Treatment outcomes for multidrug- and rifampicin-resistant tuberculosis in Central and West Africa: a systematic review and meta-analysis.

OBJECTIVES: We aimed to investigate published data on treatment outcomes of multidrug-resistant (MDR)/rifampicin-resistant tuberculosis (TB) in Central and West Africa because these, to the best of our knowledge, are sparsely available. METHODS: Systematic review and meta-analysis. RESULTS: A total of 14 studies were included, representing 4268 individuals in 14 of the 26 countries. Using a random-effects model meta-analysis, we observed a pooled success rate of 80.8% (95% confidence interval [CI] 56.0-93.3) for the Central African subgroup and 69.2% (95% CI 56.3-79.7) for the West African subgroup (P = 0.0522). The overall treatment success for all studies was 74.6% (95% CI 65.0-82.2). We found high heterogeneity among included studies (I2 = 96.1%). The estimated proportion of successfully treated individuals with MDR/rifampicin-resistant TB was considerably higher than the global estimate provided by the World Health Organization (59%), reaching the 2015 World Health Organization target of at least 75% treatment success for MDR-TB. CONCLUSION: The use of shorter treatment regimens and the standardized treatment conditions, including directly observed therapy in these studies, could have contributed to a high treatment success. Yet, the available literature was not fully representative of the regions, possibly highlighting the sparse resources in many of these countries. The review was registered at PROSPERO (https://www.crd.york.ac.uk/prospero/) (CRD42022353163).

Seroprevalence of anti-SARS-CoV-2 antibodies after the first wave of the COVID-19 pandemic in a vulnerable population in France: a cross-sectional study.

OBJECTIVES: We aimed to assess the level of prior SARS-CoV-2 infection in socially deprived neighbourhoods after the first wave of the pandemic, and to identify factors associated with seropositivity. DESIGN: A cross-sectional study. SETTING: Three socially deprived neighbourhoods of the city of Perpignan, in the south of France, where large settled Roma communities live. PARTICIPANTS: People aged 6 years old or over, living in the study area. 700 people were included in the study using two-stage stratified sampling design. INTERVENTIONS: The study included a questionnaire and SARS-CoV-2 antibody testing by the Roche Elecsys immunoassay between 29 June and 17 July 2020. PRIMARY AND SECONDARY OUTCOME MEASURES: SARS-CoV-2 antibody seroprevalence was estimated from weighted data. Associated factors and reported symptoms were investigated using univariable and multivariable logistic regressions. RESULTS: The seroprevalence of anti-SARS-CoV-2 antibodies was 35.4% (95% CI 30.2% to 41.0%). People aged 15-64 years old had increased odds of being seropositive than those aged 65 years or over. Obese people had higher odds of being seropositive (adjusted OR (aOR)=2.0, 95% CI 1.1 to 3.8). The odds of being seropositive were higher in households with clinical COVID-19 cases (one case: aOR=2.5, 95% CI 1.3 to 5.0; several cases: aOR=6.9, 95% CI 3.1 to 15.2). In the neighbourhood with the highest measured seroprevalence, people living in a dwelling with one to two rooms had higher odds of being seropositive than those living in a four-room house (aOR=2.8, 95% CI 1.2 to 6.3). Working during the lockdown was associated with lower odds of being seropositive (aOR=0.2, 95% CI 0.03 to 1.0). CONCLUSION: Transmission of SARS-COV-2 in this vulnerable population was very high during the COVID-19 pandemic's first wave. Our results highlight the need to strengthen and adapt preventive measures taking into account all social determinants of health, especially housing conditions.

High rifampicin-resistant TB cure rates and prevention of severe ototoxicity after replacing the injectable by linezolid in early stage of hearing loss.

The short treatment regimen (STR) achieves a >80% cure in rifampicin-resistant tuberculosis (RR-TB) patients. However, ototoxicity induced by the injectable is a concern. This is the first study to evaluate the replacement of injectables by linezolid in patients with audiometry abnormalities at baseline or during the treatment.We conducted a retrospective cohort study of all RR-TB patients started on the STR between 2016 and June, 2019, in Niger. Patients underwent audiometry every 2 months in 2016 and every month since 2017.Of 195 patients, 16.9% (33 out of 195) received linezolid from the start (n=17), or switched from injectables to linezolid during treatment (n=16), based on audiometry abnormalities. In 2016, two patients developed severe ototoxicity despite switching to linezolid. Since 2017, no patient developed severe hearing loss or complete deafness. Severe haematological toxicity was observed in 18.1% (six out of 33) of patients on linezolid, none of which was life threatening. The use of linezolid was associated with severe but manageable adverse events (hazard ratio 8.9, 95% CI 2.5-31.5; p=0.001). A total of 90.9% (30 out of 33) of patients on a linezolid-containing STR were cured, and none experienced treatment failure. Three died, but not due to adverse events.Baseline and monthly audiometry monitoring and using linezolid after detection of hearing abnormalities appears effective to prevent severe ototoxicity, while keeping high treatment success and manageable adverse events.

Surveillance of tuberculosis.

Surveillance of tuberculosis is one of the oldest disease surveillance systems in the world. This article briefly reviews its history, describes its methods and main results, with a specific focus on low- and middle-income countries, and underlines its main challenges and future prospects. Surveillance of tuberculosis started more than two centuries ago with the recording of tuberculosis mortality in England and Wales. After Koch's discovery of the tubercle bacillus, repeated tuberculin surveys were implemented to monitor infection, and case notification of active disease was progressively established during the 20th century. Because treatment of tuberculosis disease is the key intervention to stop transmission, monitoring of treatment outcome and more recently of drug resistance became integral parts of tuberculosis surveillance. At global level, the World Health Organization (WHO) is publishing a global TB report annually since 1997. Reports present data notified by each country as well as global estimates. Estimates of tuberculosis incidence are based on case notification adjusted by various correction factors, or on derivation from results of tuberculosis prevalence surveys, e.g. in India. In 2018, 10.1 million cases of tuberculosis are estimated to have occurred, among which about 0.5 million were resistant to rifampicin, and an estimated 1.5 million patients died. While global estimates are useful to raise public awareness and attract public and private funding, their uncertainty make them less useful to guide national policies. The backbone of tuberculosis surveillance at national and subnational level is the case notification. Newly diagnosed cases of active disease, whether new or recurrent, are reported with their key characteristics (age, sex, case category, HIV co-infection, drug resistance), and treatment outcomes are reported after scheduled treatment termination. All countries follow internationally standardized definitions. Incidence rates are compared by time to observe trends, by place to compare geographical areas, and by patient's characteristics to identify high-risk groups. The laboratory plays an essential role, since the surveillance of bacteriologically confirmed cases allows the most reliable comparisons, and because of the importance of the identification of drug resistance. The number of patients examined for tuberculosis diagnosis is also a key indicator to monitor case-finding activities. Tuberculosis surveillance is today among the most performant surveillance systems for infectious diseases. The two major changes currently observed are the move from paper-based registers to individual computerized surveillance databases and the multiplication of indicators for documenting progress towards tuberculosis elimination. There is a risk that implementation of these changes be followed by a loss in data quality. All efforts should be made to accompany these changes with adequate quality control. This will only be possible if health care workers are actively involved in the process of data production and analysis.

World Health Organization 2018 treatment guidelines for rifampicin-resistant tuberculosis: uncertainty, potential risks and the way forward.

The 2018 World Health Organization (WHO) treatment guidelines for multidrug-/rifampicin-resistant tuberculosis (MDR/RR-TB) give preference to all-oral long regimens lasting for 18-20 months. The guidelines strongly recommend combining bedaquiline, levofloxacin (or moxifloxacin) and linezolid, supplemented by cycloserine and/or clofazimine. The effectiveness of this combination in a long regimen has not been tested in any study to date, with corresponding uncertainty. The guidelines indicate that, ideally, all MDR-TB patients should have - as a minimum - the isolate tested for fluoroquinolones, bedaquiline and linezolid susceptibility before the start of treatment. Unfortunately, the capacity for drug susceptibility testing is insufficient in resource-limited settings. The risk of acquired bedaquiline resistance cannot be ignored, especially in patients with undetected resistance to fluoroquinolones. Both linezolid and cycloserine are known for their high frequency of serious adverse events. The combination of bedaquiline, moxifloxacin and clofazimine in the same regimen may excessively increase the QT interval. These expected adverse effects are difficult to monitor and manage in resource-limited settings, and may result in frequent modifications and a less effective regimen. The final STREAM results have confirmed the non-inferiority of the short regimen compared with the long regimen. Before evidence on the all-oral long and modified all-oral short treatment regimens is available, the WHO-recommended short MDR-TB regimens, with monitoring for ototoxicity, remain a better treatment option for the management of MDR/RR-TB patients who are eligible for short regimens in low- and middle-income countries. National tuberculosis programmes should also strengthen their capacity in the detection and management of fluoroquinolone-resistant MDR-TB following the WHO guidelines.

Standardised shorter regimens versus individualised longer regimens for rifampin- or multidrug-resistant tuberculosis.

We sought to compare the effectiveness of two World Health Organization (WHO)-recommended regimens for the treatment of rifampin- or multidrug-resistant (RR/MDR) tuberculosis (TB): a standardised regimen of 9-12 months (the "shorter regimen") and individualised regimens of ≥20 months ("longer regimens").We collected individual patient data from observational studies identified through systematic reviews and a public call for data. We included patients meeting WHO eligibility criteria for the shorter regimen: not previously treated with second-line drugs, and with fluoroquinolone- and second-line injectable agent-susceptible RR/MDR-TB. We used propensity score matched, mixed effects meta-regression to calculate adjusted odds ratios and adjusted risk differences (aRDs) for failure or relapse, death within 12 months of treatment initiation and loss to follow-up.We included 2625 out of 3378 (77.7%) individuals from nine studies of shorter regimens and 2717 out of 13 104 (20.7%) individuals from 53 studies of longer regimens. Treatment success was higher with the shorter regimen than with longer regimens (pooled proportions 80.0% versus 75.3%), due to less loss to follow-up with the former (aRD -0.15, 95% CI -0.17- -0.12). The risk difference for failure or relapse was slightly higher with the shorter regimen overall (aRD 0.02, 95% CI 0-0.05) and greater in magnitude with baseline resistance to pyrazinamide (aRD 0.12, 95% CI 0.07-0.16), prothionamide/ethionamide (aRD 0.07, 95% CI -0.01-0.16) or ethambutol (aRD 0.09, 95% CI 0.04-0.13).In patients meeting WHO criteria for its use, the standardised shorter regimen was associated with substantially less loss to follow-up during treatment compared with individualised longer regimens and with more failure or relapse in the presence of resistance to component medications. Our findings support the need to improve access to reliable drug susceptibility testing.

Short-Course Regimen for Multidrug-Resistant Tuberculosis: A Decade of Evidence.

About ten years ago, the first results of the so-called "Bangladesh regimen", a short regimen lasting nine months instead of 20 months, revolutionized multidrug-resistant tuberculosis (MDR-TB) treatment. Similar short regimens were studied in different settings, relying for their efficacy on a later generation fluoroquinolone, either gatifloxacin, moxifloxacin, or levofloxacin. We review the published material on short MDR-TB regimens, describe their different compositions, their results in national tuberculosis programs in middle- and low-income countries, the risk of acquiring resistance to fluoroquinolone, and the occurrence of adverse events. With over 80% success, the regimen performs much better than longer regimens (usually around 50%). Monitoring of adverse events allows adapting its composition to prevent severe adverse events such as deafness. We discuss the current applicability and usefulness of the short injectable-containing regimen given the 2019 recommendation of the World Health Organization (WHO) for a new long all-oral regimen. We conclude that the most effective fluoroquinolone is gatifloxacin, currently not listed as an essential medicine by WHO. It is a priority to restore its status as an essential medicine.

Half of rifampicin-resistant Mycobacterium tuberculosis complex isolated from tuberculosis patients in Sub-Saharan Africa have concomitant resistance to pyrazinamide.

BACKGROUND: Besides inclusion in 1st line regimens against tuberculosis (TB), pyrazinamide (PZA) is used in 2nd line anti-TB regimens, including in the short regimen for multidrug-resistant TB (MDR-TB) patients. Guidelines and expert opinions are contradictory about inclusion of PZA in case of resistance. Moreover, drug susceptibility testing (DST) for PZA is not often applied in routine testing, and the prevalence of resistance is unknown in several regions, including in most African countries. METHODS: Six hundred and twenty-three culture isolates from rifampicin-resistant (RR) patients were collected in twelve Sub-Saharan African countries. Among those isolates, 71% were from patients included in the study on the Union short-course regimen for MDR-TB in Benin, Burkina Faso, Burundi, Cameroon, Central Africa Republic, the Democratic Republic of the Congo, Ivory Coast, Niger, and Rwanda PZA resistance, and the rest (29%) were consecutive isolates systematically stored from 2014-2015 in Mali, Rwanda, Senegal, and Togo. Besides national guidelines, the isolates were tested for PZA resistance through pncA gene sequencing. RESULTS: Over half of these RR-TB isolates (54%) showed a mutation in the pncA gene, with a significant heterogeneity between countries. Isolates with fluoroquinolone resistance (but not with injectable resistance or XDR) were more likely to have concurrent PZA resistance. The pattern of mutations in the pncA gene was quite diverse, although some isolates with an identical pattern of mutations in pncA and other drug-related genes were isolated from the same reference center, suggesting possible transmission of these strains. CONCLUSION: Similar to findings in other regions, more than half of the patients having RR-TB in West and Central Africa present concomitant resistance to PZA. Further investigations are needed to understand the relation between resistance to PZA and resistance to fluoroquinolones, and whether continued use of PZA in the face of PZA resistance provides clinical benefit to the patients.

Assessment of exposure to soils contaminated with lead, cadmium, and arsenic near a zinc smelter, Cassiopée Study, France, 2008.

After 150 years of industrial activity, significant pollution of surface soils in private gardens and locally produced vegetables with lead, cadmium, and arsenic has recently been observed in Viviez (Southern France). A public health intervention was conducted in 2008 to identify individual health risks of Viviez inhabitants and to analyze their environmental exposure to these pollutants. Children and pregnant women in Viviez were screened for lead poisoning. Urinary cadmium testing was proposed to all inhabitants. Those with urinary cadmium levels over 1 µg/g creatinine were then tested for kidney damage. Urinary cadmium and arsenic levels were compared between participants with non-occupational exposure from Viviez and Montbazens, a nearby town not exposed to these two pollutants, in order to identify environmental factors contributing to impregnation. No case of lead poisoning was detected in Viviez, but 23 % of adults had urinary cadmium over 1 µg/g creatinine, 14 % of whom having markers of kidney damage. Viviez adults had higher levels of urinary cadmium, and to a lesser extent, higher levels of urinary arsenic than those from Montbazens. Consumption of local produce (vegetables and animals) and length of residence in Viviez were associated with higher urinary cadmium levels, independently of known confounding factors, suggesting persisting environmental exposure to contaminated soil. To conclude, health risks related to cadmium exposure were identified in the Viviez population living on contaminated soils. Lead and arsenic exposure did not pose health concerns. Interventions were proposed to reduce exposure and limit health consequences.

Relationships between impact on employment, working conditions, socio-occupational categories and symptoms of post-traumatic stress disorder after the industrial disaster in Toulouse, France.

OBJECTIVES: The aims of this paper were (1) to analyze the prevalence of symptoms of post-traumatic stress disorder (S-PTSD) in a population of workers 1 year after an industrial disaster; and (2) to assess the role of factors of vulnerability such as the occupational impact of a disaster and economic conditions. METHODS: A cross-sectional survey assessing the relationships between socio-occupational category, impact on employment and S-PTSD was conducted by the self-administered impact of event scale-revised. RESULTS: The prevalence of S-PTSD in workers in the peripheral zone (<3 km around the explosion site) was 12% in men and 18% in women. Factors significantly associated with S-PTSD in men were non-managerial socio-occupational category: employees (ORa = 4.3; [2.3; 7.8]), factory workers/laborers (ORa = 3.7; [1.8; 7.6]), intermediate professions (ORa = 3.3; [1.9; 5.9]), and artisans (ORa = 3; [1.3; 7.7]); and layoff (ORa = 2.6; [1.5; 4.5]) or unusable workplace after the explosion (ORa = 1.8; [1.1; 2.8]). In women, factors significantly associated with S-PTSD were the socio-occupational categories of employees and factory workers (ORa = 2.2; [1.4; 3.5]), artisans (ORa = 2.7; [1.3; 5.7]) and intermediate professions, (ORa = 1.5; [1; 2.3]) and reporting of an occupational accident (ORa = 1.5; [1.1; 2.2]). CONCLUSION: Impact on the workplace and socioeconomic conditions were associated with S-PTSD. The epidemiological approach in disaster situations needs to be improved, particularly in the social and occupational dimension when economically active populations are involved. Vulnerable subgroups, defined by occupational impact and low socioeconomic category, should be taken into account.

Psychosocial risk factors for depressive symptoms after the AZF chemical factory explosion in Toulouse, France.

BACKGROUND: On 21 September 2001, a huge explosion occurred in a chemical plant in Toulouse. The hypothesis of the study was that the level of depressive symptoms after an industrial disaster would be related to the intensity of exposure and the characteristics of the exposed population, as well as to the consequences of the disaster during the following months. METHODS: A random sample of the population living close to the plant at the time of the explosion was included in a cross-sectional study, and 811 persons aged > 18 years were interviewed at home. The depressive symptoms score was analysed by gender in relation to characteristics of the population before the explosion, immediate exposure to the explosion and post-trauma factors. RESULTS: The mean depressive symptoms scores (± SD) 18 months after the explosion were 17.8 (± 1) in women and 13.5 (± 1) in men. Age > 45 years and psychiatric treatment in the previous year; high immediate exposure (proximity to the site at the time of the explosion < 2500 m); and post-trauma factors such as financial difficulties or physical sequelae during the months after the disaster were related to a higher depressive symptoms score in both men and women. CONCLUSION: In the population living near the site of an industrial explosion, individual vulnerability, exposure and post-trauma factors were associated with depressive symptoms. All three sets of factors need to be taken into account when planning a response to a disaster and reducing the psychological aftermath.

Hearing status after an industrial explosion: experience of the AZF explosion, 21 September 2001, France.

OBJECTIVES: Following the explosion of a chemical plant in France, a study was conducted to analyse the relationship between hearing thresholds and distance from the explosion based on post- and pre-blast audiometric data, and to describe the functional symptoms and visits for hearing problems. METHODS: Audiometric tests with standard procedure of 511 workers of a company located near the explosion were proposed and conducted by the occupational medicine department after the explosion. Past occupational noise exposure, past medical history of ear problems, distance from the explosion, functional symptoms and visits for hearing problems following explosion and results of past audiometric tests if available were collected. Workers were classified as "exposed" or "less exposed" according to the distance from the explosion. Mean decibel threshold shifts for each ear were analysed by frequency with Student's t test and by multiple linear regression taking into account confounding factors. RESULTS: Of a total of 425 (83%) of the firm's workers who participated in the study, 49% had received an audiometric test before the explosion. Hearing shift between pre- and post-explosion audiograms was significantly greater for the "exposed" group than for the "less exposed" one at 2,000 and 4,000 Hz (P < 0.05, P < 0.001, respectively) and borderline at 6,000 Hz (P = 0.09) for the right ear and at 2,000 (P < 0.01), 6,000 and 8,000 Hz (P < 0.05) for the left ear. Among those of the "exposed" workers who reported any functional symptom following the explosion, 45% did not visit an ENT specialist despite these signs. CONCLUSIONS: The study demonstrated statistically significant hearing shift from 2,000 to 6,000 Hz in relation with distance from the explosion and showed that even when functional symptoms were present, people did not necessarily seek medical advice. Screening for hearing loss should be recommended for people most exposed to excess acoustic pressure, in order to offer them prevention advice.

Assessing post-disaster consequences for health at the population level: experience from the AZF factory explosion in Toulouse.

BACKGROUND: A major explosion occurred in the AZF chemical factory in Toulouse in September 2001. A comprehensive programme of epidemiological surveillance was set up. OBJECTIVES: To present an overview of the programme and discuss the methods and potential utility of post-disaster epidemiology. The programme had three objectives: (1) to analyse comprehensively the short-term and long-term effects of air, water and secondary soil pollution on health; (2) to identify health problems needing special attention; and (3) to investigate the long-term direct and indirect effects on the population's health. METHODS: The programme was organised through three committees: (1) a scientific committee, (2) an executive programme committee and (3) an institutional committee which aimed to facilitate exchanges between the epidemiologists, the regional authorities, the population and the media. As the catastrophe was an industrial disaster that had a major effect on workers and companies, and also caused severe damage to many schools and buildings all over the city, routine and ad hoc surveillance systems were used and three specific ad hoc questionnaire surveys in workers, schoolchildren and the general population were planned. RESULTS AND CONCLUSIONS: Although the routine surveillance systems had limitations, several sources provided useful information for public health decisions and were found to be concordant with ad hoc epidemiological studies. Defining a victim was central to the choice of a programme design based on an approach either to victims of the disaster or to the entire population in the surrounding region. Anticipation and preparation for such disasters are thus required.