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In Utero Cytomegalovirus Infection Increases Risk of Developing Acute Lymphocytic Leukemia in Pediatric Patients
Children who had in utero cytomegalovirus ( CMV ) infection are more likely to develop childhood acute lymphocytic leukemia ( ALL ) than matched controls without infection , suggesting a role of infection in the etiology of ALL , according to the results of a next-generation sequencing ( NGS ) study published in Blood . The study authors , led by Stephen S . Francis , PhD , from the Department of Epidemiology & Biostatistics at the University of California , San Francisco / Berkeley , also found that congenital CMV infection is more prominent in Hispanic children than in children in any other ethnic group .
Dr . Francis and authors conducted two complementary studies to determine which infections are unique to childhood ALL ( compared with acute myeloid leukemia [ AML ]) and whether these infections are risk factors for ALL .
The first study was a comprehensive NGS-based metagenomics analysis of pretreatment diagnostic bone marrow ( BM ) data from 127 children with ALL and 38 children with AML who were enrolled in the California Childhood Leukemia Study , which identified prevalence of infections . In the second study , researchers analyzed blood specimens from 268 newborn patients with ALL and 270 newborn patients without
TABLE . Results of Neonatal Blood Spot Screen cancer ( controls ) identified through the California Department of Public Health , and then screened the samples for two herpes viruses that were identified in the discovery set at diagnosis ( including CMV and Epstein-Barr virus ).
The children with ALL tended to be younger than those with AML , but all other demographic characteristics were similar .
NGS-based analyses revealed a manifold higher prevalence of CMV in the BM samples of patients with ALL , compared with patients with AML ( odds ratio [ OR ] = 18 ; p = 0.003 ), suggesting that CMV was associated with ALL . Screening revealed that children who developed
ALL were 3.71 times more likely to be CMV-positive at birth ( p = 0.0016 ).
The prevalence of congenital CMV infection was higher in white children , and the authors observed an increased risk for developing ALL in this group , though this association was not statistically significant ( OR = 2.1 ; 95 % CI 0.69-7.13 ). Hispanic ethnicity , however , was associated with a statistically significant 5.9-fold increased risk of developing ALL , compared with children of other ethnicities ( 95 % CI 1.9-26 ; p = 0.006 ).
The mean CMV viral load among positive case samples was 0.214 copies / μL , which was higher than the CMV viral load among control samples ( 0.071 copies / μL ; p = 0.003 ). Age did not affect the risk of ALL diagnosis between CMV-positive ( mean age = 4.8 years ) and CMV-negative patients ( mean age = 5.15 years ). See TABLE for the results of the neonatal blood specimen screening .
The majority of congenital CMV infections are caused by vertical transmission of reactivated virus , Dr . Francis and authors noted , because most
CMV− |
CMV + |
OR |
p Value |
EBV− |
EBV + |
OR |
p Value |
Overall ALL |
242 |
26 |
3.71 |
0.0016 |
257 |
11 |
1.01 |
1 |
|
|
|
( 95 % CI 1.71-8.95 ) |
|
|
|
( 95 % CI 0.42-2.24 ) |
|
Controls |
262 |
8 |
− |
− |
259 |
11 |
− |
− |
According to Race Hispanic ALL |
134 |
3 |
5.9 |
0.006 |
141 |
8 |
1.38 |
0.56 |
|
|
|
( 95 % CI 1.89-25.96 ) |
|
|
|
( 95 % CI 0.46-4.35 ) |
|
Hispanic controls |
152 |
10 |
− |
− |
149 |
62 |
− |
− |
White ALL |
71 |
5 |
2.1 |
|
|
|
( 95 % CI 0.69-7.13 ) |
0.204 |
79 |
5 |
0.53 |
|
|
|
( 95 % CI 0.09-2.94 ) |
White controls |
82 |
1 |
− |
− |
83 |
1 |
− |
− |
Asian / PI ALL |
25 |
0 |
N / A |
1 |
25 |
0 |
N / A |
1 |
Asian / PI Controls |
21 |
0 |
− |
− |
21 |
0 |
− |
− |
Black ALL |
10 |
0 |
− |
− |
10 |
0 |
− |
− |
Black controls |
4 |
0 |
− |
− |
4 |
0 |
− |
− |
Other ALL |
2 |
0 |
− |
− |
2 |
0 |
− |
1 |
Other controls |
3 |
0 |
− |
− |
2 |
1 |
− |
− |
CMV = cytomegalovirus ; OR = odds ratio ; EBV = Epstein-Barr virus ; ALL = acute lymphocytic leukemia ; PI = Pacific Islander ; N / A = not applicable |
0.68 women of childbearing age have been previously infected with CMV .
“ Timing of CMV infection has important implications ,” the authors wrote , explaining that the presence of CMV in the child prior to birth may have important immune control implications . “ Infection prior to the development of a robust adaptive immune response in the fetus and neonate may affect central tolerance and enable CMV to persist in an infectious course .”
Dr . Francis and authors noted two features of CMV infection that support its role in the oncogenesis of ALL : First , congenital CMV infection can cause chromosomal instability , and , second , CMV has the largest genome of any known human viral pathogen and harbors many immune evasion genes .
The study is limited by its retrospective design and lack of information on ALL subtype and cytogenetic characteristics . In addition , the low input quantity of dried blood specimen DNA used in the second study phase may have resulted in false negatives .
“ Our findings lead us to hypothesize that in utero or perinatal CMV infection initiates immune dysregulation during the critical period of fetal immune development , allowing a greater number of and more fulminant infections later in life ,” the authors concluded , adding that studies that define in utero CMV infection in terms of ALL subtype , cytogenetics , and overall prevalence are warranted .
REFERENCE
Francis SS , Wallace AD , Wendt JA , et al . In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia . Blood . 2016 December 15 . [ Epub ahead of print ]
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