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Background: Challenges remain in discerning microbiologic etiology and disease severity in childhood pneumonia. Defining host transcriptomic profiles during illness may facilitate improved diagnostic and prognostic approaches., Methods: Using whole blood ribonucleic acid sequencing from 222 hospitalized children with radiographic pneumonia and 45 age-matched controls, we identified differentially expressed genes that best identified children according to detected microbial pathogens (viral-only vs. bacterial-only and typical vs. atypical bacterial [+/- viral co-detection]) and an ordinal measure of phenotypic severity (moderate, severe, very severe)., Results: Overall, 135 (61%) children had viral-only detections, 15 (7%) had typical bacterial (+/- viral co-detections), and 26 (12%) had atypical bacterial (+/- viral co-detections). Eleven DE genes distinguished between viral-only and bacterial-only detections. Sixteen DE genes distinguished between atypical and typical bacterial detections (+/- viral co-detections). Nineteen DE genes distinguished between levels of pneumonia severity, including four genes also identified in the viral-only vs. bacterial-only model (IGHGP, PI3, CD177, RAP1GAP1) and four genes from the typical vs atypical bacterial model (PRSS23, IFI27, OLFM4, and ABO)., Conclusions: We identified transcriptomic biomarkers associated with microbial detections and phenotypic severity in children hospitalized with pneumonia. These DE genes are promising candidates for validation and translation into diagnostic and prognostic tools., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Patients with cystic fibrosis (CF) experience recurrent bacterial pulmonary exacerbations. Management of these infections is increasingly challenging due to decreased antimicrobial susceptibility to beta-lactam antibiotics. The pharmacokinetics of these agents are inadequately characterized in patients with CF., Methods: One hundred fifty-five pediatric and adult participants with CF receiving cefepime (n=82), meropenem (n=42), or piperacillin-tazobactam (n=31) were enrolled. Opportunistic blood samples were obtained during hospitalization. Population PK analysis was conducted using nonlinear mixed-effects modeling. Clinical and demographic characteristics were evaluated as potential covariates. Monte Carlo simulations were performed to evaluate probability of target attainment (PTA) for different dosing regimens., Results: Estimated creatinine clearance, and total or lean body weight, affected the pharmacokinetics of cefepime and meropenem. No covariates were identified for piperacillin and tazobactam. In the cefepime group, a 3-h infusion achieved higher PTA than a 0.5-h infusion for all participants. Estimated breakpoints (the respective minimum inhibitory concentration (MIC) up to which ≥90% of patients are predicted to reach a PK/PD target) were two- to four-fold higher in pediatric participants receiving a 3-h vs. 0.5-h infusion. In the meropenem group, increased creatinine clearance led to reduced PTA. In the piperacillin-tazobactam group, total daily dose and mode of administration were principal drivers of PTA., Conclusions: Standard dosing regimens fail to achieve specific MIC targets in patients with CF. Therefore, clinicians should incorporate local antibiograms and PK models to determine optimal dosing. Further PK optimization to account for interindividual differences could be achieved by real-time beta-lactam therapeutic drug monitoring., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Avian influenza viruses pose significant risk to human health. Vaccines targeting the hemagglutinin of these viruses are poorly immunogenic without the use of adjuvants., Methods: Twenty healthy men and women (18-49 years of age) were randomized to receive 2 doses of inactivated influenza A/H5N1 vaccine alone (IIV) or with AS03 adjuvant (IIV-AS03) 1 month apart. Urine and serum samples were collected on day 0 and on days 1, 3, and 7 following first vaccination and subjected to metabolomics analyses to identify metabolites, metabolic pathways, and metabolite clusters associated with immunization., Results: Seventy-three differentially abundant (DA) serum and 88 urine metabolites were identified for any postvaccination day comparison. Pathway analysis revealed enrichment of tryptophan, tyrosine, and nicotinate metabolism in urine and serum among IIV-AS03 recipients. Increased urine abundance of 4-vinylphenol sulfate on day 1 was associated with serologic response based on hemagglutination inhibition responses. In addition, 9 DA urine metabolites were identified in participants with malaise compared to those without., Conclusions: Our findings suggest that tryptophan, tyrosine, and nicotinate metabolism are upregulated among IIV-AS03 recipients compared with IIV alone. Metabolites within these pathways may serve as measures of immunogenicity and may provide mechanistic insights for adjuvanted vaccines., Clinical Trials Registration: NCT01573312., Competing Interests: Potential conflicts of interest. C. B. C. reports consulting fees from GSK, Pfizer, TD Cowen, Moderna, CommenseBio, and AstraZeneca for unrelated work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: A 2-dose mRNA-1273 primary series in children aged 6 months-5 years (25-µg) and 6-11 years (50-µg) had an acceptable safety profile and was immunogenic in the phase 2/3 KidCOVE study. We present data from KidCOVE participants who received an mRNA-1273 booster dose., Methods: An mRNA-1273 booster dose (10-µg for children aged 6 months-5 years; 25-µg for children aged 6-11 years; age groups based on participant age at enrollment) was administered ≥6 months after primary series completion. The primary safety objective was the safety and reactogenicity of an mRNA-1273 booster dose. The primary immunogenicity objective was to infer efficacy of an mRNA-1273 booster dose by establishing noninferiority of neutralizing antibody (nAb) responses after a booster in children compared with nAb responses observed after the mRNA-1273 primary series in young adults (18-25 years) from the pivotal efficacy study. Data were collected from March 2022 to June 2023., Results: Overall, 153 (6 months-5 years) and 2519 (6-11 years) participants received an mRNA-1273 booster dose (median age at receipt of booster: 2 and 10 years, respectively). The booster dose safety profile was generally consistent with that of the primary series in children; no new safety concerns were identified. An mRNA-1273 booster dose elicited robust nAb responses against ancestral SARS-CoV-2 among children and met prespecified noninferiority success criteria when compared with responses observed after the primary series in young adults., Conclusions: Safety and immunogenicity data support administration of a mRNA-1273 booster dose in children aged 6 months to 11 years., Clinical Trials Registration: NCT04796896., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Influenza A (H7N9) has caused multiple disease waves with evidence of strain diversification. Optimal influenza A (H7N9) prime-boost vaccine strategies are unknown., Methods: We recruited participants who had received monovalent inactivated A/Shanghai/2/2013 (H7N9) vaccine (MIV) approximately 5 years earlier, as follows: MIV with MF59 (MF59 × 2 group), MIV with AS03 (AS03 × 2 group), unadjuvanted MIV (No Adj group), MIV with MF59 or AS03 followed by unadjuvanted MIV (Adjx1 group), and A/H7-naive (unprimed group). Participants were randomized to receive 1 dose of AS03-adjuvanted or unadjuvanted A/Hong Kong/125/2017 (H7N9) MIV and were followed for safety and immunogenicity using hemagglutination inhibition (HAI) and neutralizing antibody assays., Results: We enrolled 304 participants: 153 received the adjuvanted boost and 151 received the unadjuvanted boost. At 21 days postvaccination, the proportion of participants with HAI antibody titers against the boosting vaccine strain of ≥40 in the adjuvanted and unadjuvanted arms, respectively, were 88% and 49% in MF59 × 2 group, 89% and 75% in AS03 × 2 group, 59% and 20% in No Adj group, 94% and 55% in Adjx1group, and 9% and 11% in unprimed group., Conclusions: Serologic responses to a heterologous A(H7N9) MIV boost were highest in participants primed and boosted with adjuvant-containing regimens., Clinical Trials Registration: NCT03738241., Competing Interests: Potential conflicts of interest . I. Y.’s institution received funding to conduct clinical research unrelated to this manuscript from Moderna and Pfizer; and I. Y. consults for Merck and Sanofi-Pasteur. P. W. has received research funding unrelated to this manuscript from Pfizer and Sanofi; and has consulted for Pfizer. C. B. C. serves as a consultant to Pfizer, Moderna, GSK, and Vir. K. M. E. serves as consultant to Bionet and IBM; and member of the Data Safety and Monitoring Boards for Sanofi, X-4 Pharma, Seqirus, Moderna, Pfizer, Merck, and Roche. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This clinical practice guideline for the diagnosis and treatment of acute bacterial arthritis (ABA) in children was developed by a multidisciplinary panel representing the Pediatric Infectious Diseases Society (PIDS) and the Infectious Diseases Society of America (IDSA). This guideline is intended for use by healthcare professionals who care for children with ABA, including specialists in pediatric infectious diseases and orthopedics. The panel's recommendations for the diagnosis and treatment of ABA are based upon evidence derived from topic-specific systematic literature reviews. Summarized below are the recommendations for the diagnosis and treatment of ABA in children. The panel followed a systematic process used in the development of other IDSA and PIDS clinical practice guidelines, which included a standardized methodology for rating the certainty of the evidence and strength of recommendation using the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation) (see Figure 1). A detailed description of background, methods, evidence summary and rationale that support each recommendation, and knowledge gaps can be found online in the full text., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The Antibacterial Resistance Leadership Group (ARLG) has prioritized infections caused by gram-positive bacteria as one of its core areas of emphasis. The ARLG Gram-positive Committee has focused on studies responding to 3 main identified research priorities: (1) investigation of strategies or therapies for infections predominantly caused by gram-positive bacteria, (2) evaluation of the efficacy of novel agents for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, and (3) optimization of dosing and duration of antimicrobial agents for gram-positive infections. Herein, we summarize ARLG accomplishments in gram-positive bacterial infection research, including studies aiming to (1) inform optimal vancomycin dosing, (2) determine the role of dalbavancin in MRSA bloodstream infection, (3) characterize enterococcal bloodstream infections, (4) demonstrate the benefits of short-course therapy for pediatric community-acquired pneumonia, (5) develop quality of life measures for use in clinical trials, and (6) advance understanding of the microbiome. Future studies will incorporate innovative methodologies with a focus on interventional clinical trials that have the potential to change clinical practice for difficult-to-treat infections, such as MRSA bloodstream infections., Competing Interests: Potential conflicts of interest. All authors report funding support from the ARLG of the NIH and the NIAID (UM1AI104681). S. B. D. reports grants or contracts paid to her institution from Gilead, Pfizer, F2G, Regeneron, Chan Zuckerberg Biohub, and NIAID/NIH; consulting fees paid directly to her from Genentech and Janssen/Johnson & Johnson (J&J); travel and meeting support from the Infectious Diseases Society of America (IDSA) to speak at IDWeek; a patent (US20100143379A1) for Mif agonists and antagonist and therapeutic uses thereof; a leadership role on the IDSA Antibacterial Resistance Committee, California Department of Public Health Hospital Acquired Infections Advisory Committee, and ARLG Innovations Group, Laboratory Center, Mentorship Committee, Gram-positive Committee, and Immunosuppressed Host Group; and payment directly to her for clinical events committee/adjudication committee participation from Shionogi, Basilea, and the Duke Clinical Research Institute.D. R. A. reports funding support from ContraFect and a leadership role on the ARLG Gram-positive Committee. A. B. reports funding support from the ARLG Early Faculty Seedling Award (NIAID UM1AI104681) and consulting fees from Roche. H. W. B. reports royalties from the Sanford Guide; consulting fees from the Sanford Guide, Antimicrobial Agents and Chemotherapy/American Society for Microbiology (ASM), and ID Clinics of North America/Elsevier; honoraria for Grand Rounds at Temple University; travel and meeting support for an IDWeek Lecture; membership as a voting member on the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria; and membership on the Board of Trustees at the College of the Holy Cross. B. C. reports grants or contracts paid to his institution from Moderna Vaccines and Merck Vaccines; royalties from UpToDate; consulting fees from Cowen Investments, Pfizer, Moderna, GSK, and Sanofi; payment as a medicolegal expert with multiple law firms; participation on the data and safety monitoring board (DSMB) or advisory board for Affinivax and GSK; and a leadership role as president of the Pediatric Infectious Diseases Society. S. E. C. reports grants or contracts paid to her institution from the Agency for Healthcare Research and Quality (AHRQ), the Centers for Disease Control and Prevention (CDC), the Patient-Centered Outcomes Research Institute, and the US Food and Drug Administration (FDA); consulting fees paid directly to her from the Duke Clinical Research Institute; participation on a DSMB for Debiopharm; and leadership roles as a board member of the National Foundation for Infectious Diseases and Globarl Antibiotic Research and Development Partnership North America (GARDP-NA). S. R. E. reports grants from the NIAID/NIH and De Gruyter (Editor-in-Chief for Statistical Communications in Infectious Diseases); royalties from Taylor & Francis; consulting fees from Genentech, AstraZeneca, Takeda, Microbiotix, J&J, Endologix, ChemoCentryx, Becton Dickinson, Atricure, Roviant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute (IDDI), SVB Leerink, Medtronic, Regeneron, Wake Forest University, Recor, Janssen, and IDDI; payments from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); meeting support from the FDA, Deming Conference on Applied Statistics, Clinical Trial Transformation Initiative, Council for International Organizations of Medical Sciences, International Chinese Statistical Association Applied Statistics Symposium, and Antimicrobial Resistance and Stewardship Conference; board member participation for the NIH, Breast International Group, University of Pennsylvania, Washington University, Duke University, Roche, Pfizer, Takeda, Akouos, Apellis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, AbbVie, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, Advantagene, Candel, and Novartis; and board positions with the American Statistical Association, Society for Clinical Trials, and Frontier Science Foundation. V. G. F. reports personal consulting fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, The Medicines Co, MedImmune, Bayer, Basilea, Affinergy, Janssen, ContraFect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, Roche, and Pfizer; grants from NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, ContraFect, Karius, Genentech, Regeneron, Deep Blue, Basilea, and Janssen; royalties from UpToDate; stock options from Valanbio and ArcBio; honoraria from the IDSA for his service as Associate Editor of Clinical Infectious Diseases; travel support from ContraFect to the 2019 European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); and a sepsis diagnostics patent pending. S. A. F. reports grant or contracts from NIH (P50HD103525, U01AL116400, R21AI176063) and AHRQ (R01 HS024269), honoraria from ARLG, and provision of Clorox wipes for a clinical research study. B. J. K. reports grants from CDC and NIAID; honoraria from ARLG; and leadership roles in the CDC Microbiome Working Group, IDSA Journal Club, and ARLG. T. H. reports consulting fees from Tanabe-Mitsubishi Pharma and honoraria from Duke University and Cancer and Chemo Therapy. T. P. L. reports grants paid to his institution from Wockhardt; grants paid directly to him from Paratek, Cidara, Biofire Diagnostics, and Merck; payment directly to him for lectures from Shionogi, Ferring, Seres, and Melinta; consulting fees paid directly to him from AbbVie, Cidara Therapeutics, Ferring, ICPD, Genentech, J&J, Melinta, Merck, Roche, Shionogi, Spero, Venatrox, La Jolla, Seres, Paratek, GSK, and DoseMe; and payment for the development of educational presentations from the Mayo Clinic. L. G. M. reports grants or contracts from Merck, ContraFect, Paratek, Medline, and GSK. J. M. M. reports grants from Asociación Nacional de Investigación y Desarrollo, Fondo Nacional de Desarrollo Científico y Tecnológico FONDECYT (grant number 1211947). B. S. reports advisory board fees paid directly to him from Basilia. T. T. T. reports grants from NIH paid to her institution; travel and meeting support from IDSA; and a leadership role on the IDWeek Planning Committee and a role as a Gulf Coast Consortium Cluster Reviewer (both unpaid). N. A. T. reports grants from CDC and PDI, Inc; and consulting fees from Techspert. D. J. W. reports grants paid to his institution from CDC and NIH/NIAID; a leadership role on the IDSA Childhood Pneumonia Guidelines Committee; and receipt of equipment from bioMérieux for procalcitonin assays for an observational study. T. L. H. reports grants from Karius and NIH; royalties from UpToDate; consulting fees from Aridis, Pfizer, Lysovant, and Affinivax; and participation on a DSMB for the SNAP Trial and the advisory board for Basilea. C. A. A. reports grant funding to their institution from NIH/NIAID (1 Po1 AI152999, R01AI148342, R01 AI346337, T32 AI141349, K24 Ai121296, U19 AI44297, R01 AI150685, and R21 AI151536), MeMed Diagnostics Ltd, Entasis Therapeutics, Merck Pharmaceuticals, and Harris County Public Health; royalties paid to them from UpToDate; reimbursement from IDSA for attending IDWeek as a speaker and part of the organizing committee; reimbursement from ASM to attend ASM Microbe as a speaker; reimbursement from the Society for Healthcare Epidemiology of America (SHEA) to attend SHEA as a speaker; reimbursement from the European Society for Clinical Microbiology and Infectious Diseases to attend ECCMID as a speaker; reimbursement from Mérieux Foundation to attend ICARE course as faculty; reimbursement from Sociedad Chilea de Infectiologia, Sociedad Colombiana de Infectologia, Pan American Society for Infectious Diseases, and Brazilian Society for Infectious Diseases to attend the annual meeting and act as a speaker; was an unpaid participant on a DSMB with the World Health Organization and Antibacterial Pipeline Advisory Group; received payment for participation with the NIH Grant Review Study Sections; was a voluntary member of the board of directors of IDSA; and is the Editor-in-Chief of Antimicrobial Agents and Chemotherapy. B. E. M. reports royalties from UpToDate for online chapters; consulting fees from JRD, LLC (J&J), PPD Development, LP (GSK0 and Basilea Pharmaceutical International Ltd); participation on a DSMB with NIH Therapeutic and Prevention; and held the position of Governor of the Academy with the American Academy of Microbiology. C. L. reports grant payments to their institutions from NIAID/NIH (1R01AI151038-01) and Pfizer. M. H. S. reports advisory board fees from DoseMe; consulting fees from GSK and Entasis; and has an issued patent US10688195B2. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Multisystem inflammatory syndrome in children (MIS-C) is a complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; in the United States, reporting of MIS-C after coronavirus disease 2019 (COVID-19) vaccination is required for vaccine safety monitoring. Pfizer-BioNTech COVID-19 vaccine was authorized for children aged 5-11 years on 29 October 2021. Covering a period when approximately 7 million children received vaccine, surveillance for MIS-C ≤ 90 days postvaccination using passive systems identified 58 children with MIS-C and laboratory evidence of past/recent SARS-CoV-2 infection, and 4 without evidence. During a period with extensive SARS-CoV-2 circulation, MIS-C illness in children after COVID-19 vaccination who lacked evidence of SARS-CoV-2 infection was rare (<1 per million vaccinated children)., Competing Interests: Potential conflicts of interest. S. K.'s institution has received funding from National Institutes of Health (NIH) to conduct clinical trials of Moderna and Janssen COVID-19 vaccines, and funding from Pfizer to conduct clinical trials of Pfizer-BioNTech COVID-19 vaccines. M. A. S. reports funding from NIH, CDC, Pfizer, and Merck; and royalties from UpToDate. K. E. reports grant funding from NIH and CDC; consultant to Bionet, GSK, and IBM; and membership of Data Safety and Monitoring Board for Sanofi, X-4 Pharma, Seqirus, Moderna, Pfizer, Merck, and Roche. C. B. C. reports grants from NIH and Merck; royalties from UpToDate; consulting fees from GlaxoSmithKline, Horizon Pharma, Premier Healthcare, Pfizer, Moderna, Cowen Investments, and Vindico; payment for medicolegal testimony from multiple firms (none related to this investigation); a US patent for staphylococcal antibody (number 10 981 979); participation on a data safety monitoring board or advisory board for Astellas; and is President of the Pediatric Infectious Diseases Society. E. P. S. reports grants from the NIH and Pfizer; consulting fees from Sanofi Pasteur; and serves on the Data Safety Monitoring Board for vaccine trials sponsored by the NIH's Division of Microbiology and Infectious Diseases. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Objectives: We aimed to identify rational empirical dosing strategies for cefepime treatment in critically ill patients by utilizing population pharmacokinetics and target attainment analysis., Patients and Methods: A prospective and opportunistic pharmacokinetic (PK) study was conducted in 130 critically ill patients in two ICU sites. The plasma concentrations of cefepime were determined using a validated LC-MS/MS method. All cefepime PK data were analysed simultaneously using the non-linear mixed-effects modelling approach. Monte Carlo simulations were performed to evaluate the PTA of cefepime at different MIC values following different dose regimens in subjects with different renal functions., Results: The PK of cefepime in critically ill patients was best characterized by a two-compartment model with zero-order input and first-order elimination. Creatinine clearance and body weight were identified to be significant covariates. Our simulation results showed that prolonged 3 h infusion does not provide significant improvement on target attainment compared with the traditional intermittent 0.5 h infusion. In contrast, for a given daily dose continuous infusion provided much higher breakpoint coverage than either 0.5 h or 3 h intermittent infusions. To balance the target attainment and potential neurotoxicity, cefepime 3 g/day continuous infusion appears to be a better dosing regimen than 6 g/day continuous infusion., Conclusions: Continuous infusion may represent a promising strategy for cefepime treatment in critically ill patients. With the availability of institution- and/or unit-specific cefepime susceptibility patterns as well as individual patients' renal function, our PTA results may represent useful references for physicians to make dosing decisions., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Respiratory syncytial virus (RSV) is a major cause of respiratory disease in infants, making vaccination an attractive preventive strategy. Due to earlier reports of vaccine-enhanced disease in RSV-naive children, assessing prior RSV infection is critical for determining eligibility for future infant vaccine trials. However, this is complicated by the presence of maternally transferred maternal antibodies. We sought to develop assays that measure immune responses to RSV pre-fusion (F) protein that discriminates between maternal and infant responses., Methods: We measured RSV-specific responses in two groups of children <3 years of age; those with laboratory-confirmed RSV (RSV-infected) and those enrolled prior to their first RSV season (RSV-uninfected). Serial blood samples were obtained and recent infections with RSV and other respiratory viruses were assessed during follow-up. An RSV pre-F-specific kinetic enzyme-linked immunosorbent assay (kELISA) and an F-specific reactive B cell frequency (RBF) assay were developed., Results: One hundred two young children were enrolled between July 2015 and April 2017; 74 were in the RSV-uninfected group and 28 were in the RSV-infected group. Participants were asked to provide sequential blood samples over time, but only 53 participants in the RSV-uninfected group and 22 participants in the RSV-infected groups provided multiple samples. In the RSV-infected group, most had positive kELISA and RBF during the study. In the RSV-uninfected group, two patterns emerged: declining kELISA values without reactive B cells, due to maternal transplacental antibody transfer, and persistently positive kELISA with reactive B cells, due to asymptomatic undiagnosed RSV infection., Conclusions: A kELISA targeting RSV pre-F epitopes and an RBF assay targeting RSV F-specific B cells generally allow discrimination between maternally and infant-derived antibodies., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Within 2 years after the start of the coronavirus disease 2019 (COVID-19) pandemic, novel severe acute respiratory syndrome coronavirus 2 vaccines were developed, rigorously evaluated in large phase 3 trials, and administered to more than 5 billion individuals globally. However, adverse events of special interest (AESIs) have been described post-implementation, including myocarditis after receipt of messenger RNA (mRNA) vaccines and thrombosis with thrombocytopenia syndrome after receipt of adenoviral vector vaccines. AESIs are rare (<1 to 10/100 000 vaccinees) and less frequent than COVID-19 complications, though they have associated morbidity and mortality. The diversity of COVID-19 vaccine platforms (eg, mRNA, viral vector, protein) and rates of AESIs both between and within platforms (eg, higher rate of myocarditis after mRNA-1273 vs BNT162b2 vaccines) present an important opportunity to advance vaccine safety science. The International Network of Special Immunization Services has been formed with experts in vaccine safety, systems biology, and other relevant disciplines to study cases of AESIs and matched controls to uncover the pathogenesis of rare AESIs and inform vaccine development., Competing Interests: Potential conflicts of interest. K. A. T. reports funding from the Canadian Institutes of Health Research and Public Health Agency of Canada for safety evaluation of coronavirus disease 2019 (COVID-19) vaccines and grants from GlaxoSmithKline outside the submitted work. O. L. is a named inventor on patents relating to adjuvants and human in vitro systems that predict vaccine safety assessments and reports grants for the Precision Vaccines Program from the Boston Children’s Hospital Department of Pediatrics and the Chief Scientific Office and consulting fees from Moody’s analytics. C. B. C. reports grants and contracts from the NIH and CDC for vaccine clinical trials including NIH Vaccine and Treatment Evaluation Unit (including the Moderna COVE study, Janssen ENSEMBLE study, Moderna KidCOVE study) and CDC Clinical Immunization Safety Assessment Network; grants from Merck; royalties for contributions to the UpToDate program; multiple small honoraria for lectures on COVID-19 vaccines and other vaccines; consultation fees from Altimmune (COVID-19 vaccine development), Janssen (respiratory syncytial virus vaccine development), Astellas (clinical trial data and safety monitoring board), Horizon Pharma (consultation related to care of children with chronic granulomatous disease), and Vir (influenza monoclonal antibody development); payment for expert testimony from multiple legal firms for general medical malpractice; US patent 10,981,979 B2; and serving as the president of the Pediatric Infectious Diseases Society. K. G. reports grants from the Task Force for Global Health and the CDC via the Global Vaccine Data Network for sentinel surveillance and personal fees from the CDC via the Global Vaccine Data Network for vaccine safety training materials. C. L. C. reports a grant from GAVI, the Vaccine Alliance, for vaccine safety surveillance and serving as a member of the Brighton Collaboration Scientific committee and the Institutional Biosafety committee. G. A. P. reports funding from ICW Ventures and the NIH (AI 48793, AI 33144, and AI 132348); consulting fees from Contec, Inc, 3D Communications, AstraZeneca UK Ltd, Bank of America Corporation, Eli Lily and Company, Emergent BioSolutions, Exelixis Inc, ExpertConnect, Genevant Sciences, Inc, GlaxoSmithKline, Janssen Global Services, LLC, Janssen Research & Development, LLC, Medicago USA, Medscape, LLC, Merck, Regeneron Pharmaceuticals Inc, Sanofi Pasteur SA, Syneos Health, and Vyriad; and participation on a data safety monitoring or advisory board for 3D Communications, AstraZeneca UK Ltd, Bavarian Nordic A/S, Dynavax Technologies, Genentech, Inc, GlaxoSmithKline, Janssen Global Services, LLC, and Janssen Pharmaceuticals, Inc. N. C. reports a Medical Research Future Fund grant and serving on a government advisory committee for the Australian Technical Advisory Group on Immunisation-ATAGI. B. C. reports a CDC grant and serving as a board member for the Rare Disease Foundation. R. T. C. reports grants from the Coalition for Epidemic Preparedness and Innovation and the CDC; travel support from Elsevier; honoraria payments from the Brighton Collaboration; serving as the scientific director at the Brighton Collaboration; and serving as a co-lead on the COVAX Vaccine Safety Working Group. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

This clinical practice guideline for the diagnosis and treatment of acute hematogenous osteomyelitis (AHO) in children was developed by a multidisciplinary panel representing Pediatric Infectious Diseases Society (PIDS) and the Infectious Diseases Society of America (IDSA). This guideline is intended for use by healthcare professionals who care for children with AHO, including specialists in pediatric infectious diseases, orthopedics, emergency care physicians, hospitalists, and any clinicians and healthcare providers caring for these patients. The panel's recommendations for the diagnosis and treatment of AHO are based upon evidence derived from topic-specific systematic literature reviews. Summarized below are the recommendations for the diagnosis and treatment of AHO in children. The panel followed a systematic process used in the development of other IDSA and PIDS clinical practice guidelines, which included a standardized methodology for rating the certainty of the evidence and strength of recommendation using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. A detailed description of background, methods, evidence summary and rationale that support each recommendation, and knowledge gaps can be found online in the full text., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Staphylococcus aureus skin and soft tissue infections (SA-SSTIs) are common in healthcare and community settings, and recurrences occur at variable frequency, even after successful initial treatment. Knowing the exact burden and timing of recurrent disease is critical to planning and evaluating interventions to prevent recurrent SSTIs., Methods: In this retrospective study, SSTI cases in patients aged ≥18 years at 3 US medical centers (Columbia, Chicago, Vanderbilt) between 2006 and 2016 were analyzed according to a biennial cohort design. Index SSTIs (with or without key comorbidities), either microbiologically confirmed to be SA-SSTI or not microbiologically tested (NMT-SSTI), were recorded within 1 calendar year and followed up for 12 months for recurrent infections. The number of index cases, proportion of index cases with ≥1 recurrence(s), time to first recurrence, and number of recurrences were collected for both SA-SSTI and NMT-SSTI events., Results: In the most recent cohorts, 4755 SSTI cases were reported at Columbia, 2873 at Chicago, and 6433 at Vanderbilt. Of these, 452, 153, and 354 cases were confirmed to be due to S. aureus. Most cases were reported in patients without key comorbidities. Across centers, 16.4%-19.0% (SA-SSTI) and 11.0%-19.2% (NMT-SSTI) of index cases had ≥1 recurrence(s). In patients without key comorbidities, more than 60% of index SSTIs with recurrences had only 1 recurrence, half of which occurred in the first 3 months following primary infection., Conclusions: SA-SSTI recurrences are common among healthy adults and occur in at least 1 in 6 individuals during the 1 year following the primary event., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

While adult clinical trials of coronavirus disease 2019 (COVID-19) vaccines have moved quickly into phase 3 clinical trials, clinical trials have not started in children in the United States. The direct COVID-19 impact upon children is greater than that observed for a number of other pathogens for which we now have effective pediatric vaccines. Additionally, the role of children in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission has clearly been underappreciated. Carefully conducted phase 2 clinical trials can adequately address potential COVID-19 vaccine safety concerns. Delaying phase 2 vaccine clinical trials in children will delay our recovery from COVID-19 and unnecessarily prolong its impact upon children's education, health, and emotional well-being, and equitable access to opportunities for development and social success. Given the potential direct and indirect benefits of pediatric vaccination, implementation of phase 2 clinical trials for COVID-19 vaccines should begin now., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Data from 1174 infants enrolled in a previous rotavirus vaccine study were analyzed to determine the effect of antibiotic exposure (from 14 days before to 7 days after vaccination) on rotavirus serum immunoglobulin A (IgA) responses. Serum IgA responses 1 month after the completion of vaccination were similar among antibiotic-exposed and nonexposed infants., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Vancomycin is the most commonly administered antibiotic in hospitalized patients, but optimal exposure targets remain controversial. To clarify the therapeutic exposure range, this study evaluated the association between vancomycin exposure and outcomes in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia., Methods: This was a prospective, multicenter (n = 14), observational study of 265 hospitalized adults with MRSA bacteremia treated with vancomycin. The primary outcome was treatment failure (TF), defined as 30-day mortality or persistent bacteremia ≥7 days. Secondary outcomes included acute kidney injury (AKI). The study was powered to compare TF between patients who achieved or did not achieve day 2 area under the curve to minimum inhibitory concentration (AUC/MIC) thresholds previously found to be associated with lower incidences of TF. The thresholds, analyzed separately as co-primary endpoints, were AUC/MIC by broth microdilution ≥650 and AUC/MIC by Etest ≥320., Results: Treatment failure and AKI occurred in 18% and 26% of patients, respectively. Achievement of the prespecified day 2 AUC/MIC thresholds was not associated with less TF. Alternative day 2 AUC/MIC thresholds associated with lower TF risks were not identified. A relationship between the day 2 AUC and AKI was observed. Patients with day 2 AUC ≤515 experienced the best global outcomes (no TF and no AKI)., Conclusions: Higher vancomycin exposures did not confer a lower TF risk but were associated with more AKI. The findings suggest that vancomycin dosing should be guided by the AUC and day 2 AUCs should be ≤515. As few patients had day 2 AUCs <400, further study is needed to define the lower bound of the therapeutic range., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Staphylococcus aureus is among the most commonly identified causes of invasive bacterial infection in children; however, reliable results from cultures of sterile-site samples often cannot be obtained, which necessitates prescription of a broad empiric antimicrobial agent(s). Children with invasive S aureus infection rapidly generate high antibody titers to the cytotoxin LukAB; therefore, the aim of this study was to assess the diagnostic utility of an anti-LukAB antibody assay for children with musculoskeletal infection (MSKI)., Methods: We conducted a 2-year prospective study of all eligible children admitted to Vanderbilt Children's Hospital with an MSKI. Acute and convalescent sera were obtained, and antibodies that target LukAB were measured by an enzyme-linked immunosorbent assay., Results: Forty-two children were enrolled. The median concentrations of LukAB antibodies for children with S aureus infection were 130.3 U/mL in the acute phase and 455 U/mL in the convalescent phase (P < .001). The median concentrations of LukAB antibodies in children with a non-S aureus MSKI were 8.6 U/mL in the acute phase and 9.7 U/mL in the convalescent phase. The assay discriminated between S aureus and non-S aureus infection with areas under the receiver operating characteristic curve of 0.81 (95% confidence interval, 0.67-0.95; P < .001) and 0.95 (95% confidence interval, 0.86-1; P < .001) for samples tested in the acute and follow-up periods, respectively. With no false-negative results, the assay accurately ruled out S aureus in samples obtained during the convalescent phase., Conclusion: Culture-independent diagnostics have the potential to improve care by narrowing antimicrobial therapy on the basis of the likelihood of S aureus infection. The results of this proof-of-concept study suggest that a LukAB serologic assay might be useful in the diagnosis of invasive bacterial infections, and larger-scale validation studies are warranted., (© Crown copyright 2018.)

Background: Adjuvant System 03 (AS03) markedly enhances responses to influenza A/H5N1 vaccines, but the mechanisms of this enhancement are incompletely understood., Methods: Using ribonucleic acid sequencing on peripheral blood mononuclear cells (PBMCs) from AS03-adjuvanted and unadjuvanted inactivated H5N1 vaccine recipients, we identified differentially expressed genes, enriched pathways, and genes that correlated with serologic responses. We compared bulk PBMC findings with our previously published assessments of flow-sorted immune cell types., Results: AS03-adjuvanted vaccine induced the strongest differential signals on day 1 postvaccination, activating multiple innate immune pathways including interferon and JAK-STAT signaling, Fcγ receptor (FcγR)-mediated phagocytosis, and antigen processing and presentation. Changes in signal transduction and immunoglobulin genes predicted peak hemagglutinin inhibition (HAI) titers. Compared with individual immune cell types, activated PBMC genes and pathways were most similar to innate immune cells. However, several pathways were unique to PBMCs, and several pathways identified in individual cell types were absent in PBMCs., Conclusions: Transcriptomic analysis of PBMCs after AS03-adjuvanted H5N1 vaccination revealed early activation of innate immune signaling, including a 5- to 8-fold upregulation of FcγR1A/1B/1C genes. Several early gene responses were correlated with HAI titer, indicating links with the adaptive immune response. Although PBMCs and cell-specific results shared key innate immune signals, unique signals were identified by both approaches., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

We conducted a survey of pediatric infectious diseases providers in the Emerging Infections Network regarding the workup and treatment of children with Staphylococcus aureus bacteremia (SAB). We found significant practice variation in the management of children with SAB. These findings emphasize the need for further research to guide best practices.

The Infectious Diseases Society of America, HIV Medicine Association, and Pediatric Infectious Diseases Society are concerned by the continued decline in the number of infectious diseases trainees pursuing careers as physician-scientists and the attrition of junior and midcareer physician-scientists. The inability to replace the aging physician-scientist workforce will have a negative, long-lasting impact our biomedical research enterprise and its ability to drive the discovery of new treatments for important infectious diseases. We discuss policy recommendations for securing and optimizing the infectious diseases physician-scientist workforce in the areas of education, training, compensation, and mentorship, as well as ways to improve federal research funding, cross-sector collaboration, and workforce diversity.

Chronic Granulomatous Disease is one of the classic primary immunodeficiencies of childhood. While the incidence and severity of bacterial and fungal infections have been greatly reduced in this patient population, much remains to be learned about the pathophysiology of the disease, particularly for autoinflammatory manifestations. In this review, we examine the epidemiology, pathophysiology, and genetic basis for CGD.

Background: Influenza A(H5N1) virus and other avian influenza virus strains represent major pandemic threats. Like all influenza A virus strains, A(H5N1) viruses evolve rapidly. Innovative immunization strategies are needed to induce cross-protective immunity., Methods: Subjects primed with clade 1 H5 antigen, with or without adjuvant, and H5-naive individuals were boosted with clade 2 H5 antigen. The impact of priming on T cells capable of both proliferation and cytokine production after antigen restimulation was assessed., Results: Subjects previously vaccinated with clade 1 H5 antigen developed significantly enhanced clade 2 H5 cross-reactive T cell responses detectable 6 months after vaccination with clade 2 H5 antigen. Priming dose (15 µg vs 45 or 90 µg) had no effect on magnitude of heterotypic H5 T cell responses. In contrast, age at priming negatively modulated both the magnitude and duration of heterotypic H5 T cell responses. Elderly subjects developed significantly less heterotypic H5 T cell boosting, predominantly for T cells capable of cytokine production. Adjuvant had a positive albeit weaker effect than age. The magnitude of CD4(+) interferon-γ producing T cells correlated with H5 antibody responses., Conclusions: H5 heterotypic priming prior to onset of an A(H5N1) pandemic may increase magnitude and duration of immunity against a newly drifted pandemic H5 virus., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Therapeutics blocking the activity of tumor necrosis factor (anti-TNF) are a risk factor for invasive fungal infections; however, infectious risks to infants born to mothers receiving anti-TNF therapy are not well defined. We report a case of vertical transmission of disseminated histoplasmosis in a mother-infant pair exposed to anti-TNF therapy., (© The Author 2016. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Staphylococcus aureus is the leading cause of skin and soft tissue infections in the United States, and S. aureus colonization increases the risk of infection. Although athletes have a higher risk of infection with S. aureus than the general population, most studies in athletes have not assessed colonization., Methods: We conducted a prospective cohort study of Vanderbilt University varsity athletes from August 2008 to April 2010. We assessed nasal and oropharyngeal colonization with methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains by obtaining swabs at enrollment and monthly thereafter until the end of the study. The athletes were also monitored for skin and soft tissue infections., Results: We enrolled 377 athletes and trainers (224 in contact sports and 153 in noncontact sports). The total S. aureus colonization prevalence ranged from 34% to 62%, and for MRSA it ranged from 8% to 29%. The colonization rate in the summer was significantly higher than that in the winter (odds ratio for MRSA [ORMRSA], 1.70 [95% confidence interval (CI), 1.23-2.35]; ORMSSA, 1.38 [95% CI, 1.05-1.82]). Of 603 MRSA isolates, 75% carried the staphylococcal cassette chromosome mec (SCCmec) type IV, and 5% carried the genes encoding Panton-Valentine leukocidin. Nine symptomatic S. aureus infections occurred, 7 of which were between July and September., Conclusions: The S. aureus colonization rate is higher than previously reported and fluctuated over time in this prospective cohort of athletes. The higher colonization prevalence during summer might explain the infectious outbreak during the summer months and may represent a key intervention time for preventing S. aureus disease in athletes., (© The Author 2014. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Influenza A(H5N1) vaccination strategies that improve the speed of the immunological response and cross-clade protection are desired. We compared the immunogenicity of a single 15-μg or 90-μg dose of A/H5N1/Indonesia/05/05 (clade 2) vaccine in adults who were previously primed with A/H5N1/Vietnam/1203/2004 (clade 1) vaccine. High-dose vaccine resulted in significantly higher titers to both clade 1 and 2 antigens. Clade 2 titers were unaffected by the previous dose of clade 1 vaccine. Low-dose priming with a mismatched pandemic influenza A(H5N1) vaccine would improve the rapidity, magnitude, and cross-reactivity of the immunological response following a single high-dose, unadjuvanted, pandemic vaccine., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Although pregnant women are at increased risk of severe illness following influenza infection, there is relatively little information on the immunogenicity of influenza vaccines administered during pregnancy., Methods: We conducted a clinical trial that enrolled 120 pregnant women in which participants were randomly assigned to receive an inactivated 2009 H1N1 influenza vaccine containing either 25 μg or 49 μg of hemagglutinin (HA) in a 2-dose series with a 21-day period between administration of the first and second doses., Results: Following the first vaccination, HA inhibition (HAI) titers of ≥1:40 were detected in 93% (95% confidence interval [CI], 82%-98%) of subjects who received the 25-μg dose and 97% (95% CI, 88%-100%) of subjects receiving the 49-μg dose. In cord blood samples, HAI titers of ≥1:40 were found in 87% (95% CI, 73%-96%) of samples from the 25-μg dose group and in 89% (95% CI, 76%-96%) from the 49-μg dose group. Microneutralization titers tended to be higher than HAI titers, but the patterns of response were similar., Conclusions: In pregnant women, 1 dose of an inactivated 2009 H1N1 influenza vaccine containing 25 μg of HA elicited an antibody response typically associated with protection against influenza infection. Efficient transplacental transfer of antibody was also documented.

Background: Two doses of either trivalent live attenuated or inactivated influenza vaccines (LAIV and TIV, respectively) are approved for young children (≥ 24 months old for LAIV and ≥ 6 months old for TIV) and induce protective antibody responses. However, whether combinations of LAIV and TIV are safe and equally immunogenic is unknown. Furthermore, LAIV is more protective than TIV in children for unclear reasons., Methods: Children 6-35 months old were administered, 1 month apart, 2 doses of either TIV or LAIV, or combinations of LAIV and TIV in both prime/boost sequences. Influenza-specific antibodies were measured by hemagglutination inhibition (HAI), and T cells were studied in flow cytometric and functional assays. Highly conserved M1, M2, and NP peptides predicted to be presented by common HLA class I and II were used to stimulate interferon-γ enzyme-linked immunospot responses., Results: All LAIV and/or TIV combinations were well tolerated and induced similar HAI responses. In contrast, only regimens containing LAIV induced influenza-specific CD4(+), CD8(+), and γδ T cells, including T cells specific for highly conserved influenza peptides., Conclusions: Prime/boost combinations of LAIV and TIV in young children were safe and induced similar protective antibodies. Only LAIV induced CD4(+), CD8(+), and γδ T cells relevant for broadly protective heterosubtypic immunity., Clinical Trials Registration: NCT00231907.

Immunosuppressed patients receiving oseltamivir for 2009 novel H1N1 influenza A infection may develop drug resistance, leading to treatment failure. Intravenous zanamivir was administered on a compassionate-use basis to a profoundly immunosuppressed pediatric patient with severe oseltamivir-resistant novel H1N1 pneumonia. The regimen was well tolerated and was associated with a decrease in viral burden.

We describe a child with very late-onset group B Streptococcus sepsis and meningitis, systemic shigellosis, and chronic osteomyelitis. Peripheral blood cells obtained from the patient and her brother did not respond to stimulation with either interleukin-1beta or lipopolysaccharide. Sequencing of the interleukin-1 receptor-associated kinase-4 gene revealed 2 novel mutations.

Outbreaks of invasive methicillin-resistant Staphylococcus aureus infection within families are unusual. We investigated 2 family clusters of invasive methicillin-resistant Staphylococcus aureus infection, including 1 in which a young mother died of fulminant pneumonia. Although surveillance via culture of family contacts of patients with invasive methicillin-resistant Staphylococcus aureus infection is not currently recommended, such clusters should stimulate reevaluation of preventive measures.

Background: Most patients receiving therapy for acute myeloid leukemia (AML) enter an interval in which leukemic blast cells cannot be detected by light microscopy (i.e., morphologic remission). However, many of these patients experience a subsequent relapse. Multidimensional flow cytometry, which allows the discrimination of antigens expressed on normal and malignant cells, can detect small numbers of cancer cells in bone marrow or peripheral blood specimens. This technique enables the detection of one leukemic blast cell among 10(3) to 10(2) normal regenerating hematopoietic cells., Purpose: We determined whether the presence of residual leukemic blast cells, identified in the bone marrow of pediatric patients with AML by use of multidimensional flow cytometry, would be predictive of subsequent leukemic relapse., Methods: Multidimensional flow cytometry was performed on 205 marrow specimens collected throughout the course of treatment from 39 patients who had achieved morphologic remission. The analyses employed monoclonal antibodies directed against CD45 in combination with mixed pairs of monoclonal antibodies directed against 10 other antigens. A time-varying Cox regression analysis that controlled for sample time intervals, age, sex, morphologic classification of disease, and white blood cell count at diagnosis was used to relate the multidimensional flow cytometric results to the risk of relapse after achieving remission. Reported P values are two-sided., Results: Thirty-five of the 39 patients had bone marrow specimens available from the time that first morphologic remission was achieved. Leukemic blast cells were detected in the specimens from 19 (54%) of these 35 patients. Twenty-five of the 35 patients did not receive an allogeneic (i.e., from a different genetic background) bone marrow transplant during first morphologic remission, and 13 of 14 with residual leukemic cells experienced a relapse at a median time of 153 days after diagnosis (range, 48-863 days). Nine of the 11 patients who did not receive an allogeneic bone marrow transplant and lacked evidence of leukemic blast cells at first morphologic remission relapsed at a median time of 413 days after diagnosis (range, 321-794 days). Among the 10 individuals who received an allogeneic bone marrow transplant during first morphologic remission, five were positive for leukemic blast cells and five were negative; one of these patients (positive for leukemic blast cells) experienced a relapse 265 days after diagnosis, and three others died of transplant-related complications. The estimated risk of relapse during intervals of multidimensional flow cytometric positivity (i.e., intervals of remission for which the immediately preceding cytometry measurement was positive) was 2.8 times greater than that during negative intervals (95% confidence interval = 1.1-7.0; P = .02)., Conclusions and Implications: Multidimensional flow cytometry identifies residual leukemia in more than half of the patients with AML who are in morphologic remission. The detection of leukemic blast cells in these patients by multidimensional flow cytometry is predictive of a more rapid relapse.

Flow cytometric reticulocyte enumeration measures the fluorescence intensity of the reticulocyte population, the reticulocyte mean channel fluorescence. Reticulocyte mean channel fluorescence, used as an indicator of reticulocyte maturation, is directly proportional to the amount of intracellular RNA. Other factors, such as iron stores, may affect reticulocyte mean channel fluorescence. Iron status in normal controls, patients with anemia of chronic disease, and pregnant women was evaluated by hemoglobin, hematocrit, red blood cell indices, iron, total iron-binding capacity, and ferritin. Reticulocyte mean channel fluorescence was significantly elevated (P less than 0.0001) to 85.6 +/- 4.6 (mean +/- 1 standard deviation) in iron-deficient anemic patients and to 81.1 +/- 8.4 in iron-depleted patients compared to healthy individuals (69.7 +/- 2.6). The reticulocyte mean channel fluorescence in anemia of chronic disease was 71.3 +/- 5.8 and was not significantly different from that of normal controls. Reticulocyte mean channel fluorescence showed significant correlations with total iron-binding capacity (P less than 0.0001, r = 0.62) and ferritin (P less than 0.0001, r = 0.40). A possible explanation for these findings, describing differences in cytoplasmic levels of transferrin receptor mRNA, is discussed.