In a multistate Medicaid population from 2009 to 2015, neonatal HSV infection incidence has increased markedly and is associated with substantial health care use.
Abstract
Video Abstract
OBJECTIVES:
To examine the incidence, mortality, and health care use related to neonatal herpes simplex virus (HSV) infection.
METHODS:
A retrospective longitudinal cohort study using a multistate Medicaid claims database. We identified neonates hospitalized with HSV infection from 2009 to 2015 by using discharge diagnosis codes and managed them for 6 months after discharge. Incidence rates were corrected for the imperfect sensitivity and specificity of thediagnosis codes for identifying HSV infection.
RESULTS:
Of 2 107 124 births from 2009 to 2015, 900 neonates were identified with HSV infection, with a corrected incidence rate of 4.5 (95% confidence interval [CI]: 4.2–4.8) per 10 000 births. The yearly disease incidence increased by 56%, from 3.4 (95% CI: 2.8–4.2) per 10 000 births (or 1 in 2941 births) in 2009 to 5.3 (95% CI: 4.6–6.1) per 10 000 births (or 1 in 1886 births) in 2015 (P < .001). Of the 900 neonates with HSV infection, 54 (6.0% [95% CI: 4.4%–7.6%]) died during the index hospitalization; there was no increase in the yearly mortality rate. Of the 692 (81.2%) infants with follow-up data, 316 (45.7%) had an emergency department visit, and 112 (16.2%) had a hospital readmission. Total payments at 6 months amounted to $60 620 431, a median of $87 602 per case of neonatal HSV infection.
CONCLUSIONS:
We observed an increase in neonatal HSV infection incidence over a recent 7-year period in a Medicaid population. Associated health care use and payments were substantial. Public health interventions targeting disease prevention and early diagnosis are needed.
What’s Known on This Subject:
Neonatal herpes simplex virus (HSV) infection is rare and has significant morbidity and mortality. No researchers have examined its epidemiology in recent US populations. We conducted a cohort study of neonates with HSV infection from a multistate Medicaid population.
What This Study Adds:
The incidence of neonatal HSV infection increased by 56% to 5.3 in 10 000 births in 2015. The in-hospital mortality rate was stable at 6%. At 6 months after discharge, substantial health care use and payments were observed.
Neonatal herpes simplex virus (HSV) is a rare infection that is most commonly acquired perinatally.1 The infection has a high morbidity and mortality rate, and the disease presentation predicts outcomes.2,3 The presentation is classified into 3 main categories: disseminated disease; central nervous system (CNS) disease; and skin, eyes, and mouth (SEM) disease. Disseminated disease has the highest mortality rate, and CNS disease has the most significant morbidity related to neurologic injury. Treatment with acyclovir has limited 1-year mortality rates of 29% for disseminated disease and 4% for CNS disease.4 The use of oral acyclovir for 6 months after initial treatment has further reduced morbidity; ∼20% of infants with disseminated disease and 30% of infants with CNS disease will have abnormal development at 1 year.5 SEM disease has the best outcome and almost no mortality but still has substantial morbidity associated with skin disease recurrences.
Despite the severity of HSV infection, researchers in only a few large (and no recent) US studies have assessed the disease incidence and burden of the illness on the health care system.6,7 Experts have detected anecdotally that an increase in neonatal HSV incidence has occurred over the past decade. More younger women are now susceptible to primary HSV-1 infection as they enter adolescence, and oral sex practices among adolescents and young adults have increased over the past 2 decades.8,9 These factors could increase rates of primary and nonprimary HSV-1 infection among women of childbearing ages and in turn result in higher rates of neonatal HSV because transmission rates after exposure and during delivery increase from 2% in recurrent infection to 25% and 60% in nonprimary and primary infections, respectively.10,11 However, researchers in no recent studies have systematically examined whether the incidence of neonatal HSV infection has increased. Studies in which health care use is examined have also been limited because they have only included outcomes at initial hospital presentation.6,12 The objectives of this study were to examine the incidence of neonatal HSV infection, mortality on the index hospitalization, and health care use over the first 6 months after diagnosis in a large contemporary US Medicaid population.
Methods
Study Design and Data Source
This was a retrospective, multistate, longitudinal cohort study of neonates with HSV infection at the time of first hospital diagnosis over a 7-year period (from 2009 to 2015), with follow-up at 6 months after discharge. The Institutional Review Board of Cincinnati Children’s Hospital Medical Center deemed this study exempt from review under 45 Code of Federal Regulations 46.102 (BF) because the participants were not readily identifiable.
Data were obtained from the IBM MarketScan Medicaid Database (MMD) to identify patients and to measure outcomes up to the end of follow-up. The MMD is a Medicaid claims database from IBM Watson Health (Armonk, NY) and contains all enrollees (fee-for-service and managed-care) from 10 to 12 anonymized states (depending on the specific year) from 2009 to 2015. MMD contains comprehensive claims data across the care continuum. The data set includes demographic, diagnosis, procedure, and retail pharmacy data as well as health use and payment information from inpatient, outpatient, community, long-term care, and home health care services. These outpatient data make the MMD an ideal data set for understanding health care use after discharge. For inpatient encounters, ≤15 International Classification of Diseases, Ninth Revision (ICD-9) or International Classification of Diseases, 10th Revision (ICD-10) discharge diagnosis codes and 15 procedure codes are recorded, and ≤4 diagnoses are recorded for every outpatient encounter. The data set contains a unique identifier for each child to track him or her across settings (including transfers between hospitals) and longitudinally over time.
Study Population
The study population included all Medicaid enrollees who were born on or between January 1, 2009, and December 31, 2015, as identified in the MMD. Although the MMD does not include age in days or months, we used the following methods to identify neonates with HSV infection. First, we identified enrollees born in each year over the study period. From that population, we identified neonates (age 0–28 days) who were diagnosed with HSV infection during a hospital admission from January 1, 2009, to December 31, 2015 (index admission). To do this, we used the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) (054.× and 771.2) and ICD-10 (A60, P35.2, and B00) diagnosis codes to identify infants who were hospitalized with HSV infection by using discharge diagnosis codes. We then only included those infants who were enrolled in Medicaid for ≤1 month before their HSV hospitalization to restrict the cohort to neonates. Then, we further restricted the cohort to those with a length of hospital stay of >5 days (unless they died in the first 5 days) to reduce misclassification of HSV patients.6 We wanted to reduce the possibility of including neonates who may have been prematurely assigned the HSV discharge diagnosis codes because laboratory data may not have been available to validate the final diagnosis. We included neonates who died in the first 5 days because mortality early after neonatal HSV presentation to the hospital is well described. To further reduce the potential for misclassification of HSV patients, we excluded patients with discharge diagnosis codes that are not consistent with neonatal HSV infection, such as eczema herpeticum (ICD-9-CM 0540 and ICD-10 B00.0) and stomatitis related to herpangina (ICD-9-CM 0740 and ICD-10 B00.2). We also excluded admissions that were coded as normal newborn admissions (All Patients Refined Diagnosis Related Groups 640). For follow-up after discharge to 6 months, we only retained patients who had ≥5 months of Medicaid enrollment after their HSV hospitalization discharge to exclude those infants with incomplete follow-up (eg, those who may have left the state or changed insurers).
Outcome Measures
Disease Incidence
We determined the incidence of neonatal HSV infection by year and for the entire period of January 1, 2009, to December 31, 2015. The incidence was determined by dividing the number of neonates with HSV disease by the total number of births in the MMD for the time period.
Mortality Rate
We determined the in-hospital mortality rate during the index admission in which neonatal HSV infection was diagnosed by dividing the number of deaths by the number of neonatal HSV index admissions by year and for the entire study period.
Health Care Use
We determined health care use for both the index hospital admission in which neonatal HSV was diagnosed and postdischarge use across the care continuum to age 6 months. We measured hospital length of stay and payments for the index hospitalization. For the follow-up period after discharge, we determined the use and payments for outpatient visits, home health, emergency department (ED) visits, and hospital readmissions. We estimated the cumulative total payment for the cohort and the median total payments per patient with neonatal HSV for all health care services, including the index admission and follow-up at 6 months.
Statistical Analysis
The incidence of neonatal HSV infection was calculated as a rate per 10 000 births with 95% confidence intervals (CIs). Given that International Classification of Diseases (ICD) diagnosis codes are imperfect for identifying neonatal HSV infection, we corrected incidence rates and CIs using the method described by Diggle.13 This method includes the known sensitivity and specificity of a diagnostic test (in this context, the known sensitivity and specificity of ICD diagnosis codes for neonatal HSV) to correct for bias. The sensitivity and specificity of ICD discharge diagnosis codes in infants with a hospital length of stay >5 days were determined by using microbiology results (positive polymerase chain reaction, direct fluorescent antibody, or culture from any site) for defining neonatal HSV infection from a separate multicenter cohort of hospitalized infants from 2006 to 2011 using the Pediatric Health Information System Plus database. The sensitivity and specificity of ICD-9-CM codes (054.× and 771.2) for neonatal HSV infection were 96% and 99%, respectively. Changes in yearly disease incidence and mortality were examined by using logistic regression with year as a covariate. A sensitivity analysis was performed for the analysis of change in yearly disease incidence over time with the year 2015 removed because ICD-10 codes were introduced in the last quarter of 2015. Descriptive statistics were used to present data on health care use and mortality, with mean, 95% CI, and median provided where appropriate.
Results
Study Population
We identified 900 neonates with HSV infection out of 2 107 124 births that were recorded in the MMD from 2009 to 2015. In this cohort of patients with neonatal HSV, boys and other race were more common, and Hispanic race was less common (Table 1).
TABLE 1.
Neonatal HSV Infection and All Births in a Multistate Medicaid Population (2009–2015)
| All Births (N = 2 107 124), n (%) | No Neonatal HSV (n = 2 106 224), n (%) | Neonatal HSV (n = 900), n (%) | P | |
|---|---|---|---|---|
| Sex | .036 | |||
| Boys | 1 075 569 (51.1) | 1 075 078 (51.1) | 491 (54.6) | |
| Girls | 1 030 655 (48.9) | 1 030 246 (48.9) | 409 (45.4) | |
| Race | .05 | |||
| White | 899 852 (42.7) | 899 476 (42.7) | 376 (41.8) | |
| African American | 579 014 (27.5) | 578 758 (27.5) | 256 (28.4) | |
| Hispanic | 162 840 (7.7) | 162 790 (7.7) | 50 (5.6) | |
| Other | 464 518 (22.1) | 464 300 (22.1) | 218 (24.2) |
Disease Incidence
The uncorrected and corrected incidences of neonatal HSV infection during this period were 4.3 per 10 000 births (95% CI: 4.0–4.6) and 4.5 per 10 000 births (95% CI: 4.2–4.8), respectively. The yearly corrected incidence of neonatal HSV infection in this cohort was 3.4 per 10 000 births (or 1 in 2941 births) in 2009 and 5.3 per 10 000 births (1 in 1886 births) in 2015 (see Table 2). Over the study period, there was a significant increase in the yearly disease incidence, which persisted even when the year 2015 was removed from the analysis (Table 2).
TABLE 2.
Incidence of Neonatal HSV Infection in a Multistate Medicaid Population (2009–2015)
| Year | Births, n | Neonatal HSV, n | Uncorrected HSV Infection Rate per 10 000 Births (95% CI)a | Corrected HSV Infection Rate per 10 000 Births (95% CI)a |
|---|---|---|---|---|
| 2009 | 289 903 | 94 | 3.2 (2.6–4.0) | 3.4 (2.8–4.2) |
| 2010 | 271 634 | 88 | 3.2 (2.6–4.0) | 3.4 (2.8–4.2) |
| 2011 | 224 809 | 71 | 3.2 (2.5–4.0) | 3.3 (2.6–4.2) |
| 2012 | 294 414 | 147 | 5.0 (4.2–5.9) | 5.2 (4.5–6.2) |
| 2013 | 286 604 | 145 | 5.1 (4.3–6.0) | 5.3 (4.5–6.2) |
| 2014 | 369 052 | 168 | 4.6 (3.9–5.3) | 4.8 (4.1–5.6) |
| 2015 | 369 808 | 187 | 5.1 (4.4–5.8) | 5.3 (4.6–6.1) |
| Total | 2 106 224 | 900 | 4.3 (4.0–4.6) | 4.5 (4.2–4.8) |
The increase in incidence of neonatal HSV infection rate over time was statistically significant (P < .001). When the year 2015 was removed from the analysis, the incidence of neonatal HSV infection rate over time remained statistically significant (P < .001).
Health Care Use and Mortality on Index Hospitalization
The median length of stay during the index hospitalization for neonatal HSV infection was 18 days (interquartile range [IQR]: 11–27 days). Of the 900 neonates with HSV infection, 54 died during the index hospitalization (mortality rate 6.0%; 95% CI: 4.4%–7.6%). There was no significant change in the mortality rate over time (P = .31). The median payment per neonatal HSV case for the index hospitalization was $32 683 (IQR: $18 920–$60 116). The total cumulative payment for all cases of neonatal HSV in the cohort for the initial index hospitalization was $54 448 783. Payments were less for those neonates who died. The yearly mortality rate and hospital payments by those who were discharged alive and those who died are reported in Table 3.
TABLE 3.
Mortality and Payments on Index Hospitalization for Neonatal HSV Infection in a Multistate Medicaid Population (2009–2015)
| Year | Neonatal HSV, n | Mortalitya | Paymentb | |||
|---|---|---|---|---|---|---|
| Died in Hospital, n | Rate, % (95% CI) | All Neonatal HSV, Median USD per Case (IQR) | Discharged Alive, Median USD per Patient (IQR) | Died, Median USD per Patient (IQR) | ||
| 2009 | 94 | 3 | 3.2 (0–6.7) | 36 196 (20 193–67 800) | 36 122 (20 193–67 920) | 40 295 (6405–41 237) |
| 2010 | 88 | 7 | 8.0 (2.3–13.6) | 36 883 (25 960–61 102) | 36 996 (26 719–58 832) | 27 159 (13 580–63 371) |
| 2011 | 71 | 3 | 4.2 (0–8.9) | 44 465 (24 456–83 394) | 45 577 (26 679–87 373) | 29 044 (24 203–82 291) |
| 2012 | 147 | 11 | 7.5 (3.2–11.7) | 32 683 (20 233–61 020) | 34 240 (21 206–61 915) | 16 240 (4060–46 350) |
| 2013 | 145 | 4 | 2.8 (0.1–5.4) | 30 031 (18 312–60 062) | 30 031 (18 599–60 491) | 13 013 (4880–39 616) |
| 2014 | 168 | 11 | 6.5 (2.8–10.3) | 26 807 (16 417–48 188) | 27 028 (16 616–51 511) | 20 281 (11 589–37 664) |
| 2015 | 187 | 15 | 8.0 (4.1–11.9) | 33 412 (17 058–57 175) | 33 412 (17 833–54 094) | 33 233 (14 770–73 852) |
| Total | 900 | 54 | 6.0 (4.4–7.6) | 32 683 (18 920–60 116) | 33 381 (19 279–60 902) | 24 282 (11 589–46 350) |
USD, US dollars.
Mortality did not change over time (P = .31).
Total hospital payment for the index hospitalization for the cohort was $54 448 783.
Health Care Use at 6-Month Follow-up
Of the 846 neonates with HSV who were discharged alive, 692 (81.2%) had follow-up data available. In the 6-month follow-up period after discharge from the index hospitalization, 316 infants (45.7%) had at least 1 ED visit, and 112 infants (16.2%) had at least 1 hospital readmission (Table 4). Total payment for these health care services in the 6-month follow-up period (ie, excluding payments for the index admission) was $6 171 648, with hospitalizations accounting for 57.2% of these costs, followed by outpatient medications (11.6%), outpatient primary care visits (8.3%), and outpatient specialist visits (6.3%; payments included multiple visits for patients; Table 4). Total payments (index admission and follow-up to 6 months) for the cohort of 900 infants with neonatal HSV amounted to $60 620 431, or a median of $87 602 per patient with neonatal HSV.
TABLE 4.
Health Care Use and Payments for Neonatal HSV Infection After Index Hospitalization to 6-Month Follow-up in a Multistate Medicaid Population (2009–2015)
| Health Care Service | Infants, n (%)a | Payments, USDb,c | Payments per User, USDb |
|---|---|---|---|
| Hospital readmission | 112 (16.2) | 3 531 486 | 31 531 |
| Outpatient medications | 600 (86.7) | 714 784 | 1191 |
| Outpatient PCP visits | 659 (95.2) | 513 943 | 780 |
| Outpatient specialist visits | 463 (66.9) | 390 487 | 843 |
| Outpatient testing | 734 (64.0) | 284 646 | 388 |
| Outpatient physical therapy | 196 (28.3) | 202 184 | 1030 |
| Outpatient, other | 311 (44.9) | 184 619 | 594 |
| ED visits | 316 (45.7) | 167 942 | 527 |
| Home health services | 138 (19.9) | 124 128 | 899 |
| Outpatient mental health services | 66 (9.5) | 75 432 | 977 |
| Outpatient medical equipment | 142 (20.5) | 53 058 | 374 |
PCP, primary care provider; USD, US dollars.
Includes the number of patients who had at least 1 visit for the health care service. The total number of patients available for follow-up was 692.
Payments include multiple visits per patient.
Total payments for health care services after index admission to 6-mo follow-up was $6 171 648.
Discussion
From a US multistate Medicaid population of >2 million births from 2009 to 2015, we estimated an incidence of neonatal HSV infection of ∼4.6 per 10 000 births. This amounts to 1 in 2174 births, with the upper and lower CIs around this estimate of 1 in 2083 to 1 in 2380 births, respectively. There was a significant 56% increase in disease incidence over the study period, from 3.4 per 10 000 births in 2009 (1 in 2941 births) to 5.3 per 10 000 births in 2015 (1 in 1886 births). The in-hospital mortality rate for all infants with the disease at first diagnosis was 6%, and the mortality rate remained stable over time. Follow-up health care use to 6 months revealed that 46% of neonates with HSV required an ED visit, and 16% were rehospitalized. Total payments over the first 6 months were substantial and largely driven by hospitalization.
The true incidence of neonatal HSV has been difficult to quantify because most countries do not require mandatory case reporting.14 Our estimates of the incidence of neonatal HSV are comparable to those reported in some US studies. A landmark prospective cohort study of 58 362 pregnant women from Washington state (from 1982 to 1999) revealed a neonatal HSV incidence rate of 1 in 3200 live births, with a 95% CI of 1 in 847 to 1 in 5050 live births.15 In a more recent study, Whitley et al7 estimated the incidence of neonatal HSV in a US managed-care population using administrative data and found an incidence of ∼1 in 1312 live births. In a large US study in which they used the Kids’ Inpatient Database, Flagg and Weinstock6 found an incidence of 9.6 per 100 000 births (1 in 10 416 births) in 2006. Unlike our study, these latter 2 administrative database studies did not include an algorithm for identifying infants with HSV with known diagnostic properties that could be corrected for in their analysis or that was validated. The fact that our study was focused on a Medicaid population may be 1 reason why we observed higher incidence rates. In their study, Flagg and Weinstock6 reported an incidence rate 3 times higher among the Medicaid subgroup compared with private insurance and/or managed-care populations, although the reasons for the higher incidence are unclear.7 In addition, differences in case ascertainment, study population (eg, <60 vs 28 days of age), data sources, and study methods may also explain the different disease incidence estimates across studies.
The increase in incidence of neonatal HSV infection that we observed over the study period may be plausible on the basis of the changing epidemiology of HSV-1 infection and sexual practices. Data from the NHANES suggest that there are more adolescents who are susceptible to HSV-1 infection.8 In addition, oral sex practices among adolescents and young adults have increased over the past 2 decades, which increases the risk of HSV-1 genital infection,9 and increasing HSV-1 infection rates have been documented.10 Thus, more primary or nonprimary genital HSV-1 infections among childbearing women would result in increasing numbers of neonatal HSV cases, as has been suggested.11 An alternate reason for our observation of increasing incidence might be related to disease misclassification that is related to changing diagnosis-coding practices over time. In the last quarter of 2015, ICD-10 codes were introduced. However, when we performed a sensitivity analysis by removing the year 2015 from the analysis, the increased incidence over time was still significant.
The mortality rate reported in our study of 6.0% (95% CI: 4.4%–7.6%) represents deaths that occurred during the index hospitalization. We were not able to track deaths that occurred out of the hospital because those data are unavailable in the data source. In addition, we were not able to classify disease presentation by category of neonatal HSV infection, which would be informative in interpreting the mortality rate. The following 2 studies in which an administrative data source was used revealed similar index hospitalization mortality rates (ie, overlapping CIs with our estimate): the study by Flagg and Weinstock6 in which they used the Kids’ Inpatient Database and found a mortality rate of 4.1% (95% CI: 1.6%–6.6%) and the study by Shah et al16 that revealed a mortality rate of 7.3% (95% CI: 5.8%–9.0%) in a cohort of 1086 neonates with HSV infection from 41 tertiary US children’s hospitals. Smaller retrospective hospital-based studies in which medical records were used as the data source have revealed higher mortality rates. One study from 2002 to 2012 at 2 children’s hospitals revealed a mortality rate of 14% (7 of 49), and another study from 2001 to 2011 revealed a mortality rate of 26% (13 of 150).17,18 We can only speculate on reasons for differences in mortality rates between types of studies, which might include a misclassification of children who did not have neonatal HSV as having the disease, a greater proportion of infants with less-severe diseases (ie, SEM disease) in the studies that included administrative data sources and the review of all autopsies to identify missed cases of neonatal HSV in 1 of the retrospective studies that included hospital medical record data.
We observed high health care use and associated payments over the first 6 months including and after hospitalization for neonatal HSV. ED use and hospital readmissions were common. These findings suggest a need for comprehensive, coordinated care after diagnosis of neonatal HSV. Most other studies in which health care use and costs in infants with neonatal HSV are examined have been limited to the index hospitalization without longitudinal follow-up. A study by Ambroggio et al12 of 406 infants and neonates with HSV at 42 US children’s hospitals between 2003 and 2005 revealed median hospital charges of $37 431 (IQR: 14 667–74 559) at first presentation. The study by Flagg and Weinstock6 revealed median hospitalization charges of $64 326. These latter studies included patients who were insured through private insurance, for which payments are typically significantly higher than Medicaid.19
We relied on an administrative data source and ICD discharge diagnosis codes to identify our study population. These discharge diagnosis codes are imperfect for identifying neonatal HSV infection. Thus, we used established methods to correct incidence estimates and their CIs. However, despite the high sensitivity (96%) and specificity (99%) of the ICD-9 codes for identifying neonates with laboratory-proven HSV infection on the index hospitalization, the low disease incidence means that we may have included infants without the disease and (less likely) that we may have excluded infants with the disease. In addition, because of the limitations of ICD-9 and ICD-10 coding, we were unable to categorize incidence and outcomes based on the accepted neonatal HSV disease classification (ie, SEM disease, CNS disease, and disseminated disease). Specific neonatal HSV ICD-10 diagnosis codes are needed as part of a strategy for disease surveillance and outcomes evaluation by using routinely collected data. Another limitation of the MMD data source is that states that were included may have changed during the study period. We also did not have complete follow-up after the index hospitalization. Infants may have changed insurers, moved to another state, or died. It is also important to note that the disease incidence and outcomes we report are specific to a population of Medicaid enrollees and may not be generalizable to the entire population.
Conclusions
In this retrospective multistate cohort study of neonates with HSV infection in a contemporary Medicaid population, we found a 56% increase in the incidence of neonatal HSV infection from 2009 to 2015 and a stable mortality rate. Follow-up to 6 months after hospital diagnosis revealed substantial health care use, including ED visits and hospital readmissions. Infants with neonatal HSV should receive comprehensive, coordinated care after diagnosis. Public health strategies that are targeted on disease prevention and early diagnosis and treatment are needed.
Glossary
- CI
confidence interval
- CNS
central nervous system
- ED
emergency department
- HSV
herpes simplex virus
- ICD
International Classification of Diseases
- ICD-9
International Classification of Diseases, Ninth Revision
- ICD-9-CM
International Classification of Diseases, Ninth Revision, Clinical Modification
- ICD-10
International Classification of Diseases, 10th Revision
- IQR
interquartile range
- MMD
MarketScan Medicaid Database
- SEM
skin, eyes, and mouth
Footnotes
Dr Mahant conceptualized and designed the study, reviewed, revised, and interpreted the data analysis, drafted the initial manuscript, and reviewed and revised the manuscript; Dr Hall conceptualized and designed the study, conducted data analysis, reviewed the data analysis, and reviewed and revised the manuscript; Drs Schondelmeyer, Berry, Kimberlin, and Shah conceptualized and designed the study, reviewed and interpreted the data analysis, and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Supported under contract with the Division of Microbiology and Infectious Diseases of the National Institute of Allergy and Infectious Diseases (HHSN272201600018C). Funded by the National Institutes of Health (NIH).
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
COMPANION PAPER:A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2019-0159.
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