Publications by authors named "Octavio Ramilo"

179 Publications

The larger attachment glycoprotein of respiratory syncytial virus produced in primary human bronchial epithelial cultures reduces infectivity for cell lines.

PLoS Pathog 2021 Apr 8;17(4):e1009469. Epub 2021 Apr 8.

Center for Vaccines and Immunity, The Abagail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.

Respiratory syncytial virus (RSV) infects the upper and lower respiratory tracts and can cause lower respiratory tract infections in children and elders. RSV has traditionally been isolated, grown, studied and quantified in immortalized cell lines, most frequently HEp-2 cells. However, in vivo RSV infection is modeled more accurately in primary well differentiated human bronchial epithelial (HBE) cultures where RSV targets the ciliated cells and where the putative RSV receptor differs from the receptor on HEp-2 cells. The RSV attachment (G) glycoprotein in virions produced by HEp-2 cells is a highly glycosylated 95 kDa protein with a 32 kDa peptide core. However, virions produced in HBE cultures, RSV (HBE), contain an even larger, 170 kDa, G protein (LgG). Here we show that LgG is found in virions from both subgroups A and B lab-adapted and clinical isolates. Unexpectedly, RSV (HBE) virions were approximately 100-fold more infectious for HBE cultures than for HEp-2 cells. Surprisingly, the cause of this differential infectivity, was reduced infectivity of RSV (HBE) on HEp-2 cells rather than enhanced infectivity on HBE cultures. The lower infectivity of RSV(HBE) for HEp-2 cells is caused by the reduced ability of LgG to interact with heparan sulfate proteoglycans (HSPG), the RSV receptor on HEp-2 cells. The discovery of different infectivity corresponding with the larger form of the RSV attachment protein when produced by HBE cultures highlights the importance of studying a virus produced by its native host cell and the potential impact on quantifying virus infectivity on cell lines where the virus entry mechanisms differ from their natural target cell.
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http://dx.doi.org/10.1371/journal.ppat.1009469DOI Listing
April 2021

A safe and highly efficacious measles virus-based vaccine expressing SARS-CoV-2 stabilized prefusion spike.

Proc Natl Acad Sci U S A 2021 03;118(12)

Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210;

The current pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights an urgent need to develop a safe, efficacious, and durable vaccine. Using a measles virus (rMeV) vaccine strain as the backbone, we developed a series of recombinant attenuated vaccine candidates expressing various forms of the SARS-CoV-2 spike (S) protein and its receptor binding domain (RBD) and evaluated their efficacy in cotton rat, IFNARmice, IFNAR-hCD46 mice, and golden Syrian hamsters. We found that rMeV expressing stabilized prefusion S protein (rMeV-preS) was more potent in inducing SARS-CoV-2-specific neutralizing antibodies than rMeV expressing full-length S protein (rMeV-S), while the rMeVs expressing different lengths of RBD (rMeV-RBD) were the least potent. Animals immunized with rMeV-preS produced higher levels of neutralizing antibody than found in convalescent sera from COVID-19 patients and a strong Th1-biased T cell response. The rMeV-preS also provided complete protection of hamsters from challenge with SARS-CoV-2, preventing replication in lungs and nasal turbinates, body weight loss, cytokine storm, and lung pathology. These data demonstrate that rMeV-preS is a safe and highly efficacious vaccine candidate, supporting its further development as a SARS-CoV-2 vaccine.
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http://dx.doi.org/10.1073/pnas.2026153118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000430PMC
March 2021

Viral Loads and Disease Severity in Children with Rhinovirus-Associated Illnesses.

Viruses 2021 02 13;13(2). Epub 2021 Feb 13.

Division of Infectious Diseases, Department of Pediatrics, Center for Vaccines and Immunity Nationwide Children's Hospital-The Ohio State University College of Medicine, Columbus, OH 43205, USA.

The role of rhinoviruses (RVs) in children with clinical syndromes not classically associated with RV infections is not well understood. We analyzed a cohort of children ≤21 years old who were PCR+ for RV at a large Pediatric Hospital from 2011 to 2013. Using univariate and multivariable logistic regression, we analyzed the associations between demographic, clinical characteristics, microbiology data, and clinical outcomes in children with compatible symptoms and incidental RV detection. Of the 2473 children (inpatients and outpatients) with an RV+ PCR, 2382 (96%) had compatible symptoms, and 91 (4%) did not. The overall median age was 14 months and 78% had underlying comorbidities. No differences in RV viral loads were found according to the presence of compatible symptoms, while in children with classic RV symptoms, RV viral loads were higher in single RV infections versus RV viral co-infections. Bacterial co-infections were more common in RV incidental detection (7.6%) than in children with compatible symptoms (1.9%, < 0.001). The presence of compatible symptoms independently increased the odds ratio (OR, 95% CI) of hospitalization 4.8 (3.1-7.4), prolonged hospital stays 1.9 (1.1-3.1), need for oxygen 12 (5.8-25.0) and pediatric intensive care unit (PICU) admission 4.13 (2.0-8.2). Thus, despite comparable RV loads, disease severity was significantly worse in children with compatible symptoms.
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http://dx.doi.org/10.3390/v13020295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918889PMC
February 2021

Longitudinal plasma cytokine concentrations and recurrent wheezing after RSV bronchiolitis.

Cytokine 2021 Apr 26;140:155434. Epub 2021 Jan 26.

Division of Pediatric Infectious Diseases & Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA.

Background: Respiratory syncytial virus (RSV) bronchiolitis in young children has been associated with increased risk for developing recurrent wheezing, but the underlying mechanisms, are not completely defined. We hypothesized that RSV induces a disregulated immune response defined by a distinct cytokine profile in infants at increased risk for developing recurrent wheezing.

Methods: Previously healthy infants less than 12 months of age hospitalized with a first episode of RSV bronchiolitis were enrolled and blood samples and clinical and epidemiological data collected. A group of healthy non-infected controls were enrolled in parallel. Children were followed longitudinally and subsequent blood samples collected in RSV-infected infants at one month and at one year after hospital discharge to measure longitudinal plasma concentrations of IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17 and IL1-β. Risk of post-RSV wheezing was assessed by Poisson modelling.

Results: From October 2008 to March 2012 we enrolled 37 infants hospitalized with RSV bronchiolitis and 9 healthy age-matched controls. Within the RSV cohort, 17 (46%) children developed recurrent wheezing within the following 12 months. Plasma cytokine profiles measured during the acute infection were similar in children who developed recurrent wheezing versus those who did not, but lower in healthy controls vs RSV infants who subsequently developed wheezing. At one month and 12 months post-acute RSV infection, infants who developed recurrent wheezing had higher IFN-γ plasma concentrations versus those with no-wheezing (p < 0.05). Moreover, IFN-γ concentrations were identified as independent predictor of post-RSV wheezing.

Conclusions: Children with RSV-associated recurrent wheezing had persistently elevated plasma concentrations of IFN-γ for a year after acute infection, suggesting that this cytokine could be used as a biomarker for risk of recurrent wheezing and possibly plays a role in the pathogenesis of this condition.
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http://dx.doi.org/10.1016/j.cyto.2021.155434DOI Listing
April 2021

Age-dependent Interactions Among Clinical Characteristics, Viral Loads and Disease Severity in Young Children With Respiratory Syncytial Virus Infection.

Pediatr Infect Dis J 2021 Feb;40(2):116-122

From the Center for Vaccines and Immunity.

Background: Age-dependent differences in clinical presentation and viral loads in infants and young children with respiratory syncytial virus (RSV) infection, and their correlation with disease severity are poorly defined.

Methods: Previously healthy children <2 years old with mild (outpatients) and severe (inpatients) RSV infection were enrolled and viral loads measured by polymerase chain reaction in nasopharyngeal swabs. Patients were stratified by age in 0-<3, 3-6 and >6-24 months, and multivariable analyses were performed to identify clinical and viral factors associated with severe disease.

Results: From 2014 to 2018, we enrolled 534 children with RSV infection, 130 outpatients with mild RSV infection and 404 inpatients with severe RSV disease. Median duration of illness was 4 days for both groups, yet viral loads were higher in outpatients than in inpatients (P < 0.001). In bivariate analyses, wheezing was more frequent in outpatients of older age (>3 months) than in inpatients (P < 0.01), while fever was more common in inpatients than outpatients (P < 0.01) and its frequency increased with age. Adjusted analyses confirmed that increased work of breathing and fever were consistently associated with hospitalization irrespective of age, while wheezing in infants >3 months, and higher RSV loads in children >6-24 months were independently associated with reduced disease severity.

Conclusions: Age had a significant impact defining the interactions among viral loads, specific clinical manifestations and disease severity in children with RSV infection. These observations highlight the importance of patient stratification when evaluating interventions against RSV.
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http://dx.doi.org/10.1097/INF.0000000000002914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808270PMC
February 2021

Definition of erythroid cell-positive blood transcriptome phenotypes associated with severe respiratory syncytial virus infection.

Clin Transl Med 2020 Dec;10(8):e244

Sidra Medicine, Doha, Qatar.

Biomarkers to assess the risk of developing severe respiratory syncytial virus (RSV) infection are needed. We conducted a meta-analysis of 490 unique profiles from six public RSV blood transcriptome datasets. A repertoire of 382 well-characterized transcriptional modules was used to define dominant host responses to RSV infection. The consolidated RSV cohort was stratified according to four traits: "interferon response" (IFN), "neutrophil-driven inflammation" (Infl), "cell cycle" (CC), and "erythrocytes" (Ery). We identified eight prevalent blood transcriptome phenotypes, of which three Ery+ phenotypes comprised higher proportions of patients requiring intensive care. This finding confirms on a larger scale data from one of our earlier reports describing an association between an erythrocyte signature and RSV disease severity. Further contextual interpretation made it possible to associate this signature with immunosuppressive states (late stage cancer, pharmacological immunosuppression), and with a population of fetal glycophorin A+ erythroid precursors. Furthermore, we posit that this erythrocyte cell signature may be linked to a population of immunosuppressive erythroid cells previously described in the literature, and that overabundance of this cell population in RSV patients may underlie progression to severe disease. These findings outline potential priority areas for biomarker development and investigations into the immune biology of RSV infection. The approach that we developed and employed here should also permit to delineate prevalent blood transcriptome phenotypes in other settings.
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http://dx.doi.org/10.1002/ctm2.244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733317PMC
December 2020

Clinical Disease Severity Scores and Viral Loads in Children with RSV Infection.

Clin Infect Dis 2020 Nov 20. Epub 2020 Nov 20.

Center for Vaccines and Immunity Abigail Wexner Research Institute at Nationwide Children's Hospital.

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http://dx.doi.org/10.1093/cid/ciaa1752DOI Listing
November 2020

A Novel Live Attenuated Respiratory Syncytial Virus Vaccine Candidate with Mutations in the L Protein SAM Binding Site and the G Protein Cleavage Site Is Protective in Cotton Rats and a Rhesus Macaque.

J Virol 2021 01 13;95(3). Epub 2021 Jan 13.

Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in children of <5 years of age worldwide, infecting the majority of infants in their first year of life. Despite the widespread impact of this virus, no vaccine is currently available. For more than 50 years, live attenuated vaccines (LAVs) have been shown to protect against other childhood viral infections, offering the advantage of presenting all viral proteins to the immune system for stimulation of both B and T cell responses and memory. The RSV LAV candidate described here, rgRSV-L(G1857A)-G(L208A), contains two modifications: an attenuating mutation in the -adenosylmethionine (SAM) binding site of the viral mRNA cap methyltransferase (MTase) within the large (L) polymerase protein and a mutation in the attachment (G) glycoprotein that inhibits its cleavage during production in Vero cells, resulting in virus with a "noncleaved G" (ncG). RSV virions containing the ncG have an increased ability to infect primary well-differentiated human bronchial epithelial (HBE) cultures which model the site of immunization, the ciliated airway epithelium. This RSV LAV candidate is produced efficiently in Vero cells, is highly attenuated in HBE cultures, efficiently induces neutralizing antibodies that are long lasting, and provides protection against an RSV challenge in the cotton rat, without causing enhanced disease. Similar results were obtained in a rhesus macaque. Globally, respiratory syncytial virus (RSV) is a major cause of death in children under 1 year of age, yet no vaccine is available. We have generated a novel RSV live attenuated vaccine candidate containing mutations in the L and G proteins. The L polymerase mutation does not inhibit virus yield in Vero cells, the cell type required for vaccine production, but greatly reduces virus spread in human bronchial epithelial (HBE) cultures, a logical predictor of attenuation. The G attachment protein mutation reduces its cleavage in Vero cells, thereby increasing vaccine virus yield, making vaccine production more economical. In cotton rats, this RSV vaccine candidate is highly attenuated at a dose of 10 PFU and completely protective following immunization with 500 PFU, 200-fold less than the dose usually used in such studies. It also induced long-lasting antibodies in cotton rats and protected a rhesus macaque from RSV challenge. This mutant virus is an excellent RSV live attenuated vaccine candidate.
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http://dx.doi.org/10.1128/JVI.01568-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925107PMC
January 2021

Year-Round, Routine Testing of Multiple Body Site Specimens for Human Parechovirus in Young Febrile Infants.

J Pediatr 2021 02 9;229:216-222.e2. Epub 2020 Oct 9.

Division of Infectious Diseases, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH.

Objectives: To test our hypothesis that routine year-round testing of specimens from multiple body sites and genotyping of detected virus would describe seasonal changes, increase diagnostic yield, and provide a better definition of clinical manifestations of human parechovirus (PeV-A) infections in young febrile infants.

Study Design: PeV-A reverse-transcriptase polymerase chain reaction (RT-PCR) analysis was incorporated in routine evaluation of infants aged ≤60 days hospitalized at Nationwide Children's Hospital for fever and/or suspected sepsis-like syndrome beginning in July 2013. We reviewed electronic medical records of infants who tested positive for PeV-A between July 2013 and September 2016. Genotyping was performed with specific type 3 RT-PCR and sequencing.

Results: Of 1475 infants evaluated, 130 (9%) tested positive for PeV-A in 1 or more sites: 100 (77%) in blood, 84 (65%) in a nonsterile site, and 53 (41%) in cerebrospinal fluid (CSF). Five infants (4%) were CSF-only positive, 31 (24%) were blood-only positive, and 20 (15%) were nonsterile site-only positive. PeV-A3 was the most common type (85%) and the only type detected in CSF. Although the majority (79%) of infections were diagnosed between July and December, PeV-A was detected year-round. The median age at detection was 29 days. Fever (96%), fussiness (75%), and lymphopenia (56%) were common. Among infants with PeV-A-positive CSF, 77% had no CSF pleocytosis. The median duration of hospitalization was 41 hours. Four infants had bacterial coinfections diagnosed within 24 hours of admission; 40 infants had viral coinfections.

Conclusions: Although most frequent in summer and fall, PeV-A infections were encountered in every calendar month within the 3-year period of study. More than one-half of patients had PeV-A detected at more than 1 body site. Coinfections were common. PeV-A3 was the most common type identified and the only type detected in the CSF.
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http://dx.doi.org/10.1016/j.jpeds.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546655PMC
February 2021

Severe SARS-CoV-2 disease in the context of a NF-κB2 loss-of-function pathogenic variant.

J Allergy Clin Immunol 2021 Feb 30;147(2):532-544.e1. Epub 2020 Sep 30.

Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, Ohio; Center for Vaccines and Immunity, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio; Division of Infectious Diseases, Nationwide Children's Hospital, Columbus, Ohio.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that emerged recently and has created a global pandemic. Symptomatic SARS-CoV-2 infection, termed coronavirus disease 2019 (COVID-19), has been associated with a host of symptoms affecting numerous organ systems, including the lungs, cardiovascular system, kidney, central nervous system, gastrointestinal tract, and skin, among others.

Objective: Although several risk factors have been identified as related to complications from and severity of COVID-19, much about the virus remains unknown. The host immune response appears to affect the outcome of disease. It is not surprising that patients with intrinsic or secondary immune compromise might be particularly susceptible to complications from SARS-CoV-2 infection. Pathogenic loss-of-function or gain-of-function heterozygous variants in nuclear factor-κB2 have been reported to be associated with either a combined immunodeficiency or common variable immunodeficiency phenotype.

Methods: We evaluated the functional consequence and immunologic phenotype of a novel NFKB2 loss of function variant in a 17-year-old male patient and describe the clinical management of SARS-CoV-2 infection in this context.

Results: This patient required a 2-week hospitalization for SARS-CoV-2 infection, including 7 days of mechanical ventilation. We used biologic therapies to avert potentially fatal acute respiratory distress syndrome and treat hyperinflammatory responses. The patient had an immunologic phenotype of B-cell dysregulation with decreased switched memory B cells. Despite the underlying immune dysfunction, he recovered from the infection with intense management.

Conclusions: This clinical case exemplifies some of the practical challenges in management of patients with SARS-CoV-2 infection, especially in the context of underlying immune dysregulation.
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http://dx.doi.org/10.1016/j.jaci.2020.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525247PMC
February 2021

Hydrocortisone treatment is associated with a longer duration of MODS in pediatric patients with severe sepsis and immunoparalysis.

Crit Care 2020 09 4;24(1):545. Epub 2020 Sep 4.

The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.

Background: Severe critical illness-induced immune suppression, termed immunoparalysis, is associated with longer duration of organ dysfunction in septic children. mRNA studies have suggested differential benefit of hydrocortisone in septic children based on their immune phenotype, but this has not been shown using a functional readout of the immune response. This study represents a secondary analysis of a prospectively conducted immunophenotyping study of pediatric severe sepsis to test the hypothesis that hydrocortisone will be differentially associated with clinical outcomes in children with or without immunoparalysis.

Methods: Children with severe sepsis/septic shock underwent blood sampling within 48 h of sepsis onset. Immune function was measured by quantifying whole blood ex vivo LPS-induced TNFα production capacity, with a TNFα response < 200 pg/ml being diagnostic of immunoparalysis. The primary outcome measure was number of days in 14 with MODS. Univariate and multivariable negative binomial regression models were used to examine associations between hydrocortisone use, immune function, and duration of MODS.

Results: One hundred two children were enrolled (age 75 [6-160] months, 60% male). Thirty-one subjects received hydrocortisone and were more likely to be older (106 [52-184] vs 38 [3-153] months, p = 0.04), to have baseline immunocompromise (32 vs 8%, p = 0.006), to have higher PRISM III (13 [8-18] vs 7 [5-13], p = 0.0003) and vasoactive inotrope scores (20 [10-35] vs 10 [3-15], p = 0.0002) scores, and to have more MODS days (3 [1-9] vs 1 [0-3], p = 0.002). Thirty-three subjects had immunoparalysis (TNFα response 78 [52-141] vs 641 [418-1047] pg/ml, p < 0.0001). Hydrocortisone use was associated with longer duration of MODS in children with immunoparalysis after adjusting for covariables (aRR 3.7 [1.8-7.9], p = 0.0006) whereas no association with MODS duration was seen in children without immunoparalysis (aRR 1.2 [0.6-2.3], p = 0.67).

Conclusion: Hydrocortisone use was independently associated with longer duration of MODS in septic children with immunoparalysis but not in those with more robust immune function. Prospective clinical trials using a priori immunophenotyping are needed to understand optimal hydrocortisone strategies in this population.
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http://dx.doi.org/10.1186/s13054-020-03266-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650515PMC
September 2020

Time to Positive Blood and Cerebrospinal Fluid Cultures in Febrile Infants ≤60 Days of Age.

Hosp Pediatr 2020 09;10(9):719-727

Division of Pediatric Infectious Diseases and Center for Vaccines and Immunity, Nationwide Children's Hospital and The Ohio State University, Columbus, Ohio; and.

Objectives: To determine the time to positivity for bacterial pathogens and contaminants in blood and cerebrospinal fluid (CSF) cultures in a cohort of febrile infants ≤60 days of age.

Methods: This was a secondary analysis of prospective observational multicenter study of noncritically ill infants ≤60 days of age with temperatures ≥38°C and blood cultures (December 2008 to May 2013). The main outcome was time to positivity for bacterial pathogens and contaminants.

Results: A total of 256 of 303 (84.49%) patients with positive blood cultures, and 73 of 88 (82.95%) with positive CSF cultures met inclusion criteria. Median time (interquartile range [IQR]) to positivity for blood cultures was 16.6 hours (IQR 12.6-21.9) for bacterial pathogens ( = 74) and 25.1 hours (IQR 19.8-33.0) for contaminants ( = 182); < .001. Time to bacterial pathogen positivity was similar in infants 0 to 28 days of age (15.8 hours [IQR 12.6-21.0]) and 29 to 60 days of age (17.2 [IQR 12.9-24.3]; = .328). Median time to positivity for CSF was 14.0 hours (IQR 1.5-21.0) for bacterial pathogens ( = 22) and 40.5 hours (IQR 21.2-62.6) for contaminants ( = 51); < .001. A total of 82.4% (95% confidence interval, 71.8-90.3) and 81.8% (95% confidence interval, 59.7%-94.8%) of blood and CSF cultures showed bacterial pathogen positivity within 24 hours.

Conclusions: Among febrile infants ≤60 days of age, time to blood and CSF positivity was significantly shorter for bacterial pathogens than contaminants. Most blood and CSF cultures for bacterial pathogens were positive within 24 hours. With our findings, there is potential to reduce duration of hospitalization and avoid unnecessary antibiotics.
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http://dx.doi.org/10.1542/hpeds.2020-0045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446544PMC
September 2020

Author Correction: Baseline and Disease-Induced Transcriptional Profiles in Children with Sickle Cell Disease.

Sci Rep 2020 Aug 6;10(1):13530. Epub 2020 Aug 6.

Center for Microbial Pathogenesis, The Abigail Wexner Research Institute, Columbus, OH, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-70341-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413249PMC
August 2020

Mapping systemic lupus erythematosus heterogeneity at the single-cell level.

Nat Immunol 2020 09 3;21(9):1094-1106. Epub 2020 Aug 3.

The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.

Patients with systemic lupus erythematosus (SLE) display a complex blood transcriptome whose cellular origin is poorly resolved. Using single-cell RNA sequencing, we profiled ~276,000 peripheral blood mononuclear cells from 33 children with SLE with different degrees of disease activity and 11 matched controls. Increased expression of interferon-stimulated genes (ISGs) distinguished cells from children with SLE from healthy control cells. The high ISG expression signature (ISG) derived from a small number of transcriptionally defined subpopulations within major cell types, including monocytes, CD4 and CD8 T cells, natural killer cells, conventional and plasmacytoid dendritic cells, B cells and especially plasma cells. Expansion of unique subpopulations enriched in ISGs and/or in monogenic lupus-associated genes classified patients with the highest disease activity. Profiling of ~82,000 single peripheral blood mononuclear cells from adults with SLE confirmed the expansion of similar subpopulations in patients with the highest disease activity. This study lays the groundwork for resolving the origin of the SLE transcriptional signatures and the disease heterogeneity towards precision medicine applications.
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http://dx.doi.org/10.1038/s41590-020-0743-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442743PMC
September 2020

Preventive Strategies for Respiratory Syncytial Virus Infection in Young Infants.

Neoreviews 2020 08;21(8):e535-e545

Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH.

Respiratory syncytial virus (RSV) is the leading cause of acute viral lower respiratory tract infections in young children, with the peak of severe disease occurring in infants younger than 6 months of age. Most infants who develop severe RSV infection are born full-term and previously healthy; however, premature infants represent an especially vulnerable population at high risk of developing serious sequelae because of RSV. Despite the high disease burden, the pathogenesis of the disease is not completely understood, treatment options are limited to supportive care, and no licensed vaccines are available.The young age of children affected by severe disease and incomplete understanding of the disease pathogenesis, along with prior vaccine failures, have represented major obstacles to RSV vaccine development. Nevertheless, the increasingly recognized burden associated with RSV in low-middle income countries, where RSV represents the second cause of infant mortality, has made the development of preventive strategies for RSV a global health priority. Increased awareness, together with a better understanding of the viral structure and identification of new viral targets, has led to the development of newer RSV vaccines and monoclonal antibodies to confer protection to both preterm and term infants who represent the most vulnerable population for severe RSV disease.
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http://dx.doi.org/10.1542/neo.21-8-e535DOI Listing
August 2020

Radiographic Pneumonia in Febrile Infants 60 Days and Younger.

Pediatr Emerg Care 2020 Jul 18. Epub 2020 Jul 18.

Departments of Emergency Medicine and Pediatrics, University of California Davis School of Medicine, Sacramento, CA.

Objective: Few prospective studies have assessed the occurrence of radiographic pneumonia in young febrile infants. We analyzed factors associated with radiographic pneumonias in febrile infants 60 days or younger evaluated in pediatric emergency departments.

Study Design: We conducted a planned secondary analysis of a prospective cohort study within 26 emergency departments in a pediatric research network from 2008 to 2013. Febrile (≥38°C) infants 60 days or younger who received chest radiographs were included. Chest radiograph reports were categorized as "no," "possible," or "definite" pneumonia. We compared demographics, Yale Observation Scale scores (>10 implying ill appearance), laboratory markers, blood cultures, and viral testing among groups.

Results: Of 4778 infants, 1724 (36.1%) had chest radiographs performed; 2.7% (n = 46) had definite pneumonias, and 3.9% (n = 67) had possible pneumonias. Patients with definite (13/46 [28.3%]) or possible (15/67 [22.7%]) pneumonias more frequently had Yale Observation Scale score >10 compared with those without pneumonias (210/1611 [13.2%], P = 0.002) in univariable and multivariable analyses. Median white blood cell count (WBC), absolute neutrophil count (ANC), and procalcitonin (PCT) were higher in the definite (WBC, 11.5 [interquartile range, 9.8-15.5]; ANC, 5.0 [3.2-7.6]; PCT, 0.4 [0.2-2.1]) versus no pneumonia (WBC, 10.0 [7.6-13.3]; ANC, 3.4 [2.1-5.4]; PCT, 0.2 [0.2-0.3]; WBC, P = 0.006; ANC, P = 0.002; PCT, P = 0.046) groups, but of unclear clinical significance. There were no cases of bacteremia in the definite pneumonia group. Viral infections were more frequent in groups with definite (25/38 [65.8%]) and possible (28/55 [50.9%]) pneumonias than no pneumonias (534/1185 [45.1%], P = 0.02).

Conclusions: Radiographic pneumonias were uncommon, often had viruses detected, and were associated with ill appearance, but few other predictors, in febrile infants 60 days or younger.
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http://dx.doi.org/10.1097/PEC.0000000000002187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855326PMC
July 2020

Blood genome expression profiles in infants with congenital cytomegalovirus infection.

Nat Commun 2020 07 15;11(1):3548. Epub 2020 Jul 15.

Department of Pediatrics, Division of Pediatric Infectious Diseases, Nationwide Children's Hospital -The Ohio State University College of Medicine, Columbus, OH, USA.

Congenital CMV infection (cCMVi) affects 0.5-1% of all live births worldwide, making it the leading cause of sensorineural hearing loss (SNHL) in childhood. The majority of infants with cCMVi have normal hearing at birth, but are at risk of developing late-onset SNHL. Currently, we lack reliable biomarkers to predict the development of SNHL in these infants. Here, we evaluate blood transcriptional profiles in 80 infants with cCMVi (49 symptomatic, 31 asymptomatic), enrolled in the first 3 weeks of life, and followed for 3 years to assess emergence of late-onset SNHL. The biosignatures of symptomatic and asymptomatic cCMVi are indistinguishable, suggesting that immune responses of infants with asymptomatic and symptomatic cCMVi are not different. Random forest analyses of initial samples in infants with cCMVi, irrespective of their clinical classification, identify a 16-gene classifier signature associated with the development of SNHL with 92% accuracy, suggesting its potential value as a biomarker.
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http://dx.doi.org/10.1038/s41467-020-17178-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363904PMC
July 2020

Associations Between IFI44L Gene Variants and Rates of Respiratory Tract Infections During Early Childhood.

J Infect Dis 2021 Jan;223(1):157-165

Department of Paediatrics and Adolescent Medicine, University of Turku and Turku University Hospital, Turku, Finland.

Background: Genetic heterogeneity in type I interferon (IFN)-related gene IFI44L may account for variable susceptibility to respiratory tract infections (RTIs) in children.

Methods: In 2 prospective, population-based birth cohorts, the STEPS Study and the FinnBrain Birth Cohort Study, IFI44L genotypes for rs273259 and rs1333969 were determined in relation to the development of RTIs until 1 or 2 years of age, respectively. At age 3 months, whole-blood transcriptional profiles were analyzed and nasal samples were tested for respiratory viruses in a subset of children.

Results: In the STEPS Study (n = 1135), IFI44L minor/minor gene variants were associated with lower rates of acute otitis media episodes (adjusted incidence rate ratio, 0.77 [95% confidence interval, .61-.96] for rs273259 and 0.74 [.55-.99] for rs1333969) and courses of antibiotics for RTIs (0.76 [.62-.95] and 0.73 [.56-.97], respectively. In the FinnBrain cohort (n = 971), IFI44L variants were associated with lower rates of RTIs and courses of antibiotics for RTIs. In respiratory virus-positive 3-month-old children, IFI44L gene variants were associated with decreased expression levels of IFI44L and several other IFN-related genes.

Conclusions: Variant forms of IFI44L gene were protective against early-childhood RTIs or acute otitis media, and they attenuated IFN pathway activation by respiratory viruses.
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http://dx.doi.org/10.1093/infdis/jiaa341DOI Listing
January 2021

Measuring the Burden of RSV in Children to Precisely Assess the Impact of Preventive Strategies.

Pediatrics 2020 07 16;146(1). Epub 2020 Jun 16.

Division of Pediatric Infectious Diseases and Center for Vaccines and Immunity, Nationwide Children's Hospital, Columbus, Ohio.

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http://dx.doi.org/10.1542/peds.2020-1727DOI Listing
July 2020

Baseline and Disease-Induced Transcriptional Profiles in Children with Sickle Cell Disease.

Sci Rep 2020 06 2;10(1):9013. Epub 2020 Jun 2.

Center for Microbial Pathogenesis, The Abigail Wexner Research Institute, Columbus, OH, USA.

Acute chest syndrome (ACS) is a significant cause of morbidity and mortality in sickle cell disease (SCD), but preventive, diagnostic, and therapeutic options are limited. Further, ACS and acute vasoccclusive pain crises (VOC) have overlapping features, which causes diagnostic dilemmas. We explored changes in gene expression profiles among patients with SCD hospitalized for VOC and ACS episodes to better understand ACS disease pathogenesis. Whole blood RNA-Seq was performed for 20 samples from children with SCD at baseline and during a hospitalization for either an ACS (n = 10) or a VOC episode (n = 10). Respiratory viruses were identified from nasopharyngeal swabs. Functional gene analyses were performed using modular repertoires, IPA, Gene Ontology, and NetworkAnalyst 3.0. The VOC group had a numerically higher percentage of female, older, and hemoglobin SS participants compared to the ACS group. Viruses were detected in 50% of ACS cases and 20% of VOC cases. We identified 3004 transcripts that were differentially expressed during ACS episodes, and 1802 transcripts during VOC episodes. Top canonical pathways during ACS episodes were related to interferon signaling, neuro-inflammation, pattern recognition receptors, and macrophages. Top canonical pathways in patients with VOC included IL-10 signaling, iNOS signaling, IL-6 signaling, and B cell signaling. Several genes related to antimicrobial function were down-regulated during ACS compared to VOC. Gene enrichment nodal interactions demonstrated significantly altered pathways during ACS and VOC. A complex network of changes in innate and adaptive immune gene expression were identified during both ACS and VOC episodes. These results provide unique insights into changes during acute events in children with SCD.
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http://dx.doi.org/10.1038/s41598-020-65822-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265336PMC
June 2020

Metabolomics profiling of tobacco exposure in children with cystic fibrosis.

J Cyst Fibros 2020 09 30;19(5):791-800. Epub 2020 May 30.

Division of Pulmonary Medicine, Nationwide Children's Hospital, Columbus, OH, USA; Center for Microbial Pathogenesis, The Abigail Wexner Research Institute at Nationwide Children's Hospital, W510, 700 Children's Drive, Columbus, OH 43205, USA. Electronic address:

Background: Inflammation is integral to early disease progression in children with CF. The effect of modifiable environmental factors on infection and inflammation in persons with CF is poorly understood. Our prior studies determined that secondhand smoke exposure (SHSe) is highly prevalent in young children with CF. SHSe is associated with increased inflammation, heightened bacterial burden, and worsened clinical outcomes. However, the specific metabolite and signaling pathways that regulate responses to SHSe in CF are relatively unknown.

Methods: High-resolution metabolomics was performed on plasma samples from infants (n = 25) and children (n = 40) with CF compared to non-CF controls (n = 15). CF groups were stratified according to infant or child age and SHSe status.

Results: Global metabolomic profiles segregated by age and SHSe status. SHSe in CF was associated with changes in pathways related to steroid biosynthesis, fatty acid metabolism, cysteine metabolism, and oxidative stress. CF infants with SHSe demonstrated enrichment for altered metabolite localization to the small intestine, liver, and striatum. CF children with SHSe demonstrated metabolite enrichment for organs/tissues associated with oxidative stress including mitochondria, peroxisomes, and the endoplasmic reticulum. In a confirmatory analysis, SHSe was associated with changes in biomarkers of oxidative stress and cellular adhesion including MMP-9, MPO, and ICAM-1.

Conclusions: SHSe in young children and infants with CF is associated with altered global metabolomics profiles and specific biochemical pathways, including enhanced oxidative stress. SHSe remains an important but understudied modifiable variable in early CF disease.
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http://dx.doi.org/10.1016/j.jcf.2020.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492400PMC
September 2020

Key clinical research priorities for the pediatric community during the COVID-19 pandemic.

Pediatr Res 2021 03 15;89(4):730-732. Epub 2020 May 15.

Institute for Advanced Clinical Trials for Children, Rockville, MD, USA.

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http://dx.doi.org/10.1038/s41390-020-0962-yDOI Listing
March 2021

Sleep disturbances and inflammatory gene expression among pregnant women: Differential responses by race.

Brain Behav Immun 2020 08 28;88:654-660. Epub 2020 Apr 28.

Department of Psychiatry & Behavioral Health and The Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Excessive inflammation in pregnancy predicts adverse birth outcomes, including shortened gestational length and lower birthweight, with African American women at greater risk. As substantial racial disparities in sleep quality, and evidence that African Americans have increased vulnerability for sleep-induced inflammatory dysregulation, sleep may be a critical, modifiable health behavior that contributes to racial disparities in birth outcomes. The present study examined sleep disturbance as a predictor of genome-wide transcriptome profiles of peripheral blood samples from 103 pregnant women (33 African American, 70 white) assessed at 18.7 ± 7.2 weeks gestation. We hypothesized that pregnant women with significant sleep disturbances would have gene expression profiles indicating over-expression of inflammatory pathways, with greater effects among African American compared to white women. Promoter-based bioinformatics analyses of differentially expressed genes indicated greater activation of NF-кB, AP1, and CREB transcription factors among African American women with sleep disturbances (all p < 0.05), and enhanced activation of AP1, but not NF-кB and reduced CREB activity among white women with sleep disturbances (p < 0.05). Differences in glucocorticoid receptor (GR) activity were also observed, in which African American women with sleep disturbances had reduced GR activity (p < 0.05), but white women with sleep disturbances showed a trend for enhanced GR activity (p = 0.11). Similarly, Interferon Response Factor (IRF) activity was reduced in African American women while increased in white women with sleep disturbances (p < 0.05). The current study provides novel evidence for gene expression related to inflammation, glucocorticoids, and anti-viral immunity among pregnant women with sleep disturbances, with differential effects by race. African Americans showed greater breadth and magnitude in these proinflammatory and anti-viral pathways than whites, with divergence in anti-inflammatory glucocorticoid, proinflammatory adrenergic-mediated cAMP, and anti-viral interferon responses. These data elucidate the role of sleep disturbances in intracellular inflammatory and anti-viral immunity in pregnancy and provide a potential target for intervention.
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http://dx.doi.org/10.1016/j.bbi.2020.04.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526416PMC
August 2020

Immune profiles provide insights into respiratory syncytial virus disease severity in young children.

Sci Transl Med 2020 04;12(540)

Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.

Respiratory syncytial virus (RSV) is associated with major morbidity in infants, although most cases result in mild disease. The pathogenesis of the disease is incompletely understood, especially the determining factors of disease severity. A better characterization of these factors may help with development of RSV vaccines and antivirals. Hence, identification of a "safe and protective" immunoprofile induced by natural RSV infection could be used as a as a surrogate of ideal vaccine-elicited responses in future clinical trials. In this study, we integrated blood transcriptional and cell immune profiling, RSV loads, and clinical data to identify factors associated with a mild disease phenotype in a cohort of 190 children <2 years of age. Children with mild disease (outpatients) showed higher RSV loads, greater induction of interferon (IFN) and plasma cell genes, and decreased expression of inflammation and neutrophil genes versus children with severe disease (inpatients). Additionally, only infants with severe disease had increased numbers of HLA-DR monocytes, not present in outpatients. Multivariable analyses confirmed that IFN overexpression was associated with decreased odds of hospitalization, whereas increased numbers of HLA-DR monocytes were associated with increased risk of hospitalization. These findings suggest that robust innate immune responses are associated with mild RSV infection in infants.
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http://dx.doi.org/10.1126/scitranslmed.aaw0268DOI Listing
April 2020

The journey to a respiratory syncytial virus vaccine.

Ann Allergy Asthma Immunol 2020 07 23;125(1):36-46. Epub 2020 Mar 23.

Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Division of Pediatric Infectious Diseases, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio.

Objective: The high burden associated with respiratory syncytial virus (RSV) has made the development of RSV vaccine(s) a global health high priority. This review summarizes the journey to an RSV vaccine, the different strategies and challenges associated with the development of preventive strategies for RSV, and the diverse products that are undergoing clinical testing.

Data Sources: Studies on RSV biology, immunology, epidemiology, and monoclonal antibodies (mAbs) and vaccines were searched using MEDLINE. We also searched PATH.org and ClinicalTrials.gov for updated information regarding the status of RSV vaccines and mAbs undergoing clinical trials.

Study Selections: We selected relevant studies conducted in infants and young children, pregnant women, and elderly population for the prevention of RSV infection.

Results: Identification of a safe and immunogenic vaccine has been an important but elusive initiative for more than 60 years for different reasons, including the legacy of formalin-inactivated vaccine, our limited understanding of the immune response to RSV and how it relates to clinical disease severity, or the need for different end points according to the different vaccine platforms. Nevertheless, there are currently 39 vaccines and mAbs under development and 19 undergoing clinical trials.

Conclusion: Over the past decade, there have been significant advances in our knowledge of RSV molecular and structural biology and in understanding the human immune response to RSV. Despite the barriers, there are several promising mAbs and RSV vaccines undergoing clinical trials that hope to offer protection to the most vulnerable populations.
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http://dx.doi.org/10.1016/j.anai.2020.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311299PMC
July 2020

Respiratory syncytial virus treatment and the respiratory microbiome.

Lancet Respir Med 2020 10 20;8(10):941-943. Epub 2020 Mar 20.

Center for Vaccines and Immunity, Abigail Wexner Research Institute, and Division of Pediatric Infectious Diseases, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA.

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http://dx.doi.org/10.1016/S2213-2600(20)30106-5DOI Listing
October 2020

Shock Severity Modifies Associations Between RBC Transfusion in the First 48 Hours of Sepsis Onset and the Duration of Organ Dysfunction in Critically Ill Septic Children.

Pediatr Crit Care Med 2020 08;21(8):e475-e484

Division of Critical Care Medicine, Nationwide Children's Hospital, Columbus, OH.

Objective: To test the hypothesis that early RBC transfusion is associated with duration of organ dysfunction in critically ill septic children.

Design: Secondary analysis of a single-center prospective observational study. Multivariable negative binomial regression was used to determine relationships between RBC transfusion within 48 hours of sepsis onset and number of days in 14 with organ dysfunction, or with multiple organ dysfunction syndrome.

Setting: A PICU at a quaternary care children's hospital.

Patients: Children less than 18 years old with severe sepsis/septic shock by consensus criteria were included. Patients with RBC transfusion prior to sepsis onset and those on extracorporeal membrane oxygenation support within 48 hours of sepsis onset were excluded.

Interventions: None.

Measurements And Main Results: Ninety-four patients were included. Median age was 6 years (0-13 yr); 61% were male. Seventy-eight percentage had septic shock, and 41 (44%) were transfused RBC within 48 hours of sepsis onset (early RBC transfusion). On multivariable analyses, early RBC transfusion was independently associated with 44% greater organ dysfunction days (adjusted relative risk, 1.44 [1.04-2.]; p = 0.03), although risk differed by severity of illness (interaction p = 0.004) and by shock severity (interaction p = 0.04 for Vasoactive Inotrope Score and 0.03 for shock index). Relative risks for multiple organ dysfunction syndrome days varied by shock severity (interaction p = 0.008 for Vasoactive Inotrope Score and 0.01 for shock index). Risks associated with early RBC transfusion were highest for the children with the lowest shock severities.

Conclusions: In agreement with previous studies, early RBC transfusion was independently associated with longer duration of organ dysfunction. Ours is among the first studies to document different transfusion-associated risks based on clinically available measures of shock severity, demonstrating greater transfusion-associated risks in children with less severe shock. Larger multicenter studies to verify these interaction effects are essential to plan much-needed RBC transfusion trials for critically ill septic children.
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http://dx.doi.org/10.1097/PCC.0000000000002338DOI Listing
August 2020

Live Attenuated Vaccine With a Stabilized Mutation and Gene Deletion for Prevention of Respiratory Syncytial Virus Disease in Young Children.

J Infect Dis 2020 02;221(4):501-503

Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.

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http://dx.doi.org/10.1093/infdis/jiz604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996857PMC
February 2020

Recurrent wheezing during the first 3 years of life in a birth cohort of moderate-to-late preterm infants.

Pediatr Allergy Immunol 2020 02 13;31(2):124-132. Epub 2019 Nov 13.

Division of Infectious Diseases, Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.

Background: Data addressing short- and long-term respiratory morbidity in moderate-late preterm infants are limited. We aim to determine the incidence of recurrent wheezing and associated risk and protective factors in these infants during the first 3 years of life.

Methods: Prospective, multicenter birth cohort study of infants born at 32 to 35  weeks' gestation and followed for 3 years to assess the incidence of physician-diagnosed recurrent wheezing. Allergen sensitization and pulmonary function were also studied. We used multivariate mixed-effects models to identify risk factors associated with recurrent wheezing.

Results: A total of 977 preterm infants were enrolled. Rates of recurrent wheezing during year (Y)1 and Y2 were similar (19%) but decreased to 13.3% in Y3. Related hospitalizations significantly declined from 6.3% in Y1 to 0.75% in Y3. Independent risk factors for recurrent wheezing during Y2 and Y3 included the following: day care attendance, acetaminophen use during pregnancy, and need for mechanical ventilation. Atopic dermatitis on Y2 and male sex on Y3 were also independently associated with recurrent wheezing. Palivizumab prophylaxis for RSV during the first year of life decreased the risk or recurrent wheezing on Y3. While there were no differences in rates of allergen sensitization, pulmonary function tests (FEV ) were significantly lower in children who developed recurrent wheezing.

Conclusions: In moderate-to-late premature infants, respiratory symptoms were associated with lung morbidity persisted during the first 3 years of life and were associated with abnormal pulmonary function tests. Only anti-RSV prophylaxis exerted a protective effect in the development of recurrent wheezing.
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http://dx.doi.org/10.1111/pai.13134DOI Listing
February 2020

Risk of childhood wheeze and asthma after respiratory syncytial virus infection in full-term infants.

Pediatr Allergy Immunol 2020 01 23;31(1):47-56. Epub 2019 Oct 23.

Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital & The Ohio State University, Columbus, OH, USA.

Background: Most studies addressing the association between RSV and recurrent wheezing (RW) and asthma have been conducted in patients at risk for lung morbidity. Data in full-term infants are limited.

Methods: The risk of RW/asthma during the first 5 years of life in full-term infants hospitalized with RSV during the first year (Y) of life was estimated using 2010-16 data from three claims databases in USA (Truven MarketScan Commercial Claims and Encounters Database [CCAE], Truven Health MarketScan Multi-State Medicaid [MDCD], and Optum Clinformatics Extended Data Mart-Socio-Economic Status [SES]). Full-term infants with and without RSV infection and ≥ 2 years of continuous health plan enrollment from birth were included. Incidence rates of RW/asthma, cumulative incidence, adjusted incidence rate ratios (aIRR), and odds ratios (aOR) were calculated.

Results: During the 16-year study, 38,494 (CCAE), 62 846 (MDCD), and 23 099 (SES) matched infant pairs were included in each cohort. In the CCAE database, RW/asthma incidence/1000 patient-years (69.7 vs 28.7, aIRR: 2.4 [2.3-2.5]); cumulative incidence (17.6%-25.2% vs 5.0%-11.4%); and aOR (Y2: 4.1 [3.9-4.4]; Y3: 3.2 [3.0-3.3]; Y4: 2.9 [2.7-3.1]; Y5: 2.6 [2.5-2.9]) were higher in the RSV vs. non-RSV cohort. Results in the SES insured population were comparable, while cumulative incidence and aIRR were higher in the Medicaid population (MDCD).

Conclusion: Although there are limitations in this study, including possible coding errors and missing covariates, we showed that full-term infants with severe RSV infection during the first year of life, spanning several respiratory seasons and a geographically diverse population, are at significant risk of RW/asthma during childhood.
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http://dx.doi.org/10.1111/pai.13131DOI Listing
January 2020