Systematic Review and Meta-Analysis of Sex Differences in Social Contact Patterns and Implications for Tuberculosis Transmission and Control.

Social contact patterns might contribute to excess burden of tuberculosis in men. We conducted a study of social contact surveys to evaluate contact patterns relevant to tuberculosis transmission. Available data describe 21 surveys in 17 countries and show profound differences in sex-based and age-based patterns of contact. Adults reported more adult contacts than children. Children preferentially mixed with women in all surveys (median sex assortativity 58%, interquartile range [IQR] 57%-59% for boys, 61% [IQR 60%-63%] for girls). Men and women reported sex-assortative mixing in 80% and 95% of surveys (median sex assortativity 56% [IQR 54%-58%] for men, 59% [IQR 57%-63%] for women). Sex-specific patterns of contact with adults were similar at home and outside the home for children; adults reported greater sex assortativity outside the home in most surveys. Sex assortativity in adult contacts likely contributes to sex disparities in adult tuberculosis burden by amplifying incidence among men

Sex Differences in Tuberculosis Burden and Notifications in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis

BACKGROUND: Tuberculosis (TB) case notification rates are usually higher in men than in women, but notification data are insufficient to measure sex differences in disease burden. This review set out to systematically investigate whether sex ratios in case notifications reflect differences in disease prevalence and to identify gaps in access to and/or utilisation of diagnostic services. METHODS AND FINDINGS: In accordance with the published protocol (CRD42015022163), TB prevalence surveys in nationally representative and sub-national adult populations (age ≥ 15 y) in low- and middle-income countries published between 1 January 1993 and 15 March 2016 were identified through searches of PubMed, Embase, Global Health, and the Cochrane Database of Systematic Reviews; review of abstracts; and correspondence with the World Health Organization. Random-effects meta-analyses examined male-to-female (M:F) ratios in TB prevalence and prevalence-to-notification (P:N) ratios for smear-positive TB. Meta-regression was done to identify factors associated with higher M:F ratios in prevalence and higher P:N ratios. Eighty-three publications describing 88 surveys with over 3.1 million participants in 28 countries were identified (36 surveys in Africa, three in the Americas, four in the Eastern Mediterranean, 28 in South-East Asia and 17 in the Western Pacific). Fifty-six surveys reported in 53 publications were included in quantitative analyses. Overall random-effects weighted M:F prevalence ratios were 2.21 (95% CI 1.92-2.54; 56 surveys) for bacteriologically positive TB and 2.51 (95% CI 2.07-3.04; 40 surveys) for smear-positive TB. M:F prevalence ratios were highest in South-East Asia and in surveys that did not require self-report of signs/symptoms in initial screening procedures. The summary random-effects weighted M:F ratio for P:N ratios was 1.55 (95% CI 1.25-1.91; 34 surveys). We intended to stratify the analyses by age, HIV status, and rural or urban setting; however, few studies reported such data. CONCLUSIONS: TB prevalence is significantly higher among men than women in low- and middle-income countries, with strong evidence that men are disadvantaged in seeking and/or accessing TB care in many settings. Global strategies and national TB programmes should recognise men as an underserved high-risk group and improve men's access to diagnostic and screening services to reduce the overall burden of TB more effectively and ensure gender equity in TB care

Evidence of Rickettsia and Orientia Infections Among Abattoir Workers in Djibouti.

Of 49 workers at a Djiboutian abattoir, eight (16%, 95% confidence interval [CI]: 9-29) were seropositive against spotted fever group rickettsiae (SFGR), two (4%, 95% CI: 1-14) against typhus group rickettsiae, and three (6%, 95% CI: 2-17) against orientiae. One worker (9%, 95% CI: 2-38) seroconverted against orientiae during the study period. This is the first evidence of orientiae exposure in the Horn of Africa. SFGR were also identified by polymerase chain reaction in 32 of 189 (11%, 95% CI: 8-15) tick pools from 26 of 72 (36%) cattle. Twenty-five (8%, 95% CI: 6-12) tick pools were positive for Rickettsia africae, the causative agent of African tick-bite fever. Health-care providers in Djibouti should be aware of the possibility of rickettsiae infections among patients, although further research is needed to determine the impact of these infections in the country

Speech and communication in Parkinson’s disease: a cross-sectional exploratory study in the UK

Objective: To assess associations between cognitive status, intelligibility, acoustics and functional communication in PD. Design: Cross-sectional exploratory study of functional communication, including a within-participants experimental design for listener assessment. Setting: A major academic medical centre in the East of England, UK. Participants: Questionnaire data were assessed for 45 people with Parkinson’s disease (PD), who had self-reported speech or communication difficulties and did not have clinical dementia. Acoustic and listener analyses were conducted on read and conversational speech for 20 people with PD and 20 familiar conversation partner controls without speech, language or cognitive difficulties. Main outcome measures: Functional communication assessed by the Communicative Participation Item Bank (CPIB) and Communicative Effectiveness Survey (CES). Results: People with PD had lower intelligibility than controls for both the read (mean difference 13.7%, p=0.009) and conversational (mean difference 16.2%, p=0.04) sentences. Intensity and pause were statistically significant predictors of intelligibility in read sentences. Listeners were less accurate identifying the intended emotion in the speech of people with PD (14.8% point difference across conditions, p=0.02) and this was associated with worse speaker cognitive status (16.7% point difference, p=0.04). Cognitive status was a significant predictor of functional communication using CPIB (F=8.99, p=0.005, η2 = 0.15) but not CES. Intelligibility in conversation sentences was a statistically significant predictor of CPIB (F=4.96, p=0.04, η2 = 0.19) and CES (F=13.65, p=0.002, η2 = 0.43). Read sentence intelligibility was not a significant predictor of either outcome. Conclusions: Cognitive status was an important predictor of functional communication—the role of intelligibility was modest and limited to conversational and not read speech. Our results highlight the importance of focusing on functional communication as well as physical speech impairment in speech and language therapy (SLT) for PD. Our results could inform future trials of SLT techniques for PD

Inequalities in the impact of COVID-19-associated disruptions on tuberculosis diagnosis by age and sex in 45 high TB burden countries

Background: Tuberculosis remains a major public health priority and is the second leading cause of mortality from infectious disease worldwide. TB case detection rates are unacceptably low for men, the elderly and children. Disruptions in TB services due to the COVID-19 pandemic may have exacerbated these and other inequalities. Methods: We modelled trends in age- and sex- disaggregated case notifications for all forms of new and relapse TB reported to the World Health Organization for 45 high TB, TB/HIV and MDR-TB burden countries from 2013 to 2019. We compared trend predicted notifications to observed notifications in 2020 to estimate the number of people with TB likely to have missed or delayed diagnosis. We estimated the risk ratio (RR) of missed or delayed TB diagnosis for children (aged < 15 years) or the elderly (aged ≥ 65 years) compared to adults (aged 15–64 years) and women compared to men (both aged ≥ 15 years) using a random-effects meta-analysis. Results: An estimated 195,449 children (95% confidence interval, CI: 189,673–201,562, 37.8% of an expected 517,168), 1,126,133 adults (CI: 1,107,146–1,145,704, 21.8% of an expected 5,170,592) and 235,402 elderly (CI: 228,108–243,202, 28.5% of an expected 826,563) had a missed or delayed TB diagnosis in 2020. This included 511,546 women (CI: 499,623–523,869, 22.7%, of an expected 2,250,097) and 863,916 men (CI: 847,591–880,515, 23.0% of an expected 3,763,363). There was no evidence globally that the risk of having TB diagnosis missed or delayed was different for children and adults (RR: 1.09, CI: 0.41–2.91), the elderly and adults (RR: 1.40, CI: 0.62–3.16) or men and women (RR: 0.59, CI: 0.25–1.42). However, there was evidence of disparities in risk by age and/or sex in some WHO regions and in most countries. Conclusions: There is no evidence at an aggregate global level of any difference by age or sex in the risk of disruption to TB diagnosis as a result of the COVID-19 pandemic. However, in many countries, disruptions in TB services have been greater for some groups than others. It is important to recognise these context-specific inequalities when prioritising key populations for catch-up campaigns

A four-month gatifloxacin-containing regimen for treating tuberculosis.

BACKGROUND: Shortening the course of treatment for tuberculosis would be a major improvement for case management and disease control. This phase 3 trial assessed the efficacy and safety of a 4-month gatifloxacin-containing regimen for treating rifampin-sensitive pulmonary tuberculosis. METHODS: We conducted a noninferiority, randomized, open-label, controlled trial involving patients 18 to 65 years of age with smear-positive, rifampin-sensitive, newly diagnosed pulmonary tuberculosis in five sub-Saharan African countries. A standard 6-month regimen that included ethambutol during the 2-month intensive phase was compared with a 4-month regimen in which gatifloxacin (400 mg per day) was substituted for ethambutol during the intensive phase and was continued, along with rifampin and isoniazid, during the continuation phase. The primary efficacy end point was an unfavorable outcome (treatment failure, recurrence, or death or study dropout during treatment) measured 24 months after the end of treatment, with a noninferiority margin of 6 percentage points, adjusted for country. RESULTS: A total of 1836 patients were assigned to the 4-month regimen (experimental group) or the standard regimen (control group). Baseline characteristics were well balanced between the groups. At 24 months after the end of treatment, the adjusted difference in the risk of an unfavorable outcome (experimental group [21.0%] minus control group [17.2%]) in the modified intention-to-treat population (1356 patients) was 3.5 percentage points (95% confidence interval, -0.7 to 7.7). There was heterogeneity across countries (P=0.02 for interaction, with differences in the rate of an unfavorable outcome ranging from -5.4 percentage points in Guinea to 12.3 percentage points in Senegal) and in baseline cavitary status (P=0.04 for interaction) and body-mass index (P=0.10 for interaction). The standard regimen, as compared with the 4-month regimen, was associated with a higher dropout rate during treatment (5.0% vs. 2.7%) and more treatment failures (2.4% vs. 1.7%) but fewer recurrences (7.1% vs. 14.6%). There was no evidence of increased risks of prolongation of the QT interval or dysglycemia with the 4-month regimen. CONCLUSIONS: Noninferiority of the 4-month regimen to the standard regimen with respect to the primary efficacy end point was not shown. (Funded by the Special Program for Research and Training in Tropical Diseases and others; ClinicalTrials.gov number, NCT00216385.)

Durations of asymptomatic, symptomatic, and care-seeking phases of tuberculosis disease with a Bayesian analysis of prevalence survey and notification data

This work was supported by the Wellcome Trust (206575/Z/17/Z to PM, 200901/Z/16/Z to ELC) and the UK MRC (MR/P022081/1 to PJD). This UK funded award (PJD) is part of the EDCTP2 programme supported by the European Union. KCH is supported by the European Research Council (757699) and UK FCDO (“Leaving no-one behind: transforming gendered pathways to health for TB”). This research has been partially funded by UK aid from the UK government (to KCH).Background Ratios of bacteriologically positive tuberculosis (TB) prevalence to notification rates are used to characterise typical durations of TB disease. However, this ignores the clinical spectrum of tuberculosis disease and potentially long infectious periods with minimal or no symptoms prior to care-seeking. Methods We developed novel statistical models to estimate progression from initial bacteriological positivity including smear conversion, symptom onset and initial care-seeking. Case-detection ratios, TB incidence, durations, and other parameters were estimated by fitting the model to tuberculosis prevalence survey and notification data (one subnational and 11 national datasets) within a Bayesian framework using Markov chain Monte Carlo methods. Results Analysis across 11 national datasets found asymptomatic tuberculosis durations in the range 4–8 months for African countries; three countries in Asia (Cambodia, Lao PDR, and Philippines) showed longer durations of > 1 year. For the six countries with relevant data, care-seeking typically began half-way between symptom onset and notification. For Kenya and Blantyre, Malawi, individual-level data were available. The sex-specific durations of asymptomatic bacteriologically-positive tuberculosis were 9.0 months (95% credible interval [CrI]: 7.2–11.2) for men and 8.1 months (95% CrI: 6.2–10.3) for women in Kenya, and 4.9 months (95% CrI: 2.6–7.9) for men and 3.5 months (95% CrI: 1.3–6.2) for women in Blantyre. Age-stratified analysis of data for Kenya showed no strong age-dependence in durations. For Blantyre, HIV-stratified analysis estimated an asymptomatic duration of 1.3 months (95% CrI: 0.3–3.0) for HIV-positive people, shorter than the 8.5 months (95% CrI: 5.0–12.7) for HIV-negative people. Additionally, case-detection ratios were higher for people living with HIV than HIV-negative people (93% vs 71%). Conclusion Asymptomatic TB disease typically lasts around 6 months. We found no evidence of age-dependence, but much shorter durations among people living with HIV, and longer durations in some Asian settings. To eradicate TB transmission, greater gains may be achieved by proactively screening people without symptoms through active case finding interventions.Peer reviewe

Inequalities in the impact of COVID-19-associated disruptions on tuberculosis diagnosis by age and sex in 45 high TB burden countries

BACKGROUND: Tuberculosis remains a major public health priority and is the second leading cause of mortality from infectious disease worldwide. TB case detection rates are unacceptably low for men, the elderly and children. Disruptions in TB services due to the COVID-19 pandemic may have exacerbated these and other inequalities. METHODS: We modelled trends in age- and sex- disaggregated case notifications for all forms of new and relapse TB reported to the World Health Organization for 45 high TB, TB/HIV and MDR-TB burden countries from 2013 to 2019. We compared trend predicted notifications to observed notifications in 2020 to estimate the number of people with TB likely to have missed or delayed diagnosis. We estimated the risk ratio (RR) of missed or delayed TB diagnosis for children (aged &lt; 15 years) or the elderly (aged ≥ 65 years) compared to adults (aged 15-64 years) and women compared to men (both aged ≥ 15 years) using a random-effects meta-analysis. RESULTS: An estimated 195,449 children (95% confidence interval, CI: 189,673-201,562, 37.8% of an expected 517,168), 1,126,133 adults (CI: 1,107,146-1,145,704, 21.8% of an expected 5,170,592) and 235,402 elderly (CI: 228,108-243,202, 28.5% of an expected 826,563) had a missed or delayed TB diagnosis in 2020. This included 511,546 women (CI: 499,623-523,869, 22.7%, of an expected 2,250,097) and 863,916 men (CI: 847,591-880,515, 23.0% of an expected 3,763,363). There was no evidence globally that the risk of having TB diagnosis missed or delayed was different for children and adults (RR: 1.09, CI: 0.41-2.91), the elderly and adults (RR: 1.40, CI: 0.62-3.16) or men and women (RR: 0.59, CI: 0.25-1.42). However, there was evidence of disparities in risk by age and/or sex in some WHO regions and in most countries. CONCLUSIONS: There is no evidence at an aggregate global level of any difference by age or sex in the risk of disruption to TB diagnosis as a result of the COVID-19 pandemic. However, in many countries, disruptions in TB services have been greater for some groups than others. It is important to recognise these context-specific inequalities when prioritising key populations for catch-up campaigns

Impact of Reversion of Mycobacterium tuberculosis Immunoreactivity Tests on the Estimated Annual Risk of Infection

A key metric in tuberculosis epidemiology is the annual risk of infection (ARI), which is usually derived from tuberculin skin test (TST) and interferon-gamma release assay (IGRA) prevalence surveys in children. Deriving the ARI assumes that immunoreactivity is persistent over time; however, reversion of immunoreactivity has long been documented. Here we use a deterministic, compartmental model of Mycobacterium tuberculosis (Mtb) infection to explore the impact of reversion on ARI estimation using age-specific reversion probabilities for TST and IGRA. Using empirical data of TST reversion (22.2%/year for 0-19yo), the true ARI is 2-5 times higher than estimated from immunoreactivity studies in 8-12 year-olds. Applying empirical reversion probabilities for IGRA (9.9%/year for 12-18yo) showed a 1.5-2-fold underestimation. ARIs are increasingly underestimated in older populations, due to the cumulative impact of reversion on population reactivity over time. Declines in annual risk did not largely affect the results. Ignoring reversion leads to a stark underestimation of the true ARI in populations and our interpretation of Mtb transmission intensity. Future surveys should adjust for reversion probabilities and its cumulative effect with increasing age to provide a more accurate reflection of the burden and dynamics of Mtb infection

Viral etiology, seasonality and severity of hospitalized patients with severe acute respiratory infections in the Eastern Mediterranean Region, 2007-2014.

INTRODUCTION: Little is known about the role of viral respiratory pathogens in the etiology, seasonality or severity of severe acute respiratory infections (SARI) in the Eastern Mediterranean Region. METHODS: Sentinel surveillance for SARI was conducted from December 2007 through February 2014 at 20 hospitals in Egypt, Jordan, Oman, Qatar and Yemen. Nasopharyngeal and oropharyngeal swabs were collected from hospitalized patients meeting SARI case definitions and were analyzed for infection with influenza, respiratory syncytial virus (RSV), adenovirus (AdV), human metapneumovirus (hMPV) and human parainfluenza virus types 1-3 (hPIV1-3). We analyzed surveillance data to calculate positivity rates for viral respiratory pathogens, describe the seasonality of those pathogens and determine which pathogens were responsible for more severe outcomes requiring ventilation and/or intensive care and/or resulting in death. RESULTS: At least one viral respiratory pathogen was detected in 8,753/28,508 (30.7%) samples tested for at least one pathogen and 3,497/9,315 (37.5%) of samples tested for all pathogens-influenza in 3,345/28,438 (11.8%), RSV in 3,942/24,503 (16.1%), AdV in 923/9,402 (9.8%), hMPV in 617/9,384 (6.6%), hPIV1 in 159/9,402 (1.7%), hPIV2 in 85/9,402 (0.9%) and hPIV3 in 365/9,402 (3.9%). Multiple pathogens were identified in 501/9,316 (5.4%) participants tested for all pathogens. Monthly variation, indicating seasonal differences in levels of infection, was observed for all pathogens. Participants with hMPV infections and participants less than five years of age were significantly less likely than participants not infected with hMPV and those older than five years of age, respectively, to experience a severe outcome, while participants with a pre-existing chronic disease were at increased risk of a severe outcome, compared to those with no reported pre-existing chronic disease. CONCLUSIONS: Viral respiratory pathogens are common among SARI patients in the Eastern Mediterranean Region. Ongoing surveillance is important to monitor changes in the etiology, seasonality and severity of pathogens of interest