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 institution's 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.

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

BACKGROUND: The 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. METHODS: All 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. RESULTS: Ninety-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. CONCLUSIONS: Among 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.

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 < 0.001). Most youths had mild/asymptomatic illness over two years. SARS-CoV-2 positivity was >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 < 0.001). Receipt of at least one COVID-19 vaccine dose was protective against severe COVID-19 (OR: 0.3, 95% CI: 0.11-0.80, 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.

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.

Clinical and epidemiological characteristics of SARS-CoV-2 Infection in Los Angeles County youth during the first year of the pandemic.

OBJECTIVES: The aim of this study was to characterize SARS-CoV-2 infection patterns in Los Angeles (LA) County youth followed at our institution during the first pandemic year. DESIGN: A prospective cohort of patients aged < 25 years who tested positive for SARS-CoV-2 using reverse-transcriptase polymerase chain reaction (RT-PCR) assays between March 13, 2020, and March 31, 2021, was evaluated at a large LA County health network. Demographics, age distribution, and disease severity were analyzed. RESULTS: There were 28,088 youth aged < 25 years tested for SARS-CoV-2 using RT-PCR, with 1849 positive results identified (7%). Among the positive results, 475 of 11,922 (4%) were identified at the pandemic onset (March-September 2020) (Cohort 1) and 1374 of 16,166 (9%) between October 2020 and March 2021 (Cohort 2), P < 0.001. When disease severity was compared across cohorts, Cohort 2 had a greater proportion of asymptomatic and mild/moderate disease categories than Cohort 1 (98% vs 80%, respectively); conversely, Cohort 1 had a near-10-fold higher proportion of severe disease than Cohort 2 (17% vs 1.8%). Cohort 2 comprised younger patients with a mean age of 13.7 years vs 17.3 years in Cohort 1. Older age was associated with a higher percentage of infection, with 63% of all confirmed cases found in participants aged 19 to 25 years in Cohort 1, compared with 38% of confirmed cases in Cohort 2. Age increase was also associated with greater disease severity by linear regression modeling (P< 0.001). CONCLUSION: Coronavirus disease 2019 (COVID-19) disease severity in youth decreased over time in LA County during the first pandemic year, likely a reflection of changing demographics, with younger children infected. A higher infection rate in youth did not lead to higher disease severity over time.

Predictors of SARS-CoV-2 Infection in Youth at a Large, Urban Healthcare Center in California, March-September 2020.

Objective: To understand which social, epidemiologic, and clinical risk factors are associated with SARS-CoV-2 infection in youth accessing care in a large, urban academic institution. Methods: We conducted a prospective cohort study with case-control analyses in youth who received testing for SARS-CoV-2 at our academic institution in Los Angeles during the first wave of the COVID-19 pandemic (March-September 2020). Results: A total of 27,976 SARS-CoV-2 assays among 11,922 youth aged 0-24 years were performed, including 475 youth with positive SARS-CoV-2 results. Positivity rate was higher among older, African American, and Hispanic/Latinx youth. Cases were more likely to be from non-English-speaking households and have safety-net insurance. Zip codes with higher proportion of Hispanic/Latinx and residents living under the poverty line were associated with increased SARS-CoV-2 cases. Youth were more likely to have positive results if tested for exposure (OR 21.5, 95% CI 14.6-32.1) or recent travel (OR 1.5, 95% CI 1.0-2.3). Students were less likely to have positive results than essential worker youth (OR 0.5, 95% CI 0.3-0.8). Patterns of symptom presentation varied significantly by age group; number of symptoms correlated significantly with age in SARS-CoV-2 cases (r = 0.030, p < 0.001). SARS-CoV-2 viral load did not vary by symptom severity, but asymptomatic youth had lower median viral load than those with symptoms (21.5 vs. 26.7, p = 0.009). Conclusions: Socioeconomic factors are important drivers of SARS-CoV-2 infection in youth. Presence of symptoms, exposure, and travel can be used to drive testing in older youth. Policies for school reopening and infection prevention should be tailored differently for elementary schools and universities.

Detection of undiagnosed diabetes and prediabetic states in high-risk emergency department patients.

BACKGROUND: Diabetes is often not diagnosed until complications appear, and one-third of those with diabetes may be undiagnosed. Prediabetes and diabetes are conditions in which early detection would be appropriate, because the duration of hyperglycemia is a predictor of adverse outcomes, and there are effective interventions to prevent disease progression and to reduce complications. OBJECTIVES: The objectives were to determine the prevalence of diabetes mellitus and prediabetes in emergency department (ED) patients with an elevated random glucose or risk factors for diabetes but without previously diagnosed diabetes and to identify which at-risk ED patients should be considered for referral for confirmatory diagnostic testing. METHODS: This two-part study was composed of a prospective 2-year cohort study, and a 1-week cross-sectional survey substudy, set in an urban ED in Los Angeles County, California. A convenience sample was enrolled of 528 ED patients without previously diagnosed diabetes with either 1) a random serum glucose > or = 140 mg/dL regardless of the time of last food intake or a random serum glucose > or = 126 mg/dL if more than 2 hours since last food intake or 2) at least two predefined diabetes risk factors. Measurements included presence of diabetes risk factors, ED glucose, cortisol, insulin and glycosylated hemoglobin (HbA(1c)), and 2-hour oral glucose tolerance test results, administered at 6-week follow-up. RESULTS: Glycemic status was confirmed at follow-up in 256 (48%) of the 528 patients. Twenty-seven (11%) were found to have diabetes, 141 (55%) had prediabetes, and 88 (34%) had normal results. Age, ED glucose, HbA(1c), cortisol, and random serum glucose > or = 140 mg/dL were associated with both diabetes and prediabetes on univariate analysis. A random serum glucose > or = 126 mg/dL after 2 hours of fasting was associated with diabetes but not prediabetes; ED cortisol, insulin, age > or = 45 years, race, and calculated body mass index (BMI) were associated with prediabetes but not diabetes. In multivariable models, among factors measurable in the ED, the only independent predictor of diabetes was ED glucose, while ED glucose, age > or = 45 years, and symptoms of polyuria and polydipsia were independent predictors of prediabetes. All at-risk subjects with a random ED blood glucose > 155 mg/dL had either prediabetes or diabetes on follow-up testing. CONCLUSIONS: A substantial fraction of this urban ED study population was at risk for undiagnosed diabetes and prediabetes, and among the at-risk patients referred for follow-up, the majority demonstrated diabetes or prediabetes. Notably, all patients with two risk factors and a random serum glucose > 155 mg/dL were later diagnosed with prediabetes or diabetes. Consideration should be given to referring ED patients with risk factors and a random glucose > 155 mg/dL for follow-up testing.

Orthodontic tooth movement in cholestatic and cirrhotic rats.

OBJECTIVE: To investigate whether cirrhosis and cholestasis could influence orthodontic tooth movement. DESIGN: Basic science, animal experimental study. SETTING: This study was conducted in the Department of Pharmacology, School of Medicine at Tehran University of Medical Sciences in 2007. PARTICIPANTS: A total of 40 male Sprague-Dawley rats (150-200 g) were divided into five experimental groups: non-operated, cholestatic-sham, cirrhotic-sham, cholestatic and cirrhotic groups. METHODS: An orthodontic appliance, consisting of a 5 mm nickel titanium closed coil spring, was ligated between the maxillary right incisor and first molar of each rat to deliver an initial force of 60 g. The cholestatic and cirrhotic groups underwent a bile duct ligation operation and received an orthodontic appliance for 7 days (cholestatic group) and 28 days (cirrhotic group) after surgery. Two other groups underwent a sham operation and had an orthodontic appliance inserted after 7 (cholestatic-sham) and 28 days (cirrhotic-sham). A fifth control group underwent neither bile duct ligation operation nor sham operation. RESULTS: The cirrhotic group showed significantly increased orthodontic tooth movement (OTM), compared to all other study groups (P<0.001). The mean OTM in the cholestatic group was significantly higher than in the other three groups (two sham groups and unoperated one) (P<0.01). Bone density was also significantly decreased in the bile duct ligated (cirrhotic and cholestatic) groups (P<0.01). CONCLUSION: Our data demonstrated that biliary cirrhosis could cause a significant increase in the OTM and decrease in the bone density in rats, though there was no significant alteration in bone resorption or osteoclasts detected in such animals.