Best practices for the care of pregnant people living with TB.

BACKGROUND: Each year more than 200,000 pregnant people become sick with TB, but little is known about how to optimize their diagnosis and therapy. Although there is a need for further research in this population, it is important to recognize that much can be done to improve the services they currently receive.METHODS: Following a systematic review of the literature and the input of a global team of health professionals, a series of best practices for the diagnosis, prevention and treatment of TB during pregnancy were developed.RESULTS: Best practices were developed for each of the following areas: 1) screening and diagnosis; 2) reproductive health services and family planning; 3) treatment of drug-susceptible TB; 4) treatment of rifampicin-resistant/multidrug-resistant TB; 5) compassionate infection control practices; 6) feeding considerations; 7) counseling and support; 8) treatment of TB infection/TB preventive therapy; and 9) research considerations.CONCLUSION: Effective strategies for the care of pregnant people across the TB spectrum are readily achievable and will greatly improve the lives and health of this under-served population.

Diverse clinical and social circumstances: developing patient-centred care for DR-TB patients in South Africa.

OBJECTIVE: To describe the medical, socio-economic and geographical profiles of patients with rifampicin-resistant TB (RR-TB) and the implications for the provision of patient-centred care. SETTING: Thirteen districts across three South African provinces. DESIGN: This descriptive study examined laboratory and healthcare facility records of 194 patients diagnosed with RR-TB in the third quarter of 2016. RESULTS: The median age was 35 years; 120/194 (62%) of patients were male. Previous TB treatment was documented in 122/194 (63%) patients and 56/194 (29%) had a record of fluoroquinolone and/or second-line injectable resistance. Of 134 (69%) HIV-positive patients, viral loads were available for 68/134 (51%) (36/68 [53%] had viral loads of >1000 copies/ml) and CD4 counts were available for 92/134 (69%) (20/92 [22%] had CD4 <50 cells/mm3). Patients presented with varying other comorbidities, including hypertension (13/194, 7%) and mental health conditions (11/194, 6%). Of 194 patients, 44 (23%) were reported to be employed. Other socio-economic challenges included substance abuse (17/194, 9%) and ill family members (17/194, 9%). Respectively 13% and 42% of patients were estimated to travel more than 20 km to reach their diagnosing and treatment-initiating healthcare facility. CONCLUSIONS: RR-TB patients had diverse medical and social challenges highlighting the need for integrated, differentiated and patient-centred healthcare to better address specific needs and underlying vulnerabilities of individual patients.

OBJECTIF: Décrire les profils médicaux, socioéconomiques et géographiques des patients atteints de TB résistante à la rifampicine (RR-TB) et les implications en matière de soins centrés sur le patient. CONTEXTE: Treize districts de trois provinces d'Afrique du Sud. MÉTHODE: Cette étude descriptive a analysé les dossiers médicaux et de laboratoire de 194 patients ayant reçu un diagnostic de RR-TB au troisième trimestre de 2016. RÉSULTATS: L'âge médian était de 35 ans ; 120/194 (62%) patients étaient des hommes. Un traitement antituberculeux antérieur était documenté chez 122/194 (63%) patients, et 56/194 (29%) avaient une résistance à la fluoroquinolone et/ou à un agent injectable de deuxième ligne documentée. Sur 134 (69%) patients infectés par le VIH, les charges virales étaient disponibles pour 68/134 (51%) patients (36/68 [53%] avaient des charges virales >1 000 copies/ml) et les taux de CD4 étaient disponibles pour 92/134 (69%) patients (20/92 [22%] avaient un taux de CD4 <50 cellules/mm3). Les patients présentaient diverses autres comorbidités, dont hypertension (13/194, 7%) et troubles psychiques (11/194, 6%). Sur les 194 patients, 44 (23%) avaient un emploi. Les autres problèmes socioéconomiques comprenaient la toxicomanie (17/194, 9%) et le fait d'avoir un membre de sa famille malade (17/194, 9%). Respectivement 13% et 42% des patients parcouraient plus de 20 km pour se rendre à leur centre de diagnostic et au centre de soins responsable de l'instauration du traitement. CONCLUSIONS: Les patients atteints de RR-TB avaient divers problèmes médicaux et sociaux. Ces résultats soulignent le besoin de soins intégrés, différenciés et centrés sur le patient afin de mieux répondre aux besoins spécifiques et aux vulnérabilités sous-jacentes de chaque patient.

Clinical perspectives on treatment of rifampicin-resistant/multidrug-resistant TB.

Rapid diagnostics, newer drugs, repurposed medications, and shorter regimens have radically altered the landscape for treating rifampicin-resistant TB (RR-TB) and multidrug-resistant TB (MDR-TB). There are multiple ongoing clinical trials aiming to build a robust evidence base to guide RR/MDR-TB treatment, and both observational studies and programmatic data have contributed to advancing the treatment field. In December 2019, the WHO issued their second 'Rapid Communication´ related to RR-TB management. This reiterated their prior recommendation that a majority of people with RR/MDR-TB receive all-oral treatment regimens, and now allow for specific shorter duration regimens to be used programmatically as well. Many TB programs need clinical advice as they seek to roll out such regimens in their specific setting. In this Perspective, we highlight our early experiences and lessons learned from working with National TB Programs, adult and pediatric clinicians and civil society, in optimizing treatment of RR/MDR-TB, using shorter, highly-effective, oral regimens for the majority of people with RR/MDR-TB.

Breastfeeding in women living with tuberculosis.

Breast milk provides optimal nutrition, and is recommended for neonates and infants. In women with TB, there has been uncertainty about optimal feeding practices due to the risk of transmission to the neonate and the possibility of drug exposure via breast milk. For women who have drug-susceptible TB (DS-TB) who are no longer infectious, it is safe to breastfeed as breast milk does not contain Mycobacterium tuberculosis bacilli and only minor, non-toxic quantities of the drugs pass into breast milk. Most guidelines therefore encourage breastfeeding in women with DS-TB. However, there is uncertainty and guidelines vary regarding women with DS-TB who are still infectious and in women with rifampicin-resistant TB (RR-TB). Although the transmission dynamics of DS- and RR-TB are similar, additional infection control precautions for RR-TB may be necessary until the mother is responding to treatment, as second-line therapy may be less efficacious and preventive therapy is not widely offered to infants. In addition, there are no published data describing the extent to which second-line drugs are secreted into breast milk or subsequent exposure in breastfed infants. The implications of limited information on policy and consequent dilemmas regarding patient care are illustrated in a patient scenario. Areas for future research are suggested.

Limitations and potential bias in vital registration data and tuberculosis mortality reporting in South Africa.

Tuberculosis (TB) is a curable disease, but continues to contribute to large numbers of deaths globally and remains among the leading causes of death in South Africa (SA). Evaluating trends in TB deaths and progress towards the End TB strategy target of zero deaths is particularly important to guide policy and practice in SA. TB deaths are complicated by its relationship with HIV, and SA's initial slow response to HIV compounded this. In considering the reported deaths in SA that identify TB as the underlying cause of death, it is important to be aware of potential limitations and sources of bias. We have examined the relationship between TB and HIV and the recording of underlying and contributing causes of death, and clarified the World Health Organization's methodology for estimating TB deaths.

Drug-resistant tuberculosis patient care journeys in South Africa: a pilot study using routine laboratory data.

SETTING: Thirteen districts in Eastern Cape (EC), KwaZulu-Natal (KZN) and Western Cape (WC) Provinces, South Africa.OBJECTIVE: To pilot a methodology for describing and visualising healthcare journeys among drug-resistant tuberculosis (DR-TB) patients using routine laboratory records.DESIGN: Laboratory records were obtained for 195 patients with laboratory-detected rifampicin-resistant TB (RR-TB) during July-September 2016. Health facility visits identified from these data were plotted to visualise patient healthcare journeys. Data were verified by facility visits.RESULTS: In the 9 months after the index RR-TB sample was collected, patients visited a mean of 2.3 health facilities (95% CI 2.1-2.6), with 9% visiting ≥4 facilities. The median distance travelled by patients from rural areas (116 km, interquartile range [IQR] 50-290) was greater than for urban patients (51 km, IQR 9-140). A median of 21% of patient's time was spent under the care of primary healthcare facilities: this was respectively 6%, 37% and 39% in KZN, EC and WC. Journey patterns were generally similar within districts. Some reflected a semi-centralised model of care where patients were referred to regional hospitals; other journeys showed greater involvement of primary care.CONCLUSION: Routine laboratory data can be used to explore DR-TB patient healthcare journeys and show how the use of healthcare services for DR-TB varies in different settings.

Opportunities from a new disease for an old threat: Extending COVID-19 efforts to address tuberculosis in South Africa.

The COVID-19 pandemic and phased nationwide lockdown have impacted negatively on individuals with tuberculosis (TB) and routine TB services. Through a literature review and the perspective of members of a national TB Think Tank task team, we describe the impact of the pandemic and lockdown on TB patients and services as well as the potential long-term setback to TB control in South Africa (SA). Strategies to mitigate risk and impact are explored, together with opportunities to leverage synergies from both diseases to the benefit of the National TB Programme (NTP). With the emergence of COVID-19, activities to address this new pandemic have been prioritised across all sectors. Within the health system, the health workforce and resources have been redirected away from routine services towards the new disease priority. The social determinants of health have deteriorated during the lockdown, potentially increasing progression to TB disease and impacting negatively on people with TB and their households, resulting in additional barriers to accessing TB care, with early reports of a decline in TB testing rates. Fewer TB diagnoses, less attention to adherence and support during TB treatment, poorer treatment outcomes and consequent increased transmission will increase the TB burden and TB-related mortality. People with TB or a history of TB are likely to be vulnerable to COVID-19. Modifications to current treatment practices are suggested to reduce visits to health facilities and minimise the risks of COVID-19 exposure. The COVID-19 pandemic has the potential to negatively impact on TB control in TB-endemic settings such as SA. However, there are COVID-19-related health systems-strengthening developments that may help the NTP mitigate the impact of the pandemic on TB control. By integrating TB case finding into the advanced screening, testing, tracing and monitoring systems established for COVID-19, TB case finding and linkage to care could increase, with many more TB patients starting treatment. Similarly, integrating knowledge and awareness of TB into the increased healthcare worker and community education on infectious respiratory diseases, behavioural practices around infection prevention and control, and cough etiquette, including destigmatisation of mask use, may contribute to reducing TB transmission. However, these potential gains could be overwhelmed by the impact of increasing poverty and other social determinants of health on the burden of TB.

Figures of the dead: A decade of tuberculosis mortality registrations in South Africa.

South Africa (SA) is committed to reducing tuberculosis (TB) mortality rates in line with the World Health Organization's End TB Strategy and the Sustainable Development Goal (SDG) targets. From mortality reports released by Statistics South Africa, this study analysed reported TB mortality in SA from 2006 to 2016 to inform our understanding of TB mortality and the development of strategies needed to attain the SDG targets. TB mortality includes all deaths reported to the Department of Home Affairs with TB reported as the underlying cause of death based on the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) definition. Although TB remains the leading cause of death, TB mortality rates in SA have fallen substantially in the past decade. From 2006 to 2016, the number of deaths due to TB plummeted from 76 881 to 29 399 and the proportion of all-cause mortality due to TB more than halved from 13% to <6%. Furthermore, the profile of people dying from TB has changed, with a decrease in the proportion of children aged <15 years, adults of reproductive age (15 - 49) and women, and an increase in the proportion aged ≥50. This change has largely mirrored the overall pattern of deaths in SA, with large decreases in deaths in adults aged 15 - 49, especially women, thought to be because of the scale-up of the antiretroviral treatment programme for HIV. The End TB Strategy target of a 95% reduction in TB mortality by 2035 is achievable in SA. However, sustained effort in high-risk groups together with improved vital registration data are needed to ensure attainment of the target.

Moving towards universal health coverage: Strengthening the evidence ecosystem for the South African health system.

Health policy and systems research (HPSR) guides health system reforms and is essential for South Africa (SA)'s progress towards universal coverage of high-quality healthcare. For HPSR evidence to inform and strengthen health systems, it needs to flow efficiently between evidence producers, evidence synthesisers, evidence processers and disseminators and evidence implementors in an evidence ecosystem. A substantial body of evidence for health systems strengthening is generated in SA, and this informs national and international health system guidelines and guidance. In this manuscript, in celebration of the 50th anniversary of the SA Medical Research Council, we apply an evidence ecosystem lens to the SA health system, and discuss its current functioning in support of the achievement of a high-quality health system that is able to achieve universal health coverage. We use three case studies to describe successes, challenges and gaps in the functioning of the evidence ecosystem. The first case study focuses on using evidence to strengthen health-system governance and support for community health worker programmes. The second case focuses on managing the growing epidemic of drug-resistant tuberculosis, while the third case focuses on social protection, the child support grant and its impact on health. SA scientists are part of global initiatives to strengthen the health-systems evidence ecosystem, specifically through pioneering methods to synthesise evidence and produce evidence-informed guidelines to facilitate evidence use in health-system decision-making. SA institutes of health policy analysis facilitate involvement of evidence producers and synthesisers in the national health system policy-making process. A future priority is to further strengthen national initiatives to translate evidence into policy and practice and to sustain capacity for continuous technical support to health-systems policy development and implementation.

Neonatal, infant and child health in South Africa: Reflecting on the past towards a better future.

Although the neonatal mortality rate in South Africa (SA) has remained stagnant at 12 deaths per 1 000 live births, the infant and under-5 mortality rates have significantly declined since peaking in 2003. Policy changes that have influenced this decline include policies to prevent vertical HIV transmission, earlier treatment of children living with HIV, expanded immunisation policies, strengthening breastfeeding practices, and health policies to contain tobacco and sugar use. The Sustainable Development Goals (2016 - 2030) have shifted the focus from keeping children alive, as expressed in the Millennium Development Goals (1990 - 2015), to achieving optimal health through the 'Survive, thrive and transform' global agenda. This paper focuses on important remaining causes of childhood mortality and morbidity in SA, specifically respiratory illness, environmental pollution, tuberculosis, malnutrition and vaccine-preventable conditions. The monitoring of maternal and child health (MCH) outcomes is crucial, and has improved in SA through both the District Health Information and Civil Registration and Vital Statistics systems, although gaps remain. Intermittent surveys and research augment the routinely collected data. However, availability and use of local data to inform quality and effectiveness of care is critical, and this requires ownership at the collection point to facilitate local redress. Potential game changers to improve MCH outcomes include mobile health and community-based interventions. In SA, improved MCH remains a crucial factor for human capital development. There is a pressing need to focus beyond childhood mortality and to ensure that each child thrives.

Household context and psychosocial impact of childhood multidrug-resistant tuberculosis in KwaZulu-Natal, South Africa.

SETTING: Referral hospital for drug-resistant tuberculosis (TB) in KwaZulu-Natal, South Africa. OBJECTIVES: We conducted interviews with primary care givers of children admitted with multidrug-resistant TB (MDR-TB) during a 3-month period in 2015 to identify broader household challenges. RESULTS: We interviewed 26 care givers, most of whom were women (85%). Most households had been decimated by TB/MDR-TB and human immunodeficiency virus (HIV) infection, and were dependent upon government grants. In 54% of cases, parents were absent due to illness or death, or their whereabouts were not known. The median age of the children treated for MDR-TB was 8 years (range 2-14); 72% were HIV-co-infected. Four themes emerged in the interviews: 1) the psychosocial impact of hospitalisation and separation on the child and the household, 2) the psychosocial impact of MDR-TB on children and 3) on care givers, and 4) the economic hardship of affected households. Children had to contend with multiple diseases and medications, and personal family losses; they faced behavioural, emotional and cognitive difficulties. Care givers were often anxious and concerned about the child's longer-term prospects, while the cost of hospital visits exacerbated the pre-existing economic vulnerability of affected households. CONCLUSION: The socio-economic impact of childhood MDR-TB reverberates beyond diseased children to their affected households. Enhanced social protection, psychosocial support and treatment literacy would create the foundations for family-centred care.

Drug-resistant tuberculosis in patients with minimal symptoms: favourable outcomes in the absence of treatment.

SETTING: Referral hospital for drug-resistant tuberculosis (DR-TB) in KwaZulu-Natal Province, South Africa. OBJECTIVE: To review the clinical outcomes of patients (age  14 years) with a laboratory-confirmed diagnosis of DR-TB who had minimal symptoms and/or did not have chest radiographic evidence of active disease at referral. These patients were not started on treatment, but were enrolled in an observation programme with follow-up at 2, 6 and 12 months. RESULTS: Of 3345 referred patients diagnosed with DR-TB, 192 (6%) were enrolled in the observation programme. The median duration from initial sputum collection in primary care to examination at our hospital was 92 days (IQR 64-124). After 12 months, 120 (62%) patients were well, 36 (19%) were lost to follow-up, 30 (16%) had deteriorated and were started on second-line anti-tuberculosis treatment and 6 (3%) had died. Bilateral disease (OR 4.25, 95%CI 1.14-15.77, P = 0.030) and previous TB (OR 2.14, 95%CI 1.10-4.19, P = 0.026) were independent predictors of an unfavourable end result in a multivariate model. CONCLUSION: In our high-burden setting, most patients diagnosed with DR-TB who had minimal symptoms at referral remained well without treatment. Longitudinal observation, coupled with symptom checking and chest radiograph, is a viable strategy.

Community-based care vs. centralised hospitalisation for MDR-TB patients, KwaZulu-Natal, South Africa.

SETTING: KwaZulu-Natal, South Africa, a predominantly rural province with a high burden of tuberculosis (TB), multidrug-resistant TB (MDR-TB) and human immunodeficiency virus (HIV) infection. OBJECTIVE: To determine the most effective care model by comparing MDR-TB treatment outcomes at community-based sites with traditional care at a central, specialised hospital. DESIGN: A non-randomised observational prospective cohort study comparing community-based and centralised care. Patients at community-based sites were closer to home and had easier access to care, and home-based care was available from treatment initiation. RESULTS: Four community-based sites treated 736 patients, while 813 were treated at the centralised hospital (total = 1549 patients). Overall, 75% were HIV co-infected (community: 76% vs. hospitalised: 73%, P = 0.45) and 86% received antiretroviral therapy (community: 91% vs. hospitalised: 82%, P = 0.22). On multivariate analysis, MDR-TB patients were more likely to have a successful treatment outcome if they were treated at a community-based site (adjusted OR 1.43, P = 0.01). However, outcomes at the four community-based sites were heterogeneous, with Site 1 demonstrating that home-based care was associated with an increased treatment success of 72% compared with success rates of 52-60% at the other three sites. CONCLUSION: Community-based care for MDR-TB patients was more effective than care in a central, specialised hospital. Home-based care further increased treatment success.

Exploring the innate immunological response of an alternative nonhuman primate model of infectious disease; the common marmoset.

The common marmoset (Callithrix jacchus) is increasingly being utilised as a nonhuman primate model for human disease, ranging from autoimmune to infectious disease. In order to fully exploit these models, meaningful comparison to the human host response is necessary. Commercially available reagents, primarily targeted to human cells, were utilised to assess the phenotype and activation status of key immune cell types and cytokines in naive and infected animals. Single cell suspensions of blood, spleen, and lung were examined. Generally, the phenotype of cells was comparable between humans and marmosets, with approximately 63% of all lymphocytes in the blood of marmosets being T cells, 25% B-cells, and 12% NK cells. The percentage of neutrophils in marmoset blood were more similar to human values than mouse values. Comparison of the activation status of cells following experimental systemic or inhalational infection exhibited different trends in different tissues, most obvious in cell types active in the innate immune response. This work significantly enhances the ability to understand the immune response in these animals and fortifies their use as models of infectious disease.

The treatment journey of a patient with multidrug-resistant tuberculosis in South Africa: is it patient-centred?

To improve the treatment of patients co-infected with multidrug-resistant tuberculosis (MDR-TB) and the human immunodeficiency virus, we measured the relationship between treatment outcomes and hospital performance at four decentralised MDR-TB sites in South Africa. We describe hospital performance from the patient's perspective by the use of a graphic that visually represents a patient's treatment journey. The graphic was used to report study findings to study sites and as a catalyst for a quality improvement process.

Integrated, home-based treatment for MDR-TB and HIV in rural South Africa: an alternate model of care.

SETTING: Treatment outcomes for multidrug-resistant tuberculosis (MDR-TB) in South Africa have suffered as centralized, in-patient treatment programs struggle to cope with rising prevalence and human immunodeficiency virus (HIV) co-infection rates. A new treatment model is needed to expand treatment capacity and improve MDR-TB and HIV outcomes. OBJECTIVE: To describe the design and preliminary results of an integrated, home-based MDR-TB-HIV treatment program created in rural KwaZulu-Natal. METHOD: In 2008, a decentralized center was established to provide out-patient MDR-TB and HIV treatment. Nurses, community health workers and family supporters have been trained to administer injections, provide adherence support and monitor adverse reactions in patients' homes. Physicians assess clinical response, adherence and the severity of adverse reactions to MDR-TB and HIV treatment at monthly follow-up visits. Treatment outcomes are assessed by monthly cultures and CD4 and viral load every 6 months. RESULTS: Of 80 patients initiating MDR-TB treatment from February 2008 to April 2010, 66 were HIV-co-infected. Retention has been high (only 5% defaults, 93% of visits attended), and preliminary outcomes have been favorable (77% cured/still on treatment, 82% undetectable viral load). Few patients have required escalation of care (9%), had severe adverse events (8%) or died (6%). CONCLUSION: Integrated, home-based treatment for MDR-TB and HIV is a promising treatment model to expand capacity and achieve improved outcomes in rural, resource-poor and high HIV prevalent settings.

Comparing early treatment outcomes of MDR-TB in decentralised and centralised settings in KwaZulu-Natal, South Africa.

SETTING: In KwaZulu-Natal, South Africa, a setting endemic for tuberculosis (TB) and the human immunodeficiency virus (HIV), prolonged hospitalisation for the treatment of the growing number of multidrug-resistant TB (MDR-TB) patients is neither possible nor effective. OBJECTIVE: To compare early treatment outcomes in patients with MDR-TB with and without HIV co-infection at four decentralised rural sites with a central urban referral hospital. DESIGN: This is an operational, prospective cohort study of patients between 1 July 2008 and 30 November 2009, where culture conversion, time to culture conversion, survival and predictors of these outcomes were analysed. RESULTS: Of 860 patients with MDR-TB, 419 were at the decentralised sites and 441 at the central hospital. Overall, 71% were HIV co-infected. In the 17-month study period, there was a higher proportion of culture conversion at the decentralised sites compared with the centralised hospital (54% vs. 24%, P < 0.001, OR 3.76, 95%CI 2.81-5.03). The median time to treatment initiation was significantly shorter at the decentralised sites compared with the centralised hospital (72 vs. 93 days, P < 0.001). There was no significant difference in survival following treatment initiation. CONCLUSION: In this study, early treatment outcomes suggest that decentralised care for MDR-TB patients is superior to that in a centralised setting.