Gene expression helps monitor effect of early flu therapy

Tamiflu given to patients 36 hours after being inoculated with influenza A virus reduced the time, duration and number of symptoms compared with patients who received the drug 120 hours after inoculation, according to the results of an experimental study.

In addition, researchers were able to monitor the effect of early treatment with Tamiflu (oseltamivir, Roche) through patients’ gene expression signatures. A similar approach has been used in previous studies to differentiate between bacterial, viral and noninfectious causes of illness.

“This work demonstrates that analyses of the temporal development of gene expression signatures shows promise for creating diagnostics for early detection, which may drive therapeutic decisions as well as providing insight into the biology of the host response to the onset, progression and eventual resolution of influenza infection,” researcher Micah T. McClain, MD, PhD, division of infectious diseases at Duke University Medical Center, and colleagues wrote.

McClain and colleagues evaluated 21 patients who were inoculated with influenza A H3N2 and collected blood every 8 hours and nasal lavage samples daily for the first 5 days after inoculation. Patients received 75 mg oseltamivir twice daily; however, they were randomly assigned to receive the drug at either 36 hours after inoculation in an early intervention or 120 hours after inoculation as part of a standard intervention.

Patients assigned standard treatment experienced an onset of symptoms approximately 46 hours after inoculation and saw their maximum symptoms at 112 hours, the researchers wrote. Similarly, patients in the early intervention group showed symptom onset, on average, 43 hours after inoculation, but experienced the peak of their symptoms at 73 hours vs. 94 hours in the standard treatment group. Further, patients in the early intervention group had their symptoms resolve sooner at 124 hours after inoculation compared with 144 hours in the standard treatment group.

Patients in the early intervention group also had a reduced number of overall influenza symptoms compared with the standard group (aggregate symptom scores = 23.5 points vs. 46.3 points), according to the researchers. Quantitative culture showed reduced viral shedding in the early treatment group (aggregate TCID₅₀ per patient = 7.4 vs. 9.7).

McClain and colleagues noted significantly reduced expression of inflammatory cytokines in the early treatment group, including interferon gamma, tumor necrosis factor-alpha, interleukin-4 (IL-4), IL-5 and IL-6.

“As expected from previous work in both experimental and natural infection, early treatment with oseltamivir triggered a reduction in the duration and overall severity of clinical illness as well as a reduction in the amount of viral shedding which occurred,” McClain and colleagues wrote. “However, for the first time we have been able to define the effect of early treatment on temporal dynamics of the host peripheral blood genomic responses which underlie this process.” – by Jeff Craven

References:

McClain MT, et al. Open Infect Dis J. 2016;doi:10.1093/ofid/ofw007.

Tsalik EL, et al. Sci Transl Med. 2016;doi:10.1126/scitranslmed.aad6873.

Zaas AK, et al. Sci Transl Med. 2013;doi:10.1126/scitranslmed.3006280.

Disclosure: McClain and other researchers have patents pending on host-based diagnostics for pathogen identification. Please see the full study for a list of all other authors’ relevant financial disclosures.