Open Forum Infectious Diseases最新文献

Background: Non-tuberculous mycobacterial (NTM) skin and soft tissue infections (SSTI) present a significant treatment challenge, requiring prolonged, multidrug antibiotic regimens often associated with substantial toxicity and suboptimal clinical outcomes. We aim to describe the clinical characteristics and treatment of patients with NTM-SSTI in the Netherlands, focusing on host immune status and drug toxicity.

Methods: We retrospectively collected data from adults with NTM-SSTI treated at 2 Dutch tertiary referral centers for mycobacterial disease between 2017 and 2024. Data included sociodemographics, medical history, antibiotic regimens, drug toxicity, and treatment outcomes.

Results: We included 73 patients, of whom 39 (49%) were immunocompromised. Disseminated disease was almost exclusively observed in immunocompromised patients (14/15). The most isolated species were Mycobacterium chelonae (23/73; 32%) and Mycobacterium marinum (17/73; 23%). Azithromycin, the most prescribed drug, was discontinued prematurely because of toxicity in 35% (18/52) of patients, ethambutol in 33% (9/27), and clofazimine in only 12% (3/26). These discontinuations occurred mostly within the first 4 months. Immunocompromised patients with disseminated infections had longer (median 10.1 vs 7.6 vs 6.4 months) treatment durations and lower remission rates (29% vs 59% vs 86%) compared to immunocompromised patients with localized disease and immunocompetent patients, respectively.

Conclusions: Immunocompromised status is associated with disseminated NTM-SSTI and worse treatment outcomes. Regardless of immune status, antimycobacterial drugs often cause toxicity, leading to treatment changes.

Background: Sixteen million children are HIV-exposed but uninfected (HEU) due to the prevention of vertical transmission. Despite avoiding HIV, children who are HEU face higher risks of infections and poorer growth and development than children HIV-unexposed (HU), though mechanisms remain unclear. We hypothesized that systemic and vascular inflammations contribute to disparities.

Methods: The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial recruited pregnant women at ∼12 gestational weeks between 2012 and 2015 in rural Zimbabwe (∼15% HIV prevalence, >80% antiretroviral therapy coverage). Plasma biomarkers were measured using enzyme-linked immunosorbent assay (ELISA) and multiplex assays in a subgroup of children at 1 month of age and compared using generalized estimating equations adjusted for trial arm, maternal age, birthweight, prematurity, sex, and age. Principal component analysis was used to reduce dimensionality of biomarkers.

Results: Seventy-one children who are HEU and 62 who are HU were included. Twenty-two of 27 biomarkers were raised in HEU versus HU. Systemic inflammatory markers (IL-1β/interferon-γ/TNF-α/sCD14) and vascular activation markers (L-selectin/VCAM-1) were significantly higher. HIV-exposed but uninfected infants gained 6.1 g/day less than HU infants in the first month after birth. Although one principal component, primarily driven by vascular endothelial growth factor, was associated with increased growth rate, the difference between HEU and HU growth trajectories was not affected by differences in any principal components, suggesting that inflammation does not explain lower growth amongst HEU children.

Conclusions: Children who are HEU have significantly elevated systemic and vascular inflammatory biomarkers compared with those who are HU. Understanding causes and consequences of this inflammatory imbalance may identify new intervention targets for improving outcomes in this vulnerable group.

Background: Lyme neuroborreliosis (LNB) is a common manifestation of Lyme disease in children. It is caused by the bacterium Borrelia burgdorferi and can affect both the peripheral nervous system (PNS) and the central nervous system (CNS). This study aimed to describe clinical and immunological features of LNB in children.

Methods: We performed a large retrospective cohort study of children diagnosed with LNB at the University Children's Hospital Zurich from 1 January 2006 to 31 December 2020.

Results: A total of 190 children diagnosed with LNB were included (median age, 7.6 years). Meningitis was the most frequent manifestation of LNB (n = 115, 60.5%), followed by isolated cranial neuropathy (iCN) (n = 55, 28.9%) and meningoradiculitis (n = 15, 7.9%). Five (2.7%) patients presented with rare, severe CNS manifestations, including acute myelitis and cerebral vasculitis. The most frequent specific clinical signs were facial palsy (n = 136, 71.6%) and a history of erythema migrans (n = 33, 17.4%). Borrelia burgdorferi-specific IgM and IgG antibody responses in cerebrospinal fluid (CSF) and blood were primarily directed against the following 3 antigens: VlsE, p41, and OspC, with broader responses in blood. Compared to patients with meningitis or meningoradiculitis, iCN patients had lower CSF inflammation, reduced positivity in B burgdorferi-specific tests (ELISA, immunoblot, and/or intrathecal antibody production), weaker antibody responses to VlsE, p41, and OspC, and shorter post-treatment symptom duration.

Conclusions: Lyme neuroborreliosis in children presents with a broad clinical spectrum, with meningitis and iCN being the most common manifestations. We observed distinct clinico-pathogenic subgroups of LNB: iCN reflects a more localized, PNS-restricted disease, whereas meningitis and meningoradiculitis represent a more systemic involvement of both PNS and CNS. These findings may improve diagnostic accuracy and guide the management of children with LNB.

Background: Mitochondrial dysfunction is implicated in the development of diabetes mellitus (DM), which is more common in people with HIV (PWH) than in people without HIV (PWoH). Variation in mitochondrial DNA (mtDNA) and mitochondrial-toxic antiretroviral therapy (ART) may influence the susceptibility to DM but is underexplored in men with HIV.

Methods: Men from the Multicenter AIDS Cohort Study (MACS) without DM and with fasting glucose data were included. Type 2 DM was defined by fasting glucose ≥ 126 mg/dL, DM medication use, a DM diagnosis, or hemoglobin A1c ≥ 6.5%. Exposure to mitochondrial-toxic ART (D-drugs or zidovudine) was categorized as a binary variable based on ever or never exposed. Mitochondrial DNA haplogroups were determined using HaploGrep from genotyping data. Associations between incident DM, mtDNA haplogroups of European and African origin, and interactions between mtDNA haplogroups and mitochondrial-toxic ART were analyzed.

Results: Among 2598 men (667 self-reported as non-Hispanic Black and 1616 self-reported as non-Hispanic White), 1349 were men with HIV. In PWH, African haplogroup L3 was associated with a higher risk of incident DM (hazard ratio [HR], 1.92; 95% CI, 1.19-3.10) compared to other African-ancestry haplogroups, after adjusting for principal components of nuclear genetic ancestry, age, body mass index, hepatitis B and C status, smoking, and HIV-specific factors. D-drugs were independently associated with an increased risk of developing DM (HR, 2.8; 95% CI, 1.5-5.3).

Conclusions: The African mtDNA haplogroup L3 increased the risk of incident DM in men with HIV. In PWH, D-drugs independently increased the risk of DM.

Background: The nationwide Treatment as Prevention program for Hepatitis C (TraP HepC) was initiated in Iceland in 2016, where direct-acting antivirals (DAAs) replaced interferon-based treatments for hepatitis C virus (HCV). The study aimed to assess the impact of TraP HepC on the epidemiology of HIV/HCV coinfection, the cascade of care, and HCV reinfection rates among coinfected individuals.

Methods: A nationwide retrospective study was conducted on all people with HIV in Iceland who tested HCV antibody positive during 2000-2020. Medical records, laboratory results, and treatment outcomes were reviewed and analyzed by treatment era: interferon (2000-2015) and DAA (2016-2020).

Results: Out of 648 people with HIV, 78 were HCV antibody positive during 2000-2020, of whom 61 had confirmed HCV viremia. The total number of HIV/HCV-coinfected individuals increased steadily, peaking at 41 in 2016, but decreased by >85% to 6 by 2020 following the nationwide TraP HepC program. In total, 84 active HCV infections including reinfections were diagnosed, which prompted 81 treatment initiations and yielded 66 cures. During the interferon era, 45% (13/29) achieved cure, compared with 88% (53/60; P < .001) in the DAA era. The HCV reinfection rate in this group was 9.35/100 person-years, all presumed to be acquired by injection drug use.

Conclusions: Before the nationwide elimination campaign, the incidence of HIV/HCV coinfections was steadily increasing, but it has subsequently decreased by >85%, primarily due to the widespread use of DAAs. However, high reinfection rates in this population suggest that ongoing prevention, early diagnosis, and easy access to DAAs are necessary to maintain success.

Background: Influenza virus infection remains a major cause of morbidity in allogeneic hematopoietic stem cell transplant (allo-HCT) recipients. Vaccination is a key preventive strategy; yet, clinical evidence of its benefit in this population is limited.

Methods: We conducted a retrospective, multicenter observational study including adult allo-HCT recipients (≥16 years) who developed laboratory-confirmed influenza infection between 2013 and 2023, with the aim of assessing the impact of vaccination on influenza disease severity. Vaccinated status was defined as having received the seasonal influenza vaccine during the same season and before the onset of influenza infection.

Results: A total of 143 recipients with 214 influenza episodes were analyzed. The median age was 45 years (range 18-70), and 58% had acute leukemia or myeloid malignancies. Most (64.3%) received transplants from unrelated or haploidentical family donors. Overall, 48 episodes (22%) occurred after influenza vaccination. At infection onset, 52% of vaccinated recipients were profoundly immunosuppressed (within <6 months post-transplant, experiencing active graft-versus-host disease, or receiving immunosuppressors or corticosteroids). Progression to lower respiratory tract disease (LRTD) occurred in 29% of episodes. Multivariable analysis showed influenza vaccination was significantly associated with reduced LRTD risk (HR 0.18; 95% CI: 0.06-0.50; P = .001), while a high-risk immunodeficiency scoring index (ISI) (HR 4.71; 95% CI: 1.99-11.17; P = .0004) and fever at screening (HR 2.16; 95% CI: 1.51-3.08; P < .001) independently predicted higher LRTD risk. Vaccination was also associated with decreased hospitalization risk (OR 0.20; 95% CI: 0.05-0.57; P = .005); whereas, high-risk ISI was linked to higher admission risk (OR 22.86; 95% CI: 4.82-170, P = .0003).

Conclusions: This study provides real-world evidence that seasonal influenza vaccination may reduce disease severity in allo-HCT recipients and confirms the prognostic value of the ISI for disease risk assessment.

Background: The COVID-19 pandemic caused a global disruption in respiratory syncytial virus (RSV) epidemiology. However, data on RSV epidemiology in the postpandemic period remain limited. We analyzed shifts in RSV seasonality, age distribution, and disease severity among RSV-positive children in the Netherlands before, during, and after the pandemic.

Methods: Between May 2021 and April 2024, children under two years of age, admitted with RSV to 47 Dutch hospitals were included in a prospective surveillance study. We compared demographic and clinical characteristics of RSV-positive patients with data from the pre-COVID period (2018-2020), the COVID period and the post-COVID period (2022-2024).

Results: A total of 8457 RSV-positive cases were included, with detailed data collected from 2708 patients (13 hospitals). Following an unusual off-season shift and a period of endemic circulation, RSV seasonality has reverted to its typical prepandemic winter pattern. The median age at admission increased from 2.2 months (interquartile range [IQR]: 1.1-5.6) in the prepandemic period to 4.9 months (IQR 1.8-11.4, P < .05) during the summer outbreak (2021). This subsequently returned to prepandemic median age in the winter of 2023/2024 (2.7 months, IQR 1.3-8.0, not significant). We observed no differences in the prevalence of preterm birth or comorbidities among RSV-positive children before, during or after the COVID pandemic.

Conclusions: The COVID-19 pandemic profoundly disrupted RSV epidemiology. This prospective study demonstrates a rapid re-establishment of prepandemic patterns, including a return toward the typical age distribution during early childhood.

Background: Severe fever with thrombocytopenia syndrome (SFTS), an emerging tick-borne viral hemorrhagic fever, is characterized by high mortality rates. While neurological complications (eg, seizures, encephalitis) have been identified as adverse prognostic factors in severe cases, their association with viral replication, immune responses, and neuroinflammation remain poorly defined and urgently require systematic investigation.

Method: A cohort of 277 patients with SFTS was included and stratified based on neurological symptoms. Clinical characteristics, laboratory results, and immune markers were compared between groups.

Results: Neurological symptoms developed in 78 (28.2%) patients and were associated with significantly higher 28-day mortality. These patients had higher viral loads, elevated inflammatory cytokines (IL-6, IL-10, TNF-α, and ferritin), and more severe multi-organ dysfunction. Compared with survivors, nonsurvivors showed reduced platelet and T-cell counts, and disregulated B-cell subsets with increased plasmablasts and double-negative B cells. Viral load correlated with cytokine elevation, coagulopathy (prolonged APTT), and renal impairment (reduced eGFR). Multivariate Cox proportional hazards regression identified neurological symptoms (HR = 2.565; 95% CI: 1.641-4.011; P < .001) and viral load (HR = 1.785 per log₁₀ increase; 95% CI: 1.503-2.120; P < .001) as independent predictors of mortality.

Conclusions: Neurological manifestations and elevated viral load play a central role in the progression of SFTS and are closely associated with adverse clinical outcomes. Considering neurological symptoms and immune profiles in prognostic assessments may improve early recognition of high-risk patients and inform clinical management.

Background: Mucormycosis is a severe fungal infection that is challenging to diagnose as traditional methods lack sensitivity and serological testing is unavailable. This study aimed to evaluate the MucorGenius® PCR assay on respiratory and biopsy samples from high-risk patients with probable/proven invasive pulmonary aspergillosis (IPA), mucormycosis, or possible invasive mold infections (IMIs).

Methods: This multicenter cohort study was conducted across 4 sites in Austria, Belgium and the UK. A total of 132 respiratory and biopsy samples from 114 patients with IMI diagnosed in clinical routine (10 proven IPA, 13 proven mucormycosis, 62 probable IPA, 5 probable mucormycosis, and 35 possible IMI according to EORTC/MSGERC 2020 and FUNDICU criteria; 11 IPA/mucormycosis coinfections) were analyzed using the MucorGenius® PCR assay in ISO-certified laboratories. Results were compared with standard fungal diagnostics.

Results: Mucorales DNA was detected in 37/132 samples (28%) including 29 BAL fluids, 1 bronchial aspirate, 1 endotracheal aspirate, and 6 biopsies from 37 patients. Sensitivity was 94.4% (17/18) for detecting probable/proven mucormycosis (including 11 cases routinely diagnosed with IPA/mucormycosis coinfection). Among 72 patients with probable/proven IPA, 21 (29.2%) tested positive for Mucorales DNA, including 11 missed by routine diagnostics. Mucorales DNA was also detected in 9/35 (25.7%) of patients with possible IMI.

Conclusions: MucorGenius® PCR showed high sensitivity for detecting Mucorales and may support improved diagnosis of probable mucormycosis when included as a mycological criterion. It appears particularly valuable for identifying Aspergillus-Mucorales coinfections and detecting mucormycosis in patients with host factors, clinical or radiological evidence of IMI when routine diagnostics are negative.

Background: Licensed recombinant protein respiratory syncytial virus (RSV) vaccines can prevent substantial morbidity in older adults. However, revaccination to prevent waning protection may be suboptimal, prompting the exploration of candidates for heterologous boosting. In this clinical trial of RSV vaccine-naive older adults, we evaluated SCB-1019T, a novel unadjuvanted bivalent RSV prefusion F (preF) protein vaccine stabilized via Trimer-Tag technology, in comparison to the licensed AS01_E-adjuvanted RSV vaccine Arexvy.

Methods: In this phase 1, randomized, placebo-controlled, observer-blind study, after proof-of-concept assessments in young adults (18-59 years) and older adults (60-85 years), we administered 1 dose of SCB-1019T (n = 30), Arexvy (n = 30), or placebo (n = 10) to older adults (60-85 years). Safety, reactogenicity, and immunogenicity were assessed up to 28 days postvaccination.

Results: SCB-1019T had a more favorable local safety profile, with fewer recipients reporting injection-site reactions than Arexvy recipients (17% vs 77%), whereas systemic adverse events were similar (43% vs 50%, respectively). Injection-site reactions and systemic adverse events were mild and transient, and no safety concerns were identified for SCB-1019T or Arexvy. Importantly, SCB-1019T induced similar (∼7-fold) increases of RSV-A and RSV-B neutralizing antibody titers to Arexvy. Moreover, exploratory results indicated that SCB-1019T induced potent antibodies to 3 key neutralization epitopes.

Conclusions: In older adults, SCB-1019T had an acceptable and favorable safety profile. The humoral immunogenicity SCB-1019T was similar to that of Arexvy, which contains the potent AS01_E adjuvant. Therefore, this phase 1 study supports further development of SCB-1019T, notably in heterologous booster settings.