Adverse Events Following Immunization With mRNA and Viral Vector Vaccines in Individuals With Previous Severe Acute Respiratory Syndrome Coronavirus 2 Infection From the Canadian National Vaccine Safety Network.

BACKGROUND: Adults previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop short-term immunity and may have increased reactogenicity to coronavirus disease 2019 (COVID-19) vaccines. This prospective, multicenter, active-surveillance cohort study examined the short-term safety of COVID-19 vaccines in adults with a prior history of SARS-CoV-2. METHODS: Canadian adults vaccinated between 22 December 2020 and 27 November 2021 were sent an electronic questionnaire 7 days post-dose 1, dose 2, and dose 3 vaccination. The main outcome was health events occurring in the first 7 days after each vaccination that prevented daily activities, resulted in work absenteeism, or required a medical consultation, including hospitalization. RESULTS: Among 684 998 vaccinated individuals, 2.6% (18 127/684 998) reported a prior history of SARS-CoV-2 infection a median of 4 (interquartile range: 2-6) months previously. After dose 1, individuals with moderate (bedridden) to severe (hospitalized) COVID-19 who received BNT162b2, mRNA-1273, or ChAdox1-S vaccines had higher odds of a health event preventing daily activities, resulting in work absenteeism or requiring medical consultation (adjusted odds ratio [95% confidence interval]: 3.96 [3.67-4.28] for BNT162b2, 5.01 [4.57-5.50] for mRNA-1273, and 1.84 [1.54-2.20] for ChAdox1-S compared with no infection). Following dose 2 and 3, the greater risk associated with previous infection was also present but was attenuated compared with dose 1. For all doses, the association was lower or absent after mild or asymptomatic infection. CONCLUSIONS: Adults with moderate or severe previous SARS-CoV-2 infection were more likely to have a health event sufficient to impact routine activities or require medical assessment in the week following each vaccine dose.

Canadian Association of Gastroenterology Clinical Practice Guideline for Immunizations in Patients With Inflammatory Bowel Disease (IBD)-Part 2: Inactivated Vaccines.

BACKGROUND AND AIMS: The effectiveness and safety of vaccinations can be altered by immunosuppressive therapies, and perhaps by inflammatory bowel disease (IBD) itself. These recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on immunizations in adult and pediatric patients with IBD. This publication focused on inactivated vaccines. METHODS: Systematic reviews evaluating the efficacy, effectiveness, and safety of vaccines in patients with IBD, other immune-mediated inflammatory diseases, and the general population were performed. Critical outcomes included mortality, vaccine-preventable diseases, and serious adverse events. Immunogenicity was considered a surrogate outcome for vaccine efficacy. Certainty of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. Key questions were developed through an iterative online platform, and voted on by a multidisciplinary group. Recommendations were formulated using the Evidence-to-Decision framework. Strong recommendation means that most patients should receive the recommended course of action, whereas a conditional recommendation means that different choices will be appropriate for different patients. RESULTS: Consensus was reached on 15 of 20 questions. Recommendations address the following vaccines: Haemophilus influenzae type b, recombinant zoster, hepatitis B, influenza, pneumococcus, meningococcus, tetanus-diphtheria-pertussis, and human papillomavirus. Most of the recommendations for patients with IBD are congruent with the current Centers for Disease Control and Prevention and Canada's National Advisory Committee on Immunization recommendations for the general population, with the following exceptions. In patients with IBD, the panel suggested Haemophilus influenzae type b vaccine for patients older than 5 years of age, recombinant zoster vaccine for adults younger than 50 year of age, and hepatitis B vaccine for adults without a risk factor. Consensus was not reached, and recommendations were not made for 5 statements, due largely to lack of evidence, including double-dose hepatitis B vaccine, timing of influenza immunization in patients on biologics, pneumococcal and meningococcal vaccines in adult patients without risk factors, and human papillomavirus vaccine in patients aged 27-45 years. CONCLUSIONS: Patients with IBD may be at increased risk of some vaccine-preventable diseases. Therefore, maintaining appropriate vaccination status in these patients is critical to optimize patient outcomes. In general, IBD is not a contraindication to the use of inactivated vaccines, but immunosuppressive therapy may reduce vaccine responses.

Canadian Association of Gastroenterology Clinical Practice Guideline for Immunizations in Patients With Inflammatory Bowel Disease (IBD)-Part 1: Live Vaccines.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) may be at increased risk of some vaccine-preventable diseases. The effectiveness and safety of vaccinations may be altered by immunosuppressive therapies or IBD itself. These recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on immunizations in adult and pediatric patients with IBD. This publication focused on live vaccines. METHODS: Systematic reviews evaluating the efficacy, effectiveness, and safety of vaccines in patients with IBD, other immune-mediated inflammatory diseases, and the general population were performed. Critical outcomes included mortality, vaccine-preventable diseases, and serious adverse events. Immunogenicity was considered a surrogate outcome for vaccine efficacy. Certainty of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. Key questions were developed through an iterative process and voted on by a multidisciplinary panel. Recommendations were formulated using the Evidence-to-Decision framework. Strong recommendation means that most patients should receive the recommended course of action, whereas a conditional recommendation means that different choices will be appropriate for different patients. RESULTS: Three good practice statements included reviewing a patient's vaccination status at diagnosis and at regular intervals, giving appropriate vaccinations as soon as possible, and not delaying urgently needed immunosuppressive therapy to provide vaccinations. There are 4 recommendations on the use of live vaccines. Measles, mumps, rubella vaccine is recommended for both adult and pediatric patients with IBD not on immunosuppressive therapy, but not for those using immunosuppressive medications (conditional). Varicella vaccine is recommended for pediatric patients with IBD not on immunosuppressive therapy, but not for those using immunosuppressive medications (conditional). For adults, recommendations are conditionally in favor of varicella vaccine for those not on immunosuppressive therapy, and against for those on therapy. No recommendation was made regarding the use of live vaccines in infants born to mothers using biologics because the desirable and undesirable effects were closely balanced and the evidence was insufficient. CONCLUSIONS: Maintaining appropriate vaccination status in patients with IBD is critical to optimize patient outcomes. In general, live vaccines are recommended in patients not on immunosuppressive therapy, but not for those using immunosuppressive medications. Additional studies are needed to evaluate the safety and efficacy of live vaccines in patients on immunosuppressive therapy.

Attribution of Pediatric Acute Gastroenteritis Episodes and Emergency Department Visits to Norovirus Genogroups I and II.

BACKGROUND: Norovirus is a leading cause of acute gastroenteritis. With vaccines in development, population-based estimates of norovirus burden are needed to identify target populations, quantify potential benefits, and understand disease dynamics. METHODS: We estimated the attributable fraction (AF) for norovirus infections in children, defined as the proportion of children testing positive for norovirus whose gastroenteritis was attributable to norovirus. We calculated the standardized incidence and emergency department (ED) visit rates attributable to norovirus using provincial gastroenteritis visit administrative data. RESULTS: From 3731 gastroenteritis case patients and 2135 controls we determined that the AFs were 67.0% (95% confidence interval [CI], 31.5%-100%) and 91.6% (88.8%-94.4%) for norovirus genogroups I (GI) and II (GII), respectively. Norovirus GII AF varied by season but not age. We attributed 116 episodes (95% CI, 103-129) and 59 (51-67) ED visits per 10 000 child-years to norovirus GII across all ages, accounting for 20% and 18% of all medically attended gastroenteritis episodes and ED visits, respectively. CONCLUSIONS: In children, a large proportion of norovirus GII detections reflect causation, demonstrating significant potential for norovirus GII vaccines. Seasonal variation in the norovirus GII AF may have implications for understanding the role asymptomatic carriage plays in disease dynamics.

Microbial Etiologies and Clinical Characteristics of Children Seeking Emergency Department Care Due to Vomiting in the Absence of Diarrhea.

BACKGROUND: As children with isolated vomiting are rarely able to provide a specimen suitable for routine pathogen testing, we have limited knowledge about their infecting pathogens. METHODS: Between December 2014 and August 2018, children <18 years old with presumed acute gastroenteritis who presented to 2 emergency departments (EDs) in Alberta, Canada, were recruited. Eligible participants had ≥3 episodes of vomiting and/or diarrhea in a 24-hour period, <7 days of symptoms, and provided a rectal swab or stool specimen. We quantified the proportion of children with isolated vomiting in whom an enteropathogen was identified, and analyzed clinical characteristics, types of enteropathogens, resources used, and alternative diagnoses. RESULTS: Of the 2695 participants, at the ED visit, 295 (10.9%), 1321 (49.0%), and 1079 (40.0%) reported having isolated diarrhea, vomiting and diarrhea, or isolated vomiting, respectively. An enteropathogen was detected most commonly in those with vomiting and diarrhea (1067/1321; 80.8%); detection did not differ between those with isolated diarrhea (170/295; 57.6%) and isolated vomiting (589/1079; 54.6%) (95% confidence interval of the difference: -3.4%, 9.3%). Children with isolated vomiting most often had a virus (557/1077; 51.7%), most commonly norovirus (321/1077; 29.8%); 5.7% (62/1079) had a bacterial pathogen. X-rays, ultrasounds, and urine tests were most commonly performed in children with isolated vomiting. Alternate etiologies were most common in those with isolated vomiting (5.7%; 61/1079). CONCLUSIONS: The rate of enteropathogen identification in children with isolated vomiting using molecular diagnostic tests and rectal swabs is substantial. Molecular diagnostics offer an emerging diagnostic strategy in children with isolated vomiting.

Whole-Genome Analysis of Streptococcus pneumoniae Serotype 4 Causing Outbreak of Invasive Pneumococcal Disease, Alberta, Canada.

After the introduction of pneumococcal conjugate vaccines for children, invasive pneumococcal disease caused by Streptococcus pneumoniae serotype 4 declined in all ages in Alberta, Canada, but it has reemerged and spread in adults in Calgary, primarily among persons who are experiencing homelessness or who use illicit drugs. We conducted clinical and molecular analyses to examine the cases and isolates. Whole-genome sequencing analysis indicated relatively high genetic variability of serotype 4 isolates. Phylogenetic analysis identified 1 emergent sequence type (ST) 244 lineage primarily associated within Alberta and nationally distributed clades ST205 and ST695. Isolates from 6 subclades of the ST244 lineage clustered regionally, temporally, and by homeless status. In multivariable logistic regression, factors associated with serotype 4 invasive pneumococcal disease were being male, being <65 years of age, experiencing homelessness, having a diagnosis of pneumonia or empyema, or using illicit drugs.

A Clinical Epidemiology and Molecular Attribution Evaluation of Adenoviruses in Pediatric Acute Gastroenteritis: a Case-Control Study.

The objective of this study was to characterize the etiological role of human adenovirus (HAdV) serotypes in pediatric gastroenteritis. Using a case-control design, we compared the frequencies of HAdV serotypes between children with ≥3 episodes of vomiting or diarrhea within 24 h and <7 days of symptoms (i.e., cases) and those with no infectious symptoms (i.e., controls). Stool samples and/or rectal swabs underwent molecular serotyping with cycle threshold (Ct) values provided by multiplex real-time reverse transcription-PCR testing. Cases without respiratory symptoms were analyzed to calculate the proportion of disease attributed to individual HAdV serotypes (i.e., attributable fraction). Between December 2014 and August 2018, adenoviruses were detected in 18.8% (629/3,347) of cases and 7.2% (97/1,355) of controls, a difference of 11.6% (95% confidence interval [CI], 9.6%, 13.5%). In 96% (95% CI, 92 to 98%) of HAdV F40/41 detections, the symptoms could be attributed to the identified serotype; when serotypes C1, C2, C5, and C6 were detected, they were responsible for symptoms in 52% (95% CI, 12 to 73%). Ct values were lower among cases than among controls (P < 0.001). HAdV F40/41, C2, and C1 accounted for 59.7% (279/467), 17.6% (82/467), and 12.0% (56/467) of all typed cases, respectively. Among cases, Ct values were lower for F40/41 serotypes than for non-F40/41 serotypes (P < 0.001). HAdV F40/41 serotypes account for the majority of HAdV-positive gastroenteritis cases, and when detected, disease is almost always attributed to infection with these pathogens. Non-F40/41 HAdV species have a higher frequency of asymptomatic infection and may not necessarily explain gastroenteritis symptoms. Real-time quantitative PCR may be useful in differentiating asymptomatic shedding from active infection.

2017/18 and 2018/19 seasonal influenza vaccine safety surveillance, Canadian National Vaccine Safety (CANVAS) Network.

BackgroundThe Canadian National Vaccine Safety (CANVAS) network monitors the safety of seasonal influenza vaccines in Canada.AimTo provide enhanced surveillance for seasonal influenza and pandemic influenza vaccines.MethodsIn 2017/18 and 2018/19 influenza seasons, adults (≥ 15 years of age) and parents of children vaccinated with the seasonal influenza vaccine participated in an observational study using web-based active surveillance. Participants completed an online survey for health events occurring in the first 7 days after vaccination. Participants who received the influenza vaccine in the previous season, but had not yet been vaccinated for the current season, were unvaccinated controls.ResultsIn 2017/18, 43,751 participants and in 2018/19, 47,798 completed the online safety survey. In total, 957 of 30,173 participants vaccinated in 2017/18 (3.2%; 95% confidence interval (CI): 3.0-3.4) and 857 of 25,799 participants vaccinated in 2018/19 (3.3%; 95% CI: 3.1-3.5) reported a health problem of sufficient intensity to prevent their normal daily activities and/or cause them to seek medical care (including hospitalisation). This compared to 323 of 13,578 (2.4%; 95% CI: 2.1-2.6) and 544 of 21,999 (2.5%; 95% CI: 2.3-2.7) controls in each respective season. The event rate in vaccinated adults and children was higher than the background rate and was associated with specific influenza vaccines. The higher rate of events was associated with systemic symptoms and migraines/headaches.ConclusionIn 2017/18 and 2018/19, higher rates of events were reported following seasonal influenza vaccination than in the pre-vaccination period. This signal was associated with several seasonal influenza vaccine products.

Performance of Stool-testing Recommendations for Acute Gastroenteritis When Used to Identify Children With 9 Potential Bacterial Enteropathogens.

BACKGROUND: The ability to identify bacterial pathogens that necessitate specific clinical management or public health action in children with acute gastroenteritis is crucial to patient care and public health. However, existing stool-testing guidelines offer inconsistent recommendations, and their performance characteristics are unknown. We evaluated 6 leading gastroenteritis guidelines (eg, those of the Centers for Disease Control and Prevention and Infectious Disease Society of America) that recommend when to test children's stool for bacterial enteropathogens. METHODS: Via 2 emergency departments in Alberta, Canada, we enrolled 2447 children <18 years old who presented with ≥3 episodes of diarrhea and/or vomiting in a 24-hour period. All participants were tested for 9 bacterial enteropathogens: Aeromonas, Campylobacter, Escherichia coli O157, other Shiga toxin-producing E. coli, enterotoxigenic E. coli, Salmonella, Shigella, Vibrio, and Yersinia. Patient data gathered at the index visit were used to determine whether guidelines would recommend testing. Sensitivity and specificity to recommend testing for children with bacterial enteropathogens were calculated for each guideline. RESULTS: Outcome data were available for 2391 (97.7%) participants, and 6% (144/2391) of participants tested positive for a bacterial enteropathogen. Guideline sensitivity ranged from 25.8% (95% confidence interval [CI] 18.7-33.0%) to 66.9% (95% CI 59.3-74.6%), and varied for individual pathogens. Guideline specificity for all bacterial enteropathogens ranged from 63.6% (95% CI 61.6-65.6%) to 96.5% (95% CI 95.7-97.2%). CONCLUSIONS: No guideline provided optimally balanced performance. The most sensitive guidelines missed one-third of cases and would drastically increase testing volumes. The most specific guidelines missed almost 75% of cases.

Comparative Evaluation of Enteric Bacterial Culture and a Molecular Multiplex Syndromic Panel in Children with Acute Gastroenteritis.

Although enteric multianalyte syndromic panels are increasingly employed, direct comparisons with traditional methods and the inclusion of host phenotype correlations are limited. Luminex xTAG gastrointestinal pathogen panel (GPP) and culture results are highly concordant. However, phenotypic and microbiological confirmatory testing raises concerns regarding the accuracy of the GPP, especially for Salmonella spp. A total of 3,089 children with gastroenteritis submitted stool specimens, rectal swab specimens, and clinical data. The primary outcome was bacterial pathogen detection agreement for shared targets between culture and the Luminex xTAG GPP. Secondary analyses included phenotype assessment, additional testing of GPP-negative/culture-positive isolate suspensions with the GPP, and in-house and commercial confirmatory nucleic acid testing of GPP-positive/culture-negative extracts. The overall percent agreement between technologies was >99% for each pathogen. Salmonella spp. were detected in specimens from 64 participants: 12 (19%) by culture only, 9 (14%) by GPP only, and 43 (67%) by both techniques. Positive percent agreement for Salmonella spp. was 78.2% (95% confidence interval [CI], 64.6%, 87.8%). Isolate suspensions from the 12 participants with specimens GPP negative/culture positive for Salmonella tested positive by GPP. Specimens GPP positive/culture negative for Salmonella originated in younger children with less diarrhea and more vomiting. GPP-positive/culture-negative specimen extracts tested positive using additional assays for 0/2 Campylobacter-positive specimens, 0/4 Escherichia coli O157-positive specimens, 0/9 Salmonella-positive specimens, and 2/3 Shigella-positive specimens. For both rectal swab and stool samples, the median cycle threshold (CT ) values, determined using quantitative PCR, were higher for GPP-negative/culture-positive samples than for GPP-positive/culture-positive samples (for rectal swabs, 36.9 [interquartile range {IQR}, 33.7, 37.1] versus 30.0 [IQR, 26.2, 33.2], respectively [P = 0.002]; for stool samples, 36.9 [IQR, 33.7, 37.1] versus 29.0 [IQR, 24.8, 30.8], respectively [P = 0.001]). GPP and culture have excellent overall agreement; however, for specific pathogens, GPP is less sensitive than culture and, notably, identifies samples false positive for Salmonella spp.

Pigment Visibility on Rectal Swabs Used To Detect Enteropathogens: a Prospective Cohort Study.

Data are lacking regarding the impact of visible pigment on rectal swab diagnostic accuracy. We describe the test characteristics of rectal swabs with and without pigment in children with gastroenteritis. Between December 2014 and September 2017, children (age, <18 years) with ≥3 episodes of vomiting and/or diarrhea in a 24-h period and symptoms for <7 days were enrolled through two pediatric emergency departments and from a province-wide nursing telephone advice line in Alberta, Canada. Specimens were analyzed by employing nucleic acid amplification panels. The primary outcomes were the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the rectal swabs, with stool specimen results being used as the reference standard. An enteropathogen was detected in 76.0% (1,399/1,841) of the paired specimens. A total of 54.4% (1,001/1841) of the swabs had visible pigment. The respective enteropathogen detection characteristics of swabs with and without visible pigment were as follows: 92.2% (95% confidence interval [CI], 90.0%, 94.0%) versus 83.7% (95% CI, 80.5%, 86.4%) for sensitivity, 94.3% (95% CI, 90.5%, 96.6%) versus 91.2% (95% CI, 86.3%, 94.5%) for specificity, 97.9% (95% CI, 96.4%, 98.8%) versus 96.5% (95% CI, 94.5%, 97.8%) for PPV, and 80.9% (95% CI, 76.0%, 85.1%) versus 65.8% (95% CI, 60.0%, 71.1%) for NPV. Processing of swabs without visible pigment would increase the rate of identification of positive swabs from 50.0% (682/1,365) to 88.3% (1,205/1,365). There is a modest decrease in the reliability of a negative test on swabs without evidence of pigment, but the overall yield is significantly greater when they are not excluded from testing. Hence, rectal swabs without visible feces should not be routinely rejected from testing.

A prospective comparative study of children with gastroenteritis: emergency department compared with symptomatic care at home.

Little is known about the epidemiology and severity of gastroenteritis among children treated at home. We sought to compare illness severity and etiology between children brought for emergency department (ED) care to those managed at home (i.e., community). Prospective cohort study of children enrolled between December 2014 and December 2016 in two pediatric EDs in Alberta, Canada along with children treated at home after telephone triage (i.e., community). Primary outcomes were maximal frequency of vomiting and diarrhea in the 24-h pre-enrollment period; secondary outcomes included etiologic pathogens, dehydration severity, future healthcare visits, and treatments provided. A total of 1613 patients (1317 ED, 296 community) were enrolled. Median maximal frequency of vomiting was higher in the ED cohort (5 (3, 10) vs. 5 (2, 8); P < 0.001). Proportion of children with diarrhea and its 24-h median frequency were lower in the ED cohort (61.3 vs. 82.8% and 2 (0, 6) vs. 4 (1, 7); P < 0.001, respectively). In regression analysis, the ED cohort had a higher maximum number of vomiting episodes pre-enrollment (incident rate ratio (IRR) 1.25; 95% CI 1.12, 1.40) while the community cohort had higher maximal 24-h period diarrheal episodes (IRR 1.20; 95% CI 1.01, 1.43). Norovirus was identified more frequently in the community cohort (36.8% vs. 23.6%; P < 0.001). Children treated in the ED have a greater number of vomiting episodes; those treated at home have more diarrheal episodes. Norovirus is more common among children treated symptomatically at home and thus may represent a greater burden of disease than previously thought.

A Randomized Controlled Trial of the Safety and Immunogenicity of Tetanus, Diphtheria, and Acellular Pertussis Vaccine Immunization During Pregnancy and Subsequent Infant Immune Response.

Background: Immunization of pregnant women with tetanus-diphtheria-acellular pertussis vaccine (Tdap) provides protection against pertussis to the newborn infant. Methods: In a randomized, controlled, observer-blind, multicenter clinical trial, we measured the safety and immunogenicity of Tdap during pregnancy and the effect on the infant's immune response to primary vaccination at 2, 4, and 6 months and booster vaccination at 12 months of age. A total of 273 women received either Tdap or tetanus-diphtheria (Td) vaccine in the third trimester and provided information for the safety analysis and samples for the immunogenicity analyses; 261 infants provided serum for the immunogenicity analyses. Results: Rates of adverse events were similar in both groups. Infants of Tdap recipients had cord blood levels that were 21% higher than maternal levels for pertussis toxoid (PT), 13% higher for filamentous hemagglutinin (FHA), 4% higher for pertactin (PRN), and 7% higher for fimbriae (FIM). These infants had significantly higher PT antibody levels at birth and at 2 months and significantly higher FHA, PRN, and FIM antibodies at birth and 2 and 4 months, but significantly lower PT and FHA antibody levels at 6 and 7 months and significantly lower PRN and FIM antibody levels at 7 months than infants whose mothers received Td. Differences persisted prebooster at 12 months for all antigens and postbooster 1 month later for PT, FHA, and FIM. Conclusions: This study demonstrated that Tdap during pregnancy results in higher levels of antibodies early in infancy but lower levels after the primary vaccine series. Clinical Trials Registration: NCT00553228.

Diagnostic Interpretation Guidance for Pediatric Enteric Pathogens: A Modified Delphi Consensus Process.

BACKGROUND: We sought to develop diagnostic test guidance definitions for pediatric enteric infections to facilitate the interpretation of positive test results in the era of multianalyte molecular diagnostic test platforms. METHODS: We employed a systematic, two-phase, modified Delphi consensus process consisting of three web-based surveys and an expert panel face-to-face meeting. In phase 1, we surveyed an advisory panel of North American experts to select pathogens requiring diagnostic test guidance definition development. In phase 2, we convened a 14-member expert panel to develop, refine, and select the final definitions through two web-based questionnaires interspersed with a face-to-face meeting. Both questionnaires asked panelists to rate the degree to which they agreed that if the definition is met the pathogen is likely to be causative of clinical illness. RESULTS: The advisory panel survey identified 19 pathogens requiring definitions. In the expert panel premeeting survey, 13 of the 19 definitions evaluated were rated as being highly likely ("agree" or "strongly agree") to be responsible for acute gastroenteritis symptoms by ≥67% of respondent panel members. The definitions for the remaining six pathogens (Aeromonas, Clostridium difficile, Edwardsiella, nonenteric adenovirus, astrovirus, and Entamoeba histolytica) were indeterminate. After the expert panel meeting, only two of the modified definitions, C. difficile and E. histolytica/dispar, failed to achieve the a priori specified threshold of ≥67% agreement. CONCLUSIONS: We developed diagnostic test guidance definitions to assist healthcare providers for 17 enteric pathogens. We identified two pathogens that require further research and definition development.

The Use of Routine Blood Cultures in Pediatric Appendicitis.

OBJECTIVES: To determine the proportion of true-positive blood culture results in children presenting to the ED with suspected appendicitis. To describe the current practice of obtaining blood cultures in children with suspected appendicitis. METHODS: We performed a 2-year retrospective health record review of all children aged 2 through 17 years investigated for suspected appendicitis at a tertiary Pediatric Emergency Department. Subjects were identified by searching (a) institutional records for ICD-10-CA coding, (b) diagnostic imaging records of ultrasounds for appendicitis, and (c) surgical database records for nonincidental appendectomies. Abstracted demographic and clinical data were matched to regional laboratory services data to describe the performance and result of blood cultures. RESULTS: Overall, 1315 children investigated for appendicitis were reviewed. Seven hundred fifty (57.0%) were girls, the average age was 11.7 years (SD, 4.0). Blood cultures were obtained in 288 (21.9%) of 1315 patients. Of the 11 (3.8%) cultures that were positive, only 1 (0.35%) was a true positive. Young age, high triage acuity, and presence of fever were associated with the acquisition of cultures (P < 0.001 for all). The proportion of children undergoing appendectomy and the negative appendectomy rate was similar between those with and without blood culture (P = 0.10 and P = 0.96, respectively). CONCLUSIONS: True-positive blood cultures are very rare in children presenting to the ED with suspected appendicitis. Given the potential for false-positive cultures and the social/economic implications of initial testing/retesting of false positives, the use of routine blood cultures for children with suspected appendicitis is not supported.

Physician perspectives on vaccination and diagnostic testing in children with gastroenteritis: A primary care physician survey.

OBJECTIVES: Gastroenteritis remains a common paediatric illness. Little is known about physician knowledge of enteric pathogen diagnostic tests. At the time of study conduct, Alberta lacked a publicly funded rotavirus vaccination program and knowledge of primary care physician perspectives was lacking. We sought to ascertain diagnostic testing methods and to understand knowledge and perceptions regarding enteric pathogen vaccination. METHODS: A 30-item electronic survey was distributed across Alberta's five health care zones. The survey was developed by virology, microbiology, paediatrics, family medicine and public health experts. Participants were members of Alberta's Primary Care Networks, the TARRANT network and The Society of General Pediatricians of Greater Edmonton. Study outcomes included: (1) physician knowledge of available diagnostic tests, (2) perspectives regarding stool sample collection and (3) support for an enteric vaccine program. RESULTS: Stool culture was reported as the test to identify parasites (47%), viruses (74%) and Clostridium difficile (67%). Although electron microscopy and enzyme immunoassay were used to identify viruses in Alberta during the study period, only 20% and 48% of respondents respectively identified them as tests employed for such purposes. Stool testing was viewed as being inconvenient (62%; 55/89), whereas rectal swabs were thought to have the potential to significantly improve specimen collection rates (82%; 72/88). Seventy-three per cent (66/90) of the respondent physicians support the adoption of future enteric pathogen vaccines. CONCLUSIONS: Simplification of diagnostic testing and stool sample collection could contribute to improved pathogen identification rates. Implementation of an enteric vaccine into the routine paediatric vaccination schedule is supported by the majority of respondents.

Influence of Childhood Pneumococcal Conjugate Vaccines on Invasive Pneumococcal Disease in Adults With Underlying Comorbidities in Calgary, Alberta (2000-2013).

BACKGROUND: Pneumococcal conjugate vaccine (PCV) was introduced into Alberta, Canada's routine childhood immunization programs in 2002 (7-valent [PCV7]) and 2010 (13-valent [PCV13]). We assessed the effect of these programs on the epidemiology of invasive pneumococcal disease (IPD) to determine if PCV-associated indirect protection was relatively reduced in adults with underlying comorbidities. METHODS: Demographic and clinical data were collected by a prospective, population-based surveillance system in Calgary, Alberta, Canada, from January 2000 to December 2013. An indirect cohort study design was used to assess for changes in the proportion of IPD cases with underlying comorbidities. RESULTS: There were 1598 overall and 1346 adult IPD cases from 1 January 2000 to 31 December 2013. Overall IPD incidence decreased 33% (age 0-5 months), 86% (6-23 months), 67% (2-4 years), 26% (5-17 years), 22% (18-64 years), 36% (65-84 years), and 42% (≥85 years) from the prevaccine (January 2000-July 2002) to the post-PCV13 (July 2010-December 2013) period. Over the same timeframe, PCV7 serotype disease incidence declined to ≤1 case per 100 000 persons in all age groups. Neither the proportion of adult cases with immunocompetent comorbidities (relative risk ratio [RRR], 0.93; 95% confidence interval [CI], .62-1.40) nor immunocompromising comorbidities (RRR, 0.99; 95% CI, .61-1.61) differed between the pre-PCV period and post-PCV era. CONCLUSIONS: Childhood PCV programs have provided considerable benefit, with substantial declines in overall and vaccine-serotype IPD in vaccinated children and in unvaccinated persons. Conjugate vaccine-associated indirect protection for adults with comorbidities was similar to that for healthy adults.

Alberta Provincial Pediatric EnTeric Infection TEam (APPETITE): epidemiology, emerging organisms, and economics.

BACKGROUND: Each year in Canada there are 5 million episodes of acute gastroenteritis (AGE) with up to 70% attributed to an unidentified pathogen. Moreover, 90% of individuals with AGE do not seek care when ill, thus, burden of disease estimates are limited by under-diagnosing and under-reporting. Further, little is known about the pathogens causing AGE as the majority of episodes are attributed to an "unidentified" etiology. Our team has two main objectives: 1) to improve health through enhanced enteric pathogen identification; 2) to develop economic models incorporating pathogen burden and societal preferences to inform enteric vaccine decision making. METHODS/DESIGN: This project involves multiple stages: 1) Molecular microbiology experts will participate in a modified Delphi process designed to define criteria to aid in interpreting positive molecular enteric pathogen test results. 2) Clinical data and specimens will be collected from children aged 0-18 years, with vomiting and/or diarrhea who seek medical care in emergency departments, primary care clinics and from those who contact a provincial medical advice line but who do not seek care. Samples to be collected will include stool, rectal swabs (N = 2), and an oral swab. Specimens will be tested employing 1) stool culture; 2) in-house multiplex (N = 5) viral polymerase chain reaction (PCR) panel; and 3) multi-target (N = 15) PCR commercially available array. All participants will have follow-up data collected 14 days later to enable calculation of a Modified Vesikari Scale score and a Burden of Disease Index. Specimens will also be collected from asymptomatic children during their well child vaccination visits to a provincial public health clinic. Following the completion of the initial phases, discrete choice experiments will be conducted to enable a better understanding of societal preferences for diagnostic testing and vaccine policy. All of the results obtained will be integrated into economic models. DISCUSSION: This study is collecting novel samples (e.g., oral swabs) from previously untested groups of children (e.g., those not seeking medical care) which are then undergoing extensive molecular testing to shed a new perspective on the epidemiology of AGE. The knowledge gained will provide the broadest understanding of the epidemiology of vomiting and diarrhea of children to date.

Effectiveness of the standard and an alternative set of Streptococcus pneumoniae multi locus sequence typing primers.

BACKGROUND: Multi-locus sequence typing (MLST) is a portable, broadly applicable method for classifying bacterial isolates at an intra-species level. This methodology provides clinical and scientific investigators with a standardized means of monitoring evolution within bacterial populations. MLST uses the DNA sequences from a set of genes such that each unique combination of sequences defines an isolate's sequence type. In order to reliably determine the sequence of a typing gene, matching sequence reads for both strands of the gene must be obtained. This study assesses the ability of both the standard, and an alternative set of, Streptococcus pneumoniae MLST primers to completely sequence, in both directions, the required typing alleles. RESULTS: The results demonstrated that for five (aroE, recP, spi, xpt, ddl) of the seven S. pneumoniae typing alleles, the standard primers were unable to obtain the complete forward and reverse sequences. This is due to the standard primers annealing too closely to the target regions, and current sequencing technology failing to sequence the bases that are too close to the primer. The alternative primer set described here, which includes a combination of primers proposed by the CDC and several designed as part of this study, addresses this limitation by annealing to highly conserved segments further from the target region. This primer set was subsequently employed to sequence type 105 S. pneumoniae isolates collected by the Canadian Immunization Monitoring Program ACTive (IMPACT) over a period of 18 years. CONCLUSIONS: The inability of several of the standard S. pneumoniae MLST primers to fully sequence the required region was consistently observed and is the result of a shift in sequencing technology occurring after the original primers were designed. The results presented here introduce clear documentation describing this phenomenon into the literature, and provide additional guidance, through the introduction of a widely validated set of alternative primers, to research groups seeking to undertake S. pneumoniae MLST based studies.

Clinical features and outcomes of serotype 19A invasive pneumococcal disease in Calgary, Alberta.

UNLABELLED: The recent introduction of the seven-valent pneumococcal conjugate vaccine has led to changes in the proportion of disease caused by different serotypes. The serotypes targeted by the vaccine have been reduced, and Streptococcus pneumonia serotype 19A is now the most commonly isolated serotype causing invasive pneumococcal disease. This serotype has been associated with antibiotic resistance. The authors of this article conducted a review of cases of invasive pneumococcal disease diagnosed between 2000 and 2010 in Calgary, Alberta, to examine the disease course of serotype 19A invasive pneumococcal disease compared with other serotypes. BACKGROUND: Streptoccocus pneumoniae serotype 19A (ST19A) became an important cause of invasive pneumococcal disease (IPD) after the introduction of the conjugate vaccine. OBJECTIVE: To examine the severity and outcome of ST19A IPD compared with non-ST19A IPD. METHODS: The Calgary Area Streptococcus pneumoniae Epidemiology Research (CASPER) study collects clinical and laboratory data on all IPD cases in Calgary, Alberta. Analysis was performed on data from 2000 to 2010 comparing ST19A and non-ST19A IPD cases. Adjusted linear and logistic regression models were used to examine outcomes of duration of appropriate intravenous antibiotic therapy and intensive care unit admission, respectively. RESULTS: ST19A tended to cause disease in younger patients. ST19A isolates were more often multidrug resistant (19% versus 0.3%; P<0.001). Adjusted logistic regression showed no difference in intensive care unit admission between ST19A and non-ST19A IPD cases (OR 1.4 [95% CI 0.8 to 2.7]). An adjusted linear regression model showed patients <18 years of age with a diagnosis of bacteremia and no risk factors infected with ST19A were, on average, treated with antibiotics 1.4 times (95% CI 1.1 to 1.9) as long as patients with non-19A IPD and the same baseline characteristics. DISCUSSION: ST19A IPD was associated with an increase in average time on antibiotics. Although many of the infecting strains of ST19A were within the threshold for susceptibility, they may be sufficiently resilient to require a longer duration of antibiotic therapy or higher dose to clear the infection. CONCLUSIONS: ST19A is more common in younger individuals, is more antibiotic resistant and may require longer average treatment duration.

HISTORIQUE: Le Streptoccocus pneumoniae du sérotype 19A (ST19A) est devenu une cause importante de pneumococcie invasive (PI) depuis l'introduction du vaccin conjugué. OBJECTIF: Examiner la gravité et les issues de la PI ST19A par rapport aux PI non ST19A. MÉTHODOLOGIE: L'étude CASPER de recherche épidémiologique sur le Streptococcus pneumoniae dans la région de Calgary s'intéresse à la collecte de données cliniques et de données de laboratoire sur tous les cas de PI à Calgary, en Alberta. Les chercheurs ont analysé les don-nées de 2000 à 2010 pour comparer les cas de PI ST19A aux cas de PI non ST19A. Ils ont utilisé des modèles de régression linéaire et logistique ajustés pour examiner les résultats de la durée d'une antibiothérapie intraveineuse pertinente et de l'hospitalisation à l'unité de soins intensifs, respectivement. RÉSULTATS: Le ST19A avait tendance à susciter la maladie chez des patients plus jeunes. Les isolats de ST19A étaient plus souvent multi-résistants (19 % par rapport à 0,3 %; P<0,001). La régression logistique ajustée ne démontrait aucune différence dans les hospitalisations aux soins intensifs des cas de PI ST19A et des cas de PI non ST19A (RC 1,4 [95 % IC 0,8 à 2,7]). Un modèle de régression linéaire ajusté a révélé que les patients de moins de 18 ans chez qui on avait diagnostiqué une bactériémie, mais qui n'avaient pas de facteurs de risque et qui étaient infectés par le ST19A, étaient traités en moyenne 1,4 fois plus longtemps (95 % IC 1,1 à 1,9) que ceux qui étaient atteints d'une PI non ST19A et qui présentaient les mêmes caractéristiques de départ. EXPOSÉ: La PI ST19A s'associait à une période moyenne d'antibiothérapie plus longue. Même si bon nombre de souches infectieuses du ST19A se situaient dans le seuil de susceptibilité, elles sont peut-être assez résilientes pour qu'une antibiothérapie plus longue ou à plus forte dose puisse éliminer l'infection. CONCLUSIONS: Le ST19A est plus courant chez les plus jeunes, résiste davantage aux antibiotiques et a peut-être besoin d'être traité pendant une période moyenne plus longue.