SARS-CoV-2 Infection in Children Less Than Forty Days Hospitalized in Belgium Between 2020 and 2022.

Our study aimed to assess the severity of severe acute respiratory syndrome coronavirus 2 infection in hospitalized infants under 40 days old, across 21 Belgian hospitals between 2020 and 2022. Of the 365 infants studied, 14.2% needed respiratory support. The median hospital stay was 3 days (interquartile range, 2-4), and there were no deaths. Infection severity was similar during the Omicron and Alpha/Delta periods.

A First Case of Acute Flaccid Myelitis Related to Enterovirus D68 in Belgium: Case Report.

Introduction: We describe the first case of acute flaccid myelitis (AFM) related to enterovirus D68 (EV-D68) infection in Belgium. The clinical and radiological presentation of AFM associated with EV-D68 although well described currently remains a challenging diagnosis. Through this interesting clinical case, we aimed to review the differential diagnosis of acute flaccid palsy in a child and discuss the specific point of interest related to AFM. Case Presentation: We present the case of a 4-year-old girl with a torticollis associated with an acute palsy of the right upper limb. The magnetic resonance imaging revealed an increased T2 signal intensity of the entire central gray matter of the cervical cord with involvement of the posterior brainstem. A polymerase chain reaction (PCR) conducted on a nasopharyngeal swab was found positive for EV-D68. The definition of AFM proposed by the Center for Disease Control and Prevention (CDC) is an acute-onset flaccid weakness of one or more limbs in the absence of a clear alternative diagnosis and the radiological evidence of gray matter involvement on an MRI picture, and our case fits these two criteria. A prompt and detailed workup is required to distinguish this emergent disease from other forms of acute flaccid palsy. The functional prognosis of AFM is poor, and there are no evidence-based treatment guidelines so far. Conclusion: AFM is an emerging pathology that requires the attention of pediatricians to quickly rule out differential diagnoses and adequately manage the patient. Further research is needed to optimize treatments, improve outcomes, and provide scientifically based guidelines.

Does lung function change in the months after an asthma exacerbation in children?

BACKGROUND: There are limited data describing lung function changes in children after an asthma exacerbation. Our hypothesis was that lung function does not fully recover in children in the months following an asthma exacerbation. METHODS: We used a data set of children with asthma where lung function (including FEV1 , FEV1 /FVC ratio and FEF25-75 ) was measured at 3-month intervals over a year. Mixed-level models compared spirometry measured on two occasions 3 months apart before a single exacerbation (assessments 1 and 2) with measurements made on two occasions after the exacerbation (assessments 3 and 4), with adjustment for covariates. Changes in spirometry over a year were also analysed across those with exacerbations in no, one or more than one 3-month periods. RESULTS: For the 113 children who had a single exacerbation, spirometry measured at assessments 1 or 2 did not differ from measurements at assessments 3 or 4 when the whole population was considered. When stratified into tertiles by change in %FEV1 between assessments 2 and 3, those with the greater reduction were more likely to be treated with long-acting beta-agonist, but in this category, %FEV1 at assessment 4 had returned to the value at assessment 1. %FEV1 did not change over a 12-month period within and between the three exacerbation categories (n = 809). CONCLUSION: One or more asthma exacerbation was not associated with a fall in lung function for the whole population. In a subset of individuals, lung function does fall after an exacerbation but returns to pre-exacerbation values after a period of months.

Does treatment guided by exhaled nitric oxide fraction improve outcomes in subgroups of children with asthma?

INTRODUCTION: Exhaled nitric oxide fraction (F ENO), a biomarker of eosinophilic airway inflammation, may be useful to guide asthma treatment. F ENO-guided treatment may be more effective in certain subgroups for improving asthma outcomes compared to standard treatment. METHODS: An individual patient data analysis was performed using data from seven randomised clinical trials (RCTs) which used F ENO to guide asthma treatment. The incidence of an asthma exacerbation and loss of control, and the time to first exacerbation and loss of control were described between five subgroups of RCT participants. RESULTS: Data were available in 1112 RCT participants. Among those not treated with leukotriene receptor antagonists (LTRA), but not among those who were treated with LTRA, F ENO-guided treatment was associated with reduced exacerbation risk (OR 0.68, 95% CI 0.49-0.94), longer time to first exacerbation (hazard ratio (HR) 0.76, 95% CI 0.57-0.99) and borderline reduced risk for loss of control (OR 0.70, 95% CI 0.49-1.00). Nonobese children, compared to obese children, were less likely to lose asthma control when treatment was guided by F ENO (OR 0.69, 95% CI 0.48-0.99) and time to loss of control was longer (HR 0.77, 95% CI 0.61-0.99). CONCLUSIONS: Asthma treatment guided by F ENO may be more effective in achieving better asthma outcomes for patients who are not treated with LTRA and who are not obese, compared to standard practice.

What is a clinically meaningful change in exhaled nitric oxide for children with asthma?

INTRODUCTION: Fractional exhaled nitric oxide (FE NO) may be a useful objective measurement to guide asthma treatment. What remains uncertain is what change in FE NO is clinically significant. METHODS: An individual patient data analysis was performed using data from seven randomized clinical trials which used FE NO to guide asthma treatment. The absolute and percentage intra-subject change in FE NO measurements over "stable" and also "unstable" 3-month periods were described. RESULTS: Data were available in 1112 randomized controlled trial participants and ≥1 stable period was present for 665 individuals. The interquartile range (IQR) and limits of agreement (LoA) for change in absolute FE NO among individuals whose initial FE NO was <50 parts per billion (ppb) were -7 to +9 ppb and -43 to +50 ppb, and for those with initial FE NO ≥50 ppb IQR was -29 to +17 ppb and LoA was -80 to +76 ppb. For percentage change in FE NO, the IQR and LoA for individuals whose initial FE NO was <50 ppb were -33% to +51% and -157% to +215%, and for those with initial FE NO ≥50 ppb were -33% to +35% and -159% to +192%. The variation in FE NO values for a stable period was similar irrespective of whether it was followed by a stable or unstable period. CONCLUSIONS: Over a 3-month period where FE NO is initially <50 ppb, a rise of <10 ppb or of <50% (based on IQR) is unlikely to be related to asthma. When FE NO is initially ≥50 ppb an percentage change of <50% (based on IQR) is unlikely to be asthma-related.

Change in FEV1 and Feno Measurements as Predictors of Future Asthma Outcomes in Children.

BACKGROUND: Repeated measurements of spirometry and fractional exhaled nitric oxide (Feno) are recommended as part of the management of childhood asthma, but the evidence base for such recommendations is small. We tested the hypothesis that reducing spirometric indices or increasing Feno will predict poor future asthma outcomes. METHODS: A one-stage individual patient data meta-analysis used data from seven randomized controlled trials in which Feno was used to guide asthma treatment; spirometric indices were also measured. Change in %FEV1 and % change in Feno between baseline and 3 months were related to having poor asthma control and to having an asthma exacerbation between 3 and 6 months after baseline. RESULTS: Data were available from 1,112 children (mean age, 12.6 years; mean %FEV1, 94%). A 10% reduction in %FEV1 between baseline and 3 months was associated with 28% increased odds for asthma exacerbation (95% CI, 3-58) and with 21% increased odds for having poor asthma control (95% CI, 0-45) 6 months after baseline. A 50% increase in Feno between baseline and 3 months was associated with 11% increase in odds for poor asthma control 6 months after baseline (95% CI, 0-16). Baseline Feno and %FEV1 were not related to asthma outcomes at 3 months. CONCLUSIONS: Repeated measurements of %FEV1 that are typically within the "normal" range add to clinical risk assessment of future asthma outcomes in children. The role of repeated Feno measurements is less certain because large changes were associated with small changes in outcome risk.

Adherence to asthma treatment in childhood and adolescence - a narrative literature review.

OBJECTIVES: We provide a narrative literature review on surveys used to assess the level of medication adherence in children and adolescents with asthma, the attitudes of these patients and their parents toward asthma therapy, and their expectations concerning asthma and available treatment. METHODS: A PubMed search and manual selection of the retrieved papers was conducted to identify studies using surveys or interviews that addressed one of the three topics of interest. RESULTS: Adherence to asthma medication varies across age groups and with the type of measurement used. Levels of 49-71% were observed in children and adolescents by objective measurements. Subjective measurements overestimate the level of adherence compared to objective measurements. A considerable percentage of parents expressed fear of side effects of inhaled corticosteroids, although the impact of these concerns on adherence is unclear. Many adolescents and parents adapt inhaled corticosteroids use according to the prevalence of asthma symptoms, by reducing or eliminating controller medication in the absence of symptoms. Pediatric asthma patients and their parents tend to overestimate the level of asthma control, either by underestimating asthma severity or by assuming that a better control is not possible. The knowledge of parents and adolescents concerning asthma management is suboptimal; moreover, insufficient knowledge about inhaled corticosteroids was linked to poor adherence. CONCLUSION: Medication adherence is crucial for a good control of asthma symptoms. Additional research concerning the triggers of non-adherence is still needed. Educating both the patients and their parents on proper asthma care might improve adherence.

Exhaled nitric oxide in childhood allergic asthma management: a randomised controlled trial.

OBJECTIVE: We investigated the potential yield of incorporating fractional exhaled nitric oxide (FeNO) measurements in childhood allergic asthma management. METHODS: Ninety-nine children with persistent allergic asthma were included in this multicentre, single-blind, randomized controlled trial. Treatment was based on the Global Initiative for Asthma (GINA) guidelines. In the FeNO group, asthma management was also guided by FeNO measurements. Health outcomes were evaluated over a 52-week timeframe. RESULTS: Fewer asthma exacerbations were registered in the FeNO group. 24% of the children in the FeNO group experienced one or more exacerbations per year, compared with 48% in the clinical group (P = 0.017). The proportion of symptom-free days did not differ between groups. In the FeNO group, more months of leukotriene receptor antagonist use (median (interquartile range)) were observed: 12 (9-12) months, compared with 9 (3-12) months in the clinical group (P = 0.019). Next, the evolution of inhaled corticosteroid doses between visits 1 and 5 (median change (interquartile range)) showed a significant increase of +100 µg (0, +400) in the FeNO group and a change of 0 µg (-200, +80) in the clinical group (P = 0.016). CONCLUSIONS: FeNO measurements in childhood asthma management did not improve the proportion of symptom-free days, but did result in fewer asthma exacerbations associated with an increased leukotriene receptor antagonist use and an augmentation of the inhaled corticosteroid doses.

Different T cell memory in preadolescents after whole-cell or acellular pertussis vaccination.

To better understand vaccine-induced protection and its potential failure in light of recent whooping cough resurgence, we evaluated quantity as well as quality of memory T cell responses in B. pertussis-vaccinated preadolescent children. Using a technique based on flow cytometry to detect proliferation, cytokine production and phenotype of antigen-specific cells, we evaluated residual T cell memory in a cohort of preadolescents who received a whole-cell pertussis (wP; n=11) or an acellular pertussis vaccine (aP; n=13) during infancy, and with a median of 4 years elapsed from the last pertussis booster vaccine, which was aP for all children. We demonstrated that B. pertussis-specific memory T cells are detectable in the majority of preadolescent children several years after vaccination. CD4(+) and CD8(+) T cell proliferation in response to pertussis toxin and/or filamentous hemagglutinin was detected in 79% and 60% of the children respectively, and interferon-γ or tumor necrosis factor-α producing CD4(+) T cells were detected in 65% and 53% of the children respectively. Phenotyping of the responding cells showed that the majority of antigen-specific cells, whether defined by proliferation or cytokine production, were CD45RA(-)CCR7(-) effector memory T cells. Although the time since the last booster vaccine was significantly longer for wP-compared to aP-vaccinated children, their proliferation capacity in response to antigenic stimulation was comparable, and more children had a detectable cytokine response after wP- compared to aP-vaccination. This study supports at the immunological level recent epidemiological studies indicating that infant vaccination with wP induces longer lasting immunity than vaccination with aP-vaccines.

Persistence at one year of age of antigen-induced cellular immune responses in preterm infants vaccinated against whooping cough: comparison of three different vaccines and effect of a booster dose.

Due to their high risk of developing severe Bordetella pertussis (Bp) infections, it is recommended to immunize preterm infants at their chronological age. However, little is known about the persistence of their specific immune responses, especially of the cellular responses recognized to play a role in protection. We compared here the cellular immune responses to two major antigens of Bp between three groups of one year-old children born prematurely, who received for their primary vaccination respectively the whole cell vaccine Tetracoq(®) (TC), the acellular vaccine Tetravac(®) (TV), or the acellular vaccine Infanrix-hexa(®) (IR). Whereas most children had still detectable IFN-γ responses at one year of age, they were lower in the IR-vaccinated children compared to the two other groups. In contrast, both the TV- and the IR-vaccinated children displayed higher Th2-type immune responses, resulting in higher antigen-specific IFN-γ/IL-5 ratios in TC- than in TV- or IR-vaccinated children. The IFN-γ/IL-5 ratio of mitogen-induced cytokines was also lower in IR- compared to TC- or TV-vaccinated children. No major differences in the immune responses were noted after the booster compared to the pre-booster responses for each vaccine. The IR-vaccinated children had a persistently low specific Th1-type immune response associated with high specific Th2-type immune responses, resulting in lower antigen-specific IFN-γ/IL-5 ratios compared to the two other groups. We conclude that antigen-specific cellular immune responses persisted in one year-old children born prematurely and vaccinated during infancy at their chronological age, that a booster dose did not significantly boost the cellular immune responses, and that the Th1/Th2 balance of the immune responses is modulated by the different vaccines.

Both CD4⁺ and CD8⁺ lymphocytes participate in the IFN-γ response to filamentous hemagglutinin from Bordetella pertussis in infants, children, and adults.

Infant CD4⁺ T-cell responses to bacterial infections or vaccines have been extensively studied, whereas studies on CD8⁺ T-cell responses focused mainly on viral and intracellular parasite infections. Here we investigated CD8⁺ T-cell responses upon Bordetella pertussis infection in infants, children, and adults and pertussis vaccination in infants. Filamentous hemagglutinin-specific IFN-γ secretion by circulating lymphocytes was blocked by anti-MHC-I or -MHC-II antibodies, suggesting that CD4⁺ and CD8⁺ T lymphocytes are involved in IFN-γ production. Flow cytometry analyses confirmed that both cell types synthesized antigen-specific IFN-γ, although CD4⁺ lymphocytes were the major source of this cytokine. IFN-γ synthesis by CD8⁺ cells was CD4⁺ T cell dependent, as evidenced by selective depletion experiments. Furthermore, IFN-γ synthesis by CD4⁺ cells was sometimes inhibited by CD8⁺ lymphocytes, suggesting the presence of CD8⁺ regulatory T cells. The role of this dual IFN-γ secretion by CD4⁺ and CD8⁺ T lymphocytes in pertussis remains to be investigated.

Cellular immune responses of preterm infants after vaccination with whole-cell or acellular pertussis vaccines.

Based on studies reporting specific antibody titers, it is recommended to vaccinate preterm infants against Bordetella pertussis according to their chronological age. However, as specific T-cell responses also are involved in the protection against B. pertussis, we have determined whether highly preterm infants (<31 weeks) are able to mount these immune responses during vaccination. Forty-eight premature infants were vaccinated at 2, 3, and 4 months of their chronological age with an acellular (Pa; n = 24) or a whole-cell (Pw; n = 24) tetravalent diphtheria-tetanus-pertussis-polio vaccine, and blood samples were collected at 2, 3, and 6 months of age. Most of the Pa- and Pw-vaccinated infants developed at 3 or 6 months of age a gamma interferon (IFN-gamma) response to the B. pertussis antigens, accompanied by an interleukin-5 (IL-5) and IL-13 secretion for the Pa-vaccinated infants. No association was found between a very low infant birth weight, the occurrence of severe infections, and corticosteroid treatment or the administration of gammaglobulins with a low level of antigen-induced IFN-gamma secretion. We conclude that like full-term infants, most preterm infants are able to mount a specific cellular immune response to the administration of the first doses of an acellular or a whole-cell pertussis vaccine.

A specific real-time PCR assay for the detection of Bordetella pertussis.

A novel real-time PCR (RT-PCR) assay was developed for detection of Bordetella pertussis in respiratory specimens by targeting the pertactin gene. In vitro evaluation with reference strains and quality control samples showed analytical sensitivity equivalent to and specificity superior to those of PCR assays which target the IS481 element. The pertactin-based RT-PCR assay offers better discrimination between B. pertussis and other Bordetella species than previously described assays.

Isolated tracheoesophageal fistula in a 10-year-old girl.

Isolated tracheoesophageal fistula (H-TOF) is a rare type of tracheoesophageal anomaly and is in most cases diagnosed in the neonatal period because of choking and cyanosis during feeding. Diagnosis may be delayed even until adulthood because of nonspecific and sometimes intermittent symptoms, and because false-negative results of all diagnostic tools are not uncommon. We report a 10-year-old child with H-TOF, whose symptoms had nearly disappeared completely between the ages of 4 and 10 years. Diagnosis was only possible after the recurrence of the symptoms at the time of an episode of bronchitis, profound interrogation of the child's medical history, and questioning of the results of a former diagnostic work-up. In this article, we discuss the potential pitfalls in both clinical diagnosis and diagnostic work-up.

Decreased arousals among healthy infants after short-term sleep deprivation.

OBJECTIVE: Sleep deprivation is a risk factor for sudden infant death syndrome (SIDS). Recent changes in normal life routines were more common among SIDS victims, compared with control infants. Sleep deprivation can result from handling conditions or from sleep fragmentation attributable to respiratory or digestive conditions, fever, or airway obstructions during sleep. Compared with matched control infants, future SIDS victims exhibited fewer complete arousals by the end of the night, when most SIDS cases occur. Arousal from sleep could be an important defense against potentially dangerous situations during sleep. Because the arousal thresholds of healthy infants were increased significantly under conditions known to favor SIDS, we evaluated the effects of a brief period of sleep deprivation on sleep and arousal characteristics of healthy infants. DESIGN: Fourteen healthy infants, with a median age of 8 weeks (range: 6-18 weeks), underwent polygraphic recording during a morning nap and an afternoon nap, in a sleep laboratory. The infants were sleep-deprived for 2 hours before being allowed to fall asleep. Sleep deprivation was achieved by keeping the infants awake, with playing, handling, and mild tactile or auditory stimulations, for as long as possible beyond their habitual bedtimes. To avoid any confounding effect attributable to differences in sleep tendencies throughout the day, sleep deprivation was induced before either the morning nap or the afternoon nap. Seven infants were sleep-deprived before the morning nap and 7 before the afternoon nap. The sleep and arousal characteristics of each infant were compared for the non-sleep-deprived condition (normal condition) and the sleep-deprived condition. During each nap, the infants were exposed, during rapid eye movement (REM) sleep, to white noise of increasing intensity, from 50 dB(A) to 100 dB(A), to determine their arousal thresholds. Arousal thresholds were defined on the basis of the lowest auditory stimuli needed to induce arousal. After the induced arousal, the infants were allowed to return to sleep to complete their naps. RESULTS: Sleep deprivation lasted a median of 120 minutes (range: 90-272 min). Most sleep characteristics were similar for the normal and sleep-deprived conditions, including sleep efficiency, time awake, percentages of REM sleep and non-REM sleep, frequency and duration of central apnea and of periodic breathing, duration of obstructive apnea, mean heart rate and variability, and mean breathing rates during REM sleep and non-REM sleep. After sleep deprivation, the duration of the naps increased, whereas there were decreases in the latency of REM sleep and in the density of body movements. More-intense auditory stimuli were needed for arousal when the infants were sleep-deprived, compared with normal nap sleep. Sleep deprivation was associated with a significant increase in the frequency of obstructive sleep apnea episodes, especially during REM sleep. No significant differences were noted when the effects of morning and afternoon sleep deprivation were compared. No correlation was found between the duration of sleep deprivation and either the frequency of obstructive apnea or the changes in arousal thresholds, although the infants who were more sleep-deprived exhibited tendencies toward higher auditory arousal thresholds and shorter REM sleep latencies, compared with less sleep-deprived infants. There were tendencies for a negative correlation between the auditory arousal thresholds and REM sleep latencies and for a positive correlation between the auditory arousal thresholds and the frequencies of obstructive apnea during REM sleep. CONCLUSIONS: Short-term sleep deprivation among infants is associated with the development of obstructive sleep apnea and significant increases in arousal thresholds. As already reported, sleep deprivation may induce effects on respiratory control mechanisms, leading to impairment of ventilatory and arousal responses to chemical stimulation and decreases in genioglossal electromyographic activity during REM sleep. These changes in respiratory control mechanisms could contribute to the development of obstructive apnea. The relationship between the development of obstructive apnea and increases in arousal thresholds remains to be evaluated. Adult subjects with obstructive sleep apnea exhibited both sleep fragmentation and increases in arousal thresholds. Conversely, sleep deprivation increased the frequency and severity of obstructive sleep apnea. In this study, the increases in arousal thresholds and the development of obstructive apnea seemed to result from the preceding sleep deprivation. The depressed arousals that follow sleep deprivation have been attributed to central mechanisms, rather than decreases in peripheral sensory organ function. Such mechanisms could include disturbances within the reticular formation of the brainstem, which integrates specific facilitory inputs, such as ascending pathways from auditory receptors, and inhibitory inputs from the cortex. It remains to be determined whether the combination of upper airway obstruction and depressed arousability from sleep contributes to the increased risk of sudden death reported for sleep-deprived infants.

Blood plasmacytoid dendritic cell responses to CpG oligodeoxynucleotides are impaired in human newborns.

Plasmacytoid dendritic cells (pDCs) respond to unmethylated cytosine-phosphate-guanosine (CpG) motifs present in bacterial DNA or unmethylated synthetic oligodeoxynucleotides (CpG). In order to assess the function of pDCs in human newborns, interferon-alpha (IFN-alpha) production induced by CpG 2216 and phenotypic maturation of pDCs in response to CpG 2006 were compared in cord blood and adult blood. We first observed that neonatal pDCs displayed decreased up-regulation of CD80, CD83, CD86, and CD40, whereas HLA-DR and CD54 up-regulation did not differ significantly between adults and neonates. We then found that the production of IFN-alpha in response to CpG was dramatically impaired in cord blood. This neonatal defect was detected both at protein and mRNA levels and was still present in blood of 4-day-old babies. Further experiments on enriched pDCs confirmed that these cells are intrinsically deficient in CpG-induced IFN-alpha production at birth. These findings might be relevant to the increased susceptibility of human newborns to infections as well as to the use of CpG oligodeoxynucleotides as vaccine adjuvants in the neonatal period.

Single-beat estimation of right ventricular end-systolic pressure-volume relationship.

Assessment of right ventricular (RV) contractility from end-systolic pressure-volume relationships (ESPVR) is difficult due to problems in measuring RV instantaneous volume and to effects of changes in RV preload or afterload. We therefore investigated in anesthetized dogs whether RV ESPVR and contractility can be determined without measuring RV volume and without changing RV preload or afterload. The maximal RV pressure of isovolumic beats (P(max)) was predicted from isovolumic portions of RV pressure during ejecting beats and compared with P(max) measured during the first beat after pulmonary artery clamping. In RV pressure-volume loops obtained from RV pressure and integrated pulmonary arterial flow, end-systolic elastance (E(es)) was assessed as the slope of P(max)-derived ESPVR, pulmonary artery effective elastance (E(a)) as the slope of end-diastolic to end-systolic relation, and coupling efficiency as the E(es)-to-E(a) ratio (E(es)/E(a)). Predicted P(max) correlated with observed P(max) (r = 0.98 +/- 0.02). Dobutamine increased E(es) from 1.07 to 2.00 mmHg/ml and E(es)/E(a) from 1.64 to 2.49, and propranolol decreased E(es)/E(a) from 1.64 to 0.91 (all P < 0.05). After adrenergic blockade, preload reduction did not affect E(es), whereas hypoxia and arterial constriction markedly increased E(a) and somewhat increased E(es) due to the Anrep effect. Low preload did not affect E(es)/E(a) and high afterload decreased E(es)/E(a). In conclusion, in the right ventricle 1) P(max) can be calculated from normal beats, 2) P(max) can be used to determine ESPVR without change in load, and 3) P(max)-derived ESPVR can be used to assess ventricular contractility and ventricular-arterial coupling efficiency.