Nonspecific immunomodulators for recurrent respiratory tract infections, wheezing and asthma in children: a systematic review of mechanistic and clinical evidence.

PURPOSE OF REVIEW: To provide an overview of the mechanistic and clinical evidence for the use of nonspecific immunomodulators in paediatric respiratory tract infection (RTI) and wheezing/asthma prophylaxis. RECENT FINDINGS: Nonspecific immunomodulators have a long history of empirical use for the prevention of RTIs in vulnerable populations, such as children. The past decade has seen an increase in both the number and quality of studies providing mechanistic and clinical evidence for the prophylactic potential of nonspecific immunomodulators against both respiratory infections and wheezing/asthma in the paediatric population. Orally administered immunomodulators result in the mounting of innate and adaptive immune responses to infection in the respiratory mucosa and anti-inflammatory effects in proinflammatory environments. Clinical data reflect these mechanistic effects in reductions in the recurrence of respiratory infections and wheezing events in high-risk paediatric populations. A new generation of clinical studies is currently underway with the power to position the nonspecific bacterial lysate immunomodulator OM-85 as a potential antiasthma prophylactic. SUMMARY: An established mechanistic and clinical role for prophylaxis against paediatric respiratory infections by nonspecific immunomodulators exists. Clinical trials underway promise to provide high-quality data to establish whether a similar role exists in wheezing/asthma prevention.

Neonatal and pediatric antimicrobial stewardship programs in Europe-defining the research agenda.

The relationship between suboptimal use of antimicrobials and antimicrobial resistance has become increasingly clear. Despite significant international effort aimed at reducing inappropriate antimicrobial prescribing in hospitals, antimicrobial resistance remains a major public health threat. Antimicrobial Stewardship Programs (ASPs) comprise a series of measures aimed at optimizing the use of antimicrobials, while improving the quality of patient care and promoting cost-effectiveness. This discussion article aims to summarize some of the approaches that have been used in neonatal and pediatric ASPs, with a particular focus on the European healthcare setting. Current evidence demonstrates neonatal and pediatric ASPs to be safe, practical to implement, generally cost-effective and possibly associated with a reduction in antimicrobial resistance rates. This review identified that, despite the recognized need for additional evidence and information on implementation, published data on pediatric ASPs derives mainly from the United States, with very few published reports on formal ASPs in European children's hospitals. Consequently, the optimal method of implementation remains unknown within a European setting. Future research needs to include novel study designs on how best to introduce ASPs, monitoring of clinically relevant outcomes and cost-effectiveness with improved measurement of the impact on antimicrobial resistance.

Procalcitonin guidance to reduce antibiotic treatment of lower respiratory tract infection in children and adolescents (ProPAED): a randomized controlled trial.

BACKGROUND: Antibiotics are overused in children and adolescents with lower respiratory tract infection (LRTI). Serum-procalcitonin (PCT) can be used to guide treatment when bacterial infection is suspected. Its role in pediatric LRTI is unclear. METHODS: Between 01/2009 and 02/2010 we randomized previously healthy patients 1 month to 18 years old presenting with LRTI to the emergency departments of two pediatric hospitals in Switzerland to receive antibiotics either according to a PCT guidance algorithm established for adult LRTI or standard care clinical guidelines. In intention-to-treat analyses, antibiotic prescribing rate, duration of antibiotic treatment, and number of days with impairment of daily activities within 14 days of randomization were compared between the two groups. RESULTS: In total 337 children, mean age 3.8 years (range 0.1-18), were included. Antibiotic prescribing rates were not significantly different in PCT guided patients compared to controls (OR 1.26; 95% CI 0.81, 1.95). Mean duration of antibiotic exposure was reduced from 6.3 to 4.5 days under PCT guidance (-1.8 days; 95% CI -3.1, -0.5; P = 0.039) for all LRTI and from 9.1 to 5.7 days for pneumonia (-3.4 days 95% CI -4.9, -1.7; P<0.001). There was no apparent difference in impairment of daily activities between PCT guided and control patients. CONCLUSION: PCT guidance reduced antibiotic exposure by reducing the duration of antibiotic treatment, while not affecting the antibiotic prescribing rate. The latter may be explained by the low baseline prescribing rate in Switzerland for pediatric LRTI and the choice of an inappropriately low PCT cut-off level for this population. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN17057980 http://www.controlled-trials.com/ISRCTN17057980.

Antibiotic therapy for pediatric community-acquired pneumonia: do we know when, what and for how long to treat?

Community-acquired pneumonia (CAP) is a common cause of morbidity among children in developed countries and accounts for an incidence of 10-40 cases per 1000 children in the first 5 years of life. Given the clinical, social and economic importance of CAP, there is general agreement that prompt and adequate therapy is essential to reduce the impact of the disease. The aim of this discussion paper is to consider critically the available data concerning the treatment of uncomplicated pediatric CAP and to consider when, how and for how long it should be treated. This review has identified the various reasons that make it difficult to establish a rational approach to the treatment of pediatric CAP, including the definition of CAP, the absence of a pediatric CAP severity score, the difficulty of identifying the etiology, limited pharmacokinetic (PK)/pharmacodynamic (PD) studies, the high resistance of the most frequent respiratory pathogens to the most widely used anti-infectious agents and the lack of information concerning the changes in CAP epidemiology following the introduction of new vaccines against respiratory pathogens. More research is clearly required in various areas, such as the etiology of CAP and the reasons for its complications, the better definition of first- and second-line antibiotic therapies (including the doses and duration of parenteral and oral antibiotic treatment), the role of antiviral treatment and on how to follow-up patients with CAP. Finally, further efforts are needed to increase vaccination coverage against respiratory pathogens and to conduct prospective studies of their impact.

OM-85 BV, un inmunoestimulante en las infecciones respiratorias recurrentes en pediatría: una revisión sistemática / OM-85 BV, an inmunostimulant in pediatric recurrent respiratory tract infections: a systematic review

Antecedentes: Meta-análisis para evaluar la eficacia de OM-85 BV (Broncho-Vaxom) en la prevención de las infecciones respiratorias recurrentes (IRRs) en niños. Se define a las IRRs como 23 infecciones por semestre (otoño e invierno) y se definen como el evento final primario. Métodos: Se identificaron los estudios en bases de datos. Se excluyó once estudios que no fueron doble-ciego y uno referente a la prevención primaria; y se incluyó en el meta-análisis ocho estudios controlados y randomizados. Se compararon los resultados a 6 meses. Se examinó la base de datos de acuerdo con los lineamientos Cochrane. Resultados: De los pacientes tratados con OM-85 BV (n= 435), un32% tuvo IRRs (esto es, 23 RTI/periodo de 6 meses) vs. 58.2% en la población que recibió placebo (n= 416; P<0.001). Los resultados también fueron positivos para el tratamiento activo con respecto a las variables secundarias. Conclusiones: El presente meta-análisis demuestra, que la población tratada con OM-85BV tuvo significativa y consistentemente menos casos del IRRs. El efecto es mayor en los pacientes con un mayor riesgo para desarrollar IRRs.

OM-85 BV, an immunostimulant in pediatric recurrent respiratory tract infections: a systematic review.

BACKGROUND: This study was conducted to assess the efficacy of OM-85 BV (Broncho-Vaxom) in the prevention of pediatric recurrent respiratory tract infections (RTIs). Available evidence suggests that defining recurrent RTIs as >or=3 infections per fall-winter semester is both medically and epidemiologically justified. Therefore, this criterion was chosen as a primary endpoint. METHODS: Trials were identified through consultation of bibliographic databases and other channels. Eleven non-blinded studies plus one dealing with primary prevention were excluded and eight randomized controlled trials were included in the meta-analysis. The data were compared at 6 months, which represented the end of most studies. The complete database was examined according to the guidelines of the Cochrane collaboration. RESULTS: The mean age of children and the number of RTIs in the preceding year were comparable at admission. Of the patients in the OM-85 BV treated population (n=435), 32% had recurrent RTIs (that is, >or=3 RTIs/6 months) vs. 58.2% in the placebo treated population (n=416; P<0.001). Sensitivity analysis showed that this was not driven by any particular trial. The results of this review were also positive for the active treatment regarding the secondary variables, which were represented by the number of patients with at least one RTI and the mean number of RTIs. CONCLUSIONS: This meta-analysis shows, as observed in several individual trials, that the population treated with OM-85 BV had significantly and consistently fewer cases of recurrent RTIs. The data suggest that the effect is greater in patients at increased risk of recurrent RTIs.

A 4-year study on clinical characteristics of children hospitalized with rotavirus gastroenteritis.

Rotavirus (RV) is a frequent cause of severe gastroenteritis (GE) in children. With the licensure of new RV vaccines, data on the burden of disease are important regarding immunization strategies. We reviewed the medical records of children hospitalized with RV infection in our institution between July 2002 and March 2006. Relevant data were extracted in a standardized fashion from records of hospitalized children with a positive RV antigen test in a stool sample. Severity of disease was graded by the 20-point Vesikari score. Population data were obtained from the Federal Office of Statistics. Six hundred eighty-six RVGE were identified and records of 608 hospitalizations (in 607 children) were available. In 539 (89%) cases, RVGE was the primary reason for hospitalization and 69 (11%) were nosocomial infections; yearly peaks occurred between February and May. Cumulative incidence of RVGE was 26.7/1,000 children <3 years of age. Median age of 539 children (55.6% male) with primary RVGE was 1.4 years and median stay in the hospital for both community acquired and nosocomial RVGE was 4 days (interquartile range 3-5). Thirtypercent and 94% of RV hospitalizations were in children <1 and <3 years of age, respectively. Mean Vesikari score was 15 (range 6-20; 96% >11). Intravenous fluids were administered in 378 (70%) patients, 130 (24%) patients were rehydrated via nasogastral tube, and 31 (5.7%) received rehydration by mouth. RVGE causes a substantial burden in children with an estimated risk for hospitalization due to RVGE of one in 37 children <3 years of age.

Human metapneumovirus infections--biannual epidemics and clinical findings in children in the region of Basel, Switzerland.

Human metapneumovirus (hMPV) epidemics vary in time and severity. We report findings for PCR for hMPV and respiratory syncytial virus (RSV) performed on nasopharyngeal aspirates (NPA) of hospitalized and outpatient children with respiratory tract infections between October 2004 and April 2008. A total of 3,934 NPAs were tested for hMPV and 3,859 for RSV. Of these, 198 (5%) were hMPV positive and 869 (23%) were RSV-positive. Median age was 17 months and 9 months for hMPV and RSV, respectively. Fifty-nine percent of hMPV and 58% of RSV patients were hospitalized. Proportions of hMPV positive samples for the four winter seasons were 0.4%, 11%, 0.2%, and 14%. For RSV, they were 28%, 15%, 28%, and 28%. HMPV epidemics follow a biannual variation in our area. Major epidemics were observed in winter seasons starting in odd years (2005/06 and 2007/08), minor epidemics in those starting in even years (2004/05 and 2006/07). RSV epidemics usually follow a reciprocal biannual pattern, leading to annually alternating major RSV and hMPV epidemics.

A multicenter, cross-sectional study on the prevalence and risk factors for nasal colonization with Staphylococcus aureus in patients admitted to children's hospitals in Switzerland.

The rate of nasal carriage of Staphylococcus aureus and associated risk factors were determined in a cross-sectional study involving Swiss children's hospitals. S. aureus was isolated in 562 of 1363 cases. In a stepwise multivariate analysis, the variables age, duration of antibiotic use, and hospitalization of a household member were independently associated with carriage of S. aureus.

Randomized, comparative efficacy trial of oral penicillin versus cefuroxime for perianal streptococcal dermatitis in children.

OBJECTIVE: To investigate the efficacy of penicillin compared with cefuroxime for group A beta-hemolytic Streptococcus pyogenes (GABHS) perianal dermatitis. STUDY DESIGN: Children 1 to 16 years of age with signs and symptoms of perianal dermatitis and a positive anal swab were randomized to penicillin or cefuroxime treatment and were clinically re-evaluated on day 3 and at the end of treatment (cefuroxime, day 7; penicillin, day 10). An anal swab was obtained to document eradication of GABHS at the end of treatment. Severity of disease was assessed with a clinical score (perianal erythema, 5 points; perianal itch, 3 points; painful defecation, 3 points; constipation, 2 points). RESULTS: Patients were enrolled and randomly assigned to penicillin (n = 18) or cefuroxime (n = 17) treatment. Treatment with penicillin was inferior to cefuroxime, which led to premature study termination after consultation with the ethics committee. Clinical improvement was more rapid in the cefuroxime group (P = .028) and GAHBS was not isolated from the anus the last day of therapy in 13 of 14 patients treated with cefuroxime compared with 7 of 15 patients treated with penicillin (P < .01). CONCLUSIONS: Cefuroxime was more effective than penicillin and therefore should be considered as the treatment of choice for perianal dermatitis due to GABHS.

Clinical findings and unusual epidemiologic characteristics of human metapneumovirus infections in children in the region of Basel, Switzerland.

Human metapneumovirus (hMPV) worldwide causes respiratory tract infections with features similar to those of RSV infection. We describe features of hMPV infections in children and compare some of the characteristics with those of RSV infections. From October 2004 to February 2006, 75 patients, 34 hospitalized and 41 outpatients, were diagnosed with hMPV infections by multiplex PCR applied to nasopharyngeal specimens. While hMPV was found rarely in the early phase of the study, a significant increase occurred in the second winter of the study period. Patients with hMPV infections were older than those with RSV infection; clinical characteristics were similar as was the rate of serious disease among hospitalized patients (intensive care treatment: 18% versus 8%). In conclusion, hMPV leads to endemic and epidemic respiratory disease with features similar to those of RSV and should be considered in the differential diagnosis of upper and lower respiratory tract disease.

Assessment of immunization status in hospitalized children followed by counseling of parents and primary care physicians improves vaccination coverage: an interventional study.

This prospective, intervention-control study in hospitalized, underimmunized children assessed the effect of vaccination reminders to parents during hospitalization and provides postdischarge rates of catch-up immunizations. One month after hospital discharge, significantly more children in the intervention group (27%) than the controls (8%) had received catch-up immunizations (P < .001).

Three-year surveillance of intussusception in children in Switzerland.

OBJECTIVE: We attempted to obtain baseline data on the incidence of intussusception and its association with gastroenteritis in a cross-sectional observational study in children. METHODS: Admissions to all 38 pediatric units in Switzerland because of intussusception were reported to the Swiss Pediatric Surveillance Unit from April 2003 to March 2006. Patient and disease characteristics were assessed prospectively with the use of a standardized questionnaire based on the case definition for intussusception developed by the Brighton Collaboration. Completeness of reporting was verified through capture-recapture analysis. RESULTS: There were 294 patients with reported intussusception; 35 cases were excluded for various reasons, and 29 additional patients were identified through International Classification of Diseases, 10th Revision, codes. After capture-recapture analysis, we estimated underreporting to the Swiss Pediatric Surveillance Unit to be 32% and we calculated a true number of 381 intussusception episodes. The highest level of diagnostic certainty was reached by 248 patients, and 20 fulfilled level 2 criteria; for the remaining 20 patients, available information was insufficient. The mean age of the patients was 2.7 years. The yearly mean incidence of intussusception was 38, 31, and 26 cases per 100,000 live births in the first, second, and third year of life, respectively, with no apparent seasonality. Seventy patients had a history of coinciding gastroenteritis, and 5 of 61 tested positive for rotavirus. Spontaneous devagination was observed for 38 patients; enemas reduced intussusception successfully in 183 cases, whereas surgical treatment was required in 67. All patients recovered without sequelae. CONCLUSIONS: This is the first prospective nationwide surveillance of intussusception in childhood using a standardized case definition. Most cases occurred beyond infancy, and association with rotavirus gastroenteritis was rare.

Prevalence of nasal colonization with methicillin-resistant Staphylococcus aureus (MRSA) in children a multicenter cross-sectional study.

In this cross-sectional multicenter study, we determined the rate of nasal carriage of methicillin-resistant Staphylococcus aureus (MRSA) in children admitted to 9 training hospitals in Switzerland during 1 month. From 1337 patients, 1363 nasal swabs were obtained (mean age 6.1 years, median 4.7 years, interquartile range 1.3-10.4 years) and 562 (41.3%) grew S. aureus. Only one isolate was MRSA (0.18%) which encoded mecA and femA genes as well as SCCmec type IV, whereas Panton-Valentine leukocidin (PVL) was absent.

Antibody responses induced by long-term vaccination with an octovalent conjugate Pseudomonas aeruginosa vaccine in children with cystic fibrosis.

We assessed the serological responses over 10 years to repeated immunization of cystic fibrosis (CF) patients with an O-polysaccharide (OPS)-toxin A conjugate vaccine against Pseudomonas aeruginosa. A retrospective analysis was performed with sera from 25 vaccinated and 25 unvaccinated children treated at the same CF centre and matched for clinical management, age and gender. Yearly immunization led to sustained elevations of serum immunoglobulin G (IgG) antibody levels to all vaccine components. Eighteen unvaccinated patients but only eight vaccinated ones developed chronic pseudomonal lung infections. Infection rapidly caused further marked elevations of polysaccharide- but not toxin A-specific serum IgG in both immunized and nonimmunized patients, indicating that protection did not depend on the quantity of IgG present. However, qualitative analyses revealed that the protective capacity of specific serum IgG antibodies was linked to high affinity and to specificity for OPS serotypes rather than for lipopolysaccharide core epitopes.

Seroprevalence of Varicella-Zoster virus IgG antibodies in Swiss children during the first 16 months of age.

QUESTION UNDER STUDY: To investigate the persistence of maternal IgG antibodies against Varicella-Zoster virus (VZV) in infants and young children. METHODS: Serum specimens of children aged 0-16 months who had been hospitalized in our institution between 1994 and 1999 were identified from our routine serum collection. Exclusion criteria were: preterm delivery (<37 gestational weeks); suspected varicella infection or presence of exanthema of unknown etiology at time of serum collection; transfusion of blood products during 6 months preceding serum collection; foreign born mother; and previous VZV immunization. Serotesting for IgG antibodies against VZV was performed by use of a commercially available ELISA kit. RESULTS: Two hundred and fifty three serum specimens from 240 patients were analyzed. Age distribution of patients at time of specimen collection was: 0-3 months: n=57; >3-6 months: n=47; >6-9 months: n=47; >9-12 months: n=48; >12-16 months: n=54. Seroprevalence rates for IgG antibodies against VZV in the different age groups were 90% (0-3 months), 38% (>3-6 months); 0% (>6-9 and >9-12 months); and 7% (>12-16 months). CONCLUSIONS: Our results demonstrate high levels of passively acquired humoral immunity against varicella in Swiss infants during the first 3 months of life. Beyond the first 3 months of life IgG antibodies against VZV are lacking in the majority of patients and between 6 and 12 months of age all specimens tested were negative. Beyond the first year of life antibodies against varicella were detected in four samples, probably due to previous VZV infection. In accordance with current recommendations, VZV vaccination should ideally be administered to children 9 months of age and older, although our data indicate that successful immunization may be possible at earlier age (6 months onwards) in certain circumstances.

Influenza vaccination among healthcare workers in a university children's hospital.

OBJECTIVES: To evaluate the attitudes of pediatric healthcare workers (HCWs) toward influenza vaccination and to increase their rate of immunization. METHODS: A survey was conducted among pediatric HCWs using an anonymous questionnaire. Survey results were used to design an intervention to increase the immunization rate of staff. Immunization rates before (2003-2004) and after (2004-2005) intervention were assessed using immunization clinic records. SETTING: A university children's hospital in Switzerland. INTERVENTIONS: (1) An informational letter based on misconceptions noted in the survey, (2) educational conversations with head nurses, (3) more "walk-in" immunization clinics, and (4) a direct offer of influenza immunization on the wards. RESULTS: Among vaccine nonrecipients, doubts about the efficacy and necessity of influenza immunization were prevalent and more often reported by nurses than physicians (75% vs 41%, P = .002; and 55% vs 23%, P = .001, respectively). Physicians more often than nurses reported lack of time as a reason for not receiving influenza vaccination (23% vs 5%, P = .01). After intervention, the immunization rate of HCWs increased from 19% to 24% (P = .03). The immunization rate of physicians increased from 43% to 64% (P = .004). No change was noted among nurses (13% vs 14%) and other HCWs (16% vs 16%). CONCLUSIONS: Misconceptions about influenza vaccination were prevalent among pediatric staff, particularly nurses. Active promotion and educational efforts were successful in increasing the immunization rate of physicians but not nurses and other HCWs.

Predictive value of double tympanocentesis in acute otitis media.

Advances in the understanding of acute otitis media (AOM), lessons learned from antibacterial trials, and the emergence of pathogens with decreased susceptibility to commonly used antibiotics explain the need to redefine the role of tympanocentesis. The diagnostic value of tympanocentesis at baseline to establish the bacterial cause of AOM is well accepted. However, relevant ethical and scientific arguments conclude that repeat (or double) tympanocentesis cannot be recommended as routine procedure, either for the individual patient or for each treatment trial. Relevant aspects on trial design for AOM, with special emphasis on the value of double tympanocentesis, are reviewed.