Tuesday, 31 July 2012

25% of the British Olympic Team Have Asthma


Asthma UK has taken the opportunity provided by the London Olympics 2012 to highlight the fact that a very large proportion of the Team GB have asthma - including the biggest and most highly achieving stars such as the first British Tour de France winner and the holder of six Olympic medals (3 gold)  Bradley Wiggins and dual Olympic Champion swimmer Rebecca Adlington.

Bradley is quoted as saying:
'It's only a hindrance if you make it one - it does sound quite bad if you are diagnosed with asthma and your natural instinct is to think that's it. But there is better medicine available now and I am an Olympic champion - the evidence is out there that you can succeed.'
It is certainly encouraging that if managed properly people suffering from many types of asthma can lead highly active lives, even as world class athletes.

It is also worth noting that some people living with asthma suffer from severe forms of asthma that are highly prone to serious attacks of breathing difficulty, and that 1200 die every year from asthma. How can some people suffer so much when others lead full lives?

There are some hints in the Asthma UK article as it points out air pollutants can aggravate asthma for many people and adversely affect the performance of athletes - it is certainly encouraging that despite that possibility many attain the highest status in their sports, even those that spend long hours on roads where pollution might be expected to be higher than the average!

There are also studies that strongly hint that there is a role played out by Aspergillus and some other fungi in making asthma more severe. Treatment with antifungal medication may improve symptoms and can improve the quality of life for many patients - we do not know if any of our athletes are prone to severe asthma but if they or their relatives are sensitive to fungi it might be worth suggesting to their doctors.

References

Chishimba L, Niven RM, Cooley J, Denning DW. Asthma. 2012 May;49(4):423-33. Epub 2012 Mar 2.

Knutsen AP, Bush RK, Demain JG, Denning DW, Dixit A, Fairs A, Greenberger PA, Kariuki B, Kita H, Kurup VP, Moss RB, Niven RM, Pashley CH, Slavin RG, Vijay HM, Wardlaw AJ. 
J Allergy Clin Immunol. 2012 Feb;129(2):280-91; quiz 292-3. Review.

Agarwal R. Curr Allergy Asthma Rep. 2011 Oct;11(5):403-13. Review.

Monday, 30 July 2012

Chronic Granulomatous Disorder and Aspergillus nidulans - the Odd Couple

A granuloma as seen using a microscope -
darker dots are the nuclei of cells
Chronic Granulomatous Disorder (CGD) is an inherited disorder of the immune system effecting a specific part of the the immune system - rendering individuals that suffer from this unable to produce a group of chemicals (ie. reactive oxygen) that is used by our bodies to attack invading microrganisms such as Aspergillus. As a result infection tends to persist and form granulomas as other cells of the immune system accumulate around the infection in an attempt to prevent it spreading throughout the body.

Although they are mainly vulnerable to Aspergillus fumigatus, intruigingly CGD patients tend to be infected by another species - Aspergillus nidulans. This is unusual as A. nidulans is not a common pathogen elswhere - in fact it almost never infects people other than CGD patients. This is interesting from the point of view of why this happens and may tell us something about the importance of some parts of our bodies immune system in fighting off fungi, but more importantly A. nidulans tend to behave quite aggressively in these patients so needs to be identified and  treated promptly.

Diagnosing aspergillosis can be a slow process as our current tests are quite time consuming, and identifying  which Aspergillus species is infecting is also slow. We desperately need to develop new, faster tests so that we can start treatment as early as possible.

Just as importantly we need to study the interaction between A. nidulans and CGD patients as our current understanding is clearly not complete as we cannot explain why A.nidulans can attack these individuals, so consequently we do no fully understand how our immune systems currently prevent infection by Aspergillus. A better understanding is vital to help us fight infecton. This recent review is aimed at summarising the current evidence and infection model theories in the hope of improving future research in this area.

Wednesday, 25 July 2012

Newsbite: Antifungal Surface Coating Inhibits Growth of Aspergillus

Chitinolytic enzymes produced by Trichoderma asperellum were immobilized on a biodegradable film manufactured with a blend of cashew gum polysaccharide (CGP) and polyvinyl alcohol (PVA), and tested as a fungal growth inhibitor. The presence of T-CWD enzymes immobilized by adsorption or covalent attachment resulted in effective inhibition of fungal growth. Sclerotinia sclerotiorum was the most sensitive organism, followed by Aspergillus niger and Penicillium sp. more...

Computer Program Distinguishes Invasive Aspergillosis From Aspergillus Colonisation

Ghent University Hospital
All of use breathe in the fungus Aspergillus every day as it is plentiful in the air around us, indoor or outdoors. Many people who are vulnerable to infection will be unable to clear their lungs of inhaled Aspergillus spores in the normal way most of us do and instead it will start to grow where it lands in their airways. These people tend to be the critically ill who have major health problems other than Aspergillus infection and are generally resident in hospital for the duration of their illness e.g. people undergoing treatment for some cancers.

At this stage there is limited threat to the health of the patient as the fungus tends to simply grow on the surface of the larger airways and cause no further problems, possibly even clearing up after the patient has sufficiently recovered their immune function. A few patients will not be so lucky and the infection will progress to a fully invasive aspergillosis which needs urgent treatment with antifungal drugs.

There is some suggestion that patients who are at risk should receive antifungal drugs in order to prevent infection - colonisation or invasive - but that is wasteful and expensive and may needlessly expose patients to the many side effects of antifungal drugs, some of which are quite severe. We need a way to tell the difference between patients who have colonised with Aspergillus and those who have a serious invasive infection, and a research group in Belgium (Blot et.al. 2012) has attempted to provide an answer.

The researchers have developed a clinical algorithm using a number of diagnostic criteria using a group of 115 patients with proven aspergillosis with the aim of distinguishing between patients who are colonised and those with invasive infection. The algorithm was tested on a group of more than 500 patients and found to be able to identify which group a patient with an Aspergillus infection fell into with 92% accuracy. Those without an Aspergillus infection had a 62% probability of being correctly identified. In those people where an Aspergillus infection is known to be present this is claimed to be clinically useful - perhaps enabling us to judge far more efficiently which patients need early intervention with antifungal drugs. Given that all time saved will help improve the outcome for the patients this finding could well help us improve the numbers of patients treated successfully.

Thursday, 19 July 2012

Medical Codes Inadequate for Aspergillosis

Such is the importance of defining and controlling the cost of medical treatment we have had to find a way to classify many aspects of our health services into fixed codes. Specific costs can be attached to each code and thus any particular condition can be charged accurately - be it to a private insurer or to a public funded health service.
There are of course other reasons for accurate coding. We can quickly and efficiently gather statistics for each type of diagnosis and treatment and thus quickly get an understanding of prevalence in any country or throughout the parts of the world that use the same coding system. Funding can then be given proportionatly according to demand, demands on funding can be predicted on a national basis and funding allocated after debate - be that on a local or national basis.

Accurate coding can thus make a large contribution to the amount of funding given to a condition - in fact the funding can depend on the coding so if coding is inaccurate or unrepresentative it can have a severe effect on the money available to treat a particular condition - perhaps even the efficacy of the treatment itself especially for conditions where the cost of the drugs used to treat is high.

The value of accurate, consistent coding crossed  national boundaries as they enable like to be compared to like between countries, so there is extensive effort expended to provide clear codes for use by all countries and these are maintained by the World Health Organisation (WHO) in a set of codes referred to as International Classification of Diseases (ICD).
Aspergillosis is a disease that often requires highly expensive drugs to treat. Drug costs can run into several tens of thousands for pounds per year per person, so it is vital that coding is clear, comprehensive and accurate. Unfortunately this does not seem to be the case as yet. A search of ICD codes for aspergillosis reveals a small set of codes:

B44 Aspergillosis
    Incl.: aspergilloma
  • B44.0 Invasive pulmonary aspergillosis
  • B44.1 Other pulmonary aspergillosis
  • B44.2 Tonsillar aspergillosis
  • B44.7 Disseminated aspergillosis
Incl.: Generalized aspergillosis
  • B44.8 Other forms of aspergillosis
  • B44.9 Aspergillosis, unspecified
These codes are neither comprehensive, clear or particularly logical as e.g. Tonsillar aspergillosis is highly unusual and only recently described whereas infection of the sinus' is presumably lumped into the 'other forms' category and is far more common. There is no sign of ABPA. Likewise in the listing for asthma there is no sign of Severe Asthma with Fungal Sensitivity (SAFS) - both of the latter 2 categories are thought to be groups containing tens of thousands of cases.

A significant amount of work is needed to rewrite and reorganise this listing, otherwise these important groups of Aspergillus diseases will be poorly recorded and poorly funded as a consequence.

Using a Yeast to Fight a Mould: The Antifungal Fungus

Growth of Pichia anomala on cereal grains
moistened with water.
The yeast Pichia anomala (a form of Candida pelliculosa) has been under investigation for its ability to drastically cut the amount of aflatoxin produced by Aspergillus flavus. This was noted when it was sprayed onto pistachio nut trees and the amount of aflatoxin fell by up to 97%. It has also been noted to be effective when sprayed onto other crops infected with other fungi.

P. anomala thus seems to be able to inhibit the growth of a range of potentially harmful fungi which is an important finding as many millions of pounds worth of crops are ruined by aflatoxin contamination, not to mention many people going hungry or even having to eat contaminated food.

How does Pichia do this? We know that on plants it can outcompete Aspergillus for food, starving it and preventing growth. There also seems to be evidence that Pichia directly sabotages Aspergillus' ability to generate the energy it needs to live and also attacks its cell wall when both are cultured together in the laboratory, so it can clearly very effectively attack Aspergillus and kill it as well as starve it.

Pichia is a eukaryotic organism as is Aspergillus (as are all fungi) and so in many ways they are very similar to each other, unlike fungi and bacteria which are quite different. When attacking a bacterium a fungus can use a whole variety of targets which will kill a bacterium but not effect the fungus - all it has to do is attack something that a bacterium uses to live or multiply but which is not present in a fungus, so the more differences there are between the two, the more targets we can use to attack the bacterium.
In a way there are similarities with the substances we humans have developed to protect us from bacterial infection as we too are eukaryotic organisms and we use antibiotics that attack bacterial cell walls (structure vitally important to bacteria but which we do not have) amongst other targets in order to treat bacterial infections.

The task of finding differences between two eukaryotic organisms to act as targets for attack is far more difficult as they are far more closely related. There are some differences (e.g. we already have antifungal drugs that attack the fungal cell wall as human cells have no similar structure) but they are in short supply.

How then does Pichia attack its close relative Aspergillus? Both have cell walls so that cannot be the target otherwise Picia would be poisoning itself! The mechanism Picia uses seems to be specific to a few filamentous fungi so may represent a mechanism we can exploit to attack Aspergillus without harming ourselves - in other words these may be targets we can exploit to make new antifungal chemicals and drugs.

Why not use Pichia itself to treat fungal infections, why bother developing expensive drugs? Unfortunately Pichia is a known human pathogen and would cause infections by itself if used directly.

Further research and development is needed but using a fungus to help fight a fungus may well lead to future breakthroughs in the treatment of several serious fungal infections, including aspergillosis.

Monday, 16 July 2012

Undiagnosed Aspergillosis: New Diagnostic Tests Needed

One of the main difficulties we have to overcome for the successful treatment of aspergillosis is to be able to start the treatment as early as possible as once the fungus becomes established it is very difficult to control even with our newest antifungal drugs.

The priority for future research proposed by the Fungal Research Trust is for new improved diagnostic tests that can identify an aspergillosis infection quickly and while the infection is in its early stages. If that can be achieved then our arsenal of antifungal drugs can be much more effectively used.

Diagnostic tests are however not the only problem. Aspergillosis is very rare and few doctors see more than one or two cases in their careers - certainly very few will see this kind of invasive aspergillosis in someone who has a fully functional immune system. This lack of experience leads to many diagnoses being missed until    it is too late to effectively treat the infection. One such case has been recorded in Great Yarmouth in the UK and here the doctors handling the case admit to never having seen such a case before, but encouragingly mention that they did a lot of learning while treating the patient.

Aspergillosis is rare, difficult to diagnose as it resembles other far more common types of infection and always likely to catch an unaware doctor out with terrible consequences. The Fungal Research Trust provide full details on all types of aspergillosis on the Aspergillus & Aspergillosis Website and is actively engaged on increasing awareness amongst doctors and patients. Patients are one route through which many doctors have  'discovered' and learned about aspergillosis too!

Aspergillus Webite
Aspergillosis Patients Support

Friday, 13 July 2012

The Taming of Aspergillus

Many species of Aspergillus are potential pathogens to man & animals. Many more provoke allergic reactions and cause severe discomfort. How then was a species isolated 7-9000 years ago and has been in use ever since to help make food?

Aspergillus oryzae
 Aspergillus oryzae doesn't exist in the wild. It is an entirely domesticated little beast that has none of the dangerous habits of its close cousins - rather like our domesticated dogs and cats. An isolate of Aspergillus flavus was taken from the wild, probably chosen for its inability to produce mycotoxins, and was fed a rich diet of starch on which it has existed ever since.

Once a micro-organism starts to grow on a single food source it immediately starts to adapt so as to more efficiently use that food - it is driven to do so via natural selection as any strains that develop to grow faster or more efficiently will quickly overgrow less well developed strains.
Of course man has probably offered a helping hand along the way by actively choosing the best strains for his purposes. After 9000 years of this the only strain left is highly adapted to that one food source.

Scientists have now taken a close look at the genome of 'tame' A. oryzae in an attempt to discover how it differs from the wild species it is descended from (A. flavus) and what changes have happened to optimise its use of starch and how efficiently it produces sugars. This may well give us clues on how to best alter other similar fungi to perform better in other industrial processes.

Thursday, 12 July 2012

Newsbite: Everyone has a preexisting condition for something. They just don’t know it yet.

Debate at the Cold Spring Harbour Laboratories on genome ethics:
The scientists listed several ways in which the entry of personal genome sequencing into medical practice could reduce the costs of healthcare. But this optimism was tempered by caution: economic benefits would manifest only if this process were carefully regulated and patient rights were firmly in place. The scientists emphasized the high-stakes nature of the national debates that are sure to spring up as we as a society move further into the personal genome era.  more...

Wednesday, 11 July 2012

Nine New Aspergillus Species Identified

Aspergillus and Penicillium species
It turns out that what we were calling species Aspergillus versicolor is in fact a collection of very closely related but distinct species. A recent paper describes the molecular techniques that were used to define the new species. The nine new species names are Aspergillus austroafricanus, A. creber, A. , cvjetkovicii, A. fructus, A. jensenii, A. puulaauensis, A. subversicolor, A. tennesseensis and A. venenatus, based on differences in their gene sequences. This collection of species will now be referred to as Aspergillus section Versicolores (note the capital V!).

It is probably correct to state that this will not be the last time we define new species from what we currently refer to as a single species as the original specification of fungal species were based on microscopic examination of what the fungus looked like when growing under standard conditions (often more than one set of standard conditions) - a largely artificial classification when the difference in appearance can be small. 

Once we start comparing at the precise features of the DNA of strains originally identified as belonging to one species we are already working with much more information with which to classify the fungi, the main difficulty now may be deciding which genetic differences to use to define species as there may be many.

This is a steadily ongoing process and the numbers of species are steadily growing (currently standing at 955) - in 2001 Aspergillus section Flavi was designed to contain several of the species Aspergillus flavus and there are several more groupings. There have been several attempts to rationalise the taxonomy of Aspergillus in the past and such is the complexity it is still a subject for debate and attempts to set out commonly accepted rules to define a species - see the Polyphasic approach described at a recent Advances Against Aspergillosis Conference in 2008.

For the most recent information on Aspergillus species refer to http://www.mycobank.org/

Also see http://www.aspergilluspenicillium.org/ as it continues to develop

Tuesday, 10 July 2012

Undiagnosed Aspergillosis Man 'Looked Like He Had Been Shot!'

Following on from an earlier story in this blog that mentioned the dangers of undiagnosed aspergillosis from an initial tuberculosis infection the evidence given in the Coroner's hearing reveals that when police first arrived at the scene they assumed that the victim had been shot.

Why?

If pulmonary aspergillosis is not diagnosed and effectively treated one of the most severe symptoms is haemptysis or bleeding from the lungs caused by erosion of major blood vessels by the growing fungus. Effective treatment limits the amount of bleeding by slowing fungal growth and by controlling the severity of bleeding using a variety of techniques to help block off areas prone to bleeding - there is even some evidence that some antifungal drugs have a direct effect on the formation of new blood vessels in the area of infection (angiogenesis) and thus also help to limit bleeding.

The bacterium that causes tuberculosis (Mycobacterium tuberculosis)
Untreated aspergillosis (estimates say that 2% of people diagnosed with tuberculosis may suffer from aspergillosis) looks to be a lot more common that previously thought. We need to increase awareness of this possibility and to provide appropriate diagnostic techniques & experience and then provide effective treatment to help prevent more cases like this dreadful death.

Why is this not done? Up until the very recent research carried out at The National Aspergillosis Centre (NAC), Manchester, UK we simply didn't know that large groups such as TB could be at such high risk. Medication used to be very expensive but now this is much less of an issue as itraconazole has become available from a variety of sources at a much lower cost than that it was previously available for.

The presence of the National Aspergillosis Centre serves to focus attention on this illness and staff are seeking it out everywhere it can be found! The NAC is the first centre of expertise exclusively available to fight this disease and is actively raising awareness and advising medical colleagues all over the world.

Friday, 6 July 2012

UK to be a Centre for Renewable Chemicals Using Aspergillus

The UK is investing £2.5 million into the development of a research unit to develop ways to recycle industrial waste and waste plant materials and turn it into useful chemicals and fuels (i.e. green chemicals) that will become increasingly important as the supply of oil begins to run out.

The Biorenewables Development Centre (BDC) at The University of York state on their website
The BDC offers a unique combination of internationally recognized analytical science, fast track plant breeding and novel extraction and processing technologies. Focused on business needs, we bridge the gap between laboratory development and commercial manufacture by providing open access scale-up processing facilities
Examples of their projects show how diverse the solutions offered can be:

  1. Aspergillus niger can grow on a wide range of industrial waste products, using it as food. The unit are  analysing the full genome of Aspergillus niger (already well used in industry) using computers to predict the best metabolic pathways to exploit to improve efficiency of the production of the many products already made using A. niger. Once this has been achieved they will try to generate new strains of the fungus to more accurately suit the range of different purposes it can be put to, and improve the efficiency with which it can turn waste into valuable commercial products.
  2. Use of high throughput generation and testing of new strains of the plant  Artemisia annua they have markedly increased the yield of the antimalarial drug that the plant makes naturally, helping developing countries fight malaria
  3. Treating discarded orange peel to release useful commercial chemicals instead of just dumping them in landfill waste sites
The UK government hope that projects such as this will help UK industry become a world leader in this rapidly developing future marketplace, and help reduce the amount of waste we currently throw away (industrial waste, food waste) leading to a better balanced environment - ultimately perhaps even replacing our current reliance on fossil fuels such as oil.

Jens Frisvad Given Award for work on Aspergillus

Agilent Technologies has presented its latest Thought Leader award to Jens Frisvad and the Center for Microbial Biotechnology at the Technical University of Denmark. The award will provide the Center with a LC-QTOF system for discovery metabolomics and a LC-QQQ system for target screening, which Frisvad will use to investigate the metabolites produced by fungal molds such as AspergillusPenicillium and Fusarium that commonly contaminate food.  more...

Wednesday, 4 July 2012

Newsbite: Advances Against Aspergillosis 5 - a review

The Advances Against Aspergillosis meeting is the only meeting dedicated to all aspects of diagnosing and treating aspergillosis. Highlights of the last meeting (January 2012) have been proposed in a new report by the European Confederation of Medical Mycology (ECMM) more...

Tuesday, 3 July 2012

Patients Not Taking Their Daily Medication costs US $300 billion

The treatment of aspergillosis often involves the use of antifungal medication and long term use of steroids. The use of both can cause severe side effects that can change the life of the person taking the drug, though at the same time it usually effectively treats the infection or respiratory problems they are design to work on.

Some particularly unlucky patients can have side effects that are impossible to live with and then a change is often recommended if available. Others have side effects that they just have to live with if they are to have their illness effectively controlled, as sometimes there is no alternative.

It is not surprising given the severity of some of these side effects that some patients stop taking them, or reduce their dose by taking the drug less often than recommended. Some even stop taking the drug altogether without informing their doctor. This can have severe consequences for the patient. After a short lived boost to their quality of life as the side effects recede the patient then becomes increasingly exposed to the even more severe long term consequences of the illness they were being treated for.

Although there is no doubt that the patients experiences the worst of the consequences of their decision to stop medication there are other broader implications. Failing to take a drug for a chronic condition can lead to earlier and more frequent hospitalisation and earlier nursing home requirements. Putting aside the argument that this means a hospital bed or nursing home placement is needlessly filled (blocking others) there is the question of all the extra expense needed. A recent report suggests that the cost in the US could be as high as $300 billion a year (!!), suggesting that there are extremely significant savings that could be made in the UK NHS too.

How big is this problem? This is perhaps the most shocking statistic of all - of those people given drugs to treat chronic illness in the US 50% don't take their medication as prescribed.
Researchers are working to find ways to identify those patients who are most likely to not take their medication and thus be able to target ways to assist them and reduce this massive problem.

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