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Background: Acute respiratory illnesses are a leading cause of global morbidity and mortality in children. Coinfection with multiple respiratory viruses is common. Although the effects of each virus have been studied individually, the impacts of coinfection on disease severity are less understood. Methods: A secondary analysis was performed of a maternal influenza vaccine trial conducted between 2011 and 2014 in Nepal. Prospective weekly household‐based active surveillance of infants was conducted from birth to 180 days of age. Mid‐nasal swabs were collected and tested for respiratory syncytial virus (RSV), rhinovirus, influenza, human metapneumovirus (HMPV), coronavirus, parainfluenza (HPIV), and bocavirus by RT‐PCR. Coinfection was defined as the presence of two or more respiratory viruses detected as part of the same illness episode. Results: Of 1730 infants with a respiratory illness, 327 (19%) had at least two respiratory viruses detected in their primary illness episode. Of 113 infants with influenza, 23 (20%) had coinfection. Of 214 infants with RSV, 87 (41%) had coinfection. The cohort of infants with coinfection had increased occurrence of fever lasting ≥ 4 days (OR 1.4, 95% CI: 1.1, 2.0), and so did the subset of coinfected infants with influenza (OR 5.8, 95% CI: 1.8, 18.7). Coinfection was not associated with seeking further care (OR 1.1, 95% CI: 0.8, 1.5) or pneumonia (OR 1.2, 95% CI: 0.96, 1.6). Conclusion: A high proportion of infants had multiple viruses detected. Coinfection was associated with greater odds of fever lasting for four or more days, but not with increased illness severity by other measures. [ABSTRACT FROM AUTHOR]

Background Respiratory viruses cause significant morbidity and death in infants; 99% of such deaths occur in resource-limited settings. Risk factors for initial and repeated respiratory viral infections in young infants in resource-limited settings have not been well described. Methods From 2011 to 2014, a birth cohort of infants in rural Nepal was enrolled and followed with weekly household-based active surveillance for respiratory symptoms until 6 months of age. Respiratory illness was defined as having any of the following: fever, cough, wheeze, difficulty breathing, and/or a draining ear. We tested nasal swabs of infants with respiratory illness for multiple respiratory viruses by using a reverse transcription polymerase chain reaction assay. The risk of primary and repeated infections with the same virus was evaluated using Poisson regression. Results Of 3528 infants, 1726 (49%) had a primary infection, and 419 (12%) had a repeated infection. The incidences of respiratory viral infection in infants were 1816 per 1000 person-years for primary infections and 1204 per 1000 person-years for repeated infection with the same virus. Exposure to other children and male sex were each associated with an increased risk for primary infection (risk ratios, 1.13 [95% confidence interval (CI), 1.06–1.20] and 1.14 [95% CI, 1.02–1.27], respectively), whereas higher maternal education was associated with a decreased risk for both primary and repeated infections (risk ratio, 0.96 [95% CI, 0.95–0.98]). The incidence of subsequent infection did not change when previous infection with the same or another respiratory virus occurred. Illness duration and severity were not significantly different in the infants between the first and second episodes for any respiratory virus tested. Conclusions In infants in rural Nepal, repeated respiratory virus infections were frequent, and we found no decrease in illness severity with repeated infections and no evidence of replacement with another virus. Vaccine strategies and public health interventions that provide durable protection in the first 6 months of life could decrease the burden of repeated infections by multiple respiratory viruses, particularly in low-resource countries. [ABSTRACT FROM AUTHOR]

Background Knowledge of risk factors for symptomatic human coronavirus (HCoV) infections in children in community settings is limited. We estimated the disease burden and impact of birth-related, maternal, household, and seasonal factors on HCoV infections among children from birth to 6 months old in rural Nepal. Methods Prospective, active, weekly surveillance for acute respiratory infections (ARIs) was conducted in infants over a period of 3 years during 2 consecutive, population-based randomized trials of maternal influenza immunization. Midnasal swabs were collected for acute respiratory symptoms and tested for HCoV and other viruses by reverse-transcription polymerase chain reaction. Association between HCoV incidence and potential risk factors was modeled using Poisson regression. Results Overall, 282 of 3505 (8%) infants experienced an HCoV ARI within the first 6 months of life. HCoV incidence overall was 255.6 (95% confidence interval [CI], 227.3–286.5) per 1000 person-years, and was more than twice as high among nonneonates than among neonates (incidence rate ratio [IRR], 2.53; 95% CI, 1.52–4.21). HCoV ARI incidence was also positively associated with the number of children <5 years of age per room in a household (IRR, 1.13; 95% CI, 1.01–1.28). Of the 296 HCoV infections detected, 46% were coinfections with other respiratory viruses. While HCoVs were detected throughout the study period, seasonal variation was also observed, with incidence peaking in 2 winters (December–February) and 1 autumn (September–November). Conclusions HCoV is associated with a substantial proportion of illnesses among young infants in rural Nepal. There is an increased risk of HCoV infection beyond the first month of life. [ABSTRACT FROM AUTHOR]

Background: Despite the frequency of human rhinovirus (HRV), data describing the molecular epidemiology of HRV in the community are limited. Childcare centers are optimal settings to characterize heterotypic HRV cocirculation.Methods: HRV specimens were prospectively obtained from a cohort of childcare attendees at enrollment and weekly during respiratory illness. The 5' noncoding region sequences were used to determine HRV species (A, B, C) and genotypes.Results: Among 225 children followed, sequence data were available for 92 HRV infections: HRV-A (n = 80; 59%) was most common, followed by HRV-C (n = 52, 39%), and HRV-B (n = 3, 2%). Forty-one genotypes were identified and cocirculation was common. Frequent spread between classrooms occurred with 2 HRV-A genotypes. Repeated detections within single illnesses were a combination of persistent (n = 7) and distinct (n = 7) genotypes. Prevalence of HRV among asymptomatic children was 41%. HRV-C was clinically similar to HRV-A and HRV-B.Conclusions: HRV epidemiology in childcare consists of heterotypic cocirculation of genotypes with periodic spread within and among classrooms. Based on our finding of multiple genotypes evident during the course of single illnesses, the use of sequence-based HRV type determination is critical in longitudinal studies of HRV epidemiology and transmission. [ABSTRACT FROM AUTHOR]

Background: Severe respiratory disease associated with enterovirus D68 (EV‐D68) has been reported in hospitalized pediatric patients. Virologic and clinical characteristics of EV‐D68 infections exclusively in patients presenting to a hospital Emergency Department (ED) or urgent care have not been well defined. Methods: Mid‐nasal swabs from pediatric patients with respiratory symptoms presenting to the ED or urgent care were evaluated using a commercial multiplex PCR platform. Specimens positive for rhinovirus/enterovirus (HRV/EV) were subsequently tested using real‐time reverse‐transcriptase PCR for EV‐D68. The PCR cycle threshold (CT) was used as a viral load proxy. Clinical outcomes were compared between patients with EV‐D68 and patients without EV‐D68 who tested positive for HRV/EV. Results: From August to December 2014, 511 swabs from patients with HRV/EV were available. EV‐D68 was detected in 170 (33%) HRV/EV‐positive samples. In multivariable models adjusted for age and underlying asthma, patients with EV‐D68 were more likely to require hospitalization for respiratory reasons (odds ratio (OR): 3.11, CI: 1.85‐5.25), require respiratory support (OR: 1.69, CI: 1.09‐2.62), have confirmed/probable lower respiratory tract infection (LRTI; OR: 3.78, CI: 2.03‐7.04), and require continuous albuterol or steroids (OR: 3.91, CI: 2.22‐6.88 and OR: 4.73, CI: 2.65‐8.46, respectively). Higher EV‐D68 viral load was associated with need for respiratory support and LRTI in multivariate models. Conclusions: Among pediatric patients presenting to the ED or urgent care, EV‐D68 causes more severe disease than non‐EV‐D68 HRV/EV independent of underlying asthma. High viral load was associated with worse clinical outcomes. Rapid and quantitative viral testing may help identify and risk stratify patients. [ABSTRACT FROM AUTHOR]

Human metapneumovirus (HMPV) is a respiratory virus that can cause severe lower respiratory tract disease and even death, primarily in young children. The incidence and characteristics of HMPV have not been well described in pregnant women. As part of a trial of maternal influenza immunization in rural southern Nepal, we conducted prospective, longitudinal, home-based active surveillance for febrile respiratory illness during pregnancy through 6 months postpartum. During 2011-2014, HMPV was detected in 55 of 3,693 women (16.4 cases/1,000 person-years). Twenty-five women were infected with HMPV during pregnancy, compared with 98 pregnant women who contracted rhinovirus and 7 who contracted respiratory syncytial virus. Women with HMPV during pregnancy had an increased risk of giving birth to infants who were small for gestational age. An intervention to reduce HMPV febrile respiratory illness in pregnant women may have the potential to decrease risk of adverse birth outcomes in developing countries. [ABSTRACT FROM AUTHOR]

Background: Recent data suggest that human coronavirus (HCoV) pneumonia is associated with significant mortality in hematopoietic cell transplant (HCT) recipients. Investigation of risk factors for prolonged shedding and intrahost genome evolution may provide critical information for development of novel therapeutics.Methods: We retrospectively reviewed HCT recipients with HCoV detected in nasal samples by polymerase chain reaction (PCR). HCoV strains were identified using strain-specific PCR. Shedding duration was defined as time between first positive and first negative sample. Logistic regression analyses were performed to evaluate factors for prolonged shedding (≥21 days). Metagenomic next-generation sequencing (mNGS) was conducted when ≥4 samples with cycle threshold values of <28 were available.Results: Seventeen of 44 patients had prolonged shedding. Among 31 available samples, 35% were OC43, 32% were NL63, 19% were HKU1, and 13% were 229E; median shedding duration was similar between strains (P = .79). Bivariable logistic regression analyses suggested that high viral load, receipt of high-dose steroids, and myeloablative conditioning were associated with prolonged shedding. mNGS among 5 subjects showed single-nucleotide polymorphisms from OC43 and NL63 starting 1 month following onset of shedding.Conclusions: High viral load, high-dose steroids, and myeloablative conditioning were associated with prolonged shedding of HCoV in HCT recipients. Genome changes were consistent with the expected molecular clock of HCoV. [ABSTRACT FROM AUTHOR]

Background. Metagenomic next-generation sequencing (mNGS) has been used to uncover unusual causes of infectious diseases but has not been used routinely for the investigation of putative nosocomial outbreaks. Here, we describe the use of mNGS during investigation of a cluster of human rhinovirus (HRV)-positive infections on a high-risk pulmonary ward. Methods. We performed mNGS on 6 midnasal turbinate swabs from 4 case-patients and 10 swabs from 9 control outpatients that tested positive for enterovirus/rhinovirus by the FilmArray system. Results. HRV reads were recovered in 15 (94%) of the 16 samples sequenced. Phylogenetic analysis of HRV whole genomes from the 4 case-patients and 5 outpatient controls along with partial genomes from additional outpatient controls revealed that isolates from the case-patients were not directly related and that the 2 closest case HRV genomes had an estimated time to most recent common ancestor of 172 years. Our turnaround time from receipt of the sample to phylogenetic analysis was 24 hours. Conclusions. We found the use of mNGS downstream of a rapid polymerase chain reaction respiratory panel during an investigation of 4 hospital-acquired rhinovirus infections to rapidly dispel concern of a single-source transmission event. [ABSTRACT FROM AUTHOR]

Objectives: Respiratory syncytial virus (RSV) pneumonia is a leading cause of infant mortality worldwide. The risk of RSV infection associated with preterm birth is not well-characterized in resource-limited settings. We aimed to obtain precise estimates of risk factors and disease burden of RSV in infants in rural southern Nepal.Methods: Pregnant women were enrolled, and along with their infants, followed to six months after birth with active weekly home-based surveillance for acute respiratory illness (ARI). Mid-nasal swabs were obtained and tested for RSV by PCR for all illness episodes. Birth outcomes were assessed at a postpartum home visit.Results: 311 (9%) of 3509 infants had an RSV ARI. RSV ARI incidence decreased from 551/1000 person-years in infants born between 28 and 31 weeks to 195/1000 person-years in infants born full-term (p = 0.017). Of 220 infants (71%) evaluated in the health system, 41 (19%) visited a hospital or physician. Of 287 infants with an assessment performed, 203 (71%) had a lower respiratory tract infection.Conclusions: In a rural south Asian setting with intensive home-based surveillance, RSV caused a significant burden of respiratory illness. Preterm infants had the highest incidence of RSV ARI, and should be considered a priority group for RSV preventive interventions in resource-limited settings. [ABSTRACT FROM AUTHOR]

Background. Human metapneumovirus (HMPV) is a newly identified pulmonary pathogen that can cause fatal lower respiratory tract disease (LRD) in hematopoietic cell transplantation (HCT) recipients. Little is known about progression rates from upper respiratory tract infection (URI) to LRD and risk factors associated with progression. Methods. A total of 118 HCT recipients receiving transplantation between 2004 and 2014 who had HMPV detected in nasopharyngeal, bronchoalveolar lavage, or lung biopsy samples by real-time reverse transcription polymerase chain reaction were retrospectively analyzed. Results. More than 90% of the cases were identified between December and May. Among the 118 HCT patients, 88 and 30 had URI alone and LRD, respectively. Among 30 patients with LRD, 17 patients progressed from URI to LRD after a median of 7 days (range, 2-63 days). The probability of progression to LRD within 40 days after URI was 16%. In Cox regression analysis, steroid use ≥1 mg/kg prior to URI diagnosis (hazard ratio [HR], 5.10; P = .004), low lymphocyte count (HR, 3.43; P = .011), and early onset of HMPV infection after HCT (before day 30 after HCT; HR, 3.54; P = .013) were associated with higher progression to LRD. The median viral load in nasal wash samples was 1.1 × 106 copies/mL (range, 3.3 × 102-1.7 × 109) with no correlation between the viral load and progression. Conclusions. Progression from URI to LRD occurred in up to 60% of HCT recipients with risk factors such as systemic corticosteroid use or low lymphocyte counts. Further studies are needed to define the role of viral load in the pathogenesis of progressive disease. [ABSTRACT FROM AUTHOR]

Background: Respiratory syncytial virus (RSV) is the most important cause of viral pneumonia in children worldwide. A maternal vaccine may protect both the mother and infant from RSV illness. The epidemiology and clinical presentation of RSV in pregnant and postpartum women is not well-described. Methods: Data were collected from a prospective, randomized trial of influenza immunization in pregnant women in rural southern Nepal. Women were enrolled in their second trimester of pregnancy and followed until six months postpartum. Active weekly home-based surveillance for febrile respiratory illness was performed. Mid-nasal swabs collected with episodes of respiratory illness were tested for RSV by real-time polymerase chain reaction. Results: RSV was detected in 14 (0.4%) illness episodes in 3693 women over 3554 person-years of surveillance from 2011–2014. RSV incidence was 3.9/1000 person-years overall, and 11.8/1000 person-years between September and December. Seven (50%) women sought care for RSV illness; none died. Of the 7 (50%) illness episodes during pregnancy, all had live births with 2 (29%) preterm births and a median birthweight of 3060 grams. This compares to 469 (13%) preterm births and a median birthweight of 2790 grams in women without RSV during pregnancy. Of the 7 mothers with postpartum RSV infection, RSV was detected in 4 (57%) of their infants. Conclusions: RSV was an uncommon cause of febrile respiratory illness in mothers during pregnancy in Nepal. These data will inform prevention and therapeutic strategies against RSV in resource-limited settings. [ABSTRACT FROM AUTHOR]

Influenza A(H5N1) vaccination strategies that improve the speed of the immunological response and cross-clade protection are desired. We compared the immunogenicity of a single 15-µg or 90-µg dose of A/H5N1/Indonesia/05/05 (clade 2) vaccine in adults who were previously primed with A/H5N1/Vietnam/1203/2004 (clade 1) vaccine. High-dose vaccine resulted in significantly higher titers to both clade 1 and 2 antigens. Clade 2 titers were unaffected by the previous dose of clade 1 vaccine. Low-dose priming with a mismatched pandemic influenza A(H5N1) vaccine would improve the rapidity, magnitude, and cross-reactivity of the immunological response following a single high-dose, unadjuvanted, pandemic vaccine. [ABSTRACT FROM AUTHOR]

Background Methods for the longitudinal study of respiratory virus infections are cumbersome and limit our understanding of the natural history of these infections in solid organ transplant (SOT) recipients. Objectives To assess the feasibility and patient acceptability of self-collected foam nasal swabs for detection of respiratory viruses in SOT recipients and to define the virologic and clinical course. Study design We prospectively monitored the course of symptomatic respiratory virus infection in 18 SOT patients (14 lung, 3 liver, and 1 kidney) using patient self-collected swabs. Results The initial study sample was positive in 15 patients with the following respiratory viruses: rhinovirus (6), metapneumovirus (1), coronavirus (2), respiratory syncytial virus (2), parainfluenza virus (2), and influenza A virus (2). One hundred four weekly self-collected nasal swabs were obtained, with a median of 4 samples per patient (range 1–17). Median duration of viral detection was 21 days (range 4–77 days). Additional new respiratory viruses detected during follow-up of these 15 patients included rhinovirus (3), metapneumovirus (2), coronavirus (1), respiratory syncytial virus (1), parainfluenza virus (1), and adenovirus (1). Specimen collection compliance was good; 16/18 (89%) patients collected all required specimens and 79/86 (92%) follow-up specimens were obtained within the 7 ± 3 day protocol-defined window. All participants agreed or strongly agreed that the procedure was comfortable, simple, and 13/14 (93%) were willing to participate in future studies using this procedure. Conclusion Self-collected nasal swabs provide a convenient, feasible, and patient-acceptable methodology for longitudinal monitoring of upper respiratory virus infection in SOT recipients. [ABSTRACT FROM AUTHOR]

We propose a new definition of lower respiratory tract disease (LRTD) based on the viral detection site that correlates with clinical outcome. Monocyte count, oxygen use, and high-dose steroid use are associated with mortality after parainfluenza virus LRTD.Background. Parainfluenza virus (PIV) commonly infects patients following hematopoietic cell transplantation (HCT), frequently causing lower respiratory tract disease (LRTD). The definition of LRTD significantly differs among studies evaluating the impact of PIV after HCT.Methods. We retrospectively evaluated 544 HCT recipients with laboratory-confirmed PIV and classified LRTD into 3 groups: possible (PIV detection in upper respiratory tract with new pulmonary infiltrates with/without LRTD symptoms), probable (PIV detection in lung with LRTD symptoms without new pulmonary infiltrates), and proven (PIV detection in lung with new pulmonary infiltrates with/without LRTD symptoms).Results. Probabilities of 90-day survival after LRTD were 87%, 58%, and 45% in possible, probable, and proven cases, respectively. Patients with probable and proven LRTD had significantly worse survival than those with upper respiratory tract infection (probable: hazard ratio [HR], 5.87 [P < .001]; proven: HR, 9.23 [P < .001]), whereas possible LRTD did not (HR, 1.49 [P = .27]). Among proven/probable cases, oxygen requirement at diagnosis, low monocyte counts, and high-dose steroid use (>2 mg/kg/day) were associated with high mortality in multivariable analysis.Conclusions. PIV LRTD with viral detection in lungs (proven/probable LRTD) was associated with worse outcomes than was PIV LRTD with viral detection in upper respiratory samples alone (possible LRTD). This new classification should impact clinical trial design and permit comparability of results among centers. [ABSTRACT FROM AUTHOR]

Abstract: Background: Respiratory syncytial virus (RSV) is the most important cause of serious respiratory infections in young children. No prior studies using molecular techniques to examine RSV transmission in the community childcare setting have been performed. Objectives: We seek to characterize the molecular epidemiology of RSV transmission in childcare to evaluate the impact of RSV disease in a community-based population. Methods: We sequenced RSV-positive nasopharyngeal samples from a prospective longitudinal study of respiratory illnesses among children enrolled in childcare during three winter seasons. Phylogenetic analysis was performed to identify unique viral strains. Results: RSV was detected in 59 (11%) illnesses. Compared to RSV-negative illnesses, RSV-positive illnesses were associated with longer symptom duration and increased frequency of health care visits. Another respiratory virus was detected in 42 (71%) RSV-positive illnesses. RSV viral load did not differ between RSV-positive illnesses with and without another respiratory virus identified (P =0.38). In two childcare rooms, 50% of the children had RSV detected within six days of the first case. Five (38%) of 13 illness episodes from one childcare room were sequenced and shown to be the same viral strain, suggesting rapid child-to-child transmission within the room over a 16 day period. Conclusions: RSV is rapidly transmitted within childcare. Childcare facilities may serve as ideal sites for evaluation of new prevention strategies given the high burden of RSV disease in this population and the rapidity of RSV spread between children. [Copyright &y& Elsevier]

Data are limited regarding 2 new human polyomaviruses, KI polyomavirus (KIPyV) and WU polyomavirus (WUPyV), in immunocompromised patients. We used real-time PCR to test for these and 12 respiratory viruses in 2,732 nasal wash samples collected during the first year after allogeneic hematopoietic cell transplantation from 222 patients. Specimens were collected weekly until day 100; then at least every 3 months. One year after hematopoietic cell transplantation, the cumulative incidence estimate was 26% for KIPyV and 8% for WUPyV. Age <20 years predicted detection of KIPyV (hazard ratio [HR] 4.6) and WUPyV (HR 4.4), and detection of a respiratory virus in the previous 2 weeks predicted KIPyV detection (HR 3.4). Sputum production and wheezing were associated with detection of KIPyV in the past week and WUPyV in the past month. There were no associations with polyomavirus detection and acute graft versus host disease, cytomegalovirus reactivation, neutropenia, lymphopenia, hospitalization, or death. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Martin et al. (2012) Multiple versus single virus respiratory infections: viral load and clinical disease severity in hospitalized children. Influenza and Other Respiratory Viruses 6(1), 71-77. Background Molecular testing for viral pathogens has resulted in increasing detection of multiple viruses in respiratory secretions of ill children. The clinical impact of multiple virus infections on clinical presentation and outcome is unclear. Objectives To compare clinical characteristics and viral load between children with multiple virus versus single virus illnesses. Patients/methods Eight hundred and ninety-three residual nasal wash samples from children treated for respiratory illness at Children's Hospital, Seattle, from September 2003 to September 2004 were evaluated by quantitative PCR for respiratory syncytial virus (RSV), human metapneumovirus (hMPV), influenza (Flu), parainfluenza, adenoviruses, and coronaviruses (CoV). Illness severity and patient characteristics were abstracted from medical charts. Results Coinfections were identified in 103 (18%) of 566 virus-positive samples. Adenovirus was most commonly detected in coinfections (52%), followed by CoV (50%). Illnesses with a single virus had increased risk of oxygen requirement ( P = 0·02), extended hospital stays ( P = 0·002), and admissions to the inpatient ( P = 0·02) or intensive care units ( P = 0·04). For Adv and PIV-1, multiple virus illnesses had a significantly lower viral load (log10 copies/ml) than single virus illnesses (4·2 versus 5·6, P = 0·007 and 4·2 versus 6·9, P < 0·001, respectively). RSV, Flu-A, PIV-3, and hMPV viral loads were consistently high whether or not another virus was detected. Conclusions Illnesses with multiple virus detections were correlated with less severe disease. The relationship between viral load and multiple virus infections was virus specific, and this may serve as a way to differentiate viruses in multiple virus infections. [ABSTRACT FROM AUTHOR]

Most oseltamivir-resistant pandemic (H1N1) 2009 viruses have been isolated from immunocompromised patients. To describe the clinical features, treatment, outcomes, and virologic data associated with infection from pandemic (H1N1) 2009 virus with H275Y mutation in immunocompromised patients, we retrospectively identified 49 hematology--oncology patients infected with pandemic (H1N1) 2009 virus. Samples from 33 of those patients were tested for H275Y genotype by allele-specific real-time PCR. Of the 8 patients in whom H275Y mutations was identified, 1 had severe pneumonia; 3 had mild pneumonia with prolonged virus shedding; and 4 had upper respiratory tract infection, of whom 3 had prolonged virus shedding. All patients had received oseltamivir before the H275Y mutation was detected; 1 had received antiviral prophylaxis. Three patients excreted resistant virus for >60 days. Emergence of oseltamivir resistance is frequent in immunocompromised patients infected with pandemic (H1N1) 2009 virus and can be associated with a wide range of clinical disease and viral kinetics. [ABSTRACT FROM AUTHOR]

Background Limited data exist regarding the impact of human bocavirus (BoV) in hematopoietic cell transplant (HCT) recipients. We examined incidence and disease spectrum of BoV respiratory tract infection (RTI) in HCT recipients. Methods In a longitudinal surveillance study of viral RTIs among allogeneic HCT recipients, pre-HCT and weekly post-HCT nasal washes and symptom surveys were collected through day 100, then every 3 months, and whenever respiratory symptoms occurred through 1-year post-HCT. Samples were tested by multiplex semi-quantitative PCR for RSV, parainfluenza virus 1–4, influenza A/B, adenovirus, human metapneumovirus, rhinovirus, coronavirus, and BoV. Plasma samples from BoV+ subjects were analyzed by PCR. In addition, we conducted a retrospective review of HCT recipients with BoV detected in bronchoalveolar lavage or lung biopsy. Results Among 469 patients in the prospective cohort, 21 distinct BoV RTIs (3 pre-HCT and 18 post-HCT) were observed by 1-year post-HCT in 19 patients (median 42 years old, range 0–67) without apparent seasonality. BoV was more frequently detected in the latter half of the first 100 days post-HCT (Figure 1). The frequencies of respiratory symptoms in patients with BoV detected did not appear to be higher than those without any virus detected, with the exception of watery eyes (P < 0.01) (Figure 2). Univariable models among patients with BoV RTI post-HCT showed higher peak viral load in nasal samples (P = 0.04) and presence of respiratory copathogens (P = 0.03) were associated with presence of respiratory symptoms; however, BoV detection in plasma was not (P = 0.8). Retrospective review identified 6 allogeneic HCT recipients (range 1–64 years old) with BoV detected in lower respiratory tract specimens [incidence rate of 0.4% (9/2,385) per sample tested]. Although all 6 cases presented with hypoxemia, 4 had significant respiratory copathogens or concomitant conditions that contributed to respiratory compromise. No death was attributed mainly to BoV lower RTI. Conclusion BoV is infrequently detected in respiratory tract in HCT recipients. Our studies did not demonstrate convincing evidence that BoV is a significant pathogen in either upper or lower respiratory tracts. Watery eyes were associated with BoV detection. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

• Risk factors for rhinovirus lower respiratory tract infection are not well characterized. • Several risk factors in hematopoietic cell transplant recipients were identified. • A risk score for progression to lower respiratory tract infection was developed. Human rhinovirus lower respiratory tract infection (LRTI) is associated with mortality after hematopoietic cell transplantation (HCT); however, risk factors for LRTI are not well characterized. We sought to develop a risk score for progression to LRTI from upper respiratory tract infection (URTI) in HCT recipients. Risk factors for LRTI within 90 days were analyzed using Cox regression among HCT recipients with rhinovirus URTI between January 2009 and March 2016. The final multivariable model included factors with a meaningful effect on the bootstrapped optimism corrected concordance statistic. Weighted score contributions based on hazard ratios were determined. Cumulative incidence curves estimated the probability of LRTI at various score cut-offs. Of 588 rhinovirus URTI events, 100 (17%) progressed to LRTI. In a final multivariable model allogeneic grafts, prior rhinovirus URTI, low lymphocyte count, low albumin, positive cytomegalovirus serostatus, recipient statin use, and steroid use ≥2 mg/kg/day were associated with progression to LRTI. A weighted risk score cut-off with the highest sensitivity and specificity was determined. Risk scores above this cut-off were associated with progression to LRTI (cumulative incidence 28% versus 11% below cut-off; P <.001). The weighted risk score for progression to rhinovirus LRTI can help identify and stratify patients for clinical management and for future clinical trials of therapeutics in HCT recipients. [ABSTRACT FROM AUTHOR]

The article discusses the H1N1-associated pneumonia in a hematopoietic stem-cell transplant recipient with extrapulmonary H1N1 RNA detection who was treated with intravenous peramivir. It states that viral RNA in the plasma of the patient is novel and may indicate hematologic dissemination of the virus. It infers that intravenous influenza antiviral useful for A/H1N1 infection patients.

• Acute respiratory infections, including influenza, are common among household member in Nepal. • Antenatal influenza vaccination does not confer indirect protection to household members. • Challenges include low vaccine efficacy and limited population coverage. Influenza is a significant cause of morbidity and mortality worldwide, and the World Health Organization highly recommends maternal vaccination during pregnancy. The indirect effect of maternal vaccination on other close contacts other than newborns is unknown. To evaluate this, we conducted a nested substudy between 2011 and 2012 of influenza and acute respiratory illness (ARI) among household members of pregnant women enrolled in a randomized placebo-controlled trial of antenatal influenza vaccination in the rural district of Sarlahi, Nepal. Women were assigned to receive influenza vaccination or placebo during pregnancy and then they and their household members were followed up to 6 months postpartum with weekly symptom surveillance and nasal swab collection. Swabs were tested by RT-PCR for influenza. Rates of laboratory-confirmed influenza and of ARI were compared between vaccine and placebo groups using generalized estimating equations with a Poisson link function. Overall, 1752 individuals in 520 households were eligible for inclusion. There were 82 laboratory-confirmed influenza illness episodes, for a rate of 7.0 per 100 person-years overall. Of the influenza strains able to be typed, 29 were influenza A, 40 were influenza B, and 6 were coinfections with influenza A and B. The rate did not differ significantly whether the household was in the vaccine or placebo group (rate ratio (RR) 1.37, 95% confidence interval (CI) 0.83–2.26). The rate of ARI was 28.5 per 100 person-years overall and did not differ by household group (RR 0.99, 95% CI 0.72–1.36). Influenza vaccination of pregnant women did not provide indirect protection of unvaccinated household members. [ABSTRACT FROM AUTHOR]

• Self-collected nasal swabs are sensitive for detecting respiratory virus infections. • Self-collected throat swabs add little to respiratory virus infection diagnosis. • Nasal swabs detect higher respiratory virus concentration than throat swabs. Early and accurate detection of respiratory viruses (RV) is important for patient management. We have previously shown that self-collected nasal swabs (NS) are feasible and as sensitive as clinician-collected nasal washes for detection of RV, but the additive benefit of self-collected throat swabs is unknown. To evaluate the added yield of self-collected nasal to throat swabs for detection of RV by PCR in patients with upper respiratory tract infection (URTI) symptoms. Patients with URTI symptoms self-collected paired polyurethane foam NS and nylon flocked throat swabs and completed a symptom survey. Swabs were tested for 12 RV by real-time reverse transcription (RT)-PCR. Descriptive, McNemar's, and Wilcoxon signed rank statistical tests were used. 115 paired nasal and throat swabs were collected from 63 individuals, with 71/115 (62%) positive for a RV by at least one specimen, including 51 positive by both, 17 positive by NS only, and 3 positive by throat swab only. The sensitivity of NS was 96% (95%CI: 88-99) versus 76% (95% CI: 65-85) in throat swabs, p<0.001. The median PCR cycle threshold (Ct) in 51 concordant samples was lower (indicating higher viral concentration) in NS (25.1) versus throat swabs (32.0). The three samples positive only by throat swab had high Ct values (33.8, 36.2, and 38.8, all rhinovirus). Self-collection of NS was significantly more sensitive than self collection of throat swabs for detection of RV by RT-PCR. The addition of throat sampling does not appear to increase the diagnostic load in the self-testing setting. [ABSTRACT FROM AUTHOR]

Highlights • Progression rate to PIV lower respiratory tract disease (LRTD) by day 40 was 12%. • Progression to probable/proven LRTD was associated with 4 risk factors. • No patients progressed to LRTD in the absence of all 4 risk factors. Abstract Parainfluenza virus (PIV) infection can progress from upper respiratory tract infection (URTI) to lower respiratory tract disease (LRTD) in immunocompromised hosts. Risk factors for progression to LRTD and presentation with LRTD without prior URTI are poorly defined. Hematopoietic cell transplant (HCT) recipients with PIV infection were retrospectively analyzed using standardized definitions of LRTD. PIV was detected in 540 HCT recipients; 343 had URTI alone and 197 (36%) had LRTD (possible, 76; probable, 19; proven, 102). Among 476 patients with positive nasopharyngeal samples, the cumulative incidence of progression to probable/proven LRTD by day 40 was 12%, with a median time to progression of 7 days (range, 2 to 40). In multivariable analysis monocytopenia (hazard ratio, 2.22; P =.011), steroid use ≥1mg/kg prior to diagnosis (hazard ratio, 1.89; P =.018), co-pathogen detection in blood (hazard ratio, 3.21; P =.027), and PIV type 3 (hazard ratio, 3.57; P =.032) were associated with increased progression risk. In the absence of all 4 risk factors no patients progressed to LRTD, whereas progression risk increased to >30% if 3 or more risk factors were present. Viral load or ribavirin use appeared to have no effect on progression. Among 121 patients with probable/proven LRTD, 64 (53%) presented LRTD without prior URTI, and decreased lung function before infection and lower respiratory co-pathogens were risk factors for this presentation. Mortality was unaffected by the absence of prior URTI. We conclude that the risk of progression to probable/proven LRTD exceeded 30% with ≥3 risk factors. To detect all cases of LRTD, virologic testing of lower respiratory samples is required regardless of URTI symptoms. [ABSTRACT FROM AUTHOR]

Abstract: Human metapneumovirus (HMPV), a common respiratory virus, can cause severe disease in pre- and post-hematopoietic cell transplantation (HCT) recipients. We conducted a retrospective cohort analysis in HCT patients with HMPV (n = 23) or respiratory syncytial virus (n = 23) detected in bronchoalveolar lavage samples by reverse transcription PCR between 2006 and 2011 to determine disease characteristics and factors associated with outcome. Mortality rates at 100 days were 43% for both HMPV and respiratory syncytial virus lower respiratory tract disease. Steroid therapy, oxygen requirement >2 L or mechanical ventilation, and bone marrow as cell source were significant risk factors for overall and virus-related mortality in multivariable models, whereas the virus type was not. The presence of centrilobular/nodular radiographic infiltrates was a possible protective factor for mechanical ventilation. Thus, HMPV lower respiratory tract disease is associated with high mortality in HCT recipients. Earlier detection in combination with new antiviral therapy is needed to reduce mortality among HCT recipients. [Copyright &y& Elsevier]

Abstract: Background: The epidemiology of respiratory tract infections (RTIs) in a daycare cohort has not been explored using molecular techniques. Objectives: (1) Determine the overall incidence of RTIs in a daycare cohort using real-time reverse transcriptase polymerase chain reaction (RT-PCR). (2) Determine the relative incidence and impact of specific respiratory viruses, and characterize and compare clinical features associated with these pathogens. Study design: In this prospective cohort study conducted from February 2006 to April 2008, nasal swabs were obtained from symptomatic children ages 0–30 months enrolled in fulltime daycare. RT-PCR was performed to detect respiratory syncytial virus (RSV), human metapneumovirus (MPV), influenza (Flu) viruses A and B, parainfluenza (PIV), adenovirus (AdV), human coronaviruses (CoV) and rhinovirus (RhV). Symptom diaries were completed for each illness. Results: We followed 119 children (mean age 10 months; range 2–24 months) for 115 child years. The mean annual incidence of RTI per child was 4.2 the first year and 1.2 the second year of the study. At least 1 virus was identified in 67% RTIs. Co-infections were common (27% RTIs), with RhV, CoV, and AdV the most common co-pathogens. PIV was identified in 12% of RTIs with a high incidence of PIV4. The viruses with the greatest impact on our population were RSV, RhV and AdV. Conclusions: Using molecular techniques, viruses were identified in approximately twice as many RTIs as previously reported in a daycare cohort. Infections with newly identified viruses, such as HMPV and CoV subtypes were less frequent and severe than infections with RSV, AdV and RhV. [ABSTRACT FROM AUTHOR]

Introduction Bacterial superinfection following moderate to severe respiratory viral infections (RVIs), especially influenza (Flu), is well described in immunocompetent hosts. The clinical impact of preceding RVIs on the development of bacterial superinfection in hematopoietic cell transplant (HCT) recipients may be significant although data are limited. Furthermore, the impact of upper respiratory tract infection (URTI) on this outcome has not been systematically evaluated. Objectives To investigate whether URTI due to specific respiratory viruses was associated with increased risk of developing bacteremia or bacterial pneumonia post-HCT. Methods In a longitudinal surveillance study of RVIs among allogeneic HCT recipients conducted from 2005-10, weekly post-HCT nasal washes were collected through day 100. Nasal and bronchoalveolar lavage samples were tested by multiplex PCR for respiratory syncytial virus, parainfluenza viruses (PIV)1–4, Flu A/B, human metapneumovirus (HMPV), adenovirus, rhinoviruses and coronaviruses. URTI was defined as having respiratory virus detected from nasal samples with respiratory symptoms. Bacteremia and bacterial pneumonia were defined as growth of significant bacteria (e.g., Coagulase-negative staphylococci was defined as insignificant bacteria) from blood and lower respiratory tract samples including bronchoalveolar lavage, respectively. Separate Cox proportional hazards models were used to examine associations between first URTI for individual viruses and the subsequent development of first bacteremia and/or bacterial pneumonia by 100 days post-HCT. Results We identified 471 HCT recipients (median age: 51 years, range 8 months-75 years). Number of patients for each first outcome event by 100 days post-HCT included the following: Gram-positive bacteremia (n=64), Gram-negative bacteremia (n=53), Gram-positive pneumonia (n=46), Gram-negative pneumonia (n=8), and either bacteremia or pneumonia (n=152). After adjusting for pre-transplant factors only and pre- and post-transplant factors, significant URTI variables for outcomes in both models were (1) Flu A for gram-positive bacteremia, (2) HMPV for gram-positive pneumonia, and (3) HMPV for bacteremia or bacterial pneumonia (Figure). The association between PIV URTI and development of bacteremia or pneumonia approached statistical significance. Conclusion In HCT recipients, URTIs due to Flu A and HMPV are significant risk factors for the development of gram-positive bacteremia and pneumonia, respectively. Further studies are needed to assess whether prevention or early diagnostic and treatment strategies for RVIs can reduce the risk of bacterial infection. [ABSTRACT FROM AUTHOR]

Introduction Respiratory infections after HCT lead to significant morbidity, mortality, and health care costs due to pulmonary complications. In up to a third of patients following allogeneic HCT, infection can progress from an upper to a lower respiratory tract infection. Without vaccines or effective therapeutics for most viruses, very little can be done beyond supportive care. Objectives There is a need to identify risk factors for virus acquisition in HCT recipients in order to develop and implement better preventative interventions. Methods In a prospective study, 471 HCT patients enrolled between 2005 and 2010 underwent weekly PCR-based surveillance for RSV, metapneumovirus, parainfluenza virus 1-4, influenza A and B, rhinovirus, coronavirus, and adenovirus. Detailed weekly surveys were collected from subjects for up to 1 year post-transplant on symptoms and exposures to children under 10 years or sick contacts (within 3 feet for more than 1 hour total in the past week). We performed multivariable Cox regression analysis to identify risk factors associated with the time to first positive respiratory viral detection by PCR (asymptomatic and symptomatic) within the first 100 days HCT. Results In this cohort, 211 patients (45%) acquired a respiratory virus in the first 100 days after transplant. Of those infected, 88 (42%) were symptomatic with at least 2 respiratory symptoms. We found significantly higher risk of acquiring any respiratory viral infection for patients with underlying chronic leukemia compared with other hematologic malignancies [hazard ratio (HR) 1.79 (1.16 – 2.77)], exposure to children under or over 4 years [HR 1.84 (1.36 – 2.48)], exposure to contacts with cold symptoms [HR 1.47 (1.02 – 2.12)], exposure to systemic steroids [HR 1.49 (1.07 – 2.08)], and absolute monocyte counts < 100/µL [HR 1.81 (1.12 – 2.94)]. Age, age of child exposure, gender, smoking history, season, conditioning regimen, donor relationship, cell source, presence of acute GVHD, albumin level, total IgG level, lymphocyte counts, and neutrophil counts were not associated with risk for acquisition. We also analyzed the association of these same variables with the time to first positive respiratory viral detection with symptomatic respiratory disease. We found that exposure to children [HR 1.56 (1.03 – 2.35)] and exposure to steroids [HR 1.59 (1.01 – 2.52)] remained associated with acquisition of symptomatic respiratory viral infection. Conclusions These data support the contribution of both exposure and immunologic determinants to the risk of respiratory viral acquisition with and without development of symptoms. Although many infections were asymptomatic, patients receiving steroids and those in close proximity to children may benefit from closer monitoring and counseling in the early post-transplant period. [ABSTRACT FROM AUTHOR]