Open Forum Infectious Diseases最新文献

Background: Enterovirus D68 (EV-D68) is associated with severe respiratory disease and acute flaccid myelitis (AFM). The 2022 outbreaks showed increased viral circulation and hospital admissions, but the expected rise in AFM cases did not occur. We analyzed EV-D68 genomes and infection outcomes from 2022 (a year without a national increase in AFM cases) and 2018 (a year with a national surge in AFM cases) to understand how viral genomic changes might influence disease outcomes.

Methods: Residual respiratory samples that tested positive for rhinovirus/enterovirus at the Johns Hopkins Health System between 2018 and 2022 were collected for EV-D68 polymerase chain reaction, genotyping, and whole genome sequencing. Clinical and metadata were collected in bulk from the electronic medical records.

Results: A total of 351 EV-D68 cases were identified, with most cases in children aged <5 years. Infections in 2018 were associated with higher odds of hospital admissions and intensive care unit care. Of 272 EV-D68 genomes, subclades B3 and A2/D1 were identified with B3 predominance (95.2%). A comparative analysis of the 2018 and 2022 whole genomes identified a cluster of amino acids (554D, 650T, 918T, 945N, 1445I, 1943I) that was associated with higher odds of severe outcomes.

Conclusions: Our results show significant differences in the clinical outcomes of EV-D68 infections in 2018 and 2022 and highlight a 2018 cluster of genomic changes associated with these differences. Seasonal viral genomic surveillance-with in vitro characterization of the significance of these changes to viral fitness, immune responses, and neuropathogenesis-should shed light on the viral determinants of AFM.

Background: Kaposi sarcoma (KS) is a marker of advanced HIV disease; it is still the most frequent AIDS-associated malignancy in Mexico despite universal access to antiretroviral therapy, reflecting a gap in early HIV diagnosis.

Methods: The objectives of the study were to describe people with HIV with KS who died within 30 days of admission at INCan (National Cancer Institute) and to quantify resources and years of life lost (YLL). We collected demographic data, HIV-related variables, all diagnostic and therapeutic procedures, hospitalizations, and estimated YLL and disability-adjusted life years.

Results: Eighteen (6.7%) people with HIV with KS from 270 patients admitted at INCan from 2014 to 2021 were included. The median age was 31 years (IQR 27-36), and the median days from admission to death and from HIV diagnosis to death were 15 (IQR, 6-24) and 73 (IQR, 30-857), respectively. Upon admission, the median HIV viral load was 314 476 copies/mL (IQR, 140 709-695 613); CD4+ T cells, 93 cells/mL (IQR 35-124); and CD4/CD8 ratio, 0.08 (IQR, 0.06-0.12). Coinfections were diagnosed in 14 (77.7%) patients. The average expenditure per patient was US $7685.99 USD, and the total YLL was 737.4 with a median 42 years (IQR, 37.7-47) per patient. The total care cost was US $183 947.48, equivalent to a screening program in key populations, which would have allowed the early detection of 1227 cases and saved 8410 disability-adjusted life years.

Conclusions: Reinforcement of early HIV infection detection in key population programs should be prioritized to reduce KS-associated deaths and YLL and for rational use of health budgets.

Background: Melioidosis, attributable to the soil-dwelling bacterium Burkholderia pseudomallei, stands as a paramount global health challenge, necessitating extended courses of antibiotics. While murine studies identified the gut microbiota as a modulator of bacterial dissemination during melioidosis, the human intestinal microbiota during melioidosis remains uncharacterized. Here, we characterized gut microbiota composition and antimicrobial resistance (AMR) genes at diagnosis, during treatment, and postdischarge for melioidosis. We hypothesized that the gut microbiota of melioidosis patients would be extensively distorted.

Methods: In this prospective observational cohort, stool samples of patients with culture-confirmed melioidosis admitted to a tertiary care hospital in India were collected at diagnosis, 14 days after diagnosis, or discharge (whichever occurred first) and at 6 months postinfection. Family members or neighbors served as community controls. The gut microbiota and resistome were profiled by shotgun metagenomic sequencing.

Results: We longitudinally analyzed the gut microbiota of 70 fecal samples from 28 patients and 16 community controls. At diagnosis, the gut microbiota of patients differed from that of controls, characterized by high abundances of potentially pathogenic bacteria, a loss of butyrate-producing bacteria, and higher levels of AMR genes. Microbiota composition and resistome remained different from community controls at 6 months, driven by total antibiotic exposure. During hospitalization, gut microbiota profiles were associated with secondary Klebsiella pneumoniae infections.

Conclusions: This first study on gut microbiota composition and resistome in human melioidosis showed extensive disruptions during hospitalization, with limited signs of restoration 6 months postinfection. Given the adverse outcomes linked with microbiome perturbations, limiting microbiota disruptions or using microbiota-restorative therapies (eg, butyrate-producing probiotics) may be beneficial.

Background: 4CMenB appears to be effective in reducing Neisseria gonorrhoeae (Ng) infections. Aims are to assess factors associated with breakthrough rectal Ng after 4CMenB and evaluate clinical and microbiological characteristics of breakthrough infections compared with before vaccination.

Methods: This was a retrospective study of gay, bisexual, and other men who have sex with men (GBMSM) vaccinated with 4CMenB (2 doses) between 2017 and 2023 at the San Raffaele Scientific Institute for Research, Hospitalization and Healthcare (IRCCS San Raffaele Scientific Institute), Milan, Italy, and tested for rectal Ng. Rectal Ng infection is considered breakthrough if it occurs >1 month after the second 4CMenB dose and with positive nucleic acid amplification test (NAAT) result. Follow-up was from July 2017 (first 4CMenB vaccination) to November 2023 (data freeze). Rectal Ng was screened with both NAAT and gonococcal-specific cultures. Characteristics of individuals with or without breakthrough Ng and of Ng infections before or after 4CMenB were compared using Mann-Whitney and χ²/Fisher tests.

Results: Overall, 473 GBMSM vaccinated with 4CMenB were included, with a median age (interquartile range) of 43 (37-51) years; 451 of 473 were living with human immunodeficiency virus. The percentage of NAAT-positive rectal Ng swab samples was 76 of 957 (7.7%) after 4CMenB and 51 of 456 (11.1%) before. Breakthrough rectal Ng after baseline were 76 in 57 of 473 people. People with rectal Ng after 4CMenB were younger, more likely to have a previous sexually transmitted infection, and had more sexual partners than those without (all P < .001). Breakthrough rectal Ng infections were less frequently symptomatic (34.2% vs 66.7%; P = .001) and more likely with negative gonococcal-specific culture (55.3% vs 19.6%; P < .001) compared with before vaccination.

Conclusions: Breakthrough rectal Ng infections after 4CMenB were 76 in 57/473 people, preferentially identified in GBMSM with higher-risk sexual behaviors, were less often symptomatic, and more often with negative gonococcal-specific cultures, suggesting lower infection virulence.

Following recent reports of norovirus replication in salivary gland cells, we examined whether the prototype norovirus strain, Norwalk virus (GI.1), could be detected in the saliva of 21 experimentally infected persons. Viral RNA was not detected in saliva 2 and 7 days after challenge despite high levels being present in feces.

The activity of isavuconazole and other triazoles against non-fumigatus (non-AFM) Aspergillus causing invasive aspergillosis was evaluated. A total of 390 non-AFM isolates were collected (1/patient) in 2017-2021 from 41 hospitals. Isolates were identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry and/or internal spacer region/β-tubulin sequencing and tested by Clinical and Laboratory Standards Institute (CLSI) broth microdilution. CLSI epidemiological cutoff values were applied, where available. Isavuconazole showed activity against Aspergillus sections Flavi (n = 122; minimum inhibitory concentration [MIC]_50/90, 0.5/1 mg/L), Terrei (n = 57; MIC_50/90, 0.5/0.5 mg/L), Nidulantes (n = 34; MIC_50/90, 0.12/0.25 mg/L), Versicolores (n = 7; MIC₅₀, 1 mg/L), and Circumdati (n = 2; MIC range, 0.12-2 mg/L). Similar activity was displayed by other triazoles against those Aspergillus sections. Most of the isolates from Aspergillus sections Fumigati (n = 9), Nigri (n = 146), and Usti (n = 12) exhibited elevated MIC values to isavuconazole (MIC_50/90, 2/-, 2/4, and 2/8 mg/L), voriconazole (MIC_50/90, 2/-, 1/2, and 4/8 mg/L), itraconazole (MIC_50/90, 2/-, 2/4, and 8/>8 mg/L), and posaconazole (MIC_50/90, 0.5/-, 0.5/1, and >8/>8 mg/L), respectively. Isavuconazole was active (MIC values, ≤1 mg/L) against Aspergillus parasiticus, Aspergillus tamarii, Aspergillus nomius, Aspergillus nidulans, Aspergillus unguis, Aspergillus terreus, Aspergillus alabamensis, and Aspergillus hortai, while isavuconazole MIC values between 2 and 8 mg/L were observed against cryptic isolates from Aspergillus section Fumigati. Isavuconazole inhibited 96.1% of Aspergillus niger and 80.0% of Aspergillus tubingensis at ≤4 mg/L, the CLSI wild-type cutoff value for A niger. Voriconazole, itraconazole, and posaconazole showed similar activity to isavuconazole against most cryptic species. Isavuconazole exhibited potent in vitro activity against non-AFM; however, the activity of triazoles varies among and within cryptic species.

The global burden of invasive fungal disease is substantial and escalating. Combination antifungal therapy (CAF) may improve patient outcomes by reducing development of resistance, improving drug penetration and rate of fungal clearance, and allowing for lower and less toxic antifungal drug doses; yet, increased cost, antagonism, drug-drug interactions, and toxicity are concerns. Clinical practice guidelines recommend antifungal monotherapy, rather than CAF, for most invasive fungal diseases due to a lack of comparative randomized clinical trials. An examination of the existing body of CAF research should frame new hypotheses and determine priorities for future CAF clinical trials. We performed a systematic review of CAF clinical studies for invasive candidiasis, cryptococcosis, invasive aspergillosis, and mucormycosis. Additionally, we summarized findings from animal models of CAF and assessed laboratory methods available to evaluate CAF efficacy. Future CAF trials should be prioritized according to animal models showing improved survival and observational clinical data supporting efficacy and safety.

Background: Co-inhibitory receptors (immune checkpoints) regulate activated immune cells. Their expression on T cells can limit host defense. We hypothesized that chronic Leishmania donovani infection in patients with visceral leishmaniasis (VL) leads to expression of co-inhibitory receptors that could be markers of treatment response and clinical outcome.

Method: A prospective cohort of 21 subjects with VL (7 with HIV coinfection) and 10 controls was established to measure T-cell expression of co-inhibitory receptors (PD-1, Tim-3, LAG-3, CTLA-4, and TIGIT) by flow cytometry in discarded remnants of diagnostic splenic or bone marrow aspirates and peripheral blood collected before and after treatment. Plasma levels of soluble co-inhibitory proteins (sPD-1, sTim-3, sLAG-3, and sCTLA-4) and selected cytokines were determined by immunoassay.

Results: Expression of co-inhibitory receptors in peripheral blood T cells generally reflected findings in spleen and bone marrow aspirates. PD-1 and Tim-3 were upregulated in CD4+ T cells in HIV-negative and HIV-positive subjects with VL compared to controls. CD8+ T cells from HIV-negative subjects with VL displayed a similar pattern. Plasma levels of sPD-1 and sTim-3 were also greater in VL patients than controls. CD8+ and CD4+ T cells coexpressing PD-1 and Tim-3 showed considerable decline with treatment. Mortality in HIV-negative VL patients was associated with increased CD8+ T cells coexpressing Tim-3 and PD-1, triple-positive CD4+ and CD8+ T cells (PD-1⁺Tim-3⁺LAG-3⁺), and elevated sLAG3.

Conclusions: Tim-3 and PD-1 expression on CD4+ and CD8+ T cells, and increased plasma sLAG-3, were markers of treatment response and clinical outcome in patients with VL.

We report a case of fulminant Mucorales fungemia in a heavily immunosuppressed cancer patient with hemophagocytic lymphohistiocytosis following CD70-targeted chimeric antigen receptor T-cell therapy. Although rare, Mucorales can cause true fungemia in a broad spectrum of hosts, with a range of manifestations from isolated fungemia to fungemia being part of widely disseminated, high-burden infection.

Outpatient parenteral antimicrobial therapy (OPAT) has become more common in infectious diseases practice settings. Similarly, OPAT-related publications have also increased. The objective of this article was to summarize clinically important OPAT-related publications from 2023. Eighty-one articles were found on initial search, with 52 meeting inclusion criteria. A survey containing the 19 articles that had at least 1 citation was sent to an email listserv of multidisciplinary clinicians with OPAT experience. This article summarizes the "top 10" 2023 OPAT articles from the survey results.