The Academic edition of the BMJ comes out once a month; readers may have noticed that one or more BMJ articles feature in alternate News Blogs. The most recent issue of the BMJ had less papers that caught my eye than most. There was lots of worthy stuff. For example, age-specific dementia incidence is declining slightly, antidepressants may very slightly increase the risk of autism if taken during pregnancy, specialist palliative care has rather small effects on quality of life, exercise and diet reduce the risk of high blood pressure in women who had high blood pressure in pregnancy. There was also an excellent article on the precision of cluster randomised trials by CLAHRC WM collaborator Karla Hemming. But the article that really caught my eye was a commentary on the importance of completing a full course of antibiotics as prescribed.
Of course, we always love articles that confirm our prior beliefs. I have always thought that insisting that people take a ‘full course’ of antibiotics to reduce resistance is illogical. Prolonging exposure of the bacterial population to the antibiotic is likely to increase the chance for selection to take place. And that is exactly what this study confirms. Apparently the idea that it was important to take the full course of treatment was based on Albert Alexander’s Staphylococcal sepsis, which re-established itself when Howard Florey’s penicillin ran out. However, the wisdom of continuing antibiotics until the infection is quelled somehow became translated into instructions to finish the course even if infection is no longer a threat. Remember, genetic mutations arise spontaneously and are only selected for when the antibiotic is present in the environment. It follows that the shortest course of antibiotics compatible with effective treatment should be used. And, of course, resistance does not just appear among the organisms causing the infection, but among all the organisms carried in the patient’s body, some of which may go on to infect another person. The argument against continuing to take antibiotics once the threat has passed is therefore unequivocal. It may be necessary to continue antibiotic treatment to prevent a relapse, as was the case for the hapless Alexander, and middle ear infections have a tendency to relapse, but we should not insist on taking a full course simply to prevent antibiotic resistance; the opposite is the case.
— Richard Lilford, CLAHRC WM Director
- Ahmadi-Abhari S, Guzman-Castillo M, Bandosz P, et al. Temporal trend in dementia incidence since 2002 and projections for prevalence in England and Wales to 2040: modelling study. BMJ. 2017; 358: j2856.
- Rai D, Lee BK, Dalman C, et al. Antidepressants during pregnancy and autism in offspring: population based cohort study. BMJ. 2017; 358: j2811.
- Gaerner J, Siemens W, Meerpohl JJ, et al. Effect of specialist palliative care services on quality of life in adults with advanced incurable illness in hospital, hospice, or community settings: systematic review and meta-analysis. BMJ. 2017; 357: j2925.
- The International Weight Management in Pregnancy Collaborative Group. Effect of diet and physical activity based interventions in pregnancy on gestational weight gain and pregnancy outcomes: meta-analysis of individual participant data from randomised trials. BMJ. 2017; 358: j3119.
- Hemming K, Eldridge S, Forbes G, Weijer C, Taljaard M. How to design efficient cluster randomised trials. BMJ. 2017; 358: j3064.
- Llewelyn M, Fitzpatrick JM, Darwin E, et al. The antibiotic course has had its day. BMJ. 2017; 358: j3418.
- Abraham EP, Chain E, Fletcher CM, et al. Further observations on penicillin. Lancet. 1941; 358: 177-89.
A previous News Blog  discussed the finding that a previous infection with one strain of Dengue fever can sensitise a person so that infection with a second strain will be more severe than would otherwise have been the case. There is new evidence that such Antibody Dependent Enhancement (ADE) may cross species barriers, such that a person sensitised with one type of flavivirus, say Dengue, is more likely to have a severe illness if inflected with another flavivirus, such as the Zika virus. Such cross species ADE has obvious implications for vaccination programmes. In previous News Blogs  we have drawn attention to cross-resistance such that vaccines protect against non-target organisms (e.g. small pox vaccines provide protection against HIV). The above paper shows that the reverse can also occur. This is not the first time that vaccination has been shown to have adverse consequences.
— Richard Lilford, CLAHRC WM Director
- Lilford RJ. Three hits hypothesis. NIHR CLAHRC West Midlands News Blog. 7 April 2017.
- Cohen J. Dengue may bring out the worst in Zika. Science. 2017; 355(6332): 1362.
- Lilford RJ. Two papers try to answer the question – do vaccinations for one communicable disease offer protection against others? NIHR CLAHRC West Midlands News Blog. 27 January 2017.
- Guzman MG, Alvarez M, Halstead SB. Secondary infection as a risk factor for dengue hemorrhagic fever/dengue shock syndrome: an historical perspective and role of antibody-dependent enhancement of infection. Arch Virol. 2013; 158(7): 1445-59.
Maybe not, but the CLAHRC WM Director is fascinated by stool and its contents. He shares this scatological interest with the 51-odd authors of the Global Multicenter Enteric Study who collected stool specimens from 9,439 children with diarrhoea, and no less than 13,129 control children. Then they used quantitative PCR (polymerase chain reaction) to analyse the samples. Children in low- and middle-income countries (LMICs) often harbour asymptomatic enteropathogens. However, there was evidence that the level of pathogen-derived nucleic acid could distinguish between infection and asymptomatic shedding.
The authors found:
- Types of organism that were highly prevalent with strong quantity-dependent associations with symptoms – these include rota-virus, adenovirus 40/41, Shigella spp, Cryptosporidium spp, and some types of E. coli.
- Organisms like Salmonella spp, norovirus, V. cholerae, and E. histolytica that showed strong quantitative associations with diarrhoea, but which had low prevalence.
- Organisms, such as various Campylobacter spp and other types of E. coli that were highly prevalent, but only moderately associated with diarrhoea – they are frequently found in the stool of asymptomatic people.
- Organisms that were only associated with diarrhoea in specific contexts, such as Aeromonas spp and enteroaggregative E. coli.
- Organisms that showed no association with diarrhoea, such as T. trichiura and A. duodenale.
A microbiological cause for diarrhoea could be found in 90% of cases when quantitative PCR was used, while a cause was found in only half of cases of diarrhoea using traditional methods. This is because some organisms, such as Shigella spp, are difficult to grow in culture. It had previously been thought that bloody diarrhoea is the hallmark of Shigella infection, but this study shows that many cases are associated with watery diarrhoea, rather than dysentery, at least in children. Future development of rapid quantitative assays should help identify cases that need antibiotics, and gene sequencing should also provide evidence on antibiotic resistance. Most important, we need improved sanitation to get rid of this lethal disease.
— Richard Lilford, CLAHRC WM Director
- Liu J, Platts-Millsa JA, Juma J, et al. Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study. Lancet. 2016; 388: 1291-301.
International research is undergoing a renaissance. Universities all over North America, Europe and Australia are establishing ‘Centres for Global Research’. Such centres draw funds from local donors and it is reasonable to ask whether research conducted abroad is completely altruistic, or whether it might also benefit the high-income countries that sponsor the research. Knowledge exchange is a two-way street and we should expect increasing traffic on the North-bound carriageway. The CLAHRC WM Director proposes the following classification for the potential local benefits of overseas research:
- The most obvious category relates to infectious disease. Research carried out abroad may provide early intelligence on impending risk so that countries may take steps to prevent spread, as in the recent Ebola epidemic (discussed in a previous post), or make preparations to contain the infection, as in the case of influenza, MARS and SARS.
- Research carried out in countries where a disease is common may provide information on how to treat it in countries where the diseases is rare. This would obviously apply to all tropical diseases that may affect returning travellers, visitors or immigrants, such as malaria and schistosomiasis. It would also apply to infections, such as leishmaniasis or West Nile fever that can be contracted in Europe, but with less frequency than in tropical countries. This type of knowledge transfer would also benefit people at risk of non-infectious diseases arising from habits imported from abroad, such as use of the areca nut, as discussed in a previous post.
- Providing larger populations to evaluate treatments where it would be very hard to accrue sufficient patients locally. Lelia Duley’s trial of magnesium for the treatment of eclampsia  and Ian Roberts’ ‘CRASH-2’ trial of tranexamic acid for massive haemorrhage  were both carried out over three continents. Yet the results drive practice across the world, including the UK.
- Providing a means to explore heterogeneity and thus glean deeper understanding of the role of context. For instance, the Cochrane review of trials of the effectiveness of providing additional support in labour through a layperson (so called doula) show that the service is effective in lowering the Caesarean rate where women are not accompanied by their partner, but not in countries like the UK where they usually are. The expeience of two people dying of terminal cancer, one in Kenya, the other in Scotland provides a further vivid example of the role of context.
- The success of an intervention in LMIC may encourage people to try it locally. For instance, the success of ‘women’s groups’ in improving perinatal outcomes in India, Nepal and Bangladesh  have encouraged CLAHRC North Thames to replicate the method among Bangladeshi communities in East London, as mentioned in a previous post. But we should be alert to the danger of leaping too rapidly to the conclusion that what works in one place will necessarily work in another. Studies carried out in our CLAHRC shows that clinical research produces essentially the same results when carried out in North America or Europe, but very different results across Europe and Asia.
- Research methodologies of generic utility may be developed to deal with issues in LMIC. The fabled stepped wedge design widely used in CLAHRC WM  was first used in West Africa. The lesson that much more can be learned by juxtaposing quantitative and qualitative research in systematic reviews than by either method alone, was ably demonstrated by twin Cochrane reviews on the subject,  (mentioned in a previous post).
More speculatively, the CLAHRC WM Director posits a category where there is no specific nugget of information that is returned, but rather tacit knowledge about universal features of the human condition. Certain general principles may be derived by examining health improvement projects across many countries, rich and poor, as recently pointed out by previous NHS Chief Executive, Lord Nigel Crisp. More indirect still are the cultural and political benefits of human interaction, and putative benefits of seeing the world in less parochial ways.
I invite readers of this News Blog to share other types of benefits and help populate this framework with lots of examples where LMIC research has benefited UK patients.
— Richard Lilford, CLAHRC WM Director
- Duley L. Magnesium and eclampsia. Lancet. 1995; 346:1365.
- CRASH-2 trial collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010; 376(9734): 23-32.
- Murray SA, Grant E, Grant A, Kendall M. Dying from cancer in developed and developing countries: lessons from two qualitative interview studies of patients and their carers. BMJ. 2003; 326: 368.
- Prost A, Colbourn T, Seward N, et al. Women’s groups practising participatory learning and action to improve maternal and newborn health in resource-limited settings: systematic review and meta-analysis. Lancet. 2013; 381(9879): 1736-46.
- Bowater RJ, Hartley LC, Lilford RJ. Are cardiovascular trial results systematically different between North America and Europe? A study based on intra-meta-analysis comparisons. Arch Cardiovasc Dis. 2015;108(1):23-38.
- Hartley LC, Girling AJ, Bowater RJ, Lilford RJ. A multistudy analysis investigating systematic differences in cardiovascular trial results between Europe and Asia. J Epidemiol Community Health. 2015;69(4):397-404.
- Hemming K, Haines TP, Chilton PJ, Girling AJ, Lilford RJ. The stepped wedge cluster randomised trial: rationale, design, analysis, and reporting. BMJ. 2015; 350: h391.
- The Gambia Hepatitis Study Group. The Gambia hepatitis intervention study. Cancer Res. 1987;47:5782-7.
- Lewin S, Munabi-Babigumira S, Glenton C, et al. Lay health workers in primary and community health care for maternal and child health and the management of infectious diseases. Cochrane Database Syst Rev. 2010; 3: CD004015.
- Glenton C, Colvin CJ, Carlsen B, Swartz A, Lewin S, Noyes J, Rashidian A. Barriers and facilitators to the implementation of lay health worker programmes to improve access to maternal and child health: qualitative evidence synthesis. Cochrane Database Syst Rev. 2013; 10: CD010414.
- Crisp N. Chapter 5: Turning the World Upside Down. In: Commonwealth Health Minister’s Update 2010. Geneva: World Health Organization. 2010. pp.89-933.
Derrick Crook and others have explored the cause of the dramatic drop in incidence in the colonic infection, Clostridium difficile, in English hospitals since 2010. They found that only 20% of cases of hospital-acquired C. diff infections result from patient to patient transmission of the organism – the rest are acquired from reservoirs outside the hospital. So the great majority of C. diff infections are not hospital-acquired.
The dramatic drop in incidence of C. diff enteritis was preceded by a precipitous drop in prescribing of quinolone antibiotics in both general practice and in hospitals. Moreover, the drop in incidence can be entirely explained by the decline in quinolone-resistant species of C. diff; the incidence of quinolone-sensitive C. diff infections remains unchanged.
The drop in C. diff infections in English hospitals turns out to have nothing to do with hand-washing and hospital hygiene. Moreover, washing hands in alcohol is of no value as far as this organism is concerned because C. diff spores are resistant to this disinfectant.
— Richard Lilford, CLAHRC WM Director
- Eyre DW, Cule ML, Wilson DJ, et al. Diverse Sources of C. difficile Infection Identified on Whole-Genome Sequencing. New Eng J Med. 2013; 369(13): 1195-205.
- Benning A, Dixon-Woods M, Nwulu U, et al. Multiple component patient safety intervention in English hospitals: controlled evaluation of second phase. BMJ. 2011; 342: d199.
- Jabbar U, Leischner J, Kasper D, et al. Effectiveness of alcohol-based hand rubs for removal of Clostridium difficile spores from hands. Infect Control Hosp Epidemiol. 2010; 31(6): 565-70.