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Biomedical subjects

Brett Lowe

Publications and source records attributed to Brett Lowe.

18 recordsLinked to original sources
PubMed2006

Lactate levels in severe malarial anaemia are associated with haemozoin-containing neutrophils and low levels of IL-12.

BACKGROUND: Hyperlactataemia is often associated with a poor outcome in severe malaria in African children. To unravel the complex pathophysiology of this condition the relationship between plasma lactate levels, parasite density, pro- and anti-inflammatory cytokines, and haemozoin-containing leucocytes was studied in children with severe falciparum malarial anaemia. METHODS: Twenty-six children with a primary diagnosis of severe malarial anaemia with any asexual Plasmodium falciparum parasite density and Hb < 5 g/dL were studied and the association of plasma lactate levels and haemozoin-containing leucocytes, parasite density, pro- and anti-inflammatory cytokines was measured. The same associations were measured in non-severe malaria controls (N = 60). RESULTS: Parasite density was associated with lactate levels on admission (r = 0.56, P < 0.005). Moreover, haemozoin-containing neutrophils and IL-12 were strongly associated with plasma lactate levels, independently of parasite density (r = 0.60, P = 0.003 and r = -0.46, P = 0.02, respectively). These associations were not found in controls with uncomplicated malarial anaemia. CONCLUSION: These data suggest that blood stage parasites, haemozoin and low levels of IL-12 may be associated with the development of hyperlactataemia in severe malarial anaemia.

Anemia↗
PubMed2006

A phase 2b randomised trial of the candidate malaria vaccines FP9 ME-TRAP and MVA ME-TRAP among children in Kenya.

OBJECTIVE: The objective was to measure the efficacy of the vaccination regimen FFM ME-TRAP in preventing episodes of clinical malaria among children in a malaria endemic area. FFM ME-TRAP is sequential immunisation with two attenuated poxvirus vectors (FP9 and modified vaccinia virus Ankara), which both deliver the pre-erythrocytic malaria antigen construct multiple epitope-thrombospondin-related adhesion protein (ME-TRAP). DESIGN: The trial was randomised and double-blinded. SETTING: The setting was a rural, malaria-endemic area of coastal Kenya. PARTICIPANTS: We vaccinated 405 healthy 1- to 6-year-old children. INTERVENTIONS: Participants were randomised to vaccination with either FFM ME-TRAP or control (rabies vaccine). OUTCOME MEASURES: Following antimalarial drug treatment children were seen weekly and whenever they were unwell during nine months of monitoring. The axillary temperature was measured, and blood films taken when febrile. The primary analysis was time to a parasitaemia of over 2,500 parasites/mul. RESULTS: The regime was moderately immunogenic, but the magnitude of T cell responses was lower than in previous studies. In intention to treat (ITT) analysis, time to first episode was shorter in the FFM ME-TRAP group. The cumulative incidence of febrile malaria was 52/190 (27%) for FFM ME-TRAP and 40/197 (20%) among controls (hazard ratio = 1.52). This was not statistically significant (95% confidence interval [CI] 1.0-2.3; p = 0.14 by log-rank). A group of 346 children were vaccinated according to protocol (ATP). Among these children, the hazard ratio was 1.3 (95% CI 0.8-2.1; p = 0.55 by log-rank). When multiple malaria episodes were included in the analyses, the incidence rate ratios were 1.6 (95% CI 1.1-2.3); p = 0.017 for ITT, and 1.4 (95% CI 0.9-2.1); p = 0.16 for ATP. Haemoglobin and parasitaemia in cross-sectional surveys at 3 and 9 mo did not differ by treatment group. Among children vaccinated with FFM ME-TRAP, there was no correlation between immunogenicity and malaria incidence. CONCLUSIONS: No protection was induced against febrile malaria by this vaccine regimen. Future field studies will require vaccinations with stronger immunogenicity in children living in malarious areas.

Journal Article↗
PubMed2006

Decreasing prevalence of antimicrobial resistance in non-typhoidal Salmonella isolated from children with bacteraemia in a rural district hospital, Kenya.

We analysed 336 non-typhoidal Salmonella (NTS) isolated from children <13 years of age with bacteraemia admitted to a rural district hospital in Kenya from 1994 to 2005. Pulsed-field gel electrophoresis was used to determine genetic relatedness of strains, and antimicrobial susceptibility testing was also performed. Most NTS were either Salmonella enterica serovar Typhimurium (n=114; 33.9%) or S. enterica serovar Enteritidis (n=128; 38.1%), with minimal genotypic diversity over the study period. The NTS showed a remarkable decrease in levels of resistance especially to two commonly available antimicrobials (amoxicillin and co-trimoxazole), from high of 69.2% and 68.4% during 1994-1997 to 11% and 13%, respectively, in 2002-2005 (P<0.01). All NTS remained fully susceptible to cefotaxime and ciprofloxacin. Our findings show that commonly available drugs may still be useful for treatment of invasive NTS infections in this rural population.

Anti-Bacterial Agents↗
PubMed2006

Suppression of erythropoiesis in malarial anemia is associated with hemozoin in vitro and in vivo.

Malarial anemia is a global public health problem and is characterized by a low reticulocyte response in the presence of life-threatening hemolysis. Although cytokines, in particular tumor necrosis factor-alpha (TNF-alpha), can suppress erythropoiesis, the grossly abnormal bone marrow morphology indicates that other factors may contribute to ineffective erythropoiesis. We hypothesized that the cytotoxic hemozoin (Hz) residues from digested hemoglobin (Hb) significantly contribute to abnormal erythropoiesis. Here, we show that not only isolated Hz, but also delipidated Hz, inhibits erythroid development in vitro in the absence of TNF-alpha. However, when added to cultures, TNF-alpha synergizes with Hz to inhibit erythropoiesis. Furthermore, we show that, in children with malarial anemia, the proportion of circulating monocytes containing Hz is associated with anemia (P < .001) and reticulocyte suppression (P = .009), and that this is independent of the level of circulating cytokines, including TNF-alpha. Plasma Hz is also associated with anemia (P < .001) and reticulocyte suppression (P = .02). Finally, histologic examination of the bone marrow of children who have died from malaria shows that pigmented erythroid and myeloid precursors are associated with the degree of abnormal erythroid development. Taken together, these observations provide compelling evidence for inhibition of erythropoiesis by Hz.

Anemia↗
PubMed2006

Salmonella bacteremia in Kenyan children.

BACKGROUND: Nontyphoidal Salmonella spp. are among the leading causes of childhood bacteremia in sub-Saharan Africa, yet there are few published clinical series, and the risk factors for acquiring infection are not fully understood. METHODS: We examined data from 166 cases of nontyphoidal Salmonella bacteremia identified during a large prospective study of bacteremia among all children admitted to a district hospital in Kenya. We also investigated the importance of comorbidities, including current malaria parasitemia, recent malaria (detectable Plasmodium falciparum histidine rich protein 2 in the absence of parasitemia), sickle cell disease, malnutrition and human immunodeficiency virus (HIV) infection. RESULTS: Nontyphoidal Salmonella bacteremia was associated with severe malnutrition (33% cases), HIV infection (18% cases), a history of illness >7 days, recent hospital admission, splenomegaly, anemia and recent (but not current) malaria but was not associated with diarrhea. Seventy-seven (46%) children with nontyphoidal Salmonella bacteremia fulfilled World Health Organization clinical criteria for a diagnosis of pneumonia. Independent risk factors for death were diarrhea, tachypnea, HIV infection, severe malnutrition, meningitis and young age. CONCLUSIONS: Clinical diagnosis of invasive nontyphoidal Salmonella infection in African children is difficult without microbiology facilities because clinical features overlap with other conditions. The common risk factors for nontyphoidal Salmonella infection differ from developed countries, with high a prevalence of malnutrition, HIV, malaria and anemia. Children with nontyphoidal Salmonella infection who fulfill World Health Organization clinical criteria for severe pneumonia may receive ineffective therapy in the form of penicillin.

Anemia↗
PubMed2006

Cellular reactivity to the p. Falciparum protein trap in adult kenyans: novel epitopes, complex cytokine patterns, and the impact of natural antigenic variation.

Malaria vaccines based on thrombospondin-related adhesive protein of Plasmodium falciparum (Pf TRAP) are currently undergoing clinical trials in humans. This study was designed to investigate naturally acquired cellular immunity to Pf TRAP in adults from a target population for future trials of TRAP-based vaccines in Kilifi, Kenya. We first tested reactivity to a panel of 53 peptides spanning Pf TRAP and identified 26 novel T-cell epitopes. A panel of naturally occurring polymorphic variant epitope peptides were made to the most commonly recognized epitope regions and tested for ability to elicit IFN-gamma, IL-4, and IL-10 production. These data provide for the first time a complex cytokine matrix mapping naturally induced T-cell responses to TRAP and suggest that T-cell responses boosted by vaccination with Pf TRAP could stimulate the release of competing pro- and anti-inflammatory cytokines. They further define polymorphic variants able to boost specific Th1, Th2, and possibly Tr1 reactivity.

Adult↗
PubMed2006

Frequencies of peripheral blood myeloid cells in healthy Kenyan children with alpha+ thalassemia and the sickle cell trait.

The high frequencies of both alpha+ thalassemia and the sickle cell trait (hemoglobin AS [HbAS]) found in many tropical populations are thought to reflect selection pressure from Plasmodium falciparum malaria. For HbAS, but not for alpha+ thalassemia, protection appears to be mediated by the enhanced phagocytic clearance of ring-infected erythrocytes. We have investigated the genotype-specific distributions of peripheral blood leukocyte populations in two groups of children living on the coast of Kenya: a group of healthy P. falciparum parasite-negative children sampled at cross-sectional survey during a period of low malaria transmission, and a group of children attending the hospital with acute malaria. We report distinctive distributions of peripheral blood myeloid dendritic cells and monocytes in children with alpha+ thalassemia and HbAS during healthy periods and disease, and suggest ways in which these might relate to the mechanisms of protection afforded by these conditions.

Child↗
PubMed2004

Human antibodies to recombinant protein constructs of Plasmodium falciparum Apical Membrane Antigen 1 (AMA1) and their associations with protection from malaria.

Serum antibodies from 1071 people in two Kenyan villages were assayed using eight different recombinant Apical Membrane Antigen 1 (AMA1) protein constructs to investigate their role in naturally acquired immunity. In both communities, antibodies against the full-length ectodomain (both FVO and 3D7 allele constructs) prior to a malaria transmission season were significantly associated with protection from malaria in the following 6 months, even after adjusting for age and antibody reactivity to whole parasite (schizont) extract. However, these protective associations of antibodies were only seen among subjects that were parasite slide positive at the time of pre-season serum sampling. Competition ELISAs with the FVO and 3D7 allele constructs showed that antibodies can recognise either conserved or allele-specific epitopes in AMA1. Results encourage the development of an AMA1 vaccine based on the full-length ectodomain, and indicate that the function of human antibodies to allele-specific and conserved epitopes in AMA1 should be studied further.

Adolescent↗
PubMed2004

Perturbations in electrolyte levels in kenyan children with severe malaria complicated by acidosis.

BACKGROUND: To date, information about the frequency of electrolyte disturbances among children with severe falciparum malaria is limited. METHODS: We describe changes in potassium, calcium, magnesium, and phosphate levels in 56 Kenyan children (42 who survived and 14 who died) admitted to the hospital with clinical features of severe malaria (impaired consciousness or deep breathing) complicated by acidosis (base deficit, >8 mmol/L). RESULTS: Mild-to-moderate hypercalcemia was common at admission, particularly among children with severe anemia. Severe hyperkalemia complicated falciparum malaria in 9 children (16%), of whom 7 (78%) died, generally soon after admission. Hypokalemia, hypomagnesemia, and hypophosphatemia were uncommon (<7% of children) at admission but developed in >30% of children within 24 h. Hypocalcemia was infrequent (<5% of children) at any time point. Apart from administration of potassium, electrolyte deficiencies were not corrected and were not associated with an adverse outcome. CONCLUSIONS: At admission to the hospital, hyperkalemia may complicate cases of acidosis due to severe malaria and is associated with high, early mortality. After admission, mild asymptomatic deficiencies in magnesium and phosphate levels were common but were not associated with any deleterious effect. Thus, routine correction when serial measurement of electrolyte levels cannot be performed is unwarranted. Asymptomatic potassium deficiency developed despite provision of this electrolyte at maintenance doses. Further studies are justified but are unlikely to be a major research priority because, as these data suggest, the impact on mortality would at most be limited.

Acidosis↗
PubMed2004

Hypokalemia in children with severe falciparum malaria.

OBJECTIVES: Acidosis is now recognized as an important component of the severe malaria syndrome and a predictor of fatal outcome. Alterations in plasma potassium concentrations are commonly associated with acidosis. To date, there is little information about the changes in potassium in severe malaria. DESIGN: Prospective study examining the changes in plasma potassium in the first 24 hrs following admission in children with severe malaria. Urinary fractional excretion of potassium and the transtubular gradient of potassium were examined at admission. SETTING: High-dependency unit on the coast of Kenya. PATIENTS: Kenyan children admitted to hospital with clinical features of severe malaria (impaired consciousness or deep breathing) complicated by acidosis (base deficit >8). INTERVENTIONS: Children received standard therapy for severe malaria; in addition, they received boluses of either 0.9% saline or 4.5% human albumin solution to correct hypovolemia, and intravenous potassium replacement was prescribed to children who developed hypokalemia (plasma potassium <3 mmol/L). MEASUREMENTS AND MAIN RESULTS: Thirty-eight Kenyan children were recruited with severe malaria and acidosis. At admission, serum potassium was normal (3-5.5 mmol/L) in 31 (81.6%) and low (<3 mmol/L) in four (11%) children, and three (6.3%) children had hyperkalemia (>5.5 mmol/L). Plasma potassium decreased rapidly within 4-8 hrs of admission: 15 (40%) patients were hypokalemic (<3 mmol/L); of these, five (13%) had plasma potassium of <2.5 mmol/L. Fractional excretion of potassium and the transtubular gradient of potassium were above normal range, indicating renal potassium loss. CONCLUSIONS: Hypokalemia is a common complication of severe malaria; however, it is often not apparent on admission. On correction of acidosis, plasma potassium decreases precipitously, and thus careful, serial monitoring of serum potassium is suggested in patients with severe malaria complicated by acidosis.

Acidosis↗
PubMed2004

Carboxyhemoglobin levels in Kenyan children with Plasmodium falciparum malaria.

Heme oxygenase (HO) is thought to be induced in severe malaria, but the pathophysiologic consequences have not been examined. It is induced by hemolysis, oxidative stress, and inflammation. It degrades heme, producing carbon monoxide (CO), which causes elevated levels of carboxyhemoglobin (COHb). In a prospective study of 1,520 children admitted to a Kenyan district hospital, COHb levels were no higher in children with malaria than with other infections. The COHb levels in children with severe malarial anemia were higher than in other children with malaria, but significantly lower than in children with other causes of severe anemia such as sickle cell disease. Levels of COHb were not significantly higher in children with cerebral malaria or in those dying of malaria. These results do not support a systemic increase in HO activity in malaria compared with other infectious diseases, but the roles of HO and CO in malaria require further study.

Anemia↗
PubMed2003

Phenotypic diversity of enterotoxigenic Escherichia coli (ETEC) isolated from cases of travelers' diarrhea in Kenya.

BACKGROUND: The aim of this study was to characterize phenotypically enterotoxins, colonization factors (CFs) and the antibiotic susceptibility of enterotoxigenic Escherichia coli (ETEC) strains isolated from cases of acute diarrhea that occurred in Europeans traveling to resorts in Mombasa, Kenya; this information is critical for the development of vaccines and empirical treatment. METHODS: Over a 1-year period from 1996 to 1997, five E. coli-like colonies were obtained from each of 463 cases with acute diarrhea. These strains were characterized for enterotoxins using GM-1 ELISA, for CFs using a dot-blot assay, and for antibiotic susceptibility using antibiotic disks. RESULTS: Of 164 strains characterized for ETEC phenotype, 30 (18%) expressed heat-labile toxin (LT) only, 83 (51%) heat-stable toxin (ST) only, and 51 (31%) both LT and ST. Analysis for CF expression demonstrated that 107 (65%) of the strains were positive for CFs, including CFA/IV (46%), CFA/II (35%), and CFA/I (5%), while less than 4% expressed less common CFs. All ETEC strains tested were resistant to erythromycin and sensitive to ceftriaxone. Over one-third of the strains were resistant to sulfamethoxazole-trimethoprim or tetracycline. Six strains were resistant to nalidixic acid; none of these were resistant to ciprofloxacin. CONCLUSIONS: Cumulatively, our findings indicate that ETEC in this region comprises a highly diverse group of bacterial enteropathogens, and that the development of prophylactic agents against ETEC faces major challenges because of this diversity.

Anti-Bacterial Agents↗
PubMed2003

Therapy of travelers' diarrhea with rifaximin on various continents.

OBJECTIVE: Our aim was to compare the efficacy and safety of rifaximin, a virtually nonabsorbed antibiotic, 600 and 1200 mg per day, with placebo in patients with travelers' diarrhea. METHODS: This was a multicenter, 1:1:1 randomized, parallel-group, double-blind study, conducted in Antigua, Guatemala; Guadalajara and Morelia, Mexico; and the coast of Kenya north and south of Mombasa. Adult patients with acute travelers' diarrhea were recruited; exclusion criteria included primarily medication that could influence the outcome. Subjects were treated for 3 days, three times daily; follow-up lasted 5 days. For each 24-h period, the subjects completed a diary card. Pre- and posttreatment stool, blood, and urine samples were assessed. RESULTS: Among the 380 volunteers, median time to the last unformed stool was 32.5 and 32.9 h in both rifaximin groups, compared with 60.0 h with placebo (p = 0.0001). Also, secondary clinical outcome measures were favorably influenced by the active agent. No relevant side effects were reported. CONCLUSION: Rifaximin is efficacious and safe for treatment of travelers' diarrhea at daily doses of 600 mg or higher.

Adolescent↗
PubMed2003

Ex vivo interferon-gamma immune response to thrombospondin-related adhesive protein in coastal Kenyans: longevity and risk of Plasmodium falciparum infection.

Thrombospondin-related adhesive protein (TRAP) of Plasmodium falciparum is currently being tested in human vaccine studies. However, its natural reactivity in the field remains poorly characterized. More than 40% of 217 Kenyan donors responded in an ex vivo interferon-gamma (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay to at least one of 14 20mer peptides spanning 42% of the antigen. Reactivity was comparable from early childhood (>1 year of age) to old age, and the maximal precursor frequency of TRAP-specific cells to all 14 peptides was 1 in 4,000. Prospective follow-up for one year indicated that these low-level ex vivo responses to TRAP did not protect against the subsequent development of malaria. Retesting of selected donors after one year showed a complete change in the reactivity pattern, suggesting that malaria-specific ex vivo IFN-gamma ELISPOT assay responses are short lived in naturally exposed donors, even to conserved epitopes. This study provides important information regarding natural reactivity to a key malaria antigen.

Adolescent↗
PubMed2002

Prevalence of enteric pathogens among international travelers with diarrhea acquired in Kenya (Mombasa), India (Goa), or Jamaica (Montego Bay).

Stools from tourists from Europe and North America who acquired diarrhea in Mombasa (Kenya), Goa (India), or Montego Bay (Jamaica) were examined for enteric pathogens. Enterotoxigenic Escherichia coli (ETEC) was the most common pathogen (25%) identified in the 3 locations. Isolation of Shigella species was more frequent in Goa and Mombasa than in Montego Bay (10%, 9%, and 0.3%, respectively; P <.005). Viruses (rotaviruses and enteric adenoviruses) were found in 9% of travelers to the 3 areas. Of 275 ETEC isolates in this study, 158 (57%) produced a defined colonization factor antigen (CFA). Coli surface 6 (CS6) was the most frequent and was found in 41%-52% of CFA/CS-positive ETEC isolates. The frequency of resistance among bacterial enteropathogens to traditional antimicrobial agents was particularly high throughout the study period in all 3 regions. Quinolones were active against the bacterial enteropathogens in the 3 sites.

Bacteria↗
PubMed2002

Changes in white blood cells and platelets in children with falciparum malaria: relationship to disease outcome.

Little is known about the changes in white blood cells and platelets in children with falciparum malaria in endemic areas. We measured the white cell count (WCC) and platelets of 230 healthy children from the community, 1369 children admitted to hospital with symptomatic malaria, and 1461 children with other medical conditions. Children with malaria had a higher WCC compared with community controls, and leucocytosis was strongly associated with younger age, deep breathing, severe anaemia, thrombocytopenia and death. The WCC was not associated with a positive blood culture. In children with malaria, high lymphocyte and low monocyte counts were independently associated with mortality. A platelet count of less than 150 x 109/l was found in 56.7% of children with malaria, and was associated with age, prostration and parasite density, but not with bleeding problems or mortality. The mean platelet volume was also higher in children with malaria compared with other medical conditions. This may reflect early release from the bone marrow in response to peripheral platelet destruction. Thus, leucocytosis was associated with both severity and mortality in children with falciparum malaria, irrespective of bacteraemia, whereas thrombocytopenia, although very common, was not associated with adverse outcome.

Bacteremia↗
PubMed2002

Acute bacterial meningitis in children admitted to a rural Kenyan hospital: increasing antibiotic resistance and outcome.

BACKGROUND: Acute bacterial meningitis (ABM) is an important cause of mortality in Africa, but most studies are based in urban referral hospitals. Poor laboratory facilities make diagnosis difficult, and treatment is limited to inexpensive antibiotics. METHODS: We retrospectively reviewed data from children admitted with ABM to a Kenyan district hospital from 1994 through 2000. We calculated the minimum incidence in children admitted from a defined area. We also examined the antibiotic susceptibility patterns. RESULTS: We identified 390 cases (1.3% of all admissions) of whom 88% were <5 years old. The apparent minimum annual incidence in children younger than 5 years of age increased from 120 to 202 per 100,000 between 1995 and 2000 (P < 0.001). Increasing the lumbar punctures performed by including prostrated or convulsing children significantly increased the number of cases detected (P < 0.005). The most common organisms in infants <3 months were streptococci and Enterobacteriaceae. Streptococcus pneumoniae (43.1%) and Haemophilus influenzae (41.9%) were predominant in the postneonatal period. The overall mortality was 30.1%, and 23.5% of survivors developed neurologic sequelae. Chloramphenicol resistance of H. influenzae rose from 8% in 1994 to 80% in 2000 (P < 0.0001) accompanied by an apparent increase in mortality. A short history, impaired consciousness and hypoglycemia were associated with death. Prolonged coma and low cerebrospinal fluid glucose were associated with neurologic sequelae. CONCLUSION: ABM in rural Kenya is a severe illness with substantial mortality and morbidity. Prognosis could be improved by broadening the criteria for lumbar puncture and use of appropriate antibiotics.

Acute Disease↗