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. 2018 Jul 28;18(1):353.
doi: 10.1186/s12879-018-3220-8.

Using the Influenza Patient-reported Outcome (FLU-PRO) diary to evaluate symptoms of influenza viral infection in a healthy human challenge model

Alison Han  1 , Jiat-Ling Poon  2 , John H Powers 3rd  3 , Nancy K Leidy  2 , Ren Yu  2 , Matthew J Memoli  4
Affiliations

Using the Influenza Patient-reported Outcome (FLU-PRO) diary to evaluate symptoms of influenza viral infection in a healthy human challenge model

Alison Han et al. BMC Infect Dis. .

Abstract

Background: In clinical studies involving a healthy volunteer human challenge model, a valid and reliable measure to assess the evolution of patient-reported symptom type and severity following viral exposure is necessary. This study examines the use of the InFLUenza Patient-Reported Outcome (FLU-PRO) diary as a standardized measure of symptom severity in a healthy volunteer human challenge model.

Methods: Healthy adults admitted to the NIH Clinical Center (Day - 1) underwent a 9-day inpatient quarantine after intranasal challenge with a wild-type influenza A/H1N1pdm virus (Day 0). Participants completed the 32-item FLU-PRO diary twice daily for 14 days to assess presence, severity, and duration 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 scores on Day 3 post-challenge by presence of viral shedding, and pre-challenge hemagglutinin and neuraminidase inhibition (HAI and NAI) titers.

Results: All but one subject (99%), who was lost to follow-up, completed twice daily FLU-PRO diaries on all study assessment days. FLU-PRO demonstrated that 61 of 65 subjects reported symptoms (Days: Median 5, Mean 6 ± 7), of whom 37 (61%) had viral shedding. Pre-challenge, 39 (64%) and 10 (16%) subjects had low (< 1:40) HAI and NAI titers, respectively. Nose, throat, body, and gastrointestinal (GI) symptoms reached peak intensity at Day 3, followed by chest/respiratory and eye symptoms at Day 4. Subjects with viral shedding had higher mean FLU-PRO scores compared to those without, except for Eye and GI domains (p <0.05). Mean FLU-PRO scores were significantly higher for subjects with low NAI titer (p <0.05) 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 < 0.05) (high HAI-high NAI (n = 22), low HAI-high NAI (n = 29)).

Conclusions: The FLU-PRO had high adherence and low respondent burden. It can be used to track symptom onset, intensity, duration, and recovery from influenza infection in clinical research. In this human challenge study, scores were responsive to change and distinguished known clinical subgroups.

Trial registration: NCT01971255 First Registered October 2, 2013.

Keywords: Human challenge study; Influenza; Symptoms; Virus.

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Conflict of interest statement

Ethics approval and consent to participate

This study (ClinicalTrials.gov identifier NCT01971255) was approved by the National Institute of Allergy and Infectious Diseases institutional review board and was conducted in accordance with the provisions of the Declaration of Helsinki and Good Clinical Practice guidelines. Participants signed written informed consent prior to study enrollment.

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Symptom prevalence by FLU-PRO domains and total scores of symptomatic participants. Proportion of symptomatic participants by FLU-PRO domains and total scores prior to inoculation, Day 3, and Day 10. By Day 3, more participants reported symptoms in all domains and total score compared to baseline with near resolution to baseline prevalence by Day 10
Fig. 2
Fig. 2
Trajectory of FLU-PRO scores from pre-challenge to Day 10 post-challenge. Mean FLU-PRO scores from Day − 1 (pre-inoculation) through Day 10 by FLU-PRO domains and total scores. Peak FLU-PRO scores occurred on Day 3 for Nose, Body/Systemic, Throat, and Gastrointestinal domains and total score. Peak FLU-PRO scores occurred on Day 4 for Eyes and Chest/Respiratory domains
Fig. 3
Fig. 3
Mean (SE) FLU-PRO domain and total scores on Day 3 by shedding status. Participants with viral shedding had higher scores than those without. The difference was significant for the FLU-PRO total score and the Nose, Throat, Chest/Respiratory, and Body/Systemic domains (p < 0.05). Error bars denote standard errors
Fig. 4
Fig. 4
Mean (SE) FLU-PRO domain and total scores on Day 3 by Baseline NAI status. Participants with low NAI titers (< 1:40) had significantly higher mean FLU-PRO domain and total scores compared to those with high NAI titers (all p < 0.05). Error bars denote standard errors
Fig. 5
Fig. 5
Mean (SE) FLU-PRO domain and total scores on Day 3 by Baseline HAI status. Participants with low HAI titers (< 1:40) had higher mean FLU-PRO domain and total scores than those with high HAI titers, but the differences were not statistically significant. Error bars denote standard errors
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