Mehmet Ceyhan

Genomic resolution of an aggressive, widespread, diverse and expanding meningococcal serogroup B, C and W lineage.

Summary Objectives Neisseria meningitidis is a leading cause of meningitis and septicaemia. The hyperinvasive ST-11 clonal complex (cc11) caused serogroup C (MenC) outbreaks in the US military in the 1960s and UK universities in the 1990s, a global Hajj-associated serogroup W (MenW) outbreak in 2000–2001, and subsequent MenW epidemics in sub-Saharan Africa. More recently, endemic MenW disease has expanded in South Africa, South America and the UK, and MenC cases have been reported among European and North American men who have sex with men (MSM). Routine typing schemes poorly resolve cc11 so we established the population structure at genomic resolution. Methods Representatives of these episodes and other geo-temporally diverse cc11 meningococci (n = 750) were compared across 1546 core genes and visualised on phylogenetic networks. Results MenW isolates were confined to a distal portion of one of two main lineages with MenB and MenC isolates interspersed elsewhere. An expanding South American/UK MenW strain was distinct from the ‘Hajj outbreak’ strain and a closely related endemic South African strain. Recent MenC isolates from MSM in France and the UK were closely related but distinct. Conclusions High resolution ‘genomic’ multilocus sequence typing is necessary to resolve and monitor the spread of diverse cc11 lineages globally.

Beneficial effects of dexamethasone in children with pneumococcal meningitis.

Fifty-six children older than 2 years with meningitis caused by Streptococcus pneumoniae were enrolled in a prospective, double blind, placebo-controlled trial to evaluate the efficacy of dexamethasone therapy in addition to antimicrobial therapy. Twenty-nine of 56 received dexamethasone (0.6 mg/kg/day iv, divided into 4 daily doses for 4 days) and the remaining 27 received placebo. At the beginning of therapy the clinical and laboratory characteristics of the patients in the treatment groups were comparable, except for the Glasgow coma score (P = 0.004), which was lower in the dexamethasone group. Patients were examined daily during hospitalization and 6 weeks after discharge from the hospital. Hearing was assessed 6 weeks after discharge by means of pure tone audiometry. Two patients in the dexamethasone group and one patient in the placebo group died. There were no differences between the two groups with regard to the duration of fever, the incidence of secondary fever and electrolyte imbalance, seizure activities occurring during hospitalization and rash. Although the differences were statistically insignificant, moderate or severe unilateral or bilateral sensorineural hearing loss at 6 weeks and the overall neurologic sequelae, including hearing loss, at 1 year were higher in the placebo group, at 23% vs. 7.4% (P = 0.11) and 26.9% vs. 7.4% (P = 0.062), respectively. At 3 months after discharge, because of the improvement in hearing loss in one dexamethasone-treated patient the incidence of hearing impairment was significantly less than that in the placebo group, at 3.7% vs. 23%, respectively (P = 0.044). No improvement in hearing loss was observed after 3 months.(ABSTRACT TRUNCATED AT 250 WORDS)

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.).

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

Vaccines to prevent bacterial meningitis in this region must provide reliable protection against serogroup W-135.

Role of procalcitonin and CRP in differentiating a stable from a deteriorating clinical course in pediatric febrile neutropenia.

In clinical practice, when neutropenic-fever patients present with no microbiologically and clinically defined infection, the risk of underestimating an occult infection is of major concern, the clinicians have to make a decision on when to modify antibiotic therapy. Hence, a reliable, specific, and sensitive marker, which is regulated independently from the leukocyte count and the underlying disease, is needed for the early diagnosis of infections in cases of neutropenic fever. We have evaluated the diagnostic and follow-up value of procalcitonin (PCT) compared with C-reactive protein (CRP) and erythrocyte sedimentation rate in documenting the infection in neutropenic-fever patients undergoing intensive chemotherapy, as evidenced by the durational change in these parameters in the presence of defined infection. Forty-nine patients, who had 60 febrile episodes, and who were hospitalized in the Hacettepe University Ihsan Doğramacı Childrens Hospital between January 1, 2004 and January 1, 2005 were included in this prospective study. All patients had been diagnosed with neutropenic fever after intensive chemotherapy. In our study, PCT and CRP levels were significantly higher in neutropenic-fever patients (group I and group II separately) than in control patients (P<0.001) throughout the study period; but erythrocyte sedimentation rate levels did not show any significant difference (P>0.05). In sequential analyses of patients without documented infections, the median of PCT concentrations shows a tendency to fall after the 8th hour of onset of fever, whereas in patients with documented infections PCT concentrations fell after the 48th hour. In conclusion, our study suggests that PCT, when measured periodically, is a more useful diagnostic inflammation parameter in pediatric neutropenic-fever patients than CRP, both in estimating the severity of the infection and, the duration and origin of the fever. Hence, PCT might be helpful when deciding on initial therapy modification.

Immunogenicity of the 9-Valent HPV Vaccine Using 2-Dose Regimens in Girls and Boys vs a 3-Dose Regimen in Women

Importance Human papillomavirus (HPV) infections cause anogenital cancers and warts. The 9-valent HPV vaccine provides protection against 7 high-risk types of HPV responsible for 90% of cervical cancers and 2 other HPV types accounting for 90% of genital warts. Objective To determine whether HPV type-specific antibody responses would be noninferior among girls and boys aged 9 to 14 years after receiving 2 doses of the 9-valent HPV vaccine compared with adolescent girls and young women aged 16 to 26 years receiving 3 doses. Design, Setting, and Participants Open-label, noninferiority, immunogenicity trial conducted at 52 ambulatory care sites in 15 countries. The study was initiated on December 16, 2013, with the last participant visit for this report on June 19, 2015. Five cohorts were enrolled: (1) girls aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (2) boys aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (3) girls and boys aged 9 to 14 years to receive 2 doses 12 months apart (n = 301); (4) girls aged 9 to 14 years to receive 3 doses over 6 months (n = 301); and (5) a control group of adolescent girls and young women aged 16 to 26 years to receive 3 doses over 6 months (n = 314). Interventions Two doses of the 9-valent HPV vaccine administered 6 or 12 months apart or 3 doses administered over 6 months. Main Outcomes and Measures The primary end point was prespecified as the antibody response against each HPV type assessed 1 month after the last dose using a competitive immunoassay. Each of the three 2-dose regimens was compared with the standard 3-dose schedule in adolescent girls and young women using a noninferiority margin of 0.67 for the ratio of the antibody geometric mean titers. Results Of the 1518 participants (753 girls [mean age, 11.4 years]; 451 boys [mean age, 11.5 years]; and 314 adolescent girls and young women [mean age, 21.0 years]), 1474 completed the study and data from 1377 were analyzed. At 4 weeks after the last dose, HPV antibody responses in girls and boys given 2 doses were noninferior to HPV antibody responses in adolescent girls and young women given 3 doses (P < .001 for each HPV type). Compared with adolescent girls and young women who received 3 doses over 6 months, the 1-sided 97.5% CIs for the ratio of HPV antibody geometric mean titers at 1 month after the last dose across the 9 HPV subtypes ranged from 1.36 to ∞ to 2.50 to ∞ for girls who received 2 doses 6 months apart; from 1.37 to ∞ to 2.55 to ∞ for boys who received 2 doses 6 months apart; and from 1.61 to ∞ to 5.36 to ∞ for girls and boys who received 2 doses 12 months apart. Conclusions and Relevance Among girls and boys aged 9 to 14 years receiving 2-dose regimens of a 9-valent HPV vaccine separated by 6 or 12 months, immunogenicity 4 weeks after the last dose was noninferior to a 3-dose regimen in a cohort of adolescent girls and young women. Further research is needed to assess persistence of antibody responses and effects on clinical outcomes. Trial Registration clinicaltrials.gov Identifier: NCT01984697.

Secondary hemophagocytic lymphohistiocytosis in Turkish children.

Between January 1998 and January 2005, a total of 18 children 2 weeks–72 months of age were diagnosed as having secondary hemophagocytic lymphohistiocytosis. The frequency of secondary hemophagocytic lymphohistiocytosis among total hospitalized patients during this period was 0.05% (18 of 34,250). Of the 18 patients, 8 (44.5%) had bacterial infections; cytomegalovirus and Epstein-Barr virus infections were present in 5 (28%) and 1 (5.5%), patient, respectively. Leishmaniasis was diagnosed in 2 patients (11%), and herpes simplex virus was diagnosed in 2 patients (11%). Six patients died during treatment, and 1 patient was lost to follow-up. The survival rate was 61%.

Priming effect, immunogenicity and safety of an Haemophilus influenzae type b-tetanus toxoid conjugate (PRP-T) and diphtheria-tetanus-acellular pertussis (DTaP) combination vaccine administered to infants in Belgium and Turkey.

To evaluate the priming effect, immunogenicity and safety of an Haemophilus influenzae type b (Hib) tetanus toxoid conjugate (PRP-T) and diphtheria-tetanus-acellular (two component) pertussis (DTaP) combination vaccine, a randomized, comparative study was conducted in two centers, one in Belgium and one in Turkey. A total of 410 healthy infants, 160 in Belgium and 250 in Turkey, randomly received DTaP and PRP-T vaccines in one of three fashions. One group (N = 138) received DTaP and PRP-T vaccines reconstituted immediately prior to injection at 3, 4 and 5 months of age, and are referred to as the combined, short schedule group (Co-S). A second group (N = 135) received DTaP + PRP-T simultaneously but injected at different sites according to the same schedule, and are referred to as the associated, short schedule group (As-S). The third group (N = 137) also received DTaP + PRP-T at separate sites, but at 2, 4 and 6 months, and are referred to as the associated, long schedule group (As-L). The As-L group allowed for serological bridging with a Senegalese two-component pertussis vaccine efficacy trial, using the same batch of DTaP vaccine. Children of both short-schedule groups (Co-S and As-S) received, at the age of 12-14 months, a booster dose of DTaP vaccine associated with unconjugated PRP vaccine. Mixing of the vaccines did not affect the immune response to the antigens included in the DTaP vaccine. The immune response to Hib capsular polysaccharide, however, was significantly lower after combined administration (Co-S group) than after associated (As-S group) administration (P < 0.0001), with a similar trend among both countries (GMTs, 1.78 microg/ml and 6.19 microg/ml in Belgium, and 5.02 microg/ml and 11.67 microg/ml in Turkey). Booster vaccination with the unconjugated PRP induced a vigorous and similar anamnestic response in both groups. Belgian infants showed a significantly lower immune response to all antigens than Turkish infants (P < or = 0.001 for all antigens), with a similar trend among each study group. In all groups, the incidence of adverse events was lower than that usually reported after DTwP(whole-cell) vaccine. Higher rates of systemic reactions were observed in the Belgian population, possibly due to differences in reporting practice. Our results indicate (1) that the combination vaccine, DTaP//PRP-T, represents an important improvement over the existing uncombined vaccines; (2) that immunogenicity studies should include at least one booster injection to evaluate priming effects by combined vaccines; and (3) that it is feasible and valuable to co-randomize combination vaccine studies in sufficiently different geographical areas and child populations.

Inappropriate antimicrobial use in Turkish pediatric hospitals: A multicenter point prevalence survey

OBJECTIVES Although well-defined principles of rational antimicrobial use are available, inappropriate prescribing patterns are reported worldwide. Accurate information on the usage of antimicrobials, including factors associated with and influencing their use, is valuable for improving the quality of prescription practices. METHODS In this cross-sectional point prevalence survey, data on patients hospitalized in 12 different childrens hospitals were collected on a single day. Appropriateness of prescription was compared between the types of antimicrobials prescribed, indications, wards, and presence of/consultation with an infectious disease physician (IDP). RESULTS A total 711 of 1302 (54.6%) patients evaluated were receiving one or more antimicrobial drugs. The antimicrobial prescription rate was highest in pediatric intensive care (75.7%) and lowest in the surgery wards (37.0%). Of the 711 patients receiving antimicrobials, 332 patients (46.7%) were found to be receiving at least one inappropriately prescribed drug. Inappropriate use was most frequent in surgery wards (80.2%), while it was less common in oncology wards (31.8%; p<0.001). Respiratory tract infection was the most common indication for antimicrobial use (29.4%). Inappropriate use was more common in deep-seated infections (54.7%) and respiratory infections (56.5%). Fluoroquinolones were used inappropriately more than any other drugs (81.8%, p=0.021). Consultation with an IDP appears to increase appropriate antimicrobial use (p=0.008). CONCLUSIONS Inappropriate antimicrobial use remains a common problem in Turkish pediatric hospitals. Consultation with an IDP and prescribing antimicrobial drugs according to microbiological test results could decrease the inappropriate use of antimicrobials.

Elizabethkingia meningosepticum (Chryseobacterium meningosepticum) Infections in Children

Chryseobacterium meningosepticum is a ubiquitous Gram-negative bacillus historically associated primarily with meningitis in neonates and a wide variety of infections in immunocompromised patients. Neonatal infections often occur as outbreaks with environmental contamination being the source. C. meningosepticum infections are not common but are clinically important because the organism is naturally resistant to multiple antibiotics. In this paper, we have reviewed the nosocomial outbreaks of C. meningosepticum in newborns and infants reported so far in the literature and overviewed the infection control interventions, treatment modalities, and prevention measures.