James D. Kellner

A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity

Chronic granulomatous disease (CGD), an immunodeficiency with recurrent pyogenic infections and granulomatous inflammation, results from loss of phagocyte superoxide production by recessive mutations in any 1 of 4 genes encoding subunits of the phagocyte NADPH oxidase. These include gp91(phox) and p22(phox), which form the membrane-integrated flavocytochrome b, and cytosolic subunits p47(phox) and p67(phox). A fifth subunit, p40(phox), plays an important role in phagocytosis-induced superoxide production via a phox homology (PX) domain that binds to phosphatidylinositol 3-phosphate (PtdIns(3)P). We report the first case of autosomal recessive mutations in NCF4, the gene encoding p40(phox), in a boy who presented with granulomatous colitis. His neutrophils showed a substantial defect in intracellular superoxide production during phagocytosis, whereas extracellular release of superoxide elicited by phorbol ester or formyl-methionyl-leucyl-phenylalanine (fMLF) was unaffected. Genetic analysis of NCF4 showed compound heterozygosity for a frameshift mutation with premature stop codon and a missense mutation predicting a R105Q substitution in the PX domain. Parents and a sibling were healthy heterozygous carriers. p40(phox)R105Q lacked binding to PtdIns(3)P and failed to reconstitute phagocytosis-induced oxidase activity in p40(phox)-deficient granulocytes, with premature loss of p40(phox)R105Q from phagosomes. Thus, p40(phox) binding to PtdIns(3)P is essential for phagocytosis-induced oxidant production in human neutrophils and its absence can be associated with disease.

Changing Epidemiology of Invasive Pneumococcal Disease in Canada, 1998–2007: Update from the Calgary-Area Streptococcus pneumoniae Research (CASPER) Study

BACKGROUND Routine infant vaccination with 7-valent pneumococcal conjugate vaccine (PCV7) began in the Calgary Health Region (Alberta, Canada) in 2002. We measured the impact of this vaccine program on invasive pneumococcal disease (IPD). METHODS Prospective, population-based surveillance of all cases of IPD (with culture specimens obtained from sterile sites) was conducted from January 1998 through December 2007. Demographic and clinical data were collected. All viable isolates were saved and serotyped. RESULTS There were 1182 IPD cases over the 10-year period. Comparison of the vaccine period (2003-2007) with the prevaccine period (1998-2001) revealed that the incidence of IPD due to PCV7 serotypes decreased significantly by 86%, 59%, 38%, and 78% in the 6-23-month, 2-4-year, 16-64-year, and 65-84-year age groups, respectively. The total number of IPD cases decreased by 77%, 45%, and 34% in the 6-23-month, 2-4-year, and 65-84-year age groups, respectively. The incidence of IPD due to non-PCV7 serotypes increased by 183%, and the total incidence of IPD increased by 73% among adults aged 16-64 years; however, this increase was primarily attributed to a large outbreak of serotype 5 IPD among homeless adults during the period 2005-2007. There were 5 cases of IPD due to PCV7 serotypes among vaccinated children in the vaccine period. CONCLUSIONS Since the introduction of PCV7 vaccine, there has been a profound decrease in the total number of cases of IPD among children and in cases due to PCV7 serotypes among subjects of all ages in Calgary, indicating a strong direct effect and herd effect of the vaccine. The serotypes that now cause IPD have changed significantly. The magnitude and impact of replacement IPD caused by non-PCV7 serotypes is not yet known.

Antibiotic Prescribing for Canadian Preschool Children: Evidence of Overprescribing for Viral Respiratory Infections

Antibiotic resistance is associated with prior receipt of antibiotics. An analysis of linked computerized databases for physician visits and antibiotic prescriptions was used to examine antibiotic prescribing for different respiratory infections in preschool children in Canada. In 1995, 64% of 61,165 children aged <5 years made 140,892 visits (mean, 3.6 visits per child) for respiratory infections; 74% of children who made visits received antibiotic prescriptions. Antibiotics were prescribed to 49% of children with upper respiratory tract infection, 18% with nasopharyngitis, 78% with pharyngitis or tonsillitis, 32% with serous otitis media, 80% with acute otitis media, 61% with sinusitis, 44% with acute laryngitis or tracheitis, and 24% with influenza. Acute otitis media accounted for 33% of all visits and 39% of all antibiotic prescriptions. The estimated Canadian-dollar cost of overprescribing was

Dramatic pain relief and resolution of bone inflammation following pamidronate in 9 pediatric patients with persistent chronic recurrent multifocal osteomyelitis (CRMO)

423,693, or 49% of the total cost of antibiotics (

A systematic review on the diagnosis of pediatric bacterial pneumonia: when gold is bronze.

859,893) used in this group. This population-based study confirms antibiotic overprescribing in Canada.

The effect of routine vaccination on invasive pneumococcal infections in Canadian children, Immunization Monitoring Program, Active 2000–2007

BackgroundChronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory, non-infectious osteopathy that affects predominantly patients ≤ 18 years of age. There is no uniformly effective treatment. Our objective is to describe clinical, magnetic resonance imaging (MRI), and bone resorption response to intravenous pamidronate in pediatric CRMO.MethodsWe report our prospectively documented experience with all CRMO patients treated with pamidronate between 2003 and 2008 at a tertiary pediatric centre. Pamidronate was administered as intravenous cycles. The dose of pamidronate varied among subjects but was given as monthly to every 3 monthly cycles depending on the distance the patient lived from the infusion center. Maximum cumulative dose was ≤ 11.5 mg/kg/year. Pamidronate treatment was continued until resolution of MRI documented bone inflammation. Visual analog scale for pain (VAS) and bone resorption marker urine N-telopeptide/urine creatinine (uNTX/uCr) were measured at baseline, preceding each subsequent pamidronate treatment, at final follow-up, and/or at time of MRI confirmed CRMO flare. MRI of the affected site(s) was obtained at baseline, preceding every 2nd treatment, and with suspected CRMO recurrence.ResultsNine patients (5 F: 4 M) were treated, with a median (range) age at treatment of 12.9 (4.5–16.3) years, and median (range) duration of symptoms of 18 (6–36) months. VAS decreased from 10/10 to 0–3/10 by the end of first 3–day treatment for all patients. The mean (range) time to complete MRI resolution of bone inflammation was 6.0 (2–12) months. The mean (confidence interval (CI)) baseline uNTX/uCr was 738.83 (CI 464.25, 1013.42)nmol/mmol/creatinine and the mean (CI) decrease from baseline to pamidronate discontinuation was 522.17 (CI 299.77, 744.56)nmol/mmol/creatinine. Median (range) of follow-up was 31.4 (24–54) months. Four patients had MRI confirmed CRMO recurrence, which responded to one pamidronate re-treatment. The mean (range) uNTX/uCr change as a monthly rate from the time of pamidronate discontinuation to flare was 9.41 (1.38–19.85)nmol/mmol/creatinine compared to -29.88 (-96.83–2.01)nmol/mmol/creatinine for patients who did not flare by the time of final follow-up.ConclusionPamidronate resulted in resolution of pain and MRI documented inflammation in all patients. No patient flared while his/her uNTX/uCr remained suppressed. We propose that pamidronate is an effective second-line therapy in persistent CRMO.

Progress in the prevention of pneumococcal infection

Background In developing countries, pneumonia is one of the leading causes of death in children under five years of age and hence timely and accurate diagnosis is critical. In North America, pneumonia is also a common source of childhood morbidity and occasionally mortality. Clinicians traditionally have used the chest radiograph as the gold standard in the diagnosis of pneumonia, but they are becoming increasingly aware that it is not ideal. Numerous studies have shown that chest radiography findings lack precision in defining the etiology of childhood pneumonia. There is no single test that reliably distinguishes bacterial from non-bacterial causes. These factors have resulted in clinicians historically using a combination of physical signs and chest radiographs as a ‘gold standard’, though this combination of tests has been shown to be imperfect for diagnosis and assigning treatment. The objectives of this systematic review are to: 1) identify and categorize studies that have used single or multiple tests as a gold standard for assessing accuracy of other tests, and 2) given the ‘gold standard’ used, determine the accuracy of these other tests for diagnosing childhood bacterial pneumonia. Methods and Findings Search strategies were developed using a combination of subject headings and keywords adapted for 18 electronic bibliographic databases from inception to May 2008. Published studies were included if they: 1) included children one month to 18 years of age, 2) provided sufficient data regarding diagnostic accuracy to construct a 2×2 table, and 3) assessed the accuracy of one or more index tests as compared with other test(s) used as a ‘gold standard’. The literature search revealed 5,989 references of which 256 were screened for inclusion, resulting in 25 studies that satisfied all inclusion criteria. The studies examined a range of bacterium types and assessed the accuracy of several combinations of diagnostic tests. Eleven different gold standards were studied in the 25 included studies. Criterion validity was calculated for fourteen different index tests using eleven different gold standards. The most common gold standard utilized was blood culture tests used in six studies. Fourteen different tests were measured as index tests. PCT was the most common measured in five studies each with a different gold standard. Conclusions We have found that studies assessing the diagnostic accuracy of clinical, radiological, and laboratory tests for bacterial childhood pneumonia have used a heterogeneous group of gold standards, and found, at least in part because of this, that index tests have widely different accuracies. These findings highlight the need for identifying a widely accepted gold standard for diagnosis of bacterial pneumonia in children.

Serotypes and antimicrobial susceptibilities of invasive Streptococcus pneumoniae pre- and post-seven valent pneumococcal conjugate vaccine introduction in Alberta, Canada, 2000-2006.

Active surveillance was conducted by the 12 centers of the Canadian Immunization Monitoring Program, Active from 2000-2007 in children 16 years of age and younger to determine the influence of 7-valent pneumococcal conjugate immunization programs on the prevalence, serotype and antibiotic resistance patterns of invasive pneumococcal disease (IPD) caused by Streptococcus pneumoniae. The absolute number of reported IPD cases decreased 48% (p<0.01) over the 8-year period and 56% (p<0.01) in children 0-4 years of age. The absolute number of reported IPD cases caused by serotypes in the conjugate vaccine decreased 87.5% (p<0.01) overall and 92% (p<0.01) in children 0-4 years. Although 6 non-vaccine serotypes increased over time, only serotype 19A increased significantly (p<0.01). Overall, the proportion of penicillin resistant isolates remained unchanged at 17%. Cefotaxime/ceftriaxone resistance remained unchanged at 2% of isolates annually. Universal pneumococcal conjugate infant immunization programs have dramatically decreased cases of invasive pneumococcal disease.

Effects of Routine Infant Vaccination With the 7-Valent Pneumococcal Conjugate Vaccine on Nasopharyngeal Colonization With Streptococcus pneumoniae in Children in Calgary, Canada

Streptococcus pneumoniae (pneumococcus) remains an important human pathogen more than a century after its discovery, with infections occurring most commonly among young children and elderly people. It causes a wide range of invasive infections in normally sterile body sites such as blood and

A Pharmacoeconomic Evaluation of 7-Valent Pneumococcal Conjugate Vaccine in Canada

Alberta, Canada introduced the Streptococcus pneumoniae seven valent conjugate vaccine (PCV7) program for children less than 2 years of age in September 2002. We determined the rates of invasive pneumococcal disease in Alberta, Canada 2 years pre- and 4 years post-PCV7 introduction (2000-2006) as well as the rates of antibiotic resistance and serotype distribution in this same time period. Overall, PCV7 serotypes decreased 61% from 2000 to 2006. The greatest decrease in incidence of invasive pneumococcal disease occurred in children less than 2 years of age declining from a high of 96.7/100,000 (2000) to 25.8/100,000 (2006) (P<0.0001). Non-susceptibility of S. pneumoniae isolates to penicillin dropped significantly from 14% in 2000 to 4.6% in 2006 (P<0.0001). Non-susceptible erythromycin isolates also decreased from 8.8% (2000) to 5.8% (2006) (P=0.13). The introduction of PCV7 in Alberta, Canada has decreased the incidence of invasive pneumococcal disease in Alberta as well as resulting in a decrease in antibiotic resistance over this same time frame, principally for penicillin resistance.