Evaluating Symptom Severity of Influenza Viral Infection Using the Influenza Patient-reported Outcomes Instrument (FLU-PRO) in a Healthy Human Challenge Model

BACKGROUND: To apply the validated FLU-PRO scoring method to assess influenza symptom severity in a healthy human challenge model. METHODS: Healthy adults admitted to the NIH Clinical Center (Day -1) underwent a 9 day inpatient quarantine after intranasal challenge with H1N1pdm (Day 0). Participants completed the 32 item FLU-PRO diary twice daily for 14 days to assess presence and severity of symptoms across six body systems. Secondary analyses included descriptive statistics to examine FLU-PRO scores over the course of illness and analysis of variance to compare severity scores on Day 3 post-challenge by viral shedding, and pre-challenge hemagglutinin and neuraminidase inhibition (HAI and NAI) titers. RESULTS: 61 of 65 subjects reported symptoms (Days: Median 5, Mean 6 ± 7), of which 37 (61%) had viral shedding. Pre-challenge, 39 (64%) and 10 (16%) subjects had low (<40) HAI and NAI titers, respectively. Mean daily FLU-PRO symptom severity domain and total scores are shown in Figure 1. Symptoms were present across all FLU-PRO domains from Day 1 post-challenge. Nose, throat, body, and GI symptoms reached peak severity at Day 3, followed by chest and eye symptoms at Day 4. Subjects with viral shedding had significantly higher mean FLU-PRO scores compared with those without, except for Eye and GI domains (P < .05); mean FLU-PRO scores were significantly higher for subjects with low NAI titer (P < .05) across all domains. No significant differences were observed between HAI titer groups. FLU-PRO scores of the low HAI-low NAI group (n = 10) were significantly higher (more severe) than the other two groups (P < .05) ((high HAI-low NAI (n = 22), low HAI-high NAI (n = 29)). CONCLUSION: The FLU-PRO can be used to track symptom onset, severity, and recovery from influenza infection in clinical research. In this challenge study, scores were responsive to change even in mild disease and distinguished known clinical subgroups. The use of NAI as an independent predictor of influenza disease severity was also supported. Funded by NCI Contract No. HHSN261200800001E and in part by the Intramural Research Program of the NIH, NIAID DISCLOSURES: J. L. Poon, Evidera: Employee, Salary; R. Yu, Evidera: Employee, Salary; N. K. Leidy, Evidera: Employee, Salary