Clinical Infectious Diseases

ImportancePregnant women are at increased risk of severe COVID-19, but the contribution of viral RNA load, the presence of infectious virus, and mucosal antibody responses remain understudied. ObjectiveTo evaluate the association of COVID-19 outcomes following confirmed infection with vaccination status, mucosal antibody responses, infectious virus recovery and viral RNA levels in pregnant compared with non-pregnant women. DesignA retrospective observational cohort study of remnant clinical specimens from SARS-CoV-2 infected patients between October 2020-May 2022. SettingFive acute care hospitals within the Johns Hopkins Health System (JHHS) in the Baltimore, MD-Washington, DC area. ParticipantsParticipants included confirmed SARS-CoV-2 infected pregnant women and matched non-pregnant women (matching criteria included age, race/ethnicity, and vaccination status). ExposureSARS-CoV-2 infection, with documentation of SARS-CoV-2 mRNA vaccination. Main Outcome(s)The primary dependent measures were clinical COVID-19 outcomes, infectious virus recovery, viral RNA levels, and mucosal anti-spike (S) IgG titers from upper respiratory tract samples. Clinical outcomes were compared using odds ratios (OR), and measures of virus and antibody were compared using either Fishers exact test, two-way ANOVA, or regression analyses. Results were stratified according to pregnancy, vaccination status, maternal age, trimester of pregnancy, and infecting SARS-CoV-2 variant. Results(s)A total of 452 individuals (117 pregnant and 335 non-pregnant) were included in the study, with both vaccinated and unvaccinated individuals represented. Pregnant women were at increased risk of hospitalization (OR = 4.2; CI = 2.0-8.6), ICU admittance, (OR = 4.5; CI = 1.2-14.2), and of being placed on supplemental oxygen therapy (OR = 3.1; CI =1.3-6.9). An age-associated decrease in anti-S IgG titer and corresponding increase in viral RNA levels (P< 0.001) was observed in vaccinated pregnant, but not non-pregnant, women. Individuals in their 3rd trimester had higher anti-S IgG titers and lower viral RNA levels (P< 0.05) than those in their 1st or 2nd trimesters. Pregnant individuals experiencing breakthrough infections due to the omicron variant had reduced anti-S IgG compared to non-pregnant women (P< 0.05). Conclusions and RelevanceIn this cohort study, vaccination status, maternal age, trimester of pregnancy, and infecting SARS-CoV-2 variant were each identified as drivers of differences in mucosal anti-S IgG responses in pregnant compared with non-pregnant women. Observed increased severity of COVID-19 and reduced mucosal antibody responses particularly among pregnant participants infected with the Omicron variant suggest that maintaining high levels of SARS-CoV-2 immunity may be important for protection of this at-risk population. Key PointsO_ST_ABSQuestionC_ST_ABSIs greater COVID-19 disease severity during pregnancy associated with either reduced mucosal antibody responses to SARS-CoV-2 or increased viral RNA levels? FindingIn a retrospective cohort of pregnant and non-pregnant women with confirmed SARS-CoV-2 infection, we observed that (1) disease severity, including ICU admission, was greater among pregnant than non-pregnant women; (2) vaccination was associated with reduced recovery of infectious virus in non-pregnant women but not in pregnant women; (3) increased nasopharyngeal viral RNA levels were associated with reduced mucosal IgG antibody responses in pregnant women; and (4) greater maternal age was associated with reduced mucosal IgG responses and increased viral RNA levels, especially among women infected with the Omicron variant. MeaningThe findings of this study provide novel evidence that, during pregnancy, lower mucosal antibody responses are associated with reduced control of SARS-CoV-2, including variants of concern, and greater disease severity, especially with increasing maternal age. Reduced mucosal antibody responses among vaccinated pregnant women highlight the need for bivalent booster doses during pregnancy.

BackgroundUnderstanding the kinetics and longevity of antibody responses to SARS-CoV-2 is critical to informing strategies toward reducing Coronavirus disease 2019 (COVID-19) reinfections, and improving vaccination and therapy approaches. MethodsWe evaluated antibody titers against SARS-CoV-2 nucleocapsid (N), spike (S), and receptor binding domain (RBD) of spike in 98 convalescent participants who experienced asymptomatic, mild, moderate or severe COVID-19 disease and in 17 non-vaccinated, non-infected controls, using four different antibody assays. Participants were sampled longitudinally at 1, 3, 6, and 12 months post-SARS-CoV-2 positive PCR test. FindingsIncreasing acute COVID-19 disease severity correlated with higher anti-N and anti-RBD antibody titers throughout 12 months post-infection. Anti-N and anti-RBD titers declined over time in all participants, with the exception of increased anti-RBD titers post-vaccination, and the decay rates were faster in hospitalized compared to non-hospitalized participants. <50% of participants retained anti-N titers above control levels at 12 months, with non-hospitalized participants falling below control levels sooner. Nearly all hospitalized and non-hospitalized participants maintained anti-RBD titers above controls for up to 12 months, suggesting longevity of protection against severe reinfections. Nonetheless, by 6 months, few participants retained >50% of their 1-month anti-N or anti-RBD titers. Vaccine-induced increases in anti-RBD titers were greater in non-hospitalized relative to hospitalized participants. Early convalescent antibody titers correlated with age, but no association was observed between Post-Acute Sequelae of SARS-CoV-2 infection (PASC) status or acute steroid treatment and convalescent antibody titers. InterpretationHospitalized participants developed higher anti-SARS-CoV-2 antibody titers relative to non-hospitalized participants, a difference that persisted throughout 12 months, despite the faster decline in titers in hospitalized participants. In both groups, while anti-N titers fell below control levels for at least half of the participants, anti-RBD titers remained above control levels for almost all participants over 12 months, demonstrating generation of long-lived antibody responses known to correlate with protection from severe disease across COVID-19 severities. Overall, our findings contribute to the evolving understanding of COVID-19 antibody dynamics. FundingAustin Public Health, NIAAA, Babson Diagnostics, Dell Medical School Startup.

ObjectiveTo describe demographics, causative pathogens, hospitalization, mortality, and antimicrobial resistance of bacterial bloodstream infections (BSIs) among beneficiaries in the global U.S. Military Health System (MHS), a single-provider healthcare system with 10-year longitudinal follow-up. DesignRetrospective cohort study SettingClinical and demographic data collected from the MHS Data Repository and collated with microbiological data obtained from the Defense Centers for Public Health-Portsmouth. Participants12,748 MHS beneficiaries diagnosed with 15,357 bacterial BSIs (2010-2019). Main Outcome(s) and Measure(s)Demographic data and diagnosis codes preceding BSI episodes and during hospitalizations were collected. Inpatient admission data identified acute clinical diagnoses, intensive care unit (ICU) admission, and mortality. BSI pathogens were evaluated for antimicrobial resistance, including difficult-to-treat resistance (DTR). Crude mortality trends were assessed. ResultsThe decade analyzed included 15,357 BSI episodes in 12,748 patients; 6,216 patients (48.8%) were [&ge;]65 years and 83.7% of episodes had [&ge;]1 comorbidity (12,856 of 15,357). Approximately 29% of episodes with hospitalization required ICU admission and [~]34% had concurrent urinary tract infections. Pathogen distribution was 53% and 47% for Gram-positive bacteria and Gram-negative bacilli (GNB), respectively. Inpatient mortality was 4.4%, and at one year was 23.4%; 0.5% (16 of 2,977) of deaths were associated with DTR GNB. Among an average 8,145,778 individuals receiving care annually in the MHS, annual rates of overall BSI, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp., and DTR GNB BSI were 18.9, 1.30, 0.25, and 0.05 per 100,000 beneficiaries, respectively. Over the decade, annual mortality did not significantly increase for any pathogen and decreased by [~]3% for lactose-fermenting GNB BSI (p=0.048). ConclusionsIn the global U.S. MHS, mortality burden associated with BSI was substantial (approximately 1 in 4 dying at 1 year), relatively unchanged over a decade, and associated with older age and comorbidities. First-line treatment options remained available for 99.7% of BSIs. Population-level improvements in BSI survival might be maximally influenced by focusing on prevention, early detection, prompt antibiotics, and other novel therapies not contingent on in vitro activity. Summary BoxWhat is already known on this topic: O_LIBloodstream infections (BSIs) are associated with high healthcare burden and poor patient outcomes, including high mortality. C_LIO_LIModeling data based on assumptions suggest that mortality associated with antimicrobial-resistant pathogens is increasing. C_LI What this study adds: O_LIAmong Military Health System (MHS) beneficiaries, overall and difficult-to-treat antimicrobial-resistant BSIs averaged an annual rate of 18.9 and 0.05 per 100,000 beneficiaries, respectively. C_LIO_LIOver a decade, mortality did not increase annually for any BSI group, while lactose-fermenting Gram-negative BSI mortality decreased ([~]3%) and 50% of BSIs associated with deaths at 1-year occurred >42 days after BSI diagnosis. C_LIO_LIBacterial BSI deaths in MHS are often associated with advanced age (74% [&ge;]65 years) and comorbidities (97% with [&ge;]1 comorbidity), rather than absence of first-line antimicrobial treatment options. C_LI

BackgroundTranslation of blood RNA signatures may be accelerated by identifying more parsimonious biomarkers. We tested the hypothesis that single-gene transcripts provide comparable accuracy for detection of subclinical TB to multi-gene signatures and benchmarked their clinical utility to interferon-y release assays (IGRAs). MethodsWe identified datasets where participants underwent RNA sampling and at least 12 months of follow-up for progression to TB. We performed a one-stage individual participant data meta-analysis to compare multi-gene signatures against single-gene transcripts to detect subclinical TB, defined as asymptomatic prevalent or incident TB (diagnosed [&ge;]21 days from enrolment, irrespective of symptoms) over a 12-month interval. We performed decision curve analysis to evaluate the net benefit of using RNA biomarkers and IGRA, alone or in combination, compared to treating all or no individuals with preventative treatment. ResultsWe evaluated 80 single-genes and eight multi-gene signatures in a pooled analysis of four RNAseq and three qPCR datasets, comprising 6544 total samples and including 283 samples from 214 individuals with subclinical TB. Five single-gene transcripts were equivalent to the best-performing multi-gene signature over 12 months, with areas under the receiver operating characteristic curves ranging from 0.75-0.77, but none met the WHO minimum target product profile (TPP) for a TB progression test. IGRA demonstrated much lower specificity in higher burden settings, while sensitivity and specificity of RNA biomarkers were consistent across settings. In higher burden settings, RNA biomarkers had greater net benefit than IGRA, which offered little clinical utility over treating all with preventative therapy. In low burden settings, IGRA approximated the TPP and offered greater clinical utility than RNA biomarkers, but combining both tests provided the highest net benefit for services aiming to treat <50 people to prevent a single case. InterpretationSingle-gene transcripts are equivalent to multi-gene signatures for detection of subclinical TB, with consistent performance across settings. Single transcripts demonstrate potential clinical utility to stratify treatment, particularly when used in combination with IGRA in low burden settings.

BackgroundAntiviral monoclonal antibodies (mAbs) developed for treatment of COVID-19 reduce the magnitude and duration of viral shedding and can thus potentially contribute to reducing transmission of the causative virus, severe acute respiratory coronavirus 2 (SARS-CoV-2). However, use of these mAbs in combination with a vaccine program has not been considered in public health strategic planning. MethodsWe developed an agent-based model to characterize SARS-CoV-2 transmission in the US population during an aggressive phase of the pandemic (October 2020 to April 2021), and simulated the effects on infections and mortality of combining mAbs as treatment and post-exposure prophylaxis (PEP) with a vaccine program plus non-pharmaceutical interventions. We also interrogated the impact of rapid diagnostic testing, increased mAb supply, and vaccine rollout. FindingsAllocation of mAbs as PEP or targeting those [&ge;]65 years provided the greatest incremental benefits relative to vaccine in averting infections and deaths, by up to 17% and 41%, respectively. Rapid testing, facilitating earlier diagnosis and mAb use, amplified these benefits. The model was sensitive to mAb supply; doubling supply further reduced infections and mortality, by up to two-fold, relative to vaccine. mAbs continued to provide incremental benefits even as proportion of the vaccinated population increased. InterpretationUse of anti-viral mAbs as treatment and PEP in combination with a vaccination program would substantially reduce SARS-CoV-2 transmission and pandemic burden. These results may help guide resource allocation and patient management decisions for COVID-19 and can also be used to inform public health policy for current and future pandemic preparedness. FundingRegeneron Pharmaceuticals.

BackgroundIncreased reinfection rates with SARS-CoV-2 have recently been reported, with some locations basing reinfection on a second positive PCR test at least 90 days after initial infection. MethodsWe identified cases where patients had two positive tests for SARS-CoV-2 and evaluated which of these had been sequenced as part of our surveillance efforts, and evaluated sequencing and clinical data. Results750 patients (920 samples) had a positive test at least 90 days after the initial test. The median time between tests was 377 days, and 724 (79%) of the post 90-day positives were collected after the emergence of the Omicron variant in November 2021. Sequencing was attempted on 231 samples and successful in 127. Successful sequencing spiked during the Omicron surge and showed higher median days from initial infection compared to failed sequences (median 398 days compared to 276 days, p<0.0005). A total of 122 (98%) patients showed evidence of reinfection, 45 of which had sequence proven reinfection and 77 had inferred reinfections (later sequence showed a clade that was not circulating when the patient was initially infected). Children accounted for only 4% of reinfections. 43 (96%) of 45 infections with sequence proven reinfection were caused by the Omicron variant, 41 (91%) were symptomatic, 32 (71%), were vaccinated prior to the second infection, and 6 (13%) were Immunosuppressed. Only 2 (4%) were hospitalized, and both had underlying conditions. ConclusionSequence proven reinfections increased with the Omicron variant but generally caused mild infections.

Background. Neisseria gonorrhoeae (gonorrhoea) and antimicrobial-resistant (AMR) gonorrhoea infections disproportionately affect men who have sex with men (MSM). Vaccine development is challenging, but a N. meningitidis (group B) vaccine given to children and young adults was associated with a ca. 30% reduction in gonorrhoea diagnoses. We investigated the impact of vaccination on N. gonorrhoeae AMR development and transmission in MSM. Methods. We developed a compartmental model of N. gonorrhoeae transmission among MSM. AMR to ceftriaxone was incorporated as a stepwise increases in minimum inhibitory concentrations and eventual resistance (MIC drift). We estimated the impact of a partially protective vaccine (reducing susceptibility; 2-years protection) targeting high sexual activity MSM on AMR and prevalence until 2050. We performed sensitivity analyses assuming different levels of vaccine effectiveness (VE) and other modes of vaccine action. Findings. Gonorrhoea model prevalence was 3.4% (95% credible interval 3.2% - 3.8%) in all MSM, 12.5% (95% credible interval 12.1% - 12.7%) in high sexual activity MSM. A vaccine with 30% VE cannot prevent AMR, even with high uptake or durable protection. However, it increases time to AMR development by several years. For a fixed uptake of 40% a vaccine needs a minimum VE of 90% to prevent AMR development completely. A vaccine providing complete protection to infection for those vaccinated was most effective in reducing population prevalence and preventing AMR. Interpretation. A vaccine that has limited efficacy for the prevention of gonorrhoea could delay AMR development in MSM, providing time for developing new antimicrobials and more efficacious vaccines.

BackgroundAs SARS-CoV-2 vaccination coverage increases in the United States (US), there is a need to understand the real-world effectiveness against severe Covid-19 and among people at increased risk for poor outcomes. MethodsIn a multicenter case-control analysis of US adults hospitalized March 11 - May 5, 2021, we evaluated vaccine effectiveness to prevent Covid-19 hospitalizations by comparing odds of prior vaccination with an mRNA vaccine (Pfizer-BioNTech or Moderna) between cases hospitalized with Covid-19 and hospital-based controls who tested negative for SARS-CoV-2. ResultsAmong 1210 participants, median age was 58 years, 22.8% were Black, 13.8% were Hispanic, and 20.6% had immunosuppression. SARS-CoV-2 lineage B.1.1.7 was most common variant (59.7% of sequenced viruses). Full vaccination (receipt of two vaccine doses [&ge;]14 days before illness onset) had been received by 45/590 (7.6%) cases and 215/620 (34.7%) controls. Overall vaccine effectiveness was 86.9% (95% CI: 80.4 to 91.2%). Vaccine effectiveness was similar for Pfizer-BioNTech and Moderna vaccines, and highest in adults aged 18-49 years (97.3%; 95% CI: 78.9 to 99.7%). Among 45 patients with vaccine-breakthrough Covid hospitalizations, 44 (97.8%) were [&ge;]50 years old and 20 (44.4%) had immunosuppression. Vaccine effectiveness was lower among patients with immunosuppression (59.2%; 95% CI: 11.9 to 81.1%) than without immunosuppression (91.3%; 95% CI: 85.5 to 94.7%). ConclusionDuring March-May 2021, SARS-CoV-2 mRNA vaccines were highly effective for preventing Covid-19 hospitalizations among US adults. SARS-CoV-2 vaccination was beneficial for patients with immunosuppression, but effectiveness was lower in the immunosuppressed population.

BackgroundWe aimed to estimate the burden of antibiotic-nonsusceptible non-bacteremic pneumonia and sinusitis due to Streptococcus pneumoniae (pneumococcus) in US adults ([&ge;]18 years). MethodsWe estimated antibiotic-nonsusceptible pneumococcal sinusitis and non-bacteremic pneumonia incidence as products of non-bacteremic pneumococcal pneumonia and sinusitis incidence rates, serotype distribution, and serotype-specific antimicrobial nonsusceptibility prevalences by antibiotic class and guideline-recommended agents from 2016-2019. We derived pneumonia and sinusitis incidence rates from national healthcare utilization surveys and administrative datasets; pneumococcal-attributable attributable percents and serotype distributions from published data; and serotype-specific nonsusceptibility estimates from Active Bacterial Core surveillance data. We evaluated nonsusceptibility for all serotypes and those targeted by 15-, 20- and 21-valent pneumococcal conjugate vaccines (PCV15/20/21). ResultsAn estimated 16.4% (95% confidence interval 12.8-21.4%) of non-bacteremic pneumococcal pneumonia and 19.0% (14.8-24.9%) of sinusitis cases were nonsusceptible to [&ge;]3 antibiotic classes, translating to 243,521 (179,673-333,675) and 1,844,726 (1,070,763-2,904,089) outpatient visits for pneumonia and sinusitis, respectively, and 10,155 (7,542-13,803) pneumonia hospitalizations annually. An estimated 31.2% (26.6-36.3%) of non-bacteremic pneumococcal pneumonia and 10.5% (9.4-12.0%) of pneumococcal sinusitis cases were nonsusceptible to [&ge;]1 outpatient first-line antibiotic agent. Cases attributable to serotypes targeted by PCV15, PCV20, and PCV21 that were nonsusceptible to [&ge;]3 antibiotic classes accounted for 7.4% (4.7-11.1%), 8.5% (5.8-12.1%), and 12.6% (9.2-17.5%) of all non-bacteremic pneumococcal pneumonia cases, and 8.4% (5.3-12.5%), 9.4% (6.2-13.4), and 14.4% (10.4-20.0%) of all pneumococcal sinusitis cases. ConclusionsWe demonstrated high proportions of antibiotic nonsusceptibility in non-bacteremic pneumococcal pneumonia and sinusitis in US adults. PCVs and antibiotic stewardship may mitigate antibiotic nonsusceptibility in pneumococcal disease.

Nirmatrelvir/Ritonavir (NMV/r) is used for the treatment of COVID-19 infection. However, rebound COVID-19 infections can occur after taking NMV/r. We examined neutralizing antibodies to the SARS-CoV-2 spike protein before and after infection in people who did and did not take NMV/r to determine if NMV/r impedes the humoral immune response.

BackgroundMultiple countries reported unprecedented increases in invasive group A streptococcal (iGAS) disease following widespread SARS-CoV-2 circulation. Whether this surge reflects reduced pathogen exposure during non-pharmaceutical interventions ("immunity debt") or effects of SARS-CoV-2 infection on host immunity remains unresolved. MethodsWe conducted a population-based time-series analysis of weekly iGAS incidence in central Ontario, Canada (population {approx}11 million) from March 2011 through March 2024 (676 weeks). Using negative binomial panel regression, we modeled acute (2-week lagged) and cumulative SARS-CoV-2 exposure while adjusting for seasonality, secular trends, age, and sex. Population attributable fractions (PAFs) were estimated by counterfactual prediction. Specificity was assessed through negative control analyses (influenza, RSV). The immunity debt hypothesis was evaluated using cumulative streptococcal exposure as a predictor of iGAS. ResultsAmong 2,906 iGAS episodes, 34.3% during the pandemic period were associated with acute SARS-CoV-2 effects (range by age group: 16.5-39.1%). Models incorporating cumulative SARS-CoV-2 burden showed markedly better fit ({Delta}AIC=-157.5); cumulative exposure was strongly associated with iGAS (IRR 1.193, 95% CI 1.151-1.235), increasing the estimated PAF to 66.7%. Cumulative effects were strongest in children (IRR 1.309). SARS-CoV-2 was comparably associated with non-invasive streptococcal disease, with no increase in invasion propensity. Cumulative streptococcal exposure was not protective (overall IRR 1.000, p=0.730); where significant, the association was positive, opposite to immunity debt predictions. ConclusionsCumulative SARS-CoV-2 burden was strongly associated with pandemic-era iGAS incidence. Cumulative streptococcal exposure did not support the immunity debt hypothesis. These ecological findings are consistent with SARS-CoV-2-associated immune dysregulation and warrant individual-level confirmation.

IMPORTANCENirsevimab, a long-acting monoclonal antibody, has demonstrated efficacy against RSV-related lower respiratory tract infections (LRTIs) in clinical trials. Post-licensure monitoring is essential to confirm these benefits in real-world settings. OBJECTIVETo evaluate the real-world effectiveness of nirsevimab against medically attended RSV infections in infants and to assess how effectiveness varies by disease severity, dosage, and time since immunization. DESIGN, SETTING, AND PARTICIPANTSThis test-negative case-control study used inpatient, outpatient, and emergency room data from the Yale New Haven Health System. Nirsevimab-eligible infants who were tested for RSV using polymerase chain reaction between October 1, 2023 and May 9, 2024 were included. Cases were infants with confirmed RSV infections; controls were those who tested negative. EXPOSURENirsevimab immunization, verified through state immunization registries. MAIN OUTCOMES AND MEASURESEffectiveness was estimated using multivariable logistic regression, adjusting for age, calendar month, and individual risk factors. Separate models examined effectiveness by clinical setting, disease severity, dose, and time since immunization. Broader outcomes, including all-cause LRTI and LRTI-related hospitalization, were also analyzed, with stratification by early and late respiratory seasons. RESULTSThe analytic sample included 3,090 infants (median age 6.7 months, IQR 3.6-9.7), with 680 (22.0%) RSV-positive and 2,410 (78.0%) RSV-negative. 21 (3.1%) RSV-positive and 309 (12.8%) RSV-negative infants received nirsevimab. Effectiveness against RSV infection was 68.4% (95% CI, 50.3%-80.8%). Effectiveness was 61.6% (95% CI, 35.6%-78.6%) for outpatient visits and 80.5% (95% CI, 52.0%-93.5%) for hospitalizations. The highest effectiveness, 84.6% (95% CI, 58.7%-95.6%), was observed against severe RSV outcomes requiring ICU admission or high-flow oxygen. Although effectiveness against RSV infections declined over time, it remained significant at 55% (95% credible interval, 16%-75%) at 14 weeks post-immunization. Protective effectiveness was also observed against all-cause LRTI and LRTI-related hospitalizations during peak RSV season (49.4% [95% CI, 10.7%-72.9%] and 79.1% [95% CI, 27.6%-94.9%], respectively). However, from February to May, when RSV positivity was low, effectiveness against these broader outcomes was negligible. CONCLUSIONS AND RELEVANCENirsevimab provided substantial protection against RSV-related outcomes for at least three months. These findings support the continued use of nirsevimab and provide evidence that may help build public confidence in the immunization program. Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the effectiveness of nirsevimab against medically attended respiratory syncytial virus (RSV) infections in infants? Findings680 RSV test-positive cases and 2,410 RSV test-negative controls were included in this test-negative case-control study. Nirsevimabs effectiveness was 69% against RSV infections, 81% against RSV-associated hospitalization, and 85% against severe RSV disease. Effectiveness against RSV infection declined from 79% at 2 weeks post-immunization to 55% at 14 weeks post-immunization. MeaningNirsevimab provides strong protection against a wide range of RSV outcomes, but its effectiveness diminishes over time. These data can be utilized to optimize nirsevimabs implementation and sustain its uptake.

Background In a phase III clinical trial, casirivimab and imdevimab (CAS+IMD) reduced the composite endpoint of COVID-19-related hospitalizations or all-cause mortality in outpatients at risk of severe disease. This study assessed real-world effectiveness of CAS+IMD. Methods Data from Optum(R) Clinformatics(R) Data Mart (CDM) and IQVIA Pharmetrics Plus (PMTX+) were used to identify patients diagnosed with COVID-19 in ambulatory settings between December 2020 and March 2021 (PMTX+) and June 2021 (CDM), and either treated with CAS+IMD or untreated but treatment-eligible under Emergency Use Authorization. CAS+IMD-treated patients were matched to untreated patients and followed up to 30 days for the outcome of all-cause mortality or COVID-19-related hospitalizations (CDM) and COVID-19-related hospitalizations (PMTX+). Kaplan-Meier estimators were used to calculate outcome risks; Cox proportional-hazard models estimated adjusted hazard ratios (aHR) with 95% confidence intervals (CI). Results For CDM, 1116 CAS+IMD-treated patients were matched to 5294 untreated patients; for PMTX+, 3280 CAS+IMD-treated patients were matched to 16,284 untreated patients. The 30-day outcome risk was 2.1% and 5.3% in treated and untreated cohorts, respectively (CDM), and the 30-day risk of COVID-19-related hospitalization was 1.9% and 4.8%, respectively (PMTX+); translating to a 61% lower adjusted outcome risk (CDM aHR 0.39 (95% CI 0.26-0.60; PMTX+ aHR 0.39 (95% CI 0.30-0.51). The benefit of treatment was maintained across multiple subgroups of high-risk patients; earlier intervention was associated with improved outcomes. Conclusions This real-world study further supports randomized clinical trial findings that treatment with CAS+IMD reduces the risk of hospitalization and mortality in patients infected with susceptible variants.

BackgroundDuring the 2024-25 season, a universal infant nirsevimab program was publicly funded in Quebec, Canada. We estimated effectiveness, number-needed-to-immunize (NNI) and impact against severe respiratory syncytial virus (RSV) outcomes. MethodsWe conducted a test-negative study among nirsevimab-eligible children RSV-tested during ER consultation or hospitalization between October 1st, 2024 and March 3st, 2025. Eligible children were healthy-term and born during the RSV season (at-birth group) or <6 months old on October 1st (catch-up group), preterm, with high-risk conditions or living in remote regions. We estimated adjusted effectiveness by eligible group and further used 2023-24 respiratory hospitalization rates, RSV-positivity from a systematic hospital-based surveillance network, and coverage estimates to derive the NNI and tally of averted hospitalizations and ICU admissions. ResultsEffectiveness analyses included 3,172 ER consultations (668 RSV-positive) and 1,758 hospitalizations (549 RSV-positive). Nirsevimab effectiveness against ER consultation, hospitalization and ICU admission was 86% (95%CI:82-90), 89% (95%CI:84-92) and 88% (95%CI:58-97), respectively. Effectiveness exceeded 80% for all eligible groups. We estimate 41 at-birth and 58 catch-up immunizations needed to avert one RSV-associated hospitalization between October and March. Applying Quebec catch-up coverage (64%) and timing (November launch), we estimate more than half of RSV-associated hospitalizations and ICU admissions were prevented, potentially increasing to more than three-quarters if catch-up coverage reached 90% by October 1st. ConclusionsNirsevimab is highly effective and could more substantially impact the overall burden of RSV hospitalization and ICU admission through broad and timely administration to healthy-term and high-risk infants. To inform optimal nirsevimab timing, the durability of late-season protection warrants further investigation.

ImportanceStreptococcus pneumoniae is a known etiology of acute respiratory infections (ARIs), which account for large proportions of outpatient visits and antibiotic use in children. In 2023, 15- and 20-valent pneumococcal conjugate vaccines (PCV15, PCV20) were recommended for routine use in infants. However, the burden of outpatient healthcare utilization among U.S. children attributable to the additional, non-PCV13 serotypes in PCV15/20 is unknown. ObjectiveTo estimate the incidence of outpatient visits and antibiotic prescriptions in U.S. children for acute otitis media, pneumonia, and sinusitis associated with PCV15- and PCV20-additional serotypes (non-PCV13 serotypes) to quantify potential impacts of PCV15/20 on outpatient visits and antibiotic prescriptions for these conditions. DesignMulti-component study including descriptive analyses of cross-sectional and cohort data on outpatient visits and antibiotic prescriptions from 2016-2019 and meta-analyses of pneumococcal serotype distribution in non-invasive respiratory infections. SettingOutpatient visits and antibiotic prescriptions among U.S. children. ParticipantsPediatric visits and antibiotic prescriptions among children captured in the National Ambulatory Medical Care Survey (NAMCS), the National Hospital Ambulatory Medicare Care Survey (NHAMCS), and Merative MarketScan, collectively representing healthcare delivery across all outpatient settings. Incidence denominators estimated using census (NAMCS/NHAMCS) and enrollment (MarketScan) data. Main outcome(s) and measure(s)Pediatric outpatient visit and antibiotic prescription incidence for acute otitis media, pneumonia, and sinusitis associated with PCV15/20-additional serotypes. ResultsWe estimated that per 1000 children annually, PCV15-additional serotypes accounted for 2.7 (95% confidence interval 1.8-3.9) visits and 2.4 (1.6-3.4) antibiotic prescriptions. PCV20-additional serotypes resulted in 15.0 (11.2-20.4) visits and 13.2 (9.9-18.0) antibiotic prescriptions annually per 1,000 children. Projected to national counts, PCV15/20-additional serotypes account for 173,000 (118,000-252,000) and 968,000 (722,000-1,318,000) antibiotic prescriptions among U.S. children each year, translating to 0.4% (0.2-0.6%) and 2.1% (1.5-3.0%) of all outpatient antibiotic use among children. Conclusions and relevancePCV15/20-additional serotypes account for a large burden of pediatric outpatient healthcare utilization. Compared with PCV15-additional serotypes, PCV20-additional serotypes account for >5 times the burden of visits and antibiotic prescriptions. These higher-valency PCVs, especially PCV20, may contribute to preventing ARIs and antibiotic use in children. Key pointsQuestion: What is the incidence of pediatric outpatient visits and antibiotic prescriptions for acute respiratory tract infections associated with the additional (non-13-valent pneumococcal conjugate vaccine) serotypes in 15- and 20-valent pneumococcal conjugate vaccines (PCV15, PCV20)? Findings: PCV15- and PCV20-additional serotypes account for an estimated 197,000 and 1,098,000 visits and 173,000 and 968,000 antibiotic prescriptions, respectively, for acute respiratory infections among U.S. children annually. Visit and antibiotic prescription burdens were concentrated among children aged <5 years. Meaning: Respiratory infections caused by serotypes in PCV15/20, especially PCV20, may be important contributors to outpatient visits and antibiotic use in children.

BackgroundHighly pathogenic H5 avian influenza A has caused sporadic human infections, increasing the risk for potential human-to-human spread. In 2024, the U.S. experienced outbreaks among poultry and cattle, prompting enhanced surveillance. ObjectiveTo evaluate an H5 testing algorithm in subjects with respiratory symptoms presenting for routine care during low influenza A virus circulation. DesignObservational study using clinical- and research-developed nucleic acid amplification tests (NAATs) and pooled screening methods. SettingAcademic medical center in Boston, MA. Participants5,400 symptomatic individuals contributing 6,935 respiratory specimens from June 23 to August 28, 2024. MeasurementsSpecimens underwent initial respiratory pathogen testing per clinical protocols, which did not routinely include influenza due to low summer-month prevalence. Influenza A-positive specimens were subtyped using a clinical assay for H5 assessment. SARS-CoV-2-negative specimens not tested for influenza were screened in pooled batches. Positive pools were deconvoluted to individual specimens and screened for H5 using quantitative polymerase chain reaction. ResultsInfluenza A was detected in 40 of 6,935 specimens (0.6%), comprising 35 of 5,400 unique subjects (0.7%). No H5 infections were identified. Of the 35 influenza-positive individuals, 10 cases (29%) were found through research-specific screening of SARS-CoV-2-negative specimens. No deaths attributed to influenza were recorded. LimitationsSingle center design, convenience sampling, absence of ocular specimens, and minimal sampling in high-risk areas may limit generalizability. ConclusionExpanded influenza testing using pooled NAATs successfully identified low-prevalence influenza A and ruled out H5 in this cohort. These data support targeted influenza screening to enhance surveillance for emerging subtypes rather than a broad-based clinical testing strategy for influenza A testing. Primary Funding SourceSupported by institutional resources and Center for Disease Control and Prevention contracts.

BackgroundCOVID-19 oral treatments require initiation within 5 days of symptom onset. Although antigen tests are less sensitive than RT-PCR, rapid results could facilitate entry to treatment. As SARS-CoV-2 variants and host immunity evolve, it is important to characterize the use case for rapid antigen tests for treatment entry. MethodsWe collected anterior nasal swabs for BinaxNOW and RT-PCR testing and clinical data at a walk-up, community site in San Francisco, California between January and June 2022. SARS-CoV-2 genomic sequences were generated from positive samples and classified according to subtype and variant. Monte Carlo simulations were conducted to estimate the expected proportion of SARS-CoV-2 infected persons who would have been diagnosed within 5 days of symptom onset using RT-PCR versus BinaxNOW testing. ResultsAmong 25,309 persons tested with BinaxNOW, 2,952 had concomitant RT-PCR. 1321/2952 (44.7%) were SARS-CoV-2 RT-PCR positive. We identified waves of predominant omicron BA.1, BA.2, BA.2.12, BA.4, and BA.5 among 720 sequenced samples. Among 1,321 RT-PCR positive samples, 938/1321 (71%) were detected by BinaxNOW; 95% (774/817) of those with Ct value <30 were detected by BinaxNOW. BinaxNOW detection was consistent over lineages. In analyses to evaluate entry to treatment, BinaxNOW detected 82.7% (410/496, 95% CI: 79-86%) of persons with COVID-19 within 5 days of symptom onset. In comparison, RT-PCR (24-hour turnaround) detected 83.1% (412/496 95% CI: 79-86%) and RT-PCR (48-hour turnaround) detected 66.3% (329/496 95% CI: 62-70%) of persons with COVID-19 within 5 days of symptom onset. ConclusionsBinaxNOW detected high viral load from anterior nasal swabs consistently across omicron sublineages emerging between January and June of 2022. Simulations support BinaxNOW as an entry point for COVID-19 treatment in a community field setting.

II.ImportanceThe U.S. arrival of the Omicron variant led to a rapid increase in SARS-CoV-2 infections. While numerous studies report characteristics of Omicron infections among vaccinated individuals and/or persons with a prior history of infection, comprehensive data describing infections among immunologically naive adults is lacking. ObjectiveTo examine COVID-19 acute and post-acute clinical outcomes among a well-characterized cohort of unvaccinated and previously uninfected adults who contracted SARS-CoV-2 during the Omicron (BA.1/BA.2) surge, and to compare outcomes with infections that occurred during the Delta wave. DesignA prospective cohort undergoing high-resolution symptom and virologic monitoring between June 2021 and September 2022 SettingMultisite recruitment of community-dwelling adults in 8 U.S. states ParticipantsHealthy, unvaccinated adults between 30 to 64 years of age without an immunological history of SARS-CoV-2 who were at high-risk of infection were recruited. Participants were followed for up to 48 weeks, submitting regular COVID-19 symptom surveys and nasal swabs for SARS-CoV-2 PCR testing. Exposure(s)Omicron (BA.1/BA.2 lineages) versus Delta SARS-CoV-2 infection, defined as a positive PCR that occurred during a period when the variant represented [&ge;]50% of circulating SARS-CoV-2 variants in the participants geographic region. Main Outcome(s) and Measure(s)The main outcomes examined were the prevalence and severity of acute ([&le;]28 days post-onset) and post-acute ([&ge;]5 weeks post-onset) symptoms. ResultsAmong 274 immunologically naive participants, 166 (61%) contracted SARS-CoV-2. Of these, 137 (83%) and 29 (17%) infections occurred during the Omicron- and Delta-predominant periods, respectively. Asymptomatic infections occurred among 6.7% (95% CI: 3.1%, 12.3%) of Omicron cases and 0.0% (95% CI: 0.0%, 11.9%) of Delta cases. Healthcare utilization among Omicron cases was 79% (95% CI: 43%, 92%, P =0.001) lower relative to Delta cases. Relative to Delta, Omicron infections also experienced a 56% (95% CI: 26%, 74%, P =0.004) and 79% (95% CI: 54%, 91%, P <0.001) reduction in the risk and rate of post-acute symptoms, respectively. Conclusions and RelevanceThese findings suggest that among previously immunologically naive adults, few Omicron (BA.1/BA.2) and Delta infections are asymptomatic, and relative to Delta, Omicron infections were less likely to seek healthcare and experience post-acute symptoms. KEY POINTSO_ST_ABSQuestionC_ST_ABSWhat are acute and post-acute outcomes among previously uninfected and unvaccinated adults who contracted Omicron (BA.1/BA.2), and how do these compare with Delta infections? FindingsIn this prospective cohort of 274 immunologically naive adults, 166 (61%) contracted SARS-CoV-2, with 9 (5.5%) asymptomatic infections. Compared with Delta, Omicron infections experienced a 79% relative reduction in healthcare utilization, and 56% and 79% relative reductions in the risk and rate of post-acute symptoms ([&ge;]5-weeks), respectively. MeaningThese findings suggest among immunologically naive adults, few infections are asymptomatic, and relative to Delta, Omicron infections have lower likelihoods of severe illness and post-acute symptoms.

BackgroundHighly sensitive molecular tests, like Xpert Ultra, are reshaping TB diagnosis--detecting paucibacillary TB but sometimes creating uncertainty when they detect DNA in extremely low quantities that may not signal disease. This ambiguity also complicates the evaluation of novel diagnostic strategies. We sought to monitor adults with a Trace result on an Xpert Ultra test to estimate the risk of tuberculosis disease up to 24 months later. MethodsWe conducted a multi-site clinical observational study in South Africa and Uganda, where we enrolled ambulatory participants aged >=15 years with a sputum Xpert Ultra Trace result who had not yet initiated TB treatment. All participants underwent comprehensive clinical evaluation and repeated, standard sputum TB testing. Clinicians deferred treatment recommendations if TB status remained uncertain after evaluation. Untreated participants were followed regularly until TB diagnosis and/or treatment initiation. We estimated cumulative incidence of TB disease, defined by three reference standards. ResultsOf 311 participants with Trace results (50% male, 57% PLHIV, 37% treated for TB within the last 5 years), 24% were positive for TB within 12 months by culture, 37% by sputum Xpert or culture, and 54% by culture or clinical diagnosis. After excluding those diagnosed with TB at baseline, patients identified at baseline as having recent TB history, abnormal chest x-ray, or positive tongue swab, had higher risk of TB diagnosis (hazard ratios: 2.6, 2.4, 4.5, respectively) during follow-up. This hazard was highest in the first three months after the negative baseline evaluation (0.22 [95% CI: 0.19-0.26] per person-month) and decreased to 0.01 [95% CI: 0-0.02] per person-month in both the 3-6 and 6-12-month intervals. ConclusionApproximately half of adults and adolescents with a sputum Trace result were diagnosed with TB disease within twelve months. Although most TB diagnoses were made within 3 months, risk remained higher than estimated population incidence rates through the follow-up period. Individuals with sputum Trace results should receive close clinical monitoring, despite initial clinical treatment decision. Summary resultsXpert Ultra "Trace" results detect low quantities of TB DNA, creating diagnostic uncertainty that complicates both clinical decisions and diagnostics evaluation. This clinical observational cohort study followed untreated patients with Trace results for twelve or more months, using survival analysis to estimate actual tuberculosis disease risk and identify risk factors.

BackgroundWe investigate the effects of remdesivir (RDV) treatment on intra-host SARS-CoV-2 diversity and low-frequency mutations in moderately ill hospitalized COVID-19 patients and compare them to patients without RDV treatment. MethodsSequential collections of nasopharyngeal and mid-turbinate swabs were obtained from 16 patients with and 31 patients without RDV treatment. A total of 113 samples were sequenced and mutation analyses were performed. ResultsWe did not identify any drug resistant mutations during RDV therapy. In genes encoding and associated with the replication complex, low-frequency minority variants that do not reach fixation within the sampling period were detected in 6/16 (37.5%) and 14/31 (45%) patients with and without RDV treatment respectively. We did not detect significant differences in within-host diversity and positive selection between the RDV-treated and untreated groups. ConclusionsMinimal intra-host variability and stochastic low-frequency variants detected in moderately ill patients suggests little selective pressure in patients receiving short courses of RDV. Patients undergoing short regimens of RDV therapy should continue to be monitored.