Resource implications of the latent tuberculosis cascade of care: a time and motion study in five countries.

BACKGROUND: The End TB Strategy calls for global scale-up of preventive treatment for latent tuberculosis infection (LTBI), but little information is available about the associated human resource requirements. Our study aimed to quantify the healthcare worker (HCW) time needed to perform the tasks associated with each step along the LTBI cascade of care for household contacts of TB patients. METHODS: We conducted a time and motion (TAM) study between January 2018 and March 2019, in which consenting HCWs were observed throughout a typical workday. The precise time spent was recorded in pre-specified categories of work activities for each step along the cascade. A linear mixed model was fit to estimate the time at each step. RESULTS: A total of 173 HCWs in Benin, Canada, Ghana, Indonesia, and Vietnam participated. The greatest amount of time was spent for the medical evaluation (median: 11 min; IQR: 6-16), while the least time was spent on reading a tuberculin skin test (TST) (median: 4 min; IQR: 2-9). The greatest variability was seen in the time spent for each medical evaluation, while TST placement and reading showed the least variability. The total time required to complete all steps along the LTBI cascade, from identification of household contacts (HHC) through to treatment initiation ranged from 1.8 h per index TB patient in Vietnam to 5.2 h in Ghana. CONCLUSIONS: Our findings suggest that the time requirements are very modest to perform each step in the latent TB cascade of care, but to achieve full identification and management of all household contacts will require additional human resources in many settings.

Post-treatment Mortality Among Patients With Tuberculosis: A Prospective Cohort Study of 10 964 Patients in Vietnam.

BACKGROUND: Tuberculosis is the leading infectious cause of death. Steep reductions in tuberculosis-related mortality are required to realize the World Health Organization's "End Tuberculosis Strategy." However, accurate mortality estimates are lacking in many countries, particularly following discharge from care. This study aimed to establish the mortality rate among patients with pulmonary tuberculosis in Vietnam and to quantify the excess mortality in this population. METHODS: We conducted a prospective cohort study among adult patients treated for smear-positive pulmonary tuberculosis in 70 clinics across Vietnam. People living in the same households were recruited as controls. Participants were re-interviewed and their survival was established at least 2 years after their treatment with an 8-month standardized regimen. The presence of relapse was established by linking identifying data on patients and controls to clinic registries. Verbal autopsies were performed. The cumulative mortality among patients was compared to that among a control population, adjusting for age and gender. RESULTS: We enrolled 10964 patients and 25707 household controls. Among enrolled tuberculosis patients, 9% of patients died within a median follow-up period of 2.9 years: 342 (3.1%) during treatment and 637 (5.8%) after discharge. The standardized mortality ratio was 4.0 (95% confidence interval 3.7-4.2) among patients with tuberculosis, compared to the control population. Tuberculosis was the likely cause of death for 44.7% of these deceased patients. CONCLUSIONS: Patients treated for tuberculosis had a markedly elevated risk of death, particularly in the post-treatment period. Interventions to reduce tuberculosis mortality must enhance the early detection of drug-resistance, improve treatment effectiveness, and address non-communicable diseases.

Risk factors for child pneumonia - focus on the Western Pacific Region.

Pneumonia is a major cause of disease and death in infants and young children (aged <5 years) globally, as it is in the World Health Organization Western Pacific region. A better understanding of the underlying risk factors associated with child pneumonia is important, since pragmatic primary prevention strategies are likely to achieve major reductions in pneumonia-associated morbidity and mortality in children. This review focuses on risk factors with high relevance to the Western Pacific region, including a lack of exclusive breastfeeding, cigarette smoke and air pollution exposure, malnutrition and conditions of poverty, as well as common co-morbidities. Case management and vaccination coverage have been considered elsewhere.

Epidemiology of tuberculosis immunology.

Immunological impairment plays a major role in the epidemiology of TB. Globally, the most common causes of immunological impairment are malnutrition, diabetes, HIV/AIDS, aging, and smoking. With the notable exception of HIV, each factor leads to relatively mild immunological impairment in individuals. However, as these conditions affect a significant proportion of the population, they contribute substantially to the incidence of TB at a global scale. Understanding immunological impairment is central to understanding the global TB pandemic, and vital to the development of effective disease control strategies.

The effect of medication event reminder monitoring on treatment adherence of TB patients.

BACKGROUND: TB control remains a serious public health problem, compounded by poor treatment adherence, which increases the likelihood of onward transmission. We evaluated the effectiveness of medication event reminder monitoring (MERM) upon treatment adherence in a high TB burden setting.METHODS: We conducted an open-label parallel group randomised controlled trial among pulmonary TB adults. Participants were provided with a MERM device to store their medications. In the intervention arm, the devices were set to provide daily medication intake reminders. Primary outcome was the proportion of patient-months in which at least 6/30 doses were missed. Secondary outcomes included 1) the proportion of patient-months in which at least 14/30 doses were missed, and 2) the proportion of doses missed.RESULTS: Of 2,142 patients screened, 798 (37.3%) met the inclusion criteria and 250 participants were enrolled. The mean ratio (MR) for poor adherence between the intervention and control groups was 0.72 (95% CI 0.55-0.86). The intervention was also associated with a reduction in the proportion of patients missing at least 14/30 doses (MR 0.61, 95% CI 0.54-0.68) and the percentage of total doses missed (MR 0.75, 95% CI 0.68-0.80).CONCLUSION: MERM is effective in improving TB treatment adherence in a resource-limited environment.

A scoping review of interventions to mitigate common non-communicable diseases among people with TB.

BACKGROUND: Recommendations have been made to integrate screening for common non-communicable diseases (NCDs) within TB programs. However, we must ensure screening is tied to evidence-based interventions before scale-up. We aimed to map the existing evidence regarding interventions that address NCDs that most commonly affect people with TB.METHODS: We systematically searched PubMed, Medline, and Embase for studies that evaluated interventions to mitigate respiratory disease, cardiovascular disease, alcohol and substance use disorder, and mental health disorders among people with TB. We excluded studies that only screened for comorbidity but resulted in no further intervention. We also excluded studies focusing on smoking cessation interventions for which evidence-based guidelines are well established.RESULTS: The search identified 20 studies that met our inclusion criteria. The most commonly evaluated intervention was referral for diabetes care (6 studies). Other interventions included pulmonary rehabilitation (5 studies), care programs for alcohol use disorder (4 studies), and psychosocial support or individual counselling (5 studies).CONCLUSION: There is limited robust evidence to support identified interventions in changing individual outcomes, and a significant knowledge gap remains on the long-term durability of the interventions´ clinical benefit, reach, and effectiveness. Implementation research demonstrating feasibility and effectiveness is needed before scaling up.

Clinical standards for the dosing and management of TB drugs.

BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs.METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

Ototoxicity among multidrug-resistant TB patients: a systematic review and meta-analysis.

BACKGROUND: The use of injectable antibiotics to treat multidrug-resistant TB (MDR-TB) is associated with substantial morbidity due to long-term hearing loss. This systematic review evaluates the incidence of ototoxicity among patients treated for MDR-TB, and the evidence for routine audiometric monitoring to mitigate its severity.METHODS: Studies of ototoxicity among patients with MDR-TB were identified from six databases: PubMed, MEDLINE, Web of Science, Embase, SCOPUS and the Cochrane Library. Meta-analyses were performed to determine the overall incidence of hearing loss, tinnitus and vertigo. The incidence of hearing loss was further stratified by country income status and the injectable agent used during treatment.RESULTS: Among 64 studies from 25 countries including 12 793 patients, 28.3% (95%CI 23.4-33.1) of patients treated with injectables reported hearing loss. Tinnitus and vertigo were experienced by respectively 14.5% (95%CI 10.3-18.7) and 8.1% (95%CI 4.7-11.6) of patients. The incidence of hearing loss was highest among patients treated with amikacin (33.4%, 95%CI 18.2-48.6), and lowest among those treated with capreomycin (2.0%, 95%CI 0-5.5). We found that audiometry was widely used as a method of evaluating hearing loss, and was feasible in a wide range of settings.CONCLUSION: Injectable antibiotics contribute to significant morbidity in patients with MDR-TB. In settings where they are used, routine audiometric monitoring is recommended to prevent irreversible damage.

Determining the value of TB active case-finding: current evidence and methodological considerations.

Active case-finding (ACF) is an important component of the End TB Strategy. However, ACF is resource-intensive, and the economics of ACF are not well-understood. Data on the costs of ACF are limited, with little consistency in the units and methods used to estimate and report costs. Mathematical models to forecast the long-term effects of ACF require empirical measurements of the yield, timing and costs of case detection. Pragmatic trials offer an opportunity to assess the cost-effectiveness of ACF interventions within a 'real-world´ context. However, such analyses generally require early introduction of economic evaluations to enable prospective data collection on resource requirements. Closing the global case-detection gap will require substantial additional resources, including continued investment in innovative technologies. Research is essential to the optimal implementation, cost-effectiveness, and affordability of ACF in high-burden settings. To assess the value of ACF, we must prioritize the collection of high-quality data regarding costs and effectiveness, and link those data to analytical models that are adapted to local settings.

Active case-finding in contacts of people with TB.

BACKGROUND: Exposure to people with TB substantially elevates a person's risk of tuberculous infection and TB disease. Systematic screening of TB contacts enables the early detection and treatment of co-prevalent disease, and the opportunity to prevent future TB disease. However, scale-up of contact investigation in high TB transmission settings remains limited.METHODS: We undertook a narrative review to evaluate the evidence for contact investigation and identify strategies that TB programmes may consider when introducing contact investigation and management.RESULTS: Selection of contacts for priority screening depends upon their proximity and duration of exposure, along with their susceptibility to develop TB. Screening algorithms can be tailored to the target population, the availability of diagnostic tests and preventive therapy, and healthcare worker expertise. Contact investigation may be performed in the household or at communal locations. Local contact investigation policies should support vulnerable patients, and ensure that drop-out during screening can be mitigated. Ethical issues should be anticipated and addressed in each setting.CONCLUSION: Contact investigation is an important strategy for TB elimination. While its epidemiological impact will be greatest in lower-transmission settings, the early detection and prevention of TB have important benefits for contacts and their communities.

Depression, stigma and quality of life in people with drug-susceptible TB and drug-resistant TB in Vietnam.

BACKGROUND: Drug resistance poses a major barrier to global control of TB - a leading infectious cause of death. Depression and stigma occur commonly among people with TB. However, the relationship between drug-resistant forms of TB, depression and stigma are not well understood.OBJECTIVE: To compare depression, stigma and health-related quality of life (HRQoL), among people with drug-susceptible TB (DS-TB) and multidrug-resistant TB (MDR-TB).METHODS: A cross-sectional study of people treated for DS-TB and MDR-TB in four provinces of Vietnam. The survey included a stigma scale (Vietnamese Tuberculosis Stigma Scale), depression scale (9-item Patient Health Questionnaire) and HRQoL scale (Functional Assessment of Chronic Illness Therapy - Tuberculosis). Differences between the two populations were compared using linear regression.RESULTS: Eighty-one people with DS-TB and 315 people with MDR-TB participated in the study. People with MDR-TB had a higher prevalence of depression than those with DS-TB (difference 17.8%, χ² 8.64). The mean depression and stigma scores were higher for people with MDR-TB than those with DS-TB (adjusted difference [AD] 8.6 and 7.6 respectively). People with MDR-TB reported lower HRQoL than those with DS-TB (AD -23.8).CONCLUSION: Depression and stigma are common among people with TB in Vietnam. Strategies to prevent and treat depressive symptoms and stigma in people with TB are critical to a holistic, patient-centred approach to care.

Clinical standards for the assessment, management and rehabilitation of post-TB lung disease.

BACKGROUND: Increasing evidence suggests that post-TB lung disease (PTLD) causes significant morbidity and mortality. The aim of these clinical standards is to provide guidance on the assessment and management of PTLD and the implementation of pulmonary rehabilitation (PR).METHODS: A panel of global experts in the field of TB care and PR was identified; 62 participated in a Delphi process. A 5-point Likert scale was used to score the initial ideas for standards and after several rounds of revision the document was approved (with 100% agreement).RESULTS: Five clinical standards were defined: Standard 1, to assess patients at the end of TB treatment for PTLD (with adaptation for children and specific settings/situations); Standard 2, to identify patients with PTLD for PR; Standard 3, tailoring the PR programme to patient needs and the local setting; Standard 4, to evaluate the effectiveness of PR; and Standard 5, to conduct education and counselling. Standard 6 addresses public health aspects of PTLD and outcomes due to PR.CONCLUSION: This is the first consensus-based set of Clinical Standards for PTLD. Our aim is to improve patient care and quality of life by guiding clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage PTLD.

An assessment of current tuberculosis patient care and support policies in high-burden countries.

CONTEXT: Adherence to treatment for tuberculosis (TB) is an important predictor of treatment outcomes. The World Health Organization guidelines recommend a patient-centred approach to adherence support; however, the extent to which policies in high-burden countries facilitate this approach remains uncertain.DESIGN: A cross-sectional survey of current national patient care and support policies in high TB burden countries was performed.RESULT: Responses were provided by TB care programmes in 23 of the 30 high TB burden countries, comprising 77.4% of TB cases globally. Clinic-based and household adherence support and patient education were recommended in all countries, while policies for digital technologies and social supports have been adopted in a small minority of countries. Financial or material support (such as reimbursement for transportation) and psychological support to patients-if included in the policies-was mainly recommended only for specific sub-groups of patients.CONCLUSION: National policies in many countries have not yet fully adopted global recommendations for patient care and support. Further scale-up of evidence-based approaches to care is required to improve quality of care for patients in high TB burden settings.

A comparison of digital chest radiography and Xpert® MTB/RIF in active case finding for tuberculosis.

OBJECTIVE: To compare two community screening tests for TB: sputum examination using Xpert® MTB/RIF and chest radiography (CXR).METHOD: Men aged ≥15 years and women aged >45 years living in 96 sub-communes in Ca Mau, Viet Nam, were invited to provide a single sputum specimen that was tested using Xpert. Participants were also invited to attend a nearby location for digital radiography. Participants whose sputum was Xpert MTB-positive or whose CXR was reported as 'consistent with TB´ were requested to provide two further sputum specimens for culture. The sensitivities of the two tests for detecting TB (defined as sputum culture-positive for Mycobacterium tuberculosis) were compared.RESULTS: There were 72 985 eligible participants, of whom 57 597 (78.9%) participated in Xpert screening, 12 752 (17.5%) had CXR and 11 235 (15.4%) had both tests. We estimated that there were 59 cases of TB, of whom 20 were Xpert MTB-positive (programmatic sensitivity 34.0%) and 47 had CXR reported as 'consistent with TB´ (sensitivity 80.0%, P < 0.0001).CONCLUSION: In community-wide screening for TB, CXR is more sensitive than a single spontaneously expectorated sputum sample tested using Xpert, but it has a substantially lower participation rate.

What will it take to eliminate drug-resistant tuberculosis?

Drug-resistant tuberculosis (DR-TB) is challenging to diagnose, treat, and prevent, but this situation is slowly changing. If the world is to drastically reduce the incidence of DR-TB, we must stop creating new DR-TB as an essential first step. The DR-TB epidemic that is ongoing should also be directly addressed. First-line drug resistance must be rapidly detected using universal molecular testing for resistance to at least rifampin and, preferably, other key drugs at initial TB diagnosis. DR-TB treatment outcomes must also improve dramatically. Effective use of currently available, new, and repurposed drugs, combined with patient-centered treatment that aids adherence and reduces catastrophic costs, are essential. Innovations within sight, such as short, highly effective, broadly indicated regimens, paired with point-of-care drug susceptibility testing, could accelerate progress in treatment outcomes. Preventing or containing resistance to second-line and novel drugs is also critical and will require high-quality systems for diagnosis, regimen selection, and treatment monitoring. Finally, earlier detection and/or prevention of DR-TB is necessary, with particular attention to airborne infection control, case finding, and preventive therapy for contacts of patients with DR-TB. Implementing these strategies can overcome the barrier that DR-TB represents for global TB elimination efforts, and could ultimately make global elimination of DR-TB (fewer than one annual case per million population worldwide) attainable. There is a strong cost-effectiveness case to support pursuing DR-TB elimination; however, achieving this goal will require substantial global investment plus political and societal commitment at national and local levels.

Prevalence of latent tuberculous infection among adults in the general population of Ca Mau, Viet Nam.

SETTING: The study was conducted in a randomly selected sample of persons aged 15 years living in Ca Mau Province, southern Viet Nam. OBJECTIVE: To estimate the prevalence of latent tuberculous infection (LTBI) in the general adult population of this province of Viet Nam. The secondary objective was to examine age and sex differences in prevalence. DESIGN: A cross-sectional survey was conducted in a cluster-random sample of the population. Clusters were subcommunes. The presence of LTBI was assessed using the QuantiFERON®-TB Gold In-Tube test system. RESULTS: QuantiFERON tests were performed among 1319 persons aged 15 years (77.7% of those selected). The overall prevalence of positive tests was 36.8% (95%CI 33.4-40.3). The prevalence of a positive test was lower in females than in males (31.0% vs. 44.7%, OR 0.57, 95%CI 0.45-0.72, P < 0.0001). The prevalence of positive tests increased with increasing age quintile (P < 0.0001). CONCLUSION: More than one third of the general adult population in a province in southern Viet Nam have evidence of LTBI. Although LTBI prevalence is higher in males, the sex difference is not as great as that for TB notification rates.

Preventive therapy for latent tuberculosis infection-the promise and the challenges.

Around one third of the world's population may harbour latent tuberculosis infection (LTBI), an asymptomatic immunological state that confers a heightened risk of subsequently developing tuberculosis (TB). Effectively treating LTBI will be essential if the End TB Strategy is to be realized. This review evaluates the evidence in relation to the effectiveness of preventive antibiotic therapy to treat LTBI due to both drug-susceptible and drug-resistant bacteria. Current national and international preventive therapy guidelines are summarized, as well as ongoing randomized trials evaluating regimens to prevent drug-resistant TB. Populations that may benefit most from screening and treatment for LTBI include close contacts of patients with TB (particularly children under 5 years of age) and individuals with substantial immunological impairment. The risks and benefits of treatment must be carefully balanced for each individual. Electronic decision support tools offer one way in which clinicians can help patients to make informed decisions. Modelling studies indicate that the expanded use of preventive therapy will be essential to achieving substantial reductions in the global TB burden. However, the widespread scale-up of screening and treatment will require careful consideration of cost-effectiveness, while ensuring the drivers of ongoing disease transmission are also addressed.

Preventing the spread of multidrug-resistant tuberculosis and protecting contacts of infectious cases.

Prevention of multidrug-resistant and extensively drug-resistant tuberculosis (MDR/XDR-TB) is a top priority for global TB control, given the need to limit epidemic spread and considering the high cost, toxicity and poor treatment outcomes with available therapies. We performed a systematic literature review to evaluate the evidence for strategies to reduce MDR/XDR-TB transmission and disease progression. Rapid detection and timely initiation of effective treatment is critical to rendering MDR/XDR-TB cases non-infectious. The scale-up of rapid molecular testing has transformed the capacity of high-incidence settings to identify and treat patients with MDR/XDR-TB. Optimized infection control measures in hospitals and clinics are critical to protect other patients and healthcare workers, whereas creative measures to reduce transmission within community hotspots require consideration. Targeted screening of high-risk communities may enhance early case-detection and limit the spread of MDR/XDR-TB. Among infected contacts, preventive therapy promises to reduce the risk of disease progression. This is supported by observational cohort studies, but randomized trials are urgently needed to confirm these observations and guide policy formulation. Substantial investment in MDR/XDR-TB prevention and care will be critical if the ambitious global goal of TB elimination is to be realized.