Serum proteomics reveals hemophagocytic lymphohistiocytosis-like phenotype in a subset of patients with multisystem inflammatory syndrome in children.

Children with Multisystem Inflammatory Syndrome in Children (MIS-C) can present with thrombocytopenia, which is a key feature of hemophagocytic lymphohistiocytosis (HLH). We hypothesized that thrombocytopenic MIS-C patients have more features of HLH. Clinical characteristics and routine laboratory parameters were collected from 228 MIS-C patients, of whom 85 (37%) were thrombocytopenic. Thrombocytopenic patients had increased ferritin levels; reduced leukocyte subsets; and elevated levels of ASAT and ALAT. Soluble IL-2RA was higher in thrombocytopenic children than in non-thrombocytopenic children. T-cell activation, TNF-alpha and IFN-gamma signaling markers were inversely correlated with thrombocyte levels, consistent with a more pronounced cytokine storm syndrome. Thrombocytopenia was not associated with severity of MIS-C and no pathogenic variants were identified in HLH-related genes. This suggests that thrombocytopenia in MIS-C is not a feature of a more severe disease phenotype, but the consequence of a distinct hyperinflammatory immunopathological process in a subset of children.

Eliciting and stop dose during oral food challenges for peanut and common tree nuts in different age groups.

BACKGROUND: Oral food challenges (OFCs) are used to confirm or reject a diagnosis of food allergy. However, younger children may encounter difficulties in consuming all offered doses during an OFC in the absence of symptoms, resulting in inconclusive outcomes. Our aim is to assess the eliciting dose for objective symptoms among various age groups and determine the necessity of consuming the final dose step during an uneventful OFC to avoid false negative outcomes. METHODS: OFCs for common food allergens performed between 2012 and 2019 were analyzed retrospectively. The primary outcome was the association of age with stop dose for OFCs with inconclusive outcome. Secondary outcome measures were the association of age with eliciting dose and the potential number of false negative outcomes. RESULTS: A total of 1327 OFCs were performed in 707 patients. Of these, 514 (38.7%) were positive, 589 (44.4%) negative, and 224 (16.9%) inconclusive. In OFCs with inconclusive outcome, age appeared to be a significant predictor of the stop dose only for almond (p = .005). Objective symptoms occurred after the last dose step in 2%-13% of all OFCs with positive outcome. In our cohort, potential false negative outcomes may have been drawn in 27.6% of uneventful OFCs. CONCLUSIONS: Two third of children under 6 years of age successfully consumed all the provided doses during OFCs with a negative outcome. The eliciting dose for objective symptoms was not associated with age, and in a substantial number of OFCs with positive outcome, symptoms occurred after eating the final dose. These findings suggest that in case of an uneventful OFC, the outcome should be drawn only after a cumulative dose of 4.4 g has been consumed to avoid the risk of a potential false negative outcome.

Conservative Treatment of Parapneumonic Effusion in Children: Experience From a 10-Year Consecutive Case Series.

BACKGROUND: In children with parapneumonic effusion (PPE), it remains unclear when conservative treatment with antibiotics suffixes or when pleural drainage is needed. In this study we evaluate clinical features and outcomes of children with PPE. METHODS: A retrospective, multicentre cohort study at 4 Dutch pediatric departments was performed, including patients 1-18 years treated for PPE between January 2010 and June 2020. RESULTS: One hundred thirty-six patients were included (mean age 8.3 years, SD 4.8). 117 patients (86%) were treated conservatively and 19 (14%) underwent pleural drainage. Patients undergoing pleural drainage had mediastinal shift more frequently compared with conservatively treated patients (58 vs. 3%, difference 55%; 95% CI: 32%-77%). The same accounted for pleural septations/pockets (58 vs. 11%, difference 47%; 95% CI: 24%-70%), pleural thickening (47 vs. 4%, difference 43%; 95% CI: 20%-66%) and effusion size (median 5.9 vs. 2.7 cm; P = 0.032). Conservative management was successful in 27% of patients (4 of 15) with mediastinal shift, 54% of patients (13 of 24) with septations/pockets, 36% of patients (5 of 14) with pleural thickening, and 9% of patients (3 of 32) with effusions >3 cm, all radiological signs generally warranting pleural drainage. In patients treated conservatively, median duration of hospitalization was 5 days (IQR 4-112) compared with 19 days (IQR 15-24) in the drainage group ( P < 0.001), without significant difference in readmission rate (11 vs. 4%, difference 6%; 95% CI: -8%-21%). CONCLUSION: This study suggests that the greater amount of children with PPE could be treated conservatively with antibiotics only, especially in absence of mediastinal shift, pleural septations/pockets, pleural thickening or extensive effusions.

Detection of Salivary Tryptase Levels in Children following Oral Food Challenges.

BACKGROUND: Oral food challenge (OFC) is commonly used to diagnose food allergy. This test is time and resource intensive, and conclusions are not always unequivocal as this relies on the interpretation of symptoms. Therefore, an objective marker would improve the accuracy of the diagnostic workup of food allergy. OBJECTIVES: The aim of this study was to investigate whether tryptase can be detected in saliva of children following OFC. METHOD: Children from 3 to 18 years of age were eligible for inclusion if an OFC for peanut or tree nut had been recommended. Saliva samples were collected prior to the first dose and 5, 10, and 15 min following the last administered dose during OFC. Assay precision, spike-and-recovery, and assessment of lower limit of detection of the tryptase immunoassay were examined before analysis of tryptase in saliva was performed. RESULTS: A total of 30 children were included (median age 8 years, 63.3% male, 53.3% positive OFC outcome). Tryptase was detected in saliva samples. The mean of the change in baseline tryptase value to each saliva collecting time point was significantly different in patients with a positive OFC outcome compared to a negative outcome (p < 0.01). CONCLUSIONS: This study showed that tryptase can be detected in saliva of children following OFC. Increased levels of tryptase compared to baseline were found if the OFC outcome was positive, suggesting that measuring tryptase in saliva may be useful in the diagnosis of food allergy. Further research is needed to evaluate the potential association between tryptase levels and symptoms.

The dilemma of open or double-blind food challenges in diagnosing food allergy in children: Design of the ALDORADO trial.

BACKGROUND: It is of major importance to diagnose food allergy accurately. Current guidelines support the use of oral food challenges to do so. The double-blind placebo-controlled food challenge (DBPCFC) has been regarded as the 'gold standard' for decades. However, DBPCFCs are costly, and time- and resource-intensive procedures. Structural implementation of less demanding open food challenges will only find support if research demonstrates that their outcome is comparable to DBPCFC, yet this has been proven difficult to investigate. METHODS: We performed a literature review to investigate the diagnostic accuracy of oral food challenges and interviewed 19 parents of children with proven or suspected food allergy about the design of a trial to study this. RESULTS: An overview of the dilemma of diagnosing food allergy using oral food challenges, and the methodological issues and parents' opinions to study this. No comparative studies have been performed using the latest guidelines on oral food challenges. CONCLUSIONS: There is an urgent need to investigate the diagnostic accuracy of different oral food challenge protocols. We present the rationale and design of the ALDORADO trial (ALlergy Diagnosed by Open oR DOuble-blind food challenge) that has been set up to investigate whether the outcome of the open food challenge is comparable to DBPCFC.

Can the Childhood Physical Activity Questionnaire Be Used to Identify Physical Activity Levels in Children With Asthma?

Objective: Children with asthma who are physically active have a better quality of life, emphasizing the importance of activity monitoring and promotion in daily life. The validity of self-reported activity measurements has been questioned in pediatric populations. In this study, we aim to compare the Physical Activity Questionnaire for Children (PAQ-C) with objectively measured PA using accelerometry. Design: In this comparison study, the pooled dataset of two cross-sectional studies was used, which prospectively home-monitored PA using the alternative self-report PAQ-C questionnaire as well as with the criterion standard accelerometry (Actigraph wGT3X-BT and GT1M). Participants:Ninety children with pediatrician-diagnosed asthma participated in the study. Main Outcome Measures:Correlation coefficients were calculated to determine the relation between the PAQ-C and accelerometer data. The predictive value of the PAQ-C in differentiating between achieving and failing the recommended daily level of moderate-to-vigorous activity (MVPA) was evaluated with receiver operator characteristic (ROC) analysis. Results: The results showed weak to moderate correlations of the PAQ-C with the accelerometer data (r = 0.29-0.47). A PAQ-C cutoff of 3.09 showed the best performance on predicting whether the recommended level of MVPA was achieved. With this cutoff, 21 of the 39 children that did achieve their daily MVPA level (53.8% sensitivity) and 33 of the 46 children that did fail their daily MVPA level (71.7% specificity) were correctly classified. A PAQ-C score of 3.5 revealed a negative predictive value of 100% for assessing physical inactivity. Conclusion: This study revealed a weak relation between the PAQ-C and PA assessed with accelerometry. However, a PAQ-C score of 3.5 or higher might be used as a low-cost and easy-to-use PA screening tool for ruling out physical inactivity in a portion of the pediatric asthma population. Clinical Trial Registration: Netherlands Trial Register: Trial NL6087.

Multicentre study found that adherence to national antibiotic recommendations for neonatal early-onset sepsis was low.

AIM: Our aim was to evaluate adherence to the Dutch neonatal early-onset sepsis (EOS) guidelines, adapted from UK guidance. We also looked at the effect on antibiotic recommendations and duration. METHOD: This was a multicentre, prospective observational cross-sectional study carried out in seven hospitals in the Netherlands between 1 September 2018 and 1 November 2019. We enrolled 1024 neonates born at 32 weeks of gestation or later if they demonstrated at least one EOS risk factor or clinical signs of infection. RESULTS: The Dutch guidelines recommended antibiotic treatment for 438/1024 (42.8%) of the neonates designated at risk, but only 186/438 (42.5%) received antibiotics. The guidelines advised withholding antibiotics for 586/1024 (57.2%) of neonates and in 570/586 (97.3%) cases the clinicians adhered to this recommendation. Blood cultures were obtained for 182/186 (97.8%) infants who started antibiotics and only four were positive, for group B streptococci. Antibiotic treatment was continued for more than 3 days in 56/178 (31.5%) neonates, despite a negative blood culture. CONCLUSION: Low adherence to the Dutch guidelines meant that the majority of neonates did not receive the antibiotic treatment that was recommended, while some antibiotic use was prolonged despite negative blood cultures. The guidelines need to be revised.

Nurse-driven Clinical Pathway Based on an Innovative Asthma Score Reduces Admission Time for Children.

We recently demonstrated that an innovative asthma score independent of auscultation could accurately predict the requirement for bronchodilator nebulization compared to the physician's routine clinical judgment to administer bronchodilators. We aimed to standardize inpatient care for children with acute asthma by implementing a clinical pathway based on this innovative asthma score. METHODS: We designed a nurse-driven clinical pathway. This pathway included standardized respiratory assessments and a protocol for the nursing staff to administer bronchodilators without a specific order from the physician. We compared the length of stay and the number of readmissions to a historical cohort. RESULTS: Seventy-nine patients with moderate acute asthma completed the pathway. We obtained a total of 858 Childhood asthma scores in these patients, with a median of 11 scores per patient (interquartile range 8-17). Patients treated according to the nurse-driven protocol were 3.3 times more likely to be discharged earlier (hazard ratio, 3.29; 95% confidence interval, 2.33-4.66; P < 0.05), and length of stay was significantly reduced (median 28 versus 53 h) compared to the historical standard practice. On request, the attending physician assessed the patient's respiratory status 42 times (4.9% of all childhood asthma score assessments). Patient safety was not compromised, and none of the patients were removed from the pathway. In each group, we readmitted two (2.5%) patients within 1 week after discharge. CONCLUSION: This nurse-driven clinical pathway for children with acute asthma based on an asthma score independent of auscultation findings significantly decreased length of stay without compromising patient safety.

Successful introduction of milk after a negative double-blind placebo-controlled food challenge test is independent of the total dose and milk product used during the challenge test.

BACKGROUND: Failure of milk introduction after a negative food challenge test is reported in a substantial number of patients. For this reason, guidelines recommend that the total dose of milk protein for a food challenge test should be comparable to a normal serving. OBJECTIVE: Our aim is to compare the success rate of milk introduction after a negative double-blind placebo-controlled challenge test performed with different doses of milk protein and different milk products. METHODS: We conducted a retrospective chart review of 485 patients challenged with a low or high dose of milk protein. Pasteurized milk and milk protein powder were used for the low-dose challenge tests, and condensed milk for the high-dose challenge tests. Successful introduction was defined as regular milk consumption, and discontinuation of further introduction due to the reappearance of symptoms as unsuccessful introduction. We also evaluated the association between milk products and successful introduction. RESULTS: The outcome of 288 (59.4%) double-blind placebo-controlled food challenge tests was negative. There were no significant differences between the low and high dose of milk protein in patient characteristics, percentage of patients lost to follow-up (15% vs 20%), in whom introduction had not yet been performed (4% vs 3.1%), reappearance of symptoms (18% vs 17%), and successful introduction (88.0% and 83.4%). Age, gender, specific immunoglobulin E for milk, dose of milk protein, and atopy were not associated with successful introduction. Children who experienced symptoms during the introduction were less likely to consume milk (P < .001). There was a nonsignificant trend toward higher successful introduction rate if pasteurized milk was used as test material compared to milk protein powder, and condensed milk. CONCLUSION AND CLINICAL RELEVANCE: Successful introduction of milk after a negative challenge test is independent of the total dose of milk protein, and milk product used during the challenge test.

Attenuated salivary cortisol response after exercise test in children with asthma.

OBJECTIVE: The clinical relevance of lower basal cortisol levels in children with asthma is unclear. We compared the salivary cortisol response after a standardized exercise test in children with asthma versus the salivary cortisol response in healthy children. METHODS: Nineteen prepubertal children with asthma and 20 prepubertal healthy children performed a standardized exercise test twice. Salivary cortisol levels were determined before exercise and immediately and 15 min after exercise. Morning salivary cortisol levels were determined from saliva collected at home. RESULTS: Salivary cortisol levels increased in 84.2% of the healthy children compared to 35.0% in children with asthma after the 20-m shuttle-run test. Median increase in salivary cortisol levels was 200.3% [95% confidence interval (CI), 141.8-346.1] in healthy children compared to 89.8% (95% CI, 56.9-181.6) in children with asthma. The response was not related to the morning salivary cortisol level or maintenance dose of inhaled corticosteroids. The mean time to exhaustion of both shuttle-run tests was significantly shorter in children with asthma (mean difference 1.4 min; 95% CI, 0.7-2.3). None of the children had to stop because of dyspnea. CONCLUSION: Our study demonstrates that children with asthma using a maintenance dose of inhaled corticosteroids (ICS) have an attenuated salivary cortisol response compared with healthy children.

An innovative childhood asthma score predicts the need for bronchodilator nebulization in children with acute asthma independent of auscultative findings.

BACKGROUND: We sought to compare the accuracy of a newly developed childhood asthma score (CAS) with routine clinical assessment of respiratory status in children with acute asthma in predicting requirements for bronchodilator nebulization. METHODS: In this prospective observational study in children 2-18 y old with acute asthma, we evaluated the association between the CAS and routine clinical assessment as well as inter-rater agreement. RESULTS: The need for bronchodilator nebulization was assessed during 134 episodes of acute asthma in 47 children. Overall, bronchodilators were administered after routine clinical assessment in 74 episodes (55.2%). The median CAS was 2.5 (interquartile range of 2.0-3.0) for subjects who did not receive nebulization and 6.0 (interquartile range of 4.0-7.0) for subjects who did receive nebulization (P < .001). A CAS cutoff score of 4 yielded a sensitivity of 0.91 (95% CI 0.84-0.97) and a specificity of 0.77 (95% CI 0.66-0.87), with a positive predictive value of 0.83 (95% CI 0.75-0.91) and a negative predictive value of 0.87 (95% CI 0.78-0.96). In 79 episodes, the CAS was assessed by 2 independent raters. With a weighted kappa of 0.77, a good inter-rater agreement was obtained. CONCLUSIONS: Using a cutoff value of 4, the newly developed CAS accurately predicts the requirement for bronchodilator nebulization in children with acute asthma without use of auscultative findings.

Children with asthma have significantly lower long-term cortisol levels in their scalp hair than healthy children.

AIM: Noninvasive measurement of long-term cortisol levels is a useful way of evaluating the effect of chronic disease on the hypothalamic-pituitary-adrenal axis in children. The aim of this pilot study was to compare hair cortisol levels in children using inhaled corticosteroids for asthma and healthy children and to determine the association with short-term salivary cortisol levels. METHODS: Cortisol levels were measured in the scalp hair and saliva of prepubertal children with asthma (n = 10) and without asthma (n = 10). Asthma control was assessed using an asthma questionnaire and pulmonary function tests. RESULTS: The median (95% CI) cortisol level in the scalp hair of the children with asthma (2.0 pg/mg; 1.4-4.1) was significantly lower than the healthy children (4.3 pg/mg; 1.8-5.9). Morning salivary cortisol levels were significantly lower for the children with asthma (5.9 nmol/L; 3.2-11.1) than the healthy children (9.0 nmol/L; 4.4-31.6). There was no significant association between cortisol levels in hair and saliva. CONCLUSION: Long-term cortisol levels were significantly lower in children with asthma than healthy children. Measuring long-term cortisol levels in scalp hair is an attractive, noninvasive tool that can evaluate the effect of asthma and its treatment on the hypothalamic-pituitary-adrenal axis.

Non-invasive measurement of adrenal response after standardized exercise tests in prepubertal children.

OBJECTIVE: To determine the feasibility of non-invasive evaluation of adrenal response in healthy prepubertal children by standardized exercise tests. METHODS: On separate occasions, healthy prepubertal children performed a submaximal cycling test, a maximal cycling test, and a 20-m shuttle-run test. Salivary cortisol levels were determined before exercise, and 1 and 15 min after exercise. RESULTS: Immediately after cessation of the cycling and shuttle-run tests, salivary cortisol levels remained unchanged or decreased. Fifteen minutes after the shuttle-run test, salivary cortisol levels increased significantly. This increase in salivary cortisol levels was not observed 15 min after the cessation of the cycling tests. CONCLUSION: The results of this study demonstrate a different response in salivary cortisol levels after standardized cycling and running tests in prepubertal children. The increase in salivary cortisol levels found after a short standardized running test suggests that this may be a practical non-invasive method for evaluating adrenal response in healthy prepubertal children.

A rare presentation of cleidocranial dysplasia.

Cleidocranial dysplasia (CCD) is a rare skeletal dysplasia characterised by a defect in ossification. Frequently reported clinical findings are delayed closure of the fontanelles and cranial sutures, hypoplastic clavicles, dental abnormalities and short stature. Our patient suffered from complete absence of ossification of both parietal bones. This is a rare and severe defect that has been reported in only a few patients with CCD.

Occult pneumonia in a child.

We describe the case of a 10-year-old boy who presented with high fever, vomiting and diarrhoea. There were no respiratory symptoms and auscultation and percussion of the lungs were normal. The combination of the clinical picture with a high C reactive protein value prompted us to perform a diagnostic work-up. A chest radiograph showed abscess formation in a lobar pneumonia in the right upper lobe and intravenous antibiotic therapy was started. The patient recovered and treatment was continued with oral antibiotics. Radiologically confirmed pneumonia in a febrile patient without respiratory symptoms is described as occult pneumonia. An increased number of leucocytes and/or an increased C reactive protein value can predict occult pneumonia in febrile children. This case highlights the diagnostic challenge of pneumonia in febrile children without respiratory symptoms and reminds clinicians to consider occult pneumonia in the differential diagnosis of fever without source.

Salivary cortisol levels in prepubertal children using inhaled corticosteroids with or without concurrent intranasal corticosteroids.

BACKGROUND: Inhaled corticosteroids (ICS) and intranasal steroids (INS) are frequently co-administered in children with asthma and rhinitis. In contrast to monotherapy with ICS or INS, little is known about the safety of concurrent use of topical steroids on hypothalamic-pituitary-adrenal (HPA) axis function in prepubertal children. OBJECTIVE: Comparison of morning salivary cortisol levels in prepubertal children using maintenance treatment with ICS with and without concurrent use of INS to steroid naïve control groups (healthy children, and children with constipation who are under pediatric care). METHODS: Cross-sectional observational study in prepubertal children (6-12 years) using ICS alone (n = 41) or in combination with INS (n = 22), compared to different control groups with no steroid treatment (18 healthy children, and 28 children with constipation). Morning salivary cortisol levels were determined from saliva samples collected at home. RESULTS: The morning salivary cortisol levels of the healthy children (8.7 nmol/L; 95% CI 5.9-18.8), and the children with constipation (8.9 nmol/L; 8.0-11.3) were comparable. The salivary cortisol levels of prepubertal children using ICS (median 4.7 nmol/L; 95% CI 4.6-6.9) or a combination of ICS and INS (5.1 nmol/L; 4.2-7.6) were comparable, but significantly reduced compared to both control groups. There was no correlation between salivary cortisol level and age, duration of disease, or cumulative daily dose of topical steroids. CONCLUSION: Salivary cortisol levels in prepubertal children using ICS, with or without concurrent use of INS, were comparable. However, salivary cortisol levels were significantly reduced compared to steroid naïve controls, irrespective of the cumulative daily dose of topical steroids. Pediatr. Pulmonol. 2011; 46:1055-1061. © 2011 Wiley Periodicals, Inc.

Arthritis associated with antithyroid therapy in a 15-year-old girl.

A 15-year-old white girl with autoimmune thyroiditis developed arthritis 3 weeks after starting therapy with the antithyroid drug thiamazole. Because an adverse drug reaction of thionamide therapy was suspected, thiamazole was withdrawn, and symptoms disappeared rapidly. Thionamide therapy is indicated for hyperthyroidism and has been widely used since 1948. Reported adverse drug reactions range from mild to potentially life threatening. Arthritis is an uncommon but serious side effect and can develop as a part of the antithyroid arthritis syndrome or as a part of antineutrophil cytoplasmic antibody-associated vasculitis that is induced by antithyroid drugs. Little is known about the exact pathogenesis. Therapy consists of prompt discontinuation of the drug, where upon symptoms rapidly disappear. Because of possible cross-reactivity with alternative thionamides, another form of treatment for hyperthyroidism is recommended. Clinical awareness is important, and prompt withdrawal of the antithyroid drug is necessary when serious side effects occur.