Viral meningoencephalitis in pediatric solid organ or hematopoietic cell transplant recipients: a diagnostic and therapeutic approach.

Neurologic complications, both infectious and non-infectious, are frequent among hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients. Up to 46% of HCT and 50% of SOT recipients experience a neurological complication, including cerebrovascular accidents, drug toxicities, as well as infections. Defects in innate, adaptive, and humoral immune function among transplant recipients predispose to opportunistic infections, including central nervous system (CNS) disease. CNS infections remain uncommon overall amongst HCT and SOT recipients, compromising approximately 1% of total cases among adult patients. Given the relatively lower number of pediatric transplant recipients, the incidence of CNS disease amongst in this population remains unknown. Although infections comprise a small percentage of the neurological complications that occur post-transplant, the associated morbidity and mortality in an immunosuppressed state makes it imperative to promptly evaluate and aggressively treat a pediatric transplant patient with suspicion for viral meningoencephalitis. This manuscript guides the reader through a broad infectious and non-infectious diagnostic differential in a transplant recipient presenting with altered mentation and fever and thereafter, elaborates on diagnostics and management of viral meningoencephalitis. Hypothetical SOT and HCT patient cases have also been constructed to illustrate the diagnostic and management process in select viral etiologies. Given the unique risk for various opportunistic viral infections resulting in CNS disease among transplant recipients, the manuscript will provide a contemporary review of the epidemiology, risk factors, diagnosis, and management of viral meningoencephalitis in these patients.

La Crosse Virus Neuroinvasive Disease in Children: A Contemporary Analysis of Clinical/Neurobehavioral Outcomes and Predictors of Disease Severity.

BACKGROUND: La Crosse virus (LACV) is the most common neuroinvasive arboviral infection in children in the United States. However, data regarding predictors of disease severity and neurologic outcome are limited. Additionally, long-term neurologic and neurobehavioral outcomes remain relatively sparse. METHODS: This was a single-center, retrospective cohort study, followed by recruitment for a cross-sectional analysis of long-term neurobehavioral outcomes, among children aged 0-18 years with proven or probable LACV neuroinvasive disease (LACV-ND) between January 2009 and December 2018. Case ascertainment was assured by International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification codes cross-referenced with laboratory results detecting LACV. Demographics, diagnostics, radiographs, and outcomes were evaluated. Recruitment of patients with prior diagnosis of LACV-ND occurred from January 2020 to March 2020, with assessment performed by validated pediatric questionnaires. RESULTS: One-hundred fifty-two children (83 males; median age, 8 years [interquartile range, 5-11.5 years]) were diagnosed with proven (n = 61 [47%]) and probable (n = 91 [60%]) LACV-ND. Sixty-five patients (43%) had severe disease. Altered mental status (AMS) (odds ratio [OR], 6.36 [95% confidence interval {CI}, 2.03-19.95]; P = .0002) and seizures at presentation (OR, 10.31 [95% CI, 3.45-30.86]; P = .0001) were independent predictors of severe disease. Epileptiform discharges on electroencephalogram (EEG) were independently associated with epilepsy diagnosis at follow-up (OR, 13.45 [95% CI, 1.4-128.77]; P = .024). Fifty-four patients were recruited for long-term neurobehavioral follow-up, with frequent abnormal assessments identified (19%-54%) irrespective of disease severity. CONCLUSIONS: Severe disease was observed frequently among children with LACV-ND. Seizures and AMS at presentation were independent predictors of severe disease. EEG may help determine long-term epilepsy risk. Long-term neurobehavioral issues are frequent and likely underrecognized among children with LACV-ND.

Adoptive Immunotherapy for Prophylaxis and Treatment of Cytomegalovirus Infection.

Cytomegalovirus (CMV), a member of the Herpesviridae family, is frequent among hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients in absence of antiviral prophylaxis, and is a major cause of morbidity and mortality in these vulnerable populations. Antivirals such ganciclovir, valganciclovir, and foscarnet are the backbone therapies, however drug toxicity and antiviral resistance may render these agents suboptimal in treatment. Newer therapies such as letermovir and maribavir have offered additional approaches for antiviral prophylaxis as well as treatment of drug resistant CMV infection, though may be limited by cost, drug intolerance, or toxicity. Adoptive immunotherapy, the transfer of viral specific T-cells (VSTs), offers a new approach in treatment of drug-resistant or refractory viral infections, with early clinical trials showing promise with respect to efficacy and safety. In this review, we will discuss some of the encouraging results and challenges of widespread adoption of VSTs in care of immunocompromised patients, with an emphasis on the clinical outcomes for treatment and prophylaxis of CMV infection among high-risk patient populations.

Disseminated Toxoplasmosis in a Child Following Allogeneic Hematopoietic Cell Transplantation.

A 23-month old female with hypoplastic myelodysplastic syndrome underwent allogenic hematopoietic cell transplantation (HCT), complicated by development of acute exotropia. Bilateral chorioretinal scars and a ring enhancing brain lesion were identified in further workup. Disseminated toxoplasmosis post-allogeneic HCT was subsequently confirmed by serologic and polymerase chain reaction testing results.

Osteomyelitis Due to Mycobacterium goodii in an Adolescent, United States.

Osteomyelitis is a rare clinical manifestation of infection with nontuberculous mycobacteria (NTM). We report an adolescent with femoral osteomyelitis associated with prosthetic material due to an emerging pathogen, Mycobacterium goodii. Application of secA1 and 16S ribosomal RNA gene sequencing reliably determined the NTM species, enabling targeted antimicrobial therapy.

Blood genome expression profiles in infants with congenital cytomegalovirus infection.

Congenital CMV infection (cCMVi) affects 0.5-1% of all live births worldwide, making it the leading cause of sensorineural hearing loss (SNHL) in childhood. The majority of infants with cCMVi have normal hearing at birth, but are at risk of developing late-onset SNHL. Currently, we lack reliable biomarkers to predict the development of SNHL in these infants. Here, we evaluate blood transcriptional profiles in 80 infants with cCMVi (49 symptomatic, 31 asymptomatic), enrolled in the first 3 weeks of life, and followed for 3 years to assess emergence of late-onset SNHL. The biosignatures of symptomatic and asymptomatic cCMVi are indistinguishable, suggesting that immune responses of infants with asymptomatic and symptomatic cCMVi are not different. Random forest analyses of initial samples in infants with cCMVi, irrespective of their clinical classification, identify a 16-gene classifier signature associated with the development of SNHL with 92% accuracy, suggesting its potential value as a biomarker.

Central Venous Catheter Management in High-risk Children With Bloodstream Infections.

BACKGROUND: National guidelines recommend removal of central venous catheters (CVCs) for central line-associated bloodstream infections (CLABSIs) caused by Staphylococcus aureus, Pseudomonas aeruginosa, and fungi. Data regarding guideline compliance and rates of associated treatment failures in pediatric patients with attempted CVC salvage are limited. METHODS: We performed a retrospective analysis of high-risk children (age ≤ 21 years) hospitalized from 1/2009 to 12/2015 with a long-term CVC and CLABSI due to S. aureus, Pseudomonas spp., and Candida spp. Enterococcus spp. was included given differing management recommendations between short and long-term CVCs. Compliance with national guideline recommendations, as well as treatment failures including infection relapse, recurrence, and death were evaluated in relation to CVC retention or removal. Multivariate logistic regression modeling was performed to account for confounders impacting treatment failure. RESULTS: Fifty-three children had 108 CLABSI episodes requiring 84 hospitalizations. CVCs were removed in 36 (33%) CLABSI episodes per guideline recommendations. Optimal antimicrobial management, including targeted agent and adequate duration was provided in 54 (50%) of 106 treated episodes; no significant difference in treatment failure rates were noted compared with episodes with suboptimal management. The treatment failure rate was significantly higher in patients with CVC retention compared those with CVC removal within 7 days of the first positive blood culture (31% vs. 6%, P = 0.003). CONCLUSIONS: Despite pathogen-specific guideline recommendations for CVC removal, compliance with national guidelines was poor. CVC salvage was attempted in the majority of CLABSI episodes in our cohort and resulted in a significantly higher treatment failure rate.

Pediatric Histoplasmosis in an Area of Endemicity: A Contemporary Analysis.

BACKGROUND: Data on pediatric histoplasmosis have been limited to those from outbreak and case reports. We sought to evaluate the contemporary clinical manifestations, laboratory findings, and outcomes in children with histoplasmosis living in an area of endemicity. METHODS: This study was a single-center retrospective review of proven and probable cases of histoplasmosis in children aged 0 to 18 years between April 2008 and April 2014. Case ascertainment was ensured by us using International Classification of Diseases, Ninth Revision codes cross-referenced with laboratory, microbiology, and histopathology tests that detected Histoplasma capsulatum. Demographics, diagnostics, clinical management, and outcomes were evaluated. RESULTS: Seventy-three children with histoplasmosis (41 males; median age, 13 years [range, 3-18 years]) were diagnosed with proven (n = 17 [23%]) or probable (n = 56 [77%]) histoplasmosis, which manifested as pulmonary (n = 52 [71%]) or disseminated (n = 21 [29%]) disease. Symptoms at presentation were nonspecific; the examination of 21 (29%) patients revealed abnormal physical findings. Detection of H capsulatum by serologic methods occurred in 93% (63 of 68) of the patients tested. Histoplasma antigen in blood or urine was detected in 42% (20 of 48) and 28% (15 of 53) of the patients tested, respectively. The 16 (22%) patients who were immunocompromised had significantly higher rates of disseminated disease (56% vs 21%, respectively; P = .01), antigenuria (62% vs 18%, respectively; P = .004), and antigenemia (69% vs 31%, respectively; P = .02) and longer durations of antigenuria (403 vs 120 days, respectively; P = .003) and antigenemia (451 vs 149 days, respectively; P < .0001) than did the immunocompetent children. CONCLUSIONS: Pediatric histoplasmosis manifests most frequently as pulmonary disease. The highest diagnostic yield was achieved when multiple diagnostic modalities were used. Presentation with disseminated disease and evidence of antigenemia, antigenuria, and delayed antigen clearance were more likely to be seen in immunocompromised children.

Detection of cytomegalovirus in saliva from infants undergoing sepsis evaluation in the neonatal intensive care unit: the VIRIoN-C study.

Objective To determine the frequency of detection of cytomegalovirus (CMV) among infants evaluated for late-onset sepsis in the neonatal intensive care unit (NICU). Methods This study was a prospective cohort study. Results During the 13-month study, 84 infants underwent 116 sepsis evaluations, and CMV DNA was detected in saliva in three (4%) infants (median: gestational age 28 weeks, birth weight 950 g), representing 5% (n=6) of all sepsis evaluations. One infant had CMV DNA detected in saliva in all four sepsis evaluations. Two infants had acquired CMV infection, while the timing of CMV acquisition could not be determined in one infant. Two of the three infants had concomitant Gram-negative bacteremia and urinary tract infections (UTIs), two developed severe bronchopulmonary dysplasia (BPD) and none died. Conclusion Detection of CMV DNA in saliva occurred in 4% of infants and 5% of sepsis evaluations. Persistence of CMV DNA shedding in saliva made attribution of clinical illness difficult to ascertain.

Multiorgan Involvement Confounding the Diagnosis of Bartonella henselae Infective Endocarditis in Children With Congenital Heart Disease.

Two children with congenital heart disease status post surgical correction presented with prolonged constitutional symptoms, hepatosplenomegaly and pancytopenia. Concern for malignancy prompted bone marrow biopsies that were without evidence thereof. In case 1, echocardiography identified a multilobulated vegetation on the conduit valve. In case 2, transthoracic, transesophageal and intracardiac echocardiography were performed and were without evidence of cardiac vegetations; however, pulmonic emboli raised concern for infective endocarditis. Both patients underwent surgical resection of the infected material and had histopathologic evidence of infective endocarditis. Further diagnostics identified elevated cytoplasmic antineutrophil cytoplasmic antibodies and antiproteinase 3 antibodies in addition to acute kidney injury with crescentic glomerulonephritis on renal biopsy. Serologic evidence of infection with Bartonella henselae was observed in both patients. These 2 cases highlight the potential multiorgan involvement that may confound the diagnosis of culture-negative infective endocarditis caused by B. henselae.

Successful Treatment of Bloodstream Infection Due to Metallo-ß-Lactamase-Producing Stenotrophomonas maltophilia in a Renal Transplant Patient.

Stenotrophomonas maltophilia is an emerging multidrug-resistant (MDR) opportunistic pathogen for which new antibiotic options are urgently needed. We report our clinical experience treating a 19-year-old renal transplant recipient who developed prolonged bacteremia due to metallo-ß-lactamase-producing S. maltophilia refractory to conventional treatment. The infection recurred despite a prolonged course of colistimethate sodium (colistin) but resolved with the use of a novel drug combination with clinical efficacy against the patient's S. maltophilia isolate.

Aptamer-based endocytosis of a lysosomal enzyme.

Enzyme replacement therapy for lysosomal storage diseases is currently based on endocytosis of lysosomal enzymes via the mannose or mannose 6-phosphate receptors. We are developing a technology for endocytosis of lysosomal enzymes that depends on generic, chemically conjugated reagents. These reagents are aptamers (single-stranded nucleic acid molecules) selected to bind to the extracellular domain of the mouse transferrin receptor. After selection, an RNA aptamer and a DNA aptamer were modified with biotin and linked to dye-labeled streptavidin for detection by confocal microscopy. Aptamer-streptavidin conjugates showed saturable uptake into mouse fibroblasts (Ltk(-) cells), which could be inhibited by an excess of free aptamer but not by tRNA, calf thymus DNA, or transferrin. The RNA aptamer-streptavidin conjugate was mouse-specific, as human cells (293T) did not take it up unless first transfected with the mouse transferrin receptor. Some streptavidin separated from the recycling pathway of transferrin and colocalized with lysosomes. After characterization in the model system, the DNA aptamer was conjugated to a lysosomal enzyme, alpha-l-iduronidase, from which mannose 6-phosphate had been removed. The aptamer had been modified by attachment of terminal glycerol for oxidation by periodate and reaction of the resulting aldehyde with amino groups on the protein. Dephospho-alpha-L-iduronidase-aptamer conjugate was taken up in saturable manner by alpha-L-iduronidase-deficient mouse fibroblasts, with half-maximal uptake estimated as 1.6 nM. Endocytosed enzyme-aptamer conjugate corrected glycosaminoglycan accumulation, indicating that it reached lysosomes and was functional in those organelles. Both uptake and correction were inhibited by unconjugated aptamer, confirming the role of the aptamer in receptor-mediated endocytosis.