Can BCG be useful to mitigate the COVID-19 pandemic? A Canadian perspective.

There is ample evidence from in vitro, animal and human studies that the Bacillus Calmette-Guerin (BCG) vaccine epigenetically reprograms innate immunity to provide "off target" protection against pathogens other than mycobacteria. This process has been termed "trained immunity". Although recent ecological studies suggested an association between BCG policies and the frequency or severity of COVID-19 in different countries, the interpretation of these results is challenging. For this reason, a case-control study aiming to test this hypothesis has been initiated in Quebec. Several phase III clinical trials are underway, including one in Canada, to assess the efficacy of BCG against SARS-CoV-2 infection (results expected in 2021). In the past, BCG has been widely used in Canada but current indications are restricted to high-risk individuals and communities experiencing TB outbreaks as well as for the treatment of bladder cancer. The potential implication of BCG as an interim measure to mitigate COVID-19 is the subject of widespread discussion in the scientific community and can be considered for the vulnerable population in Canada. To conclude, BCG vaccination should be placed on the agenda of research funding agencies, scientific advisory committees on immunization and federal/provincial/territorial public health authorities.

RéSUMé: Il existe de nombreuses preuves issues d'études in vitro, chez l'animal et chez l'humain qui montrent que le vaccin bacillaire de Calmette et Guérin (BCG) peut reprogrammer de manière épigénétique l'immunité naturelle et procurer ainsi une protection « hors-cible ¼ contre des pathogènes autres que les mycobactéries. Ce processus a été appelé « immunité entraînée ¼. Bien que des études écologiques récentes aient suggéré l'existence d'une association entre les politiques d'utilisation du BCG et la fréquence ou sévérité de la COVID-19 dans différents pays, l'interprétation de leurs résultats est difficile. Pour cette raison, une étude cas-témoin a été entreprise au Québec en vue de tester cette hypothèse. Plusieurs essais cliniques de Phase III sont en cours, dont un au Canada, pour évaluer l'efficacité du BCG contre les infections causées par le SRAS-CoV-2 (résultats attendus en 2021). Dans le passé, le BCG a été utilisé à large échelle au Canada, mais actuellement, les indications sont limitées aux individus à haut risque et aux communautés dans lesquelles se produisent des éclosions de tuberculose, ainsi que pour le traitement du cancer de la vessie. L'intérêt potentiel du BCG en tant que mesure intérimaire pour contrôler la COVID-19 fait l'objet de discussions intenses dans la communauté scientifique et cela pourrait être envisagé pour des populations vulnérables au Canada. Pour conclure, la vaccination avec le BCG devrait être placée sur l'agenda des organismes de recherche, des comités scientifiques consultatifs et des autorités de santé publique fédérale, provinciales et territoriales.

Pediatric Pleural Empyema in the Province of Quebec: Analysis of a 10-Fold Increase Between 1990 and 2007.

BACKGROUND: Although the frequency of pneumonia has decreased over time, an increase in pleural empyema has been observed in different settings worldwide. This study assessed the epidemiology of community-acquired pediatric pleural empyema in the province of Quebec through validation of cases found in a hospitalization discharge database. METHODS: We used the national administrative database of hospitalization to identify children (6 months-14 years) hospitalized for pleural empyema or pleural effusion with drainage from January 1990 until December 2007 and reviewed their medical charts. Patients with pleural effusion secondary to chest trauma, thoracic surgery, malignancies, cardiac failure, or metabolic disorders were excluded. RESULTS: Predictive positive value (PPV) of empyema code in any position among discharge diagnostics in the administrative database was 86.5% (95% confidence interval: 81.9%-90.3%). After chart revision, 292 met the inclusion criteria. Age-adjusted incidence of pleural empyema in the pediatric population increased from 0.23 in 1990 to 4.01/100,000 person-years in 2007. A bacterial pathogen was identified in 46.5%; Streptococcus pneumoniae (Sp) (42%) and S pyogenes (30%) were most frequent. There was no obvious change in the PPV and proportions of children with chronic disease or asthma and in identified pathogens over time, but an increase in pre-admission respiratory symptoms duration (from 3.8 days to 5.7) and nonsteroidal anti-inflammatory drug use (from 0% to 19%) was observed. CONCLUSIONS: From 1990 to 2007, we observed a 10-fold increase in the incidence of pediatric hospitalizations associated with pleural empyema. This increase preceded the introduction of a pneumococcal conjugated vaccine program in Quebec. Sp remained the major pathogen identified.

Factors associated with HPV vaccination among adult women in Quebec.

BACKGROUND AND OBJECTIVE: Human papillomavirus (HPV) infections are the most common sexually transmitted infections in North America and are associated with cervical cancer. A publicly-funded HPV immunization program was launched in the province of Quebec, Canada, in the fall of 2008. The aim of this study was to explore factors associated with HPV immunization among young adult women not targeted by this program. METHODS: A questionnaire was mailed to 2400 24-y-old women randomly selected from the Quebec provincial health insurance database and 56% responded. Factors associated with vaccination status were analyzed using a multivariate logistic regression model. RESULTS: Few women had received at least one dose of HPV vaccine among the 1347 respondents. Age at first sexual intercourse ≥ 20 y, participating in cervical cancer screening, higher education level, being born in Quebec and some positive beliefs about HPV were associated with vaccination. CONCLUSIONS: The rate of immunization in women who had to pay for the HPV vaccine was very low and was associated with characteristics that are generally associated with a lower risk for HPV infection and cervical cancer. Efforts are needed to reach at-risk adult women.

Biopsychosocial determinants of pregnancy length and fetal growth.

The causes and mechanisms related to preterm delivery and intrauterine growth restriction are poorly understood. Our objective was to assess the direct and indirect effects of psychosocial and biomedical factors on the duration of pregnancy and fetal growth. A self-administered questionnaire was distributed to pregnant women attending prenatal ultrasound clinics in nine hospitals in the Montérégie region in the province of Quebec, Canada, from November 1997 to May 1998. Prenatal questionnaires were linked with birth certificates. Theoretical models explaining pregnancy length and fetal growth were developed and tested, using path analysis. In order to reduce the number of variables from the questionnaire, a principal component analysis was performed, and the three most important new dimensions were retained as explanatory variables in the final models. Data were available for 1602 singleton pregnancies. The biophysical score, covering both maternal age and the pre-pregnancy body mass index, was the only variable statistically associated with pregnancy length. Smoking, obstetric history, maternal health and biophysical indices were direct predictors of fetal growth. Perceived stress, social support and self-esteem were not directly related to pregnancy outcomes, but were determinants of smoking and the above-mentioned biomedical variables. More studies are needed to identify the mechanisms by which adverse psychosocial factors are translated into adverse biological effects.

Estimating the number needed to vaccinate to prevent diseases and death related to human papillomavirus infection.

BACKGROUND: A vaccine against human papillomavirus (HPV) types 6, 11, 16 and 18 is now licensed for use in Canada and many other countries. We sought to estimate the number needed to vaccinate to prevent HPV-related diseases and death. METHODS: A cohort model of the natural history of HPV infection was developed. Model simulations were based on 209 different parameter sets that reproduced Canadian HPV type-specific data for infection, cervical intraepithelial neoplasia, cervical cancer and genital warts. The number needed to vaccinate was calculated as the number of women who would need to be vaccinated to prevent an HPV-related event during their lifetime. RESULTS: Among 12-year-old girls, we estimated that the number needed to vaccinate to prevent an episode of genital warts would be 8 (80% credibility interval [CrI] 5-15) and a case of cervical cancer 324 (80% CrI 195-757). These estimates were based on the assumption that the vaccine procures lifelong protection and that its efficacy is 95%. If vaccine protection is assumed to wane at 3% per year, the predicted number needed to vaccinate would increase to 14 (80% CrI 6-18) and 9080 (80% CrI 1040-does not prevent), respectively. The latter number would be greatly reduced with the addition of a booster dose, to 480 (80% CrI 254-1572). INTERPRETATION: Our model predictions suggest that vaccination with the currently available HPV vaccine may significantly reduce the incidence of genital warts, cervical intraepithelial neoplasia and cervical cancer. However, the benefits (particularly in terms of cervical cancer reduction) are highly dependent on the duration of vaccine protection, on which evidence is currently limited.

Reduction in neural-tube defects after folic acid fortification in Canada.

BACKGROUND: In 1998, folic acid fortification of a large variety of cereal products became mandatory in Canada, a country where the prevalence of neural-tube defects was historically higher in the eastern provinces than in the western provinces. We assessed changes in the prevalence of neural-tube defects in Canada before and after food fortification with folic acid was implemented. METHODS: The study population included live births, stillbirths, and terminations of pregnancies because of fetal anomalies among women residing in seven Canadian provinces from 1993 to 2002. On the basis of published results of testing of red-cell folate levels, the study period was divided into prefortification, partial-fortification, and full-fortification periods. We evaluated the relationship between baseline rates of neural-tube defects in each province and the magnitude of the decrease after fortification was implemented. RESULTS: A total of 2446 subjects with neural-tube defects were recorded among 1.9 million births. The prevalence of neural-tube defects decreased from 1.58 per 1000 births before fortification to 0.86 per 1000 births during the full-fortification period, a 46% reduction (95% confidence interval, 40 to 51). The magnitude of the decrease was proportional to the prefortification baseline rate in each province, and geographical differences almost disappeared after fortification began. The observed reduction in rate was greater for spina bifida (a decrease of 53%) than for anencephaly and encephalocele (decreases of 38% and 31%, respectively). CONCLUSIONS: Food fortification with folic acid was associated with a significant reduction in the rate of neural-tube defects in Canada. The decrease was greatest in areas in which the baseline rate was high.

The potential cost-effectiveness of prophylactic human papillomavirus vaccines in Canada.

AIM: Clinical trials have shown prophylactic human papillomavirus (HPV) vaccines to be effective against infection and disease. We examined whether HPV vaccination has the potential to be cost-effective. METHODS: A cohort model of the natural history of HPV was developed, which fits simultaneously Canadian age and type-specific data for infection, cervical intraepithelial neoplasia, cervical cancer (CC) and genital warts (GW). Quality-Adjusted Life-Years (QALYs) lost and costs were estimated using data from the literature. RESULTS: Vaccinating 12-year-old girls (efficacy=95%, no waning, cost/course=CAN$ 400) against HPV-16/18 and HPV-6/11/16/18 is estimated to cost the health provider CAN$ 31,000 (80%CrI: 15,000-55,000) and CAN$ 21,000 (80%CrI: 11,000-33,000) per QALY-gained, respectively. Results were most sensitive to age at vaccination, duration of vaccine protection, vaccine cost and QALY-lost due to GW, and were least sensitive to the medical costs. CONCLUSION: Vaccinating adolescent girls against HPV is likely to be cost-effective. The main benefit of vaccination will be in reducing CC mortality. However, unless screening is modified, the treatment costs saved through vaccination will be insignificant compared to the cost of HPV immunization.

Validity of death and stillbirth certificates and hospital discharge summaries for the identification of neural tube defects in Quebec City.

The objectives of this study were 1) to assess the validity of different databases which identify neural tube defect (NTD) cases in the population, and 2) to examine the temporal trends in NTD rates and the impact of prenatal diagnoses among pregnancies referred to a tertiary care hospital in Quebec City, Canada, from 1993 to 2002. Infant death and stillbirth certificates were a highly reliable source for ascertaining NTD cases, but their overall sensitivity was poor (13 percent). Med-Echo had very good sensitivity (92 percent), but there were many coding errors in the database and some diagnostic categories were not specific for NTD. The average NTD prevalence proportion was 6.5/1,000 births during the entire study period, decreasing from 12.2/1,000 in 1993 to 3.9/1,000 in 2002. Overall, 78.6 percent of NTD cases were diagnosed prenatally and the pregnancy was terminated in 52.6 percent of these. These two proportions were stable over the study years. To conclude, the combination of hospital discharge summaries and infant death and stillbirth certificates is a highly sensitive method for the ascertainment of NTD cases, including terminations of pregnancies, but medical records must be reviewed to exclude coding errors and to clarify unspecific diagnostic categories.

Trend in prevalence of neural tube defects in Quebec.

BACKGROUND: In Canada, the first recommendations on the use of folic acid (FA) supplements by women planning a pregnancy or capable of becoming pregnant were issued in 1993. In 1998, fortification of flour with FA became mandatory. The objective of this study was to assess the impact of these measures on the prevalence of neural tube defects (NTDs) in the province of Quebec. METHODS: The study population included stillbirths, live births, and elective terminations for fetal malformations that were reported in 1992-2000 for women residing in the province of Quebec. NTD cases were identified from stillbirth certificates and hospital discharge summaries. RESULTS: There was a marked decrease in the total NTD rate after 1997. The average NTD rate was 1.89 per 1000 total births during the period of 1992-1997, and 1.28 per 1000 in 1998-2000, a 32% reduction (p < 0.001). CONCLUSIONS: Fortification of flour, which began in early 1997 and gradually became widespread, is a very plausible explanation for the timing, shape, and magnitude of the decrease in NTD prevalence observed in Quebec and other Canadian provinces. An increase in FA supplement use may have played only a minor role. Birth Defects Research (Part A) 67:000-000, 2003.

Pregnancy planning: a determinant of folic acid supplements use for the primary prevention of neural tube defects.

OBJECTIVE: Daily consumption of supplements containing 400 micrograms of folic acid in the periconception period may reduce the risk of neural tube defects (NTDs) by as much as 70%. However, despite explicit recommendations, folic acid consumption among women likely to become pregnant remains low. The objectives of this study were: to evaluate women's knowledge and beliefs with regard to folic acid; to estimate the frequency of vitamin supplement consumption; and to identify its determinants during the periconception period. METHODS: In 1999-2000, a questionnaire was completed by 1,240 pregnant women in 10 Quebec hospitals. RESULTS: Seventy percent of the respondents were aware of the preventive role of folic acid but only 25% had taken the recommended dose of supplements during the periconception period. Supplement consumption is associated with the pregnancy planning intensity score (OR: 1.06; 95% CI: 1.02-1.11), knowledge score (OR: 1.11; 95% CI: 1.07-1.16) and belief in the usefulness of supplements (OR: 1.56; 95% CI: 1.02-2.39). CONCLUSION: These results indicate that further efforts are needed to inform the population and promote the optimal use of folic acid supplements.

Pregnancy planning and folic acid supplement use: results from a survey in Quebec.

BACKGROUND: To decrease the risk of neural tube defects, all women planning pregnancy or capable of becoming pregnant should take folic acid supplements. The aim of the study was to describe the association between pregnancy planning and vitamin supplement use. METHODS: A total of 1,858 pregnant women registered for a prenatal ultrasound examination in the Montérégie region, Province of Quebec, Canada, completed a questionnaire between November 1997 and May 1998. Pregnancy planning was described by six ordinal variables, which were included in a nonlinear principal component analysis. The main dimension representing the intensity of pregnancy planning was used as the dependent variable in a multivariate linear regression model, and as a basis for assessing vitamin use according to four levels of planning. RESULTS: A majority of women scored high for intensity of pregnancy planning. Planning intensity score increased with age and was higher among women who attended university, had a family income greater than CAD $30,000, and were married. Vitamin use in the period prior to conception occurred with a frequency of 27.5%, increasing moderately with planning intensity scores. Overall, only 13.5% of fetuses were exposed to adequate doses of folic acid. CONCLUSION: A promotion campaign selectively targeting women likely to plan a pregnancy could have a significant impact in reducing neural tube defect incidence.