Theron G.,Lung Infection and Immunity Unit |
Zijenah L.,University of Zimbabwe |
Chanda D.,University of Lusaka |
Clowes P.,National Institute of Medical Research |
And 16 more authors.
The Lancet | Year: 2014
Background: The Xpert MTB/RIF test for tuberculosis is being rolled out in many countries, but evidence is lacking regarding its implementation outside laboratories, ability to inform same-day treatment decisions at the point of care, and clinical effect on tuberculosis-related morbidity. We aimed to assess the feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing at primary-care health-care facilities in southern Africa. Methods: In this pragmatic, randomised, parallel-group, multicentre trial, we recruited adults with symptoms suggestive of active tuberculosis from five primary-care health-care facilities in South Africa, Zimbabwe, Zambia, and Tanzania. Eligible patients were randomly assigned using pregenerated tables to nurse-performed Xpert MTB/RIF at the clinic or sputum smear microscopy. Participants with a negative test result were empirically managed according to local WHO-compliant guidelines. Our primary outcome was tuberculosis-related morbidity (measured with the TBscore and Karnofsky performance score [KPS]) in culture-positive patients who had begun anti-tuberculosis treatment, measured at 2 months and 6 months after randomisation, analysed by intention to treat. This trial is registered with Clinicaltrials. gov, number NCT01554384. Findings: Between April 12, 2011, and March 30, 2012, we randomly assigned 758 patients to smear microscopy (182 culture positive) and 744 to Xpert MTB/RIF (185 culture positive). Median TBscore in culture-positive patients did not diff er between groups at 2 months (2 [IQR 0-3] in the smear microscopy group vs 2 [0·25-3] in the MTB/RIF group; p=0·85) or 6 months (1 [0-3] vs 1 [0-3]; p=0·35), nor did median KPS at 2 months (80 [70-90] vs 90 [80-90]; p=0·23) or 6 months (100 [90-100] vs 100 [90-100]; p=0·85). Point-of-care MTB/RIF had higher sensitivity than microscopy (154 [83%] of 185 vs 91 [50%] of 182; p=0·0001) but similar specificity (517 [95%] 544 vs 540 [96%] of 560; p=0·25), and had similar sensitivity to laboratory-based MTB/RIF (292 [83%] of 351; p=0·99) but higher specificity (952 [92%] of 1037; p=0·0173). 34 (5%) of 744 tests with point-of-care MTB/RIF and 82 (6%) of 1411 with laboratory-based MTB/RIF failed (p=0·22). Compared with the microscopy group, more patients in the MTB/RIF group had a same-day diagnosis (178 [24%] of 744 vs 99 [13%] of 758; p<0·0001) and same-day treatment initiation (168 [23%] of 744 vs 115 [15%] of 758; p=0·0002). Although, by end of the study, more culture-positive patients in the MTB/RIF group were on treatment due to reduced dropout (15 [8%] of 185 in the MTB/RIF group did not receive treatment vs 28 [15%] of 182 in the microscopy group; p=0·0302), the proportions of all patients on treatment in each group by day 56 were similar (320 [43%] of 744 in the MTB/RIF group vs 317 [42%] of 758 in the microscopy group; p=0·6408). Interpretation: Xpert MTB/RIF can be accurately administered by a nurse in primary-care clinics, resulting in more patients starting same-day treatment, more culture-positive patients starting therapy, and a shorter time to treatment. However, the benefits did not translate into lower tuberculosis-related morbidity, partly because of high levels of empirical-evidence-based treatment in smear-negative patients. Funding European and Developing Countries Clinical Trials Partnership, National Research Foundation, and Claude Leon Foundation.
Ngalamika O.,Central South University |
Ngalamika O.,University of Lusaka |
Zhang Y.,Central South University |
Yin H.,Central South University |
And 3 more authors.
Journal of Autoimmunity | Year: 2012
The relationships between immunological dysfunction, loss of tolerance and hematologic malignancies have been a focus of attention in attempts to understand the appearance of a higher degree of autoimmune disease and lymphoma in children with congenital immunodeficiency. Although multiple hypotheses have been offered, it is clear that stochastic processes play an important role in the immunopathology of these issues. In particular, accumulating evidence is defining a role of epigenetic mechanisms as being critical in this continuous spectrum between autoimmunity and lymphoma. In this review, we focus attention predominantly on the relationships between T helper 17 (Th17) and T regulatory populations that alter local microenvironments and ultimately the expression or transcription factors involved in cell activation and differentiation. Abnormal expression in any of the molecules involved in Th17 and/or Treg development alter immune homeostasis and in genetically susceptible hosts may lead to the appearance of autoimmunity and/or lymphoma. These observations have clinical significance in explaining the discordance of autoimmunity in identical twins. They are also particularly important in the relationships between primary immune deficiency syndromes, immune dysregulation and an increased risk of lymphoma. Indeed, defining the factors that determine epigenetic alterations and their relationships to immune homeostasis will be a challenge greater or even equal to the human genome project. © 2012 Elsevier Ltd.
Andrews B.,Vanderbilt University |
Andrews B.,University of Zambia |
Muchemwa L.,University of Zambia |
Lakhi S.,University of Zambia |
And 3 more authors.
Critical Care Medicine | Year: 2014
Objective: To assess the efficacy of a simple, goal-directed sepsis treatment protocol for reducing mortality in patients with severe sepsis in Zambia. Design: Single-center nonblinded randomized controlled trial. Setting: Emergency department, ICU, and medical wards of the national referral hospital in Lusaka, Zambia. Patients: One hundred twelve patients enrolled within 24 hours of admission with severe sepsis, defined as systemic inflammatory response syndrome with suspected infection and organ dysfunction Interventions: Simplified Severe Sepsis Protocol consisting of up to 4 L of IV fluids within 6 hours, guided by jugular venous pressure assessment, and dopamine and/or blood transfusion in selected patients. Control group was managed as usual care. Blood cultures were collected and early antibiotics administered for both arms. Measurements and Main Results: Primary outcome was in-hospital all-cause mortality. One hundred nine patients were included in the final analysis and 88 patients (80.7%) were HIV positive. Pulmonary infections were the most common source of sepsis. In-hospital mortality rate was 64.2% in the intervention group and 60.7% in the control group (relative risk, 1.05; 95% CI, 0.79-1.41). Mycobacterium tuberculosis complex was isolated from 31 of 82 HIV-positive patients (37.8%) with available mycobacterial blood culture results. Patients in Simplified Severe Sepsis Protocol received significantly more IV fluids in the first 6 hours (2.7 L vs 1.7 L, p = 0.002). The study was stopped early because of high mortality rate among patients with hypoxemic respiratory failure in the intervention arm (8/8, 100%) compared with the control arm (7/10, 70%; relative risk, 1.43; 95% CI, 0.95-2.14). Conclusion: Factors other than tissue hypoperfusion probably account for much of the end-organ dysfunction in African patients with severe sepsis. Studies of fluid-based interventions should utilize inclusion criteria to accurately capture patients with hypovolemia and tissue hypoperfusion who are most likely to benefit from fluids. Exclusion of patients with severe respiratory distress should be considered when ventilatory support is not readily available. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.
Topp S.M.,University of Alabama at Birmingham |
Chipukuma J.M.,University of Lusaka
Health Policy and Planning | Year: 2015
Background Despite being central to achieving improved population health outcomes, primary health centres in low-and middle-income settings continue to underperform. Little research exists to adequately explain how and why this is the case. This study aimed to test the relevance and usefulness of an adapted conceptual framework for improving our understanding of the mechanisms and causal pathways influencing primary health centre performance. Methods A theory-driven, case-study approach was adopted. Four Zambian health centres were purposefully selected with case data including health-care worker interviews (n = 60); patient interviews (n = 180); direct observation of facility operations (2 weeks/centre) and key informant interviews (n = 14). Data were analysed to understand how the performance of each site was influenced by the dynamic interactions between system 'hardware' and 'software' acting on mechanisms of accountability. Findings Structural constraints including limited resources created challenging service environments in which work overload and stockouts were common. Health workers' frustration with such conditions interacted with dissatisfaction with salary levels eroding service values and acting as a catalyst for different forms of absenteeism. Such behaviours exacerbated patient-provider ratios and increased the frequency of clinical and administrative shortcuts. Weak health information systems and lack of performance data undermined providers' answerability to their employer and clients, and a lack of effective sanctions undermined supervisors' ability to hold providers accountable for these transgressions. Weak answerability and enforceability contributed to a culture of impunity that masked and condoned weak service performance in all four sites. Conclusions Health centre performance is influenced by mechanisms of accountability, which are in turn shaped by dynamic interactions between system hardware and system software. Our findings confirm the usefulness of combining Sheikh et al.'s (2011) hardware-software model with Brinkerhoff's (2004) typology of accountability to better understand how and why health centre micro-systems perform (or under-perform) under certain conditions. © 2014 The Author.
Cryptococcal meningitis screening and community-based early adherence support in people with advanced HIV infection starting antiretroviral therapy in Tanzania and Zambia: An open-label, randomised controlled trial
Mfinanga S.,National Institute for Medical Research |
Chanda D.,University of Lusaka |
Kivuyo S.L.,National Institute for Medical Research |
Guinness L.,London School of Hygiene and Tropical Medicine |
And 11 more authors.
The Lancet | Year: 2015
Summary Background Mortality in people in Africa with HIV infection starting antiretroviral therapy (ART) is high, particularly in those with advanced disease. We assessed the effect of a short period of community support to supplement clinic-based services combined with serum cryptococcal antigen screening. Methods We did an open-label, randomised controlled trial in six urban clinics in Dar es Salaam, Tanzania, and Lusaka, Zambia. From February, 2012, we enrolled eligible individuals with HIV infection (age 18 years, CD4 count of <200 cells per μL, ART naive) and randomly assigned them to either the standard clinic-based care supplemented with community support or standard clinic-based care alone, stratified by country and clinic, in permuted block sizes of ten. Clinic plus community support consisted of screening for serum cryptococcal antigen combined with antifungal therapy for patients testing antigen positive, weekly home visits for the first 4 weeks on ART by lay workers to provide support, and in Tanzania alone, re-screening for tuberculosis at 6-8 weeks after ART initiation. The primary endpoint was all-cause mortality at 12 months, analysed by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISCRTN 20410413. Findings Between Feb 9, 2012, and Sept 30, 2013, 1001 patients were randomly assigned to clinic plus community support and 998 to standard care. 89 (9%) of 1001 participants in the clinic plus community support group did not receive their assigned intervention, and 11 (1%) of 998 participants in the standard care group received a home visit or a cryptococcal antigen screen rather than only standard care. At 12 months, 25 (2%) of 1001 participants in the clinic plus community support group and 24 (2%) of 998 participants in the standard care group had been lost to follow-up, and were censored at their last visit for the primary analysis. At 12 months, 134 (13%) of 1001 participants in the clinic plus community support group had died compared with 180 (18%) of 998 in the standard care group. Mortality was 28% (95% CI 10-43) lower in the clinic plus community support group than in standard care group (p=0·004). Interpretation Screening and pre-emptive treatment for cryptococcal infection combined with a short initial period of adherence support after initiation of ART could substantially reduce mortality in HIV programmes in Africa. Funding European and Developing Countries Clinical Trials Partnership. © 2015 Elsevier Ltd.
Leadford A.E.,University of Alabama at Birmingham |
Warren J.B.,Oregon Health And Science University |
Manasyan A.,University of Alabama at Birmingham |
Manasyan A.,Center for Infectious Disease Research in |
And 4 more authors.
Pediatrics | Year: 2013
BACKGROUND AND OBJECTIVES: Hypothermia contributes to neonatal mortality and morbidity, especially in preterm and low birth weight infants in developing countries. Plastic bags covering the trunk and extremities of very low birth weight infants reduces hypothermia. This technique has not been studied in larger infants or in many resourcelimited settings. The objective was to determine if placing preterm and low birth weight infants inside a plastic bag at birth maintains normothermia. METHODS: Infants at 26 to 36 weeks' gestational age and/or with a birth weight of 1000 to 2500 g born at the University Teaching Hospital in Lusaka, ZMB, were randomized by using a 1:1 allocation and parallel design to standard thermoregulation (blanket or radiant warmer) care or to standard thermoregulation care plus placement inside a plastic bag at birth. The primary outcome measure was axillary temperature in the World Health Organization-defined normal range (36.5-37.5°C) at 1 hour after birth. RESULTS: A total of 104 infants were randomized. At 1 hour after birth, infants randomized to plastic bag (n = 49) were more likely to have a temperature in the normal range as compared with infants in the standard thermoregulation care group (n = 55; 59.2% vs 32.7%; relative risk 1.81; 95% confidence interval 1.16-2.81; P = .007). The temperature at 1 hour after birth in the infants randomized to plastic bag was 36.5 ± 0.5°C compared with 36.1 ± 0.6°C in standard care infants (P < .001). Hyperthermia (>38.0°C) did not occur in any infant. CONCLUSIONS: Placement of preterm/low birth weight infants inside a plastic bag at birth compared with standard thermoregulation care reduced hypothermia without resulting in hyperthermia, and is a lowcost, low-technology tool for resource-limited settings. Pediatrics 2013;132:e128-e134. Copyright © 2013 by the American Academy of Pediatrics.
Tikly M.,University of Witwatersrand |
Njobvu P.,University of Lusaka |
McGill P.,Stobhill NHS Trust Hospital
Current Rheumatology Reports | Year: 2014
Spondyloarthritis (SpA) is generally uncommon in sub-Saharan Africa, in part because of the rarity of HLA-B27 in this region. However, the relationship between HLA-B27 and SpA, particularly ankylosing spondylitis (AS), is complex. Despite the HLA-B*27:05 risk allele occurring in some West African populations, associated AS is not seen. In fact, most patients with AS are HLA-B27-negative, although there is emerging evidence that another class I HLA molecule, HLA-B*14:03, is associated with AS in black Africans. The Assessment of SpondyloArthritis International Society criteria for detecting early axial disease are of limited value in sub-Saharan Africa, because of both the rarity of HLA-B27 and very limited access to magnetic resonance imaging. Reactive arthritis (ReA), psoriatic arthritis, and undifferentiated SpA are seen mainly in the context of HIV infection, although the exact effect of the virus in the pathogenesis of arthritis is unclear. In Zambia, ReA is associated with the HLA-B*57:03 allele, which is paradoxically also associated with slow progression of HIV infection. HIV-associated ReA has a more protracted and aggressive course than standard ReA. Enthesitis-related arthritis is more common in children infected with HIV by vertical mother-to child transmission. Use of TNF inhibitors for axial disease is problematic, mainly because of cost, but also because of potential safety problems, especially reactivation of tuberculosis. © Springer Science+Business Media 2014.
Filteau S.,University of Lusaka |
Baisley K.,London School of Hygiene and Tropical Medicine |
Chisenga M.,University of Lusaka |
Kasonka L.,University of Lusaka |
Gibson R.S.,University of Otago
Journal of Acquired Immune Deficiency Syndromes | Year: 2011
Background: HIV-exposed, uninfected (HIV-EU) children represent a large proportion of children in southern Africa. The reasons for their poorer growth and higher morbidity and mortality than their HIV-unexposed peers are unclear. Objective: We compared anthropometry of 125 HIV-EU with 382 HIV-unexposed young Zambian children participating in a trial of micronutrient-fortified complementary/replacement food. Design: The randomized controlled trial provided children from age 6 to 18 months with a porridge flour containing either a basal or a rich level of micronutrients. Weight and length were measured 3 monthly and head and arm circumferences and triceps and subscapular skinfolds 6 monthly. Results: There were no significant anthropometric differences between the 2 treatment groups. In unadjusted analyses, most anthropometric Z scores of HIV-EU children were lower than those of HIV-unexposed children; after adjustment for treatment arm, socioeconomic factors, breastfeeding and sex, head and arm circumference Z scores remained lower. Subscapular skinfold Z scores were lower among HIV-EU than HIV-unexposed children at 6 months but not 18 months. Conclusions: Socioeconomic factors accounted for some but not all of the impaired growth of HIV-EU children. Micronutrient malnutrition may not be the socioeconomic factor responsible for the growth faltering. Factors acting earlier in life had irreversible effects. © 2011 Lippincott Williams & Wilkins.
Prendergast A.,Zvitambo Project |
Prendergast A.,University of Lusaka |
Prendergast A.,Queen Mary, University of London |
Kelly P.,Zvitambo Project |
And 2 more authors.
American Journal of Tropical Medicine and Hygiene | Year: 2012
A spectrum of enteropathies, characterized by small intestinal inflammation, reduced absorptive capacity, and increased intestinal permeability, commonly affect people in developing countries. This subclinical intestinal pathology facilitates microbial translocation across the compromised intestinal barrier, leading to chronic systemic inflammation that may adversely impact health. Environmental enteropathy (EE), ubiquitous among people living in unhygienic conditions, likely mediates two interlinked public health problems of childhood, stunting and anemia, and underlies poor oral vaccine efficacy in developing countries. Human immunodeficiency virus (HIV) enteropathy, which frequently overlaps with EE, may contribute to immune activation and modulate HIV disease progression. The interacting effects of infection and enteropathy drive a vicious cycle that can propagate severe acute malnutrition, which underlies almost half of under-5-y deaths. Enteropathies are therefore highly prevalent, interacting causes of morbidity and mortality in developing countries. Interventions to prevent or ameliorate enteropathies have potential to improve the health of millions of people in developing countries. Copyright © 2012 by The American Society of Tropical Medicine and Hygiene.
Hayashida K.,Hokkaido University |
Hayashida K.,Obihiro University of Agriculture and Veterinary Medicine |
Kajino K.,Hokkaido University |
Hachaambwa L.,University of Lusaka |
And 2 more authors.
PLoS Neglected Tropical Diseases | Year: 2015
Loop-mediated isothermal amplification (LAMP) is a rapid and sensitive tool used for the diagnosis of a variety of infectious diseases. One of the advantages of this method over the polymerase chain reaction is that DNA amplification occurs at a constant temperature, usually between 60–65°C; therefore, expensive devices are unnecessary for this step. However, LAMP still requires complicated sample preparation steps and a well-equipped laboratory to produce reliable and reproducible results, which limits its use in resource-poor laboratories in most developing countries. In this study, we made several substantial modifications to the technique to carry out on-site diagnosis of Human African Trypanosomiasis (HAT) in remote areas using LAMP. The first essential improvement was that LAMP reagents were dried and stabilized in a single tube by incorporating trehalose as a cryoprotectant to prolong shelf life at ambient temperature. The second technical improvement was achieved by simplifying the sample preparation step so that DNA or RNA could be amplified directly from detergent-lysed blood samples. With these modifications, diagnosis of HAT in local clinics or villages in endemic areas becomes a reality, which could greatly impact on the application of diagnosis not only for HAT but also for other tropical diseases. © 2015 Hayashida et al.