Congenital Cytomegalovirus Targeted Screening Implementation and Outcomes: A Retrospective Chart Review.

OBJECTIVE: To assess the effectiveness and outcomes of a targeted cytomegalovirus (CMV) testing protocol. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care institution. METHODS: Targeted screening for CMV in children who did not pass the newborn hearing screening (NHS) was introduced in July 2015 for the level 2 and 3 nurseries at our hospital. In January 2016, this policy was extended to include all nurseries. Retrospective chart review was performed for all newborns who did not pass their NHS between 2013 and 2020. CMV testing rates and related outcomes were compared before and after rollout. RESULTS: A total of 891 charts were reviewed for infants who did not pass their NHS: 530 (60%) had CMV testing, of which 8 (1.5%) tested positive. Three cases were detected prior to and 5 occurred after initiation of targeted screening. Six CMV+ infants demonstrated hearing loss on confirmatory auditory brainstem response, all of whom began treatment with oral valganciclovir. Hearing remained stable in 3 patients, progressed in 2, and improved in 1. The rate of CMV testing in children who did not pass their NHS increased from 14% to 88% after full implementation of targeted screening (P < .001). The average age at initial infectious disease consultation was significantly younger for infants born after targeted screening (P < .001). CONCLUSION: Targeted screening is a feasible and effective method to identify CMV+ infants early in life. Implementation of a targeted screening program for CMV in children who do not pass the NHS resulted in significantly higher rates of CMV testing and earlier referral to infectious disease.

Ten Years of Newborn Screening for Severe Combined Immunodeficiency (SCID) in Massachusetts.

BACKGROUND: Massachusetts began newborn screening (NBS) for severe combined immunodeficiency (SCID) using measurement of T-cell receptor excision circles (TRECs) from dried blood spots. OBJECTIVE: We describe developments and outcomes from the first 10 years of this program (February 1, 2009, to January 31, 2019). METHODS: TREC values, diagnostic, and outcome data from all patients screened for SCID were evaluated. RESULTS: NBS of 720,038 infants prompted immunologic evaluation of 237 (0.03%). Of 237, 9 were diagnosed with SCID/leaky SCID (4% of referrals vs 0.001% general population). Another 7 were diagnosed with other combined immunodeficiencies, and 3 with athymia. SCID/leaky SCID incidence was approximately 1 in 80,000, whereas approximately 1 in 51,000 had severe T-cell lymphopenia for which definitive treatment was indicated. All patients with SCID/leaky SCID underwent hematopoietic cell transplant or gene therapy with 100% survival. One patient with athymia underwent successful thymus transplant. No known cases of SCID were missed. Compared with outcomes from the 10 years before SCID NBS, survival trended higher (9 of 9 vs 4 of 7), likely due to a lower rate of infection before treatment. CONCLUSIONS: Our data support a single NBS testing-and-referral algorithm for all gestational ages. Despite lower median TREC values in premature infants, the majority for all ages are well above the TREC cutoff and the algorithm, which selects urgent (undetectable TREC) and repeatedly abnormal TREC values, minimizes referral. We also found that low naïve T-cell percentage is associated with a higher risk of SCID/CID, demonstrating the utility of memory/naïve T-cell phenotyping as part of follow-up flow cytometry.

Immunoglobulin A Dysgammaglobulinemia Is Associated with Pediatric-Onset Obsessive-Compulsive Disorder.

Background: Inflammation and immune dysregulation have been implicated in the pathogenesis of pediatric-onset obsessive-compulsive disorder (OCD) and tic disorders such as Tourette syndrome (TS). Though few replicated studies have identified markers of immune dysfunction in this population, preliminary studies suggest that serum immunoglobulin A (IgA) concentrations may be abnormal in these children with these disorders. Methods: This observational retrospective cohort study, conducted using electronic health records (EHRs), identified 206 children with pediatric-onset OCD and 1024 adults diagnosed with OCD who also had testing for serum levels of IgA. IgA deficiency and serum IgA levels in pediatric OCD were compared with IgA levels from children diagnosed with autism spectrum disorders (ASD; n = 524), tic disorders (n = 157), attention-deficit/hyperactivity disorder (ADHD; n = 534), anxiety disorders (n = 1206), and celiac disease, a condition associated with IgA deficiency (n = 624). Results: Compared with ASD and anxiety disorder cohorts, the pediatric OCD cohort displayed a significantly higher likelihood of IgA deficiency (OR = 1.93; 95% CI = 1.18-3.16, and OR = 1.98; 95% CI = 1.28-3.06, respectively), though no difference was observed between pediatric OCD and TS cohorts. Furthermore, the pediatric OCD cohort displayed similar rates of IgA deficiency and serum IgA levels when compared with the celiac disease cohort. The pediatric OCD cohort also displayed the highest percentage of IgA deficiency (15%,) when compared with TS (14%), celiac disease (14%), ADHD (13%), ASD (8%), and anxiety disorder (8%) cohorts. When segregated by sex, boys with OCD displayed a significantly higher likelihood of IgA deficiency when compared with all comparison cohorts except for celiac disease and tic disorders; no significant difference in IgA deficiency was observed between female cohorts. Pediatric OCD subjects also displayed significantly lower adjusted serum IgA levels than the ASD and anxiety disorder cohorts. Adults with OCD were also significantly less likely than children with OCD to display IgA deficiency (OR = 2.71; 95% CI = 1.71-4.28). When compared with children with celiac disease, no significant difference in IgA levels or rates of IgA deficiency were observed in the pediatric OCD cohort. Conclusions: We provide further evidence of IgA abnormalities in pediatric-onset OCD. These results require further investigation to determine if these abnormalities impact the clinical course of OCD in children.

Using Physician-Level Emergency Department Utilization Reports to Address Avoidable Visits by Patients Managed by Pediatric Specialists.

OBJECTIVES: Emergency department (ED) utilization is a major driver of cost. Specialist physicians have an important role in addressing ED utilization, especially at tertiary medical centers that treat highly specialized patients. We analyzed if reporting of ED utilization to pediatric specialist physicians can decrease ED visits. METHODS: Physicians within pediatric neurology, hematology and oncology, infectious diseases, and pulmonary divisions received their ED use reports. By using control charts, we examined if this intervention decreased the rate of ED utilization. RESULTS: Overall, for the 4 divisions, specialty-related ED utilization decreased significantly during all hours, weekdays, and office hours. This was in the setting of ED utilization increasing for all diagnoses ED visits. Pediatric ED volume did not change during the study period. CONCLUSIONS: Physician-level reporting of ED utilization was associated with a reduction in ED use by patients managed by our pediatric specialists.

Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part III-Treatment and Prevention of Infections.

Objectives: Pediatric acute-onset neuropsychiatric syndrome (PANS) and its subset, pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS), are emerging autoimmune encephalopathies of childhood. Management guidelines are needed. This article, from the PANS/PANDAS Consortium, presents a consensus management guideline for the infection components. Accompanying papers from the Consortium discuss psychiatric and immunomodulatory management. Methods: Literature was reviewed and integrated with the clinical experience of the authors to provide a set of practical guidelines. This article was submitted to all members of the PANS/PANDAS Consortium, and their additional comments were added. Results: The relationships between PANS and infections are reviewed. An approach to the retrospective diagnosis of group A streptococcal infection for an operational definition of PANDAS is proposed. An initial course of anti-streptococcal treatment is proposed for all newly diagnosed PANS cases. Chronic secondary antimicrobial prophylaxis is suggested for children with PANDAS who have severe neuropsychiatric symptoms or recurrent group A Streptococcus-associated exacerbations. Guidelines for children with non-streptococcal PANS include vigilance for streptococcal pharyngitis or dermatitis in the patient and close contacts. All patients with PANS or PANDAS should also be closely monitored for other intercurrent infections, including sinusitis and influenza. Intercurrent infections should be diagnosed and treated promptly according to current standard guidelines. A guideline for the assessment of infection at initial onset or during neuropsychiatric exacerbations is also presented. Standard immunizations and attention to vitamin D are encouraged. Data indicating limited utility of adenotonsillectomy and probiotics are presented. Conclusion: A working guideline for the management of infection issues in PANS and PANDAS, based on literature and expert opinion, is provided.

Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part II-Use of Immunomodulatory Therapies.

Introduction: Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a clinically heterogeneous disorder with a number of different etiologies and disease mechanisms. Inflammatory and postinfectious autoimmune presentations of PANS occur frequently, with some clinical series documenting immune abnormalities in 75%-80% of patients. Thus, comprehensive treatment protocols must include immunological interventions, but their use should be reserved only for PANS cases in which the symptoms represent underlying neuroinflammation or postinfectious autoimmunity, as seen in the PANDAS subgroup (Pediatric Autoimmune Neuropsychiatric Disorders associated with Streptococcal infections). Methods: The PANS Research Consortium (PRC) immunomodulatory task force is comprised of immunologists, rheumatologists, neurologists, infectious disease experts, general pediatricians, psychiatrists, nurse practitioners, and basic scientists with expertise in neuroimmunology and PANS-related animal models. Preliminary treatment guidelines were created in the Spring of 2014 at the National Institute of Health and refined over the ensuing 2 years over conference calls and a shared web-based document. Seven pediatric mental health practitioners, with expertise in diagnosing and monitoring patients with PANS, were consulted to create categories in disease severity and critically review final recommendations. All authors played a role in creating these guidelines. The views of all authors were incorporated and all authors gave final approval of these guidelines. Results: Separate guidelines were created for the use of immunomodulatory therapies in PANS patients with (1) mild, (2) moderate-to-severe, and (3) extreme/life-threatening severity. For mildly impairing PANS, the most appropriate therapy may be "tincture of time" combined with cognitive behavioral therapy and other supportive therapies. If symptoms persist, nonsteroidal anti-inflammatory drugs and/or short oral corticosteroid bursts are recommended. For moderate-to-severe PANS, oral or intravenous corticosteroids may be sufficient. However, intravenous immunoglobulin (IVIG) is often the preferred treatment for these patients by most PRC members. For more severe or chronic presentations, prolonged corticosteroid courses (with taper) or repeated high-dose corticosteroids may be indicated. For PANS with extreme and life-threatening impairment, therapeutic plasma exchange is the first-line therapy given either alone or in combination with IVIG, high-dose intravenous corticosteroids, and/or rituximab. Conclusions: These recommendations will help guide the use of anti-inflammatory and immunomodulatory therapy in the treatment of PANS.

Juvenile Mandibular Chronic Osteomyelitis: Role of Surgical Debridement and Antibiotics.

PURPOSE: To document outcomes of management of juvenile mandibular chronic osteomyelitis (JMCO) using a standardized treatment protocol including open biopsy, decortication, microbial culture, and long-term antibiotic therapy. MATERIALS AND METHODS: This was a retrospective case study of pediatric patients with JMCO treated at Massachusetts General Hospital for Children from 1996 through 2014. Inclusion criteria included age younger than 18 years, diagnosis of JMCO, management by the protocol, adequate clinical and radiographic data in the record, and follow-up of at least 1 year after initial treatment. Inpatient and outpatient records were reviewed for demographics, clinical and radiographic findings, and histologic and laboratory evaluations. The predictor variable was the standardized treatment protocol and the primary outcome variables were disease status at end of treatment and complications of treatment. RESULTS: Twenty patients (mean age at onset, 10.7 yr; range, 3 to 14 yr) were treated, 12 (11 girls) of whom met the inclusion criteria. Management of all patients consisted of biopsy (extraoral when feasible, n = 9; intraoral, n = 3), decortication, cultures, and long-term antibiotic therapy. Nonsteroidal anti-inflammatory drugs (NSAIDs) were administered only as needed for pain control. There was complete resolution of osteomyelitis with no recurrence in 7 of 12 patients (mean follow-up, 4.3 yr; range, 1 to 11 yr). Five patients had partial responses, with decreased frequency and severity of disease recurrence. These were well controlled with short courses of antibiotics (4 to 12 weeks) with NSAIDs only as needed for pain control (mean follow-up, 1.4 yr; range, 1 to 3 yr). There were no major complications related to antibiotic therapy. Minor complications included rash (n = 2), nausea and vomiting (n = 1), and vaginal candidiasis (n = 1). CONCLUSION: The results of this study indicate that 58.3% of patients were cured and had no recurrent symptoms (mean follow-up, 4.3 yr). The remaining patients continue on intermittent treatment with antibiotics for recurrent episodes of swelling and pain. Favorable responses to antibiotic therapy support the hypothesis that JMCO is an infectious disease and that negative cultures might represent a failure of standard culture techniques to isolate the responsible organisms.

Clinical evaluation of youth with pediatric acute-onset neuropsychiatric syndrome (PANS): recommendations from the 2013 PANS Consensus Conference.

On May 23 and 24, 2013, the First PANS Consensus Conference was convened at Stanford University, calling together a geographically diverse group of clinicians and researchers from complementary fields of pediatrics: General and developmental pediatrics, infectious diseases, immunology, rheumatology, neurology, and child psychiatry. Participants were academicians with clinical and research interests in pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS) in youth, and the larger category of pediatric acute-onset neuropsychiatric syndrome (PANS). The goals were to clarify the diagnostic boundaries of PANS, to develop systematic strategies for evaluation of suspected PANS cases, and to set forth the most urgently needed studies in this field. Presented here is a consensus statement proposing recommendations for the diagnostic evaluation of youth presenting with PANS.

Cerebrospinal fluid proteome of patients with acute Lyme disease.

During acute Lyme disease, bacteria can disseminate to the central nervous system (CNS), leading to the development of meningitis and other neurologic symptoms. Here we have analyzed pooled cerebrospinal fluid (CSF) allowing a deep view into the proteome for patients diagnosed with early disseminated Lyme disease and CSF inflammation. Additionally, we analyzed individual patient samples and quantified differences in protein abundance employing label-free quantitative mass spectrometry-based methods. We identified 108 proteins that differ significantly in abundance in patients with acute Lyme disease from controls. Comparison between infected patients and control subjects revealed differences in proteins in the CSF associated with cell death localized to brain synapses and others that likely originate from brain parenchyma.

Incidence of catheter-associated bloodstream infection after introduction of minocycline and rifampin antimicrobial-coated catheters in a pediatric burn population.

The Centers for Disease Control and Prevention guidelines for prevention of intravascular catheter-related infections suggest that antimicrobial-coated catheters can decrease the risk of developing catheter-related bloodstream infection in a variety of adult patient populations. There are limited data on their efficacy in the pediatric population, particularly among children with burn injuries. A study was conducted at Shriners Hospitals for Children®, Boston, to determine whether minocycline/rifampin (MR)-coated catheters could decrease the incidence of catheter-associated bloodstream infection (CABSI) in a pediatric burn population. A historical control group included all patients with double- or triple-lumen catheters inserted in the 18-month period from January 2006 to June 2007. The study group included all patients with MR antimicrobial double- or triple-lumen catheters inserted in the subsequent 18-month period, July 2007 to December 2008. Data collected included name, age, date of burn/injury, date of admission, percent TBSA area burn injury or other diagnosis, catheter site (subclavian, internal jugular, or femoral), method of insertion (new percutaneous stick or guidewire), type of catheter (double or triple lumen), date inserted, duration of catheter placement (days), and positive blood cultures recovered while the central venous catheter was in place. CABSI was defined using the Centers for Disease Control and Prevention definition of laboratory-confirmed bloodstream infection. There were a total of 66 patients with 252 catheters (1780 catheter days) in the control group and 75 patients with 263 catheters (1633 catheter days) in the study group. Age, percent burn injury, catheter site, and method of insertion were not statistically different between the two groups. The percentage of infected catheters and the rate of infection were significantly different for the two groups, with the MR antimicrobial catheters only half as likely to become infected. In a subset of these patients with catheters in place for more than 4 days, the percentage of infected catheters and rate of infection were also significantly different with results similar to those in the entire group. MR antimicrobial-coated catheters significantly reduced the incidence of CABSI in this pediatric burn population compared with noncoated catheters.

Guidelines for implementation of population-based newborn screening for severe combined immunodeficiency.

Severe combined immunodeficiency (SCID) is a Primary Immune Deficiency that is under consideration for population-based newborn screening (NBS) by many NBS programs, and has recently been recommended for inclusion in the US uniform panel of newborn screening conditions. A marker of SCID, the T cell receptor excision circle (TREC), is detectable in the newborn dried blood spot using a unique molecular assay as a primary screen. The New England Newborn Screening Program developed and validated a multiplex TREC assay in which both the TREC analyte and an internal control are acquired from a single punch and run in the same reaction. Massachusetts then implemented a statewide pilot SCID NBS program. The authors describe the rationale for a pilot SCID NBS program, a comprehensive strategy for successful implementation, the screening test algorithm, the screening follow-up algorithm and preliminary experience based on statewide screening in the first year. The Massachusetts experience demonstrates that SCID NBS is a program that can be implemented on a population basis with reasonable rates of false positives.

The ATP-dependent helicase RUVBL1/TIP49a associates with tubulin during mitosis.

RUVBL1/TIP49a/Pontin52 is a recently identified multi-functional protein with 2 ATP binding (WALKER) sites, which is essential for cell proliferation. We recovered and identified RUVBL1/TIP49a as a tubulin-binding protein from Triton X-100 lysates of U937 promonocytic cells by protein affinity chromatography and tryptic peptide microsequencing. Performing co-immunoprecipitation using newly generated RUVBL1/TIP49a-specific antibodies (mAb and rabbit polyclonal Ab) and RUVBL1/TIP49a-GST fusion protein-pull down assays we demonstrate co-precipitation of alpha- and gamma tubulin with RUVBL1/TIP49a. Confocal immunoflourescence microscopy reveals that RUVBL1/TIP49a was present not only in the nucleus, as expected, but was also concentrated at the centrosome and at the mitotic spindle in colocalization with tubulin. The topology of RUVBL1/TIP49a at the mitotic spindle varied, depending on the mitotic stage. The protein was localized at the centrosome and at the polar and astral microtubules in metaphase, and was detectable at the zone of polar tubule interdigitation in anaphase B and telophase. During cytokinesis the protein reappeared at the area of decondensing chromosomes. Whereas preincubation of U937 cells with colcemid resulted in inhibition of mitotic spindle formation with subsequent loss of RUVBL1/TIP49a mitotic spindle staining, no relevant influence of colcemid on RUVBL1/TIP49a-tubulin binding was observed. An agonistic effect of RUVBL1/TIP49a on in vitro tubulin assembly is demonstrated. Our results reveal a new functional aspect of RUVBL1/TIP49a.

Bilateral cavernous sinus thromboses and intraorbital abscesses secondary to Streptococcus milleri.

PURPOSE: To report the first case of bilateral cavernous sinus thromboses and bilateral intraorbital abscesses secondary to Streptococcus milleri. STUDY DESIGN: Single interventional case report. INTERVENTION AND TESTING: The findings of the ophthalmic evaluation, radiographic imaging, medical and surgical intervention, specimen cultures, and clinical course were analyzed. RESULTS: A 17-year-old female had bilateral proptosis, decreased vision in the left eye, and altered mental status at presentation. An orbital compartment syndrome developed in the left eye and purulent material was present after lateral canthotomy, suggestive of an intraorbital abscess. Magnetic resonance imaging (MRI) scans revealed bilateral cavernous sinus thromboses, and subsequent computed tomographic (CT) scans revealed bilateral intraorbital abscesses in the setting of acute ethmoid and sphenoid sinusitis. Antibiotic treatment and surgical drainage of the orbital abscess and sinuses was performed, and specimen cultures revealed S. milleri. After surgery, the patient experienced hearing loss and a right internal capsule infarct, in addition to complete vision loss in the left eye. A second intraorbital abscess developed in the right eye and was drained surgically. The vision remained 20/20. CONCLUSIONS: Streptococcus milleri is a virulent organism with a propensity to form abscesses in multiple areas of the body and should be considered as a possible etiologic agent in abscess formation of the orbit and cavernous sinus thrombosis.

The complement response against an oncolytic virus is species-specific in its activation pathways.

A variety of oncolytic viruses (OVs) are being tested in clinical trials for different human cancers. Although the innate immune response is critical as the first line of defense in thwarting viral infection of mammalian cells, little is known of this response in the context of OV therapy of tumors. Investigations of activities against a herpes simplex OV demonstrated that HSV-seronegative sera from rats, mice, and humans efficiently neutralize this OV in vitro. Although this neutralization is due to complement, activation of this innate host defense differs in its pathways among species routinely used in preclinical tumor trials. In rats, both natural immunoglobulins and mannan-binding lectin (MBL) activate complement against the OV, while in mice only MBL is relevant to this activation. However, in humans only natural immunoglobulins play a role in complement activity. Quantitative analyses confirm that in vivo complement depletion facilitates the initial infection of tumors by systemic OVs. Therefore, complement activation against oncolytic HSV vectors proceeds through different pathways in different species. These findings are relevant to preclinical rodent studies of OV therapy and their application to human clinical trials.

Impact and management of Campylobacter in human medicine--US perspective.

Viruses, enteric bacteria and parasites can all produce similar syndromes of acute enteritis, although the pathophysiology and molecular pathogenesis may vary widely. The severity of acute enteritis varies greatly, and only a small fraction of cases undergo medical evaluation. There are over 200 000 000 episodes of acute enteritis annually in the USA, of which approximately 75 000 000 are foodborne. Fewer than 20% of estimated cases have a known etiology. Nearly half of the more than 4 000 000 cases of known foodborne bacterial enteritis are attributed to Campylobacter infections. The FoodNet active population-based surveillance system has demonstrated geographic variation in the incidence of Campylobacter infection, and generally declining incidence since 1996. Campylobacter jejuni infections vary in severity and duration. Antimicrobial therapy, especially if administered early, may hasten clinical resolution by 2-3 days. Therapy is generally restricted to individuals with moderate-to-severe disease and high-risk individuals (underlying immunodeficiency, chronic illness, extremes of age, etc.). Approximately 10-15% of C. jejuni isolates are fluoroquinolone resistant, although most strains are macrolide susceptible. Several acute intra-abdominal as well as extraintestinal complications can occur following C jejuni enteritis, although bacteremia and metastatic infection are rare, except in high-risk patients. Post-infectious syndromes include post-dysenteric bowel dysfunction, the less frequent but more severe reactive arthritis (1%), and Guillain-Barre syndrome (0.1%). The recent demonstration that antibiotic administration for Escherichia coli O157:H7 hemorrhagic enteritis increases the risk of hemolytic-uremic syndrome 5-10-fold forces reconsideration of empirical broad-spectrum antibiotic therapy for acute hemorrhagic enteritis, and supports narrow-spectrum erythromycin therapy for acute enteritis.