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1.  Oropharyngeal and nasal Staphylococcus aureus carriage by healthy children 
BMC Infectious Diseases  2014;14(1):723.
Background
As healthy children are the main reservoir of respiratory pathogens and the main cause of bacterial diffusion in the community, it could be interesting to investigate the type of screening that should be used during the early years of life in order to obtain a more precise estimate of Staphylococcus aureus circulation. The aim of this study was to evaluate oropharyngeal and nasal S. aureus carriage in otherwise healthy children and adolescents aged 6–17 years.
Methods
The oropharyngeal and nasal samples were collected in December 2013 from 497 healthy students attending five randomly selected schools in Milan, Italy, using an ESwab kit, and S. aureus was identified using the RIDA®GENE methicillin-resistant S. aureus (MRSA) system.
Results
Two hundred and sixty-four subjects (53.1%) were identified as S. aureus carriers: 129 (25.9%) oropharyngeal carriers and 195 (39.2%) nasal carriers, of whom 60 (12.1%) were both oropharyngeal and nasal carriers. Oropharyngeal carriage increased with age (p < 0.001), whereas nasal carriage decreased. There was little or no agreement between oropharyngeal and nasal carriage in any of the age groups. MRSA was identified in only three cases (0.6%), always in nasal samples. There were no differences between the carriers and non-carriers in terms of the distribution of age, gender, ethnicity, the number of siblings in the household, exposure to passive smoking, previous clinical history, allergic sensitisation, or previous influenza, pneumococcal and meningococcal vaccinations. The frequency of male children was higher among the subjects with positive nasal and oropharyngeal swabs (66.7%) than among those with positive oropharyngeal swabs alone (46.4%; p = 0.02).
Conclusions
The oropharyngeal carriage of mainly methicillin-sensitive S. aureus is frequent in otherwise healthy children, including a relatively high proportion of those without nasal colonisation. These findings highlight the importance of adding throat to nasal screening when monitoring the circulation of S. aureus in the community.
doi:10.1186/s12879-014-0723-9
PMCID: PMC4299802  PMID: 25551464
Methicillin-resistant Staphylococcus aureus; Methicillin-sensitive Staphylococcus aureus; MRSA; MSSA; Staphylococcus aureus
2.  The change in Ig regulation from children to adults disconnects the correlation with the 3′RR hs1.2 polymorphism 
BMC Immunology  2014;15(1):45.
Background
In the immune system, the serum levels of immunoglobulin (Ig) increase gradually during ageing. Through B cell development, the Ig heavy chain expression is modulated by a regulatory region at the 3’ of the constant alpha gene (3’RR), in single copy in rodents and, due to a large duplication, in two copies in apes. The human 3’RR1 and 3’RR2 are both characterized by three enhancers, the central of which, namely hs1.2, is highly polymorphic. Human hs1.2 has four different variants with unique binding sites for transcription factors (e.g. NF-kB and SP1) and shows variable allelic frequencies in populations with immune disorders. In previous works, we have reported that in several autoimmune diseases the *2 allele of hs1.2 is genetically associated to high level of IgM in peripheral blood. In subjects with altered levels of circulating Ig, an increased level was associated to *2 allele of hs1.2 and low levels corresponded to high frequency of *1 allele.
During ageing there is a physiological increase of Ig concentrations in the serum. Therefore, for this study, we hypothesized that the hs1.2 variants may impact differently the levels of secreted Ig during the growth.
Results
We have correlated the allelic frequencies of hs1.2 with IgM, IgG and IgA serum concentrations in two cohorts of healthy people of different age and after three years follow-up in children homozygous for the allele. Here we show that when the expression levels of Ig in children are low and medium, the frequencies of *1 and *2 alleles are the same. Instead, when the Ig expression levels are high, there is a significantly higher frequency of the allele *2. The follow-up of children homozygous for *1 and *2 alleles showed that the increase or decrease of circulating Ig was not dependent on the number of circulating mature B cells.
Conclusions
These data support the idea that under physiologic condition there is a switch of regulative pathways involved in the maturation of Ig during ageing. This mechanism is evidenced by hs1.2 variants that in children but not in adults participate to Ig production, coordinating the three class levels.
Electronic supplementary material
The online version of this article (doi:10.1186/s12865-014-0045-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12865-014-0045-0
PMCID: PMC4234878  PMID: 25391515
Genotyping; B cell markers; Immunoglobulin heavy chain; Enhancer hs1.2; Immune system regulation; NF-κB; SP1; Transcription factor consensus; Aging
3.  Genetic characteristics of Neisseria meningitidis serogroup B strains carried by adolescents living in Milan, Italy 
Human Vaccines & Immunotherapeutics  2013;9(11):2296-2303.
Before a protein vaccine is introduced into a country, it is essential to evaluate its potential impact and estimate its benefits and costs. The aim of this study was to determine the genetic characteristics of Neisseria meningitidis B (NmB) in the pharyngeal secretions of 1375 healthy adolescents aged 13–19 y living in Milan, Italy, in September 2012, and the possible protection offered by the two currently available NmB protein vaccines. Ninety-one subjects were Nm carriers (6.6%), 29 (31.9%) of whom carried the NmB capsular gene. The 29 identified strains belonged to eight clonal complexes (CCs), the majority of which were in the ST-41/44/Lin.3 CC (n = 11; 37.9%). All of the identified strains harboured ƒHbp alleles representing a total of 15 sub-variants: the gene for NHBA protein was found in all but three of the studied strains (10.3%) with 13 identified sub-variants. There were 15 porA sub-types, seven of which were identified in just one CC. The findings of this study seem to suggest that both of the protein vaccines proposed for the prevention of invasive disease due to NmB (the 4-protein and the 2-protein products) have a composition that can evoke a theoretically effective antibody response against the meningococcal strains currently carried by adolescents living in Northern Italy. The genetic characteristics of NmB strains can be easily evaluated by means of molecular methods, the results of which can provide an albeit approximate estimate of the degree of protection theoretically provided by the available vaccines, and the possible future need to change their composition.
doi:10.4161/hv.25800
PMCID: PMC3981836  PMID: 23880917
meningococcal vaccine; meningococcus B; meningococcus B vaccine; Neisseria meningitides; invasive bacterial disease
4.  Intestinal tuberculosis in a child living in a country with a low incidence of tuberculosis: a case report 
BMC Research Notes  2014;7(1):762.
Background
Relatively common in adults, intestinal tuberculosis is considered rare in children and adolescents. The protean manifestations of intestinal tuberculosis mean that the diagnosis is often delayed (sometimes even for years), thus leading to increased mortality and unnecessary surgery. The main diagnostic dilemma is to differentiate intestinal tuberculosis and Crohn’s disease because a misdiagnosis can have dramatic consequences.
Case presentation
A 13-year-old Caucasian, Italian female adolescent attended the Emergency Department complaining of abdominal pain, a fever of up to 38°C, night sweats, diarrhea with blood in stool, and a weight loss of about three kilograms over the previous two months. Physical examination revealed a marked skin pallor and considerable abdominal distension with relevant discomfort in all the abdominal quadrant. Laboratory tests revealed a decreased white blood cell count with anemia and increased C-reactive protein levels. The Mantoux tuberculin skin test was negative. A chest X-ray and an abdominal ultrasonography did not reveal any significant findings. The patient underwent colonoscopy that showed diffuse mucosal congestion and significant blood loss, and laparatomy showed small bowel and colon loops with a whitish appearance. A biopsy of the ileal mucosa revealed inflammation with noncaseating granulomas possibly due to bacterial infection. Given the suspicion of an opportunistic bacterial infection in a child with chronic inflammatory bowel disease (possibly Crohn’s disease), treatment with a third-generation cephalosporin was started. However, the abdominal pain, fever and poor general condition persisted and so, after 11 days, the patient underwent total body computed tomography and magnetic resonance imaging of the brain. On the basis of the radiological findings, miliary tuberculosis was suspected and bronchoscopy was performed and resulted positive for Mycobacterium tuberculosis. Miliary tuberculosis was confirmed and an effective treatment with four drugs was started.
Conclusion
This case shows that the manifestations of intestinal tuberculosis can be very difficult to diagnose and mimic those of Chron’s disease. Total body computed tomography and laparotomy with an intestinal biopsy for the detection of Mycobacterium tuberculosis are the means of avoid the risks of a misdiagnosis in children with unexplained chronic abdominal problems.
doi:10.1186/1756-0500-7-762
PMCID: PMC4219019  PMID: 25346193
Emerging infections; Gastrointestinal infections; Intestinal tuberculosis; Mycobacterium tuberculosis; Tuberculosis
5.  Genetic polymorphisms and risk of recurrent wheezing in pediatric age 
BMC Pulmonary Medicine  2014;14(1):162.
Background
Wheezing during early life is a very common disorder, but the reasons underlying the different wheezing phenotypes are still unclear. The aims of this study were to analyse the potential correlations between the risk of developing recurrent wheezing and the presence of specific polymorphisms of some genes regulating immune system function, and to study the relative importance of the associations of different viruses and genetic polymorphisms in causing recurrent episodes.
Methods
The study involved 119 otherwise healthy infants admitted to hospital for a first episode of wheezing (74 of whom subsequently experienced recurrent episodes) and 119 age- and sex-matched subjects without any history of respiratory problem randomly selected from those attending our outpatient clinic during the study period. All of the study subjects were followed up for two years, and 47 single nucleotide polymorphisms (SNPs) in 33 candidate genes were genotyped on whole blood using an ABI PRISM 7900 HT Fast Real-time instrument.
Results
IL8-rs4073AT, VEGFA-rs833058CT, MBL2-rs1800450CT and IKBKB-rs3747811AT were associated with a significantly increased risk of developing wheezing (p = 0.02, p = 0.03, p = 0.05 and p = 0.0018), whereas CTLA4-rs3087243AG and NFKBIB-rs3136641TT were associated with a significantly reduced risk (p = 0.05 and p = 0.04). IL8-rs4073AT, VEGFA-rs2146323AA and NFKBIA-rs2233419AG were associated with a significantly increased risk of developing recurrent wheezing (p = 0.04, p = 0.04 and p = 0.03), whereas TLR3-rs3775291TC was associated with a significantly reduced risk (p = 0.03). Interestingly, the study of gene-environment interactions showed that rhinovirus was significantly associated with recurrent wheezing in the presence of IL4Ra-rs1801275GG and G (odds ratio [OR] 6.03, 95% confidence interval [CI]: 1.21-30.10, p = 0.03) and MAP3K1-rs702689AA (OR 4.09, 95% CI: 1.14-14.61, p = 0.03).
Conclusions
This study shows a clear relationship between the risk of wheezing and polymorphisms of some genes involved in the immune response. Although further studies are needed to confirm the results, these findings may be useful for the early identification of children at the highest risk of developing recurrent episodes and possibly subsequent asthma.
doi:10.1186/1471-2466-14-162
PMCID: PMC4210469  PMID: 25326706
Asthma; Genetic polymorphisms; Lower respiratory tract infection; Recurrent wheezing; Respiratory viruses; Wheezing
6.  Tuberculosis in children 
Italian Journal of Pediatrics  2014;40(Suppl 1):A4.
doi:10.1186/1824-7288-40-S1-A4
PMCID: PMC4132475
8.  Impact of air pollution on respiratory diseases in children with recurrent wheezing or asthma 
BMC Pulmonary Medicine  2014;14:130.
Background
Air pollution has many negative health effects on the general population, especially children, subjects with underlying chronic disease and the elderly. The aims of this study were to evaluate the effects of traffic-related pollution on the exacerbation of asthma and development of respiratory infections in Italian children suffering from asthma or wheezing compared with healthy subjects and to estimate the association between incremental increases in principal pollutants and the incidence of respiratory symptoms.
Methods
This prospective study enrolled 777 children aged 2 to 18 years (375 with recurrent wheezing or asthma and 402 healthy subjects). Over 12 months, parents filled out a daily clinical diary to report information about respiratory symptoms, type of medication used and healthcare utilization. Clinical data were combined with the results obtained using an air pollution monitoring system of the five most common pollutants.
Results
Among the 329 children with recurrent wheezing or asthma and 364 healthy subjects who completed follow-up, children with recurrent wheezing or asthma reported significantly more days of fever (p = 0.005) and cough (p < 0.001), episodes of rhinitis (p = 0.04) and tracheitis (p = 0.01), asthma attacks (p < 0.001), episodes of pneumonia (p < 0.001) and hospitalizations (p = 0.02). In the wheezing/asthma cohort, living close to the street with a high traffic density was a risk factor for asthma exacerbations (odds ratio [OR] = 1.79; 95% confidence interval [CI], 1.13-2.84), whereas living near green areas was found to be protective (OR = 0.50; 95% CI, 0.31 -0.80). An increase of 10 μg/m3 of particulates less than 10 microns in diameter (PM10) and nitrogen dioxide (NO2) increased the onset of pneumonia only in wheezing/asthmatic children (continuous rate ratio [RR] = 1.08, 95% CI: 1.00-1.17 for PM10; continuous RR = 1.08, 95% CI: 1.01-1.17 for NO2).
Conclusions
There is a significant association between traffic-related pollution and the development of asthma exacerbations and respiratory infections in children born to atopic parents and in those suffering from recurrent wheezing or asthma. These findings suggest that environmental control may be crucial for respiratory health in children with underlying respiratory disease.
doi:10.1186/1471-2466-14-130
PMCID: PMC4126992  PMID: 25098250
Air pollution; Asthma; NO2; PM10; Respiratory disease; Traffic-related pollutant; Wheezing
9.  Genetic Polymorphisms and Sepsis in Premature Neonates 
PLoS ONE  2014;9(7):e101248.
Identifying single nucleotide polymorphisms (SNPs) in the genes involved in sepsis may help to clarify the pathophysiology of neonatal sepsis. The aim of this study was to evaluate the relationships between sepsis in pre-term neonates and genes potentially involved in the response to invasion by infectious agents. The study involved 101 pre-term neonates born between June 2008 and May 2012 with a diagnosis of microbiologically confirmed sepsis, 98 pre-term neonates with clinical sepsis and 100 randomly selected, otherwise healthy pre-term neonates born during the study period. During the study, 47 SNPs in 18 candidate genes were genotyped on Guthrie cards using an ABI PRISM 7900 HT Fast real-time and MAssARRAY for nucleic acids instruments. Genotypes CT and TT of rs1143643 (the IL1β gene) and genotype GG of rs2664349GG (the MMP-16 gene) were associated with a significantly increased overall risk of developing sepsis (p = 0.03, p = 0.05 and p = 0.03), whereas genotypes AG of rs4358188 (the BPI gene) and CT of rs1799946 (the DEFβ1 gene) were associated with a significantly reduced risk of developing sepsis (p = 0.05 for both). Among the patients with bacteriologically confirmed sepsis, only genotype GG of rs2664349 (the MMP-16 gene) showed a significant association with an increased risk (p = 0.02). Genotypes GG of rs2569190 (the CD14 gene) and AT of rs4073 (the IL8 gene) were associated with a significantly increased risk of developing severe sepsis (p = 0.05 and p = 0.01). Genotype AG of rs1800629 (the LTA gene) and genotypes CC and CT of rs1341023 (the BPI gene) were associated with a significantly increased risk of developing Gram-negative sepsis (p = 0.04, p = 0.04 and p = 0.03). These results show that genetic variability seems to play a role in sepsis in pre-term neonates by influencing susceptibility to and the severity of the disease, as well as the risk of having disease due to specific pathogens.
doi:10.1371/journal.pone.0101248
PMCID: PMC4085055  PMID: 25000179
10.  Nasal saline irrigation in preschool children: a survey of attitudes and prescribing habits of primary care pediatricians working in northern Italy 
Background
It has been shown that nasal saline irrigation (NSI) alone can be effective in children with infectious and/or allergic respiratory problems, but no study has assessed the awareness or clinical use of NSI among practising pediatricians. The main aim of this study was to evaluate the use of NSI in pre-school children by primary care pediatricians working in northern Italy.
Methods
Nine hundred randomly selected National Health Service primary care pediatricians with an e-mail address were sent an e-mail asking whether they were willing to respond to a questionnaire regarding the use of NSI. The 870 who answered positively were sent an anonymous questionnaire by post and e-mail that had 17 multiple-choice items.
Results
Completed questionnaires were received from 860 of the 870 primary care pediatricians (98.8%). NSI was used by almost all the respondents (99.3%), although with significant differences in frequency. It was considered both a prophylactic and a therapeutic measure by most of the respondents (60.3%), who prescribed it every day for healthy children and more frequently when they were ill. Most of the primary care pediatricians (87%) indicated an isotonic solution as the preferred solution, and the most frequently recommended administration devices were a nasal spray (67.7%) and bulb syringe (20.6%). Most of the pediatricians (75.6%) convinced parents to use NSI by explaining it could have various beneficial effects, and two-thirds (527/854; 61.7%) thought that most of the parents agreed about the importance of NSI. Analysis of possible associations between NSI prescribing behaviour and the demographic data revealed an associations with age and gender, with pediatricians aged <50 years prescribing NSI more frequently than their older counterparts (p < 0.01), and females prescribing NSI more frequently than males (p < 0.01).
Conclusions
In Northern Italy, most primary care pediatricians prescribe NSI for both the prophylaxis and therapy of upper respiratory tract problems in pre-school children. However, many aspects of the procedure are not clarified, and this reduces parental compliance. Given the medical and economic advantages of NSI, this situation should be changed as soon as possible.
doi:10.1186/1824-7288-40-47
PMCID: PMC4041066  PMID: 24887239
Isotonic saline solution; Hypertonic saline solution; Nasal saline irrigation; Nasal spray; Respiratory tract infection
11.  Vaccine administration and the development of immune thrombocytopenic purpura in children 
Human Vaccines & Immunotherapeutics  2013;9(5):1158-1162.
The most important reasons cited by the opponents of vaccines are concerns about vaccine safety. Unlike issues such as autism for which no indisputable documentation of direct relationship with vaccine use is available, immune thrombocytopenic purpura (ITP) is an adverse event that can really follow vaccine administration, and may limit vaccine use because little is known about which vaccines it may follow, its real incidence and severity, the risk of chronic disease, or the possibility of recurrences after new doses of the same vaccine. The main aim of this review is to clarify the real importance of thrombocytopenia as an adverse event and discuss how it may interfere with recommended vaccination schedules. The available data clearly indicate that ITP is very rare and the only vaccine for which there is a demonstrated cause-effect relationship is the measles, mumps and rubella (MMR) vaccine that can occur in 1 to 3 children every 100,000 vaccine doses. However, also in this case, the incidence of ITP is significantly lower than that observed during the natural diseases that the vaccine prevents. Consequently, ITP cannot be considered a problem limiting vaccine use except in the case of children suffering from chronic ITP who have to receive MMR vaccine. In these subjects, the risk-benefit ratio of the vaccine should be weighed against the risk of measles in the community.
doi:10.4161/hv.23601
PMCID: PMC3899154  PMID: 23324619
adverse events; immune thrombocytopenic purpura; MMR; platelets; vaccine safety; vaccine
12.  Impact of vitamin D administration on immunogenicity of trivalent inactivated influenza vaccine in previously unvaccinated children 
As vitamin D (VD) has a significant regulatory effect on innate and adaptive immunity, the aim of this prospective, randomized, single-blinded, placebo-controlled study was to measure the impact of VD administration on the immune response to trivalent influenza vaccination (TIV). A total of 116 children (61 males, 52.6%; mean age 3.0 ± 1.0 y) with a history of recurrent acute otitis media (AOM), who had not been previously vaccinated against influenza, were randomized to receive daily VD 1,000 IU or placebo by mouth for four months. All of them received two doses of TIV (Fluarix, GlaxoSmithKline Biologicals) one month apart, with the first dose administered when VD supplementation was started. There was no difference in seroconversion or seroprotection rates, or antibody titers, in relation to any of the three influenza vaccine antigens between the VD and placebo groups, independently of baseline and post-treatment VD levels. The safety profile was also similar in the two groups. These data indicate that the daily administration of VD 1,000 IU for four months from the time of the injection of the first dose of TIV does not significantly modify the antibody response evoked by influenza vaccine.
doi:10.4161/hv.23540
PMCID: PMC3899163  PMID: 23324599
acute otitis media, children; influenza, influenza vaccination, trivalent influenza vaccine, vitamin D, vitamin D supplementation
13.  Vitamin D and influenza vaccination 
doi:10.4161/hv.23848
PMCID: PMC3899165  PMID: 23404340
acute otitis media; influenza; influenza vaccine; vitamin D; vitamin D supplementation
14.  Performance of lung ultrasonography in children with community-acquired pneumonia 
Background
There are few prospective evaluations of point-of-care ultrasonography (US) for the diagnosis of pediatric community-acquired pneumonia (CAP). In particular, there are very few data concerning the efficiency of US in comparison with that of chest radiography (CR) in defining different kinds of lung alterations in the various pulmonary sections. The aim of this study was to bridge this gap in order to increase our knowledge of the performance of US in diagnosing CAP in childhood.
Methods
A total of 103 children (56 males, 54.4%; mean age ± standard deviation 5.6 ± 4.6 years) admitted to hospital with a clinical diagnosis of suspected CAP were prospectively enrolled and underwent CR (evaluated by an independent expert radiologist) and lung US (performed by a resident in paediatrics with limited experience in US). The performance of US in diagnosing CAP (i.e. its sensitivity, specificity, and positive and negative predictive values) was compared with that of CR.
Results
A total of 48 patients had radiographically confirmed CAP. The sensitivity, specificity, and positive and negative predictive values of US in comparison with CR were respectively 97.9%, 94.5%, 94.0% and 98.1%. US identified a significantly higher number of cases of pleural effusion, but the concordance of the two methods in identifying the type of CAP was poor.
Conclusion
US can be considered a useful means of diagnosing CAP in children admitted to an Emergency Department with a lower respiratory tract infection, although its usefulness in identifying the type of lung involvement requires further evaluation.
doi:10.1186/1824-7288-40-37
PMCID: PMC4012508  PMID: 24742171
Chest radiography; Community-acquired pneumonia; Lower respiratory tract infection; Lung ultrasonography; Pneumonia; Radiology
15.  Do children’s upper respiratory tract infections benefit from probiotics? 
BMC Infectious Diseases  2014;14:194.
Background
The microbiota of the gastrointestinal tract have profound influence at multiple levels, even on the development and maintenance of lung immunity and inflammation. Aim of this review is to evaluate the current knowledge about the specific impact on children’s respiratory tract infections from probiotics, live microbes with the power to modify intestinal microbial populations and exert subsequent benefits for the host.
Discussion
The role of probiotics in gastrointestinal and allergic diseases has been largely assessed, but the number of studies performed so far in the field of respiratory tract infections is small, though some data show that probiotic administration might display clinical advantages. Probiotic strain identity and host genetic differences may account for differential modulation of immune responses by probiotics. Current laboratory and clinical data regarding the possibility of the role of probiotics on preventing the development of respiratory tract infections are contradictory, and are somewhat insufficient to recommend strongly their routine use. Further study of gastrointestinal-respiratory interactions is likely to yield important insights into the pathogenesis of different pulmonary diseases, and improve our knowledge in the prophylactic role of probiotics in children affected by recurrent upper respiratory tract infections.
Summary
A better understanding of the effects of different probiotic strains and a deeper insight into their mechanisms of action are needed for the validation of specific strains carrying a potential to modify the frequency and severity of RTIs in infants and children. No data have been collected in pediatric patients with chronic underlying diseases, and yet there are no published data concerning treatment of RTIs with probiotics. The very few studies published so far do not indicate which micro-organism or administration regimen might exert beneficial effects as a prevention tool of RTIs both in healthy children and in those with recurrent RTIs. Further research to establish the role of probiotics in the treatment and prevention of RTIs, including those involving the lower respiratory tract, are required and should also clarify if any susceptible subgroups of respiratory diseases exist, and how these subgroups benefit from supplementation with certain probiotic strains.
doi:10.1186/1471-2334-14-194
PMCID: PMC3984429  PMID: 24720809
Acute otitis media; Children; Prevention; Probiotics; Respiratory tract infection; Upper respiratory tract infections
16.  Immune history shapes specificity of pandemic H1N1 influenza antibody responses 
The Journal of Experimental Medicine  2013;210(8):1493-1500.
The specificity of H1N1 antibody responses can be shifted to epitopes near the HA receptor–binding domain after sequential infections with viral strains that share homology in this region.
Human antibody responses against the 2009 pandemic H1N1 (pH1N1) virus are predominantly directed against conserved epitopes in the stalk and receptor-binding domain of the hemagglutinin (HA) protein. This is in stark contrast to pH1N1 antibody responses generated in ferrets, which are focused on the variable Sa antigenic site of HA. Here, we show that most humans born between 1983 and 1996 elicited pH1N1 antibody responses that are directed against an epitope near the HA receptor–binding domain. Importantly, most individuals born before 1983 or after 1996 did not elicit pH1N1 antibodies to this HA epitope. The HAs of most seasonal H1N1 (sH1N1) viruses that circulated between 1983 and 1996 possess a critical K133 amino acid in this HA epitope, whereas this amino acid is either mutated or deleted in most sH1N1 viruses circulating before 1983 or after 1996. We sequentially infected ferrets with a 1991 sH1N1 virus and then a pH1N1 virus. Sera isolated from these animals were directed against the HA epitope involving amino acid K133. These data suggest that the specificity of pH1N1 antibody responses can be shifted to epitopes near the HA receptor–binding domain after sequential infections with sH1N1 and pH1N1 viruses that share homology in this region.
doi:10.1084/jem.20130212
PMCID: PMC3727314  PMID: 23857983
17.  Phylogenetic Analysis of Human Rhinovirus Isolates Collected from Otherwise Healthy Children with Community-Acquired Pneumonia during Five Successive Years 
PLoS ONE  2013;8(11):e80614.
In order to evaluate the circulation of the different human rhinovirus (HRV) species and genotypes in Italian children with radiographically confirmed community-acquired pneumonia (CAP), a nasopharyngeal swab was obtained from 643 children admitted to hospital because of CAP during five consecutive winter and early spring seasons (2007-2012). Real-time reverse transcriptase polymerase chain reaction (RT-PCR) was used to identify HRV, and the HRV-positive samples were used for sequencing analysis and to reconstruct the phylogenetic tree. HRV was identified in 198 samples (42.2%), and the VP4/VP2 region was successfully amplified in 151 (76.3%). HRV-A was identified in 78 samples (51.6%), HRV-B in 14 (9.3%) and HRV-C in 59 (39.1%). Forty-seven (31.1%) of the children with HRV infection were aged <1 year, 71 (47.0%) were aged 1-3 years, and 33 (21.9%) were aged ≥4 years. Blast and phylogenetic analyses showed that the HRV strains were closely related to a total of 66 reference genotypes, corresponding to 29 HRV-A, 9 HRV-B and 28 HRV-C strains. Nucleotide variability was 37% between HRV-A and HRV-B, 37.3% between HRV-A and HRV-C, and 39.9% between HRV-B and HRV-C. A number of sequences clustered with known serotypes and, within these clusters, there were strains circulating during several seasons. The most frequently detected genotypes were HRV-A78 (n=17), HRV-A12 (n=9) and HRV-C2 (n=5). This study shows that, although it is mainly associated with HRV-A, pediatric CAP can also be diagnosed in subjects infected by HRV-C and, more rarely, by HRV-B. Moreover, a large number of genotypes may be involved in causing pediatric CAP and can be different from year to year. Although the prolonged circulation of the same genotypes can sometimes be associated with a number of CAP episodes in different years.
doi:10.1371/journal.pone.0080614
PMCID: PMC3833952  PMID: 24260436
18.  A case of meningitis due to varicella zoster virus reactivation in an immunocompetent child 
Background
The development of neurological complications due to varicella zoster virus (VZV) reactivation is relatively uncommon, particularly in the case of immunocompetent patients. Only a few cases have been described in the literature, most of which involved adult or elderly patients.
Clinical presentation
Two days after his pediatrician had diagnosed herpes zoster and prescribed oral acyclovir 400 mg three times a day, a 14-year-old boy was admitted to our hospital because of mild fever, severe headache, slowness, drowsiness and vomiting. A cerebrospinal fluid examination was performed and showed an increased protein concentration (95 mg/dL), normal glucose level (48 mg/dL; blood glucose level, 76 mg/dL) and lymphocytic pleocytosis (1,400 lymphocytes/μL), and VZV DNA was detected by means of polymerase chain reaction (1,250 copies/mL). The results of immunological screening for HIV, lymphocyte subpopulation counts, serum immunoglobulin and complement (C3 and C4) levels, vaccine responsiveness and lymphocytes stimulation tests were unremarkable. Acyclovir was administered intravenously at a dose of 10 mg/kg three times a day and continued for 10 days. The therapy was highly effective and the patient’s clinical condition rapidly improved: fever disappeared after two days, and all of the signs and symptoms of neurological involvement after four days. The skin lesions resolved in about one week, and no pain or dysesthesia was ever reported. Given the favourable evolution of the illness, the child was discharged without further therapy after the 10-day treatment. The findings of a magnetic resonance examination immediately after the discontinuation of the antiviral therapy were normal, and a control examination carried out about four weeks later did not find any sign or symptom of disease.
Conclusion
VZV reactivation can also lead to various neurological complications in immunocompetent children. Prompt therapy with acyclovir and the integrity of the immune system are important in conditioning outcome, but other currently unknown factors probably also play a role.
doi:10.1186/1824-7288-39-72
PMCID: PMC3832881  PMID: 24224976
Herpes zoster; Varicella; Varicella zoster virus; VZV reactivation
19.  Clinical profile of recurrent community-acquired pneumonia in children 
Background
The aim of this case–control study was to analyse the clinical characteristics of children with recurrent community-acquired pneumonia (rCAP) affecting different lung areas (DLAs) and compare them with those of children who have never experienced CAP in order to contribute to identifying the best approach to such patients.
Methods
The study involved 146 children with ≥2 episodes of radiographically confirmed CAP in DLA in a single year (or ≥3 episodes in any time frame) with radiographic clearing of densities between occurrences, and 145 age- and gender-matched controls enrolled in Milan, Italy, between January 2009 and December 2012. The demographic and clinical characteristics of the cases and controls were compared, and a comparison was also made between the cases with rCAP (i.e. ≤3 episodes) and those with highly recurrent CAP (hrCAP: i.e. >3 episodes).
Results
Gestational age at birth (p = 0.003), birth weight (p = 0.006), respiratory distress at birth (p < 0.001), and age when starting day care attendance (p < 0.001) were significantly different between the cases and controls, and recurrent infectious wheezing (p < 0.001), chronic rhinosinusitis with post-nasal drip (p < 0.001), recurrent upper respiratory tract infections (p < 0.001), atopy/allergy (p < 0.001) and asthma (p < 0.001) were significantly more frequent. Significant risk factors for hrCAP were gastroesophageal reflux disease (GERD; p = 0.04), a history of atopy and/or allergy (p = 0.005), and a diagnosis of asthma (p = 0.0001) or middle lobe syndrome (p = 0.001). Multivariate logistic regression analysis, adjusted for age and gender, showed that all of the risk factors other than GERD and wheezing were associated with hrCAP.
Conclusions
The diagnostic approach to children with rCAP in DLAs is relatively easy in the developed world, where the severe chronic underlying diseases favouring rCAP are usually identified early, and patients with chronic underlying disease are diagnosed before the occurrence of rCAP in DLAs. When rCAP in DLAs does occur, an evaluation of the patients’ history and clinical findings make it possible to limit diagnostic investigations.
doi:10.1186/1471-2466-13-60
PMCID: PMC3852007  PMID: 24106756
Allergy; Asthma; Atopy; Children; Community-acquired pneumonia; Lower respiratory tract infection; Pneumonia; Recurrent pneumonia; Respiratory tract infection; Wheezing
20.  Subcutaneous emphysema as the first relevant clinical sign of complicated tubercular lymph node disease in a child 
BMC Infectious Diseases  2013;13:461.
Background
Children make up a significant proportion of the global tuberculosis (TB) caseload, and experience considerable TB-related morbidity and mortality. Unfortunately, it is not easy to diagnose TB in the first years of life because of the diversity of its clinical presentation and the non-specific nature of most of its symptoms.
Case presentation
A 26-month-old male child was admitted to hospital because of the sudden onset of rapidly increasing swelling of the neck, face and upper trunk a few hours before. Upon admission, his temperature was 36.5°C, pulse rate 120/min, respiratory rate 36/min, and O2 saturation 97% in air. Palpation revealed subcutaneous emphysema (SE) over the swollen skin areas, and an examination of the respiratory system revealed crepitations in the left part of the chest without any significant suggestion of mediastinal shift. Chest radiography showed enlargement of the left lung hilum with pneumomediastinum and diffuse SE. Bronchoscopy was carried out because of the suspicion that the SE may have been due to the inhalation of a peanut. This excluded the presence of a foreign body but showed that the left main bronchus was partially obstructed with caseous material and showed significant signs of granulomatous inflammation on the wall. Contrast-enhanced computed tomography of the lungs confirmed the SE and pneumomediastinum, and revealed bilateral hilum lymph node disease with infiltration of the adjacent anatomical structure and a considerable breach in the left primary bronchus wall conditioning the passage of air in the mediastinum and subcutaneous tissue. As a tuberculin skin test and polymerase chain reaction for Mycobacterium tuberculosis on bronchial material and gastric aspirate were positive, a diagnosis of TB was made and oral anti-TB therapy was started, which led to the elimination of M. tuberculosis and a positive clinical outcome.
Conclusions
This is the first case in which SE was the first relevant clinical manifestation of TB and arose from infiltration of the bronchial wall secondary to caseous necrosis of the hilum lymph nodes. Physicians should be aware of the fact that SE is one of the possible initial signs and symptoms of early TB infection, and act accordingly.
doi:10.1186/1471-2334-13-461
PMCID: PMC3851260  PMID: 24094042
Children; Mycobacterium tuberculosis; Subcutaneous emphysema; Tuberculosis
22.  Genome Characterisation of Enteroviruses 117 and 118: A New Group within Human Enterovirus Species C 
PLoS ONE  2013;8(4):e60641.
The more than 120 genotypes of human enteroviruses (HEVs) reflect a wide range of evolutionary divergence, and there are 23 currently classified as human enterovirus C species (HEV-C). Two new HEV-C (EV-C117 and EV-C118) were identified in the Community-Acquired Pneumonia Pediatric Research Initiative (CAP-PRI) study, and the present paper describes the characterisation of the complete genome of one EV-C117 strain (LIT22) and two EV-C118 (ISR38 and ISR10) strains. The EV-C117 and EV-C118 5′UTR sequences were related to those of EV-C104, EV-C105 and EV-C109, and were slightly shorter than those of other HEV A-D species. Similarity plot analyses showed that EV-C117 and EV-C118 have a P1 region that is highly divergent from that of the other HEV-C, and phylogenetic analyses highly supported a monophyletic group consisting of EV-C117, EV-C118, EV-C104, EV-C105 and EV-C109 strains. Phylogenetic, Simplot and Bootscan analyses indicated that recombination was not the main mechanism of EV-C117 and EV-C118 evolution, thus strengthening the hypothesis of the monophyletic origin of the coding regions, as in the case of other HEV-C. Phylogenetic analysis also revealed the emergence of a new group within HEV-C that is divided into two subgroups. Nucleotide and amino acid identity in VP1 sequences have been established as useful criteria for assigning new HEV types, but analysis of the complete P1 region improves resolution.
doi:10.1371/journal.pone.0060641
PMCID: PMC3614900  PMID: 23565264
23.  Complete Genome Sequence of a Novel Human Enterovirus C (HEV-C117) Identified in a Child with Community-Acquired Pneumonia 
Journal of Virology  2012;86(19):10888-10889.
The new enterovirus C-117 strain belongs to the human enterovirus C species in the Picornaviridae family. We describe the characterization of the complete genome of this strain identified in a respiratory specimen of a child enrolled in the Community-Acquired Pneumonia Pediatric Research Initiative (CAP-PRI) study evaluating the etiology of community-acquired pneumonia (CAP).
doi:10.1128/JVI.01721-12
PMCID: PMC3457295  PMID: 22966184
24.  Full Genome Sequence of a Novel Human Enterovirus C (EV-C118) Isolated from Two Children with Acute Otitis Media and Community-Acquired Pneumonia in Israel 
Genome Announcements  2013;1(1):e00121-12.
The new enterovirus C strain EV-C118 belongs to the human enterovirus C species of the Picornaviridae family. We report the complete genome sequence of this strain, which was identified in respiratory specimens of two children hospitalized in Israel because of acute otitis media and community-acquired pneumonia who were enrolled in the Community-Acquired Pneumonia Pediatric Research Initiative (CAP-PRI) study.
doi:10.1128/genomeA.00121-12
PMCID: PMC3569292  PMID: 23405305
25.  Toll-like receptor 3 gene polymorphisms and severity of pandemic A/H1N1/2009 influenza in otherwise healthy children 
Virology Journal  2012;9:270.
Background
Toll-like receptors (TLRs) form an essential part of the innate immune system, which plays a fundamental role in rapidly and effectively controlling infections and initiating adaptive immunity. There are no published data concerning the importance of polymorphisms of TLRs in conditioning susceptibility to influenza or the severity of the disease. The aim of this study was to evaluate whether selected polymorphisms of TLR2, TLR3 and TLR4 influence the incidence and clinical picture of pandemic A/H1N1/2009 influenza.
Results
The study involved 272 healthy children attending our Emergency Room for influenza-like illness (ILI), including 51 (18.8%) with pandemic A/H1N1/2009 influenza as revealed by real-time polymerase chain reaction, and 164 healthy controls examined after minor surgery. Genomic DNA was extracted from whole blood samples and five single-nucleotide polymorphisms (SNPs) were studied: TLR2 rs5743708, TLR3 rs5743313, TLR3 rs5743315, TLR4 rs4986790 and TLR4 rs4986791. The TLR3 rs5743313/CT polymorphism was found in all of the children with pneumonia and influenza infection, but in a significantly smaller number of those with A/H1N1/2009 influenza without pneumonia (<0.0001). TLR2, TLR3 rs5743315/AC and TLR4 polymorphisms were equally distributed in all of the groups regardless of the presence of the pandemic A/H1N1/2009 virus and clinical diagnosis. Viral load was comparable in all of the study groups.
Conclusions
There is a close relationship between the presence of TLR3 rs5743313/CT and an increased risk of pneumonia in children infected by the pandemic A/H1N1/2009 influenza virus.
doi:10.1186/1743-422X-9-270
PMCID: PMC3511245  PMID: 23151015
Children; Innate immunity; Influenza; Pandemic A/H1N1/2009 influenza virus; TLR3; Toll-like receptors

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