Showing papers in "Lancet Infectious Diseases in 2010"
University of Madras1, Cardiff University2, Health Protection Agency3, Karolinska University Hospital4, Aga Khan University5, Amrita Institute of Medical Sciences and Research Centre6, University of Queensland7, Gleneagles Hospital8, Northumbria Healthcare NHS Foundation Trust9, Apollo Hospitals10, Institute of Medical Sciences, Banaras Hindu University11
TL;DR: The prevalence of NDM-1, in multidrug-resistant Enterobacteriaceae in India, Pakistan, and the UK is investigated, and co-ordinated international surveillance is needed.
Abstract: Summary Background Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-β-lactamase 1 (NDM-1) are potentially a major global health problem. We investigated the prevalence of NDM-1, in multidrug-resistant Enterobacteriaceae in India, Pakistan, and the UK. Methods Enterobacteriaceae isolates were studied from two major centres in India—Chennai (south India), Haryana (north India)—and those referred to the UK's national reference laboratory. Antibiotic susceptibilities were assessed, and the presence of the carbapenem resistance gene bla NDM-1 was established by PCR. Isolates were typed by pulsed-field gel electrophoresis of XbaI-restricted genomic DNA. Plasmids were analysed by S1 nuclease digestion and PCR typing. Case data for UK patients were reviewed for evidence of travel and recent admission to hospitals in India or Pakistan. Findings We identified 44 isolates with NDM-1 in Chennai, 26 in Haryana, 37 in the UK, and 73 in other sites in India and Pakistan. NDM-1 was mostly found among Escherichia coli (36) and Klebsiella pneumoniae (111), which were highly resistant to all antibiotics except to tigecycline and colistin. K pneumoniae isolates from Haryana were clonal but NDM-1 producers from the UK and Chennai were clonally diverse. Most isolates carried the NDM-1 gene on plasmids: those from UK and Chennai were readily transferable whereas those from Haryana were not conjugative. Many of the UK NDM-1 positive patients had travelled to India or Pakistan within the past year, or had links with these countries. Interpretation The potential of NDM-1 to be a worldwide public health problem is great, and co-ordinated international surveillance is needed. Funding European Union, Wellcome Trust, and Wyeth.
2,680 citations
TL;DR: Riedel DJ, Gonzalez-Cuyar LF, Zhao XF, Redfi eld RR, Gilliam BL as discussed by the authors, and Redfellow RR have reported CD138-negative plasmablastic lymphoma cases (such as this case).
Abstract: Riedel DJ, Gonzalez-Cuyar LF, Zhao XF, Redfi eld RR, Gilliam BL. Plasmablastic lymphoma of the oral cavity: a rapidly progressive lymphoma associated with HIV infection. Lancet Infect Dis 2008; 8: 261–67. In this Grand Round, the references for the sentence “Occasionally, CD138-negative plasmablastic lymphoma cases (such as this case) have been reported” (page 265) should be 32, 34, and 38. Book Systematic reviews: CRD’s guidance for undertaking reviews in health care
1,743 citations
TL;DR: Enterovirus 71 is a major public health issue across the Asia-Pacific region and beyond, with new outbreaks occurring across Asia in regular cycles, and virus gene subgroups seem to differ in clinical epidemiological properties.
Abstract: First isolated in California, USA, in 1969, enterovirus 71 (EV71) is a major public health issue across the Asia-Pacific region and beyond. The virus, which is closely related to polioviruses, mostly affects children and causes hand, foot, and mouth disease with neurological and systemic complications. Specific receptors for this virus are found on white blood cells, cells in the respiratory and gastrointestinal tract, and dendritic cells. Being an RNA virus, EV71 lacks a proofreading mechanism and is evolving rapidly, with new outbreaks occurring across Asia in regular cycles, and virus gene subgroups seem to differ in clinical epidemiological properties. The pathogenesis of the severe cardiopulmonary manifestations and the relative contributions of neurogenic pulmonary oedema, cardiac dysfunction, increased vascular permeability, and cytokine storm are controversial. Public health interventions to control outbreaks involve social distancing measures, but their effectiveness has not been fully assessed. Vaccines being developed include inactivated whole-virus, live attenuated, subviral particle, and DNA vaccines.
1,050 citations
TL;DR: The proportion of cases with unknown cause was higher than that for any specific identified cause, and patients who died were more likely to be immunocompromised than were those who survived (OR = 3·44).
Abstract: Summary Background Encephalitis has many causes, but for most patients the cause is unknown. We aimed to establish the cause and identify the clinical differences between causes in patients with encephalitis in England. Methods Patients of all ages and with symptoms suggestive of encephalitis were actively recruited for 2 years (staged start between October, 2005, and November, 2006) from 24 hospitals by clinical staff. Systematic laboratory testing included PCR and antibody assays for all commonly recognised causes of infectious encephalitis, investigation for less commonly recognised causes in immunocompromised patients, and testing for travel-related causes if indicated. We also tested for non-infectious causes for acute encephalitis including autoimmunity. A multidisciplinary expert team reviewed clinical presentation and hospital tests and directed further investigations. Patients were followed up for 6 months after discharge from hospital. Findings We identified 203 patients with encephalitis. Median age was 30 years (range 0–87). 86 patients (42%, 95% CI 35–49) had infectious causes, including 38 (19%, 14–25) herpes simplex virus, ten (5%, 2–9) varicella zoster virus, and ten (5%, 2–9) Mycobacterium tuberculosis ; 75 (37%, 30–44) had unknown causes. 42 patients (21%, 15–27) had acute immune-mediated encephalitis. 24 patients (12%, 8–17) died, with higher case fatality for infections from M tuberculosis (three patients; 30%, 7–65) and varicella zoster virus (two patients; 20%, 2–56). The 16 patients with antibody-associated encephalitis had the worst outcome of all groups—nine (56%, 30–80) either died or had severe disabilities. Patients who died were more likely to be immunocompromised than were those who survived (OR=3·44). Interpretation Early diagnosis of encephalitis is crucial to ensure that the right treatment is given on time. Extensive testing substantially reduced the proportion with unknown cause, but the proportion of cases with unknown cause was higher than that for any specific identified cause. Funding The Policy Research Programme, Department of Health, UK.
1,021 citations
TL;DR: In this article, the authors propose a method to solve the problem of "unknown unknown" and "unknown" variables: unknown, unknown, and unknown variables, unknown and unknown.
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834 citations
TL;DR: A writing committee was appointed to finalise a consensus case definition for tuberculous meningitis for use in future clinical research and this case definition is applicable irrespective of the patient's age, HIV infection status, or the resources available in the research setting.
Abstract: Tuberculous meningitis causes substantial mortality and morbidity in children and adults. More research is urgently needed to better understand the pathogenesis of disease and to improve its clinical management and outcome. A major stumbling block is the absence of standardised diagnostic criteria. The different case definitions used in various studies makes comparison of research findings difficult, prevents the best use of existing data, and limits the management of disease. To address this problem, a 3-day tuberculous meningitis workshop took place in Cape Town, South Africa, and was attended by 41 international participants experienced in the research or management of tuberculous meningitis. During the meeting, diagnostic criteria were assessed and discussed, after which a writing committee was appointed to finalise a consensus case definition for tuberculous meningitis for use in future clinical research. We present the consensus case definition together with the rationale behind the recommendations. This case definition is applicable irrespective of the patient's age, HIV infection status, or the resources available in the research setting. Consistent use of the proposed case definition will aid comparison of studies, improve scientific communication, and ultimately improve care.
638 citations
TL;DR: Metaregression analyses showed that the risk of IRIS is associated with CD4 cell count at the start of ART, with a high risk in patients with fewer than 50 cells per microL, and might be reduced by initiation of ART before immunodeficiency becomes advanced.
Abstract: In patients with HIV-1 infection who are starting combination antiretroviral therapy (ART), the incidence of immune reconstitution inflammatory syndrome (IRIS) is not well defined. We did a meta-analysis to establish the incidence and lethality of the syndrome in patients with a range of previously diagnosed opportunistic infections, and examined the relation between occurrence and the degree of immunodeficiency. Systematic review identified 54 cohort studies of 13 103 patients starting ART, of whom 1699 developed IRIS. We calculated pooled cumulative incidences with 95% credibility intervals (CrI) by Bayesian methods and did a random-effects metaregression to analyse the relation between CD4 cell count and incidence of IRIS. In patients with previously diagnosed AIDS-defining illnesses, IRIS developed in 37.7% (95% CrI 26.6-49.4) of those with cytomegalovirus retinitis, 19.5% (6.7-44.8) of those with cryptococcal meningitis, 15.7% (9.7-24.5) of those with tuberculosis, 16.7% (2.3-50.7) of those with progressive multifocal leukoencephalopathy, and 6.4% (1.2-24.7) of those with Kaposi's sarcoma, and 12.2% (6.8-19.6) of those with herpes zoster. 16.1% (11.1-22.9) of unselected patients starting ART developed any type of IRIS. 4.5% (2.1-8.6) of patients with any type of IRIS died, 3.2% (0.7-9.2) of those with tuberculosis-associated IRIS died, and 20.8% (5.0-52.7) of those with cryptococcal meningitis died. Metaregression analyses showed that the risk of IRIS is associated with CD4 cell count at the start of ART, with a high risk in patients with fewer than 50 cells per microL. Occurrence of IRIS might therefore be reduced by initiation of ART before immunodeficiency becomes advanced.
636 citations
TL;DR: Understanding and appreciation of the effect of sex and pregnancy on immune responses might change the strategies used by public health officials to start efficient vaccination programmes, ensure sufficient levels of immune responses, minimise adverse effects, and allow for more efficient protection of populations that are high priority.
Abstract: The biological differences associated with the sex of an individual are a major source of variation, affecting immune responses to vaccination. Compelling clinical data illustrate that men and women differ in their innate, humoral, and cell-mediated responses to viral vaccines. Sex affects the frequency and severity of adverse effects of vaccination, including fever, pain, and inflammation. Pregnancy can also substantially alter immune responses to vaccines. Data from clinical trials and animal models of vaccine efficacy lay the groundwork for future studies aimed at identifying the biological mechanisms that underlie sex-specific responses to vaccines, including genetic and hormonal factors. An understanding and appreciation of the effect of sex and pregnancy on immune responses might change the strategies used by public health officials to start efficient vaccination programmes (optimising the timing and dose of the vaccine so that the maximum number of people are immunised), ensure sufficient levels of immune responses, minimise adverse effects, and allow for more efficient protection of populations that are high priority (eg, pregnant women and individuals with comorbid conditions).
619 citations
TL;DR: It is shown that bloodstream infections are common and associated with high mortality, and improved clinical microbiology services and reassessment of empirical treatment guidelines that account for the epidemiology of bloodstream infections might contribute to better outcomes.
Abstract: Summary Data on the prevalence and causes of community-acquired bloodstream infections in Africa are scarce. We searched three databases for studies that prospectively studied patients admitted to hospital with at least a blood culture, and found 22 eligible studies describing 58 296 patients, of whom 2051 (13·5%) of 15 166 adults and 3527 (8·2%) of 43 130 children had bloodstream infections. 1643 (29·1%) non-malaria bloodstream infections were due to Salmonella enterica (58·4% of these non-typhoidal Salmonella ), the most prevalent isolate overall and in adults, and 1031 (18·3% overall) were due to Streptococcus pneumoniae , the most common isolate in children. Other common isolates included Staphylococcus aureus (531 infections; 9·5%) and Escherichia coli (412; 7·3%). Mycobacterium tuberculosis complex accounted for 166 (30·7%) of 539 isolates in seven studies that used mycobacterial culture techniques. HIV infection was associated with any bloodstream infection, particularly with S enterica and M tuberculosis complex bacteraemia. Where recorded, patients with bloodstream infections had an in-hospital case fatality of 18·1%. Our results show that bloodstream infections are common and associated with high mortality. Improved clinical microbiology services and reassessment of empirical treatment guidelines that account for the epidemiology of bloodstream infections might contribute to better outcomes.
579 citations
TL;DR: The evidence available for each drug is described and the basis for recommendations for the treatment of patients with MDR and XDR tuberculosis is discussed, which is the combination of at least four drugs to which the Mycobacterium tuberculosis isolate is likely to be susceptible.
Abstract: Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are generally thought to have high mortality rates. However, many cases can be treated with the right combination and rational use of available antituberculosis drugs. This Review describes the evidence available for each drug and discusses the basis for recommendations for the treatment of patients with MDR and XDR tuberculosis. The recommended regimen is the combination of at least four drugs to which the Mycobacterium tuberculosis isolate is likely to be susceptible. Drugs are chosen with a stepwise selection process through five groups on the basis of efficacy, safety, and cost. Among the first group (the oral first-line drugs) high-dose isoniazid, pyrazinamide, and ethambutol are thought of as an adjunct for the treatment of MDR and XDR tuberculosis. The second group is the fluoroquinolones, of which the first choice is high-dose levofloxacin. The third group are the injectable drugs, which should be used in the following order: capreomycin, kanamycin, then amikacin. The fourth group are called the second-line drugs and should be used in the following order: thioamides, cycloserine, then aminosalicylic acid. The fifth group includes drugs that are not very effective or for which there are sparse clinical data. Drugs in group five should be used in the following order: clofazimine, amoxicillin with clavulanate, linezolid, carbapenems, thioacetazone, then clarithromycin.
526 citations
TL;DR: Estimates of carriage prevalence across all ages are provided, which is important for understanding the epidemiology and transmission dynamics of meningococcal infection.
Abstract: Summary Background Neisseria meningitidis is an important cause of meningitis and septicaemia, but most infected individuals experience a period of asymptomatic carriage rather than disease. Previous studies have shown that carriage rates vary by age and setting; however, few have assessed carriage across all ages. We aimed to estimate the age-specific prevalence of meningococcal carriage. Methods We searched Embase, Medline, Web of Science, the Cochrane Library, and grey literature for papers reporting carriage of N meningitidis in defined age groups in European countries or in countries with a similar epidemiological pattern (where disease caused by serogroups B and C predominates). We used mixed-effects logistic regression with a natural cubic spline to model carriage prevalence as a function of age for studies that were cross-sectional or serial cross-sectional. The model assessed population type, type of swab used, when swabs were plated, use of preheated plates, and time period (decade of study) as fixed effects, with country and study as nested random effects (random intercept). Findings Carriage prevalence increased through childhood from 4·5% in infants to a peak of 23·7% in 19-year olds and subsequently decreased in adulthood to 7·8% in 50-year olds. The odds of testing positive for carriage decreased if swabs were not plated immediately after being taken compared with if swabs were plated immediately (odds ratio 0·46, 95% CI 0·31–0·68; p=0·0001). Interpretation This study provides estimates of carriage prevalence across all ages, which is important for understanding the epidemiology and transmission dynamics of meningococcal infection. Funding None.
TL;DR: The burden of malaria in countries in sub-Saharan Africa has declined with scaling up of prevention, diagnosis, and treatment, and the contribution of specific malaria interventions and other general factors in bringing about these changes was assessed.
Abstract: The burden of malaria in countries in sub-Saharan Africa has declined with scaling up of prevention, diagnosis, and treatment. To assess the contribution of specific malaria interventions and other general factors in bringing about these changes, we reviewed studies that have reported recent changes in the incidence or prevalence of malaria in sub-Saharan Africa. Malaria control in southern Africa (South Africa, Mozambique, and Swaziland) began in the 1980s and has shown substantial, lasting declines linked to scale-up of specific interventions. In The Horn of Africa, Ethiopia and Eritrea have also experienced substantial decreases in the burden of malaria linked to the introduction of malaria control measures. Substantial increases in funding for malaria control and the procurement and distribution of effective means for prevention and treatment are associated with falls in malaria burden. In central Africa, little progress has been documented, possibly because of publication bias. In some countries a decline in malaria incidence began several years before scale-up of malaria control. In other countries, the change from a failing drug (chloroquine) to a more effective drug (sulphadoxine plus pyrimethamine or an artemisinin combination) led to immediate improvements; in others malaria reduction seemed to be associated with the scale-up of insecticide-treated bednets and indoor residual spraying.
TL;DR: In this paper, the risks of major and minor sequelae caused by bacterial meningitis, estimate the distribution of the different types of sequelae, and compare risk by region and income.
Abstract: Few data sources are available to assess the global and regional risk of sequelae from bacterial meningitis. We aimed to estimate the risks of major and minor sequelae caused by bacterial meningitis, estimate the distribution of the different types of sequelae, and compare risk by region and income. We systematically reviewed published papers from 1980 to 2008. Standard global burden of disease categories (cognitive deficit, bilateral hearing loss, motor deficit, seizures, visual impairment, hydrocephalus) were labelled as major sequelae. Less severe, minor sequelae (behavioural problems, learning difficulties, unilateral hearing loss, hypotonia, diplopia), and multiple impairments were also included. 132 papers were selected for inclusion. The median (IQR) risk of at least one major or minor sequela after hospital discharge was 19.9% (12.3-35.3%). The risk of at least one major sequela was 12.8% (7.2-21.1%) and of at least one minor sequela was 8.6% (4.4-15.3%). The median (IQR) risk of at least one major sequela was 24.7% (16.2-35.3%) in pneumococcal meningitis; 9.5% (7.1-15.3%) in Haemophilus influenzae type b (Hib), and 7.2% (4.3-11.2%) in meningococcal meningitis. The most common major sequela was hearing loss (33.9%), and 19.7% had multiple impairments. In the random-effects meta-analysis, all-cause risk of a major sequela was twice as high in the African (pooled risk estimate 25.1% [95% CI 18.9-32.0%]) and southeast Asian regions (21.6% [95% CI 13.1-31.5%]) as in the European region (9.4% [95% CI 7.0-12.3%]; overall I(2)=89.5%, p<0.0001). Risks of long-term disabling sequelae were highest in low-income countries, where the burden of bacterial meningitis is greatest. Most reported sequelae could have been averted by vaccination with Hib, pneumococcal, and meningococcal vaccines.
TL;DR: Initial clinical data support the use of fosfomycin for the treatment of urinary tract infections caused by members of the family Enterobacteriaceae with advanced resistance to antimicrobial drugs, although further research is needed.
Abstract: Summary Rising rates of resistance to antimicrobial drugs among Enterobacteriaceae limit the choice of reliably active forms of these drugs. We evaluated the evidence on fosfomycin as a treatment option for infections caused by members of the family Enterobacteriaceae with advanced resistance to antimicrobial drugs, including producers of extended-spectrum β-lactamase (ESBL). We systematically reviewed studies evaluating the antimicrobial activity, or the clinical effectiveness of fosfomycin. 17 antimicrobial-susceptibility studies were found and included in our Review, accounting for 5057 clinical isolates of Enterobacteriaceae with advanced resistance to antimicrobial drugs (4448 were producers of ESBL); 11 of the 17 studies reported that at least 90% of the isolates were susceptible to fosfomycin. Using a provisional minimum inhibitory concentration susceptibility breakpoint of 64 mg/L or less, 1604 (96·8%) of 1657 Escherichia coli isolates producing ESBL were susceptible to fosfomycin. Similarly, 608 (81·3%) of 748 Klebsiella pneumoniae isolates producing ESBL were susceptible to fosfomycin. In two clinical studies, oral treatment with fosfomycin–trometamol was clinically effective against complicated or uncomplicated lower urinary tract infections caused by ESBL-producing E coli in, cumulatively, 75 (93·8%) of the 80 patients evaluated. Initial clinical data support the use of fosfomycin for the treatment of urinary tract infections caused by these pathogens, although further research is needed.
TL;DR: An understanding of the epidemiology of community-associated MRSA is essential to guide new control initiatives to prevent these organisms from becoming endemic in Europe.
Abstract: Over the past decade, community-associated meticillin-resistant Staphylococcus aureus (MRSA) has emerged in patients without health-care contact, especially in the USA. Although data are limited, the prevalence of community-associated MRSA in Europe seems to be low but is increasing. The organism has been reported in most European countries, including The Netherlands and Nordic countries, which have low rates of health-care-associated MRSA. In Greece, rates of community-associated MRSA in some centres approach those of the USA. By contrast with North America, where the USA300 clone (ST8-IV) predominates, community-associated MRSA in Europe is characterised by clonal heterogeneity. The most common European strain is the European clone (ST80-IV), although reports of USA300 are increasing. Several community-associated MRSA clones have arisen in Europe, most notably the ST398-V pig-associated MRSA clone in The Netherlands and Denmark. An understanding of the epidemiology of community-associated MRSA is essential to guide new control initiatives to prevent these organisms from becoming endemic in Europe.
TL;DR: The pathogenesis of coronary artery disease is summarised and the evidence linking acute infections with the development of acute coronary syndromes is presented, which strongly support a role for acute infections in triggering these events.
Abstract: Acute coronary syndromes are a leading cause of morbidity and mortality worldwide. The mechanisms underlying the triggering of these events are diverse and include increased coronary and systemic inflammatory activity, dominant prothrombotic conditions, increased biomechanical stress on coronary arteries, variations in the coronary arterial tone, disturbed haemodynamic homoeostasis, and altered myocardial metabolic balance. There is experimental evidence that acute infections can promote the development of acute coronary syndromes, and clinical data strongly support a role for acute infections in triggering these events. In our Review, we summarise the pathogenesis of coronary artery disease and present the evidence linking acute infections with the development of acute coronary syndromes. Greater awareness of this association is likely to encourage research into ways of protecting patients who are at high risk.
TL;DR: Although the most effective interventions and potential adverse outcomes remain unclear, public campaigns can probably contribute to more careful use of antibiotics in outpatients, at least in high-prescribing countries.
Abstract: The worldwide increase in resistance to antimicrobial drugs has made reducing the unnecessary use of antibiotics a public health priority. There have been campaigns in many countries to educate the public about appropriate use of antibiotics in outpatients. By use of a comprehensive search strategy and structured interviews, we were able to identify and review the characteristics and outcomes of 22 campaigns done at a national or regional level in high-income countries between 1990 and 2007. The intensity of the campaigns varied widely, from simple internet to expensive mass-media campaigns. All but one campaign targeted the public and physicians simultaneously. Most campaigns that were formally evaluated seemed to reduce antibiotic use. The effect on resistance to antimicrobial drugs cannot be assessed accurately at present. Although the most effective interventions and potential adverse outcomes remain unclear, public campaigns can probably contribute to more careful use of antibiotics in outpatients, at least in high-prescribing countries.
TL;DR: The emergence of the Beijing genotype family might represent an evolutionary response of M tuberculosis to vaccination or antibiotic treatment, with an important negative impact on tuberculosis control.
Abstract: The wide geographic distribution of one clade of Mycobacterium tuberculosis, the Beijing genotype family, and its genetic homogeneity, suggests that strains belonging to this grouping might have a selective advantage over other M tuberculosis strains. This hypothesis was addressed by reviewing molecular-epidemiological, experimental, and clinical studies. Beijing strains represent about 50% of strains in east Asia and at least 13% of strains worldwide. Their emergence might be linked to escape from BCG vaccination, and to multidrug resistance, which is associated with the Beijing genotype in many areas. Different animal models have shown Beijing strains to be more virulent, and to cause more histopathological changes, higher outgrowth, and increased mortality. At a molecular level, Beijing strains have specific properties in terms of protein and lipid structures and their interaction with the human immune system. Finally, the Beijing genotype has been linked to polymorphisms in immune genes, suggesting the possibility of human-mycobacterial co-evolution. The emergence of the Beijing genotype family might represent an evolutionary response of M tuberculosis to vaccination or antibiotic treatment, with an important negative impact on tuberculosis control. More research is needed to further unravel the mechanisms underlying the emergence of M tuberculosis Beijing genotype strains, and examine the implications for future control strategies.
TL;DR: Insights into intracellular mechanisms and implications of enhanced pathogenesis after ligation of macrophage Fcγ receptors by infectious immune complexes are reviewed.
Abstract: Summary A wide range of microorganisms can replicate in macrophages, and cell entry of these pathogens via non-neutralising IgG antibody complexes can result in increased intracellular infection through idiosyncratic Fcγ-receptor signalling. The activation of Fcγ receptors usually leads to phagocytosis. Paradoxically, the ligation of monocyte or macrophage Fcγ receptors by IgG immune complexes, rather than aiding host defences, can suppress innate immunity, increase production of interleukin 10, and bias T-helper-1 (Th1) responses to Th2 responses, leading to increased infectious output by infected cells. This intrinsic antibody-dependent enhancement (ADE) of infection modulates the severity of diseases as disparate as dengue haemorrhagic fever and leishmaniasis. Intrinsic ADE is distinct from extrinsic ADE, whereby complexes of infectious agents with non-neutralising antibodies lead to an increased number of infected cells. Intrinsic ADE might be involved in many protozoan, bacterial, and viral infections. We review insights into intracellular mechanisms and implications of enhanced pathogenesis after ligation of macrophage Fcγ receptors by infectious immune complexes.
TL;DR: This Review summarises information on the epidemiology, pathogenesis, new diagnostic methods, empirical antimicrobial regimens, and adjunctive treatment of acute bacterial meningitis in infants and children.
Abstract: Bacterial meningitis continues to be an important cause of mortality and morbidity in neonates and children throughout the world. The introduction of the protein conjugate vaccines against Haemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis has changed the epidemiology of bacterial meningitis. Suspected bacterial meningitis is a medical emergency and needs empirical antimicrobial treatment without delay, but recognition of pathogens with increasing resistance to antimicrobial drugs is an important factor in the selection of empirical antimicrobial regimens. At present, strategies to prevent and treat bacterial meningitis are compromised by incomplete understanding of the pathogenesis. Further research on meningitis pathogenesis is thus needed. This Review summarises information on the epidemiology, pathogenesis, new diagnostic methods, empirical antimicrobial regimens, and adjunctive treatment of acute bacterial meningitis in infants and children.
University of Alberta1, University of Pittsburgh2, University of Miami3, Cleveland Clinic Lerner College of Medicine4, University of California, San Francisco5, Northwestern University6, Washington University in St. Louis7, University of Washington8, Johns Hopkins University9, Ohio State University10, Mayo Clinic11, University of Toronto12, University of Colorado Denver13, Emory University14, McGill University15, Icahn School of Medicine at Mount Sinai16, University of Chicago17, University of Calgary18, Pennsylvania State University19, University of Pennsylvania20, Yeshiva University21, University of Florida22, MedStar Washington Hospital Center23, Leiden University24, University of Illinois at Chicago25
TL;DR: In this paper, a multicentre cohort study of adults and children who had received organ transplants with microbiological confirmation of influenza A infection from April to December, 2009 was conducted.
Abstract: Summary Background There are few data on the epidemiology and outcomes of influenza infection in recipients of solid-organ transplants. We aimed to establish the outcomes of pandemic influenza A H1N1 and factors leading to severe disease in a cohort of patients who had received transplants. Methods We did a multicentre cohort study of adults and children who had received organ transplants with microbiological confirmation of influenza A infection from April to December, 2009. Centres were identified through the American Society of Transplantation Influenza Collaborative Study Group. Demographics, clinical presentation, treatment, and outcomes were assessed. Severity of disease was measured by admission to hospital and intensive care units (ICUs). The data were analysed with descriptive statistics. Proportions were compared by use of χ 2 tests. We used univariate analysis to identify factors leading to pneumonia, admission to hospital, and admission to an ICU. Multivariate analysis was done by use of a stepwise logistic regression model. We analysed deaths with Kaplan-Meier survival analysis. Findings We assessed 237 cases of medically attended influenza A H1N1 reported from 26 transplant centres during the study period. Transplant types included kidney, liver, heart, lung, and others. Both adults (154 patients; median age 47 years) and children (83; 9 years) were assessed. Median time from transplant was 3·6 years. 167 (71%) of 237 patients were admitted to hospital. Data on complications were available for 230 patients; 73 (32%) had pneumonia, 37 (16%) were admitted to ICUs, and ten (4%) died. Antiviral treatment was used in 223 (94%) patients (primarily oseltamivir monotherapy). Seven (8%) patients given antiviral drugs within 48 h of symptom onset were admitted to an ICU compared with 28 (22·4%) given antivirals later (p=0·007). Children who received transplants were less likely to present with pneumonia than adults, but rates of admission to hospital and ICU were similar. Interpretation Influenza A H1N1 caused substantial morbidity in recipients of solid-organ transplants during the 2009–10 pandemic. Starting antiviral therapy early is associated with clinical benefit as measured by need for ICU admission and mechanical ventilation. Funding None.
TL;DR: Profiles of drug resistance suggest that a second-line treatment regimen based on protease inhibitors, with a backbone of nucleoside reverse transcriptase inhibitor, is a reasonable option for patients with HIV in sub-Saharan Africa who experience first- line treatment failure.
Abstract: Following large-scale roll-out of antiretroviral therapy in sub-Saharan Africa, the non-clinical efficacy of antiretroviral therapy has received little attention. We aimed to systematically review virological efficacy and drug-resistance outcomes of programmes of antiretroviral therapy in sub-Saharan Africa. 89 studies with heterogeneous design, definitions, and methods were identified. Overall, in on-treatment analysis, 10 351 (78%) of 13 288 patients showed virological suppression after 6 months of antiretroviral therapy, 7413 (76%) of 9794 after 12 months, and 3840 (67%) of 5690 after 24 months. Long-term virological data are scarce. Genotyping results were available for patients with virological failure (HIV-1 RNA greater than 1000 copies per mL). Most patients (839 of 849; 99%) were infected with a non-B HIV-1 subtype. However, drug-resistance patterns were largely similar to those in subtype B. Resistance profiles were associated with the antiretroviral drugs commonly used: the lamivudine-associated M184V mutation was most common, followed by K103N which is associated with non-nucleoside reverse transcriptase inhibitors. Thymidine-analogue mutations and the K65R mutation were less common. First-line antiretroviral therapy regimens used in sub-Saharan Africa are effective. Profiles of drug resistance suggest that a second-line treatment regimen based on protease inhibitors, with a backbone of nucleoside reverse transcriptase inhibitors, is a reasonable option for patients with HIV in sub-Saharan Africa who experience first-line treatment failure.
TL;DR: How the volume and appropriateness of antibiotic use in hospitals vary between countries, hospitals, and physicians is described.
Abstract: Antibiotics have dramatically changed the prognoses of patients with severe infectious diseases over the past 50 years. However, the emergence and dissemination of resistant organisms has endangered the effectiveness of antibiotics. One possible approach to the resistance problem is the appropriate use of antibiotic drugs for preventing and treating infections. This Review describes how the volume and appropriateness of antibiotic use in hospitals vary between countries, hospitals, and physicians. At each specific level-cultural, contextual, and behavioural-we discuss the determinants that influence hospital antibiotic use and the possible improvement strategies to make it more appropriate. Changing hospital antibiotic use is a challenge of formidable complexity. On each level, many determinants play a part, so that the measures or strategies undertaken to improve antibiotic use need to be equally diverse. Although various strategies for improving antibiotic use are available, a programme with activities at all three levels is needed for hospitals. Evaluating these programme activities in a way that provides external validity of the conclusions is crucial.
Université libre de Bruxelles1, Ben-Gurion University of the Negev2, Boston Children's Hospital3, Ghent University Hospital4, University of Pittsburgh5, University of Milan6, National Institutes of Health7, Kaiser Permanente8, University Medical Center Utrecht9, University of Colorado Denver10, University of Oulu11, Katholieke Universiteit Leuven12, Boston University13
TL;DR: An international group of multidisciplinary experts on middle-ear and paediatric infections met to explore where consensus exists on the management of acute otitis media and to propose to clinicians and public health officials their views on the actions needed to be taken to reduce the disease burden and the microbial antibiotic resistance.
Abstract: An international group of multidisciplinary experts on middle-ear and paediatric infections met to explore where consensus exists on the management of acute otitis media. After informal discussions among several specialists of paediatric infectious disease, the group was expanded to include a larger spectrum of professionals with complementary expertise in middle-ear disease. Acute otitis media is a very common bacterial infection in children worldwide, leading to excessive antibiotic consumption in children in most countries and to a substantial burden of deafness and suppurative complications in developing countries. The group attempted to move beyond the existing controversies surrounding guidelines on acute otitis media, and to propose to clinicians and public health officials their views on the actions needed to be taken to reduce the disease burden caused by acute otitis media and the microbial antibiotic resistance from the resulting use of antibiotics. Definition of acute otitis media and diagnostic accuracy are crucial steps to identify children who will potentially benefit from treatment with antibiotics and to eliminate unnecessary prescribing. Although the group agreed that antibiotics are distributed indiscriminately, even to children who do not seem to have the disease, no consensus could be reached on whether antibiotics should be given to all appropriately diagnosed children, reflecting the wide range of practices and lack of convincing evidence from observational studies. The major unanimous concern was an urgent need to reduce unnecessary prescribing of antibiotics to prevent further increases in antibiotic resistance. Prevention of acute otitis media with existing and future viral and bacterial vaccines seems the most promising approach to affect disease burden and consequences, both in developed and developing countries.
TL;DR: The evidence and potential for combination therapy, and the criteria for the choice of drugs in such regimens, are reviewed, suggesting that combination therapy is more cost-effective and reduces indirect costs for patients.
Abstract: Combination therapy for the treatment of visceral leishmaniasis has increasingly been advocated as a way to increase treatment efficacy and tolerance, reduce treatment duration and cost, and limit the emergence of drug resistance. We reviewed the evidence and potential for combination therapy, and the criteria for the choice of drugs in such regimens. The first phase 2 results of combination regimens are promising, and have identified effective and safe regimens as short as 8 days. Several phase 3 trials are underway or planned in the Indian subcontinent and east Africa. The limited data available suggest that combination therapy is more cost-effective and reduces indirect costs for patients. Additional advantages are reduced treatment duration (8-17 days), with potentially better patient compliance and lesser burden on the health system. Only limited data are available on how best to prevent acquired resistance. Patients who are coinfected with visceral leishmaniasis and HIV could be a reservoir for development and spread of drug-resistant strains, calling for special precautions. The identification of a short, cheap, well-tolerated combination regimen that can be given in ambulatory care and needs minimal clinical monitoring will most likely have important public health implications. Effective monitoring systems and close regulations and policy will be needed to ensure effective implementation. Whether combination therapy could indeed help delay resistance, and how this is best achieved, will only be known in the long term.
King's College London1, University of KwaZulu-Natal2, Institute of Tropical Medicine Antwerp3, University of Antwerp4, University of Cape Town5, University of London6, Burnet Institute7, Alfred Hospital8, Makerere University9, Johns Hopkins University School of Medicine10, University of Minnesota11, Mahidol University12, Royal Perth Hospital13, University of Western Australia14
TL;DR: A consensus case definition for paradoxical crytopcoccal IRIS in patients with HIV-1 and known cryptococcal disease before ART, and a separate definition for incident cryptococosis developed during ART (termed ART-associated cryptococcosis) were developed in this article.
Abstract: Cryptococcal immune reconstitution inflammatory syndrome (IRIS) may present as a clinical worsening or new presentation of cryptococcal disease after initiation of antiretroviral therapy (ART), and is thought to be caused by recovery of cryptococcus-specific immune responses. We have reviewed reports of cryptococcal IRIS and have developed a consensus case definition specifically for paradoxical crytopcoccal IRIS in patients with HIV-1 and known cryptococcal disease before ART, and a separate definition for incident cryptococcosis developed during ART (termed ART-associated cryptococcosis), for which a proportion of cases are likely to be unmasking cryptococcal IRIS. These structured case definitions are intended to aid design of future clinical, epidemiological, and immunopathological studies of cryptococcal IRIS, to standardise diagnostic criteria, and to facilitate comparisons between studies. As for definitions of tuberculosis-associated IRIS, definitions for cryptococcal IRIS should be regarded as preliminary until further insights into the immunopathology of IRIS permit their refinement.
TL;DR: It is put forward an argument that donor funds would be more effectively spent on the development of a multi-faceted, integrated control programme, which would have a greater and longer lasting effect on disease transmission than the current chemotherapy-based programmes.
Abstract: Schistosomiasis is a major neglected tropical disease, with more than 200 million people infected and close to 800 million at risk. The disease burden is estimated to exceed 70 million disability-adjusted life-years. The anthelmintic drug praziquantel is highly effective in killing adult schistosome worms, but it is unable to kill developing schistosomes and so does not prevent reinfection. As a result, current praziquantel-based control programmes in Asia and sub-Saharan Africa are not effective or sustainable in the long term. The control of neglected tropical diseases, including schistosomiasis, is a funding priority for several donor agencies, with over US$350 million committed until 2013. Here we put forward an argument that donor funds would be more effectively spent on the development of a multi-faceted, integrated control programme, which would have a greater and longer lasting effect on disease transmission than the current chemotherapy-based programmes. The development of a transmission-blocking vaccine is also of great importance. A multi-faceted integrated control programme that incorporates a vaccine, even if only partly effective, has the potential to eliminate schistosomiasis. This integrated-approach model has the potential to improve the health of a billion of the world's poorest people and its effect cannot be underestimated.
TL;DR: Both sputum-smear microscopy and mycobacterial culture during tuberculosis treatment have low sensitivity and modest specificity for predicting failure and relapse.
Abstract: Summary WHO has previously recommended sputum-smear examination at the end of the second month of treatment in patients with recently diagnosed pulmonary tuberculosis, and, if positive, extension of the intensive therapy phase. We did a systematic review and meta-analysis to assess the accuracy of a positive sputum smear or culture during treatment for predicting failure or relapse in pulmonary tuberculosis. We searched PubMed, Embase, and the Cochrane Library for studies published in English through December, 2009. We included randomised controlled trials, cohort, and case-control studies of previously untreated pulmonary tuberculosis patients who had received a standardised regimen with rifampicin in the initial phase. Accuracy results were summarised in forest plots and pooled by use of a hierarchical regression approach. 15 papers (28 studies) met the inclusion criteria. The pooled sensitivities for both 2-month smear (24% [95% CI 12–42%], six studies) and culture (40% [95% CI 25–56%], four studies) to predict relapse were low. Corresponding specificities (85% [95% CI 72–90%] and 85% [95% CI 77–91%]) were higher, but modest. For failure, 2-month smear (seven studies) had low sensitivity (57% [95% CI 41–73%]) and higher, although modest, specificity (81% [95% CI 72–87%]). Both sputum-smear microscopy and mycobacterial culture during tuberculosis treatment have low sensitivity and modest specificity for predicting failure and relapse. Although we pooled a diverse group of patients, the individual studies had similar performance characteristics. Better predictive markers are needed.
TL;DR: The evidence for the relative benefits and disadvantages of the existing separate treatment approach versus a unified ACT-based strategy for treating Plasmodium falciparum and P vivax infections in regions where both species are endemic (co-endemic) is reviewed.
Abstract: Early parasitological diagnosis and treatment with artemisinin-based combination therapies (ACTs) are key components of worldwide malaria elimination programmes. In general, use of ACTs has been limited to patients with falciparum malaria whereas blood-stage infections with Plasmodium vivax are mostly still treated with chloroquine. We review the evidence for the relative benefits and disadvantages of the existing separate treatment approach versus a unified ACT-based strategy for treating Plasmodium falciparum and P vivax infections in regions where both species are endemic (co-endemic). The separate treatment scenario is justifiable if P vivax remains sensitive to chloroquine and diagnostic tests reliably distinguish P vivax from P falciparum. However, with the high number of misdiagnoses in routine practice and the rise and spread of chloroquine-resistant P vivax, there might be a compelling rationale for a unified ACT-based strategy for vivax and falciparum malaria in all co-endemic regions. Analyses of the cost-effectiveness of ACTs for both Plasmodium species are needed to assess the role of these drugs in the control and elimination of vivax malaria.
TL;DR: The optimum duration of treatment with doxycycline and hydroxychloroquine in Q fever endocarditis is 18 months for native valves and 24 months for prosthetic valves and this duration should be extended only in the absence of favourable serological outcomes.
Abstract: Summary Background Q fever endocarditis caused by Coxiella burnetii is a potentially fatal disease characterised by a chronic evolution. To assess the long-term outcome and identify prognostic factors for mortality, surgical treatment, and serological changes in Q fever endocarditis, we did a retrospective study in the French National Referral Centre. Methods Patients included were diagnosed with Q fever endocarditis at our centre from May, 1983, to June, 2006, and followed up for a minimum of 3 years for each patient, history and clinical characteristics were recorded with a standardised questionnaire. Prognostic factors associated with death, surgery, serological cure, and serological relapse were assessed by Cox regression analysis. Excised heart valve analysis was assessed according to duration of treatment. Findings 104 patients were identified for inclusion in the study, although one was lost to follow-up; median follow-up was 100 months (range 37–310 months). 18 months of treatment was sufficient to sterilise the valves of all the patients except three, and 2 years of treatment sterilised all valves except one. In a multivariate Cox regression analysis, the major determinants associated with mortality were age (hazard ratio 1·11, 95% CI 1·05–1·18, p=0·003), stroke at diagnosis (7·09, 2·00–25·10, p=0·001), endocarditis on a prosthetic valve (6·04, 1·47–24·80, p=0·044), an absence of a four-times decrease of phase I IgG and IgA at 1 year (5·69, 1·00–32·22, p=0·049), or the presence of phase II IgM at 1 year (12·08, 3·11–46·85, p=0·005). Surgery was associated with heart failure (2·68, 1·21–5·94, p=0·015) or a cardiac abscess (4·71, 1·64–13·50, p=0·004). The determinants of poor serological outcome were male sex (0·47, 0·26–0·86, p=0·014), a high level of phase I IgG (0·65, 0·45–0·95, p=0·027), and a delay in the start of treatment with hydroxychloroquine (0·20, 0·04–0·91, p=0·037). Factors associated with relapse were endocarditis on a prosthetic valve (21·3, 2·05–221·86, p=0·01) or treatment duration less than 18 months (9·69, 1·08–86·72, p=0·042). Interpretation The optimum duration of treatment with doxycycline and hydroxychloroquine in Q fever endocarditis is 18 months for native valves and 24 months for prosthetic valves. This duration should be extended only in the absence of favourable serological outcomes. Patients should be serologically monitored for at least 5 years because of the risk of relapse. Funding French National Referral Centre for Q Fever.