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Tuberculosis (TB) in young children differs from adult TB in that the risk of rapid progression to active TB (aTB) is higher in children than in adults. The reasons for this increased risk are not fully understood. Early differentiation remains difficult between children at risk to develop aTB from those who will remain healthy and develop a latent TB infection (LTBI). Biomarkers to differentiate aTB from LTBI in children, especially in very young children, are urgently needed. To identify M. tuberculosis-specific functional T cell subsets related to clinical manifestations in children, we enrolled 87 children exposed to M. tuberculosis. After standard clinical assessment, the children were classified as aTB, LTBI, or uninfected. Their CD4+ T cell cytokine profiles (IFN-γ, TNF-α, IL-2, IL-17) were analyzed at the single-cell level by flow cytometry after stimulation with three mycobacterial antigens, purified protein derivative (PPD), early-secreted-antigenic target-6 (ESAT-6), or heparin-binding hemagglutinin (HBHA). This approach identified age-related discriminative markers between aTB and LTBI. Whereas among the 3- to 15-year-old children, an excellent discrimination between aTB and LTBI was provided by comparing the ratio between the proportions of ESAT-6-induced IFN-γsingle+ and ESAT-6-induced TNF-αsingle+CD4+ T lymphocytes, this was not the case for children younger than 3 years. By contrast, in this group ( < 3years), the analysis of HBHA-induced IL-17single+CD4+ T lymphocytes allowed us to identify children with LTBI by the high proportion of this cellular lymphocyte subset, whereas this was not the case for children with aTB. The analysis at the single-cell level of T cell immune responses induced by mycobacterial antigens are, thus, different in infected children younger or older than 3 years of age. HBHA-induced IL-17 production by CD4+ T lymphocytes was associated with protection only in children under 3 years who are at high risk for rapid progression to aTB. This suggests that the HBHA-induced IL-17 production by CD4+ T lymphocytes is a potential new correlate of protection against M. tuberculosis in humans, and that the distinction between children with LTBI and those with aTB is possible based on age-related diagnostic markers., SCOPUS: ar.j, info:eu-repo/semantics/published

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., Journal Article, SCOPUS: ar.j, info:eu-repo/semantics/published

Background Gastro-oesophageal reflux (GOR) is common in patients with cystic fibrosis (CF). The aim of this study was to investigate the relationship between gastric emptying (GE) and GOR in children with CF. Methods Multichannel intraluminal impedance-pH monitoring (MII-pH) to measure GOR and GE breath test (GEBT) to measure GE were performed in 28 children with symptoms suggestive for GOR disease (GORD) (group 1). GEBT was performed in another 28 children with/without GOR symptoms who agreed to undergo GEBT but not MII-pH (group 2). Results In group 1, we found increased acid GOR (AGOR) in 46.4% and delayed GE (DGE) in 21.4% but no relationship between increased AGOR and DGE. There was no DGE in group 2. We found DGE in 10.7% and rapid GE in 12.5% of the whole group. Conclusions Almost half of the children with CF and symptoms suggestive for GORD have increased AGOR and almost a quarter has DGE. However, there was no relation between GOR and GE.

In countries where the incidence of tuberculosis is low, perinatal tuberculosis is seldom diagnosed. With increasing numbers of human immunodeficiency virus-infected people and increasing immigrant population from high tuberculosis incidence countries, one might expect perinatal tuberculosis to become more frequent. Early recognition of newborns at risk for perinatal tuberculosis infection is of utmost importance to prevent disease by chemoprophylaxis. We describe a case of latent perinatal tuberculosis infection in a newborn infected from a mother with extrapulmonary primary tuberculosis. Tuberculin skin test was negative, and latent tuberculosis infection was eventually diagnosed by specific immunological tests. We discuss the difficulties in diagnosis of recent tuberculosis infection in neonates and infants, and the risk factors for vertical transmission of tuberculosis, which need to be taken into account in considering the need for chemoprophylaxis in the newborn. Although perinatal TB infection is a rare condition and diagnosis is difficult due to poor diagnostic testing in pregnancy and newborns, a high index of suspicion is needed to limit the diagnostic delay and to avoid progression to perinatal TB disease.

We confirmed that chlorhexidine decontamination yielded more nontuberculous mycobacteria than did the N -acetyl- l -cysteine-NaOH-oxalic acid procedure from respiratory samples of cystic fibrosis patients on solid cultures. However, this improved recovery is mostly balanced if the latter is combined with liquid culture. Furthermore, none of the 145 cough swabs, used to sample young children, cultured positive, suggesting that swabs are low-quality samples.

Studies performed in several countries have demonstrated the recent emergence and subsequent dominance of circulating Bordetella pertussis strains harboring pertactin and pertussis toxin variants not included in pertussis vaccines. Determination of the pertactin gene variants is commonly performed using a time-consuming and expensive sequence analysis. We developed a simple and reliable pertactin typing algorithm suitable for large-scale screening. The assay correctly identified all pertactin alleles in representative strains. The typing of 231 clinical strains of B. pertussis routinely isolated in Belgium showed that this algorithm was adequate to identify less-frequent prn types like prn9 and prn11 .

Community-acquired pneumonia (CAP) is a major cause of morbidity in children. This study estimated the proportion of children with pneumococcal CAP among children hospitalised with CAP in Belgium and describes the causative serotype distribution after implementation of the 7-valent pneumococcal conjugate vaccine. Children 0-14 years hospitalised with X-ray-confirmed CAP were prospectively enrolled in a multicentre observational study. Acute and convalescent blood samples were collected. Pneumococcal aetiology was assessed by conventional methods (blood or pleural fluid cultures with Quellung reaction capsular typing or polymerase chain reaction [PCR] in pleural fluid), and recently developed methods (real-time PCR in blood and World Health Organization-validated serotype-specific serology). A total of 561 children were enrolled. Pneumococcal aetiology was assessed by conventional methods in 539, serology in 171, and real-time PCR in blood in 154. Pneumococcal aetiology was identified in 12.2% (66/539) of the children by conventional methods alone but in 73.9% by the combination of conventional and recently developed methods. The pneumococcal detection rate adjusted for the whole study population was 61.7%. Serotypes 1 (42.3%), 5 (16.0%), and 7F(7A) (12.8%) were predominant. In conclusion, Streptococcus pneumoniae remains the predominant bacteria in children hospitalised for CAP in Belgium after implementation of 7-valent pneumococcal conjugate vaccine, with non-vaccine-serotypes accounting for the majority of cases. The use of recently developed methods improves diagnosis of pneumococcal aetiology., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

OBJECTIVES:Clinical data are lacking on optimal levels of specific antipneumococcal antibodies (PnPsAbs) in patients with primary immunodeficiency (PID) receiving intravenous immunoglobulin (IVIG) replacement. Objectives were to conduct a prospective multicenter study providing data on total immunoglobulin G (IgG) and peak/trough levels of PnPsAbs specifically targeting the 16 most prevalent pneumococcal serotypes in IVIG-treated children with PID; to compare trough PnPsAb levels with those measured in healthy adults and the IVIG product; and to evaluate PnPsAb protection correlates with thresholds based on World Health Organization.METHODS:Patients received 7 consecutive IVIG infusions. Total IgG and PnPsAb levels were determined on plasma samples obtained before and after infusion.RESULTS:Twenty-two children with PID were treated with IVIG (mean weekly dose: 0.10 g/kg). The mean trough and peak levels of total IgG were 7.77 and 13.93 g/L, respectively. Trough and peak geometric mean concentrations and distribution curves differed between serotypes and showed wide dispersion (0.17–7.96 µg/mL). In patients (89%–100%), antibodies against most serotypes reached trough levels ≥0.2 µg/mL, a threshold considered protective against invasive pneumococcal infection. For several serotypes, trough levels reached ≥1.0 to 1.3 µg/mL, the level found in adults. Trough geometric mean concentrations correlated well with the PnPsAb contents of the IVIG product.CONCLUSIONS:In IVIG-treated children with PID, protective PnPsAb levels for most pathogenic serotypes were obtained. A correlation was observed between PnPsAb levels in patients and in the IVIG product. This offers the potential to improve infection prevention by adapting the IVIG product and dose according to epidemiology.

It is presumed that bronchial hyperreactivity (BHR) can occur with any inhaled agent and may be a reason for discontinuation of inhalation therapy in cystic fibrosis (CF) patients. On the other hand, inhalation of antibiotics is being increasingly used to eradicate or treat infections. This review focuses on identifying the mechanisms of BHR for a better understanding of its impact on inhalation treatment. BHR in CF is suggested to be secondary to underlying airway disease (associated to poor pulmonary function, chronic inflammation and aerosol distribution) or to be a separate condition occurring more in CF. Furthermore, certain characteristics of the aerosol solution itself, such as the active molecule, chemical additives and particle size, can cause BHR. Recombinant human DNase (rhDNase), hypertonic saline (HS) and the antibiotics tobramycin, colistin and aztreonam lysine for inhalation (AZLI) are frequently used inhalation drugs in the treatment of CF. Prevalence of BHR related to both short and long-term inhalation of these drugs as reported in the literature was investigated. Acute BHR is documented in up to two thirds of CF patients. Despite the widespread use of rhDNase, HS, tobramycin, colistin and AZLI, only one long-term trial looked for, but did not demonstrate, BHR at the end of the trial period.

Background & Aims: Among children hospitalized for pneumonia, those with parapneumonic effusion (PPE) are at particular risk for nutritional deterioration. This study aimed to 1) investigate the evolution of the nutritional status during hospitalization and at outpatient follow-up; 2) determine clinical risk factors for weight loss during hospitalization; 3) describe the nutritional interventions for these children. Methods: Retrospective chart review (January '07 - September '12) of 56 children with pneumonia, complicated by PPE in two Belgian hospitals for data on body weight and height at admission (t0) and discharge (t1), and two weeks (t2) and one month (t3) after discharge. Length of hospitalization (LoS), length of stay in paediatric intensive care (LoS PICU) and maximal in-hospital weight loss (tmax) were calculated and nutritional interventions were recorded. Results: The median (range) age was 3.5 (1.0-14.8) years. Weight or height was lacking in five (8.9%) children at t0 and in 28 (50%) at t1; 21.4% was weighed only once during hospitalization. At tmax, respectively 17/44 and 5/44 children lost ?5% and ?10% of their weight. Median (range) LoS and LoSPICU were 18.0 (10-41) and 4.0 (0-23) days. One-fourth received a nutritional intervention. Weight for height at admission (WFH(t 0)) significantly predicted maximal weight loss (? (95% CI) = -0.34 (-2.0--0.1); p = 0.03). At t2 and t3, 13/32 and 5/22 of the children with available follow-up data did not reach WFH(t0), whilst in 4/35 and 5/26 body weight remained ?5% under the weight(t 0). Conclusions: One-third of children with pneumonia complicated by PPE and monitored for weight and height, lost ?5% of their body weight during hospitalization. One-fourth did not reach initial WFH one month after discharge. Those with a higher WFH at admission were at higher risk of weight loss. More attention for monitoring of weight loss and the nutritional policy during and after hospitalization is warranted. 2014 Huysentruyt et al., SCOPUS: ar.j, info:eu-repo/semantics/published

Summary Background Characterisation of risk groups who may benefit from pneumococcal vaccination is essential for the generation of recommendations and policy. Methods We reviewed the literature to provide information on the incidence and risk of invasive pneumococcal disease (IPD) in at-risk children in Europe and North America. The PubMed database was searched using predefined search terms and inclusion/exclusion criteria for papers reporting European or North American data on the incidence or risk of IPD in children with underlying medical conditions. Results Eighteen references were identified, 11 from North America and 7 from Europe, with heterogeneous study methods, periods and populations. The highest incidence was seen in US children positive for human immunodeficiency virus infection, peaking at 4167 per 100,000 patient-years in 2000. Studies investigating changes in incidence over time reported decreases in the incidence of IPD between the late 1990s and early 2000s. The highest risk of IPD was observed in children with haematological cancers or immunosuppression. Overall, data on IPD in at-risk children were limited, lacking incidence data for a wide range of predisposing conditions. There was, however, a clear decrease in the incidence of IPD in at-risk children after the introduction of 7-valent pneumococcal conjugate vaccine into immunisation programmes, as previously demonstrated in the general population. Conclusion Despite the heterogeneity of the studies identified, the available data show a substantial incidence of IPD in at-risk children, particularly those who are immunocompromised. Further research is needed to determine the true risk of IPD in at-risk children, particularly in the post-PCV period, and to understand the benefits of vaccination and optimal vaccination schedules.

BMC infectious diseases 12, 207 (2012). doi:10.1186/1471-2334-12-207, Published by BioMed Central, London

Background: Young children with persistent wheezing pose a diagnostic and therapeutical challenge to the pediatrician.We aimed to evaluate bacterial bronchial infection as a possible reason for non response to conventional asthma therapy, and to identify and characterise the predominant pathogens involved.Methods: We retrospectively analysed microbiological and cytological findings in a selected population of young wheezers with symptoms unresponsive to inhaled corticosteroid (ICS) therapy, who underwent flexible bronchoscopy with bronchoalveolar lavage (BAL). Procedural measures were taken to limit contamination risk and quantitative bacterial culture of BAL fluid (significance cut-off ≥ 104 colony-forming units/ml) was used. Modern microbiological methods were used for detection of a wide panel of pathogens and for characterisation of the bacterial isolates.Results: 33 children aged between 4 and 38 months, without structural anomalies of the conductive airways were evaluated. Significant bacterial BAL cultures were found in 48,5 % of patients. Haemophilus influenzae was isolated in 30,3 %, Streptococcus pneumoniae in 12,1 % and Moraxella catarrhalis in 12,1 %. All H. influenzae isolates were non-encapsulated strains and definitely distinguished from non-haemolytic H. haemolyticus. Respiratory viruses were detected in 21,9 % of cases with mixed bacterial-viral infection in 12,1 %. Cytology revealed a marked neutrophilic inflammation.Conclusions: Bacterial infection of the bronchial tree is common in persistent preschool wheezers and provides a possible explanation for non response to ICS therapy. Non-typeable H. influenzae seems to be the predominant pathogen involved, followed by S. pneumoniae and M. catarrhalis. © 2012 De Schutter et al. licensee BioMed Central Ltd., SCOPUS: ar.j, info:eu-repo/semantics/published

Childhood community-acquired pneumonia (CAP) is a heterogeneous and polymicrobial entity. Using flexible fiberoptic bronchoscopy with bronchoalveolar lavage, we identified nontypeable Haemophilus influenzae as one of the major pathogens involved in recurrent or non-responsive CAP in children., Background. Precise etiologic diagnosis in pediatric community-acquired pneumonia (CAP) remains challenging. Methods. We conducted a retrospective study of CAP etiology in 2 groups of pediatric patients who underwent flexible bronchoscopy (FOB) with bronchoalveolar lavage (BAL); children with acute nonresponsive CAP (NR-CAP; n = 127) or recurrent CAP (Rec-CAP; n = 123). Procedural measures were taken to limit contamination risk and quantitative bacterial culture of BAL fluid (significance cutoff point, ≥104 colony-forming units/mL) was used. Blood culture results, serological test results, nasopharyngeal secretion findings, and pleural fluid culture results were also assessed, where available. Results. An infectious agent was detected in 76.0% of cases. In 51.2% of infections, aerobic bacteria were isolated, of which 75.0%, 28.9%, and 13.3% were Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae, respectively. Most (97.9%) of the H. influenzae strains were nontypeable (NTHi). H. influenzae was detected in 26.0% of NR-CAP cases and 51.2% of Rec-CAP cases, whereas Mycoplasma pneumoniae was the predominant pathogen in the NR-CAP group (accounting for 34.9% of cases) but not in the Rec-CAP group (19.3%). Viruses were found in 30.4% of cases, with respiratory syncytial virus, parainfluenzaviruses, and influenzaviruses detected most frequently. Mixed infections were found in 18.9% of NR-CAP cases and 30.1% of Rec-CAP cases. Conclusions. A variety of microorganisms were isolated with frequent mixed infection. NTHi was one of the major pathogens found, especially in association with recurrent CAP, possibly because of improved detection with the FOB with BAL procedure. This suggests that the burden of pediatric CAP could be reduced by addressing NTHi as a major causative pathogen.

During the 2009 influenza A/H1N1v pandemic, children were identified as a specific "at risk" group. We conducted a multicentric study to describe pattern of influenza A/H1N1v infection among hospitalized children in Brussels, Belgium., Journal Article, SCOPUS: ar.j, info:eu-repo/semantics/published

Aspiration is a suspected cause of chronic respiratory disease in infants. We assessed the probability of aspiration by immunocytochemical staining of alveolar macrophages for milk proteins (α-lactalbumin and β-lactoglobulin) and compared these findings with the Oil-Red-O staining score. Broncho-alveolar lavage (BAL), 24-hr esophageal pH-measurement and/or gastro-esophageal scintigraphy were performed in 111 children. Seventy-nine patients were enrolled. Ten exclusively soya milk formula fed children served as a control group. Individual scores, expressed as the mean percentage of positive staining macrophages counted by three blinded authors were made. Relying on the control group, a positive score was defined as a value higher than 1%. A positive score was found in 26% (18/69). Forty-four percent (8/18) of them had positive gastro-esophageal reflux (GER) tests. In 61% (11/18) a concomitant diagnosis of laryngo-/tracheomalacia was made. A positive score was found in 48% (11/23) of patients with laryngo-/tracheomalacia, compared to 15% (7/46) in infants with normal laryngeal and tracheal anatomy. No correlation was found between the immunocytochemical staining score for milk proteins and the Oil-Red-O staining score. We conclude that assuming the 1% criterion, persistent respiratory symptoms were associated with a positive immunostaining score, suggestive for aspiration, in 26% of infants, in 48% in case of concomitant laryngo- and/or tracheomalacia and in 15% of infants with normal laryngeal and tracheal anatomy. No correlation was found between the immunocytochemical staining score for cow milk proteins and the Oil-Red-O staining score. Pediatr Pulmonol. 2010;45:1213–1219. © 2010 Wiley-Liss, Inc.

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.

Background Although the causative pneumococcal serotypes of invasive diseases are already extensively studied, few data are available about the pneumococcal serotypes additionally isolated from broncho-alveolar lavage samples in childhood pneumonia. Study aim To identify the causative pneumococcal serotypes in culture proven childhood community acquired pneumonia (CAP) and to calculate the effectiveness of the heptavalent and nonavalent pneumococcal vaccine (7- and 9-valent PnV) in severe pneumococcal pneumonia. Methods All pneumococcal isolates stored from broncho-alveolar lavage, blood culture and pleural fluid in healthy children with CAP were characterized. Results Seventy children (median age 2 years 3.5 months) could be included. The most prevalent serotypes were: SGT1 (21.4%), SGT6 (20.0%), SGT19 (12.8%), SGT23 (10.0%), and SGT14 (7.1%). SGT1 was especially prevalent in complicated cases and children >5 years. This first ranking of SGT1 is not reported in invasive pneumococcal disease studies. The overall theoretical coverage of the 7-valent PnV and the 9-valent PnV for pneumococcal pneumonia was 45.7% and 72.8%. The theoretical coverage of both vaccines was equal for non-invasive pneumonia (64%) but the theoretical coverage of the 9-valent PnV for invasive pneumonia was much higher (79% vs. 37.2%). Antibiotic susceptibility to penicillin was 84%, 70% to tetracycline and 61% to erythromycin; however only one strain (MIC = 4 mg/L) was highly resistant to penicillin. Conclusions Based on this serotyping, the theoretical coverage of the 7-valent PnV for proven pneumococcal pneumonia is good but decreases with age. A 9-valent PnV containing SGT1 could significantly increase the coverage, especially for invasive pneumonia. According to these data, penicillin remains the first choice antibiotic treatment for childhood CAP in Belgium. Pediatr Pulmonol. 2006; 41: 765–770. © 2006 Wiley-Liss, Inc.

Two CF patients developed Cushing's syndrome during administration of inhaled budesonide (400 μg/d) with oral itraconazole in one and with clarithromycin in the other patient. Clinical features appeared respectively after 2 and 6 weeks of drug co-administration, with prolonged adrenal suppression, and a slow recovery after ceasing the drugs. Inhibitors of the cytochrome P450 interfere with the metabolism of corticosteroids. Combination of these drugs even with moderate doses of budesonide should be closely monitored.

A 4-year-old boy with cystic fibrosis developed hypertension, rapid weight gain and a moon face 2 weeks after starting a combined treatment of oral itraconazole and inhaled budesonide for a suspected allergic bronchopulmonary aspergillosis. Adrenal suppression was documented and found to persist 3 months after stopping this combined treatment. Conclusion:to the best of our knowledge, this is the first time that an iatrogenic Cushing syndrome in a young child with cystic fibrosis after such combined treatment is reported. The inhibition of cytochrome P4503A by intraconazole and a higher glucocorticoid tissue sensitivity is suggested as the underlying mechanism.