Routinized Syphilis Screening Among Men Living With Human Immunodeficiency Virus: A Stepped Wedge Cluster Randomized Controlled Trial.

BACKGROUND: We implemented an opt-out clinic-based intervention pairing syphilis tests with routine human immunodeficiency virus (HIV) viral load testing. The primary objective was to determine the degree to which this intervention increased the detection of early syphilis. METHODS: The Enhanced Syphilis Screening Among HIV-Positive Men (ESSAHM) Trial was a stepped wedge cluster-randomized controlled trial involving 4 urban HIV clinics in Ontario, Canada, from 2015 to 2017. The population was HIV-positive adult males. The intervention was standing orders for syphilis serological testing with viral loads, and control was usual practice. We obtained test results via linkage with the centralized provincial laboratory and defined cases using a standardized clinical worksheet and medical record review. We employed a generalized linear mixed model with a logit link to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of the intervention. RESULTS: A total of 3895 men were followed over 7471 person-years. The mean number of syphilis tests increased from 0.53 to 2.02 tests per person per year. There were 217 new diagnoses of syphilis (control, 81; intervention, 136), for which 147 (68%) were cases of early syphilis (control, 61 [75%]; intervention, 86 [63%]). The annualized proportion with newly detected early syphilis increased from 0.009 to 0.032 with implementation of the intervention; the corresponding time-adjusted OR was 1.25 (95% CI, .71-2.20). CONCLUSIONS: The implementation of standing orders for syphilis testing with HIV viral loads was feasible and increased testing, yet produced less-than-expected increases in case detection compared to past uncontrolled pre-post trials. CLINICAL TRIALS REGISTRATION: NCT02019043.

Derivation and Validation of Clinical Prediction Rules for COVID-19 Mortality in Ontario, Canada.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently causing a high-mortality global pandemic. The clinical spectrum of disease caused by this virus is broad, ranging from asymptomatic infection to organ failure and death. Risk stratification of individuals with coronavirus disease 2019 (COVID-19) is desirable for management, and prioritization for trial enrollment. We developed a prediction rule for COVID-19 mortality in a population-based cohort in Ontario, Canada. METHODS: Data from Ontario's provincial iPHIS system were extracted for the period from January 23 to May 15, 2020. Logistic regression-based prediction rules and a rule derived using a Cox proportional hazards model were developed and validated using split-halves validation. Sensitivity analyses were performed, with varying approaches to missing data. RESULTS: Of 21 922 COVID-19 cases, 1734 with complete data were included in the derivation set; 1796 were included in the validation set. Age and comorbidities (notably diabetes, renal disease, and immune compromise) were strong predictors of mortality. Four point-based prediction rules were derived (base case, smoking excluded, long-term care excluded, and Cox model-based). All displayed excellent discrimination (area under the curve for all rules > 0.92) and calibration (P > .50 by Hosmer-Lemeshow test) in the derivation set. All performed well in the validation set and were robust to varying approaches to replacement of missing variables. CONCLUSIONS: We used a public health case management data system to build and validate 4 accurate, well-calibrated, robust clinical prediction rules for COVID-19 mortality in Ontario, Canada. While these rules need external validation, they may be useful tools for management, risk stratification, and clinical trials.

Can enhanced screening of men with a history of prior syphilis infection stem the epidemic in men who have sex with men? A mathematical modelling study.

OBJECTIVES: The aim of this study is to determine the transmission impact of using prior syphilis infection to guide a focused syphilis screening intervention among men who have sex with men (MSM). METHODS: We parameterised a deterministic model of syphilis transmission in MSM to reflect the 2011-2015 syphilis outbreak in Winnipeg, Canada. Enhanced screening of 75% of men with prior syphilis every 3 months (A) was compared with distributing equivalent number tests to all MSM (B) or those with the highest partner number (C). We compared early syphilis incidence, diagnoses and prevalence after 10 years, relative to a base case of 30% of MSM screened annually. RESULTS: Strategy A was expected to avert 52% of incident infections, 44% of diagnosed cases and reduce early syphilis prevalence by 89%. Strategy B had the least impact. Strategy C was most effective, averting 59% of incident cases. When screening frequency was semiannual or annual, strategy A was the most effective. CONCLUSIONS: Enhanced screening of MSM with prior syphilis may efficiently reduce transmission, especially when identification of high-risk men via self-reported partner numbers or high-frequency screening is difficult to achieve.

Go big or go home: impact of screening coverage on syphilis infection dynamics.

OBJECTIVES: Syphilis outbreaks in urban men who have sex with men (MSM) are an ongoing public health challenge in many high-income countries, despite intensification of efforts to screen and treat at-risk individuals. We sought to understand how population-level coverage of asymptomatic screening impacts the ability to control syphilis transmission. METHODS: We developed a risk-structured deterministic compartmental mathematical model of syphilis transmission in a population of sexually active MSM. We assumed a baseline level of treatment of syphilis cases due to seeking medical care in all scenarios. We evaluated the impact of sustained annual population-wide screening coverage ranging from 0% to 90% on syphilis incidence over the short term (20 years) and at endemic equilibrium. RESULTS: The relationship between screening coverage and equilibrium syphilis incidence displayed an inverted U-shape relationship, with peak equilibrium incidence occurring with 20-30% annual screening coverage. Annual screening of 62% of the population was required for local elimination (incidence <1 case per 100 000 population). Results were qualitatively similar in the face of differing programmatic, behavioural and natural history assumptions, although the screening thresholds for local elimination differed. With 6-monthly or 3-monthly screening, the population coverage required to achieve local elimination was reduced to 39% or 23%, respectively. CONCLUSIONS: Although screening has the potential to control syphilis outbreaks, suboptimal coverage may paradoxically lead to a higher equilibrium infection incidence than that observed in the absence of intervention. Suboptimal screening programme design should be considered as a possible contributor to unsuccessful syphilis control programmes in the context of the current epidemic.

Cost-effectiveness of enhanced syphilis screening among HIV-positive men who have sex with men: a microsimulation model.

BACKGROUND: Syphilis co-infection risk has increased substantially among HIV-infected men who have sex with men (MSM). Frequent screening for syphilis and treatment of men who test positive might be a practical means of controlling the risk of infection and disease sequelae in this population. PURPOSE: We evaluated the cost-effectiveness of strategies that increased the frequency and population coverage of syphilis screening in HIV-infected MSM receiving HIV care, relative to current standard of care. METHODS: We developed a state-transition microsimulation model of syphilis natural history and medical care in HIV-infected MSM receiving care for HIV. We performed Monte Carlo simulations using input data derived from a large observational cohort in Ontario, Canada, and from published biomedical literature. Simulations compared usual care (57% of the population screened annually) to different combinations of more frequent (3- or 6-monthly) screening and higher coverage (100% screened). We estimated expected disease-specific outcomes, quality-adjusted survival, costs, and cost-effectiveness associated with each strategy from the perspective of a public health care payer. RESULTS: Usual care was more costly and less effective than strategies with more frequent or higher coverage screening. Higher coverage strategies (with screening frequency of 3 or 6 months) were expected to be cost-effective based on usually cited willingness-to-pay thresholds. These findings were robust in the face of probabilistic sensitivity analyses, alternate cost-effectiveness thresholds, and alternate assumptions about duration of risk, program characteristics, and management of underlying HIV. CONCLUSIONS: We project that higher coverage and more frequent syphilis screening of HIV-infected MSM would be a highly cost-effective health intervention, with many potentially viable screening strategies projected to both save costs and improve health when compared to usual care. The baseline requirement for regular blood testing in this group (i.e., for viral load monitoring) makes intensification of syphilis screening appear readily practicable.

Screen more or screen more often? Using mathematical models to inform syphilis control strategies.

BACKGROUND: Syphilis incidence among men who have sex with men (MSM) continues to rise despite attempts to increase screening and treatment uptake. We examined the marginal effect of increased frequency versus increased coverage of screening on syphilis incidence in Toronto, Canada. METHODS: We developed an agent-based, network model of syphilis transmission, representing a core population of 2,000 high-risk MSM. Epidemiological and biological parameters were drawn from regional surveillance data and literature-derived estimates. The pre-intervention period of the model was calibrated using surveillance data to identify 1000 credible simulations per strategy. Evaluated strategies included: annual syphilis screening at baseline coverage, increased screening frequency at baseline coverage, and increased coverage of annual screening. Intervention impact was measured as annual prevalence of detected infectious cases and syphilis incidence per year over 10 years. RESULTS: Of the strategies evaluated, increasing the frequency of syphilis screening to every three months was most effective in reducing reported and incident syphilis infections. Increasing the fraction of individuals tested, without increasing test frequency, resulted a smaller decline in incidence, because reductions in infectious syphilis via treatment were counterbalanced by increased incident syphilis among individuals with prior latent syphilis. For an equivalent number of additional tests performed annually, increased test frequency was consistently more effective than improved coverage. CONCLUSIONS: Strategies that focus on higher frequency of testing in smaller fractions of the population were more effective in reducing syphilis incidence in a simulated MSM population. The findings highlight how treatment-induced loss of immunity can create unexpected results in screening-based control strategies.

The impact of infection on population health: results of the Ontario burden of infectious diseases study.

BACKGROUND: Evidence-based priority setting is increasingly important for rationally distributing scarce health resources and for guiding future health research. We sought to quantify the contribution of a wide range of infectious diseases to the overall infectious disease burden in a high-income setting. METHODOLOGY/PRINCIPAL FINDINGS: We used health-adjusted life years (HALYs), a composite measure comprising premature mortality and reduced functioning due to disease, to estimate the burden of 51 infectious diseases and associated syndromes in Ontario using 2005-2007 data. Deaths were estimated from vital statistics data and disease incidence was estimated from reportable disease, healthcare utilization, and cancer registry data, supplemented by local modeling studies and national and international epidemiologic studies. The 51 infectious agents and associated syndromes accounted for 729 lost HALYs, 44.2 deaths, and 58,987 incident cases per 100,000 population annually. The most burdensome infectious agents were: hepatitis C virus, Streptococcus pneumoniae, Escherichia coli, human papillomavirus, hepatitis B virus, human immunodeficiency virus, Staphylococcus aureus, influenza virus, Clostridium difficile, and rhinovirus. The top five, ten, and 20 pathogens accounted for 46%, 67%, and 75% of the total infectious disease burden, respectively. Marked sex-specific differences in disease burden were observed for some pathogens. The main limitations of this study were the exclusion of certain infectious diseases due to data availability issues, not considering the impact of co-infections and co-morbidity, and the inability to assess the burden of milder infections that do not result in healthcare utilization. CONCLUSIONS/SIGNIFICANCE: Infectious diseases continue to cause a substantial health burden in high-income settings such as Ontario. Most of this burden is attributable to a relatively small number of infectious agents, for which many effective interventions have been previously identified. Therefore, these findings should be used to guide public health policy, planning, and research.

Discrete choice experiment produced estimates of acceptable risks of therapeutic options in cancer patients with febrile neutropenia.

OBJECTIVE: To use a discrete choice experiment (DCE) to describe patient/proxy tolerance for the number of clinic visits, and chances of readmission, intensive care unit admission, and mortality to accept oral outpatient management of low-risk febrile neutropenia. STUDY DESIGN AND SETTING: Adults and children aged 12-18 years with cancer and parents of pediatric cancer patients were asked to choose between outpatient oral and inpatient intravenous management of low-risk febrile neutropenia. Using a DCE, we varied the attribute levels with the outpatient option and kept them constant for the inpatient option. RESULTS: Seventy-eight adults, 153 parents, and 43 children provided responses. All four attributes significantly affected choices. The mean tolerance (95% confidence interval) for the number of clinic visits per week was 3.6 (2.2-4.8), 2.1 (1.1-3.2), and 4.3 (2.5-6.0) to accept outpatient management among adults, parents, and children, respectively. With thrice weekly clinic visits and 7.5% chance of readmission, probabilities of accepting the outpatient strategy were 50% (44-54%) for adults, 43% (39-48%) for parents, and 53% (46-59%) for children. CONCLUSION: Using a DCE, we determined that a 7.5% chance of readmission and clinic visits more frequently than thrice weekly are unlikely to be acceptable.

Estimation of the burden of disease and costs of genital Chlamydia trachomatis infection in Canada.

BACKGROUND: Rates of Chlamydia trachomatis (CT) infection in Canada have been increasing since the mid-1990s. We sought to estimate the burden of CT in this population. METHODS: We developed an age- and sex-structured mathematical model parameterized to reproduce trends in CT prevalence between 1991 and 2009 in the Canadian population aged 10 to 39 years. Costs were identified, measured, and valued using a modified societal perspective and converted to year 2009 Canadian dollars. Cost-effectiveness of the implemented policy of enhanced screening for asymptomatic infections was estimated by comparison with model-projected trends in the absence of increased screening. Main outcome measures were current net cost and burden of illness attributable to CT infection, and incremental cost-effectiveness ratios. RESULTS: Under base case model assumptions, there was a trend of increasing detection of CT cases (due to increases in screening), despite an underlying stabilization of actual CT infections. Average estimated costs associated with CT infection over this period were $51.4 million per year. Costs of screening and treatment of asymptomatic infections as a proportion of total CT costs were estimated to have increased over time, whereas costs of long-term sequelae associated with untreated infections declined over the same period. Compared with no change in screening, enhanced screening was estimated to be highly cost-effective, with an incremental cost-effectiveness ratio of $2910 per quality-adjusted life year. CONCLUSIONS: Despite increases in screening, the economic burden of CT in Canada remains high. Further investigation of trends in chlamydia-associated complications is required to better understand the impact of screening on incidence.

Relative risk of cervical cancer in indigenous women in Australia, Canada, New Zealand, and the United States: a systematic review and meta-analysis.

We performed a systematic review and meta-analysis of cervical cancer risk in indigenous women in Australia, Canada, New Zealand, and the United States, in order to identify whether risks of cervical dysplasia, cervical cancer, and cervical cancer-related mortality are higher in indigenous relative to non-indigenous populations. We identified 35 studies published in 1969-2008. In our findings, indigenous populations did not have an elevated risk of cervical dysplasia or carcinoma in situ relative to non-indigenous populations, but had elevated risks of invasive cervical cancer (pooled RR=1.72) and cervical cancer-related mortality (pooled RR=3.45). There was a log-linear relationship between relative risk and disease stage. In conclusion, the indigenous women have a markedly higher risk of cervical cancer morbidity and mortality than non-indigenous women, but no increased risk of early-stage disease, suggesting that structural, social, or individual barriers to screening, rather than baseline risk factors, are influencing poor health outcomes.

Pertussis resurgence in Toronto, Canada: a population-based study including test-incidence feedback modeling.

BACKGROUND: Pertussis continues to challenge medical professionals; recently described increases in incidence may be due to age-cohort effects, vaccine effectiveness, or changes in testing patterns. Toronto, Canada has recently experienced increases in pertussis incidence, and provides an ideal jurisdiction for evaluating pertussis epidemiology due to centralized testing. We evaluated pertussis trends in Toronto using all available specimen data, which allowed us to control for changing testing patterns and practices. METHODS: Data included all pertussis culture and PCR test records for Greater Toronto from 1993 to 2007. We estimated incidence trends using Poisson regression models; complex relationships between disease incidence and test submission were explored with vector autoregressive models. RESULTS: From 1993 to 2007, 26988 specimens were submitted for testing; 2545 (9.4%) were positive. Pertussis incidence was 2 per 100,000 from 1993 to 2004 and increased to 10 per 100,000 from 2005-2007, with a concomitant 6-fold surge in test specimen submissions after the introduction of a new, more sensitive PCR assay. The relative change in incidence was less marked after adjustment for testing volumes. Bidirectional feedbacks between test positivity and test submissions were identified. CONCLUSIONS: Toronto's recent surge in pertussis reflects a true increase in local disease activity; the apparent size of the outbreak has likely been magnified by increasing use of pertussis testing by clinicians, and by improved test sensitivity since 2005. These findings may be applicable to changes in pertussis epidemiology that have been noted elsewhere in North America.

The laboratory impact of changing syphilis screening from the rapid-plasma reagin to a treponemal enzyme immunoassay: a case-study from the Greater Toronto Area.

BACKGROUND: In 2005, syphilis screening in the Greater Toronto Area of Canada moved from the rapid plasma reagin (RPR) to a treponemal enzyme immunoassay (EIA). We sought to understand the consequences of this change on laboratory results and testing patterns with a population-based retrospective study of laboratory-based diagnoses of syphilis. METHODS: Samples positive under RPR (1998-2005) and EIA (2005-2008) screening were confirmed with an alternate treponemal test, and during the latter period underwent RPR testing. We compared monthly rates and the forecasting relationship between positives and future submissions with time-series methods, and assessed risk factors for EIA(+)/RPR(-) results using Poisson regression. RESULTS: A total of 3,092,938 submissions were included. Following EIA implementation, confirmed positive rates increased by 10.3 per 100,000 population (P<0.001). 0.59% of EIA(+)/RPR(-) individuals converted to RPR(+) within 2 months. EIA(+)/RPR(-) patients were more likely to be male (incidence rate ratio [IRR]: 2.3, 95% confidence interval [CI]: 1.6-2.5), asymptomatic (IRR: 1.8, 95% CI: 1.3-2.8), and aged>50 years (IRR: 2.4, 95% CI: 1.6-3.5) than those with EIA(+)/RPR(+) results. We detected a significant positive feedback loop between positive tests and subsequent submissions. This relationship was only transiently evident for EIA(+)/RPR(-) results up to 1 year following the changeover. CONCLUSIONS: EIA screening facilitates identification of probable latent syphilis and earlier serological detection of infectious syphilis, but may transiently cause increases in testing and indirectly suggests that physicians' interpretation of RPR(-) serology may lead to partner testing. In the absence of a true gold standard, implementation of EIA screening warrants careful communication regarding serological interpretation.

Derivation and validation of a clinical prediction rule for nosocomial pneumonia after coronary artery bypass graft surgery.

BACKGROUND: Nosocomial pneumonia is an important cause of morbidity and mortality among surgical patients in the United States. The emergence of effective but potentially costly or risky preventive interventions makes perioperative risk stratification desirable. We sought to develop a prediction rule for pneumonia after coronary artery bypass grafting (CABG), a common surgical procedure. METHODS: Data on individuals undergoing CABG at 32 hospitals in 6 states were extracted from Tenet Healthcare's Quality and Resource Management System. A logistic regression-based prediction rule was developed in half of the study sample and validated in the remaining patients. RESULTS: Of 17,143 individuals undergoing CABG from January 1999 through February 2004, 361 (2%) developed pneumonia without a known aspiration etiology. Thirteen independent predictors of pneumonia were identified in the derivation subset of the sample: body mass index <18.5 (defined as the weight in kilograms divided by the square of the height in meters), smoking history, admission from a nonresidential setting, cancer history, chronic obstructive pulmonary disease, Canadian Cardiovascular Society score 3, prior internal mammary artery CABG, emergency status, serum creatinine level >1.2 mg/dL, percutaneous transluminal coronary angioplasty, blood transfusion, preoperative vancomycin administration, and receipt of mechanical ventilation for >1 day. The model-based rule was well calibrated (Hosmer-Lemeshow X(2)=5.51; P=.70) and demonstrated good discrimination (area under the receiver-operating characteristic curve [ROC AUC], 0.78) in the derivation group. Discriminatory ability was also reasonable in the validation cohort (ROC AUC, 0.75; P=.18, for difference in ROC AUC between groups). CONCLUSIONS: Using a large cohort of patients treated at community and teaching hospitals, we derived and validated a prediction rule for pneumonia after CABG. This index may prove to be useful in prioritizing receipt of preventive interventions.

Let the sun shine in: effects of ultraviolet radiation on invasive pneumococcal disease risk in Philadelphia, Pennsylvania.

BACKGROUND: Streptococcus pneumoniae is a common cause of community acquired pneumonia and bacteremia. Excess wintertime mortality related to pneumonia has been noted for over a century, but the seasonality of invasive pneumococcal disease (IPD) has been described relatively recently and is poorly understood. Improved understanding of environmental influence on disease seasonality has taken on new urgency due to global climate change. METHODS: We evaluated 602 cases of IPD reported in Philadelphia County, Pennsylvania, from 2002 to 2007. Poisson regression models incorporating seasonal smoothers were used to identify associations between weekly weather patterns and case counts. Associations between acute (day-to-day) environmental fluctuations and IPD occurrence were evaluated using a case-crossover approach. Effect modification across age and sex strata was explored, and meta-regression models were created using stratum-specific estimates for effect. RESULTS: IPD incidence was greatest in the wintertime, and spectral decomposition revealed a peak at 51.0 weeks, consistent with annual periodicity. After adjustment for seasonality, yearly increases in reporting, and temperature, weekly incidence was found to be associated with clear-sky UV index (IRR per unit increase in index: 0.70 [95% CI 0.54-0.91]). The effect of UV index was highest among young strata and decreased with age. At shorter time scales, only an association with increases in ambient sulphur oxides was linked to disease risk (OR for highest tertile of exposure 0.75, 95% CI 0.60 to 0.93). CONCLUSION: We confirmed the wintertime predominance of IPD in a major urban center. The major predictor of IPD in Philadelphia is extended periods of low UV radiation, which may explain observed wintertime seasonality. The mechanism of action of diminished light exposure on disease occurrence may be due to direct effects on pathogen survival or host immune function via altered 1,25-(OH)2-vitamin-D metabolism. These findings may suggest less diminution in future IPD risk with climate change than would be expected if wintertime seasonality was driven by temperature.

Of gastro and the gold standard: evaluation and policy implications of norovirus test performance for outbreak detection.

BACKGROUND: The norovirus group (NVG) of caliciviruses are the etiological agents of most institutional outbreaks of gastroenteritis in North America and Europe. Identification of NVG is complicated by the non-culturable nature of this virus, and the absence of a diagnostic gold standard makes traditional evaluation of test characteristics problematic. METHODS: We evaluated 189 specimens derived from 440 acute gastroenteritis outbreaks investigated in Ontario in 2006-07. Parallel testing for NVG was performed with real-time reverse-transcriptase polymerase chain reaction (RT2-PCR), enzyme immunoassay (EIA) and electron microscopy (EM). Test characteristics (sensitivity and specificity) were estimated using latent class models and composite reference standard methods. The practical implications of test characteristics were evaluated using binomial probability models. RESULTS: Latent class modelling estimated sensitivities of RT2-PCR, EIA, and EM as 100%, 86%, and 17% respectively; specificities were 84%, 92%, and 100%; estimates obtained using a composite reference standard were similar. If all specimens contained norovirus, RT2-PCR or EIA would be associated with > 99.9% likelihood of at least one test being positive after three specimens tested. Testing of more than 5 true negative specimens with RT2-PCR would be associated with a greater than 50% likelihood of a false positive test. CONCLUSION: Our findings support the characterization of EM as lacking sensitivity for NVG outbreaks. The high sensitivity of RT2-PCR and EIA permit identification of NVG outbreaks with testing of limited numbers of clinical specimens. Given risks of false positive test results, it is reasonable to limit the number of specimens tested when RT2-PCR or EIA are available.

Environmental exposures and invasive meningococcal disease: an evaluation of effects on varying time scales.

Invasive meningococcal disease (IMD) is an important cause of meningitis and bacteremia worldwide. Seasonal variation in IMD incidence has long been recognized, but mechanisms responsible for this phenomenon remain poorly understood. The authors sought to evaluate the effect of environmental factors on IMD risk in Philadelphia, Pennsylvania, a major urban center. Associations between monthly weather patterns and IMD incidence were evaluated using multivariable Poisson regression models controlling for seasonal oscillation. Short-term weather effects were identified using a case-crossover approach. Both study designs control for seasonal factors that might otherwise confound the relation between environment and IMD. Incidence displayed significant wintertime seasonality (for oscillation, P < 0.001), and Poisson regression identified elevated monthly risk with increasing relative humidity (per 1% increase, incidence rate ratio = 1.04, 95% confidence interval: 1.004, 1.08). Case-crossover methods identified an inverse relation between ultraviolet B radiation index 1-4 days prior to onset and disease risk (odds ratio = 0.54, 95% confidence interval: 0.34, 0.85). Extended periods of high humidity and acute changes in ambient ultraviolet B radiation predict IMD occurrence in Philadelphia. The latter effect may be due to decreased pathogen survival or virulence and may explain the wintertime seasonality of IMD in temperate regions of North America.