Biomedical subjects

Kevin Marsh

Publications and source records attributed to Kevin Marsh.

At least 37 records · Page 2Linked to original sources

PubMed2005

Negative epistasis between the malaria-protective effects of alpha+-thalassemia and the sickle cell trait.

The hemoglobinopathies, disorders of hemoglobin structure and production, protect against death from malaria. In sub-Saharan Africa, two such conditions occur at particularly high frequencies: presence of the structural variant hemoglobin S and alpha(+)-thalassemia, a condition characterized by reduced production of the normal alpha-globin component of hemoglobin. Individually, each is protective against severe Plasmodium falciparum malaria, but little is known about their malaria-protective effects when inherited in combination. We investigated this question by studying a population on the coast of Kenya and found that the protection afforded by each condition inherited alone was lost when the two conditions were inherited together, to such a degree that the incidence of both uncomplicated and severe P. falciparum malaria was close to baseline in children heterozygous with respect to the mutation underlying the hemoglobin S variant and homozygous with respect to the mutation underlying alpha(+)-thalassemia. Negative epistasis could explain the failure of alpha(+)-thalassemia to reach fixation in any population in sub-Saharan Africa.

Africa South of the Sahara↗

PubMed2005

Plasmodium falciparum antigenic variation: relationships between in vivo selection, acquired antibody response, and disease severity.

BACKGROUND: Variant surface antigens (VSA) on Plasmodium falciparum-infected erythrocytes are potentially important targets of immunity to malaria. We previously identified a VSA phenotype--VSA with a high frequency of antibody recognition (VSA(FoRH))--that is associated with young host age and severe malaria. We hypothesized that VSA(FoRH) are positively selected by host molecules such as intercellular adhesion molecule 1 (ICAM1) and CD36 and dominate in the absence of an effective immune response. Here, we assessed, in 115 Kenyan children, the potential role played by in vivo selection pressures in either favoring or selecting against VSA(FoRH) among parasites that cause malaria. METHODS: We tested for associations between VSA(FoRH) and (1) the repertoire of VSA antibodies carried by children at the time of acute malaria and (2) polymorphisms in ICAM1 (K29M) and CD36 (T188G) that could potentially reduce the positive selection of VSA(FoRH). RESULTS: An expected negative association between VSA antibody repertoire and VSA(FoRH) was observed in children with nonsevere malaria. However, this association did not extend to children with severe malaria, many of whom apparently had well-developed VSA antibody responses despite being infected by parasites expressing VSA(FoRH). There was no evidence for involvement of CD36 or ICAM1 in positive selection of VSA(FoRH). On the contrary, a weak positive association between carriage of the CD36 (T188G) allele and VSA(FoRH) was observed in children with severe malaria. CONCLUSION: The association between the VSA(FoRH) parasite phenotype and severe malaria cannot be explained simply in terms of the total repertoire of VSA antibodies carried at the time of acute disease.

Amino Acid Substitution↗

PubMed2005

High levels of serum antibodies to merozoite surface protein 2 of Plasmodium falciparum are associated with reduced risk of clinical malaria in coastal Kenya.

The merozoite surface protein (MSP) 2 is a vaccine candidate antigen of Plasmodium falciparum that is polymorphic in natural populations. In a prospective cohort study in two coastal populations of Kenya using recombinant proteins derived from the two major allelic types of MSP2, high serum levels of IgG to MSP2 were associated with protection from clinical malaria. This protection was independent of that associated with antibodies to another vaccine candidate antigen (AMA1) in these populations. However, low antibody levels to MSP2 appeared to be associated with increased susceptibility to malaria within people who were parasite negative at the time of serum collection. These data suggest that an MSP2 based vaccine should be designed to induce high level antibody responses against the different MSP2 types present globally in P. falciparum populations and that MSP2 could be combined with other P. falciparum antigens to form a multi-component malaria vaccine.

Adolescent↗

PubMed2005

Sickle cell trait and the risk of Plasmodium falciparum malaria and other childhood diseases.

BACKGROUND: The gene for sickle hemoglobin (HbS) is a prime example of natural selection. It is generally believed that its current prevalence in many tropical populations reflects selection for the carrier form (sickle cell trait [HbAS]) through a survival advantage against death from malaria. Nevertheless, >50 years after this hypothesis was first proposed, the epidemiological description of the relationships between HbAS, malaria, and other common causes of child mortality remains incomplete. METHODS: We studied the incidence of falciparum malaria and other childhood diseases in 2 cohorts of children living on the coast of Kenya. RESULTS: The protective effect of HbAS was remarkably specific for falciparum malaria, having no significant impact on any other disease. HbAS had no effect on the prevalence of symptomless parasitemia but was 50% protective against mild clinical malaria, 75% protective against admission to the hospital for malaria, and almost 90% protective against severe or complicated malaria. The effect of HbAS on episodes of clinical malaria was mirrored in its effect on parasite densities during such episodes. CONCLUSIONS: The present data are useful in that they confirm the mechanisms by which HbAS confers protection against malaria and shed light on the relationships between HbAS, malaria, and other childhood diseases.

Child, Preschool↗

PubMed2005

An immune basis for malaria protection by the sickle cell trait.

BACKGROUND: Malaria resistance by the sickle cell trait (genotype HbAS) has served as the prime example of genetic selection for over half a century. Nevertheless, the mechanism of this resistance remains the subject of considerable debate. While it probably involves innate factors such as the reduced ability of Plasmodium falciparum parasites to grow and multiply in HbAS erythrocytes, recent observations suggest that it might also involve the accelerated acquisition of malaria-specific immunity. METHODS AND FINDINGS: We studied the age-specific protection afforded by HbAS against clinical malaria in children living on the coast of Kenya. We found that protection increased with age from only 20% in the first 2 y of life to a maximum of 56% by the age of 10 y, returning thereafter to 30% in participants greater than 10 y old. CONCLUSIONS: Our observations suggest that malaria protection by HbAS involves the enhancement of not only innate but also of acquired immunity to the parasite. A better understanding of the underlying mechanisms might yield important insights into both these processes.

Age Factors↗

PubMed2005

Invasive Gram-negative bacilli are frequently resistant to standard antibiotics for children admitted to hospital in Kilifi, Kenya.

OBJECTIVES: To determine the pattern of resistance among Gram-negative bacilli causing invasive bacterial disease for the antibiotics that are already in common use in Kilifi, Kenya and for two potential alternatives, ciprofloxacin and cefotaxime. Also, to determine whether prevalence and severity of resistance was increasing over time, to identify patients who are particularly at risk of resistant infections, and to explore which factors are associated with the development of resistance in our setting. METHODS: We used Etest to study antibiotic susceptibility patterns of 90 Gram-negative bacilli cultured in blood or CSF from paediatric inpatients over 8 years. RESULTS: Susceptibility to amoxicillin 28%, cefotaxime 95% and ciprofloxacin 99% did not vary significantly with age. Susceptibilities for isolates from children aged less than 14 days were: chloramphenicol, 81%; trimethoprim/sulfamethoxazole, 71%; and gentamicin, 91%. From older children, susceptibilities were: chloramphenicol, 62%; trimethoprim/sulfamethoxazole, 39%; and gentamicin, 73%. Chloramphenicol susceptibility was significantly more common among non-typhi salmonellae than other species (79% versus 53%, P < 0.0005). The combination of gentamicin and chloramphenicol covered 91% of all isolates. The prevalence of resistance did not increase over time and was not more common in patients with HIV or malnutrition. Age was the only clinical feature that predicted resistance. CONCLUSIONS: Gentamicin or chloramphenicol alone was suboptimal therapy for Gram-negative sepsis, although in this retrospective study, there was no association between resistance and mortality.

Anti-Bacterial Agents↗

PubMed2005

Case definitions of clinical malaria under different transmission conditions in Kilifi District, Kenya.

BACKGROUND: Clear case definitions of malaria are an essential means of evaluating the effectiveness of present and proposed interventions in malaria. The clinical signs of malaria are nonspecific, and parasitemia accompanied by a fever may not be sufficient to define an episode of clinical malaria in endemic areas. We defined and quantified cases of malaria in people of different age groups from 2 areas with different rates of transmission of malaria. METHODS: A total of 1602 people were followed up weekly for 2 years, and all the cases of fever accompanied by parasitemia were identified. Logistic regression methods were used to derive case definitions of malaria. RESULTS: Two case definitions of malaria were derived: 1 for children 1-14 years old and 1 for infants (<1 year old) and older children and adults (> or =15 years old). We also found a higher number of episodes of clinical malaria per person per year in people from an area of low transmission of malaria, compared with the number of episodes in those from an area of higher transmission (0.84 vs. 0.55 episodes/person/year; incidence rate ratio, 0.66 [95% confidence interval, 0.61-0.72]; P<.001). CONCLUSIONS: Case definitions of malaria are bound to be altered by factors that affect immunity, such as age and transmission. Case definitions may, however, be affected by other immunity-altering factors, such as HIV and vaccination status, and this needs to be borne in mind during vaccine trials.

Adolescent↗

PubMed2005

Neonatal measles immunity in rural Kenya: the influence of HIV and placental malaria infections on placental transfer of antibodies and levels of antibody in maternal and cord serum samples.

INTRODUCTION: Young infants are protected from measles infection by maternal measles antibodies. The level of these antibodies at birth depends on the level of antibodies in the mother and the extent of placental transfer. We investigated predictors of levels of measles antibodies in newborns in rural Kenya. METHODS: A total of 747 paired maternal-cord serum samples (91 from human immunodeficiency virus [HIV]-infected and 656 from HIV-uninfected mothers) were tested for measles immunoglobulin G antibodies. Placental malaria infection was determined by biopsy. Data on pregnancy history, gestational age, and anthropometric and socioeconomic status were collected. RESULTS: Infants born to HIV-infected mothers were more likely (odds ratio, 4.6 [95% confidence interval {CI}, 2.2-9.7]) to be seronegative and had 35.1% (95% CI, 9.8%-53.2%) lower levels of measles antibodies than did those born to HIV-uninfected mothers. Preterm delivery, early maternal age, and ethnic group were also associated with reduced levels of measles antibodies. There was little evidence that placental malaria infection was associated with levels of measles antibodies in newborns. CONCLUSION: Our results suggest that maternal HIV infection may reduce levels of measles antibodies in newborns. Low levels of measles antibodies at birth render children susceptible to measles infection at an early age. This is of concern in sub-Saharan African countries, where not only is the prevalence of HIV high, but measles is the cause of much morbidity and mortality.

Adolescent↗

PubMed2005

Genomewide analysis of the host response to malaria in Kenyan children.

Malaria is a global problem, and there is a critical need for further understanding of the disease process. When malarial parasites invade and develop within the bloodstream, they stimulate a profound host response whose main clinical sign is fever. To explore this response, we measured host gene expression in whole blood from Kenyan children hospitalized with either acute malaria or other febrile illnesses. Genomewide analysis of expression identified 2 principal gene-expression profiles related to neutrophil and erythroid activity. In addition to these general acute responses, a third gene-expression profile was associated with host parasitemia; mediators of erythrophagocytosis and cellular stress were notable components of this response. The delineation of subjects on the basis of patterns of gene expression provides a molecular perspective of the host response to malaria and further functional insight into the underlying processes of pathogenesis.

Child↗

PubMed2005

B cell memory to 3 Plasmodium falciparum blood-stage antigens in a malaria-endemic area.

To gain insight into why antibody responses to malarial antigens tend to be short lived, we studied antigen-specific memory B cells from donors in an area where malaria is endemic. We compared antibody and memory B cell responses to tetanus toxoid with those to 3 Plasmodium falciparum candidate vaccine antigens: the C-terminal portion of merozoite surface protein 1 (MSP1(19)), apical membrane antigen 1 (AMA1), and the cysteine-rich interdomain region 1 alpha (CIDR1 alpha ) of a protein from the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. These data are the first to be generated on memory B cells in children who are in the process of acquiring antimalarial immunity, and they reveal defects in B cell memory to P. falciparum antigens. Compared with the results for tetanus toxoid, more donors who were positive for antibody to AMA1 and CIDR1 alpha were negative for memory B cells. These data imply that some exposures to malaria do not result in the establishment of stable populations of circulating antigen-specific memory B cells, suggesting possible mechanisms for the short-lived nature of many anti-malarial antibody responses.

Adult↗

PubMed2005

Use of clinical syndromes to target antibiotic prescribing in seriously ill children in malaria endemic area: observational study.

OBJECTIVES: To determine how well antibiotic treatment is targeted by simple clinical syndromes and to what extent drug resistance threatens affordable antibiotics. DESIGN: Observational study involving a priori definition of a hierarchy of syndromic indications for antibiotic therapy derived from World Health Organization integrated management of childhood illness and inpatient guidelines and application of these rules to a prospectively collected dataset. SETTING: Kilifi District Hospital, Kenya. PARTICIPANTS: 11,847 acute paediatric admissions. MAIN OUTCOME MEASURES: Presence of invasive bacterial infection (bacteraemia or meningitis) or Plasmodium falciparum parasitaemia; antimicrobial sensitivities of isolated bacteria. RESULTS: 6254 (53%) admissions met criteria for syndromes requiring antibiotics (sick young infants; meningitis/encephalopathy; severe malnutrition; very severe, severe, or mild pneumonia; skin or soft tissue infection): 672 (11%) had an invasive bacterial infection (80% of all invasive bacterial infections identified), and 753 (12%) died (93% of all inpatient deaths). Among P falciparum infected children with a syndromic indication for parenteral antibiotics, an invasive bacterial infection was detected in 4.0-8.8%. For the syndrome of meningitis/encephalopathy, 96/123 (76%) isolates were fully sensitive in vitro to penicillin or chloramphenicol. CONCLUSIONS: Simple clinical syndromes effectively target children admitted with invasive bacterial infection and those at risk of death. Malaria parasitaemia does not justify withholding empirical parenteral antibiotics. Lumbar puncture is critical to the rational use of antibiotics.

Anti-Bacterial Agents↗

PubMed2005

Randomized trial of volume expansion with albumin or saline in children with severe malaria: preliminary evidence of albumin benefit.

BACKGROUND: Metabolic acidosis is the best predictor of death in children with severe falciparum malaria; however, its treatment presents a therapeutic dilemma, because acidosis and hypovolemia may coexist with coma, which can be associated with elevated intracranial pressure. We postulated that volume resuscitation with albumin might correct acidosis and hypovolemia with a lower risk of precipitating cerebral edema than crystalloid. In an open-label, randomized, controlled trial, we compared the safety of resuscitation with albumin to saline in Kenyan children with severe malaria. METHODS: We randomly assigned children with severe malaria and metabolic acidosis (base deficit, >8 mmol/L) to receive fluid resuscitation with either 4.5% albumin or normal saline. A control (maintenance only) group was only included for patients with a base deficit of <15 mmol/L. The primary outcome measure was the percentage reduction in base deficit at 8 h. Secondary end points included death, the requirement for rescue therapies, and neurological sequelae in survivors. RESULTS: Of 150 children recruited for the trial, 61 received saline, 56 received albumin, and 33 served as control subjects. There was no significant difference in the resolution of acidosis between the groups; however, the mortality rate was significantly lower among patients who received albumin (3.6% [2 of 56 patients]) than among those who received saline (18% [11 of 61]; relative risk, 5.5; 95% confidence interval, 1.2-24.8; P=.013). CONCLUSIONS: In high-risk children with severe malaria and acidosis, fluid resuscitation with albumin may reduce mortality. Our study design did not enable us to determine whether saline administration is preferable to fluid restriction or whether saline administration is actually hazardous. Further studies are needed to confirm our findings before definitive treatment recommendations can be made.

Acidosis↗

PubMed2005

Bacteremia among children admitted to a rural hospital in Kenya.

BACKGROUND: There are few epidemiologic data on invasive bacterial infections among children in sub-Saharan Africa. We studied every acute pediatric admission to a rural district hospital in Kenya to examine the prevalence, incidence, types, and outcome of community-acquired bacteremia. METHODS: Between August 1998 and July 2002, we cultured blood on admission from 19,339 inpatients and calculated the incidence of bacteremia on the basis of the population served by the hospital. RESULTS: Of a total of 1783 infants who were under 60 days old, 228 had bacteremia (12.8 percent), as did 866 of 14,787 children who were 60 or more days of age (5.9 percent). Among infants who were under 60 days old, Escherichia coli and group B streptococci predominated among a broad range of isolates (14 percent and 11 percent, respectively). Among infants who were 60 or more days of age, Streptococcus pneumoniae, nontyphoidal salmonella species, Haemophilus influenzae, and E. coli accounted for more than 70 percent of isolates. The minimal annual incidence of community-acquired bacteremia was estimated at 1457 cases per 100,000 children among infants under a year old, 1080 among children under 2 years, and 505 among children under 5 years. Of all in-hospital deaths, 26 percent were in children with community-acquired bacteremia. Of 308 deaths in children with bacteremia, 103 (33.4 percent) occurred on the day of admission and 217 (70.5 percent) within two days. CONCLUSIONS: Community-acquired bacteremia is a major cause of death among children at a rural sub-Saharan district hospital, a finding that highlights the need for prevention and for overcoming the political and financial barriers to widespread use of existing vaccines for bacterial diseases.

Bacteremia↗

PubMed2005

Comparative folate metabolism in humans and malaria parasites (part I): pointers for malaria treatment from cancer chemotherapy.

New inhibitors are urgently needed to overcome the burgeoning problem of drug resistance in the treatment of Plasmodium falciparum infection. Targeting the folate pathway has proved to be a powerful strategy for drug development against rapidly multiplying systems such as cancer cells and microorganisms. Antifolates have long been used for malaria treatment but, despite their success, much less is known about parasite folate metabolism than about that of the human host. In this article, we focus on folate enzymes used clinically as anticancer drug targets, in addition to those that have potential to be used as drug targets, for which there are inhibitors at various stages of development. We discuss how this information could lead to the identification of new targets in malaria parasites.

Animals↗

PubMed2005

Comparative folate metabolism in humans and malaria parasites (part II): activities as yet untargeted or specific to Plasmodium.

The folate pathway represents a powerful target for combating rapidly dividing systems such as cancer cells, bacteria and malaria parasites. Whereas folate metabolism in mammalian cells and bacteria has been studied extensively, it is understood less well in malaria parasites. In two articles, we attempt to reconstitute the malaria folate pathway based on available information from mammalian and microbial systems, in addition to Plasmodium-genome-sequencing projects. In part I, we focused on folate enzymes that are already used clinically as anticancer drug targets or that are under development in drug-discovery programs. In this article, we discuss mammalian folate enzymes that have not yet been exploited as potential drug targets, and enzymes that function in the de novo folate-synthesis pathway of the parasite--a particularly attractive area of attack because of its absence from the mammalian host.

Animals↗

PubMed2005

Why has the dihydrofolate reductase 164 mutation not consistently been found in Africa yet?

Resistance to the antifolate sulfadoxine-pyrimethamine (SP), the current mass-treatment antimalarial drug, is associated with selection of point mutations in dihydrofolate reductase and dihydropteroate synthase. Among these mutations, the leucine 164 dihydrofolate reductase mutation (Leu-164) is associated with higher levels of SP resistance; this mutation is also associated with a decrease in the efficacy of chlorproguanil/dapsone, a newly developed antifolate antimalarial drug. Leu-164 has been detected in Southeast Asia and South America, regions where SP is no longer effective. Surprisingly, this mutation has not yet been detected in Africa, using the standard protocol based on PCR-RFLP, despite high SP resistance. In this paper, we discuss briefly the reasons why Leu-164 has not yet been selected in Africa and we propose a means that may slow down the selection of this mutation.

Africa↗

PubMed2005

Clinical algorithms for malaria diagnosis lack utility among people of different age groups.

We conducted a study to determine whether clinical algorithms would be useful in malaria diagnosis among people living in an area of moderate malaria transmission within Kilifi District in Kenya. A total of 1602 people of all age groups participated. We took smears and recorded clinical signs and symptoms (prompted or spontaneous) of all those presenting to the study clinic with a history of fever. A malaria case was defined as a person presenting to the clinic with a history of fever and concurrent parasitaemia. A set of clinical signs and symptoms (algorithms) with the highest sensitivity and specificity for diagnosing a malaria case was selected for the age groups </=5 years, 6-14 years and >/=15 years. These age-optimized derived algorithms were able to identify about 66% of the cases among those <15 years of age but only 23% of cases among adults. Were these algorithms to be used as a basis for a decision on treatment among those presenting to the clinic, 16% of children </=5 years, 44% of those 6-14 years of age and 66% of the adults who had a history of fever and parasitaemia >/=5000 parasites/microl of blood would be sent home without treatment. Clinical algorithms therefore appear to have little utility in malaria diagnosis, performing even worse in the older age groups, where avoiding unnecessary use of anti-malarials would make more drugs available to the really needy population of children under 5 years of age.

Adolescent↗

PubMed2005

Progressive increase in antimicrobial resistance among invasive isolates of Haemophilus influenzae obtained from children admitted to a hospital in Kilifi, Kenya, from 1994 to 2002.

Etest susceptibilities to amoxicillin, chloramphenicol, and trimethoprim-sulfamethoxazole of 240 invasive isolates of Haemophilus influenzae cultured from children in rural Kenya were 66%, 66%, and 38%, respectively. Resistance increased markedly over 9 years and was concentrated among serotype b isolates. In Africa, the increasing cost of treating resistant infections supports economic arguments for prevention through conjugate H. influenzae type b immunization.

Anti-Bacterial Agents↗