James A. Dickinson

Association between the 2008-09 seasonal influenza vaccine and pandemic H1N1 illness during Spring-Summer 2009: four observational studies from Canada.

BACKGROUND In late spring 2009, concern was raised in Canada that prior vaccination with the 2008-09 trivalent inactivated influenza vaccine (TIV) was associated with increased risk of pandemic influenza A (H1N1) (pH1N1) illness. Several epidemiologic investigations were conducted through the summer to assess this putative association. METHODS AND FINDINGS STUDIES INCLUDED (1) test-negative case-control design based on Canadas sentinel vaccine effectiveness monitoring system in British Columbia, Alberta, Ontario, and Quebec; (2) conventional case-control design using population controls in Quebec; (3) test-negative case-control design in Ontario; and (4) prospective household transmission (cohort) study in Quebec. Logistic regression was used to estimate odds ratios for TIV effect on community- or hospital-based laboratory-confirmed seasonal or pH1N1 influenza cases compared to controls with restriction, stratification, and adjustment for covariates including combinations of age, sex, comorbidity, timeliness of medical visit, prior physician visits, and/or health care worker (HCW) status. For the prospective study risk ratios were computed. Based on the sentinel study of 672 cases and 857 controls, 2008-09 TIV was associated with statistically significant protection against seasonal influenza (odds ratio 0.44, 95% CI 0.33-0.59). In contrast, estimates from the sentinel and three other observational studies, involving a total of 1,226 laboratory-confirmed pH1N1 cases and 1,505 controls, indicated that prior receipt of 2008-09 TIV was associated with increased risk of medically attended pH1N1 illness during the spring-summer 2009, with estimated risk or odds ratios ranging from 1.4 to 2.5. Risk of pH1N1 hospitalization was not further increased among vaccinated people when comparing hospitalized to community cases. CONCLUSIONS Prior receipt of 2008-09 TIV was associated with increased risk of medically attended pH1N1 illness during the spring-summer 2009 in Canada. The occurrence of bias (selection, information) or confounding cannot be ruled out. Further experimental and epidemiological assessment is warranted. Possible biological mechanisms and immunoepidemiologic implications are considered.

Low 2012–13 Influenza Vaccine Effectiveness Associated with Mutation in the Egg-Adapted H3N2 Vaccine Strain Not Antigenic Drift in Circulating Viruses

Background Influenza vaccine effectiveness (VE) is generally interpreted in the context of vaccine match/mismatch to circulating strains with evolutionary drift in the latter invoked to explain reduced protection. During the 2012–13 season, however, detailed genotypic and phenotypic characterization shows that low VE was instead related to mutations in the egg-adapted H3N2 vaccine strain rather than antigenic drift in circulating viruses. Methods/Findings Component-specific VE against medically-attended, PCR-confirmed influenza was estimated in Canada by test-negative case-control design. Influenza A viruses were characterized genotypically by amino acid (AA) sequencing of established haemagglutinin (HA) antigenic sites and phenotypically through haemagglutination inhibition (HI) assay. H3N2 viruses were characterized in relation to the WHO-recommended, cell-passaged vaccine prototype (A/Victoria/361/2011) as well as the egg-adapted strain as per actually used in vaccine production. Among the total of 1501 participants, influenza virus was detected in 652 (43%). Nearly two-thirds of viruses typed/subtyped were A(H3N2) (394/626; 63%); the remainder were A(H1N1)pdm09 (79/626; 13%), B/Yamagata (98/626; 16%) or B/Victoria (54/626; 9%). Suboptimal VE of 50% (95%CI: 33–63%) overall was driven by predominant H3N2 activity for which VE was 41% (95%CI: 17–59%). All H3N2 field isolates were HI-characterized as well-matched to the WHO-recommended A/Victoria/361/2011 prototype whereas all but one were antigenically distinct from the egg-adapted strain as per actually used in vaccine production. The egg-adapted strain was itself antigenically distinct from the WHO-recommended prototype, and bore three AA mutations at antigenic sites B [H156Q, G186V] and D [S219Y]. Conversely, circulating viruses were identical to the WHO-recommended prototype at these positions with other genetic variation that did not affect antigenicity. VE was 59% (95%CI:16–80%) against A(H1N1)pdm09, 67% (95%CI: 30–85%) against B/Yamagata (vaccine-lineage) and 75% (95%CI: 29–91%) against B/Victoria (non-vaccine-lineage) viruses. Conclusions These findings underscore the need to monitor vaccine viruses as well as circulating strains to explain vaccine performance. Evolutionary drift in circulating viruses cannot be regulated, but influential mutations introduced as part of egg-based vaccine production may be amenable to improvements.

Effectiveness of AS03 adjuvanted pandemic H1N1 vaccine: case-control evaluation based on sentinel surveillance system in Canada, autumn 2009

Objective To assess the effectiveness of the pandemic influenza A/H1N1 vaccine used in Canada during autumn 2009. Design Test negative incident case-control study based on sentinel physician surveillance system. Setting Community based clinics contributing to sentinel networks in British Columbia, Alberta, Ontario, and Quebec, Canada. Participants 552 patients who presented to a sentinel site within seven days of onset of influenza-like illness during the primary analysis period between 8 November and 5 December 2009; participants were mostly (>80%) children and adults under 50 years old. Interventions Monovalent AS03 adjuvanted pandemic influenza A/H1N1 vaccine as the predominant formulation (>95%) distributed in Canada. Main outcome measures Vaccine effectiveness calculated as 1−(odds ratio for influenza in vaccinated (received pandemic H1N1 vaccine at least two weeks before onset of influenza-like illness) versus unvaccinated participants), with adjustment for age, comorbidity, province, timeliness of specimen collection, and week of illness onset. Sensitivity analyses explored the influence of varying analysis periods between 1 November and 31 December, receipt of trivalent seasonal influenza vaccine, and restriction to participants without comorbidity. Results During the primary analysis period, pandemic H1N1 was detected by reverse transcription polymerase chain reaction in 209/552 (38%) participants; rates were highest in children and young adults (40%) and lowest in people aged 65 or over (9%). Among the 209 cases, 35 (17%) reported comorbidity compared with 80/343 (23%) controls. Two (1%) cases had received pandemic H1N1 vaccine at least two weeks before the onset of illness, compared with 58/343 (17%) controls, all single dose. Adjusted vaccine effectiveness overall was 93% (95% confidence interval 69% to 98%). High estimates of vaccine protection—generally at least 90%—were maintained across most sensitivity analyses. Conclusions Although limited by a small number of vaccine failures, this study suggests that the monovalent AS03 adjuvanted vaccine used in Canada during autumn 2009 was highly effective in preventing medically attended, laboratory confirmed pandemic H1N1 illness, with reference in particular to a single dose in children and young adults.

Recommendations on screening for cervical cancer

cervical cancer were diagnosed in Canada, with about 350 deaths. The number of cases of diagnosed cervical cancer in creases among women aged 25 years and older, peaking during the fifth decade of life (Figure 1). The incidence of and mortality due to cervical cancer in Canada have decreased substantially in the past 50 years, and long-term survival rates after treatment are high. Lifetime incidence was 1.5% in 1972, and is now 0.7%; risk of death from cervical cancer is now 0.2%. Most advanced cervical cancer (and associated mortality) occurs among women who have never undergone screening or who have had a long interval between Papanicolaou (Pap) tests. Screening for cervival cancer using the Pap test detects precursor lesions, thereby allowing earlier and potentially less invasive treatment than is re quired for disease that causes symptoms. The benefits of such screening on the incidence of invasive disease and death due to cervical cancer have been consistently shown in cohort and case–control studies. It is likely that much of the change seen in the incidence of cervical cancer in Canada is due to screening, but early and frequent (often annual) cervical screening is unnecessary: other countries have achieved similar outcomes with less frequent testing and starting screening at older ages. The similar levels of success with different approaches highlights uncertainties regarding the best ages at which to start and stop screening, screening intervals and screening methods. Furthermore, the benefits of screening must be balanced against its potential harms, such as additional follow-up tests for abnormal results and unnecessary treatment (e.g., owing to false -positives and overdiagnosis). The likelihood of abnormal Pap test results is highest for young women, and decreases with increasing age. Because the prevalence of highgrade abnormalities declines steadily with age, al though the incidence of cancer is higher, the proportion of abnormal results that represent serious abnormalities is greater among older women. Women whose initial Pap test result is abnormal may be asked to undergo a repeat test or have a colposcopy. The colposcopist may then biopsy the cervix. If the biopsy shows cervical intra epithelial neoplasia, the colposcopist may then treat the cervix by excising the transformation zone using various methods. These procedures cause short-term pain, bleeding and discharge, and may cause early loss of future pregnancies or premature labour. It is likely that many of these procedures can be considered overtreatment, because fewer than one-third of even high-grade abnormalities progress to cancer. This guideline provides updated recommendations for screening for cervical cancer in Canada based on new information about the epidemiology and diagnosis of cervical cancer and a new systematic search of the literature. This guideline updates the recommendations of the Canadian Task Force on Preventive Health Care that were last revised in 1994. Recommendations are presented for the use of Pap tests for women with no symptoms of cervical cancer who are or who have been sexually active, regardless of sexual orientation. Separate recommendations are provided for screening in women in the following age categories: younger than 20 years, 20–24 years, 25–29 years, 30– 69 years and 70 years or older. Re com mend ations Recommendations on screening for cervical cancer

A Sentinel Platform to Evaluate Influenza Vaccine Effectiveness and New Variant Circulation, Canada 2010–2011 Season

BACKGROUND During the 2010-2011 winter, a large number of outbreaks due to influenza A/H3N2 at long-term care facilities, including higher-than-expected attack rates among vaccinated staff, were reported in some regions of Canada. Interim analysis from the community-based sentinel surveillance system showed circulating H3N2 variants and suboptimal vaccine effectiveness (VE), assessed here for the entire seasons data set. METHODS Nasal/nasopharyngeal swabs and epidemiologic details were collected from patients presenting to sentinel sites within 7 days of onset of influenza-like illness. Cases tested positive for influenza by real-time reverse-transcription polymerase chain reaction; controls tested negative. Odds ratios for medically attended, laboratory-confirmed influenza in vaccinated vs nonvaccinated participants were used to derive adjusted VE. Viruses were characterized by hemagglutination inhibition (HI), and the hemagglutinin genes of a subset were sequenced to explore vaccine relatedness. RESULTS Final 2010-2011 VE analysis included 1718 participants (half aged 20-49 years), 93 with A(H1N1)pdm09, 408 with A/H3N2, and 199 with influenza B. Among adults aged 20-49 years, adjusted VE was 65% (95% confidence interval [CI], 8%-87%) for A(H1N1)pdm09 and 66% (95% CI, 10%-87%) for influenza B. Vaccine effectiveness was substantially lower for A/H3N2, at 39% (95% CI, 0%-63%). Phylogenetic analysis identified 2 circulating H3N2 variant clades, A/HongKong/2121/2010 (87%) and A/Victoria/208/2009 (11%), bearing multiple amino acid substitutions at antigenic sites (12 and 8, respectively) compared with the H3N2 vaccine component used in Canada (A/Victoria/210/2009[NYMC X-187]). However, HI characterized all H3N2 isolates as well matched to the vaccine. CONCLUSIONS Public health observations of increased facility H3N2 outbreaks were consistent with the sentinel networks detection of genetic variants and suboptimal VE but not with conventional HI characterization. We highlight the utility of a multicomponent sentinel surveillance platform that incorporates genotypic, phenotypic, and epidemiologic indicators into the assessment of influenza virus, new variant circulation, vaccine relatedness, and VE.

Recommendations on screening for depression in adults

See related commentary by Bland and Streiner on page [753][1] and at [www.cmaj.ca/lookup/doi/10.1503/cmaj.130634][2] Depression is a mood disorder that affects the way a person feels, thinks or behaves, which may impair social or occupational functioning.[1][3] The onset of depression can be

Recommendations on screening for type 2 diabetes in adults.

ans (6.8%) had either type 1 or type 2 diabetes, and an additional 480 000 (1.4%) were unaware that they were affected. The most recent Canadian data indicate that, from 1998/99 to 2008/09, the prevalence of diagnosed diabetes increased by 70% (Figure 1). The greatest relative increase in prevalence was seen in the age groups 35–39 and 40–44 years, in which the proportion doubled. In 2008/09, almost 50% of people with newly diagnosed diabetes were 45–64 years old (Figure 2). Substantial increases in prevalence are projected over the next decade. Because type 1 diabetes is much less common than type 2 diabetes and is generally symptomatic, we focused on type 2 diabetes in these guidelines. Laboratory values used to define the diagnosis of diabetes have become more inclusive over time (Appendix 1). In 2002, a new diagnostic category (now commonly known as prediabetes) was created to describe patients at very high risk of diabetes. More recently, glycated hemoglobin (herein referred to as A1C), which reflects an individual’s average plasma glucose level over the previous 2–3 months, has been accepted as an alternative diagnostic test for type 2 diabetes. Long-term consequences of type 2 diabetes include microvascular (retinopathy, nephropathy, neuropathy) and macrovascular (stroke, myocardial infarction) complications. An estimated 65%–80% of people with diabetes will die of a cardiovascular event, many without prior signs or symptoms of cardiovascular disease. Type 2 diabetes is a prevalent and costly chronic illness that demands lifestyle interventions, effective monitoring and pharmacologic management. Management of risk factors, including physical inactivity, blood pressure and blood lipid levels as well as blood glucose levels, is required to prevent long-term complications. Uncertainties remain about how best to prevent diabetes, the relative benefits of population screening and risk assessment, the ideal frequency of screening in high-risk populations and the potential harms of screening. This document updates the 2005 Canadian Task Force on Preventive Health Care recommendations on screening asymptomatic adults for type 2 diabetes. It does not apply to people with symptoms of diabetes or those who are at risk of type 1 diabetes.

A Perfect Storm: Impact of Genomic Variation and Serial Vaccination on Low Influenza Vaccine Effectiveness During the 2014–2015 Season

Using an integrated surveillance platform, we incorporated genetic, antigenic, and epidemiologic indicators to evaluate agent–host factors that contributed to low vaccine effectiveness during the 2014–2015 influenza season, including variation in the viral genome and negative effects of serial vaccination.

Recommendations on screening for prostate cancer with the prostate-specific antigen test

See related commentary on page [1201][1] and at [www.cmaj.ca/lookup/doi/10.1503/cmaj.141252][2] Prostate cancer is the most commonly diagnosed non–skin cancer in men and the third leading cause of cancer-related death among men in Canada.[1][3] The current estimated lifetime risk of diagnosis is

Recommendations on screening for colorectal cancer in primary care

340 CMAJ, March 15, 2016, 188(5) ©2016 8872147 Canada Inc. or its licensors Colorectal cancer is the second most common cause of cancer-related death in men and the third most common in women;1 the lifetime probabilities of dying from colorectal cancer among men and women are 3.5% and 3.1%, respectively.2 Although the burden of colorectal cancer varies across Canada,3 it is estimated that 25 000 Canadians received a diagnosis of colorectal cancer in 2015 (incidence 49 per 100 000 population) and that 9300 will die from the disease (mortality 17 per 100 000).1 The incidence and mortality of colorectal cancer are low until middle age and rise rapidly thereafter (Figure 1).1,4 Most colorectal cancers appear to arise from colonic polyps that develop slowly and sometimes transform to cancers.5 This is the ration ale for screening programs that aim to reduce deaths due to colorectal cancer by detecting and removing polyps and/or early-stage colorectal cancers. Implementation of organized screening programs in some Canadian provinces has been associated with an increase in the number of individuals screened,6 and other provinces are in the process of implementing such programs (Appendix 1, available at www.cmaj.ca/lookup/ suppl/doi:10.1503/cmaj.151125/-/DC1). Currently, all Canadian programs recommend screening with guaiac fecal occult blood testing (gFOBT) or fecal immunochemical testing (FIT). This guideline presents recommendations for screening for colorectal cancer in asymptomatic adults aged 50 years and older who are not at high risk for colorectal cancer, and it updates previous Canadian Task Force on Preventive Health Care recommendations from 2001.7 The 2001 guideline recommended annual or biennial FOBT (grade A recommendation) and flexible sigmoidoscopy every five years (grade B recommendation) in asymptomatic people older than 50 years. The guideline did not recommend whether these screening modalities should be used alone or in combination (grade C),7,8 or whether to include or exclude colonoscopy as an initial screening test for colorectal cancer. Given the major changes in technology and practice since 2001, the guideline has been updated based on the most recent data available to provide guidance for primary care practitioners on different screening tests, screening intervals and recommended ages to start and stop screening.