Natural resistance to Meningococcal Disease related to CFH loci: Meta-analysis of genome-wide association studies.

Meningococcal disease (MD) remains an important infectious cause of life threatening infection in both industrialized and resource poor countries. Genetic factors influence both occurrence and severity of presentation, but the genes responsible are largely unknown. We performed a genome-wide association study (GWAS) examining 5,440,063 SNPs in 422 Spanish MD patients and 910 controls. We then performed a meta-analysis of the Spanish GWAS with GWAS data from the United Kingdom (combined cohorts: 897 cases and 5,613 controls; 4,898,259 SNPs). The meta-analysis identified strong evidence of association (P-value ≤ 5 × 10-8) in 20 variants located at the CFH gene. SNP rs193053835 showed the most significant protective effect (Odds Ratio (OR) = 0.62, 95% confidence interval (C.I.) = 0.52-0.73; P-value = 9.62 × 10-9). Five other variants had been previously reported to be associated with susceptibility to MD, including the missense SNP rs1065489 (OR = 0.64, 95% C.I.) = 0.55-0.76, P-value = 3.25 × 10-8). Theoretical predictions point to a functional effect of rs1065489, which may be directly responsible for protection against MD. Our study confirms the association of CFH with susceptibility to MD and strengthens the importance of this link in understanding pathogenesis of the disease.

Development and Validation of a New Clinical Scale for Infants with Acute Respiratory Infection: The ReSVinet Scale.

BACKGROUND AND AIMS: A properly validated scoring system allowing objective categorization of infants with acute respiratory infections (ARIs), avoiding the need for in-person assessment and that could also be used by non-health professionals is currently not available. We aimed to develop a new clinical assessment scale meeting these specifications. METHODS: We designed a clinical scale (ReSVinet scale) based on seven parameters (feeding intolerance, medical intervention, respiratory difficulty, respiratory frequency, apnoea, general condition, fever) that were assigned different values (from 0 to 3) for a total of 20 points.170 children under two years of age with ARI were assessed independently by three pediatricians using this scale. Parents also evaluated their offspring with an adapted version of the scale in a subset of 61 cases. The scale was tested for internal consistency (Cronbach's alpha), Pearson correlation coefficient for the items in the scale, inter-observer reliability (kappa index) and floor-ceiling effect. RESULTS: Internal consistency was good for all the observers, with the lowest Cronbach's alpha being 0.72. There was a strong correlation between the investigators (r-value ranged 0.76-0.83) and also between the results obtained by the parents and the investigators(r = 0.73). Light's kappa for the observations of the three investigators was 0.74. Weighted kappa in the group evaluated by the parents was 0.73. The final score was correlated with length of hospital stay, PICU admission and Wood-Downes Score. CONCLUSIONS: The ReSVinet scale may be useful and reliable in the evaluation of infants with ARI, particularly acute bronchiolitis, even with data obtained from medical records and when employed by parents. Although further studies are necessary, ReSVinet scale already complies with more score validation criteria than the vast majority of the alternatives currently available and used in the clinical practice.

Does Viral Co-Infection Influence the Severity of Acute Respiratory Infection in Children?

BACKGROUND: Multiple viruses are often detected in children with respiratory infection but the significance of co-infection in pathogenesis, severity and outcome is unclear. OBJECTIVES: To correlate the presence of viral co-infection with clinical phenotype in children admitted with acute respiratory infections (ARI). METHODS: We collected detailed clinical information on severity for children admitted with ARI as part of a Spanish prospective multicenter study (GENDRES network) between 2011-2013. A nested polymerase chain reaction (PCR) approach was used to detect respiratory viruses in respiratory secretions. Findings were compared to an independent cohort collected in the UK. RESULTS: 204 children were recruited in the main cohort and 97 in the replication cohort. The number of detected viruses did not correlate with any markers of severity. However, bacterial superinfection was associated with increased severity (OR: 4.356; P-value = 0.005), PICU admission (OR: 3.342; P-value = 0.006), higher clinical score (1.988; P-value = 0.002) respiratory support requirement (OR: 7.484; P-value < 0.001) and longer hospital length of stay (OR: 1.468; P-value < 0.001). In addition, pneumococcal vaccination was found to be a protective factor in terms of degree of respiratory distress (OR: 2.917; P-value = 0.035), PICU admission (OR: 0.301; P-value = 0.011), lower clinical score (-1.499; P-value = 0.021) respiratory support requirement (OR: 0.324; P-value = 0.016) and oxygen necessity (OR: 0.328; P-value = 0.001). All these findings were replicated in the UK cohort. CONCLUSION: The presence of more than one virus in hospitalized children with ARI is very frequent but it does not seem to have a major clinical impact in terms of severity. However bacterial superinfection increases the severity of the disease course. On the contrary, pneumococcal vaccination plays a protective role.

Bacteremia in Children Hospitalized with Respiratory Syncytial Virus Infection.

BACKGROUND: The risk of bacteremia is considered low in children with acute bronchiolitis. However the rate of occult bacteremia in infants with RSV infection is not well established. The aim was to determine the actual rate and predictive factors of bacteremia in children admitted to hospital due to confirmed RSV acute respiratory illness (ARI), using both conventional culture and molecular techniques. METHODS: A prospective multicenter study (GENDRES-network) was conducted between 2011-2013 in children under the age of two admitted to hospital because of an ARI. Among those RSV-positive, bacterial presence in blood was assessed using PCR for Meningococcus, Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus, in addition to conventional cultures. RESULTS: 66 children with positive RSV respiratory illness were included. In 10.6% patients, bacterial presence was detected: H. influenzae (n = 4) and S. pneumoniae (n = 2). In those patients with bacteremia, there was a previous suspicion of bacterial superinfection and had received empirical antibiotic treatment 6 out of 7 (85.7%) patients. There were significant differences in terms of severity between children with positive bacterial PCR and those with negative results: PICU admission (100% vs. 50%, P-value = 0.015); respiratory support necessity (100% vs. 18.6%, P-value < 0.001); Wood-Downes score (mean = 8.7 vs. 4.8 points, P-value < 0.001); GENVIP scale (mean = 17 vs. 10.1, P-value < 0.001); and length of hospitalization (mean = 12.1 vs. 7.5 days, P-value = 0.007). CONCLUSION: Bacteremia is not frequent in infants hospitalized with RSV respiratory infection, however, it should be considered in the most severe cases.

Role of Vitamin D in Hospitalized Children With Lower Tract Acute Respiratory Infections.

BACKGROUND: Vitamin D is known to have modulatory actions in the immune system. Its influence on the severity of lower tract acute respiratory infections (LT-ARIs) is unclear. OBJECTIVES: The aim of the present study was to evaluate the role of vitamin D on LT-ARI in paediatric patients. METHODS: Children admitted to hospital with LT-ARI were prospectively recruited through the GENDRES network (March 2009-May 2013). The 25-hydroxyvitamin D (25-OHD) levels were measured by immunoassay. The severity of the illness was evaluated according to clinical scales, length of hospital stay, ventilatory requirements, and pediatric intensive care unit admission. RESULTS: A total of 347 patients with a median (interquartile range) age of 8.4 (2.6-21.1) months were included. The mean (SD) 25-OHD levels in our series were 27.1 (11.3) ng/mL. In this study, a cutoff value of ≥30 ng/mL was considered optimal vitamin status. Patients with 25-OHD levels <20 ng/mL were at a higher risk of showing severe signs of respiratory difficulties (OR 5.065, 95% confidence interval 1.998-12.842; P = 0.001) than patients with normal values, and had a 117% higher risk of oxygen necessity and 217% higher risk of ventilatory requirement than those patients with normal values. An inverse correlation was found between 25-OHD levels and the severity in the evaluated scales. 25-OHD levels did not influence PICU admission rate or length of hospital stay. CONCLUSIONS: 25-OHD levels of children admitted because of a LT-ARI are <30 ng/mL. Lower levels of 25-OHD were found to be correlated with severity of the disease. The possible role of abnormal 25-OHD levels as a facilitator or consequence of the infection needs further evaluation.

Viral Co-Infections in Pediatric Patients Hospitalized with Lower Tract Acute Respiratory Infections.

BACKGROUND: Molecular techniques can often reveal a broader range of pathogens in respiratory infections. We aim to investigate the prevalence and age pattern of viral co-infection in children hospitalized with lower tract acute respiratory infection (LT-ARI), using molecular techniques. METHODS: A nested polymerase chain reaction approach was used to detect Influenza (A, B), metapneumovirus, respiratory syncytial virus (RSV), parainfluenza (1-4), rhinovirus, adenovirus (A-F), bocavirus and coronaviruses (NL63, 229E, OC43) in respiratory samples of children with acute respiratory infection prospectively admitted to any of the GENDRES network hospitals between 2011-2013. The results were corroborated in an independent cohort collected in the UK. RESULTS: A total of 204 and 97 nasopharyngeal samples were collected in the GENDRES and UK cohorts, respectively. In both cohorts, RSV was the most frequent pathogen (52.9% and 36.1% of the cohorts, respectively). Co-infection with multiple viruses was found in 92 samples (45.1%) and 29 samples (29.9%), respectively; this was most frequent in the 12-24 months age group. The most frequently observed co-infection patterns were RSV-Rhinovirus (23 patients, 11.3%, GENDRES cohort) and RSV-bocavirus / bocavirus-influenza (5 patients, 5.2%, UK cohort). CONCLUSION: The presence of more than one virus in pediatric patients admitted to hospital with LT-ARI is very frequent and seems to peak at 12-24 months of age. The clinical significance of these findings is unclear but should warrant further analysis.

Impact of Rotavirus Vaccination on Childhood Hospitalization for Seizures.

BACKGROUND: Rotavirus vaccine (RV) might reduce the risk of hospitalization due to childhood seizures (CS). We aimed to identify and assess variations in the incidence of hospitalizations for CS among children <5 years of age before and after RV introduction. METHODS: Annual hospitalization rates for any kind of CS, before and after RV introduction in 2007, were calculated using the official surveillance system for hospitalization data. RESULTS: Our study cohort totaled 6149 children <5 years of age admitted to the hospital between 2003 and 2013 with any kind of CS (780.3* + 779.0* + 333.2* + 345* ICD-9-CM code). The annual hospitalization rates for any kind of CS in children <5 years of age were correlated with RV coverage (r = -0.673; P = 0.033) and rotavirus acute gastroenteritis admission rates (ρ = 0.506; P = 0.001), with decrease rates ranging from 16.2% (95% confidence interval: 8.3-23.5%) in 2007 to 34.0% (27.3-40.1%) in 2010, as compared with the median rate of the pre-vaccination period (2003 to 2006). Similarly, for convulsions (780.3*ICD-9-CM code), the decrease seen in children <5 years of age was significantly correlated with the increase in RV coverage (r = -0.747; P = 0.013) and rotavirus acute gastroenteritis admission rates (ρ = 0.543; P < 0.001), with decrease rates ranging from 18.7% (9.6-26.8%) in 2007 to 42.5% (35.3-48.9%) in 2012. Significant results were also obtained for infants <12 months and infants 1-2 years of age. In the remaining age groups or diagnostic categories analyzed, changes were either not significant or not related to vaccination changes or rotavirus acute gastroenteritis admission rates. CONCLUSIONS: Our results show that rotavirus vaccination may have a significant impact in the decrease in seizure-related hospitalizations in childhood. This additional benefit of rotavirus vaccination seems more marked in the youngest infants.

A reverse evidence of rotavirus vaccines impact.

In 2010, and due to a quality problem identified in the vaccine manufacture, the rotavirus (RV) vaccination was withheld in Spain during 5 months. Our study aimed to evaluate the impact that this sudden cease had on rotavirus acute gastroenteritis (RAGE) hospitalizations. An increase in RAGE hospitalization was observed in parallel to the drop in vaccine coverage. Here, we report the first reverse evidence of rotavirus vaccine impact.

Pleural antigen assay in the diagnosis of pediatric pneumococcal empyema.

PURPOSE: The purpose of the study was to assess the diagnostic value of rapid pneumococcal antigen detection (PAD) in pleural fluid samples of children with empyema. MATERIAL AND METHODS: We performed a prospective evaluation in a pediatric intensive care unit of a tertiary university hospital of children aged 1 month to 14 years admitted with empyema. Standard cultures (conventional microbiological culture [CMC]), PAD by immunochromatographic testing (Binax NOW Streptococcus pneumoniae; Binax, Portland, ME), and/or real-time polymerase chain reactions (RTPs) on pleural samples were performed in all included patients. RESULTS: Fifty-five cases with a mean (SD) age of 6.5 (6.1) years were enrolled. Streptococcus pneumoniae was identified in 28 cases (51%): by CMC in 15 cases and by RTP in a further 13 cases. Using CMC and/or RTP as the criterion standard, PAD showed a sensitivity of 96% (95% confidence interval, 86%-100%), a specificity of 100% (75%-100%), a positive predictive value of 100% (98%-100%), and a Youden index of 0.96 (0.88-1.04). CONCLUSIONS: Pneumococcal antigen detection in pleural fluid specimens from children provides a rapid, simple, sensitive, and reliable method of diagnosis for pneumococcal empyema at bedside.

Prospective evaluation of indirect costs due to acute rotavirus gastroenteritis in Spain: the ROTACOST study.

BACKGROUND: The effect of rotavirus in developed countries is mainly economic. This study aimed to assess the indirect costs induced by rotavirus acute gastroenteritis (RVAGE) in Spain. METHODS: A prospective observational study was conducted from October 2008 to June 2009. It included 682 children up to 5 years of age with acute gastroenteritis (AGE) who attended primary care (n = 18) and emergency room/hospital settings (n = 10), covering the regions of Galicia and Asturias (North-west Spain). All non-medical expenses incurred throughout the episode were recorded in detail using personal interviews and telephone contact. RESULTS: Among the 682 enrolled children, 207 (30.4%) were rotavirus positive and 170 (25%) had received at least one dose of rotavirus vaccine. The mean (standard deviation) indirect cost caused by an episode of AGE was estimated at 135.17 (182.70) Euros. Costs were 1.74-fold higher when AGE was caused by rotavirus compared with other etiologies: 192.7 (219.8) Euros vs. 111.6 (163.5) Euros (p < .001). The costs for absenteeism were the most substantial with a mean of 91.41 (134.76) Euros per family, resulting in a loss of 2.45 (3.17) days of work. In RVAGE patients, the absenteeism cost was 120.4 (154) Euros compared with 75.8 (123) for the other etiologies (p = .002), because of loss of 3.5 (3.6) vs 1.9 (2.9) days of work (p < .001). Meals costs were 2-fold-higher (48.5 (55) vs 24.3 (46) Euros, p < .001) and travel costs were 2.6-fold-higher (32 (92) vs 12.5 (21.1) Euros, p = .005) in RVAGE patients compared with those with other etiologies. There were no differences between RVAGE and other etiologies groups regarding costs of hiring of caregivers or purchase of material. Patients with RVAGE were admitted to hospital more frequently than those with other etiologies (47.8% vs 14%, p < .001). CONCLUSIONS: Rotavirus generates a significant indirect economic burden. Our data should be considered in the decision-making process of the eventual inclusion of rotavirus vaccine in the national immunization schedule of well developed countries.

Effectiveness of rotavirus vaccination in Spain.

With the aim of determining rotavirus vaccine effectiveness (RVVE) in Spain, from Oct-2008/Jun-2009, 467 consecutive children below 2 years old with acute gastroenteritis (AGE) were recruited using a pediatric research network (ReGALIP-www.regalip.org) that includes primary, emergency and hospital care settings. Of 467 enrolled children, 32.3% were rotavirus positive and 35.0% had received at least one dose of any rotavirus vaccine. RRVE to prevent any episode of rotavirus AGE was 91.5% (95% CI: 83.7%-95.6%). RVVE to prevent hospitalization by rotavirus AGE was 95.6% (85.6-98.6%). No differences in RVVE were found regarding the vaccine used. Rotavirus vaccines have showed an outstanding effectiveness in Spain.

Nasal continuous positive airway pressure with heliox versus air oxygen in infants with acute bronchiolitis: a crossover study.

OBJECTIVE: The purpose of this work was to evaluate the effects of administering either heliox or air oxygen in combination with nasal continuous positive airway pressure in infants with refractory bronchiolitis. PATIENT AND METHODS: We conducted a prospective, interventional, single-center, crossover study in a teaching hospital including infants 1 month to 2 years of age, consecutively admitted to the PICU from February 2004 to February 2005 for treatment of severe acute bronchiolitis unresponsive to therapy. Patients with a clinical score (Modified Wood's Clinical Asthma Score) of >5, arterial oxygen saturation of <92%, or transcutaneous CO(2) pressure of >50 mmHg despite supportive therapy, nebulized L-epinephrine, and heliox therapy through a nonrebreathing reservoir face mask were eligible. During the study period, 40 infants with bronchiolitis were admitted to the PICU; 12 fulfilled inclusion criteria. A predetermined balanced sequential allocation to either 30 minutes of treatment with nasal continuous positive airway pressure with heliox or to air-oxygen nasal continuous positive airway pressure was performed. Measurements were taken at baseline and after 30 minutes of each treatment. RESULTS: Baseline mean values were as follows: nasal continuous positive airway pressure of 7.2 cmH(2)O; clinical score of 7.7 points; transcutaneous CO(2) pressure of 61.6 mmHg; and arterial oxygen saturation of 88.6%, with the fraction of inspired oxygen at 35.4%. Clinical score, transcutaneous CO(2) pressure, and arterial oxygen saturation improved during the study time with both heliox-nasal continuous positive airway pressure and air-oxygen-nasal continuous positive airway pressure: after 1 hour, the clinical score fell 1.7 points, transcutaneous CO(2) pressure decreased 8.2 mmHg, and arterial oxygen saturation increased by 7.7%. Improvement in clinical score was double with heliox-nasal continuous positive airway pressure compared with the air-oxygen-nasal continuous positive airway pressure (2.12 vs 1.08 points), and the fall in the transcutaneous CO(2) pressure was greater with heliox-nasal continuous positive airway pressure compared with air-oxygen-nasal continuous positive airway pressure (9.7 vs 5.4 mm Hg). There was no difference in arterial oxygen saturation between groups. No patients required endotracheal intubation. No adverse effects attributable to either of the study interventions were detected. CONCLUSIONS: Nasal continuous positive airway pressure improves the clinical score and the CO(2) elimination of infants with refractory bronchiolitis. These positive effects are significantly enhanced when nasal continuous positive airway pressure is combined with heliox instead of air oxygen. Both techniques are noninvasive, seem safe, and may reduce the need for endotracheal intubation.

Nasal continuous positive airway pressure with heliox in infants with acute bronchiolitis.

This is the first study aiming to assess the effects of heliox in combination with nasal continuous positive airway pressure (Hx-nCPAP) as a rescue treatment in infants with refractory acute bronchiolitis. Fifteen out of 78 infants with acute bronchiolitis consecutively admitted to PICU fulfilled the inclusion criteria: clinical score>or=5 or arterial oxygen saturation (SatO2)50 mmHg, despite supportive therapy, nebulized L-epinephrine, and heliox therapy through non-rebreathing reservoir facemask. Hx-nCPAP was added as a rescue treatment. Baseline mean (standard deviation) values were: clinical score of 7.4 (1.2) points; PCO2 of 63.8 (12) mmHg; respiratory rate (RR) of 66.4 (9.9); and SatO2 of 88.6 (4.7)%. Clinical score, PCO2, RR and SatO2 improved during the study time (P<0.05). After 1 h the mean clinical score decreased by 1.5 points, with a total average decrease of 3.5 points at the end of the study period. The mean PCO2 diminished by 9 and 25 mmHg, after 1 and 48 h, respectively. The mean RR decreased 13 rpm after 1 h and 30 rpm after 48 h. The Hx-nCPAP total duration ranged from 2 to 14 days. Only one patient required endotracheal intubation. No adverse effects were detected. All patients recovered fully. In conclusion, Hx-nCPAP improved the clinical score, decreased the tachypnea and enhanced the CO2 elimination of infants with refractory acute bronchiolitis within 1h of administration, in a safe and non-invasive manner. Hx-nCPAP might reduce the need for endotracheal intubation. Further studies are needed.

Terlipressin for catecholamine-resistant septic shock in children.

OBJECTIVE: To report the effects of terlipressin treatment in four paediatric patients with catecholamine-resistant hypotensive septic shock. DESIGN AND SETTING: Case report in the pediatric intensive care unit of a university hospital. PATIENTS: Four children with severe septic shock and hypotension resistant to high doses of norepinephrine and other cathecolamines. INTERVENTIONS: Terlipressin was added to the standard treatment, by intravenous bolus at a dose of 0.02 mg/kg every 4 h during a maximum time of 3 days. MEASUREMENT AND RESULTS: In all cases, terlipressin induced a rapid and sustained improvement in mean arterial pressure, which allowed the lessening or even withdrawal of norepinephrine infusion. No related adverse effects were detected. CONCLUSION: Terlipressin might be considered, at least as a rescue therapy, for hypotension resistant to catecholamines in children with septic shock. Further studies are needed to confirm the beneficial effects found in our patients. The optimal administration schedule remains to be elucidated.

Heliox therapy in infants with acute bronchiolitis.

OBJECTIVE: To assess the therapeutic effects of breathing a low-density gas mixture (heliox: 70% helium and 30% oxygen) in infants with bronchiolitis. DESIGN: Prospective, interventional, comparative study. SETTING: A pediatric intensive care unit (PICU) in a tertiary care, teaching hospital. PATIENTS: Thirty-eight infants, 1 month to 2 years old, consecutively admitted to the PICU for treatment of moderate-to-severe acute respiratory syncytial virus bronchiolitis. INTERVENTIONS: The first 19 patients were enrolled as the control group and received supportive care and nebulized epinephrine. In the next 19 patients, heliox therapy was added through a nonrebreather reservoir face mask. Measurements and Outcomes. Respiratory distress score, respiratory rate, heart rate, end-tidal CO(2) (etCO(2)), and pulse oximetry oxygen saturation (satO(2)) values were recorded at baseline and at regular intervals. Data obtained during the first 4 hours were analyzed for comparison purposes. Demographic data, age, time elapsed from the start of the symptoms to the admission to PICU, length of stay in PICU (PICU-LOS), and duration of heliox therapy were also collected for each patient. Reductions in clinical scores and PICU-LOS were considered primary outcomes. Main Results. At baseline, the heliox and control groups had similar age (5.5 +/- 3.1 vs 5.9 +/- 3 months), previous length of course (47.3 +/- 19.3 vs 45.4 +/- 18.6 hours), clinical score (6.7 +/- 1.1 vs 6.6 +/- 1), heart rate (160 +/- 24 vs 165 +/- 20 beats per minute), respiratory rate (64 +/- 7 vs 61 +/- 7 respirations per minute), satO(2) (91 +/- 2.3 vs 91 +/- 2.5%), and etCO(2) (34 +/- 7 vs 33 +/- 6 mm Hg). Clinical score, heart rate, respiratory rate, and satO(2) improved during the study in both groups. After 1 hour, the improvement in clinical score was significantly higher in the heliox group than in the control group (3.6 +/- 1.16 vs 5.5 +/- 0.89), and these differences continued to be significant at the end of the observation period (2.39 +/- 0.69 and 4.07 +/- 0.96, respectively), with a total average decrease in the score of 4.2 points in the heliox group versus 2.5 points in the control group. Heart and respiratory rates were also significantly lower in the heliox group compared with the control group after 1 hour and stayed lower throughout the rest of the study period. No changes were noted either in satO(2) between groups or in etCO(2) within or between groups throughout the study. Mean duration of heliox administration was 53 +/- 24 hours (range: 24-112 hours) and no adverse effects were detected. PICU-LOS was significantly shorter in the heliox group (3.5 +/- 1.1 days) than in the control group (5.4 +/- 1.6 days). CONCLUSIONS: In infants with moderate-to-severe respiratory syncytial virus bronchiolitis, heliox therapy enhanced their clinical respiratory status, according to the marked improvement in their clinical scores and the reduction of the accompanying tachycardia and tachypnea. This beneficial response occurred within the first hour of its administration and was maintained as long as heliox therapy continued. In addition, PICU-LOS was reduced in heliox-treated patients. Long-term prospective studies are required to corroborate these findings and to establish the proper place of heliox in the therapeutic schedule of bronchiolitis.