Clinical Features and Follow-up of Referred Children and Young People With Long COVID.

BACKGROUND: Patient-level data on the clinical features and outcomes of children and young people referred for possible long coronavirus disease (COVID) can guide clinicians on what to expect in managing patients and advising families. METHODS: A Post-Acute COVID Clinic for persons <21 years of age was established in October 2020. Intake was standardized and management was tailored to presenting symptoms. Data were abstracted from the charts of all patients evaluated through December 2021, and the study cohort consisted of patients who had a history of confirmed severe acute respiratory syndrome coronavirus 2 infection, had ≥1 symptom persisting for ≥12 weeks and had no pre-existing diagnosis that explained the symptoms. A structured follow-up interview was conducted in early 2022. RESULTS: A total of 104 patients were referred, 81 of whom met inclusion criteria. The median age was 14 years (interquartile range, 13-16), and most were female, White/Caucasian and had commercial health insurance. Patients reported previously good health but over half reported moderate-to-severe disability at their first visit. Two clusters of presenting symptoms-fatigue with multiple symptoms, and fatigue and headache with cardiopulmonary symptoms-were identified. Extensive routine testing did not affirm alternative diagnoses. Incident conditions-most commonly anxiety, depression and/or panic disorder; migraines; and autonomic dysfunction-were diagnosed on clinical grounds. Telephone interviews (N = 55) revealed that 78% of patients were improved by about 6 months. CONCLUSIONS: Within the limits of a single-center, referral-based, observational cohort, this study provides reassurance to patients and parents in that most cases of long COVID were self-limited. Extensive evaluations may be more useful in ruling out alternative diagnoses than in affirming specific physiologic disturbances.

Spotting a potential threat: Measles among pediatric solid organ transplantation recipients.

BACKGROUND: Low-vaccination rates worldwide have led to the re-emergence of vaccine-preventable infections, including measles. Immunocompromised patients, including pediatric solid organ transplant (SOT) recipients, are at risk for measles because of suboptimal vaccination, reduced or waning vaccine immunity, lifelong immunosuppression, and global re-emergence of measles. OBJECTIVES: To review published cases of measles in pediatric SOT recipients to heighten awareness of its clinical manifestations, summarize diagnostic and treatment strategies, and identify opportunities to optimize prevention. METHODS: We conducted a literature review of published natural measles infections in SOT recipients ≤21 years of age, summarizing management and outcomes. We describe measles epidemiology, recommended diagnostics, treatment, and highlight prevention strategies. RESULTS: There are seven published reports of measles infection in 12 pediatric SOT recipients, the majority of whom were unvaccinated or incompletely vaccinated. Subjects had atypical or severe clinical presentations, including lack of rash and complications, most frequently with encephalitis and pneumonitis, resulting in 33% mortality. Updated recommendations on testing and vaccination are provided. Treatment options beyond supportive care and vitamin A are limited, with no approved antivirals. CONCLUSION: While measles is infrequently reported in pediatric SOT recipients, morbidity and mortality remain significant. A high index of suspicion is warranted in susceptible SOT recipients with clinically compatible illness or exposure. Providers must recognize this risk, educate families, and be aware of both classic and atypical presentations of measles to rapidly identify, isolate, and diagnose measles in pediatric SOT recipients. Continued efforts to optimize measles vaccination both pre- and post-SOT are warranted.

Return to School and COVID-19 Vaccination for Pediatric Solid Organ Transplant Recipients in the United States: Expert Opinion for 2021-2022.

The COVID-19 pandemic continues to generate challenges for pediatric solid organ transplant (SOT) recipients and their families. As rates of COVID-19 fluctuate, new SARS-CoV-2 variants emerge, and adherence to and implementation of mitigation strategies vary from community to community, questions remain about the best and safest practices to prevent COVID-19 in vulnerable patients. Notably, decisions about returning to school remain difficult. We assembled a team of specialists in pediatric infectious diseases, transplant infectious diseases, public health, transplant psychology, and infection prevention and control to re-address concerns about school re-entry, as well as COVID-19 vaccines, for pediatric SOT recipients in the United States in 2021. Based on available literature and guidance from national organizations, we generated expert statements specific to pediatric SOT recipients focused on school attendance in 2021.

Standardized Vaccine-Hesitant Patients in the Assessment of the Effectiveness of Vaccine Communication Training.

OBJECTIVES: To determine if training residents in a structured communication method elicits specific behaviors in a laboratory model of interaction with vaccine-hesitant parents. STUDY DESIGN: Standardized patients portraying vaccine-hesitant parents were used to assess the effectiveness of training in the Announce, Inquire, Mirror, Secure (AIMS) Method for Healthy Conversations. Blinded pediatric residents were pseudorandomized to receive AIMS or control training and underwent pre- and post-training encounters with blinded standardized patients. Encounters were assessed by blinded raters using a novel tool. Participant confidence and standardized patient evaluations of the participants' general communication skills were assessed. RESULTS: Ratings were available for 27 AIMS and 26 control participants. Statistically significant increases in post-training scores (maximum = 30) were detected in AIMS, but not in control, participants (median, 21.3 [IQR, 19.8-24.8] vs 18.8 [IQR, 16.9-20.9]; P < .001). Elements (maximum score = 6) with significant increases were Inquire (0.67 [IQR, 0-1.76] vs -0.33 [IQR, -0.67 to 0.33]; P < .001); Mirror (1.33 [IQR, 0 to 2] vs -0.33 [IQR, -0.92 to 0]; P < .001) and Secure (0.33 [IQR, 0 to 1.67] vs -0.17 [IQR, -0.67 to 0.33]; P = .017). Self-confidence increased equally in both groups. Standardized patients did not detect a difference in communication skills after training and between groups. Internal consistency and inter-rater reliability of the assessment tool were modest. CONCLUSIONS: Standardized patients proved useful in studying the effectiveness of structured communication training, but may have been limited in their ability to perceive a difference between groups owing to the predetermined encounter outcome of vaccine refusal. AIMS training should be studied in real-world scenarios to determine if it impacts vaccine acceptance.

Safety, Tolerability, and Population Pharmacokinetics of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients.

Isavuconazole, administered as the water-soluble prodrug isavuconazonium sulfate, is a new triazole agent used to treat invasive fungal infections. This phase 1 study evaluated the pharmacokinetics (PK), safety, and tolerability of isavuconazole in 46 immunocompromised pediatric patients, stratified by age (1 to <6 [intravenous (i.v.) only], 6 to <12, and 12 to <18 years), receiving 10 mg/kg body weight (maximum, 372 mg) isavuconazonium sulfate either i.v. or orally. A population PK model using weight-based allometric scaling was constructed with the pediatric i.v. and oral data plus i.v. data from a phase 1 study in adults. The best model was a 3-compartment model with combined zero-order and first-order input, with linear elimination. Stepwise covariate modeling was performed in Perl-speaks-NONMEM version 4.7.0. None of the covariates examined, including age, sex, race, and body mass index, were statistically significant for any of the PK parameters. The area under the concentration-time curve at steady state (AUCSS) was predicted for pediatric patients using 1,000 Monte Carlo simulations per age cohort for each administration route. The probability of target attainment (AUCSS range, 60 to 233 µg · h/ml) was estimated; this target range was derived from plasma drug exposures in adults receiving the recommended clinical dose. Predicted plasma drug exposures were within the target range for >80% and >76% of simulated pediatric patients following i.v. or oral administration, respectively. Intravenous and oral administration of isavuconazonium sulfate at the studied dosage of 10 mg/kg was well tolerated and resulted in exposure in pediatric patients similar to that in adults. (This study has been registered at ClinicalTrials.gov under identifier NCT03241550).

Management of Hepatitis C in Children and Adolescents.

The management of hepatitis C virus (HCV) infections has changed dramatically in recent years with the use of direct antiviral agents (AADs). New AADs have excellent safety profile and demonstrated to be highly effective. Interferon free regimens are now recommended for children and adolescents but significant barriers for treatment exist. Overcoming those barriers will facilitate HCV elimination. This review covers varied topics to familiarize providers with the current status of pediatric HCV management in light of newly available DAAs medications.

Return to School for Pediatric Solid Organ Transplant Recipients in the United States During the Coronavirus Disease 2019 Pandemic: Expert Opinion on Key Considerations and Best Practices.

The coronavirus disease 2019 (COVID-19) pandemic has created many challenges for pediatric solid organ transplant (SOT) recipients and their families. As the pandemic persists, patients and their families struggle to identify the best and safest practices for resuming activities as areas reopen. Notably, decisions about returning to school remain difficult. We assembled a team of pediatric infectious diseases (ID), transplant ID, public health, transplant psychology, and infection prevention and control specialists to address the primary concerns about school reentry for pediatric SOT recipients in the United States. Based on available literature and guidance from national organizations, we generated consensus statements pertaining to school reentry specific to pediatric SOT recipients. Although data are limited and the COVID-19 pandemic is highly dynamic, our goal was to create a framework from which providers and caregivers can identify the most important considerations for each pediatric SOT recipient to promote a safe return to school.

Immunization Adherence in Children With Sickle Cell Disease: A Single-Institution Experience.

OBJECTIVES: The Advisory Committee on Immunization Practices (ACIP) recommends additional immunizations for people with asplenia or functional asplenia, such as children with sickle cell disease. Adherence rate to the recommended immunization schedule for functional asplenia remains low for children with sickle cell disease. The purpose of this study was to assess the immunization adherence for this population at a single institution in Kentucky and to evaluate the use of the Kentucky Immunization Registry (KYIR) by providers. METHODS: A single-center retrospective chart review was conducted for 107 children with sickle cell disease ages 2 through 18 years. Immunization histories were obtained from the hospital EMRs, the sickle cell clinic EMR, the KYIR, and by requesting records from primary care physicians. Each patient was documented as either missing or having complete records in the KYIR. RESULTS: The complete adherence rate to the ACIP-recommended immunization schedule for children with functional asplenia was 6% (6 of 107). Nearly all children were compliant with the Haemophilus influenzae type B vaccination, whereas the adherence rate for the meningococcal and pneumococcal vaccines ranged from 25% to 77%. The lowest immunization rate was observed in children eligible for the meningococcal B vaccine (25%). Only 3 patients had a complete immunization history documented in the KYIR. CONCLUSIONS: Adherence to the ACIP-recommended immunization schedule for functionally asplenic patients is poor among children with sickle cell disease included in this study. Quality improvement measures should focus on increasing immunization adherence and improving documentation of immunization records in the KYIR for this patient population.

Long-term Health Outcomes of Patients Evaluated for Unexplained Fever in a Pediatric Infectious Diseases Clinic.

A telephone interview was conducted with parents of 120 children seen in a pediatric infectious diseases clinic for unexplained fever who received no definitive diagnosis or were thought to have recurrent self-limited illnesses. Only 3 were diagnosed with a fever-related condition after 8 years of follow-up. The majority remained well.

Immunogenicity and safety of a quadrivalent inactivated influenza vaccine in children 6-59 months of age: A phase 3, randomized, noninferiority study.

BACKGROUND: In the Southern Hemisphere 2010 influenza season, Seqirus' split-virion, trivalent inactivated influenza vaccine was associated with increased reports of fevers and febrile reactions in young children. A staged clinical development program of a quadrivalent vaccine (Seqirus IIV4 [S-IIV4]; Afluria® Quadrivalent/Afluria Quad™/Afluria Tetra™), wherein each vaccine strain is split using a higher detergent concentration to reduce lipid content (considered the cause of the increased fevers and febrile reactions), is now complete. METHODS: Children aged 6-59 months were randomized 3:1 and stratified by age (6-35 months/36-59 months) to receive S-IIV4 (n = 1684) or a United States (US)-licensed comparator IIV4 (C-IIV4; Fluzone® Quadrivalent; n = 563) during the Northern Hemisphere 2016-2017 influenza season. The primary objective was to demonstrate noninferior immunogenicity of S-IIV4 versus C-IIV4. Immunogenicity was assessed by hemagglutination inhibition (baseline, 28 days postvaccination). Solicited, unsolicited, and serious adverse events were assessed for 7, 28, and 180 days postvaccination, respectively. RESULTS: S-IIV4 met the immunogenicity criteria for noninferiority. Adjusted geometric mean titer ratios (C-IIV4/S-IIV4) for the A/H1N1, A/H3N2, B/Yamagata, and B/Victoria strains were 0.79 (95% CI: 0.72, 0.88), 1.27 (1.15, 1.42), 1.12 (1.01, 1.24), and 0.97 (0.86, 1.09), respectively. Corresponding values for differences in seroconversion rates (C-IIV4 minus S-IIV4) were -10.3 (-15.4, -5.1), 2.6 (-2.5, 7.8), 3.1 (-2.1, 8.2), and 0.9 (-4.2, 6.1). Solicited, unsolicited, and serious adverse events were similar between vaccines in both age cohorts, apart from fever. Fever rates were lower with S-IIV4 (5.8%) than C-IIV4 (8.4%), with no febrile convulsions reported with either vaccine during the 7 days postvaccination. CONCLUSION: S-IIV4, manufactured with a higher detergent concentration, demonstrated noninferior immunogenicity to the US-licensed C-IIV4, with similar postvaccination safety and tolerability, in children aged 6-59 months. This completes the program demonstrating the immunogenicity and safety of S-IIV4 in participants aged 6 months and older. FUNDING: Seqirus Pty Ltd; ClinicalTrials.gov identifier:NCT02914275.

Evaluation of Prolonged and Recurrent Unexplained Fevers.

Fever is a common symptom in children. Some children may present to their primary care physician with undifferentiated fever; that is, fever for which there is no obvious source from the history or physical examination. Undifferentiated fevers may be prolonged or recurrent. Distinguishing between the two is helpful for narrowing the differential diagnosis, which can be broad and include infections and inflammatory diseases and, rarely, malignancies and autoinflammatory disorders. The evaluation of such children requires a step-wise approach. Taking a detailed history, performing a thorough physical examination, and reviewing a fever and symptom diary is crucial in recognizing clues that may ultimately lead to a diagnosis. Some children who look good and whose fever disappears may never have a diagnosis, whereas referral to a specialist may be prudent for others. [Pediatr Ann. 2018;47(9):e347-e353.].

Oligoarticular Hemarthroses and Osteomyelitis Complicating Pasteurella Meningitis in an Infant.

A 5-month-old previously healthy female presented with a one-week history of fever and increased fussiness. Her presentation revealed an ill-appearing infant with an exam and cerebrospinal fluid (CSF) studies concerning bacterial meningitis; CSF cultures grew Pasteurella multocida. Additionally, brain magnetic resonance imaging (MRI) demonstrated cervical osteomyelitis. Despite multiple days of antibiotic therapy, she remained febrile with continued pain; MRI showed oligoarticular effusions, and aspiration of these joints yielded bloody aspirates. Evaluations for coagulopathy and immune complex-mediated arthropathy were negative. The patient improved following appropriate antibiotic therapy and spontaneous resolution of hemarthroses, and was discharged to a short-term rehabilitation hospital. P. multocida is a small, encapsulated coccobacillus that is part of the commensal oral flora of animals. It most commonly causes skin infections in humans, yet is a rare cause of meningitis in the pediatric population, especially in children <1 year of age. Transmission due to P. multocida is most commonly due to direct contact with animals. To our knowledge, this is the first case of oligoarticular hemarthroses and cervical osteomyelitis complicating P multocida meningitis. This case highlights the physician's potential for cognitive bias and premature anchoring, and the resulting implications in delivering excellent patient care.

Characteristics of Patients Referred to a Pediatric Infectious Diseases Clinic With Unexplained Fever.

BACKGROUND: Older case series established diagnostic considerations for children meeting a priori definitions of fever of unknown origin (FUO). No recent study has examined the final diagnoses of children referred for unexplained fever. METHODS: This study was conducted with a retrospective chart review of patients referred to a pediatric infectious diseases clinic from 2008 to 2012 for unexplained fever. RESULTS: Sixty-nine of 221 patients were referred for "prolonged" unexplained fever. Ten of these were not actually having fever, and 11 had diagnoses that were readily apparent at the initial visit. The remaining 48 were classified as having FUO. The median duration of reported fever for these patients was 30 days; 15 had a diagnosis made, 5 of which were serious. None of the serious FUO diagnoses were infections. Of 152 patients with "recurrent" unexplained fever, 92 had an "intermittent" fever pattern, and most of these had sequential, self-limited viral illnesses or no definitive diagnosis made. Twenty of the 60 patients with a "periodic" fever pattern were diagnosed with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome. Overall, 166 patients either were not having fever, had self-limited illnesses, or ultimately had no cause of fever discovered. Only 12 had a serious illness, 2 of which were infections (malaria and typhoid fever). CONCLUSIONS: Most children referred with unexplained fever had either self-limited illnesses or no specific diagnosis established. Serious diagnoses were unusual, suggesting that these diagnoses rarely present with unexplained fever alone, or that, when they do, the diagnoses are made by primary care providers or other subspecialists.