities have been reported as a result of preterm infants contracting CMV in the postnatal period from breast milk.9The American Academy of PediatricsPolicy statement: breastfeeding and the use of human milk.Pediatrics. 2012; 129: e827-e841Crossref PubMed Scopus (3445) Google Scholar Consequently, the American Academy of Pediatrics Policy Statement concludes that the benefits of breast-feeding a preterm infant outweigh the risks of the CMV clinical syndrome. Given that infants with SCID are severely immunocompromised, the risk of contracting CMV may outweigh the benefit of breast-feeding in CMV-positive mothers.9The American Academy of PediatricsPolicy statement: breastfeeding and the use of human milk.Pediatrics. 2012; 129: e827-e841Crossref PubMed Scopus (3445) Google Scholar Further research will need to answer this question. Infants with SCID are severely immunocompromised, so the risk may outweigh the benefit of breast-feeding in this population. Limitations of this study include the small number of infants, noninclusion of infants who died before qualifying for HSCT, and the inability to determine whether the patients who contracted CMV did so congenitally, perinatally, or due to breast-feeding. In this cohort, 95% of breast-fed infants with SCID who received HSCT did not contract CMV infection, with no significant differences in CMV transmission rate in breast-fed versus non–breast-fed SCID infants or in outcomes. Although not powered for statistical significance, the low rate of transmission seen in the available data supports the need to further assess whether the benefits of breast-feeding may outweigh the risks of CMV infection in infants with SCID with CMV-seropositive mothers. Figure E1Questionnaire.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table E1Infection status in infants with or without breast-feeding,∗Breast-feeding data were unavailable for 10 of 51 infants. incidence of GvHD,†GvHD data were not available for 6 of 51 infants, 2 negative for infection and 4 positive for infection. 1-y and 5-y post-HSCT survival, number of transplants, and days to engraftment in patients with and without pre-HSCT infection∗Breast-feeding data were unavailable for 10 of 51 infants.Infant characteristicsNegative for any infectionPositive for any infectionP valueTotal patients (n = 51)2526Breast-fed patients (n = 27)1611Non–breast-fed patients (n = 14)59GvHD, n (%) Total4 of 23 (17%)6 of 22 (27%).491 Breast-fed3 of 15 (20%)3 of 10 (30%).653 Non–breast-fed‡No breast-feeding data for 4 infants negative for infection and 4 infants positive for infection.0 of 4 (0%)3 of 8 (38%).491One-year survival, n (%)§Breast-feeding data were unavailable for 10 of 51 patients. Total25 of 25 (100%)22 of 26 (85%).11 Breast-fed16 of 16 (100%)11 of 11 (100%)1.0 Non–breast-fed5 of 5 (100%)7 of 9 (78%).505Five-year survival, n (%)‖Five-year survival, n (%): 13 of 51 infants surviving and <60 mo post-HSCT. Total14 of 14 (100%)20 of 24 (83%).276 Breast-fed5 of 5 (100%)11 of 11 (100%)1.0 Non–breast-fed3 of 3 (100%)5 of 7 (71%)1.0No. of transplants, n (%).999 1Total20 (80)19 (73)Breast-fed∗Breast-feeding data were unavailable for 10 of 51 infants.1111Non–breast-fed67 2Total1 (4)2 (8)Breast-fed∗Breast-feeding data were unavailable for 10 of 51 infants.00Non–breast-fed10 3Total4 (16)5 (19)Breast-fed§Breast-feeding data were unavailable for 10 of 51 patients.30Non–breast-fed02Days to engraftment, median (25th, 75th)15 (2, 18)15 (13, 24)GvHD, Graft versus host disease.∗ Breast-feeding data were unavailable for 10 of 51 infants.† GvHD data were not available for 6 of 51 infants, 2 negative for infection and 4 positive for infection.‡ No breast-feeding data for 4 infants negative for infection and 4 infants positive for infection.§ Breast-feeding data were unavailable for 10 of 51 patients.‖ Five-year survival, n (%): 13 of 51 infants surviving and <60 mo post-HSCT. Open table in a new tab GvHD, Graft versus host disease. CMV-Seropositive Mothers of SCID: To Breastfeed or Not?The Journal of Allergy and Clinical Immunology: In PracticeVol. 7Issue 8PreviewCytomegalovirus (CMV) is a herpesvirus commonly found in milk from CMV-seropositive mothers (40%) and infects around two-thirds of exposed infants around birth.1 However, healthy term infants exposed to milk-born CMV rarely develop symptomatic disease from this source.1,2 This is likely secondary to the protective effect of passively acquired anti-CMV antibodies. In contrast, very low birth weight (<1500 g) premature infants (<28 weeks) do not have this protection and are susceptible to clinical infection (40%) with viremia, cytopenia, hepatitis, pneumonia, enteritis, and a sepsis-like syndrome. Full-Text PDF