Using databases capturing all hospitalizations in 4 states across 2 influenza seasons, we found that children with SCD were hospitalized for influenza at 56 times the rate of children without SCD and twice the rate of children with CF. The disparity for the subset of children with SCA was even wider. This result is consistent with previous research demonstrating increased IRH rates among children with high-risk chronic conditions, but is the first to quantify this disparity for children with SCD. Had children with SCD had IRH rates identical to children without SCD across the 2 study years, 156 of 159 IRH among children with SCD would have been prevented in these 4 states, with an associated reduction of $1.9 million in direct hospital charges. Associated reductions in parent work absenteeism and other indirect costs would have added to these savings.
We chose to compare IRH rates among children with SCD to those among children with CF for several reasons. Like SCD, CF is a genetic condition for which comprehensive preventive care is essential to minimize disease complications. Children with CF have a plausible mechanism by which they could be at elevated risk for complications from influenza infection (i.e., compromised pulmonary function) and are a CDC-designated high-risk group for influenza vaccine administration.16
Our finding that IRH occur at twice the rate among children with SCD compared to those with CF, therefore, is potentially concerning, particularly given that several authors have recently highlighted the disparities that exist between research and clinical care for children with CF compared to those with SCD.34, 35
Further research is needed to better understand the underlying determinants of these disparities in chronic disease outcomes and their potential relationships to disparities in preventive services delivery.
Our finding that IRH occur among children with SCD at substantially higher rates than among children without SCD has several possible explanations warranting further study. One possibility is that this disparity is vaccine-related. Children with SCD may receive influenza vaccination less reliably than children without SCD, and/or the vaccine may be less efficacious in children with SCD. The ACIP for the CDC has strongly and consistently recommended influenza vaccination for children with these target conditions since 1978.25
Despite these recommendations, influenza vaccination among children with high risk conditions remains suboptimal, though typically better than children without high risk conditions (Appendix 1
). In a recent study of adolescents with high-risk conditions, influenza vaccination rates ranged from 8.3 to 15% across 10 influenza seasons; subjects with hemoglobinopathies were as likely as children with asthma to receive influenza vaccination in adjusted models.36
In one surveillance study of influenza-related hospitalizations, children with high-risk chronic conditions reported receiving influenza vaccination in that season only one-fourth of the time, though they were 3 times more likely than healthy children to report influenza vaccination (26% vs. 9%, respectively).6
To counter these low rates, reminder/recall systems have shown promise in improving influenza vaccination rates among children with high-risk conditions, even during periods of vaccine shortage.37–39
It remains unclear, however, whether hematologists or primary care physicians assume primary responsibility for influenza vaccination delivery to children with SCD.
While the influenza vaccine has been shown to be immunogenic in children with SCD,21, 40
its effectiveness in this population compared to children without SCD is unknown. Influenza vaccination reduces influenza-related complications in healthy children.41
Evidence for the benefit of influenza vaccination in ‘high risk’ pediatric populations is weaker. For example, a systematic review of influenza vaccination in children with asthma was unable to demonstrate a clear benefit,42
and no randomized trials of influenza vaccination for children with cystic fibrosis or SCD have been conducted.43
New recommendations to immunize all children against influenza16
make it extremely unlikely that such trials will be conducted in the future.
A second possibility is that influenza is a more morbid illness in children with SCD than those without. This could result through direct effects (e.g., episodes of pneumonia, acute chest syndrome,44
or pain crises caused by influenza) or indirect effects (e.g., influenza-induced asthma exacerbations, given the probable increased prevalence of asthma in children with SCD compared to those without).22–24
Our finding that 1 in 7 hospitalizations for influenza among children with SCD also included a diagnosis code for asthma, a condition associated with increased IRH rates itself,12, 13
provides preliminary support for the latter hypothesis. Nonetheless, our findings that IRH associated with SCD were neither longer, more expensive, nor more likely to result in ICU admission or death than those not associated with SCD argues against the notion that influenza is a more morbid illness in children with SCD.
A third possibility is that children with SCD who develop fever with influenza are more likely to be hospitalized than children with fever but without SCD, presumably to exclude the possibility of invasive bacterial disease, for which children with SCD are at elevated risk. One in 8 IRH occurring in children with SCD included the diagnosis ‘fever of unknown origin’, supporting this possibility. However, a substantial fraction of IRH among children with SCD occurred among children greater than 3 years of age, in whom outpatient management with antibiotics is probably more common than among younger children.45
Our data cannot discriminate between hospitalizations for acute care versus those for evaluation and monitoring. A diagnostic testing bias may also partly explain the observed disparity in IRH, if children with SCD are more likely to receive influenza testing when hospitalized compared to children without SCD. It is likely that a combination of all of the above factors explains the wide disparity observed in rates of IRH between children with and without SCD and further study will be needed to untangle the relative contributions of each. Nonetheless, the potential of influenza vaccination in children with SCD to decrease influenza infection and subsequent health care utilization is clear.
A fourth possibility is that children with SCD have increased exposure to the risk of nosocomial influenza infection due to frequent hospitalizations for other SCD-related complications (e.g., pain crises). Precise pediatric nosocomial influenza rates are unknown, as most data originate from outbreak investigations, but surveillance studies suggest that nosocomial transmission of influenza in hospital settings is fairly common.46, 47
Nonetheless, our data from 2 states providing “present on admission” data for influenza diagnoses argue strongly against this hypothesis as an explanation for the elevated rates of IRH observed among children with SCD.
Our study has several limitations. We depended on discharge diagnosis coding to identify IRH. A recent surveillance study conducted influenza testing for all children less than 5 years of age hospitalized with acute respiratory tract infections or fever in 3 counties. At the time of discharge, only 28% of hospitalizations in which the surveillance testing was ultimately influenza positive received a discharge diagnosis of “influenza”. This was due, in large part, to low rates of provider-initiated testing for influenza as part of standard clinical care, suggesting that the true burden of IRH is greater than that indicated by discharge diagnosis codes.6
Another recent study of laboratory-confirmed, IRH found that the sensitivity for influenza ICD-9-CM codes was 65%.48
This latter study analyzed only provider-initiated testing and more closely reflects real-world clinical practice. Nonetheless, we have no reason to believe that undercoding of influenza was different across children with and without SCD. In addition, we suspect that SCD is more likely to be undercoded than overcoded. If so, the observed disparity in influenza-related hospitalization rates between children with and without SCD likely underestimates the true disparity, since a subset of IRH occurring among children with SCD would be misclassified as having occurred in children without SCD.