Circulating cytokines in pulmonary tuberculosis according to HIV status and dietary iron content.

OBJECTIVE: To evaluate human immunodeficiency virus (HIV) serology, dietary iron and serum concentrations of markers of T-helper type (Th) 1 and Th-2 immune pathways in the setting of tuberculosis (TB). METHODS: A total of 49 patients with pulmonary TB in rural Zimbabwe, 32 of whom were HIV-positive, were evaluated at presentation and over 10 weeks of anti-tuberculosis treatment. RESULTS: Interleukin (IL) 12 and neopterin, Th-1 markers, were both elevated at presentation in 92% of the subjects. In contrast, only 23% had elevation of the Th-2 marker, IL-4. Neopterin and IL-6 concentrations decreased over 10 weeks of treatment (P

Hypertension and diabetes mellitus: the critical role of evidence based decision making in patient management.

Many diabetic hypertensives are inadequately managed because of the doctor's misplaced emphasis on possible differences in efficacy and risk profile of antihypertensive drugs. These patients are at higher risk of various cardiovascular events, and evidence shows they experience greater reduction in adverse clinical outcomes as a result of tight control of blood pressure than do nondiabetic hypertensives. It is, therefore, critically important that such patients be identified and that the blood pressure is tightly treated. Several drugs often have to be used in combination in order to achieve adequate blood pressure control. Nonpharmacologic measures, such as exercise, have been shown to reduce blood pressure and to reduce the rate complications in diabetic patients. All classes of antihypertensives have been shown to be equivalent in reducing all adverse cardiovascular events in diabetic hypertensives. Although there is nothing to choose between diuretics, calcium channel blockers, beta-blockers, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, the choice of drug should be tailored for the individual patient. Drug selection should be based on the complication that is most likely in the given patient. Available data suggests that the lower the blood pressure the better the prognoses, with no threshold of the lower limit of the ideal value. Many professional associations advise that a target blood pressure in the diabetic hypertensive under treatment should be below 130/80 mm Hg. There is no evidence to support the avoidance of thiazide diuretics in these patients, and indeed some patients derive specific benefits from the use of these drugs. Tight control of blood pressure is the overriding priority, and this takes precedence over the theoretical debate of which drug is the best choice or concern over possible adverse reactions.

Clinical and genetic heterogeneity in hereditary haemochromatosis: association between lymphocyte counts and expression of iron overload.

To identify a new marker of expression of disease, independent of HFE genotype in patients with hereditary haemochromatosis (HHC), the total peripheral blood lymphocyte counts were analysed according to iron status in two groups of subjects with HFE mutations. The groups consisted of 38 homozygotes for C282Y, and 107 heterozygotes for the C282Y or compound heterozygotes for C282Y and H63D. For control purposes, total lymphocyte counts and iron status were also examined in 20 index patients with African dietary iron overload, a condition not associated with HFE mutations, and in 144 members of their families and communities. Mean lymphocyte numbers were lower in C282Y homozygous HHC index subjects with cirrhosis and higher iron stores than in those without cirrhosis and with lower iron burdens [(1.65 +/- 0.43) x 10(6)/mL vs. (2.27 +/- 0.49) x 10(6)/mL; p = 0.008]. Similarly, mean lymphocyte counts were significantly lower in C282Y heterozygotes and C282Y/H63D compound heterozygotes with iron overload and increased serum ferritin concentrations compared to those with normal serum ferritin concentrations (p < 0.05). Statistically significant negative correlations were found, in males, between lymphocyte counts and the total body iron stores, either in C282Y homozygous HHC patients (p = 0.031 in a multiple regression model dependent on age) and in C282Y heterozygotes or C282Y/H63D compound heterozygotes with iron overload (p = 0.029 in a simple linear model). In contrast, lymphocyte counts increased with increasing serum ferritin concentrations among the index subjects with African iron overload (r = 0.324, not statistically significant) and among the members of their families and communities (r = 0.170, p = 0.042). These results suggest that a lower peripheral blood lymphocyte count is associated with a greater degree of iron loading in HFE haemochromatosis but not in African iron overload, and they support the notion that the lymphocyte count may serve as a marker of a non-HFE gene that influences the clinical expression of HFE haemochromatosis.

Association of pulmonary tuberculosis with increased dietary iron.

To determine whether increased dietary iron could be a risk factor for active tuberculosis, dietary iron history and human immunodeficiency virus (HIV) status were studied in 98 patients with pulmonary tuberculosis and in 98 control subjects from rural Zimbabwe. Exposure to high levels of dietary iron in the form of traditional beer is associated with increased iron stores in rural Africans. HIV seropositivity was associated with a 17.3-fold increase in the estimated odds of developing active tuberculosis (95% confidence interval [95% CI], 7.4-40.6; P<.001), and increased dietary iron was associated with a 3.5-fold increase (95% CI, 1.4-8.9; P=.009). Among patients treated for tuberculosis, HIV seropositivity was associated with a 3.8-fold increase in the estimated hazard ratio of death (95% CI, 1.0-13.8; P=.046), and increased dietary iron was associated with a 1.3-fold increase (95% CI, 0.4-6.4; P=.2). These findings are consistent with the hypothesis that elevated dietary iron may increase the risk of active pulmonary tuberculosis.

Dysentery in patients infected with human immunodeficiency virus in Zimbabwe: an emerging role for Schistosoma mansoni and Escherichia coli O157?

Information on bloody diarrhoea in HIV-positives is scarce. A prospective study was therefore performed, in Zimbabwe, to determine and compare the pathogens associated with bloody diarrhoea in 25 antiretroviral-naïve HIV-infected patients and 15 non-HIV-infected patients. Stool cultures and colonic biopsies were performed. Shigella was isolated from 18 (45%) of the subjects, Schistosoma mansoni from eight (16%), Escherichia coli H7:O157 from three (8%) and Campylobacter jejunii from two (5%). There was no evidence of Salmonella, Entamoeba histolytica or cytomegalovirus infection. Shigella dysenteriae type-1 occurred more often in the HIV-negatives than the HIV-positives (P = 0.02). Although HIV-associated bloody diarrhoea in Zimbabwe appears to be most frequently caused by Shigella, it may also be commonly the result of infection with Sc. mansoni or shiga-toxin-producing E. coli. A larger study specifically to examine the role of Sc. mansoni and E. coli O157 is warranted.

Carbohydrate-deficient transferrin and chronic alcohol ingestion in subjects with transferrin CD-variants.

Carbohydrate-deficient transferrin (CDT) is widely accepted as screening test for excessive alcohol consumption. However, results from subjects with transferrin variants must be interpreted with caution since chromatography-based methods may give false-positive results. Furthermore, due to the co-elution in HPLC or the co-migration in capillary zone electrophoresis (CZE) of the di- and trisialylated C transferrins with the tetrasialylated D peak, exact measurement of CDT is impossible in CD-variants. Therefore, in this study, we tried to offer a different solution, including only the asialo-D, asialo-C, monosialo-D, monosialo-C, disialo-D and trisialo-D transferrins in the CDT calculation and referring to a different cut-off value for CDT in transferrin CD-variants. Comparison of alcohol consumers with teetotalers demonstrated area under the receiver operating characteristic curve of 0.79 and 0.76 for carbohydrate-deficient transferrin, 0.71 and 0.71 for mean corpuscular volume and 0.51 and 0.68 for gamma-glutamyltransferase in 43 subjects with transferrin CD-variants and 225 subjects with CC-phenotypes, respectively. Since false-positive carbohydrate-deficient transferrin results due to a transferrin CD-variant have major social implications, capillary electrophoresis-based or similar methods (HPLC, FPLC) should be preferred in populations carrying a high D-allele frequency.

Transferrin polymorphism influences iron status in blacks.

BACKGROUND: Genetic variants of human transferrin (TF) have been described, but little is known about their functional differences. We studied iron status according to TF phenotype in a healthy Zimbabwean population and in subjects at risk of African iron overload. METHODS: The study population consisted of 483 nondrinkers, 31 drinking spouse pairs, and 5 family pedigrees (n = 88) with index cases of iron overload. TF phenotypes were determined using starch gel electrophoresis. To evaluate iron status, serum iron, total iron-binding capacity (TIBC), ferritin, and soluble TF receptors were measured, and the percentage of saturation and the serum iron:TF ratio were calculated. The binding of the TF variants was studied by equilibrium dialysis. RESULTS: The reference population was characterized by a high TF D allele frequency (0.050) and a complete absence of homozygous TF DD individuals. Similar allele frequencies were observed in subjects at risk of African iron overload. In the reference population, male TF CD heterozygotes had significantly lower (P <0.01) values for serum iron, TIBC, TF saturation, and serum iron:TF ratio than the TF CC homozygotes; in females, only TIBC was significantly different. Overall red blood cell indices did not differ according to TF phenotype. In the population at risk of African iron overload, only serum iron:TF ratio was consistently significantly lower in TF CD phenotypes (P <0.05). After equilibrium dialysis, the amount of iron bound by TF was significantly lower (P <0.01) in TF CD individuals. CONCLUSIONS: The present data demonstrate a functional difference between TF phenotypes in blacks.

Haptoglobin polymorphism and mortality in patients with tuberculosis.

SETTING: A rural Zimbabwean hospital and the surrounding community. OBJECTIVES: To determine whether a particular haptoglobin phenotype is associated with increased susceptibility to clinical pulmonary tuberculosis, and to determine the outcome of treatment for pulmonary tuberculosis according to haptoglobin phenotype. DESIGN: A case-control study, and a prospective cohort study. RESULTS: We studied 98 consecutive patients with sputum-positive pulmonary tuberculosis and 98 sex- and age-matched controls. The haptoglobin (Hp) phenotype distributions did not differ significantly between the tuberculosis patients and controls (P = 0.5). During the 18-month follow-up period after the start of tuberculosis treatment, 6/18 (33%) cases with Hp 2-2 phenotype died compared to 9/47 (19%) with Hp 2-1 and 3/31 (10%) with Hp 1-1. In a logistic regression model, the odds of dying were 6.1-fold greater with Hp 2-2 than with Hp 1-1 (95%CI 1.04-35.1, P = 0.04). CONCLUSION: Our results suggest that there is equal susceptibility to clinical pulmonary tuberculosis disease amongst different haptoglobin phenotypes. Nonetheless, tuberculosis patients with Hp 2-2 phenotype had a higher risk of mortality.

Impact of HIV infection on meningitis in Harare, Zimbabwe: a prospective study of 406 predominantly adult patients.

OBJECTIVE: To determine the causative organisms and characteristics of patients presenting with features of meningitis. DESIGN: A prospective cross-sectional study. SETTING: Two tertiary university-affiliated hospitals in Harare, Zimbabwe. PATIENTS: Four-hundred and six patients clinically suspected to have meningitis. MAIN OUTCOME MEASURES: Causative organisms of meningitis; clinical and cerebrospinal fluid characteristics. RESULTS: Four-hundred and six predominantly adult (95% were aged > or = 18 years) patients were suspected to have meningitis. Of the 200 patients confirmed to have meningitis, 89 (45%) had cryptococcal meningitis (CM), 54 (27%) had mononuclear meningitis (MM), 31 (16%) had pyogenic meningitis (PM), 24 (12%) had tuberculous meningitis (TBM) and 2 (1%) had undefined meningitis. HIV seropositivity was 100% in CM, 83% in MM, 81% in PM and 88% in TBM patients. In-hospital mortality rate was 38.8% for CM, 34.9% for MM, 68% for PM and 66.7% for TBM. HIV seropositivity was 80% in the 206 patients not found to have meningitis. CONCLUSIONS: All patients suspected to have meningitis had a high HIV sero positivity irrespective of whether they were later confirmed to have meningitis or not. CM was the most common type of meningitis seen. In-hospital mortality was high irrespective of the cause of meningitis.

African iron overload.

African iron overload has been recognised in sub-Saharan Africa for seventy years. The condition is distinct from the well-characterised HLA-linked haemochromatosis described in Caucasians. Increased dietary iron intake predisposes to the condition. Recent evidence suggest that African iron overload may be caused by an interaction between increased dietary iron and a genetic defect not associated with the HLA-locus. Iron deposition is prominent both in macrophages and in hepatic parenchymal cells. Iron overload is distinct from alcoholic liver disease, although the excess dietary iron is derived from a traditional beverage that contains alcohol. African iron overload has clinical consequences. It is a cause of hepatic fibrosis and cirrhosis, and associations with diabetes mellitus, peritonitis, scurvy and osteoporosis have been described. African iron overload may be a cause of hepatocellular carcinoma. The disorder is associated with a poor outcome in tuberculosis, an infection that is highly prevalent in sub-Saharan Africa.

Reference range of serum haptoglobin is haptoglobin phenotype-dependent in blacks.

Reference values for serum haptoglobin (Hp), were established in a Black Zimbabwean population. The upper limit (2.15 g/l) is comparable to the one in Caucasians, but the lower limit (0.12 g/l) is much lower than the proposed interim international reference limit (0.3 g/l). Subjects that typed as Hp 0-0 by starch gel electrophoresis technique were retyped using high performance gel permeation chromatography. This resulted in a 32% decrease in the frequency of Hp 0-0, but an increase in Hp 2-2 and Hp 2-1M phenotype frequencies. In the Zimbabwean Blacks, the Hp 0-0 frequency was estimated to be 2.9%. Haptoglobin reference values were found to be Hp phenotype-dependent; highest values were found in Hp 1-1 (median 0.88 g/l; range 0.31-1.69 g/l) and in Hp 2-1 (median 0.90 g/l; range 0.31-2.22 g/l) and lower values (median 0.66 g/l; range 0.13-1.79 g/l) in Hp 2-2 subjects. The Hp 2-1M phenotype was characterized by low reference values (0.18-1.25 g/l) (P<0.05). In three cases of the rare variant Hp Johnson, high Hp concentrations were found (median 1. 57 g/l; range 0.98-1.57 g/l).

Enterocytozoon bieneusi infection in patients without evidence of immunosuppression: two cases from Zimbabwe found to have positive stools by PCR.

Patients infected with human immunodeficiency virus (HIV) often also have intestinal infections with Enterocytozoon bieneusi. Recently, infection with this microsporidian has been described in immunocompetent subjects, mainly from Europe. When the stools of six HIV-negative patients who presented with diarrhoea in Zimbabwe were investigated, using a recently described protocol based on PCR, two patients were found to have E. bieneusi infections. These two individuals presented with a self limited diarrhoea, abdominal cramping and nausea. These data indicate that E. bieneusi may be a more common cause of diarrhoea in Zimbabwe than previously thought. Larger, prospective studies are needed.

A traditional beverage prevents iron deficiency in African women of child bearing age.

OBJECTIVE: To determine if a traditional item in the diet might be useful in preventing iron deficiency in African women of child-bearing age. DESIGN: In a prospective study, the iron status of women who did and did not drink traditional beer high in iron and folic acid, was compared. Iron status was determined by a combination of haemoglobin, serum ferritin and transferrin saturation. SETTING: The study was conducted amongst rural villagers in the Murehwa and Zaka districts of Zimbabwe and in Mpumalanga Province, South Africa. SUBJECTS: 112 women aged between 12 and 50 y from a population of 425 rural people participating in on-going family genetic studies. RESULTS: Women who consumed traditional beer had significantly higher serum ferritin concentrations and transferrin saturations compared to non-drinkers (P = 0.0001 and 0.03 respectively). Iron deficiency anaemia was not present in drinkers but the prevalence in non-drinkers was 13%. Forty seven percent of the non-drinkers and only 14% of the drinkers had evidence of iron deficiency (P = 0.002). Six (21%) of the drinkers and none of the non-drinkers had evidence of iron overload (transferrin saturation > 55% and serum ferritin > 400 ug/l). CONCLUSION: We conclude that the consumption of traditional beer, rich in iron, protects women against iron deficiency. While the use of an alcoholic beverage is not ideal, our findings suggest that indigenous cultural practices might be successfully employed or adapted for promoting iron nutrition.

Iron overload in urban Africans in the 1990s.

BACKGROUND: In a previously described model, heterozygotes for an African iron loading locus develop iron overload only when dietary iron is high, but homozygotes may do so with normal dietary iron. If an iron loading gene is common, then homozygotes with iron overload will be found even in an urban population where traditional beer, the source of iron, is uncommon. AIMS: To determine whether iron overload and the C282Y mutation characteristic of hereditary haemochromatosis are readily identifiable in an urban African population. METHODS: Histological assessment, hepatocellular iron grading, and dry weight non-haem iron concentration were determined in post mortem tissue from liver, spleen, heart, lungs, and skin. DNA of subjects with elevated hepatic iron indexes was analysed for the C282Y mutation. Iron concentrations in other tissues were compared. RESULTS: A moderate increase (>30 micromol/g) in hepatic iron concentrations was found in 31 subjects (23%; 95% confidence interval 15.9 to 30.1%), and they were considerably elevated (>180 micromol/g) in seven subjects (5.2%; 95% confidence interval 1.5 to 8.9%). Appreciably elevated hepatic iron concentrations were associated with heavy iron deposition in both hepatocytes and macrophages, and either portal fibrosis or cirrhosis. All were negative for the C282Y mutation. Very high concentrations were uncommon in subjects dying in hospital. Concentrations of iron in spleen, heart, lung, and skin were significantly higher in subjects with elevated hepatic iron. CONCLUSIONS: Iron overload is readily identified among urban Africans and is associated with hepatic damage and iron loading of several tissues. The condition is unrelated to the genetic mutation found in hereditary haemochromatosis.

Intestinal parasites in patients with diarrhea and human immunodeficiency virus infection in Zimbabwe.

OBJECTIVES: To determine the prevalence of intestinal parasites and risk factors for infection associated with diarrhea in HIV-infected patients in Harare, Zimbabwe. DESIGN: Prospective observational study. METHODS: Single stool samples were collected from 88 HIV-infected individuals presenting with diarrhea of greater than 1 week duration. Stools were examined for intestinal parasites using modified acid fast stain, fluorescence- labeled monoclonal antibody for Cryptosporidium parvum, as well as a modified trichrome stain and a PCR-based protocol for Enterocytozoon bieneusi. RESULTS: C. parvum was detected in 9% (seven out of 82) of samples evaluated, but no Cyclospora was detected. E. bieneusi was detected in 18% (10 out of 55) of stool by trichrome staining and in 51% (28 out of 55) of stool examined by PCR. Risk factors for E. bieneusi infection were: living in rural areas, consumption of nonpiped water, contact with cow dung and household contact with an individual with diarrhea. CONCLUSION: E. bieneusi infection was common in HIV-infected patients with diarrhea in Zimbabwe and may be acquired through person-to-person and fecal-oral transmission.

Pancytopenia in Zimbabwe.

BACKGROUND: There has been little systematic study of the clinical spectrum of pancytopenia, and the optimal diagnostic approach to pancytopenia remains undefined. METHODS: The authors studied 134 hospitalized pancytopenic patients in Zimbabwe in both consecutive and nonconsecutive fashion. RESULTS: The most common cause of pancytopenia was megaloblastic anemia, followed by aplastic anemia, acute leukemia, acquired immunodeficiency syndrome (AIDS), and hypersplenism. Severe pancytopenia was usually due to aplastic anemia. Patients with aplastic anemia and acute leukemia were usually children, whereas those with megaloblastic anemia were adults. Moderate to severe anemia was noted throughout the series, but was most striking in patients with megaloblastic anemia, aplastic anemia, and acute leukemia. The mean corpuscular volume (MCV) was elevated in most patients with megaloblastic hematopoiesis, aplastic anemia, and acute nonlymphocytic leukemia. Normal or low MCV values were noted in almost one third of patients with megaloblastic anemia. Anisocytosis, poikilocytosis, macroovalocytosis, microcytosis, fragmentation, and teardrop erythrocytes were more prominent on the blood films of patients with megaloblastic anemia. CONCLUSIONS: Megaloblastic anemia, aplastic anemia, and AIDS are the most common causes of pancytopenia in Zimbabwe. Aplasia is the most frequent cause of severe pancytopenia. The authors have formulated tentative guidelines for the evaluation of pancytopenic patients in this setting.