Infectious Diseases and Therapy最新文献

Viral diseases represent a significant global health challenge. N-glycosylation, a critical post-translational modification, plays diverse and essential roles throughout the viral life cycle. This review outlines the initiation of N-glycosylation, elucidating its role in facilitating viral protein synthesis within the endoplasmic reticulum (ER). This process ensures proper protein folding and functionality through stringent quality control mechanisms. Consequently, targeting N-glycosylation offers substantial potential for developing antiviral therapies. Specific antiviral strategies include inhibiting glycosyltransferase activity to block the initial glycosylation step and employing glucosidase inhibitors to disrupt viral protein glycosylation, leading to envelope protein misfolding. Additionally, this review explores other mechanisms of glucosidase inhibitors, including their dual role in modulating the ER-associated degradation (ERAD) pathway. The clinical evaluation of investigational antiviral agents is also addressed, providing a comprehensive analysis of their efficacy in suppressing viral replication and associated adverse effects. To advance precise antiviral interventions, future research must deepen the understanding of these mechanisms while optimizing the balance between efficacy and long-term safety in drug design. Such efforts are crucial for translating laboratory findings into effective clinical applications.

Introduction: Respiratory syncytial virus (RSV) in older adults can cause a variable spectrum of symptoms, ranging from mild manifestations to hospitalization and sometimes adverse outcomes. However, its true epidemiological burden is underestimated due to non-specific symptoms, lack of standardized diagnostic criteria, limited lab confirmation, and inadequate attribution in administrative datasets.

Methods: We conducted a time-series analysis using hospital discharge data from the Veneto Region, Italy, between 2018 and 2024. Respiratory infections (RI) and RSV-related hospitalizations were identified using International Classification of Diseases codes. A generalized additive mixed model (GAMM) was applied to weekly RI admissions, incorporating circulating pathogen data from the RespiVirNet surveillance system. Seasonal patterns and age-stratified risk were modeled using smoothing terms.

Results: Among individuals aged ≥ 65 years, RSV accounted for an estimated 3.0% to 4.6% of RI hospitalizations. Age-specific hospitalization rates attributable to RSV were 26.8, 109.4, and 317.4 per 100,000 person-years in the 65-74, 75-84, and ≥ 85 age groups, respectively. Explicit RSV coding underestimated the true burden by a factor of up to 7.6. Incidence rates and underreporting were highest in post-acute COVID-19 seasons.

Conclusions: RSV-related hospitalizations in older adults are substantially underreported in administrative data. Improved surveillance and prospective clinical studies are needed to validate model estimates and assess diagnostic test performance. Statistical modeling represents a valid approach to estimate the burden of RSV hospitalizations in underdiagnosed populations, such as the elderly, when direct data are lacking.

Introduction: Vesatolimod (VES), a toll-like receptor 7 agonist, is being investigated as part of a strategy for human immunodeficiency virus (HIV) cure. VES is metabolized through the CYP3A pathway and is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). This study evaluated the impact of coadministration of VES with cobicistat (COBI; a P-gp, BCRP, and strong CYP3A inhibitor) or voriconazole (VOR; a strong CYP3A inhibitor with no effect on transporters) on the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of VES in people with HIV (PWH).

Methods: A total of 15 people with virally suppressed HIV on antiretroviral therapy received 2 mg VES (on day 1 in period 1, day 2 in period 2, and day 3 in period 3), 150 mg COBI once daily for 5 days in period 2, and 400 mg VOR on day 1 and 200 mg twice daily on days 2-6 in period 3. Blood samples were collected to measure VES PK, expression of interferon-stimulated genes (ISGs), cytokine/chemokine levels, and immune-cell phenotyping.

Results: Coadministration of VES with VOR did not impact VES PK. In contrast, coadministration of COBI increased VES maximum plasma concentration (C_max), area under the concentration-time curve extrapolated to infinity (AUC_inf), and half-life (t_1/2) 7.5-, 4.3-, and 1.2-fold, respectively, but did not increase the mRNA expression levels of ISGs, serum cytokines/chemokines, or expression of activation markers on peripheral natural killer or T cells compared with VES alone. There were no serious adverse events, and no participants discontinued study drugs due to study-drug-related adverse events.

Conclusions: VES was well tolerated when administered alone or in combination with COBI or VOR in PWH. Coadministration of COBI, but not VOR, increased plasma VES concentrations, suggesting that inhibition of transporters (P-gp and/or BCRP) may have a greater impact on VES PK than inhibition of the drug-metabolizing enzyme (CYP3A).

Trial registration: ClinicalTrials.gov NCT05458102.

Introduction: The zoonotic parasite Echinococcus multilocularis emerged in Hungary in the early 2000s. During the next two decades, it continuously spread in both wildlife and the human population. The first comprehensive epidemiological study on human alveolar echinococcosis (HAE) was carried out in 2018. Then, a remarkable increase in HAE cases was detected in Hungary.

Methods: Our study aimed to identify the potential causes of trend alterations in the epidemiology of HAE. Thus, we compared the terms before (2003-2018) and after (2019-2024) the comprehensive analysis, focusing on disease outcomes and their associated background factors.

Results: We found that, during the latter study period, the prognosis of HAE improved (proportion of improving cases increased from 23.5% to 60.9%, p = 0.0006) owing to the shortening of diagnostic delay (47.1% versus 78.3% of delay within 12 months, p = 0.029), development in surgery (17.6% versus 26.1% of surgeries were R1/R2, p = 0.57) and medication (35.3% versus 73.9% of medications proved adequate, p = 0.015); however, the proportion of advanced-stage cases entering the healthcare system remained high (56.25% versus 56.52%). On the other hand, a non-significant increase in case numbers was experienced in the southwestern part of the country (11.77% versus 26.09% of all cases in Hungary).

Conclusion: We conclude that public interest arose from the first comprehensive HAE study that increased disease awareness within the healthcare system and contributed to better diagnoses and more efficient therapy. However, public awareness needs improvement, since the proportion of advanced-stage HAE did not decrease between the two study periods. Besides, the southwestern hotspot needs more attention and intervention.

Introduction: Carbapenem-resistant Gram-negative bacteria pose significant global health threats due to high infection rates and limited treatment options. Polymyxin B (PMB) has reemerged as a last-line therapy against these pathogens, despite nephrotoxicity and neurotoxicity concerns. However, the precise correlation between PMB exposure and response/toxicity has not been well established. The objective of this study was to assess the impact of polymyxin B pharmacokinetics on clinical outcomes in critically ill patients.

Methods: This single-center, retrospective study included 146 critically ill patients treated with PMB from January 2020 to July 2023. The primary outcome was 28-day mortality, while secondary outcomes included clinical efficacy, length of hospital and intensive care unit (ICU) stay and new onset acute kidney injury (AKI).

Results: The 28-day mortality rate was 43.2%. Multivariable Cox regression analysis showed PMB pharmacokinetic parameters, an area under the concentration-time curve across 24 h at steady state (AUCss, 24 h), C6h, and Cmin were associated with mortality. The receiver operating characteristic (ROC) analysis indicated an AUCss, 24 h cutoff of 81.6 mg·h/l for predicting mortality. AKI occurred in 40.6% of patients. Logistic regression revealed that baseline estimated glomerular filtration rate (eGFR) (adjusted OR 0.979, 95% CI 0.963-0.994, P = 0.007) and PMB treatment duration (adjusted OR 1.101, 95% CI 1.007-1.204, P = 0.034) were independent risk factors for AKI.

Conclusions: PMB pharmacokinetics are closely related to patient outcomes. An AUCss, 24 h ≥ 81.6 mg·h/l may reduce mortality. Baseline eGFR and PMB treatment duration are independent risk factors for AKI during PMB therapy.

Introduction: Antiviral combinations have been successfully used to treat COVID-19 in immunocompromised patients, especially those with prolonged viral shedding or relapses. This study assessed outcomes of antiviral combination therapy, stratified by clinical indication.

Methods: In this retrospective single-center study (October 2022-March 2024), patients receiving antiviral combinations were stratified according to treatment indication: prolonged/relapsed infection (group 1), severe COVID-19 (group 2), or early treatment of non-severe COVID-19 (group 3). Outcomes included virological clearance at day 14, and success rate at days 30 and 100.

Results: Seventy-one patients were included (group 1: 43; group 2 and 3: 14 each); 52% had non-Hodgkin lymphoma, 39.4% prior anti-CD20 therapy, 32% transplant/CAR-T. Most (92.6%) were vaccinated (median three doses). Treatment consisted of two antivirals in 59 patients (82%), mainly 10 days of both remdesivir and nirmatrelvir/ritonavir (n = 52, 73%), two antivirals plus single-dose tixagevimab/cilgavimab in 11 (15%), and three antivirals in 1. Virological clearance by day 14 was achieved in 79% (52/66 evaluable patients): 85% (34/40) in group 1, 58% (7/12) in group 2, 78.6% (11/14) in group 3. In group 1, predictors of day 14 clearance were prior vaccination and combination treatment with ≥ 10 days of oral antiviral. Success rates at days 30 and 100 were 80% (57/71) and 79% (56/71), respectively, with no significant differences between groups. Five patients required further treatment courses. COVID-19-related mortality was 12.5% (9/71). Three grade 2 adverse events occurred.

Conclusions: Antiviral combination therapy was effective in prolonged/relapsed and severe COVID-19 while its role in early mild infections warrants further study. Stratifying patients by treatment indication facilitates outcome interpretation and comparisons.

Introduction: Understanding the temporal dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is crucial for optimizing diagnostic strategies. This prospective cohort study aimed to quantify the temporal viral transmission dynamics and biomarker profiles among households containing a SARS-CoV-2-positive index patient (IP) and uninfected household contacts (HHCs).

Methods: IPs entered the study within 48 h after confirmation of SARS-CoV-2 through reverse transcription polymerase chain reaction (RT-PCR). During 10-13 follow-up visits at days 0-7, and every 3-4 days thereafter until day 30 (± 6 days), nasopharyngeal swab and saliva samples were collected from participants (IP and HHC), and quantified via RT-PCR. Viral loads were estimated from cycle threshold values using three independently validated reference curved. Temporal viral dynamics for HHCs were evaluated as median times to first positive test (T_f+), symptom onset (T_so), and peak viral load (T_pvl), using a within-host target cell-limited framework.

Results: We prospectively screened 30 households with SARS-CoV-2-negative index cases; nine had a subsequent index-HHC conversion to PCR-positive, and 89 samples were generated. The results revealed a median T_f+ of 2 days, T_so of 4 days, and T_pvl of 5 days, which underscores significant gaps between viral detection and peak viral load. Nasal samples exhibited higher viral replication rates (β = 0.77/day) and prolonged virus production as compared to saliva samples, while infected cells in saliva cleared more rapidly (δ = 0.65 day^-1 vs 0.25 day^-1).

Conclusion: These findings suggest that SARS-CoV-2 viral RNA is detectable before symptom onset, and emphasize the need for testing immediately after exposure with repeated testing in the first week. This study provides critical insights into the temporal interplay of viral kinetics, aiding the development of targeted diagnostic and public health interventions. Further research is needed to validate these findings across larger, diverse cohorts and evolving viral variants. Testing immediately after exposure, with repeat testing during the first week may improve case detection.

Introduction: Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infection in infants. This study examined the preferences of Dutch parents and expectant parents for two RSV prevention strategies for infant protection: a maternal vaccine versus an infant monoclonal antibody (mAb) injection.

Methods: An online survey including a discrete choice experiment was conducted. Participants chose between two immunisation options for 'a common virus among infants' that represented RSV. These differed based on six attributes: timing and recipient of the injection, costs, recommended by a healthcare provider (HCP), included in the National Immunisation Programme (NIP), administration location, and co-administered with other injections. The main outcomes were preference weights, conditional relative attribute importance (CRAI), and willingness to be immunised.

Results: The survey was completed by 150 participants (90% female; 49% parents; 51% expectant parents; mean age 31.23 ± 5.61 years). Participants preferred an immunisation option that is administered to pregnant women [mean = 1.48 (95% confidence interval (CI) 1.18-1.82)], free of charge [mean = 1.36 (95% CI 1.10-1.67)], recommended by an HCP [mean = 0.50 (95% CI, 0.34-0.66)], and included in the NIP [mean = 0.42 (95% CI, 0.26-0.58)]. The most important attributes were timing and recipient of the injection [CRAI = 32% (95% CI, 28-35%)] and costs [CRAI = 24% (95% CI, 20-28%)]. Willingness to be immunised was higher when the maternal vaccine and infant mAb injection were in the NIP than when only the infant mAb injection was available (89% vs 74%).

Conclusions: The results suggest that most Dutch parents and expectant parents would prefer a maternal vaccine to an infant mAb injection to immunise their infants against an RSV-like virus. An NIP that incorporates both strategies may enhance uptake and protect the most infants. However, as the attributes were not exhaustively or explicitly presented in the context of RSV prevention, the results may not be completely transferable.

Introduction: In the absence of a national varicella vaccine program, it is assumed that the annual proportion of children in Denmark acquiring a varicella infection (chickenpox) corresponds to the birth cohort size, approximately 60,000 per year. Varicella infections impose a burden on families and increase healthcare utilization. Previous studies have estimated the disease burden of severe varicella cases requiring hospitalization. However, information about the burden of mild-to-moderate varicella cases is scarce. We aim to provide insights into the burden of mild-to-moderate varicella cases at the community level.

Method: We utilized data from the non-emergency medical helpline (1813 helpline) and national hospital admission register to provide adjusted estimates of the burden of moderate varicella cases at the community level among children (< 18 years) in Denmark from 2015 to 2023, applying time series regression analysis to counteract underreporting in the 1813 helpline.

Results: We estimated that 20,439 (95% CI 17,378-23,501) calls to the 1813 helpline were attributed to varicella infections (VZV-associated calls), a 103.1% additional proportion to the 10,068 calls documented in the call notes. The average yearly number of VZV-associated calls was 2271 calls. When correcting for irregular patterns of infection during the COVID-19 pandemic, the average yearly estimated number of VZV-associated calls was 2561. In the first 6 months of 2023, we estimated 2552 calls (95% CI 2170-2934). The overall incidence of VZV-associated calls is 623 per 100,000 person-years (95% CI 529.49-716.06), with annual incidence ranging from 291 in 2021 to 910 in 2017.

Conclusion: The 1813 helpline calls attributed to varicella were double the numbers reported previously in the call notes, indicating a larger impact of mild-to-moderate cases on healthcare services than initially thought. This highlights the importance of addressing challenges with varicella infection burden estimates and adds considerably to the burden of mild-to-moderate cases of varicella on a community level.

Introduction:  Protease inhibitors (PIs) remain an effective antiretroviral therapy (ART) option for people with human immunodeficiency virus (HIV) (PWH), particularly in complex clinical and virological scenarios. However, they are associated with greater metabolic toxicity and drug-drug interactions (DDI) compared with newer ART classes. This study aimed to characterize PWH currently receiving PI-based ART and to explore the reasons for maintaining these regimens.

Methods:  We conducted a cross-sectional, observational study of all PWH on PI-based ART as of 30 June 2024 at the HIV Unit of Hospital Clínic de Barcelona. Demographic, clinical, laboratory, ART history, and genotypic resistance data were extracted from the institutional database and compared with the rest of the cohort.

Results:  Among 6261 PWH on ART, 724 (11.6%) were receiving a regimen including a PI; their use progressively declined over the last two decades (p < 0.001). The most frequent reasons for PI prescription were prior virological failure (36%) and toxicity to previous ART (41%). Compared with other PWH, those on PIs were older (median 54 versus 48 years, p < 0.001), more frequently female patients (19% versus 13%, p < 0.001), and had higher rates of heterosexual (33% versus 21%, p < 0.001) and injection-drug-use transmission (15% versus 7%, p < 0.001). Virological suppression was significantly lower among PWH on PIs (88% versus 96%, p < 0.001). Genotypic resistance testing prior to PI prescription was available for 435 PWH; 74% had at least one major resistance substitution, and 70.4% had substitutions affecting two or more antiretroviral classes. In total, 299 PWH had experienced either virological failure or toxicity to non-nucleoside reverse transcriptase inhibitor (NNRTI)- or integrase strand transfer inhibitor (InSTI)-based regimens prior to initiating a PI-based regimen. Among them, 42 had documented failure of or toxicity to both drug classes.

Conclusions:  Although their use has declined, a substantial number of PWH remain on regimens including a PI. These PWH typically have long-standing infections, prior ART failures, and documented resistance substitutions, supporting the continued use of PIs when other therapeutic options are limited.