Susanna Esposito

Superior relative efficacy of live attenuated influenza vaccine compared with inactivated influenza vaccine in young children with recurrent respiratory tract infections.

Background: Young children have a high incidence of influenza and influenza-related complications. This study compared the efficacy and safety of cold-adapted influenza vaccine, trivalent (CAIV-T) with trivalent inactivated influenza vaccine (TIV) in young children with a history of recurrent respiratory tract infections (RTIs). Methods: Children 6 to 71 months of age were randomized to receive 2 doses of CAIV-T (n = 1101) or TIV (n = 1086), 35 ± 7 days apart before the start of the 2002–2003 influenza season and were followed up for culture-confirmed influenza, effectiveness outcomes, reactogenicity, and adverse events. Results: Overall, 52.7% (95% confidence interval [CI] = 21.6%–72.2%) fewer cases of influenza caused by virus strains antigenically similar to vaccine were observed in CAIV-T than in TIV recipients. Greater relative efficacy for CAIV-T was observed for the antigenically similar A/H1N1 (100.0%; 95% CI = 42.3%–100.0%) and B (68.0%; 95% CI = 37.3%–84.8%) strains but not for the antigenically similar A/H3N2 strains (−97.1%; 95% CI = −540.2% to 31.5%). Relative to TIV, CAIV-T reduced the number of RTI-related healthcare provider visits by 8.9% (90% CI = 1.5%–15.8%) and missed days of school, kindergarten, or day care by 16.2% (90% CI = 10.4%–21.6%). Rhinitis and rhinorrhea, otitis media, and decreased appetite were the only events that were reported more frequently in CAIV-T subjects. There was no difference between groups in the incidence of wheezing after vaccination. Conclusions: CAIV-T was well tolerated in these children with RTIs and demonstrated superior relative efficacy compared with TIV in preventing influenza illness.

Immunogenicity and Tolerability of Recombinant Serogroup B Meningococcal Vaccine Administered With or Without Routine Infant Vaccinations According to Different Immunization Schedules: A Randomized Controlled Trial

CONTEXT In the absence of an effective vaccine, serogroup B Neisseria meningitidis (MenB) remains a major cause of invasive disease in early childhood in developed countries. OBJECTIVE To determine the immunogenicity and reactogenicity of a multicomponent MenB vaccine (4CMenB) and routine infant vaccines when given either concomitantly or separately. DESIGN, SETTING, AND PARTICIPANTS Phase 2b, multicenter, open-label, parallel-group, randomized controlled study of 1885 infants enrolled at age 2 months from August 2008 to July 2010 in Europe. INTERVENTION Participants were randomized 2:2:1:1 to receive (1) 4CMenB at 2, 4, and 6 months with routine vaccines (7-valent pneumococcal and combined diphtheria, tetanus, acellular pertussis, inactivated polio, hepatitis B, Haemophilus influenzae type b vaccines); (2) 4CMenB at 2, 4, and 6 months and routine vaccines at 3, 5, and 7 months; (3) 4CMenB with routine vaccines at 2, 3, and 4 months; or (4) routine vaccines alone at 2, 3, and 4 months. MAIN OUTCOME MEASURES Percentage of participants with human complement serum bactericidal activity (hSBA) titer of 1:5 or greater against 3 MenB strains specific for vaccine antigens (NZ98/254, 44/76-SL, and 5/99). RESULTS After three 4CMenB vaccinations, 99% or more of infants developed hSBA titers of 1:5 or greater against strains 44/76-SL and 5/99. For NZ98/254, this proportion was 79% (95% CI, 75.2%-82.4%) for vaccination at 2, 4, and 6 months with routine vaccines, 86.1% (95% CI, 82.9%-89.0%) for vaccination at 2, 4, and 6 months without routine vaccines, and 81.7% (95% CI, 76.6%-86.2%) for vaccination at 2, 3, and 4 months with routine vaccines. Responses to routine vaccines given with 4CMenB were noninferior to routine vaccines alone for all antigens, except for the responses to pertactin and serotype 6B pneumococcal polysaccharide. Fever was seen following 26% (158/602) to 41% (247/607) of 4CMenB doses when administered alone, compared with 23% (69/304) to 36% (109/306) after routine vaccines given alone and 51% (306/605) to 61% (380/624) after 4CMenB and routine vaccines administered together. CONCLUSION A 4CMenB vaccine is immunogenic against reference strains when administered with routine vaccines at 2, 4, and 6 or at 2, 3, and 4 months of age, producing minimal interference with the response to routine infant vaccinations. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00721396.

Role of Mycoplasma pneumoniae and Chlamydia pneumoniae in Children with Community-Acquired Lower Respiratory Tract Infections

In order to evaluate the role of Mycoplasma pneumoniae and Chlamydia pneumoniae, we studied 613 children aged 2-14 years who were hospitalized for community-acquired lower respiratory tract infections (LRTIs). The patients were enrolled in the study by 21 centers in different regions of Italy from May 1998 through April 1999. Paired serum samples were obtained on admission and after 4-6 weeks to assay the titers of M. pneumoniae and C. pneumoniae antibodies. Nasopharyngeal aspirates for the detection of M. pneumoniae and C. pneumoniae were obtained on admission. Acute M. pneumoniae infections in 210 patients (34.3%) and acute C. pneumoniae infections in 87 (14.1%) were diagnosed. Fifteen of the 18 children with M. pneumoniae and/or C. pneumoniae infections whose treatments were considered clinical failures 4-6 weeks after enrollment had not been treated with macrolides. Our study confirms that M. pneumoniae and/or C. pneumoniae plays a significant role in community-acquired LRTIs in children of all ages and that such infections have a more complicated course when not treated with adequate antimicrobial agents.

Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials

BACKGROUND Meningococcal serogroup B disease disproportionately affects infants. We assessed lot-to-lot consistency, safety and immunogenicity, and the effect of concomitant vaccination on responses to routine vaccines of an investigational multicomponent vaccine (4CMenB) in this population. METHODS We did primary and booster phase 3 studies between March 31, 2008, and Aug 16, 2010, in 70 sites in Europe. We used two series of sponsor-supplied, computer-generated randomisation envelopes to allocate healthy 2 month-old infants to receive routine vaccinations (diphtheria-tetanus-acellular pertussis, inactivated poliovirus, hepatitis B plus Haemophilus influenzae type b, and seven-valent pneumococcal vaccine) at 2, 4, and 6 months of age alone, or concomitantly with 4CMenB or serogroup C conjugate vaccine (MenC) in: 1) an open-label, lot-to-lot immunogenicity and safety substudy of three 4CMenB lots compared with routine vaccines alone (1:1:1:1, block size eight); or 2) an observer-blind, lot-to-lot safety substudy of three 4CMenB lots compared with MenC (1:1:1:3, block size six). At 12 months, 4CMenB-primed children from either substudy were randomised (1:1, block size two) to receive 4CMenB booster, with or without measles-mumps-rubella-varicella (MMRV) vaccine. Immunogenicity was assessed by serum bactericidal assay with human complement (hSBA) against serogroup B test strains, and on randomly selected subsets of serum samples for routine vaccines; laboratory personnel were masked to assignment. The first coprimary outcome was lot-to-lot consistency (hSBA geometric mean ratio of all lots between 0·5 and 2·0), and the second was an immune response (hSBA titre ≥5) for each of the three strains. The primary outcome for the booster study was immune response to booster dose. Immunogenicity data for 4CMenB were for the modified intention-to-treat population, including all infants from the open-label substudy who provided serum samples. The safety population included all participants who contributed safety data after at least one dose of study vaccine. These trials are registered with ClinicalTrials.gov, numbers NCT00657709 and NCT00847145. FINDINGS We enrolled 2627 infants in the open-label phase, 1003 in the observer-blind phase, and 1555 in the booster study. Lot-to-lot consistency was shown for the three 4CMenB lots, with the lowest 95% lower confidence limit being 0·74 and the highest upper limit being 1·33. Of 1181–1184 infants tested 1 month after three 4CMenB doses (all lots pooled), 100% (95% CI 99–100) had hSBA titres of 5 or more against strains selective for factor H binding protein and neisserial adhesin A, and 84% (82–86) for New Zealand outer-membrane vesicle. In a subset (n=100), 84% (75–91) of infants had hSBA titres of 5 or more against neisseria heparin binding antigen. At 12 months of age, waning titres were boosted by a fourth dose, such that 95–100% of children had hSBA titres of 5 or more for all antigens, with or without concomitant MMRV. Immune responses to routine vaccines were much the same with or without concomitant 4CMenB, but concomitant vaccination was associated with increased reactogenicity. 77% (1912 of 2478) of infants had fever of 38·5°C or higher after any 4CMenB dose, compared with 45% (295 of 659) after routine vaccines alone and 47% (228 of 490) with MenC, but only two febrile seizures were deemed probably related to 4CMenB. INTERPRETATION 4CMenB is immunogenic in infants and children aged 12 months with no clinically relevant interference with routine vaccines, but increases reactogenicity when administered concomitantly with routine vaccines. This breakthrough vaccine offers an innovative solution to the major remaining cause of bacterial meningitis in infant and toddlers. FUNDING Novartis Vaccines and Diagnostics.

Socioeconomic impact of influenza on healthy children and their families

Background. Recent studies indicate that influenza can be clinically important in otherwise healthy children. However, the interpretation of many studies is limited because of lack of laboratory confirmation of influenza-like illnesses. Therefore it is difficult to conclude whether the socioeconomic impact of influenza justifies vaccinating all children regardless of age or underlying chronic disorders. Methods. We prospectively collected data from 3771 children younger than 14 years of age presenting to emergency departments or primary care pediatricians with symptoms of respiratory tract infection during the influenza season of 2001 to 2002. Influenza infections were verified by virus culture or polymerase chain reaction. We additionally randomized 303 children age 6 months to 5 years to receive either influenza vaccine (n = 202) or no vaccination (n = 101) before the influenza season. The socioeconomic impact of influenza was assessed for both the participating children and their household contacts. Results. Influenza was documented in 352 (9.3%) of the 3771 children. Compared with influenza-negative children, children with influenza had longer durations of fever and absenteeism from day care or school (P < 0.0001). Further the numbers of medical visits, missed work or school days and the need for help at home to care for the sick children were higher among the household contacts of influenza-positive children (P < 0.0001). Influenza vaccination reduced significantly the direct and indirect influenza-related costs in healthy children and their unvaccinated family members. Conclusions. The findings of this study support a wider use of influenza vaccine in healthy children of all ages to reduce the socioeconomic burden of influenza on the community.

Transition process of patients with type 1 diabetes (T1DM) from paediatric to the adult health care service: a hospital‐based approach

Introduction  The outcomes of different types of transitions of young people with chronic diseases have been poorly investigated.

Safety and Immunogenicity of a 13-Valent Pneumococcal Conjugate Vaccine Compared to Those of a 7-Valent Pneumococcal Conjugate Vaccine Given as a Three-Dose Series with Routine Vaccines in Healthy Infants and Toddlers

ABSTRACT A 13-valent pneumococcal conjugate vaccine (PCV13) has been developed to improve protection against pneumococcal disease beyond that possible with the licensed 7-valent vaccine (PCV7). This study compared the safety and immunogenicity of PCV13 with those of PCV7 when given as part of the pediatric vaccination schedule recommended in Italy. A total of 606 subjects were randomly assigned to receive either PCV13 or PCV7 at 3, 5, and 11 months of age; all subjects concomitantly received diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio-Haemophilus influenzae type B (DTaP-HBV-IPV/Hib) vaccine. Vaccine reactions were monitored. Antibody responses to DTaP-HBV-IPV/Hib antigens, serotype-specific anticapsular polysaccharide IgG responses, and antipneumococcal opsonophagocytic assay (OPA) activity were measured 1 month after the two-dose primary series and 1 month after the toddler dose. Overall, the safety profile of PCV13 was similar to that of PCV7. The response to DTaP-HBV-IPV/Hib antigens was substantially the same with both PCV13 and PCV7. PCV13 elicited antipneumococcal capsular IgG antibodies to all 13 vaccine serotypes, with notable increases in concentrations seen after the toddler dose. Despite a lower immunogenicity for serotypes 6B and 23F after the primary series of PCV13, responses to the seven common serotypes were comparable between the PCV13 and PCV7 groups when measured after the toddler dose. PCV13 also elicited substantial levels of OPA activity against all 13 serotypes following both the infant series and the toddler dose. In conclusion, PCV13 appeared comparable to PCV7 in safety profile and immunogenicity for common serotypes, demonstrated functional OPA responses for all 13 serotypes, and did not interfere with immune responses to concomitantly administered DTaP-HBV-IPV/Hib vaccine.

Emerging role of Mycoplasma pneumoniae and Chlamydia pneumoniae in paediatric respiratory- tract infections

Increased use of specialised diagnostic techniques over the past 10 years has allowed considerable new information to be obtained concerning Mycoplasma pneumoniae and Chlamydia pneumoniae infections. In children, these pathogens seem to have a more important role in causing respiratory-tract infections than previously thought; they have been associated with wheezing, and they are also frequent in children aged under 5 years. Contrary to original belief, no clinical, laboratory, or radiological findings seem to be unique to M. pneumoniae or C. pneumoniae; furthermore, there is no rapid and cost-effective diagnostic test capable of identifying these pathogens. Appropriate antimicrobial treatment of the infections they cause is needed to reduce the recurrent episodes of wheezing and other respiratory symptoms, to decrease morbidity, and to avoid the spread of the pathogens. However, a number of therapeutic issues remain unsolved.

Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data

Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect. Design Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials. Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015. Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome. Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality. Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit. Systematic review registration PROSPERO CRD42014013953.

Burden of influenza in healthy children and their households

Objective: A prospective, multicentre study was conducted to evaluate the burden of laboratory confirmed influenza in healthy children and their household contacts. Methods: The patients were enrolled in four emergency departments (EDs) and by five primary care paediatricians (PCPs) in different Italian municipalities 2 days a week between November 1, 2001 and April 30, 2002. The study involved 3771 children less than 14 years of age with no chronic medical conditions who presented with a respiratory tract infection in EDs or PCP outpatient clinics during the study period. Nasopharyngeal swabs were collected for the isolation of influenza viruses and RNA detection. Information was also collected concerning respiratory illnesses and related morbidities among the study children and their household contacts. Results: Influenza virus was demonstrated in 352 cases (9.3%). In comparison with the influenza negative children, those who were influenza positive had an older mean age, were more often attending day care centres or schools, more frequently experienced fever and croup, received more antipyretics, and had a longer duration of fever and school absence. Furthermore, their parents and siblings had more respiratory illnesses, received more antipyretics and antibiotics, needed more medical visits, missed more work or school days, and needed help at home to care for the ill children for a longer period of time. Conclusions: Influenza has a significant clinical and socioeconomic impact on healthy children and their families. Prevention strategies should also focus on healthy children regardless of their age because of their role in disease transmission.