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Progress and Challenges in the Prevention, Diagnosis, and Management of Cytomegalovirus Infection in Transplantation

Clin Microbiol Rev

2021 Michael Boeckh

SUMMARYHosts with compromised or naive immune systems, such as individuals living with HIV/AIDS, transplant recipients, and fetuses, are at the highest risk for complications from cytomegalovirus (CMV) infection. Despite substantial progress in prevention, diagnostics, and treatment, CMV continues to negatively impact both solid-organ transplant (SOT) and hematologic cell transplant (HCT) recipients. In this article, we summarize important developments in the field over the past 10 years and highlight new approaches and remaining challenges to the optimal control of CMV infection and disease in transplant settings.

Infectious Disease Complications in Patients with Cancer

Crit Care Clin

2021 Catherine Liu

Critically ill patients with cancer are vulnerable to infections because of the underlying malignancy, tumor-directed therapy, immunosuppression, breaches in mucosa or skin, malnutrition, and other factors. Neutropenia remains the most important risk factor for infection. Infectious complications occurring in critically ill patients with cancer can affect the bloodstream, lungs, gastrointestinal tract, central nervous system, urinary tract, and the skin. Pneumonias are the leading cause of infection in patients with cancer admitted to the intensive care unit. Consideration of opportunistic pathogens in the differential diagnosis is important in patients with impaired cellular and/or humoral immunity or compromised splenic function.

Risk Factors for Cytomegalovirus Reactivation and Association with Outcomes in Critically Ill Adults with Sepsis: A Pooled Analysis of Prospective Studies

J Infect Dis

2020 Ying Chen; Michael Boeckh; Hannah Imlay; Sayan Dasgupta

We performed a multivariable analysis of potential risk factors (including CMV reactivation) for clinical outcomes by day 28 (death or continued hospitalization, ventilator-free days [VFD], ICU-free days [ICUFD], hospital free days [HFD]) from pooled cohorts of two previous prospective studies of CMV seropositive adults with sepsis. CMV reactivation at any level, >100, >1,000 IU/mL, peak viral load, and area under the curve were independently associated with the clinical outcomes. We identified the potential effect size of CMV on outcomes that could be used as endpoints for future interventional trials of CMV prevention using antiviral prophylaxis in ICU patients with sepsis.

Human Metapneumovirus Infection and Genotyping of Infants in Rural Nepal

J Pediatric Infect Dis Soc

2020 Keith Jerome; Janet Englund

BACKGROUND: Acute respiratory tract infections are a serious clinical burden in infants; human metapneumovirus (HMPV) is an important etiological agent. We investigated genotypic variation and molecular epidemiological patterns among infants infected with HMPV in Sarlahi, Nepal, to better characterize infection in a rural, low-resource setting. METHODS: Between May 2011 and April 2014, mid-nasal swabs were collected from 3528 infants who developed respiratory symptoms during a longitudinal maternal influenza vaccine study. Sequencing glycoprotein genes permitted genotyping and analyses among subtypes. RESULTS: HMPV was detected by reverse-transcriptase polymerase chain reaction (RT-PCR) in 187 (5%) infants, with seasonality observed during fall and winter months. Phylogenetic investigation of complete and partial coding sequences for the F and G genes, respectively, revealed that 3 genotypes were circulating: A2, B1, and B2. HMPV-B was most frequently detected with a single type predominating each season. Both HMPV genotypes exhibited comparable median viral loads. Clinically significant differences between genotypes were limited to increased cough duration and general respiratory symptoms for type B. CONCLUSIONS: In rural Nepal, multiple HMPV genotypes circulate simultaneously with an alternating predominance of a single genotype and definitive seasonality. No difference in viral load was detected by genotype and symptom severity was not correlated with RT-PCR cycle threshold or genotype.

Liquid biopsy for invasive mold infections in hematopoietic cell transplant recipients with pneumonia through next-generation sequencing of microbial cell-free DNA in plasma

Clin Infect Dis

2020 Joshua Hill; Jacob Keane-Candib; Michael Boeckh; Terry Stevens-Ayers; Cynthia Fisher; Joyce Maalouf

BACKGROUND: Non-invasive diagnostic options are limited for invasive mold infections (IMI). We evaluated the performance of a plasma microbial cell-free DNA sequencing (mcfDNA-Seq) test for diagnosing pulmonary IMI after hematopoietic cell transplant (HCT). METHODS: We retrospectively assessed the diagnostic performance of plasma mcfDNA-Seq NGS in 114 HCT recipients with pneumonia after HCT who had stored plasma obtained within 14 days of diagnosis of Proven/Probable Aspergillus IMI (n=51), Proven/Probable non-Aspergillus IMI (n=24), Possible IMI (n=20), and non-IMI controls (n=19). Sequences were aligned to a database including >400 fungi. Organisms above a fixed significance threshold were reported. RESULTS: Among 75 patients with Proven/Probable pulmonary IMI, mcfDNA-Seq detected 1 pathogenic mold in 38 patients (sensitivity, 51%; 95% CI, 39%-62%). When restricted to samples obtained within 3 days of diagnosis, sensitivity increased to 61%. McfDNA-Seq had higher sensitivity for Proven/Probable non-Aspergillus IMI (sensitivity, 79%; 95% CI, 56%-93%) compared to Aspergillus IMI (sensitivity, 31%; 95% CI, 19%-46%). McfDNA-Seq also identified non-Aspergillus molds in an additional 7 patients in the Aspergillus subgroup and Aspergillus in 1 patient with Possible IMI. Among 19 non-IMI pneumonia controls, mcfDNA-Seq was negative in all samples suggesting a high specificity (95% CI, 82%-100%) and up to 100% positive predictive value (PPV) with estimated negative predictive values (NPV) of 81%-99%. The mcfDNA-seq assay was complementary to serum GMI testing; in combination, they were positive in 84% of individuals with Proven/Probable pulmonary IMI. CONCLUSIONS: Non-invasive mcfDNA-Seq had moderate sensitivity and high specificity, NPV, and PPV for pulmonary IMI after HCT, particularly for non-Aspergillus.

Bacterial communities associated with abnormal Nugent score are different in pre- versus postmenopausal women

J Infect Dis

2020 Sujatha Srinivasan; Tina Fiedler; Noah Hoffman; Susan Reed; Katherine Guthrie; Daniel Valint; Sean Proll; Michael Wu; David Fredricks

Nugent score is the gold standard for bacterial vaginosis (BV) diagnosis but has not been validated in postmenopausal women. We compared relative abundances from 16S rRNA gene sequencing of vaginal microbiota with Nugent score in cohorts of premenopausal (n = 220) and postmenopausal (n = 144) women. In premenopausal women 33 taxa were significantly correlated with Nugent score, including the classic BV-associated taxa Gardnerella, Atopobium, Sneathia, Megasphaera and Prevotella. In postmenopausal women, 11 taxa were significantly associated with Nugent score, including Prevotella but no other BV-associated genera. High Nugent score should not be used to infer BV in postmenopausal women.

COVID-19 - Lessons Learned and Questions Remaining

Clin Infect Dis

2020 David Fredricks

In this article, the editors of Clinical Infectious Diseases review some of the most important lessons they have learned about the epidemiology, clinical features, diagnosis, treatment and prevention of SARS-CoV-2 infection and identify essential questions about COVID-19 that remain to be answered.

Potency and timing of antiviral therapy as determinants of duration of SARS-CoV-2 shedding and intensity of inflammatory response

Sci Adv

2020 Ashish Goyal; Joshua Schiffer; Erwing Cardozo Ojeda

To impact the COVID-19 pandemic, lifesaving antiviral therapies must be identified. The number of clinical trials that can be performed is limited. We developed mathematical models to project multiple therapeutic approaches. Our models recapitulate off-treatment viral dynamics and predict a three-phase immune response. Simulated treatment with remdesivir, selinexor, neutralizing antibodies or cellular immunotherapy demonstrates that rapid viral elimination is possible if in vivo potency is sufficiently high. Therapies dosed soon after peak viral load when symptoms develop, may decrease shedding duration and immune response intensity, but have little effect on viral area under the curve (AUC), which is driven by high early viral loads. Potent therapy dosed prior to viral peak during pre-symptomatic infection, could lower AUC. Drug resistance may emerge with a moderately potent agent dosed before viral peak. Our results support early treatment for COVID-19 if shedding duration and not AUC is most predictive of clinical severity.

Sensitive recovery of complete SARS-CoV-2 genomes from clinical samples using Swift Biosciences' SARS-CoV-2 multiplex amplicon sequencing panel

J Clin Microbiol

2020 Keith Jerome; Alex Greninger; Pavitra Roychoudhury

Whole genome sequencing (WGS) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a better understanding of the virus's origin, transmission, and evolution (1-6).….

The Seattle Flu Study: a multiarm community-based prospective study protocol for assessing influenza prevalence, transmission and genomic epidemiology

BMJ Open

2020 Debbie Nickerson; Lea Starita; Jay Shendure; Trevor Bedford; Michael Boeckh; Louise Kimball; Thomas Sibley; Janet Englund

INTRODUCTION: Influenza epidemics and pandemics cause significant morbidity and mortality. An effective response to a potential pandemic requires the infrastructure to rapidly detect, characterise, and potentially contain new and emerging influenza strains at both an individual and population level. The objective of this study is to use data gathered simultaneously from community and hospital sites to develop a model of how influenza enters and spreads in a population. METHODS AND ANALYSIS: Starting in the 2018-2019 season, we have been enrolling individuals with acute respiratory illness from community sites throughout the Seattle metropolitan area, including clinics, childcare facilities, Seattle-Tacoma International Airport, workplaces, college campuses and homeless shelters. At these sites, we collect clinical data and mid-nasal swabs from individuals with at least two acute respiratory symptoms. Additionally, we collect residual nasal swabs and data from individuals who seek care for respiratory symptoms at four regional hospitals. Samples are tested using a multiplex molecular assay, and influenza whole genome sequencing is performed for samples with influenza detected. Geospatial mapping and computational modelling platforms are in development to characterise the regional spread of influenza and other respiratory pathogens. ETHICS AND DISSEMINATION: The study was approved by the University of Washington's Institutional Review Board (STUDY00006181). Results will be disseminated through talks at conferences, peer-reviewed publications and on the study website (<a href="http://www.seattleflu.org">www.seattleflu.org</a>).