Elucidating the Clinical Interpretation and Impact of a Positive Plasma Cell-Free DNA Metagenomics Test Result—A Single Center Retrospective Study

BackgroundThe Karius Test (KT), a cell-free DNA metagenomic next-generation sequencing assay, has potential to improve diagnostic evaluation of infectious diseases. Published data describing clinical impact of positive KT results are limited. We attempt to elucidate the clinical interpretation and impact of positive KT results based on types and patterns of detected pathogens and patient characteristics.MethodsAll positive KT results from a single institution in 2022 were screened. Patients with results that met predefined categories were included for review by a panel of 3 infectious diseases physicians and one clinical microbiologist. Predefined categories included reports with fungal, parasitic, notable bacterial, notable viral pathogens, or polybacterial results (≥3 bacteria). Polybacterial results were further classified into patterns of microbiome detected. Clinical impact and its correlation with result or patient characteristics were explored.ResultsNinety-two patients met the inclusion criteria, most were immunocompromised (73%). Positive KT results that met predefined categories had the following clinical impact: positive in 30.4%, negative in 2.2%, and none in 65.2%. Polybacterial results, especially interpreted as oral flora had lowest clinical impact (7.1% and 0.0%, respectively), while detection of parasites or notable bacterial pathogens had the highest clinical impact (100% and 77.8%, respectively). There was no correlation between patient characteristics and clinical impact.ConclusionsAmong a cohort of largely immunocompromised patients, we were able to demonstrate clinical impact of specific KT result types and patterns but did not find correlation between patient characteristics and clinical impact. Our results should be confirmed in future larger cohorts

Multi-Year Analysis of Respiratory Viral Dynamics Reveals Significance of Rhinovirus in Young Children with Severe Respiratory Illness

Objectives: We aimed to analyze the landscape of viral respiratory illnesses (VRIs) in a large metropolitan area in Southern California with a focus on the COVID-19 pandemic. Methods: We conducted a retrospective cohort study within the UCLA Health System, which evaluated children aged 0-5 years who received comprehensive respiratory viral panel (cRVP) testing during August-February of 2018-2023. The patient demographics, disease severity, and clinical course were specifically compared during the pandemic. Predictors of significant VRI were determined by multivariate logistic regression. Results: A total of 1321 children underwent cRVP testing, and 753 positive subjects were identified during the study period. Rhinovirus (RV) was by far the most frequent virus detected across 5 years, even during the COVID-19 pandemic, followed by respiratory syncytial virus (RSV). Along with RSV and human metapneumovirus, RV was identified as an independent risk for significant disease and occurred irrespective of co-infection with other viruses. Conclusions: RV was the most common viral pathogen in young children, even during the height of the COVID-19 pandemic, and was an independent driver of moderate-to-severe disease, particularly in children with comorbidities. Ethnic disparities were also observed as a risk for significant disease, underscoring the need for targeted interventions and heightened clinical vigilance in pediatric populations

Real-world clinical impact of plasma cell-free DNA metagenomic next-generation sequencing assay.

To describe the real-world clinical impact of a commercially available plasma cell-free DNA metagenomic next-generation sequencing assay, the Karius test (KT). We retrospectively evaluated the clinical impact of KT by clinical panel adjudication. Descriptive statistics were used to study associations of diagnostic indications, host characteristics, and KT-generated microbiologic patterns with the clinical impact of KT. Multivariable logistic regression modeling was used to further characterize predictors of higher positive clinical impact. We evaluated 1000 unique clinical cases of KT from 941 patients between January 1, 2017-August 31, 2023. The cohort included adult (70%) and pediatric (30%) patients. The overall clinical impact of KT was positive in 16%, negative in 2%, and no clinical impact in 82% of the cases. Among adult patients, multivariable logistic regression modeling showed that culture-negative endocarditis (OR 2.3; 95% CI, 1.11-4.53; P .022) and concern for fastidious/zoonotic/vector-borne pathogens (OR 2.1; 95% CI, 1.11-3.76; P .019) were associated with positive clinical impact of KT. Host immunocompromised status was not reliably associated with a positive clinical impact of KT (OR 1.03; 95% CI, 0.83-1.29; P .7806). No significant predictors of KT clinical impact were found in pediatric patients. Microbiologic result pattern was also a significant predictor of impact. Our study highlights that despite the positive clinical impact of KT in select situations, most testing results had no clinical impact. We also confirm diagnostic indications where KT may have the highest yield, thereby generating tools for diagnostic stewardship

New and old lessons from a devastating case of neonatal E coli meningitis.

BACKGROUND: Neonatal Escherichia coli (E coli) meningitis results in significant morbidity and mortality. We present a case of a premature infant with extensive central nervous system (CNS) injury from recurrent E coli infection and the non-traditional methods necessary to identify and clear the infection. CASE PRESENTATION: The infant was transferred to our institutions pediatric intensive care unit (PICU) after recurrence of E coli CNS infection requiring neurosurgical intervention. He had been treated for early onset sepsis (EOS) with ampicillin and gentamicin for 10 days followed by rapid development of ampicillin-resistant E coli septic shock and meningitis after discontinuation of antibiotics. Sterility of the CNS was not confirmed at the end of 21 days of cefepime therapy and was subsequently followed by recurrent ampicillin-resistant E coli septic shock and CNS infection. Despite 6 weeks of appropriate therapy with sterility of CSF by traditional methods, he suffered from intractable seizures with worsening hydrocephalus. Transferred to our institution, he underwent endoscopic 3rd ventriculostomy with cyst fenestration revealing purulent fluid and significant pleocytosis. An additional 3 weeks of systemic and intraventricular antibiotics with cefepime and tobramycin were given but a significant CNS neutrophil-predominant pleocytosis persisted (average of ∼ 21,000 cells/mm3). Repeated gram stains, cultures, polymerase chain reaction (PCR) testing, and metagenomic next generation sequencing (NGS) testing of CSF were negative for pathogens but acridine orange stain (AO) revealed numerous intact rod-shaped bacteria. After the addition of ciprofloxacin, sterility and resolution of CSF pleocytosis was finally achieved. CONCLUSION: Neonatal E coli meningitis is a well-known entity but unlike other bacterial infections, it has not proven amenable to shorter, more narrow-spectrum antibiotic courses or limiting invasive procedures such as lumbar punctures. Further, microbiologic techniques to determine CSF sterility suffer from poorly understood limitations leading to premature discontinuation of antibiotics risking further neurologic damage in vulnerable hosts

The Impact of the COVID-19 Pandemic on Influenza Vaccination Coverage Among Young U.S. Children: A Socioeconomic Analysis

The COVID-19 pandemic disrupted healthcare delivery across the United States (U.S.), including childhood vaccine administration. This study analyzed data from the National Health Interview Survey (NHIS), a nationally representative survey of the U.S. population, assessing trends and predictors of influenza vaccination uptake among children ≤ 5 years before and amid the COVID-19 pandemic. Influenza vaccination coverage declined significantly, from 56% in 2019 to 46% in 2022 (p p p p = 0.018). Uninsured children were less likely to be vaccinated than insured children (OR = 0.71, p = 0.022). Regional analysis showed the Northeast had the highest vaccination rates (60% in 2019, 56% in 2022), while the South had the lowest (52% in 2019, 41% in 2022). These findings underscore the need for targeted strategies to address socioeconomic disparities and improve influenza vaccine uptake in young children in the U.S

Case report: Disseminated histoplasmosis in a renal transplant recipient from a non-endemic region

Histoplasmosis is the most common endemic fungal infection in the USA. The majority of cases are asymptomatic and have clear exposure to endemic regions. In contrast, we present an adolescent immunocompromised patient with systemic and relatively non-specific symptoms including abdominal pain, weight loss, lower extremity edema, and scabbing skin lesions, without known exposure to endemic areas for histoplasmosis. Histologic analysis of gastrointestinal and skin biopsies eventually revealed a diagnosis of disseminated histoplasmosis; the patient was successfully treated with amphotericin B followed by itraconazole maintenance therapy. Ultimately, a high bar of suspicion for fungal disease must be maintained in immunosuppressed individuals even without apparent exposure history to endemic areas. This case report serves as a valuable reference for practitioners evaluating differential diagnosis of infections in immunocompromised patients

Epidemiology and SARS-CoV-2 Infection Patterns among Youth Followed at a Large Los Angeles Health Network during 2020–2022: Clinical Presentation, Prevalent Strains, and Correlates of Disease Severity

Background: Outcomes of SARS CoV-2 infection in infants, children and young adults are reported less frequently than in older populations. The evolution of SARS-CoV-2 cases in LA County youths followed at a large health network in southern California over two years was evaluated. Methods: A prospective cohort study of patients aged 0–24 years diagnosed with COVID-19 was conducted. Demographics, age distribution, disease severity, circulating variants of concern (VOCs), and immunization rates were compared between first and second pandemic years. Logistic regression estimated odds ratios (OR) and 95% confidence intervals (CI) of factors associated with severe/critical COVID-19. Results: In total, 61,208 patients 0–24 years of age were tested for SARS-CoV-2 by polymerase chain reaction (PCR); 5263 positive patients (8.6%) with available data were identified between March 2020 and March 2022. In Year 1, 5.8% (1622/28,088) of youths tested positive, compared to 11% (3641/33,120) in Year 2 (p 12% across all age groups in the second half of Year 2, when Omicron prevailed. Pulmonary disease was associated with higher risk of severe COVID-19 in both years (OR: 2.4, 95% CI: 1.4–4.3, p = 0.002, Year 1; OR: 11.3, 95% CI: 4.3–29.6, Year 2, p p < 0.05). Conclusions: Despite different VOCs and higher rates of test positivity in Year 2 compared to Year 1, most youths with COVID-19 had asymptomatic/mild disease. Underlying pulmonary conditions increased the risk of severe COVID-19, while vaccination was highly protective against severe disease in youths