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Influenza in Children With Special Risk Medical Conditions

A Systematic Review and Meta-analysis

Tuckerman, Jane MPH*,†; Misan, Siobhan MBBS; Crawford, Nigel W. PhD§,¶; Marshall, Helen S. MD*,†,‖

Author Information
The Pediatric Infectious Disease Journal: September 2019 - Volume 38 - Issue 9 - p 912-919
doi: 10.1097/INF.0000000000002405


Influenza is a seasonal respiratory infection that causes a wide spectrum of disease. The risk for complications or severe disease varies depending on an individual’s age, comorbidities, influenza strain and vaccination status.1–5 For children in general, the predominate complications from influenza are well documented6–12 and a recommendation for vaccination of children believed to be at increased risk is now recognized public health policy.5,13–15

Special risk medical conditions (SRMC) such as severe asthma, lung or heart disease, immune compromise or diabetes may predispose an individual to increased influenza severity. Infection in those with a SRMC can lead to exacerbations of underlying comorbidities, neurologic complications, primary viral or secondary bacterial pneumonia, and death.5,16,17 For children with SRMC, influenza is thought to have a protracted disease course resulting from reduced immunity and the disease can compromise medical comorbidities translating to higher rates of hospitalization and more severe outcomes such as a requirement for higher-level care and/or death.18 A recent review found neurologic and immune disorders, prematurity and age younger than 2 years to be strong risk factors for influenza-related hospitalization, although most were studies of pandemic influenza.19 However, the impact that a SRMC has on the severity of influenza hospitalizations in children has yet to be clarified.

Quantifying complications from influenza in children with SRMC is necessary to facilitate both clinical and policy decision-making and assist in parents’ education. We hypothesized that among children hospitalized with influenza infection both severity and prevalence of complications are increased in children with SRMCs compared with their healthy counterparts. The aim of this study was to systematically assess the current evidence of severity, complications and resource use experienced by children with SRMC who were hospitalized with influenza infection.


Search Strategy

This systematic review is reported following the Meta-analysis of Observational Studies in Epidemiology recommendations.20 Details of the protocol developed for this review, along with the search strategy are available in PROSPERO (CRD 42017074648). Broadly, we searched MEDLINE and EMBASE for studies published from 1990 to March 2018, the reference lists of included studies and contacted investigators of studies containing unpublished data relevant for the review. The review outcomes were selected based on current literature16,17,19,21 and were the probability of pneumonia, intensive care unit (ICU) admission, mechanical ventilation requirement, neurologic complications (encephalopathy or seizures), death and length of stay (LOS) in the hospital and the ICU.

Study Selection

Studies were screened initially by one author (JT) based on title and abstract, followed by full-text screening by two authors (SM and JT); disagreements were resolved by a third author (HM) (see Figure, Supplemental Digital Content 1, We included English-language articles that presented quantitative information on hospitalizations of clinical influenza in children (≤18 years of age) that included a breakdown by risk group(s) and additionally for any one of the listed outcomes. Where a study included individuals >18 years of age, we included only studies in which the majority were ≤18 years or if children’s data were reported separately. Clinical influenza was defined as cases either confirmed through laboratory testing [laboratory-confirmed influenza (LCI)], ICD coding or hospital discharge coding.

We excluded studies with no breakdown by risk group for hospitalizations or where total numbers for an outcome were not presented. When studies with duplicate data sources were identified, we endeavored to include the first published study except where a subsequent study provided more comprehensive outcome data or a more recent recommendation was used to define those ‘at risk.’ If study cohorts overlapped in such a way that excluding one would have omitted valuable data, then both studies were retained.

Data Extraction and Quality Assessment

Two authors (JT and SM) independently extracted all data and assessed study quality using The Quality in Prognosis Studies tool22,23; with risk of bias (RoB) provided for all included studies in Table 1.

Quality Appraisal of Included Studies

The following six domains were assessed: (1) study participation; (2) study attrition; (3) prognostic factor measurement; (4) outcome measurement; (5) study confounding and (6) statistical analysis and reporting. Judgments of low, moderate, high risk of bias were made for each domain.23 Additionally, where insufficient information was reported, we included a judgment of ‘unable to determine.’ Differences were discussed with all reviewers, and a decision made by agreement. The quality of evidence for each outcome was assessed according to the GRADE framework adapted to judge the quality of prognostic evidence.43

Statistical Analysis

We presented individual study data on the proportion of children with a SMRC and summary data visually for each outcome. For dichotomous outcomes: probability of ICU admission, mechanical ventilation, death and neurologic outcomes, we calculated the odds ratio (OR) when sufficient data enabled construction of a 2 × 2 table. We calculated the average effect summary using a random effects model (Mantel Haenszel method) in ReviewManager 5.0 (Cochrane Collaboration)44 including I2. We classified an I2 of 50% or above as a substantial level of heterogeneity.45 We planned to explore heterogeneity by subgroup analysis of studies with LCI, RoB and influenza vaccination status. Outcomes with data unsuitable for a meta-analysis were presented using a qualitative summary only.


Selection of Studies

Electronic databases and searching the reference lists of included papers identified 1377 records, including one study in-press (since published). We assessed 129 full-text articles and included 22 articles that reported data on the probability of complications or resource use in pediatric influenza hospitalizations for at least one SRMC (see Figure, Supplemental Digital Content 1, The review included data on 42,875 children, of whom 12,225 (28.5%) had a SRMC. Three studies46–48 that met inclusion criteria were excluded as they presented either the same cohort or a subgroup of another included study. Additionally, two studies27,39 comprised participants that overlapped with a third study, but due to the difference in age groups and study periods we retained the death and ICU admission outcomes,27,39 in addition to those reported in the larger study26 with more restrictive age range.

Methodologic Quality

Overall, inadequate reporting restricted study quality assessment (Table 1). Study participation RoB was upgraded due to insufficient reporting of the source population or the methods used to identify participants such as ICD coding, the exclusion criteria and the proportion of eligible population who participated. Study attrition was largely unable to be determined, with only two studies providing the proportion of participants with complete data. While many studies had low RoB for prognostic factor measurement (presence of SRMC), few reported missing data or the validity of the method used. Few studies provided a clear definition for each outcome measurement such as calculation of bed days or ICU admissions; none reported the validity of the method used. Confounding RoB was upgraded due to inadequate reporting of potential confounders and adjustment methods. Many studies had insufficiently described the statistical methods used. Across all outcomes, we were restricted from further exploration of heterogeneity: few studies reported vaccination status; leaving subgrouping impossible, all pooled studies used laboratory confirmation of influenza, and subgrouping by risk of bias was not helpful because most evidence was from studies at moderate or unclear risk of bias.

Study Characteristics

Study characteristics are presented in Supplemental Digital Content 2, (Table). Outcomes of influenza were associated with LCI (n = 18)7,9,24–27,31,33–42,49 or an ICD or discharge code of influenza (n = 4).28–30,32 Some studies limited recruitment to one influenza season (n = 3)29,36,42; while others restricted participation to only cases admitted during the official influenza season (n = 9).24,25,27,31,32,34,35,39,40 Studies also excluded cases for the following reasons: being a subsequent influenza admission in the same influenza season (n = 1)7; onset of symptoms >5 days before admission (n = 1)42; diagnosis >14 days following positive influenza test (n = 1)39; co-viral infection (n = 2)34,37; LOS >100 days (n = 1)49 or nosocomial influenza (n = 9).7,25,34,35,37–39,41,49 In studies that defined nosocomial influenza infection, the timeframe for diagnosis ranged from 48 hours to 7 days post admission. Nosocomial influenza cases were either included (n = 3)24,28,40; excluded (n = 9)7,25,34,35,37–39,41,49 or their inclusion not reported (n = 10).9,26,27,29–33,36,42 When specified (n = 6), nosocomial cases ranged from 3.5% to 17.4% of the original cohorts, with SRMCs over-represented in these data. Few studies reported vaccination status (9/22)24,25,27,31,34–36,39,40 or use of antivirals (12/22).24–27,31–36,38,39 Antiviral use ranged from 6.6% to 95.1%, with increased use for those with SRMC, although few studies (n = 4)27,31,34,35 provided these specific data.

The underlying medical conditions included varied between studies with the majority using official recommendations to determine risk status of participants; however, these differed by country and study periods (1977 to 2013). Overall, 44 separate disorders or principle groups of conditions were reported. Often a risk group was listed as a number of separate disorders or clustered with others making comparison difficult. As children may have had more than one risk condition within a principle risk category, it was not possible to combine subgroups together. Most notably this occurred with neurologic disorders, neuromuscular disorders and immunocompromised conditions. Neurologic and neuromuscular disorders were reported as a principle group in 10 studies,7,24–26,31,33,35,36,38,39 while an additional three studies9,27,34 reported a neurologic and neuromuscular category in addition to other neurologic conditions such as myotonic muscular dystrophy, developmental disorders, febrile seizures, seizure disorder, spina bifida and cerebral palsy. Immunocompromised conditions and malignancies were often combined; when listed separately as immunosuppressive or immunodeficiency categories, there was insufficient detail as to what these specific conditions were.

Proportion of Pediatric Influenza Hospitalizations With a SRMC

The proportion of pediatric influenza hospitalizations that included a child with any SRMC ranged from 14.2% to 54% (see Table, Supplemental Digital Content 2,, while the proportion of pediatric influenza hospitalizations with a SRMC sub-risk category ranged from 0.1% for liver cirrhosis, diabetes and aspirin therapy and up to 24.3%–28.3% for asthma and pulmonary conditions respectively (see Table, Supplemental Digital Content 3,

Probability of Pneumonia if Hospitalized

Only one study7 presented data on the probability of pneumonia, more specifically bacterial pneumonia. Those with SRMCs were more likely to develop suspected bacterial pneumonia than healthy counterparts [crude OR 1.71; 95% confidence interval (CI): 1.13–2.59] (see Table, Supplemental Digital Content 2,

Probability of ICU Admission

For children with SRMCs, the probability of ICU admission ranged from 8.3% to 22.6% (see Table, Supplemental Digital Content 4,,24–26,31,34,35,37–39 Using crude data and excluding the study with zero events in healthy children, risk of ICU admission increased in children with SRMCs OR 1.66 (95% CI: 1.25–2.21; I2 68%, n = 9) (Table 2 and Fig. 1A). In two studies28,32 examining children with a specific SRMC (acute lymphoblastic leukemia ± other SRMCs; or liver transplant), the probability of ICU admission ranged from 10.5% to 25.9%. Two additional studies30,41 reporting on ICU admissions only, indicated that 40.8%–44.1% of admissions comprised children with a SRMC.

Summary of Findings and Quality Assessment of Outcomes
Meta-analyses of severity and complications from influenza infection in children with SRMC compared with healthy counterparts. “A: Probability for admission to ICU”; “B: Probability for mechanical ventilation”; “C: Probability of death.”

Probability of Mechanical Ventilation

Estimates of the probability of mechanical ventilation ranged from 5.5% to 44% (median 8.3%) for those with SRMCs and 2%–34.8% (median 6.1%) for children without SRMCs (see Table, Supplemental Digital Content 5,,9,25,26,31,34,35,38,40–42 The presence of a SRMC increased the requirement for ventilation [crude OR 1.53 (95% CI: 0.93–2.52); I2 64% n = 10] (Table 2 and Fig. 1B).

Hospital LOS

Studies reviewed presented different measures of hospital LOS including the mean, median and study specific definitions such as LOS >6 or 14 days (see Table, Supplemental Digital Content 6, Of those presenting the median difference in hospital LOS, comparing SRMC to healthy, all but one showed the LOS to be longer in the SRMC group.9,25,26,31 While another study24 found prolonged LOS for those with comorbidities after adjusting for indigeneity, ICU admission and antiviral use [adjusted rate ratio 1.75 (95% CI: 1.44–2.11)].


Only one study30 compared SRMCs to non-SRMC, finding longer mean ICU LOS in those with a SRMC over a 16-year period (see Table, Supplemental Digital Content 6, and Table 2).

Probability of Neurologic Complications

Only two studies [7,34] presented data on the probability of neurologic outcomes following influenza infection. Both studies showed influenza-related encephalopathy was higher for children without SRMCs (range 1%–1.7%) compared with SRMCs (range 0.5%–0.8%), yet the number of events captured was extremely low. In contrast, the same two studies reported conflicting evidence on the effect of a SRMC on the probability of seizures (SRMC range: 7.1%–9% versus without SRMCs: range 6%–10.2%) (Table 2).

Probability of Dying From Influenza

The probability of hospitalized mortality with influenza ranged from 0% to 4.88% (median 0.53%) in children with SRMC (see Table, Supplemental Digital Content 7, In four studies, no deaths occurred.31,33,35,36 The case fatality rate in studies that comprised only single risk categories such as malignancy or solid organ transplant ranged from 1.4% to 2.1 %.28,32 In studies with more diverse special risk groups, using crude data and excluding studies with zero events, the probability of dying was increased for SRMC versus healthy [crude OR 1.34 (95% CI: 0.74–2.41; I2 0% n = 9)][7,9,24–27,34,38,40] (Table 2 and Fig. 1C).


Influenza infection disproportionally affects children with SRMCs by increasing the risk of severe disease and complications. Our review found only limited data were available to differentiate between children with SRMC and healthy children in terms of influenza severity, complications and hospital resource use. This should be distinguished from finding evidence suggesting no difference in the probability of severity, complications or resource use in those with SRMCs compared with those without SRMCs.

While individual studies showed marginal differences across outcomes, overall there was evidence that the probability of ICU admission increased for children with SRMC. Despite an increase in the pooled point estimates, there was not strong evidence to suggest that having a SRMC had an effect on either the probability of mechanical ventilation or death. The more severe and prolonged disease course experienced by children with SRMC may be a consequence of enhanced susceptibility to infection due to reduced immune response, respiratory or cardiac compromise with less reserve when infected by influenza and a compromise to existing medical comorbidities. While ICU admission was most common in studies comprising large proportions of young children (<5 years) or where inclusion was restricted to the very young (<1 year), it is unclear why we identified such variation in the probability of ICU admission between studies. It is possible that one contributing factor was that smaller studies with less event data would have been insufficient to detect a meaningful difference between the two groups of children. Additionally, studies showed wide variation across years even when identical methodology was used, such as the requirement for ICU admission and mechanical ventilation in studies using data from Canada’s Immunization Monitoring Program ACTive.25,35 This suggests outcomes are potentially modified by variables related to the seasonal variation in the circulating strain of the virus, such as severity of the strain, efficacy and uptake of the vaccine, along with antivirals that may affect disease severity.

While the probability of death appeared higher among children with a SRMC the small number of overall deaths in individual studies limited further interpretation of this outcome, such as by country, which may have highlighted differences between the underlying health services. Studies reporting lower or zero deaths had increased use of antivirals. The difference in I2 identified between outcomes is interesting. Although we found moderate to substantial heterogeneity for ICU admission and mechanical ventilation but conversely a zero I2 for deaths is likely to reflect inconsistences across studies and CI that do not overlap for both ICU admission and mechanical ventilation. In contrast, the studies for the death outcome are less precise (wide CIs), and so disparities in the point estimates across studies are not necessarily reflected in the I2 value, and it is possible that heterogeneity, similar to ICU admission and mechanical ventilation is also present. In terms of hospital resource use (hospital LOS, ICU LOS), we found limited data that distinguished between children with SRMC and healthy children. However, when differences in resource use were presented for both groups, it was not always in a uniform way that enabled comparison across studies. In the studies that did report a median hospital LOS, most of these studies comprised large proportions of children aged <5 years or excluded older aged children, limiting translation to the wider age group of children with SRMC.

Our review provides a comprehensive summary of the available evidence and included MEDLINE and EMBASE databases, as well as hand-searching included papers. Our resources restricted the inclusion to articles published in English only. The review is subject to the same limitations as the included studies, acknowledging the challenges of evidence synthesis and reporting of prognostic studies.50–52 There were weaknesses related to study design, and reporting and publication bias was strongly suspected. In all but three studies, the data extracted were from secondary outcomes. Given children with SRMCs experience a higher burden of nosocomial influenza,53 the results may not encapsulate all influenza episodes as nosocomial cases were often excluded. Additionally, there were differences between study groups and the assembly of each cohort in terms of influenza season, participant ages, country, method of influenza diagnosis and definition for SRMC; with comparisons across studies likely distorted by risk disorders not well defined. Accordingly, given the limited evidence identified, including low event numbers and quality of studies, the summary effect measures presented in this review should be interpreted with caution.

The absence of a transparent description comparing the characteristics between those with and without SRMC in studies was universal across studies, as was lack of adjustment for confounding factors such as children’s age, influenza strain and vaccination status, consistent with similar reviews in this area.19,21 Few studies contributed data on influenza vaccine uptake or antiviral use and when vaccination data were provided (often parent reported), there was uncertainty regarding receipt of the second dose of the vaccine for children (when indicated) and identifying these children was problematic. The fact that the majority of studies included a significant proportion aged <5 years is important. Given the very young are recognized as a risk group on their own and included in many official recommendations, this may have had consequences on the effect of SRMC. Additionally, vaccination may have attenuated the effect of influenza infection but not necessarily prevented hospitalization. If more children with SRMC received the vaccine (as they are recommended), then lower events for severe outcomes in this group would be expected. However, current literature suggests there is low uptake of the vaccine in children overall and for those with SRMCs.1,54–67

It is likely that the prognosis of influenza is determined by a number of factors, including the social climate toward both influenza and vaccination, parental expectations, health-seeking behavior, presence of SRMC or other risk factor, the level of care received and variation in influenza virulence by season. Additionally, seasons are often dominated by a particular influenza strain (A or B) or subtype such as H1 or H3, which is relevant as both B strains are not included in the Trivalent Influenza Vaccine which was the predominate vaccine available in these studies.

Despite a recommendation for children with SRMC to receive an influenza vaccination in many countries worldwide, estimates of vaccine uptake remain suboptimal.50,51,55,61,65,66 While the relative lack of eligible studies on seasonal influenza and clinical outcomes for these children was surprising, it was expected, given the absence of data on vaccination coverage at the population level. The implications of this review suggest an urgent need to further our understanding of the burden of influenza for children with SRMCs. This would enable clinicians and policy makers to contemplate alternative ways to improve protection and potentially reduce severity of influenza disease for these children. It would also empower clinicians to clearly communicate simple but important messages related to risk, tailor education toward a vaccination recommendation, and help improve levels of acceptance toward influenza vaccination and coverage in these children.

Ascertaining an accurate picture of complications and resource use from influenza in children with SRMCs will require well-designed studies reported with attention to the STROBE statement.52 Notably, data collection should extend to potentially modifiable factors such age appropriate influenza vaccination status and use of antivirals. Data encompassing multiple influenza seasons powered to detect meaningful differences would help to progress further policy and clinical practice for this vulnerable group.


This systematic review provides a comprehensive summary of the available evidence to distinguish influenza severity, complications and hospital resource use in children with SRMC compared with healthy children. While there was evidence that ICU management and bacterial pneumonia increases in children with SRMC, evidence showing the probability of death or increased need for mechanical ventilation was inconsistent. The volume of evidence identified was limited, with major areas of weakness related to study design and reporting. Further research using large datasets should evaluate the impact of complications and associated morbidity from influenza in SRMC children. Policy-directed research to further support vaccination recommendations for clinicians and parents in this area is urgently warranted.


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influenza; children; complications; outcomes; medical condition

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