Open Forum Infectious Diseases最新文献

Background: The enteric parasite Cryptosporidium remains a treatment challenge for drinking water utilities globally due to its resistance to chlorine disinfection. However, the lack of an in vitro culture system for Cryptosporidium that is both cost-effective and reliable remains a key bottleneck in Cryptosporidium research.

Methods: Here we report that the microfluidic culture of human ileocecal colorectal adenocarcinoma (HCT-8) cells under fluid shear stress enables the extended development of Cryptosporidium parvum. Specifically, the growth of C. parvum in a user-friendly pumpless microfluidic device was assessed using immunofluorescence assays, scanning electron microscopy, and quantitative polymerase chain reaction, which revealed that development continued for 10 days in total.

Results: Oocysts produced within the microfluidic device were infective to fresh HCT-8 monolayers; however, these oocysts were only present at low levels.

Conclusions: We anticipate that such microfluidic approaches will facilitate a wide range of in vitro studies on Cryptosporidium and may have the potential to be further developed as a routine infectivity assessment tool for the water industry.

Background: Severe coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome (MIS-C) are characterized by excessive inflammatory cytokines/chemokines. In adults, disease severity is associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunoglobulin G (IgG) Fc afucosylation, which induces proinflammatory cytokine secretion from innate immune cells. This study aimed to define spike IgG Fc glycosylation following SARS-CoV-2 infection in adults and children and following SARS-CoV-2 vaccination in adults and the relationships between glycan modifications and cytokines/chemokines.

Methods: We analyzed longitudinal (n = 146) and cross-sectional (n = 49) serum/plasma samples from adult and pediatric COVID-19 patients, MIS-C patients, adult vaccinees, and adult and pediatric controls. We developed methods for characterizing bulk and spike IgG Fc glycosylation by capillary electrophoresis and measured levels of 10 inflammatory cytokines/chemokines by multiplexed enzyme-linked immunosorbent assay.

Results: Spike IgG was more afucosylated than bulk IgG during acute adult COVID-19 and MIS-C. We observed an opposite trend following vaccination, but it was not significant. Spike IgG was more galactosylated and sialylated and less bisected than bulk IgG during adult COVID-19, with similar trends observed during pediatric COVID-19/MIS-C and following SARS-CoV-2 vaccination. Spike IgG glycosylation changed with time following adult COVID-19 or vaccination. Afucosylated spike IgG exhibited inverse and positive correlations with inflammatory markers in MIS-C and following vaccination, respectively; galactosylated and sialylated spike IgG inversely correlated with proinflammatory cytokines in adult COVID-19 and MIS-C; and bisected spike IgG positively correlated with inflammatory cytokines/chemokines in multiple groups.

Conclusions: We identified previously undescribed relationships between spike IgG glycan modifications and inflammatory cytokines/chemokines that expand our understanding of IgG glycosylation changes that may impact COVID-19 and MIS-C immunopathology.

[This corrects the article DOI: 10.1093/ofid/ofae539.].

The 2022 monkeypox virus (MPXV) outbreaks spurred global public health concern. In response, we undertook a living systematic review of its zoonotic characteristics, including potential reservoirs and susceptible species, transmissibility, and clinical presentation in nonhuman species. Electronic database searches yielded 148 eligible records published between 2000 and 2022. Primary reservoirs remain unidentified, with natural isolation identified in 2 species, the sooty mangabey monkey and rope squirrel. Transmission primarily occurs from animals to humans, but evidence of reverse zoonosis has emerged. Data on clinical infection and manifestations are sparse, with evidence of potentially susceptible species drawn primarily from experimental studies. Only 10% of articles were appropriate for quality assessment and most of these were rated as critically low. Overall, while evidence regarding MPXV exists, the quality of data are extremely poor, resulting in significant uncertainty regarding MPXV's zoonotic traits. High-quality empirical research to understand the impact of MPXV on animal and human populations is warranted.

This study showed that a severe acute respiratory syndrome coronavirus 2 infection reduced the risk of reinfection among vaccinated individuals by 0.50 (95% CI, 0.39-0.64) over a 1-year period, after accounting for unreported infections using avidity-based serology. Reciprocally, chronic symptoms increased from a baseline of 21% (95% CI, 16%-28%) among infection-naïve individuals to 43% (95% CI, 30%-61%) in reinfected individuals.

The 2022 mpox epidemic predominantly affected gay, bisexual, and other men who have sex with men (GBM). Led by a provincial community program and co-galvanized by clinician-researchers, GBM community leaders in Ontario coordinated a robust response, representing a reproducible strategy for community engagement and mobilization during future epidemics.

Background: The standard of care for Lassa fever is the use of ribavirin with supportive therapy. There is little information on the course of viremia and its relationship with clinical outcomes in patients treated with ribavirin.

Methods: We conducted a retrospective analysis of virologic and clinical parameters of 152 reverse transcription polymerase chain reaction-confirmed Lassa fever cases admitted and treated with ribavirin therapy. We describe the Lassa virus RNA kinetics in blood in relation to the clinical course of the patients.

Results: The overall mortality was 9%. The median duration (interquartile range [IQR]) of illness before admission was 8 (5-12) days. Median (IQR) Ct values on admission (t₀ ) were lower among patients who died (21 [20-27]) than in those who survived (34 [30-37]; P < .01). The receiver operating characteristics curve of the association between outcome and Ct value at t₀ had a high classification performance, with an AUC of 0.92 (95% CI, 0.86-0.98). The median time to viral clearance (IQR) was 10 (5-15) days. The viral load decreased steadily with the duration of treatment, and all survivors achieved viral clearance within 25 days of hospitalization.

Conclusions: Our study demonstrates that the Ct value on admission has prognostic value and Lassa fever patients treated with ribavirin typically clear the virus within 3-4 weeks of hospitalization. This kinetics has implications for the design of clinical case management and future clinical trial protocols.

Background: The World Health Organization is pushing to accelerate the study of new human immunodeficiency virus drugs in pregnant women. However, regulatory guidelines do not specify when to conduct pharmacokinetic studies in postpartum women. This knowledge gap carries the potential to jeopardize the outcomes and conclusions of clinical trials aiming to study the effect of pregnancy on drug exposure. We used physiologically based pharmacokinetic (PBPK) modeling along with clinical data to determine the time needed after delivery for drug exposure to return to prepregnancy levels.

Methods: A literature review was conducted to collect physiological parameters of pregnant and postpartum women. Regression analyses were performed to derive equations describing the parameters trajectory throughout pregnancy and post partum to inform our PBPK model. Published pharmacokinetic data in pregnant and postpartum women were used for the model verification. The PBPK model was subsequently applied to investigate pharmacokinetic changes throughout pregnancy and post partum.

Results: In agreement with the clinical data the PBPK model was able to describe the different effects of pregnancy on drug exposure, with bictegravir showing the largest reduction in exposure (approximately 50%) during the third trimester while ritonavir and raltegravir showing the lowest (approximately 30%). The successfully verified PBPK model predicted that all evaluated antiretrovirals mostly return to prepregnancy exposure 4 weeks after delivery.

Conclusions: Pharmacokinetic investigations on hepatically cleared drugs should not be conducted before the fifth week after delivery to fully characterize the effect of pregnancy on drug exposure. Because physiological changes remain after delivery, early measurements can underestimate the pregnancy effect on pharmacokinetics, leading to suboptimal dosing recommendations during pregnancy.

Migration routes determine exposure to endemic infections. We present a case of complex cutaneous leishmaniasis in a man with HIV infection who migrated to the United States from Haiti, where Leishmania is uncommon, acquiring leishmaniasis while on his journey via South America and Central America. His presentation included hyperpigmented, nonulcerated plaques and nodules on his extremities, chest, back, face, palms, and soles; initially he had no mucosal lesions. Infection with Leishmania panamensis was confirmed via polymerase chain reaction. He was prescribed bictegravir/tenofovir alafenamide/emtricitabine with rapid suppression of HIV and liposomal amphotericin B for diffuse cutaneous leishmaniasis with a limited initial response. He subsequently developed mucosal lesions in the setting of immune reconstitution and was retreated with amphotericin dosed for mucocutaneous disease. A thorough migration history was critical to diagnosis. This case highlights the different presentations of leishmaniasis in people with HIV and the elevated risk for treatment failure.