Oral Valganciclovir Initiated Beyond 1 Month of Age as Treatment of Sensorineural Hearing Loss Caused by Congenital Cytomegalovirus Infection: A Randomized Clinical Trial.

OBJECTIVE: The objective of this study was to determine if valganciclovir initiated after 1 month of age improves congenital cytomegalovirus-associated sensorineural hearing loss. STUDY DESIGN: We conducted a randomized, double-blind, placebo-controlled phase 2 trial of 6 weeks of oral valganciclovir at US (n = 12) and UK (n = 9) sites. Patients of ages 1 month through 3 years with baseline sensorineural hearing loss were enrolled. The primary outcome was change in total ear hearing between baseline and study month 6. Secondary outcome measures included change in best ear hearing and reduction in cytomegalovirus viral load in blood, saliva, and urine. RESULTS: Of 54 participants enrolled, 35 were documented to have congenital cytomegalovirus infection and were randomized (active group: 17; placebo group: 18). Mean age at enrollment was 17.8 ± 15.8 months (valganciclovir) vs 19.5 ± 13.1 months (placebo). Twenty (76.9%) of the 26 ears from subjects in the active treatment group did not have worsening of hearing, compared with 27 (96.4%) of 28 ears from subjects in the placebo group (P = .09). All other comparisons of total ear or best ear hearing outcomes were also not statistically significant. Saliva and urine viral loads decreased significantly in the valganciclovir group but did not correlate with change in hearing outcome. CONCLUSIONS: In this randomized controlled trial, initiation of antiviral therapy beyond the first month of age did not improve hearing outcomes in children with congenital cytomegalovirus-associated sensorineural hearing loss. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01649869.

Epidemiology and long-term outcomes of cytomegalovirus DNAemia and disease in pediatric solid organ transplant recipients.

Despite prevention strategies, cytomegalovirus (CMV) remains a common infection in pediatric solid organ transplant recipients (SOTR). We sought to determine the frequency, associations with, and long-term outcomes of CMV DNAemia in pediatric SOTR. We performed a single-center retrospective cohort study, including 687 first time SOTR ≤21 years receiving universal prophylaxis from 2011 to 2018. Overall, 159 (23%) developed CMV DNAemia, the majority occurring after completing primary prophylaxis. CMV disease occurred in 33 (5%) SOTR, 25 (4%) with CMV syndrome and 10 (1%) with proven/probable tissue-invasive disease. CMV contributed to the death of three (0.4%) patients (all lung). High-risk (OR 6.86 [95% CI, 3.6-12.9]) and intermediate-risk (4.36 [2.3-8.2]) CMV status and lung transplantation (4.63 [2.33-9.2]) were associated with DNAemia on multivariable analysis. DNAemia was associated with rejection in liver transplant recipients (p < .01). DNAemia was not associated with an increase in graft failure, all-cause mortality, or other organ-specific poor outcomes. We report one of the lowest rates of CMV disease after SOTR, showing that universal prophylaxis is effective and should be continued. However, we observed CMV morbidity and mortality in a subset of patients, highlighting the need for research on optimal prevention strategies. This study was IRB approved.

Clinical Importance of Placental Testing among Suspected Cases of Congenital Zika Syndrome.

Contemporaneous Zika virus (ZIKV) strains can cause congenital Zika syndrome (CZS). Current ZIKV clinical laboratory testing strategies are limited and include IgM serology (which may wane 12 weeks after initial exposure) and nucleic acid testing (NAT) of maternal serum, urine, and placenta for (+) strand ZIKV RNA (which is often transient). The objectives of this study were to determine if use of additional molecular tools, such as quantitative PCR and microscopy, would add to the diagnostic value of current standard placental ZIKV testing in cases with maternal endemic exposure and indeterminate testing. ZIKV RNA was quantified from dissected sections of placental villi, chorioamnion sections, and full cross-sections of umbilical cord in all cases examined. Quantitation with high-resolution automated electrophoresis determined relative amounts of precisely verified ZIKV (74-nt amplicons). In order to localize and visualize stable and actively replicating placental ZIKV in situ, labeling of flaviviridae glycoprotein, RNA ISH against both (+) and (⁻) ZIKV-specific ssRNA strands, and independent histologic examination for significant pathologic changes were employed. We demonstrate that the use of these molecular tools added to the diagnostic value of placental ZIKV testing among suspected cases of congenital Zika syndrome with poorly ascribed maternal endemic exposure.

A Severe Case of Murine Typhus Presenting With Anemia and Severe Thrombocytopenia.

We discuss a child with severe thrombocytopenia and mild anemia admitted to the Hematology service who quickly deteriorated to a life-threatening state. However, once rickettsial disease was considered in the differential diagnosis and empiric doxycycline begun, she quickly and fully recovered. A diagnostic panel, including Rickettsia typhi serology, confirmed the diagnosis of murine typhus but this occurred weeks after she had recovered. Given the potential severity of rickettsial diseases and the ease of modern travel across geographic borders, hematology-oncology providers everywhere must consider rickettsial diseases in their differential diagnosis of critically ill children and begin empiric therapy with doxycycline promptly.

The unhealthy food environment does not modify the association between obesity and participation in the Supplemental Nutrition Assistance Program (SNAP) in Los Angeles County.

BACKGROUND: Participation in the Supplemental Nutrition Assistance Program (SNAP) has been linked to an increased risk of obesity, but not much is known about the mechanisms behind this association. The objective of this study was to determine if the neighborhood density of unhealthy food outlets modifies the association between obesity and participation in SNAP. METHODS: Data comes from the first wave of the Los Angeles Family and Neighborhood Survey; included are a subsample of adults (18+ years) who were SNAP participants or eligible non-participants (N = 1,176). We carried out multilevel analyses with obesity (BMI ≥ 30 Kg/m2), SNAP participation, and the neighborhood density of unhealthy food outlets as dependent, independent and modifying variables, respectively, controlling for age, gender, race/ethnicity, marital status, working status, mental health, and neighborhood poverty. RESULTS: SNAP participants had double the odds of obesity compared to eligible non-participants (OR = 2.02; 95%CI = 1.44-2.83). However, the neighborhood density of unhealthy food outlets did not modify this association. CONCLUSIONS: SNAP participation was associated with higher odds of obesity in our primarily Hispanic sample in Los Angeles County, with no effect modification found for the unhealthy portion of the food environment. More research is needed with additional food environment measures to confirm our null findings. Additional research is needed to elucidate the mechanisms linking SNAP participation and obesity as they remain unclear.

Food Insecurity and Cost-Related Medication Underuse Among Nonelderly Adults in a Nationally Representative Sample.

OBJECTIVES: We investigated whether nonelderly US adults (aged 18-64 years) in food-insecure households are more likely to report cost-related medication underuse than the food-secure, and whether the relationship between food insecurity and cost-related medication underuse differs by gender, chronic disease, and health insurance status. METHODS: We analyzed data from the 2011 and 2012 National Health Interview Survey (n = 67 539). We examined the relationship between food insecurity and cost-related medication underuse with the χ(2) test and multivariate logistic regression with interaction terms. RESULTS: Bivariate and multivariate analyses showed a dose-response relationship between food insecurity and cost-related medication underuse, with an increasing likelihood of cost-related medication underuse with increasing severity of food insecurity (P < .001). This association was conditional on health insurance status, but not substantially different by gender or chronic disease status. Being female, low-income, having no or partial health insurance, chronic conditions, functional limitations, or severe mental illness were positively associated with cost-related medication underuse. CONCLUSIONS: Using food insecurity as a risk factor to assess cost-related medication underuse could help increase identification of individuals who may need assistance purchasing medications and improve health for those in food-insecure households.

Progressive Thrombocytopenia, Splenomegaly, and Abnormal Tone in an Infant With Growth Faltering.

A 4-month-old full-term female presented with growth faltering associated with progressive feeding difficulty, rash, abdominal distension, and developmental delays. She was found to have disconjugate gaze, abnormal visual tracking, mixed tone, bruising, and splenomegaly on examination. Initial workup was notable for thrombocytopenia and positive cytomegalovirus (CMV) immunoglobulin G and immunoglobulin M antibodies. She initially presented to the infectious diseases CMV clinic, where she was noted to have severe malnutrition, prompting referral to the emergency department for hospital admission to optimize nutrition with nasogastric tube feeding and facilitate additional evaluation. An active CMV infection with viruria and viremia was confirmed, but elements of her presentation and workup including brain magnetic resonance imaging were not consistent with isolated CMV infection. To avoid premature diagnostic closure, a multidisciplinary workup was initiated and ultimately established her diagnosis.

Congenital Cytomegalovirus Testing Outcomes From the ValEAR Trial.

OBJECTIVE: To determine the positivity rate of congenital cytomegalovirus (cCMV) testing among universal, hearing-targeted CMV testing (HT-cCMV) and delayed targeted dried blood spot (DBS) testing newborn screening programs, and to examine the characteristics of successful HT-cCMV testing programs. STUDY DESIGN: Prospective survey of birth hospitals performing early CMV testing. SETTING: Multiple institutions. METHODS: Birth hospitals participating in the National Institutes of Health ValEAR clinical trial were surveyed to determine the rates of cCMV positivity associated with 3 different testing approaches: universal testing, HT-cCMV, and DBS testing. A mixed methods model was created to determine associations between successful HT-cCMV screening and specific screening protocols. RESULTS: Eighty-two birth hospitals were surveyed from February 2019 to December 2021. Seven thousand six hundred seventy infants underwent universal screening, 9017 infants HT-cCMV and 535 infants delayed DBS testing. The rates of cCMV positivity were 0.5%, 1.5%, and 7.3%, respectively. The positivity rate for universal CMV screening was less during the COVID-19 pandemic than that reported prior to the pandemic. There were no statistically significant drops in positivity for any approach during the pandemic. For HT-cCMV testing, unique order sets and rigorous posttesting protocols were associated with successful screening programs. CONCLUSION: Rates of cCMV positivity differed among the 3 approaches. The rates are comparable to cohort studies reported in the literature. Universal CMV prevalence decreased during the pandemic but not significantly. Institutions with specific order set for CMV testing where the primary care physician orders the test and the nurse facilitates the testing process exhibited higher rates of HT-cCMV testing.

Utility of Dried Blood Spots for the Diagnosis of Congenital Cytomegaloviruses within the First 21 Days of Life in a Single Center.

In this retrospective study, we aimed to evaluate the performance of dried-blood-spot (DBS) testing as a diagnostic method for the congenital cytomegalovirus (cCMV). We reviewed the medical records and DBS test results of 89 patients who had also undergone diagnostic cCMV testing within the first 21 days of life. The DBS test had a sensitivity of 83.9%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 73%. Patients with a true-positive DBS had a higher median level of CMV in blood according to PCR than those with a false-negative result. Additionally, all patients with cCMV and hearing loss had a positive DBS test, with higher median viremia levels observed in those with hearing loss compared to those without a CMV PCR blood test. These results suggest that DBS-based testing is useful in the diagnosis of cCMV, and its performance may be related to levels of CMV viremia. DBS testing accurately identified those patients with congenital/early onset hearing loss and those at risk of developing late-onset hearing loss.

Parental Perspectives on Communication from Health Care Providers following a Newborn Diagnosis of Congenital Cytomegalovirus Infection: A Secondary Analysis of a Qualitative Study.

The study objective was to identify communication messages that parents of children diagnosed with congenital cytomegalovirus (cCMV) infection reported as essential and helpful. We performed a secondary analysis of focus groups and interviews conducted with 41 parents of children with cCMV who had enrolled in a long-term follow-up cCMV study at an academic medical center. Three groups of parents who had children with cCMV participated in the study: parents with children symptomatic at birth, parents with children asymptomatic at birth who later developed sensorineural hearing loss, and parents with children asymptomatic at birth who remained asymptomatic into adulthood. Using a health marketing approach, we identified six general themes from the focus group sessions: initial diagnosis, likely health outcome(s), comfort and coping, symptom watch, resources, and prevention. Receiving the initial diagnosis was shocking for many parents, and they wanted to know how their child would or could be affected. They valued access to the information, follow-up visits for early detection of hearing loss and other developmental delays, and support from other parents. Parents wished to obtain this information from their pediatrician but felt that experts offered more up-to-date knowledge about prognosis, monitoring, and treatment. With more U.S. states implementing cCMV screening strategies which would lead to more infant diagnoses, it will be necessary for providers to meet parents' expectations and communication needs.

Infectious profiles in pediatric anti-N-methyl-d-aspartate receptor encephalitis.

Anti-N-methyl-d-aspartate receptor autoimmune encephalitis (NMDAR AE) is an antibody-mediated neurological disorder that may be caused by post-herpes simplex virus-1 meningoencephalitis (HSV ME) and ovarian teratomas, although most pediatric cases are idiopathic. We sought to evaluate if other infections precede NMDAR AE by conducting a single-center, retrospective, case-control study of 86 pediatric cases presenting to Texas Children's Hospital between 2006 and 2022. HSV ME (HSV-1 and HSV-2) was a significantly more common preceding infection in the experimental group compared to control patients with idiopathic intracranial hypertension, while there was no difference in remote HSV infection between the two groups. Recent Epstein-Barr virus infection was evident in 8/42 (19%) tested experimental patients in comparison to 1/25 (4%) tested control patients which provided evidence for a genuine measure of effect but was not statistically significant due to small sample size (p = 0.07). The other 25 infectious etiologies were not different among the two groups and not all variables were clinically indicated or obtained in every subject, highlighting the need for future standardized, multi-institutional studies on underlying infectious precursors of autoimmune encephalitis.

Derivation of human T lymphocytes from cord blood and peripheral blood with antiviral and antileukemic specificity from a single culture as protection against infection and relapse after stem cell transplantation.

Viral infections and leukemic relapse account for the majority of treatment failures in patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving allogeneic hematopoietic stem cell (HSC) or cord blood (CB) transplants. Adoptive transfer of virus-specific cytotoxic T lymphocytes (CTLs) provides protection against common viruses causing serious infections after HSC transplantation without concomitant graft-versus-host disease. We have now generated CTL lines from peripheral blood (PB) or CB units that recognize multiple common viruses and provide antileukemic activity by transgenic expression of a chimeric antigen receptor (CAR) targeting CD19 expressed on B-ALL. PB-derived CAR(+) CTLs produced interferon-gamma (IFNgamma) in response to cytomegalovirus-pp65, adenovirus-hexon, and Epstein-Barr virus pepmixes (from 205 +/- 104 to 1034 +/- 304 spot-forming cells [SFCs]/10(5) T cells) and lysed primary B-ALL blasts in (51)Cr-release assays (mean, 66% +/- 5% specific lysis; effector-target [E/T] ratio, 40:1) and the CD19(+) Raji cell line (mean, 78% +/- 17%) in contrast to nontransduced controls (8% +/- 8% and 3% +/- 2%). CB-derived CAR(+) CTLs showed similar antiviral and antitumor function and both PB and CB CAR(+) CTLs completely eliminated B-ALL blasts over 5 days of coculture. This approach may prove beneficial for patients with high-risk B-ALL who have recently received an HSC or CB transplant and are at risk of infection and relapse.

Preschool enrollment is associated with lower odds of childhood obesity among WIC participants in LA County.

The prevalence of obesity among children in the United States has increased rapidly during the past few decades. Research into social and behavioral determinants of obesity could lead to innovative strategies for prevention. The objective of the present study was to examine the association between childhood obesity and preschool enrollment and number of hours in child care among low-income preschool-aged children who were participants in the Special Supplemental Nutrition Program for Women, Infants and Children (WIC). We conducted a case-control study including 556 3- to 4-year-old children who were either obese (BMI > 95th percentile of reference standard) or normal-weight (BMI 25-75th percentile). The population was largely (96%) Hispanic, an ethnic group that has one of the highest rates of overweight and obesity in adults and children in the US. In multiple logistic regression analysis, controlling for a variety of psychosocial and cognitive home environment variables, key demographics and maternal variables, the odds ratio of being obese was 0.61 for children who attended preschool more than 4 days a week (95% CI: 0.41-0.90). Watching television or videos for an hour or more on a typical day (odds ratio 1.71 (95% CI 1.07-2.75)), and higher maternal BMI (odds ratio 1.08 (95% CI 1.05-1.11)) were independently related to odds of obesity. The impact of preschool attendance and TV viewing are potentially instructive in terms of preventive interventions for children at this age.

A 14-Year-Old Female With Chest Mass, Shortness of Breath, and Hypertension.

BACKGROUND: A previously healthy 14-year-old girl was evaluated in the emergency department (ED) with 2 months of shortness of breath and fatigue. METHODS: She initially presented to her primary pediatrician, where a complete blood count was only significant for mild anemia, thyroid function tests were normal, and a chest x-ray revealed a chest mass. This prompted her primary pediatrician to order a computed tomography scan and refer to the ED. RESULTS: Her computed tomography scan confirmed a mediastinal mass versus necrotic lymphadenopathy. Her initial physical exam was unremarkable, except for hypertension. From the ED, she was admitted to the pediatric hospital medicine service. Infectious disease, oncology, and nephrology services were consulted to guide diagnostic evaluation. CONCLUSIONS: Eventually, during her hospitalization, further history and workup led to a definitive diagnosis.

Progressive, Long-Term Hearing Loss in Congenital CMV Disease After Ganciclovir Therapy.

BACKGROUND: Long-term hearing outcomes among children with symptomatic congenital cytomegalovirus (CMV) disease who received 6-week ganciclovir therapy early in life are unknown. METHODS: Longitudinal study of 76 children with symptomatic congenital CMV disease, born 1983-2005, who were categorized into three groups: group A treated with ganciclovir; group B untreated who had microcephaly, chorioretinitis, or sensorineural hearing loss (SNHL; ≥25 dB) diagnosed in the first month of life (congenital); and group C untreated who did not meet criteria for group B. RESULTS: Patients in groups A (n = 17), B (n = 27), and C (n = 32) were followed to median age of 13, 11, and 13 years, respectively. In group A, patients received ganciclovir for median of 40 (range, 11-63) days; 7 (41%) had grade 3 or 4 neutropenia. Congenital SNHL was diagnosed in 11 (65%) patients in group A, 15 (56%) in group B, and none in group C. Early-onset SNHL was diagnosed between ages ≥1-12 months in an additional 4 (24%), 6 (22%), and 8 (25%) patients in groups A, B, and C, respectively. By the end of follow-up, 12 (71%), 16 (59%), and 7 (22%) of patients in groups A, B, and C, respectively, had severe (>70 dB) SNHL in the better-hearing ear. CONCLUSIONS: In this study, most patients with symptomatic congenital CMV disease and congenital or early-onset SNHL eventually developed hearing loss severe enough to have been potential candidates for cochlear implantation, with or without 6-week ganciclovir therapy. Understanding long-term hearing outcomes of patients treated with 6-month oral valganciclovir (current standard of care) is needed.

Management of Extensive Central Nervous System Cladophialophora bantiana Infection in a 9-Year-Old Child.

BACKGROUND: Pediatric central nervous system (CNS) phaeohyphomycosis is a rare invasive fungal infection associated with high mortality. METHODS: We describe a child with progressive neurologic symptoms whose ultimate diagnosis was Cladophialophora bantiana -associated CNS phaeohyphomycosis. We discuss her clinical presentation, medical and surgical management and review the current literature. RESULTS: A 9-year-old female presented with acute onset of headaches, ophthalmoplegia and ataxia. Initial infectious work-up was negative, including serial fungal cerebrospinal fluid cultures. Over 2 months, she experienced progressive cognitive and motor declines, and imaging revealed worsening meningitis, ventriculitis and cerebritis. Ultimately, Cladophialophora was detected by plasma metagenomic next-generation sequencing (mNGS). Fourth ventricle fluid sampling confirmed the diagnosis of C. bantiana infection. Given the extent of her disease, complete surgical resection was not feasible. She required multiple surgical debridement procedures and prolonged antifungal therapy, including the instillation of intraventricular amphotericin B. With aggressive surgical and medical management, despite her continued neurologic deficits, she remains alive 3 years after her initial diagnosis. To our knowledge, this is one of a few published pediatric cases of CNS phaeohyphomycosis and the first with the causative pathogen identified by plasma mNGS. CONCLUSION: CNS phaeohyphomycosis is a serious, life-threatening infection. The preferred management includes a combination of surgical resection and antifungal therapy. In cases complicated by refractory ventriculitis, intraventricular antifungal therapy can be considered as adjuvant therapy. Direct sampling of the CNS for pathogen identification and susceptibility testing is the gold standard for diagnosis; however, the use of plasma mNGS may expedite the diagnosis.