Update on nonpolio enterovirus and parechovirus infections in neonates and young infants.

PURPOSE OF REVIEW: To review the epidemiology, clinical manifestations, and treatment strategies of nonpolio enterovirus and parechovirus (PeV) infections, and identify research gaps. RECENT FINDINGS: There is currently no approved antiviral agent for enterovirus or PeV infections, although pocapavir may be provided on a compassionate basis. Elucidation of the structure and functional features of enterovirus and PeV may lead to novel therapeutic strategies, including vaccine development. SUMMARY: Nonpolio human enterovirus and PeV are common childhood infections that are most severe among neonates and young infants. Although most infections are asymptomatic, severe disease resulting in substantial morbidity and mortality occurs worldwide and has been associated with local outbreaks. Long-term sequelae are not well understood but have been reported following neonatal infection of the central nervous system. The lack of antiviral treatment and effective vaccines highlight important knowledge gaps. Active surveillance ultimately may inform preventive strategies.

Quality improvement methodology can reduce hospitalisation for abscess management.

BACKGROUND: Abscesses are a common reason for ED visits. While many are drained in the ED, some require drainage in the operating room (OR). We observed that a higher percentage of patients at our institution in Columbus, Ohio, were admitted to the hospital with abscesses for incision and drainage (I&D) in the OR than other institutions, including paediatric institutions. Our aim was to decrease hospitalisations for abscess management. METHODS: A multidisciplinary team convened to decrease hospitalisation for patients with abscesses and completed multiple 'Plan-Do-Study-Act' cycles, including increasing I&Ds performed in the ED. Other interventions included implementation of a clinical pathway, training of procedure technicians (PT), updating the electronic medical record (EMR), credentialing advanced practice nurses in sedation and individual follow-up with providers for admitted patients. Data were analysed using statistical process control charts. Gross average charges were assessed. RESULTS: Admissions for I&D decreased from 26.3% to 13.7%. Abscess drainage in the ED improved from 79.3% to 96.5%. Mean length of stay decreased from 19.5 to 11.5 hours for all patients. Patients sedated increased from 3.3% to 18.2%. The number of repeat I&Ds within 30 days decreased from 4.3% to 1.7%. CONCLUSION: We decreased hospitalisations for abscess I&D by using quality improvement methodology. The most influential intervention was an initiative to increase I&Ds performed in the ED. Additional interventions included expanded training of PTs, implementation of a clinical pathway, updating the EMR, improving interdepartmental communication and increasing sedation providers.

Year-Round, Routine Testing of Multiple Body Site Specimens for Human Parechovirus in Young Febrile Infants.

OBJECTIVES: To test our hypothesis that routine year-round testing of specimens from multiple body sites and genotyping of detected virus would describe seasonal changes, increase diagnostic yield, and provide a better definition of clinical manifestations of human parechovirus (PeV-A) infections in young febrile infants. STUDY DESIGN: PeV-A reverse-transcriptase polymerase chain reaction (RT-PCR) analysis was incorporated in routine evaluation of infants aged ≤60 days hospitalized at Nationwide Children's Hospital for fever and/or suspected sepsis-like syndrome beginning in July 2013. We reviewed electronic medical records of infants who tested positive for PeV-A between July 2013 and September 2016. Genotyping was performed with specific type 3 RT-PCR and sequencing. RESULTS: Of 1475 infants evaluated, 130 (9%) tested positive for PeV-A in 1 or more sites: 100 (77%) in blood, 84 (65%) in a nonsterile site, and 53 (41%) in cerebrospinal fluid (CSF). Five infants (4%) were CSF-only positive, 31 (24%) were blood-only positive, and 20 (15%) were nonsterile site-only positive. PeV-A3 was the most common type (85%) and the only type detected in CSF. Although the majority (79%) of infections were diagnosed between July and December, PeV-A was detected year-round. The median age at detection was 29 days. Fever (96%), fussiness (75%), and lymphopenia (56%) were common. Among infants with PeV-A-positive CSF, 77% had no CSF pleocytosis. The median duration of hospitalization was 41 hours. Four infants had bacterial coinfections diagnosed within 24 hours of admission; 40 infants had viral coinfections. CONCLUSIONS: Although most frequent in summer and fall, PeV-A infections were encountered in every calendar month within the 3-year period of study. More than one-half of patients had PeV-A detected at more than 1 body site. Coinfections were common. PeV-A3 was the most common type identified and the only type detected in the CSF.

Tinea faciei caused by Trichophyton benhamiae in a child.

Tinea faciei is a common pediatric skin disease, most often caused by fungi of the genus Trichophyton. T benhamiae has been recently reclassified as a distinct species and is recognized as an emerging zoonotic dermatophyte with a wide range of possible infectious reservoirs worldwide. We present a previously healthy 7-year-old child presenting with unusual inflammatory facial plaques due to T benhamiae, confirmed by mass spectroscopy.

Manifestations of Toxic Shock Syndrome in Children, Columbus, Ohio, USA, 2010-20171.

Data are limited on the incidence and management of streptococcal toxic shock syndrome (TSS) and nonstreptococcal TSS in children. We aimed to define the clinical patterns of TSS at Nationwide Children's Hospital in Ohio as they relate to published criteria, diagnostic decisions, and treatment options. Through retrospective chart reviews, we identified 58 patients with TSS (27 streptococcal, 31 nonstreptococcal) during January 2010-September 2017. We observed clinical and laboratory findings that are not part of TSS criteria, such as pyuria in streptococcal TSS (50% of patients) and pulmonary involvement (85%) and coagulopathy (92%) in nonstreptococcal TSS patients. Recommended treatment with clindamycin and intravenous immunoglobulin was delayed in streptococcal TSS patients without rash (3.37 days vs. 0.87 days in patients with rash), leading to prolonged hospitalization and complications. Incorporation of additional TSS signs and symptoms would be helpful in TSS diagnosis and management.

Irbesartan in Marfan syndrome (AIMS): a double-blind, placebo-controlled randomised trial.

BACKGROUND: Irbesartan, a long acting selective angiotensin-1 receptor inhibitor, in Marfan syndrome might reduce aortic dilatation, which is associated with dissection and rupture. We aimed to determine the effects of irbesartan on the rate of aortic dilatation in children and adults with Marfan syndrome. METHODS: We did a placebo-controlled, double-blind randomised trial at 22 centres in the UK. Individuals aged 6-40 years with clinically confirmed Marfan syndrome were eligible for inclusion. Study participants were all given 75 mg open label irbesartan once daily, then randomly assigned to 150 mg of irbesartan (increased to 300 mg as tolerated) or matching placebo. Aortic diameter was measured by echocardiography at baseline and then annually. All images were analysed by a core laboratory blinded to treatment allocation. The primary endpoint was the rate of aortic root dilatation. This trial is registered with ISRCTN, number ISRCTN90011794. FINDINGS: Between March 14, 2012, and May 1, 2015, 192 participants were recruited and randomly assigned to irbesartan (n=104) or placebo (n=88), and all were followed for up to 5 years. Median age at recruitment was 18 years (IQR 12-28), 99 (52%) were female, mean blood pressure was 110/65 mm Hg (SDs 16 and 12), and 108 (56%) were taking ß blockers. Mean baseline aortic root diameter was 34·4 mm in the irbesartan group (SD 5·8) and placebo group (5·5). The mean rate of aortic root dilatation was 0·53 mm per year (95% CI 0·39 to 0·67) in the irbesartan group compared with 0·74 mm per year (0·60 to 0·89) in the placebo group, with a difference in means of -0·22 mm per year (-0·41 to -0·02, p=0·030). The rate of change in aortic Z score was also reduced by irbesartan (difference in means -0·10 per year, 95% CI -0·19 to -0·01, p=0·035). Irbesartan was well tolerated with no observed differences in rates of serious adverse events. INTERPRETATION: Irbesartan is associated with a reduction in the rate of aortic dilatation in children and young adults with Marfan syndrome and could reduce the incidence of aortic complications. FUNDING: British Heart Foundation, the UK Marfan Trust, the UK Marfan Association.

Clinical and Radiologic Manifestations of Bone Infection in Children with Cat Scratch Disease.

We identified 13 patients with cat scratch (Bartonella henselae) bone infection among those admitted to a large tertiary care children's hospital over a 12-year period. The median age was 7 years and the median time from onset of illness to diagnosis was 10 days. Multifocal osteomyelitis involving spine and pelvis was common; no patient had a lytic bone lesion. Median treatment duration was 28 days (IQR, 24.5 days). Despite significant variations in treatment duration and antimicrobial therapy choices, all patients showed improvement.

Design and rationale of a prospective, collaborative meta-analysis of all randomized controlled trials of angiotensin receptor antagonists in Marfan syndrome, based on individual patient data: A report from the Marfan Treatment Trialists' Collaboration.

RATIONALE: A number of randomized trials are underway, which will address the effects of angiotensin receptor blockers (ARBs) on aortic root enlargement and a range of other end points in patients with Marfan syndrome. If individual participant data from these trials were to be combined, a meta-analysis of the resulting data, totaling approximately 2,300 patients, would allow estimation across a number of trials of the treatment effects both of ARB therapy and of ß-blockade. Such an analysis would also allow estimation of treatment effects in particular subgroups of patients on a range of end points of interest and would allow a more powerful estimate of the effects of these treatments on a composite end point of several clinical outcomes than would be available from any individual trial. DESIGN: A prospective, collaborative meta-analysis based on individual patient data from all randomized trials in Marfan syndrome of (i) ARBs versus placebo (or open-label control) and (ii) ARBs versus ß-blockers will be performed. A prospective study design, in which the principal hypotheses, trial eligibility criteria, analyses, and methods are specified in advance of the unblinding of the component trials, will help to limit bias owing to data-dependent emphasis on the results of particular trials. The use of individual patient data will allow for analysis of the effects of ARBs in particular patient subgroups and for time-to-event analysis for clinical outcomes. The meta-analysis protocol summarized in this report was written on behalf of the Marfan Treatment Trialists' Collaboration and finalized in late 2012, without foreknowledge of the results of any component trial, and will be made available online (http://www.ctsu.ox.ac.uk/research/meta-trials).

Severe hypokalemia probably associated with sertraline use.

OBJECTIVE: To report a case of ventricular fibrillation caused by severe hypokalemia probably associated with sertraline use. CASE SUMMARY: A 48-year-old male patient experienced ventricular fibrillation and cardiac arrest 2 hours after an uneventful coronary angiography procedure, which revealed normal, unobstructed coronary arteries. Blood chemistry was immediately obtained, revealing a very low potassium (K+) level of 2.44 mEq/L. Other blood electrolytes, including magnesium, ECG, and corrected QT intervals, were all within normal limits. A thorough search for an etiology of hypokalemia, including adrenal gland causes, herbal product consumption, and toxic exposure, did not reveal any identifiable cause. This led us to consider the only drug he was on--sertraline 50 mg per day--as the possible culprit. DISCUSSION: There has been no clear identification of severe hypokalemia associated with sertraline use in the literature. However, there have been a considerable number of self-reported cases of hypokalemia in patients on sertraline therapy. Scoring according to the Naranjo adverse drug reaction scale revealed a probable relationship between severe hypokalemia and sertraline use in our patient. No clear pathogenic mechanism for the effect of sertraline on serum K equilibrium is known. However, considering the number of self-reported incidences and this case report, the effect of sertraline on serum K levels warrants consideration. CONCLUSIONS: This is the first documented case report of severe hypokalemia probably associated with sertraline use.

Multisystem inflammatory syndrome in children associated with COVID-19: from pathophysiology to clinical management and outcomes.

Multisystem inflammatory syndrome in children (MIS-C), also known as pediatric inflammatory multisystem syndrome (PIMS), is a new postinfectious illness associated with COVID-19, affecting children after SARS-CoV-2 exposure. The hallmarks of this disorder are hyperinflammation and multisystem involvement, with gastrointestinal, cardiac, mucocutaneous, and hematologic disturbances seen most commonly. Cardiovascular involvement includes cardiogenic shock, ventricular dysfunction, coronary artery abnormalities, and myocarditis. Now entering the fourth year of the pandemic, clinicians have gained some familiarity with the clinical presentation, initial diagnosis, cardiac evaluation, and treatment of MIS-C. This has led to an updated definition from the Centers for Disease Control and Prevention in the USA driven by increased experience and clinical expertise. Furthermore, the available evidence established expert consensus treatment recommendations supporting a combination of immunoglobulin and steroids. However, the pathophysiology of the disorder and answers to what causes this remain under investigation. Fortunately, long-term outcomes continue to look promising, although continued follow-up is still needed. Recently, COVID-19 mRNA vaccination is reported to be associated with reduced risk of MIS-C, while further studies are warranted to understand the impact of COVID-19 vaccines on MIS-C. We review the findings and current literature on MIS-C, including pathophysiology, clinical features, evaluation, management, and medium- to long-term follow-up outcomes.

Ventilator-associated respiratory infections in children on home invasive mechanical ventilation.

Ventilator-associated respiratory tract infections (VARTI) are among the most common indications for hospitalization among children with chronic respiratory failure requiring at-home ventilation. This review aims to provide an overview of the key clinical features, diagnostic approaches, and management strategies for home VARTIs while highlighting the challenges in diagnosis and management.

Use of Advanced Diagnostics for Timely Identification of Travel-associated Leptospira santarosai Infection in Four Adolescents Through Plasma Microbial Cell-free DNA Sequencing With the Karius Test.

BACKGROUND: Leptospirosis is an important zoonotic infection worldwide. Diagnosis of leptospirosis is challenging given its nonspecific clinical symptoms that overlap with other acute febrile illnesses and limitations with conventional diagnostic testing. Alternative advanced diagnostics, such as microbial cell-free DNA (mcfDNA), are increasingly being used to aid in the diagnosis of infections and can be applied to pathogens with public health importance such as Leptospira , a nationally notifiable disease. METHODS: The Karius Test uses plasma mcfDNA sequencing to detect and quantify DNA-based pathogens. This test offered through the Karius lab detected 4 cases of Leptospira santarosai during a 5-month period across the United States in 2021 and were clinically reviewed. RESULTS: In our case series, 4 adolescents with recent travel to Central America (Costa Rica, n = 3 and Belize, n = 1) from April to August 2021 were diagnosed with leptospirosis. While a large workup was performed in all cases, mcfDNA testing was the first test to detect L. santarosai as the microbiological diagnosis in all cases. CONCLUSIONS: Results of the Karius Test enabled rapid, noninvasive diagnosis of leptospirosis allowing for targeted therapy. Use of mcfDNA can be utilized for diagnosis of pathogens where conventional testing is challenging or limited. This in turn can enable quick diagnosis for targeted treatment and potentially aid in supporting case definitions of reportable diseases of public health concern.

Direct Admission Program Implementation: A Qualitative Analysis of Variation Across Health Systems.

OBJECTIVES: Direct admission (DA) to the hospital has the potential to improve family satisfaction and timeliness of care by bypassing the emergency department. Using the RE-AIM implementation framework, we sought to characterize variation across health systems in the reach, effectiveness, adoption, and implementation of a DA program from the perspectives of parents and multidisciplinary clinicians. METHODS: As part of a stepped-wedge cluster randomized trial to compare the effectiveness of DA to admission through the emergency department, we evaluated DA rates across 69 clinics and 3 health systems and conducted semi-structured interviews with parents and clinicians. We used thematic analysis to identify themes related to the reach, effectiveness, adoption, and implementation of the DA program and applied axial coding to characterize thematic differences across sites. RESULTS: Of 2599 hospitalizations, 171 (6.6%) occurred via DA, with DA rates varying 10-fold across health systems from 0.9% to 9.3%. Through the analysis of 137 interviews, including 84 with clinicians and 53 with parents, we identified similarities across health systems in themes related to perceived program effectiveness and patient and family engagement. Thematic differences across sites in the domains of program implementation and clinician adoption included variation in transfer center efficiency, trust between referring and accepting clinicians, and the culture of change within the health system. CONCLUSIONS: The DA program was adopted variably, highlighting unique challenges and opportunities for implementation in different hospital systems. These findings can inform future quality improvement efforts to improve transitions to the hospital.

Multisystem Inflammatory Syndrome in Children and Cardiac Involvement: A Quaternary Center Experience.

We prospectively analyzed clinical and laboratory characteristics associated with cardiac involvement and severe presentation in multisystem inflammatory syndrome in children. Of 146 patients, 66 (45.2%) had cardiac dysfunction and 26 (17.8%) had coronary artery abnormalities. Lower serum albumin levels, absolute lymphocyte and platelet counts, and elevated ferritin, fibrinogen, d-dimer and interleukin-6 levels were associated with cardiac dysfunction. Possible treatment complications were identified.

Metapneumovirus Infections are Uncommon in Infants Younger than 60 Days of Age Admitted for Sepsis Evaluation.

The epidemiology and clinical manifestations of human metapneumovirus are not well studied in infants younger than 60 days of age. In this retrospective review of infants admitted for sepsis evaluation, we identified HMPV less frequently than other viral etiologies via nasopharyngeal multiplex polymerase chain reaction testing; in only 16 (1.9%) infants. Two infants had apneic episodes, but none had wheezing.

Asymptomatic COVID-19 Reinfection in a Pediatric Patient with Heterotaxy Syndrome.

We report an asymptomatic child with heterotaxy syndrome who had recurrent positive SARS-CoV-2 polymerase chain reaction testing. An aberrant lymphocyte population expressing CD19, CD16, and CD56 was identified; its phenotyping revealing atypical NK cells. This subset's role in protection from severe disease or in reinfection cannot be ascertained.

Calcineurin inhibitor treatment of intravenous immunoglobulin-resistant Kawasaki disease.

OBJECTIVE: To describe the clinical course and outcome of 10 patients with Kawasaki disease (KD) treated with a calcineurin inhibitor after failing to respond to multiple therapies. STUDY DESIGN: Demographic and clinical data were prospectively collected using standardized case report forms. T-cell phenotypes were determined by flow cytometry, and KD risk alleles in ITPKC (rs28493229), CASP3 (rs72689236), and FCGR2A (rs1801274) were genotyped. RESULTS: Intravenous followed by oral therapy with cyclosporine (CSA) or oral tacrolimus was well tolerated and resulted in defervescence and resolution of inflammation in all 10 patients. There were no serious adverse events, and a standardized treatment protocol was developed based on our experiences with this patient population. Analysis of T-cell phenotype by flow cytometry in 2 subjects showed a decrease in circulating activated CD8(+) and CD4(+) T effector memory cells after treatment with CSA. However, suppression of regulatory T-cells was not seen, suggesting targeting of specific, proinflammatory T-cell compartments by CSA. CONCLUSION: Treatment of refractory KD with a calcineurin inhibitor appears to be a safe and effective approach that achieves rapid control of inflammation associated with clinical improvement.

Systematic review and meta-analysis of randomized controlled trials on safety and effectiveness of oral anticoagulants for atrial fibrillation in older people.

A meta-analysis of prospective, randomized controlled trials on novel oral anticoagulants (NOACs) versus warfarin, as most commonly used vitamin K antagonists (VKAs), was done to evaluate their effect on stroke risk and bleeding complications in nonvalvular atrial fibrillation (AF) patients. The study aims to evaluate efficacy and safety of NOACs versus warfarin between patients < 75 years and ≥ 75 years old. Prospective, randomized controlled trials (RCTs) comparing NOACs with warfarin with at least 1-year follow-up in nonvalvular AF patients were included. Search was done at MEDLINE, without time and language restriction. "Cochrane risk of bias 2.0 tool" was used to assess risk of bias. In meta-analysis, random effect model was used. Q statistics was used to assess heterogeneity where it was indicated and I2 was used to assess inconsistency across studies. Five studies as RELY, ARISTOTLE, ENGAGE-AF, ROCKET-AF, and J-ROCKET-AF were included. Overall risk of bias was low for trials. Total patient number in meta-analysis was 73,122. Mean age was between 70 and 73 as a whole. Follow-up period was between 499 days and 2.8 years. Analysis of major stroke and systemic embolism was favoring NOACs than warfarin in older patients group period (RR (95% CI) = 0.57 (0.42, 0.76)). Similar trend was seen in younger patient group without statistical significant (RR (95% CI) = 0.74 (0.43, 1.27)). Analysis of major bleeding showed a general statistically significant trend of occurrence of major bleeding in whole group (RR (95% CI) = 0.70 (0.58, 0.86)) with NOACs. In subgroup analysis, it was consistent for both younger and older patients. Older patients have higher stroke risk that leads to more benefit with anticoagulation than younger patients. NOACs have better efficacy profile than warfarin as they decrease stroke more than warfarin, without increasing bleeding risk. Need for real-world data in old population is necessary.