News from the press

The Lancet Series Exposes Global Paucity of Care for Life Threatening Fungal Infections

Influential medical journal 'The Lancet' has a long history (first published in 1832)  of taking on difficult issues in health and politics. In keeping with this traditions it has commissioned a new Global Health Series calling for global action on improving the awareness,  diagnosis and treatment of life threatening fungal infections. This is the first time a series on this topic has featured in any journal, but what is the problem that is being addressed?

In the developed world there have been huge strides taken over the last two or three decades such that many more infections are being detected and treated, though still by no means are we diagnosing or successfully treating all. However in many parts of the developing, lower income world there are vulnerable people with fungal infections who receive little or no diagnosis or treatment. Currently 1.5 million people a year that we know of die a preventable death due to fungal infection and over 1 billion people are infected worldwide. Of these it is estimated that aspergillosis (allergic bronchopulmonary aspergillosis (ABPA) or chronic pulmonary aspergillosis (CPA)) accounts for 5 million cases each year.

Part of the reason for this neglect is that many fatal fungal infections are 'hidden' from the statistics that drive awareness and investment. A patient who has HIV or cancer that causes a vulnerability to infection that allowed Aspergillus to grow is likely to be recorded as a death due to HIV or cancer rather than aspergillosis. There is also the possibility that diagnosis of the fungal infection will be missed completely even in developed countries as diagnosis is difficult and requires specialist skills and tests. 

Diagnosis is often very slow in the developed world as clear differentials are not available for fungal diseases such as ABPA or CPA. Patients who are referred to the National Aspergillosis Centre in Manchester, UK often relate stories of having respiratory illness for years before finally being referred and subsequently diagnosed with ABPA or CPA. This often results in a poorer outcomes for the patient.

Professors David Denning and Juan Luis Rodriguez Tudela of the University of Manchester have co-ordinated the series and it will take the form of eight new authoritative papers that outline some of the systematic problems that are holding back better care for fungal infections worldwide. The authors of the papers are collectively from all six populated continents of the world giving the series a broad scope of experience.

A broad range of clinical contexts for fungal infection are covered in the series including HIV, cancer, TB, asthma, genetic immunodeficiency and after transplantation and surgery: all common causes or comorbidities of aspergillosis.

In many countries there is insufficient resource in terms of training, staff, diagnostic equipment and access to antifungal drugs to adequately challenge fungal disease.  Usefully the International Foundation GAFFI (Global Action Fund for Fungal Infections) has mapped out the availability an cost of some antifungal drugs across the globe in its collection of drug maps. One map reveals that although itraconazole seems widely available, access to itraconazole is very variable as the price in different countries ranges from $0.01 per day in Sri Lanka up to $98.2 per day in Sweden

In many countries there is no proposal to integrate fungal diseases into the healthcare system at all, or limited monitoring of what is available. To address this Professor Donald Cole of the University of Toronto calls for 'combined health systems and public health approaches' with examples from Mozambique, Kenya, India and South Africa.

The fast emerging problem of antifungal drug resistance accompanied by its spread via environmental sources is a topic along with the need for researching new drugs and especially new antifungal drug classes or different ways to deliver medication is the subject of another article in the series.

Summing up, Professor Denning added:

“The evidence gathered in this article series shows not only the scale of the global problem but also that hundreds of thousands of deaths a year could be avoided."

“The expertise is available, now it just needs government and international action to make it a reality.”

There are nine published papers in this 'Fungal Infections' series as follows:

Fungal Disease expert urges Government to review house building regulations

Professor Denning speaks to the Parliamentary and Scientific Committee in the House of Commons.

London, UK, July 17, 2017 (House of Commons) – At a meeting of the Parliamentary and Scientific committee in the House of Commons, Professor David Denning from Manchester University called on government to review current building regulations to address the rise in asthma cases caused by a lack of ventilation in buildings. There is a direct link between a lack of ventilation and subsequent growth of moulds that can cause asthma.

Professor Denning said:

"Major opportunities exist to reduce new asthma cases by improving ventilation in homes and offices, as well as improving asthma symptoms. In addition, with 120,000 to 450,000 fungal asthma sufferers in the UK, earlier recognition by GPs and specialists and a trial of antifungal therapy, major health benefits are tangible."

 

“We should take the example of Scandinavia”, Professor David Denning further added. “They are using a system of heat exchange that is very effective, as households are not consuming energy, while keeping the air clean”.

The parliamentarians were also told that there are over a billion people across the world affected by fungal diseases resulting in 11.5 million life-threatening infections and over 1.5 million deaths every year.

Recent advances in diagnostics, robust screening programmes and improved access to low cost antifungal drugs could provide an unprecedented opportunity to reduce the burdens of ill health and death, especially in those with HIV/AIDS.

Professor Denning made three further requests of the parliamentarians:
1. Improved building regulations for older houses to optimise ventilation to reduce mould and condensation, commensurate with housing stock and heat conservation. 
2. Ensure that any new antifungal drug for human use cannot be sprayed on crops or used in the environment. 
3. To look at a code of practice greatly restricting the use of five azole antifungals in non-essential food crops, across Europe. 

 

Notes to editors:

Professor David Denning is a practising physician at the University Hospital South Manchester (UHSM) with expertise in fungal infections, particularly aspergillosis, antifungal resistance, the treatment of fungal infection and infection in the immunocompromised patient.

(http://www.nationalaspergillosiscentre.org.uk/)

He is also the president of the Global Action Fund for Fungal Infections (GAFFI).

GAFFI is a charitable foundation (NGO) focused on reducing deaths and illness caused by fungal disease. 
Fungal diseases are neglected worldwide by public health authorities. GAFFI efforts are directed at:

1. Identifying and publicising gaps in diagnostics and treatments for fungal diseases
2. Consulting on how healthcare could be improved through facilitating training, encouraging companies to expand their markets and recommending improvements in infrastructure
3. Estimating the burden of serious fungal diseases, country by country. Over 68 country estimates are complete, and many of these are published
4. Developing, implementing and evaluating countrywide diagnostic programs - Guatemala (fungal infections in AIDS) the first
5. Influencing national and international agencies to ‘adopt’ fungal diseases alongside existing programs including TB, microbiology, AMR, NTDs and incorporation of key generic antifungals onto the WHO Essential Medicines List.
6. Focusing diagnostic improvements for GAFFI’s priority diseases. 

(http://www.gaffi.org/)

One of the first countries of the world where researchers suggested the generation of triazole antifungal drug resistance originates in the environment was the Netherlands which is a world leader for the production of plant bulbs, with almost nine billion bulbs, mostly tulips, exported every year. These bulbs are sold throughout the world with major markets in the US, Japan, China, EU and Russia.

 

(http://www.life-worldwide.org/media-centre/article/beautiful-bulbs-and-flowers-are-spreading-a-deadly-legacy-triazole-resistan

TULIPS FROM AMSTERDAM: ROSES FROM COLUMBIA - HOW THESE BEAUTIFUL BULBS AND FLOWERS ARE SPREADING A DEADLY LEGACY

Researchers in Manchester are questioning the legal use of certain fungicides used on imported flowers and bulbs following evidence that they induce resistance to the drugs used to treat patients with Aspergillus fumigatus, a virulent type of fungal disease.                        

One of the first countries of the world where researchers suggested the generation of triazole antifungal drug resistance originates in the environment was the Netherlands which is a world leader for the production of plant bulbs, with almost nine billion bulbs, mostly tulips, exported every year. These bulbs are sold throughout the world with major markets in the US, Japan, China, EU and Russia.

Professor Malcolm Richardson, Director of the Mycology Reference Centre at the University Hospital of South Manchester, Wythenshawe Hospital, Manchester, UK says the transfer of azole resistance on bulbs from the world’s resistance hotspot in the Netherlands has an “Armageddon feel to it” for the many millions of patients on or requiring anti-Aspergillus therapy.

He explains; “Five azole fungicides induce resistance in A. fumigatus and can still be legally used on bulbs – is this sensible from a public health perspective? With no backup agents available orally, and the massive proliferation potential of Aspergillus, this problem needs urgent attention from public health authorities, who have been silent to date.”

In March, a team of researchers from Trinity University, in Dublin examined samples of plant bulbs imported into Ireland from the Netherlands.  Samples taken from 2014, 2015 and 2016 all bore isolates of A.fumigatus that had resistance to one or more triazole antifungal drug.  Quite apart from the risk to people handling these bulbs this is a clear example of how resistant strains can be spread from country to country.

This is not a problem restricted to Europe. Colombia is the second most prolific exporter of cut flowers in the world. It is also a heavy user of triazole fungicides and a team of researchers from Columbia, France and Holland also detected triazole resistant strains of A. fumigatus in 9 per cent of samples taken from soil collected from places where flowers are grown.

Professor Richardson and his team believe these reports provide clues as to how resistant strains are being generated and spread. and why they are now present on all six continents of the world, but there are likely to be many more examples when we consider the amount of trade in materials likely to be contaminated with Aspergillus fumigatus that is exchanged internationally every day, and the amount of use of triazole fungicides for agricultural purposes throughout the world.

For more information please contact Sean Curtis- Ward at The Goodwork Organisation on  0208 747 1488 or mobile 07836 690318.

 

NOTES TO EDITORS

The availability of triazole antifungal drugs has had a huge impact on the treatment of serious fungal diseases such as Invasive Aspergillosis (IA), Chronic Pulmonary Aspergillosis (CPA) and are starting to have a positive impact on severe forms of asthma [1]. The first such drugs became available in 1997 (itraconazole) and several more are now available to clinicians (e.g. voriconazole, posaconazole and isavuconazole ) and are used extensively, collectively referred to as triazole antifungal drugs. Several millions of patients rely on treatment with triazole antifungals every year worldwide.

Antifungal drug resistance in Aspergillus fumigatus (the species that causes the most serious infections) is emerging as a significant risk factor when treating patients for acute and chronic serious fungal infections. Mortality rates for patients with IA are high (40-60%) when infected with an antifungal sensitive strain of A. fumigatus, but can reach 88% where resistance is detected[2].

An established route for the generation of antifungal resistance in the clinic would begin when infected patients are treated with a triazole. Once the infecting fungus is exposed to a triazole in vivo in time it can result in the outgrowth of a triazole resistant strain of A. fumigatus. However doctors have noted strains of triazole resistant A. fumigatus in patients who had NO prior exposure to antifungal drugs suggesting that there is an additional route for resistance acquisition.

Evidence has been rapidly accumulating that some strains of antifungal drug-resistant Aspergillus fumigatus originate in the environment and are associated with widespread and heavy agricultural use of triazole fungicides to protect crops from fungal infection 1. Inhalation of the spores of these fungi automatically renders treatment with some or all triazole antifungal drugs ineffective, with grave possible consequences.

1.         Verweij, P.E., et al., Azole Resistance in Aspergillus fumigatus: Can We Retain the Clinical Use of Mold-Active Antifungal Azoles? Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2016. 62(3): p. 362-8.

2.         Denning, D.W. and P. Bowyer, Voriconazole resistance in Aspergillus fumigatus: should we be concerned? Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2013. 57(4): p. 521-3.

3.         Ribas, E.R.A.D., et al., Is the emergence of fungal resistance to medical triazoles related to their use in the agroecosystems? A mini review. Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology], 2016. 47(4): p. 793-799.

4.         uk.ibulb.org. The flower bulb sector within an international perspective. 2017  [cited 2017 June 2017]; Available from: http://uk.ibulb.org/275/the-flower-bulb-sector-within-an-international-perspective.html.

5.         Dunne, K., et al., Inter-country transfer of triazole-resistant Aspergillus fumigatus on plant bulbs. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2017.

6.         Alvarez-Moreno, C., et al., Azole-resistant Aspergillus fumigatus harboring TR34/L98H, TR46/Y121F/T289A and TR53 mutations related to flower fields in Colombia. Scientific reports, 2017. 7: p. 45631.

 

OVER A MILLION AIDS DEATHS PREVENTABLE BY 2020, SAYS GAFFI -  CALL ISSUED FOR IMPROVED DIAGNOSIS AND TREATMENT OF FUNGAL INFECTION

GENEVA: [24th October 2016] Fungal infection causes around half of AIDS-related deaths, of which there were 1,100,000 in 20151.  A first of its kind analysis – ‘Modelling reduction in AIDS deaths’ by the University of Manchester’s Professor David W Denning2 and published today in Philosophical Transactions of the Royal Society B3 – suggests that the opportunity to save lives is being missed. 

Using 2013 data of 1.5m deaths from AIDS, around 47% (700,000) were attributable to the four most common lethal fungal infections4 and 24% (360,000) to tuberculosis (TB).  Scenarios and projections to 2020 for the reduction of avoidable deaths were constructed based on published outcomes of the real-life impact of diagnostics and generic antifungal drugs.  The Global Action Fund for Fungal Infections (GAFFI) concluded that access to rapid diagnostics and antifungals could prevent just over 1,000,000 deaths by 2020.

GAFFI analysis predicts that on the current trajectory there will be 740,000 AIDS-related deaths in 2020. GAFFI is calling for a global focus on identifying and treating fungal diseases which could reduce this figure by 42% to 426,000.

Accelerating a reduction in AIDS-related deaths: With improved access to antiretroviral therapy and a focus on diagnosing TB co-infection, deaths from AIDS have been falling.  However, progress is slower than anticipated across the world.  The UNAIDS aspirational target of zero AIDS deaths by 2015 was not met5: however, on UNAIDS numbers, there was a 41% reduction in lives lost (from 2010 at 1.76 m to 1.1 m in 2015). 

Continued failure to focus efforts on advanced HIV infection and the 47% with fungal infections means the current UNAIDS target of fewer than 500,000 annual deaths by 20206 will almost certainly be missed - as was the aspirational target of zero AIDS deaths by 2015.  Retention in care is a major factor but it is late presentation with overwhelming infection that is GAFFI’s primary concern. 

On the third anniversary of GAFFI’s inception, the Foundation established to address access to fungal diagnostics and therapy worldwide, an urgent call is being made to focus attention on preventable opportunistic infections which account for most AIDS-related mortality, with a median age of death in the mid-30s. 

Professor David Denning of GAFFI and the University of Manchester, comments: “Too many people die from AIDS, most of them adults in the prime of life.  Our analysis shows that diagnosing and treating fungal diseases complicating HIV infection will drive down AIDS deaths in the short term.  Action could and should be taken by donors, national and international public health agencies, non-governmental organisations and governments toward achieving the UNAIDS mortality reduction target and the recently announced 2030 Millennium Development Goals.”

Denning continues, “Our projections reveal that by improving access to just 60% of those who need it, over 300,000 lives could be saved per year.  By 2020, a total of over a million lives could have been saved, helping to meet the UNAIDS mortality reduction target reducing AIDS deaths to 500,000 per year.”

”Dr Meg Doherty, Department of HIV and Global Hepatitis Programme, World Health Organisation, says: “The HIV/AIDS epidemic is one of the greatest global health challenges. We commend GAFFI’s call for global concerted action to address the large number of AIDS deaths caused by fungal infection. Widespread adoption of rapid tests for fungal disease and adoption of the WHO’s cryptococcal guidelines should reduce mortality.  Country-level integration of fungal disease interventions and treatment guidelines into existing HIV and TB programmes and national strategies would offer a leap forward in achieving everyone’s goal of reducing AIDS deaths.” 

 

-Ends-

Notes to editors

 

References:

11.1 million [940 000 – 1.3 million] people died from AIDS-related illnesses in 2015 (Fact sheet 2016 | UNAIDS (http://www.unaids.org/en/resources/fact-sheet) and 1,340,000 is the figure used in the GAFFI analysis.   The absence of accurate death registration in many countries precludes highly accurate mortality statistics.

 

2 David W. Denning FRCP FRCPath FMedSci is the current President of GAFFI.  He is also Professor of Medicine and Medical Mycology, University of Manchester and the Director of the National Aspergillosis Centre (NAC), University Hospital of South Manchester, UK.

The NAC has been commissioned by the Department of Health to provide long term care for patients with chronic pulmonary aspergillosis.

 

3 Publication: Denning DW. How the UNAIDS target of reducing annual AIDS deaths below 500,000 by 2020 can be achieved. Phil Trans Roy Soc B, In press.  The analysis used a linear prediction scenario exercise, and compared the current slow downward trajectory of AIDS deaths with gradually increasing efforts to diagnose and treat fungal disease, as well as the benefits of increased ARVs. The HIV statistics used by GAFFI were based on 2013 deaths of 1.5 million, which were readjusted downwards in 2014 to 1.2 million, by UNAIDS, after the analysis was done. The absence of accurate death registration in many countries precludes highly accurate mortality statistics.

 

4 The major fungal causes of death in AIDS patients are: cryptococcal meningitis, Pneumocystis pneumonia (PCP), disseminated histoplasmosis and aspergillosis. Rapid diagnostic tools and antifungal agents are available for these diseases, and the study found that with 60% coverage, annual deaths for cryptococcal disease could fall by 70,000, PCP by 162,500, disseminated histoplasmosis by 48,000 and chronic pulmonary aspergillosis by 33,500.

 

5 UNAIDS 2011 – 2015 Strategy ‘Getting to Zero’

http://www.unaids.org/sites/default/files/sub_landing/files/JC2034_UNAIDS_Strategy_en.pdf

 

6 UNAIDS 2016 United Nations political declaration 2016: http://www.unaids.org/en/resources/presscentre/pressreleaseandstatementarchive/2016/june/20160608_PS_HLM_PoliticalDeclaration

 

The Global Action Fund for Fungal Infections (GAFFI www.gaffi.org): GAFFI’S vision is to reduce illness and death associated with fungal diseases worldwide. GAFFI works to improve the health of patients suffering from serious fungal infections through better patient care, improved access to diagnostics and treatment, and by provision of educational resources to health professionals. As a Geneva-based Foundation, GAFFI is the major advocacy and fund raising body for a number of implementing partners, including governments and both national and international global health agencies. GAFFI issued a 10 year Roadmap in 2015 entitled ’95-95 by 2025’ calling for 95% of the world’s population to have access to fungal diagnostics and antifungal therapy by 2025.

 

For further information and interviews contact: Kat McCamley, Iona Cousland or Julie Flexen (tbc) at Munro & Forster Communications on 020 7089 6100 or [email protected]

LIVING WITH UK BURDEN OF FUNGAL ASTHMA GREATLY EXCEEDS PRIOR ESTIMATES NEW STUDY WARNS

Experts at the National Aspergillosis Centre and Manchester Academic Health Science Centre are warning of a significant increase in the number of people in the UK who are living with invasive and serious fungal diseases that affect the lungs, bloodstream and brain and can sometimes lead to death.

While invasive fungal infections were estimated by the Health Protection Agency in 20061 a new report published today* is the first comprehensive attempt to capture how many people in the UK suffer from fungal asthma.

Asthma in adults is common in the UK with over 4 million reported cases, and researchers in Manchester believe as many as 300,000 of them are affected by fungal asthma.

The research from the National Aspergillosis Centre and MAHSC (Manchester Academic Health Sciences Centre), based at The University of Manchester – is published by the British Infection Association.

Fungal asthma is such a big problem because the UK has one of the highest rates of asthma internationally. The range of estimate reflects uncertainty as no community study has ever been done, despite the large number affected. Asthmatics allergic to and exposed to higher amounts of fungi that they breathe in usually have poor asthma control and require steroid boosters. Antifungal therapy benefits these people, and may prevent deaths from asthma, doctors believe.

Invasive aspergillosis is the commonest missed infectious diagnosis in intensive care in the UK. It is always fatal without therapy and affects from 3,288 to 4,257 patients each year, most undiagnosed. Treated invasive aspergillosis has a 30-85 per cent mortality depending on the patient group.

Dr Bradford Winters in 2012 analysed deaths in intensive care, and invasive aspergillosis was the commonest missed infectious diagnosis2.

Pneumocystis pneumonia has been increasing, especially in the non-HIV group, and probably affects over 500 annually. 15-50 per cent of these patients die, even if treated.

Although 1,700 cases of Candida bloodstream infections are reported annually, the actual estimate of tissue invasive cases in hospitalised and critically ill people is 5,124. This carries a ~45% mortality, if diagnosed and treated.

A Health Protection Agency report from 2006 estimated that ~66 per cent of those who die of fungal infection could have been saved with faster recognition and rapid diagnosis.

Experts believe rarer infections and antifungal resistant infections are probably on the increase, including Candida auris and multi-resistant Aspergillus fumigatus derived from the environment.

Professor David Denning Director of the National Aspergillosis Centre at the University Hospital of South Manchester, explained: ‘While the UK is rich in data sources, there is a remarkable poverty of contemporary studies of fungal diseases. An accurate estimate of total burden will ultimately rely on improved diagnostic testing and laboratory reporting.

“This report gets us closer to true burden of fungal diseases in the UK – necessary for improved diagnosis and reducing death. The scale of the ‘fungal asthma’ problem is staggering, and potentially remediable with antifungal therapy, as I know from treating hundreds of affected patients,” he added.

 

For more in formation please contact Susan Osborne, Director of Communications at The Goodwork Organisation on 07836 229208.

Note to Editors

1.http://webarchive.nationalarchives.gov.uk/20140714084352/http://www.hpa.org.uk/webc/hpawebfile/hpaweb_c/1196942156347

2. Winters B, Custer J, Galvagno SM Jr, Colantuoni E, Kapoor SG, Lee H, Goode V,  Robinson K, Nakhasi A, Pronovost P, Newman-Toker D. Diagnostic errors in the intensive care unit: a systematic review of autopsy studies. BMJ Qual Saf. 2012 Nov;21(11):894-902. Link http://qualitysafety.bmj.com/content/21/11/894

Fungal asthma is an umbrella term for allergic bronchopulmonary aspergillosis (ABPA), severe asthma with fungal sensitization (SAFS) and fungal-associated airways disease. Almost all patients are adults, as these condictions are rare in children. Patients sensitized (ie allergic) to fungi have much worse asthma, attend and are admitted to hospital more often, need more corticosteroids and probably are more likely to die of asthma. About 197 million adults have asthma across the world and an estimated 4.8 million have ABPA and over 6.5 million (3%) have SAFS.

Cases of fungal disease compared with other health problems in the UK:

TB – 5,758 cases in 2015

Malaria – 1,400 cases in 2015

New HIV diagnoses - 6,151 in 2014

Meningococcal (meningitis) disease – 805 cases in 2015/16

Multiple sclerosis – 107,000 in 2016

Breast cancer - 53,696 in 2013, with 11,433 deaths

Rheumatoid arthritis 297,600 in 2002

Pages

Subscribe to News from the press