Congenital CMV infection in symptomatic infants in Delhi and surrounding areas
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《美国医学杂志》
1 Department of Microbiology, National Institute of Communicable Diseases, Directorate General of Health Services, 22 Shamnath Marg, Delhi, India
2 Additional DG & Director, National Institute of Communicable Diseases, Directorate General of Health Services, 22 Shamnath Marg, Delhi, India
Many viral infections are associated with significant maternal and fetal consequences during pregnancy among which cytomegalovirus is one of the most important agent, globally. Both primary and recurrent infection due to this virus can result in fetal infection. Samples from Congenital Anoammaled babies are referred to NICD from Delhi based Government hospitals and surrounding areas for diagnosis of congenital infections like Toxoplasm, Rubella, CMV and Herpes. In the present study, accumulated data is presented for the most common teratogenic virus - Cytomegalovirus prevalence as a causative agent for congenital infection in New Born babies at Delhi and surrounding areas. 96 samples from symptomatic babies in the age group of few days to 6 months exhibiting different congenital anomalies, were reported between 1 st Jan 04 to 30 th April/05. All the blood samples were tested for the detection of CMV (IgM) antibodies using m-capture ELISA technique. 18(18.75%) samples from babies showed positive titres for CMV-IgM antibodies. None of the mothers of positive babies were found positive for CMV-IgM antibodies but all were serologically exposed to CMV virus previously as their serum samples were positive for CMV -IgG antibodies indicating primary infection in the past or reactivation/reinfection with a different strain of CMV in the early pregnancy.
Keywords: Cytomegalovirus; Congenital infection
Maternal infections are now being increasingly recognized as a major cause of birth defects in newborn babies. CMV infection in general is probably one of the most common infections known to human being and is characterized by mild, self limiting infection with fever in healthy individuals. In pregnant women the virus can cross placenta and result in fetal infection. The prevalence of CMV infection varies from 0.3% to 2.4% and atleast 90% congenital infected infants have no clinical sign.[1],[2] The disease causes illness ranging from no apparent clinical signs to prematurity, encephalitis, deafness, hemolytic disorders and death.[3],[4] Congenital CMV infection is described in 30000 to 40000 new borns each year in the US, approximately 9000 of these children have permanent neurological sequelae.[4] The death rate of symptomatic CMV infection is approximately 30%.[5]
In India, serological surveys in different parts have shown the prevalence of 80-90% seropositivity[6],[7],[8],[9] of CMV antibodies (IgG) in women of child bearing age. Studies regarding prevalence of birth defects due to congenital CMV infection are limited in India. In the present study, samples of babies with signs and symptoms compatible with acute CMV infection and their mothers were referred to this Institute between 1 st Jan.2004 and 30th April 2005. They were assayed for CMV -IgM antibodies to establish the evidence of congenital CMV infection.
Material and Methods
During the period of present study (lst Jan 2004-30th April 2005), 96 serum samples from chil
The children were in the age group of few days to 6 months. The various clinical features in these children reported were Hepatosplenomegaly, Convulsions, Hydrocephaly, Microcephaly, NN cholestasis, Jaundice, Anemia, Chorioretinitis etc. The referred samples belonged to mixed population of Urban and Rural areas but mostly from lower socio-economic strata.
Blood samples received from all the cases were clotted and centrifuged for serum separation prior to testing. All the sera were stored at -20°C till tested.
The serum samples were tested for CMV-IgM antibodies using commercially available m-capture enzyme immunoassay method (ELISA kits -RADIM in this study) for qualitative detection. In this test system "Biotin-Streptaviridin Complex" has been used to increase the sensitivity of the procedure. The specificity of the procedure used is also 100% with no non specific binding due to rheumatoid or other herpatic viruses. Mothers of positive babies were subjected to CMV-IgG and IgM serology using commercial ELISA kits. Kit instructions were strictly adhered to while processing the samples.
Interpratation of the results was based on the controls provided with the kit. Test sample was said to be positive for IgM antibodies when it absorbance value was higher than the absorbance value of the cut-off control. Positivity of IgM antibodies against CMV in a sample indicates active infection of CMV.
Results
Eighteen (18.75%) out of 96 samples from children showed presence of IgM antibodies giving serological evidence of exposure to in-utero cytomegalovirus infection.
None of the mothers from positive congenital CMV infected babies were positive for CMV - IgM antibodies but all showed IgG seropositivity against CMV virus indicating primary infection in the past or reactivation or reinfection with a different strain of the virus in early pregnancy.
Congenital CMV related clinical manifestations when compiled in the present study showed Hepatosplenomegaly as the most common clinical feature [Table - 1] followed by bronchopneumonia, jaundice, anemia, neonatal seizures, microcephaly, hydrocephaly, retinitis etc.
Discussion
High incidence ofCMV related congenital defects in reported cases of New. Borns (18.75%) with congenital anomalies can be seen in the present study, similar to few other studies carried out in India.[10],[11],[12] In the present study false positivity for CMV IgM antibodies was ruled out by using m-capture ELISA system, which is highly specific and sensitive.
The clinical presentation in the infants positive for CMV -IgM antibodies was typical of congenitally acquired CMV infection. Hepatosplenomegaly was the commenest clinical feature(12 cases), next common features was Neonatal jaundice, Bronchopneumonia and Anemia (4 cases each). Other notable clinical symptoms like neonatal seizures, microcephaly, hydrocephaly, retinitis, cataract. etc. are compatible with Congenital CMV infectionThis finding is in accordance with other studies from India and abroad.[12],[13]
CMV is common in all socio-economic groups but congenital infection with significant impairment is seen at highest rate in population in which women in child bearing age have highest risk of acquiring primary infection.[6],[8],[11] In addition to the placental route, CMV can be transmitted at delievery via the maternal genital tract, during the post parturn period in breast milk and transfused blood products.
Symptomatic cytomegalovirus infection in fetus can occur after maternal recurrent infection but the incidence of these cases is still not established.[14] Seropositive women reinfected by a different strain of cytomegalovirus can transmit the infection to the fetus and deliever a symptomatic child.[15],[16] High rate of seropositivity of CMV IgG (80-90%) in child bearing age.[8],[9] delievering high no. of symptomatic congenital CMV babies (present study) support the above mentioned studies.
Antenatal screening for CMV infection has been widely practiced in most developed countries which can substantially reduce the incidence of congenital CMV infection by advising MTP' in case of intrauterine symptomatic CMV infected fetus diagnosed by amniocentasis or ultrasound[16],[17] rather than giving birth to infants having congenital infections with high sequele. However, mandatory testing during antenatal period is rudimentary in India due to various reasons. The diagnosis is done most of the times after the mother gives birth to a baby with congenital anomalies and that is why the incidence of birth defects due to CMV virus is high in India. Good hygine and general infection control practice is, the best way to prevent transmission of CMV infection in developing countries. Though the only drug currently available for congenital CMV infection is Ganciclovir[18],[19] yet the side effects due to this drug in most patients during the course of therapy[20] has limited its role.
Conclusion
The facts presented in the present study conclude beyond doubt that maternal infection like CMV cause considerable burden on society in terms of huge number of babies with birth defects.
Good hygiene, antenatal screening, antiviral therapies, development and introduction of good vaccine may achieve the goal of controlling CMV related congenital defects in the New Borns. The importance may primarily be given to introduction of antenatal screening for CMV infection in the developing countries like India as has been implemented against HIV. Data generated will help the health authorities to make policy against congenital CMV infection prevailing in the country.
References
1.Trincado DE, Rawlison WD. Congenital and perinatal infection with cytomegalovirus. J Peadia Child Health 2001; 37: 187-92.
2.Willi son WD, Perry AK, Yow MD et al. Asymptomatic Congenital Cytomegalovirus infection. Am J Dis Child 1990; 144: 1365-1368.
3.Harris S, Ahlfors K, Ivarsson S, Lermark B, Svanberg L. Congenital Cytomegalovirus infection and sensorineural hearing loss. Ear Hear 1984; 5 : 352-355.
4.Damato EG, Winnen CW.Cytomegalo infection perinatal implications. J Obstet Gynecol Neonatal Nurs 2002; 31 : 86-92.
5.Peckam C, Tookay P, Logan S, Giaquinto C. Screening options for prevention of congenital cytomegalovirus infection. J Med Screen 2001; 8 : 119-124.
6.S, Jindal N, Aggarwal A. Apilot seroepidemiological study of cytomegalovirus infection in women of child bearing age. Indian J Med Microbiol 2005; 23 : 34-36.
7.Mathur A, Jindal L Chaturvedi VC. A serological study of cytomegalovirus infection at Lucknow. Ind, J Med Res 1981; 73: 678-681.
8.Arvind Rai, S Kumari, S Khare, I Gandhoke, R Bhatia, KK Datta. Maternal Viral Infections and their implications in Congenital defects of new borns. J Basic and Applied Biomedicine 1995; 3(2) : 1-9.
9.Turbadkar D, Mathur M, Rele M., Seroprevalence of Torch Infection in BOH. IJMM 2003; 21 : 108-110.
10.N. Thapliyal, PK Shukla, B. Kumar, S. Upadhyay, G. Jain. TORCH infection in women with bad obstetric history- a piolet study in Kumaon region. Indian J Pathol Microbiol 2005; 48(4) : 551-553.
11.A. Chakravarty, B. Kashyap, K. Rathi. The seroepidemiological study on cytomegalovirus in woman of child-bearing age with special reference to pregnancy and maternal-fetal transmission. Indian J Pathol Microbiol 2005; 48(4) : 518-521.
12.M. Abraham, P. Abraham, A K Jana, K A Kuruvilla, T.Cherian, P D Moses, E. Mathai, T J John, G. Sridharan. Serology in Congenital Infections: Experience in Selected Symptomatic Infants. Indian Pediatrics 1999; 36 : 697-700.
13.D Trincado, P. Palasanthrian, M. Ferson, D. Smith, G. Higgins, M. Catton, A. McGregor, A. Kesson. Congenital Anomalies December 2004; vo1.44(4) : AI9-A62.
14.Remington JS, McLeod R, Des onts SG, Inf. Diseases of Fetus and new born infants. Philadelphia. WB Saunder 1995; 140-267
15.Boppana SB, Rivers LB, Fowler KB, Mach M, Britt WJ. Intrauterine transmission of Cytomegalovirus to infants of women with preconceptional immunity. N Engl J Med 2001; 344 : 1366-1371.
16.Mana Grazia Revello, Maurizio Zavattoni, Milena Furione, Fausto Baldanti and Giuseppe Gerna. Quantification of Human Cytomegalovirus DNA in Amniotic Fluid of Mothers of congenitally Infected Fetuses: Jr Clinical Microbiology Oct. 1999; 37(10) pp. 3350-3352.
17.P Hohlfeld, Y Vial, C Maillard-Brignen, B Vaudauxand CL Fawer. Cytomegalovirus fetal infection: prenatal diagnosis. Obstetrics and Gyn 1991; 78: 615-618.
18.Friedman S, Ford-Jones EL. Congenital cytomeg ovirus infection :an update. Pediatr Child Health 1999;4(1): 35-38.
19.Benjamin Bar-02, Matitahu Berkovitch, Lee Ford-Jones, Gideon Koren. Congenital cytomegalo virus infection. Is there breakthrough Canadian Family Physician 2001; 47: 1179-1181.
20.Whilley RJ, Cloud G, Gruber W, Storch GA, Demmler GJ, Jacobs RF et al. Ganciclovir treatment of symptomatic congenital cytomegalovirus infection: results of a phase 11 study. National Institute of Allergy and Infectious Diseases. Collaborative Antiviral study Group. J Infect Dis 1997; 175 (5): 1080-1086.(Gandhoke Inderjeet, Aggarwal Ramesh, Lal)
2 Additional DG & Director, National Institute of Communicable Diseases, Directorate General of Health Services, 22 Shamnath Marg, Delhi, India
Many viral infections are associated with significant maternal and fetal consequences during pregnancy among which cytomegalovirus is one of the most important agent, globally. Both primary and recurrent infection due to this virus can result in fetal infection. Samples from Congenital Anoammaled babies are referred to NICD from Delhi based Government hospitals and surrounding areas for diagnosis of congenital infections like Toxoplasm, Rubella, CMV and Herpes. In the present study, accumulated data is presented for the most common teratogenic virus - Cytomegalovirus prevalence as a causative agent for congenital infection in New Born babies at Delhi and surrounding areas. 96 samples from symptomatic babies in the age group of few days to 6 months exhibiting different congenital anomalies, were reported between 1 st Jan 04 to 30 th April/05. All the blood samples were tested for the detection of CMV (IgM) antibodies using m-capture ELISA technique. 18(18.75%) samples from babies showed positive titres for CMV-IgM antibodies. None of the mothers of positive babies were found positive for CMV-IgM antibodies but all were serologically exposed to CMV virus previously as their serum samples were positive for CMV -IgG antibodies indicating primary infection in the past or reactivation/reinfection with a different strain of CMV in the early pregnancy.
Keywords: Cytomegalovirus; Congenital infection
Maternal infections are now being increasingly recognized as a major cause of birth defects in newborn babies. CMV infection in general is probably one of the most common infections known to human being and is characterized by mild, self limiting infection with fever in healthy individuals. In pregnant women the virus can cross placenta and result in fetal infection. The prevalence of CMV infection varies from 0.3% to 2.4% and atleast 90% congenital infected infants have no clinical sign.[1],[2] The disease causes illness ranging from no apparent clinical signs to prematurity, encephalitis, deafness, hemolytic disorders and death.[3],[4] Congenital CMV infection is described in 30000 to 40000 new borns each year in the US, approximately 9000 of these children have permanent neurological sequelae.[4] The death rate of symptomatic CMV infection is approximately 30%.[5]
In India, serological surveys in different parts have shown the prevalence of 80-90% seropositivity[6],[7],[8],[9] of CMV antibodies (IgG) in women of child bearing age. Studies regarding prevalence of birth defects due to congenital CMV infection are limited in India. In the present study, samples of babies with signs and symptoms compatible with acute CMV infection and their mothers were referred to this Institute between 1 st Jan.2004 and 30th April 2005. They were assayed for CMV -IgM antibodies to establish the evidence of congenital CMV infection.
Material and Methods
During the period of present study (lst Jan 2004-30th April 2005), 96 serum samples from chil
The children were in the age group of few days to 6 months. The various clinical features in these children reported were Hepatosplenomegaly, Convulsions, Hydrocephaly, Microcephaly, NN cholestasis, Jaundice, Anemia, Chorioretinitis etc. The referred samples belonged to mixed population of Urban and Rural areas but mostly from lower socio-economic strata.
Blood samples received from all the cases were clotted and centrifuged for serum separation prior to testing. All the sera were stored at -20°C till tested.
The serum samples were tested for CMV-IgM antibodies using commercially available m-capture enzyme immunoassay method (ELISA kits -RADIM in this study) for qualitative detection. In this test system "Biotin-Streptaviridin Complex" has been used to increase the sensitivity of the procedure. The specificity of the procedure used is also 100% with no non specific binding due to rheumatoid or other herpatic viruses. Mothers of positive babies were subjected to CMV-IgG and IgM serology using commercial ELISA kits. Kit instructions were strictly adhered to while processing the samples.
Interpratation of the results was based on the controls provided with the kit. Test sample was said to be positive for IgM antibodies when it absorbance value was higher than the absorbance value of the cut-off control. Positivity of IgM antibodies against CMV in a sample indicates active infection of CMV.
Results
Eighteen (18.75%) out of 96 samples from children showed presence of IgM antibodies giving serological evidence of exposure to in-utero cytomegalovirus infection.
None of the mothers from positive congenital CMV infected babies were positive for CMV - IgM antibodies but all showed IgG seropositivity against CMV virus indicating primary infection in the past or reactivation or reinfection with a different strain of the virus in early pregnancy.
Congenital CMV related clinical manifestations when compiled in the present study showed Hepatosplenomegaly as the most common clinical feature [Table - 1] followed by bronchopneumonia, jaundice, anemia, neonatal seizures, microcephaly, hydrocephaly, retinitis etc.
Discussion
High incidence ofCMV related congenital defects in reported cases of New. Borns (18.75%) with congenital anomalies can be seen in the present study, similar to few other studies carried out in India.[10],[11],[12] In the present study false positivity for CMV IgM antibodies was ruled out by using m-capture ELISA system, which is highly specific and sensitive.
The clinical presentation in the infants positive for CMV -IgM antibodies was typical of congenitally acquired CMV infection. Hepatosplenomegaly was the commenest clinical feature(12 cases), next common features was Neonatal jaundice, Bronchopneumonia and Anemia (4 cases each). Other notable clinical symptoms like neonatal seizures, microcephaly, hydrocephaly, retinitis, cataract. etc. are compatible with Congenital CMV infectionThis finding is in accordance with other studies from India and abroad.[12],[13]
CMV is common in all socio-economic groups but congenital infection with significant impairment is seen at highest rate in population in which women in child bearing age have highest risk of acquiring primary infection.[6],[8],[11] In addition to the placental route, CMV can be transmitted at delievery via the maternal genital tract, during the post parturn period in breast milk and transfused blood products.
Symptomatic cytomegalovirus infection in fetus can occur after maternal recurrent infection but the incidence of these cases is still not established.[14] Seropositive women reinfected by a different strain of cytomegalovirus can transmit the infection to the fetus and deliever a symptomatic child.[15],[16] High rate of seropositivity of CMV IgG (80-90%) in child bearing age.[8],[9] delievering high no. of symptomatic congenital CMV babies (present study) support the above mentioned studies.
Antenatal screening for CMV infection has been widely practiced in most developed countries which can substantially reduce the incidence of congenital CMV infection by advising MTP' in case of intrauterine symptomatic CMV infected fetus diagnosed by amniocentasis or ultrasound[16],[17] rather than giving birth to infants having congenital infections with high sequele. However, mandatory testing during antenatal period is rudimentary in India due to various reasons. The diagnosis is done most of the times after the mother gives birth to a baby with congenital anomalies and that is why the incidence of birth defects due to CMV virus is high in India. Good hygine and general infection control practice is, the best way to prevent transmission of CMV infection in developing countries. Though the only drug currently available for congenital CMV infection is Ganciclovir[18],[19] yet the side effects due to this drug in most patients during the course of therapy[20] has limited its role.
Conclusion
The facts presented in the present study conclude beyond doubt that maternal infection like CMV cause considerable burden on society in terms of huge number of babies with birth defects.
Good hygiene, antenatal screening, antiviral therapies, development and introduction of good vaccine may achieve the goal of controlling CMV related congenital defects in the New Borns. The importance may primarily be given to introduction of antenatal screening for CMV infection in the developing countries like India as has been implemented against HIV. Data generated will help the health authorities to make policy against congenital CMV infection prevailing in the country.
References
1.Trincado DE, Rawlison WD. Congenital and perinatal infection with cytomegalovirus. J Peadia Child Health 2001; 37: 187-92.
2.Willi son WD, Perry AK, Yow MD et al. Asymptomatic Congenital Cytomegalovirus infection. Am J Dis Child 1990; 144: 1365-1368.
3.Harris S, Ahlfors K, Ivarsson S, Lermark B, Svanberg L. Congenital Cytomegalovirus infection and sensorineural hearing loss. Ear Hear 1984; 5 : 352-355.
4.Damato EG, Winnen CW.Cytomegalo infection perinatal implications. J Obstet Gynecol Neonatal Nurs 2002; 31 : 86-92.
5.Peckam C, Tookay P, Logan S, Giaquinto C. Screening options for prevention of congenital cytomegalovirus infection. J Med Screen 2001; 8 : 119-124.
6.S, Jindal N, Aggarwal A. Apilot seroepidemiological study of cytomegalovirus infection in women of child bearing age. Indian J Med Microbiol 2005; 23 : 34-36.
7.Mathur A, Jindal L Chaturvedi VC. A serological study of cytomegalovirus infection at Lucknow. Ind, J Med Res 1981; 73: 678-681.
8.Arvind Rai, S Kumari, S Khare, I Gandhoke, R Bhatia, KK Datta. Maternal Viral Infections and their implications in Congenital defects of new borns. J Basic and Applied Biomedicine 1995; 3(2) : 1-9.
9.Turbadkar D, Mathur M, Rele M., Seroprevalence of Torch Infection in BOH. IJMM 2003; 21 : 108-110.
10.N. Thapliyal, PK Shukla, B. Kumar, S. Upadhyay, G. Jain. TORCH infection in women with bad obstetric history- a piolet study in Kumaon region. Indian J Pathol Microbiol 2005; 48(4) : 551-553.
11.A. Chakravarty, B. Kashyap, K. Rathi. The seroepidemiological study on cytomegalovirus in woman of child-bearing age with special reference to pregnancy and maternal-fetal transmission. Indian J Pathol Microbiol 2005; 48(4) : 518-521.
12.M. Abraham, P. Abraham, A K Jana, K A Kuruvilla, T.Cherian, P D Moses, E. Mathai, T J John, G. Sridharan. Serology in Congenital Infections: Experience in Selected Symptomatic Infants. Indian Pediatrics 1999; 36 : 697-700.
13.D Trincado, P. Palasanthrian, M. Ferson, D. Smith, G. Higgins, M. Catton, A. McGregor, A. Kesson. Congenital Anomalies December 2004; vo1.44(4) : AI9-A62.
14.Remington JS, McLeod R, Des onts SG, Inf. Diseases of Fetus and new born infants. Philadelphia. WB Saunder 1995; 140-267
15.Boppana SB, Rivers LB, Fowler KB, Mach M, Britt WJ. Intrauterine transmission of Cytomegalovirus to infants of women with preconceptional immunity. N Engl J Med 2001; 344 : 1366-1371.
16.Mana Grazia Revello, Maurizio Zavattoni, Milena Furione, Fausto Baldanti and Giuseppe Gerna. Quantification of Human Cytomegalovirus DNA in Amniotic Fluid of Mothers of congenitally Infected Fetuses: Jr Clinical Microbiology Oct. 1999; 37(10) pp. 3350-3352.
17.P Hohlfeld, Y Vial, C Maillard-Brignen, B Vaudauxand CL Fawer. Cytomegalovirus fetal infection: prenatal diagnosis. Obstetrics and Gyn 1991; 78: 615-618.
18.Friedman S, Ford-Jones EL. Congenital cytomeg ovirus infection :an update. Pediatr Child Health 1999;4(1): 35-38.
19.Benjamin Bar-02, Matitahu Berkovitch, Lee Ford-Jones, Gideon Koren. Congenital cytomegalo virus infection. Is there breakthrough Canadian Family Physician 2001; 47: 1179-1181.
20.Whilley RJ, Cloud G, Gruber W, Storch GA, Demmler GJ, Jacobs RF et al. Ganciclovir treatment of symptomatic congenital cytomegalovirus infection: results of a phase 11 study. National Institute of Allergy and Infectious Diseases. Collaborative Antiviral study Group. J Infect Dis 1997; 175 (5): 1080-1086.(Gandhoke Inderjeet, Aggarwal Ramesh, Lal)