Recommendations for the management of adult chronic myeloid leukaemia in South Africa.

INTRODUCTION: Chronic myeloid leukaemia (CML) is a chronic myeloproliferative disorder characterised by a chromosomal translocation between the long arms of chromosomes 9 and 22 [corrected] resulting in the formation of the BCR-ABL fusion gene. The management of CML has undergone major changes over the past decade. Novel treatment approaches have had a dramatic impact on patient outcomes and survival. Nevertheless, these outcomes can only be achieved in the context of expert management, careful monitoring of disease response, appropriate management of adverse events and timeous adjustments to therapy when responses are not achieved within stated time-frames. AIM: With the advent of novel treatments providing molecular responses, both the monitoring and management of CML have become more complicated. The aim of these recommendations was to provide a pragmatic yet comprehensive roadmap to negotiate these complexities. METHODS: Recommendations were developed based on local expert opinion from both the academic and private medical care arenas after careful review of the relevant literature and taking into account the most widely used international guidelines. About five meetings were held at which these recommendations were discussed and debated in detail. RESULTS: A comprehensive set of recommendations was compiled with an emphasis on diagnosis, investigation, treatment and monitoring of disease. Careful attention was given to circumstances unique to South Africa, funding constraints, availability and access to laboratory resources, as well as the effects of concurrent HIV infection. CONCLUSION: Most patients with CML can live a reasonably normal life if their disease is appropriately managed. These recommendations should be of value to all specialists involved in the treatment of haematological disorders.

Guidelines for the treatment of myelodysplastic syndromes (MDS) in South Africa.

INTRODUCTION: Myelodysplastic syndromes (MDS) encompass a heterogeneous group of clonal haematopoietic disorders characterised by chronic and progressive cytopenias resulting from ineffective haematopoiesis. Treatment is complicated by differences in disease mechanisms in different subgroups, variable clinical phenotypes and risk of progression to acute myeloid leukaemia. RATIONALE: Changes in disease classification, prognostic scoring systems, the availability of novel treatment options and the absence of South African guidelines for the diagnosis and management of these complex disorders underpinned the need for the development of these recommendations. METHODS: These recommendations are based on the opinion of a number of experts in the field from the laboratory as well as clinical settings and came from both the private and institutional academic environments. The most recent literature as well as available guidelines from other countries were discussed and debated at a number of different meetings held over a 2-year period. RESULTS: A comprehensive set of recommendations was developed focusing on risk stratification, supportive management and specific treatment. Novel agents and their indications are discussed and recommendations are made based on best available evidence and taking into account the availability of treatments in South Africa. CONCLUSION: Correct diagnosis, risk stratification and appropriate therapeutic choices are the cornerstones of success in the management of patients with myelodysplastic syndromes.

Hematological recovery in male ultramarathon runners: the effect of variations in training load and running time.

AIM: Haematological response to the 2001 downhill Comrades Marathon was compared in high (>120 km/w in training; 3 weeks of pre-race taper) and low (<80 km/w in training; 2 weeks of pre-race taper) training status groups. METHODS: Full blood counts, differential lymphocyte counts (CD3, CD4, CD8, CD19, CD56), serum cortisol, C-reactive protein (CRP) and creatine kinase (CK) were measured in blood samples donated 21 hours before and 16 hours after a 90 km ultramarathon. RESULTS: Despite significantly faster mean race finishing time (8.03 h vs 10.53 h; p<0.001) and greater percentage incidence (55.6% vs 40%) of post-race upper respiratory tract infection (URTI) in the highly trained group, these faster runners did not show evidence of a slower post-race recovery in terms of total leukocyte, neutrophil, total or differential lymphocyte counts (p>0.05). CRP concentrations were, however, markedly higher in the slower, less trained group (65.3+/-10.7 vs 38.3+/-5.9; p<0.01). CONCLUSIONS: Despite greater systemic evidence of post-race muscle inflammation and an acute phase response in the slower runners in a downhill ultramarathon race, the haematological recovery of well trained runners who undergo a 3-week taper period prior to the ultramarathon is not different to that in less trained runners who spend almost 3 hours longer on the road. The higher prevalence of post-race URTI symptoms in the fast, well trained group does not appear to be related to lymphocyte recovery in peripheral blood.

Vitamin C supplementation attenuates the increases in circulating cortisol, adrenaline and anti-inflammatory polypeptides following ultramarathon running.

The effects of vitamin C supplementation on the alterations in the circulating concentrations of cortisol, adrenaline, interleukin-10 (IL-10) and interleukin-1 receptor antagonist (IL-1Ra) which accompany ultramarathon running were measured using immuno-chemiluminescence, radioimmunoassay and ELISA procedures. Forty-five participants in the 1999 Comrades 90 km marathon were divided into equal groups (n = 15) receiving 500 mg/day Vit C (VC-500), 1500 mg/day Vit C (VC-1500) or placebo (P) for 7 days before the race, on the day of the race, and for 2 days following completion. Runners recorded dietary intake before, during and after the race and provided 35 ml blood samples 15 - 18 hrs before the race, immediately post-race, 24 hrs post race and 48 hrs post-race. Twenty-nine runners (VC-1500, n = 12; VC-500, n = 10; P, n = 7) complied with all study requirements. All post-race concentrations were adjusted for plasma volume changes. Analyses of dietary intakes and blood glucose and anti-oxidant status on the day preceding the race and the day of the race did not reveal that carbohydrate intake or plasma vitamins E and A were significant confounders in the study. Mean pre-race concentrations of serum vitamin C in VC-500 and VC-1500 groups (128 +/- 31 and 153 +/- 34 micromol/l) were significantly higher than in the P group (83 +/- 39 micromol/l). Immediate post-race serum cortisol was significantly lower in the VC-1500 group (p < 0.05) than in P and VC-500 groups. When the data from VC-500 and P groups was combined (n = 17), immediate post-race plasma adrenaline, IL-10 and IL-1Ra concentrations were also significantly lower (p < 0.05) in the VC-1500 group. The study demonstrates an attenuation, albeit transient, of both the adrenal stress hormone and anti-inflammatory polypeptide response to prolonged exercise in runners who supplemented with 1500 mg vitamin C per day when compared to < or = 500 mg per day.

Nutritional status and dietary intakes of children aged 2-5 years and their caregivers in a rural South African community.

The objective of this study was to determine the nutritional status regarding vitamin A, iron and anthropometric indices and dietary intakes of children aged 2-5 years and their caregivers in a rural South African community. Micronutrient, haematological, anthropometric and dietary indicators were used to assess nutritional status during a cross-sectional survey. The setting was a low socioeconomic rural African community (Ndunakazi), approximately 60 km northwest of the coastal city of Durban in KwaZulu-Natal, South Africa. The subjects were children aged 2-5 years (n = 164), and their caregivers (n = 137). Of the preschool children, 50% had a low vitamin A status (serum retinol < 20 micrograms/dL), 54% were anaemic (Hb < 11 micrograms/dL), 33% had depleted iron stores (serum ferritin levels < 10 micrograms/L), and 21% were stunted (Z-score for height-for-age < -2SD). Of the caregivers, 30% had a low vitamin A status (serum retinol < 30 micrograms/dL), 44% were anaemic (Hb < 11 micrograms/dL), 19% had depleted iron stores (serum ferritin levels < 12 micrograms/L), and 40% and 26% were overweight (BMI > or = 24 and < 30) and obese (BMI > or = 30), respectively. The children and caregivers consumed a cereal-based diet, with phutu (a stiff porridge made with maize meal), rice and bread as staple foods. Quantitative dietary analysis showed that the dietary intakes were high in carbohydrates (approximately 70% of total energy), while fat intake was within the prudent dietary guideline of 30% of total energy intake. Median dietary intakes were below 50% of the RDA for calcium, zinc (children only), vitamin A, riboflavin, niacin (children only) and vitamin B12. These preschool children and their caregivers consumed a high carbohydrate diet deficient in most of the essential micronutrients. The poor quality of the diet was reflected in a poor vitamin A and iron status, and one-fifth of the children showed linear growth retardation. Nutrition education and intervention programmes should address micronutrient deficiencies, with the focus not only on quantity, but also quality of the diet.

The effect of different anthelmintic treatment regimens combined with iron supplementation on the nutritional status of schoolchildren in KwaZulu-Natal, South Africa: a randomized controlled trial.

A randomized controlled trial in KwaZulu-Natal (South Africa) of 428 primary-school pupils (stratified into 6 groups by age, sex and intervention) measured the effect of different anthelmintic treatments and iron supplementation regimens provided twice at 6-monthly intervals for 1 year (1996/97). Half the pupils received iron supplementation (ferrous fumarate 200 mg weekly for 10 weeks). Pupils received 2 anthelmintic regimens, either (i) albendazole 400 mg plus praziquantel 40 mg/kg or (ii) albendazole 400 mg on 3 consecutive days plus praziquantel 40 mg/kg or (iii) placebo. Baseline prevalences of Ascaris 55.9%, Trichuris 83.6%, hookworm spp. 59.4%, were reduced after 12 months for single-dose albendazole treatment to Ascaris 17.4% (P < 0.005), Trichuris 61.5% (NS), hookworm spp. 0% (P < 0.005), and for triple-dose albendazole treatment to Ascaris 14.8% (P < 0.005), Trichuris 25.0% (P < 0.01), hookworm 0% (P < 0.005). Schistosoma haematobium 43.4% was reduced among treated groups to 8.3% (P < 0.005). There were no significant changes in the anthropometry of the different treatment groups at either 6 or 12 months post treatment. Twelve months after treatment there was a significant increase in haemoglobin levels (P = 0.02) among pupils receiving triple-dose albendazole, praziquantel and ferrous fumarate; pupils receiving no anthelmintic treatment showed a significant decrease as did pupils who received triple-dose albendazole and praziquantel but no iron. Regular 6-monthly anthelmintic treatment significantly reduced the prevalence of Ascaris, hookworm spp. and S. haematobium infections (P < 0.05). Triple-dose treatment for Trichuris was significantly more effective than a single dose of albendazole 400 mg (P = 0.002). In areas with schistosomiasis, hookworm infection and high prevalence of Trichuris infection, combination treatment with praziquantel, triple-dose albendazole, plus iron supplementation, is likely to improve pupils' health and haemoglobin levels.

Long-term evaluation of a micronutrient-fortified biscuit used for addressing micronutrient deficiencies in primary school children.

OBJECTIVE: To evaluate the long-term effect on micronutrient status of a beta-carotene-, iron- and iodine-fortified biscuit given to primary school children as school feeding. DESIGN: Children receiving the fortified biscuit were followed in a longitudinal study for 2.5 years (n = 108); in addition, cross-sectional data from three subsequent surveys conducted in the same school are reported. SETTING: A rural community in KwaZulu-Natal, South Africa. SUBJECTS: Children aged 6-11 years attending the primary school where the biscuit was distributed. RESULTS: There was a significant improvement in serum retinol, serum ferritin, haemoglobin, transferrin saturation and urinary iodine during the first 12 months of the biscuit intervention. However, when the school reopened after the summer holidays, all variables, except urinary iodine, returned to pre-intervention levels. Serum retinol increased again during the next 9 months, but was significantly lower in a subsequent cross-sectional survey carried out directly after the summer holidays; this pattern was repeated in two further cross-sectional surveys. Haemoglobin gradually deteriorated at each subsequent assessment, as did serum ferritin (apart from a slight increase at the 42-month assessment at the end of the school year). CONCLUSIONS: This study has shown that fortification of a biscuit with beta-carotene at a level of 50% of the Recommended Dietary Allowance (RDA) was enough to maintain serum retinol concentrations from day to day, but not enough to sustain levels during the long school holiday break. Other long-term solutions, such as local food production programmes combined with nutrition education, should also be examined. The choice of the iron compound used as fortificant in the biscuit needs further investigation.

Membranous fat necrosis due to subcutaneous elemental mercury injections.

Membranous fat necrosis (MFN) is a distinct abnormality in systemic and subcutaneous fatty tissue. Although ischemia and trauma have been implicated in its causation, the exact pathogenesis of MFN remains unknown. The deposition of metallic mercury in subcutaneous tissue due to accidental penetration or deliberate injection of mercury is unusual. Depending on the duration of the deposition, localized necrosis, suppuration, and granuloma formation have been described at mercury injection sites. We report subcutaneous MFN, a hitherto unrecognized histopathologic phenomenon at sites of mercury deposition, in a 21-year-old soccer player who had deliberate subcutaneous and intramuscular elemental mercury injections to improve his sporting performance.

Refractory Castleman's Disease.

Angiofollicular lymph node hyperplasia is an uncommon low-grade lymphoproliferative disorder first described by Castleman. It is typically asymptomatic with diagnosis incidentally made in young males on chest radiology. Biopsy, in 90% of cases, shows the hyaline vascular variant. In contrast the plasma cell sub-type is accompanied by fever, sweating, weight loss, anaemia, lymphadenopathy, splenomegaly and hypergammaglobulinaemia. Treatment, when necessary because of symptoms, has variable outcome in response to corticosteroids, combinations of cytotoxic drugs, or radiotherapy. Failure to promptly achieve disease control has ominous significance and most patients die. High-dose chemoradiotherapy with bone marrow salvage, using haematopoietic stem and progenitor cells derived from bone marrow or peripheral blood, has precedent in this situation. We report a second successful outcome to this procedure in a 37 year old man with profound constitutional complaints of weight loss, drenching sweats, relentless high fevers and massive organomegaly, resistant to all previous therapy. After conditioning with total body irradiation, cyclophosphamide and high-dose melphalan followed by total nodal irradiation, he underwent peripheral blood stem cell allograft from an HLA-compatible sister. Despite his course being complicated by pulmonary tuberculosis he achieved immediate complete remission, and restaging at one year confirms this to be durable. This further anecdotal case report supports this option in refractory aggressive variants of this disease.

Distribution of beta-thalassemia mutations in three Asian Indian populations with distant geographical locations.

We have identified the beta-thalassemia alleles in 47 pediatric patients with transfusion-dependent thalassemia major from a clinic in New Delhi and in 105 heterozygous relatives. Surprisingly, only five mutations were present in 94 beta-thalassemia chromosomes with frequencies from 10 to 32%. This observation greatly facilitated the initiation of a prenatal diagnostic program. Similar studies were conducted for seven Asian Indian patients from Calgary, Canada, seven Asian Indian patients from Durban, South Africa, and from heterozygous relatives, and persons with a beta-thalassemia trait who were not related. Besides beta-thalassemia alleles, common to Asian Indian beta-thalassemia patients, some unexpected alleles were observed in the patients from South Africa, including a newly discovered frameshift at codon 15 (-T).

Pancytopaenia associated with disseminated tuberculosis, reactive histiocytic haemophagocytic syndrome and tuberculous hypersplenism.

A 38-year-old black male is reported with a rare combination of disseminated tuberculosis together with a reactive histiocytic haemophagocytic syndrome and tuberculosis hypersplenism. Tuberculosis and histiocytic haemophagocytosis were diagnosed on bone marrow examination. The pancytopaenia and splenomegaly which were present on admission did not resolve despite adequate anti-tuberculosis chemotherapy. Prior to splenectomy the patient continued to have a marked thrombocytopenia which resulted in recurrent bouts of epistaxis; splenectomy together with tuberculostatic therapy was curative for the condition. The patient remains well with normal blood counts 1 year later.

Combinations of three different forms of alpha-thalassemia in a large Indian family from Durban, South Africa: hematological observations.

We have identified three types of alpha-thalassemia in 28 members of an Indian family from Durban, South Africa. The rare South African (SA) type of alpha-thalassemia-1, which is characterized by an approximately 23-kb deletion involving the psi zeta, psi alpha 2, psi alpha 1, alpha 2, alpha 1, and theta 1 genes, was present in 13 members [6 simple heterozygotes, 5 with Hb H disease of the --(SA)/-alpha(-3.7 kb) type, and 2 with Hb H disease of the --(SA)/-alpha(-4.2 kb) type]. Seven others were heterozygotes for alpha-thalassemia-2 (-3.7 kb), 1 was homozygous for this deletion, and 1 was a compound heterozygote [-alpha(-3.7 kb/-alpha(-4.2 kb)]. Hematological and hemoglobin composition data indicated a moderate anemia in all 7 patients with Hb H disease with severe microcytosis and hypochromia, no elevation of gamma-chain synthesis, low levels of Hb A2 (0.3-0.7%), and low levels of Hb H. The most severe disease was present in 2 teenagers with the --(SA)/-alpha(-4.2 kb) combination.

Lymphomatoid granulomatosis. A report of 4 cases.

Only 1 case of lymphomatoid granulomatosis has previously been reported from South Africa. Experience with 4 such adult patients (2 blacks and 2 whites) is described. These patients were followed up for 15-48 months and none developed evidence of a lymphoma during this period. Fever, weight loss, cough and breathlessness were prominent symptoms in all patients. One patient, a black woman, with a diffuse interstitial pattern of lung involvement, had digital clubbing--a rare accompaniment that resolved after therapy. Dilated congestive cardiomyopathy was found in association with pulmonary nodules in a black male patient. All 4 patients were treated with cytotoxic regimens. The 2 patients treated with oral cyclophosphamide and prednisolone responded favourably. The possible explanation for paucity of reports of lymphomatoid granulomatosis from South Africa could be under-reporting, underdiagnosis or a true geographic/ethnic variation in the incidence of this condition.

Hb natal or alpha 2(minus Tyr-Arg) beta 2: a high oxygen affinity alpha chain variant with a deleted carboxy-terminus resulting from a TAC----TAA (Tyr----terminating codon) mutation in codon alpha 140.

The discovery is reported of a fast-moving alpha chain variant (Hb Natal) which is characterized by a shortened alpha polypeptide chain because of the deletion of the Tyr-Arg carboxy-terminal residues. Through amplification of appropriate segments of DNA and hybridization with synthetic oligonucleotide probes, it was possible to detect a C----A mutation in codon 140 of the alpha 2 globin gene, which causes a change in the codon for tyrosine to a terminating codon. Hb Natal or alpha 2 (minus Tyr-Arg) beta 2 has a high affinity for oxygen without a Bohr effect and heme-heme interaction. These results provide direct evidence for the importance of the tyrosine residue at alpha 140 in the oxygenation-deoxygenation process.

Typhoid fever and haemolytic anaemia in a black patient with glucose-6-phosphate dehydrogenase deficiency. A case report.

A young Zulu man was admitted for investigation of anaemia, jaundice and fever. He had a haemolytic anaemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency and typhoid fever. Reports on haemolysis as a complication of typhoid fever in patients with G6PD deficiency are exceedingly rare in countries where the gene frequency of G6PD deficiency is low.

Thrombocytosis associated with tuberculous peritonitis.

A young African female is described who showed marked thrombocytosis (platelet count 1372 X 10(9)/l) in association with tuberculous peritonitis, a rare association.