Prevalence of subclinical pulmonary tuberculosis in adults in community settings: an individual participant data meta-analysis.

BACKGROUND: Subclinical pulmonary tuberculosis, which presents without recognisable symptoms, is frequently detected in community screening. However, the disease category is poorly clinically defined. We explored the prevalence of subclinical pulmonary tuberculosis according to different case definitions. METHODS: We did a one-stage individual participant data meta-analysis of nationally representative surveys that were conducted in countries with high incidence of tuberculosis between 2007 and 2020, that reported the prevalence of pulmonary tuberculosis based on chest x-ray and symptom screening in participants aged 15 years and older. Screening and diagnostic criteria were standardised across the surveys, and tuberculosis was defined by positive Mycobacterium tuberculosis sputum culture. We estimated proportions of subclinical tuberculosis for three case definitions: no persistent cough (ie, duration ≥2 weeks), no cough at all, and no symptoms (ie, absence of cough, fever, chest pain, night sweats, and weight loss), both unadjusted and adjusted for false-negative chest x-rays and uninterpretable culture results. FINDINGS: We identified 34 surveys, of which 31 were eligible. Individual participant data were obtained and included for 12 surveys (620 682 participants) across eight countries in Africa and four in Asia. Data on 602 863 participants were analysed, of whom 1944 had tuberculosis. The unadjusted proportion of subclinical tuberculosis was 59·1% (n=1149/1944; 95% CI 55·8-62·3) for no persistent cough and 39·8% (773/1944; 36·6-43·0) for no cough of any duration. The adjusted proportions were 82·8% (95% CI 78·6-86·6) for no persistent cough and 62·5% (56·6-68·7) for no cough at all. In a subset of four surveys, the proportion of participants with tuberculosis but without any symptoms was 20·3% (n=111/547; 95% CI 15·5-25·1) before adjustment and 27·7% (95% CI 21·0-36·4) after adjustment. Tuberculosis without cough, irrespective of its duration, was more frequent among women (no persistent cough: adjusted odds ratio 0·79, 95% CI 0·63-0·97; no cough: adjusted odds ratio 0·76, 95% CI 0·62-0·93). Among participants with tuberculosis, 29·1% (95% CI 25·2-33·3) of those without persistent cough and 23·1% (18·8-27·4) of those without any cough had positive smear examinations. INTERPRETATION: The majority of people in the community who have pulmonary tuberculosis do not report cough, a quarter report no tuberculosis-suggestive symptoms at all, and a quarter of those not reporting any cough have positive sputum smears, suggesting infectiousness. In high-incidence settings, subclinical tuberculosis could contribute considerably to the tuberculosis burden and to Mycobacterium tuberculosis transmission. FUNDING: Mr Willem Bakhuys Roozeboom Foundation.

How "Subclinical" is Subclinical Tuberculosis? An Analysis of National Prevalence Survey Data from Zambia.

BACKGROUND: Pulmonary tuberculosis infection can manifest in different states, including subclinical tuberculosis. It is commonly defined as confirmed tuberculosis without the classic symptoms (commonly, persistent cough for ≥2 weeks). This narrow definition likely poses limitations for surveillance and control measures. The aims of the current study were to characterize the clinical presentation of tuberculosis; estimate the prevalence of subclinical tuberculosis among individuals with bacteriologically confirmed tuberculosis, using various definitions; and investigate risk factors for subclinical as opposed to clinical tuberculosis in a population-based survey. METHODS: We conducted a secondary analysis of data from a nationally representative tuberculosis prevalence survey from Zambia in 2013-2014, in which participants were screened for tuberculosis based on chest radiographic findings and symptoms. Tuberculosis was defined as culture-positive or GeneXpert MTB/RIF test-positive sputum. Risk factors for subclinical tuberculosis were assessed by means of multivariable logistic regression. RESULTS: Of 257 participants with confirmed tuberculosis, 104 (40.5%) were without cough persisting ≥2 weeks. Only 23 (22.1%) of these did not present with any other common symptoms. Those without cough persisting ≥2 weeks frequently reported other symptoms, particularly chest pain (46.2%) and weight loss (38.5%); 36 (34.6%) reported experiencing other symptoms persisting ≥4 weeks. Female subjects were more likely to report no cough persisting ≥2 weeks, as were relatively wealthier individuals. CONCLUSIONS: The commonly used definition of subclinical tuberculosis includes a large proportion of individuals who have other tuberculosis-suggestive symptoms. Requiring cough ≥2 weeks for tuberculosis diagnosis likely misses many active tuberculosis infections and allows a large reservoir of likely transmissible tuberculosis to remain undetected.

Community case management of malaria using ACT and RDT in two districts in Zambia: achieving high adherence to test results using community health workers.

BACKGROUND: Access to prompt and effective treatment is a cornerstone of the current malaria control strategy. Delays in starting appropriate treatment is a major contributor to malaria mortality. WHO recommends home management of malaria using artemisininbased combination therapy (ACT) and Rapid Diagnostic tests (RDTs) as one of the strategies for improving access to prompt and efective malaria case management. METHODS: A prospective evaluation of the effectiveness of using community health workers (CHWs) as delivery points for ACT and RDTs in the home management of malaria in two districts in Zambia. RESULTS: CHWs were able to manage malaria fevers by correctly interpreting RDT results and appropriately prescribing antimalarials. All severe malaria cases and febrile non-malaria fevers were referred to a health facility for further management. There were variations in malaria prevalence between the two districts and among the villages in each district. 100% and 99.4% of the patients with a negative RDT result were not prescribed an antimalarial in the two districts respectively. No cases progressed to severe malaria and no deaths were recorded during the study period. Community perceptions were positive. CONCLUSION: CHWs are effective delivery points for prompt and effective malaria case management at community level. Adherence to test results is the best ever reported in Zambia. Further areas of implementation research are discussed.

Relative costs and effectiveness of treating uncomplicated malaria in two rural districts in Zambia: implications for nationwide scale-up of home-based management.

BACKGROUND: Malaria case management is one of the key strategies to control malaria. Various studies have demonstrated the feasibility of home management of malaria (HMM). However, data on the costs and effectiveness of artemisinin-based combination therapy (ACT) and rapid diagnostic tests via HMM is limited. METHOD: Cost-effectiveness of home management versus health facility-based management of uncomplicated malaria in two rural districts in Zambia was analysed from a providers' perspective. The sample included 16 community health workers (CHWs) and 15 health facilities. The outcome measure was the cost per case appropriately diagnosed and treated. Costs of scaling-up HMM nationwide were estimated based on the CHW utilisation rates observed in the study. RESULTS: HMM was more cost effective than facility-based management of uncomplicated malaria. The cost per case correctly diagnosed and treated was USD 4.22 for HMM and USD 6.12 for facility level. Utilization and adherence to diagnostic and treatment guidelines was higher in HMM than at a health facility. CONCLUSION: HMM using ACT and RDTs was more efficient at appropriately diagnosing and treating malaria than the health facility level. Scaling up this intervention requires significant investments.

Impact of the large-scale deployment of artemether/lumefantrine on the malaria disease burden in Africa: case studies of South Africa, Zambia and Ethiopia.

Malaria is one of the most significant causes of morbidity and mortality worldwide. Every year, nearly one million deaths result from malaria infection. Malaria can be controlled in endemic countries by using artemisinin-based combination therapy (ACT) in combination with indoor residual spraying (IRS) and insecticide-treated nets (ITNs). At least 40 malaria-endemic countries in sub-Saharan Africa now recommend the use of ACT as first-line treatment for uncomplicated falciparum malaria as a cornerstone of their malaria case management. The scaling up of malaria control strategies in Zambia has dramatically reduced the burden of malaria. Zambia was the first African country to adopt artemether/lumefantrine (AL; Coartem) as first-line therapy in national malaria treatment guidelines in 2002. Further, the vector control with IRS and ITNs was also scaled up. By 2008, the rates of in-patient malaria cases and deaths decreased by 61% and 66%, respectively, compared with the 2001-2002 reference period. Treatment with AL as first-line therapy against a malaria epidemic in the KwaZulu-Natal province of South Africa, in combination with strengthening of vector control, caused the number of malaria-related outpatient cases and hospital admissions to each fall by 99% from 2001 to 2003, and malaria-related deaths decreased by 97% over the same period. A prospective study also showed that gametocyte development was prevented in all patients receiving AL. This reduction in malaria morbidity has been sustained over the past seven years. AL was introduced as first-line anti-malarial treatment in 2004 in the Tigray region of Ethiopia. During a major malaria epidemic from May-October 2005, the district in which local community health workers were operating had half the rate of malaria-related deaths compared with the district in which AL was only available in state health facilities. Over the two-year study period, the community-based deployment of AL significantly lowered the risk of malaria-specific mortality by 37%. Additionally, the malaria parasite reservoir was three-fold lower in the intervention district than in the control district during the 2005 high-transmission season. Artemisinin-based combination therapy has made a substantial contribution to reducing the burden of malaria in sub-Saharan Africa.

Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria.

BACKGROUND: Although the molecular basis of resistance to a number of common antimalarial drugs is well known, a geographic description of the emergence and dispersal of resistance mutations across Africa has not been attempted. To that end we have characterised the evolutionary origins of antifolate resistance mutations in the dihydropteroate synthase (dhps) gene and mapped their contemporary distribution. METHODS AND FINDINGS: We used microsatellite polymorphism flanking the dhps gene to determine which resistance alleles shared common ancestry and found five major lineages each of which had a unique geographical distribution. The extent to which allelic lineages were shared among 20 African Plasmodium falciparum populations revealed five major geographical groupings. Resistance lineages were common to all sites within these regions. The most marked differentiation was between east and west African P. falciparum, in which resistance alleles were not only of different ancestry but also carried different resistance mutations. CONCLUSIONS: Resistant dhps has emerged independently in multiple sites in Africa during the past 10-20 years. Our data show the molecular basis of resistance differs between east and west Africa, which is likely to translate into differing antifolate sensitivity. We have also demonstrated that the dispersal patterns of resistance lineages give unique insights into recent parasite migration patterns.

Cost-effectiveness analysis of the available strategies for diagnosing malaria in outpatient clinics in Zambia.

BACKGROUND: Malaria in Zambia accounts for about 4 million clinical cases and 8 000 deaths annually. Artemether-lumefantrine (ACT), a relatively expensive drug, is being used as first line treatment of uncomplicated malaria. However, diagnostic capacity in Zambia is low, leading to potentially avoidable wastage of drugs due to unnecessary anti malarial treatment. METHODS: A cost-effectiveness evaluation of the three current alternatives to malaria diagnosis (clinical, microscopy and Rapid Diagnostic Tests- RDT) was conducted in 12 facilities from 4 districts in Zambia. The analysis was conducted along an observational study, thus reflecting practice in health facilities under routine conditions. Average and incremental cost effectiveness ratios were estimated from the providers' perspective. Effectiveness was measured in relation to malaria cases correctly diagnosed by each strategy. RESULTS: Average cost-effectiveness ratios show that RDTs were more efficient (US$ 6.5) than either microscopy (US$ 11.9) or clinical diagnosis (US$ 17.1) for malaria case correctly diagnosed. In relation to clinical diagnoses the incremental cost per case correctly diagnosed and treated was US$ 2.6 and US$ 9.6 for RDT and microscopy respectively. RDTs would be much cheaper to scale up than microscopy. The findings were robust to changes in assumptions and various parameters. CONCLUSION: RDTs were the most cost effective method at correctly diagnosing malaria in primary health facilities in Zambia when compared to clinical and microscopy strategies. However, the treatment prescription practices of the health workers can impact on the potential that a diagnostic test has to lead to savings on antimalarials. The results of this study will serve to inform policy makers on which alternatives will be most efficient in reducing malaria misdiagnosis by taking into account both the costs and effects of each strategy.

Early results of integrated malaria control and implications for the management of fever in under-five children at a peripheral health facility: a case study of Chongwe rural health centre in Zambia.

BACKGROUND: Zambia has taken lead in implementing integrated malaria control so as to attain the National Health Strategic Plan goal of "reducing malaria incidence by 75% and under-five mortality due to malaria by 20% by the year 2010". The strategic interventions include the use of long-lasting insecticide-treated nets and indoor residual spraying, the use of artemisinin-based combination therapies (ACT) for the treatment of uncomplicated malaria, improving diagnostic capacity (both microscopy and rapid diagnostic tests), use of intermittent presumptive treatment for pregnant women, research, monitoring and evaluation, and behaviour change communication. Financial barriers to access have been removed by providing free malaria prevention and treatment services. METHODS: Data involving all under-five children reporting at the health facility in the first quarter of 2008 was evaluated prospectively. Malaria morbidity, causes of non-malaria fever, prescription patterns treatment patterns and referral cases were evaluated RESULTS: Malaria infection was found only in 0.7% (10/1378), 1.8% (251378) received anti-malarial treatment, no severe malaria cases and deaths occurred among the under-five children with fever during the three months of the study in the high malaria transmission season. 42.5% (586/1378) of the cases were acute respiratory infections (non-pneumonia), while 5.7% (79/1378) were pneumonia. Amoxicillin was the most prescribed antibiotic followed by septrin. CONCLUSION: Malaria related OPD visits have reduced at Chongwe rural health facility. The reduction in health facility malaria cases has led to an increase in diagnoses of respiratory infections. These findings have implications for the management of non-malaria fevers in children under the age of five years.

From chloroquine to artemether-lumefantrine: the process of drug policy change in Zambia.

BACKGROUND: Following the recognition that morbidity and mortality due to malaria had dramatically increased in the last three decades, in 2002 the government of Zambia reviewed its efforts to prevent and treat malaria. Convincing evidence of the failing efficacy of chloroquine resulted in the initiation of a process that eventually led to the development and implementation of a new national drug policy based on artemisinin-based combination therapy (ACT). METHODS: All published and unpublished documented evidence dealing with the antimalarial drug policy change was reviewed. These data were supplemented by the authors' observations of the policy change process. The information has been structured to capture the timing of events, the challenges encountered, and the resolutions reached in order to achieve implementation of the new treatment policy. RESULTS: A decision was made to change national drug policy to artemether-lumefantrine (AL) in the first quarter of 2002, with a formal announcement made in October 2002. During this period, efforts were undertaken to identify funding for the procurement of AL and to develop new malaria treatment guidelines, training materials, and plans for implementation of the policy. In order to avoid a delay in implementation, the policy change decision required a formal adoption within existing legislation. Starting with donated drug, a phased deployment of AL began in January 2003 with initial use in seven districts followed by scaling up to 28 districts in the second half of 2003 and then to all 72 districts countrywide in early 2004. CONCLUSION: Drug policy changes are not without difficulties and demand a sustained international financing strategy for them to succeed. The Zambian experience demonstrates the need for a harmonized national consensus among many stakeholders and a political commitment to ensure that new policies are translated into practice quickly. To guarantee effective policies requires more effort and recognition that this becomes a health system and not a drug issue. This case study attempts to document the successful experience of change to ACT in Zambia and provides a realistic overview of some of the painful experiences and important lessons learnt.

Improved diagnostic testing and malaria treatment practices in Zambia.

CONTEXT: Improving the accuracy of malaria diagnosis with rapid antigen-detection diagnostic tests (RDTs) has been proposed as an approach for reducing overtreatment of malaria in the current era of widespread implementation of artemisinin-based combination therapy in sub-Saharan Africa. OBJECTIVE: To assess the association between use of microscopy and RDT and the prescription of antimalarials. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional, cluster sample survey, carried out between March and May 2006, of all outpatients treated during 1 working day at government and mission health facilities in 4 sentinel districts in Zambia. MAIN OUTCOME MEASURE: Proportions of patients undergoing malaria diagnostic procedures and receiving antimalarial treatment. RESULTS: Seventeen percent of the 104 health facilities surveyed had functional microscopy, 63% had RDTs available, and 73% had 1 or more diagnostics available. Of patients with fever (suspected malaria), 27.8% (95% confidence interval [CI], 13.1%-42.5%) treated in health facilities with malaria diagnostics were tested and 44.6% had positive test results. Of patients with negative blood smear results, 58.4% (95% CI, 36.7%-80.2%) were prescribed an antimalaria drug, as were 35.5% (95% CI, 16.0%-55.0%) of those with a negative RDT result. Of patients with fever who did not have diagnostic tests done, 65.9% were also prescribed antimalarials. In facilities with artemether-lumefantrine in stock, this antimalarial was prescribed to a large proportion of febrile patients with a positive diagnostic test result (blood smear, 75.0% [95% CI, 51.7%-98.3%]; RDT, 70.4% [95% CI, 39.3%-100.0%]), but also to some of those with a negative diagnostic test result (blood smear, 30.4% [95% CI, 8.0%-52. 9%]; RDT, 26.7% [95% CI, 5.7%-47.7%]). CONCLUSIONS: Despite efforts to expand the provision of malaria diagnostics in Zambia, they continue to be underused and patients with negative test results frequently receive antimalarials. Provision of new tools to reduce inappropriate use of new expensive antimalarial treatments must be accompanied by a major change in clinical treatment of patients presenting with fever but lacking evidence of malaria infection.

Paediatric malaria case-management with artemether-lumefantrine in Zambia: a repeat cross-sectional study.

BACKGROUND: Zambia was the first African country to change national antimalarial treatment policy to artemisinin-based combination therapy--artemether-lumefantrine. An evaluation during the early implementation phase revealed low readiness of health facilities and health workers to deliver artemether-lumefantrine, and worryingly suboptimal treatment practices. Improvements in the case-management of uncomplicated malaria two years after the initial evaluation and three years after the change of policy in Zambia are reported. METHODS: Data collected during the health facility surveys undertaken in 2004 and 2006 at all outpatient departments of government and mission facilities in four Zambian districts were analysed. The surveys were cross-sectional, using a range of quality of care assessment methods. The main outcome measures were changes in health facility and health worker readiness to deliver artemether-lumefantrine, and changes in case-management practices for children below five years of age presenting with uncomplicated malaria as defined by national guidelines. RESULTS: In 2004, 94 health facilities, 103 health workers and 944 consultations for children with uncomplicated malaria were evaluated. In 2006, 104 facilities, 135 health workers and 1125 consultations were evaluated using the same criteria of selection. Health facility and health worker readiness improved from 2004 to 2006: availability of artemether-lumefantrine from 51% (48/94) to 60% (62/104), presence of artemether-lumefantrine dosage wall charts from 20% (19/94) to 75% (78/104), possession of guidelines from 58% (60/103) to 92% (124/135), and provision of in-service training from 25% (26/103) to 41% (55/135). The proportions of children with uncomplicated malaria treated with artemether-lumefantrine also increased from 2004 to 2006: from 1% (6/527) to 27% (149/552) in children weighing 5 to 9 kg, and from 11% (42/394) to 42% (231/547) in children weighing 10 kg or more. In both weight groups and both years, 22% (441/2020) of children with uncomplicated malaria were not prescribed any antimalarial drug. CONCLUSION: Although significant improvements in malaria case-management have occurred over two years in Zambia, the quality of treatment provided at the point of care is not yet optimal. Strengthening weak health systems and improving the delivery of effective interventions should remain high priority in all countries implementing new treatment policies for malaria.

A cost-effectiveness analysis of artemether lumefantrine for treatment of uncomplicated malaria in Zambia.

BACKGROUND: Malaria remains a leading cause of morbidity, mortality and non-fatal disability in Zambia, especially among children, pregnant women and the poor. Data gathered by the National Malaria Control Centre has shown that recently observed widespread treatment failure of SP and chloroquine precipitated a surge in malaria-related morbidity and mortality. As a result, the Government has recently replaced chloroquine and SP with combination therapy as first-line treatment for malaria. Despite the acclaimed therapeutic advantages of ACTs over monotherapies with SP and CQ, the cost of ACTs is much greater, raising concerns about affordability in many poor countries such as Zambia. This study evaluates the cost-effectiveness analysis of artemether-lumefantrine, a version of ACTs adopted in Zambia in mid 2004. METHODS: Using data gathered from patients presenting at public health facilities with suspected malaria, the costs and effects of using ACTs versus SP as first-line treatment for malaria were estimated. The study was conducted in six district sites. Treatment success and reduction in demand for second line treatment constituted the main effectiveness outcomes. The study gathered data on the efficacy of, and compliance to, AL and SP treatment from a random sample of patients. Costs are based on estimated drug, labour, operational and capital inputs. Drug costs were based on dosages and unit prices provided by the Ministry of Health and the manufacturer (Norvatis). FINDINGS: The results suggest that AL produces successful treatment at less cost than SP, implying that AL is more cost-effective. While it is acknowledged that implementing national ACT program will require considerable resources, the study demonstrates that the health gains (treatment success) from every dollar spent are significantly greater if AL is used rather than SP. The incremental cost-effectiveness ratio is estimated to be 4.10 US dollars. When the costs of second line treatment are considered the ICER of AL becomes negative, indicating that there are greater resource savings associated with AL in terms of reduction of costs of complicated malaria treatment. CONCLUSION: This study suggests the decision to adopt AL is justifiable on both economic and public health grounds.

Assessment of the therapeutic efficacy of a paediatric formulation of artemether-lumefantrine (Coartesiane) for the treatment of uncomplicated Plasmodium falciparum in children in Zambia.

BACKGROUND: Sentinel site surveillance of antimalarials by in-vivo therapeutic efficacy studies in Zambia is one of the key activities ear-marked for monitoring and evaluation. The studies are conducted annually in order to provide timely and reliable information on the status of the recommended regimens for malaria case management. The findings of the therapeutic efficacy of an artemisinin-based combination therapy of pediatric artemether-lumefantrine (Coartesiane) are reported. METHOD: The design is a simple, one-arm, prospective evaluation of the clinical and parasitological response to directly observed treatment for uncomplicated malaria. The study was conducted in sentinel sites using the WHO standardized protocol for the assessment of therapeutic efficacy of antimalarial drugs (WHO 2000) in children under five years of age, weighing less than 10 Kg. The study was conducted at two clinics, one in Chongwe (Lusaka Province) and Chipata (Eastern Province). The 28-day follow-up period was used coupled with PCR genotyping for MSP1 and MSP2 in order to differentiate recrudescence from re-infections for parasites that appeared after Day 14. RESULTS: 91/111 children enrolled in the study, were successfully followed up. Artemether-lumefantrine (Coartesiane) was found to produce significant gametocyte reduction. The Adequate Clinical and Parasitological Response (ACPR) was found to be 100% (95% CI 96.0;100). CONCLUSION: Coartesiane was effective in treating uncomplicated malaria in Zambian children weighing less than 10 kg, an age group normally excluded from taking the tablet formulation of artemether-lumefantrine (Coartem).

Assessment of the therapeutic efficacy of a paediatric formulation of artemether-lumefantrine (Co-artesiane(R)) for the treatment of uncomplicated Plasmodium falciparumin children in Zambia

Background Sentinel site surveillance of antimalarials by in-vivo therapeutic efficacy studies in Zambia is one of the key activities ear-marked for monitoring and evaluation. The studies are conducted annually in order to provide timely and reliable information on the status of the recommended regimens for malaria case management. The findings of the therapeutic efficacy of an artemisinin-based combination therapy of pediatric artemether-lumefantrine (Coartesiane(R)) are reported. Method The design is a simple; one-arm; prospective evaluation of the clinical and parasitological response to directly observed treatment for uncomplicated malaria. The study was conducted in sentinel sites using the WHO standardized protocol for the assessment of therapeutic efficacy of antimalarial drugs (WHO 2000) in children under five years of age; weighing less than 10Kg. The study was conducted at two clinics; one in Chongwe (Lusaka Province) and Chipata (Eastern Province). The 28-day follow-up period was used coupled with PCR genotyping for MSP1 and MSP2 in order to differentiate recrudescence from re-infections for parasites that appeared after Day 14. Results 91/111 children enrolled in the study; were successfully followed up. Artemether-lumefantrine (Co-artesiane(R)) was found to produce significant gametocyte reduction. The Adequate Clinical and Parasitological Response (ACPR) was found to be 100(95CI 96.0;100). Conclusion Coartesiane(R) was effective in treating uncomplicated malaria in Zambian children weighing less than 10 kg; an age group normally excluded from taking the tablet formulation of artemether-lumefantrine (Coartem(R))