Vital Sign Predictors of Severe Influenza
Vital Sign Predictors of Severe Influenza
Vital Sign Predictors of Severe Influenza
RESEARCH ARTICLE
Abstract
OPEN ACCESS
Methods
This study underwent full board review and was approved by the Colorado Multiple Institu-
tions Review Board (COMIRB No.15-2308). This is a secondary analysis of a prospective study
to evaluate a new moderate to severe classification of influenza in children [18]. Briefly, chil-
dren 6 months-8 years of age presenting with influenza-like-illness (ILI) to the Children’s Hos-
pital Colorado (CHCO) ED and an affiliated Urgent Care center were enrolled during two
influenza seasons (January-April 2017 and November 2017-April 2018). ILI was defined as a
temperature of �37.8⁰C and at least one of the following: cough, sore throat, runny nose or
nasal congestion [19]. Children were excluded if they had respiratory symptom duration of
greater than 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 children and tested using the
Cepheid Xpert1 influenza real time RT- PCR (Sunnyvale, CA). Written informed consent
was sought from all study participants. For children less than 7 years of age, written consent
was obtained from parents/guardians, and for children 7 years of age and older, in addition to
written consent from parents/guardians, additional written assent was obtained from children
participating in the study per institutional policies. We evaluated our primary outcome firstly
with the entire cohort, and secondly, with the subset of children who tested positive for influ-
enza. Caregivers were interviewed in the ED or Urgent care regarding the child’s demographic
characteristics, presenting symptoms, medical comorbidities, influenza vaccination status and
household size. Vital sign data (heart rate, respiratory rate, oxygen saturation, blood pressure,
capillary refill time) collected by chart abstraction, included the first set of vital signs and the
highest heart rate/respiratory rate or temperature. Children were characterized as high-risk if
they had a comorbidity increasing their risk of complications from influenza [20]. A vacci-
nated individual was defined as a child who received the adequate number of influenza vac-
cines for a given season, as defined by the Advisory Committee on Immunization Practices
[21].
The primary outcome was hospitalization or recurrent ED or UC visits within 72 hours of
the index visit. Data were summarized descriptively using frequencies for categorical variables
and measures of central tendency for continuous variables. Proportions were compared using
the Chi-square test or the Fisher’s exact test when needed. Mean values were compared using
student’s t test. To examine the predictive value of vital sign data for PCR-confirmed influenza
of subjects in the study cohort and hospitalization of the influenza-positive subjects, multivari-
able logistic regression was used. Heart rate and respiratory rate z score by age were calculated
using a reference for expected heart rate and respiratory rate in hospitalized children [21].
Heart rate z scores were further adjusted for temperature [22]. A bivariable analysis was per-
formed for each predictor of interest with outcome. Correlation between predictors was
assessed with Pearson and Spearman correlation coefficients. Model performance was assessed
with the scaled Brier score with higher values indicating better model performance. Discrimi-
native ability was evaluated with the C statistic (Values >0.7 indicate good model discrimina-
tion) [23]. SAS v 9.4 (Cary, NC) was used for all analyses.
Results
Among 1516 children with ILI enrolled in the study, 38 (2.5%) were excluded due to study
withdrawal, meeting exclusion criteria or for other reasons. Of the remaining 1478 chil-
dren, 252 were hospitalized, 45 had a recurrent ED visit within 72 hours of study enroll-
ment; 411 (27.8%) tested positive for influenza type A or B, of which 28 (6.8%) were
hospitalized and 14 (3.4%) had a recurrent ED visit within 72 hours of study enrollment.
No hospitalized children who tested positive for influenza in our study required intensive
care. We excluded 24 children who had a recurrent ED or UC visit after 72 hours from
these analyses. The mean age of children with influenza was 4.2 years (IQR 2.2–6.1); 27%
were considered at high-risk for influenza complications, and 37% were completely vacci-
nated against influenza for that season. Sociodemographic and clinical characteristics
among children with influenza infection with and without hospitalization or recurrent ED
visits are shown in Table 1. Children with influenza infection who were hospitalized or
had a recurrent ED visit within 72 hours were more likely to have a high-risk medical con-
dition (57% vs 23%, p < 0.01). The commonest reason for hospitalization among influenza
positive patients was due to respiratory distress, hypoxia and dehydration. A higher pro-
portion of children who were influenza negative were admitted for hypoxia compared
with children who were influenza positive (3.8% vs 2.7%; p < 0.01).
https://doi.org/10.1371/journal.pone.0272029.t001
Table 2. Predictive value of vital sign data on hospitalization or recurrent ED visit within 72 hours among children with ILI and PCR-confirmed influenza evalu-
ated in an ED and urgent care setting- bivariable analyses.
Variables Total Hospitalized/ Not hospitalized/ p- Influenza Influenza positive Influenza negative not p-
(n = 1454) recurrent ED recurrent ED visit value positive hospitalized Hospitalized/ valuea
visit (n = 1157) (n = 405) /recurrent ED visit recurrent ED visit
(n = 297) value (%) (n = 42) value (%) (n = 363)
value (%)
Duration of fever (days), mean 2.8 (2.1) 3.0 (2.4) 2.7 (2.0) 0.43 2.9 (2.3) 3.9 (3.4) 2.7 (2.1) 0.06
(SD)
Highest temperature in ED/ 38.4 (1.1) 38.6 (1.0) 38.3 (1.1) < .01 38.6 (1.1) 38.9 (1.2) 38.6 (1.1) 0.19
UC, mean (SD)
Initial heart Rate, mean (SD) 143.5 151.5 (23.3) 141.5 (24.2) < .01 138.3 (23.6) 144.3 (25.7) 137.6 (23.3) 0.08
(24.4)
Heart rate during highest 143.5 151.6 (23.2) 141.4 (24.1) < .01 138.3 (23.4) 144.7 (24.8) 137.6 (23.1) 0.06
temperature in ED/UC, mean (24.4)
(SD)
Peak heart rate z score (age/ 0.5 (0.9) 0.7 (1.0) 0.4 (0.9) < .01 0.2 (0.9) 0.4 (0.9) 0.2 (0.9) 0.24
temp adjusted)
Initial heart rate z score (age/ 0.6 (1.0) 0.9 (1.0) 0.5 (0.9) < .01 0.3 (0.9) 0.5 (1.0) 0.3 (0.9) 0.21
temp adjusted), mean (SD)
Initial oxygen Saturation, 95.3 (3.2) 93.3 (4.3) 95.8 (2.7) < .01 95.9 (2.7) 94.6 (3.8) 96.0 (2.5) < .01
mean (SD)
Initial respiratory Rate, mean 35.3 (11.7) 42.5 (14.7) 33.4 (10.0) < .01 31.2 (9.4) 36.1 (13.2) 30.7 (8.7) < .01
(SD)
Initial respiratory rate z score 0.8 (0.9) 1.3 (0.9) 0.7 (0.8) < .01 0.6 (0.8) 1.1 (0.8) 0.6 (0.7) < .01
(age adjusted), mean (SD)
https://doi.org/10.1371/journal.pone.0272029.t002
logistic regression. In multivariable analyses, among children with influenza infection, only
higher adjusted respiratory rate z score remained a significant predictor of hospitalization or
recurrent ED visits (OR 1.84, 95%CI 1.17–2.90) (Fig 1). However, the model had poor discrim-
ination (c-index = 0.67) and performance (Scaled Brier score = 0.05). For improved model
performance, we conducted analyses using a second model that adjusted for age, high risk co-
morbidities and school or daycare attendance. Initial higher adjusted respiratory rate
remained a significant predictor of hospitalization or recurrent ED visits (OR 1.97 1.22–3.19),
with overall improved discrimination (c-index 0.77) and performance (Scaled Brier score
0.12) (Fig 1).
Discussion
Our observational cohort study of children with influenza like illness being evaluated in the
ED/UC setting demonstrated that higher respiratory rate adjusted for age was the most signifi-
cant vital sign predictor of hospitalization or recurrent ED/UC visits within 72 hours among
young children with PCR-confirmed influenza. While adjusted heart rate during peak temper-
ature and lower oxygen saturation were significant in bivariable analyses, they were no longer
significant in our adjusted analyses. Model performance improved significantly after including
age, high risk co-morbidities and school or daycare attendance. For children with ILI, the
most important vital signs predicting hospitalization among children with ILI were both age
adjusted respiratory rate, and oxygen saturation. Our findings demonstrate that a predictive
model which includes age, respiratory rate z score, high risk co-morbidities and school or
Fig 1. Odds of hospitalization and recurrent ED visits among children with PCR-confirmed influenza using vital sign data as clinical
predictors, model adjusted for age, high risk co-morbidities, school or daycare attendance.
https://doi.org/10.1371/journal.pone.0272029.g001
daycare attendance can help risk-stratify children with more severe outcomes from influenza
infection.
Early vital sign data predicting more severe outcomes among children with influenza is lim-
ited in the literature. One matched case-control study among outpatients with respiratory
symptoms showed that fever was an independent predictor for influenza, however, the study
did not investigate other vital sign measurements nor its applicability to hospitalization and
severity [16]. Another study of hospitalized children reported that low initial oxygen saturation
at admission predicted the need for intensive care [17], but this was not found to be an inde-
pendent predictor in multivariate analysis. Low oxygen saturation has also been shown to be a
useful predictor of severe outcomes in a respiratory index of severity in children (RISC) score,
which forecasts the probability of death in a young child with lower respiratory tract infection
[24].
Studies of influenza infection in children and adults have similarly demonstrated the value
of respiratory rate in predicting hospitalization. One study evaluating vital signs as predictors
of hospitalization of children and adults with H1N1 influenza, demonstrated that in multivari-
ate regression analyses of all vital signs, tachypnea was a significant risk factor for hospital
admission (OR = 1.1; 95% CI 1.02 to 1.13, p<0.01) [25]. Our findings are also consistent with
another study evaluating adults with H1N1 influenza demonstrating that tachypnea is a signifi-
cant risk factor for hospitalization [26].
Respiratory rate has been shown to be a useful predictor of severity for acute respiratory
infections and pneumonia. For example, children with tachypnea as defined by the World
Health Organization (WHO) respiratory rate thresholds are more likely to have pneumonia
than children without tachypnea [27]. However, using tachypnea as a dichotomous variable
may decrease the overall model performance. While using vital sign z scores rather than the
presence or absence of tachypnea is more complex, it enhances the statistical power over using
a dichotomous threshold, and these data can be effectively used in EHR systems and computer
algorithms to risk-stratify children [28, 29]. The utility of this approach has been shown in
model predictors for identifying children with serious bacterial infections, showing that the
most robust model used age adjusted heart rate and respiratory rates [30].
Other studies have also demonstrated that hypoxia or requirement for oxygen was also an
important risk factor for hospitalization or ICU admission [31, 32], which we found in our
bivariable analyses for influenza-confirmed infection, but after adjusting for other important
covariates, this was no longer significant. Our study suggests that respiratory rate is a more
reliable predictor of influenza severity than oxygen saturation in children, but our findings
may be difficult to interpret since the effects of higher altitude in Colorado may have impacted
the interpretation of oxygen saturation in this study [33–35]. Further, the higher proportion of
hypoxia among children testing negative for influenza likely represented younger children
with RSV infection, which was co-circulating during the enrollment period of our study,
known to be associated with hypoxia in children [36]. The stronger association of hypoxia due
to RSV may also explain why oxygen saturation was a significant predictor for our ILI cohort,
but not for our influenza-confirmed cohort.
Decisions regarding the investigation and treatment of children with influenza and infec-
tion rely on factors such as incidence of influenza in the community and likelihood of severe
disease. Early predictors can help the clinician target testing and treatment to high-risk indi-
viduals, which is especially crucial during times of limited testing capacity, as evidenced by the
current pandemic. Existing respiratory severity assessment scores may underestimate the risk
of influenza severity, especially in younger individuals [37], and therefore a model specific to
influenza is necessary. A predictive model using objective early clinical parameters can be
incorporated in the clinical setting through clinical decision support tools in the EHR, for risk
stratification for influenza infection, which can help to standardize care, while reducing
unnecessary testing and antiviral use. The ED and inpatient floors are potential settings in
which such clinical tools can have a high impact, since the population of interest is sicker, reli-
able testing platforms are available, thus enhancing the diagnosis, prompt initiation of antivi-
rals and ongoing monitoring among those with confirmed influenza infection [38]. Such
clinical guidance would be especially important when resources are limited, as evidenced dur-
ing the COVID-19 pandemic, to help the provider triage the appropriate level of care and
determine appropriate therapies, while conserving resources.
There are several limitations that warrant discussion. First, our study was conducted at a
single center among children evaluated in an ED or UC setting, which may limit its external
validity to other sites and settings. Extrapolation of our clinical prediction tool to other settings
is underway. Our cohort of children with influenza had a low rate of hospitalization, so we
used a composite outcome of hospitalization or recurrent visits, but limited the recurrent visits
to within 72 hours of the index hospitalization. Given the rare outcome, the model was sensi-
tive to overfitting, but when comparing our logistic regression model with 3 covariates com-
pared with 6 covariates, there was little change in the 95% confidence intervals, indicating
stability of our expanded model, which is considered an acceptable analytic approach [39, 40].
Next, we used vital sign data collected during the index visit and were not able to account for
day of illness in our model, and thus our vital sign data was collected during different phases
of the illness course, when they sought care. Our study was conducted in a setting that used
machine-read heart rate and respiratory rate data, but these have been shown to correlate well
with electrocardiograph heart rate and physician measures [41, 42]. Finally, we did not explore
other predictive modeling approaches, such as including influenza results as a covariate in the
ILI model, but will be the subject of future study.
Our study demonstrates the clinical utility of a prediction model that incorporates age, high
risk medical condition, school or daycare attendance and respiratory rate z score in predicting
hospitalization or recurrent ED visits for children aged 6 months to 8 years of age with influ-
enza infection. This study has important implications for researchers as well as clinicians,
because determining early, objective measures that do not require laboratory or radiographic
testing is of high value to help improve the pre-test probability for determining which children
are at risk for higher morbidity, to help guide providers’ clinical decision-making process
regarding testing and treatment. These findings are especially timely during a time when influ-
enza is co-circulating with COVID-19, when there may be shortages in testing reagents,
trained personnel and more restrictive testing capabilities, highlighting an important need to
identify which children should be tested for influenza as well as SARS-CoV-2. Further work
including z score thresholds and external validation is ongoing, but these findings show prom-
ise for use in clinical prediction tools in the ED and hospital setting.
Supporting information
S1 Table. Multivariable logistic regression analyses evaluating association between vital
sign data and hospitalization/recurrent ED visits among children with ILI.
(DOCX)
Acknowledgments
We would like to acknowledge the children and their families who participated in the study
and the ED/Urgent care nurses and laboratory personnel who participated in their care. We
give a special thanks to our study co-ordinators Kathleen Grice and Reagan Miller, the
research assistants Chandini Patel, Nathan Ostlie, Amira Herstic, Tate Closson-Niese, Daniela
Santos and Tony Marshlain, and to Mimi Munroe for her administrative support.
Author Contributions
Conceptualization: Suchitra Rao, Molly Lamb, Bruce L. Innis, Edwin J. Asturias.
Data curation: Molly Lamb.
Formal analysis: Suchitra Rao, Angela Moss, Molly Lamb.
Funding acquisition: Suchitra Rao, Edwin J. Asturias.
Methodology: Suchitra Rao, Molly Lamb, Edwin J. Asturias.
Supervision: Suchitra Rao, Bruce L. Innis.
Validation: Angela Moss.
Writing – original draft: Suchitra Rao.
Writing – review & editing: Angela Moss, Molly Lamb, Bruce L. Innis, Edwin J. Asturias.
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