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A 7-year-old boy presented to the emergency department with fever, cough, congestion, abdominal pain, myalgias, and morbilliform rash. Several aspects of the patient’s history, including recent travel, living on a farm, exposure to sick contacts, and new medications, resulted in a wide differential diagnosis. Initial laboratory testing revealed leukocytosis with neutrophilia and elevated atypical lymphocytes, but did not reveal any infectious causes of illness. He was discharged from the hospital, but then represented to the emergency department a day later with worsening rash, continued fever, abdominal pain, and poor intake. He was then admitted. A more comprehensive laboratory evaluation was initiated. During this hospital course, the patient’s physical examination changed when he developed head and neck edema, and certain laboratory trends became clearer. With the assistance of several specialists, the team was able to reach a more definitive diagnosis and initiate treatment to appropriately manage his condition.

* Abbreviations: COVID-19 — : coronavirus disease 2019 nAb — : neutralizing antibody SARS-CoV-2 — : severe acute respiratory syndrome coronavirus 2 After having coronavirus disease 2019 (COVID-19), patients develop a humoral immune response thought to protect against reinfection, but antibody levels can decline over time. Understanding how long antibody levels remain high enough to prevent infection is important in understanding, absent vaccination, whether children may be vulnerable to COVID-19 and in modeling how COVID-19 spreads through the population. The levels of antibodies capable of neutralizing the virus (neutralizing antibodies [nAbs]) provide a direct marker of a protective humoral immune response. The nAbs can be measured directly by determining how well a patient’s serum inactivates virus when a known amount of virus is placed on cells in tissue culture, which is known as a plaque reduction neutralization test. The remarkably safe and effective approved COVID-19 vaccines elicit potent antibody responses against portions of the virus mediating attachment to host cells and viral entry, the spike protein and its receptor-binding domain. The concentration of antibodies a patient has against spike … Address correspondence to: Andrea T. Cruz, Department of Pediatrics, Baylor College of Medicine, 6621 Fannin St, Suite A2210, Houston, TX 77030. E-mail: acruz{at}bcm.edu

Multisystem inflammatory syndrome in children (MIS-C) is a serious, sometimes life-threatening late complication of coronavirus disease 2019 (COVID-19) with multiorgan involvement and evidence of immune activation. The pathogenesis of MIS-C is not known, nor is the pathogenesis of the severe organ damage that is the hallmark of MIS-C. Human herpesvirus 6 (HHV-6), the virus responsible for roseola, is a ubiquitous herpesvirus that causes close to universal infection by the age of 3 years. HHV-6 remains latent for life and can be activated during inflammatory states, by other viruses, and by host cell apoptosis. HHV-6 has been associated with end-organ diseases, including hepatitis, carditis, and encephalitis. In addition, ∼1% of people have inherited chromosomally integrated human herpesvirus 6 (iciHHV-6), which is HHV-6 that has been integrated into chromosomal telomeric regions and is transmitted through the germ line. iciHHV-6 can be reactivated and has been associated with altered immune responses. We report here a case of MIS-C in which an initial high HHV-6 DNA polymerase chain reaction viral load assay prompted testing for iciHHV-6, which yielded a positive result. Additional research may be warranted to determine if iciHHV-6 is commonly observed in patients with MIS-C and, if so, whether it may play a part in MIS-C pathogenesis.

* Abbreviations: COVID-19 — : coronavirus disease 2019 MIS-C — : multisystem inflammatory syndrome in children RBD — : receptor-binding domain S — : severe acute respiratory syndrome coronavirus 2 spike protein SARS-Co-V-2 — : severe acute respiratory syndrome coronavirus 2 Coronavirus disease 2019 (COVID-19) is arguably the most socially and economically disruptive pandemic since the 1918 influenza pandemic. Although pediatric COVID-19 shares features with the adult disease, there are several differences. Children produce virus in amounts at least equal to adults, if not higher,1 and can transmit the virus, just as adults can.2 School-aged children are generally less-severely affected than infants or adults, but some children without significant underlying disease become ill or die in a disease process analogous to the one most commonly seen in adults: severe pulmonary disease and respiratory failure.3–6 Children and adults appear to have different humoral immune responses to COVID-19.7 A small fraction of children with COVID-19 experience a hyperinflammatory process,8–13 termed multisystem inflammatory syndrome in children (MIS-C) in the United States, with features distinct from Kawasaki disease.14 This case definition includes ≥2 of these symptoms: rash, conjunctivitis, or mucocutaneous inflammation; hypotension; cardiac disease; coagulopathy; or acute gastrointestinal problems.15 MIS-C, which is not correlated with viral load levels, typically appears some time after initial infection.13 MIS-C’s incidence is difficult to determine, given the high rate of asymptomatic infection.12 Adults with COVID-19 also can experience inflammatory disorders: coagulopathies, vasculitis, cardiomyositis, and neuroinflammatory processes.16–18 That the most effective therapy to reduce mortality in adults with severe COVID-19 yet established is an immune suppressant, dexamethasone,19 reveals the importance of inflammatory and immune-mediated pathologies. In this issue of … Address correspondence to Steven Zeichner, MD, PhD, Department of Pediatrics, University of Virginia, Box 801349, Charlottesville, VA 22908. E-mail: zeichner{at}virginia.edu

* Abbreviation: COVID-19 — : coronavirus disease of 2019 The impact of the coronavirus disease of 2019 (COVID-19), which is caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2,1 has been widespread, with >500 000 cases diagnosed in >170 countries since the virus was identified in January 2020.2 The preliminary data have been focused on severe respiratory manifestations, which are seen predominantly in adults, with scant initial data on the burden of COVID-19 in children.3 We, therefore, read with interest the findings of Dong et al,4 who reported in this issue of Pediatrics a series of >2000 children with suspected or confirmed COVID-19. The authors found that 4% of virologically confirmed cases had asymptomatic infection, and this rate almost certainly understates the true rate of asymptomatic infection because many children who are asymptomatic are unlikely to be tested. Among children who were symptomatic, 5% had dyspnea or hypoxemia (a substantially lower percentage than what has been reported for adults3), and 0.6% progressed to acute respiratory distress syndrome or multiorgan system dysfunction (a rate that is also lower than that seen in adults). Preschool-aged children and infants were more likely than older children to have severe clinical manifestations. There are several salient points … Address correspondence to Andrea T. Cruz, MD, MPH, Department of Pediatrics, Baylor College of Medicine, 6621 Fannin St, Suite A2210, Houston, TX 77030. E-mail: acruz{at}bcm.edu

A 16-year-old girl presented to the emergency department with intermittent fevers and worsening abdominal pain of 5 weeks duration. She had a history of travel to a less developed country and exposure to possible infectious diseases. Abdominal imaging and blood tests revealed diffuse mesenteric lymphadenopathy, elevated transaminases, and elevation of inflammatory markers. Gastroesophageal and colon endoscopies revealed gastric ulcers, and the patient was discharged with a presumptive diagnosis of systemic juvenile idiopathic arthritis given the lymphadenopathy seen on imaging, serositis, sacroiliac joint stiffness noted on physical examination, and pain relief with celecoxib. She presented again 4 days later with worsening abdominal tenderness, elevated transaminases, and new-onset abdominal distention. Tissue biopsy yielded the diagnosis and directed appropriate treatment.

Objective. To characterize the type and frequency of biochemical lipid abnormalities and physical changes in body composition associated with the use of protease inhibitor (PI)-containing antiretroviral therapy among human immunodeficiency virus-infected children treated for up to 6 years. Methods. A retrospective study of human immunodeficiency virus-infected pediatric patients enrolled in research protocols between August 1995 and December 2001 was performed. All patients who had received a PI for ≥2 years as part of their investigational antiretroviral treatment regimens during the study period were eligible. Of the 110 patients identified as having received PI therapy, 94 met the study criteria. Results. Of the 94 patients evaluated, 9 patients (10%) developed fat redistribution as well as dyslipidemia, 49 patients (52%) developed dyslipidemia without associated physical changes, and 36 patients (38%) exhibited no elevation of lipid levels or physical signs of fat redistribution. For all 9 patients with fat redistribution, the onset of the physical changes was closely associated with changes during pubertal development. Fat redistribution was also associated with lower viral loads and higher, more sustained levels of dyslipidemia. The onset of dyslipidemia and fat redistribution peaked between 10 and 15 years of age. Conclusion. Among pediatric patients receiving PI therapy, there seems to be an age range in which children are at greater risk of developing hypercholesterolemia and subsequent fat redistribution, suggesting that unidentified physiologic changes associated with puberty may predispose pediatric patients treated with PI therapy to developing lipodystrophy.

OBJECTIVE. Tenofovir disoproxil fumarate, a nucleotide analog HIV reverse transcriptase inhibitor with demonstrated activity against nucleoside-resistant HIV, is approved for use in adults but not children. Metabolic bone abnormalities have been seen in young animals given high-dose tenofovir and HIV-infected adults that were treated with oral tenofovir disoproxil fumarate. However, tenofovir disoproxil fumarate is being used in children despite a lack of bone safety data. We hypothesized that, given the higher rate of bone turnover that is associated with normal skeletal growth, the potential for TDF-related bone toxicity may be greater in children than in adults. METHODS. Fifteen highly antiretroviral-experienced HIV-infected children who were 8 to 16 years of age (mean ± SD: 12 ± 2) and required a change in therapy received tenofovir disoproxil fumarate 175 to 300 mg/m2 per day (adult dose equivalent) as part of highly active antiretroviral therapy for up to 96 weeks. Bone mineral density of the lumbar spine, femoral neck, and total hip by dual-energy x-ray absorptiometry and blood and urine markers of bone metabolism were measured at 0, 24, 48, 72, and 96 weeks. RESULTS. Median z score (SD score compared with age, gender, and ethnicity-matched control subjects) of the lumbar spine, femoral neck, and total hip were decreased from baseline at 24 weeks and 48 weeks and then stabilized. Lumbar spine bone mineral apparent density (which estimates volumetric bone mineral density independent of bone size) z scores also decreased at 24 weeks. Absolute decreases in bone mineral density were observed in 6 children; the mean age of these children was significantly younger than the bone mineral density stable group (10.2 ± 1.1 vs 13.2 ± 1.8 years). The change in lumbar spine bone mineral density correlated with decreases in HIV plasma RNA during treatment. Metabolic markers of bone formation and resorption were variable. Two children in whom tenofovir disoproxil fumarate was discontinued because of bone loss that exceeded protocol allowances demonstrated partial or complete recovery of bone mineral density by 96 weeks. CONCLUSIONS. Tenofovir disoproxil fumarate use in children seems to be associated with decreases in bone mineral density that, in some children, stabilize after 24 weeks. Increases in bone markers and calcium excretion suggest that tenofovir disoproxil fumarate may stimulate bone resorption. Bone turnover is higher in children than in older adolescents and adults because of skeletal growth, potentially explaining the greater effect seen in young children. Decreases in bone mineral density correlate with decreases in viral load and young age, suggesting that young responders may be at greater risk for bone toxicity.

Objectives. Highly active antiretroviral therapy has altered the course of HIV infection among children, but new antiretroviral agents are needed for treatment-experienced children with drug-resistant virus. Tenofovir disoproxil fumarate (DF) is a promising agent for use in pediatric salvage therapy, because of its tolerability, efficacy, and resistance profile. We designed this study to provide preliminary pediatric safety and dosing information on tenofovir DF, while also providing potentially efficacious salvage therapy for heavily treatment-experienced, HIV-infected children.Methods. Tenofovir DF, alone and in combination with optimized background antiretroviral regimens, was studied among 18 HIV-infected children (age range: 8.3–16.2 years) who had progressive disease with ≥2 prior antiretroviral regimens, in a single-center, open-label trial. Tenofovir DF monotherapy for 6 days was followed by the addition of individualized antiretroviral regimens. Subjects were monitored with HIV RNA reverse transcription-polymerase chain reaction, flow cytometry, and routine laboratory studies; monitoring for bone toxicity included measurement of lumbar spine bone mineral density (BMD) with dual-energy x-ray absorptiometry. Subjects were monitored through 48 weeks.Results. Two subjects developed grade 3 elevated hepatic transaminase levels during monotherapy and were removed from the study. The remaining 16 subjects had a median of 4 antiretroviral agents (range: 3–5 agents) added to tenofovir DF. HIV plasma RNA levels decreased from a median pretreatment level of 5.4 log10 copies per mL (range: 4.1–5.9 log10 copies per mL) to 4.21 log10 copies per mL at week 48 (n = 15), with 6 subjects having 6% decrease in BMD for 5 of 15 subjects evaluated at week 48, necessitating the discontinuation of tenofovir DF therapy for 2; all 5 subjects experienced >2 log10 copies per mL decreases in HIV plasma RNA levels.Conclusions. Tenofovir DF-containing, individualized, highly active antiretroviral therapy regimens were well tolerated and effective among heavily treatment-experienced, HIV-infected children. Loss of BMD may limit tenofovir DF use among prepubertal patients.

This case series describes 4 children with vertically acquired human immunodeficiency virus (HIV) infection who exhibited immunologic, virologic, and clinical stability while on a protease inhibitor-containing highly active antiretroviral therapy (HAART) regimen, yet demonstrated significant cognitive decline as measured by standardized intelligence tests.A retrospective review of 107 patient records of children with HIV infection on HAART treatment protocols was conducted. Four patients were identified who responded to protease inhibitor-containing HAART therapy with sustained viral load suppression, and stable immunologic and medical parameters, yet demonstrated significant cognitive decline. Such discordance between biological and clinical markers previously has been reported in adults with HIV disease but not in children. This observed decline in neurocognitive functioning despite stable medical parameters suggests that HAART regimens that are effective for systemic disease may not be as effective for the central nervous system (CNS), perhaps because the antiretrovirals do not penetrate adequately into the CNS.Of note, 3 of these 4 patients did not have zidovudine (ZDV) included in their HAART regimen. The only patient who was treated with ZDV containing regimen received 90 mg/m2 every 6 hours, which is at the lower end of the recommended ZDV pediatric full-dose range (90 mg/m2 to 120 mg/m2). Two of the 4 patients began ZDV at 120 mg/m2 every 6 hours following the decline in their cognitive test scores and subsequently showed improved or stable functioning as evidenced by the results of follow-up psychometric testing.Long-term prospective studies using both systemic and CNS measures are necessary to further investigate the effects of HAART in children with HIV disease. Longitudinal cognitive assessments of children receiving HAART appear indicated to identify cognitive decline and to provide appropriate therapeutic intervention when manifestations of HIV-related CNS disease progression occur.