Vaccine for prevention of mild and moderate-to-severe influenza in children.

BACKGROUND: Commonly used trivalent vaccines contain one influenza B virus lineage and may be ineffective against viruses of the other B lineage. We evaluated the efficacy of a candidate inactivated quadrivalent influenza vaccine (QIV) containing both B lineages. METHODS: In this multinational, phase 3, observer-blinded study, we randomly assigned children 3 to 8 years of age, in a 1:1 ratio, to receive the QIV or a hepatitis A vaccine (control). The primary end point was influenza A or B confirmed by real-time polymerase chain reaction (rt-PCR). Secondary end points were rt-PCR-confirmed, moderate-to-severe influenza and rt-PCR-positive, culture-confirmed influenza. The vaccine efficacy and the effect of vaccination on daily activities and utilization of health care resources were assessed in the total vaccinated cohort (2584 children in each group) and the per-protocol cohort (2379 children in the QIV group and 2398 in the control group). RESULTS: In the total vaccinated cohort, 62 children in the QIV group (2.40%) and 148 in the control group (5.73%) had rt-PCR-confirmed influenza, representing a QIV efficacy of 59.3% (95% confidence interval [CI], 45.2 to 69.7), with efficacy against culture-confirmed influenza of 59.1% (97.5% CI, 41.2 to 71.5). For moderate-to-severe rt-PCR-confirmed influenza, the attack rate was 0.62% (16 cases) in the QIV group and 2.36% (61 cases) in the control group, representing a QIV efficacy of 74.2% (97.5% CI, 51.5 to 86.2). In the per-protocol cohort, the QIV efficacy was 55.4% (95% CI, 39.1 to 67.3), and the efficacy against culture-confirmed influenza 55.9% (97.5% CI, 35.4 to 69.9); the efficacy among children with moderate-to-severe influenza was 73.1% (97.5% CI, 47.1 to 86.3). The QIV was associated with reduced risks of a body temperature above 39°C and lower respiratory tract illness, as compared with the control vaccine, in the per-protocol cohort (relative risk, 0.29 [95% CI, 0.16 to 0.56] and 0.20 [95% CI, 0.04 to 0.92], respectively). The QIV was immunogenic against all four strains. Serious adverse events occurred in 36 children in the QIV group (1.4%) and in 24 children in the control group (0.9%). CONCLUSIONS: The QIV was efficacious in preventing influenza in children. (Funded by GlaxoSmithKline Biologicals; ClinicalTrials.gov number, NCT01218308.).

The epidemiology and economic impact of varicella-related hospitalizations in Turkey from 2008 to 2010: a nationwide survey during the pre-vaccine era (VARICOMP study).

Varicella can cause complications that are potentially serious and require hospitalization. Our current understanding of the causes and incidence of varicella-related hospitalization in Turkey is limited and sufficiently accurate epidemiological and economical information is lacking. The aim of this study was to estimate the annual incidence of varicella-related hospitalizations, describe the complications, and estimate the annual mortality and cost of varicella in children. VARICOMP is a multi-center study that was performed to provide epidemiological and economic data on hospitalization for varicella in children between 0 and 15 years of age from October 2008 to September 2010 in Turkey. According to medical records from 27 health care centers in 14 cities (representing 49.3% of the childhood population in Turkey), 824 children (73% previously healthy) were hospitalized for varicella over the 2-year period. Most cases occurred in the spring and early summer months. Most cases were in children under 5 years of age, and 29.5% were in children under 1 year of age. The estimated incidence of varicella-related hospitalization was 5.29-6.89 per 100,000 in all children between 0-15 years of age in Turkey, 21.7 to 28 per 100,000 children under 1 year of age, 9.8-13.8 per 100,000 children under 5 years of age, 3.96-6.52 per 100,000 children between 5 and 10 years of age and 0.42 to 0.71 per 100,000 children between 10 and 15 years of age. Among the 824 children, 212 (25.7%) were hospitalized because of primary varicella infection. The most common complications in children were secondary bacterial infection (23%), neurological (19.1%), and respiratory (17.5%) complications. Secondary bacterial infections (p < 0.001) and neurological complications (p < 0.001) were significantly more common in previously healthy children, whereas hematological complications (p < 0.001) were more commonly observed in children with underlying conditions. The median length of the hospital stay was 6 days, and it was longer in children with underlying conditions (<0.001). The median cost of hospitalization per patient was $338 and was significantly higher in children with underlying conditions (p < 0.001). The estimated direct annual cost (not including the loss of parental work time and school absence) of varicella-related hospitalization in children under the age of 15 years in Turkey was $856,190 to $1,407,006. According to our estimates, 882 to 1,450 children are hospitalized for varicella each year, reflecting a population-wide occurrence of 466-768 varicella cases per 100,000 children. In conclusion, this study confirms that varicella-related hospitalizations are not uncommon in children, and two thirds of these children are otherwise healthy. The annual cost of hospitalization for varicella reflects only a small part of the overall cost of this disease, as only a very few cases require hospital admission. The incidence of this disease was higher in children <1 year of age, and there are no prevention strategies for these children other than population-wide vaccination. Universal vaccination is therefore the only realistic option for the prevention of severe complications and deaths. The surveillance of varicella-associated complications is essential for monitoring of the impact of varicella immunization.

Multicenter prospective study on the burden of rotavirus gastroenteritis in Turkey, 2005-2006: a hospital-based study.

Rotavirus is the main cause of gastroenteritis and dehydration requiring hospitalization among infants and children. Despite the high diarrhea-related mortality rate, there are limited studies describing the prevalence of rotavirus in Turkey. The disease burden of rotavirus gastroenteritis in Turkey was assessed by active, prospective surveillance conducted in accordance with a modified World Health Organization generic protocol from 1 June 2005 through 1 June 2006. A total of 411 children aged <5 years who were hospitalized for gastroenteritis in 4 centers were enrolled. Rotavirus was identified in 53% of samples from the 338 children tested; the range for individual centers was 32.4%-67.4%. Overall, 83.8% of rotavirus-positive children were aged <2 years. Rotavirus gastroenteritis occurred year-round but peaked in the winter. G1P[8] was the most widely prevalent strain (76% of strains), followed by G2P[4] (12.8%). G9P[8] was reported in samples from 3.9% of children. These data support the need for a rotavirus vaccine in Turkey.

A prospective study of etiology of childhood acute bacterial meningitis, Turkey.

Determination of the etiology of bacterial meningitis and estimating cost of disease are important in guiding vaccination policies. To determine the incidence and etiology of meningitis in Turkey, cerebrospinal fluid (CSF) samples were obtained prospectively from children (1 month-17 years of age) with a clinical diagnosis of acute bacterial meningitis. Multiplex PCR was used to detect DNA evidence of Streptococcus pneumoniae, Haemophilus influenzae type b (Hib), and Neisseria meningitidis. In total, 408 CSF samples were collected, and bacterial etiology was determined in 243 cases; N. meningitidis was detected in 56.5%, S. pneumoniae in 22.5%, and Hib in 20.5% of the PCR-positive samples. Among N. meningitidis-positive CSF samples, 42.7%, 31.1%, 2.2%, and 0.7% belonged to serogroups W-135, B, Y, and A, respectively. This study highlights the emergence of serogroup W-135 disease in Turkey and concludes that vaccines to prevent meningococcal disease in this region must provide reliable protection against this serogroup.

Terlipressin as a rescue therapy for catecholamine-resistant septic shock in children.

OBJECTIVE: To evaluate the effect of terlipressin on oxygenation, PaO2/FIO2, heart rate, mean arterial pressure, and mortality in children with septic shock refractory to high doses of dopamine/dobutamine and adrenaline. DESIGN AND SETTING: A randomized, nonblind study in the pediatric intensive care unit of a university hospital. PATIENTS AND MEASUREMENTS: We studied 58 children with septic shock and refractory hypotension despite fluid loading and high doses of catecholamines, randomly enrolled to terlipressin (TP, n=30) or control (n=28). TP was administered as intravenous bolus doses of 20 microg/kg every 6 h for a maximum of 96 h. Hemodynamic changes, PaO2/FIO2 rates, length of stay, and mortality rate in PICU were recorded prospectively. RESULTS: Mean arterial pressure and PaO2/FIO2 significantly increased, and heart rate significantly decreased 30 min after each TP treatment, but mortality did not differ from control (67.3% vs. 71.4%). Mean stay in the PICU was shorter in the TP group (13.4+/-7.9 vs. 20.2+/-9.7 days and was longer among nonsurvivors of the TP group vs. control (10.4+/-6.9 vs. 6.2+/-3.4 days). Blood urea nitrogen, creatinine, AST, ALT, and urine output of patients in the TP group did not change after terlipressin. CONCLUSIONS: Although terlipressin infusion had no effect on mortality, it significantly increases mean arterial pressure, PaO2/FIO2, and survival time in nonsurvivors. Terlipressin seems to cause no adverse effect but warrants further evaluation as a rescue therapy in refractory septic shock.

Genetic dilemma: eNOS gene intron 4a/b VNTR polymorphism in sepsis and its clinical features in Turkish children.

The role of endothelial nitric oxide synthase gene intron 4 a/b (eNOS4a/b) variable number of tandem repeats (VNTR) polymorphism in various diseases was investigated. We investigated whether this polymorphism is associated with susceptibility to sepsis and its clinical features such as acute respiratory distress syndrome (ARDS), multiorgan dysfunction syndrome (MODS) and shock. eNOS4a/b VNTR polymorphism was determined by the polymerase chain reaction in 100 children with sepsis and in 134 healthy controls. The genotype distribution of eNOS4 was not different between the patients and controls (p=0.44). There was no statistically significant association between genotypes/allele frequency and outcomes like mortality, MODS, ARDS, and shock (p>0.05). This is the first study that evaluates the effect of eNOS4a/b polymorphism in sepsis. We were unable to show a relationship between eNOS gene intron 4 a/b VNTR polymorphism and MODS, ARDS, mortality and shock. Larger studies that do research on the interaction of such genes are needed to clarify the association between eNOS4a/b polymorphism and sepsis.

Diagnostic dilemma in an adolescent boy: hemophagocytic syndrome in association with kala azar.

Leishmaniasis is caused by infection with the hemoparasite Leishmania. The disease is a major public health problem in at least 88 countries, including Turkey. Prolonged fever with anorexia and loss of appetite are the major presenting features of visceral leishmaniasis. It is rarely defined as an etiological cause of hemophagocytic syndrome. The clinical course triggered by leishmania infection and hemophagocytosis may coincide, and this may lead to considerable diagnostic difficulty, especially in young children. In this report, we describe an adolescent boy with visceral leishmaniasis as a rare cause of the hemophagocytic syndrome. This is the first reported association between hemophagocytosis and visceral leishmaniasis in an adolescent.

Bacterial agents causing meningitis during 2013-2014 in Turkey: A multi-center hospital-based prospective surveillance study.

This is an observational epidemiological study to describe causes of bacterial meningitis among persons between 1 month and 18 y of age who are hospitalized with suspected bacterial meningitis in 7 Turkish regions. covering 32% of the entire population of Turkey. We present here the results from 2013 and 2014. A clinical case with meningitis was defined according to followings: any sign of meningitis including fever, vomiting, headache, and meningeal irritation in children above one year of age and fever without any documented source, impaired consciousness, prostration and seizures in those < 1 y of age. Single tube multiplex PCR assay was performed for the simultaneous identification of bacterial agents. The specific gene targets were ctrA, bex, and ply for N. meningitidis, Hib, and S. pneumoniae, respectively. PCR positive samples were recorded as laboratory-confirmed acute bacterial meningitis. A total of 665 children were hospitalized for suspected acute meningitis. The annual incidences of acute laboratory-confirmed bacterial meningitis were 0.3 cases / 100,000 population in 2013 and 0.9 cases/100,000 in 2014. Of the 94 diagnosed cases of bacterial meningitis by PCR, 85 (90.4%) were meningococcal and 9 (9.6%) were pneumococcal. Hib was not detected in any of the patients. Among meningococcal meningitis, cases of serogroup Y, A, B and W-135 were 2.4% (n = 2), 3.5% (n = 3), 32.9% (n = 28), and 42.4% (n = 36). No serogroup C was detected among meningococcal cases. Successful vaccination policies for protection from bacterial meningitis are dependent on accurate determination of the etiology of bacterial meningitis. Additionally, the epidemiology of meningococcal disease is dynamic and close monitoring of serogroup distribution is comprehensively needed to assess the benefit of adding meningococcal vaccines to the routine immunization program.

Children with breakthrough varicella infection requiring hospitalization in Turkey (VARICOMP Study 2008-2013).

INTRODUCTION: Varicella in previously immunized individuals, known as "breakthrough varicella". While the majority of breakthrough cases are mild, some may be severe, requiring hospitalization in previously healthy children or children with an underlying condition. METHODS: This report, as a part of the prospective national pediatric varicella hospitalizations study (including 29 centers, represent 50% of pediatric population) in Turkey, is aimed to evaluate breakthrough varicella infection requiring hospitalization before the routine use of single-dose live varicella vaccine in national program from 2008 to 2013 (<10% of the pediatric age group received a single-dose vaccine). RESULTS: In the time period, 1939 children were hospitalized due to varicella infection in Turkey; 36 children (20 boys, 16 girls, mean age 68.0+37.6 months, all received single dose live varicella vaccine) with breakthrough varicella infection. Breakthrough varicella infection might be severe in previously healthy children (61.1%) and children with immune-compromising conditions (38.9%). The time elapsed between vaccination and hospitalization was approximately 5 years, and neurological complications, mainly encephalitis and meningitis, were the most common reason for hospitalization in previously healthy children. CONCLUSION: Pediatric breakthrough varicella requiring hospitalization have been seen in Turkey, is mainly observed in previously healthy children at 5 years after a single-dose varicella vaccine. The varicella vaccine has been implemented as part of the National Immunization Program in Turkey in 2013 (a single dose at age 12 months). Further surveillance in the same settings could evaluate the effectiveness of national immunization with single-dose varicella vaccine at 12 months of age and potential need for second dose of vaccine.

Bacillary angiomatosis in an immunocompetent child with a grafted traumatic wound.

Bacillary angiomatosis is an infectious disease which usually develops in immunocompromised patients. Contact with cats is implicated in its pathogenesis. We report a seven-year-old immunocompetent boy with bacillary angiomatosis without a history of direct contact with cats. The clinical diagnosis of bacillary angiomatosis was made following histopathological examination of a biopsy sample from the infected facial wound, in the vicinity of which angiomatous lesions had developed. Surprisingly, similar lesions also appeared at the donor site of the skin graft which was grafted on the facial wound. This case demonstrates that bacillary angiomatosis may also be seen in immunocompetent patients and that it may contaminate wounds without the intermediary of cats.

Intramuscular Dipyrone versus Oral Ibuprofen or Nimesulide for Reduction of Fever in the Outpatient Setting.

OBJECTIVE: To compare the effectiveness and rate of temperature reduction of three antipyretic medications in febrile children. DESIGN: A single-dose, randomised, prospective, modified double-blind, parallel clinical trial. SETTING: The paediatric emergency department of a university hospital that has 13 000 annual visits. STUDY PARTICIPANTS: 252 otherwise healthy children aged 6 months to 14 years with acute, intercurrent, febrile illness. INTERVENTIONS: Enrolled children were assigned to receive a single dose of oral ibuprofen 10 mg/kg, oral nimesulide 2.5 mg/kg, or parenteral dipyrone 10 mg/kg. MAIN OUTCOME MEASURES AND RESULTS: Axillary temperature was measured at the time of antipyretic administration and at 30, 45, 60 and 120 minutes thereafter. All three medications were effective in reducing the axillary temperature during the 2-hour testing period. The rates of axillary temperature change between the three medications were significantly different for the ibuprofen and dipyrone groups (p = 0.023). In addition, the axillary temperature in the dipyrone group was significantly lower than that in the ibuprofen group (p = 0.036) at 120 minutes. There was no significant difference in antipyretic effect between the nimesulide group and the other two groups during the testing period. Within each group the difference between initial temperature and the temperature at the end of the testing period was statistically significant (p = 0.036) for the dipyrone group only. CONCLUSIONS: All three antipyretic medications were effective in reducing the axillary temperature in febrile children. Although administration of intramuscular dipyrone seemed to be more effective than ibuprofen, this relationship was not significant when nimesulide was considered. In addition, in view of its known side effects and the problems associated with intramuscular administration in children, the preference for orally administered nimesulide or ibuprofen over dipyrone in the setting of the emergency department seems more logical provided that the child accepts oral therapy.

Prevalence of hepatitis A in children and adolescents in Adana, Turkey.

The present study was aimed at determining the seroprevalence of anti-HAV in children and adolescents in the city of Adana, Turkey. The overall prevalence of anti-HAV was 44.4% (316/711). The prevalence increased with advancing age i.e. 28.8% (2.1-6 yr), 49.8% (6.1-12 yr), and 68% (12.1-16.5 yr) (P < 0.0001). Seroprevalence was significantly lower in children less than 6 years and belonging to higher socioeconomic status.

Epidemiological shift of hepatitis A in central Adana, Turkey.

BACKGROUND/AIMS: The aim of the study was to determine the epidemiological shift that may have occurred in the last 11 years of Hepatitis A virus (HAV) seroprevalence. MATERIALS AND METHODS: In 1998, we reported the anti-HAV seroprevalence in 711 children aged between 2 and 16 years children in Adana city center. Eleven years later we repeated the same study at the same locations in a similar population with the same method. RESULTS: From 1998 to 2009 anti-HAV seroprevalence declined from 33.9% to 22.2%, 29.5% to 25.3% (p>0,05), 52.2% to 30.8%, 69.7% to 35.2%, 66.9% to 37.7% and 71.4% to 47.3% (p<0,0001) in the age groups of 48-71, 72-95, 96-119, 120-143, 144-167 and 168-198 months respectively. CONCLUSION: Our study showed that anti-HAV seroprevalence has decreased statistically significantly during the last 11 years in school-aged children. Results showed that anti-HAV seroprevalence has shifted to further ages. Since adolescents and young adults are at risk of symptomatic HAV infection, routine hepatitis A vaccination of children will be initiated in 2012 in Turkey.

Molecular epidemiology and antibiotic susceptibility pattern of Acinetobacter baumannii isolated from children in a Turkish university hospital.

The aim of the present study is to investigate the types of healthcare-associated infections (HC-AIs) caused by Acinetobacter baumannii and the related antibiotic susceptibility patterns as well as the genotypic characteristics of the Acinetobacter baumannii isolates from our center. Sixty-nine Acinetobacter baumannii isolates originating from various samples collected from 69 pediatric patients during their hospital stays were included in the study. The types of healthcare-associated infections caused by these isolates were evaluated, and the antibiotic susceptibility pattern and the genotypic characteristics of the isolates were determined using the pulsed-field gel electrophoresis (PFGE) method. Fifty of the 69 children were observed to have HC-AIs, and 19 children had Acinetobacter baumannii colonization. Healthcare-associated pneumonia (58%) was the most common type of these infections. The rate of carbapenem resistance was found as 91.3%, while tigecycline resistance was found as 18.84%. No colistin resistance was observed in any of the isolates. A total of 10 groups, comprising eight major and two minor groups, were determined using the pulsed-field gel electrophoresis method. Acinetobacter baumannii isolates are the leading cause of healthcare-associated infections, and they show high rates of multidrug antibiotic resistance. Molecular epidemiological evaluation using PFGE plays an important role in preventing healthcare-associated infections.

Meningitis caused by Neisseria Meningitidis, Hemophilus Influenzae Type B and Streptococcus Pneumoniae during 2005-2012 in Turkey. A multicenter prospective surveillance study.

Successful vaccination policies for protection from bacterial meningitis are dependent on determination of the etiology of bacterial meningitis. Cerebrospinal fluid (CSF) samples were obtained prospectively from children from 1 month to ≤18 years of age hospitalized with suspected meningitis, in order to determine the etiology of meningitis in Turkey. DNA evidence of Neisseria meningitidis (N. meningitidis), Streptococcus pneumoniae (S. pneumoniae), and Hemophilus influenzae type b (Hib) was detected using multiplex polymerase chain reaction (PCR). In total, 1452 CSF samples were evaluated and bacterial etiology was determined in 645 (44.4%) cases between 2005 and 2012; N. meningitidis was detected in 333 (51.6%), S. pneumoniae in 195 (30.2%), and Hib in 117 (18.1%) of the PCR positive samples. Of the 333 N. meningitidis positive samples 127 (38.1%) were identified as serogroup W-135, 87 (26.1%) serogroup B, 28 (8.4%) serogroup A and 3 (0.9%) serogroup Y; 88 (26.4%) were non-groupable. As vaccines against the most frequent bacterial isolates in this study are available and licensed, these results highlight the need for broad based protection against meningococcal disease in Turkey.

Distribution of Streptococcus pneumoniae serotypes that cause parapneumonic empyema in Turkey.

Streptococcus pneumoniae is the most common etiological cause of complicated pneumonia, including empyema. In this study, we investigated the serotypes of S. pneumoniae that cause empyema in children. One hundred fifty-six children who were diagnosed with pneumonia complicated with empyema in 13 hospitals in seven geographic regions of Turkey between 2010 and 2012 were included in this study. Pleural fluid samples were collected by thoracentesis and tested for 14 serotypes/serogroups using a Bio-Plex multiplex antigen detection assay. The serotypes of S. pneumoniae were specified in 33 of 156 samples. The mean age ± the standard deviation of the 33 patients was 6.17 ± 3.54 years (range, 0.6 to 15 years). All of the children were unvaccinated according to the vaccination reports. Eighteen of the children were male, and 15 were female. The serotypes of the non-7-valent pneumococcal conjugated vaccine (non-PCV-7), serotype 1, serotype 5, and serotype 3, were detected in eight (14.5%), seven (12.7%), and five (9.1%) of the samples, respectively. Serotypes 1 and 5 were codetected in two samples. The remaining non-PCV-7 serotypes were 8 (n = 3), 18 (n = 1), 19A (n = 1), and 7F/A (n = 1). PCV-7 serotypes 6B, 9V, 14, 19F, and 23F were detected in nine (16.3%) of the samples. The potential serotype coverages of PCV-7, PCV-10, and PCV-13 were 16.3%, 45.4%, and 60%, respectively. Pediatric parapneumonic empyema continues to be an important health problem despite the introduction of conjugated pneumococcal vaccines. Active surveillance studies are needed to monitor the change in S. pneumoniae serotypes that cause empyema in order to have a better selection of pneumococcal vaccines.

Effectiveness of a new bioequivalent formulation of oseltamivir (Enfluvir®) on 2010-2011 seasonal influenza viruses: an open phase IV study.

OBJECTIVE: The aim of this multicenter prospective study was to evaluate the efficacy of a new bioequivalent formulation of oseltamivir for the treatment of influenza A, influenza B, and H1N1 during the 2010-2011 influenza season. METHODS: We compared the symptoms and signs of 300 pediatric patients presenting to three university hospitals with an influenza-like illness between January and March 2011. Nasal swab specimens were collected from all children and tested by reverse-transcription polymerase chain reaction (RT-PCR) for influenza viruses. After randomization, half of the participants were prescribed oseltamivir, while the other half were observed conservatively. Forty patients who were followed-up for influenza prior to the study were also included in the evaluation. RESULTS: Influenza was confirmed by RT-PCR in 129 children, 71 of whom were prescribed oseltamivir. The durations of the symptoms fever, cough, nasal congestion, and rhinorrhea were significantly shorter for patients who were treated with oseltamivir compared with untreated patients (p<0.002 for all symptoms). Early initiation of oseltamivir therapy (within 48 h of the onset of symptoms) was associated with more favorable outcomes and an earlier recovery than in patients for whom treatment was delayed (beyond 48 h). Thirty-seven patients (28.7%) had H1N1, 44 (34.1%) had influenza A, 46 (35.7%) had influenza B, one (0.8%) had H1N1 plus influenza A, and one (0.8%) had influenza A plus influenza B viruses. In the comparison of the duration of symptoms according to the different virus types, a statistically significant difference was only observed in patients with influenza B who had a longer duration of cough (p<0.001), nasal congestion (p<0.001), and rhinorrhea (p<0.001). CONCLUSIONS: Oseltamivir is an effective treatment for the management of seasonal influenza and H1N1, and should be initiated immediately without waiting for laboratory confirmation of diagnosis.

Serotypes of Streptococcus pneumoniae isolates from children with invasive pneumococcal disease in Turkey: baseline evaluation of the introduction of the pneumococcal conjugate vaccine nationwide.

Before use of the pneumococcal conjugate vaccine PCV7 became widespread in Turkey, 202 invasive pneumococcus isolates were analyzed. The most common serotypes were 19F and 6B. In children ≤2 years of age, the potential coverage rate of PCV7 was 69.5%. The most frequent non-PCV7 serotypes were 19A, 3, 1, 6A, and 8.