Showing papers in "Lancet Infectious Diseases in 2002"
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TL;DR: The status of vaccine development is described and it is emphasised that the only alternative that the authors have today to control the disease is through control of its vector Aedes aegypti.
Abstract: This review is an update of dengue and dengue haemorrhagic fever (DHF) based on international and Cuban experience. We describe the virus characteristics and risk factors for dengue and DHF, and compare incidence and the case fatality rates in endemic regions (southeast Asia, western Pacific, and the Americas). The clinical picture and the pathogenesis of the severe disease are explained. We also discuss the viral, individual, and environmental factors that determine severe disease. Much more research is necessary to clarify these mechanisms. Also reviewed are methods for viral isolation and the serological, immunohistochemical, and molecular methods applied in the diagnosis of the disease. We describe the status of vaccine development and emphasise that the only alternative that we have today to control the disease is through control of its vector Aedes aegypti.
1,309 citations
TL;DR: This analysis suggests that throughout the world 1.9 million children died from ARI in 2000, 70% of them in Africa and southeast Asia.
Abstract: Acute respiratory infections (ARI) are among the leading causes of childhood mortality. Estimates of the number of children worldwide who die from ARI are needed in setting priorities for health care. To establish a relation between deaths due to ARI and all-cause deaths in children under 5 years we show that the proportion of deaths directly attributable to ARI declines from 23% to 18% and then 15% (95% confidence limits range from +/- 2% to +/- 3%) as under-5 mortality declines from 50 to 20 and then to 10/1000 per year. Much of the variability in estimates of ARI in children is shown to be inherent in the use of verbal autopsies. This analysis suggests that throughout the world 1.9 million (95% CI 1.6-2.2 million) children died from ARI in 2000, 70% of them in Africa and southeast Asia.
862 citations
TL;DR: The most important aspects of the pathogenic potential of S saprophyticus, S lugdunensis, and S schleiferi are described, although, compared with S epidermidis, much less is known in these species concerning their virulence factors.
Abstract: As a group, the coagulase-negative staphylococci (CoNS) are among the most frequently isolated bacteria in the clinical microbiology laboratory and are becoming increasingly important, especially as causes of hospital-acquired infections. These bacteria are normal inhabitants of human skin and mucous membranes and, therefore, one of the major challenges of daily diagnostic work is to distinguish clinically significant CoNS from contaminant strains. This overview addresses current knowledge of the pathogenesis of infections due to CoNS and particularly focuses on virulence factors of the species Staphylococcus epidermidis. S epidermidis has been identified as a major cause of nosocomial infections, especially in patients with predisposing factors such as indwelling or implanted foreign polymer bodies. Most important in the pathogenesis of foreign-body-associated infections is the ability of these bacteria to colonise the polymer surface by the formation of a thick, multilayered biofilm. Biofilm formation takes place in two phases. The first phase involves the attachment of the bacteria to polymer surfaces that may be either unmodified or coated with host extracellular matrix proteins. In the second phase, the bacteria proliferate and accumulate into multilayered cell clusters that are embedded in an extracellular material. The bacterial factors involved in both phases of biofilm formation are discussed in this review. In addition, the most important aspects of the pathogenic potential of S saprophyticus, S lugdunensis, and S schleiferi are described, although, compared with S epidermidis, much less is known in these species concerning their virulence factors.
857 citations
TL;DR: The various features of drug resistance in Plasmodium falciparum, including its determinants, current status in diverse geographical areas, molecular markers, and their implications are described.
Abstract: Since the first reports of chloroquine-resistant falciparum malaria in southeast Asia and South America almost half a century ago, drug-resistant malaria has posed a major problem in malaria control. By the late 1980s, resistance to sulfadoxine-pyrimethamine and to mefloquine was also prevalent on the Thai-Cambodian and Thai-Myanmar (Thai-Burmese) borders, rendering them established multidrug-resistant (MDR) areas. Chloroquine resistance spread across Africa during the 1980s, and severe resistance is especially found in east Africa. As a result, more than ten African countries have switched their first-line drug to sulfadoxine-pyrimethamine. Of great concern is the fact that the efficacy of this drug in Africa is progressively deteriorating, especially in foci in east Africa, which are classified as emerging MDR areas. Urgent efforts are needed to lengthen the lifespan of sulfadoxine-pyrimethamine and to identify effective, affordable, alternative antimalarial regimens. Molecular markers for antimalarial resistance have been identified, including pfcrt polymorphisms associated with chloroquine resistance and dhfr and dhps polymorphisms associated with sulfadoxine-pyrimethamine resistance. Polymorphisms in pfmdr1 may also be associated with resistance to chloroquine, mefloquine, quinine, and artemisinin. Use of such genetic information for the early detection of resistance foci and future monitoring of drug-resistant malaria is a potentially useful epidemiological tool, in conjunction with the conventional in-vivo and in-vitro drug-sensitivity assessments. This review describes the various features of drug resistance in Plasmodium falciparum, including its determinants, current status in diverse geographical areas, molecular markers, and their implications.
819 citations
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TL;DR: In palliative care situations and in patients with terminal dementia, the decision whether or not to treat an infectious disease is becoming a difficult ethical issue.
Abstract: Average life expectancy throughout developed countries has rapidly increased during the latter half of the 20th century and geriatric infectious diseases have become an increasingly important issue. Infections in the elderly are not only more frequent and more severe, but they also have distinct features with respect to clinical presentation, laboratory results, microbial epidemiology, treatment, and infection control. Reasons for increased susceptibility include epidemiological elements, immunosenescence, and malnutrition, as well as a large number of age-associated physiological and anatomical alterations. Moreover, ageing may be the cause of infection but infection can also be the cause of ageing. Mechanisms may include enhanced inflammation, pathogen-dependent tissue destruction, or accelerated cellular ageing through increased turnover. In most instances, treatment of infection leads to a satisfactory outcome in the elderly. However, in palliative care situations and in patients with terminal dementia, the decision whether or not to treat an infectious disease is becoming a difficult ethical issue.
818 citations
TL;DR: The current situation and perspectives for diagnosis, treatment, and control of visceral leishmaniasis are reviewed, and some priorities for research and development are listed.
Abstract: Visceral leishmaniasis is common in less developed countries, with an estimated 500000 new cases each year. Because of the diversity of epidemiological situations, no single diagnosis, treatment, or control will be suitable for all. Control measures through case finding, treatment, and vector control are seldom used, even where they could be useful. There is a place for a vaccine, and new imaginative approaches are needed. HIV co-infection is changing the epidemiology and presents problems for diagnosis and case management. Field diagnosis is difficult; simpler, less invasive tests are needed. Current treatments require long courses and parenteral administration, and most are expensive. Resistance is making the mainstay of treatment, agents based on pentavalent antimony, useless in northeastern India, where disease incidence is highest. Second-line drugs (pentamidine and amphotericin B) are limited by toxicity and availability, and newer formulations of amphotericin B are not affordable. The first effective oral drug, miltefosine, has been licensed in India, but the development of other drugs in clinical phases (paromomycin and sitamaquine) is slow. No novel compound is in the pipeline. Drug combinations must be developed to prevent drug resistance. Despite these urgent needs, research and development has been neglected, because a disease that mainly affects the poor ranks as a low priority in the private sector, and the public sector currently struggles to undertake the development of drugs and diagnostics in the absence of adequate funds and infrastructure. This article reviews the current situation and perspectives for diagnosis, treatment, and control of visceral leishmaniasis, and lists some priorities for research and development.
750 citations
TL;DR: Recent large-scale surveys of yeasts isolated from blood cultures, based on standardised methodology and resistance definitions, do not support the view that antifungal resistance in pathogenic yeasts constitutes a significant or growing therapeutic problem.
Abstract: Candida albicans and related species pathogenic for man become resistant to antifungal agents, in particular triazole compounds, by expression of efflux pumps that reduce drug accumulation, alteration of the structure or concentration of antifungal target proteins, and alteration of membrane sterol composition. The clinical consequences of antifungal resistance can be seen in treatment failures in patients and in changes in the prevalences of Candida species causing disease. These effects were seen unequivocally in HIV-infected patients with oropharyngeal candida infections, but their incidence has decreased dramatically with the introduction of highly active antiretroviral therapy. The evidence for similar emergence of antifungal-resistant yeast strains and species in other types of candida infections is confounded by non-standardised susceptibility testing methods and definitions of a resistant fungal isolate. Recent large-scale surveys of yeasts isolated from blood cultures, based on standardised methodology and resistance definitions, do not support the view that antifungal resistance in pathogenic yeasts constitutes a significant or growing therapeutic problem.
749 citations
TL;DR: The hepatitis B vaccination can protect children against HCC and fulminant hepatitis, as has been shown in Taiwan as mentioned in this paper, however, the implementation of worldwide vaccination against hepatitis B requires greater effort to overcome the social and economic hurdles.
Abstract: Summary Worldwide about 350 million people are chronic carriers of the hepatitis B virus (HBV). The infection can cause acute and chronic liver disease including cirrhosis and hepatocellular carcinoma (HCC). Hepatocellular injuries of HBV infection are predominantly immune-mediated, and the natural history of chronic infection can be divided into three phases based on virus-host interactions—namely, immune tolerance, immune clearance, and viral integration phases. Four serotypes ( adw, ayw, adr , and ayr ) and seven genotypes (A to G) of HBV have been identified, and they show some distinct geographic distributions. The HBV genotypes may have clinical relevance and are currently under investigation. On the basis of disease burden and the availability of safe and effective vaccines, the WHO recommended that by the end of the 20th century hepatitis B vaccine be incorporated into routine infant and childhood immunisation programmes for all countries. The efficacy of universal immunisation has been shown in different countries, with striking reductions of the prevalence of HBV carriage in children. Most important, hepatitis B vaccination can protect children against HCC and fulminant hepatitis, as has been shown in Taiwan. Nevertheless, the implementation of worldwide vaccination against HBV requires greater effort to overcome the social and economic hurdles. Safe and effective antiviral treatments are available but are still far from ideal, a situation that, hopefully, will be improved soon. With hepatitis B immunisation, the global control of HBV infection is possible by the end of the first half of 21st century.
733 citations
TL;DR: A substantial body of evidence that cytokines, chemokines, proteolytic enzymes, and oxidants are involved in the inflammatory cascade that leads to tissue destruction in bacterial meningitis is found.
Abstract: Until the introduction of antibiotics in the 1930s and 1940s, acute bacterial meningitis was fatal in most cases. Since then it has become curable with a variable mortality and morbidity rate for individual pathogens and patients. Neuropathological and clinical studies have shown that a fatal outcome of the disease is often due to central nervous system (CNS) complications including cerebrovascular involvement, brain oedema formation, and hydrocephalus resulting in increased intracranial pressure and seizure activity. During recent years, experimental studies with animal models have substantially increased our knowledge of the interactions of bacterial pathogens with mammalian cells and their entry into the CNS, and the complex pathophysiological mechanisms of brain dysfunction during acute bacterial meningitis. There is now a substantial body of evidence that cytokines, chemokines, proteolytic enzymes, and oxidants are involved in the inflammatory cascade that leads to tissue destruction in bacterial meningitis. Genetic targeting and/or pharmacological blockade of these pathways was beneficial in experimental bacterial meningitis. Apart from dexamethasone, these treatment strategies hold major promise for the adjunctive therapy of acute bacterial meningitis in clinical practice.
545 citations
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TL;DR: Examination of occult hepatitis B in people co-infected with hepatitis C is examined, in whom Occult hepatitis B has been associated with advanced fibrosis and diminished response to interferon alpha.
Abstract: Summary Worldwide, chronic hepatitis B virus (HBV) infection is the primary cause of cirrhosis and hepatocellular carcinoma and is one of the ten leading causes of death. Traditionally, people with chronic HBV infection have been identified with blood tests for HBV antigens and antibodies. Recently, another group of patients with chronic HBV infection has been identified by sensitive, molecular testing for HBV DNA. Members of this group are often referred to as having occult hepatitis B because they are HBV-DNA positive, but hepatitis B surface antigen negative. Occult hepatitis B occurs in a number of clinical settings. In this review, we examine occult hepatitis B in people co-infected with hepatitis C, in whom occult hepatitis B has been associated with advanced fibrosis and diminished response to interferon α. Although much more research is needed, existing reports justify a heightened awareness of the medical importance and means of testing for occult hepatitis B.
535 citations
TL;DR: It is suggested that the secrets of effectiveness of MRSA could be hidden in the unique genetic background of a surprisingly few lineages of S aureus particularly well able to cope with the contemporary clinical environment.
Abstract: Summary The first European isolate of meticillin-resistant Staphylococcus aureus (MRSA) was detected in 1960. Since then MRSA has become a leading cause of nosocomial infections worldwide. Using molecular typing techniques—primarily pulsed-field gel electrophoresis (PFGE)—we identified five major MRSA clones that accounted for almost 70% of the over 3000 MRSA isolates recovered in hospitals mainly in southern and eastern Europe, South America, and the USA. Most of our surveillance studies were done in these areas. Multilocus sequencing typing (MLST) of representative isolates of this collection showed that these five pandemic MRSA clones have evolved from only two distinct ancestral genetic backgrounds, one of which can be traced back to the very first European MRSA isolates and also to meticillin susceptible S aureus strains circulating in Danish hospitals during the mid to late 1950s—ie, shortly before the introduction of meticillin into therapy. The second lineage with a completely different MLST profile included MRSA frequently recovered in the USA, Japan, and among paediatric isolates from several parts of the world. A few isolates with a third distinct MLST type corresponding to that of EMRSA-16 were also detected in the early Danish isolates. The four structural types of mec element, the heterologous DNA segment containing the meticillin resistance determinant mecA , were present in unique combinations with the MRSA clonal types. Our findings establish evolutionary associations in the most widely spread pandemic clones of MRSA. The epidemiological factors that contributed to the massive dissemination of a few MRSA clones are not well understood. We suggest, however, that the secrets of effectiveness of MRSA could be hidden in the unique genetic background of a surprisingly few lineages of S aureus particularly well able to cope with the contemporary clinical environment.
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TL;DR: Although it is a major zoonosis, canine rabies can be eliminated, and application of new vaccine technologies permits significant disease control among wildlife species, despite much technical progress in the past century, rabies is a disease of neglect and presents a modern public-health conundrum.
Abstract: Rabies is an acute, progressive, incurable viral encephalitis. The causative agents are neurotropic RNA viruses in the family Rhabdoviridae, genus Lyssavirus. Mammalian reservoirs include the Carnivora and Chiroptera, but rabid dogs still pose the greatest hazard worldwide. Viral transmission occurs mainly via animal bite, and once the virus is deposited in peripheral wounds, centripetal passage occurs towards the central nervous system. After viral replication, there is centrifugal spread to major exit portals, the salivary glands. The epidemiological significance of any host "carrier" state remains highly speculative. Although incubation periods average 1-3 months, disease occurrence days or years after exposure has been documented. Rabies should be suspected in patients with a concomitant history of animal bite and traditional clinical presentation, but a lack of such clues makes antemortem diagnosis a challenge. Pathogenetic mechanisms remain poorly understood, and current care entails palliative measures only. Current medical emphasis relies heavily on prevention of exposure and intervention before clinical onset. Prophylaxis encompasses thorough wound treatment, vaccine administration, and inoculation of rabies immunoglobulin. Although it is a major zoonosis, canine rabies can be eliminated, and application of new vaccine technologies permits significant disease control among wildlife species. Nevertheless, despite much technical progress in the past century, rabies is a disease of neglect and presents a modern public-health conundrum.
TL;DR: Vaccine-recommending bodies and national health-care organisations must have locally relevant information on the transmission of pertussis from adults to infants to be able to make decisions on the advisability, feasibility, and priority for booster immunisation against pertussedis.
Abstract: Bordetella pertussis continues to circulate even in populations where a high vaccine coverage of infants and children is achieved. Cases in adolescents and adults are reported with increasing frequency in many countries. Adults are a reservoir for infections in very young infants, in whom pertussis may be severe and life-threatening. The salient clinical feature of pertussis in adolescents and adults is prolonged coughing, and recognising that pertussis does occur in these age groups is the most important step in its diagnosis. A laboratory diagnosis can be made by bordetella-PCR from nasopharyngeal swabs or secretions and by detection of antibodies, mainly to pertussis toxin; laboratory diagnosis is, however, not well standardised. Vaccination of adolescents and adults is now possible with acellular pertussis vaccines, which are well tolerated, immunogenic, and effective. Adolescent boosters and the vaccination of health-care workers are already included in vaccination calendars in some countries. Vaccine-recommending bodies and national health-care organisations must have locally relevant information on the transmission of pertussis from adults to infants to be able to make decisions on the advisability, feasibility, and priority for booster immunisation against pertussis.
TL;DR: Optimal control of influenza in the acute-care setting should focus upon reducing potential influenza reservoirs in the hospital, including: isolating patients with suspected or documented influenza, sending home healthcare providers or staff who exhibit typical symptoms of influenza, and discouraging persons with febrile respiratory illness from visiting the hospital during a known influenza outbreak in the community.
Abstract: Summary Influenza poses special hazards inside healthcare facilities and can cause explosive outbreaks of illness. Healthcare workers are at risk of acquiring influenza and thus serve as an important reservoir for patients under their care. Annual influenza immunisation of high-risk persons and their contacts, including healthcare workers, is the primary means of preventing nosocomial influenza. Despite influenza vaccine effectiveness, it is substantially underused by healthcare providers. Influenza can be diagnosed by culturing the virus from respiratory secretions and by rapid antigen detection kits; recognition of a nosocomial outbreak is important in order to employ infection-control efforts. Optimal control of influenza in the acute-care setting should focus upon reducing potential influenza reservoirs in the hospital, including: isolating patients with suspected or documented influenza, sending home healthcare providers or staff who exhibit typical symptoms of influenza, and discouraging persons with febrile respiratory illness from visiting the hospital during a known influenza outbreak in the community. (Note: influenza and other respiratory viruses can cause non-febrile illness but are still transmissible.) The antiviral M2 protein inhibitors (amantadine, rimantadine) and neuraminidase inhibitors (zanamivir, oseltamivir) have proven efficacy in treating and preventing influenza illness; however, their role in the prevention and control of influenza in the acute hospital setting remains to be more fully studied.
TL;DR: From all this evidence, LTA can be considered a virulence factor that has an important role in infections and in postinfectious sequelae caused by Gram-positive bacteria.
Abstract: Summary Lipoteichoic acid (LTA) is a surface-associated adhesion amphiphile from Gram-positive bacteria and regulator of autolytic wall enzymes (muramidases). It is released from the bacterial cells mainly after bacteriolysis induced by lysozyme, cationic peptides from leucocytes, or beta-lactam antibiotics. It binds to target cells either non-specifically, to membrane phospholipids, or specifically, to CD14 and to Toll-like receptors. LTA bound to targets can interact with circulating antibodies and activate the complement cascade to induce a passive immune kill phenomenon. It also triggers the release from neutrophils and macrophages of reactive oxygen and nitrogen species, acid hydrolases, highly cationic proteinases, bactericidal cationic peptides, growth factors, and cytotoxic cytokines, which may act in synergy to amplify cell damage. Thus, LTA shares with endotoxin (lipopolysaccharide) many of its pathogenetic properties. In animal studies, LTA has induced arthritis, nephritis, uveitis, encephalomyelitis, meningeal inflammation, and periodontal lesions, and also triggered cascades resulting in septic shock and multiorgan failure. Binding of LTA to targets can be inhibited by antibodies, phospholipids, and specific antibodies to CD14 and Toll, and in vitro its release can be inhibited by non-bacteriolytic antibiotics and by polysulphates such as heparin, which probably interfere with the activation of autolysis. From all this evidence, LTA can be considered a virulence factor that has an important role in infections and in postinfectious sequelae caused by Gram-positive bacteria. The future development of effective antibacteriolytic drugs and multidrug strategies to attenuate LTA-induced secretion of proinflammatory agonists is of great importance to combat septic shock and multiorgan failure caused by Gram-positive bacteria.
TL;DR: Research into the best methods of deploying and using existing approaches, particularly insecticide-treated mosquito nets, rapid methods of diagnosis, and artemisinin-based combination treatments should provide evidence on these approaches that would justify much-needed increases in global support for appropriate and effective malaria control.
Abstract: 564 Rolling back malaria is possible. Tools are available but they are not used. Several countries deploy, as their national malaria control treatment policy, drugs that are no longer effective. New and innovative methods of vector control, diagnosis, and treatment should be developed, and work towards development of new drugs and a vaccine should receive much greater support. But the pressing need, in the face of increasing global mortality and general lack of progress in malaria control, is research into the best methods of deploying and using existing approaches, particularly insecticidetreated mosquito nets, rapid methods of diagnosis, and artemisinin-based combination treatments. Evidence on these approaches should provide national governments and international donors with the costbenefit information that would justify much-needed increases in global support for appropriate and effective malaria control.
TL;DR: Given low sexual transmission of HCV and infrequency of intravenous drug use in Sub-Saharan Africa, iatrogenic causes ofHCV transmission need to be further evaluated.
Abstract: Hepatitis C virus (HCV) is a major cause of chronic liver disease in the world. The WHO estimates that 3% (170 million) of the world’s population are chronically infected with HCV. Sub-Saharan Africa is of great interest because it is reported to have the highest HCV prevalence rate (5·3%), and a concurrent HIV epidemic. In our review of the published literature we found consistent evidence of high HCV prevalence in many countries of Africa. We estimate the overall prevalence of HCV in Sub-Saharan Africa is 3·0%. The central African region has the highest estimated prevalence of 6%, west Africa has an estimated prevalence of 2.4%, and southern and east Africa with the lowest estimated prevalence of 1·6%. Given low sexual transmission of HCV and infrequency of intravenous drug use in Sub-Saharan Africa, iatrogenic causes of HCV transmission need to be further evaluated.
TL;DR: It is now apparent that superantigens have a wider role in the pathology of infectious diseases than has previously been appreciated and research is beginning to shed light on the more subtle parts these molecules play in causing disease and to produce some real possibilities for specific treatment of superantigen-induced toxicity.
Abstract: Summary Microbial Superantigens are a family of protein exotoxins that share the ability to trigger excessive and aberrant activation of T cells. The best characterised are the staphylococcal enterotoxins and the streptococcal pyrogenic exotoxins that trigger the staphylococcal and streptococcal toxic shock syndromes. It is now apparent that Superantigens have a wider role in the pathology of infectious diseases than has previously been appreciated. Staphylococcus aureus and Streptococcus pyogenes together produce 19 different Superantigens. The range of microorganisms known to produce Superantigens has expanded to include Gram negative bacteria, mycoplasma, and viruses. Research is beginning to shed light on the more subtle parts these molecules play in causing disease and to produce some real possibilities for specific treatment of superantigen-induced toxicity. We aim to highlight these new developments and review the science behind these fascinating molecules.
TL;DR: If HAART is able to prevent spreading of KS, local therapy of KS may become an essential component of patient management and rationales and graduated treatment algorithms for local and systemic therapy in patients with KS are presented to appropriately meet the challenges of this extraordinary neoplasm.
Abstract: Kaposi's sarcoma (KS) is a mesenchymal tumour involving blood and lymphatic vessels. Only recently has the pathogenesis of this extraordinary neoplasm been elucidated. Viral oncogenesis and cytokine-induced growth together with some state of immunocompromise represent important conditions for this tumour to develop. In 1994, a novel virus was discovered and termed human herpesvirus 8 (HHV8), also known as Kaposi's sarcoma-associated herpes virus, which can be found in all types of KS, whether related to HIV or not. In the era of highly active antiretroviral therapy (HAART), the incidence of AIDS-KS has considerably declined, probably due to enhanced immune reconstitution and anti-HHV8-specific immune responses. If HAART is able to prevent spreading of KS, local therapy of KS may become an essential component of patient management. Part 1 of the review covers the epidemiology, environmental predispositions, clinical manifestations, and therapy of KS. Newer treatments such as pegylated liposomal anthracyclines and experimental strategies are discussed. We also present rationales and graduated treatment algorithms for local and systemic therapy in patients with KS to appropriately meet the challenges of this extraordinary neoplasm. Part 2, to be published next month, will summarise recent insights in the pathogenesis of KS and will discuss other HHV8-related diseases such as Castleman's disease and primary effusion lymphoma.
TL;DR: In this article, the authors highlighted the importance of careful use of these agents in appropriate patients and doses, as well as careful infection-control practices, and emphasized the utility of a valuable class of antimicrobial agents.
Abstract: Summary Resistance to fluoroquinolones among Gram-positive cocci has emerged as these antimicrobial agents have become extensively used in clinical medicine. Resistance is effected by changes in the bacterial target enzymes DNA gyrase and topoisomerase IV, which reduce drug binding, and by action of native bacterial membrane pumps that remove drug from the cell. In both cases, quinolone exposure selects for spontaneous mutants that are present in large bacterial populations, and which contain chromosomal mutations that alter the target protein or increase the level of pump expression. Resistance among clinical isolates has been greatest in Staphylococcus aureus and particularly among meticillinresistant strains, in which both selection by quinolone exposure and transmission of clonal strains in health-care settings have contributed to high prevalence. Resistance in Streptococcus pneumoniae has also emerged in the community. Fluoroquinolone resistance has arisen in multidrug-resistant clones and its prevalence has been especially high in Hong Kong and Spain. Further spread and selection of such resistance could compromise the utility of a valuable class of antimicrobial agents, a point that emphasises the importance of the careful use of these agents in appropriate patients and doses, as well as careful infection-control practices.
TL;DR: The most effective approach to taeniosis and cysticercosis is prevention, which should be a primary public-health focus for less developed countries.
Abstract: Summary Taeniosis and cysticercosis, diseases caused by the parasitic tapeworm Taenia solium , are distributed worldwide where pigs are eaten and sanitation is poor, and also in the more developed countries as a result of increasing migration. Neurocysticercosis is the commonest parasitic disease of the human nervous system. Immunological assays detect positivity for human cysticercosis in 8–12% of people in some endemic regions, which indicates the presence of antibodies against the parasite but not necessarily active or central-nervous-system infection. The only reliable tool for diagnosis of neurocysticercosis is imaging by CT or MRI. The presence of viable cysts with a mural nodule, associated with degenerative cysts and calcifications, is typical. Classification of neurocysticercosis into active, transitional, and inactive forms gives a good clinical-imaging correlation and facilitates medical and surgical treatment. The main clinical manifestations of neurocysticercosis are seizures, headache, and focal neurological deficits, and it can have such sequelae as epilepsy, hydrocephalus, and dementia. Treatment should be individually fitted for each patient, with antiepileptic drugs, analgesics, corticosteroids, or a combination of these. Anthelmintic drugs (praziquantel and albendazole) are used routinely, but so far no controlled clinical trial has established specific indications or definitive doses of treatment. Parenchymal forms of neurocysticercosis have a good prognosis in terms of clinical remission. The most effective approach to taeniosis and cysticercosis is prevention, which should be a primary public-health focus for less developed countries.
TL;DR: Larval-control methods were neglected after the advent of dichlorodiphenyl trichloroethane (DDT) and global malaria-control policy shifted toward domestic adulticide methods and should now be re-prioritised for research, development, and implementation.
Abstract: Current malaria-control strategies emphasise domestic protection against adult mosquitoes with insecticides, and improved access to medical services. Malaria prevention by killing adult mosquitoes is generally favoured because moderately reducing their longevity can radically suppress community-level transmission. By comparison, controlling larvae has a less dramatic effect at any given level of coverage and is often more difficult to implement. Nevertheless, the historically most effective campaign against African vectors is the eradication of accidentally introduced Anopheles gambiae from 54 000 km 2 of largely ideal habitat in northeast Brazil in the 1930s and early 1940s. This outstanding success was achieved through an integrated programme but relied overwhelmingly upon larval control. This experience was soon repeated in Egypt and another larval control programme successfully suppressed malaria for over 20 years around a Zambian copper mine. These affordable approaches were neglected after the advent of dichlorodiphenyltrichloroethane (DDT) and global malariacontrol policy shifted toward domestic adulticide methods. Larval-control methods should now be re-prioritised for research, development, and implementation as an additional way to roll back malaria.
TL;DR: New antifungal drugs, inhibitors of beta glucan synthesis and second-generation azole and triazole derivatives have characteristics that render them potentially suitable agents against some resistant fungi.
Abstract: There is an increased awareness of the morbidity and mortality associated with fungal infections caused by resistant fungi in various groups of patients. Epidemiological studies have identified risk factors associated with antifungal drug resistance. Selection pressure due to the continuous exposure to azoles seems to have an essential role in developing resistance to fluconazole in Candida species. Haematological malignancies, especially acute leukaemia with severe and prolonged neutropenia, seem to be the main risk factors for acquiring deep-seated mycosis caused by resistant filamentous fungi, such us Fusarium species, Scedosporium prolificans, and Aspergillus terreus. The still unacceptably high mortality rate associated with some resistant mycosis indicates that alternatives to existing therapeutic options are needed. Potential measures to overcome antifungal resistance ranges from the development of new drugs with better antifungal activity to improving current therapeutic strategies with the present antifungal agents. Among the new antifungal drugs, inhibitors of beta glucan synthesis and second-generation azole and triazole derivatives have characteristics that render them potentially suitable agents against some resistant fungi. Other strategies including the use of high doses of lipid formulations of amphotericin B, combination therapy, and adjunctive immune therapy with cytokines are under investigation. In addition, antifungal control programmes to prevent extensive and inappropriate use of antifungals may be needed.
TL;DR: Seroepidemiological studies suggest an association between several microbes and coronary heart disease, and several intervention trials with antibiotics are underway, and will hopefully shed new light on the role of bacteria in atherosclerosis.
Abstract: Summary During the past decade, several novel risk factors for atherosclerosis, including inflammation and infections, have been reported. Seroepidemiological studies suggest an association between several microbes and coronary heart disease. Microbes or their structural components are found in atherosclerotic plaques, but the only intact microbes commonly present are herpes viruses and Chlamydia pneumoniae . These agents are able to initiate and accelerate atherosclerosis in animal models. If they cause persistent infection in the vessel wall, they can directly promote a proinflammatory, procoagulant, and proatherogenic environment. Microbes could also have a remote effect—eg, bacterial heat shock proteins with high sequence homology with human counterpart could, in the presence of a chronic infection, induce autoimmunity against vascular cells, and lead to an atherosclerotic process. Several intervention trials with antibiotics are underway, and will hopefully shed new light on the role of bacteria in atherosclerosis. The causal relationship can be proved by use of vaccination to prevent infections.
TL;DR: There may soon be no effective drugs available to treat trypanosomiasis patients, especially second-stage cases, because of resistance to and limited number of current treatments, and ambitious research programmes for new compounds must be supported to ensure the sustainable development of new drugs.
Abstract: Human African trypanosomiasis re-emerged in the 1980s. However, little progress has been made in the treatment of this disease over the past decades. The first-line treatment for second-stage cases is melarsoprol, a toxic drug in use since 1949. High therapeutic failure rates have been reported recently in several foci. The alternative, eflornithine, is better tolerated but difficult to administer. A third drug, nifurtimox, is a cheap, orally administered drug not yet fully validated for use in human African trypanosomiasis. No new drugs for second-stage cases are expected in the near future. Because of resistance to and limited number of current treatments, there may soon be no effective drugs available to treat trypanosomiasis patients, especially second-stage cases. Additional research and development efforts must be made for the development of new compounds, including: testing combinations of current trypanocidal drugs, completing the clinical development of nifurtimox and registering it for trypanosomiasis, completing the clinical development of an oral form of eflornithine, pursuing the development of DB 289 and its derivatives, and advancing the pre-clinical development of megazol, eventually engaging firmly in its clinical development. Partners from the public and private sector are already engaged in joint initiatives to maintain the production of current drugs. This network should go further and be responsible for assigning selected teams to urgently needed research projects with funds provided by industry and governments. At the same time, on a long term basis, ambitious research programmes for new compounds must be supported to ensure the sustainable development of new drugs.
TL;DR: Continuing research is attempting to assess the effect of these genetic alterations on properties of BCG strains, with the goals of suggesting the ideal BCG for vaccination and providing avenues for improvement on existing BCG vaccines.
Abstract: After nearly a century of use, BCG vaccines continue to generate controversy and confusion. Their ability to prevent tuberculosis in studies has been inconsistent. When they have been protective, no clear mechanism of action has been established. Furthermore, the existence of different BCG strains has been described since the 1940s. These strains vary according to several laboratory properties, which may or may not translate into a discernible effect on vaccination. With recent genomic comparisons, it is now clear that different BCG vaccine strains have evolved and differ from each other and from the original BCG first used in 1921. Some of these genetic alterations explain certain variations in laboratory properties of BCG. However, these mutations in BCG strains have yet to be shown to affect BCG-associated protection and/or adverse effects. Continuing research is attempting to assess the effect of these genetic alterations on properties of BCG strains, with the goals of suggesting the ideal BCG for vaccination and providing avenues for improvement on existing BCG vaccines.
TL;DR: Despite methodological strengths and limitations of the studies assessed, the weight of evidence collectively suggests that personal and environmental hygiene reduces the spread of infection.
Abstract: Summary Even in an era in which access to personal "cleanliness" and a public health infrastructure are readily available in developed countries, illnesses associated with day care centres and homes continue to be a problem. The inhabitants of less developed countries, on the other hand, must contend with an inadequate public health infrastructure, lack of education programmes, and economic limitations in obtaining hygiene products. Therefore, less developed countries carry a greater burden of morbidity and mortality from infectious illnesses. The objective of this review is to examine and assess the epidemiological evidence for a causal relation between hygiene practices and infections. The Medline database was searched from January 1980 to June 2001 and studies were included if the outcome(s) was infection or symptoms of infection, and if the independent variable(s) was one or more hygiene measures. The strength of the association as measured by the relative reduction in risk of illness was appreciable and generally greater than 20%. Despite methodological strengths and limitations of the studies assessed, the weight of evidence collectively suggests that personal and environmental hygiene reduces the spread of infection. The results from this review demonstrate that there is a continued, measurable, positive effect of personal and community hygiene on infections.
TL;DR: Data suggest that non-cytolytic intracellular viral inactivation by cytokines released by virus-inactivated lymphomononuclear cells could have an important role in the clearance of this virus without killing the infected cell.
Abstract: The immune response initiated by the T-cell response to viral antigens is thought to be fundamental for viral clearance and disease pathogenesis in hepatitis B virus (HBV) infection. The T-cell response during acute self-limited hepatitis B in people is characterised by a vigorous, polyclonal, and multispecific cytotoxic and helper-T-cell response. By contrast, the immune response in chronic carriers, not able to eliminate the virus, is weak or undetectable. Thus a dominant cause of viral persistence could be the existence of a weak antiviral immune response. Methodological progress in animal models allows more precise investigation of the mechanisms by which the immune system resolves viral infection or develops chronic infection. Although clearance of most virus infections is widely thought to indicate the killing of infected cells by virus-specific T cells, data suggest that non-cytolytic intracellular viral inactivation by cytokines released by virus-inactivated lymphomononuclear cells could have an important role in the clearance of this virus without killing the infected cell. Additional factors that could contribute to viral persistence, which have been partly proven in animal models, are viral inhibition of antigen processing or presentation, modulation of the response to cytotoxic mediators, immunological tolerance to viral antigens, viral mutations, and infection of immunologically privileged sites. In view of the central role of cellular immunity in disease pathogenesis, strategies have been proposed to manipulate this cellular immune response in favour of protection from disease.
TL;DR: Efficient targeting of the extensive genetic diversity of HIV-1 constitutes one of the major challenges in present efforts against the pandemic, although the significance of HIV -1 genetic forms for vaccine development and therapy remains to be defined.
Abstract: Summary Since their initial expansion in human beings roughly seven decades ago in central Africa, the HIV-1 pandemic strains have diversified extensively through mutation and recombination. 24 circulating genetic forms of the main HIV-1 group are presently recognised, including 11 subtypes or sub-subtypes and 13 circulating recombinant forms. New genetic forms are being introduced in different areas of the world, changing the molecular epidemiology of the infection. It is generally agreed that the control of the HIV-1 pandemic requires the development of vaccines that efficiently protect against the range of HIV-1 genetic forms. The introduction of effective antiretroviral therapies in areas of high HIV-1 prevalence may also contribute to the control of the pandemic, as has been documented in developed countries. Efficient targeting of the extensive genetic diversity of HIV-1 constitutes one of the major challenges in present efforts against the pandemic, although the significance of HIV-1 genetic forms for vaccine development and therapy remains to be defined.
TL;DR: It is concluded that ARV can function as an effective HIV-prevention tool, even with high levels of drug resistance and risky sex, and even a high-prevalence HIV epidemic could be eradicated using current ARV.
Abstract: THE LANCET Infectious Diseases Vol 2 August 2002 http://infection.thelancet.com 487 Current combination antiretroviral therapies (ARV) are widely used to treat HIV. However drug-resistant strains of HIV have quickly evolved, and the level of risky behaviour has increased in certain communities. Hence, currently the overall impact that ARV will have on HIV epidemics remains unclear. We have used a mathematical model to predict whether the current therapies: are reducing the severity of HIV epidemics, and could even lead to eradication of a highprevalence (30%) epidemic. We quantified the epidemiclevel impact of ARV on reducing epidemic severity by deriving the basic reproduction number (R0 ARV ). R0 ARV