[Leading Edge] Are genome-wide association studies of infection any value?

Host genetic effects on susceptibility to infectious diseases has long been recognised. Genes encoding sickle-cell traits or β-thalassaemia protect against malaria, and polymorphism of the T-cell receptor CCR5 affects susceptibility to plague, smallpox, and HIV. Knowledge of genetic associations has helped to inform understanding of disease pathogenesis and inspired new approaches to treatment. The past year or so has seen an increased focus on the finer aspects of genetic influences on disease susceptibility with a growing number of genome-wide association studies. But will this approach have any clinical implications for infectious disease?

[Reflection and Reaction] The latest threat in the war on antimicrobial resistance

Enterobacteriaceae, most notably Escherichia coli and Klebsiella pneumoniae, are among the most important causes of serious nosocomial and community-associated bacterial infections in people, and resistance of these bacteria to antimicrobial drugs is a serious concern. Of particular concern is development of resistance to the carbapenems (ie, imipenem, meropenem, ertapenem, and doripenem), because these drugs are often the last line of effective treatment available for infections with multiresistant Enterobacteriaceae. Resistance is due to carbapenemases, of which there are three types: K pneumoniae carbapenemases, metallo-β-lactamases, and oxacillinases.

[Reflection and Reaction] ACTs for schistosomiasis: do they act?

There is evidence that crude extracts of the medicinal herbs Artemisia annua and Artemisia apiacea were used in China more than 2000 years ago. Indeed, herbalists prescribed tea that included dried leaves of the Artemisia plants to treat fever and other ailments. However, the active component of A annua was only identified more recently and named Qinghaosu, now known as artemisinin. This breakthrough discovery made in the early 1970s stemmed from screening more than 2000 Chinese herb preparations by the phytochemist You-You Tu.

[Reflection and Reaction] Research into tuberculosis diagnosis in children

Tuberculosis is an important cause of morbidity and mortality in children worldwide, but estimates of disease burden are inaccurate because most cases are not confirmed. The most common form of childhood tuberculosis is pulmonary disease, and in tuberculosis-endemic communities, most cases present in young children. Collection of respiratory specimens for laboratory diagnosis is difficult in this age group. Most cases are paucibacillary, and therefore mycobacterial culture of specimens is required to optimise diagnostic yield. Studies of tuberculosis diagnosis in children are hampered by the lack of a gold standard for tuberculosis disease and infection, with the limitations of mycobacterial culture and tuberculin skin test well recognised. During the past decade, there has been a surge in development of new diagnostics aiming to provide more accurate and rapid diagnosis. Despite the challenges, new diagnostic techniques need to be studied in children.

[Reflection and Reaction] Biosafety and tuberculosis laboratories in Africa

As a major concern of laboratory biosafety, Mycobacterium tuberculosis has been classified as a category 3 pathogen, meaning that culture-based work can only be done in a biosafety level 3 (BSL3) laboratory (smear microscopy can be done in BSL2 laboratories because the risk of significant aerosolisation is low). However, most tuberculosis burden is in low-income countries, such as those in sub-Saharan Africa, that do not have the financial resources to build or maintain expensive and complex BSL3 laboratories (). Some people have even suggested that extensively drug-resistant (XDR) strains of tuberculosis should be classified as category 4 organisms; however, because a strain cannot be identified as an XDR before culture and sensitivity tests, all culture-based work with M tuberculosis would have to be done in a BSL4 laboratory.

[Cross-talk] It'll be fine with a bit of ice and lemon

The presumptive coliform count, the classic foundation of water testing, has long been supplanted by more sophisticated membrane filtration and most-probable-number tests. Yet these modern versions of the traditional technique are still based on the idea of distinguishing between water containing coliforms, which should not be consumed, and water lacking them, which is probably safe. Although Escherichia coli dies out in a watery environment outside the body, it does not die more quickly than bacterial pathogens.

[Newsdesk] The real cost of counterfeit medicines

In April 2010, the Cambodian Ministry of Health announced that the previous 5 months had seen the enforced closure of nearly 65% of the illegal pharmacies operating in the country. The US Agency for International Development (USAID)-backed Promoting the Quality of Medicines Programme—which is active in 30 nations—had gathered evidence that these pharmacies were a significant source of counterfeit and substandard medicines in Cambodia.

[Newsdesk] Trial results finally show potential for microbicidal HIV gel

Salim and Quarraisha Abdool Karim, husband and wife, and co-principle researchers on the Centre for AIDS Programme of Research in South Africa (CAPRISA) trial, received a standing ovation at the recent International AIDS Society Conference in Vienna when they announced their results, which showed—for the first time—that the use of an antiretroviral microbicidal gel can protect against HIV transmission. Mathematical modelling suggests that, in South Africa alone, this gel can prevent up to 1·3 million new infections and 8000 HIV-related deaths during the next 20 years.

[Newsdesk] Smallpox: should we destroy the last viral stocks?

An International Symposium held in Rio de Janeiro, Brazil, on August 24–27, has focused on the lessons learned from the smallpox experience and featured debates on one very thorny issue still surrounding smallpox—whether we should destroy all stocks of the viral strains held in the world. WHO declared smallpox officially eradicated 30 years ago and it is still the only infectious disease that vaccination has succeeded in completely removing from the human population worldwide. Smallpox was highly virulent and killed 20–60% of those it infected, and caused long-term disability, such as deafness and blindness, in many of the rest. “Originally, stocks of the smallpox virus were held at dozens of locations but this was reduced to only two WHO Collaborating Center repositories—the State Research Centre of Virology and Biotechnology (VECTOR) in Russia and one at the Centers for Disease Control (CDC) in the USA”, notes Gilberto Hochman (Oswaldo Cruz Foundation, Rio de Janeiro, Brazil), one of the conference organisers. “The others were destroyed after the accidental infection and death of a lab worker in Birmingham in the UK in 1978.”

[Newsdesk] Infectious disease surveillance update

On August 10, the WHO Director-General's statement after the ninth meeting of the Emergency Committee declared the 2009–10 influenza A H1N1 pandemic over. WHO estimates that 18 449 people have died as a result of the virus in 214 countries and overseas territories or communities.

[Newsdesk] Research brief

Ticks transmit several pathogens to people and animals. Many animals develop immunity to ticks after repeat infestations but the nature of this acquired immunity is unclear. Researchers now report that antibodies and IgFc receptor expression on basophils is required for acquired resistance to Haemaphysalis longicornis ticks in mice. Furthermore, mice that lack basophils fail to acquire resistance to this vector for the human pathogens that cause Q fever, babesiosis, and Russian encephalitis. The discovery that basophils are essential for antibody-mediated immunity against ticks might suggest new strategies for the control of tick-borne diseases.

[Media Watch] Books: Health law, human rights, and public health

As shown in this two-volume set of previously published articles, public health is a vast field, encompassing most areas of human activity. Public health covers poverty and warfare to genetics and climate change through governmental actions taken to prevent disease and improve people's quality of life. When discussion turns to public health ethics, bioethicists and health lawyers are often called upon to give comment—the editor, Michael Freeman, Professor of English Law at University College London, UK, has done just that to compile this book.

[Media Watch] Books: Georg Letham: physician and murderer

His life story itself is the stuff of novels. Born in 1882 to a well-to-do Jewish family in what was then the Austro-Hungarian Empire—now the Czech Republic—Ernst Weiss spent his youth in some of central Europe's most agreeable cities: Prague, Brno, Litomerice, and Berlin. He studied medicine in Vienna and later became a surgeon. 1912 saw Weiss take up a berth on a ship bound for India and Japan. When he returned to Europe, the storm clouds were gathering. He served with distinction as a military physician in the Great War: they awarded him the Golden Cross for bravery. Afterwards, he settled in Prague, but he didn't want to be a doctor anymore.

[Correspondence] Invasive infections and sickle-cell disease

The burden of disease caused by bacterial infections in patients with sickle-cell disease has long been neglected. Meenakshi Ramakrishnan and colleagues emphasise the scarcity of data for the association between sickle-cell disease and invasive bacterial disease in Africa. However, four of the seven studies included in this meta-analysis were from Kinshasa, Democratic Republic of the Congo (formerly Zaire). Although the reviewers present these as independent studies, the same data are shared in these reports. The first study by Eeckles and colleagues, published in 1967, included data for blood and cerebrospinal fluid (CSF) infections, recorded from 1959 to 1966. The second study, by Lontie and colleagues published in 1973, included data for CSF samples collected from 1959 to 1972. The third study, by Omanga published in 1981, from the same clinics as the first and second studies, included data for all types of invasive infections; the investigators do not mention dates of sample collection. In a fourth study by Omanga published in 1989, data were collected from 1964 to 1985. This study reported 69 patients with sickle-cell disease and bacteraemia. At least 14 of these 69 patients also had positive CSF cultures. A fifth study, published in 1977 (not included in Ramakrishnan and colleagues review), also by Omanga and colleagues, examined meningitis in 47 patients with sickle-cell disease, nine of whom also had positive blood cultures. These CSF samples were collected from 1964 to 1974. Because Eeckles and colleagues' 1967 study, reported 45 patients with sickle-cell disease, few new cases are likely to have been added in the last study published in 1989 (conflict in the Democratic Republic of the Congo meant microbiology laboratories might not have been functional).

[Correspondence] Invasive infections and sickle-cell disease – Authors' reply

In our meta-analysis, we found seven articles from Africa with sufficient data to examine the association between invasive bacterial disease and sickle-cell status. We appreciate the comment by Thomas Adamkiewicz about the potential overlap in four studies done at Kinshasa University Hospital; the studies did not provide sufficient data to establish the extent of overlap in the populations. We therefore included all four articles in our original analysis but acknowledged that the generalisability of our results was limited by the fact that many studies enrolled patients in the same hospital setting, used the same control group, and might have overlapping populations. We repeated our meta-analysis for invasive bacterial disease without the three studies that might overlap with the largest Kinshasa study of 568 cases of bactaeremia and meningitis. Lontie and colleagues' study remains in the separate meta-analysis for bacterial meningitis because it is the only study in Kinshasa to present separate data for meningitis.

[Correspondence] Cervical cancer incidence can increase despite HPV vaccination

We read with interest the conclusion that Chris Bauch and colleagues presented, indicating that the incidence of cervical cancer would be very unlikely to increase as a result of human papillomavirus (HPV) vaccination. The investigators conclude that screening coverage in a population is unlikely to decline to levels that would be necessary to lead to an increase cervical cancer incidence—this being an 80% decrease in screening with 30% vaccine coverage. We refute their conclusions and present data from the UK and Finland that show that screening less than 20% of young women resulted in a substantial increase in cervical cancer incidence in an unvaccinated female population. With increasing background exposure to high-risk HPV, the incidence of cervical cancer did not decrease in the UK until at least 70% of the population were appropriately screened. Likewise, when less than 70% of the population is screened, only individual benefits result and the population incidence of cervical cancer is not reduced.

[Correspondence] Cervical cancer incidence can increase despite HPV vaccination – Author's reply

Our Personal View presents a mathematical model to determine the conditions under which a decline in screening adherence in vaccinated women would outweigh the benefits of a human papillomvirus (HPV) immunisation programme, and thus result in a net increase in cervical cancer incidence. In their refutation, Diane Harper and colleagues' create a misrepresentation of our model and then refute that misrepresentation. First, Harper and colleagues interpret our model as showing that human papillomavirus (HPV) vaccination will prevent any future increase in incidence of cervical cancer. We find that such an increase is indeed possible, especially when screening coverage is high before vaccine introduction, however, it does not occur unless the decline in screening adherence is steep. Second, Harper and colleagues incorrectly cite the opportunistic screening scenario; for comparison to the situation in Finland, for which the organised screening scenario (high coverage) should be cited. Our model predicts that a rise in cervical cancer incidence in vaccinated women is more likely with organised screening than with opportunistic screening, and so data from Finland might actually validate our model.

[Correspondence] Acute bacterial meningitis

I read with great interest Kwang Sik Kim's excellent Review of acute bacterial meningitis in infants and children in The Lancet Infectious Diseases. I am grateful for Kim's contribution to the knowledge of bacterial meningitis in children; however, he states that concomitant “dexamethasone and vancomycin can reduce penetration of vancomycin into the CSF [cerebrospinal fluid] by virtue of the anti-inflammatory activity of dexamethasone”. Findings from one multicentre study have shown that the crossing of the blood–brain barrier by vancomycin is unaffected by steroid use. Furthermore, in agreement with previous data, after administration of the conjugate antipneumococcal vaccine, some pneumococcal serotypes are replaced via the emergence of serotypes that are not included in the vaccine. Hence, in severe cases of pneumococcal meningitis, vancomycin should be added despite concerns of a decrease in blood–brain barrier penetration with the concomitant use of steroids, because it can reduce the incidence of neurological sequelae. This finding should be kept in mind, especially after the increase of pneumococcal serotype 19A that has led to increased antimicrobial resistance to β lactams.

[Correspondence] Tuberculosis and diabetes mellitus: is vitamin D the missing link?

We read with interest Kelly Dooley and Richard Chaisson's review of the association between diabetes mellitus and tuberculosis. Although the investigators discussed several mechanisms that might underlie this association, we feel that that one potentially important consideration was omitted—vitamin D.

[Articles] Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study

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.

[Articles] Efficacy of artesunate with sulfalene plus pyrimethamine versus praziquantel for treatment of Schistosoma mansoni in Kenyan children: an open-label randomised controlled trial

Schistosomiasis is an important parasitic disease in Kenya. Decreasing susceptibility of schistosomes to praziquantel, the major drug used to reduce disease morbidity, has made assessment of new antischistosomal drugs a priority. We aimed to assess the safety and efficacy of an artesunate-based combination drug in the treatment of schistosomiasis.

[Articles] Diagnostic approaches for paediatric tuberculosis by use of different specimen types, culture methods, and PCR: a prospective case-control study

The diagnosis of pulmonary tuberculosis presents challenges in children because symptoms are non-specific, specimens are difficult to obtain, and cultures and smears of Mycobacterium tuberculosis are often negative. We assessed new diagnostic approaches for tuberculosis in children in a resource-poor country.

[Review] Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis

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.

[Review] Do children infected with HIV receiving HAART need to be revaccinated?

No official recommendations have been made on whether children infected with HIV on highly active antiretroviral therapy (HAART) should be revaccinated. We reviewed published work to establish whether these children have protective immunity to vaccine-preventable diseases and to assess short-term and long-term immune responses to vaccination of children given HAART. In general, children on HAART had low levels of immunity to vaccines given before treatment. Most children on HAART, however, responded to revaccination, although immune reconstitution was not sufficient to ensure long-term immunity for some children. These results suggest that children on HAART would benefit from revaccination, but levels of protective immunity might need to be monitored and some children might need additional vaccine doses to maintain protective immunity. Vaccination policies and strategies for children infected with HIV on HAART should be developed in regions of high HIV prevalence to ensure adequate individual and population immunity.

[Review] Guillain-Barré syndrome after exposure to influenza virus

Guillain-Barré syndrome (GBS) is an acute, acquired, monophasic autoimmune disorder of peripheral nerves that develops in susceptible individuals after infection and, in rare cases, after immunisation. Exposure to influenza via infection or vaccination has been associated with GBS. We review the relation between GBS and these routes of exposure. Epidemiological studies have shown that, except for the 1976 US national immunisation programme against swine-origin influenza A H1N1 subtype A/NJ/76, influenza vaccine has probably not caused GBS or, if it has, rates have been extremely low (less than one case per million vaccine recipients). By contrast, influenza-like illnesses seem to be relevant triggering events for GBS. The concerns about the risk of inducing GBS in mass immunisation programmes against H1N1 2009 do not, therefore, seem justified by the available epidemiological data. However, the experiences from the 1976 swine flu vaccination programme emphasise the importance for active and passive surveillance to monitor vaccine safety.

[Clinical Picture] Cutaneous septic emboli from Candida tropicalis

An 11-year-old girl with acute lymphoblastic leukemia presented 1 month after induction chemotherapy with febrile neutropenia, a new diastolic murmur, and a subtle asymptomatic persistent rash.