Sequence analysis of transplacentally acquired human herpesvirus 6 DNA is consistent with transmission of a chromosomally integrated reactivated virus.

The majority of human herpesvirus 6 (HHV-6) congenital infections (86%) originate from germ line transmission of chromosomally integrated HHV-6 (ciHHV-6). To determine whether transplacentally acquired HHV-6 could derive from the transmission of reactivated maternal ciHHV-6, we identified mother-infant pairs in which infants had proven transplacentally acquired HHV-6 and mothers had documented ciHHV-6, and we sequenced and compared the HHV-6 gB gene sequences for each pair. Our data indicate that the gB gene sequence found in each cord blood specimen was identical to that of the corresponding mother but divergent from that of other known HHV-6 isolates. These results are consistent with transplacentally acquired HHV-6 originating from the transmission of reactivated ciHHV-6.

The burden of respiratory syncytial virus infection in young children.

BACKGROUND: The primary role of respiratory syncytial virus (RSV) in causing infant hospitalizations is well recognized, but the total burden of RSV infection among young children remains poorly defined. METHODS: We conducted prospective, population-based surveillance of acute respiratory infections among children under 5 years of age in three U.S. counties. We enrolled hospitalized children from 2000 through 2004 and children presenting as outpatients in emergency departments and pediatric offices from 2002 through 2004. RSV was detected by culture and reverse-transcriptase polymerase chain reaction. Clinical information was obtained from parents and medical records. We calculated population-based rates of hospitalization associated with RSV infection and estimated the rates of RSV-associated outpatient visits. RESULTS: Among 5067 children enrolled in the study, 919 (18%) had RSV infections. Overall, RSV was associated with 20% of hospitalizations, 18% of emergency department visits, and 15% of office visits for acute respiratory infections from November through April. Average annual hospitalization rates were 17 per 1000 children under 6 months of age and 3 per 1000 children under 5 years of age. Most of the children had no coexisting illnesses. Only prematurity and a young age were independent risk factors for hospitalization. Estimated rates of RSV-associated office visits among children under 5 years of age were three times those in emergency departments. Outpatients had moderately severe RSV-associated illness, but few of the illnesses (3%) were diagnosed as being caused by RSV. CONCLUSIONS: RSV infection is associated with substantial morbidity in U.S. children in both inpatient and outpatient settings. Most children with RSV infection were previously healthy, suggesting that control strategies targeting only high-risk children will have a limited effect on the total disease burden of RSV infection.

Residential crowding and severe respiratory syncytial virus disease among infants and young children: a systematic literature review.

BACKGROUND: The objective of this literature review was to determine whether crowding in the home is associated with an increased risk of severe respiratory syncytial virus (RSV) disease in children younger than 5 years. METHODS: A computerized literature search of PubMed and EMBASE was conducted on residential crowding as a risk factor for laboratory-confirmed RSV illness in children younger than 5 years. Study populations were stratified by high-risk populations, defined by prematurity, chronic lung disease of prematurity, hemodynamically significant congenital heart disease, or specific at-risk ethnicity (i.e. Alaska Native, Inuit), and mixed-risk populations, including general populations of mostly healthy children. The search was conducted for articles published from January 1, 1985, to October 8, 2009, and was limited to studies reported in English. To avoid indexing bias in the computerized databases, the search included terms for multivariate analysis and risk factors to identify studies in which residential crowding was evaluated but was not significant. Methodological quality of included studies was assessed using a Cochrane risk of bias tool. RESULTS: The search identified 20 relevant studies that were conducted in geographically diverse locations. Among studies of patients in high-risk populations, 7 of 9 found a statistically significant association with a crowding variable; in studies in mixed-risk populations, 9 of 11 found a significant association with a crowding variable. In studies of high-risk children, residential crowding significantly increased the odds of laboratory-confirmed RSV hospitalization (i.e. odds ratio ranged from 1.45 to 2.85). In studies of mixed-risk populations, the adjusted odds ratios ranged from 1.23 to 9.1. The findings on the effect of residential crowding on outpatient RSV lower respiratory tract infection were inconsistent. CONCLUSIONS: Residential crowding was associated with an increased risk of laboratory-confirmed RSV hospitalization among high-risk infants and young children. This association was consistent despite differences in definitions of residential crowding, populations, or geographic locations.

Transplacental congenital human herpesvirus 6 infection caused by maternal chromosomally integrated virus.

Congenital human herpesvirus 6 (HHV-6) infection results from germline passage of chromosomally integrated HHV-6 (CI-HHV-6) and from transplacental passage of maternal HHV-6 infection. We aimed to determine whether CI-HHV-6 could replicate and cause transplacentally acquired HHV-6 infection. HHV-6 DNA, variant type, and viral loads were determined with samples (cord blood, peripheral blood, saliva, urine, and hair) obtained from 6 infants with transplacentally acquired HHV-6 and with samples of their parents' hair. No fathers but all mothers of infants with transplacentally acquired HHV-6 had CI-HHV-6, and the mother's CI-HHV-6 variant was the same variant causing the transplacentally acquired congenital HHV-6 infection. This suggests the possibility that CI-HHV-6 replicates and may cause most, if not all, congenital HHV-6 infections.

Diagnostic assays for respiratory syncytial virus disease.

Respiratory syncytial virus (RSV) infection in the United States and worldwide is a major cause of morbidity and mortality and of outpatient visits, hospitalizations, and increased healthcare costs. Effective diagnosis of viral respiratory infections, as well as recognition and understanding of the benefits and limitations of diagnostic laboratory testing, is essential. Serology is not useful for diagnosing acute respiratory illness. Antigen-based assays are widely available, easy to use, provide rapid results, and are inexpensive; however, they are less sensitive than cell culture utilizing good specimen collection and processing techniques. Cell culture, which was previously considered the gold standard for identification of respiratory viruses, in many settings is being replaced by nucleic acid amplification assays that have even greater sensitivity and provide more rapid results. Although available chiefly at large hospitals and reference laboratories, molecular assays may fulfill the need for more sensitive and rapid diagnosis of illnesses caused by respiratory viruses. The seasonality of RSV as measured by nucleic acid amplification-based assays appears to be broader with better identification of patient populations that harbor RSV between yearly epidemic peaks compared with the seasonality of RSV as measured by the older techniques. As these new diagnostic methodologies emerge, guidelines will be needed to direct their appropriate use in the diagnostic laboratory.

Respiratory syncytial virus in healthy adults: the cost of a cold.

Respiratory syncytial virus (RSV) is well recognized as a major pathogen of lower respiratory tract infection and hospitalization in young infants. More recently the pathogenicity of RSV has been demonstrated in elderly adults, institutionalized individuals, and those with compromised immune function. In these populations RSV spreads with ease and frequently results in severe or fatal cardiopulmonary complications. In younger, healthy adults, however, the manifestations and importance of RSV infection have been studied little, and RSV is generally not considered as a cause of respiratory illness in this healthy, working population. RSV occurs in yearly outbreaks and is highly contagious. Immunity after infection is neither complete nor durable. Repeated infections, therefore, occur throughout life. In most cases these recurrent infections involve the upper respiratory tract and thus do not receive a specific diagnosis. However, recent studies indicate that in the younger, healthy adult these respiratory illnesses tend to be more severe than the average 'cold' and may have manifestations similar to influenza. An appreciable proportion results in work absence. Thus, the emerging information suggests that RSV infection clearly occurs frequently in healthy adults in contact with children, but is generally not diagnosed. The potential burden on the healthcare system is unestimated, possibly unappreciated, and should be considered in strategies being developed for preventing RSV infection.

Respiratory syncytial virus-associated hospitalizations among children less than 24 months of age.

BACKGROUND: Respiratory syncytial virus (RSV) infection is a leading cause of hospitalization among infants. However, estimates of the RSV hospitalization burden have varied, and precision has been limited by the use of age strata grouped in blocks of 6 to ≥ 12 months. METHODS: We analyzed data from a 5-year, prospective, population-based surveillance for young children who were hospitalized with laboratory-confirmed (reverse-transcriptase polymerase chain reaction) RSV acute respiratory illness (ARI) during October through March 2000-2005. The total population at risk was stratified by month of age by birth certificate information to yield hospitalization rates. RESULTS: There were 559 (26%) RSV-infected children among the 2149 enrolled children hospitalized with ARI (85% of all eligible children with ARI). The average RSV hospitalization rate was 5.2 per 1000 children <24 months old. The highest age-specific rate was in infants 1 month old (25.9 per 1000 children). Infants ≤ 2 months of age, who comprised 44% of RSV-hospitalized children, had a hospitalization rate of 17.9 per 1000 children. Most children (79%) were previously healthy. Very preterm infants (<30 weeks' gestation) accounted for only 3% of RSV cases but had RSV hospitalization rates 3 times that of term infants. CONCLUSIONS: Young infants, especially those who were 1 month old, were at greatest risk of RSV hospitalization. Four-fifths of RSV-hospitalized infants were previously healthy. To substantially reduce the burden of RSV hospitalizations, effective general preventive strategies will be required for all young infants, not just those with risk factors.

The burgeoning burden of respiratory syncytial virus among children.

Respiratory syncytial virus (RSV) was first isolated from infants by Chanock and colleagues in 1957. However, control of this ubiquitous agent has yet to be achieved. RSV is recognized as the primary cause of hospitalization for acute lower respiratory tract illness (LRTI) among infants worldwide. Among children < 5 years old, annual hospitalization rates in the United States (US) is 3/1000 children, and rates in Canada and European countries are similar. In the US the hospitalization rate is 3 times higher than that from influenza or parainfluenza viral infections. Much less appreciated is the clinical and economic burden from RSV outpatients, as few have specific diagnostic testing. Nevertheless, RSV in the US is estimated to cause 1 of 334 hospitalizations, 1 of 38 emergency department visits, but 1 of 13 private practice visits. These outpatient children tend to have moderate to severe illness with approximately three-fourths manifesting labored respirations. RSV burden among outpatients, therefore, is considerable both in size and severity. The global burden of RSV infection is unknown as few studies are from developing countries. Estimates indicate about one-fourth of all acute LRTI occur among children < 5 years, and the greatest burden is among children in developing countries. Currently the only approved means of RSV prophylaxis is passive immunization with humanized F protein monoclonal antibody. Such prophylaxis, however, has limited availability, is expensive, and is recommended only for infants most at risk for severe RSV disease. Only widespread immunization of children is likely to diminish the current burden of RSV infection.

Effectiveness of non-adjuvanted pandemic influenza A vaccines for preventing pandemic influenza acute respiratory illness visits in 4 U.S. communities.

We estimated the effectiveness of four monovalent pandemic influenza A (H1N1) vaccines (three unadjuvanted inactivated, one live attenuated) available in the U.S. during the pandemic. Patients with acute respiratory illness presenting to inpatient and outpatient facilities affiliated with four collaborating institutions were prospectively recruited, consented, and tested for influenza. Analyses were restricted to October 2009 through April 2010, when pandemic vaccine was available. Patients testing positive for pandemic influenza by real-time RT-PCR were cases; those testing negative were controls. Vaccine effectiveness was estimated in logistic regression models adjusted for study community, patient age, timing of illness, insurance status, enrollment site, and presence of high-risk medical conditions. Pandemic virus was detected in 1,011 (15%) of 6,757 enrolled patients. Fifteen (1%) of 1,011 influenza positive cases and 1,042 (18%) of 5,746 test-negative controls had record-verified pandemic vaccination >14 days prior to illness onset. Adjusted effectiveness (95% confidence interval) for pandemic vaccines combined was 56% (23%, 75%). Adjusted effectiveness for inactivated vaccines alone (79% of total) was 62% (25%, 81%) overall and 32% (-92%, 76%), 89% (15%, 99%), and -6% (-231%, 66%) in those aged 0.5 to 9, 10 to 49, and 50+ years, respectively. Effectiveness for the live attenuated vaccine in those aged 2 to 49 years was only demonstrated if vaccination >7 rather than >14 days prior to illness onset was considered (61%∶ 12%, 82%). Inactivated non-adjuvanted pandemic vaccines offered significant protection against confirmed pandemic influenza-associated medical care visits in young adults.

Bronchiolitis: recent evidence on diagnosis and management.

Viral bronchiolitis is a leading cause of acute illness and hospitalization of young children. Research into the variation in treatment and outcomes for bronchiolitis across different settings has led to evidence-based clinical practice guidelines. Ongoing investigation continues to expand this body of evidence. Authors of recent surveillance studies have defined the presence of coinfections with multiple viruses in some cases of bronchiolitis. Underlying comorbidities and young age remain the most important predictors for severe bronchiolitis. Pulse oximetry plays an important role in driving use of health care resources. Evidence-based reviews have suggested a limited role for diagnostic laboratory or radiographic tests in typical cases of bronchiolitis. Several large, recent trials have revealed a lack of efficacy for routine use of either bronchodilators or corticosteroids for treatment of bronchiolitis. Preliminary evidence suggests a potential future role for a combination of these therapies and other novel treatments such as nebulized hypertonic saline.

Diagnostic assays for active infection with human herpesvirus 6 (HHV-6).

BACKGROUND: Human herpesvirus 6 (HHV-6) causes ubiquitous infection in early childhood with lifelong latency or persistence. Reactivation of HHV-6 has been associated with multiple diseases including encephalitis. Chromosomal integration of HHV-6 also occurs. Previous studies have suggested that the detection of HHV-6 DNA in plasma is an accurate marker of active viral replication. OBJECTIVE: We sought to determine whether PCR assays on plasma could correctly differentiate between primary HHV-6 infection, chromosomal integration of HHV-6 and latent HHV-6 infection. STUDY DESIGN: We performed qualitative PCR, real-time quantitative PCR (RQ-PCR), and reverse-transcriptase PCR (RT-PCR) assays on samples of peripheral and cord blood mononuclear cells, as well as plasma, from groups of subjects with well defined HHV-6 infection, including subjects with chromosomally integrated HHV-6. RESULTS AND CONCLUSIONS: The detection of HHV-6 DNA in plasma was 92% sensitive compared to viral isolation for the identification of primary infection with HHV-6. All plasma samples from infants with chromosomally integrated HHV-6 had HHV-6 DNA detectable in plasma while only 5.6% were positive by RT-PCR. The specificity of plasma PCR for active replication of HHV-6 was 84% compared to viral culture while the specificity of RT-PCR was 98%. Our results demonstrate that qualitative or quantitative PCR of plasma is insufficient to distinguish between active viral replication and chromosomal integration with HHV-6. We found a higher specificity of RT-PCR performed on PBMC samples compared to PCR or RQ-PCR performed on plasma when evaluating samples for active HHV-6 replication.