Mid-level healthcare workers knowledge on non-communicable diseases in Tanzania: a district-level pre-and post-training assessment.

INTRODUCTION: Over the past two decades, Tanzania's burden of non-communicable diseases has grown disproportionately, but limited resources are still prioritized. A trained human resource for health is urgently needed to combat these diseases. However, continuous medical education for NCDs is scarce. This paper reports on the mid-level healthcare workers knowledge on NCDs. We assessed the knowledge to measure the effectiveness of the training conducted during the initiation of a Package for Essential Management of Severe NCDs (PEN Plus) in rural district hospitals in Tanzania. METHODS: The training was given to 48 healthcare employees from Dodoma Region's Kondoa Town Council District Hospital. For a total of five (5) days, a fundamental course on NCDs featured in-depth interactive lectures and practical workshops. Physicians from Tanzania's higher education institutions, tertiary university hospitals, research institutes, and medical organizations served as trainers. Before and after the training, a knowledge assessment comprising 28 questions was administered. Descriptive data analysis to describe the characteristics of the specific knowledge on physiology, diagnosis and therapy of diabetes mellitus, rheumatic fever, heart disease, and sickle cell disease was done using Stata version 17 (STATA Corp Inc., TX, USA). RESULTS: Complete assessment data for 42 out of the 48 participants was available. Six participants did not complete the training and the assessment. The mean age of participants was 36.9 years, and slightly above half (52%) were above 35 years. Two-thirds (61.9%) were female, and about half (45%) were nurses. The majority had the experience of working for more than 5 years, and the average was 9.4 years (+/- 8.4 years). Overall, the trainees' average scores improved after the training (12.79 vs. 16.05, p < 0.0001) out of 28 possible scores. Specifically, trainees' average scores were better in treatment than in diagnosis, except for sickle cell disease (1.26 vs. 1.83). Most were not able to diagnose rheumatic heart disease (47.6% able) compared to diabetes mellitus (54.8% able) or sickle cell disease (64.3% able) at baseline. The proportion of trainees with adequate knowledge of the treatment of sickle cell disease and diabetes mellitus was 35% and 38.1%, respectively, and there was a non-statistical difference after training. Those working for less than 5 years had a higher proportion of adequate knowledge (30.8%) compared to their more experienced colleagues (6.9%). After the training, participants' knowledge of NCDs increased by three times (i.e., aPR 3, 95% CI = 1.1, 1.5, and 6.0). CONCLUSION AND RECOMMENDATIONS: PEN Plus training improved the knowledge of healthcare workers at Kondoa Town Council District Hospital. Training is especially needed among nurses and those with a longer duration of work. Continuing education for human resources for health on the management of NCDs is highly recommended in this setting.

Transcranial Doppler and Magnetic Resonance in Tanzanian Children With Sickle Cell Disease.

Background and Purpose- We determined prevalences of neurological complications, vascular abnormality, and infarction in Tanzanian children with sickle cell disease. Methods- Children with sickle cell disease were consecutively enrolled for transcranial Doppler; those with slightly elevated (>150 cm/s), low (<50 cm/s) or absent cerebral blood flow velocity (CBFv) were invited for brain magnetic resonance imaging and magnetic resonance angiography. Results- Of 200 children (median age 9; range 6-13 years; 105 [2.5%] boys), 21 (11%) and 15 (8%) had previous seizures and unilateral weakness, respectively. Twenty-eight (14%) had elevated and 39 (20%) had low/absent CBFv, all associated with lower hemoglobin level, but not higher indirect bilirubin level. On multivariable analysis, CBFv>150 cm/s was associated with frequent painful crises and low hemoglobin level. Absent/low CBFv was associated with low hemoglobin level and history of unilateral weakness. In 49 out of 67 children with low/absent/elevated transcranial Doppler undergoing magnetic resonance imaging, 43% had infarction, whereas 24 out of 48 (50%) magnetic resonance angiographies were abnormal. One had hemorrhagic infarction; none had microbleeds. Posterior circulation infarcts occurred in 14%. Of 11 children with previous seizure undergoing magnetic resonance imaging, 10 (91%) had infarction (5 silent) compared with 11 out of 38 (29%) of the remainder ( P=0.003). Of 7 children with clinical stroke, 2 had recurrent stroke and 3 died; 4 out of 5 had absent CBFv. Of 193 without stroke, 1 died and 1 had a stroke; both had absent CBFv. Conclusions- In one-third of Tanzanian children with sickle cell disease, CBFv is outside the normal range, associated with frequent painful crises and low hemoglobin level, but not hemolysis. Half have abnormal magnetic resonance angiography. African children with sickle cell disease should be evaluated with transcranial Doppler; those with low/absent/elevated CBFv should undergo magnetic resonance imaging/magnetic resonance angiography.

A pilot study of a non-invasive oral nitrate stable isotopic method suggests that arginine and citrulline supplementation increases whole-body NO production in Tanzanian children with sickle cell disease.

BACKGROUND: Low bioavailability of nitric oxide (NO) is implicated in the pathophysiology of sickle cell disease (SCD). We designed a nested pilot study to be conducted within a clinical trial testing the effects of a daily ready-to-use supplementary food (RUSF) fortified with arginine (Arg) and citrulline (Citr) vs. non-fortified RUSF in children with SCD. The pilot study evaluated 1) the feasibility of a non-invasive stable isotope method to measure whole-body NO production and 2) whether Arg+Citr supplementation was associated with increased whole-body NO production. SUBJECTS: Twenty-nine children (70% male, 9-11years, weight 16.3-31.3 kg) with SCD. METHODS: Sixteen children received RUSF+Arg/Citr (Arg, 0.2  g/kg/day; Citr, 0.1  g/kg/day) in combination with daily chloroquine (50 mg) and thirteen received the base RUSF in combination with weekly chloroquine (150 mg). Plasma amino acids were assessed using ion-exchange elution (Biochrom-30, Biochrom, UK) and whole-body NO production was measured using a non-invasive stable isotopic method. RESULTS: The RUSF+Arg/Citr intervention increased plasma arginine (P = .02) and ornithine (P = .003) and decreased the ratio of asymmetric dimethylarginine to arginine (P = .01), compared to the base RUSF. A significant increase in whole-body NO production was observed in the RUSF-Arg/Citr group compared to baseline (weight-adjusted systemic NO synthesis 3.38 ± 2.29 µmol/kg/hr vs 2.35 ± 1.13 µmol/kg/hr, P = .04). No significant changes were detected in the base RUSF group (weight-adjusted systemic NO synthesis 2.64 ± 1.14 µmol/kg/hr vs 2.53 ± 1.12 µmol/kg/hr, P = .80). CONCLUSIONS: The non-invasive stable isotopic method was acceptable and the results provided supporting evidence that Arg/Citr supplementation may increase systemic NO synthesis in children with SCD.

Bacteraemia in sickle cell anaemia is associated with low haemoglobin: a report of 890 admissions to a tertiary hospital in Tanzania.

Bacteraemia is a leading cause of morbidity in sickle cell anaemia (SCA), but information from studies in Africa is limited. We evaluated 890 admissions from 648 SCA patients at a tertiary hospital in Tanzania. Bacteraemia was present in 43 admissions (4·8%); isolates included Staphylococcus aureus (12/43; 28%), non-Typhi Salmonella (9/43; 21%), Streptococcus pneumoniae (3/43; 7%) and Salmonella Typhi (2/43; 5%). Compared to SCA patients without bacteraemia, SCA patients with bacteraemia had significantly lower haemoglobin [71 g/l vs. 62 g/l, odds ratio 0·72 (95% confidence interval 0·56-0·91), P < 0·01]. Further exploration is needed of the relationship between anaemia and bacterial infections in SCA in Africa.

Health policy for sickle cell disease in Africa: experience from Tanzania on interventions to reduce under-five mortality.

Tanzania has made considerable progress towards reducing childhood mortality, achieving a 57% decrease between 1980 and 2011. This epidemiological transition will cause a reduction in the contribution of infectious diseases to childhood mortality and increase in contribution from non-communicable diseases (NCDs). Haemoglobinopathies are amongst the most common childhood NCDs, with sickle cell disease (SCD) being the commonest haemoglobinopathy in Africa. In Tanzania, 10,313 children with SCD under 5 years of age (U5) are estimated to die every year, contributing an estimated 7% of overall deaths in U5 children. Key policies that governments in Africa are able to implement would reduce mortality in SCD, focusing on newborn screening and comprehensive SCD care programmes. Such programmes would ensure that interventions such as prevention of infections using penicillin plus prompt diagnosis and treatment of complications are provided to all individuals with SCD.

Haptoglobin, alpha-thalassaemia and glucose-6-phosphate dehydrogenase polymorphisms and risk of abnormal transcranial Doppler among patients with sickle cell anaemia in Tanzania.

Transcranial Doppler ultrasonography measures cerebral blood flow velocity (CBFv) of basal intracranial vessels and is used clinically to detect stroke risk in children with sickle cell anaemia (SCA). Co-inheritance in SCA of alpha-thalassaemia and glucose-6-phosphate dehydrogenase (G6PD) polymorphisms is reported to associate with high CBFv and/or risk of stroke. The effect of a common functional polymorphism of haptoglobin (HP) is unknown. We investigated the effect of co-inheritance of these polymorphisms on CBFv in 601 stroke-free Tanzanian SCA patients aged <24 years. Homozygosity for alpha-thalassaemia 3·7 deletion was significantly associated with reduced mean CBFv compared to wild-type (ß-coefficient -16·1 cm/s, P = 0·002) adjusted for age and survey year. Inheritance of 1 or 2 alpha-thalassaemia deletions was associated with decreased risk of abnormally high CBFv, compared to published data from Kenyan healthy control children (Relative risk ratio [RRR] = 0·53 [95% confidence interval (CI):0·35-0·8] & RRR = 0·43 [95% CI:0·23-0·78]), and reduced risk of abnormally low CBFv for 1 deletion only (RRR = 0·38 [95% CI:0·17-0·83]). No effects were observed for G6PD or HP polymorphisms. This is the first report of the effects of co-inheritance of common polymorphisms, including the HP polymorphism, on CBFv in SCA patients resident in Africa and confirms the importance of alpha-thalassaemia in reducing risk of abnormal CBFv.

Peripheral vascular response to inspiratory breath hold in paediatric homozygous sickle cell disease.

There is increasing evidence that autonomic dysfunction in adults with homozygous sickle cell (haemoglobin SS) disease is associated with enhanced autonomic nervous system-mediated control of microvascular perfusion. However, it is unclear whether such differences are detectable in children with SS disease. We studied 65 children with SS disease [38 boys; median age 7.2 (interquartile range 5.1-10.6) years] and 20 control children without symptoms of SS disease [8 boys; 8.7 (5.5-10.8) years] and recorded mean arterial blood pressure (ABP) and daytime haemoglobin oxygen saturation (S(pO(2))). Cutaneous blood flux at rest (RBF) and during the sympathetically activated vasoconstrictor response to inspiratory breath hold (IBH) were measured in the finger pulp of the non-dominant hand using laser Doppler fluximetry. Local factors mediating flow motion were assessed by power spectral density analysis of the oscillatory components of the laser Doppler signal. The RBF measured across the two study groups was negatively associated with age (r = -0.25, P < 0.0001), ABP (r = -0.27, P = 0.02) and daytime S(pO(2)) (r = -0.30, P = 0.005). Children with SS disease had a higher RBF (P = 0.005) and enhanced vasoconstrictor response to IBH (P = 0.002) compared with control children. In children with SS disease, higher RBF was associated with an increase in the sympathetic interval (r = -0.28, P = 0.022). The SS disease status, daytime S(pO(2)) and age explained 22% of the variance in vasoconstrictor response to IBH (P < 0.0001). Our findings suggest that blood flow and blood flow responses in the skin of young African children with SS disease differ from those of healthy control children, with increased resting peripheral blood flow and increased sympathetic stimulation from a young age in SS disease. They further suggest that the laser Doppler flowmetry technique with inspiratory breath hold manoeuvre appears to be robust for use in young children with SS disease, to explore interactions between S(pO(2)), ABP and autonomic function with clinical complications, e.g. skin ulceration.

Newborn screening for sickle cell disease: an innovative pilot program to improve child survival in Dar es Salaam, Tanzania.

BACKGROUND: Sickle cell disease (SCD) is a recognized cause of childhood mortality. Tanzania has the fifth highest incidence of SCD (with an estimated 11 000 SCD annual births) worldwide. Although newborn screening (NBS) for SCD and comprehensive healthcare have been shown to reduce under-5 mortality by up to 94% in high-income countries such as the USA, no country in Africa has maintained NBS for SCD as a national health program. The aims of this program were to establish and evaluate NBS-SCD as a health intervention in Tanzania and to determine the birth prevalence of SCD. METHODS: Muhimbili University of Health and Allied Sciences conducted NBS for SCD from January 2015 to November 2016. Dried blood spot samples were collected and tested for SCD using isoelectric focusing. RESULTS: Screening was conducted on 3981 newborns. Thirty-one (0.8%) babies had SCD, 505 (12.6%) had sickle cell trait and 26 (0.7%) had other hemoglobinopathies. Twenty-eight (90.3%) of the 31 newborns with SCD were enrolled for comprehensive healthcare. CONCLUSIONS: This is the first report on NBS as a health program for SCD in Tanzania. The SCD birth prevalence of 8 per 1000 births is of public health significance. It is therefore important to conduct NBS for SCD with enrollment into a comprehensive care program.

Ready-to-use food supplement, with or without arginine and citrulline, with daily chloroquine in Tanzanian children with sickle-cell disease: a double-blind, random order crossover trial.

BACKGROUND: Sickle-cell disease increases the risk of malnutrition. Low arginine and nitric oxide bioavailability are implicated in morbidity related to sickle-cell disease. Simple interventions are required, especially in low-income settings. We aimed to test the hypotheses that: (1) supplementary arginine, citrulline, and daily chloroquine increase bioavailable arginine and flow-mediated dilatation (FMD; maximal diameter change; FMDmax%), a measure of nitric oxide-dependent endothelial function; and (2) protein energy supplementation in the form of ready-to-use supplementary food (RUSF) improves the height-for-age and body-mass index-for-age Z-scores in children with sickle-cell disease. METHODS: We performed a double-blind, random order crossover trial with two 4-month intervention periods (each followed by 4-month washout periods) in Muhimbili National Hospital in Dar-es-Salaam, Tanzania. We enrolled 119 children from the Muhimbili Sickle Cohort who were aged 8-12 years, naive to hydroxyurea, and had documented HbSS phenotype. Two formulations of RUSF (providing 500 kcal/day) were tested: basic (RUSF-b), with which children also received weekly chloroquine (150 mg or 225 mg chloroquine base, dependent on bodyweight); and vascular (RUSF-v), which was fortified with arginine and citrulline (designed to achieve mean intakes of 0·2 g/kg per day of arginine and 0·1 g/kg per day of citrulline), and with which children received daily chloroquine (maximum 3 mg chloroquine base/kg per day). Children were randomly allocated to receive either RUSF-b first or RUSF-v first and, after a washout period, were then given the other treatment. The primary outcomes in comparing the two RUSF formulations were mean plasma arginine, arginine to ornithine ratio, and arginine to asymmetric dimethylarginine ratio, and mean FMDmax%. The primary outcomes of the combined effect of both RUSF interventions were mean height-for-age Z-score and body-mass index-for-age Z-score. Analyses were done on the eligible intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01718054; and with ISRCTN74331412. FINDINGS: Between Aug 9, 2012, and Feb 26, 2014, 145 children were randomised (71 children to RUSF-v first and 74 children to RUSF-b first) and 119 children were treated, of whom 114 children yielded complete data for all reported endpoints. The ratio of arginine to ornithine (mean of individual differences -8·67%, 95% CI -19·55 to 2·20; p=0·12) and the mean FMDmax% (1·00, -0·47 to 2·47; p=0·18) did not significantly differ between the RUSF-b and RUSF-v treatments. However, the arginine to asymmetric dimethylarginine ratio was significantly increased by RUSF-v compared with RUSF-b (56·26%, 31·13 to 81·38; p<0·0001). In planned analyses that used mixed effects models to estimate the effect of each intervention compared with the participants at baseline or during washout periods, the arginine to asymmetric dimethylarginine ratio increased following both RUSF-v treatment (86%; p<0·0001) and RUSF-b treatment (40%; p<0·0001). However, FMDmax% was higher after treatment with RUSF-v (0·92; p<0·0001) but not RUSF-b (0·39; p=0·22). Following either intervention (RUSF-b and RUSF-v, pooled) body-mass index-for-age Z-score (0·091; p=0·001) and height-for-age Z-score (0·013; p=0·081) increased compared with baseline and washout timepoints. In 83 participants in the treated population, there were 71 adverse events during the intervention, of which 21 (30%) were serious, and 81 adverse events during the washout periods, of which 26 (32%) were serious (p=0·31), including one patient who died in the second washout period. INTERPRETATION: RUSF providing 500 kcal/day results in small weight gains in children with sickle-cell disease. However, even without arginine and citrulline fortification, RUSF seems to ameliorate arginine dysregulation and might improve endothelial function. Long-term studies are required to assess whether these physiological effects translate to improved clinical outcomes and better growth and development in patients with sickle-cell disease. FUNDING: Wellcome Trust.

Complications of sickle cell anaemia in children in Northwestern Tanzania.

OBJECTIVES: Tanzania has the third highest birth rate of sickle cell anaemia (SCA) in Africa, but few studies describe severity of complications or available treatments, especially in Northwest Tanzania around Lake Victoria where the sickle gene is most prevalent. This is a report of the spectrum of clinical disease and range of interventions available at Bugando Medical Centre (Bugando) in Northwest Tanzania in Africa. METHODS: A cross-sectional study was carried out in Bugando between 1 August 2012 and 30 September 2012. Children (<15 years old) with SCA attending Bugando were sequentially enrolled. A trained research assistant completed a Swahili questionnaire with the parent or guardian of each participant concerning demographic information, clinical features of disease, and treatments received. RESULTS: Among the 124 participants enrolled, the median age was 6 years (interquartile range [IQR] 4-8.5), and only 13 (10.5%) were < 3 years old. Almost all participants (97.6%) had a prior history of a vaso-occlusive episode, 83 (66.9%) had prior acute chest syndrome, and 21 (16.9%) had prior stroke. In the preceding 12 months, 120 (96.8%) had been hospitalized, and a vaso-occlusive episode was the most common reason for hospitalization (35.5%). Prescriptions for folic acid (92.7%) and malaria prophylaxis (84.7%) were common, but only one had received a pneumococcal vaccine, and none had received hydroxyurea or prophylactic penicillin. CONCLUSION: Children with SCA receiving care in Tanzania are diagnosed late, hospitalized frequently, and have severe complications. Opportunities exist to improve care through wider access to screening and diagnosis as well as better coordination of comprehensive care.

Negative Epistasis between Sickle and Foetal Haemoglobin Suggests a Reduction in Protection against Malaria.

BACKGROUND: Haemoglobin variants, Sickle (HbS) and foetal (HbF) have been associated with malaria protection. This study explores epistatic interactions between HbS and HbF on malaria infection. METHODS: The study was conducted between March 2004 and December 2013 within the sickle cell disease (SCD) programme at Muhimbili National Hospital, Tanzania. SCD status was categorized into HbAA, HbAS and HbSS using hemoglobin electrophoresis and High Performance Liquid Chromatography (HPLC). HbF levels were determined by HPLC. Malaria was diagnosed using rapid diagnostic test and/or blood film. Logistic regression and generalized estimating equations models were used to evaluate associations between SCD status, HbF and malaria. FINDINGS: 2,049 individuals with age range 0-70 years, HbAA 311(15.2%), HbAS 241(11.8%) and HbSS 1,497(73.1%) were analysed. At enrolment, malaria prevalence was significantly higher in HbAA 13.2% compared to HbAS 1.24% and HbSS 1.34% (p<0.001). Mean HbF was lower in those with malaria compared to those without malaria in HbAA (0.43% vs 0.82%) but was the reverse in HbSS (8.10% vs 5.59%). An increase in HbF was associated with a decrease in risk of malaria OR=0.50 (95%CI: 0.28, 0.90; p=0.021) in HbAA, whereas for HbSS the risk of malaria increased OR=2.94 (1.44, 5.98; p=0.003). A similar pattern was seen during multiple visits; HbAA OR=0.52 (0.34, 0.80; p=0.003) vs HbSS OR=2.01 (1.27, 3.23; p=0.003). CONCLUSION: Higher prevalence of malaria in HbAA compared to HbAS and HbSS confirmed the protective effect of HbS. Lower prevalence of malaria in HbAA with high HbF supports a protective effect of HbF. However, in HbSS, the higher prevalence of malaria with high levels of HbF suggests loss of malaria protection. This is the first epidemiological study to suggest a negative epistasis between HbF and HbS on malaria.