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.

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.

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.

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.

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.

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.

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.

ANKLE2-related microcephaly: A variable microcephaly syndrome resembling Zika infection.

OBJECTIVE: This study delineates the clinical and molecular spectrum of ANKLE2-related microcephaly (MIC), as well as highlights shared pathological mechanisms between ANKLE2 and the Zika virus. METHODS: We identified 12 individuals with MIC and variants in ANKLE2 with a broad range of features. Probands underwent thorough phenotypic evaluations, developmental assessments, and anthropometric measurements. Brain imaging studies were systematically reviewed for developmental abnormalities. We functionally interrogated a subset of identified ANKLE2 variants in Drosophila melanogaster. RESULTS: All individuals had MIC (z-score ≤ -3), including nine with congenital MIC. We identified a broad range of brain abnormalities including simplified cortical gyral pattern, full or partial callosal agenesis, increased extra-axial spaces, hypomyelination, cerebellar vermis hypoplasia, and enlarged cisterna magna. All probands had developmental delays in at least one domain, with speech and language delays being the most common. Six probands had skin findings characteristic of ANKLE2 including hyper- and hypopigmented macules. Only one individual had scalp rugae. Functional characterization in Drosophila recapitulated the human MIC phenotype. Of the four variants tested, p.Val229Gly, p.Arg236*, and p.Arg536Cys acted as partial-loss-of-function variants, whereas the c.1421-1G>C splicing variant demonstrated a strong loss-of-function effect. INTERPRETATION: Deleterious variants in the ANKLE2 gene cause a unique MIC syndrome characterized by congenital or postnatal MIC, a broad range of structural brain abnormalities, and skin pigmentary changes. Thorough functional characterization has identified shared pathogenic mechanisms between ANKLE2-related MIC and congenital Zika virus infection. This study further highlights the importance of a thorough diagnostic evaluation including molecular diagnostic testing in individuals with MIC.

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.

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.

Family Perceptions of Newborn Cytomegalovirus Screening: A Qualitative Study.

OBJECTIVES: We sought to understand long-term retrospective parental perceptions of the utility of newborn screening in a context where many affected children never develop sequelae but where intensive support services and ongoing healthcare were provided. STUDY DESIGN: Qualitative study. METHODS: Focus groups and interviews among parents (N = 41) of children with congenital CMV who had been enrolled in a long-term follow-up study at a large medical college for a mean of 22 years following diagnosis. Groups included parents whose children were: symptomatic at birth; initially asymptomatic but later developed sensorineural hearing loss; and who remained asymptomatic into adulthood. RESULTS: With proper follow-up support, newborn CMV screening was viewed positively by parents, who felt empowered by the knowledge, though parents often felt that they and healthcare providers needed more information on congenital CMV. Parents in all groups valued newborn CMV screening in the long term and believed it should be embedded within a comprehensive follow-up program. CONCLUSIONS: Despite initial distress, parents of CMV-positive children felt newborn CMV screening was a net positive. Mandatory or opt-out screening for conditions with variable presentations and treatment outcomes may be valuable in contexts where follow-up and care are readily available.

Severe congenital chorioretinitis caused by congenital lymphocytic choriomeningitis virus infection.

PURPOSE: To describe a case of congenital lymphocytic choriomeningitis virus (LCMV), a potentially severe and under-diagnosed etiology of congenital chorioretinitis. OBSERVATIONS: A 5-month old boy presented with esotropia. Examination revealed light perception vision in the right eye and normal fixation and following behavior in the left eye, and a 50PD esotropia with full versions. The external, anterior segment, and pupil exams were normal. Fundus examination demonstrated slightly pale optic nerves, numerous geographic atrophic and hyperpigmented lesions along the vascular arcades in both eyes that extended into the fovea of the right eye. Head computed tomography (CT) imaging demonstrated bilateral cerebral volume loss with consequential ex vacuo dilation of the lateral ventricles and scattered intracranial calcifications. Serum IgG and IgM titers for toxoplasmosis, rubella, cytomegalovirus (CMV), herpes simplex virus (HSV), syphilis, and zika were all negative. Upon communication of negative TORCHS titers, the mother recalled a severe rat infestation of their home during the pregnancy. A LCMV antibody titer was then ordered and which resulted positive for IgG antibodies. CONCLUSIONS AND IMPORTANCE: Congenital LCMV infection is an under-recognized cause of congenital chorioretinitis.

Coronavirus Infections in the Nervous System of Children: A Scoping Review Making the Case for Long-Term Neurodevelopmental Surveillance.

BACKGROUND: The objective of this study was to describe the case literature of human coronavirus infections in the nervous system of children, including from SARS-CoV-2, and to provide guidance to pediatric providers for managing the potential long-term effects on neurodevelopment of human coronavirus infections in the nervous system. METHODS: Using a structured strategy, the PubMed and Ovid:Embase databases were queried for articles about the clinical presentation and pathophysiology of coronavirus infections in the nervous system of children and young adults, aged 0 to 24 years. RESULTS: Of 2302 articles reviewed, 31 described SARS-CoV-2 infections in the nervous system of children and 21 described other human coronaviruses: HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, MERS-CoV, SARS-CoV-1. Excepting MERS-CoV, we found cases of neurological disease in children from each human coronavirus. Children with non-SARS-CoV-2 infections have suffered acute flaccid paralysis, acute disseminated encephalomyelitis, encephalitis, and seizures. In addition, cases of ischemic, hemorrhagic, and microvascular strokes have occurred in children with SARS-CoV-2. Patients with multisystem inflammatory syndrome in children have suffered encephalitis, stroke, pseudotumor cerebri syndrome, and cytotoxic lesions of deep brain structures. Despite these reports, few articles evaluated the impact of human coronavirus infections on long-term neurodevelopmental domains including cognitive, language, academic, motor, and psychosocial outcomes. CONCLUSIONS: Neurological manifestations of human coronavirus infections can cause severe disease in children. The case literature suggests a critical gap in knowledge of the long-term effects on child neurodevelopment of these infections. As the current SARS-CoV-2 pandemic continues, this gap must be filled to facilitate optimal outcomes in recovering children.

The Impact of Asymptomatic Congenital Cytomegalovirus on Adult Quality of Life.

OBJECTIVE: Children born with asymptomatic congenital cytomegalovirus infection (AcCMV) have increased risk for hearing loss, which may affect their quality of life into adulthood. We aim to determine quality of life outcomes among adults who were identified at birth with AcCMV compared with controls, using the cohort of the Houston Congenital CMV Longitudinal Study. METHODS: Quality of life was determined using the self-reported Quality of Life Inventory (QOLI). Sixty-one of 109 AcCMV subjects and 23 of 51 controls completed QOLI. Percentile scores of subjects were compared with percentile scores of controls using Student t tests. QOLI percentile scores were compared among AcCMV subjects with (N = 14) and without hearing loss (N = 47). RESULTS: There was no difference in mean percentile scores on QOLI between AcCMV subjects (59.8 [SD = 27.6]) and controls (57.3 [SD = 35.3]; p = 0.754). Percentile scores indicate an average overall quality of life classification for AcCMV subjects and controls. There was no difference in mean percentile scores on the QOLI between AcCMV subjects with and without hearing loss (54.8 [SD = 25.2]) and 61.3 [SD = 28.3]; p = 0.440, respectively). CONCLUSION: Adults born with AcCMV do not seem to have lower ratings of quality of life compared with uninfected controls. Although our study had small sample size, hearing loss does not seem to be a significant predictor of QOLI percentile scores among AcCMV subjects. Quality of life in adulthood does not seem to be affected by an individual's awareness of screening positive for CMV, which supports the notion of "no harm" occurring from universal newborn screening for congenital CMV infection.

Maternal cytomegalovirus immune status and hearing loss outcomes in congenital cytomegalovirus-infected offspring.

OBJECTIVES: The purpose of this study is to determine the relationship between maternal primary and recurrent CMV infection during pregnancy, symptoms at birth in the newborn, and long term hearing loss through18 years of age. PATIENTS AND METHODS: 237 mother-infant pairs in the Houston, Texas area identified through maternal CMV IgG and IgM antibody serologic screening and newborn screening using urine CMV culture to identify congenital CMV infection were enrolled in the Houston Congenital CMV Longitudinal Study. Mothers were categorized as having primary or recurrent or unknown maternal CMV infections, and newborns were categorized at birth as having symptomatic or asymptomatic congenital CMV infection, or as uninfected controls. All three newborn groups were followed longitudinally with serial hearing evaluations up to 18 years of age. The relationship between type of maternal CMV infection, newborn classification, and the occurrence of hearing loss over time was determined through Kaplan-Meier survival analysis, life table analysis, and a simulated ascertainment of maternal infection type for the unknown categories. RESULTS: Of 77 newborns with symptomatic congenital CMV infection, 12 (16%) of mothers had a primary CMV infection during pregnancy; 4 (5%) had a non-primary infection, and the type of infection in 48 (79%) could not be determined and were classified as unknown type of maternal infection. Fifty Seven (74%) of the 77 symptomatic children had hearing loss by 18 years of age, including 9 of the 12 (75%) who were born to mothers with primary infection and 48 (79%) of the 61 with unknown type of maternal infection. Of the 109 newborns with asymptomatic congenital CMV infection, 51 (47%) were born to mothers with a primary CMV infection during pregnancy, 18 (17%) to mothers with a recurrent infection; and 40 (37%) had unknown type of infection. Of these 109 asymptomatic cases, 22 (20%) developed hearing loss, including 14 out of 51 (28%) of those born to mothers with primary infection, two out of the 18 (11%) born to mothers with recurrent infection, and 6 out of the 40 (15%) to mothers of unknown infection type. Of the 51 uninfected newborn controls, 10 (20%) of mothers had a primary CMV infection during pregnancy, 5 (10%) had a non-primary infection, 10 (20%) were never infected, and 26 (51%) were assigned unknown type of infection. Three controls (6%) developed hearing loss, with 1 being born to a mother with primary infection and 1 to a mother never infected with CMV. CONCLUSIONS: Both primary and non-primary maternal CMV infections during pregnancy resulted in symptomatic and asymptomatic congenital CMV infection. Symptomatic congenital CMV infection was more likely to occur after primary maternal CMV infection. Sensorineural hearing loss occurred in children born to mothers with both primary and non-primary CMV infections, and in both asymptomatic and symptomatic congenital CMV infection, but was more common after maternal primary infection. Most, but not all, hearing loss in children with cCMV associated hearing loss was first detected within the first year of life.