Clinical and pathophysiological aspects of severe falciparum malaria

Malaria is a major global public health problem. One-fifth of the world's population is at risk of malaria and drug resistance is spreading. Nearly five times as many cases of malaria were reported in 2000 as tuberculosis, AIDS, measles and leprosy cases combined. In the time it takes to say the word "malaria," ten children will contract the disease and begin fighting for their lives. Since the cinchona alkaloids were introduced as a specific treatment for agues 350 years ago, the treatment of severe malaria has changed little and therapy remains largely empirical. Quinine and quinidine remain the drugs of choice for severe chloroquine-resistant malaria due to Plasmodium falciparum, and with the spread of these resistant parasites, the usage of these drugs is increasing. In 1972 scientists in China discovered the antimalarial properties of a group of sesquiterpene lactone peroxides derived from the qinghao plant (Artemisia annua). The principal component, qinghaosu (artemisinin), and two derivatives - the water-soluble hemisuccinate artesunate and the oil-soluble artemether - are the most rapidly acting and potent of all antimalarial drugs. Although much research effort has been invested in optimizing antimalarial drug regimes, severe malaria remains a major cause of adult mortality in the Asiatic tropics. Despite many clinical trials reducing the mortality from severe malaria has proved difficult. Artemether has been shown to be as good as quinine but not better. This thesis set out to determine whether Artemether or Artesunate was the the better drug, how to manage acute renal failure in severe malaria, to design a severity score for malaria and assess whether there had been any change in the parasite clearance times in Viet Nam over a 18 year period. The results from a series of clinical trials and research from one hospital in Viet Nam are presented. This thesis undertook the following studies: 1. A randomised clinical trial of artesunate vs artemether in the treatment of severe malaria in adults in Viet Nam. 2. A randomized comparison of pumped venovenous haemofiltration and peritoneal dialysis in acute renal failure associated with severe infection. 3. Fluid management in severe malaria. 4. The stage of the development of the falciparum parasites at the time of clinical presentation with severe malaria is important in predicting outcome. 5. Development of a predictive score of outcome in adults with severe falciparum malaria. 6. Assessment of the efficacy of the artemisinin derivatives in the treatment of severe falciparum malaria in Viet Nam 1991-2008

Magnitude and patterns of severe Plasmodium vivax monoinfection in Vietnam: a 4-year single-center retrospective study

IntroductionInfection with Plasmodium vivax is a recognized cause of severe malaria including deaths. The exact burden and patterns of severe P. vivax monoinfections is however still not well quantified, especially in P. vivax endemic regions. We examined the magnitude and patterns of severe malaria caused by monoinfections of P. vivax and associated predictors among patients admitted to a tertiary care center for malaria in Vietnam.MethodsA retrospective cohort study was conducted based on the patients’ medical records at the Hospital for Tropical Diseases from January 2015 to December 2018. Extracted information included demographic, epidemiologic, clinical, laboratory and treatment characteristics.ResultsMonoinfections with P. vivax were found in 153 (34.5, 95% CI 30.3–39.1%) patients of whom, uncomplicated and severe malaria were documented in 89.5% (137/153, 95% CI 83.7–93.5%) and 10.5% (16/153, 95% CI 6.5–16.3%), respectively. Patterns of severe malaria included jaundice (8 cases), hypoglycemia (3 cases), shock (2 cases), anemia (2 cases), and cerebral malaria (1 case). Among 153 patients, 73 (47.7%) had classic malaria paroxysm, 57 (37.3%) had >7 days of illness at the time of admission, and 40 (26.1%) were referred from other hospitals. A misdiagnosis as having other diseases from malaria cases coming from other hospitals was up to 32.5% (13/40). Being admitted to hospital after day 7th of illness (AOR = 6.33, 95% CI 1.14–35.30, p = 0.035) was a predictor of severe malaria. Severe malaria was statistically associated with longer hospital length of stay (p = 0.035). Early and late treatment failures and recrudescence were not recorded. All patients recovered completely.DiscussionThis study confirms the emergence of severe vivax malaria in Vietnam which is associated with delayed hospital admission and increased hospital length of stay. Clinical manifestations of P. vivax infection can be misdiagnosed which results in delayed treatment. To meet the goal of malaria elimination by 2030, it is crucial that the non-tertiary hospitals have the capacity to quickly and correctly diagnose malaria and then provide treatment for malaria including P. vivax infections. More robust studies need to be conducted to fully elucidate the magnitude of severe P. vivax in Vietnam

Concomitant Bacteremia in Adults With Severe Falciparum Malaria.

BackgroundApproximately 6% of children hospitalized with severe falciparum malaria in Africa are also bacteremic. It is therefore recommended that all children with severe malaria should receive broad-spectrum antibiotics in addition to parenteral artesunate. Empirical antibiotics are not recommended currently for adults with severe malaria.MethodsBlood cultures were performed on sequential prospectively studied adult patients with strictly defined severe falciparum malaria admitted to a single referral center in Vietnam between 1991 and 2003.ResultsIn 845 Vietnamese adults with severe falciparum malaria admission blood cultures were positive in 9 (1.07%: 95% confidence interval [CI], .37-1.76%); Staphylococcus aureus in 2, Streptococcus pyogenes in 1, Salmonella Typhi in 3, Non-typhoid Salmonella in 1, Klebsiella pneumoniae in 1, and Haemophilus influenzae type b in 1. Bacteremic patients presented usually with a combination of jaundice, acute renal failure, and high malaria parasitemia. Four bacteremic patients died compared with 108 (12.9%) of 836 nonbacteremic severe malaria patients (risk ratio, 3.44; 95% CI, 1.62-7.29). In patients with >20% parasitemia the prevalence of concomitant bacteremia was 5.2% (4/76; 95% CI, .2-10.3%) compared with 0.65% (5/769; 0.08-1.2%) in patients with ConclusionsIn contrast to children, the prevalence of concomitant bacteremia in adults with severe malaria is low. Administration of empirical antibiotics, in addition to artesunate, is warranted in the small subgroup of patients with very high parasitemias, emphasizing the importance of quantitative blood smear microscopy assessment, but it is not indicated in most adults with severe falciparum malaria

The clinical implications of thrombocytopenia in adults with severe falciparum malaria: a retrospective analysis

BackgroundThrombocytopenia is a common finding in adults with severe falciparum malaria, but its clinical and prognostic utility is incompletely defined.MethodsClinical and laboratory data from 647 adults with severe falciparum malaria were analysed retrospectively to determine the relationship between a patient’s platelet count on admission to hospital and their subsequent clinical course.ResultsOn admission, 614 patients (94.9%) were thrombocytopenic (platelet count <150 × 109/L) and 328 (50.7%) had a platelet count <50 × 109/L. The admission platelet count was inversely correlated with parasite biomass (estimated from plasma PfHRP2 concentrations, rs = −0.28, P = 0.003), the degree of microvascular sequestration (measured with orthogonal polarizing spectral imaging, rs = −0.31, P = 0.001) and disease severity (the number of World Health Organization severity criteria satisfied by the patient, rs = −0.21, P <0.001). Platelet counts were lower on admission in the patients who died (median: 30 (interquartile range 22 to 52) × 109/L versus 50 (34 to 78) × 109/L in survivors; P <0.001), but did not predict outcome independently from other established laboratory and clinical prognostic indices. The 39 patients (6%) with profound thrombocytopenia (platelet count <20 × 109/L) were more likely to die (odds ratio: 5.00, 95% confidence interval: 2.56 to 9.75) than patients with higher platelet counts, but these high-risk patients could be identified more rapidly with simple bedside clinical assessment. The admission platelet count did not reliably identify the 50 patients (7.7%) with major bleeding during the study.ConclusionsThrombocytopenia is a marker of disease severity in adults with falciparum malaria, but has limited utility in prognostication, triage and management

An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis

Background: Cryptococcal meningitis has high mortality. Flucytosine is a key treatment but is expensive and rarely available. The anti-cancer agent tamoxifen has synergistic anti-cryptococcal activity with amphotericin in vitro. It is off-patent, cheap, and widely available. We performed a trial to determine its therapeutic potential. Methods:Open label randomized controlled trial. Participants received standard care - amphotericin combined with fluconazole for the first two weeks - or standard care plus tamoxifen 300mg/day. The primary end point was Early Fungicidal Activity (EFA) - the rate of yeast clearance from cerebrospinal fluid (CSF). Trial registration https://clinicaltrials.gov/ct2/show/NCT03112031 . Results: 50 patients were enrolled, (median age 34 years, 35 male). Tamoxifen had no effect on EFA (- 0.48log10 colony-forming units/mL/CSF control arm versus -0.49 tamoxifen arm, difference - 0.005log10CFU/ml/day, 95%CI: -0.16, 0.15, P=0.95). Tamoxifen caused QTc prolongation. Conclusion: High dose tamoxifen does not increase the clearance rate of Cryptococcus from CSF. Novel, affordable therapies are needed. Funding:The trial was funded through the Wellcome Trust Asia Programme Vietnam Core Grant 106680 and a Wellcome Trust Intermediate Fellowship to JND grant number WT097147MA