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1.  The Burden of Influenza in Young Children, 2004–2009 
Pediatrics  2013;131(2):207-216.
To characterize the health care burden of influenza from 2004 through 2009, years when influenza vaccine recommendations were expanded to all children aged ≥6 months.
Population-based surveillance for laboratory-confirmed influenza was performed among children aged <5 years presenting with fever and/or acute respiratory illness to inpatient and outpatient settings during 5 influenza seasons in 3 US counties. Enrolled children had nasal/throat swabs tested for influenza by reverse transcriptase-polymerase chain reaction and their medical records reviewed. Rates of influenza hospitalizations per 1000 population and proportions of outpatients (emergency department and clinic) with influenza were computed.
The study population comprised 2970, 2698, and 2920 children from inpatient, emergency department, and clinic settings, respectively. The single-season influenza hospitalization rates were 0.4 to 1.0 per 1000 children aged <5 years and highest for infants <6 months. The proportion of outpatient children with influenza ranged from 10% to 25% annually. Among children hospitalized with influenza, 58% had physician-ordered influenza testing, 35% had discharge diagnoses of influenza, and 2% received antiviral medication. Among outpatients with influenza, 7% were tested for influenza, 7% were diagnosed with influenza, and <1% had antiviral treatment. Throughout the 5 study seasons, <45% of influenza-negative children ≥6 months were fully vaccinated against influenza.
Despite expanded vaccination recommendations, many children are insufficiently vaccinated, and substantial influenza burden remains. Antiviral use was low. Future studies need to evaluate trends in use of vaccine and antiviral agents and their impact on disease burden and identify strategies to prevent influenza in young infants.
PMCID: PMC3557405  PMID: 23296444
influenza; epidemiology; influenza vaccine; hospitalization; ambulatory care
2.  Understanding the association between chromosomally integrated human herpesvirus 6 and HIV disease: a cross-sectional study 
F1000Research  2013;2:269.
We conducted a cross-sectional investigation to identify evidence of a potential modifying effect of chromosomally integrated human herpes virus 6 (ciHHV-6) on human immunodeficiency virus (HIV) disease progression and/or severity. ciHHV-6 was identified by detecting HHV-6 DNA in hair follicle specimens of 439 subjects. There was no statistically significant relationship between the presence of ciHHV-6 and HIV disease progression to acquired immunodeficiency syndrome. However, after adjusting for use of antiretroviral therapy, all subjects with ciHHV-6 had low severity HIV disease; these findings were not statistically significant. A multi-center study with a larger sample size will be needed to more precisely determine if there is an association between ciHHV-6 and low HIV disease severity.
PMCID: PMC3892924  PMID: 24555113
Among infants with prematurity and/or chronic lung disease for whom respiratory syncytial virus immunoprophylaxis is recommended, we examined adherence in infants enrolled during healthcare visits for acute respiratory illness in 3 US counties from 2001 to 2007. Immunoprophylaxis among infants who met national criteria for prophylaxis increased from 33% to 83% over the 6-year period; 17% (11/65) of infants who received immunoprophylaxis did not meet eligibility criteria.
PMCID: PMC3773819  PMID: 22760537
respiratory syncytial virus; adherence; palivizumab
4.  Burden of Human Metapneumovirus Infection in Young Children 
The New England journal of medicine  2013;368(7):633-643.
The inpatient and outpatient burden of human metapneumovirus (HMPV) infection among young children has not been well established.
We conducted prospective, population-based surveillance for acute respiratory illness or fever among inpatient and outpatient children less than 5 years of age in three U.S. counties from 2003 through 2009. Clinical and demographic data were obtained from parents and medical records, HMPV was detected by means of a reverse-transcriptase polymerase-chain-reaction assay, and population-based rates of hospitalization and estimated rates of outpatient visits associated with HMPV infection were determined.
HMPV was detected in 200 of 3490 hospitalized children (6%), 222 of 3257 children in outpatient clinics (7%), 224 of 3001 children in the emergency department (7%), and 10 of 770 asymptomatic controls (1%). Overall annual rates of hospitalization associated with HMPV infection were 1 per 1000 children less than 5 years of age, 3 per 1000 infants less than 6 months of age, and 2 per 1000 children 6 to 11 months of age. Children hospitalized with HMPV infection, as compared with those hospitalized without HMPV infection, were older and more likely to receive a diagnosis of pneumonia or asthma, to require supplemental oxygen, and to have a longer stay in the intensive care unit. The estimated annual burden of outpatient visits associated with HMPV infection was 55 clinic visits and 13 emergency department visits per 1000 children. The majority of HMPV-positive inpatient and outpatient children had no underlying medical conditions, although premature birth and asthma were more frequent among hospitalized children with HMPV infection than among those without HMPV infection.
HMPV infection is associated with a substantial burden of hospitalizations and outpatient visits among children throughout the first 5 years of life, especially during the first year. Most children with HMPV infection were previously healthy. (Funded by the Centers for Disease Control and Prevention and the National Institutes of Health.)
PMCID: PMC3662802  PMID: 23406028
5.  Comparison of 2 Assays for Diagnosing Rotavirus and Evaluating Vaccine Effectiveness in Children with Gastroenteritis 
Emerging Infectious Diseases  2013;19(8):1245-1252.
We compared rotavirus detection rates in children with acute gastroenteritis (AGE) and in healthy controls using enzyme immunoassays (EIAs) and semiquantitative real-time reverse transcription PCR (qRT-PCR). We calculated rotavirus vaccine effectiveness using different laboratory-based case definitions to determine which best identified the proportion of disease that was vaccine preventable. Of 648 AGE patients, 158 (24%) were EIA positive, and 157 were also qRT-PCR positive. An additional 65 (10%) were qRT-PCR positive but EIA negative. Of 500 healthy controls, 1 was EIA positive and 24 (5%) were qRT-PCR positive. Rotavirus vaccine was highly effective (84% [95% CI 71%–91%]) in EIA-positive children but offered no significant protection (14% [95% CI −105% to 64%]) in EIA-negative children for whom virus was detected by qRT-PCR alone. Children with rotavirus detected by qRT-PCR but not by EIA were not protected by vaccination, suggesting that rotavirus detected by qRT-PCR alone might not be causally associated with AGE in all patients.
PMCID: PMC3739503  PMID: 23876518
rotavirus; enzyme immunoassay; RT-PCR; viruses; diagnosis; children; acute gastroenteritis
6.  Vaccine Effectiveness Against Laboratory-Confirmed Influenza in Children 6 to 59 Months of Age During the 2003–2004 and 2004–2005 Influenza Seasons 
Pediatrics  2008;122(5):911-919.
The goal was to estimate the effectiveness of influenza vaccination against laboratory-confirmed influenza during the 2003–2004 and 2004–2005 influenza seasons in children aged 6-59 months.
We conducted a case-control study in children with a medically attended acute respiratory infection who received care in the inpatient, emergency department or outpatient clinic setting during two consecutive influenza seasons. All children resided in Monroe County, NY, Davidson County, TN or Hamilton County, OH, were prospectively enrolled at the time of acute illness, and had nasal/throat swabs tested for influenza by culture and/or polymerase chain reaction. Children with laboratory-confirmed influenza were cases and children who tested negative for influenza were controls. Child vaccination records from the parent and from the child's physician were used to determine and validate influenza vaccination status. Influenza vaccine effectiveness was calculated as (1 – adjusted odds ratio) × 100.
We enrolled 288 cases and 744 controls during the 2003–2004 season, and 197 cases and 1,305 controls during the 2004–2005 season. Six percent and 19% of all study children were fully vaccinated according to immunization guidelines in the respective seasons. Full vaccination was associated with significantly fewer influenza-related inpatient, emergency department, or outpatient clinic visits in 2004-2005 [vaccine effectiveness = 57% (95% CI: 28%-74%)], but not in 2003-2004 [vaccine effectiveness = 44% (95% CI: -42%-78%)]. Partial vaccination was not effective in either season.
Receipt of all recommended doses of influenza vaccine was associated with halving of laboratory-confirmed influenza-related medical visits among children aged 6-59 months in one of two study years, despite suboptimal matches between the vaccine and circulating influenza strains in both years.
PMCID: PMC3695734  PMID: 18977968
Children; Vaccine Effectiveness; Laboratory-confirmed; Influenza
7.  Human Coronavirus in Young Children Hospitalized for Acute Respiratory Illness and Asymptomatic Controls 
Human coronaviruses (HCoVs) have been detected in children with upper and lower respiratory symptoms but little is known about their relationship with severe respiratory illness.
To compare the prevalence of HCoV species among children hospitalized for acute respiratory illness and/or fever with asymptomatic controls and to assess the severity of outcomes among hospitalized children with HCoV compared with other respiratory viruses.
From December 2003–April 2004 and October 2004–April 2005, we conducted prospective, population-based surveillance of children <5 years of age hospitalized for ARI/fever in three U.S. counties. Asymptomatic outpatient controls were enrolled concurrently. Nasal/throat swabs were tested for HCoV species HKU1, NL63, 229E, and OC43 by RT-PCR. Specimens from hospitalized children were also tested for other common respiratory viruses. Demographic and medical data were collected by parent/guardian interview and medical chart review.
Overall, HCoV was detected in 113 (7.6%) of 1,481 hospitalized children (83 [5.7%] after excluding 30 cases coinfected with other viruses) and 53 (7.1%) of 742 controls. The prevalence of HCoV or individual species was not significantly higher among hospitalized children than controls. Hospitalized children testing positive for HCoV alone tended to be less ill than those infected with other viruses, while those coinfected with HCoV and other viruses were clinically similar to those infected with other viruses alone.
In this study of children hospitalized for acute respiratory illness and/or fever, HCoV infection was not associated with hospitalization or with increased severity of illness.
PMCID: PMC3288315  PMID: 22094637
coronavirus; hospitalizations; asymptomatic controls; children
8.  Immunogenicity of Trivalent Influenza Vaccine in Extremely-Low-Birth-Weight, Premature versus Term Infants 
Influenza vaccine immunogenicity in premature infants is incompletely characterized.
To assess the immunogenicity of trivalent, inactivated influenza vaccine (TIV) in extremely low-birth-weight (ELBW, ≤1000 grams birth weight), premature (<30 weeks gestation) infants. We hypothesized that geometric mean titers (GMT) of influenza antibody would be lower in premature than in full-term (≥37 week) infants.
In this prospective, multicenter study, former premature and full-term infants ages, 6–17 months, received 2 doses of TIV during the 2006–7 or 2007–8 influenza seasons. Sera were drawn before dose 1 and 4–6 weeks after dose 2. Antibody was measured by hemagglutination inhibition.
Over two years, 41 premature and 42 full-term infants were enrolled; 36 and 33 of these infants, respectively, had post-vaccination titers available. Premature infants weighed less (mean 1.3 – 1.8 kg difference) at the time of immunization than full-term infants. Pre-vaccination titers did not differ between groups. Premature infants had higher post-vaccination antibody GMT than full-term infants to H1 (2006–7, 1:513 v. 1:91, P=0.03; 2007–8, 1:363 v. 1:189, P=0.02) and B/Victoria (2006–7, 1:51 v. 1:10, P=0.02). More premature than full-term infants had antibody titers ≥ 1:32 to B/Victoria (85% v. 60%, p=0.04) in 2007–8. Two (5%) premature and 8 (19%) full-term infants had adverse events, primarily fever, within 72 hours after vaccination. No child had medically-diagnosed influenza.
Former premature infants had antibody responses to two TIV doses greater than or equal to those of full-term children. Two TIV doses are immunogenic and well tolerated in ELBW, premature infants 6–17 months old.
PMCID: PMC3090695  PMID: 21273938
Premature infant; very low birth weight infant; influenza vaccines; immunization; vaccines
9.  Population-Based Incidence of Human Metapneumovirus in Hospitalized Children 
The Journal of infectious diseases  2010;201(12):1890-1898.
Human metapneumovirus (HMPV) is a leading cause of acute respiratory illness (ARI) in children. Population-based incidence rates and comprehensive clinical characterizations of disease have not been established.
We conducted population-based prospective surveillance for HMPV in two U.S. counties among children <5 years hospitalized with ARI or fever for two years. Nasal/throat swabs were tested for HMPV by real-time RT-PCR and genotyped.
Forty-two of 1104 (3.8%) children tested positive for HMPV. The overall annual rate of HMPV-associated hospitalizations per 1000 children <5 years was 1.2 (95%CI 0.9–1.6). This rate was highest in infants 0–5 months (4.9/1000 [95%CI 2.9–7.2]), followed by children 6–11 months (2.9/1000 [95%CI 1.4–4.7]). The annual rate of HMPV-associated hospitalizations was less than respiratory syncytial virus, but similar to influenza and parainfluenzavirus (PIV) 3 in all age groups. The mean age of children hospitalized with HMPV was 6 months. Bronchiolitis, pneumonia and asthma were the most common diagnoses in children with HMPV. All four HMPV subgroups were detected during both years at both sites. HPMV was most prominent from March through May.
HMPV was detected in 3.8% of children hospitalized with ARI or fever, with a population incidence similar to that of influenza and PIV3.
PMCID: PMC2873123  PMID: 20446850
human metapneumovirus; children; bronchiolitis; hospitalized
10.  Coronavirus Infection and Hospitalizations for Acute Respiratory Illness in Young Children 
Journal of medical virology  2009;81(5):853-856.
There is only limited knowledge on the burden of disease due to both new (HCoV-NL63 and HKU-1) and previously discovered coronaviruses (OC43 and 229E) in children.
Method of Study
Respiratory specimens and clinical data were prospectively collected in an active, population-based surveillance study over a two-year period from children aged <5 years hospitalized with acute respiratory symptoms or fever. These samples were retrospectively tested by real-time RT-PCR for HCoV-NL63, HKU1, OC43 and 229E.
Human coronaviruses (HCoVs) were identified in 2.2% of study children <2 years of age. Rates of HCoV-associated hospitalization per 10,000 were 10.2 (95% CI 4.3, 17.6), 4.2 (95% CI 1.9, 6.9), and 0 (95% CI 0, 3.7) in children aged <6 months, 6-23 months, and 24-59 months, respectively.
Coronaviruses were identified in a modest number of hospitalized children.
PMCID: PMC2767383  PMID: 19319948
acute respiratory infection; OC43; 229E; HCoV-NL63; HCoV-HKU
11.  Real-Time Reverse Transcription-PCR Assay for Comprehensive Detection of Human Rhinoviruses▿  
Journal of Clinical Microbiology  2007;46(2):533-539.
Human rhinoviruses (HRVs) are important contributors to respiratory disease, but their healthcare burden remains unclear, primarily because of the lack of sensitive, accurate, and convenient means of determining their causal role. To address this, we developed and clinically validated the sensitivity and specificity of a real-time reverse transcription-PCR (RT-PCR) assay targeting the viral 5′ noncoding region defined by sequences obtained from all 100 currently recognized HRV prototype strains and 85 recently circulating field isolates. The assay successfully amplified all HRVs tested and could reproducibly detect 50 HRV RNA transcript copies, with a dynamic range of over 7 logs. In contrast, a quantified RNA transcript of human enterovirus 68 (HEV68) that showed the greatest sequence homology to the HRV primers and probe set was not detected below a concentration of 5 × 105 copies per reaction. Nucleic acid extracts of 111 coded respiratory specimens that were culture positive for HRV or HEV were tested with the HRV real-time RT-PCR assay and by two independent laboratories that used different in-house HRV/HEV RT-PCR assays. Eighty-seven HRV-culture-positive specimens were correctly identified by the real-time RT-PCR assay, and 4 of the 24 HEV-positive samples were positive for HRV. HRV-specific sequences subsequently were identified in these four specimens, suggesting HRV/HEV coinfection in these patients. The assay was successfully applied in an investigation of a coincidental outbreak of HRV respiratory illness among laboratory staff.
PMCID: PMC2238069  PMID: 18057136
12.  Human Metapneumovirus Infection among Children Hospitalized with Acute Respiratory Illness 
Emerging Infectious Diseases  2004;10(4):700-705.
Recent studies have associated human Metapneumovirus (HMPV) infection in children with respiratory disease of similar severity as respiratory syncytial virus (RSV) infection. We studied 668 banked swab specimens (one per admission) collected from a population-based, prospective study of acute respiratory illness among inpatient children from two U.S. cities. Specimens were tested for HMPV, RSV, influenza, and parainfluenza viruses by reverse transcription–polymerase chain reaction assays. Twenty-six (3.9%) were positive for HMPV; 125 (18.7%) for RSV; 45 (6.7%) for parainfluenza 1, 2, or 3; and 23 (3.4%) for influenza. HMPV-positive children were significantly older than RSV-positive children. HMPV-positive children required medical intensive care and received supplemental oxygen in similar frequencies to RSV-positive children. Among children hospitalized with respiratory illness, the incidence of HMPV infection was less than RSV, but clinical disease severity mirrored that of RSV infection. Further investigations to better characterize HMPV infection and its clinical effect are needed.
PMCID: PMC3323105  PMID: 15200863
Respiratory tract infections; metapneumovirus; Respiratory Syncytial Virus; prospective studies
13.  Chromosomally integrated human herpesvirus 6: questions and answers 
Reviews in Medical Virology  2011;22(3):144-155.
Chromosomally integrated human herpesvirus 6 (ciHHV-6) is a condition in which the complete HHV-6 genome is integrated into the host germ line genome and is vertically transmitted in a Mendelian manner. The condition is found in less than 1% of controls in the USA and UK, but has been found at a somewhat higher prevalence in transplant recipients and other patient populations in several small studies. HHV-6 levels in whole blood that exceed 5.5 log10 copies/ml are strongly suggestive of ciHHV-6. Monitoring DNA load in plasma and serum is unreliable, both for identifying and for monitoring subjects with ciHHV-6 due to cell lysis and release of cellular DNA. High HHV-6 DNA loads associated with ciHHV-6 can lead to erroneous diagnosis of active infection. Transplant recipients with ciHHV-6 may be at increased risk for bacterial infection and graft rejection. ciHHV-6 can be induced to a state of active viral replication in vitro. It is not known whether ciHHV-6 individuals are put at clinical risk by the use of drugs that have been associated with HHV-6 reactivation in vivo or in vitro. Nonetheless, we urge careful observation when use of such drugs is indicated in individuals known to have ciHHV-6. Little is known about whether individuals with ciHHV-6 develop immune tolerance for viral proteins. Further research is needed to determine the role of ciHHV-6 in disease. Copyright © 2011 John Wiley & Sons, Ltd.
PMCID: PMC3498727  PMID: 22052666

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