Enterovirus infection and progression from islet autoimmunity to type 1 diabetes: the Diabetes and Autoimmunity Study in the Young (DAISY).
OBJECTIVE
To investigate whether enterovirus infections predict progression to type 1 diabetes in genetically predisposed children repeatedly positive for islet autoantibodies.


METHODS
Since 1993, the Diabetes and Autoimmunity Study in the Young (DAISY) has followed 2,365 genetically predisposed children for islet autoimmunity and type 1 diabetes. Venous blood and rectal swabs were collected every 3-6 months after seroconversion for islet autoantibodies (against GAD, insulin, or insulinoma-associated antigen-2 [IA-2]) until diagnosis of diabetes. Enteroviral RNA in serum or rectal swabs was detected using reverse transcriptase PCR with primers specific for the conserved 5' noncoding region, detecting essentially all enterovirus serotypes.


RESULTS
Of 140 children who seroconverted to repeated positivity for islet autoantibodies at a median age of 4.0 years, 50 progressed to type 1 diabetes during a median follow-up of 4.2 years. The risk of progression to clinical type 1 diabetes in the sample interval following detection of enteroviral RNA in serum (three diabetes cases diagnosed among 17 intervals) was significantly increased compared with that in intervals following a negative serum enteroviral RNA test (33 cases diagnosed among 1,064 intervals; hazard ratio 7.02 [95% CI 1.95-25.3] after adjusting for number of autoantibodies). Results remained significant after adjustment for ZnT8-autoantibodies and after restriction to various subgroups. Enteroviral RNA in rectal swabs was not predictive of progression to type 1 diabetes. No evidence for viral persistence was found.


CONCLUSIONS
This novel observation suggests that progression from islet autoimmunity to type 1 diabetes may increase after an enterovirus infection characterized by the presence of viral RNA in blood.
Stene
Lars C
LC
Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway. marian.rewers@ucdenver.edu
Oikarinen
Sami
S
Hyöty
Heikki
H
Barriga
Katherine J
KJ
Norris
Jill M
JM
Klingensmith
Georgeanna
G
Hutton
John C
JC
Erlich
Henry A
HA
Eisenbarth
George S
GS
Rewers
Marian
M
D000293:Adolescent; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000453:epidemiology* / Q000276:immunology; D018450:Disease Progression; D004769:Enterovirus Infections / Q000150:complications* / Q000276:immunology*; D005500:Follow-Up Studies; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D007223:Infant; D007515:Islets of Langerhans / Q000276:immunology; D016016:Proportional Hazards Models; D012367:RNA, Viral / Q000097:blood; D013997:Time Factors
D001323:Autoantibodies; D006680:HLA Antigens; D012367:RNA, Viral