Prior to implementation of routine rotavirus immunization in the United States in 2006, rotavirus gastroenteritis caused an estimated 20 to 60 deaths annually among US children.1 As no specific diagnostic code for rotavirus was available in the International Classification of Diseases—ninth revision (ICD-9), indirect measures were used to generate rotavirus death estimates, based on national vital statistics data for deaths coded for diarrheal illness. Specifically, diarrheal deaths that occurred during the nonrotavirus season (June–November) were subtracted from those during the rotavirus season (December–May), and the “winter excess” deaths were presumed to be caused by rotavirus.2 Given the imprecise nature of these estimates, concerns regarding their validity remain.
Recent postlicensure data from international settings have identified a possible low level of risk of intussusception (∼1 case per 50–100,000 vaccinated infants) associated with current rotavirus vaccines.3 While a risk has not been confirmed in the United States, available data from US populations are insufficient to exclude a risk of this magnitude. Although uncommon, intussusception requires surgery in about one-third of US infants hospitalized with this condition and results in the death of about 0.5% (∼10 deaths per year).4 Thus, it is important to better understand the burden of severe rotavirus disease in US children, particularly rotavirus-associated deaths, to help weigh the benefits of vaccination against the potential risk of intussusception.
In 1999, the International Classification of Diseases—10th revision (ICD-10) was adopted for US death certificate coding, and a specific code for rotavirus disease was included. Although rotavirus-coded deaths likely account for only a small portion of all rotavirus deaths due to incomplete coding,5 they identify cases that may be further investigated to ascertain the role of rotavirus in these deaths. We investigated clinical and laboratory features of rotavirus-coded death records among US children from 1999 to 2007, the latest year with available national data.
MATERIALS AND METHODS
Multiple cause-of-death data for the United States was obtained from the National Center for Health Statistics for the years 1999–2007. We identified rotavirus-coded deaths, defined as deaths among children 1 to 59 months of age with the ICD-10 code A08.0 listed anywhere on the death record, including underlying and contributing causes of death. Demographic information and all associated diagnostic codes from identified deaths were extracted. Clinical and laboratory data were requested from the health departments where each pediatric death occurred. Clinical features included medical history, clinical presentation, immunization status, and circumstances leading up to death. Laboratory data included microbiologic and histopathologic confirmation of rotavirus infection at the time of death. Postmortem histopathology and interpretation were also examined.
During 1999 to 2007, 38 rotavirus-coded deaths among children 1 to 59 months of age were identified in 18 US states. Of them, 22 (58%) were male and 26 (68%) were white. Of the total 38 cases, 7 (18%) were 1 to 3, 12 (32%) were 4 to 11, 16 (42%) were 12 to 23, and 3 (8%) were 24 to 59 months of age. Rotavirus was listed as the underlying cause of death in 29 (76%) of deaths. The most common additional ICD-10 codes were for dehydration (E86 and E87.2) and/or metabolic acidosis (R57.1), which were listed on 20 (53%) of the 38 death certificates.
Results of rotavirus laboratory testing and complete clinical information could be obtained from 21 of the 38 (55%) rotavirus-coded deaths. All 21 deaths had confirmation of rotavirus by either microbiologic (n = 20) stool testing using culture or enzyme immunoassay or small bowel histopathology (n = 1). Of the 21 deaths, 8 occurred in previously healthy children, among whom 6 had in-hospital deaths. The remaining 13 deaths occurred in children who had some type of underlying condition, most commonly, prematurity (N = 4), congenital abnormalities (N = 4), and failure to thrive (N = 2). Of the 18 deaths among children older than 3 months of age on whom we obtained immunization history, 7 were reported to be up-to-date with recommended childhood immunizations. Rotavirus vaccine was available in the United States during the first and last year of the study period; however, none of the children had specific documentation of rotavirus vaccination in their medical charts (Table 1).
Child A was a previously healthy full-term infant born by vaginal delivery with no antenatal complications. Up to 20 months of age, the child was taken to regular pediatric visits, received all immunizations, and was appropriately growing and reaching development milestones. At 20 months of age, child A developed diarrhea and vomiting for 4 days. Child A had minimal oral intake over 2 days, and was taken to the local emergency room for evaluation. At presentation to the emergency room, the infant was bradycardic, hypotensive, and extremely dehydrated; hence, intravenous fluids and inotropic medication were rapidly administered. Initial blood gas revealed a pH of 6.8, pCO2 of 91 mm Hg, and pO2 of 37 mm Hg with electrolyte imbalances including hypernatremia (sodium, 150 mEq/L) and hyperkalemia (potassium, 6 mEq/L). Child A went into asystole 3 separate times in the emergency room, and after multiple cardiopulmonary resuscitations, was transferred to a pediatric intensive care unit for further care. Child A had intermittent dysrhythmia and eventually died 2 days after initial presentation. Postmortem rotavirus testing from a stool specimen was positive; no autopsy was performed.
Our analysis offers clinical and microbiologic validation that deaths associated with rotavirus occur in US children. Of the 38 diarrheal deaths during 1999 to 2007 that were assigned a diagnostic code for rotavirus, we confirmed a diagnosis of rotavirus in all 21 deaths with available microbiologic of histopathologic data. Many of these deaths occurred among children with previous medical conditions—a group known to be at high risk for complications from rotavirus disease. However, as many as 38% of deaths occurred in a clinical setting among previously healthy children with no identifiable risk factors for more severe outcomes, such as prematurity and failure to thrive. Rotavirus vaccination, if available at the time, may have been offered to more than 80% of these children who were 3 months or older (age eligible to receive at least 1 vaccine dose), thereby preventing some of these deaths.
The pathophysiology of rotavirus deaths is not well understood. In an analysis of 21 fatal rotavirus cases in the 1970s, dehydration with electrolyte imbalance leading to cardiac arrest was the primary cause of death in 16 cases.6 Diarrheal deaths in US children have declined substantially from ∼1300 per year in 1968 to ∼480 per year in 2006,2,7 a decline largely attributed to improved clinical management. However, diarrheal deaths continue to occur in developed settings, in part due to underappreciation of early signs and symptoms of dehydration.8 In our study, dehydration and/or metabolic acidosis were present in more than half of the deaths, indicating that these complications contributed to diarrheal deaths in US children. Over the past decade, studies have documented the presence of antigenemia in 50% to 80% of patients with severe rotavirus diarrhea,9 and extraintestinal infection among children who have died of rotavirus disease.10 An evaluation of 3 children who died of rotavirus disease found that 2 had histopathologic evidence of rotavirus genome in extraintestinal tissue.11 Neither antigenemia nor extraintestinal infection was evaluated in our study patients. Further study may clarify the role of dehydration versus viremia and end-organ involvement in the pathophysiology of rotavirus deaths. Additionally, among the 3 children with bacteremia and 1 child with bacterial pneumonia, rotavirus infection was unlikely to be the primary cause of death.
Some limitations should be considered. In spite of active investigation of all 38 identified death records with a rotavirus code, medical records of 17 US children were not available to state and local health departments. Barriers to medical record retrieval included variability in rotavirus reporting requirements and difficulty in accessing medical records from clinical and laboratory facilities. Even among children with available medical records, incomplete reporting made it difficult to interpret the circumstances around a child's death. For instance, some child deaths were considered “in-hospital deaths” even though they occurred within hours of presentation to an emergency room. In these situations, the child may have had significant clinical decompensation before obtaining medical attention, similar to “community deaths.” Also, although our data validate the rotavirus etiology of some diarrhea deaths, the figures likely greatly underestimate the overall number of rotavirus deaths because testing for rotavirus is often not performed in the clinical setting.12 This is particularly true among diarrhea fatalities, because minimal stool may remain in the intestinal tract, making stool collection difficult. Additionally, searching by ICD-10 coding excludes death records with text-based diagnosis (eg, “rotavirus infection”) without the associated code A08.0. Finally, immunization status information relied on medical chart reporting and may be incomplete or inaccurate because it was not vaccination card confirmed.
In summary, our analysis documents rotavirus deaths that have occurred in recent years among US children, many of which occurred among children who were age-eligible to receive rotavirus vaccine. Given the striking reduction in rotavirus hospitalizations and emergency room visits seen in US children following implementation of rotavirus vaccination program,13 a decline in rotavirus deaths in US children should be assessed as data for future years become available.
The authors acknowledge Dana L. Haberling in the Division of High-Consequence Pathogens and Pathology, at Centers for Disease Control and Prevention, Atlanta, GA; the many state and local health departments that contributed to this manuscript; and the work of Jennifer Zipprich of California Department of Public Health, Amie Worthington of Kansas Department of Health and Environment, Marceia Barabin Walker of Louisiana Department of Health and Hospitals, Tiffany Silmon of Virginia Department of Health, John Kiesow of Wisconsin Department of Health Services, and Katie Bryan of Wyoming Department of Health.
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