Monday, 20 December 2010

Are We Going to Run Out of Antibiotics??

Antibiotics have been the mainstay of treatment for bacterial infections for 60 years, a time before which it was routine to have to have a hospital stay to treat a bacterial infection. We have several generations of patients and doctors who have grown up assuming that bacterial infections are trivial as there will always be a cheap, safe, accessible packet of capsules that cause few side effects and have very low toxicity which will quickly bring the infection under control & eradicate it.

But this is gradually changing. Bacteria are fighting back, becoming resistant to antibiotics in larger numbers every year. Many old antibiotics are now useless and the usefulness of enough of the more modern drugs is threatened by the rise of resistance. There are several reasons for this trend but the outcome is clear - we must reserve the most recently developed antibiotics for only the most necessary applications to try to delay the development of resistance to them as long as possible.

In addition we need to develop new antibacterial drugs and keep on developing them to prevent the supply of effective antibiotics running dry. But there is a snag - antibiotics are cheap so there is minimal profit to be made out of them. Secondly in the last paragraph we have just discussed why new antibiotics must be used minimally, at least at first. As far as drug companies are concerned this is a 'double whammy' as they can neither charge enough money or sell enough product to raise enough to pay back the investment it needs to make to develop a new drug. In its latest newsletter the Infectious Diseases Society of America (IDSA) mentions that only five of the 13 largest drug development companies are still searching for new antibiotics, suggesting that they prefer to invest in the development of more lucrative drugs.

This situation has now got so serious the US government are introducing new legislation to try to increase financial incentives for antibiotic development (Generating Antibiotic Incentives Now Act of 2010) by extending the time a company has rights to stop any other company reproducing a new drug (and thus reducing the profit) by 5 years. In practice this could mean a 40-50% increase in the time the company that made the original investment in the new antibiotic has to make money out of it. Hopefully this will make a substantial difference, however IDSA and partners are pushing the government to go further, lobbying for the need for 10 new antifungal drugs by 2020


Detailed article

Tuesday, 14 December 2010

Deaths caused by Tragic Error in Dosage of an Antifungal

Paul Richards was undergoing treatment for a fungal infection at Birmingham Heartlands Hospital in UK and was receiving one of the more recent formulations of Amphotericin, an antifungal that has been in use for many years. The new formulations (Ambisome and Abelcet) are much less toxic than the original formulation (Fungizone) and as such are often given in much higher doses, 3-5mg per kg of patient weight. Fungizone has a maximum dose of 1.25mg per kg.

In this incident an inexperienced doctor who was new to the hospital had apparently been instructed to administer the patient his antifungal medication. The information presented on the patient's chart led the doctor to understand that they were to give Fungizone when in fact the intended drug was one of the more modern formulations. Presumably the chart gave the dose as 5mg/kg.
More established staff members understood what was required but this doctor was new and did not come to the same conclusion. The confusion led to Paul Richards and another patient being given Fungizone at 5mg/kg, both of whom subsequently died.

This tragic story illustrates the consequence of a series of small errors and contributing factors adding up to a huge error: including:
  1. The doctor was new and was not familiar with the convention on that ward
  2. Senior nursing staff failed to notice the error or inform the doctor of the convention
  3. The doctor failed to read the notes supplied with the drug that warned of the maximum safe dose
  4. Labelling of the chart was inaccurate
 The article in the British Medical Journal made the following points:
In a report on patient safety alerts published last August, the charity Action against Medical Accidents (AvMA), said an alert in March 2007, Promoting Safer Use of Injectable Medicines, might have saved Mr Richards’s life but 104 trusts had still not implemented it nearly two years after the deadline set.
After his death the National Patient Safety Agency issued a rapid response alert on the safer use of amphotericin to all NHS trusts in September 2007. But AvMA research published in February 2010 found that 10 NHS trusts had still not implemented it.

Monday, 13 December 2010

Abby Beats Serious Acute Aspergillosis and Leads a Normal Life

In 1999 leukemia patient Abby Rosen received news that was difficult to take, she had developed an invasive aspergillus infection that had spread to her brain. The infection was so serious that she had to endure the removal of part of her skull (craniectomy) to prevent damage caused by swelling of her brain - it essentially gives the swollen tissue somewhere to go to and prevents the brain tissue being crushed by the buildup of pressure.
Treatment for leukemia causes a severe reduction in the effectiveness of the patients' immune system until it recovers from the first stage of chemotherapy treatment. This gives infectious agents including aspergillus fungi a 'window of opportunity' that they are more than happy to climb through.
Bacterial infections are common in this situation but antibiotic treatments are so effective and plentiful these do not normally cause too much of a problem. Fungal infections such as aspergillus are a different story.

Fungal infections have to be treated using one of a limited number of antifungal drugs. Some of these are quite toxic and cannot be used for some patients e.g. those with impaired kidney or liver function. This cuts the choice down further. More modern antifungals tend to be very expensive which can make then unattractive to use! On top of all this there is difficulty getting antifungals into the brain as there is a blood/brain barrier that prevents easy passage of drugs into the brain. How do fungi cross this barrier? It isn't really known for sure but one possibility is that it simply grows across it using the ability of its hyphae to 'push' through tissue.

All of this sounds like there is no hope, surely any patient faced with these odds might as well give up?! The happy answer is NO not at all. 12 years after suffering from cancer and this major infection Abby is back at work as an accountant and has been for the last 6 years. Thanks to the treatment she received she  recovered, regaining so much of what was lost that on November 21st 2010 Abby was married to Andy and has spent the last few weeks on honeymoon in Hawaii.

Abby's mum Sandra commented:
When my husband first contacted Dr. Denning in 1999 and he told him about a five year old boy that had survived aspergillus that was a great deal of encouragement for me. I hope Abby's story of hope and success will help other families who are in need of that encouragement. It is an amazing story to be told.
I have to say that it was a long journey to get to where she is today. One can't imagine how delighted we all are that she is with us and how much progress she has made after her brain injury.  She is still improving daily. There definitely is a life after cancer and a brain injury.
I don't think there is anything to add to that!

Wednesday, 8 December 2010

Clinical trial examines intravenous micafungin versus voriconazole for chronic pulmonary aspergillosis

The chronic form of aspergillosis is a slowly progressive lung illness caused by Aspergillus infection. There have been many clinical case reports on the treatment of CPA and also a few retrospective studies.
The Infectious Diseases Society of America recommends oral azoles as primary therapy for CPA, but data from large scale clinical trials have not been available.
The use of intravenous antifungal treatment as induction therapy, followed by oral antifungals as a maintenance therapy, have now been trialed in a larger group of CPA patients in Japan (Kohno et al 2010) as reported in the Journal of Infection.
In this drug trial, intravenous micafungin was compared with intravenous voriconazole as induction therapy for 2 weeks in CPA patients needing immediate treatment. A total of 107 patients were studied.
Clinical effectiveness was defined by clinical, mycological, radiological and serological responses.
The study indicated no difference in efficacy between the two IV drugs but fewer adverse effects occurred in the micafungin group than with IV voriconazole. The overall treatment success rate for both drugs was around 60%.

The take home message is that there was not much difference between the efficacy of micafungin and voriconazole intravenously - but the side effects of micafungin were less severe and less frequent - meaning that more patients could be successfully treated with micafungin (IV) as a primary therapy for CPA.

Monday, 29 November 2010

Latest update on Isavuconazole trials


Isavuconazole is a novel, water-soluble, broad spectrum antifungal medicine developed by Basilea. It is available in an intravenous form or orally - with high bio-availability, as a capsule. It is currently undergoing multiple clinical trials - for yeast infections, aspergillus infections, aspergillosis in renally impaired patients and for rarer mould infections.

The pharmaceutical companies Astellas and Basilea have a co-development and co-promotion agreement for a worldwide license - agreed earlier this year.

Pre-clinical and clinical data so far indicated that isavuconazole has the potential to overcome many limitations of current therapies for invasive fungal infections. It has predictable and dose proportional pharmacokinetics - which is important to maintain therapeutic drug levels in patients.

Importantly the IV- dose form has a good potential to be given safely to patients with kidney impairment.

The phase III clinical trial for the treatment of invasive aspergillus infections will be continued as recommended by the Data Safety Monitoring Board based on results from the first 180 patients. Basilea and Astellas have announced a change in the primary endpoint for monitoring the phase III trial (more info here) which will mean that the trial will need to show that isavuconazole is actually saving lives instead of just improving clinical symptoms- when compared to first line treatment - in this case voriconazole. Basilea states that this change will not impact on the trial's timeline, which should be complete by early 2011 with results due in 2013. Isavuconazole has been fast tracked in the US by the FDA.

Thursday, 25 November 2010

Advice for people with asthma as temperatures set to plummet

Asthma UK is today urging people with asthma to prepare themselves for the extreme cold weather as Britain braces itself for temperatures reaching as low as -5C this week.

Cold weather can have a severe impact on the 5.4 million people with asthma in the UK. Three quarters of people with asthma tell us that cold air is a trigger for their symptoms and 90% highlighted that having a cold or flu makes their asthma considerably worse.

Cher Piddock, lead nurse for Asthma UK says: ‘Hospital admissions for asthma traditionally peak during periods of particularly cold weather. This can be due to breathing cold air into the lungs which can in turn trigger asthma, as well as picking up colds and flu.

‘People whose asthma is well-controlled are more likely to be able to withstand the dangers of winter months and you can help keep your asthma under control by making sure you have a regular asthma review with your doctor or asthma nurse and that you have a personal asthma action plan. This is a plan which should be completed by your doctor or asthma nurse in discussion with you, and contains the information you need to manage your asthma, including information about your medicines, key things to tell you when your asthma is getting worse and what you should do about it, as well as emergency information on what to do if you have an asthma attack.’

To help minimise the need to go to hospital during this cold spell, Asthma UK is offering the following important advice about how to control asthma symptoms during the cold weather.

5 tips for keeping asthma at bay as the weather gets colder
Asthma UK recommends:

  1. Keep taking your regular preventer medicines as prescribed by your doctor
  2. If you know that cold air triggers your asthma, take one or two puffs of your reliever inhaler before going outside
  3. Keep your blue reliever inhaler with you at all times
  4. Wrap up well and wear a scarf over your nose and mouth – this will help to warm up the air before you breathe it in
  5. Take extra care when exercising in cold weather. Warm up for 10–15 minutes and take one or two puffs of your reliever inhaler before you start.

You might be having an asthma attack if: you are coughing more than usual, experiencing shortness of breath, wheezing, feeling tightness in the chest, having difficulty speaking in full sentences

The steps to take if you are having an asthma attack:

  • Keep calm – do not panic
  • Sit down and try to take slow steady breaths
  • Take one or two puffs of your reliever inhaler (usually blue), immediately

If there is no improvement – Continue to take two puffs of your reliever inhaler every two minutes. You should take up to ten puffs.

Call 999 urgently if:
  • your symptoms do not improve in 5 – 10 minutes
  • you are too breathless to talk
  • you are worried at any time

If an ambulance does not arrive within 15 minutes, repeat step 3 while you wait.

Even if your symptoms improve and you didn’t need to call 999, you should still see a doctor or asthma nurse within 24 hours.

For more information about managing asthma during the cold months please visit asthma.org.uk or call our dedicated asthma nurse specialists on the Asthma UK Adviceline 0800 121 62 44   

Monday, 22 November 2010

Recreational Divers Need Awareness of Aspergillus

A recent case in the diving world has outlined the lethal perils of not thinking before you breathe & ensuring any air you breathe in is coming from a verified clean source.

Mike Firth was a very accomplished recreational diver who was technically capable of diving to depths of 50m (160 feet) in search of rarely found wrecks to explore - not a feat to be taken lightly unless highly trained with a lot of specialist equipment.

In 2008 he started having breathing problems`following dives with symptoms including hacking cough, shaking and intermittantly raised temperature. After some time this was identified as a huge Aspergillus infection (aspergillosis) of his lungs which soon resulted in him being unable to walk for 25m as he rapidly lost lung function.

He was referred to the National Aspergillosis Centre in Manchester, UK which managed to get some control over his symptoms but it was still something of a mystery how this highly fit & active man could be infected by a fungus that normally only affects those who are heavily immunocompromised.

We know that this type of infection can sometimes occurr in a fully fit person if they directly inhaled huge amounts of fungal spores. These spores are incredibly tiny, some being only 2-3micrometre in diameter and as such can penetrate our lung very deeply, ultimately into the smallest air sacs (alveoli) from where if enough spores are involved our immune systems can sometimes be overwhelmed. A recent case involving a person opening a sac of compost for his garden and being exposed to a cloud of spores was probably a similar situation.

In this situation Mike seems to have inhaled spores when testing past of his equipment was working fully. The Bouyancy Compensation Device (BCD) bladder is not part of the normal breathing apparatus (and thus was not subject to the normal routine of cleaning & sterilizing of all parts that are breathed through) but is used to provide bouyancy while the diver swims - it helps the diver maintain a 'flat' position as he swims through the water by being filled with air.

Mike admitted that he liked the safeguard of being able to take a few breaths from the BSD should his main source of air fail while underwater - it was an emergency measure. For this reason he liked to be sure that the tube it was manually filled and emptied from was clear and unobstructed. Prior to going diving he blew into the tube and also sucked to check it worked in both directions, and indeed it checked out perfectly but he remembered that there was a strange taste.

After he was admitted, researchers at the National Aspergillosis Centre tested and verified that the BCD bladder was infested with Aspergillus - consequently Mike would have breathed in large amounts of Aspergillus spores when he sucked air out of the bladder.

Mike's lungs were so badly damaged that his only chance of a cure would now be a lung transplant. He submitted his story to many Divers publications in order to raise awareness of this serious problem and to try to prevent anyone else suffering the same fate as himself. We do it here for the same reason

Friday, 19 November 2010

Mycotoxins Linked to Low Growth Rate in Children

Scientists in Tanzania, Africa have found that one year old children fed on a staple diet of corn flour-based foods tend to consume levels of the mycotoxin fumonisin above that with is considered to be safe. The fumonisin comes from fungi (principally made by Fusarium but also Aspergillus) growing on the corn as it is grown and stored. The contamination can happen invisibly, giving no clues to the farmer that there is a problem and there is no way for most poor farmers to test his crop for mycotoxins.

Corn is staple food in many parts of the world (around a billion tons are produced annually) and is widely grown in warmer climates, so this problem could be far more widely spread than Africa, though in the developed world storage techniques after harvesting and screening for mycotoxins will help prevent the problem cropping up in those countries.

It is thought that this could be an important reason why many of these children have a low growth rate and is in addition to other possibilities such as poor diet and sanitation. Now this problem has been identified steps can be taken to reduce the levels of fumonisin in corn meal fed to humans and in particular young children.

Fumonisin levels are controllable by improving storage conditions and this can be achieved by greater investment in drying machinery and better education of the farmers.

NICE loses power to ban use of new drugs

Many of the new drugs used to treat aspergillosis are extremely expensive to use. A course of Voriconazole to treat a chronic infection for example could cost £30 000 per year. Naturally this causes significant problems for the funding bodies and a decision must be made on whether the cost is affordable and justifiable.

There are several factors taken in for account prior to this decision being made, but one of the basic decisions that have to be arrived at is whether the cost is justified for a given group of patients as judged by questions on how much improvement they will see in their general condition, symptoms, longevity or quality of life. An important part of the answer to some of these questions are published research that demonstrates the effectiveness of a drug for that group of patients.

Once all the information that can be collected to support a particular drug application has been gathered it has to be sent to the organisation required to make the funding decision. In the UK that responsibility belonged to the National Institute for Clinical Excellence (NICE). This single body was able to pass binding resolutions that banned the purchase of any drugs using NHS funds that it found to be too expensive to use considering the benefit it brought a particular group of patients. As you might imagine many battles were fought by patients groups against NICE each time new evidence of efficacy of a new drug came to light, and the decisions of NICE were often controversial.
Decisions often took years to arrive and now health budgets are falling all round the world it is likely that more controversy will follow. Despite this NICE is used as a model system around the world to control spending on drugs.

The UK government is now proposing to take the power to ban the use of new drugs away from NICE and give it to local funding bodies run by local general doctors (GP's in the UK) who they think will be better suited to deciding which patients groups get new drugs. These groups may well be less remote from patients but they will be bound by the same shortage of money that NICE had to deal with - in fact probably worse! At least patients groups can now appeal to authorities closer to home and some may get funding rather than there being a single blanket ban.

NICE had yet to produce guidelines for the use of antifungals in respiratory infections, or at least I cannot find any on their website. They will apparently continue to work on those documents.

So how are antifungal funded for respiratory infections in the UK? The decisions are already made at a local level, currently by the Primary Care Trust. Funding is allowed in the NHS until such time as NICE guidelines say otherwise - and of course now NICE guidelines will not have the power to ban the use of antifungals for this purpose - perhaps that is good news for some patients as the status quo may continue but not for those patients already waiting for funding as they have had funding refused by their local PCT.

Tuesday, 9 November 2010

Migration of Loon 55482 ended by Aspergillosis

The annual migration of the Common Loon (listen to their call ) is regularly followed by scientist from the Upper Midwest Environmental Centre in Wisconsin, USA. Little is known about their route after they leave their inland breeding lakes with many turning up on the Atlantic shoreline weeks later.
This study is an important part of efforts to care for the welfare of this bird as once it is known where it goes and how long it stays in various places then we can start to take action to reduce the hazards - natural and man made - that these birds come across on their journey.
In order to track these birds nine were given a radio transmitter implant and the re-released. The signal from these implants can be picked up by satellite telemetry and the location of each bird recorded at regular intervals. The locations are presented for each bird here - remarkably viewers can follow the route as the bird migrates.

Unfortunately one bird was tracked to its doom. Loon 55482 was tracked over 500 miles to the shores of Green Bay near Lake Michigan whereupon it stopped moving. It remains were found and a post mortem revealed that it had died of pulmonary aspergillosis.

This is usually a symptom of a bird that has become stressed by lack of food/poor food/exhaustion/cold/age weather as under these condition their immune system tends to work less well and they can become infected - much as happens in humans when their immune system fails. Perhaps in this case exhaustion was a key as it was a member of the group that seems to have migrated the furthest?

Wednesday, 3 November 2010

Regulation of herbal remedies in Europe

April 1st 2011 marks the day when all products sold as herbal remedies or food supplements (including fungi) over the counter in the European Union will have to conform to new regulations. Specifically they will have to have:
  1. Proved to the satisfaction of the regulatory authority that the drug has a beneficial effect
  2. Be provided with full instructions on what specific use the medication is intended for and how to use it
  3. Be proven to have no harmful effects
In other words, herbal remedies will have to pass some of the regulatory checks that 'conventional' drugs have to pass prior to going to market.

There is some opposition to the new regulations as there are large numbers of herbal medications that will have to comply and relatively little time to do so (though the industry has known that this regulation was coming into force since 2004).
Sceptics may say that the herbal industry will not be happy because many of their current medications have no scientific evidence to support their use and little hope of obtaining any proof  because they are either ineffective or testing would cost too much money. They may also argue that many herbs have been in use for thousands of years and thus must work and must be safe otherwise they would no longer be used.

Hard headed scientists would no doubt contend that if a substance cannot be proven to be effective or safe then it has no business being sold by multibillion dollar industries as remedies for a multitude of ills, regardless of their quaint antiquity.

There does still seem to be a way to access otherwise illegal herbalist remedies after April 1st and again this looks like an effort to bring them into line with 'conventional' drugs - these remedies will still be available via qualified herbalist practitioners after consultation with the patient.

From a neutral viewpoint it is difficult to criticise the new regulations. If the remedy has never been tested and proved to be safe & effective then its sale is at best a gamble for the patient. At worst a patient may feel embarrassed about telling their doctor about this untested remedy or feel that because it is marketed as a 'natural' product it must be harmless. They may then experience harmful effects caused by taking it alongside a conventional drug ordered by their doctor.

Once the regulations are in place people will be able  take a herbal remedy with more confidence that it has a proven value and that it is safe on its own and alongside other medications - the remedies move out of the 'housewives cure' category and into the realm of a properly verified treatment.

Tuesday, 26 October 2010

Nanoparticles deliver improved antifungal activity

The hydrophobic nature of many antifungal drugs is problematical for effective drug delivery and absorption in patients.
Considerable research on a drug delivery system based on bio-degradable polymers has been productive in identifying suitable carriers such as the thermoplastic polyesters eg poly(lactide-co-glycolide), which exhibit good biocompatibility and biodegradability alongside mechanical strength. These bio-degradable polymers have been developed into a new type of drug delivery system called nanoparticles - which can be used to deliver a wide range of drug classes including anti cancer drugs, antihypertensive agents and various peptides, proteins, and vaccines.
Last month a publication by Patel et al describes the development of nanoparticles loaded with the hydrophobic antifungal drug - itraconazole.
The particles were characterised for morphology and also for their ability to inhibit growth of Aspergillus flavus. The itraconazole loaded nanoparticles achieved an inhibition of A. flavus growth for an 11 day period at a concentration of 0.03mg/ml or rather 1/100th of the concentration of itraconazole alone (in emulsified form). It is envisioned that the use of nanoparticles loaded with itraconazole increases its bioavailability by improving its dispersion in water and greatly enhances its antifungal activity.
These results are promising for a significant improvement in the delivery of antifungal drugs and hence their efficiency, but more in vivo studies will help to advance this technology.

Another advantage of the nanoparticle technology which will hopefully prove fruitful, is targeting specific organ delivery.
For example the blood brain barrier precludes the transport of many drugs to the brain. However Chen et al published data in June this year that an itraconazole loaded nanoparticle with a special tag on it derived from the rabies virus, allowed transport of the itraconazole into the brain when compared to nanoparticles without the rabies derived tag. The potential for targeting intracranial fungal infections in this way is exciting.

From the perspective of delivering targeted treatment to lung infections -a special type of nanoparticle that penetrates mucus - was reviewed by Lai et al last year. If a nanoparticle/antifungal drug can be developed which avoids the normal rapid mucus clearance mechanisms, the prospect of delivering antifungal drugs right to the site of infection should greatly improve the chances of effective treatment. This approach would be particularly useful for cystic fibrosis patients too.

Tuesday, 19 October 2010

Oral Amphotericin Receives Orphan Drug Status

Amphotericin has long been a highly effective antifungal drug and is still widely used to treat aspergillosis. One of its strengths is that it attacks the cell wall of the fungus in a way that is highly specific to fungi (& insects) so the drug itself is potentially low in toxicity to humans. Most other available antifungal drugs (azoles)  attack the cell membrane but as human cells also have cell membranes there is potential for toxicity to human cells as well as fungal cells. This requires clinicians to carry out careful dose management.

Unfortunately amphotericin has poor solubility in water so cannot be given to patients without dissolving in substances that are fairly toxic to some patients, particularly affecting kidney and liver. This makes this drug tricky to give, requires accurate dose management and cannot be given as a pill or capsule as it will not dissolve in the stomach.

Fortunately there has now been a breakthrough in reformulation of amphotericin which we reported last year. The new drug is referred to as iCo-009. iCo-009 has already been shown to be able to achieve similar drug levels in the blood compared with giving its predecessor by intravenous injection, and there have been only low levels kidney toxicity, albeit in animal tests so far.

We can now report that the development of that drug has received another boost. iCo-009 (iCo Therapeutics) has been awarded orphan drug status by the American drug regulatory body the US Food and Drug Administration (FDA). This status is awarded to drugs that are intended to treat rare diseases and entitles them to extra funding to aid development, so it is great news for this next generation of amphotericin drugs and great news for everyone looking for antifungal drugs with fewer side effects.

Wednesday, 13 October 2010

The Natural Antifungal Properties of Garlic

A recent news story mentions that garlic has many beneficial properties including antifungal, antibacterial, antiparasitic all without damaging our normal microbial flora, stimulates the immune system, clears out the blood vessels, lowers blood cholesterol, cures cancer and more - quite an impressive list. How much of this is true?

Much of it is based on laboratory experiments in test tubes with little or no evidence on its properties when used in humans (wikipedia). In those cases where it has been tested in humans the results are variable e.g. it has been found to be completely non-active in reducing blood cholesterol levels, but has been found to be a useful antiseptic and to alleviate some complications of diabetes - the latter to such an extent that it needs careful monitoring if used alongside some conventional drugs used to treat diabetes.

Is it useful to treat fungal infections, in particular infections by Aspergillus? This research paper from 2007 clearly demonstrates that garlic does have good antifungal activity in the laboratory but again no work is done on humans. Perhaps applying garlic directly to a superficial fungal infection might help but if eaten it seems highly unlikely that the levels used in the laboratory would be reached unless huge amounts of garlic were consumed. There is more bad news - the garlis must be eaten fresh and raw! Not a palatable option for most of us or our nearest & dearest.

This is a case of wait and see. We can look at the substances in garlic that are antifungal and they might provide a clue to a new way to attack fungi. This could lead to the development of new antifungal drugs that could be produced in concentrated (and odour-free) pill form.

Will eating a clove or two a day help prevent fungal infections? Probably not - even if eaten raw there is too little active ingredient when absorbed into our bodies. A clove might weight a few grams and that would be effectively diluted into our bodies that weigh many tens of kilos - a dilution rate of many thousands.

But never mind - it still tastes good!

Wednesday, 6 October 2010

Aspergillus is found to be the predominant organism in a group of paediatric Cystic fibrosis patients

Patients with cystic fibrosis are often susceptible to lung infections. Fibreoptic bronchoscopy (FB) and bronchoalveolar lavage (BAL) are often performed to aid the management of children with cystic fibrosis (CF). A study of a group of CF children ages 0-18 who had FB between 2005-8 in the NE of England, has revealed that 16 out of 45 patients tested positive for Aspergillus fumigatus - either in isolation or in combination with other organisms.
Other organisms such as pseudomonas aeruginosa and haemophilus influenza were isolated from some samples but Aspergillus was the most prevalent organism identified in BAL from these children. Of interest half of those with Aspergillus were also diagnosed with ABPA. (Report from the recent 20th ERS meeting, Davidson et al).
Cystic fibrosis patients generally have a poor response to the antifungal drug itraconazole (and posaconazole) - in part because they lack pancreatic enzymes necessary to absorb fats which are also required for itraconazole absorption; also because CF patients may need to take antacid medicines - acid helps to allow absorption of itraconazole.

A second report from the 20th ERS meeting has studied the pharmacokinetics of oral voriconazole in adult CF patients (Clifton et al ). They showed by monitoring blood levels of voriconazole that the drug was absorbed by the CF patients and blood levels achieved were sufficient for treatment of aspergillus. Two patients had to withdraw due to drug side effects - but they were shown to have high levels of the drug in their blood- underpinning the need to monitor antifungal drug levels for optimal effectiveness.
The study shows that voriconazole can be absorbed by CF patients and may be useful in the treatment of fungal infections in cystic fibrosis.

Friday, 1 October 2010

Promising new approach for rapid diagnosis of Invasive Aspergillosis


Scientists in San Antonio, Texas, presenting at the recent 5oth ICAAC conference in Boston, have been investigating a new approach looking at secreted proteases from Aspergillus fumigatus, hoping to find a more rapid diagnosis of invasive aspergillosis (IA). The A. fumigatus genome secretes nearly 100 proteases many of which are secreted in vivo during infection.

By designing fluorogenically labelled substrates for these enzymes - the protease activity in either the serum or broncheolar lavage fluid can be tested in infected patients, using the unique thermotolerance of Aspergillus proteases to distinguish them from host proteases.


The technique requires the identification of fungus specific substrates which were identified using a library of fluorescent probe/substrates in comparison with human serum. The tests were carried out in a guinea pig model of invasive aspergillus where a number of substrate probes proved specific for the A. fumigatus proteases at temperatures up to 50C.
The next stage of the work will be to identify which labelled substrates may be specifically broken down by fungal proteases during infection - these would be promising diagnostic candidates.

Fluorogenic probes have already been used successfully to image protease activity in oncology and in inflammation, if successful this paves the way for alternative methods for rapid diagnosis of IA and potentially for following the progress of treatment as well.

(Report from Abstract M1819 from 50th ICAAC by D Watson et al. 2010)

Wednesday, 29 September 2010

New Research to Help Identify Targets for New Antifungals

One of the first requirements to begin development of a new antifungal drug is to identify what target the drug will be aimed at. The target must be specific and not exist in human cells so that the drug does not affect the patient, and it must be effective in that it must attack part of the fungus that is vital for its growth.
Currently we have a series of antifungal drugs that fall into three broad categories,
  • those that target the cell wall (something that does not exist in mammals) that the fungus relies on for physical cell integrity e.g. echinocandins: caspofungin, micafungin, and anidulafungin. These tend to be very safe and have fewer side effects.
  • those that target the cell membrane e.g. amphotericin B, azoles (Itraconazole, voriconazole, posaconazole etc). Mammalian (including human)  cells have a cell membrane so this is a less specific target. These drugs target chemicals (ergosterols) that are far more plentiful in fungal cell membranes than they are in mammalian cell membranes so fungi are hit a lot harder than mammalian cells by these drugs. Consequently these drugs are effective at tackling fungal infections but do become toxic to humans if the dose is too high - a lot of care is taken with the use of these drugs to ensure dose is optimised and side effects are minimised. 
  • those that target DNA/RNA synthesis e.g. flucytosine. Mammalian cells make extensive use of DNA & RNA so this drug lacks specificity. Difficult to use.
Clearly the best existing target in terms of specificity is the cell wall. In this news report it states that this research group have just announced the $1.5 million funding of new research into drugs that will act on a component of the construction of cell walls (UDP-galactopyranose mutase) in fungi with the aim of disrupting the process and thus making it very difficult for the fungus to make its own cell wall and grow normally. This particular target has not been utilised for antifungal drugs before now and we already know that if the gene for UDP-galactopyranose mutase is knocked out by genetic manupulation the ability of Aspergillus fumigatus to infect mammals is significantly impaired (reduced virulence) so it is likely that inhibiting its activity using a new drug will inhibit infection.

Galactofuranose (the chemical made by UDP-galactopyranose mutase) is extensively used by A. fumigatus and is already being  investigated as a molecule we could use to detect infection by this fungal pathogen, so further research into this molecule has the potential to improve diagnosis, detection and treatment of A. fumigatus infections.

The prospects for this antifungal target look good though of course there are many hurdles to overcome yet, but this is certainly one of the possibilities for improving the treatment of fungal infections, possibly serious fungal infections caused by Aspergillus fumigatus.

References
Characterization of recombinant UDP-galactopyranose mutase from Aspergillus fumigatus
Targeted Gene Deletion of
Leishmania major UDP-galactopyranose Mutase Leads to Attenuated Virulence

Thursday, 23 September 2010

Aspergillus Genomics and Metabolic Pathways - AsperCyc

Genomics is the study of the  effect of genes and gene expression on the entire genome. Originating in the1970's the huge advances in DNA sequencing techniques, in particular sequencing carried out by robots in the last 10 years or so at huge dedicated centres has led to large numbers of organisms having their entire genomes sequenced, including humans.
There are thousands of bacteria and virus genomes sequenced as they are small and simple in terms of genome size. It is a far larger task to sequence the genome of fungi, plants and animals - collectively referred to as eukaryotes - so fewer of these have been sequenced but even there the process is accelerating.

We have sequence information for the whole genomes of at least 9 species of Aspergillus (CADRE and aspGD) with many more planned. This means that we have access to the entire book of life for each species, each consisting of 7 or 8 volumes and a total of 30 million 'letters' (base pairs) or 10 million 'words' (codons). To give you an idea of how big that is, the combined plays of Shakespeare number 39 in all with a total of less than 1 million words. The Bible totals less than 600 000 words. We are storing enough information to fill 150 Bibles 0r 100 collections of the plays of Shakespeare!

Just as books looked at word by word are less informative that when we read whole pages, codons are not particularly informative unless we can link them together into functional genes. Aspergillus codons form nearly 30 000 genes of which 10 000 are known to be in use - already we have a big piece of information that we could only guess at before genome sequencing. 20 years ago scientists would have looked at an expressing gene, cut it out of the genome, sequenced it and characterised its expression. All of that could have taken several years to complete. Even then we would have only gathered information about that particular gene and often only the parts of the gene that are actually expressed - little was known about how neighbouring DNA sequences influence the expression of that gene.

Now we already have all of the gene information we need for every gene in an organism and it is stored in the context that it is stored in in our cells so we can look at all of the sequences either side of the gene - and this is all at the tips of our fingers in freely available computer databases. We can now look for sequences either side of a gene that are known to control the expression of similar genes, we can locate unique sequences and extract whole genes for examination very quickly, and we can even construct genes completely artificially if we need to - this is technology beyond the wildest dreams of 30 years ago  which along with other similarly revolutionary techniques is massively speeding up the accumulation of knowledge.

Massively important though all this is, we have still only begun to look at single pages in the genome 'book', much more information is available. Single genes are only capable of one function each. Most of the substances that our cells make that enable us to stay alive are complex and are built up from other materials. Substrates have to be broken down and then rebuilt into a useful form and no gene is capable of doing that on its own. Several, sometimes dozens of genes must be expressed and their products utilised sequentially, each one providing the means for another step in pathways that can be many steps long. These are known as Metabolic Pathways.

Genome information and pathway information are currently in the process of being put together for each sequenced organism (MetaCyc, BioCyc). This is the equivalent af starting to put the pages of our genome 'book' together into chapters. We are helping this process for Aspergillus by the introduction of AsperCyc. So far we are largely relying on computers identifying potential pathways as there is such a huge amount of data to be processed but there is a slow process of manual curation ongoing where a human will cross check what the computer has decided with what is known through published papers.

This is the next step in the ultimate dream of being able to give a computer a genome sequence (or even some DNA) and then stand back as it detects the genes, assesses their potential for expression, assigns them to pathways, and then runs a full simulation of how all of the genes interact with each other to form a living cell. We could then introduce changes to gene expression and watch the consequences, discover new drug targetsand ultimately test new drugs. To continue the analogy we would be reading the whole genome 'book' and analysing the full meaning of the contents. This could have innumerable benefits, for example if someone has a genetic disorder we would be able to work out how to counter the effects of the mutation as we would have a full picture of all of the effects of that disorder presented to us by the computer.

There is some way to go yet but progress is being made and computer power is getting cheaper all the time - adopt an optimistic attitude it is not too difficult to see a positive conclusion!

Tuesday, 21 September 2010

Be Aware of the Risks of Inhaling Cannabis

Recent reports show that the number of cannabis farms in the UK may well be on the rise with twice as many detected and closed down in 2009/10 compared with 2007/8 according to a report from the Association of Chief Police Officers in the UK.
Increase in production is not something restricted to the UK as rises in production are also reported in Mexico with detection rates also on the rise in the US.

In the face of these increases in supply and presumably use it is worth making the point again that plant material such as marijuana is an excellent food source for fungi such as Aspergillus. Once cut the material must be dried rapidly and consistently to a very low moisture level to avoid it becoming mouldy. Once dried it must be stored in completely dry conditions to prevent it becoming damp and once again quickly becoming mouldy.
Storing marijuana or any other plant material in small sealed containers or wrapped in plastic will only help if the material is completely dry in the first place, otherwise you are effectively locking the mould in with its own supply of food and water whereupon it will flourish. Mould does not need light or much heat to grow.

Once it has run out of food it will sporulate, emitting billions of tiny spores that are small enough to float on the slightest draught of air. If this material were to be wrapped up in a paper tube or placed in a pipe, one end lit and inhaled then billions of spores would very easily penetrate the lungs of the smoker to its deepest depths as they are small enough to spread to the smallest air pockets in the lungs.

 Even if the smoker has a completely normal immune system it would only be able to clear so many spores in a given time. If they have any pre-existing debris or scar tissue in their lungs the spores may well be able to evade the immune system and start to grow in a similar way that the bacteria that cause tuberculosis (Tb) grow and cause cavities in the lung. Tuberculosis can be treated successfully using strong antibiotics. Deep infections by Aspergillus are far harder to eradicate and tend to become chronic infections, even with all the latest antifungal medication attacking it - the marijuana smoker is more likely to have lifelong infections that become highly debilitating.

Marijuana is a special case as it is produced and stored under a wide variety of conditions. The material you purchase is of unknown origin so its mould status is unknown. Checking its dryness on delivery is no guide to how quickly it has been dried and thus no guide to how many spores it may carry. Needless to say there is no official monitoring system controlling the quality of the supply.

Aspergillus can be black, green, brown, white, yellow or blue in colour - it is all bad and you will not necessarily be able to see it at all. Picking a few bits of mould off the material makes no difference. If you inhale in the form of a cigarette you are inhaling smoke from the burning tip through an entire tube of mouldy material - it will not be sterilised.

Breathe this material in at your own risk in full knowledge of the potential hazards.

Tuesday, 14 September 2010

Mouldy Films Can Project More Than Movies

An examination of old film stock by members of the Dept Biology, Chemistry and Health Science at Manchester Metropolitan University has revealed something more sinister than damaged movie footage. If the film is subjected to a 'mock projection' it can release enough spores into the air than is safe for the person working with the film to breathe in.

The team at Manchester Metropolitan University (MMU), headed by Professor Joanna Verran recently reported their finding to the Society for General Microbiology autumn meeting (September 2010). Research student Gavin Bingley presented his work describing how they collected a range of contaminated film from archives at the North West Film Archive and the British Film Institute National Archives and subjected the film to mock inspections, much as an archivist would carry out with a view to assessing the film for further preservation work. On the worst affected films the levels of spores released during this process where considered to be dangerous to health - Aspergillus was a common fungus found and is a known allergen & pathogen..

Traditionally photographic film is largely made out of cellulose & gelatin and as such is vulnerable to microbial attack if not stored correctly. Any damp getting into the film stock can quickly lead to fungal growth as the gelatin makes an excellent food source. Older films are thus actively collected and assessed for damage. Many (most) have already been lost and many techniques have been developed to halt this loss with a lot of resources now going into preserving what is left, hopefully forever.

The MMU group are working to assist the safe continuation of this valuable work by developing a sensor that will indicate if viable mould is present in a can of film and thus signal to the person handling the film whether or not it is safe to open the can without taking further precautions e.g. using an airflow hood to suck spores away from the person concerned and face masks designed to prevent inhalation of mould spores.

Of course even if there is no viable fungal material present then there could still be dead fungal matter that could be released into the air and could still cause allergy problems, so an assessment of the past state of the film is also important from the point of view of the health of the people working on the film. The MMU team are also working on standard recommendations for the safety of people handling mouldy film, viable or not.

Friday, 10 September 2010

Why are some people vulnerable to Aspergillosis?

Acute invasive aspergillosis is mainly a threat to patients who have a severely compromised immune system. By definition they are poor at fighting off infection and thus run a high risk of infection by all micro-organisms, including Aspergillus.

Once of the reasons why people become severely immunocompromised is when they are undergoing a stem cell transplant (HSCT) for the purpose of replacing their entire immune system. This is most often carried out as a treatment for leukaemia or myeloma, cancers of the immune system, and to treat other blood disorders. HSCT requires a donor to contribute the healthy immune cells and requires the complete removal of the recipient's immune cells. This leads to a short period of a few days when the recipient has few immune cells while they wait for the donors cells to start working fully and it is at this time that the infection can occur. Once infected the fungus is difficult to eradicate, even for the rapidly returning immune cells. Some people seem to be more vulnerable to this infection that others and we don't yet know why.

Dectin is known to be important in our immune response to Aspergillus infection, switching on the inflammatory response when exposed to Aspergillus fumigatus spores. Dectin, in common with other genes, has small variations in its DNA code (Single Nuclear Polymorphism - SNP) from person to person. Most SNP's are rare and have small if any detectable effect but some do and there is one in Dectin (named the DECTIN1 Y238X polymorphism) that has a severe effect on the gene.  Theoretically it might be that those people who carry this SNP are more susceptible to fungal infection. If we knew the answer to that question we would be able to screen HSCT recipients and donors for the SNP and reject the donor or take extra steps to reduce the chances of fungal infection if the recipient is effected.

This recent paper has carried out experiments to try to provide answers.
  • It turns out that recipients who carry the Y238X polymorphism have twice the chance of developing invasive aspergillosis up to 36 months post transplant compared with those who do not. 
  • If the donated cells carry the Y238X polymorphism then the recipient has twice the chance of developing invasive aspergillosis
  • If both the recipient and the donor carry the Y238X polymorphism the chances of developing invasive aspergillosis is even higher at 2.5 to 3x those who do not carry the faulty gene.
This result is fairly clear - HSCT patients need to know their Y238X SNP status and that of their donors.

There is an interesting extra experiment in this paper. The authors set up a mouse model system for HSCT using a mouse strain that lacked Dectin. Those mice that expressed Dectin showed a mild inflammatory response  when Aspergillus fumigatus conidia where used to infect their lungs whereas mice that had no Dectin became highly inflamed.

The conclusions are that Dectin controls resistance to A. fumigatus infection and also controls inflammation in response to A. fumigatus conidia. The latter may well be linked to the former as inflammation is a two ended sword for our ability to fight off infections, including aspergillosis. Inflammation that follows shortly after an infection is part of the normal process of eradicating that infection, but inflammation can also prevent eradication of an infection if it becomes uncontrolled. Examples included Chronic Granulomatous Disorder where there is chronic inflammation but persistent infection at the same time (link).

This paper illustrates the progress being made to identify people vulnerable to infection by Aspergillus and provides hope that in this case at least we now know a little more about preventing aspergillosis.

Friday, 3 September 2010

Aspergillus is Associated with Worsening Asthma

Recent studies have led us to start to think that the presence of fungus colonising the lungs of asthma sufferers contributes to the severity of their symptoms & disease. This paper takes a look at the current relationship between:
  • Sensitisation to Aspergillus (i.e. the patient has been shown to be reacting to Aspergillus by looking for the present of specific antibodies to Aspergillus in their blood)
  • Asthma status (GINA scale)
  • Presence of A.fumigatus in sputum (i.e. an indication that Aspergillus is living in their lungs)
79 patients were involved in the trial, divided up into 3 different groups according to their level of sensitivity to Aspergillus fumigatus.

The numbers of patients who had Aspergillus fumigatus recovered from their sputum correlated with their level of sensitivity to Aspergillus, suggesting that sensitisation is a consequence of their exposure to the organism living in their lungs - an observation that is not as obvious as it might seem as we all breathe in Aspergillus in the air without necessarily becoming colonised.

Patients sensitised to Aspergillus also had lower lung function, more bronchiectasis, and more neutrophils.

This study concludes that there is an association between Aspergillus in sputum and sensitisation, numbers of neutrophils and reduced lung function.

It is easy to construct a model system using these results whereby an asthmatic person becomes colonised by Aspergillus and as the colonisation proceeds the asthma deteriorates, the latter being a consequence of the former. The earlier paper mentioned seems to show that if that group of people are treated with an antifungal their asthma improves, and that would support this model.

Does Aspergillus therefore cause at least some severe asthma? Perhaps but there is some way to go yet before we can come to firm conclusions. Some centres are already treating fungally-sensitive severe asthmatics (SAFS) with antifungals with good results so the future for this hypothesis does look promising.

NB Colonisation could be defined as an organism living in the lungs without causing noticeable symptoms. This is distinct from inflammation which is where the organism is causing a response from the immune system of the host i.e. inflammation.

Friday, 27 August 2010

Increasing Levels of Mycotoxins in Animal Feed

Mycotoxins in our food is not something people in the developed world hear much about. We have our basic food hygiene and a natural innate distaste for eating mouldy food that protects us, and we have a rigid food testing regime that ensures we do not have significant mycotoxin contamination of the foods we buy from producers. But how much are we exposed to and how often?

Bearing in mind that foodstuffs intended for animals are of a lower quality than food intended for human consumption, so mycotoxin prevalence is far more likely to be widespread, this survey is still quite striking. Also bear in mind that the company undertaking this survey seem to be involved in providing mycotoxin management services to the producer, so do have a vested interest in emphasising the positive!


There are five toxin groups surveyed; aflatoxins (Afla), zearalenone (ZON), deoxynivalenol (DON), fumonisins (FUM) and ochratoxin A (OTA) which are produced in the main by three different fungi; Aspergillus, Penicillium and Fusarium. Most strikingly the number of samples testing as positive (see map for regional variations) vary from 28% (OTA) to 56% (FUM) - a very large proportion, leading to the natural conclusion that most food animals are feeding on mycotoxins most of the time. The terms of reference for the producer are of course how this would impact the wellbeing of his stock animals, there is no attempt to record the levels of mycotoxin in the resulting meat & other products in this survey.

NB Mycotoxin levels in food derived from animals is strictly controlled throughout the developed world - see Foodrisk.org, so we could conclude that although animal feeds are frequently contaminated by mycotoxins, those mycotoxins are not passed down through the food chain to us at levels thought to do us harm. The safe levels set seem to be largely based on tests on laboratory animals eating large amounts of toxin and laboratory experiments on human cell lines- see toxicology.

It is also mentioned in this survey that more than one mycotoxin was found in many samples, and it is implied that this may well increase the harm to the stock, though no evidence is referred to to back this up. This is a poorly understood subject for both animal and human food.

Chronic low level exposure to mycotoxins is starting to be defined on an international scale, cheap, consistent testing is being developed and international regulations harmonised. There are some reports of health problems (link) but this is still a poorly understood area of some concern (link).

Overall the levels of mycotoxins we are exposed to in our food is under strict control in developed countries, but there are still poorly defined risks with serious difficulties tracing the results of an exposure that might not emerge until several years later. We cannot regulate our own exposure on a personal level as we cannot know what foods we eat contain mycotoxins, all we know is that some are likely to contain mycotoxins at low levels  and that as far as we can tell there are no major health effects from eating our food. Much more research is needed to define these risks.

Monday, 23 August 2010

Steps to Proving Inhaled Mycotoxins are Harmful to Human Health?

This fierce debate has raged for some years now and shows few signs of abating, but as both sides of the argument have much to lose that isn't too much of a surprise.

Recent events in Africa have illustrated the dreadful consequences of  mycotoxin getting into food, but these levels are far more strictly controlled in the developed parts of the world such as EU & USA, not least because food storage conditions are much better controlled.

The home & work environment is a different matter. Major floods cause massive damage to property and leave what is left standing very wet & mouldy. The occupants often have no choice but to carry on living in their damaged houses and thus are forced to breathe in air inevitably charged with mould spores.
There are of course many more buildings that become contaminated by moulds without the need for huge natural disasters - a simple unattended pipe leak can cause the growth of a lot of mould in a few days. Moulds need no light to grow (are in fact inhibited by light) so there are many examples of moulds growing in closed appliances such as air conditioning units and consequently causing lots of mould spores to be released into the air.

The difficulty lies in assessing whether or not the spores being breathed in are causing health problems. One part of the debate is fairly clear - the breathing in of mould spores can trigger allergies and can do it over a very long time if the source of the mould remains undetected. These allergies can trigger more serious health problems such as asthma, particularly amongst children - damp, mouldy homes are proven to be bad for our health.

What about mycotoxin toxicity? Toxins cause problems to health depending on how much enters the body of the victim i.e. toxicity is dose dependant. A fair amount is known about what dose causes health problems when food is contaminated, but this is generally based on acute outbreaks of mycotoxicity when people or animals eat heavily contaminated food for a relatively short time. The people at risk often have no other food to eat so do tend to get high doses.

What is a safe amount to eat, given that even in the developed world it is virtually impossible to totally eliminate mycotoxins from our diet? (Some enlightening UK figures here).
The various national and international authorities set 'safe limits' for food and animal feed based on individual toxin levels.
Small amounts are thought to have minimal effect as they are usually quickly removed by our livers (all of us will be being exposed to low or very low levels of toxins in our food), but what about continued chronic inhalation of low amounts of several different types of toxin every day- a scenario that is quite likely in a damp building?

The debate comes down to the accumulation of  toxins in tissues. Much has been written about what dose a person living in a building would get by breathing in spores, rudimentary calculations have been done on the number of spores they need to inhale and how likely it would be that they could inhale that amount under reasonable circumstances but little of the resulting data is robust. Perhaps it is better to measure the amount of mycotoxin in the different tissues of each person exposed and thus get a direct idea of the level of their exposure? That is exactly what the researchers in this paper have set out to do.

Hooper et.al. have demonstrated that is it possible to detect several different mycotoxins in samples taken from patients known to have been exposed to mould (though they don't say what their criteria for this were) and to determine the amount of each mycotoxin in each sample. The techniques are simple adaptions of current technology so should be widely applicable. The amounts measured are correlated with reported clinical signs of illness, though most seem to be quite vague..

Amounts measured for each mycotoxin (trichothecenes, aflatoxins, and ochratoxins) tested in urine in this paper seem to be of the order of 0.2 to >2 parts per billlion which equates to 0.2 to >2 microgrammes per litre. Assuming a litre of urine produced per person per day that could be 0.2 to >2 microgrammes per day.

If we look at ochratoxin levels in the urine of normal healthy people in this paper we find up to 0.025 microgramme per litre per day - ten to a hundred fold less than that in people exposed to mould in the previous paper.

If this study is borne out we now seem to have some of the tools needed to directly measure exposure to mycotoxins in the body tissues of people exposed to moulds in their environment. Further studies will  be needed to determine the effects of that exposure on human health and what factors in low level chronic exposure are important - e.g. current dose, total cumulative dose, length of exposure, which mycotoxin or combination of mycotoxins has worst effects.

Tuesday, 17 August 2010

Vitamin D could be used to treat ABPA in Cystic Fibrosis?

A research paper due to be published in September 2010 reports the observation that some patients who have Cystic Fibrosis (CF) are prone to becoming infected with Aspergillus fumigatus and then developing Allergic Bronchopulmonary Aspergillosis (ABPA - Wiki) while others are infected but do not go on to develop ABPA.

Entitled 'Vitamin D3 attenuates Th2 responses to Aspergillus fumigatus mounted by CD4+ T cells from cystic fibrosis patients with allergic bronchopulmonary aspergillosis' the research focusses on finding differences between these two types of CF patient and one of the differences noted was the lower concentration of vitamin D in the blood of patients who suffered from ABPA. In other words most patients who had ABPA also had lower levels of vitamin D.
This observation leads to an obvious next step - what happens if you increase the blood levels of vitamin D in those patients? More specifically what happens to their ABPA? That question is now open, hopefully the subject of a clinical trial and we will know the answer in due course however we have had a hint at the answer in the next part of this paper.

Some of the major symptoms of ABPA are essentially the result of an over-response to the presence of Aspergillus by part of the immune system known as Th2 - part of the inflammatory response pathway that caused inflammation when we injure ourselves of become infected.
The group carrying out this research have set up a laboratory 'model system' whereby cells from each type of patient were isolated and grown in culture. They can then be stimulated to induce the Th2 'inflammatory' signalling pathway and their response noted. The result was that those cells taken from patients with ABPA responded by initiating inflammation whereas those taken from non-ABPA patients did not respond. Intriguingly we now have a result that parallels the clinical observation that cells in the airways of ABPA-CF patients respond to stimulation by Aspergillus by becoming inflamed whereas the non-ABPA-CF patients cells do not repond.

What happens if you add in vitamin D to each culture in the laboratory? Now cells from both types of patients do not respond with signals that would initiate inflammation - the abnormal inflammatory respond has been prevented. This is encouraging and suggests that vitamin D might be a good supplement to the diet of  CF sufferers to prevent them developing ABPA, though as this is a conclusion based on a single laboratory experiment rather than on real people we cannot be sure.

Needless to say supplementation of the diet of ABPA patients would be a very cheap and thus eminently do-able, especially as vitamin D has few notable side effects when taken in moderation. Success cannot be guaranteed however as it is very simplistic to suggest that all ABPA sufferers (CF and non-CF) have low vitamin D levels in their blood and to assume that the reason for that is dietary deficiency, but it might be worth patients self-checking their diets for foods rich in vitamin D.
Foods rich in vitamin D are oily fish, liver, cod liver oil and dairy products and of course sunshine is an important source.

Thursday, 12 August 2010

Aflatoxins claim victims in Africa

Recent reports from Africa tell of a major outbreak of aflatoxin poisoning in Kenya which has already resulted in one death, a small child.
Aflatoxin is produced by a wide variety of Aspergillus species and is highly toxic to people & animals when eaten in contaminated food.

In this case the contaminated food is known to be maize that is grown and then stored without sufficient drying or is stored in damp conditions. Maize is the main staple food in many parts of Africa and is grown for food and for profit. It is interesting to note that this has happened in this case at the end of a period of drought and famine as  we  know that Aspergillus is good at infecting a crop that is stressed by damage or water shortage so perhaps that is a factor in this outbreak?

This is the latest in a series of outbreaks of aflatoxin contamination. The largest recorded recent outbreak was in 2004 which led to 317 cases of aflatoxicosis and 125 deaths. Apart from the cost in human lives there is a huge cost to the livelihood of many farmers across a large area - the report mentions 29 districts affected. Contaminated grain cannot be sold for a good price or cannot be sold at all (depending on the level of contamination) and millions of bags of grain have been affected.

We have written several times of the methods being developed to limit aflatoxin contamination of crops:

New biopesticide Aflasafe™ may solve Kenya's ongoing maize contamination problem.



New biocontrol agent for Aspergillus contamination of peanuts


but clearly there are some more immediate basic solutions that can be tried first. Education of farmers about how to avoid creating conditions condusive to mycotoxin production is one mentioned in the report, and the Kenyan government is looking at providing drying machines to dry grain properly in the area affected to try to avoid future problems.

For the maximum allowable limits of mycotoxins in Africa: see www.knowmycotoxins.com
For a lot more information on worldwide mycotoxin foodstuff regulations see http://www.knowmycotoxins.com

Monday, 2 August 2010

Major Breakthrough in Understanding of Disease-Causing Fungi.

Scientists at the Departments of Biology and Chemistry, National University of Ireland Maynooth (NUI Maynooth), led by Professor Sean Doyle, in collaboration with Austrian collaborators, have made a major breakthrough in the area of the molecular microbiology of pathogenic fungi.

They have discovered how a pathogenic fungus protects itself against one of the toxins it can produce to reduce our immune response and so cause infection. The fungus in question is called Aspergillus fumgatus, which can cause severe disease and death in organ transplant patients.

The findings have just been published in the prestigious journal, PLOS Pathogens.

Doyle explained, “The fungus, Aspergillus fumigatus, is the major opportunistic pathogen of immunocompromised individuals, including bone marrow and solid organ transplant patients. We wondered why the organism could produce a molecule, called gliotoxin, which both kills cells and disrupts our immune response, yet had no effect the fungus itself? We found that a single gene called gli-T is present in Aspergillus fumigatus and ultimately acts to ‘inactivate’ gliotoxin. What really surprised us was that although gli-T is just one gene in a cluster of 13, all of which had been thought only to make gliotoxin, it can operate independently of all other genes in the cluster to protect the fungus against gliotoxin. This is quite an unusual phenomenon in fungi, explains a number of recent observations by others working in this research area, and has significant biotechnological potential.”

The work started almost four years ago, as a small component of an inter-institutional PRTLI programme with DCU (Professor Martin Clynes), and an EU programme at Maynooth co-ordinated by Dr Shirley O’Dea. It has involved significant inter-disciplinary and cutting-edge research at the interface of molecular biology and chemistry. For instance, the techniques used to reliably study gene function in Aspergillus fumigatus have only become available in the past few years and Maynooth is one of a small number of laboratories, along with that of collaborator Professor Hubertus Haas (Innsbruck, Austria), where this technology is used. In addition, the work involved the study of proteins of fungal origin, so-called ‘fungal proteomics’.

Maynooth has won competitive funding for the high-throughput instrumentation required for proteomic studies and has significant expertise in this area, not just for the study of human pathogens like Aspergillus fumigatus, but also to investigate plant pathogenic fungi like Armillaria mellea.

As for the future, the researchers intend to commercialise aspects of their findings and a European patent application has been filed on the technology, which has significant potential to improve the quality and yield of diagnostic and therapeutic proteins produced by fungi.

 



Image 1: Aspergillus fumigatus growing on petri dishes. It can be clearly seen that once the protective gene has been removed from the fungus that it can no longer grow in the presence of one of its own toxins (gliotoxin). This tells us that this gene is responsible ‘self-protection’ against gliotoxin.



Image 2: Microscopic image of Aspergillus fumigatus. It is a filamentous fungus and so grows in a strand-like manner. Panel A shows a green-tagged form of Gli-T. When the toxin (gliotoxin) is added it can be seen in panel B that more tagged Gli-T is produced to protect against the toxin.

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