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

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)

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

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1646 ◽

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)

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

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1403 ◽

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)

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

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.441 ◽

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)

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

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1385 ◽

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)

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1499. Incidence of Community Acquired Pneumonia by Age and Comorbid Conditions in the Veterans Health Administration (VHA)

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1680 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S751-S752

Author(s):

Taissa A Bej ◽

Sunah Song ◽

Brigid Wilson ◽

Richard Banks ◽

Janet Briggs ◽

...

Keyword(s):

At Risk ◽

High Risk ◽

Panel Member ◽

Community Acquired Pneumonia ◽

Comorbid Conditions ◽

Moderate Risk ◽

Research Support ◽

Review Panel ◽

Risk Condition ◽

Research Grant

Abstract Background Community acquired pneumonia (CAP) remains a major cause of morbidity and mortality. Risk factors for CAP are often grouped as moderate- (e.g., diabetes mellitus, chronic liver, lung, or heart disease) and high-risk (e.g., immunosuppressive) conditions, which in turn influences preventative strategies, notably pneumococcal vaccination. Here, we use the national VHA databases to assess the risk of CAP among adults, expanding on previous work by using administrative data to assess the incidence of CAP among people with > 1 moderate risk condition Methods We used the national VHA databases merged with claims summaries from the Centers for Medicare and Medicaid Services (CMS) to identify patients receiving clinical care in the VHA without clinical Medicare claims in 2016-2017. Within this population, we identified CAP cases defined by the presence of a diagnostic code for pneumonia, chest X-ray, and antibiotics as well as the absence of healthcare exposure or antibiotics in prior 90 days. We determined the total patient years at risk and calculated incidence rates by age group and by moderate- and high-risk comorbid conditions. Results We identified 37,348 CAP cases in 7.9 million person-years at risk and observed similar annual rates in 2016 and 2017 (468.9 and 472.2 cases/100,000 person-years, respectively). The prevalence of high-risk conditions and incidence of CAP increased with age whereas the prevalence of >1 moderate-risk condition peaked for ages 50-64 and 65-74 years (Table). The incidence of CAP among those with > 1 moderate-risk condition exceeded that of patients with high-risk conditions across all age strata (Figure). Table Figure Conclusion Age-adjusted analysis revealed that the greatest burden of CAP occurs in patients with > 1 moderate-risk condition, even compared to those with a high-risk condition. Our analysis of CAP based on national VHA data suggest that additional preventative health measures directed at individuals older than 50 years with > 1 moderate-risk condition may help to reduce the burden of CAP and limit its morbidity and mortality. Disclosures Robin Jump, MD, PhD, Accelerate (Grant/Research Support)Merck (Grant/Research Support)Pfizer (Grant/Research Support, Advisor or Review Panel member)Roche (Advisor or Review Panel member) Federico Perez, MD, MS, Accelerate (Research Grant or Support)Merck (Research Grant or Support)Pfizer (Research Grant or Support)

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

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.079 ◽

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)

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1325. Recalibrating Estimates of Pneumococcal Disease in Hospitalized Canadian adults from 2010 to 2017 with Use of an Extended Spectrum Serotype-specific Urine Antigen Detection

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1517 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S750-S750

Author(s):

Jason J LeBlanc ◽

May ElSherif ◽

Lingyun Ye ◽

Donna MacKinnon-Cameron ◽

Ardith Ambrose ◽

...

Keyword(s):

Pneumococcal Disease ◽

Panel Member ◽

Community Acquired Pneumonia ◽

Antigen Detection ◽

Research Support ◽

Review Panel ◽

Urine Antigen ◽

Vaccine Recommendations ◽

Over Time ◽

Research Grant

Abstract Background Pneumococcal vaccine recommendations in Canada include both age- and risk-based guidance. This study aimed to describe the burden of vaccine-preventable pneumococcal community acquired pneumonia (pCAP) and invasive pneumococcal disease (IPD) by age in hospitalized adults. Methods Active surveillance for all-cause CAP and IPD in hospitalized adults was performed from 2010 to 2017, including laboratory results, patient demographics, and outcomes. Streptococcus pneumoniae was detected using blood and sputum culture, or urine antigen detection (UAD). Serotype was assigned using Quellung reaction, PCR, or serotype-specific UADs spanning the 24 serotypes in PCV13 and PPV23 vaccines. Data were categorized by age (16-49, 50-64, 65+, and 50+ years) and over time. Results 11129 ACP cases and 216 cases of IPD (non-CAP) were identified. A laboratory test for S. pneumoniae was performed in 8912 of ACP cases, identifying 1264 (14.2%) as pCAP. Compared to non-pCAP, pCAP cases were more likely to be admitted to intensive care units and require mechanical ventilation. These serious outcomes, as well as mortality, were more prominent in bacteremic pCAP and IPD. Risk factors for death in pCAP included aged 75+ years, immune compromising conditions, and BMI < 18.5. When categorized by age, the proportion of individuals aged 65+ years for pCAP and IPD was 49.8% and 48.6%, and the 50-64 year age cohort represented 31.3% and 29.9%, respectively. The contributions of PCV13 and PPV23 serotypes remained relatively stable over time, and overall represented 57.6% and 90.9% for pCAP, and 35.0% and 72.0% for IPD, respectively. Conclusion Seven years following infant PCV13 immunization programs in Canada, PCV13 and PPV23 serotypes in pCAP and IPD remained predominant causes of pneumococcal disease. Serious outcomes were particularly evident in adults 50+, suggesting pneumococcal vaccines should be encouraged in this age group. Disclosures Jason J. LeBlanc, PhD, FCCM, D[ABMM], GSK (Research Grant or Support)Merck (Grant/Research Support)Pfizer (Grant/Research Support) Todd F Hatchette, MD, GSK (Grant/Research Support)Pfizer (Grant/Research Support) Melissa K. Andrew, MD, PhD, GSK (Grant/Research Support)Pfizer (Grant/Research Support, Advisor or Review Panel member)Sanofi (Consultant, Grant/Research Support, Advisor or Review Panel member)Seqirus (Advisor or Review Panel member) 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) Louis Valiquette, MD, M.Sc., Cubist (Consultant)GSK (Grant/Research Support)Merck (Consultant)Optimer (Consultant)Pfizer (Grant/Research Support) Shelly McNeil, FRCPC, MD, GSK (Grant/Research Support)Pfizer (Grant/Research Support)Sinofi Pasteur (Grant/Research Support)

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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

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1198 ◽

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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1104. Risk Factors and Outcomes of Refractory and/or Resistant Cytomegalovirus (CMV) Infection after Allogeneic Hematopoietic Stem Cell Transplantation

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1290 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S582-S583

Author(s):

Eleni Karantoni ◽

Yiqi Su ◽

Anat Stern ◽

Phaedon D Zavras ◽

Sergio Giralt ◽

...

Keyword(s):

Risk Factors ◽

Overall Survival ◽

T Cell ◽

Panel Member ◽

Multivariable Model ◽

Research Support ◽

Review Panel ◽

Material Support ◽

Advisory Boards ◽

Research Grant

Abstract Background The epidemiology of CMV end-organ disease (EOD) after Hematopoietic Cell Transplant (HCT) in the era of preemptive therapy (PET) is defined. In contrast, less data exists on refractory and/or resistant (R/R) CMV. We report on 1) the incidence; 2) risk factors and outcomes of R/R CMV by 1-year post HCT. Methods Retrospective review of 167 CMV seropositive (R+) recipients of first marrow or peripheral blood HCT from 1/2014 - 12/2017 managed by PET. Refractory CMV was defined as failure to achieve >1 log10 decrease in CMV viral load (VL) and having VL >1,000 IU/mL after ≥14 day of PET. Resistant CMV required genotypic confirmation of resistance mutation(s) in UL54 and/or UL97 genes. End organ disease (EOD) was defined by standard criteria. Patients (pts) were followed through 1-year post HCT and were categorized in two mutually exclusive groups as R/R and no R/R. Demographics, clinical characteristics and outcomes were extracted from medical records and hospital databases. Univariable and multivariable logistic models were used to identify risk factors for R/R CMV. Results Of 167 PET recipients, 91 (54.5%) received ex vivo T cell depleted (TCD) HCT; 40 (24.0%) had mismatched donor; and 26 (15.6%) had multiple myeloma. 66/167 (39.5%) pts developed refractory CMV (6 pts also had resistant CMV). Time from HCT to CMV viremia was shorter in R/R group: median (IQR) 21.5 (17.2-27.8) days compared to no R/R group: 26 (19-32) days (p=0.031). Maximum VL was higher for R/R compared to no R/R: median (IQR) 9,118 (2,849-18,456) and 868 (474-1,908), respectively (p< 0.001). In multivariable model, risk factors for R/R included TCD HCT (p< 0.0001) and higher VL at PET initiation (p=0.0002). In contrast, CMV seropositive donor (p=0.035) was protective (Figure 1). CMV EOD developed in 28.2% of R/R and 16.2% of no R/R groups (p=0.085) (Figure 2). Overall survival at 1 year was 59.1% for R/R compared to 83.1% for no R/R group (p=0.00027) (Figure 3). Figure 1. Adjusted odds ratio (OR) and 95% confidence interval (CI) from multivariable model evaluating risk factors of refractory/resistant (R/R) CMV. Figure 2. Cumulative incidence curves of CMV end-organ disease (EOD) at 1-year post HCT Figure 3. Kaplan-Meier survival curves of overall survival (OS) at 1-year post HCT Conclusion 1) Refractory and/or resistant CMV occurred in 39,5% of PET recipients. 2) T-cell depletion and higher CMV VL at PET initiation were risk factors for R/R CMV in multivariable models. 3) R/R CMV was associated with more EOD and worse overall survival. Disclosures Sergio Giralt, MD, Amgen (Advisor or Review Panel member, Research Grant or Support, Served an advisory board for Amgen, Actinuum, Celgene, Johnson & Johnson, JAZZ pharmaceutical, Takeda, Novartis, KITE, and Spectrum pharma and has received research support from Amgen, Actinuum, Celgene, Johnson & Johnson, and Miltenyi, Takeda.) Miguel-Angel Perales, MD, Abbvie (Other Financial or Material Support, Honoraria from Abbvie, Bellicum, Celgene, Bristol-Myers Squibb, Incyte, Merck, Novartis, Nektar Therapeutics, Omeros, and Takeda.)ASTCT (Other Financial or Material Support, Volunteer member of the Board of Directors of American Society for Transplantation and Cellular Therapy (ASTCT), Be The Match (National Marrow Donor Program, NMDP), and the CIBMTR Cellular Immunotherapy Data Resource (CIDR) Committee)Cidara Therapeutics (Advisor or Review Panel member, Other Financial or Material Support, Serve on DSMBs for Cidara Therapeutics, Servier and Medigene, and the scientific advisory boards of MolMed and NexImmune.)Kite/Gilead (Research Grant or Support, Other Financial or Material Support, Received research support for clinical trials from Incyte, Kite/Gilead and Miltenyi Biotec.) Genovefa Papanicolaou, MD, Chimerix (Research Grant or Support)Merck&Co (Research Grant or Support, Investigator and received funding and consulting fees from Merck, Chimerix, Shire and Astellas)

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652. Comparison of fosfomycin (FOF) activity and prevalence of subpopulations between Escherichia coli (EC) and Klebsiella pneumoniae (KP) during susceptibility testing

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.846 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S384-S384

Author(s):

Jadyn C Anderson ◽

Amanda R Krueger ◽

Elizabeth C Smith ◽

Morgan L Bixby ◽

Hunter V Brigman ◽

...

Keyword(s):

Clinical Efficacy ◽

Inhibitory Concentration ◽

Panel Member ◽

Colony Growth ◽

The United States ◽

Research Support ◽

Review Panel ◽

Agreement Rate ◽

Future Studies ◽

Agar Dilution

Abstract Background In the United States, interpretive criteria for FOF are established only for EC, yet those criteria are often extrapolated to KP. Recent studies have highlighted both inferior clinical outcomes after FOF treatment and difficulties in interpretation of inner colony subpopulations, the presence of which may affect clinical efficacy. We sought to compare FOF activity against EC and KP and to determine the prevalence of inner colony subpopulations following disk diffusion (DD) testing of the two species. Methods A convenience collection of 73 KP and 42 EC isolates from 3 U.S. institutions were included. Minimal inhibitory concentration (MIC) testing was performed in duplicate on separate days using agar dilution (AD) and DD as recommended by the Clinical and Laboratory Standards Institute guidelines, with application of EC susceptibility (≤ 64mg/L) breakpoints. The frequency and counts of inner colonies observed during DD testing was calculated, and colonies were subcultured for use in future studies. Results MIC50/90 values were 1/16 mg/L and 32/256 mg/L for EC and KP respectively. All EC isolates were considered susceptible and therefore categorical agreement was 100%. The majority of KP isolates were considered susceptible (83.6% with AD and 86.3% with DD) and categorical agreement between the methods was 84.9%. Inner colonies were observed during DD testing in 88.1% of EC isolates and 80.8% of KP isolates during at least one replicate, with 47.6% of EC isolates and 39.7% of KP isolates showing inner colony growth during both DD test replicates. More than 10 inner colonies were observed in 50% of EC isolates compared to 12.3% of KP isolates. Conclusion KP isolates demonstrated considerably higher FOF MIC values compared to EC, as evidenced by MIC50/90 values 4-5 dilutions higher than those for EC. The categorical agreement rate was higher among EC than KP, highlighting concerns regarding the practice of extrapolating FOF susceptibility breakpoints for EC to KP. The high frequency of inner colonies observed in DD for both species necessitates further studies to determine best practices for interpreting their relevance, fitness, and resistance in order to identify potential impacts to clinical efficacy of FOF. Disclosures Elizabeth B. Hirsch, PharmD, Merck (Grant/Research Support)Nabriva Therapeutics (Advisor or Review Panel member)

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