Point-of-care routine laboratory testing for patients with suspected viral hemorrhagic fevers

View abstract When a suspected viral hemorrhagic fever (VHF) case presents to a healthcare facility, healthcare personnel must be able to safely provide initial stabilizing care, which may involve performing basic routine laboratory testing. Current gaps exist in the ability of frontline acute care hospitals to safely perform routine laboratory tests on patients with suspected VHFs that generate category A waste. This review outlines a potential solution for frontline acute care hospitals to perform electrolytes, hemoglobin/hematocrit, and malaria testing, in accordance with National Special Pathogens System guidelines, in the patient’s isolation room. We discuss guidance on laboratory risk assessment, equipment considerations, space requirements, staffing solutions, waste management, cost estimates, and remaining challenges. Our manuscript provides frontline acute care hospitals with a potential solution to safely provide a minimum set of routine laboratory tests for patients with suspected VHF.

cambridge.org

[Articles] Clinical, molecular, and in vitro evidence of artemisinin partial resistance in Ethiopian Plasmodium falciparum: a prospective, multisite, surveillance study

Ethiopia is the fifth sub-Saharan African country now meeting WHO confirmation criteria for ART-R. High R622I prevalence and double deletion rates, consistent with distinct selective pressures, represent a dual threat to treatment and HRP2-based diagnosis of P falciparum malaria in this region.

thelancet.com

Development and Application of an Anaerobic Activity Index

Antibiotics with anaerobic activity may result in adverse patient outcomes. Here, we report the development and application of an Anaerobic Activity Index (AAI) to quantify anti-anaerobic antibiotic exposure.MethodsThe numeric AAI was generated for 21 antibiotics using in vitro susceptibility data for seven anaerobic bacterial groups. A binning strategy was applied to susceptibility proportions to result in the fewest antibiotic tied scores. In a cohort of patients with burns, 7-day anaerobic exposure was calculated, multiplied by days of therapy, and summed. Multivariable logistic regression models assessed the association between AAI quartiles and a 90-day composite outcome including culture positivity with bacteria of interest, healthcare-associated infection, and/or death.ResultsWe included 88 papers reporting on anaerobic activity. The AAI ranged from 4 to 59. Meropenem (59), ertapenem (58), and tigecycline (57) were the highest ranked antibiotics, whereas penicillin (20), doxycycline (13), and aztreonam (4) had the lowest scores. Several antibiotics could not be included for lack of data. In a cohort of patients with burns, the highest seven-day AAI quartile was associated with increased odds of the 90-day composite outcome compared to the lowest quartile (OR: 2.90; 95% CI: 1.65-5.08), adjusting for Baux score and Charlson comorbidity index.ConclusionsWe propose an anaerobic activity index (AAI) assigning numeric scores to commonly used antibiotics. We anticipate that this score will require updating as additional susceptibility data become available. The AAI may be used as a research tool evaluating the impact of anti-anaerobic antibiotics on patient outcomes.

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2024–2025 COVID-19 mRNA Vaccine Effectiveness Against Severe Disease

This study evaluated the effectiveness of the 2024–2025 coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccine against COVID-19 emergency department (ED) visits and hospitalizations.MethodsUsing electronic health records from a large South Carolina health system, we emulated a target trial comparing adults aged 18 years and older who did and did not receive the 2024–2025 COVID-19 mRNA vaccine. Vaccinated individuals during September 1, 2024–March 15, 2025, were risk-set matched 1:2 to unvaccinated individuals on demographic and clinical covariates using propensity score matching. Primary outcomes were time to COVID-19 ED or more severe care and time to hospitalization through April 16, 2025, analyzed using Cox proportional hazards models.ResultsThe final matched cohort included 30,080 individuals, including 10,029 vaccinated participants. Mean age was 65.5 years, 36.5% male, 66.7% Caucasian; 85.6% had a pre-existing condition. Vaccine effectiveness against ED or more severe care was 41.3% (95% CI, 17.2%–58.4%) and 46.1% (95% CI, 13.6%–66.3%) against hospitalization.ConclusionsThe 2024–2025 mRNA COVID-19 vaccine provided moderate protection against COVID-19 ED visits and hospitalizations among an older population with a high burden of pre-existing conditions, supporting continued efforts to improve vaccine uptake in higher-risk adults.

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Risk Factors for Immunological Sensitization to Mycobacterium tuberculosis and Progression to Incident TB Disease Among HIV-uninfected Adults in a High Burden Setting

Identifying risk factors for Mycobacterium tuberculosis (Mtb) sensitization (defined as interferon-gamma release assays [IGRA]-positive) and progression to tuberculosis (TB) disease is critical to guide targeted prevention strategies.MethodsWe analyzed data from a prospective cohort of adults (18–60 years) without HIV, enrolled at five high-incidence South African sites. Participants underwent testing for Mtb sensitization and microbiologically confirmed TB at baseline, and during 15 months follow-up. Multivariable logistic and Cox regression models were used to assess factors associated with Mtb sensitization and TB progression. Sampling weights were applied to reflect the screened population.ResultsAmong 2912 participants with valid IGRA results, 63.4% (n = 1895) were Mtb-sensitized. Prevalent TB was detected in 1.81% (62/1895) of Mtb-sensitized vs 0.62% (12/1017) of Mtb-unsensitized individuals (P = .01). During follow-up of participants without prevalent TB, 2.01% (48/1833) Mtb-sensitized and 0.53% (8/1005) Mtb-unsensitized individuals developed TB (P = .01). Factors associated with Mtb sensitization included increasing age (adjusted odds ratio [aOR] = 1.02, 95% CI 1.01–1.03), male sex (aOR = 1.34, 95% CI 1.08–1.67), smoking (aOR = 1.31, 95% CI 1.05–1.64), prior TB (aOR = 2.20, 95% CI 1.40–3.47), and TB contact history (aOR = 1.40, 95% CI 1.08–1.83). Risk factors for progression to TB were Mtb sensitization (adjusted hazard ratio [aHR] = 3.05, 95% CI 1.14–8.18), smoking history (aHR = 2.34, 95% CI 1.03–5.31), and lower body mass index (BMI) (aHR = 0.89, 95% CI .82–.97).ConclusionsMtb-sensitized individuals had a 3-fold higher risk of prevalent TB and progressing to TB compared to Mtb-unsensitized individuals. In high-prevalence settings, identifying individuals at greatest risk—such as those recently infected, with a history of smoking, or low BMI—could help refine TB prevention efforts and reduce community-level transmission.

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RSV shapes serotype-specific invasive pneumococcal disease dynamics in children: an observational study

Pneumococcal nasopharyngeal colonization is the first step toward invasive pneumococcal disease (IPD). Respiratory syncytial virus (RSV) may trigger IPD, particularly for serotypes with low disease potential.We aimed to analyse the distribution of pneumococcal serotypes among paediatric IPD according to RSV circulation level.MethodsWe used data from three continuous French surveillance systems on IPD, pneumococcal carriage and RSV infections from 2008 to 2023. Based on the RSV epidemics threshold, we assessed the proportion of each serotype among IPD, depending on “RSV season” and “non-RSV season”. We assessed the correlation between the likelihood of serotype-specific involvement in IPD according to non-RSV season vs RSV season and the estimated disease potential of each serotype.ResultsAmong 4,574 IPD cases, the serotype distribution strongly varied during non-RSV season vs RSV season. The lower the disease potential of serotypes, the more RSV circulation enhanced their involvement in IPD (Rho=0.60, CI95% 0.28 to 0.80, p-value = 0.0012).ConclusionsThe role of RSV in triggering IPD strongly varies across pneumococcal serotypes. The impact of RSV-targeted interventions should be evaluated in light of these data.

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Emergence of Trichophyton indotineae: in vitro susceptibility data from a mycology reference laboratory in Australia

Management of Trichophyton indotineae dermatophytosis is challenged by high terbinafine resistance rates within this species. Antifungal susceptibility data for Australian T. indotineae isolates are lacking. Here we determined the in vitro activity of five antifungal agents, including olorofim, against T. indotineae to guide therapeutic choices.MethodsForty-four clinical T. indotineae isolates (cultured from skin, 2005–2025) across several Australian jurisdictions were tested for susceptibility to itraconazole, voriconazole, posaconazole, terbinafine and olorofim using CLSI broth microdilution methodology. MIC endpoints were determined at 80% growth inhibition for azoles and terbinafine, and 100% inhibition for olorofim. Isolates with terbinafine MICs ≥0.5 mg/L were considered as non-WT or resistant.ResultsTwenty-eight of 44 (63.6%) T. indotineae isolates had terbinafine MICs ≥0.5 mg/L [geometric mean (GM) MIC 0.570 mg/L; MIC90 4 mg/L] with 21 (47.7%) displaying MICs ≥4 mg/L. The modal terbinafine MIC was 4 mg/L. Lower MICs were observed for azoles, with posaconazole demonstrating the greatest activity, i.e. posaconazole (GM 0.058 mg/L; MIC90 0.25 mg/L), itraconazole (GM 0.087 mg/L; MIC90 0.5 mg/L) and voriconazole (GM 0.201 mg/L; MIC90 1 mg/L). Olorofim demonstrated good in vitro activity with all 44 isolates exhibiting MICs  ≤ 0.06 mg/L (GM 0.023 mg/L; MIC90 0.06 mg/L).ConclusionsTerbinafine resistance in T. indotineae is common in Australia but not universal. Susceptibility testing can inform treatment choice. The azoles and olorofim demonstrate good in vitro activity.

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Comparison of Respiratory Syncytial Virus (RSV)–Specific Antibody Durability in Pregnant/Postpartum Individuals and Older Adults After RSV Vaccination

AbstractRespiratory syncytial virus (RSV) vaccination is recommended in pregnancy. Limited data exist regarding antibody (Ab) durability to inform revaccination timing. We conducted prospective cohort studies among pregnant and older adults after first RSV vaccination in 2023–2024. Longitudinal samples from 50 pregnant (36 vaccinated) and 16 vaccinated older adults were collected until 12–15 months after vaccination and tested for RSV binding and neutralizing Ab. Mean Ab levels 12–15 months after vaccination were similar between vaccinated maternal and older adult participants (P = .73), suggesting Ab durability up to 1 year after maternal RSV vaccination. RSV binding and neutralizing Ab titers were strongly correlated (R = .73).

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Prevalence, Serotype Distribution, and Risk Factors Associated With Streptococcus pneumoniae Carriage in Older Adults in Denmark, 2019–2022

The burden of pneumococcal disease in older adults remains high in the postpneumococcal conjugate vaccine (PCV) era. We hypothesized that older adults may represent a carriage reservoir of Streptococcus pneumoniae.MethodsPaired naso- and oropharyngeal (NP and OP) swabs and questionnaires were collected during 2019–2022 from adults ≥65 years of age. Pneumococcal carriage and serotype distribution were determined by phenotypical and molecular methods.ResultsA total of 172/1764 participants (9.8% [95% confidence interval {CI} 8.4–11.2]) were positive for carriage of S. pneumoniae by either culture (0.3%) or lytA/piaB DNA in NP (2.0%) or OP (8.4%) samples. Overall, 118 serogroup- or serotype-specific carriage events were identified by multiplex polymerase chain reaction across 16 distinct serospecificities in 93 samples, while 79 samples were nontypeable. PCV13 types accounted for 8.0%, nonvaccine types for 11.0% and polysaccharide pneumococcal vaccine 23 (PPV23)/non-PCV13 types for 81.0%. All carriage serotypes, except serotype 2, had been identified in invasive pneumococcal disease (IPD) isolates among adults ≥65 years during 2019–2022. Having young grandchildren was associated with increased odds of carriage (adjusted odds ratio [OR] 1.8, 95% CI 1.2–2.5, P = .0031). No association between PPV23 immunization and carriage was observed (OR 0.8, 95% CI .5–1.3).ConclusionsOlder adults were carriers of a wide range of IPD-causing serotypes. Both carriage and IPD serotypes were mainly comprised of non-PCV13 serotypes. Immunization with higher valency conjugated vaccines is likely required to reduce residual pneumococcal disease among older adults.

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A Multidesign Study of 4CMenB Vaccine Effectiveness and Impact on Meningococcal Carriage and Gonorrhea in Northern Territory Adolescents and Young People

Emerging evidence suggests the 4CMenB vaccine provides moderate protection against gonorrhea, likely due to the close genetic relationship between Neisseria gonorrhoeae and Neisseria meningitidis. 4CMenB has an impact on unencapsulated meningococcal oropharyngeal carriage, where outer membrane proteins are exposed, potentially exerting selective pressure on these strains. We assessed the impact of 4CMenB immunization on gonorrhea disease and oropharyngeal meningococcal carriage among adolescents in the Northern Territory (NT), Australia.MethodsAll adolescents aged 14–19 years in the NT were eligible to receive two doses of 4CMenB between 2021 and 2023. Participants had oropharyngeal swabs collected at baseline and 12 months. Vaccine effectiveness (VE) against gonorrhea was assessed using linked notification and immunization data. A Cox proportional hazards model stratified by sex, age, and geography estimated VE. Mixed-effects logistic regression estimated postvaccination odds of meningococcal carriage.ResultsA total of 30 650 adolescents were included in the VE analysis, with 9.6% receiving 2 doses of 4CMenB, and 42.4% of the population identifying as Aboriginal or Torres Strait Islanders. Gonococcal notifications were reduced in vaccinated adolescents (VE 38.4%, 95% CI: 18.6–53.4). Overall, meningococcal carriage increased from 4.0% to 6.2% (OR 1.68, 95% CI: 1.14–2.48), driven by genogroup B and nongroupable strains. Carriage of disease-associated meningococci remained stable.Conclusions4CMenB confers modest protection against gonorrhea in a real-world setting with higher adolescent disease prevalence. These findings are important for women, considering infections are often asymptomatic and have the potential for serious complications. The NT has now introduced a 4CMenB infant and adolescent program.

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Antimicrobial Use in U.S. Hospitals: Comparison of 2015 and 2023 Prevalence Surveys

Prevalence surveys in U.S. hospitals in 2011 and 2015 showed that half of inpatients received antimicrobials on the survey day or day before. We repeated the survey in 2023 to assess changes in antimicrobial use (AU).MethodsTen Emerging Infections Program (EIP) sites recruited up to 25 hospitals each, prioritizing prior participants. EIP staff reviewed medical records of randomly selected inpatients from the survey day morning census and documented AU on the survey day or day before. We compared AU and stewardship characteristics between 2023 and 2015 and used multivariable log-binomial regression to identify factors associated with AU in 2023.ResultsAntimicrobial stewardship programs were present in 215/218 hospitals in 2023 (98.6%) compared with 158/199 (79.4%) in 2015. Of 13 653 patients in 2023, 6785 (49.7%) received ≥1 antimicrobial on the survey day or day before. Among 151 hospitals participating in both surveys, overall AU prevalence was similar in 2015 and 2023 (49.2% vs 49.1%), with decreases in neonatal critical care (23.4% to 17.1%) and increases in mother–baby units (24.4% to 32.8%). Fluoroquinolone use declined (9.2% to 2.8%), while third- or fourth-generation cephalosporin use increased (12.3% to 18.6%). In 2023, higher AU was associated with patient factors (medical devices, inpatient location, obesity, 4–17 day hospital stays, and suburban residence) and hospital factors (Northeast and South regions, AU audits).ConclusionsOne in two inpatients received an antimicrobial in 2023, similar to 2015. However, changes in AU by inpatient location and antimicrobial class suggest evolving prescribing practices and may inform targeted surveillance and stewardship efforts.

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Severe Lower Respiratory Tract Infection in Patients With Human Bocavirus Monoinfection in Southeast China

This study aims to investigate the severity and risk factors of acute lower respiratory tract infections (LRTIs) caused by human bocavirus (HBoV) in children.MethodsWe conducted a prospective cohort study of children hospitalized with LRTIs and confirmed HBoV monoinfection via polymerase chain reaction from March 2022 to February 2024. Viral load and genome analysis were performed, with clinical data collected. Patients were followed for 1 year post-discharge.ResultsAmong 412 hospitalized patients with HBoV-positive LRTIs, 268 (65.0%) had HBoV monoinfection. Severe infection occurred in 45.5%, with 10.8% critical, 6.3% requiring ICU admission, and 2 (0.7%) deaths. Higher HBoV-DNA loads (>10⁶ copies/mL) significantly increased critical disease risk (OR1 = 9.33, 95% CI 2.90–30.09). IFN-γ levels weakly correlated positively with DNA loads (r = 0.20, P = .024) and neutrophil counts (r = 0.26, P = .003). Furthermore, elevated neutrophil counts (>60%) were associated with hypoxemia (P < .001), pulmonary consolidation (P = .034), critical LRTI (P < .001), and ICU admission (P < .001). Despite high HBoV conservation, the VP1_40 (L→S) amino acid variation significantly increased critical LRTI risk (P = .03).ConclusionsHBoV monoinfection can cause critical LRTI in children. High DNA load, associated with elevated IFN-γ levels and neutrophilia, along with the viral VP1_L40S variant, may be key factors contributing to severe disease outcomes.

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Clinical Predictors of Nose/Throat Bacteriome and Fungal Colonization in Skilled Nursing Facility Residents

Microbiomes resist or facilitate pathogen invasion and modulate host immune responses and infection susceptibility. We describe nose/throat bacteriome composition and predicted functional changes associated with Candida albicans colonization, antibiotic use, and medical devices among adults receiving short-term subacute care in a skilled nursing facility (SNF).MethodsWe collected combined nose/throat swab samples from 301 adults every 3 days for up to 5 visits. Bacteriome composition was detected via 16S ribosomal RNA amplicon sequencing and C. albicans colonization by quantitative polymerase chain reaction. Functional potential was inferred using PICRUSt2 software. We used ADAPT (Analysis of Microbiome Differential Abundance by Pooling Tobit Models) software to evaluate bacteriome compositional and functional differences based on C. albicans colonization, adjusting for age, sex, antibiotic exposure, and medical device presence.ResultsC. albicans colonization was more common among participants with devices and antibiotic use, but this difference was not statistically significant. Participants had mean age of 77 years, 63.8% were female, 48.5% received antibiotics, and 20.3% had a medical device at entry. Nose/throat bacteriome was significantly less diverse and rich in the presence of C. albicans, antibiotic exposure, and device use (P < .05), but composition varied little during follow-up. With C. albicans, predicted bacteriome function favored acid-tolerant, biofilm-forming species (Scardovia wiggsiae and Lactobacillus fermentum; P < .01), and depleted glycolate degradation (log10 fold change, −0.45; adjusted P = .01).ConclusionsNose/throat bacteriome composition and function were significantly associated with C. albicans colonization, and C. albicans colonization was strongly associated with antibiotic exposure and medical device use. These findings underline the importance of integrating fungal colonization assessment and clinical factors into microbiome studies aimed at preserving bacteriome resilience and reducing infection risk in vulnerable populations.

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Incidence of Herpes Zoster Infection (Shingles) Among Adults Living With and Without HIV in British Columbia, Canada: A Population-based Study

Herpes zoster (HZ) incidence is elevated among immunocompromised populations, including people living with HIV (PLWH). We evaluated HZ incidence, associated risk factors, recurrence, and postvaccination HZ occurrence among PLWH compared with people living without HIV (PLWoH) in British Columbia, Canada.MethodsWe conducted a retrospective, population-based matched cohort study using data from the Comparative Outcomes and Service Utilization Trends study (2000–2019). PLWH aged ≥19 years initiating antiretroviral therapy were propensity-score matched to PLWoH from the general population. Incident HZ was identified from administrative health records using a 12-month washout. Age-stratified time-to-event, competing-risk, and multivariable models were used to estimate incidence, risk factors, recurrence, and vaccination-associated outcomes.ResultsAmong 9053 PLWH and 9053 matched PLWoH, HZ incidence rates were higher among PLWH overall. Before vaccine availability, PLWH experienced substantially higher HZ hazards than PLWoH, particularly among participants aged <50 years. After 2009, HZ risk remained elevated among younger PLWH, while hazards were similar between groups among those aged ≥50 years. HZ recurrence was approximately twice as frequent among PLWH. Among PLWH, advanced immunosuppression, including low CD4 cell counts and unsuppressed viral load, and selected comorbidities were independently associated with higher HZ risk. Postvaccination HZ incidence was low in both populations, with no meaningful difference between PLWH and PLWoH; breakthrough events were uncommon.ConclusionsPLWH remain at increased risk of HZ and recurrence, especially if younger or immunosuppressed. Vaccination was associated with a lower HZ risk supporting expanded access to recombinant zoster vaccination for immunocompromised adults irrespective of age.

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Comparison of Immune Activation and Gut Barrier Dysfunction Between Long COVID and HIV Infection

Human immunodeficiency virus (HIV) infection is characterized by persistent immune dysregulation and inflammation, with emerging evidence suggesting overlapping pathophysiological mechanisms with long coronavirus disease (COVID). Biomarkers of systemic inflammation and gut integrity may provide insight into shared and distinct pathways underlying these conditions. The status of the anti-inflammatory vitamin K may play a role in sustained inflammation in these conditions.MethodsThis cross-sectional study enrolled participants belonging to 1 of 3 groups: individuals with long COVID without HIV (n = 108); participants with HIV (PWH) virologically suppressed with no previous COVID-19 infection (n = 256); and controls without long COVID or HIV (n = 193). Plasma samples were analyzed for inflammatory, gut integrity biomarkers, and dephosphorylated-uncarboxylated matrix Gla protein (dp-ucMGP) as an established marker of vitamin K status. Associations were assessed using multivariable linear and logistic regression models adjusted for demographic, metabolic, and lifestyle covariates.ResultsIn total, 557 participants were included. Long COVID was independently associated with elevated oxidized low-density lipoprotein (β = .39 vs HIV, β = .54 vs controls; P < .001 for both). PWH had higher odds of worse vitamin K status (odds ratio, 1.5; 95% CI, 1.02–2.2; P = .04). Independent of long COVID or HIV status, worse vitamin K status was strongly associated with higher levels of inflammatory markers.ConclusionsLong COVID and HIV share chronic immune dysregulation features but demonstrate distinct inflammatory profiles. These findings highlight the importance of large longitudinal studies to delineate shared versus unique inflammatory pathways to guide potential long COVID therapeutic strategies.

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Durability and Breadth of Neutralizing Antibodies Against SARS-CoV-2 Variants Following XBB.1.5 Vaccination in a Multiply Exposed Cohort

Widespread immunity from vaccination and infection has reduced COVID-19 morbidity and mortality, but this immunity varies across the population. Understanding how repeated antigenic exposures influence antibody responses helps to inform future vaccination strategies.MethodsWe characterized neutralizing antibody (nAb) responses in serum samples collected 1- and 6-months after XBB.1.5 vaccination from 25 healthcare workers with varying, complex histories of vaccination and reported infections. Neutralizing activity was assessed against a range of variants, from pre-Omicron to recent Omicron JN.1 sublineage, and divergent BA.3.2 variants using lentiviral pseudoviruses. Participants were stratified into 5 exposure groups based on their documented vaccination and reported infection history.ResultsXBB.1.5 vaccination elicited broad neutralizing responses, with strong boosting against previously encountered antigens relative to vaccine-matched XBB.1.5 and newer variants. Geometric mean neutralization titers were generally comparable across exposure groups, though small subgroup sizes and considerable intragroup heterogeneity precluded definitive conclusions about the influence of prior exposure history. At 6 months, titers declined by 36–62% across all variants. Titers remained highest against pre-Omicron variants and were lowest against JN.1 sublineage variants, with some falling to very low levels.ConclusionsIn this cohort with extensive prior antigenic exposures, broad nAb profiles were observed following XBB.1.5 vaccination, though these responses waned substantially after 6 months. The observed waning of cross-neutralizing antibodies against emerging variants underscores the challenge of maintaining durable protection and supports the need for continued monitoring of antibody responses to guide evidence-based updates to COVID-19 vaccines.

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Mucosal IgG Interacts with Herpes Simplex Virus Glycoprotein E, an Fcγ Receptor Mimetic, and Neutralizes Viral Infection: Activity is Reduced in the Setting of Vaginal Dysbiosis

Small studies have documented variable neutralizing activity of cervicovaginal lavage (CVL) against herpes simplex viruses (HSV). This neutralizing activity is lower in women with bacterial vaginosis (BV), a syndrome associated with HSV recurrences. However, the mechanisms have not been fully defined.MethodsWe took advantage of a biobank of CVL and linked data including HSV neutralizing activity measured by plaque reduction assay, Nugent scores and concentrations of CVL immune mediators. We fractionated CVL to enrich or deplete candidates and quantified neutralizing activity.ResultsCVL reduced viral plaque formation by 40.82 ± 37.59% (mean ± SD, n=361). Activity was independent of HSV serostatus, significantly lower in those with a Nugent score of 7-10 (n=176, p<0.05) and correlated positively with CVL concentrations of IgG (p=0.001, n=87) and HNP1-3 (p<0.001, n=119). Activity was enriched in the immunoglobulin fraction but was reduced when IgG (but not IgA) was depleted. Increasing concentrations of an anti-glycoprotein E (gE) monoclonal antibody overcame the neutralizing activity, suggesting that interactions between IgG Fc and gE, a viral Fc gamma receptor, contribute. Moreover, CVL had less HSV inhibitory activity against a gE-null virus. Treatment of CVL with Peptide-N-Glycosidase F, which cleaves IgG N-glycans, reduced HSV neutralizing activity.ConclusionsInteractions between IgG Fc and viral gE, independent of Fab specificity, contribute to cervicovaginal antiviral activity. Antiviral activity is reduced with dysbiosis, presumably reflecting lower IgG levels and differences in N-glycans that lead to decreased gE interactions. Results highlight the importance of developing and implementing strategies to protect against vaginal dysbiosis.

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Early Corticosteroids in West Nile Virus Infection: Outcome Definitions, Residual Confounding, and Sparse-Event Uncertainty

To  The  Editor—In The Journal of Infectious Diseases, we read with interest the retrospective cohort study by Poran et al evaluating early systemic corticosteroid therapy among hospitalized people with West Nile virus (WNV) infection during the 2024 outbreak in Israel. The authors are to be commended for addressing a clinically important and understudied question and for applying inverse probability of treatment weighting (IPTW) to improve covariate balance in an observational setting. With this valuable contribution in mind, we would be grateful for clarification of several methodological aspects that may help readers interpret the reported association with in-hospital mortality [1].

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Evaluation of the Safety, Genetic Stability, and Immunogenicity of an Attenuated Shigella Live Vector Expressing Enterotoxigenic Escherichia coli Antigens, Vaccine Strain CVD 1208S-122

There are no licensed vaccines to protect against Shigella or enterotoxigenic Escherichia coli (ETEC), yet they are among the most common causes of bacterial diarrhea. We engineered an attenuated Shigella flexneri 2a expressing colonization factor antigen 1 (CFA/I) and heat-labile enterotoxin B subunit (LTB) from ETEC and conducted a first-in-human randomized-controlled trial of ascending doses of the vaccine (CVD 1208S-122).MethodsDose-escalating cohorts received a single oral dose of 108–1010 colony-forming units (CFU) of CVD 1208S-122 or placebo. A fourth cohort received 1 or 2 oral doses of 108 CFU CVD 1208S-122 or placebo. We measured the safety and clinical acceptability of the vaccine, genetic stability of fecally shed vaccine organisms, and immune responses elicited.ResultsThe 108 CFU doses were well tolerated (100%, 6/6). One recipient of 109 CFU (20%, 1/5) manifested diarrhea and 4 individuals who ingested 1010 CFU had either fever or diarrheal reactogenicity (67%, 4/6). Fecal shed vaccine organisms were genetically stable. Responses were observed to the lipopolysaccharide (LPS) and invasion plasmid antigen B (IpaB) of Shigella and CFA/I fimbriae and LTB of ETEC in serum, among antibody secreting cells, antibody in lymphocyte supernatant, and fecal samples. Serum antibodies exhibited Shigella bactericidal activity and inhibition of ETEC adherence in vitro.ConclusionsThis study demonstrates safety with low-dose but unacceptable reactogenicity following highest-dose ingestion, genetic stability of all recovered fecal isolates, and immunogenicity of a prototype combined monovalent Shigella-ETEC vaccine. These results encourage expansion to a multivalent formulation to elicit broader protection against the most prevalent Shigella serotypes and ETEC CFA types that cause diarrheal disease.Clinical Trials RegistrationNCT04634513.

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Hepatitis C Treatment Outcomes Among Immigrants: A CANUHC Cohort Analysis

Immigrants to Canada are disproportionately affected by hepatitis C virus (HCV) infection. Little is known about treatment outcomes among immigrants at the national level or how outcomes vary across Canadian provinces.MethodsWe used data from the Canadian Network Undertaking against Hepatitis C (CANUHC), a prospective cohort enrolling HCV RNA–positive patients from 17 sites across 6 Canadian provinces between 2015 and 2025. Sociodemographic data, clinical characteristics, immigration details, time to first consult, and treatment outcomes were evaluated. Treatment outcomes included direct-acting antiviral (DAA) initiation, sustained virological response (SVR) bloodwork completion, and SVR achievement.ResultsOf 2521 patients, 427 (16.9%) were immigrants to Canada. Immigrants had higher educational attainment (60.8% vs 28.2% college/university, P < .001), higher employment (47.1% vs 28.0%, P < .001), and lower proportions with a history of injection drug use (25.8% vs 75.3%, P < .001), incarceration (12.9% vs 49.1%, P < .001), or recreational drug use (43.5% vs 91.8%, P < .001). Immigrants demonstrated excellent DAA treatment outcomes with higher crude rates of DAA initiation (95.6% vs 92.2%, P = .02), posttreatment SVR bloodwork completion (81.6% vs 70.5%, P < .001), and SVR (100% vs 98.6%, P = .03). However, after adjustment for age, sex, race, and key socioeconomic measures, immigration status was not independently associated with these outcomes. The mean time from immigration to specialist assessment was 24.9 years (standard deviation, 18.6 years). The delay in accessing care trended downward with each 5-year interval from 1990 to the present (median years, 26, 22, 16, 12, 7, and 2; P < .001).ConclusionsImmigrants in the CANUHC cohort achieved excellent DAA treatment outcomes comparable to or exceeding those of Canadian-born patients. When engaged in care, immigrants can successfully complete the HCV treatment cascade.

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Clinical Features of Clostridial Necrotizing Soft-tissue Infections: Analysis of a Prospective Scandinavian Cohort Study

Necrotizing soft-tissue infections (NSTI) caused by Clostridium spp. are rare. High rates of amputation and mortality are reported, but knowledge on clinical characteristics and outcome is largely based on retrospective cohorts. The role of Clostridium spp. as part of polymicrobial NSTI is also unclear.MethodWe identified all clostridial cases from the INFECT cohort, a prospective study including patients with confirmed NSTI admitted to 5 Scandinavian referral hospitals over a 4-year period. Selected parameters were compared to a control group of nonclostridial polymicrobial infections. Additionally, we analyzed polymicrobial infections with clostridial species.ResultsTen cases of clostridial NSTIs were identified, evenly divided between cases caused by Clostridium perfringens and Clostridium septicum. Immunodeficiency (4/10) and penetrating trauma (3/10) were significantly more frequent compared to polymicrobial controls. Clostridial NSTI was also associated with extremity involvement (10/10) and severe pain (7/9). Radiological evidence of gas (4/7) did not distinguish clostridial from polymicrobial infections. Two patients underwent amputation, and 2 others died within 30 days. The cohort also included seven polymicrobial NSTIs with Clostridium spp., with higher rates of both comorbidity (7/7) and 30-day mortality (4/7).ConclusionsClostridial NSTIs were associated with extremity infection, immunodeficiency, and penetrating trauma. The cases demonstrate a wide spectrum of severity. In polymicrobial NSTIs involving Clostridium spp., the mortality was particularly high, but the pathogenetic role of clostridia in these infections is unclear.

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Severe Lower Respiratory Tract Infection in Patients With Human Bocavirus Monoinfection in Southeast China

This study aims to investigate the severity and risk factors of acute lower respiratory tract infections (LRTIs) caused by human bocavirus (HBoV) in children.MethodsWe conducted a prospective cohort study of children hospitalized with LRTIs and confirmed HBoV monoinfection via polymerase chain reaction from March 2022 to February 2024. Viral load and genome analysis were performed, with clinical data collected. Patients were followed for 1 year post-discharge.ResultsAmong 412 hospitalized patients with HBoV-positive LRTIs, 268 (65.0%) had HBoV monoinfection. Severe infection occurred in 45.5%, with 10.8% critical, 6.3% requiring ICU admission, and 2 (0.7%) deaths. Higher HBoV-DNA loads (>10⁶ copies/mL) significantly increased critical disease risk (OR1 = 9.33, 95% CI 2.90–30.09). IFN-γ levels weakly correlated positively with DNA loads (r = 0.20, P = .024) and neutrophil counts (r = 0.26, P = .003). Furthermore, elevated neutrophil counts (>60%) were associated with hypoxemia (P < .001), pulmonary consolidation (P = .034), critical LRTI (P < .001), and ICU admission (P < .001). Despite high HBoV conservation, the VP1_40 (L→S) amino acid variation significantly increased critical LRTI risk (P = .03).ConclusionsHBoV monoinfection can cause critical LRTI in children. High DNA load, associated with elevated IFN-γ levels and neutrophilia, along with the viral VP1_L40S variant, may be key factors contributing to severe disease outcomes.

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Association of anti-anaerobic antibiotics with mortality and the gut microbiome: a sub-study of the BALANCE randomized clinical trial

Patients with suspected bloodstream infection often receive broad-spectrum antibiotics with anaerobic activity in the absence of clinical indication for anaerobic coverage. Anti-anaerobic antibiotics have been linked to adverse clinical outcomes in other populations, potentially by depleting intestinal anaerobes.MethodsWe conducted a planned sub-study of the multisite BALANCE randomized controlled trial of antibiotic duration for bloodstream infection to assess the impact of anti-anaerobic antibiotics (receipt from three days pre-index culture to seven days post-index) on mortality and gut microbiome composition with metagenomic sequencing in patients without clinical indication for anaerobic coverage who survived to seven days post-index culture. The primary exposure was receipt of anti-anaerobic antibiotics from three days prior to the index culture to seven days post-index culture.ResultsAmong the 2851 eligible patients included in our primary analysis, 2106 (74%) received anti-anaerobic antibiotics and 745 (26%) did not. After balancing measured potential confounders through inverse probability of treatment weighting, anti-anaerobic antibiotics were associated with higher 90-day mortality (OR = 1.41, 95% CI 1.03 to 1.92, p = 0.03) and depletion of gut anaerobe relative abundance (fixed effect estimate = -16.59, 95% CI -30.67 to -2.52, p = 0.02). Increased duration of anti-anaerobic antibiotics was associated with greater mortality risk and additional gut anaerobe depletion.ConclusionsAnti-anaerobic antibiotics are associated with increased mortality and gut microbiome disruption in patients with bloodstream infection. Minimizing exposure to anti-anaerobic antibiotics for bloodstream infection should be further explored in clinical trials as a potential treatment strategy to improve patient outcomes.

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Gut Microbiota and Intestinal Monodomination as a Predictor for Bacteremia in Allogeneic Hematopoietic Cell Transplant Recipients

Bacteremia is a frequent complication in patients undergoing allogeneic hematopoietic cell transplantation (HCT). Alterations to the gut microbiota after HCT have been associated with adverse outcomes including bacteremia and reduced overall survival. Previous studies suggest that loss of gut bacterial diversity and domination by a single species may predict bloodstream infections, but the degree of domination leading to the optimal positive predictive value (PPV) has not been defined.MethodsStool samples were collected weekly from allogeneic HCT recipients and were analyzed by 16S rRNA gene PCR with sequencing to determine gut microbiota composition and document domination events. Bacteremia events were captured by review of medical records. The PPV for bacteremia of any detection of that species in stool and for domination events at 10%, 30%, and 50% abundance were calculated.ResultsOf 277 HCT recipients, 95 experienced bacteremia, with 130 bacteremia events. Intestinal domination was associated with but not highly predictive for bacteremia, reflected by low PPV. Presence of coagulase-negative Staphylococcus in the gut at >30% relative abundance was associated with increased risk of coagulase-negative Staphylococcus bloodstream infections with PPV of 38%.ConclusionsHematopoietic cell transplantation is associated with significant disruption to the gut microbiota, particularly in patients who subsequently develop bacteremia. Intestinal domination may not be as useful as previously thought given its low PPV for most species implicated in bloodstream infections. The association between gut colonization with Staphylococcus and bacteremia events suggests that the gut may be an under-recognized portal of entry for these organisms in patients after HCT.

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Clinical outcomes and treatment effectiveness in patients with carbapenem-resistant Enterobacterales infections: a multicenter retrospective cohort study

View abstract Background:Carbapenem-resistant Enterobacterales (CRE) infections carry high mortality and limited treatment options. We evaluated outcomes among adults with CRE infections at Ministry of National Guard-Health Affairs facilities in Saudi Arabia, comparing monotherapy with combination therapy.Methods:This multicenter retrospective cohort study included adults (≥18 years) with CRE infections during 2020–2024 at King Abdulaziz Medical City (Jeddah and Riyadh). CRE was defined phenotypically per CLSI criteria (first isolate per patient). Bivariate analyses, multivariate logistic regression, and Kaplan–Meier survival analysis compared monotherapy and combination therapy.Results:Among 224 patients (median age 70 years; 62.5% male), overall mortality was 43.3%, and Klebsiella pneumoniae accounted for 96.0% of isolates. Combination therapy was associated with higher mortality than monotherapy (44.5% vs. 26.7%; P = .047) and remained independently associated with mortality after adjustment for age, gender, and comorbidities (adjusted OR = 2.28, 95% CI: 1.08–4.83; P = .032). A significant treatment–mortality difference was seen in patients without solid tumors (P = .031) but not in those with solid tumors (P = 1.000). Respiratory and blood infections carried the highest mortality (58.3% and 55.3%).Conclusions:CRE infections carry a high mortality burden among adults in Saudi Arabia. The higher mortality with combination therapy may, in part, reflect confounding by indication, with broader-spectrum regimens prescribed for sicker patients whose severity was not captured. Prospective studies with disease-severity scoring and individualized treatment are needed, particularly for immunocompromised patients.

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Infant Infection With Respiratory Syncytial Virus Genotypes and Subsequent Childhood Asthma Risk

AbstractOur objective was to test the hypothesis that respiratory syncytial virus (RSV) infection during infancy with genotypes containing previously reported G gene sequence duplications (Gdups) is associated with an increased risk of childhood asthma. In a population-based, prospective, birth cohort of healthy, term children, we found that children with RSV-A Gdup+ (adjusted odds ratio [aOR] = 2.00, 95%CI = 1.15–3.47) and RSV-B Gdup  + (aOR = 1.78, 95%CI = 1.01–3.11) infections during infancy had higher odds of 5-year current asthma than those without RSV infection during infancy. These findings are proof-of-concept evidence that RSV genetic variation is associated with variable childhood asthma risk.

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Measles in Ugandan Children Under 18 Months of Age: A Retrospective Study of Case-based Surveillance, 2018–2024

Measles remains a significant public health threat in Uganda, with regular outbreaks. The current national immunization schedule offers the first measles-containing vaccine dose (MCV) at 9 months, and a second dose at 18 months. We investigated the epidemiology of measles in Ugandan children aged 18 months and younger.MethodsWe analyzed the national measles surveillance data from 2018 to the first quarter (Q1) of 2024, probing the demographic and geographic distribution. We categorized children as under 6 months, 6 to under 9 months, and 9–18 months. Suspected measles cases were classified as clinical, epidemiologically linked, laboratory-confirmed or discarded (not measles).Results1316/2274 (57.9%) of the suspected cases were diagnosed with measles. One hundred and forty-nine cases (11.3%; 95% CI: 9.7–13.0) were aged under 6 months, 390 (29.6%; 27.0–32.0) 6 to under 9 months, and 777 (59.0%; 56.0–62.0) 9–18 months. 717/1208 (59.4%; 57.0–62.0) of vaccine-eligible children, with a captured vaccination history, had received at least 1 dose of MCV. 59.5% (95%CI: 55.0–63.0) of measles cases were unvaccinated vaccine-eligible children. Several districts did not achieve the WHO-recommended measles surveillance threshold of at least 2 discarded cases per 100 000 population.ConclusionsMost measles cases among Ugandan children ≤18 months are unvaccinated. Infants nine to 18 months old comprise most of the measles cases (59.0%; 777/1316). To achieve better control of measles transmission, review of the current vaccination policies with strengthened vaccination and surveillance systems are recommended.

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Immune-Based Cytokine Signatures of Prolonged Pandemic-Associated Chilblains

AbstractMost pandemic-associated chilblains (PAC) resolve spontaneously, but a subset of patients develops persistent or recurrent disease. We analyzed peripheral cytokine profiles in 17 patients with prolonged PAC and identified elevated IFN-γ, CXCL10, CX3CL1, IL-16, CCL22, and S100A8. In contrast to the transient type I interferon response described in acute PAC, prolonged disease was characterized by a type II interferon-skewed inflammatory signature with T-cell activation and endothelial involvement. Frequent autoimmune comorbidities suggest baseline immune dysregulation contributing to chronicity. These findings highlight potential therapeutic targets, including JAK inhibition and IFN-γ–directed therapies.

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Supporting CDC's Elimination of Research on Nonhuman Primates

To  The  Editor—We read with interest Chan's “The Contribution and Importance of Animal Research in HIV Prevention in the United States” [1]. We understand that experiments using “nonhuman primate models” led to advances in Human Immunodeficiency Virus (HIV) prevention in humans. We, however, applaud the Centers for Disease Control and Prevention for eliminating studies involving nonhuman primates [2].

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Addition of Clofazimine Enhances the Activity of Standard Treatment Regimen in a Mouse Model of Tuberculous Meningitis

AbstractTuberculous meningitis causes substantial mortality due to limited penetration of antibiotics to the central nervous system and excessive neuroinflammation. This study evaluated clofazimine as an adjunct to the standard first-line tuberculosis regimen, in a mouse model. Mice were infected intracerebrally with Mycobacterium tuberculosis and treated for 6 weeks. Addition of clofazimine markedly reduced the brain bacterial burden, achieving measurable brain tissue concentrations despite minimal cerebrospinal fluid penetration, as well as attenuated brain tissue inflammation. These findings indicate that clofazimine enhances bactericidal activity of the standard regimen and mitigate neuroinflammation, supporting further investigation and clinical evaluation for tuberculous meningitis.

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