Sylvia M LaCourse,Jaclyn N Escudero,Wendy E Whatney,Krista N Krish,Arijita Subuddhi,Sara Belauret,Rachel A Pearson,Lisa Marie Cranmer,Jerphason Mecha,Daniel Matemo,Elizabeth Maleche-Obimbo,John Kinuthia,Barbra A Richardson,Grace John-Stewart,Cheryl L Day
BACKGROUNDReduced early life IFN-γ production capacity may limit sensitivity of IFN-γ release assays (IGRAs) to detect M. tuberculosis (Mtb)-specific responses in young children. Measurement of non-interferon-γ (IFN-γ) cytokine responses may improve detection of these responses in children.METHODSPBMCs from HIV-exposed uninfected (cHEU) and HIV-unexposed (cHUU) children in Western Kenya collected between 6-10 weeks, and at 12 and 24 months of age were incubated overnight with Mtb-specific CFP-10/ESAT-6 peptides and staphylococcus enterotoxin B (SEB, positive control). CD4 and CD8 T cell expression of IFN-γ and non-IFN-γ (IL-2, TNF) cytokines was measured by flow cytometry.RESULTSAmong 213 children, 28.6% had CFP-10/ESAT-6 CD4 and/or CD8 responses up to 24 months of age. No children with a positive Mtb-specific response had a reported known TB exposure. More children exhibited Mtb-specific non-IFN-γ+ (IL-2+ and/or TNF+) responses than IFN-γ+ responses (26.3% vs. 10.3%, p<0.001), including 18.3% identified by non-IFN-γ+ responses alone (non-IFN-γ+ alone 18.3% vs. IFN-γ+ alone 2.4%, p <0.001). Proportion of children with Mtb-specific responses were similar regardless of HIV exposure (cHEU 31.5% vs. cHUU 25.5%, p=0.33). At 6-10 weeks of age, children were more likely to have non-IFN-γ+ vs. IFN-γ+ responses to SEB (positive control) (96.3% vs. 77.8%, p=0.004); however, by 24 months of age 100% of children had both IFN-γ+ and non-IFN-γ+ SEB responses.CONCLUSIONMtb-specific CD4/CD8 responses were common among young Kenyan children up to 24 months of age, despite limited reported TB exposures. Non-IFN-γ+ T cell cytokine expression identified more children than IFN-γ+ who would be potentially missed by commercially available IGRAs.
{"title":"Mtb-specific CFP-10/ESAT-6 CD4 and CD8 T cell non-IFN-γ+ responses are common in young Kenyan children despite low reported TB exposure.","authors":"Sylvia M LaCourse,Jaclyn N Escudero,Wendy E Whatney,Krista N Krish,Arijita Subuddhi,Sara Belauret,Rachel A Pearson,Lisa Marie Cranmer,Jerphason Mecha,Daniel Matemo,Elizabeth Maleche-Obimbo,John Kinuthia,Barbra A Richardson,Grace John-Stewart,Cheryl L Day","doi":"10.1093/infdis/jiag039","DOIUrl":"https://doi.org/10.1093/infdis/jiag039","url":null,"abstract":"BACKGROUNDReduced early life IFN-γ production capacity may limit sensitivity of IFN-γ release assays (IGRAs) to detect M. tuberculosis (Mtb)-specific responses in young children. Measurement of non-interferon-γ (IFN-γ) cytokine responses may improve detection of these responses in children.METHODSPBMCs from HIV-exposed uninfected (cHEU) and HIV-unexposed (cHUU) children in Western Kenya collected between 6-10 weeks, and at 12 and 24 months of age were incubated overnight with Mtb-specific CFP-10/ESAT-6 peptides and staphylococcus enterotoxin B (SEB, positive control). CD4 and CD8 T cell expression of IFN-γ and non-IFN-γ (IL-2, TNF) cytokines was measured by flow cytometry.RESULTSAmong 213 children, 28.6% had CFP-10/ESAT-6 CD4 and/or CD8 responses up to 24 months of age. No children with a positive Mtb-specific response had a reported known TB exposure. More children exhibited Mtb-specific non-IFN-γ+ (IL-2+ and/or TNF+) responses than IFN-γ+ responses (26.3% vs. 10.3%, p<0.001), including 18.3% identified by non-IFN-γ+ responses alone (non-IFN-γ+ alone 18.3% vs. IFN-γ+ alone 2.4%, p <0.001). Proportion of children with Mtb-specific responses were similar regardless of HIV exposure (cHEU 31.5% vs. cHUU 25.5%, p=0.33). At 6-10 weeks of age, children were more likely to have non-IFN-γ+ vs. IFN-γ+ responses to SEB (positive control) (96.3% vs. 77.8%, p=0.004); however, by 24 months of age 100% of children had both IFN-γ+ and non-IFN-γ+ SEB responses.CONCLUSIONMtb-specific CD4/CD8 responses were common among young Kenyan children up to 24 months of age, despite limited reported TB exposures. Non-IFN-γ+ T cell cytokine expression identified more children than IFN-γ+ who would be potentially missed by commercially available IGRAs.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"68 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"CXCR6 in the Blood Is Not the Liver: Clarifying NK-Cell 'Homing' and Post-Cure ADCC Imprints in Acute Hepatitis C.","authors":"Anxin Wen","doi":"10.1093/infdis/jiag044","DOIUrl":"https://doi.org/10.1093/infdis/jiag044","url":null,"abstract":"","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"123 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Silvia Lucena Lage,Joseph M Rocco,Cihan Oguz,Francisco Otaizo-Carrasquero,Adam Rupert,Kristin L Boswell,Brian P Epling,Logan Cook,Eduardo Pinheiro Amaral,Elizabeth Laidlaw,Frances Galindo,Richard A Koup,Princy Kumar,Rita Poon,Glenn W Wortmann,Andrea Lisco,Maura Manion,Irini Sereti
BACKGROUNDDespite the efficacy of therapeutics and vaccines in reducing risk of severe COVID-19, SARS-CoV-2 infections continue to occur and rebound symptoms after initial improvement has been well-described. The mechanisms driving COVID-19 rebound remain unclear.METHODSCritical inflammatory responses were assessed by Imagestream, flow cytometry and single-cell RNA sequencing in peripheral blood mononuclear cells from vaccinated individuals presenting with early [EA, 3 days post-infection (PI), n=6] or late (LA, 8 days PI, n=6) acute symptoms and clinical rebound (rebound, 16 days PI, n=8), as well as healthy volunteers (HV, n=7).RESULTSAn overall decline in key inflammatory responses is observed in groups with longer time from symptom onset when compared to EA infection. However, RNA sequencing revealed a partial resurgence of inflammatory, stress and antiviral responses during clinical rebound, with a unique cluster of monocytes with greater activation of antigen presentation pathways and type-I IFN signaling. Monocytes from patients with rebound COVID-19 also showed elevated inflammasome activation when compared to HV, along with an accumulation of oxidized lipids and decreased levels of glutathione, both hallmarks of the oxidative stress response. Inflammatory measurements positively associated with serum SARS-CoV-2 nucleocapsid antigen and inversely correlated with adaptive immune responses, suggesting adaptive immunity limits inflammation in patients with rebound.CONCLUSIONSOur findings potentially reflect viral reappearance post-treatment in participants with clinical rebound and outline mechanisms why rebound symptoms are typically milder than during acute presentations. Extending the antiviral treatment period and/or targeting inflammatory pathways could potentially prevent virological rebound or help mitigate associated symptoms.
{"title":"Inflammasome activation and oxidative stress in SARS-CoV-2 infection and symptomatic rebound.","authors":"Silvia Lucena Lage,Joseph M Rocco,Cihan Oguz,Francisco Otaizo-Carrasquero,Adam Rupert,Kristin L Boswell,Brian P Epling,Logan Cook,Eduardo Pinheiro Amaral,Elizabeth Laidlaw,Frances Galindo,Richard A Koup,Princy Kumar,Rita Poon,Glenn W Wortmann,Andrea Lisco,Maura Manion,Irini Sereti","doi":"10.1093/infdis/jiag037","DOIUrl":"https://doi.org/10.1093/infdis/jiag037","url":null,"abstract":"BACKGROUNDDespite the efficacy of therapeutics and vaccines in reducing risk of severe COVID-19, SARS-CoV-2 infections continue to occur and rebound symptoms after initial improvement has been well-described. The mechanisms driving COVID-19 rebound remain unclear.METHODSCritical inflammatory responses were assessed by Imagestream, flow cytometry and single-cell RNA sequencing in peripheral blood mononuclear cells from vaccinated individuals presenting with early [EA, 3 days post-infection (PI), n=6] or late (LA, 8 days PI, n=6) acute symptoms and clinical rebound (rebound, 16 days PI, n=8), as well as healthy volunteers (HV, n=7).RESULTSAn overall decline in key inflammatory responses is observed in groups with longer time from symptom onset when compared to EA infection. However, RNA sequencing revealed a partial resurgence of inflammatory, stress and antiviral responses during clinical rebound, with a unique cluster of monocytes with greater activation of antigen presentation pathways and type-I IFN signaling. Monocytes from patients with rebound COVID-19 also showed elevated inflammasome activation when compared to HV, along with an accumulation of oxidized lipids and decreased levels of glutathione, both hallmarks of the oxidative stress response. Inflammatory measurements positively associated with serum SARS-CoV-2 nucleocapsid antigen and inversely correlated with adaptive immune responses, suggesting adaptive immunity limits inflammation in patients with rebound.CONCLUSIONSOur findings potentially reflect viral reappearance post-treatment in participants with clinical rebound and outline mechanisms why rebound symptoms are typically milder than during acute presentations. Extending the antiviral treatment period and/or targeting inflammatory pathways could potentially prevent virological rebound or help mitigate associated symptoms.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anil K Chaturvedi,Gregory Haber,Barry I Graubard,Li C Cheung,Maura L Gillison,Rebecca Landy
HPV vaccination of US individuals aged 27-45 years is recommended through shared clinical decision-making. To enable shared decision-making, we used a microsimulation-based state-transition model to develop and validate a risk-prediction model to identify heterosexual men aged 27-45 at high-risk of acquiring oral HPV16 infections. A risk model for incident oral HPV16 infections had good discrimination (AUC=0.73) and calibration (E/O=1.01) in internal cross-validation. Compared to vaccinating all men aged 27-45, vaccinating 44% of men with highest model-predicted risk would prevent 80% of incident oral HPV16 infections through age 45 and reduce the NNV to prevent 1 infection by 45% (184 vs. 100).
{"title":"Risk-based prophylactic HPV vaccination of heterosexual US men aged 27 to 45 years for prevention of oropharyngeal cancer.","authors":"Anil K Chaturvedi,Gregory Haber,Barry I Graubard,Li C Cheung,Maura L Gillison,Rebecca Landy","doi":"10.1093/infdis/jiag038","DOIUrl":"https://doi.org/10.1093/infdis/jiag038","url":null,"abstract":"HPV vaccination of US individuals aged 27-45 years is recommended through shared clinical decision-making. To enable shared decision-making, we used a microsimulation-based state-transition model to develop and validate a risk-prediction model to identify heterosexual men aged 27-45 at high-risk of acquiring oral HPV16 infections. A risk model for incident oral HPV16 infections had good discrimination (AUC=0.73) and calibration (E/O=1.01) in internal cross-validation. Compared to vaccinating all men aged 27-45, vaccinating 44% of men with highest model-predicted risk would prevent 80% of incident oral HPV16 infections through age 45 and reduce the NNV to prevent 1 infection by 45% (184 vs. 100).","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jing Sun,Lolita S Nidadavolu,Hsing-Yu Hsu,Rohan G Rajagopal,Jacquie Astemborski,Yuqiong Wu,Yutong Jiang,Jonah B Sacha,Paul Kievit,Beth D Jamieson,Charles T Roberts,Gregory D Kirk,Todd T Brown,Peter M Abadir
BACKGROUNDCirculating cell-free mitochondrial DNA (ccf-mtDNA) fragments are released into the bloodstream following cell death and are associated with comorbidities seen in people with HIV-1 (PWH). However, ccf-mtDNA dynamics in acute and chronic HIV infection remain unclear.METHODSWe quantified short and long ccf-mtDNA fragments in serum from 2 cohorts of PWH and people without HIV (PWoH), collected at 1, 3, and 5 years in the first cohort (N = 890) and 1 and 5 years in the second (N = 427). Mixed-effect linear regression models were used to analyze longitudinal associations of ccf-mtDNA levels with HIV status and markers (CD4-cell count, viral load). In parallel, we examined ccf-mtDNA levels in nonhuman primates (NHPs) before and after simian immunodeficiency virus (SIV) infection and following 3 and 6 months of ART.RESULTSIn both human cohorts, PWH had significantly lower levels of short and long ccf-mtDNA fragments compared with PWoH. Individuals with lower CD4 T-cell counts exhibited further reductions in ccf-mtDNA levels. In NHPs, short ccf-mtDNA levels increased after infection, peaking before ART initiation (P = .001), and subsequently declined, reaching levels below baseline after 6 months on ART. Long ccf-mtDNA fragments remained stable during the early post-ART phase but declined significantly by 6 months (P = .02).CONCLUSIONSChronic HIV infection and treated SIV infection are associated with reduced ccf-mtDNA levels, particularly in advanced disease stages. Further research is needed to clarify their role in immune activation, chronic inflammation, and aging-related comorbidities in PWH and their applicability as clinically relevant biomarkers of these processes.
{"title":"Mitochondrial DNA Fragment Dynamics in Acute and Chronic Human Immunodeficiency Virus: Insights From Human and Nonhuman Primate Models.","authors":"Jing Sun,Lolita S Nidadavolu,Hsing-Yu Hsu,Rohan G Rajagopal,Jacquie Astemborski,Yuqiong Wu,Yutong Jiang,Jonah B Sacha,Paul Kievit,Beth D Jamieson,Charles T Roberts,Gregory D Kirk,Todd T Brown,Peter M Abadir","doi":"10.1093/infdis/jiag014","DOIUrl":"https://doi.org/10.1093/infdis/jiag014","url":null,"abstract":"BACKGROUNDCirculating cell-free mitochondrial DNA (ccf-mtDNA) fragments are released into the bloodstream following cell death and are associated with comorbidities seen in people with HIV-1 (PWH). However, ccf-mtDNA dynamics in acute and chronic HIV infection remain unclear.METHODSWe quantified short and long ccf-mtDNA fragments in serum from 2 cohorts of PWH and people without HIV (PWoH), collected at 1, 3, and 5 years in the first cohort (N = 890) and 1 and 5 years in the second (N = 427). Mixed-effect linear regression models were used to analyze longitudinal associations of ccf-mtDNA levels with HIV status and markers (CD4-cell count, viral load). In parallel, we examined ccf-mtDNA levels in nonhuman primates (NHPs) before and after simian immunodeficiency virus (SIV) infection and following 3 and 6 months of ART.RESULTSIn both human cohorts, PWH had significantly lower levels of short and long ccf-mtDNA fragments compared with PWoH. Individuals with lower CD4 T-cell counts exhibited further reductions in ccf-mtDNA levels. In NHPs, short ccf-mtDNA levels increased after infection, peaking before ART initiation (P = .001), and subsequently declined, reaching levels below baseline after 6 months on ART. Long ccf-mtDNA fragments remained stable during the early post-ART phase but declined significantly by 6 months (P = .02).CONCLUSIONSChronic HIV infection and treated SIV infection are associated with reduced ccf-mtDNA levels, particularly in advanced disease stages. Further research is needed to clarify their role in immune activation, chronic inflammation, and aging-related comorbidities in PWH and their applicability as clinically relevant biomarkers of these processes.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"65 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Beyond Transplantation: Cytomegalovirus Viremia as a Therapeutic Target in Non-Cytomegalovirus Syndromes.","authors":"Ghady Haidar","doi":"10.1093/infdis/jiaf648","DOIUrl":"https://doi.org/10.1093/infdis/jiaf648","url":null,"abstract":"","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background & Aims Limited research exists on immune checkpoint inhibitors (ICIs)’ antiviral efficacy in HBV-related hepatocellular carcinoma (HCC). This study aimed to evaluate the impact of ICIs on multiple HBV markers and its correlation with HCC prognosis. Methods A retrospective cohort study was performed on 318 HBV-related HCC patients, including 268 who received ICIs (with/without targeted therapy; ICI group) and 50 who received targeted therapy alone (non-ICI group). Levels of quantitative HBsAg (qHBsAg), HBV DNA, HBV RNA and HBcrAg were monitored. Tumor response was evaluated using RECIST 1.1. Results Over a median 8.1-month follow-up, the ICI group showed a significantly greater decrease in all HBV markers. At week 96, the ICI group showed significantly higher cumulative incidences of HBsAg response (loss or ≥0.5 Log10 decline) (41.6% vs. 14.9%, p=0.006) and HBcrAg response (negativity or ≥1 Log10 decline) (46.3% vs. 18.1%, p=0.007) than non-ICI group, and a significantly faster achievement rate of HBV RNA response (negativity or ≥0.5 Log10 decline) (HR: 1.80, 95% CI: 1.08-2.99, p=0.021). Notably, the PD-1 inhibitors showed significantly better virological response efficacy than PD-L1 inhibitors (HR=2.04-5.43). The patients with lower levels of HBV markers at enrollment demonstrated significantly better overall survival (OS). Moreover, patients achieving virological response were associated with significantly better survival outcomes and tumor response, with HR ranging 1.64-8.06. Conclusions ICIs demonstrate dual therapeutic effects in HBV-related HCC, significantly reducing multiple HBV markers while concurrently enhancing prognosis in combination with antiviral therapy, emphasizing the importance of sustained virological suppression for optimal HCC outcomes.
{"title":"Immune checkpoint inhibitor-induced rapid decline in HBV markers improves the prognosis of HBV-related hepatocellular carcinoma patients","authors":"Yujie Ran, Minghui Zhu, Kunyuan Wang, Ying Xia, Yun Zhu, Mengya Zang, Shuai Kang, Qi Li, Xiaoyun Hu, Ying Wang, Fang Liu, Xiaowei Chen, Qian Zhao, Hongyan Liu, Dingli Liu, Huaiyu Chen, Jinzhang Chen, Yabing Guo, Rong Fan","doi":"10.1093/infdis/jiag036","DOIUrl":"https://doi.org/10.1093/infdis/jiag036","url":null,"abstract":"Background & Aims Limited research exists on immune checkpoint inhibitors (ICIs)’ antiviral efficacy in HBV-related hepatocellular carcinoma (HCC). This study aimed to evaluate the impact of ICIs on multiple HBV markers and its correlation with HCC prognosis. Methods A retrospective cohort study was performed on 318 HBV-related HCC patients, including 268 who received ICIs (with/without targeted therapy; ICI group) and 50 who received targeted therapy alone (non-ICI group). Levels of quantitative HBsAg (qHBsAg), HBV DNA, HBV RNA and HBcrAg were monitored. Tumor response was evaluated using RECIST 1.1. Results Over a median 8.1-month follow-up, the ICI group showed a significantly greater decrease in all HBV markers. At week 96, the ICI group showed significantly higher cumulative incidences of HBsAg response (loss or ≥0.5 Log10 decline) (41.6% vs. 14.9%, p=0.006) and HBcrAg response (negativity or ≥1 Log10 decline) (46.3% vs. 18.1%, p=0.007) than non-ICI group, and a significantly faster achievement rate of HBV RNA response (negativity or ≥0.5 Log10 decline) (HR: 1.80, 95% CI: 1.08-2.99, p=0.021). Notably, the PD-1 inhibitors showed significantly better virological response efficacy than PD-L1 inhibitors (HR=2.04-5.43). The patients with lower levels of HBV markers at enrollment demonstrated significantly better overall survival (OS). Moreover, patients achieving virological response were associated with significantly better survival outcomes and tumor response, with HR ranging 1.64-8.06. Conclusions ICIs demonstrate dual therapeutic effects in HBV-related HCC, significantly reducing multiple HBV markers while concurrently enhancing prognosis in combination with antiviral therapy, emphasizing the importance of sustained virological suppression for optimal HCC outcomes.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"81 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sumanth Cherukumilli,Adama M Keita,William Still,Kuangyi Charles Wei,Jane Juma,Hamidou Diallo,Allaye Traore,Oumar Coulibaly,Boubacar Togo,Mark A Holmes,Kate S Baker,J Kristie Johnson,Milagritos D Tapia,Samba O Sow,Karen L Kotloff
BACKGROUNDDespite data demonstrating the high prevalence of third-generation cephalosporin resistant gram-negative Enterobacterales (GNE) among children in sub-Saharan Africa, longitudinal descriptions of resistance among these pathogens from Francophone West Africa remain rare.METHODSWe conducted a retrospective analysis of pathogen-positive children 0-15 years old included in an invasive bacterial infection study at l'Hôpital Gabriel Touré (in Bamako, Mali) from 2005-2023. We aimed to describe changes in pathogen burden and non-Salmonella GNE resistance over time and compare in-hospital mortality between patients with and without non-Salmonella GNE pathogens. Isolates from 2021-2023 underwent whole genome sequencing to identify genes conferring antimicrobial resistance.RESULTSOf 3,803 pathogen-positive patients, 392 grew at least one non-Salmonella GNE pathogen. The proportion of pathogen-positive patients with non-Salmonella GNE increased (6% vs. 38%) from 2005-2023. Third-generation cephalosporin and multidrug resistance among non-Salmonella GNE increased from 30% and 55%, respectively, in 2005-2009, to 93% (both) by 2021-2023. Children 0-2 months old from outside Bamako and 3 months-15 years old from and from outside Bamako with non-Salmonella GNE had higher mortality odds (3.17, 95% CI 1.69-5.95; 2.13, 95% CI 1.44-3.14; and 2.25, 95% CI 1.38-3.66, respectively) than similar patients with other pathogens. Sequencing confirmed the presence of the emerging pathogen Pantoea dispersa and revealed genes conferring multidrug resistance.CONCLUSIONSData from this large pediatric referral center in Mali show a high and rising burden of multidrug-resistant gram-negative Enterobacterales. These patterns reflect concerns increasingly reported across sub-Saharan Africa, highlighting the urgency of strengthening antimicrobial access, diagnostics, and stewardship strategies in similar settings.
背景：尽管数据显示撒哈拉以南非洲儿童中第三代耐头孢菌素革兰氏阴性肠杆菌（GNE）的流行率很高，但西非法语区这些病原体的耐药性的纵向描述仍然很少。方法回顾性分析2005-2023年在l'Hôpital Gabriel tour（位于马里巴马科）进行的一项侵袭性细菌感染研究中0-15岁的病原体阳性儿童。我们的目的是描述病原体负担和非沙门氏菌GNE耐药性随时间的变化，并比较有和没有非沙门氏菌GNE病原体的患者的住院死亡率。对2021-2023株分离株进行全基因组测序，以确定赋予抗菌素耐药性的基因。结果3803例病原菌阳性患者中，392例至少有一种非沙门氏菌GNE病原菌。2005-2023年，非沙门氏菌GNE的病原体阳性患者比例增加（6%对38%）。第三代头孢菌素和非沙门氏菌GNE的多药耐药性分别从2005-2009年的30%和55%增加到2021-2023年的93%。巴马科城外0-2个月大的儿童和巴马科城外3 -15个月大的非沙门氏菌GNE患儿的死亡率高于其他病原体的类似患者（分别为3.17,95% CI 1.69-5.95; 2.13, 95% CI 1.44-3.14; 2.25, 95% CI 1.38-3.66）。测序证实了新出现的病原体泛菌的存在，并揭示了赋予多药耐药的基因。结论：来自马里这个大型儿科转诊中心的数据显示，多重耐药革兰氏阴性肠杆菌的负担很高，而且还在不断上升。这些模式反映了撒哈拉以南非洲各地越来越多报告的关切，突出了在类似环境中加强抗微生物药物获取、诊断和管理战略的紧迫性。
{"title":"Longitudinal Trends in Pediatric Non-Salmonella Gram-negative Enterobacterales Infections at a Tertiary Care Center in West Africa, 2005-2023.","authors":"Sumanth Cherukumilli,Adama M Keita,William Still,Kuangyi Charles Wei,Jane Juma,Hamidou Diallo,Allaye Traore,Oumar Coulibaly,Boubacar Togo,Mark A Holmes,Kate S Baker,J Kristie Johnson,Milagritos D Tapia,Samba O Sow,Karen L Kotloff","doi":"10.1093/infdis/jiag027","DOIUrl":"https://doi.org/10.1093/infdis/jiag027","url":null,"abstract":"BACKGROUNDDespite data demonstrating the high prevalence of third-generation cephalosporin resistant gram-negative Enterobacterales (GNE) among children in sub-Saharan Africa, longitudinal descriptions of resistance among these pathogens from Francophone West Africa remain rare.METHODSWe conducted a retrospective analysis of pathogen-positive children 0-15 years old included in an invasive bacterial infection study at l'Hôpital Gabriel Touré (in Bamako, Mali) from 2005-2023. We aimed to describe changes in pathogen burden and non-Salmonella GNE resistance over time and compare in-hospital mortality between patients with and without non-Salmonella GNE pathogens. Isolates from 2021-2023 underwent whole genome sequencing to identify genes conferring antimicrobial resistance.RESULTSOf 3,803 pathogen-positive patients, 392 grew at least one non-Salmonella GNE pathogen. The proportion of pathogen-positive patients with non-Salmonella GNE increased (6% vs. 38%) from 2005-2023. Third-generation cephalosporin and multidrug resistance among non-Salmonella GNE increased from 30% and 55%, respectively, in 2005-2009, to 93% (both) by 2021-2023. Children 0-2 months old from outside Bamako and 3 months-15 years old from and from outside Bamako with non-Salmonella GNE had higher mortality odds (3.17, 95% CI 1.69-5.95; 2.13, 95% CI 1.44-3.14; and 2.25, 95% CI 1.38-3.66, respectively) than similar patients with other pathogens. Sequencing confirmed the presence of the emerging pathogen Pantoea dispersa and revealed genes conferring multidrug resistance.CONCLUSIONSData from this large pediatric referral center in Mali show a high and rising burden of multidrug-resistant gram-negative Enterobacterales. These patterns reflect concerns increasingly reported across sub-Saharan Africa, highlighting the urgency of strengthening antimicrobial access, diagnostics, and stewardship strategies in similar settings.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tanya E Libby, Angela Karani, Kirkby D Tickell, Donald Akech, Benson Singa, Doreen Rwigi, Kevin Kariuki, Nancy Onamu, Derrick Ounga, James A Berkley, Judd L Walson, J Anthony G Scott, Patricia B Pavlinac
Background Mass azithromycin distribution reduces child mortality in some settings, potentially through reductions in nasopharyngeal carriage of Streptococcus pneumoniae, but has been associated with increased antimicrobial resistance. Individual-level data are lacking on the impact of azithromycin on antimicrobial resistance over time. Methods We analyzed data from a double-blind, randomized placebo-controlled trial (ClinicalTrials.gov; NCT02414399) which followed 1,398 hospitalized Kenyan children to evaluate the impact of a 5-day course of oral azithromycin at discharge from hospital on pneumococcal carriage and the proportion of isolates (among a random sample) resistant to azithromycin. Randomization to azithromycin or placebo (1:1) was stratified by enrollment county (Kisii or Homa Bay). Using generalized estimating equations, we calculated prevalence ratios (PRs) and 95% confidence intervals for the intervention, adjusting for enrollment site. Results Overall, 1,253/1398 (89.6%) enrolled children received antibiotics during their hospitalization. Pneumococcal carriage at discharge was similar among children randomized to the azithromycin group (158/702 [22.5%]) compared to the placebo group (171/696 [24.6%]; p = 0.4) and did not differ at month 3 (65.6% vs 67.0%; PR:0.98[0.90, 1.06]) or month 6 (66.7% vs 66.5%; PR:1.00[0.92, 1.08]). At discharge, 15.7% of isolates were resistant to azithromycin and there was no difference between azithromycin-treated and placebo groups at month 3 (35/266 [13.2%] vs 32/256 [12.5%]; PR:1.06[0.86, 1.66]) or month 6 (41/245 [16.7%] vs 43/243 [17.6%]; PR:1.01[0.69,1.49]). Conclusions Azithromycin treatment did not effect pneumococcal carriage or antimicrobial resistance 3- or 6-months post-randomization. High inpatient antibiotic use in this recently discharged population may have reduced any further impact of azithromycin.
{"title":"The effect of a 5-day course of azithromycin on Streptococcus pneumoniae carriage and antimicrobial resistance among Kenyan children discharged from hospital","authors":"Tanya E Libby, Angela Karani, Kirkby D Tickell, Donald Akech, Benson Singa, Doreen Rwigi, Kevin Kariuki, Nancy Onamu, Derrick Ounga, James A Berkley, Judd L Walson, J Anthony G Scott, Patricia B Pavlinac","doi":"10.1093/infdis/jiag028","DOIUrl":"https://doi.org/10.1093/infdis/jiag028","url":null,"abstract":"Background Mass azithromycin distribution reduces child mortality in some settings, potentially through reductions in nasopharyngeal carriage of Streptococcus pneumoniae, but has been associated with increased antimicrobial resistance. Individual-level data are lacking on the impact of azithromycin on antimicrobial resistance over time. Methods We analyzed data from a double-blind, randomized placebo-controlled trial (ClinicalTrials.gov; NCT02414399) which followed 1,398 hospitalized Kenyan children to evaluate the impact of a 5-day course of oral azithromycin at discharge from hospital on pneumococcal carriage and the proportion of isolates (among a random sample) resistant to azithromycin. Randomization to azithromycin or placebo (1:1) was stratified by enrollment county (Kisii or Homa Bay). Using generalized estimating equations, we calculated prevalence ratios (PRs) and 95% confidence intervals for the intervention, adjusting for enrollment site. Results Overall, 1,253/1398 (89.6%) enrolled children received antibiotics during their hospitalization. Pneumococcal carriage at discharge was similar among children randomized to the azithromycin group (158/702 [22.5%]) compared to the placebo group (171/696 [24.6%]; p = 0.4) and did not differ at month 3 (65.6% vs 67.0%; PR:0.98[0.90, 1.06]) or month 6 (66.7% vs 66.5%; PR:1.00[0.92, 1.08]). At discharge, 15.7% of isolates were resistant to azithromycin and there was no difference between azithromycin-treated and placebo groups at month 3 (35/266 [13.2%] vs 32/256 [12.5%]; PR:1.06[0.86, 1.66]) or month 6 (41/245 [16.7%] vs 43/243 [17.6%]; PR:1.01[0.69,1.49]). Conclusions Azithromycin treatment did not effect pneumococcal carriage or antimicrobial resistance 3- or 6-months post-randomization. High inpatient antibiotic use in this recently discharged population may have reduced any further impact of azithromycin.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"56 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Danuta M Skowronski, Charlene Ranadheera, Samantha E Kaweski, Suzana Sabaiduc, Lea Separovic, Gaby Makowski, Johnny Ung, Romina C Reyes, Bonnie Henry, Arianne Albert, Felicity Clemens, Darwyn Kobasa, Nathalie Bastien
Background Pre-existing immunity to emerging influenza viruses informs pandemic risk assessment. We compared cross-reactive neuraminidase (NA) antibody levels against avian influenza A(H5N1) by age and birth (imprinting) cohorts defined by periods of human influenza A subtype (H1N1, H2N2 or H3N2) circulation over the past century. Methods We used anonymized, residual sera collected from ten age groups spanning one to >80 years during an August 2024 cross-sectional serosurvey conducted in British Columbia, Canada. We assessed NA inhibition antibody titres by enzyme-linked lectin assay against clade 2.3.4.4b H5N1, and 2009 H1N1pdm09 and 1968 H3N2 pandemic strains Results Among 575 participants with median age 32 (IQR: 15-62) years, 404 (70%) had detectable anti-N1 titres >10 against H5N1, with 260 (45%), 182 (32%) and 98 (17%) having titres >40, >80 and >160, respectively. Anti-N1 titres against 2009 H1N1pdm09 and H5N1 were strongly correlated (r=0.86; 95%CI: 0.82-0.89), with both highest among young adults born 1997-2003 who were school-aged children during the 2009 H1N1 pandemic (427.9, 100.8), lowest among the youngest and least influenza-experienced pediatric cohorts born 2015-2023 (20.7, 6.8) and middle-aged adults born during the 1957-1967 H2N2 era (25.1, 10.7), thereafter increasing toward a similar secondary peak among the oldest cohorts born during the pre-1947 H1N1 era (387.3, 81.0). Conclusions A substantial proportion of the population has pre-existing anti-N1 against H5N1, with age-related variation reflecting H1N1 imprinting and exposure opportunities. Through heightened attack rates and shifts in immunological hierarchies, historic pandemics shape and expand the immune repertoire with implications for pre-immunity to emerging zoonotic threats.
{"title":"Cross-reactive H5N1 neuraminidase antibodies by age and influenza A imprinting cohorts of the past century: population-based serosurvey, British Columbia, Canada","authors":"Danuta M Skowronski, Charlene Ranadheera, Samantha E Kaweski, Suzana Sabaiduc, Lea Separovic, Gaby Makowski, Johnny Ung, Romina C Reyes, Bonnie Henry, Arianne Albert, Felicity Clemens, Darwyn Kobasa, Nathalie Bastien","doi":"10.1093/infdis/jiag030","DOIUrl":"https://doi.org/10.1093/infdis/jiag030","url":null,"abstract":"Background Pre-existing immunity to emerging influenza viruses informs pandemic risk assessment. We compared cross-reactive neuraminidase (NA) antibody levels against avian influenza A(H5N1) by age and birth (imprinting) cohorts defined by periods of human influenza A subtype (H1N1, H2N2 or H3N2) circulation over the past century. Methods We used anonymized, residual sera collected from ten age groups spanning one to &gt;80 years during an August 2024 cross-sectional serosurvey conducted in British Columbia, Canada. We assessed NA inhibition antibody titres by enzyme-linked lectin assay against clade 2.3.4.4b H5N1, and 2009 H1N1pdm09 and 1968 H3N2 pandemic strains Results Among 575 participants with median age 32 (IQR: 15-62) years, 404 (70%) had detectable anti-N1 titres &gt;10 against H5N1, with 260 (45%), 182 (32%) and 98 (17%) having titres &gt;40, &gt;80 and &gt;160, respectively. Anti-N1 titres against 2009 H1N1pdm09 and H5N1 were strongly correlated (r=0.86; 95%CI: 0.82-0.89), with both highest among young adults born 1997-2003 who were school-aged children during the 2009 H1N1 pandemic (427.9, 100.8), lowest among the youngest and least influenza-experienced pediatric cohorts born 2015-2023 (20.7, 6.8) and middle-aged adults born during the 1957-1967 H2N2 era (25.1, 10.7), thereafter increasing toward a similar secondary peak among the oldest cohorts born during the pre-1947 H1N1 era (387.3, 81.0). Conclusions A substantial proportion of the population has pre-existing anti-N1 against H5N1, with age-related variation reflecting H1N1 imprinting and exposure opportunities. Through heightened attack rates and shifts in immunological hierarchies, historic pandemics shape and expand the immune repertoire with implications for pre-immunity to emerging zoonotic threats.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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