Michele Moscariello

Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials

Objective Tofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for IBD. We evaluated the efficacy and safety of tofacitinib for induction and maintenance treatment in patients with moderate-to-severe Crohns disease (CD). Design We conducted two randomised, double-blind, placebo-controlled, multicentre phase IIb studies. Adult patients with moderate-to-severe CD were randomised to receive induction treatment with placebo, tofacitinib 5 or 10 mg twice daily for 8 weeks. Those achieving clinical response-100 or remission were re-randomised to maintenance treatment with placebo, tofacitinib 5 or 10 mg twice daily for 26 weeks. Primary endpoints were clinical remission at the end of the induction study, and clinical response-100 or remission at the end of the maintenance study. Results 180/280 patients randomised in the induction study were enrolled in the maintenance study. At week 8 of induction, the proportion of patients with clinical remission was 43.5% and 43.0% with 5 and 10 mg twice daily, respectively, compared with 36.7% in the placebo group (p=0.325 and 0.392 for 5 and 10 mg twice daily vs placebo). At week 26 of maintenance, the proportion of patients with clinical response-100 or remission was 55.8% with tofacitinib 10 mg twice daily compared with 39.5% with tofacitinib 5 mg twice daily and 38.1% with placebo (p=0.130 for 10 mg twice daily vs placebo). Compared with placebo, the change in C-reactive protein from baseline was statistically significant (p<0.0001) with 10 mg twice daily after both induction and maintenance treatments. Conclusions Primary efficacy endpoints were not significantly different from placebo, although there was evidence of a minor treatment effect. No new safety signals were observed for tofacitinib. Trial registration numbers NCT01393626 and NCT01393899.

Hospital-based surveillance of invasive pneumococcal disease and pneumonia in South Bangalore, India

ObjectiveTo estimate the incidence of invasive pneumococcal disease and pneumonia, distribution of pneumococcal serotypes, and antibiotic susceptibility in children aged 28 days to <60 months.DesignHospital-based surveillance.SettingSouth Bangalore, India.Participants9950 children aged 28 days to <60 months with clinical suspicion of invasive pneumococcal disease or pneumonia.ResultsThe estimated at-risk population included 224,966 children <5 years of age. Forty cases of invasive pneumococcal disease were identified. Estimated invasive pneumococcal disease incidence was 17.8/100,000 with incidence being highest among children aged 6 months to <12 months (49.9/100,000). Clinical pneumonia syndrome was the most frequent diagnosis (12.5/100,000). Pneumococcal serotypes included: 6A (n=6, 16.7%); 14 (n=5, 13.9%); 5 (n=4, 11.1%); 6B (n=4, 11.1%); 1, 18C, and 19A (n=3 each, 8.3%); 9V (n=2, 5.6%); and 3, 4, 10C, 18A, 18F, and 19F (n=1 each, 2.8%). Serotypes 6A, 14, 6B, 1, 18C, 19A, 9V, 4, 10C, and 18A showed antibiotic resistance. Clinical pneumonia incidence was 2109/100,000, with incidence being highest among children aged 28 days to <6 months (5033/100,000). Chest radiograph-confirmed pneumonia incidence was 1114/100,000, with incidence being highest among children aged 28 days to <6 months (2413/100,000).ConclusionInvasive pneumococcal disease and pneumonia were found to be common causes of morbidity in young children living in South Bangalore, India.

Prospective Surveillance Study of Invasive Pneumococcal Disease Among Urban Children in the Philippines

Background: Worldwide, invasive pneumococcal disease (IPD) causes considerable morbidity and mortality among children, but incidence data in Asia are lacking. This 2-year hospital-based, prospective, surveillance study was conducted at 3 study sites in urban areas of the Philippines to estimate IPD and pneumonia incidence in children and describe the serotype distribution of invasive Streptococcus pneumoniae isolates. Methods: Children aged 28 days to <60 months residing within the 3 surveillance areas presenting with possible IPD were enrolled. Initial diagnosis, history of pneumococcal vaccine receipt and previous antimicrobial treatment were recorded. Blood specimens were collected for S. pneumoniae identification and serotyping. Final diagnosis was determined for hospitalized subjects, subjects whose culture yielded S. pneumoniae and subjects with clinically suspected meningitis. Results: A total of 5940 subjects were enrolled, 47 IPD cases identified. IPD site rates were 33.49 per 100,000, 25.38 per 100,000 and 25.85 per 100,000. Chest radiograph-confirmed pneumonia incidence ranged from 633.74 to 1683.59 per 100,000. Highest chest radiograph-confirmed pneumonia incidence occurred in those 28 days to <6 months of age at 2 sites (2166.16 and 3891.94 per 100,000) and those 6–12 months of age at the third site (3847.52 per 100,000). Thirty-five S. pneumoniae isolates were serotyped; most commonly identified were serotypes 1, 2, 5, 6B, 14 and 18F. One serotype 14 isolate was erythromycin resistant. Previous antibiotic therapy was documented in 17–53% of subjects; 2 subjects had received pneumococcal vaccine. At 2 sites, one-third of IPD subjects died. Conclusions: IPD is an important cause of morbidity and mortality among urban children in the Philippines. Our data support the expectation that widespread immunization would decrease IPD disease burden.

Long-term immune responses to pneumococcal conjugate vaccines in children previously vaccinated with 7-valent pneumococcal conjugate vaccine.

Background: Seven-valent pneumococcal conjugate vaccine (PCV7) has reduced incidence of vaccine-serotype pneumococcal diseases. Using a single dose of 13-valent pneumoccal conjugate vaccine (PCV13), we evaluated late immune responses 10 years after vaccination with PCV7 in infancy, compared with a PCV7-naïve cohort. Methods: In this open-label study, we administered 1 dose of PCV13 to children aged 11–14 years who had previously received PCV7 (PCV7/PCV13) or meningococcal group C conjugate vaccine (MnCC/PCV13) during infancy. We evaluated serotype-specific immunoglobulin G concentrations and opsonophagocytic activity prevaccination and 1 week and 1 month postvaccination. We recorded local reactions and systemic events for 4 days postvaccination and adverse events for 6 months. Results: Seventy-four subjects received PCV13 (PCV7/PCV13, n = 38; MnCC/PCV13, n = 36). Prevaccination with PCV13, >62.9% of subjects had immunoglobulin G concentrations ≥0.35 µg/mL for all serotypes except serotype 4 (28–29%); proportions increased at 1 month postvaccination to 100% for all serotypes except serotypes 3 (PCV7/PCV13, 94.7%; MnCC/PCV13, 97.0%) and 14 (MnCC/PCV13, 97.1%). Immunoglobulin G and opsonophagocytic activity concentrations for the 7 common and 6 additional serotypes were similar in both groups prevaccination and increased in both groups from prevaccination to 1 week and 1 month postvaccination. Local reactions and fever were mild or moderate; no serious adverse events were reported. Conclusion: Late immune responses after a single dose of PCV13 were similar in children aged 11–14 years regardless of previous vaccination with PCV7 or MnCC. PCV13 was immunogenic, safe and well tolerated.

Active hospital-based surveillance of invasive pneumococcal disease and clinical pneumonia in infants and young children in two Polish counties

Introduction Invasive pneumococcal disease (IPD) incidence, serotype distribution, and antibiotic susceptibility of Streptococcus pneumoniae were estimated in children aged 28 days to < 60 months. Material and methods One-year prospective, hospital-based surveillance was conducted starting on February 15, 2008, at two childrens hospitals serving the city and surrounding county of Poznań and Poznański, Poland. Eligible children had fever ≥ 39.0°C or physician-suspected IPD. Blood cultures were obtained from all children, cerebrospinal fluid in suspected meningitis cases, and chest radiographs (CXRs) in suspected pneumonia cases. Results Seven of 1,581 eligible children had confirmed IPD. Estimated IPD incidence per 100,000 children was 11.89 (95% CI: 4.78–24.50) overall and 20.1 (95% CI: 6.52–46.84) in subjects aged 28 days to < 24 months. One S. pneumoniae isolate of each of the following serotypes was obtained: 6B, 14, 23A, 23F, and 33F. Two isolates were resistant to both trimethoprim-sulfamethoxazole and erythromycin. Clinical pneumonia incidence among children aged 28 days to < 24 months and 24 months to < 60 months was 3,151.3 (95% CI: 2934.7–3379.7) and 962.7 (95% CI: 861.2–10,072.9) per 100,000 children, respectively. CXR-confirmed pneumonia rates in the same groups were 1,035.7 (95% CI: 913.2–1,170.1) and 379.8 (95% CI: 317.1–451.3) per 100,000 children, respectively. Conclusions IPD is an important cause of morbidity in Poznań and Poznański county, Poland. Among participants aged < 5 years with fever or suspected IPD, pneumonia was the most common diagnosis and was highest in children aged < 24 months.