Nadine Rouphael,Ralph Tanios,Jessica Traenkner,Matthew D Pauly,Nishit Shetty,Meredith J Shephard,A J Campbell,Christelle Radi,Shamika Danzy,Jin Pan,Andrew P Catchpole,Alex Mann,Joshua F Detelich,Anice C Lowen,Linsey C Marr,Seema S Lakdawala,
BACKGROUNDControlled human infection models are widely used to study infectious diseases. Since the 1960s, these studies have primarily relied on intranasal inoculation, as earlier aerosol-based methods raised safety concerns and were largely abandoned despite better mimicking the natural route of infection.METHODSUtilizing modern advances in aerosol delivery, we conducted a dose-escalation study to evaluate the safety and feasibility of aerosol inoculation for human influenza challenge. Healthy adults aged 18-49 years were inoculated with influenza A/Perth/16/2009 (H3N2) using either a flow-focusing monodisperse aerosol generator (FMAG) delivering coarse particles or a medical nebulizer delivering fine particles. Participants were monitored in a controlled inpatient setting with symptom tracking, virologic sampling, and serology. Doses were escalated according to predefined safety and attack rate thresholds.RESULTSFourteen participants were enrolled. Flow-focusing monodisperse aerosol generator delivery at higher dose levels resulted in infection in 75% of participants (3/4), while nebulizer delivery produced infection in 50% (2/4). Illnesses were mild and self-limited. Viral shedding was detected at multiple respiratory sites, and adverse events were infrequent and generally mild. No serious adverse events occurred. Antibody responses were observed in a subset of infected participants.CONCLUSIONSIn this small pilot, aerosolized challenge using modern delivery systems was feasible under controlled conditions; no safety concerns were identified, and MMID was induced in a subset of participants. These data establish a methodological framework for future studies evaluating pathogenesis and mucosal immune responses to a variety of respiratory pathogens.
{"title":"Feasibility and Safety of Aerosolized Influenza Virus Challenge in Humans Using Two Modern Delivery Systems.","authors":"Nadine Rouphael,Ralph Tanios,Jessica Traenkner,Matthew D Pauly,Nishit Shetty,Meredith J Shephard,A J Campbell,Christelle Radi,Shamika Danzy,Jin Pan,Andrew P Catchpole,Alex Mann,Joshua F Detelich,Anice C Lowen,Linsey C Marr,Seema S Lakdawala, ","doi":"10.1093/infdis/jiaf603","DOIUrl":"https://doi.org/10.1093/infdis/jiaf603","url":null,"abstract":"BACKGROUNDControlled human infection models are widely used to study infectious diseases. Since the 1960s, these studies have primarily relied on intranasal inoculation, as earlier aerosol-based methods raised safety concerns and were largely abandoned despite better mimicking the natural route of infection.METHODSUtilizing modern advances in aerosol delivery, we conducted a dose-escalation study to evaluate the safety and feasibility of aerosol inoculation for human influenza challenge. Healthy adults aged 18-49 years were inoculated with influenza A/Perth/16/2009 (H3N2) using either a flow-focusing monodisperse aerosol generator (FMAG) delivering coarse particles or a medical nebulizer delivering fine particles. Participants were monitored in a controlled inpatient setting with symptom tracking, virologic sampling, and serology. Doses were escalated according to predefined safety and attack rate thresholds.RESULTSFourteen participants were enrolled. Flow-focusing monodisperse aerosol generator delivery at higher dose levels resulted in infection in 75% of participants (3/4), while nebulizer delivery produced infection in 50% (2/4). Illnesses were mild and self-limited. Viral shedding was detected at multiple respiratory sites, and adverse events were infrequent and generally mild. No serious adverse events occurred. Antibody responses were observed in a subset of infected participants.CONCLUSIONSIn this small pilot, aerosolized challenge using modern delivery systems was feasible under controlled conditions; no safety concerns were identified, and MMID was induced in a subset of participants. These data establish a methodological framework for future studies evaluating pathogenesis and mucosal immune responses to a variety of respiratory pathogens.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"118 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760075","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}
Our viewpoint summarizes key points of a recently published review on the evolution of our understanding of airway infections in the era of highly effective modulators. Herein we discuss how this will shape our current and future research and practice endeavors.
{"title":"Clearing the air: Rethinking airway infection with CFTR modulators","authors":"Edith T Zemanick, Ranjani Somayaji","doi":"10.1093/infdis/jiaf625","DOIUrl":"https://doi.org/10.1093/infdis/jiaf625","url":null,"abstract":"Our viewpoint summarizes key points of a recently published review on the evolution of our understanding of airway infections in the era of highly effective modulators. Herein we discuss how this will shape our current and future research and practice endeavors.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"157 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765310","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}
Valentine Faure Bardon, Naim Bouazza, Gilles Peytavin, Minh Patrick Le, Sihem Benaboud, Frantz Foissac, Gabrielle Lui, Léo Froelicher-Bournaud, Saïk Urien, Bettina Bessieres, Tiffany Guilleminot, Laurence Bussieres, Jean-Marc Treluyer, Marianne Leruez-Ville, Yves Ville
Background Cytomegalovirus (CMV) affects 0.5-2.0% of all live births and is the main nongenetic cause of congenital sensorineural hearing loss and neurological damage, yet no validated prenatal treatment exists for infected fetuses. Letermovir, a CMV-specific antiviral, is approved for prophylaxis in transplant recipients. Objective This study aimed to quantify maternal-fetal exposure to letermovir following maternal administration, focusing on CMV-target fetal organs, particularly the brain. Methods Seven pregnant women undergoing second-trimester termination of pregnancy for fetal anomalies received oral letermovir (240 or 480 mg once daily) for three days. On the day of termination, samples from maternal and fetal blood, placenta, and fetal organs were collected and analyzed. Plasma and tissue drug concentrations were compared to the EC50Letermovir to assess potential antiviral efficacy. Results Letermovir achieved therapeutic levels in all compartments. Complementary physiologically-based-pharmacokinetic modeling confirmed adequate fetal exposure across pregnancy stages. No maternal adverse events were observed. Conclusion These unique in vivo data provide the first pharmacological rationale supporting letermovir use during pregnancy for congenital CMV therapy.
{"title":"Maternal-Fetal Letermovir Exposure in Vivo and PBPK-based: A Rationale for Congenital CMV Therapy","authors":"Valentine Faure Bardon, Naim Bouazza, Gilles Peytavin, Minh Patrick Le, Sihem Benaboud, Frantz Foissac, Gabrielle Lui, Léo Froelicher-Bournaud, Saïk Urien, Bettina Bessieres, Tiffany Guilleminot, Laurence Bussieres, Jean-Marc Treluyer, Marianne Leruez-Ville, Yves Ville","doi":"10.1093/infdis/jiaf619","DOIUrl":"https://doi.org/10.1093/infdis/jiaf619","url":null,"abstract":"Background Cytomegalovirus (CMV) affects 0.5-2.0% of all live births and is the main nongenetic cause of congenital sensorineural hearing loss and neurological damage, yet no validated prenatal treatment exists for infected fetuses. Letermovir, a CMV-specific antiviral, is approved for prophylaxis in transplant recipients. Objective This study aimed to quantify maternal-fetal exposure to letermovir following maternal administration, focusing on CMV-target fetal organs, particularly the brain. Methods Seven pregnant women undergoing second-trimester termination of pregnancy for fetal anomalies received oral letermovir (240 or 480 mg once daily) for three days. On the day of termination, samples from maternal and fetal blood, placenta, and fetal organs were collected and analyzed. Plasma and tissue drug concentrations were compared to the EC50Letermovir to assess potential antiviral efficacy. Results Letermovir achieved therapeutic levels in all compartments. Complementary physiologically-based-pharmacokinetic modeling confirmed adequate fetal exposure across pregnancy stages. No maternal adverse events were observed. Conclusion These unique in vivo data provide the first pharmacological rationale supporting letermovir use during pregnancy for congenital CMV therapy.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765311","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}
Jeanne Pascard, Sophie Desgraupes, Aurélie Chiche, Patricia Jeannin, Rebecca Kanaan, Antoine Gessain, Han Li, Pierre-Emmanuel Ceccaldi, Aurore Vidy
Background Yellow fever virus (YFV), a mosquito-borne Orthoflavivirus, remains a significant public health concern, especially in regions with low vaccine coverage. Since 2010, yellow fever vaccination is not recommended for breastfeeding women due to reported cases of vaccine strain transmission through breast milk causing neonatal meningoencephalitis. However, breastfeeding transmission efficiency of the vaccine strains remains unknown, and wild-type strains transmission has been suggested following viral RNA detection in milk. Obtaining direct evidence of breastfeeding-related transmission in humans is challenging as vector-borne exposure confounds analyses, making animal models essential for assessing this risk. Methods We used A129 mouse model to investigate YFV transmission via breastfeeding for wild-type and vaccine strains, and human epithelial in vitro models to explore mechanisms of mammary and intestinal barrier crossing. Results Wild-type and vaccine strains spread to mammary glands, targeting mainly stromal and immune cells, and are excreted into milk as free and cell-associated virus. In vitro, mammary epithelial cells also support infection, suggesting two mechanisms of epithelial crossing. Neonates are susceptible to oral infection, showing higher infection rates for wild-type virus but evidence of neuroinvasion for both strains. These strains infect and cross an in vitro human intestinal barrier model, suggesting this epithelium as a potential viral entry site for neonates. Finally, the virus can be transmitted from infected dams to suckling pups via breastfeeding, though rarely. Conclusion This study demonstrates YFV transmission through breastfeeding in an animal model and supports the biological plausibility of this route, highlighting its potential among YFV transmission risks.
{"title":"In vivo risk assessment of yellow fever virus transmission through breastfeeding, and mechanistic insights","authors":"Jeanne Pascard, Sophie Desgraupes, Aurélie Chiche, Patricia Jeannin, Rebecca Kanaan, Antoine Gessain, Han Li, Pierre-Emmanuel Ceccaldi, Aurore Vidy","doi":"10.1093/infdis/jiaf637","DOIUrl":"https://doi.org/10.1093/infdis/jiaf637","url":null,"abstract":"Background Yellow fever virus (YFV), a mosquito-borne Orthoflavivirus, remains a significant public health concern, especially in regions with low vaccine coverage. Since 2010, yellow fever vaccination is not recommended for breastfeeding women due to reported cases of vaccine strain transmission through breast milk causing neonatal meningoencephalitis. However, breastfeeding transmission efficiency of the vaccine strains remains unknown, and wild-type strains transmission has been suggested following viral RNA detection in milk. Obtaining direct evidence of breastfeeding-related transmission in humans is challenging as vector-borne exposure confounds analyses, making animal models essential for assessing this risk. Methods We used A129 mouse model to investigate YFV transmission via breastfeeding for wild-type and vaccine strains, and human epithelial in vitro models to explore mechanisms of mammary and intestinal barrier crossing. Results Wild-type and vaccine strains spread to mammary glands, targeting mainly stromal and immune cells, and are excreted into milk as free and cell-associated virus. In vitro, mammary epithelial cells also support infection, suggesting two mechanisms of epithelial crossing. Neonates are susceptible to oral infection, showing higher infection rates for wild-type virus but evidence of neuroinvasion for both strains. These strains infect and cross an in vitro human intestinal barrier model, suggesting this epithelium as a potential viral entry site for neonates. Finally, the virus can be transmitted from infected dams to suckling pups via breastfeeding, though rarely. Conclusion This study demonstrates YFV transmission through breastfeeding in an animal model and supports the biological plausibility of this route, highlighting its potential among YFV transmission risks.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770807","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}
Ighovwerha Ofotokun,Kehmia Titanji,Sadaf Dabeer,Ashish Kumar Tripathi,Brahmchetna Bedi,Caitlin M Kirkpatrick,Tran B Nguyen,M Neale Weitzmann
BACKGROUNDFractures are common in people with HIV (PWH). Interleukin 4 (IL-4), an antiosteoclastogenic product of CD4 Th2 T cells, becomes depleted in PWH; however, its role in skeletal deterioration in PWH is unknown. We therefore examined associations between IL-4 and bone mineral density (BMD), bone resorption and formation markers (β-C-terminal telopeptide of type I collagen and osteocalcin), and the osteoclastogenic regulators receptor activator of NF-κB ligand (RANKL) and osteoprotegerin in PWH who were antiretroviral therapy (ART) naive and people without HIV (PWoH).METHODSCommercial enzyme-linked immunosorbent assays were used to measure factors in a cohort of 37 ART-naive PWH and 28 PWoH and in an independent cohort of 29 ART-experienced PWH. BMD was quantified by bone densitometry, and IL-4 associations were analyzed by sex and HIV status via Spearman correlation and multivariable linear regression.RESULTSIL-4 was significantly lower in ART-naive PWH as compared with PWoH and higher in ART-experienced PWH vs ART-naive PWH. With ART-naive PWH and PWoH combined, IL-4 correlated inversely with β-C-terminal telopeptide of type I collagen, RANKL, and RANKL/osteoprotegerin ratio in males and females, individually and when aggregated, but not in ART-naive PWH or PWoH individually. In PWoH and ART-naive PWH combined, IL-4 was significantly associated with higher lumbar spine Z score and most femoral BMD T and Z scores in males but not females.CONCLUSIONSIL-4 levels are reduced in treatment-naive PWH and higher in ART-experienced PWH. IL-4 positively correlates with BMD in men but not women, suggesting that IL-4 protects the male skeleton and that IL-4 decline may contribute to bone loss in men with HIV.
{"title":"IL-4 Correlates With Bone Mineral Density in Men, and IL-4 Depletion May Drive Bone Loss in Men With HIV.","authors":"Ighovwerha Ofotokun,Kehmia Titanji,Sadaf Dabeer,Ashish Kumar Tripathi,Brahmchetna Bedi,Caitlin M Kirkpatrick,Tran B Nguyen,M Neale Weitzmann","doi":"10.1093/infdis/jiaf570","DOIUrl":"https://doi.org/10.1093/infdis/jiaf570","url":null,"abstract":"BACKGROUNDFractures are common in people with HIV (PWH). Interleukin 4 (IL-4), an antiosteoclastogenic product of CD4 Th2 T cells, becomes depleted in PWH; however, its role in skeletal deterioration in PWH is unknown. We therefore examined associations between IL-4 and bone mineral density (BMD), bone resorption and formation markers (β-C-terminal telopeptide of type I collagen and osteocalcin), and the osteoclastogenic regulators receptor activator of NF-κB ligand (RANKL) and osteoprotegerin in PWH who were antiretroviral therapy (ART) naive and people without HIV (PWoH).METHODSCommercial enzyme-linked immunosorbent assays were used to measure factors in a cohort of 37 ART-naive PWH and 28 PWoH and in an independent cohort of 29 ART-experienced PWH. BMD was quantified by bone densitometry, and IL-4 associations were analyzed by sex and HIV status via Spearman correlation and multivariable linear regression.RESULTSIL-4 was significantly lower in ART-naive PWH as compared with PWoH and higher in ART-experienced PWH vs ART-naive PWH. With ART-naive PWH and PWoH combined, IL-4 correlated inversely with β-C-terminal telopeptide of type I collagen, RANKL, and RANKL/osteoprotegerin ratio in males and females, individually and when aggregated, but not in ART-naive PWH or PWoH individually. In PWoH and ART-naive PWH combined, IL-4 was significantly associated with higher lumbar spine Z score and most femoral BMD T and Z scores in males but not females.CONCLUSIONSIL-4 levels are reduced in treatment-naive PWH and higher in ART-experienced PWH. IL-4 positively correlates with BMD in men but not women, suggesting that IL-4 protects the male skeleton and that IL-4 decline may contribute to bone loss in men with HIV.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"146 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752662","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}
Brent Lindquist-Kleissler,Peter Kfoury,Keith Kuo,Cameron Elwood,Ashlea Wilkes,Albert H Park,Joseph E Rower
BACKGROUNDCongenital cytomegalovirus (cCMV) infection is the most common cause of non-hereditary pediatric sensorineural hearing loss (SNHL). Importantly, cCMV is treatable, with the primary option being ganciclovir (GCV) or its orally bioavailable pro-drug valganciclovir (VGCV). A challenge for treating cCMV is the elevated risk for neutropenia associated with standard dosing. Optimizing and individualizing VGCV dosing could ameliorate the risk of neutropenia and improve efficacy but requires an understanding of the complex intracellular phosphorylation processes that govern the formation of the active GCV-triphosphate (GCV-TP) moiety. This study utilizes dried blood spot (DBS) samples from cCMV-infected infants to quantify GCV-TP and explore the kinetics of GCV-TP in this matrix.METHODSDBS samples were collected from infants with CMV infection receiving 16 mg/kg VGCV twice-daily as part of either a randomized, placebo-controlled clinical trial (ValEAR) or an open-label PK study. GCV-TP concentrations in DBS were determined using LC-MS/MS.RESULTSData indicate that GCV-TP is long-lived in DBS, with a half-life approximating 21 days. This leads to extensive GCV-TP accumulation in this matrix (primarily consisting of erythrocytes), with an expected ∼62-fold difference in first-dose and steady-state concentrations. Simulated data highlight the potential for DBS GCV-TP to be used as an objective adherence marker.CONCLUSIONSThese findings underscore the need to define the kinetics of GCV-TP in cell matrices relevant to its activity to determine appropriate VGCV dosing strategies in this population and establish safe and define effective therapeutic concentration targets.
{"title":"Intracellular Ganciclovir Tri-Phosphate Concentrations in Children with Congenital Cytomegalovirus Infection.","authors":"Brent Lindquist-Kleissler,Peter Kfoury,Keith Kuo,Cameron Elwood,Ashlea Wilkes,Albert H Park,Joseph E Rower","doi":"10.1093/infdis/jiaf633","DOIUrl":"https://doi.org/10.1093/infdis/jiaf633","url":null,"abstract":"BACKGROUNDCongenital cytomegalovirus (cCMV) infection is the most common cause of non-hereditary pediatric sensorineural hearing loss (SNHL). Importantly, cCMV is treatable, with the primary option being ganciclovir (GCV) or its orally bioavailable pro-drug valganciclovir (VGCV). A challenge for treating cCMV is the elevated risk for neutropenia associated with standard dosing. Optimizing and individualizing VGCV dosing could ameliorate the risk of neutropenia and improve efficacy but requires an understanding of the complex intracellular phosphorylation processes that govern the formation of the active GCV-triphosphate (GCV-TP) moiety. This study utilizes dried blood spot (DBS) samples from cCMV-infected infants to quantify GCV-TP and explore the kinetics of GCV-TP in this matrix.METHODSDBS samples were collected from infants with CMV infection receiving 16 mg/kg VGCV twice-daily as part of either a randomized, placebo-controlled clinical trial (ValEAR) or an open-label PK study. GCV-TP concentrations in DBS were determined using LC-MS/MS.RESULTSData indicate that GCV-TP is long-lived in DBS, with a half-life approximating 21 days. This leads to extensive GCV-TP accumulation in this matrix (primarily consisting of erythrocytes), with an expected ∼62-fold difference in first-dose and steady-state concentrations. Simulated data highlight the potential for DBS GCV-TP to be used as an objective adherence marker.CONCLUSIONSThese findings underscore the need to define the kinetics of GCV-TP in cell matrices relevant to its activity to determine appropriate VGCV dosing strategies in this population and establish safe and define effective therapeutic concentration targets.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728381","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}
Jessica T Lin, Derrick K Mathias, Guozheng Yang, Mwajabu Loya, Meredith S Muller, Christopher Basham, Vincent Nyasembe, Kano Amagai, Isaack Rutha, Claudia Gaither, Mwanaidi Nyange, Hamza Said, Srijana B Chhetri, Brian Swinehart, Feng-Chang Lin, Rhoel R Dinglasan, Jonathan J Juliano, Brian Tarimo, Billy Ngasala
Background Asymptomatic malaria carriers often harbor low parasite densities missed by rapid diagnostic tests (RDTs), yet they contribute to transmission. Direct skin feeding assays (DSFs) can sensitively measure their infectiousness to mosquitoes. Methods To characterize human-to-mosquito transmission from the asymptomatic reservoir in Bagamoyo, Tanzania, DSFs were performed in persons >5 years of age positive for P. falciparum by RDT or real-time PCR. Fifty colony-reared Anopheles gambiae were fed on the posterior calves. Successful mosquito infection was defined as ≥1 oocyst-positive mosquito midgut among 25 dissected eight days post-skin feeding. Results Among 491 participants with median parasite density of 5.1 parasites/uL who underwent DSF, 22% were infectious to mosquitoes. RDT-positive participants infected roughly twice as many mosquitoes compared to RDT-negative/PCR-positive persons. However, up to 21% of infectious carriers were PCR-negative at the time of skin feeding, after screening PCR-positive a few days earlier. Overall, 9.1% (342/3,741) of mosquitoes fed on infectious carriers were parasite-positive at dissection. Half of infectious individuals infected a single mosquito, while the top 16 transmitters (3% of those undergoing DSF) cumulatively infected 57% of infected mosquitoes. RDT-positive school-age children (6-15yo), 27% of the DSF cohort, contributed to 58% of infected mosquitoes. Unexpectedly, mosquito midguts from 39 DSFs (44% of oocyst-positive feeds analyzed) tested positive for Plasmodium ovale. Conclusions Parasites circulating at the limit of PCR detection commonly infect mosquitoes. However, a small proportion of highly infectious carriers contribute disproportionately to transmission, offering potential for targeted interventions. Plasmodium ovale was frequently co-transmitted with P. falciparum to mosquitoes.
{"title":"Uneven Plasmodium falciparum transmission and cryptic ovale transmission from the asymptomatic reservoir in Bagamoyo, Tanzania","authors":"Jessica T Lin, Derrick K Mathias, Guozheng Yang, Mwajabu Loya, Meredith S Muller, Christopher Basham, Vincent Nyasembe, Kano Amagai, Isaack Rutha, Claudia Gaither, Mwanaidi Nyange, Hamza Said, Srijana B Chhetri, Brian Swinehart, Feng-Chang Lin, Rhoel R Dinglasan, Jonathan J Juliano, Brian Tarimo, Billy Ngasala","doi":"10.1093/infdis/jiaf634","DOIUrl":"https://doi.org/10.1093/infdis/jiaf634","url":null,"abstract":"Background Asymptomatic malaria carriers often harbor low parasite densities missed by rapid diagnostic tests (RDTs), yet they contribute to transmission. Direct skin feeding assays (DSFs) can sensitively measure their infectiousness to mosquitoes. Methods To characterize human-to-mosquito transmission from the asymptomatic reservoir in Bagamoyo, Tanzania, DSFs were performed in persons >5 years of age positive for P. falciparum by RDT or real-time PCR. Fifty colony-reared Anopheles gambiae were fed on the posterior calves. Successful mosquito infection was defined as ≥1 oocyst-positive mosquito midgut among 25 dissected eight days post-skin feeding. Results Among 491 participants with median parasite density of 5.1 parasites/uL who underwent DSF, 22% were infectious to mosquitoes. RDT-positive participants infected roughly twice as many mosquitoes compared to RDT-negative/PCR-positive persons. However, up to 21% of infectious carriers were PCR-negative at the time of skin feeding, after screening PCR-positive a few days earlier. Overall, 9.1% (342/3,741) of mosquitoes fed on infectious carriers were parasite-positive at dissection. Half of infectious individuals infected a single mosquito, while the top 16 transmitters (3% of those undergoing DSF) cumulatively infected 57% of infected mosquitoes. RDT-positive school-age children (6-15yo), 27% of the DSF cohort, contributed to 58% of infected mosquitoes. Unexpectedly, mosquito midguts from 39 DSFs (44% of oocyst-positive feeds analyzed) tested positive for Plasmodium ovale. Conclusions Parasites circulating at the limit of PCR detection commonly infect mosquitoes. However, a small proportion of highly infectious carriers contribute disproportionately to transmission, offering potential for targeted interventions. Plasmodium ovale was frequently co-transmitted with P. falciparum to mosquitoes.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145730782","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}
Julien Tran,Kate Maddaford,Jason J Ong,Ei T Aung,Christopher K Fairley,Eric P F Chow
INTRODUCTIONPrimary anorectal syphilis may go unnoticed in men who have sex with men (MSM) engaging in receptive anal sex. This study examined whether weekly digital anorectal examination (DARE) could help men self-detect abnormalities indicative of primary anorectal syphilis.METHODSA cohort study of MSM aged ≥18 years who engage in receptive anal sex was conducted at the Melbourne Sexual Health Centre from 9 March 2022 to 4 August 2023. Participants received instructions on how to perform DARE, along with weekly text reminders for 48 weeks. Those who self-detected abnormalities were advised to seek clinical consultation. The primary outcome was the proportion of syphilis cases detected via DARE. Secondary outcomes included reports of DARE-related abnormalities, adherence, and experiences.RESULTSOf the 222 men recruited, 181 (81.5%) completed the study. Six men (2.7%; 95% CI: 0.9 to 5.8) were diagnosed with syphilis-one primary anorectal infection detected by DARE, two secondary infections and three early latent syphilis infections. There were 32 clinical consultations prompted by DARE. On average, men performed 78.2% (95% CI: 77.3 to 79.0) of their weekly DARE which showed no significant variation over time (ptrend=0.26). Most found DARE easy to perform (>95.0%) and would continue performing it if recommended for early syphilis detection (77.6%).CONCLUSIONSMen's high adherence to performing we DARE suggests that it may complement routine screening for primary anorectal syphilis. However, its sensitivity may be limited, as five out of six early syphilis cases did not have primary lesions that were self-detected by the five men.
{"title":"Digital anorectal examination to self-detect primary syphilis: a prospective cohort study.","authors":"Julien Tran,Kate Maddaford,Jason J Ong,Ei T Aung,Christopher K Fairley,Eric P F Chow","doi":"10.1093/infdis/jiaf628","DOIUrl":"https://doi.org/10.1093/infdis/jiaf628","url":null,"abstract":"INTRODUCTIONPrimary anorectal syphilis may go unnoticed in men who have sex with men (MSM) engaging in receptive anal sex. This study examined whether weekly digital anorectal examination (DARE) could help men self-detect abnormalities indicative of primary anorectal syphilis.METHODSA cohort study of MSM aged ≥18 years who engage in receptive anal sex was conducted at the Melbourne Sexual Health Centre from 9 March 2022 to 4 August 2023. Participants received instructions on how to perform DARE, along with weekly text reminders for 48 weeks. Those who self-detected abnormalities were advised to seek clinical consultation. The primary outcome was the proportion of syphilis cases detected via DARE. Secondary outcomes included reports of DARE-related abnormalities, adherence, and experiences.RESULTSOf the 222 men recruited, 181 (81.5%) completed the study. Six men (2.7%; 95% CI: 0.9 to 5.8) were diagnosed with syphilis-one primary anorectal infection detected by DARE, two secondary infections and three early latent syphilis infections. There were 32 clinical consultations prompted by DARE. On average, men performed 78.2% (95% CI: 77.3 to 79.0) of their weekly DARE which showed no significant variation over time (ptrend=0.26). Most found DARE easy to perform (>95.0%) and would continue performing it if recommended for early syphilis detection (77.6%).CONCLUSIONSMen's high adherence to performing we DARE suggests that it may complement routine screening for primary anorectal syphilis. However, its sensitivity may be limited, as five out of six early syphilis cases did not have primary lesions that were self-detected by the five men.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728379","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":"Clinical Commentary on: Targeting Tryptophan Metabolism for Tuberculosis Biomarkers and Host Directed Therapy.","authors":"Joel D Ernst","doi":"10.1093/infdis/jiaf624","DOIUrl":"https://doi.org/10.1093/infdis/jiaf624","url":null,"abstract":"","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728380","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}
Maribeth R Nicholson, Siyuan Ma, Britton A Strickland, Mia Cecala, Lisa Zhang, Seth Reasoner, Emma R Guiberson, Matthew J Munneke, Meghan H Shilts, Eric P Skaar, Suman R Das
Background and Aims Symptomatic Clostridioides difficile infection (CDI) can cause significant morbidity and mortality. Conversely, patients can be colonized with toxigenic C. difficile in the absence of symptoms, termed asymptomatic colonization. We previously demonstrated that the presence and function of C. difficile toxins do not differentiate between asymptomatic colonization and CDI in children, suggesting the influence of other factors. This study aimed to interrogate the intestinal microbiome and butyrate in stool samples from children with CDI and asymptomatic colonization. Methods Design: Case-control study Setting: Tertiary care children’s hospital Participants and measures: Asymptomatic children had stool tested for C. difficile by nucleic-acid amplification-based testing (NAAT) and were considered colonized if positive (N=50). Residual stool was also obtained from symptomatic children who tested positive for C. difficile by NAAT (N=55). The microbiome was assessed via 16S rRNA sequencing and butyrate via liquid chromatography-mass spectrometry. Results Compared to clinical co-variates and comorbidities, C. difficile symptom status (i.e., asymptomatic colonization versus symptomatic CDI) demonstrated the strongest differential abundance association on gut microbes. Symptomatic CDI was associated with increased abundance of Escherichia/Shigella (Benjamini-Hochberg adjusted q=3.94x10-5), Haemophilus (q=0.022), and Gemella (q=0.085), and depleted abundance of gut commensals such as Faecalibacterium (q=0.041), Blautia (q=0.041), and Bifidobacterium (q=0.063). We also observed depletion in the abundance of microbial butyrate producers and fecal butyrate in participants with symptomatic CDI versus asymptomatic colonization. Conclusion The gut microbiota and butyrate differ between participants with asymptomatic C. difficile colonization and symptomatic CDI, suggesting their potential role in symptom development.
{"title":"The Gut Microbiome and Butyrate Differentiate Clostridioides difficile Colonization and Infection in Children","authors":"Maribeth R Nicholson, Siyuan Ma, Britton A Strickland, Mia Cecala, Lisa Zhang, Seth Reasoner, Emma R Guiberson, Matthew J Munneke, Meghan H Shilts, Eric P Skaar, Suman R Das","doi":"10.1093/infdis/jiaf631","DOIUrl":"https://doi.org/10.1093/infdis/jiaf631","url":null,"abstract":"Background and Aims Symptomatic Clostridioides difficile infection (CDI) can cause significant morbidity and mortality. Conversely, patients can be colonized with toxigenic C. difficile in the absence of symptoms, termed asymptomatic colonization. We previously demonstrated that the presence and function of C. difficile toxins do not differentiate between asymptomatic colonization and CDI in children, suggesting the influence of other factors. This study aimed to interrogate the intestinal microbiome and butyrate in stool samples from children with CDI and asymptomatic colonization. Methods Design: Case-control study Setting: Tertiary care children’s hospital Participants and measures: Asymptomatic children had stool tested for C. difficile by nucleic-acid amplification-based testing (NAAT) and were considered colonized if positive (N=50). Residual stool was also obtained from symptomatic children who tested positive for C. difficile by NAAT (N=55). The microbiome was assessed via 16S rRNA sequencing and butyrate via liquid chromatography-mass spectrometry. Results Compared to clinical co-variates and comorbidities, C. difficile symptom status (i.e., asymptomatic colonization versus symptomatic CDI) demonstrated the strongest differential abundance association on gut microbes. Symptomatic CDI was associated with increased abundance of Escherichia/Shigella (Benjamini-Hochberg adjusted q=3.94x10-5), Haemophilus (q=0.022), and Gemella (q=0.085), and depleted abundance of gut commensals such as Faecalibacterium (q=0.041), Blautia (q=0.041), and Bifidobacterium (q=0.063). We also observed depletion in the abundance of microbial butyrate producers and fecal butyrate in participants with symptomatic CDI versus asymptomatic colonization. Conclusion The gut microbiota and butyrate differ between participants with asymptomatic C. difficile colonization and symptomatic CDI, suggesting their potential role in symptom development.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145729061","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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