1398. A host transcriptome signature arises in the pre-symptomatic period soon after Influenza exposure and accurately detects pandemic H1N1 infection
Session: Oral Abstract Session: Host Susceptibility to Viral Infections
Sunday, October 23, 2011: 7:45 AM
Room: 156ABC
Background: The emergence of pandemic H1N1 influenza in 2009 highlights the need for new approaches to diagnosis of respiratory tract infections to help mitigate pandemic spread.

Methods: We inoculated human volunteers with either influenza A (A/Brisbane/59/2007 (H1N1) or A/Wisconsin/67/2005 (H3N2)), and assayed the peripheral blood transcriptome every 8 hours for 7 days. Latent factor regression analysis was utilized to generate gene signatures for prediction.

Results: Of 41 total inoculated volunteers, 18 (44%) developed symptomatic infection. Using unbiased sparse latent factor regression analysis, we generated a gene signature (or factor) for symptomatic influenza capable of detecting 89% (H1N1) and 100% (H3N2) of infected cases.  We found that the temporal dynamics of the host response to influenza infection are continuously evolving. The genomic factor trajectory remains fairly flat for the first 25-30 hours following viral exposure before beginning to gradually increase over time.  Once initiated, the genomic pathways represented by the factor exhibit a rapid escalation of activity before reaching a peak at around 80-84 hours post-inoculation, and then gradually decline as disease resolves. The trajectory of the gene signature over time correlates broadly with clinical symptom scores, although increasing factor scores can be detected well before the time of maximal clinical symptoms (103 (H1N1) and 91 (H3N2) hours).  Even with clinical variability and relatively limited sample size, the divergence of the symptomatic-infected genomic factor trajectory becomes significant by 53 hours (H3N2, p=0.005) and 60 hours (H1N1, p=0.003) post-inoculation.  Furthermore, in order to test the relevance of these findings in naturally-acquired disease, a composite influenza A signature built from these trials was applied to Emergency Department patients where it discriminates between swine-origin influenza A/H1N1 (2009) infected and non-infected individuals with 93% accuracy.

Conclusion: The host genomic response to influenza infection is robust and may provide the means for diagnosis and detection before typical clinical symptoms are apparent.


Subject Category: V. Virology including clinical and basic studies of viral infections, including hepatitis

Micah McClain, MD, PhD1, Christopher Woods, MD, MPH2, Minhua Chen3, Aimee Zaas, MD, MHS4, Brad Nicholson, PhD5, Jay Varkey, MD6, Timothy Veldman7, Stephen Kingsmore, MD8, Yongsheng Huang9, Alfred Hero III, PhD9, Elizabeth Ramsburg, PhD3, Joseph Lucas, PhD10, Lawrence Carin, PhD3, Seth Glickman, MD11 and Geoffrey S. Ginsburg, MD., PhD12, (1)Internal Medicine/Division of Infectious Diseases, Duke University Medical Center, Durham, NC, (2)Internal Medicine, Duke University Medical Center/Durham VAMC, Durham, NC, (3)Duke University, Durham, NC, (4)Duke University Medical Center, Chapel Hill, NC, (5)Durham VA Medical Center, Durham, NC, (6)Emory University, Atlanta, GA, (7)Duke University Medical Center, Durham, NC, (8)National Center for Genome Resources, Santa Fe, NM, (9)University of Michigan, Ann Arbor, MI, (10)Duke University Medical Center-IGSP, Durham, NC, (11)University of North Carolina School of Medicine, Chapel Hill, NC, (12)Director, Center for Genomic Medicine in the Duke Institute for Genome Sciences & Policy, Duke University, Durham, NC

Disclosures:

M. McClain, None

C. Woods, None

M. Chen, None

A. Zaas, None

B. Nicholson, None

J. Varkey, None

T. Veldman, None

S. Kingsmore, None

Y. Huang, None

A. Hero III, None

E. Ramsburg, None

J. Lucas, None

L. Carin, None

S. Glickman, None

G. S. Ginsburg, None

Findings in the abstracts are embargoed until 12:01 a.m. EST Thursday, Oct. 20 with the exception of research findings presented at IDSA press conferences.