Abstract
Background
A moderate to severe (M/S) influenza clinical endpoint has been proposed in children, defined as fever >39°C, otitis media, lower respiratory tract infection, or serious extrapulmonary manifestations. The objective of the study was to evaluate the M/S measure against clinically relevant outcomes including hospitalization, emergency room visits, antimicrobial use, and child/parental absenteeism.
Methods
We conducted a prospective observational study of children aged 6 months–8 years at the Children’s Hospital Colorado emergency department (ED) and urgent care site during 2016–2017 and 2017–2018. Children with influenza-like illness (ILI) underwent influenza testing by polymerase chain reaction (PCR); children who tested positive and a subset of matched test-negative controls underwent follow-up at 2 weeks. The primary outcome was the proportion of children who were hospitalized. Secondary outcomes included recurrent ED visits, antimicrobial use, hospital charges, and child/parental absenteeism within 14 days.
Results
Among 1478 children enrolled with ILI, 411 (28%) tested positive for influenza by PCR. Of children with influenza illness, 313 (76%) met the M/S definition. Children with M/S influenza were younger (3.8 years vs 4.8 years), infected with influenza A (59% vs 44%), and more frequently hospitalized (unadjusted risk difference [RD], 6.3%; 95% confidence interval [CI], 2.1–10.4; P = .03) and treated with antibiotics (unadjusted RD, 13.3%; 95% CI, 4.3–22.4; P < .01) compared to those with mild disease.
Conclusions
Children with M/S influenza have a higher risk of hospitalization and antibiotic use compared with mild disease. This proposed definition may be a useful clinical endpoint to study the public health and clinical impact of influenza interventions in children.
Clinical Trials Registration
Keywords: absenteeism, antibiotics, clinical endpoint, hospitalization, influenza-like illness, influenza, severity
Young children classified with moderate to severe influenza illness had a higher rate of hospitalization and antibiotic use, suggesting the clinical usefulness of this measure to study the public health impact of influenza interventions in children.
Influenza infection contributes to significant morbidity and mortality in children [1–3], causing 1–7 hospitalizations per 10 000 in children <18 years of age and an average of 100 related deaths per year in the United States (US) [4–9]. The social and economic impacts of influenza include substantial healthcare costs and decreased productivity due to parental absenteeism [10]. Annual influenza vaccination remains the most effective strategy to prevent influenza illness, and is recommended for all children 6 months of age and older in the United States [11]. While the ultimate goal of influenza vaccination is to prevent influenza infection, available inactivated influenza vaccines have been shown to inconsistently provide adequate protection due to the elusive nature of the influenza virus. Despite this partial protection from infection, current vaccines can attenuate disease, with effects including decreased rates of hospitalization, intensive care utilization, and death [12–15]. However, a standardized and validated definition of influenza severity has not been established to allow comparative measurement of vaccine effectiveness against these important public health outcomes.
Recently, a moderate to severe influenza clinical endpoint has been proposed, defined as the presence of (1) fever >39°C; (2) otitis media per the American Academy of Pediatrics guideline criteria; (3) lower respiratory tract infection (LRTI; eg, shortness of breath, pulmonary congestion, pneumonia, bronchiolitis, bronchitis, wheezing, croup); or (4) serious extrapulmonary manifestations (eg, myocarditis, encephalitis, seizure) [16]. The relationship between this definition of moderate to severe influenza when compared with mild disease has not been evaluated prospectively in children in the US, nor has the validity of this definition been measured against important clinical and public health outcomes such as emergency department (ED) visits, hospitalization, child and parental absenteeism, use of antimicrobials, and recurrent healthcare utilization. Therefore, the objectives of this study were to evaluate if the proposed definition of moderate to severe influenza in children predicts hospitalization and other clinically relevant healthcare endpoints including recurrent ED visits, use of antimicrobials (including antivirals), school/daycare or parental work absenteeism, and increased healthcare costs during 2 recent influenza seasons.
METHODS
We conducted a prospective observational cohort study of children 6 months–8 years of age presenting with influenza-like illness (ILI) to the Children’s Hospital Colorado (CHCO) ED and an affiliated urgent care (UC) center from January to April 2017 and from November 2017 to April 2018. ILI was defined as a temperature of ≥37.8 °C and at least 1 of the following: cough, sore throat, runny nose, or nasal congestion [17]. Children were excluded if they had respiratory symptom duration of >14 days, if they were enrolled in the study within the prior 14 days, or if they had nurse-only visits. Nasopharyngeal swabs were obtained from all enrolled children, which were tested for influenza using the Cepheid Xpert influenza real-time reverse-transcription polymerase chain reaction (PCR) assay, which detects influenza A and influenza B and provides the influenza A 2009 H1N1 subtype [18].
Parents were interviewed in the ED or UC regarding the child’s demographic characteristics, presenting symptoms, medical comorbidities, influenza vaccination status, household size, and preferred method of contact for follow-up. Vaccination status was confirmed with review of medical records, including review of the Colorado Immunization Information System Registry. A symptom diary card was provided to family members upon discharge from the ED/UC setting as a memory aid for the follow up interview. Each influenza-positive case was randomly matched in a 1:1 ratio with an influenza-negative control by age (closest age match), sex, and enrollment week, and parents of these matched cases and controls were contacted for follow-up 2 weeks later by phone or email regarding symptom duration, child and parental absenteeism, and additional healthcare visits. Children with ILI symptoms who tested positive for influenza but did not meet criteria for moderate to severe influenza were classified as having mild influenza. Children were characterized as high-risk if they had a comorbidity increasing their risk of complications from influenza, as defined by the Committee on Infectious Diseases [19]. A vaccinated individual was defined as a child who received the adequate number of influenza vaccines for a given season. A partially vaccinated individual was defined as a child who required 2 influenza vaccines within the same season but only received 1 vaccine. An unvaccinated individual did not receive any influenza vaccines for a given season.
Data were entered into REDCap [20] and verified by a second research assistant. Medical record review was conducted by the research assistant, and any discrepancies were discussed and finalized by the principal investigator. This study underwent full board review and was approved by the Colorado Multiple Institutional Review Board (COMIRB number 15–2308). The study was registered at ClinicalTrials.gov (NCT02979626).
The primary outcome was the proportion of children with influenza who were hospitalized. The secondary outcomes included any additional ED or UC visits within 14 days of initial presentation, antibiotic and antiviral use, parental and child absenteeism, and ED charges. We summarized data descriptively using frequencies for categorical variables and measures of central tendency for continuous variables. We then assessed bivariable associations between moderate to severe vs mild influenza for covariates including demographic factors and clinical factors outlined above. Proportions were compared using the χ 2 test or the Fisher exact test when needed. Mean values were compared using Student t test for normally distributed data, otherwise the Wilcoxon rank-sum or Kruskal-Wallis test was used. For categorical outcomes, 2 × 2 tables presenting the number of patients in each category of the independent variable (eg, mild vs moderate/severe influenza) by outcome (eg, hospitalization vs no hospitalization) were evaluated and unadjusted risk differences (RDs), P values, and 95% confidence intervals (CIs) were estimated. We conducted multivariable Poisson regression with robust error variance, adjusting for potential confounding variables selected a priori (high-risk medical condition, age, influenza virus type, and vaccination status) for a composite outcome of hospitalization or recurrent ED visits. We obtained charge data for each influenza-related ED or UC visit and hospitalization. The median and interquartile range (IQR) for charge data were calculated and compared using Wilcoxon rank-sum tests for nonnormally distributed data. We calculated adjusted vaccine effectiveness for moderate to severe and mild influenza illness using the same test-negative design methods utilized by the Centers for Disease Control and Prevention [21, 22]. Analyses were conducted using SAS version 9.4 software.
A sample size of 408 patients (of whom we assumed 30% have mild influenza and 70% have moderate/severe influenza) provided 80% power at a .05 significance level to detect an RD of approximately 10% for hospitalization among the moderate to severe compared to the mild cases.
RESULTS
Among 1516 children with ILI enrolled in the study, 38 were excluded after consent (21 meeting exclusion criteria, 12 families withdrew from the study, and 5 were withdrawn for other reasons). Of the remaining 1478 children, 514 and 964 children were enrolled in season 1 and season 2, respectively. We were able to contact 523 of 811 (64%) families selected for follow-up. Overall, 411 tested positive for influenza (Figure 1), for a point prevalence of 28%. The mean age of children with influenza was 4.0 years (IQR, 2.2–6.1 years); 21% were considered high-risk for influenza complications and 36% were completely vaccinated against influenza for that season. There were 313 (76%) children who met the definition for moderate to severe influenza. Among children with moderate to severe influenza, 274 (88%) had fever of >39°C, and 83 (27%) had LRTI (Figure 2).
Figure 1.
Consolidated Standards of Reporting Trials (CONSORT)–style flow diagram for children with influenza-like illness evaluated at the Children’s Hospital Colorado emergency department and affiliated urgent care, during the 2016–2017 and 2017–2018 influenza seasons.
Figure 2.
Proportion of children classified as having moderate to severe influenza by each clinical criterion during the 2016–2017 and 2017–2018 influenza seasons (n = 313).
The sociodemographic and clinical characteristics of children with moderate to severe influenza and those with mild influenza are presented in Table 1. Compared with children with mild influenza, children with moderate to severe influenza were younger (3.8 vs 4.8 years; P = .03), were of non-Hispanic white race (29% vs 15%; P = .004), and had infection with influenza A (59% vs 44%; P = .01). Among children with moderate to severe influenza, 8.3% were hospitalized, compared with 2.0% with mild influenza, for an unadjusted RD of 6.3% (95% CI, 2.1%–10.4%; P = .03). Children with moderate to severe influenza were more likely to receive antibiotics (RD, 13.3%; 95% CI, 4.3%–22.4%; P = .0099), and to be hospitalized or have recurrent ED visits within 14 days of initial presentation (RD, 7.3%; 95% CI, 1.2%–13.4%; P = .0497). There was no significant RD for antiviral use, recurrent ED visits, or child/parental absenteeism between the groups (Figure 3). Given the low incidence of hospitalization, we were unable to calculate an adjusted relative risk for our primary outcome of interest, but used a composite of hospitalization or ED revisit, and after adjusting for high-risk medical conditions, age, and influenza type/subtype, children classified as having moderate to severe influenza had 1.83 (95% CI, .83–4.05) times higher risk of hospitalization or ED revisit compared with those with mild disease. There were no significant differences in median ED or hospitalization charges between patients with mild vs moderate to severe influenza (data not shown).
Table 1.
Demographic and Clinical Characteristics of the Influenza-Positive Cohort Aged 6 Months–8 Years, Children’s Hospital Colorado, Aurora, 2016–2017 and 2017–2018 Seasons
| Variables | Total(N = 411) | MildInfluenza(n = 98) | Moderateto SevereInfluenza(n = 313) | P Valuea |
|---|---|---|---|---|
| Age, y, median (IQR) | 4.0 (2.2–6.1) | 4.8 (2.5–6.5) | 3.8 (2.0–5.9) | .03b |
| Male sex | 206 (50) | 45 (46) | 161 (51) | .34 |
| Race/ethnicity | ||||
| Hispanic/Latino | 236 (57) | 65 (66) | 171 (55) | .004 |
| White non-Hispanic | 108 (26) | 15 (15) | 93 (29) | |
| Black non-Hispanic | 38 (9) | 14 (14) | 24 (8) | |
| Other | 29 (7) | 4 (4) | 25 (8) | |
| Primary insurance status | ||||
| Private | 100 (24) | 18 (18) | 82 (26) | |
| Medicaid | 297 (72) | 78 (80) | 219 (70) | |
| Other | 14 (3) | 2 (2) | 12 (4) | .17 |
| Influenza strain (n = 409) | ||||
| Influenza A | 229 (56) | 43 (45) | 186 (59) | .012 |
| Influenza B | 180 (44) | 53 (55) | 127 (41) | |
| Vaccination status (n = 398) | ||||
| Completely vaccinated | 149 (36) | 30 (31) | 119 (38) | .29 |
| Partially vaccinated | 42 (10) | 8 (8) | 34 (11) | |
| Unvaccinated | 207 (50) | 55 (56) | 152 (49) | |
| High-risk medical condition | 87 (21) | 16 (16) | 71 (23) | .18 |
| Attends daycare or school | 284 (69) | 67 (68) | 217 (69) | .86 |
| Age of those attending daycare/school | ||||
| <3 y | 62 (15) | 12 (12) | 50 (16) | .37 |
| 3–8 y | 222 (54) | 55 (56) | 167 (53) |
Data are presented as No. (%) unless otherwise indicated.
Abbreviations: ED, emergency department; IQR, interquartile range.
aPearson χ 2 test unless otherwise indicated.
bWilcoxon rank-sum test.
Figure 3.
Forest plot demonstrating unadjusted risk difference among children with moderate to severe vs mild influenza during the 2016–2017 and 2017–2018 influenza seasons for primary and secondary outcomes of interest. Abbreviations: CI, confidence interval; ED, emergency department; RD, risk difference.
Table 2 reports various clinical outcomes when children are classified by each individual criterion that comprises the definition of moderate to severe influenza. The presence of fever >39°C alone was not associated with hospitalization or other clinical outcomes, but was a predictor of persistent fever. The presence of LRTI was most strongly associated with hospitalization (RD, 18%; P = .001), home oxygen requirement (RD, 14%; P = .001), and child absenteeism from school or daycare (4 days vs 3 days; P = .05). Finally, the presence of acute otitis media was significantly associated with antibiotic use (RD, 77%; P = .001).
Table 2.
Clinical Outcomes Associated With Each Clinical Criterion Comprising the Moderate to Severe Definition Among Children Aged 6 Months–8 Years With Influenza, Children’s Hospital Colorado, Aurora, 2016–2017 and 2017–2018 Seasons
| Criteria/Outcome | Total Cohort |
Absence of Category Used in Moderate to Severe Definition | Presence of Category Used in Moderate to Severe Definition | P Valuea |
|---|---|---|---|---|
| Otitis media | 411 | 372 | 39 | |
| Hospitalization | 28 (7) | 27 (7) | 1 (3) | .50b |
| Antibiotic use | 113 (27) | 75 (20) | 38 (97) | < .0001 b |
| Antivirals | 80 (19) | 80 (22) | 0 (0) | < .0001 b |
| Fever >38.4°C since ED visit | 135 (53) | 127 (54) | 8 (40) | .18 |
| Duration of fever, d, median (IQR) (n = 135) | 2.0 (2.0–4.0) | 2.0 (2.0–4.0) | 2.5 (1.5–5.0) | .65c |
| Home oxygen therapy | 8 (3) | 5 (2) | 3 (15) | .02 b |
| Child absenteeism, d, median (IQR) (n = 187) | 3.0 (1.0–5.0) | 3.0 (2.0–5.0) | 2.0 (1.0–3.0) | .04 c |
| Parent absenteeism, d, median (IQR) (n = 209) | 1.0 (0.0–3.0) | 1.0 (0.0–3.0) | 1.0 (0.0–2.0) | .21c |
| Temperature >39°C | 411 | 137 | 274 | |
| Hospitalization | 28 (7) | 6 (4) | 22 (8) | .17 |
| Antibiotic use | 113 (27) | 35 (26) | 78 (28) | .53 |
| Antiviral use | 80 (19) | 22 (16) | 58 (21) | .22 |
| Fever >38.4°C since ED visit | 135 (53) | 34 (42) | 101 (57) | .02 |
| Duration of fever, d, median (IQR) (n = 135) | 2.0 (2.0–4.0) | 2.0 (1.0–3.0) | 3.0 (2.0–4.0) | .02 c |
| Home oxygen therapy | 8 (3) | 4 (5) | 4 (2) | .26 |
| Child absenteeism, d, median (IQR) (n = 187) | 3.0 (1.0–5.0) | 3.0 (1.0–5.0) | 3.0 (1.0–5.0) | .30c |
| Parent absenteeism, d, median (IQR) (n = 209) | 1.0 (0.0–3.0) | 1.0 (0.0–3.0) | 1.0 (0.0–3.0) | .70c |
| Lower respiratory tract illness | 411 | 328 | 83 | |
| Hospitalization | 28 (7) | 10 (3) | 18 (22) | < .001 |
| Antibiotics | 113 (27) | 86 (26) | 27 (33) | .25 |
| Antivirals | 80 (19) | 59 (18) | 21 (25) | .13 |
| Repeat visits to ED/UC related to respiratory symptoms | 25 (6) | 21 (6) | 4 (5) | .59 |
| Fever >38.4°C since ED visit | 135 (53) | 106 (53) | 29 (51) | .80 |
| Duration of fever, d, median (IQR) (n = 135) | 2.0 (2.0–4.0) | 2.0 (2.0–4.0) | 2.0 (1.0–3.0) | .52c |
| Home oxygen therapy | 8 (3) | 0 (0) | 8 (14) | < .0001 b |
| Child absenteeism, d, median (IQR) (n = 187) | 3.0 (1.0–5.0) | 3.0 (1.0–5.0) | 4.0 (2.0–6.0) | .05c |
| Parent absenteeism, d, median (IQR) (n = 209) | 1.0 (0.0–3.0) | 1.0 (0.0–3.0) | 2.0 (0.0–3.0) | .34c |
| Extrapulmonary manifestations | 411 | 404 | 7 | |
| Hospitalization | 28 (7) | 27 (7) | 1 (14) | .39b |
| Antibiotics | 113 (27) | 113 (28) | 0 (0) | .10 |
| Antivirals | 80 (19) | 80 (20) | 0 (0) | .19 |
| Repeat visits to ED/UC related to respiratory symptoms | 25 (6) | 25 (6) | 0 (0) | .50 |
| Fever >38.4°C since ED visit | 135 (53) | 132 (52) | 3 (60) | .79 |
| Duration of fever, d, median (IQR) (n = 135) | 2.0 (2.0–4.0) | 2.0 (2.0–4.0) | 5.0 (1.0–5.0) | .42c |
| Child absenteeism, d, median (IQR) (n = 187) | 3.0 (1.0–5.0) | 3.0 (1.0–5.0) | 3.5 (2.0–4.5) | .89c |
| Parent absenteeism, d, median (IQR) (n = 209) | 1.0 (0.0–3.0) | 1.0 (0.0–3.0) | 1.5 (1.0–3.0) | .39c |
Data are presented as No. (%) unless otherwise indicated. Values in bold indicate statistical significance.
Abbreviations: ED, emergency department; IQR, interquartile range; UC, urgent care.
aPearson χ 2 test unless otherwise specified.
bFisher exact test.
cWilcoxon rank-sum test.
The unadjusted RD for moderate to severe influenza among completely/partially vaccinated (80%) vs unvaccinated (73%) children was 7.6% (95% CI, –1.6% to 14.9%; P = .12). Using a test-negative study design and adjusting for age, high-risk medical condition, race, and insurance, children with moderate to severe influenza had an adjusted vaccine effectiveness estimate of 49% (95% CI, 37%–65%; P < .0001). Children with mild influenza had an adjusted vaccine effectiveness of 59% (95% CI, 34%–97%; P = .0614; data not shown).
DISCUSSION
In this prospective observational cohort study evaluating the usefulness of a new clinical severity endpoint for influenza, we found that our new clinical endpoint for moderate to severe influenza is potentially useful for disease severity assessment in children. In our cohort, classification as moderate to severe influenza was significantly associated with several important clinical outcomes. Children with moderate to severe influenza were 4 times more likely to be hospitalized than children with mild disease, were significantly more likely to receive antibiotics during their ED visits, and were more likely to have recurrent ED or UC visits or be hospitalized (as a composite outcome). Our data support the clinical and research usefulness of the new moderate to severe influenza definition by demonstrating a greater risk of clinically relevant healthcare endpoints among young children with this classification.
Traditional methods used to measure influenza vaccine effectiveness assume that all clinical endpoints are medically equivalent, overlooking the potential for vaccination to modify disease intensity; these traditional methods provide a wide variation of seasonal effectiveness that do not necessarily correlate with outcomes of public health importance (such as healthcare utilization and hospitalizations). Therefore, clinically meaningful endpoints that evaluate characteristics beyond the presence and absence of infection are needed to measure the full public health impact of current and future influenza vaccines for children. While initial data regarding the benefits of influenza vaccination in reducing hospitalization and need for intensive care in children have been obtained [12–15], most of these outcomes are dependent on the study setting (population and healthcare practices) and are subject to underestimation and confounding. Furthermore, the ability to classify influenza severity earlier in the illness course would be more practical for conducting research. The moderate to severe definition overcomes these limitations as it is a more objective endpoint, can be applied to children early in the illness course, and uses simple clinical parameters that have applications in the clinical and research realms.
The moderate to severe influenza definition in this study was originally proposed, though not previously validated, in a multicenter phase 3 randomized controlled trial to evaluate the efficacy of a new quadrivalent inactivated influenza vaccine among 3- to 8-year-old children. This study found that influenza vaccination had 74% efficacy against moderate to severe influenza vs 42% for mild influenza [16]. A more recent phase 3 multicenter trial evaluating a different quadrivalent inactivated influenza vaccine in children aged 6–35 months demonstrated influenza vaccine efficacy of 63% against moderate to severe influenza and 50% against all influenza [23]. A meta-analysis using the same moderate to severe definition to evaluate the efficacy of live attenuated influenza vaccines in children 2–5 years of age showed similar efficacy between children with moderate to severe compared with mild illness [24]. In contrast, we found lower vaccine effectiveness against moderate to severe vs mild influenza infection in our study of children presenting to an ED/UC setting, which is skewed to a sicker population of children, in which >70% of children met moderate to severe criteria. Heikkinen et al retrospectively reviewed data from 2 prospective influenza studies in children evaluated in primary care settings in Finland and found that moderate to severe influenza was associated with longer illness duration, child and parental absenteeism, and antibiotic use [10]. However, this study represented lower-acuity healthcare of their population, as only 1 child was hospitalized and 3 attended the ED. Another retrospective study at Kaiser Permanente Northern California of children aged 6–36 months reported that children with moderate to severe influenza were 9 times more likely to receive antibiotics compared with mild cases. However, this cohort also had low rates of hospitalization (5%) [25]. Our study is the first prospective evaluation of this definition in US children against outcomes of public health importance, and demonstrates similar findings to these 2 prior studies in terms of higher risk of antibiotic use among children with moderate to severe influenza illness, but more importantly how this classification is also associated with hospitalization of children.
We also examined the potential key drivers of hospitalization, antibiotic use, and other clinical outcomes, for each clinical criterion used in the definition of moderate to severe influenza. Our data demonstrated that fever >39°C itself was not a significant risk factor for hospitalization or antibiotic use, but predicted a more prolonged febrile illness course. However, lower respiratory tract illness was the strongest predictor of hospitalization, and the presence of otitis media was strongly correlated with antibiotic use in this population of children. This is an important first step in understanding how the moderate to severe definition of influenza in children determines these healthcare outcomes. A recent systematic and narrative review on the risk of LRTI following influenza infection showed that there were only 3 prospective studies that linked influenza infection to this attributable outcome [26]. Therefore, determining the burden of severe LRTI that is attributable to influenza is necessary to estimate the benefits of influenza vaccine on this important outcome. For otitis media, our findings align with those from the 2 prior studies conducted in ambulatory settings that comprised a higher proportion of children with otitis media (48% in the Finnish study and 28% in the California study) compared with 12% in our study, which may explain their stronger association with antibiotic use. While otitis media may not be associated with illness severity requiring hospitalization, it is a key driver of health-seeking behavior and antimicrobial use, which are highly relevant outcomes when studying the impact of influenza vaccines.
There were several other interesting findings from our study that warrant discussion. We found that both younger age and influenza A infection were more common among children with moderate to severe influenza, which have been previously shown to be associated with increased influenza disease severity [9, 27, 28]. However, in contrast to our findings, in most other studies, nonwhite race/ethnicity is more frequently associated with influenza hospitalization in children [29, 30]. We also found that less than a third of children with ILI had PCR-confirmed influenza, which is lower than other reports [31, 32], and highlights the low specificity of the standard ILI definition and the importance of laboratory confirmation for influenza illness both in the clinical and research settings. Next, among PCR-confirmed influenza cases seen in the ED/UC, only 21% of children had a high-risk medical condition, with no difference between children with moderate to severe vs mild illness. This suggests that the driver of illness severity may not be based solely on medical comorbidities and provides further justification for the need to target all children with influenza vaccination, not just those with a high-risk condition. Finally, influenza vaccination rates in our cohort were <40%, which are lower than state and national rates. A potential explanation for this is that our study sample may reflect a selection bias toward children without a medical home, who are more likely to seek medical care in an ED/UC setting, and are less likely to get vaccinated.
Our study has several limitations. First, being located at a single center may limit its external validity. Second, we were only able to contact approximately two-thirds of the selected families for follow-up, which may have introduced selection bias and influenced our findings regarding child and parental absenteeism. Our cohort of children had a low rate of hospitalization, and given the low number of hospitalized children with mild influenza, we were unable to conduct adjusted analyses for our primary outcome and therefore only present the unadjusted RD for this outcome. Third, the small number of patients in this group also prevented us from evaluating other potential confounders that could influence our results. Instead, we used a composite of recurrent ED visits and hospitalization, and adjusted for the presence of a high-risk medical condition, influenza strain, and age. Finally, there was potential for recall bias during our follow-up survey. We attempted to minimize this bias by providing a diary card to the family to serve as a memory aid while completing the survey, but the reliability of this method could not be assessed. We also minimized recall bias of influenza vaccination status by verifying parental report using data from the electronic health record and state immunization registry database.
CONCLUSIONS
Our prospective cohort study of young children evaluated in the ED/UC setting demonstrated that the new moderate to severe influenza endpoint is associated with a higher risk of hospitalization, recurrent healthcare visits, and antibiotic use. Therefore, our proposed moderate to severe definition is a useful clinical endpoint to evaluate the public health and clinical impact of influenza interventions including vaccines and therapeutics in children. Additional research is needed to further refine the moderate to severe definition to quantify the risk of illness severity due to influenza, and to elucidate the immune-mediated mechanistic drivers of this definition in children.
Notes
Acknowledgments. The authors acknowledge the children and their families who participated in the study and the emergency department/urgent care nurses and laboratory personnel who participated in their care. The authors give a special thanks to our study coordinators, Kathleen Grice and Reagan Miller; the research assistants Chandini Patel, Nathan Ostlie, Amira Herstic, Tate Closson-Niese, Daniela Santos, and Tony Marshlain; and Mimi Munroe for administrative support.
Financial support. This work was supported by a collaborative research grant from GlaxoSmithKline Biologicals SA; and by the National Institutes of Health/National Center for Advancing Translational Sciences Colorado Clinical and Translational Sciences Institute (grant number UL1 TR002535).
Potential conflicts of interest. A. S., R. B.-B., and E. Y. are employed by the GSK group of companies and hold shares in the GSK group of companies. B. L. I. was employed by the GSK group of companies at the time of the study. E. A. receives research support from the GSK group of companies and Pfizer. S. R. receives funding support from the GSK group of companies and Biofire. All other authors report no potential conflicts of interest.
All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
References
- 1. Thompson WW, Comanor L, Shay DK. Epidemiology of seasonal influenza: use of surveillance data and statistical models to estimate the burden of disease. J Infect Dis 2006; 194(Suppl 2):S82–91. [DOI] [PubMed] [Google Scholar]
- 2. Grohskopf LA, Olsen SJ, Sokolow LZ, et al. Centers for Disease Control and Prevention Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP)—United States, 2014-15 influenza season. MMWR Morb Mortal Wkly Rep 2014; 63:691–7. [PMC free article] [PubMed] [Google Scholar]
- 3. Grohskopf LA, Sokolow LZ, Olsen SJ, et al. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices, United States, 2015-16 influenza season. MMWR Morb Mortal Wkly Rep 2015; 64:818–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Ampofo K, Gesteland PH, Bender J, et al. Epidemiology, complications, and cost of hospitalization in children with laboratory-confirmed influenza infection. Pediatrics 2006; 118:2409–17. [DOI] [PubMed] [Google Scholar]
- 5. Coffin SE, Zaoutis TE, Rosenquist AB, et al. Incidence, complications, and risk factors for prolonged stay in children hospitalized with community-acquired influenza. Pediatrics 2007; 119:740–8. [DOI] [PubMed] [Google Scholar]
- 6. Dawood FS, Fiore A, Kamimoto L, et al. Emerging Infections Program Network Burden of seasonal influenza hospitalization in children, United States, 2003 to 2008. J Pediatr 2010; 157:808–14. [DOI] [PubMed] [Google Scholar]
- 7. Schrag SJ, Shay DK, Gershman K, et al. Emerging Infections Program Respiratory Diseases Activity Multistate surveillance for laboratory-confirmed, influenza-associated hospitalizations in children: 2003-2004. Pediatr Infect Dis J 2006; 25:395–400. [DOI] [PubMed] [Google Scholar]
- 8. Izurieta HS, Thompson WW, Kramarz P, et al. Influenza and the rates of hospitalization for respiratory disease among infants and young children. N Engl J Med 2000; 342:232–9. [DOI] [PubMed] [Google Scholar]
- 9. Neuzil KM, Mellen BG, Wright PF, et al. The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N Engl J Med 2000; 342:225–31. [DOI] [PubMed] [Google Scholar]
- 10. Heikkinen T, Silvennoinen H, Heinonen S, Vuorinen T. Clinical and socioeconomic impact of moderate-to-severe versus mild influenza in children. Eur J Clin Microbiol Infect Dis 2016; 35:1107–13. [DOI] [PubMed] [Google Scholar]
- 11. Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2018-19 influenza season. MMWR Recomm Rep 2018; 67:1–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Hadler JL, Baker TN, Papadouka V, et al. Effectiveness of 1 dose of 2009 influenza A (H1N1) vaccine at preventing hospitalization with pandemic H1N1 influenza in children aged 7 months–9 years. J Infect Dis 2012; 206:49–55. [DOI] [PubMed] [Google Scholar]
- 13. Cowling BJ, Chan KH, Feng S, et al. The effectiveness of influenza vaccination in preventing hospitalizations in children in Hong Kong, 2009-2013. Vaccine 2014; 32:5278–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Menniti-Ippolito F, Da Cas R, Traversa G, et al. Italian Multicentre Study Group for Drug and Vaccine Safety in Children Vaccine effectiveness against severe laboratory-confirmed influenza in children: results of two consecutive seasons in Italy. Vaccine 2014; 32:4466–70. [DOI] [PubMed] [Google Scholar]
- 15. Ferdinands JM, Olsho LE, Agan AA, et al. Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Effectiveness of influenza vaccine against life-threatening RT-PCR-confirmed influenza illness in US children, 2010-2012. J Infect Dis 2014; 210:674–83. [DOI] [PubMed] [Google Scholar]
- 16. Jain VK, Rivera L, Zaman K, et al. Vaccine for prevention of mild and moderate-to-severe influenza in children. N Engl J Med 2013; 369:2481–91. [DOI] [PubMed] [Google Scholar]
- 17. Budd ABL, Grohskopf L, Campbell A, et al. Manual for the surveillance of vaccine-preventable diseases. Atlanta, GA: Centers for Disease Control and Prevention. Available at: https://www.cdc.gov/vaccines/pubs/surv-manual/front-portion.pdf. Accessed October 10, 2019.
- 18. Salez N, Ninove L, Thirion L, et al. Evaluation of the Xpert Flu test and comparison with in-house real-time RT-PCR assays for detection of influenza virus from 2008 to 2011 in Marseille, France. Clin Microbiol Infect 2012; 18:E81–3. [DOI] [PubMed] [Google Scholar]
- 19. Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2017-18 influenza season. MMWR Recomm Rep 2017; 66:1–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42:377–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Jackson ML, Chung JR, Jackson LA, et al. Influenza vaccine effectiveness in the United States during the 2015-2016 season. N Engl J Med 2017; 377:534–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Jackson ML, Nelson JC. The test-negative design for estimating influenza vaccine effectiveness. Vaccine 2013; 31:2165–8. [DOI] [PubMed] [Google Scholar]
- 23. Claeys C, Zaman K, Dbaibo G, et al. Flu4VEC Study Group Prevention of vaccine-matched and mismatched influenza in children aged 6-35 months: a multinational randomised trial across five influenza seasons. Lancet Child Adolesc Health 2018; 2:338–49. [DOI] [PubMed] [Google Scholar]
- 24. Ambrose CS, Wu X, Caspard H, Belshe RB. Efficacy of live attenuated influenza vaccine against influenza illness in children as a function of illness severity. Vaccine 2014; 32:5546–8. [DOI] [PubMed] [Google Scholar]
- 25. Hsiao A, Buck PO, Yee A, et al. Health outcomes associated with mild versus moderate-to-severe laboratory-confirmed influenza in 6- to 35-month-old children. In: IDWeek, San Diego, CA, October 2017. [Google Scholar]
- 26. Malosh RE, Martin ET, Ortiz JR, Monto AS. The risk of lower respiratory tract infection following influenza virus infection: a systematic and narrative review. Vaccine 2018; 36:141–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Jules A, Grijalva CG, Zhu Y, et al. Influenza-related hospitalization and ED visits in children less than 5 years: 2000-2011. Pediatrics 2015; 135:e66–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Lafond KE, Nair H, Rasooly MH, et al. Global Respiratory Hospitalizations—Influenza Proportion Positive (GRIPP) Working Group Global role and burden of influenza in pediatric respiratory hospitalizations, 1982-2012: a systematic analysis. PLoS Med 2016; 13:e1001977. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Iwane MK, Chaves SS, Szilagyi PG, et al. Disparities between black and white children in hospitalizations associated with acute respiratory illness and laboratory-confirmed influenza and respiratory syncytial virus in 3 US counties—2002-2009. Am J Epidemiol 2013; 177:656–65. [DOI] [PubMed] [Google Scholar]
- 30. Thompson DL, Jungk J, Hancock E, et al. Risk factors for 2009 pandemic influenza A (H1N1)-related hospitalization and death among racial/ethnic groups in New Mexico. Am J Public Health 2011; 101:1776–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Kasper MR, Wierzba TF, Sovann L, et al. Evaluation of an influenza-like illness case definition in the diagnosis of influenza among patients with acute febrile illness in Cambodia. BMC Infect Dis 2010; 10:320. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Monto AS, Gravenstein S, Elliott M, et al. Clinical signs and symptoms predicting influenza infection. Arch Intern Med 2000; 160:3243–7. [DOI] [PubMed] [Google Scholar]