Dried Blood Spots and Universal Newborn Screening for Congenital Cytomegalovirus Infection

Newborns in the United States and in many other developed countries are routinely tested for inherited metabolic disease using blood samples collected in hospital nurseries. Drops of newborn blood, typically collected from a heel stick, are blotted within circles marked on filter paper. These dried blood spots (DBSs) are submitted to central laboratories for testing. Although the diagnosis of congenital cytomegalovirus (CMV) infection requires detection of virus in body fluids collected during the first 3 weeks of life, retrospective diagnosis has been made years after birth using polymerase chain reaction (PCR) to detect CMV DNA in stored newborn DBSs [1, 2]. The ability to make a diagnosis of congenital CMV infection from DBSs and the fact that the logistics of collecting these samples, routing them to central laboratories, and reporting results to caregivers are already in place suggested the possibility of implementing universal newborn screening for congenital CMV infection. The American College of Medical Genetics (ACMG) established basic principles for defining criteria for newborn screening and selecting conditions for which screening should be mandatory or at least considered [3]. The ACMG reviewed 84 conditions including 3 infectious diseases (human immunodeficiency virus infection, congenital toxoplasmosis, and congenital CMV infection) and scored them on the basis of clinical characteristics, including potential for treatment, analytical characteristics of the screening test, and availability of resources to diagnose, treat, and provide care for screen-positive patients. Congenital CMV infection was ranked 72, with a score that indicated deficiencies in meeting several of the evaluation criteria. However, the ACMG did state, ‘‘Because of the limited involvement of infectious disease experts, the expert group chose to defer decision-making on infectious diseases’’ (page S300, reference 3). In their report, it was stated that, ‘‘to be included as a primary target condition in a newborn screening program, a condition should meet the following minimal criteria: it can be identified at a time (24–48 hours after birth) at which it would not ordinarily be detected clinically; a test with appropriate sensitivity and specificity is available for it; and there are demonstrated benefits of early detection, timely intervention and efficacious treatment of the condition’’ (page S298, reference 3). The paper by Leruez-Ville et al [4] in this issue of Clinical Infectious Diseases proposes a screening test for congenital CMV infection that could use DBS and possibly be incorporated into the routine newborn screening program. An inhouse real-time PCR assay based on amplification of conserved sequences from the CMV major immediate early co-transactivator (UL123) and a commercial PCR assay were used in parallel to test 10-mm dried blood spots from a group of newborns who had symptoms of congenital infection or were born to mothers with primary CMV infection—clearly a study population with a much higher pretest probability of a positive result than one would encounter in screening unselected newborns. The DBS PCR results compared very favorably with detection of virus in urine specimens using the same PCR assays, achieving sensitivity of 95%– 100%, specificity of 98%–99%, positive predictive value of 94%–97%, and negative predictive value of 99%–100%. PCR testing of DBSs worked well as a diagnostic tool for symptomatic newborns or those born to mothers with primary CMV infection. However, it is not clear from these results that the same approach would be satisfactory for newborn screening. With the in-house assay, 4 of 207 DBS samples obtained from Received 22 November 2010; accepted 17 December 2010. Correspondence: Robert F. Pass, MD, Childrens Hospital, 1600 7th Ave S, CHB 309, Birmingham, AL 35233 (rpass@peds.uab.edu). Clinical Infectious Diseases 2011;52(5):582–584 The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. 1058-4838/2011/525-0001$37.00 DOI: 10.1093/cid/ciq253