Establishing correlates of maternal-fetal cytomegalovirus transmission-one step closer through predictive modeling.

BACKGROUND: Determinants of maternal-fetal cytomegalovirus (CMV) transmission and factors influencing the severity of congenital CMV (cCMV) infection are not well understood. METHODS: We conducted a descriptive, multi-center study in pregnant women ≥18 years old with primary CMV infection and their newborns (NCT01251744) to explore maternal immune responses to CMV and determine potential immunologic/virologic correlates of cCMV following primary infection during pregnancy. We developed alternative approaches looking into univariate/multivariate factors associated with cCMV, including a participant clustering/stratification approach and an interpretable predictive model-based approach using trained decision trees for risk prediction (post-hoc analyses). RESULTS: Pregnant women were grouped in three distinct clusters with similar baseline characteristics, particularly gestational age at diagnosis. We observed a trend for higher viral loads in urine and saliva samples from mothers of infants with cCMV versus without cCMV. When using a trained predictive-model approach that accounts for interaction effects between variables, anti-pentamer IgG antibody concentration and viral load in saliva were identified as biomarkers jointly associated with the risk of maternal-fetal CMV transmission. CONCLUSION: We identified biomarkers of CMV maternal-fetal transmission. After validation in larger studies, our findings will guide the management of primary infection during pregnancy and the development of vaccines against cCMV.

The human cytomegalovirus (CMV) is common and usually causes no symptoms in healthy individuals. However, CMV infections can be life-threatening in individuals with improperly functioning or immature immune systems, such as fetuses. Women can become infected with CMV for the first time (primary infection) during pregnancy. If CMV is transmitted from mother to fetus before the second trimester, the infant can suffer from severe disorders such as hearing loss and delayed development. We aimed to identify characteristics of pregnant women with a primary CMV infection that may increase the likelihood of transmitting CMV to the fetus. We considered demographical, clinical, and behavioral characteristics, as well as immune responses and the quantity of virus detected in the women's blood, urine, saliva, and vaginal mucus. Because we could not identify one single characteristic that could predict a high risk of CMV transmission, we developed new data analysis models to study how they can be combined. We found that antibodies targeting a pentameric antigen of the virus envelope and the presence of virus in saliva can together predict the risk of CMV transmission from mother to fetus. Our results can help improve the care of CMV-infected pregnant women and the design of CMV vaccines.

Proactive Contact Tracing.

The COVID-19 pandemic has spurred an unprecedented demand for interventions that can reduce disease spread without excessively restricting daily activity, given negative impacts on mental health and economic outcomes. Digital contact tracing (DCT) apps have emerged as a component of the epidemic management toolkit. Existing DCT apps typically recommend quarantine to all digitally-recorded contacts of test-confirmed cases. Over-reliance on testing may, however, impede the effectiveness of such apps, since by the time cases are confirmed through testing, onward transmissions are likely to have occurred. Furthermore, most cases are infectious over a short period; only a subset of their contacts are likely to become infected. These apps do not fully utilize data sources to base their predictions of transmission risk during an encounter, leading to recommendations of quarantine to many uninfected people and associated slowdowns in economic activity. This phenomenon, commonly termed as "pingdemic," may additionally contribute to reduced compliance to public health measures. In this work, we propose a novel DCT framework, Proactive Contact Tracing (PCT), which uses multiple sources of information (e.g. self-reported symptoms, received messages from contacts) to estimate app users' infectiousness histories and provide behavioral recommendations. PCT methods are by design proactive, predicting spread before it occurs. We present an interpretable instance of this framework, the Rule-based PCT algorithm, designed via a multi-disciplinary collaboration among epidemiologists, computer scientists, and behavior experts. Finally, we develop an agent-based model that allows us to compare different DCT methods and evaluate their performance in negotiating the trade-off between epidemic control and restricting population mobility. Performing extensive sensitivity analysis across user behavior, public health policy, and virological parameters, we compare Rule-based PCT to i) binary contact tracing (BCT), which exclusively relies on test results and recommends a fixed-duration quarantine, and ii) household quarantine (HQ). Our results suggest that both BCT and Rule-based PCT improve upon HQ, however, Rule-based PCT is more efficient at controlling spread of disease than BCT across a range of scenarios. In terms of cost-effectiveness, we show that Rule-based PCT pareto-dominates BCT, as demonstrated by a decrease in Disability Adjusted Life Years, as well as Temporary Productivity Loss. Overall, we find that Rule-based PCT outperforms existing approaches across a varying range of parameters. By leveraging anonymized infectiousness estimates received from digitally-recorded contacts, PCT is able to notify potentially infected users earlier than BCT methods and prevent onward transmissions. Our results suggest that PCT-based applications could be a useful tool in managing future epidemics.

Human resource implications of expanding latent tuberculosis patient care activities.

Introduction: The World Health Organization (WHO) declared increasing services for latent tuberculosis infection (LTBI) a priority to eliminate tuberculosis (TB) by 2035. Yet, there is little information about thehuman resource needs required to implement LTBI treatment scale-up. Our study aimed to estimate the change in healthcare workers (HCW) time spent on different patient care activities, following an intervention to strengthen LTBI services. Methods: We conducted a time and motion (TAM) study, observing HCW throughout a typical workday before and after the intervention (Evaluation and Strengthening phases, respectively) at 24 health facilities in five countries. The precise time spent on pre-specified categories of work activities was recorded. Time spent on direct patient care was subcategorized as relating to one of three conditions: LTBI, active or suspected TB, and non-TB (i.e., patients with any other medical condition). A linear mixed model (LMM) was fit to estimate the change in HCW time following the intervention. Results: A total of 140 and 143 HCW participated in the TAMs during the Evaluation and Strengthening phases, respectively. Results from intervention facilities showed an increase of 9% (95% CI: 3%, 15%) in the proportion of HCW time spent on LTBI-related services, but with a corresponding change of -11% (95% CI: -21%, -1%) on active TB services. There was no change in the proportion of time spent on LTBI care in control facilities; this remained low in both phases of the study. Discussion: Our findings suggest that additional HCW personnel will be required for expansion of LTBI services to ensure that this expansion does not reduce the time available for care of active TB patients.

Effect of implementation of a 12-dose once-weekly treatment (3HP) in addition to standard regimens to prevent TB on completion rates: Interrupted time series design.

OBJECTIVES: We aimed to determine if offering a 12-dose once-weekly treatment (3HP) as an additional treatment option would result in an increase in the overall proportion of patients completing TB preventive treatment (TPT) above the baseline rate. METHODS: We analyzed outcomes in consecutive adults referred to a TB clinic from January 2010 to May 2019. Starting December 2016, 3HP was offered as an alternative to standard clinic regimens which included 9 months of daily isoniazid or 4 months of daily rifampin. The primary outcome was the proportion of patients who completed TPT among all patients who started treatment. Using segmented autoregression analysis, we compared completion at the end of the study with projected completion had the intervention not been introduced. RESULTS: A total of 2803 adults were referred for assessment over the study period. There was an absolute increase in completions among those who started a treatment of 19.0% at the end of the study between the observed intervention completion rate and the projected completion rate from the baseline study period (the completion rate had the 3HP intervention not been introduced) (76% observed vs 57% projected; 95% CI 6.6 to 31.4%; p = 0.004) and an absolute increase among those who were offered treatment (17.3%; 95% CI, 2.3 to 32.3%; p = 0.025). CONCLUSIONS: The introduction of 3HP for TPT as an alternative to the regular regimens offered resulted in a significant increase in the proportion of patients completing treatment. Our study provides evidence to support accelerated use of 3HP in Canada.

Tracking changes in national BCG vaccination policies and practices using the BCG World Atlas.

The BCG vaccine is a widely given vaccine against tuberculosis (TB), yet studies on effectiveness have shown considerable heterogeneity; as a result, BCG vaccine policies vary greatly across the globe and change across geography, and with time and disease burden. The recently updated third BCG World Atlas (www.bcgatlas.org) is a publicly available online database with information on BCG practices across 194 countries. This helpful resource has been used for over 10 years to support clinicians, TB researchers and TB vaccine development worldwide. Here, we summarise main findings from the third BCG Atlas' most recent update which included additional data collected around BCG strain type, vaccine stockouts and associated changes. Longitudinal analysis enables evaluation of changes in TB incidence over time, a method becoming more common in legislation interventions. A large number of countries in the BCG Atlas (156/194 countries) maintain universal neonatal BCG vaccination, of which 51 are considered low TB burden countries. We demonstrate the majority of countries who changed their national policy moved to targeted vaccination for high-risk groups, were in Europe and also had significant decreases in TB incidence both before and after policy change. Globally, the most common BCG strain continues to be the Danish strain, despite its worldwide manufacturing interruption in 2015. Substantial variation and disproportionality exists in which regions were most affected by stockouts between 2009 and 2019. Tracking and understanding the reasoning behind changes to national BCG practices and their impact on TB burden is critical for decision makers as they contemplate how to include BCG vaccination in future immunisation guidelines in low and high TB burden countries.

Effectiveness and cost-effectiveness of a health systems intervention for latent tuberculosis infection management (ACT4): a cluster-randomised trial.

BACKGROUND: Reaching the UN General Assembly High-Level Meeting on Tuberculosis target of providing tuberculosis preventive treatment to at least 30 million people by 2022, including 4 million children under the age of 5 years and 20 million other household contacts, will require major efforts to strengthen health systems. The aim of this study was to evaluate the effectiveness and cost-effectiveness of a health systems intervention to strengthen management for latent tuberculosis infection (LTBI) in household contacts of confirmed tuberculosis cases. METHODS: ACT4 was a cluster-randomised, open-label trial involving 24 health facilities in Benin, Canada, Ghana, Indonesia, and Vietnam randomly assigned to either a three-phase intervention (LTBI programme evaluation, local decision making, and strengthening activities) or control (standard LTBI care). Tuberculin and isoniazid were provided to control and intervention sites if not routinely available. Randomisation was stratified by country and restricted to ensure balance of index patients with tuberculosis by arm and country. The primary outcome was the number of household contacts who initiated tuberculosis preventive treatment at each health facility within 4 months of the diagnosis of the index case, recorded in the first or last 6 months of our 20-month study. To ease interpretation, this number was standardised per 100 newly diagnosed index patients with tuberculosis. Analysis was by intention to treat. Masking of staff at the coordinating centre and sites was not possible; however, those analysing data were masked to assignment of intervention or control. An economic analysis of the intervention was done in parallel with the trial. ACT4 is registered at ClinicalTrials.gov, NCT02810678. FINDINGS: The study was done between Aug 1, 2016, and March 31, 2019. During the first 6 months of the study the crude overall proportion of household contacts initiating tuberculosis preventive treatment out of those eligible at intervention sites was 0·21. After the implementation of programme strengthening activities, the proportion initiating tuberculosis preventive treatment increased to 0·35. Overall, the number of household contacts initiating tuberculosis preventive treatment per 100 index patients with tuberculosis increased between study phases in intervention sites (adjusted rate difference 60, 95% CI 4 to 116), while control sites showed no statistically significant change (-12, -33 to 10). There was a difference in rate differences of 72 (95% CI 10 to 134) contacts per 100 index patients with tuberculosis initiating preventive treatment associated with the intervention. The total cost for the intervention, plus LTBI clinical care per additional contact initiating treatment was estimated to be CA$1348 (range 724 to 9708). INTERPRETATION: A strategy of standardised evaluation, local decision making, and implementation of health systems strengthening activities can provide a mechanism for scale-up of tuberculosis prevention, particularly in low-income and middle-income countries. FUNDING: Canadian Institutes of Health Research.

Quality of tuberculosis care in high burden countries: the urgent need to address gaps in the care cascade.

Despite the high coverage of directly observed treatment short-course (DOTS), tuberculosis (TB) continues to affect 10.4 million people each year, and kills 1.8 million. High TB mortality, the large number of missing TB cases, the emergence of severe forms of drug resistance, and the slow decline in TB incidence indicate that merely expanding the coverage of TB services is insufficient to end the epidemic. In the era of the End TB Strategy, we need to think beyond coverage and start focusing on the quality of TB care that is routinely offered to patients in high burden countries, in both public and private sectors. In this review, current evidence on the quality of TB care in high burden countries, major gaps in the quality of care, and some novel efforts to measure and improve the quality of care are described. Based on systematic reviews on the quality of TB care or surrogates of quality (e.g., TB diagnostic delays), analyses of TB care cascades, and newer studies that directly measure quality of care, it is shown that the quality of care in both the public and private sector falls short of international standards and urgently needs improvement. National TB programs will therefore need to systematically measure and improve quality of TB care and invest in quality improvement programs.

The cascade of care in diagnosis and treatment of latent tuberculosis infection: a systematic review and meta-analysis.

BACKGROUND: WHO estimates that a third of the world's population has latent tuberculosis infection and that less than 5% of those infected are diagnosed and treated to prevent tuberculosis. We aimed to systematically review studies that report the steps from initial tuberculosis screening through to treatment for latent tuberculosis infection, which we call the latent tuberculosis cascade of care. We specifically aimed to assess the number of people lost at each stage of the cascade. METHODS: We did a systematic review and meta-analysis of study-level observational data. We searched MEDLINE (via OVID), Embase, and Health Star for observational studies, published between 1946 and April 12, 2015, that reported primary data for diagnosis and treatment of latent tuberculosis infection. We did meta-analyses using random and fixed effects analyses to identify percentages of patients with latent tuberculosis infection completing each step in the cascade. We also estimated pooled proportions in subgroups stratified by different characteristics of interest to assess risk factors for losses. RESULTS: We identified 58 studies, describing 70 distinct cohorts and 748 572 people. Steps in the cascade associated with greater losses included completion of testing (71·9% [95% CI 71·8-72·0] of people intended for screening), completion of medical evaluation (43·7% [42·5-44·9]), recommendation for treatment (35·0% [33·8-36·4]), and completion of treatment if started (18·8% [16·3-19·7]). Steps with fewer losses included receiving test results, referral for evaluation if test positive, and accepting to start therapy if recommended. Factors associated with fewer losses were immune-compromising medical indications, being part of contact investigations, and use of rifamycin-based regimens. INTERPRETATION: We identify major losses at several steps in the cascade of care for latent tuberculosis infection. Improvements in management of latent tuberculosis will need programmatic approaches to address the losses at each step in the cascade. FUNDERS: Canadian Institutes of Health Research.

Skin disorders among construction workers following Hurricane Katrina and Hurricane Rita: an outbreak investigation in New Orleans, Louisiana.

OBJECTIVES: To determine the extent and scope of the outbreak of skin eruptions, to identify the causes of the acute skin diseases, to identify risk factors for the conditions, and to reduce the dermatologic morbidity among workers repairing buildings damaged by Hurricane Katrina and Hurricane Rita. DESIGN: Retrospective cohort study. SETTING: Military base in New Orleans, Louisiana. PARTICIPANTS: Civilian construction workers living and working at a New Orleans military base between August 30, 2005, and October 3, 2005. Living conditions were mainly wooden huts and tents with limited sanitation facilities. MAIN OUTCOME MEASURES: Survey of risk factors, physical examination, skin biopsy specimens, and environmental investigation of the occupational and domiciliary exposures. RESULTS: Of 136 workers, 58 reported rash, yielding an attack rate of 42.6%. The following 4 clinical entities were diagnosed among 41 workers who had a physical examination (some had >1 diagnosis): 27 (65.9%) having papular urticaria, 8 (19.5%) having bacterial folliculitis, 6 (14.6%) having fiberglass dermatitis, and 2 (4.9%) having brachioradial photodermatitis. All diagnoses except brachioradial photodermatitis were confirmed by histopathologic examination. After adjusting for race/ethnicity and occupation, sleeping in previously flooded huts was statistically significantly (adjusted odds ratio, 20.4; 95% confidence interval, 5.9-70.2) associated with developing papular urticaria, the most common cause of rash in this cluster. CONCLUSIONS: We identified 4 distinct clinical entities, although most workers were diagnosed as having papular urticaria. Huts previously flooded as a result of the hurricanes and used for sleeping may have harbored mites, a likely source of papular urticaria. To reduce the morbidity of hurricane-related skin diseases, we suggest avoiding flooded areas, fumigating with an acaricide, and wearing protective clothing.