Clinical trials - what do we mean by 'no-effect'?

This is a more difficult question than one might think.  The traditional randomised controlled trial (RCT) randomly selects people from a population of interest; then randomly allocates them to one of two or more treatments, one of which may be a placebo or 'dummy' drug.  The purpose of the placebo is to account for the beneficial (or sometimes detrimental) effect that one sometimes gets just through being given a treatment irrespective of whether it works or not.  So far so good..but..

There is a problem.  In most cases the actual clinical treatment options are not new drug versus dummy drug; but new drug versus some other treatment, which may be something or it may be nothing.  New drug versus dummy drug is almost never the actual option given to patients.  Imagine the conversation with your doctor, "the treatment for condition XXX currently is a drug which we think is of no benefit apart from the fact that it tastes nice and comes in a fancy bottle". 

Traditionally the effect that is seen just by being given something has been termed the 'placebo' effect, Latin for 'I shall please'.  This is a link to the Wikipedia page, (but I did actually know the Latin bit).  In some circumstances the pacebo can be a problem, for example if people just feel better without getting better they may miss treatment that they need.  In studies if they feel better from being given a placebo it may hide a benefit from the active drug (this is termed a Type II error - missing a beneficial effect from a treatment).  There are also ethical issues about people not understanding what they are taking.

However, where the desired outcome is comfort, maybe anything that provides comfort is ok, and if that is a placebo maybe that does not matter.  This may, for example be the case in the treatment of children with a fever, where the desired outcome of treatment is not temperature reduction but relief of discomfort.  If a medicine looks nice, tastes nice, and reduces anxiety in parents and children does it actually matter if it is the active ingredient or a placebo effect?

The reason why this is topical now, is that there is a paper in JAMA Pediatrics which looks at this very subject in the treatment of autism, finding a strong placebo effect compared to the active treatment, indeed in some groups the placebo group actually did better.  Puzzling.. 

What to make of this?  Firstly don't underestimate the power of the placebo - it may be as simple as someone taking an interest in the patient making them feel better.  Secondly, as educated informed consumers of research always check, when comparisons are made, to what was the new treatment being compared?  This brings us to a wider point of efficacy v effectiveness - efficacy is can it work in ideal circumstances (as one would see in a RCT) while effectiveness is does it work in practice? - These are often not the same.  Check to see if your new treatment works outside of the lab!

King et al JAMA Pediatr. Published online September 23, 2013. doi:10.1001/jamapediatrics.2013.2698

The importance of intellegence - certainly when it comes to influenza.

The complexity of understating the spread of influenza was again highlighted in a paper in Eurosurveillance recently.  In this paper the authors have looked at antibody levels and antibody quality to H3N2 and H1N1 influenza A viruses from pigs that have been known to spread to humans.   H and N; or haemagglutinin and neuraminidase to give them their full names, are two molecules found on the outside of the influenza virus, and it is changes in these molecules which mean that it is necessary to revaccinate against influenza each year.  They constantly change in a process called antigenic drift, and sometimes change suddenly in a process known as antigenic shift; the latter often occurring when an animal virus passes into and then spreads between humans. 

This is a particular problem with influenza because unusually humans share influenza viruses with a variety of animals with which we have frequent contact, namely birds and pigs.  A sudden antigenic shift, as occurred in 2009 with the introduction of a new H1N1 virus into the human population can spread because, being a new virus, there will be little immunity in humans.  The important thing to remember here is that it is not the jump into humans that is the problem (unless you are that human of course); but the subsequent transmission between humans.  That was the difference between avian influenza in 2005 and swine influenza in 2009, the former did not transmit widely between humans and the latter did.  Incidentally the latest virus to worry the world, H7N9 has made the first step, and there are tentative signs that it might have made the second, being transmitted between humans, but so far only a very small number of very close contacts.

Understanding the make-up of the H and N of viruses that are likely to circulate in the human population is important to ensure that vaccine can be made and that preparations can be put in place for health services.  However, it is a bit more complicated than just characterising the H and N numbers, since not all H1N1 for example are the same.

In this study the authors looked at antibody titres (levels) to different strains of influenza of pig origin, remembering that the last pandemic strain came from pigs.  When they looked at a variety of different H1N1 and H3N2 viruses what they found was that there were marked differences in antibody levels in different age groups to different viruses.  For example, those born between 1968 and 1999 had high levels to one type of H3N2, but very low levels to another more recent variety.  These differences reflect exposure to viruses over time, and have been seen before, for example older people tended to be less at risk of catching the last H1N1 pandemic virus because of existing immunity from previous exposure to a similar virus.

What we learn from this is that influenza should probably not be considered to be a single virus, but a large and ever changing family of viruses that can affect different groups in different ways.  The other thing that comes across is that immunity, like knowledge, is a life-long affair.  Just as we learn and collect knowledge, so we learn and collect immunity.  The key is to avoid damage while we are collecting it, which once again emphasises the importance of age and group-specific vaccination policies that reflect the ever-changing world of influenza.  If you want to know more about the UK situation, Public Health England is the place to look.  It is worth keeping an eye on this page, because the situation is constantly changing.

Hoschler (2013) Eurosurveillance 18, 36, 05 September 2013  

Guidlines-keep them simple otherwise we won't remember them! The example of weight estimation.

One of the most important variables in paediatrics is development, and one important measure of physical development is weight.  This is used for all sorts of things, including drug doses, fluid calculations and body surface area estimation.  Normally of course we can weigh children, so this should be pretty accurate.

Unfortunately, sometimes we can’t do this, most notably in emergency situations; and in such cases it is necessary to estimate the child’s weight.  While this is never going to be as accurate as weighing the child, a good estimate is the best that can often be achieved.  However, this obviously requires two things: 

1. A formula for estimating weight
2. That the person using it can remember it and use it correctly.

A number of methods for estimating weight exist, however a recent letter published in Archives of Disease in Childhood describing a survey among 25 paediatric trainees suggest that this may be a cause of some confusion.   The authors start by reviewing the current Advanced Paediatric Life Support (APLS) Guidelines, which contain three methods of estimating weight:

·         Infants from 1-12 months (0.5 x age in months +4)

·         Children aged 1-5 years (2 x age in years +8)

·         Children aged 6-12 years (3 x age in years +7)

These replace the previous Guidelines which had one formula for children aged 1-10 years, and which still used in some Guidelines.

The study found that only 2 of the participants (8%) were able to correctly apply the new formulae to examples that they were given, and that around half used the old formula.  The extent to which this matters is debatable, but clearly someone thought it was worth changing the guidance on this, and this is what is now taught, so one would expect that paediatric trainees at least would know them.

The lesson from this is that Guidelines should always be as simple as possible if we expect people to remember them.  For parents, it might be worth knowing roughly how much your child weighs!

What to do about young men?

This is somewhat out of my normal comfort zone of infections, but a recent review in Pediatrics looks at the subject of health in adolescent boys and young men, and makes some suggestions about activities that might be undertaken to improve their health through screening and other measures.

The paper itself is American, and does not necessarily translate directly to a UK or European setting, but much of it does.  The list of conditions that young men might suffer is quite extensive, and in addition to the various medical conditions there are many other issues such as violence and suicide that while they may differ in degree, are definitely issues for many young men.  The other really interesting issues are those surrounding sexuality and the role of men in society.  This struck me because many of the regular drama programmes in the UK (particularly EastEnders) have a really negative image of men, they all seem to be crooks, emotionally unstable, or generally not very nice.  While this is only drama, the drip, drip, drip effect of negativity may be significant.

One of my jobs here in the College is to run the HIV Course, and the assignment for this includes planning a health education intervention.  A lot of the students decide to target gay men; but when asked how they will access them they only seem to know about gay men in terms of those who go to nightclubs and bars.  Now while many gay men do, I am pretty sure there are many who don't frequent nightclubs and bars, so how best to access them?  The same problem occurs with young men, how do you access them, and when you do what interventions actually work?

Since writing the NICE Fever Guidelines, and being a fully paid up convert to the idea of traffic light tables, maybe one idea might be to do a traffic light for young men.  What characteristics are indicative of low, intermediate and high risk of morbidity?  I know they have limitations, they are either too sensitive or too specific........but they are a start, and they do make people think about what we know, and more importantly what we don't, what is the level of uncertainty and where does it lie?

One particularly fascinating idea is the concept of the positive development approach, where one acknowledges and promotes the young persons strengths and assets rather than problems and weaknesses.  It seems obvious, but actually we don't often do that, indeed the NHS in the UK often referred to as the National Sickness Service rather than the National Health Service.  Then it struck me, promoting strengths and assets, and being positive; wouldn't it be nice if we could do that to everyone?

Diagnosing infection in children – what is the problem?

One of the big problems in terms of treating children is diagnosing the illness in the first place.  In no group is this more of a challenge than in infants with infections, because many of the classical signs of infection, such as inflammation are absent because of their relatively immature immunity.  A similar problem occurs with people of all ages whose immune systems are damaged, either by disease, old-age, or sometimes medical treatment.  The key to diagnosing infection is often not the bug, but the immune response to the bug, and if you don’t have a good immune response it makes it all the more difficult.  Often the only sign of infection is a fever, hence the importance of fever as a diagnostic sign in immunosuppressed people.

The answer to this is to either have a very low suspicion for disease, which might mean over-treating; or to have a higher suspicion, but then risk missing disease.  The problem with the first is that it is expensive, and in the case of antibiotics might lead to the development of resistance; while the latter leads to the risk of missing potentially fatal infections.  It was partly for this reason that the NICE Guidelines on the treatment of fever in children were developed, but many of the symptoms in the amber and red categories are fairly general, and anyway they don’t tell you what infection the child has, just that they probably do have one.

The answer is better and quicker diagnostic tests.  We have a whole range of tests now, but none that are completely accurate.  Additionally, some are highly dependent on the skills of the person performing the tests or on the organism itself: for example, blood cultures, the gold standard test for many infections may become contaminated with skin bacteria, or the bacteria themselves may not grow in the lab.  Even if they do grow, it is not always the case that the bacteria that grow are the ones actually causing the disease; and there may be other organisms, for example viruses or fungi that do not grow in the lab.  Such methods are sometimes referred to as 'phenotypic' - they look for behaviours such as growth or the response to different conditions or chemicals.  If the thing is dead in the test tube or does not grow it won't have a phenotype!

There are many new diagnostic techniques that avoid such problems being developed, some of which are reviewed in a recent paper in JAMA Pediatrics.  In particular these are tending to use molecular methods to either identify the pathogen directly, such as those which look for the genes of the organism; or to identify the host response to the organism.  The latter is helped by the rapidly increasing knowledge of the human immune system and genomic techniques. These methods don’t rely on culturing (‘growing’) the organism in the lab, and so avoid many of the problems inherent in observing growth or behaviour, but they bring their own issues, not least of which is expense.  One method, known as PCR(Polymerase Chain Reaction) which looks for pathogen genomes has been used for some time, and is widely used to diagnose HIV in young children, but is not widely used elsewhere for diagnostic purposes.  Molecular is definitely the way forward, but it may not be a quick journey.

The lesson from this is that testing is fine, but it must not replace the clinical judgement of either parents or healthcare professionals.  Even if you have the best diagnostic test in the world…..ever, it still relies on someone to notice that the child is ill in the first place.  Parents and clinicians are both, in their own ways, generally quite good at this, and so should trust their instincts.  Incidentally, if you want to know if someone really understands this stuff ask them: if they say yes - they probably don't!  There is much of the immune system, and our relationship with micro organisms that we don't understand and probably never will.

(Mahajan, P (2013) The future possibilities of diagnostic testing for the evaluation of febrile infants. JAMA Pediatrics)

More children being admitted to hospital in the UK - why and what can be done?

According to a study recently published in Archives of Disease in Childhood it appears that more children are being admitted to  hospital (Gill et al 2008 Arch Dis Child 98 328-334).  While the figures are a bit rough and ready, the trends presented are fairly clear and include:

1. A fairly continuous increase in the number of admissions since 2003; in the preceding 4 years (1999-2003) it was fairly static.
2. Overall the increase in admissions since 1999 is 28%: in those under 1 year of age it is 33% which is the highest, the lowest was in the 10-14 year age group which was only (!) 13%.
3. This increase is not because children are getting much sicker, as mortality fell over the same period.
4. Much of the increase is the result of infectious diseases and other conditions such as asthma that could be managed in the community.
5. Admissions for chronic conditions fell a little.
6. Most of the increase was for very short stays, the largest increase being among children admitted for less than one day.

This presents a challenge, because this is clearly not sustainable, and is not good for the children concerned.  It is now over 50 years since the Platt Report which said, should only be admitted to hospital when "the medical treatment they require cannot be given in other ways without disadvantage."  Ironically, the report goes on to say "This may seem obvious but ...... evidence submitted to us suggests that it is still often overlooked."

What is even more perplexing is that over this same period there has been a strong emphasis upon caring for children in the community; provision of alternative methods of getting health care advice such as NHS Direct, the introduction of Children's Centres, and the publication of guidelines such as the NICE Fever Guidelines.

The authors give a long list of possible reasons for this increase.  These seem to fall into 3 categories:

• Social - parents are less able or willing to look after children at home; or their threshold for seeking hospital advice is lower.
• Clinical - more children are being sent to hospital by NHS Direct/GPs; hospitals are not as good at triaging as they were; or practice is becoming more defensive, leading to more children being admitted to be on the safe side
• Organisational - admitting children to avoid breaching A&E targets by observing for longer; changes in contracts and financial incentives that reward admission.

Positives are that the increase in shorter stays may be party due to the fact that we discharge quicker.  That is about it for the positives!

Whatever the reason, this is not good and we must find a way of changing this trend.  One example of innovative thinking is the Traffic Light contained within the NICE Fever Guidelines which splits symptoms into categories (red, amber, green) which is designed to help divide symptoms into those indicative of high; low and intermediate risk of serious illness.  More is needed.  This may be an area where pharmaceutical companies can help, using their marketing expertise to produce quality parent friendly information.

How accurate are the doses of medicines given to children?

An interesting letter in Archives of Disease in Childhood published online ahead of print publication goes some way to answering that very question, and the answer is, in many cases not very.

An audit of children's wards at two hospitals in England looked at the doses of liquid medicines that were prescribed, and how easy these were to give using the syringes available on the ward.  For example, one 1.48 mg dose of morphine which came in a concentration of 10 mg/mL should have been 1.48 mL - a dose that was not possible to give accurately with either a 1 mL or 2.5 mL syringe, requiring either rounding up/down, or the use of two syringes.

Across all of the drugs given 34% of antimicrobials, 25% of analgesics; 11% of steroids and 5% of sedatives were not accurately measurable using the syringes available.  This leads to two issues:

1. The technical issue of whether an unmeasurable dose that is rounded up/down, and so which is  not really correct, is a prescribed wrongly or administered wrongly.  In crude terms 'whose fault is it?' (in a no blame, new open NHS kind of way).
2. Secondly, and of course much more important, is does it matter?  That depends on many things, the child; the dose; the amount of the rounding; other medicines that the child may be on....the list could go on and on.  Also when rounding up, do you round up to the line on the syringe, go half way through it, or go to the top of the line?

The other interesting thing that the authors speculate on is if it is like this in hospital, what might be going on in homes?   To this I would add the issue of crushed tablets; never recommended but it probably still goes on.

Does it matter?  Probably not in most cases, but the authors do conclude that research into the clinical implications of this would be helpful.  Probably the most important thing is not the variation per se, but the judgement of those giving the medicines.  The dangerous people are those who don't know what they don't know.