Prof Jeremy Farrar

Research Area: Global Health
Scientific Themes: Tropical Medicine & Global Health
Keywords: Central Nervous System Infections, Dengue, Emerging Infections, Influenza and Tuberculous
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Jeremy Farrar's research interests are in Infectious Diseases and Global Health and include work on Emerging Infections, Infections of the Central Nervous System, TB, Dengue, Typhoid Malaria, and Influenza.  The work integrates clinical research with epidemiology, basic science and policy.

There are no collaborations listed for this principal investigator.

Arjyal A, Basnyat B, Koirala S, Karkey A, Dongol S, Agrawaal KK, Shakya N, Shrestha K et al. 2011. Gatifloxacin versus chloramphenicol for uncomplicated enteric fever: an open-label, randomised, controlled trial. Lancet Infect Dis, 11 (6), pp. 445-454. Read abstract | Read more

We aimed to investigate whether gatifloxacin, a new generation and affordable fluoroquinolone, is better than chloramphenicol for the treatment of uncomplicated enteric fever in children and adults. Hide abstract

Khor CC, Pang J, Long HT, Hibberd ML, Davila S, Ong RTH, Chau TNB, Dunstan SJ et al. 2011. Genome-wide association study identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1 Nature Genetics, 43 (11), pp. 1139-1141. Read abstract | Read more

Hypovolemic shock (dengue shock syndrome (DSS)) is the most common life-threatening complication of dengue. We conducted a genome-wide association study of 2,008 pediatric cases treated for DSS and 2,018 controls from Vietnam. Replication of the most significantly associated markers was carried out in an independent Vietnamese sample of 1,737 cases and 2,934 controls. SNPs at two loci showed genome-wide significant association with DSS. We identified a susceptibility locus at MICB (major histocompatibility complex (MHC) class I polypeptide-related sequence B), which was within the broad MHC region on chromosome 6 but outside the class I and class II HLA loci (rs3132468, P = 4.41 × 10 , per-allele odds ratio (OR) = 1.34 (95% confidence interval: 1.23-1.46)). We identified associated variants within PLCE1 (phospholipase C, epsilon 1) on chromosome 10 (rs3765524, P = 3.08 × 10 , per-allele OR = 0.80 (95% confidence interval: 0.75-0.86)). We identify two loci associated with susceptibility to DSS in people with dengue, suggesting possible mechanisms for this severe complication of dengue. © 2011 Nature America, Inc. All rights reserved. Hide abstract

van de Beek D, Farrar JJ, de Gans J, Mai NT, Molyneux EM, Peltola H, Peto TE, Roine I et al. 2010. Adjunctive dexamethasone in bacterial meningitis: a meta-analysis of individual patient data. Lancet Neurol, 9 (3), pp. 254-263. Read abstract | Read more

Dexamethasone improves outcome for some patients with bacterial meningitis, but not others. We aimed to identify which patients are most likely to benefit from dexamethasone treatment. Hide abstract

Tran TH, Ruiz-Palacios GM, Hayden FG, Farrar J. 2009. Patient-oriented pandemic influenza research. Lancet, 373 (9681), pp. 2085-2086. | Read more

Farrar J. 2007. Global health science: a threat and an opportunity for collaborative clinical science. Nat Immunol, 8 (12), pp. 1277-1279. | Read more

Nguyen TH, Tran TH, Thwaites G, Ly VC, Dinh XS, Ho Dang TN, Dang QT, Nguyen DP et al. 2007. Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis. N Engl J Med, 357 (24), pp. 2431-2440. Read abstract | Read more

It is uncertain whether all adults with bacterial meningitis benefit from treatment with adjunctive dexamethasone. Hide abstract

de Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ, Chau TN, Hoang DM, Chau NV et al. 2006. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med, 12 (10), pp. 1203-1207. Read abstract | Read more

Avian influenza A (H5N1) viruses cause severe disease in humans, but the basis for their virulence remains unclear. In vitro and animal studies indicate that high and disseminated viral replication is important for disease pathogenesis. Laboratory experiments suggest that virus-induced cytokine dysregulation may contribute to disease severity. To assess the relevance of these findings for human disease, we performed virological and immunological studies in 18 individuals with H5N1 and 8 individuals infected with human influenza virus subtypes. Influenza H5N1 infection in humans is characterized by high pharyngeal virus loads and frequent detection of viral RNA in rectum and blood. Viral RNA in blood was present only in fatal H5N1 cases and was associated with higher pharyngeal viral loads. We observed low peripheral blood T-lymphocyte counts and high chemokine and cytokine levels in H5N1-infected individuals, particularly in those who died, and these correlated with pharyngeal viral loads. Genetic characterization of H5N1 viruses revealed mutations in the viral polymerase complex associated with mammalian adaptation and virulence. Our observations indicate that high viral load, and the resulting intense inflammatory responses, are central to influenza H5N1 pathogenesis. The focus of clinical management should be on preventing this intense cytokine response, by early diagnosis and effective antiviral treatment. Hide abstract

Deen JL, Harris E, Wills B, Balmaseda A, Hammond SN, Rocha C, Dung NM, Hung NT, Hien TT, Farrar JJ. 2006. The WHO dengue classification and case definitions: time for a reassessment. Lancet, 368 (9530), pp. 170-173. | Read more

Simmons CP, Thwaites GE, Quyen NT, Torok E, Hoang DM, Chau TT, Mai PP, Lan NT et al. 2006. Pretreatment intracerebral and peripheral blood immune responses in Vietnamese adults with tuberculous meningitis: diagnostic value and relationship to disease severity and outcome. J Immunol, 176 (3), pp. 2007-2014. Read abstract

Tuberculous meningitis (TBM) is the most devastating form of tuberculosis. Both intracerebral and peripheral blood immune responses may be relevant to pathogenesis, diagnosis, and outcome. In this study, the relationship between pretreatment host response, disease phenotype, and outcome in Vietnamese adults with TBM was examined. Before treatment, peripheral blood IFN-gamma ELISPOT responses to the Mycobacterium tuberculosis Ags ESAT-6, CFP-10, and purified protein derivative (PPD) were a poor diagnostic predictor of TBM. Cerebrospinal fluid IL-6 concentrations at presentation were independently associated with severe disease presentation, suggesting an immunological correlate of neurological damage before treatment. Surprisingly however, elevated cerebrospinal fluid inflammatory cytokines were not associated with death or disability in HIV-negative TBM patients at presentation. HIV coinfection attenuated multiple cerebrospinal fluid inflammatory indices. Low cerebrospinal fluid IFN-gamma concentrations were independently associated with death in HIV-positive TBM patients, implying that IFN-gamma contributes to immunity and survival. Collectively, these results reveal the effect of HIV coinfection on the pathogenesis of TBM and suggest that intracerebral immune responses, at least in HIV-negative cases, may not be as intimately associated with disease outcome as previously thought. Hide abstract

de Jong MD, Tran TT, Truong HK, Vo MH, Smith GJ, Nguyen VC, Bach VC, Phan TQ et al. 2005. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med, 353 (25), pp. 2667-2672. Read abstract | Read more

Influenza A (H5N1) virus with an amino acid substitution in neuraminidase conferring high-level resistance to oseltamivir was isolated from two of eight Vietnamese patients during oseltamivir treatment. Both patients died of influenza A (H5N1) virus infection, despite early initiation of treatment in one patient. Surviving patients had rapid declines in the viral load to undetectable levels during treatment. These observations suggest that resistance can emerge during the currently recommended regimen of oseltamivir therapy and may be associated with clinical deterioration and that the strategy for the treatment of influenza A (H5N1) virus infection should include additional antiviral agents. Hide abstract

Simmons CP, Thwaites GE, Quyen NT, Chau TT, Mai PP, Dung NT, Stepniewska K, White NJ, Hien TT, Farrar J. 2005. The clinical benefit of adjunctive dexamethasone in tuberculous meningitis is not associated with measurable attenuation of peripheral or local immune responses. J Immunol, 175 (1), pp. 579-590. Read abstract

Outcome from tuberculous meningitis (TBM) is believed to be dependent on the severity of the intracerebral inflammatory response. We have recently shown that dexamethasone improved survival in adults with TBM and postulated that the clinical effect would be associated with a measurable systemic and intracerebral impact on immunological markers of inflammation. Prolonged inflammatory responses were detected in all TBM patients irrespective of treatment assignment (placebo or dexamethasone). The inflammatory response in the cerebrospinal fluid was characterized by a leukocytosis (predominantly CD3(+)CD4(+) T lymphocytes, phenotypically distinct from those in the peripheral blood), elevated concentrations of inflammatory and anti-inflammatory cytokines, chemokines, and evidence of prolonged blood-brain barrier dysfunction. Dexamethasone significantly modulated acute cerebrospinal fluid protein concentrations and marginally reduced IFN-gamma concentrations; other immunological and routine biochemical indices of inflammation were unaffected. Peripheral blood monocyte and T cell responses to Mycobacterium tuberculosis Ags were also unaffected. Dexamethasone does not appear to improve survival from TBM by attenuating immunological mediators of inflammation in the subarachnoid space or by suppressing peripheral T cell responses to mycobacterial Ags. These findings challenge previously held theories of corticosteroid action in this disease. An understanding of how dexamethasone acts in TBM may suggest novel and more effective treatment strategies. Hide abstract

Hien TT, Davis TM, Chuong LV, Ilett KF, Sinh DX, Phu NH, Agus C, Chiswell GM, White NJ, Farrar J. 2004. Comparative pharmacokinetics of intramuscular artesunate and artemether in patients with severe falciparum malaria. Antimicrob Agents Chemother, 48 (11), pp. 4234-4239. Read abstract | Read more

The first-dose pharmacokinetic properties of intramuscular (i.m.) artesunate (ARTS; 2.4 mg/kg immediately [stat], followed by 1.2 mg/kg i.m. daily) and artemether (ARM; 3.2 mg/kg i.m. stat, followed by 1.6 mg/kg i.m. daily) were compared in Vietnamese adults with severe falciparum malaria. A total of 19 patients were studied; 9 received ARTS, and 10 received ARM. ARTS was absorbed very rapidly; concentrations in plasma peaked between 1,362 and 8,388 nmol/liter (median, 5,710 nmol/liter) within 20 min of injection and then declined with a median (range) half-life (t(1/2)) of 30 (3 to 67) min. ARTS was hydrolyzed rapidly and completely to the biologically active metabolite dihydroartemisinin (DHA). Peak DHA concentrations in plasma ranged between 1,718 and 7,080 nmol/liter (median, 3,060 nmol/liter) and declined with a t(1/2) of 52 (26 to 69) min. In contrast, ARM was slowly and erratically absorbed. The absorption profile appeared biphasic. Maximum ARM concentrations in plasma ranged between 67 nmol/liter (a value close to the 50% inhibitory concentration for some Plasmodium falciparum isolates) and 1,631 nmol/liter (median, 574 nmol/liter) and occurred at a median (range) of 10 (1.5 to 24) h. There was relatively little conversion to DHA. After i.m. injection in cases of severe malaria, absorption of the water-soluble ARTS is rapid and extensive, whereas the oil-based ARM is slowly and erratically absorbed, with relatively little conversion to the more active DHA. On the basis of this pharmacological study, parenteral ARTS is preferable to ARM as an initial antimalarial therapy, particularly in the most seriously ill patients. These findings should be formally assessed by a randomized clinical trial. Hide abstract

Thwaites GE, Nguyen DB, Nguyen HD, Hoang TQ, Do TT, Nguyen TC, Nguyen QH, Nguyen TT et al. 2004. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med, 351 (17), pp. 1741-1751. Read abstract | Read more

Tuberculous meningitis kills or disables more than half of those affected with the disease. Previous studies have been too small to determine whether adjunctive treatment with corticosteroids can reduce the risk of disability or death among adults with tuberculous meningitis, and the effect of coinfection with the human immunodeficiency virus (HIV) is unclear. Hide abstract

Tran TH, Nguyen TL, Nguyen TD, Luong TS, Pham PM, Nguyen VV, Pham TS, Vo CD et al. 2004. Avian influenza A (H5N1) in 10 patients in Vietnam. N Engl J Med, 350 (12), pp. 1179-1188. Read abstract | Read more

Recent outbreaks of avian influenza A (H5N1) in poultry throughout Asia have had major economic and health repercussions. Human infections with this virus were identified in Vietnam in January 2004. Hide abstract

Tran TH, Dolecek C, Pham PM, Nguyen TD, Nguyen TT, Le HT, Dong TH, Tran TT, Stepniewska K, White NJ, Farrar J. 2004. Dihydroartemisinin-piperaquine against multidrug-resistant Plasmodium falciparum malaria in Vietnam: randomised clinical trial. Lancet, 363 (9402), pp. 18-22. Read abstract | Read more

Southeast Asia has the most resistant malaria parasites in the world, which severely limits treatment options. There is general acceptance that to combat resistance, combinations of antimalarial drugs that include an artemisinin derivative should be used, and, if possible, these should be formulated in a single tablet. Hide abstract

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