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RNA interference (RNAi) is a natural mechanism regulating protein expression that is mediated by small interfering RNAs (siRNA). Harnessing RNAi has potential to treat human disease; however, clinical evidence for the effectiveness of this therapeutic approach is lacking. ALN-RSV01 is an siRNA directed against the mRNA of the respiratory syncytial virus (RSV) nucleocapsid (N) protein and has substantial antiviral activity in a murine model of RSV infection. We tested the antiviral activity of ALN-RSV01 in adults experimentally infected with wild-type RSV. Eighty-eight healthy subjects were enrolled into a randomized, double-blind, placebo-controlled trial. A nasal spray of ALN-RSV01 or saline placebo was administered daily for 2 days before and for 3 days after RSV inoculation. RSV was measured serially in nasal washes using several different viral assays. Intranasal ALN-RSV01 was well tolerated, exhibiting a safety profile similar to saline placebo. The proportion of culture-defined RSV infections was 71.4 and 44.2% in placebo and ALN-RSV01 recipients, respectively (P = 0.009), representing a 38% decrease in the number of infected and a 95% increase in the number of uninfected subjects. The acquisition of infection over time was significantly lower in ALN-RSV01 recipients (P = 0.007 and P = 0.03, viral culture and PCR, respectively). Multiple logistic regression analysis showed that the ALN-RSV01 antiviral effect was independent of other factors, including preexisting RSV antibody and intranasal proinflammatory cytokine concentrations. ALN-RSV01 has significant antiviral activity against human RSV infection, thus establishing a unique proof-of-concept for an RNAi therapeutic in humans and providing the basis for further evaluation in naturally infected children and adults. antiviral | RNA interference | small interfering RNA | RSV doi/10.1073/pnas.0912186107

Respiratory syncytial virus (RSV) is the most common cause of hospitalization for respiratory tract infection in young children. It is also a significant cause of morbidity and mortality in elderly individuals and in persons with asthma and chronic obstructive pulmonary disease. Currently, no reliable vaccine or simple RSV antiviral therapy is available. Recently, we determined that the minor pulmonary surfactant phospholipid, palmitoyl-oleoyl-phosphatidyl-glycerol (POPG), Could markedly attenuate inflammatory responses induced by lipopolysaccharide through direct interactions with the Toll-like receptor 4 (TLR4) interacting proteins CD14 and MD-2. CD14 and TLR4 have been implicated in the host response to RSV. Treatment of bronchial epithelial cells with POPG significantly inhibited interleukin-6 and -8 production, as well as the cytopathic effects induced by RSV. The phospholipid bound RSV with high affinity and inhibited viral attachment to HEp2 cells. POPG blocked viral plaque formation in vitro by 4 log units, and markedly suppressed the expansion of plaques from cells preinfected with the virus. Administration of POPG to mice, concomitant with viral infection, almost completely eliminated the recovery of virus from the lungs at 3 and 5 days after infection, and abrogated IFN-[gamma] (IFN-[gamma]) production and the enhanced expression of surfactant protein D (SP-D). These findings demonstrate an important approach to prevention and treatment of RSV infections using exogenous administration of a specific surfactant phospholipid. antiviral | innate immunity | respiratory epithelium www.pnas.org/cgi/doi/10.1073/pnas.0909361107

OBJECTIVE. Respiratory syncytial virus (RSV) infection is the foremost cause of serious lower respiratory tract infection in young children and infants. Because higher rates of hospitalization for bronchiolitis and pneumonia have been noted in high-altitude regions, we hypothesized that physiologic responses to altitude would predispose children to more severe illness from RSV infection. This study examined the effect of residential altitude on hospitalizations for RSV infection in Colorado from 1998 through 2002. METHODS. A geographic information system was used to assemble data for altitude and demographic variables by zip code-tabulation areas. Data then were linked with hospital discharge data for RSV infections. Poisson regression models were developed to explore correlations between hospitalization rates and residential altitude, after adjustment for socioeconomic differences in the underlying population. RESULTS. RSV-associated hospitalizations averaged 15.9 per 1000 infants who were younger than 1 year and 1.8 per 1000 children who were 1 to 4 years of age per season. A multivariate analysis suggested that the rate of hospitalization for RSV-specific International Classification of Diseases, Ninth Revision, Clinical Modification codes increased 25% among infants who were younger than 1 year and 53% among children who were 1 to 4 years of age for every 1000-m increase in altitude. The risk for RSV-associated hospitalization was highest at elevations above 2500 m. CONCLUSIONS. High altitude above 2500 m is a modest predictor for RSV-associated hospitalization. Practitioners in these regions should consider additional efforts to educate parents about RSV infection and its prevention and the importance of early treatment. Key Words environmental factors, epidemiology, hospitalization rates, respiratory syncytial virus, risk factors Abbreviations RSV--respiratory syncytial virus CHA--Colorado Health and Hospital Association ICD-9-CM--Intemotional Classification of Diseases, Ninth Revision, Clinical Modification ZCTA--zip code-tabulation area GIS--geographic information systems RR--rate ratio, RESPIRATORY SYNCYTIAL VIRUS (RSV) infection is the foremost cause of bronchiolitis and pneumonia in infants and young children, causing > 100 000 hospitalizations annually in the United States. (1) A [...]

Objective To assess the burden of respiratory syncytial virus (RSV)-associated lower respiratory infections (LRI) in children in four developing countries. Methods A WHO protocol for prospective population-based surveillance of acute respiratory infections in children aged less than 5 years was used at sites in Indonesia, Mozambique, Nigeria and South Africa. RSV antigen was identified by enzyme-linked immunosorbent assay performed on nasopharyngeal specimens from children meeting clinical case definitions. Findings Among children aged < 5 years, the incidence of RSV-associated LRI per 1000 child-years was 34 in Indonesia and 94 in Nigeria. The incidence of RSV-associated severe LRI per 1000 child-years was 5 in Mozambique, 10 in Indonesia, and 9 in South Africa. At all study sites, the majority of RSV cases occurred in infants. Conclusion These studies demonstrate that RSV contributes to a substantial but quite variable burden of LRI in children aged < 5 years in four developing countries. The possible explanations for this variation include social factors, such as family size and patterns of seeking health care; the proportion of children infected by human immunodeficiency syndrome (HIV); and differences in clinical definitions used for obtaining samples. The age distribution of cases indicates the need for an RSV vaccine that can protect children early in life. Keywords Respiratory syncytial virus infections/epidemiology/immunology; Respiratory tract infections/virology/diagnosis Child, Preschool; Infant; Severity of ness index; Indonesia; Mozambique; Nigeria; South Africa (source. MeSH, NLM). Mots cles Virus respiratoire syncytial, Infection/epidemiologie/immunologie; Voles aeriennes superieures, Infection/virologie/diagnostic; Enfant age pre-scolaire; Nourrisson; Indice de gravite; Indonesie; Mozambique; Nigeria; Afrique du Sud. (source: MeSH, INSERM). Palabras clave Infecciones por virus sincitial del tracto respiratorio/virologia/diagnostico; Preescolar; Lactante; Indice de severidad de la enfermedad; Indonesia; Mozambique; Nigeria; Sudafrica (fuente: DeCS, BIREME). [TEXT NOT REPRODUCIBLE IN ASCII.], Resume Infection a virus respiratoire syncytial (VRS): etudes de morbidite en population en Indonesie, au Mozambique, au Nigeria et en Afrique du Sud Objectif Evaluer la charge de morbidite due [...]

Aim: To examine over time, the cellular response within the lungs of infants ventilated with respiratory syncytial virus (RSV) bronchiolitis and to compare this response in infants born at term [...]

Objective. Respiratory tract infections are a leading cause of morbidity and mortality worldwide. Recently, a newly identified human respiratory virus, human metapneumovirus (hMPV), was reported by investigators in the Netherlands. We sought to determine whether hMPV was circulating in our community and to determine the clinical features associated with hMPV infection. Methods. Respiratory specimens from children who were younger than 5 years and had a negative result for respiratory syncytial virus, influenza A and B, parainfluenza viruses 1 to 3, and adenovirus by direct fluorescent antibody test were screened for hMPV by reverse transcriptase-polymerase chain reaction. Samples were collected from October 30, 2001, to February 28, 2002. Results. Of the 296 patients screened, 19 (6.4%) had evidence of hMPV infection, hMPV was identified in patients with either upper or lower respiratory tract infection or both. Clinical manifestations included wheezing, hypoxia, and abnormal findings on chest radiographs (eg, focal infiltrates, peribronchial cuffing). Nosocomial infection occurred in at least 1 patient. Conclusions. hMPV is circulating in the United States and is associated with respiratory tract disease in patients with respiratory illnesses not caused by respiratory syncytial virus, influenza, parainfluenza viruses, and adenovirus. Additional studies are required to define the epidemiology and the extent of disease in the general population caused by hMPV. Pediatrics 2003;111:1407-1410; human metapneumovirus, clinical features., ABBREVIATIONS. RSV, respiratory syncytial virus; hMPV, human metapneumovirus; DFA, direct fluorescent antibody; RT-PCR, reverse transcriptase-polymerase chain reaction. Respiratory tract infections are a major cause of morbidity and mortality. The World [...]

Byline: B. Resch (1), W. Gusenleitner (1), W. Muller (1) Keywords: Key Words Respiratory syncytial virus; Epidemiology; Palivizumab; Preterm infant; Hospitalization Abstract: Background: We analyzed the influence of respiratory syncytial virus (RSV) on the clinical course and management of infants hospitalized due to viral upper and lower respiratory tract infections (U/LRTI). Patients and Methods: Infants younger than 2 years were prospectively tested for RSV infection by antigen detection in nasopharyngeal aspirates between November 1999 and October 2000. Results: Of 281 infants hospitalized during the study period, 58 (21%) tested RSV positive. Seasonal distribution of RSV infections showed a peak in March (45% of all U/LRTI). Infants with RSV infection (12% were preterm, 5% had congenital heart disease) were younger (p &lt 0.001), had more severe U/LRTI (p &lt 0.001), longer hospitalizations (p &lt 0.001), more days with oxygen requirement (p &lt 0.001) and respiratory support (p = 0016) and more frequent requirements for bronchoditators (p = 0.002) and corticosteroids (p = 0.02). Conclusion: RSV contributed to prolonged hospitalizations and more severe clinical courses of disease both in very young term and preterm infants. Author Affiliation: (1) Division of Neonatology, Dept. of Pediatrics, University Hospital Graz, Auenbruggerplatz 30, A-8036 Graz, Austria Phone: (+43/31) 6385-2605, Fax: -2678, e-mail: bernhard.resch@kfunigraz.ac.at, AT Article note: Received: September 6, 2001 * Revision accepted: April 23, 2002

Objective. To assess the therapeutic effects of breathing a low-density gas mixture (heliox: 70% helium and 30% oxygen) in infants with bronchiolitis. Design. Prospective, interventional, comparative study. Setting. A pediatric intensive care unit (PICU) in a tertiary care, teaching hospital. Patients. Thirty-eight infants, 1 month to 2 years old, consecutively admitted to the PICU for treatment of moderate-to-severe acute respiratory syncytial virus bronchiolitis. Interventions. The first 19 patients were enrolled as the control group and received supportive care and nebulized epinephrine. In the next 19 patients, heliox therapy was added through a nonrebreather reservoir face mask. Measurements and Outcomes. Respiratory distress score, respiratory rate, heart rate, end-tidal C[O.sub.2] (etC[O.sub.2]), and pulse oximetry oxygen saturation (sat[O.sub.2]) values were recorded at baseline and at regular intervals. Data obtained during the first 4 hours were analyzed for comparison purposes. Demographic data, age, time elapsed from the start of the symptoms to the admission to PICU, length of stay in PICU (PICU-LOS), and duration of heliox therapy were also collected for each patient. Reductions in clinical scores and PICU-LOS were considered primary outcomes. Main Results. At baseline, the heliox and control groups had similar age (5.5 [+ or -] 3.1 vs 5.9 [+ or -] 3 months), previous length of course (47.3 [+ or -] 19.3 vs 45.4 [+ or -] 18.6 hours), clinical score (6.7 [+ or -] 1.1 vs 6.6 [+ or -] 1), heart rate (160 [+ or -] 24 vs 165 [+ or -] 20 beats per minute), respiratory rate (64 [+ or -] 7 vs 61 [+ or -] 7 respirations per minute), sat[O.sub.2] (91 [+ or -] 2.3 vs 91 [+ or -] 2.5%), and etC[O.sub.2] (34 [+ or -] 7 vs 33 [+ or -] 6 mm Hg). Clinical score, heart rate, respiratory rate, and sat[O.sub.2] improved during the study in both groups. After 1 hour, the improvement in clinical score was significantly higher in the heliox group than in the control group (3.6 [+ or -] 1.16 vs 5.5 [+ or -] 0.89), and these differences continued to be significant at the end of the observation period (2.39 [+ or -] 0.69 and 4.07 [+ or -] 0.96, respectively), with a total average decrease in the score of 4.2 points in the heliox group versus 2.5 points in the control group. Heart and respiratory rates were also significantly lower in the heliox group compared with the control group after 1 hour and stayed lower throughout the rest of the study period. No changes were noted either in sat[O.sub.2] between groups or in etC[O.sub.2] within or between groups throughout the study. Mean duration of heliox administration was 53 [+ or -] 24 hours (range: 24-112 hours) and no adverse effects were detected. PICU-LOS was significantly shorter in the heliox group (3.5 [+ or -] 1.1 days) than in the control group (5.4 [+ or -] 1.6 days). Conclusions. In infants with moderate-to-severe respiratory syncytial virus bronchiolitis, heliox therapy enhanced their clinical respiratory status, according to the marked improvement in their clinical scores and the reduction of the accompanying tachycardia and tachypnea. This beneficial response occurred within the first hour of its administration and was maintained as long as heliox therapy continued. In addition, PICU-LOS was reduced in heliox-treated patients. Long-term prospective studies are required to corroborate these findings and to establish the proper place of heliox in the therapeutic schedule of bronchiolitis. Pediatrics 2002;109:68-73; infant, helium-oxygen mixture, heliox, bronchiolitis, respiratory syncytial virus infections, airway obstruction, respiratory therapy, work of breathing, epinephrine, pediatrics. ABBREVIATIONS. RSV, respiratory syncytial virus, PICU, pediatric intensive care unit; M-WCAS, modified Wood&apos;s Clinical Asthma Score; 1pm, liters per minute; sat[O.sub.2], pulse oximetry oxygen saturation; etC[O.sub.2], end-tidal C[O.sub.2]; PICU-LOS, length of stay in pediatric intensive care unit., Since use of helium-oxygen mixtures (heliox) was proposed by Barach, (1,2) as a medical therapy for severe asthma and upper airway obstruction, several studies on its role in respiratory therapy [...]

Intravenous treatment with respiratory syncytial virus (RSV) immunoglobulin (RSVIG) may not reduce the severity of RSV disease in all children, but could decrease intensive care unit (ICU) and total hospital stays in the worst cases. One hundred and one children previously in good health were hospitalized with RSV lower respiratory infections (LRI). About half were given RSVIG, the others a placebo. Only the children scoring the worst on the entry respiratory scores showed a trend toward fewer hospital and ICU days with treatment. There were no adverse effects seen due to the therapy., Objective. To evaluate the efficacy of high titer respiratory syncytial virus (RSV) immune globulin (RSVIG) in the treatment of previously healthy children hospitalized with proven RSV lower tract infection (LRI). Method. Infants and young children [is less than or equal to] 2 years of age with RSV LRI of [is less than or equal to] 4 days duration, and respiratory scores [is greater than or equal to] 2.5 were enrolled. Results. One hundred and one previously healthy children hospitalized with RSV LRI received either 1500 mg/kg of RSVIG (RespiGam, MedImmune Inc, Gaithersburg, MD) or albumin placebo in a randomized, doubleblind, placebo-controlled trial. Forty-six RSVIG and 52 recipients of placebo met all eligibility criteria. Demographic characteristics of the two groups were similar. More RSVIG recipients (46% vs 29%) had an [SaO.sub.2] [is less than or equal to] 85% at entry than did placebo recipients, but a higher proportion of placebo recipients required intensive care unit (ICU) care and mechanical ventilation at study entry. The mean RSV hospital stay was 5.52 [+ or -] 0.69 days (SE) for placebo and 4.58 [+ or -] 0.40 days for RSVIG. Additionally, there was an interaction between treatment group and entry respiratory score, which led to subgroup analysis. Children with modest respiratory illness did not receive any benefit from RSVIG therapy. RSVIG recipients with more severe illness (entry respiratory scores 23.0) had 1.6 fewer hospital days and 2.7 days less ICU stays. Conclusion. RSVIG infusions seemed safe and generally well tolerated. Although some beneficial effect trends were seen for those with more severe disease who were treated there was no evidence that treatment with RSVIG resulted in reduced hospitalization and reduced ICU stays in all children with RSV disease. Pediatrics 1997;100:937-942; respiratory syncytial virus; bronchiolitis; lower respiratory tract infections; respiratory syncytial virus immune globulin; randomized, controlled trial., ABBREVIATIONS. RSV, respiratory syncytial virus; LRI, lower respiratory tract infection; RSVIG, respiratorY syncytial virus immune globulin; pfu, plaque-forming units; ICU, intensive care unit; PIV3, parainfluenza virus. Respiratory syncytial virus (RSV) [...]

Treatment of human cells with 2[prime],5[prime] oligoadenylate covalently linked to antisense (2-5A-antisense) results in the selective cleavage of targeted RNA species by 2-5A-dependent RNase L. Here we show that 2-5A-antisense containing stabilizing modifications at both termini are effective in suppressing the replication of respiratory syncytial virus (RSV) in human tracheal epithelial cells. The affinity of 2-5A-antisense for different regions in the RSV M2 and L mRNAs was predicted from a computer-generated model of the RNA secondary structure. The most potent 2-5A-antisense molecule caused a highly effective, dose-dependent suppression of RSV yields when added to previously infected cells. In contrast, control oligonucleotides, including an inactive dimeric form of 2-5A linked to antisense, 2-5A linked to a randomized sequence of nucleotides, and antisense molecules lacking 2-5A, had minimal effects on virus replication. The specificity of this approach was shown by reverse transcriptase-coupled PCR analysis of RSV M2, P, and N mRNA and of cellular glyceraldehyde-3-phosphate dehydrogenase mRNA. The RSV M2 mRNA amounts were depleted after treating RSV-infected cells with 2-5A-antisense targeted to this mRNA, whereas the amounts of the other RNA species were unchanged. These studies demonstrate that 2[prime],5[prime] oligoadenylate covalently linked to antisense (2-5A-antisense) can effectively suppress RSV replication by directing the cellular RNase L to selectively degrade an essential viral mRNA.

There do not seem to be any available and effective treatments for infections caused by the respiratory syncytial virus (RSV), particularly for high-risk infants. Researchers have evaluated the use of ribavirin, steroids, and most recently an RSV specific antibody treatment called RSV immune globulin (RSVIG). None of the studies have shown significant improvements with any of the therapies. Combination therapies have had some preliminary success but need further study. Potential complications with routine RSVIG preventive therapy include transmitting the infection to others, cost, and efforts required for lengthy monthly treatments., ABBREVIATIONS. RSV, respiratory syncytial virus; RSVIG, respiratory syncytial virus immune globulin; IVIG, intravenous immune globulin; BPD, bronchopulmonary dysplasia. The most savage controversies are those about matters as to which there [...]

Few treatments for respiratory syncytial virus (RSV) infections in infants have proved to be effective. Research is inconclusive whether prompt ribavirin treatment in infants with severe infections is effective. There have been a number of obstacles in developing an effective RSV vaccine. Bronchodilators and corticosteroids have not proved to be effective treatments. RSV immune globulin and monoclonal antibody treatments may prove to be effective.

A nutritional screen for patients in pediatric intensive care appears to accurately identify those who are at risk of poor outcomes. Researchers evaluated the nutritional status of 25 children with respiratory syncytial virus infection in intensive care by examining their medical condition, their growth, their laboratory results, and their dietary intake. The results of this screen were significantly associated with the patients' outcomes, as measured by the days the children spent in the hospital, on mechanical ventilation, given oxygen, or not given food enterally. Eleven of the children were considered low risk, and the other 14 were considered high risk. Each of the outcome indicators showed significant differences between the low risk and high risk groups. The nutritional screen may have general usefulness in determining which pediatric patients require special intervention., Objective. We sought to validate a nutritional screen that was easy to perform and accurate in identifying pediatric patients at risk for adverse clinical outcomes based on their nutritional status. Methods. Twenty-five consecutive patients admitted to our pediatric intensive care complex between July 1992 and July 1993 with a primary diagnosis of respiratory syncytial virus infection were evaluated. Nutritional screen parameters included historical (disease and condition), growth (anthropometrics), and laboratory (hemoglobin, lymphocyte count, and albumin) data. Outcome measures included days in the hospital, days of mechanical ventilation, days not fed enterally, and days receiving oxygen. Results. Regression analysis indicated that a score of 5 or less signified a low risk of adverse outcome and a score of greater than 5 signified a high risk. Eleven of 25 patients had low scores, and 14 of 25 had high scores. All outcome measures differed significantly between the low- and high-risk groups: median number of days in the hospital, 7 and 13.5, respectively, median number of days of ventilation, 0 and 8.5, respectively; median number of days without enteral feeding, 3 and 8.5, respectively; and median number of days receiving oxygen, 4 and 20, respectively. Conclusions. Our nutritional screen identifies patients in the pediatric intensive care complex with respiratory syncytial virus at increased risk for adverse outcome. This screen may be useful in identifying pediatric patients at risk for adverse clinical outcomes from other medical diagnoses. Pediatrics 1996;97:543-546; respiratory syncytial virus, nutritional screen, pediatrics, intensive care., Hospitalized patients with nutritional deficits are at risk for increased morbidity and mortality. Early identification of these patients would allow timely intervention, potentially decreasing the length of hospital stays, cost [...]

ABBREVIATIONS. RSV, respiratory syncytial virus; FDA, Food and Drug Administration. Progress in the field of passive immunoprophylaxis for protection of high-risk infants and children against respiratory syncytial virus (RSV) infection [...]

ABBREVIATION. RSV, respiratory syncytial virus. In a commentary in the November 1999 issue of Pediatrics, Dr Jessie Groothuis[1] characterized our estimate of the risk of rehospitalization for respiratory syncytial virus [...]