scholarly journals 1465. Age-Dependent Interactions Among Clinical Characteristics, Viral Loads and Disease Severity in Young Children with Respiratory Syncytial Virus Infection (RSV) Infection

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S734-S735
Author(s):  
Helena Brenes-Chacon ◽  
Cristina Garcia-Maurino ◽  
Melissa Moore-Clingenpeel ◽  
Sara Mertz ◽  
Fang Ye ◽  
...  
Keyword(s):  
Young Children ◽  
Disease Severity ◽  
Age Groups ◽  
Panel Member ◽  
Signs And Symptoms ◽  
Research Support ◽  
Review Panel ◽  
Viral Loads ◽  
Age Dependent ◽  
Rsv Infection

Abstract Background Differences in clinical presentation and viral loads according to age in young children with RSV, and their correlation with disease severity are poorly defined. The aim of this study was to define age-dependent the differences in demographic, clinical factors and viral loads between children < 2 years of age with mild RSV infection evaluated as outpatients versus those hospitalized with severe RSV infection. Figure 1. Sign and Symptoms according to disease severity and age in infants with RSV infection. Most relevant signs and symptoms were stratified in outpatients (orange) vs inpatients (blue) by age in (A) < 3 months, (B) between 3 and 6 months, and (C) > 6 to 24 months of age. The Y axis represents the signs and symptoms in the two disease severity groups and the X axis the frequency of that specific symptom (%). Numbers next to bars represent the exact number of patients with that specific sign/symptom. Comparisons by Fisher exact test. Symbol (*) indicate significant 2-sided p values Figure 2. Viral load differences according to age in infants with RSV infection. The Y axis represents RSV loads in log10 copies/mL and the X axis differences in viral loads in outpatients (orange) and inpatients (blue) in the three age groups. Comparisons by Mann Whitney test. Methods Previously healthy children < 2 years old with mild (outpatients) and severe (inpatients) RSV infection were enrolled and nasopharyngeal swabs were obtained for RSV typing and quantitation by real-time PCR. Patients were stratified by age (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 2014-2018 we enrolled 534 children with RSV infection: 130 outpatients and 404 inpatients. Median duration of illness was 4 days for both groups, yet viral loads were higher in outpatients than inpatient in the three age groups (Fig 1). Wheezing was more frequent in outpatients of older age (>3 months) than in inpatients (p< 0.01), while fever was more common in inpatients that outpatients (p< 0.01) and increased with age (Fig 2). 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. Conclusion 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. Disclosures Octavio Ramilo, MD, Bill & Melinda Gates Foundation (Grant/Research Support)Janssen (Grant/Research Support, Advisor or Review Panel member)Medimmune (Grant/Research Support)Merck (Advisor or Review Panel member)NIH/NIAID (Grant/Research Support)Pfizer (Consultant, Advisor or Review Panel member)Sanofi/Medimmune (Consultant, Advisor or Review Panel member) Asuncion Mejias, MD, PhD, MsCS, Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Advisor or Review Panel member)Roche (Advisor or Review Panel member)

scholarly journals 131. The Protective Role of Mucosal Interferons in Infants with Respiratory Syncytial Virus (RSV) Infection

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S195-S196
Author(s):  
Jeanette Taveras ◽  
Cristina Garcia-Maurino ◽  
Melissa Moore-Clingenpeel ◽  
Sara Mertz ◽  
Mark E Peeples ◽  
...  
Keyword(s):  
Disease Severity ◽  
Severe Disease ◽  
Panel Member ◽  
Type I ◽  
Research Support ◽  
Review Panel ◽  
Duration Of Symptoms ◽  
Lower Odds ◽  
Rsv Infection ◽  
Ifn Γ

Abstract Background Despite the high burden associated with RSV infection in young children the factors that determine disease severity are not well understood. The objective of this study was to assess the association of mucosal cytokine profiles, RSV loads (VL) and RSV disease severity. Methods Single-center, prospective study in previously healthy infants with mild (outpatients; OP), moderate (inpatient-IP; ward) or severe (IP-PICU) RSV infection. Mid-turbinate swabs were obtained to measure VL by PCR, and cytokine concentrations (conc.) using a 13-plex panel that included type I (IFN-α2), II (IFN-γ), and III (IFN-λ2/λ3) interferons (IFN), and inflammatory cytokines. Multivariable analyses were performed to identify factors predictive of disease severity. Results From 2014 to 2019 we enrolled 219 infants: 78 with mild RSV infection (OP; median [IQR] age, 6 [3.4–10.5] mo.), 101 with moderate disease (3.5 [1.3–8.3] mo.), and 40 with severe disease (2.3 [1.5–5.7] mo.). Duration of symptoms at enrollment was 4 (3–5) days and comparable between OP and IP, yet RSV VL in OP were significantly higher than in IP (8.1 [7.4–8.6] vs 7.4 [6.4–8.1] log10 copies/mL; p< 0.01) with no differences between ward and PICU infants. Median conc. of IFN-α2, IFN-γ, and IFN-λ2/λ3 were significantly higher in OP vs IP irrespective of hospitalization unit (Table 1). IP-10 conc. were also higher in OP and in ward patients vs PICU patients (p< 0.0001) and were independently associated with lower odds of supplemental O2 needs (OR, 95% CI: 0.4 [0.22–0.69]; p< 0.01) and PICU admission (0.4 [0.23–0.67]; p=0.001). In addition, higher IFN-λ2/λ3 conc. were nearly associated with lower odds of prolonged O2 use (OR: 0.35 [0.11–1.07]; p=0.07), and prolonged hospitalization (OR: 0.42 [0.16–1.03]; p=0.06). Conclusion Infants with mild RSV infection had higher RSV VL and higher conc. of IP-10 and type-I, III IFN than those hospitalized with severe disease. These findings suggest that IP-10 and mucosal IFNs are associated with protection against severe RSV disease and could be used as biomarkers for patient stratification in the clinical setting. Disclosures Octavio Ramilo, MD, Bill & Melinda Gates Foundation (Grant/Research Support)Janssen (Grant/Research Support, Advisor or Review Panel member)Medimmune (Grant/Research Support)Merck (Advisor or Review Panel member)NIH/NIAID (Grant/Research Support)Pfizer (Consultant, Advisor or Review Panel member)Sanofi/Medimmune (Consultant, Advisor or Review Panel member) Asuncion Mejias, MD, PhD, MsCS, Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Advisor or Review Panel member)Roche (Advisor or Review Panel member)

scholarly journals 1193. Mucosal Antibody Responses to Respiratory Syncytial Virus (RSV) in Infants and Young Children

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S688-S688
Author(s):  
Cristina Tomatis Souverbielle ◽  
Fang Ye ◽  
Sara Mertz ◽  
Mark E Peeples ◽  
Octavio Ramilo ◽  
...  
Keyword(s):  
Disease Severity ◽  
Panel Member ◽  
Healthy Children ◽  
Upper Respiratory Tract ◽  
Limited Information ◽  
Research Support ◽  
Review Panel ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Research Grant

Abstract Background The burden associated with RSV infection is substantial. Although RSV initially infects the upper respiratory tract, there is limited information of the mucosal concentrations of antibodies (Abs) directed to RSV specific proteins and whether patient’s age and disease severity influence production of mucosal Abs. Methods From 2017 to2019 we enrolled previously healthy children < 2 years of age hospitalized with RSV infection and obtained acute and convalescent (day; D30) nasopharyngeal (NP) samples to measure preF and postF specific IgG and IgA Abs by ELISA. Demographic and clinical data were collected and analyzed according to Abs responses. Results We enrolled 77 children (median [IQR] age: 2.8 [1.5-5.2] months; 49 % females) within the first 24 hours of hospitalization. Of those 25 (33%) patients required PICU care. A significant increase in convalescent IgG preF Abs titers was detected in 62 (81%) children, while IgA preF titers significantly increased in all but one child on D30. The magnitude of the increase was 56-fold higher for preF IgA versus preF IgG (p< 0.0001). PostF IgG and IgA titers were also increased on D30 but at significant lower levels. Infants < 3 months of age compared with those >3-24 months had significantly higher baseline preF and postF IgG Abs titers (p < 0.001) but not IgA antibodies. D30 preF and post F IgG titers were higher in children > 6 months of age (p < 0.0001) but only preF titers fold change significantly correlated with age (r=0.4, p< 0.0001). These correlations were not identified with IgA preF antibodies. There were no statistical differences in antibody titers at baseline and on D30 according to breastfeeding, and disease severity as defined by the need for PICU care. Conclusion Children hospitalized with RSV infection demonstrated significantly increased titers of mucosal preF and post F IgG and IgA specific Abs in convalescent samples. Baseline IgG Abs where higher in younger infants, which likely reflects maternally acquired antibodies. Age significantly correlated with Abs production, suggesting a more robust immune response in older children. Disclosures Mark E. Peeples, PhD, Janssen (Research Grant or Support)Pfizer (Research Grant or Support) Octavio Ramilo, MD, Adagio (Consultant)Bill & Melinda Gates Foundation (Grant/Research Support)Janssen (Grant/Research Support)Lilly (Consultant)Merck (Consultant, Grant/Research Support)NIH (Grant/Research Support)Pfizer (Consultant)SANOFI (Board Member) Asuncion Mejias, MD, PhD, MsCS, Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Roche (Advisor or Review Panel member)Sanofi (Advisor or Review Panel member)

scholarly journals 79. Children with COVID-19 Demonstrate Distinct Serum Cytokines Profiles According to Clinical Presentations

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S51-S52
Author(s):  
Zhaohui Xu ◽  
Rebecca M Glowinski ◽  
Shira H Cohen ◽  
Cameron Mertz ◽  
Sara Mertz ◽  
...  
Keyword(s):  
Disease Severity ◽  
Universal Screening ◽  
Panel Member ◽  
Healthy Controls ◽  
Research Support ◽  
Review Panel ◽  
Viral Loads ◽  
Serum Cytokines ◽  
Clinical Presentations ◽  
D Dimer

Abstract Background Almost 4 million children have tested positive for Coronavirus Disease 2019 (COVID-19) as of June 3 2021, representing 14% of all cases in USA. Children present with diverse clinical findings including the multisystem inflammatory syndrome in children (MIS-C). In this study, we measured serum cytokine concentrations in children with COVID-19 to identify differences in immune profiles according to clinical presentations. Methods A total of 133 children 0-21 years of age with COVID-19 were enrolled at Nationwide Children’s Hospital, in Columbus, Ohio. Nasopharyngeal swab RT-PCR testing was used for SARS-CoV-2 detection and quantification. Clinical and laboratory information were obtained, and blood samples were collected for measurement of cytokines with a 92-plex inflammation assay (Olink). Normalized cytokine expression levels in patients were compared with serum samples from 66 pre-pandemic age-matched healthy controls. Results COVID-19 children included: 1) those identified by universal screening (n=47); 2) moderate disease (ward; n=48); 3) severe disease (PICU; n=20); 4) MIS-C (n=18). Children identified by universal screening were hospitalized for trauma, appendicitis or new onset diabetes among others. Children with symptomatic COVID-19 had significantly higher SARS-CoV-2 viral loads than children with MIS-C or those identified via universal screening. Concentrations of interferon (IFN) related cytokines (IFNg, CXCL9, CXCL10, CXCL11), interleukins (IL6, IL8, IL10, IL17A, IL18, IL24) and other inflammatory cytokines (TGF, TNF, VEGF, MCP, CD40) were significantly increased in children with acute COVID-19 and MIS-C compared with children identified by universal screening and healthy controls. These cytokines were positively correlated with C-reactive protein, D-dimer and disease severity in COVID-19, but negatively correlated with viral loads (Fig 1). MIS-C showed stronger inflammatory response than acute COVID-19 (Fig 2). Correlation of Age-adjusted cytokine expression values with viral load, disease severity, CRP and D-dimer. Pearson correlation coefficient is shown for each pair. Red: positive correlation; blue: negative correlation Cytokines that differentiate MIS-C from acute COVID-19 Heatmap shows the differential expressed cytokines between MIS-C and acute severe COVID-19 (padj<0.05, FC>2). The age-adjusted expression values are normalized the median of healthy controls. Red: up-regulation, blue: down-regulation. Conclusion We identified three cytokine clusters in children with COVID-19 according to clinical presentations. Correlations of serum cytokines with clinical/laboratory parameters could be used to identify potential biomarkers associated with disease severity in COVID-19 Disclosures Asuncion Mejias, MD, PhD, MsCS, Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Roche (Advisor or Review Panel member)Sanofi (Advisor or Review Panel member) Octavio Ramilo, MD, Adagio (Consultant)Bill & Melinda Gates Foundation (Grant/Research Support)Janssen (Grant/Research Support)Lilly (Consultant)Merck (Consultant, Grant/Research Support)NIH (Grant/Research Support)Pfizer (Consultant)SANOFI (Board Member)

scholarly journals 1211. Incidence of All-Cause Community-Acquired Pneumonia in Ontario and British Columbia, Canada, 2002-2018; a Canadian Immunization Research Network (CIRN) study

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S695-S696
Author(s):  
Sharifa Nasreen ◽  
John Wang ◽  
Jeffrey Kwong ◽  
Natasha S Crowcroft ◽  
Manish Sadarangani ◽  
...  
Keyword(s):  
Older Adults ◽  
British Columbia ◽  
Pneumococcal Conjugate Vaccine ◽  
Age Groups ◽  
Panel Member ◽  
Community Acquired Pneumonia ◽  
Annual Incidence ◽  
Research Support ◽  
Review Panel ◽  
Research Grant

Abstract Background Community-acquired pneumonia (CAP) causes substantial morbidity and mortality. There is a lack of data on the comprehensive burden of CAP across the life span in Canada. We estimated the incidence of all-cause CAP in all age groups in Ontario and British Columbia (BC), Canada. Methods We identified hospitalized and outpatient CAP episodes from the Discharge Abstract Database (DAD) and physician billing claims databases (Ontario Health Insurance Plan in Ontario and Medical Services Plan in BC) in both provinces. The National Ambulatory Care Reporting System was used to identify CAP episodes from emergency department visits in Ontario. CAP recorded with a primary or secondary diagnosis was identified using International Classification of Diseases 9 (480–486, 510, 513) and 10 (J10.0, J11.0, J12–J18, J86.9, J85.1) codes. We estimated the age and sex adjusted annual incidence of CAP overall, and by age groups (0–4, 5–17, 18–39, 40–64, 65–74, 75–84 and ≥85 years) according to routine childhood pneumococcal conjugate vaccine (PCV) immunization periods from 2005–2018 in Ontario and from 2002–2018 in BC. Poisson regression models were fitted with population denominators from Statistics Canada to estimate the incidence rates. Results Ontario had 3,607,186 CAP episodes from 2005–2015 with a mean annual incidence of 2,801 (95% confidence interval [CI]: 2,748, 2,854) per 100,000 population; incidence declined from 3,077/100,000 in 2005 to 2,604/100,000 in 2010 before increasing to 2,843/100,000 in 2018. BC had 1,146,172 CAP episodes from 2002–2008, with a mean annual incidence of 2,146 (95% CI: 2105, 2189); the incidence increased from 2,005 /100,000 in 2002 to 2,199/100,000 in 2018. A high incidence of CAP was observed in children aged 0–4 years and older adults, particularly in adults aged ≥85 years in both provinces across all PCV program periods (Figure 1). Figure 1: Age group-specific incidence of all-cause community-acquired pneumonia according to childhood pneumococcal conjugate vaccine (PCV) program periods in Ontario (PCV7 [1 Jan 2005–30 Sep 2009]), PCV10 [1 Oct 2009–31 Oct 2010] and PCV13 [1 Nov 2010–31 Dec 2018]) and British Columbia (PCV7 [1 Sep 2003–31 May 2010] and PCV13 [1 Jun 2010–31 Dec 2018]), Canada Conclusion CAP continues to be a public health burden in Canada despite publicly funded pneumococcal vaccination programs. Ontario seems to have higher CAP burden than British Columbia that warrants further investigation. The youngest cohort of children and older adults contribute significantly to the CAP burden. Disclosures Manish Sadarangani, BM BCh, DPhil, GlaxoSmithKline (Grant/Research Support)Merck (Grant/Research Support)Pfizer (Grant/Research Support)Sanofi Pasteur (Grant/Research Support)Seqirus (Grant/Research Support)Symvivo (Grant/Research Support)VBI Vaccines (Research Grant or Support) Allison McGeer, MSc,MD,FRCPC,FSHEA, GlaxoSmithKline (Advisor or Review Panel member)Merck (Advisor or Review Panel member, Research Grant or Support)Pfizer (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member) James D. Kellner, MD, FRCPC, FIDSA, Pfizer, Merck, GSK, Moderna (Grant/Research Support) Shaun Morris, MD, MPH, DTM&H, FRCPC, FAAP, GSK (Speaker’s Bureau)Pfizer (Advisor or Review Panel member)Pfizer (Grant/Research Support) Shaza A. Fadel, PhD MPH, Merck (Other Financial or Material Support, Salary is paid by the University of Toronto via a donation by Merck to the Centre for Vaccine Preventable Diseases to support educational and operational activities.) Fawziah Marra, BSc(Pharm), PharmD, Pfizer Canada (Research Grant or Support)

scholarly journals 1186. Increased Respiratory Syncytial Virus (RSV) Viral Replication Leads to Increased Cytokine Production and Polarized Interferon Response in Infant Mucosal Epithelium

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S684-S685
Author(s):  
Rebecca M Glowinski ◽  
Ki Wook Yun ◽  
Asuncion Mejias ◽  
Octavio Ramilo
Keyword(s):  
Viral Replication ◽  
Inflammatory Cytokines ◽  
Cytokine Production ◽  
Severe Disease ◽  
Panel Member ◽  
Interferon Response ◽  
Research Support ◽  
Review Panel ◽  
Basolateral Side ◽  
Rsv Infection

Abstract Background RSV is the most frequent etiology of pediatric lower respiratory tract infection. Most children hospitalized for RSV are previously healthy without known risk factors. Children with mild disease managed as outpatients (OP) have higher viral loads than those hospitalized with severe disease. OP children have higher concentrations of the mucosal interferon (IFN), IFNλ2/3, and IP-10, but no differences in IFNλ1. We examined how RSV replication impacts cytokine production kinetics in the nasal mucosa. Methods Primary infant human nasal epithelial (iHNE) cells were collected from nasopharyngeal swabs and cultured on an air-liquid interface. Cultures were infected with 0.1 or 0.001 multiplicity of infection (MOI) of RSV-A, or mock infected. Concentrations of IFN-related (IFNα2, β, γ, λ1, λ2/3, and IP-10) and inflammatory (IL-1β, -6, -12, and TNFα) cytokines secreted to the apical and basolateral surfaces were quantified via immunoassay. Kinetics according to viral inocula were compared by ANOVA with Dunn post-hoc testing of the area under the curve (AUC) for each cytokine. Peak concentrations were compared according to MOI and secretion surface by 2-way ANOVA. Results AUC of IFNs in both surfaces of RSV infected cells were significantly higher than those of mock infected. The 0.1 MOI RSV inoculum resulted in significantly higher AUCs for all IFN cytokines on both surfaces than the 0.001 MOI. Peak IFNλ1 concentrations were higher on the apical than basolateral side; peak IFNλ2/3 concentrations were higher on the basolateral side than apical. AUCs of inflammatory cytokines in RSV infection were significantly higher on the basolateral, but not apical, surfaces than mock; all basolateral inflammatory cytokines were higher in the 0.1 MOI than the 0.001 MOI. Conclusion Higher RSV inoculum induces higher concentrations of IFN-related cytokines on both sides of epithelial cells, and higher concentrations of inflammatory cytokines on the basolateral side. Differential secretion of IFNλ1 and IFNλ2/3 to the apical and basolateral surfaces suggests they may play different roles in immune response during RSV infection. These data support viral replication as an important factor influencing RSV pathogenesis and severity through cytokine production. Disclosures Asuncion Mejias, MD, PhD, MsCS, Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Roche (Advisor or Review Panel member)Sanofi (Advisor or Review Panel member) Octavio Ramilo, MD, Adagio (Consultant)Bill & Melinda Gates Foundation (Grant/Research Support)Janssen (Grant/Research Support)Lilly (Consultant)Merck (Consultant, Grant/Research Support)NIH (Grant/Research Support)Pfizer (Consultant)SANOFI (Board Member)

scholarly journals 77. Risk of Virologic Failure Among Treatment-experienced Suppressed People with HIV (PWH) Treated with Single-Tablet 2-Drug (2DR) vs 3-Drug (3DR) Regimens

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S50-S51
Author(s):  
Paul Sax ◽  
Joseph J Eron ◽  
Janna Radtchenko ◽  
Helena Diaz-Cuervo ◽  
Mark Moore ◽  
...  
Keyword(s):  
Research Study ◽  
Virologic Failure ◽  
Scientific Research ◽  
Panel Member ◽  
Research Support ◽  
Review Panel ◽  
Viral Loads ◽  
Study Investigator ◽  
Baseline Characteristics ◽  
Research Grant

Abstract Background The single-tablet regimen (STR) dolutegravir/rilpivirine (DTG/RPV) was approved in 2017 for use in virologically suppressed PWH, followed by approval in 2019 of dolutegravir/lamivudine (DTG/3TC). There is a need to evaluate outcomes of 2DR regimens in stable switch population by measuring risk of virologic failure. Methods This retrospective observational study of the Trio Health HIV Research Network cohort of nearly 60,000 PWH evaluated risk of virologic failure among treatment-experienced virologically suppressed PWH switching to a 2DR or 3DR STR (index = time of switch). Eligible patients (pts) were ≥ 18 yrs, treatment-experienced, suppressed at index, with post-index viral loads, ≥ 6 mo pre-index history, with dispenses for DTG/RPV, DTG/3TC or commonly used 3DR STRs initiated after Nov. 2017. Univariate comparisons were performed using Χ2 for categorical and t-test for continuous variables; Kaplan-Meier analysis was used to evaluate time to virologic failure and Cox Proportional Hazards analysis was used to evaluate risk of virologic failure accounting for age, gender, race, and baseline eGFR. Virologic failure was defined as 2 consecutive viral loads >200 cells/ml. Results Of 1668 pts, 132 (8%) received 2DR. Significant differences in baseline characteristics between groups are shown in Table 1. In unadjusted analysis the difference in proportion of pts with virologic failure did not reach significance: 7% (9 pts) on 2DR experienced virologic failure vs 4% (65 pts) on 3DR (p=0.166). Additionally, unadjusted risk of virologic failure and time to virologic failure were not statistically different [Figure 1, Table 2]. Based on prespecified adjusted analysis accounting for race, gender, age, and baseline eGFR, the risk of virologic failure was higher for 2DR compared to 3DR STRs (HR=2.2 CI 95% 1.1-4.5, p=0.032) [Table 2]. Adjusting for baseline CD4 was not feasible due to high proportion of missing CD4 at index. Table 1 Baseline (index) characteristics Figure 1 Unadjusted time to virologic failure Table 2 Risk of virologic failure Conclusion This early evaluation showed higher risk of virologic failure among virologically suppressed pts who switched to 2DR vs 3DR STRs after adjusting for differences in baseline characteristics. Future analysis is warranted using a larger sample of 2DR pts with additional adjustment for prior regimen failure. Disclosures Paul Sax, MD, Gilead Sciences (Consultant, Grant/Research Support)Janssen (Consultant)Merck (Consultant, Research Grant or Support)ViiV (Consultant, Research Grant or Support) Joseph J. Eron, MD, Gilead Sciences (Consultant, Research Grant or Support)Janssen (Consultant, Research Grant or Support)Merck (Consultant)ViiV (Consultant, Research Grant or Support) Janna Radtchenko, MBA, Trio Health (Employee) Helena Diaz-Cuervo, PhD, Gilead Sciences (Employee) Mark Moore, PhD, Gilead Sciences (Employee) Steven Santiago, MD, Gilead Sciences (Advisor or Review Panel member, Speaker's Bureau)Janssen (Speaker's Bureau) Moti Ramgopal, MD FIDSA, Abbvie (Scientific Research Study Investigator, Speaker's Bureau)Gilead (Consultant, Scientific Research Study Investigator, Speaker's Bureau)Janssen (Consultant, Scientific Research Study Investigator, Research Grant or Support, Speaker's Bureau)Merck (Consultant, Scientific Research Study Investigator)ViiV (Consultant, Scientific Research Study Investigator, Speaker's Bureau) Karam Mounzer, MD, Epividian (Advisor or Review Panel member)Gilead Sciences Inc. (Consultant, Scientific Research Study Investigator, Research Grant or Support, Speaker’s Bureau)Janssen (Consultant, Research Grant or Support, Speaker's Bureau)Merck (Research Grant or Support, Speaker's Bureau)ViiV Healthcare (Consultant, Speaker's Bureau) Richard Elion, MD, Gilead Sciences (Grant/Research Support, Advisor or Review Panel member, Speaker's Bureau)Janssen (Speaker's Bureau)Proteus (Grant/Research Support)Trio Health (Employee)ViiV (Advisor or Review Panel member)

scholarly journals 999. Nasal Mucosal Cytokines: Potential Biomarkers for Pediatric Pneumonia Severity and Etiology

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S590-S591
Author(s):  
Rouba Sayegh ◽  
Ki Wook Yun ◽  
Zhaohui Xu ◽  
Rebecca Wallihan ◽  
Sarah Marzec ◽  
...  
Keyword(s):  
Protein Expression ◽  
Disease Severity ◽  
Panel Member ◽  
Community Acquired Pneumonia ◽  
Arbitrary Unit ◽  
Research Support ◽  
Review Panel ◽  
Whitney Test ◽  
Mild Disease ◽  
Mann Whitney Test

Abstract Background Community acquired pneumonia (CAP) is a leading cause of mortality in children < 5 years, but our understanding of disease pathogenesis remains limited. The objective of this study was to define the local host immune response in the respiratory tract by measuring nasal mucosal cytokine (NMC) concentrations (conc.). We hypothesized that NMC represent a potential biomarker to help assessing disease severity and pathogen classification. Methods We leveraged nasopharyngeal (NP) samples and clinical data from an observational multicenter study [Children’s Hospital’s Initiative for Research in Pneumonia (CHIRP)] conducted between 2015 and 2018. We measured conc. of 92 NMC using the Olink immunoassay. NMC conc. were compared by severity-defined by need for hospitalization, mild (outpatient) and severe (inpatient), and by identified pathogen using Mann-Whitney U test. Results This substudy included 182 children with CAP (mild=61; severe=121) and 30 healthy controls (HC). The pathogens identified included: 101 viruses; 32 bacteria (pyogenic=10; atypical=22); 12 with >1 pathogen; and 37 with no pathogen. Children with severe CAP had greater CCL23 and MCP-3 conc. than those with mild disease (p=0.012; p=0.011 respectively). When comparing NMC profiles of children with CAP of viral and bacterial etiology, the viral group had greater conc. of proinflammatory cytokines IL-6 and TNF, (p=0.0002; p=0.0098 respectively). Further subgroup analysis showed that CAP secondary to influenza virus had greater conc. of IL-6, TNF, and antiviral INF-γ and IP-10 compared with CAP caused by pyogenic bacteria. IL-6 and MCP1-4 were significantly increased in the influenza group compared to the atypical bacteria group. Quantification of NMC in children with CAP based on disease severity NMC nasal mucosal cytokine; CAP: community acquired pneumonia; NPX: normalized protein expression, arbitrary unit used in Olink assay that is log 2 scale. Mann-Whitney test was used to determine differences between mild and severe pneumonia Quantification of NMC in children with CAP based on pathogen classification NMC: nasal mucosal cytokine; CAP: community acquired pneumonia; NPX: normalized protein expression, arbitrary unit used in Olink assay that is log 2 scale. Mann-Whitney test was used to determine differences between bacterial CAP and viral CAP. Conclusion Children with severe CAP had higher monocyte chemoattractant NMC conc. than children with mild disease. Children with viral CAP, particularly influenza, had a more robust mucosal response including both proinflammatory and antiviral NMC than children with bacterial CAP. These findings show differences in NMC conc. based on etiology and disease severity. Further studies are needed to determine whether NMC are reliable predictive biomarkers of CAP etiology and severity. Disclosures Lilliam Ambroggio, PhD, MPH, Pfizer Inc (Grant/Research Support) Asuncion Mejias, MD, PhD, MsCS, Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Roche (Advisor or Review Panel member)Sanofi (Advisor or Review Panel member) Octavio Ramilo, MD, Adagio (Consultant)Bill & Melinda Gates Foundation (Grant/Research Support)Janssen (Grant/Research Support)Lilly (Consultant)Merck (Consultant, Grant/Research Support)NIH (Grant/Research Support)Pfizer (Consultant)SANOFI (Board Member)

scholarly journals 204. Mucosal Cytokine Profiles in Children with COVID-19

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S1-S1
Author(s):  
Shira H Cohen ◽  
Cameron Mertz ◽  
Rebecca M Glowinski ◽  
Sara Mertz ◽  
Fang Ye ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Clinical Presentation ◽  
Panel Member ◽  
Multiple Comparisons ◽  
Research Support ◽  
Review Panel ◽  
Viral Loads ◽  
Non Invasive ◽  
Cytokine Profiles ◽  
Gates Foundation

Abstract Background The mechanisms associated with COVID-19 in children are not well understood. We sought to define the differences in nasopharyngeal (NP) cytokine profiles according to clinical presentation in children with COVID-19. Methods Single-center, prospective study in 137 children and adolescents < 21 years of age hospitalized with COVID-19, and 35 age, sex and race matched pre-pandemic (2016-2019) healthy controls. Children with COVID-19 were categorized according to their clinical presentation in: COVID-19-symptomatic; COVID-19-screening, and multisystem inflammatory syndrome (MIS-C). NP swabs were obtained within 24 hours of admission to measure SARS-CoV-2 loads by rt-PCR, and a 92-cytokine panel. Unsupervised and supervised analysis adjusted for multiple comparisons were performed. Results From 3/2020 to 1/2021, we enrolled 76 COVID-19-symptomatic children (3.5 [0.2-15.75] years); 45 COVID-19-screening (11.1 [4.2-16.1] years), and 16 MIS-C (11.2 [5.9-14.6] years). Median NP SARS-CoV-2 loads were higher in COVID-19-symptomatic versus screening and MIS-C (6.8 vs 3.5 vs 2.82 log10 copies/mL; p< 0.001). Statistical group comparisons identified 15 cytokines that consistently differed between groups and were clustered in three functional categories: (1) antiviral/regulatory, (2) pro-inflammatory/chemotactic, and (3) a combination of (1) and (2); (Fig 1). All 15 cytokines were higher in COVID-19-symptomatic versus controls (p< 0.05). Similarly, and except for TNF, CCL3, CCL4 and CCL23, which were comparable in COVID-19-symptomatic and screening patients, the remaining cytokines were higher in symptomatic children (p< 0.05). PDL-1 (p=0.01) and CCL3 (p=0.03) were the only cytokines significantly decreased in children with MIS-C versus symptomatic COVID-19 children. The 15 cytokines identified by multiple comparisons were correlated using Person’s in R software. Red reflects a positive correlation and blue a negative correlation with the intensity of the color indicating the strength of the association. Conclusion Children with symptomatic COVID-19 demonstrated higher viral loads and greater mucosal cytokines concentrations than those identified via screening, whereas in MIS-C concentrations of regulatory cytokines were decreased. Simultaneous evaluation of viral loads and mucosal immune responses using non-invasive sampling could aid with the stratification of children and adolescents with COVID-19 in the clinical setting. Disclosures Octavio Ramilo, MD, Adagio (Consultant)Bill & Melinda Gates Foundation (Grant/Research Support)Janssen (Grant/Research Support)Lilly (Consultant)Merck (Consultant, Grant/Research Support)NIH (Grant/Research Support)Pfizer (Consultant)SANOFI (Board Member) Asuncion Mejias, MD, PhD, MsCS, Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Roche (Advisor or Review Panel member)Sanofi (Advisor or Review Panel member).

scholarly journals 1012. Efficacy, safety and tolerability of switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in HIV-1 infected virologically-suppressed older adults in a real-world setting

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S534-S535
Author(s):  
Charlotte-Paige M Rolle ◽  
Vu Nguyen ◽  
Kiran Patel ◽  
Dan Cruz ◽  
Federico Hinestrosa ◽  
...  
Keyword(s):  
Older Adults ◽  
Drug Interactions ◽  
Real World ◽  
Research Study ◽  
Panel Member ◽  
Median Number ◽  
Research Support ◽  
Review Panel ◽  
Study Investigator ◽  
Hiv 1

Abstract Background Approximately 50% of people living with HIV (PLWH) in the United States are ≥50 years old. Efforts are ongoing to identify antiretrovirals associated with fewer drug-drug interactions (DDIs) and long-term side effects in this group. Clinical trials of B/F/TAF demonstrated favorable efficacy and safety in older adults, however, data from real-word settings are needed to validate these results. Methods This retrospective analysis evaluated records from PLWH aged ≥ 50 years at the Orlando Immunology Center who were switched to B/F/TAF between 2/7/2018 and 5/31/2019. Eligible patients had baseline HIV-1 RNA< 50 copies/mL and were followed for 48 weeks post-switch. The primary endpoint was maintenance of HIV-1 RNA< 50 copies/mL at week 48. The impact of switching to B/F/TAF on DDIs, adverse events (AEs) and safety parameters were analyzed throughout the study. Results 306 patients met inclusion criteria. 62 (20%) were female, 126 (41%) were non-white, median age was 58 years (range [r] 50-81), median duration of HIV infection was 19.5 years (r 2-40), median number of chronic co-morbid conditions was 5 (r 0-20), and median number of baseline concomitant medications was 4 (r 0-23). 159 (52%) patients were switched from regimens containing ritonavir or cobicistat. The most commonly documented reason for switch was simplification (Table 1). At Week 48, 287 (94%) patients maintained an HIV-1 RNA< 50 copies/ml and 19 (6%) had an HIV-1 RNA between 50-200 copies/mL (Figure 1). 1 patient discontinued due to lack of efficacy. A total of 123 potential DDIs were identified in 104 (34%) patients taking a boosting agent or rilpivirine at baseline (Table 2). At Week 48, there was a significant median decline in total cholesterol (15.5 mg/dL, 95% confidence interval [CI]: 9.5; 21.5), LDL cholesterol (9.5 mg/dL, 95% CI: 4; 15.5) and triglycerides (20 mg/dL, 95% CI: 9.5; 32.5), and median weight increased by 2.5 pounds (95% CI: 1.5; 3.5). Treatment-related AEs occurred in 33 (11%) patients (all Grade 1-2) and led to 7 (2%) discontinuations. Table 1-Baseline demographic and clinical characteristics Table 2-Avoidance of Drug-Drug Interactions (DDIs) following switch to B/F/TAF Figure 1-Subgroup analysis of virologic outcomes at Week 48 Conclusion In this real-world cohort, switching to B/F/TAF was associated with maintenance of virologic control, improvement in lipid parameters, and avoidance of DDIs in a large proportion of patients. These data support use of B/F/TAF as a treatment option in older PLWH. Disclosures Charlotte-Paige M. Rolle, MD MPH, Gilead Sciences (Grant/Research Support, Scientific Research Study Investigator, Speaker’s Bureau)Janssen Infectious Disease (Grant/Research Support)ViiV Healthcare (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau) Kiran Patel, PharmD, Gilead Sciences (Employee) Federico Hinestrosa, MD, AbbVie (Speaker’s Bureau)Gilead Sciences (Speaker’s Bureau)Merck (Speaker’s Bureau)Theratechnologies (Speaker’s Bureau) Edwin DeJesus, MD, Gilead Sciences (Advisor or Review Panel member)

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