Tuesday, 17 December 2013

Longer Lasting Christmas Trees - Better for Those Allergic to Aspergillus.

It was announced a few years ago in this blog that it is a good idea to minimise the amount of time a 'live' freshly cut Christmas tree spends in your home before moving it outside. This is because just as with any other cut plant it is gradually dying (even though it may appear to be far from it) and will start to generate fungal spores as it starts to decompose - which would be bad news if you are sensitive to fungal spores such as Aspergillus.

We now have two additions to that advice.

  1. Recent research is working on ways to make a cut Christmas tree last longer once moved indoors. If we can delay the decomposition process then we can prolong the amount of time before it starts to produce too many spores. 
It has been known for many years that many plants release a signal when wounded & dying in the form of the gas ethylene. It seems to function as a hormone to trigger lots of different events including ripening. This is the basis of advice to keep ripening bananas away from other fruit as the ethylene released by the banana will accelerate the ripening of other fruit and cause spoilage.

The Canadian group researching ethylene and its influence on early needle drop of Christmas trees have managed to block the effect of ethylene and have lengthened the cut life of the tree two-fold. Such a tree could stay in a home of people who are sensitive to fungi for twice as long.

    2. If you have an artificial tree remember that during use and storage it needs to be kept dust free to reduce the amount of fungal growth as dust is an excellent food for moulds and is very good at absorbing moisture from the air.

Take care and have a very Happy Christmas!

Monday, 16 December 2013

Economic burden of lung diseases in Europe exceeds €370 billion and commonly is complicated by fungal disease

A joint publication by the European Lung Foundation and European Respiratory Society provides detailed statistics on lung health in Europe. 1 in 8 deaths in the EU are as a result of respiratory disease and 6 million people are admitted to hospital each year. It is estimated for several diseases that this represents the “tip of the iceberg”, as many disease deaths are improperly recorded.

The report concludes that there are almost 10 million people under the age of 45 living with asthma in Europe, of which approximately 1 million have severe asthma which difficult to manage clinically. It is thought that around 50% of patients with severe asthma have sensitisation to various fungi (SAFS), of which Aspergillus fumigatus is the most common.

 Moderate or severe COPD is present in 5-10% of the European population (25-50 million people). This results in around 300,000 deaths in Europe every year. The majority of this burden comes from lifelong cigarette smokers, of which 40-50% will develop COPD in their lifetime. Invasive aspergillosis in COPD is thought to affect about 1.2% of the 3,600,000 people admitted to hospital each year; about 34,000 people. It carries an 85% mortality. Chronic pulmonary aspergillosis also affects COPD patients.

 Previously the prevalence of cystic fibrosis in the EU was estimated at around 37,000 cases. Allergic bronchopulmonary aspergillosis (ABPA) affects about 15% of teenagers and adults with cystic fibrosis. The report summarises that 15% of these patients are hospitalised at least once per year. Approximately 200 people with CF will undergo a lung transplant every year, although this figure is rising.

Interstitial lung diseases (ILD) are a collection of over 300 diseases, but mostly made up of idiopathic pulmonary fibrosis and sarcoidosis. Together they account for 50% of all ILDs in Europe, with hospitalisation and death rates peaking at 40 and 2.5 per 100,000 respectively. Aspergillosis is a common complication of fibrosing sarcoidosis, with a predicted prevalence of almost 166,000 people in Europe. 

The total economic burden of respiratory disease was estimated at €379.6 billion, with COPD and asthma causing over €200 billion of this. 


Thursday, 12 December 2013

Detecting Hidden Chronic Respiratory Deaths

Statistics of what types of disease are causing the most deaths (and how many deaths result)  in an area of the world are important for governments and other authorities to calculate what provisions to make for the healthcare in each country. Those that cause high death rates are likely to receive priority for higher funding and drug companies are likely to respond by investing in research to produce appropriate drugs if they can see that there is a large enough market for it to get a return on its investment.

In areas of the world where health services are well funded, widely available and have a long history of well organised research into the use of those services healthcare data has been routinely collected for many years.

This is not the case in parts of the world where there are barriers to the use of healthcare provision due to factors like cost & distance. People get ill and die possibly without ever seeing a healthcare worker in for example rural areas of large countries like India, where there are 10 million deaths per year. Cause of death is often not recorded and this valuable information used to be lost. Estimates of causes of death nationwide are made by organisations such as the World Health Organisation based on the recorded causes of deaths of people who died in hospital - but this may be vastly different to the rates of cause of death in the very different rural areas where risks could be quite different.

An initiative was launched in 1997 by Canadian researcher Prabhat Jha to address this shortcoming. In the absence of official figures he realised that a reasonable impression of cause of death could be attained by talking to relatives about the symptoms noted leading up to the death. These 'verbal autopsies' have now been carried out throughout India and have reached 1 million records to date.

The results of this survey when compared with WHO figures suggest that in particular there are far more cases of malaria and snake bite than are currently recorded, but others differ too.

'Correcting' existing figures to take in for account these new mortality figures we can see that in a country like India there is massively more chronic respiratory disease (6 fold high frequency) and TB (90 fold higher frequency) in age range 30 - 69 compared with high income countries (e.g. UK, USA), while there is less cancer.

Such figures strongly suggest that the demand for drug development in those areas is far higher than previously thought and hopefully this will open the way for due consideration of higher investment by drug companies, individual countries and international communities.

Thursday, 5 December 2013

Cryptococcuc gattii - Killer or Accident of Evolution?

A recent copy of the journal Scientific American reported on the strange incident of hundreds of dead dolphins suddenly being washed up on the shore of a remote island of the Pacific North West, their lungs filled with yeast!

This fungus family is well know to us and we have used it for thousands of years to help us make food & drink, so we know it is usually a benign friend, occasionally causing an irritating, superficial infection in many of us (Thrush) and sometimes causing serious infection but certainly nothing like this had been seen before.

This island infection outbreak spread to pets and even people, but this particular yeast had never been found on this island before nor anywhere close by - it is a native of the tropics which are many thousands of miles south of this island. So why did it suddenly become a virulent pathogen?

After a lot of work scientists have found this species living in places they weren't expecting to find it. It sounds like the yeast is quite widely present around the world and one reason for its spread north might be global warming. Perhaps the warmer environment is making it possible for some fungi to spread, perhaps the animals that live in those areas are becoming more vulnerable to infection because of climate change but regardless there does seem to be a trend to increasing numbers of fungal infections in some parts of the world.

Amoeba (magnified many times)
So why did it suddenly gain the ability to infect humans? Like many fungi it has a natural home in the rotting material on the ground and in that environment it has predators e.g. amoeba. Scientists are theorising that as the yeast develops the means to avoid being eaten by amoeba it may also have quite unwittingly also developed the means to avoid parts of the immune systems of animals, as parts of our immune system contains cells that look and act just like amoeba.A strain of yeast (C gattii) that can evade amoeba might also be able to avoid similar cells in the immune system of animals, and humans!

See a schematic of the infection cycle here.

This C. gattii outbreak is ongoing and work to discover how it happened is also ongoing.

Read the full article in Scientific American

Wednesday, 4 December 2013

Press Release: Antifungal Drugs Increase 'flu Susceptibility

Common anti-fungal drug deactivates protein that protects against flu in mice

Researchers have found that a commonly used anti-fungal treatment increases susceptibility to severe influenza infection in mice. This treatment deactivates an important protein that protects against viral infections such as influenza.

Amphotericin B is an important anti-fungal treatment for people with already suppressed immune systems such as cancer patients and bone marrow transplant patients. Cells and mice treated with Amphotericin B lost the protective effects of IFITM3, a protein critical for protecting against viral infection. This increased their susceptibility to influenza infection.

“This is an important discovery and the consequences for patients on certain anti-fungal treatments should now be investigated,”
says Professor Paul Kellam, author from the Wellcome Trust Sanger Institute.
“Preventative flu vaccinations, rapid antiviral therapy or alternative anti-fungal treatment could be offered to these patients when at risk of flu infection.”

The team discovered that when cell samples were treated with Amphotericin B, the protective effects of IFITM3 were rendered inactive. This allowed the influenza virus to easily infect the cells.
“When we treated lung cancer cells with the anti-fungal drug, we saw the anti-viral protection from IFITM3 pretty much disappear” 
explained Christopher Chin, co-first author from the University of Massachusetts Medical School.

To fully understand the affects Amphotericin B has on IFITM proteins, the team treated mice with the anti-fungal drug. Once the mice contracted influenza, they displayed the same flu symptoms as mice completely lacking the protective ifitm3 gene. In the absence of the influenza virus, the mice treated with the Amphotericin B showed no signs of illness.

Previous studies from the Sanger Institute found that people who have a genetic variant in the IFITM3 gene are more susceptible to severe influenza than people without the variant.
This research indicates that patients undergoing Amphotericin B anti-fungal treatments could potentially lose the protective effects of IFITM3. The loss of IFITM3 could increase the risk of flu infections in patients with already compromised immune systems.

“Sometimes a very useful drug can also have unforeseen effects,”

says Dr Abraham Brass, senior author in the Microbiology and Physiological Systems Dept. at University of Massachusetts Medical School.
“We now see that a major part of the body‟s natural defences to influenza virus is rendered inactive by Amphotericin B in cells and mice. It‟s our hope that reporting the consequences of this interaction may stimulate further translational studies and potentially guide patient care.”

The researchers agree that further work is now needed to evaluate if this effect has any clinical significance for patients receiving Amphotericin B-based treatments.

“It's a fascinating study, and vital that we now work out if these effects in mice are also seen in people,”
says Professor Peter Openshaw, Director of the Centre for Respiratory Infections, Imperial College London.
“Patients on amphotericin often have complicated medical conditions and may be immune supressed; we need to work out if the treatments these patients were getting for other conditions made their influenza worse, as seen in the mice. If this is the case, we need to vaccinate those at risk, use these treatments sparingly and give antiviral drugs as early as possible when flu is developing. Clinical studies are urgently needed”.
This research was part of an ongoing collaboration between University of Massachusetts Medical School and the Wellcome Trust Sanger Institute.

Full article here

Father of Genomics: Fred Sanger Dies Leaving the World a Far Better Place

Without a doubt one of the greats of British science and the world, Fred Sanger invented a relatively simple, reliable and quick technique that allowed thousands of labs around the world to carry out DNA sequencing.
The consequences of that work are difficult to comprehend and a vast amount of subsequent work on living organisms has since been carried out using Sanger's technique.

Sanger reads DNA sequence

As an example, if we search the research paper database Pubmed with the words 'dna sequence' we find that in 1977 (the year Sanger published his technique) there were 1000 papers published. 10 years later there were 10 000 papers being published per year, and since 1995 there have been 35 000 research papers published per year. Sanger sequencing continued to be the most used technology until highly intensive automation was possible using robots to manipulate samples and very powerful computers to assemble sequences in around 2005.

The amount of papers published reflects the amount of gene sequencing that has been carried out - also see the figure below (from this paper) showing us the exponential rise in numbers of sequences submitted to public record (Genbank) since 1982.

Sanger made a second huge contribution to sequencing when he invented shotgun sequencing, a refinement that speeded up the process of generating sequence radically, enabling the practical use of his techniques to sequence entire genomes.

The invention of a technique to sequence large amounts of DNA triggered the start of the effort to sequence the DNA of entire organisms - i.e. their genomes. First small viruses (5400 base pairs, achieved in 1977 by Sanger himself), then more complex eukaryotes (12.5 million base pairs, achieved in 1996) and finally ourselves, humans (3 billion base pairs, achieved in 2001). The human genome is predicted to transform medicine and our understanding of ourselves and all human kind. The prospect of personal genome-driven medicine is looming large as new sequencing techniques drive costs down. That work will lead directly to improvements in the prevention and treatment of many illnesses including aspergillosis and other fungal infections.

For these achievements alone Sanger was awarded the Nobel prize in 1980 but his story is more extraordinary than that. This was his second Nobel prize, the first being achieved for the first sequencing of a protein, insulin. He remains one of only four people to win two Nobel Prizes.

Since 1993 the Sanger name has been given to the hugely successful Wellcome Institute housing the Human Genome Project in Cambridge, UK and his name is used extensively elsewhere in the world.

It isn't too much to say that a fair proportion of our hopes for the future of British (and worldwide) science, medicine,  improvements in our quality of life & health and much more rests on the solid foundations built using the tools fashioned by Fred Sanger.

Sanger's own description of the early years of DNA sequencing
BBC report of his death
What impact did Fred Sanger have on our lives?
A history of genome sequencing

Mushrooms Create Their Own Breeze

Journal Scientific American has reported a mushroom mystery and the story of how the solution was discovered. We have thought for a long time that when a mushroom or other fungal fruiting body starts producing spores they are dispersed on air currents, so it was assumed that anything from a breeze to a strong wind would be needed to move the spores around.

Puff ball releasing cloud of spores
However it was then noted that mushrooms were able to disperse spores even in the absence of wind - in completely still air! This was a mystery - how could this be possible as few fungal fruiting bodies have any obvious sort of mechanism to project spores. There are one or two exceptions - puff balls for example are large bags of air that forcibly eject spores when the puff ball is struck with a drop of rain, but these are exceptions to the rule!

Emilie Dressaire et. al. have reported the finding that a mushroom can actively cool the air surrounding them and consequently create upward air currents eminating from the mushroom itself, and spores are carried away in those air currents.

So even in the stillest of air, a mushroom can effectively disperse its own spores far and wide!

The author of the Scientific American story (Katherine Harmon) has released an audio podcast describing the finding

Friday, 29 November 2013

FDA Approves NOXAFIL Delayed Release Tablets - Posaconazole Dosing is Now Once Per Day!

The US drug regulatory body FDA have just approved a new form of the antifungal drug posaconazole that is slowly released into the bloodstream after the patient takes the tablet. This provides two important advantages over the current formulation of posaconazole (which is a liquid that has to be taken by mouth three times a day).

  1. for the most part a single dose is taken per day. This improves convenience for the patient and potentially improves compliancy as it may be more reliable for some people to remember to take a dose once per day
  2. a single dose, slow release regimen encourages a more consistent blood level of the drug and possibly a higher overall blood level
Posaconazole (NOXAFIL) is an important antifungal for the treatment of several forms of aspergillosis and is used as a prophylactic for those patients undergoing treatment that makes them extremely immunocompromised. This improvement in dosing technology will hopefully contribute to improving outcomes in those cases.

The drug is predicted to be available in the second quarter of 2014.

Wednesday, 27 November 2013

Aspergillosis in animals

We routinely discuss fungal infections in humans, especially those due to Aspergillus, but fungal disease is anything but limited to humans. From the fungi which cause skin conditions (such as Tinea capitis) to those which can cause invasive infections (e.g. Candida albicans or Aspergillus fumigatus), they are all found to affect a wide range of animals including cats, dogs, horses and cattle. Not only that, but also more exotic animals like parakeets or whales.

As with humans, diagnosis of fungal infections in animals is a significant hindrance to successful treatment. Diagnostic tests for galactomannan, regularly used in humans, have been found useful in the diagnosis of feline aspergillosis. Most cases do require imaging tests to determine if signs of certain infections are present, such as aspergilloma.

In the UK there are only seven licensed antifungal drugs for veterinary use, a number much smaller than those available to humans for dermatological and systemic fungal infections. The only systemic antifungal available for veterinary use is griseofulvin, effective only against dermatophytes, and even that is only registered for use in cattle and horses. For regular pets such as cats and dogs, there are several drugs to treat skin infections but none licensed to treat systemic infection.

So how do veterinarians treat diseases such as nasal or invasive aspergillosis in common pets like cats and dogs? They have to use drugs licensed in humans but off-license in animals, including the triazole drugs such as itraconazole and drugs such as amphotericin B. Similar to human use, these drugs must be monitored even more carefully given their unregulated nature in animals. If the disease is limited to the nasal sinuses, often surgical procedures are used in addition to antifungal drug treatment.

Wednesday, 20 November 2013

Universal health care

A recent article in the BMJ discusses the trials and tribulations associated with implementation of universal healthcare globally. However, it also notes the great progress that is being made (even in countries engrained in medical insurance culture such as the United States) and notes that an increase of 10% in governmental, prepaid funds for healthcare could save around 500,000 children under 5 in India and Nigeria alone (Save The Children report, 2013).

Low and middle income citizens in less developed nations often have to pay what is termed 'catastrophic healthcare spending' to pay for treatment, with billions of people worldwide resorting to selling assets, acquiring large debts or keeping children out of school in order to fund often inadequate healthcare. (Health Affairs, 2009) The authors suggest moving away from medical insurance models such as those throughout Africa, and towards the UK/France/Canada model where taxes pay for healthcare, ultimately redistributing wealth from the rich to the poor and encouraging access to healthcare on the basis of who needs it, rather than who can afford it.

This is particularly beneficial for diseases of a chronic nature, which require long-term and often multiple sessions of treatments to cure. The data that GAFFI is acquiring will increase public awareness to the costs that people worldwide have to pay for often fatal fungal diseases.

Importantly, medicine costs can seem low to people in Western countries; for example, people in Bangladesh pay just under $1 USD for a daily treatment of fluconazole, an essential antifungal drug. However, the proportion of people living on less than $2 USD a day in Bangladesh is around 75%, meaning that 75% of people would have to spend half their daily earnings on just one day's worth of treatment.

Such data collection is essential to put pressure of pharmaceutical companies and governments to reduce point-of-care costs of medication to the poor. More must be done to reduce access costs to medication but this can only be tackled through global collaboration between national governments, pharmaceutical companies and global health organisations.

Wednesday, 13 November 2013

Poetry at the GAFFI Launch

Rupert Everett talking to patient Gail Iddon at the launch of GAFFI
During the launch of GAFFI last week (6th November) Rupert Everett read a series of poems each of which related to fungal disease in a different way. There were several new original works - perhaps most poignantly one written by a group of patients who have aspergillosis in its various forms and who meet once a month for a support meeting run by the National Aspergillosis Centre.

The Centre has a Poet in Residence (Caroline Hawkridge) who organises group writing events to take place at the meeting. The poetry is inspired by a number of influences, one by the hospital car park(!) but this one was inspired by the name of the daughter of a doctor who presented a talk at one of the meetings. Her name was Hope and from that we all contributed to the poem 'Hope is...' giving our individual impression of what hope means to each of us. There was a wide range of contribution, some from patients, some from carers and some from staff.

Rupert performed our poem outside the Houses of Parliament as video recording is not normally allowed within its walls. Watch & listen here (once on the website click on Rupert's picture).

Tuesday, 12 November 2013

Congratulations Tom Walsh

The European Journal of Clinical Investigation has published a study that attempts to list the 400 most influential biomedical researchers living between 1996 and 2011.

The authors make the point that it is ever more important to know who has the best experience of carrying out high-impact research, what it is that brings about work that has high impact:

The world of modern science has become increasingly competitive in recent years. Literature-based metrics are playing a greater role in decision-making than in the past [1]. Many researchers are highly aware of their so-called status, and check diverse metrics related to the impact of their work on a regular basis. The differing dimensions of impact and reasons for citing are receiving renewed discussion and analysis [2-6]. Although citation counts and related metrics (e.g. journal impact factor, h-index for individual researchers) are typically considered as proxy for impact [7], the nature of that impact is rarely, if ever, specified.
It is within this context of creating a better understanding of impact(s) that we have created a list of highly influential biomedical researchers. Ranking of scientists is explicitly not the main purpose of this list. Rather, we wanted to identify a pool of researchers who have had sustained success in highly influential work and who would thus presumably have substantial insight into differing features that could be associated with high impact. This list is being used in an ongoing survey where highly cited researchers are asked about the features of their most-cited articles. However, the list may be of use for many other purposes, as we discuss below.
Thomas Walsh is a leader in antimicrobial drug research including antifungal drugs and it is of great credit to him and his team that he is named on this list of the research & influence elite of the medical profession. His work has been cited nearly 29 000 times in the period covered by this study, which is a measure of the interest there is in his work amongst his peers. He published over 500 papers in the 15 years mentioned - a rate equivalent to one every 10 days! Phenomenal and inspirational!

Friday, 8 November 2013

Fungal infections in cystic fibrosis

Cystic fibrosis (CF) is the most common acquired genetic disease in the Caucasian population, with approximately 1 in 25 people in the UK being 'carriers' for the disease. When two carriers have children, there is a 1 in 4 chance that the child will have CF.

CF is characterised by abnormal ion transport in several cell types, but most notably in cells which line the airways. This leads to a build-up of thick mucus which sticks to the airways, resulting in a 'remodelling' of the lungs. This increases the prevalence of bacterial and fungal infections in the airways, though the underlying reason for this is still disputed. One theory is that the make-up of the secretions—which are different in CF sufferers compared to the general population—allow bacteria and fungi to evade the immune system with more success.

It's widely accepted that both Candida and Aspergillus species colonise the airways in CF patients, and this is most likely due to long-term exposure to antibiotics. Candida spp. are usually considered relatively benign in most patients, and there is insufficient scientific evidence to treat the presence of Aspergillus species unless it is present and causing allergic bronchopulmonary aspergillosis (ABPA).

Whilst not itself an invasive disease, ABPA exacerbates existing CF disease through wheezing and, potentially, damaging the lung structure through scarring (fibrosis). Unfortunately the diagnosis of ABPA in CF patients is challenging, since many symptoms overlap. Strong laboratory evidence is essential to confirm diagnosis of ABPA. Once diagnosed, the gold standard treatment consists of steroid drugs to help suppress the excessive immune response, alongside itraconazole (an azole antifungal drug) to help prevent fungi taking advantage of any reduced immune response. This halts progression of disease and successfully manages most patient's symptoms.

Whilst Candida and Aspergillus make up the large majority of cultured fungi from CF patients, there are still  significant numbers of other pathogenic fungi which infect in CF. Scedosporium and Penicillium species are found in around 15% and 8% of cultures respectively. Similar treatment options exist to those of Aspergillus infections, with laboratory testing again essential to determine which drugs are most effective to the particular organism.

Thursday, 7 November 2013

Global Action Fund for Fungal Infections (GAFFI) Launched in London, New York

GAFFI was formally launched at the Houses of Parliament yesterday on the 6th of November during a glamorous event that featured world-renowned actor Rupert Everett performing several poetic works in support of the aims of GAFFI and the support and music of Singer/Songwriter Katie Melua.

Katie's music has sold 4 million albums so far, won several awards and memorably sang "Too Much Love Will Kill You" with Brian May at the 46664 concert in George, South Africa for Nelson Mandela 's HIV charity.

One of the poems performed by Rupert Everett was written with the Patients Support Group at the National Aspergillosis Centre as part of their creative writing project run by Poet-in-Residence Caroline Hawkridge. It is based on the theme of 'Hope' and was inspired by the name of the daughter of one of our doctors.

The launch in London began with a welcome from Paul Goggins MP, in who's constituency resides the National Aspergillosis Centre, University Hospital of South Manchester. GAFFI is about raising the awareness and funding for the need to be able to diagnose and treat all fungal infections throughout the world but aspergillosis is prominent in ongoing illness as a result of TB and in severe asthma (contributing to 1 350 000 deaths every year) and in the loss of sight caused by infection after damage to the eyes of tens of millions of people every year.

AIDS is an illness with very high public awareness and high levels of funding to attempt to treat infection with the HIV virus, but did you know many of the 1 350 000 deaths every year caused by fungi are AIDS sufferers?

We were then treated to a stunning presentation using the lyrics of Katie Melua's song 'I'd love to kill you (with a kiss)" to evoke a series of images of the suffering caused by fungal infection.

Most memorably two accounts of what it is like to live with a fungal disease were related by patients themselves. Gail Iddon and Woodrow Maitland-Brown shared their compelling stories of how beneficial access to good diagnosis and treatment can be when suffering from a fungal infection. Gail and Woodrow were great examples of how effective treatment can improve quality of life.

Professor of Global Health at Manchester University David Denning outlined the aims of GAFFI and made the striking (and very shocking) point that 150 people die from a fungal infection somewhere in the world every hour of every day, many more than that are severely disabled with life changing symptoms. In many poorer parts of the world this is highly preventable for a large proportion of cases (up to 75%).

The launch in London was brought to a close by Lord Turnberg (former president of the Royal College of Physicians).

David Perlin launches GAFFI in New York

In New York the launch was led and performed by Professor David Perlin, David Warnock (ex-CDC) and Liise-Anne Pirofski (Albert Einstein) to a packed audience.

We wish GAFFI well on its journey to make life better for many millions of people throughout the world.

Further information on GAFFI and this event can be found on their website

Katie Melua "I'd Love to Kill You"

Katie Melua singing "Too Much Love Will Kill You" at Nelson Mandela's Charity concert, 2005


GAFFI Leaflet - feel free to print out and distribute

Thursday, 31 October 2013

Causes of chronic allergies

Allergic bronchopulmonary aspergillosis (ABPA) is a potential complication in asthmatic people, and can potentially lead to chronic pulmonary aspergillosis (CPA) when left untreated. Only recently have global incidences been estimated, with potentially 4.8 million people affected worldwide. (Denning et al., 2013)

There is a great quantity of on-going research into asthma and associated allergies, but how do such allergies begin? In recent years scientists have made large strides towards discovering how our immune systems malfunction—ultimately attacking substances which are not harmful. The science behind those mechanisms is complex, involving multitudes of small molecules which play individual roles in various allergic diseases.

There is a strong familial link to allergies; if one parent has an allergy, the child will acquire an allergy in 33% of cases. If both parents have an allergy, that risk doubles to around 70%. Similarly, identical twins have the same allergies in 70% of cases, further corroborating the familial link. It appears that children inherit the likelihood of developing an allergy; however, it is not always the same allergy which occurs in the parent(s). For example, a parent with a peanut allergy may not necessarily pass that specific vulnerability to peanuts to their children.

A number of theories exist attempting to explain why allergies initially occur (i.e. why the body’s immune cells decide to attack a particular allergen). These theories range from genetic to environmental, but there is no conclusive mechanism.

Nevertheless, the processes leading to allergic disease can be described more simply under two stages: sensitisation to an allergen (something which initiates an allergic response), and activation (the process by which the body responds to that allergen). The first stage, sensitisation, can occur with no symptoms, acting as a priming mechanism behind the disease, with no consequences on its own until your body encounters the same allergen again.

During re-exposure, antibodies developed during the sensitisation stage ‘recognise’ the allergen, triggering a cascading immune response. This is the same mechanism which protects us from colds and infections we've previously had, but happening against something non-infectious. This is the reason that allergies and colds have similar symptoms: runny nose, fatigue and sneezing, to name a few.

Tuesday, 29 October 2013

World Medical Association adopts statement on fungal disease diagnosis and management

At their 64th General Assembly in Brazil, the World Medical Association adopted a statement on Fungal Disease Diagnosis and Management’.The statement reads:
“The WMA stresses the need to support the diagnosis and management of fungal diseases and urges national
Professor Arnaldo
governments to ensure that both diagnostic tests and antifungal therapies are available for their populations. Depending on the prevalence of fungal diseases and their underlying conditions, specific antigen testing or microscopy and culture are essential. These tests, and personnel trained to administer and interpret the tests, should be available in all countries where systemic fungal infections occur. This will likely include developing at least one diagnostic centre of excellence with a sufficient staff of trained diagnostic personnel. Monitoring for antifungal toxicities should be available.
Physicians will be the first point of contact for most patients with a fungal infection and should be sufficiently educated about the topic in order to ensure an effective diagnostic approach.
The proposal to the WMA was prepared by Professor Arnaldo from Sao Paulo who commented: “This is the first time that the World Medical Association had considered the size and severity of the problem of fungal disease. Their proposal to ensure that essential diagnostic tests done by trained personnel in all countries is critical to ensuring better patient care.”

Thursday, 24 October 2013

Support Patients Research Group at North West Lung Centre (Home of the National Aspergillosis Centre)

Support Danielle Yuill's project to set up a group of patients (& carers) to assist with research at the North West Lung Centre and National Aspergillosis Centre, Manchester, UK. Danielle has organised a meeting in Manchester to begin with. People from other parts of the UK & world might also be useful - those who cannot make the meeting this Saturday could send an email.

For a full explanation of the project see our last Patients Support Meeting

Danielle's appeal for help:

Join me… Saturday 26th October Britannia Country House Hotel Palatine Road Didsbury, Manchester 12.30 till 2.30pm Lunch and refreshments provided. We are able to offer you a payment of £25.00 for taking part and will also reimburse your travel expenses.

Contact details Danielle Yuill Clinical Project Manager Tel. 0161 291 5906 (Mon-Tue) 0161 291 5031 (Wed-Thu) Email. danielle.yuill@manchester.ac.uk

Monday, 21 October 2013

Fungal infections pose a significant threat to the health of our plants and animals and ecosystem

At  the recent 6th Trends in Medical Mycology conference held in Copenhagen, Dr Fisher presented a significant case that fungi are emerging as a serious threat to both animal and plant health and to the health of the ecosystem worldwide.
The fungal kingdom is incredibly diverse with an estimated 1.5 million species but probably 500 times more may exist.
Amphibian chytridiomycosis

Whilst we use fungi to our benefit in a variety of ways - from drug development to food production - emerging infectious fungi nevertheless represent a serious threat to the Earth's ecosystem. Several animals species, including various amphibians, bats, honeybees and snakes, have been the victims of pandemic fungal diseases and this threat appears to be widespread amongst animals including turtles (Fusarium solani) and corals(Aspergillus sydowii).
Many types of fungi can cause life threatening infections in humans and related hospital admissions are rising. Plants are not exempt from the fungal attack- they represent a serious threat to plant health worldwide. Here in the UK, Chalara fraxinea (Hymenoscyphus pseudoalbidus), or ash dieback is spreading through our ash tree population like wildfire, having destroyed over 100,000 ash trees since discovery of the disease in 2012. Global disease alerts show that fungal alerts are increasing in relation to other pathogenic causes; and fungi have become the highest threat to extinction (by infection) in both animal (72% of extinctions)  and  plant (64% of extinctions) species. Alarmingly this threat is increasing with time. The bat species Myotis lucifugus  is almost certain to become extinct in just over a decade as the Pseudogymnoascus destructans fungi spreads.

Humans are spreading the problem by transportation - accidentally and  commercially, but evidence (Bebber et al 2013) now shows that climate change is enhancing the spread of fungi - by allowing establishment in previously unsuitable locations. They report a shift in distribution of many pathogens (since 1960) as measured by a poleward shift annually since that time, of many pathogens including fungi. The distribution of some other taxonomic groups such as nematodes have shifted away from the poles.

These increasing trends represent a threat, in both the short and long term, to human, animal and plant health. The high socio-economic cost to crops and healthcare provide good impetus for further research, as the battle is not one which we can afford to lose.

(Fisher, M et al . (2013) Emerging fungal threats to animal, plant and ecosystem health. Presented at the 6th Trends in Medical Mycology, Copenhagen, Denmark: Presentation) view

Tuesday, 15 October 2013

Pcovery wins funding to improve fungal treatment options

As previously reported on this blog, the options available to clinicians treating fungal infections are narrow. As a whole, the pharmaceutical market is reluctant to invest heavily in developing new antifungal medication because of the comparatively small (though still extensive) market.

Clinicians and patients may find some happiness in the recent news that the Wellcome Trust has awarded £3.7 million in funding to Pcovery, a Danish biotechnology company aiming to break into the antifungal drug market. The company is currently identifying lead target compounds before moving on to pre-clinical drug trials.

Pcovery CEO, Casper Tind Hansen, expressed his delight at the news: "The generous funding is an acknowledgement of our work, and the money allows us to focus on developing a novel compound to treat invasive fungal infections. We now have a team of the right competences, and access to world class expertise within anti-fungal drug development."

"We have set up an ambitious and well-structured plan to come up with a novel treatment of invasive fungal infections, which will hopefully help this group of severely sick patients."

(Pcovery website)

Friday, 11 October 2013

Cardiotoxicity of antifungal drugs

The treatment of fungal disease is significantly hampered by the unavailability of new antifungal drugs, and increasing resistance towards registered antifungals such as the triazoles. With the introduction of the echinocandin class of antifungals (Caspofungin (Merck) in 2001, followed shortly by Micafungin (Astellas) and Anidulafungin in 2005 and 2006 respectively), the situation has improved but not resolved. There is still a widespread shortfall of antifungal treatment options.

Of the drugs currently available, cardiotoxicity appears to be a side effect in some patients with pre-existing cardiac disease. Some traditional antifungal drugs, such as the polyene amphoteracin B (AmB) have been associated with reduced cardiac function. Other examples include itraconazole, which has been implicated in heart failure in some patients, and voriconazole, which has been linked with Torsades de pointes -- an electrical disturbance in the heart which, left untreated, can lead to fatal heart disease.

A study into echinocandin cardiotoxicity by Stover et al. (2013) has shown that rat hearts treated with Anidulafungin and Caspofungin display reduced function, including at doses similar to that in humans after administration. Notably, and interestingly, Micafungin was not associated with statistically significant changes in this study, which coincides with the fact that there are no adverse cardiac events noted with patients taking Micafungin. On the other hand, Caspofungin and Anidulafungin have both been reported, with the former being responsible for sudden cardiac death in one patient and the latter being responsible for a case of flash pulmonary oedema.

The current advice to clinicians at the moment is to monitor all patients with pre-existing cardiac disease who are on AmB or triazole antifungals. More research is needed into the potential cardiotoxicity of echinocandin drugs in patients with pre-existing cardiac disease.

Thursday, 10 October 2013

Improving active and healthy aging

In late 2012, MEPs met to discuss the impact of early diagnosis and control on those with chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD)—projected to become the third leading cause of death by 2030 worldwide. Other chronic respiratory illnesses face similarly large increases in prevalence over the coming decades, including asthma, allergic rhinitis and allergic bronchopulmonary aspergillosis (ABPA).

One issue raised at the meeting was the role of patients' organisations in the fight against chronic respiratory disease. Patients are generally not well placed to campaign directly for improvement to public health initiatives, and it's vital that non-profit organisations can rally on their behalf. As part of the Aspergillus website, we run a patient's website which links in directly to patients at the National Aspergillosis Centre and elsewhere.

The final aim is to improve active and healthy ageing (AHA). This can be achieved through prioritised research, particularly tackling at-risk groups such as children. Since children with asthma are at a higher risk of developing COPD when older, improvements to future clinical and scientific research disciplines is vital to help develop novel therapies for this risk group.

Tuesday, 8 October 2013

The digital media age

Last year Amazon and Waterstones announced that, for the first time in history, electronic book sales eclipsed printed book sales for the first time. It is reasonably safe to assume this is an ongoing trend—engineered by the increased use of the internet in our everyday lives—and hence this finding is unlikely to reverse soon, if ever. Does that, then, point to the demise of the printed book?

On the face of it, it seems a straightforward conclusion. If a book provides no additional benefit to it's reader, and the needs of that reader can be met equally and more efficiently with another commensurate medium, what purpose does such a book serve? Medical journals are moving faster than ever into the digital age; whilst some preserve printed copies for monthly subscribers, most at least publish a digital equivalent and, increasingly, journals are moving to a digital-only subscription model.

It's not quite a done fight just yet, however. There is a particular aesthetic benefit that conveys an advantage to printed books; owners become more attached to printed books than they do to ebooks. Heritage and style are less emphatic read as a PDF compared with the distinct smelling, aging books.

Does that negate from the fact that ebooks are cheaper, more accessible and transportable than their printed versions? Not at all, but for many people those attributes are not essential but optional.

Monday, 7 October 2013

Evidence-based... funding?

White HouseSince the US Government shutdown is on-going, with an impasse between the House and Senate revolving around 'Obamacare', it seems pertinent to discuss how health care services should be funded (or indeed cut). Several Western governments, including the US and the UK, routinely create vast expenses that exceed their incomes, leading to a budgetary crisis similar to the current one. The temptation for governments is to slash funding to the fiscally more 'greedy' programmes; in essence, to force reductions in expenditure in those areas, hoping they adapt to the new fiscal pressure.

It has been suggested, as an article written in the Nature journal back in April discusses, that a more sensible approach is t o allocate funds based upon evidence; that is, to fund what is proven to work, and cut what funding to failed initiatives. In fact it appears as though the US government is taking this route in order to fund all programmes within the sciences. From the April budget, it is made clear all branches need to follow six core practices:

  1. Goal-setting;
  2. Frequent measurement of performance and other indicators;
  3. On-going analysis;
  4. Use of evidence in decision-making;
  5. Data-driven reviews; and
  6. Information dissemination that is timely, accessible, and user-friendly.
One method, currently being trialled for teen pregnancy prevention in the US, is a tiered funding approach which is not dissimilar to the phases in clinical trials. At the lower stages there is initial funding to explore and assess ideas and developments, but that funding is limited. To progress through the tiers, and hence receive more funding, one would need to acquire more evidence to support the case for development.

Another method, more commonly used here in the UK, is through the use of social impact bonds (better known by the term 'Pay for Success'). This is particularly relevant under the increasing privatisation of medical services; outsider investors are required to meet set targets and prove they are saving the public money in order to receive compensation from the NHS. 

Wednesday, 2 October 2013

Isavuconazole Shows Promise for Invasive Aspergillosis

The Wall Street Journal have reported that Astellas, developer of a new antifungal drug isavuconazole, have published some results from their phase III trials on the treatment of invasive aspergillosis that show its promise in comparison to voriconazole.

 In particular in a sample of 500 patients there was 7% lower mortality and only 40% drug related adverse events with isavuconazole versus 60% drug related adverse events for voriconazole, so there may well be advantages to using isavuconazole for the treatment of invasive aspergillosis as although there is little difference in mortality there may be fewer side effects for the patient. NB significant numbers of patients have to stop taking voriconazole due to excessive side effects.

Overall effectiveness at the end of the study (42 days) was comparable and certainly no worse than using voriconazole - so effectively we can conclude isavuconazole is no worse in terms of outcome for the patient and may well cause fewer adverse events so may be tolerable by more patients.

Wall Street Journal report

Tuesday, 1 October 2013

Better Healthcare: What Does the World Want Most? Why Does the US Want More?

The United Nations are currently running a survey in 194 countries of the world to ask what we all want most from future development. There were 16 options offered and contributors could choose 6 from the list.

These are the overall results so far

We can see that overall the desire for better healthcare is the second highest priority around the world, whereas the desire to take action on climate change is the least most important.

Interestingly the desire for better healthcare is not consistent from country to country. In the UK it is our 8th priority and this is consistent with UK being a more highly developed country thus we can spend more on our health services, presumably generating better services - the situation is the same in similar countries. Perhaps we are happier with our health services relative to other priorities, perhaps we are have more leisure and thus have time to consider other priorities whereas poorer countries have to concentrate on living! 

There is however one exception to this rule. If we take a look at the amount each country spends on healthcare and correlate it to the number of people in that country who profess a desire for better healthcare we get this table:

We can see a reasonable correlation (the red line) between health spend and desire for better healthcare - the more we spend the less the desire. The exception is the US - it spends nearly 3x the UK, 4x that of Czech Republic but has more people asking for a better health service and occupies a spot well above the red line. Why?

We know that the US system is based on insurance and tends to be more expensive to run - but other countries have largely private health systems and spend much less. Perhaps ironically as today marks the beginning of the partial shutdown of US public services because one political party are blocking the introduction of a policy that would give a measure of healthcare to everyone in the US, one possible explanation is that 17% (50 million people) of the population of the US have minimal healthcare - a third world population in a first world country in terms of healthcare.

Friday, 27 September 2013

Is Peer Review Broken?

The centuries-old process of assessing the worth of a piece of research prior to it being published is coming under attack and calls for reassessment. All research papers submitted to a scientific journal since the 1650's have been subjected to examination by experts in the field of research that the paper addresses.

This is undertaken to ensure that the paper offers something new but also try to ensure that when someone (usually several people) who is familiar with that type of research has time to look deeply into the data presented, they cannot find and major faults or omissions. Only then is the paper published.

This gives us a minimum standard of trust in the results of that paper. If this system goes wrong and a 'rogue' paper slips through that paper can still be questioned and withdrawn if found to be at fault. Peer review has sustained scientific research for nearly 350 years and the results are difficult to argue with - science has achieved so much that it would not have been able to do without ensuring the bedrocks of the process are of high quality.

 It is however not a perfect system. In a small field there may be only a few people who could thoroughly review an article. This leads to an increase in the probability that the reviewer will know the author of the paper personally (the authors are never told who their reviewers are) and thus rumours of foul play begin to circulate as friends may mutually support each others work. This is not usually a problem of fraud (but fraud does happen measured at 0.3% of all papers) but accusations that a paper has been published in a higher ranked journal than it deserved on merit. Occasionally we hear of a suspicion from a disgruntled researcher who has had lengthy problems getting a paper published and in the meantime someone else has published the same thing or misused their early access to an original work in some other way - perhaps a reviewer has read their paper and stolen their ideas? - always very difficult to prove either way.

In our modern world the system comes under new pressures. This talk outlines some of them:

Full discussion here

Thursday, 26 September 2013

Patients & carers support, National Aspergillosis Centre, UK

The National Aspergillosis Centre holds a meeting every month that tries to inform & support people suffering from aspergillosis. The meeting is recorded and made available at Slideshare where you can watch the whole series.

You can also watch the meetings live on the third friday of the month at 1.30pm local time (UK).

Tuesday, 24 September 2013

Genome sequencing & the Special Case of Henrietta Lacks

Henrietta Lacks
Henrietta Lacks died in Johns Hopkins University Hospital in 1951 of an aggressive cancer. In itself that was not a remarkable event except for close friends and family but Mrs Lacks was not going to be forgotten and for a very special reason.

At that time cancer research was just starting to find ways to grow cancer cells to use to work on and to try to find information that might lead to medication that has since led to increase in the life expectation of many millions of cancer sufferers. Researcher George Gay took some of the cells from tumour tissue after Mrs Lacks had surgery to try to treat her cancer, and he was successful at getting it to grow outside of a human body in a laboratory for the first time. George's work was so important that within a very short time Henrietta Lacks' tumour cells (referred to as HeLa cells) were in use all over the world in cancer research labs and they continue to be to this day. A cursory search of all published articles in the medical research database Pubmed reveals that there are well over 76000 published scientific papers that prominently feature HeLa cells and without doubt many more that use Henrietta Lacks' cells to help their research.

There has been some controversy over the use of HeLa cells as Henrietta was never asked to give her permission for her cells to be used in this way. Back in 1951 that wasn't something that was thought to be necessary but today we regard it as fundamentally important, and now even more so as we are able to read the entire genome of each and every one of us quickly and efficiently.

Readers of this blog will know that we have discussed some of the ethical questions raised by this new technology before, and there are several problems including:

  1. Does the person want to know all of the possible health problems that are revealed by a complete sequencing of their genome?
  2. Should the family of the person be told? Which members? When?
In this case the family of Henrietta Lacks are faced with the entire genome sequence of HeLa cells being published without their consent last year. Should they have had to right to privacy and publication been prevented? Some researchers have stated that as HeLa cells have been in culture for so long there have been many changes to the genome sequence and as a consequence the sequence information does not resemble that of the Lacks family in any meaningful way - which is at least partially true.

Lacks family members and officials & scientists in charge of the National Institute for Health (NIH) have reached an agreement for further use of HeLa cell sequence data - a landmark agreement that once again adds to our knowledge of how we should treat genome seqiencing projects and those who have their genomes sequenced:

The HeLa Genome Use Data Agreement establishes a six-person panel—including two representatives from the Lacks family—to review applications for access to the HeLa genome and set parameters for its use.

During a press briefing this morning, NIH Director Francis Collins, NIH Deputy Director for Science, Outreach, and Policy Kathy Hudson, and three members of the Lacks family presented the Agreement and discussed the circumstances that precipitated it.

"NIH is grateful to this remarkable family for their willingness to collaborate with us on this very important issue," Collins said during the press conference. "It's fitting--given the priceless contributions Henrietta Lacks's family has made to science and medicine--that her story is now catalyzing changes in policy. We should all count Henrietta Lacks and her family as among the greatest philanthropists of our time when you consider how they contributed to the advancement of science and our health."

Under the terms of the HeLa Genome Use Data Agreement, biomedical researchers who agree to abide by the terms of the agreement will be able to apply to NIH for access to the full genome sequence data from HeLa cells. Along with representatives from the medical, scientific, and bioethics communities, two representatives of the Lacks family--David Lacks Jr., Henrietta's grandson and Veronica Spencer, Henrietta's great granddaughter--will serve on NIH’s newly formed, six-member working group that will review proposals for access to the HeLa full genome sequence data.

NIH-funded researchers who generate full genome sequence data from HeLa cells will be expected to deposit their data into the NIH HeLa dbGaP database for future sharing through this process, while other researchers are expected to respect the family’s wishes and do the same. All researchers who use or generate full genomic data from HeLa cells are formally asked to include in their publications an acknowledgement and expression of gratitude to the Lacks family for their contributions. The agreement also mandates that researchers not attempt to contact any members of the Lacks family. 

The last words of this remarkable story should perhaps go to members of Henrietta's family:

“The HeLa genome is another chapter to the never ending story of our Henrietta Lacks,” said Henrietta’s granddaughter Jeri Lacks-Whye and Lacks family spokesperson. “She is a phenomenal woman who continues to amaze the world. The Lacks family is honored to be part of an important agreement that we believe will be beneficial to everyone.”

Full story

Thursday, 19 September 2013

US Cornerback Fights Back Against Aspergillosis

Marcus Rios
Marcus Rios plays for a UCLA American Football team and had the severe misfortune of contracting one of the rare types of invasive aspergillosis that affects the sinuses.

As is usual diagnosis was quite slow - though in this case his doctors were pretty sharp and may have identified the problem quicker than perhaps many others would have, perhaps others not having access to state of the art equipment.
As a result the infection is usually well established before treatment begins. In this case Marcus suffered the loss of sight in one eye at one point and the fungus had infected his brain but his resilience is remarkable and he maintained a positive attitude throughout.

Marcus is now back playing football. Read his remarkable story in the Los Angeles Times here

Monday, 16 September 2013

Cytisine: A Cheap Way to Stop Smoking?

One of the prime causes of worsened respiratory disease (including aspergillosis) is tobacco smoking. Consequently one of the most effective

"Nearly 50 years ago, and before any smoking cessation aids were approved in the Western world, cytisine was being used in eastern and central Europe to help people quit smoking. An alkaloid with high affinity for the α4β2 nicotinic acetylcholine receptor subtype, cytisine is derived from the plant Cytisus laburnum. It was discovered in 1818, first isolated in 1865,1 and its actions were documented as “qualitatively indistinguishable from that of nicotine” in 1912.2 It was smoked as an accessible and cheap tobacco substitute by German and Russian soldiers during the second world war, and it was brought to market in 1964 as a cessation aid under the brand name Tabex, now produced by Sopharma, a Bulgarian drug company. "

The research data supporting the use of cytisine is insufficient in itself to enable us to recommend its use to help people quit smoking so more work is needed but here we have a problem - this substance is freely available and cheap, much cheaper than any other tobacco substitute and the data that we have suggests that it is at least as good as replacement products costing much more. Consequently there is relatively little potential profit for a drug company to carry out all of the required and meticulous work needed to formally bring this substance to market - in fact they would be costing themselves money as sales would be likely to fall of the commercial products manufactured by those companies.

The authors of this editorial in the British Medical Journal suggest that governments should fund this research in the public interest particularly in countries where incomes are low.

Friday, 13 September 2013

ICAAC 2013: Invasive Mycoses: Consider the Source, Consider the Host

Introduction and Overview of Host Issues


  • HSCT Patient with a Mold Infection
  • Pediatric Patient with a Fever in the Pediatric ICU
  • SOT Patient with Suspected Fungal Infection

Program Overview
Invasive fungal infections (IFIs) remain a substantial source of morbidity and mortality. While the increasing burden of IFIs is generally seen as a byproduct of modern medicine and an increasing net state of immunosuppression, emerging data on genomics and the immunologic response of the host are informing a deeper understanding of what happens at the level of the patient. This activity will address the differences in IFIs among pediatric patients, solid organ transplant (SOT) patients, and hematopoietic stem cell transplant (HSCT) patients in terms of causative pathogens (the source), the host response to the pathogens, diagnostic considerations, and response to therapeutic interventions.

This activity will explore whether our increased understanding of these interrelated factors can lead to personalized therapy for IFIs, as is occurring in oncology. Against this backdrop, we have documented gaps in managing IFIs per evidence-based society guidelines, such as in initiating prophylactic, pre-emptive, and empiric therapy (when appropriate) and definitive treatment across these host types. Finally, as emerging diagnostics and therapeutics are developed, their efficacy in these varied host populations as well as their interactions with host factors are key considerations. All of these topics will also be addressed in this initiative using a case-based, interactive format.

More details posted here when available

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Contact us at admin@aspergillus.org.uk