Cytomegalovirus infection in neonates following exchange transfusion
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《印度儿科学杂志》
Abstract
Objectives. This study was undertaken to ascertain the acquisition of cytomegalovirus infection following exchange transfusion and factors affecting such transmission in newborn infants at a tertiary care hospital in India. Methods. Neonates undergoing double volume exchange transfusion (for any indication) with whole blood in the Neonatal Intensive Care Unit were enrolled over a 8 month period. Serum samples from the infant were collected for CMV serology before exchange transfusion, and at 6 and 12 weeks following the exchange. CMV serology was also conducted on samples obtained from the respective maternal and donor blood. Results. Of 47 neonates who received exchange transfusion during the study period; only 26 (55.3%) neonates were finally followed up till 12 weeks of age. Only 3 (11.5%) children demonstrated CMV seroconversion during follow-up; all were low birth weight and small for gestational age. None of them demonstrated any clinical, hematological, biochemical, or radiological signs suggestive of perinatal CMV infection either at birth or during the course of follow-up. Conclusion. Exchange transfusion in neonates can result in perinatal transmission of CMV infection in low birth weight neonates. Such transmission does not result in any immediate manifestations. Data are not sufficient to warrant routine CMV screening of donor blood for exchange transfusion in our setting.
Keywords: Cytomegalovirus; Newborn; Exchange transfusion
How to cite this article:
Kothari A, Ramachandran VG, Gupta P. Cytomegalovirus infection in neonates following exchange transfusion. Indian J Pediatr 2006;73:519-521
How to cite this URL:
Kothari A, Ramachandran VG, Gupta P. Cytomegalovirus infection in neonates following exchange transfusion. Indian J Pediatr [serial online] 2006 [cited 2006 Jul 14];73:519-521. Available from: http://www.ijppediatricsindia.org/article.asp?issn=0019-5456;year=2006;volume=73;issue=6;spage=519;epage=521;aulast=Kothari
Exchange transfusion is an important intervention to address certain situations in neonates.[1] Double and single volume exchange replaces approximately 90 and 75% red cells, respectively.[2] Thus, in this procedure, recipient's exposure to donor blood is far greater than it is for a simple blood or component transfusion. In a contaminated blood unit, the infectious load is likely to be high, and chances of infection related events are far greater in the newborn.[3]
Transfusion acquired cytomegalovirus (CMV) infection in a premature infant is associated with significant morbidity and mortality. Pneumonia, hepatitis, thrombocytopenia and anemia associated with CMV infection may compound the problem.[4] Western guidelines propose pre-screening of donor for CMV before transfusion in very low birth weight infants.[5] No such guidelines exist in most developing countries including India.
Data are available from the industrialized world describing the risk of CMV infection following exchange transfusion.[6],[7],[8],[9] In India, perinatal CMV infection in neonates has been documented following transfusion of blood or blood products.[10],[11],[12] However, little information is available regarding the risk of transmission of CMV following exchange transfusion in neonates.[13] This study was undertaken to ascertain the acquisition of cytomegalovirus infection following exchange transfusion and various factors affecting such transmission in newborn infants at a tertiary care hospital in India.
Materials and Methods
The study population consisted of neonates who underwent double volume exchange transfusion (for any indication) with whole blood in the Neonatal Intensive Care Unit, Guru Teg Bahadur Hospital, Delhi between March to October 2001. Blood for exchange transfusion was obtained from voluntary donors at the Regional Blood Transfusion Center, Guru Teg Bahadur Hospital, and prescreened for HBsAg, anti-HCV antibodies, anti-HIV antibodies and VDRL reactivity. Baseline clinical and anthropometric data were collected in all these neonates. Baby, mother and donor samples were collected prior to exchange transfusion for estimation of CMV specific IgG and IgM.
All children were followed up in the high-risk clinic at 6±1 and 12±1 weeks of age. They were examined and investigated to detect any evidence of CMV disease along with relevant investigations. Serum samples were also obtained for CMV antibodies at each visit. Sera were stored at -20°C until testing. CMV specific IgM and IgG were detected in stored sera using commercial cytomegalovirus antibody test kits (HUMAN) based on a sandwich enzyme immunoassay. Positive control was calibrated against Paul-Ehrlich-Institute reference material. A positive CMV infection was defined as positive CMV specific titer > 25HU/mL or a 4 fold rise in CMV IgG titers.
Results
A total of 47 neonates received exchange transfusion during the study period; 3 (6.4%) died in hospital, 13 (27.7%) did not report for the first follow-up, and 5 (10.6%) more dropped out by 12 weeks. Thus of the initial cohort, only 26 (55.3%) neonates were finally followed up till 12 weeks of age. Of the 26 completed cases, 14 (53.8%) were males. The mean (SD, range) birth weight and gestational age were 1876 (574.5, 1000-3000) g and 35.9 (3.9, 28-40) weeks, respectively. Primary indication for exchange transfusion was hyperbilirubinemia. Four of the 26 required exchange transfusion twice.
No significant differences were observed between 26 neonates who completed follow-up of 12 weeks and those (n=21) who dropped out with regard to sex ratio, birth weight, gestational age, risk factors/problems at birth, and CMV status of baby, mother and donor. Detailed results of serological follow-up testing for CMV are provided in [Table - 1]. Overall, 3 children demonstrated CMV IgM during follow-up but none demonstrated a 4 fold rise in IgG titer over the baseline. Details of 3 cases who had evidence of recent CMV infection are summarized in [Table - 2]. None of the three CMV IgM positive cases demonstrated any clinical (anthropometric, developmental, systemic, ophthalmological), hematological (blood counts and smear), biochemical (liver enzymes) or radiological (chest and skull skiagram, sonography and CT of brain) signs suggestive of perinatal CMV infection either at birth or during the course of follow-up.
Discussion
In our study, 3 out of 26 (11.5 %) children demonstrated CMV IgM seroconversion, indicating a perinatal infection. In the third neonate (first of a pair of twins), passage through the infected vaginal tract or breastfeeding could be responsible for the infection as the mother also had a possible primary CMV infection; the other twin did not develop infection during the study period. In the other two cases, the probable source of infection was donor blood, though none of the donor units tested positive for CMV IgM. All infected babies were low birth weight and small for their respective gestational age. Presence of low-avidity IgG antibodies or antigen detection by PCR would have indicated primary infection in the donors even in the absence of CMV IgM antibody[14]; however these were not determined due to lack of resources.
Similar studies in Japan and the United States showed an infection rate of 75 percent and 33 percent respectively following exchange transfusion with unfiltered blood.[6],[8] Another study in Oxford gave an infection rate of 25 percent following exchange transfusion.[9] Our results are different from these published studies. This could be due to difference in the characteristics of enrolled subjects, e.g., the study in Japan was carried out exclusively in pre-term low birth weight infants (￡ 2000 g), which in itself is a risk factor for transmission.
None of the three cases with perinatal infection developed any clinical sign of CMV disease, which is unusual. This calls for further focusing on both host and pathogen related factors; including lack of receptors for the virus, cytokine related defence mechanisms and failure to switch on the transcription mode for viral multiplication etc. Further, the circulating strain in the community may be less virulent, causing silent infection. Moreover, our study follow-up period was too short to show up any long term sequel in growth and development. It is difficult to comment on the clinical implication of seropositivity in absence of development of clinical disease and a short follow-up. A follow-up period of at least two years and possibly longer has been suggested to detect any growth retardation or other developmental anomalies in asymptomatic CMV infections in infants.[15]
Western guidelines[5] suggest that only CMV seronegative blood or filtered/leukocyte depleted blood be used in very low birth weight infant. However, similar proposal in India do not seem valid at present in the light of the results obtained in our study. In our study, following exchange transfusion with unscreened donor blood, only 11.5 percent babies developed CMV infection; none exhibited clinical manifestations. We have shown earlier the seroprevalence of CMV IgG in voluntary blood donors of Delhi to be near 95%.[16] The high endemicity and the consequent seropositivity may act as an independent deterrent for overt transmission and CMV disease following infection, be it perinatal or horizontal. Also, the lack of serious clinical disease following transfusion does not warrant such a step at present.
However, these proposals are at best only tentative. A much larger study, preferably multi-centric, with a bigger sample size on exchange transfusion and CMV infection along with at least a two year follow-up period of all cases needs to be carried out to give a truer picture of transmission rate. Also, IgG avidity index should be determined in all the cases, specially blood donors to detect early primary infection and reactivation. Moreover, serology for diagnosis of CMV disease or infection has its own fallacies. Virus isolation and/or antigen detection by PCR would be more useful, if available. Current guidelines in India regarding screening of donated blood for CMV could then be re-appraised in the light of new knowledge from such studies.
References
1. Stockman JA III. Red Cell Transfusions in Pediatrics. In: Rossi EC, Simon TL, Moss GS, Gould SA, editors. Principles of Transfusion Medicine . Baltimore: Williams and Wilkins; 1996. p. 167-176.
2. Alverson DC, Izquierdo LA. Hemolytic Disease of the Newborn: Treatment and Prevention. In: Rossi EC, Simon TL, Moss GS, Gould SA, editors. Principles of Transfusion Medicine. Baltimore: Williams and Wilkins; 1996. p. 127-140.
3. MacMohan JR, Stevenson DK, Oski FA. Management of neonatal hyperbilirubinemia. In: Taeusch HW, Ballard RA, editors. Avery 's Diseases of the Newborn . Philadelphia: W. B. Saunders Company; 1998: p. 1033-1044.
4. Pass RF. Cytomegalovirus. In: Knipe DM, Howley PM, editors. Fields Virology. Philadelphia: Lippincott Williams and Wilkins; 2001. p. 2675-2706.
5. Holland PV, Schmitt PJ. Standards for Blood Banks and Transfusion Services, 12th edn. Arlington, Va., Committee on Standards. American Association of Blood Banks 1987: 30-1.
6. Kumar A, Nankervis GA, Cooper AR, Gold E, Kumar ML. Acquisition of cytomegalovirus infection in infants following exchange transfusion: a prospective study. Transfusion 1980; 20(3): 327-331.
7. Brossard Y, Parnet-Mathieu F. Post-transfusion cytomegalovirus infection in newborn infants. Rev Fr Transfus Immunohematol 1984; 27(3): 345-353.
8. Xu D, Yonetani M, Uetani Y, Nakamura H. Acquired cytomegalovirus infection and blood transfusion in preterm infants. Acta Pediatr Jpn 1995; 37(4): 444-449.
9. Benson JW, Bodden SJ, Tobin JO. Cytomegalovirus and blood transfusion in neonates. Arch Dis Child 1979; 54(7): 538-541.
10. Gupta P, Gupta D, Ramachandran VG, Faridi MMA. Transfusion transmitted cytomegalovirus infection in a neonate. Indian Pediatr 2001; 38: 780-782.
11. Rekha S, Chandrasekhara MK, Yeshwanth M. Cytomegalovirus infection acquired through blood transfusions. Indian Pediatr 1995; 32(5): 575-577.
12. Gupta P, Chaturvedi D, Rai R, Dua T, Ramachandran VG. Cytomegalovirus infection in neonates following blood component therapy. Ann Trop Pediatr 2005; 25: 139-140.
13. Patil RS, Wadgaonkar P, Joshi SH, Merchant RH, Gupte SC. Viral infection in newborns through exchange transfusion. Indian J Pediatr 1998; 65: 723-728.
14. Lazzarotto T, Spezzacatena P, Pradelli P, Abate DA, Varani S, Landini MP. Avidity of immunoglobulin G directed against human cytomegalovirus during primary and secondary infections in immunocompetent and immunocompromised subjects. Clin Diagn Lab Immunol 1997; 4: 469-473.
15. Dworsky ME, Yow M, Stagno S, Pass RF, Alford CA. Cytomegalovirus infection of breast milk and transmission in infancy. Pediatrics 1983; 72: 295-299.
16. Kothari A, Ramachandran VG, Gupta P, Singh B, Talwar V. Seroprevalence of cytomegalovirus among voluntary blood donors in Delhi, India. J Health Popul Nutr 2002; 20(4): 348-351.(Kothari Atul, Ramachandra)
Objectives. This study was undertaken to ascertain the acquisition of cytomegalovirus infection following exchange transfusion and factors affecting such transmission in newborn infants at a tertiary care hospital in India. Methods. Neonates undergoing double volume exchange transfusion (for any indication) with whole blood in the Neonatal Intensive Care Unit were enrolled over a 8 month period. Serum samples from the infant were collected for CMV serology before exchange transfusion, and at 6 and 12 weeks following the exchange. CMV serology was also conducted on samples obtained from the respective maternal and donor blood. Results. Of 47 neonates who received exchange transfusion during the study period; only 26 (55.3%) neonates were finally followed up till 12 weeks of age. Only 3 (11.5%) children demonstrated CMV seroconversion during follow-up; all were low birth weight and small for gestational age. None of them demonstrated any clinical, hematological, biochemical, or radiological signs suggestive of perinatal CMV infection either at birth or during the course of follow-up. Conclusion. Exchange transfusion in neonates can result in perinatal transmission of CMV infection in low birth weight neonates. Such transmission does not result in any immediate manifestations. Data are not sufficient to warrant routine CMV screening of donor blood for exchange transfusion in our setting.
Keywords: Cytomegalovirus; Newborn; Exchange transfusion
How to cite this article:
Kothari A, Ramachandran VG, Gupta P. Cytomegalovirus infection in neonates following exchange transfusion. Indian J Pediatr 2006;73:519-521
How to cite this URL:
Kothari A, Ramachandran VG, Gupta P. Cytomegalovirus infection in neonates following exchange transfusion. Indian J Pediatr [serial online] 2006 [cited 2006 Jul 14];73:519-521. Available from: http://www.ijppediatricsindia.org/article.asp?issn=0019-5456;year=2006;volume=73;issue=6;spage=519;epage=521;aulast=Kothari
Exchange transfusion is an important intervention to address certain situations in neonates.[1] Double and single volume exchange replaces approximately 90 and 75% red cells, respectively.[2] Thus, in this procedure, recipient's exposure to donor blood is far greater than it is for a simple blood or component transfusion. In a contaminated blood unit, the infectious load is likely to be high, and chances of infection related events are far greater in the newborn.[3]
Transfusion acquired cytomegalovirus (CMV) infection in a premature infant is associated with significant morbidity and mortality. Pneumonia, hepatitis, thrombocytopenia and anemia associated with CMV infection may compound the problem.[4] Western guidelines propose pre-screening of donor for CMV before transfusion in very low birth weight infants.[5] No such guidelines exist in most developing countries including India.
Data are available from the industrialized world describing the risk of CMV infection following exchange transfusion.[6],[7],[8],[9] In India, perinatal CMV infection in neonates has been documented following transfusion of blood or blood products.[10],[11],[12] However, little information is available regarding the risk of transmission of CMV following exchange transfusion in neonates.[13] This study was undertaken to ascertain the acquisition of cytomegalovirus infection following exchange transfusion and various factors affecting such transmission in newborn infants at a tertiary care hospital in India.
Materials and Methods
The study population consisted of neonates who underwent double volume exchange transfusion (for any indication) with whole blood in the Neonatal Intensive Care Unit, Guru Teg Bahadur Hospital, Delhi between March to October 2001. Blood for exchange transfusion was obtained from voluntary donors at the Regional Blood Transfusion Center, Guru Teg Bahadur Hospital, and prescreened for HBsAg, anti-HCV antibodies, anti-HIV antibodies and VDRL reactivity. Baseline clinical and anthropometric data were collected in all these neonates. Baby, mother and donor samples were collected prior to exchange transfusion for estimation of CMV specific IgG and IgM.
All children were followed up in the high-risk clinic at 6±1 and 12±1 weeks of age. They were examined and investigated to detect any evidence of CMV disease along with relevant investigations. Serum samples were also obtained for CMV antibodies at each visit. Sera were stored at -20°C until testing. CMV specific IgM and IgG were detected in stored sera using commercial cytomegalovirus antibody test kits (HUMAN) based on a sandwich enzyme immunoassay. Positive control was calibrated against Paul-Ehrlich-Institute reference material. A positive CMV infection was defined as positive CMV specific titer > 25HU/mL or a 4 fold rise in CMV IgG titers.
Results
A total of 47 neonates received exchange transfusion during the study period; 3 (6.4%) died in hospital, 13 (27.7%) did not report for the first follow-up, and 5 (10.6%) more dropped out by 12 weeks. Thus of the initial cohort, only 26 (55.3%) neonates were finally followed up till 12 weeks of age. Of the 26 completed cases, 14 (53.8%) were males. The mean (SD, range) birth weight and gestational age were 1876 (574.5, 1000-3000) g and 35.9 (3.9, 28-40) weeks, respectively. Primary indication for exchange transfusion was hyperbilirubinemia. Four of the 26 required exchange transfusion twice.
No significant differences were observed between 26 neonates who completed follow-up of 12 weeks and those (n=21) who dropped out with regard to sex ratio, birth weight, gestational age, risk factors/problems at birth, and CMV status of baby, mother and donor. Detailed results of serological follow-up testing for CMV are provided in [Table - 1]. Overall, 3 children demonstrated CMV IgM during follow-up but none demonstrated a 4 fold rise in IgG titer over the baseline. Details of 3 cases who had evidence of recent CMV infection are summarized in [Table - 2]. None of the three CMV IgM positive cases demonstrated any clinical (anthropometric, developmental, systemic, ophthalmological), hematological (blood counts and smear), biochemical (liver enzymes) or radiological (chest and skull skiagram, sonography and CT of brain) signs suggestive of perinatal CMV infection either at birth or during the course of follow-up.
Discussion
In our study, 3 out of 26 (11.5 %) children demonstrated CMV IgM seroconversion, indicating a perinatal infection. In the third neonate (first of a pair of twins), passage through the infected vaginal tract or breastfeeding could be responsible for the infection as the mother also had a possible primary CMV infection; the other twin did not develop infection during the study period. In the other two cases, the probable source of infection was donor blood, though none of the donor units tested positive for CMV IgM. All infected babies were low birth weight and small for their respective gestational age. Presence of low-avidity IgG antibodies or antigen detection by PCR would have indicated primary infection in the donors even in the absence of CMV IgM antibody[14]; however these were not determined due to lack of resources.
Similar studies in Japan and the United States showed an infection rate of 75 percent and 33 percent respectively following exchange transfusion with unfiltered blood.[6],[8] Another study in Oxford gave an infection rate of 25 percent following exchange transfusion.[9] Our results are different from these published studies. This could be due to difference in the characteristics of enrolled subjects, e.g., the study in Japan was carried out exclusively in pre-term low birth weight infants (￡ 2000 g), which in itself is a risk factor for transmission.
None of the three cases with perinatal infection developed any clinical sign of CMV disease, which is unusual. This calls for further focusing on both host and pathogen related factors; including lack of receptors for the virus, cytokine related defence mechanisms and failure to switch on the transcription mode for viral multiplication etc. Further, the circulating strain in the community may be less virulent, causing silent infection. Moreover, our study follow-up period was too short to show up any long term sequel in growth and development. It is difficult to comment on the clinical implication of seropositivity in absence of development of clinical disease and a short follow-up. A follow-up period of at least two years and possibly longer has been suggested to detect any growth retardation or other developmental anomalies in asymptomatic CMV infections in infants.[15]
Western guidelines[5] suggest that only CMV seronegative blood or filtered/leukocyte depleted blood be used in very low birth weight infant. However, similar proposal in India do not seem valid at present in the light of the results obtained in our study. In our study, following exchange transfusion with unscreened donor blood, only 11.5 percent babies developed CMV infection; none exhibited clinical manifestations. We have shown earlier the seroprevalence of CMV IgG in voluntary blood donors of Delhi to be near 95%.[16] The high endemicity and the consequent seropositivity may act as an independent deterrent for overt transmission and CMV disease following infection, be it perinatal or horizontal. Also, the lack of serious clinical disease following transfusion does not warrant such a step at present.
However, these proposals are at best only tentative. A much larger study, preferably multi-centric, with a bigger sample size on exchange transfusion and CMV infection along with at least a two year follow-up period of all cases needs to be carried out to give a truer picture of transmission rate. Also, IgG avidity index should be determined in all the cases, specially blood donors to detect early primary infection and reactivation. Moreover, serology for diagnosis of CMV disease or infection has its own fallacies. Virus isolation and/or antigen detection by PCR would be more useful, if available. Current guidelines in India regarding screening of donated blood for CMV could then be re-appraised in the light of new knowledge from such studies.
References
1. Stockman JA III. Red Cell Transfusions in Pediatrics. In: Rossi EC, Simon TL, Moss GS, Gould SA, editors. Principles of Transfusion Medicine . Baltimore: Williams and Wilkins; 1996. p. 167-176.
2. Alverson DC, Izquierdo LA. Hemolytic Disease of the Newborn: Treatment and Prevention. In: Rossi EC, Simon TL, Moss GS, Gould SA, editors. Principles of Transfusion Medicine. Baltimore: Williams and Wilkins; 1996. p. 127-140.
3. MacMohan JR, Stevenson DK, Oski FA. Management of neonatal hyperbilirubinemia. In: Taeusch HW, Ballard RA, editors. Avery 's Diseases of the Newborn . Philadelphia: W. B. Saunders Company; 1998: p. 1033-1044.
4. Pass RF. Cytomegalovirus. In: Knipe DM, Howley PM, editors. Fields Virology. Philadelphia: Lippincott Williams and Wilkins; 2001. p. 2675-2706.
5. Holland PV, Schmitt PJ. Standards for Blood Banks and Transfusion Services, 12th edn. Arlington, Va., Committee on Standards. American Association of Blood Banks 1987: 30-1.
6. Kumar A, Nankervis GA, Cooper AR, Gold E, Kumar ML. Acquisition of cytomegalovirus infection in infants following exchange transfusion: a prospective study. Transfusion 1980; 20(3): 327-331.
7. Brossard Y, Parnet-Mathieu F. Post-transfusion cytomegalovirus infection in newborn infants. Rev Fr Transfus Immunohematol 1984; 27(3): 345-353.
8. Xu D, Yonetani M, Uetani Y, Nakamura H. Acquired cytomegalovirus infection and blood transfusion in preterm infants. Acta Pediatr Jpn 1995; 37(4): 444-449.
9. Benson JW, Bodden SJ, Tobin JO. Cytomegalovirus and blood transfusion in neonates. Arch Dis Child 1979; 54(7): 538-541.
10. Gupta P, Gupta D, Ramachandran VG, Faridi MMA. Transfusion transmitted cytomegalovirus infection in a neonate. Indian Pediatr 2001; 38: 780-782.
11. Rekha S, Chandrasekhara MK, Yeshwanth M. Cytomegalovirus infection acquired through blood transfusions. Indian Pediatr 1995; 32(5): 575-577.
12. Gupta P, Chaturvedi D, Rai R, Dua T, Ramachandran VG. Cytomegalovirus infection in neonates following blood component therapy. Ann Trop Pediatr 2005; 25: 139-140.
13. Patil RS, Wadgaonkar P, Joshi SH, Merchant RH, Gupte SC. Viral infection in newborns through exchange transfusion. Indian J Pediatr 1998; 65: 723-728.
14. Lazzarotto T, Spezzacatena P, Pradelli P, Abate DA, Varani S, Landini MP. Avidity of immunoglobulin G directed against human cytomegalovirus during primary and secondary infections in immunocompetent and immunocompromised subjects. Clin Diagn Lab Immunol 1997; 4: 469-473.
15. Dworsky ME, Yow M, Stagno S, Pass RF, Alford CA. Cytomegalovirus infection of breast milk and transmission in infancy. Pediatrics 1983; 72: 295-299.
16. Kothari A, Ramachandran VG, Gupta P, Singh B, Talwar V. Seroprevalence of cytomegalovirus among voluntary blood donors in Delhi, India. J Health Popul Nutr 2002; 20(4): 348-351.(Kothari Atul, Ramachandra)