Flu vaccines in the elderly-40 years of expensive policy with no evidence?
“Vaccine” is a medical term that is part of the vernacular. They are our childhood immunizations and the backbone of public health programmes at national and international level, in both rich and poor countries. They are the holy grail of research against the biggest infectious disease killers of our time, from malaria and HIV/AIDS to influenza, and, more recently swine flu. They are multi-billion dollar business to drug companies. The World Health Organisation defines a vaccine as “any preparation intended to produce immunity to a disease by stimulating the production of antibodies…..The most common method of administering vaccines is by injection.”
Vaccines have been used in the elderly for over 40 years to reduce the impact of influenza (or flu) in this part of the population that is at higher risk of complications and death from flu. In 2000, 40 out of 51 high-income or middle-income countries recommended flu vaccination for all persons aged 60 or 65 or older, with over 290 million doses of vaccine distributed worldwide in 2003. You would think that a health policy of that scale would be firmly grounded on scientific evidence. Well think again.
Because influenza vaccines are produced and tested using surrogate outcomes (antibody stimulation) ahead of each influenza "season", past performance is probably the only reliable way to predict future performance. A new Cochrane systematic review looked through over 40 years of experimental and non-experimental studies of effectiveness of flu vaccines, and found very poor evidence for effectiveness of flu vaccination in the elderly. Of the 75 studies included in their analysis, they found only one recent randomised controlled trial which used “real” outcomes (e.g. actual flu cases or deaths from flu), as opposed to surrogate outcomes (e.g. influenza antibodies). All other studies were of low quality and open to bias. Current flu vaccines prevented 45% of pneumonia cases, hospital admissions and flu-related deaths in long-term care facilities (for example, nursing homes), compared to 25% vaccine efficacy in community settings. Tom Jefferson, lead author of the review, said, “Our estimates are consistently below those usually quoted by economists and in decision making." He calls for “an adequately powered publicly-funded randomised placebo-controlled trial run over several seasons”, and emphasis on “strategies to complement vaccinations”, such as personal hygiene, food and water.
The current swine flu pandemic has caused renewed interest in influenza vaccines and their performance, and this timely review surely gives us lessons on why we should base global health policy on evidence, before spending billions of pounds, dollars and many other currencies. Perhaps the most cautionary part of this review is the analysis of study funding and quality. High quality studies were 16 times more likely to make conclusions that agreed with the presented results, and less likely to favour effectiveness of vaccines. Government-funded studies were less likely to have conclusions favouring vaccines. Studies published in prestigious journals that were most frequently cited were associated with partial or complete industry funding. How much more evidence do we need that profits are trumping public health and evidence when it comes to flu?
How good are we at diagnosing serious infection in children?
When I started in evidence-based medicine, it was a big shock that probably the most under-researched area of health is how health practitioners should diagnose illness; i.e. “diagnostic strategies”. Individual studies and systematic reviews have focused on drugs and interventions, but it is now recognised that such reviews are also necessary to evaluate diagnostic tests. In children, clinical signs (e.g. a raised temperature) or test results are even more important than in adults, because the child may not be able to describe his or her symptoms, particularly when they are very unwell.
In the Lancet “online first” this week, a systematic review studied the value of rapid breathing, poor peripheral circulation and other factors in confirming or excluding the possibility of serious infection in children presenting to general practice or other outpatient care. After looking through nearly 2000 potentially relevant articles, the authors included 30 studies in their analysis. They collated information from the individual studies to calculate “likelihood ratios” for each factor or test; i.e. how likely a disease is after a test result. A likelihood ratio of >1 indicates the test result is associated with the disease. A likelihood ratio <1 indicates that the result is associated with absence of the disease. Clinical features with a positive likelihood ratio of more than 5 were termed “red flags” (i.e. warning signs for serious infection).
Cyanosis, or a blue colouration of the skin, led to a positive likelihood ratio range of 3–52, whilst the same ranges for rapid breathing and petechial rash (the non-blanching rash parents are taught to look for if we are worried about meningitis) were 1–10 and 6–84 respectively. Put another way, a petechial rash increases the odds of serious infection by between 6-fold and 84-fold. The likelihood of the disease is influenced by the prevalence of the disease in the population. For example, in a setting where meningitis or infection is very rare, the likelihood of meningitis if you have a petechial rash is increased. No single clinical sign could rule-out serious infection but some combinations could be used to exclude the possibility of serious infection. For example, pneumonia is very unlikely if the child is not short of breath and there is no parental concern.
It is amazing that only one study was set in primary care, where such information would change practice most since GPs often have to make decisions based on simple clinical signs. That study highlighted two red flags that are rarely evaluated: parental concern and doctor’s instinct. Parental concern gave a positive likelihood ratio of 14 and clinician instinct increased the likelihood of serious infection by 24 times. This study only looked at developed country research, and not research from developing countries, but the authors concluded, “Most of the red flags already recommended by WHO for use in developing countries can be used in the initial assessment of children presenting to ambulatory care settings in developed countries.” The next step is “to identify the level of risk at which clinical action should be taken”, based on these red flag tests.
Why everyone should know about solar disinfection
The advantage of living and working in Oxford is you don’t have to travel far to meet interesting people, particularly in the field of epidemiology. Last week, I met with Mike Clarke, Director of the UK Cochrane Centre, and our wide ranging discussion turned to the recent release of the Cochrane Evidence Aid: resources for Haiti earthquake.
I have always thought release of materials in this way is more of a publicity stunt than a useful resource. This time I couldn’t have been more wrong. Indeed, I can’t believe I’ve never heard of solar disinfection. When I mention this to colleagues, most have never heard of it either, and if you have, then you are definitely in the minority.
So what is solar disinfection and what is it good for? It is simply disinfection by heat, either by boiling or pasteurization) and the use of ultraviolet radiation, either using the sun (solar disinfection) or by using an artificial ultraviolet light lamp. The evidence for its effects comes from a systematic review of Interventions to improve water quality for preventing diarrhoea.
In two trials of solar disinfection in this review both intervention and control households received plastic bottles for storing their drinking water. The intervention group was instructed to place the bottles on roofs to expose them to the sun, while control groups were told to keep the filled bottles indoors. Solar disinfection was statistically significantly better than the control for reducing diarrhoea episodes in people of all ages. For diarrhoea the odds ratio odds ratio for prevention was 0.69 95 % confidence interval 0.63 to 0.74 basically a 30 percent reduction in diarrhoea. In addition since controls also received bottles this may have provided some protection against diarrhoea by means of improved storage, thus underestimating the true effect.
Knowing about solar disinfection, and implementing it, is great Evidence-Based Medicine. From now on I will view evidence aid resources from the Cochrane Library in a different light.