Prof Jeremy Farrar
| Research Area: | Global Health |
|---|---|
| Scientific Themes: | Tropical Medicine & Global Health |
| Keywords: | Central Nervous System Infections, Dengue, Emerging Infections, Influenza and Tuberculous |
| Web Links: |
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.
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
2011. Genome-wide association study identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1 Nature Genetics, 43 (11), pp. 1139-1141.
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
2009. Patient-oriented pandemic influenza research. Lancet, 373 (9681), pp. 2085-2086. | Read more
2007. Global health science: a threat and an opportunity for collaborative clinical science. Nat Immunol, 8 (12), pp. 1277-1279. | Read more
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
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
2006. The WHO dengue classification and case definitions: time for a reassessment. Lancet, 368 (9530), pp. 170-173. | Read more
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
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
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
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
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
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
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
Adaptive Design in Enteric Fever
Enteric Fever, cause by S.typhi and S.paratyphi remains a major global health problem. It is estimated that there are 22 million cases of enteric fever worldwide each year, of which approximately 215,000 people die. Most of these cases occur in the developing world, and are strongly associated with poverty, poor sanitation, and lack of clean drinking water. Annual incidence rate of 198 per 100,000 in southern Vietnam and 980 per 100,000 in Delhi have been reported. The greatest burden lies ...
Clincial Research in Epidemics
A key lesson from a series of recent outbreaks of emerging pathogens of global public health importance including SARS-CoV, highly pathogenic avian influenza A (H5N1) virus, EV71, Nipah virus and the 2009 pandemic was that mounting clinical research in response to a rapidly emerging infectious disease is extremely challenging and often delayed. The clinical research response was cumbersome and slow despite years of global preparations for a potentially devastating influenza pandemic of avian ...
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