Salbutamol nebuliser solution shortage
We have been informed that there is an ongoing shortage of salbutamol solutions for nebulisers that is likely to last until summer 2024. If you live in Greater Manchester and you have COPD or asthma your GP has been provided with guidelines to ensure that any impact on your care is minimised, and your GP will be able to advise you further.
GPs elsewhere in the UK will also need to prepare, and update your action plan accordingly.
If at all concerned contact your GP for advice, as all should be aware of this situation.
Interactive tool for asthma patients to help self-assessment
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Asthma is a complex disease with many different causes & triggers. Sometimes asthma symptoms gradually get worse despite all efforts to control them, and one way that happens is when someone becomes allergic to Aspergillus. Allergic BronchoPulmonary Aspergillosis (ABPA) and Severe asthma with fungal sensitisation (SAFS) are two possible outcomes. This progression usually happens slowly and gradually so it is difficult to tell when the allergy began. This tool can help you assess if you need more help from your doctors, and what help may be available.
Asthma + Lung UK has developed an interactive tool to enable people with poorly controlled asthma to self-assess their likelihood of having severe asthma and ask for the support they need. This can be a useful way to find out if you could benefit from biologics (or other therapy).
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Do you need a Patient Information Leaflet for your medication?
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Patient Information leaflets (PIL) are meant to be enclosed with every pack of medication, in fact, it is a legal requirement unless all the relevant information is on the packaging. The PIL must contain all the information needed for a patient to be able to take the medication safely and effectively, so the leaflet includes details of dose, how to take the medication, side effects, and much more. It is strongly suggested that the patient read through all the information before taking the medication, especially if it is the first time that the patient has taken the enclosed drug.
Despite the law, there may be reasons why you might not have received a PIL with your latest drug. Sometimes a pack has been split by the pharmacist between more than one patient for example. If you need a PIL and you didn't receive one you can return to your pharmacist who should be able to source one for you, and for those who have access to the internet, you can also find a PIL for all medications online.
Go to medicines.org.uk and search for your prescription drug. The documents on this website are fully verified by UK govenment authorities.
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Unvalidated Laboratory Testing
Commercial laboratories can sell their diagnostic tests directly to the public, or they can be ordered by non-NHS providers of healthcare. The reasons given can sound very persuasive about how useful those test results can be - for example, testing for organic acids in your urine to check your nutritional status or testing for mycotoxins in your urine to assess if you have been exposed to excessive airborne mould spores. Unfortunately, these results are often useless for the purpose intended.
It is important that testing is validated for clinical use for the purpose it is being used for, for example:
- An Organic acid profile in urine is validated and used by the NHS for testing patients for very rare genetic problems that lead to an accumulation of an organic acid and a deficiency in certain cellular products. These levels are likely to be high and the result is clear and consistent from test to test. These tests are likely to be carried in in very young children who have inherited an abnormal gene. https://www.southtees.nhs.uk/services/pathology/tests/organic-acids-urine/.
- An Organic acid profile in urine is NOT validated to run on adults who have a normal genetic profile and have no signs or symptoms of metabolic disease. The results are going to need highly specialised doctors to interpret the results. If used for the purpose of, for example, assessing the nutritional status of a patient there is no evidence that the result will tell you or your doctor anything useful. Consequently these are very unlikely to be worth the cost.
If you are tempted to purchase one of these tests it is well worth checking this website for advice https://labtestsonline.org.uk/tests/unvalidated-or-misleading-laboratory-tests
Osteoporosis (Thinning bones)
Many people with aspergillosis are vulnerable to osteoporosis, partly due to some of the medication they take, partly due to their genetics and partly age.
There is a complete guide for the treatment of osteoporosis by the NHS at the National Institute for Health and Care Excellence (NICE) called Osteoporosis - prevention of fragility fractures and you can read it here.
However, you may prefer the easier-to-read guidelines offered by the Royal Osteoporosis Society which is comprehensive and excellent. There is even a helpline manned by a specialist nurse during office hours Monday-Friday.
There are lots of options for treatment available!
Learning to control antifungal drug resistance from the environment
Spores of fungi including Aspergillus fumigatus, the main species that causes aspergillosis, have been found to propagate the growth of strains of fungi that are already resistant to those antifungal medications most commonly used in medical clinics to treat aspergillosis. This can render the most common treatments for aspergillosis useless, which is a concern for doctors.
Where do these strains come from? Most experts suggest that the use of commercial fungicides by farmers exposes the fungus to pesticides that closely resemble the antifungal drugs used by doctors. This exposure is likely to enrich the numbers of resistant spores found in the environment ie in compost, soil, and of course in/on the plant material produced by the farmers e.g. food crops, and flowering plants.
Can we stop using these antifungal chemicals as pesticides? A multi-disciplinary meeting designed to bring together experts from all sides of the debate took place in London on 13th July and those representing the growers outlined how important it is that farmers use these fungicides to prevent crop damage and to produce enough food to feed us all! Completely stopping their use on crops does not seem to be an option.
Given that it seems that there will be antifungal-resistant spores in the environment we live in for the foreseeable future we need to:
- know where they are
- know how to avoid inhaling them
Where might patients come into contact with most antifungal-resistant spores?
Farmers use antifungal pesticides on many crops including:
- Fruits: Apples, grapes, peaches, strawberries, and tomatoes
- Vegetables: Potatoes, onions, corn, and soybeans
- Grains: Wheat, corn, and rice.
- Nursery crops: Roses, trees, and shrubs
Researchers have found antifungal-resistant Aspergillus fumigatus spores on many of these crops or the soil around them, at low levels (0 - 10% of samples).
Is this level of antifungal-resistant spores increasing?
When scientists looked at spore numbers they found that the number of resistant spores increased during the growing season as antifungal pesticides were applied to the crops, but this resistance did not survive the winter (1) and levels were back down to where they were the previous year.
It is apparent that handling crops, or the soil around them is a potential way to come into contact with some spores that are resistant to antifungal medications given in the clinic.
What is the likelihood of these spores causing an antifungal-resistant infection?
Researchers (1) have looked at how resistant the resistant spores are to the level of antifungal medication they will be exposed to in a patient and found that the proportion of the isolates that were resistant to the levels of antifungal medication used in patients was 1-4% - so very low.
Which crops are worst affected?
The most common material found to contain antifungal-resistant material was plant material waste originating from cut flowers and flowering bulbs and other types of waste produced in the industry in The Netherlands (2), so it is clear that composting can promote the growth of resistant spores. Ways to prevent this from happening are under development.
Other materials tested were household waste, wheat grain, poultry manure, cattle manure, horse manure, maize silage & fruit waste and of those antifungal-resistant spores were found only in fresh household waste.
Other researchers across the world (3) have detected antifungal-resistant spores in a range of crops and soils. Highest numbers of resistant spores (or perhaps in places where most research has been done) tend to be in India (rice), China (maize, some house plants, potato), USA (wheat, roses, apples), The Netherlands (orchids), Spain (onions, strawberries), Colombia (carrots) & Italy (grapes).
These were not exhaustive studies and we know that Aspergillus fumigatus (i.e. not antifungal-resistant) itself is found on far more plants/fruits/vegetables, so it stands to reason that if they are treated with antifungal pesticides then it may be possible to isolate resistant spores from them. It is clear that although there is a risk of inhaling antifungal-resistant spores from this plant material, the risk to the domestic consumer is low. Nonetheless, out of an abundance of caution, it might be best to take a few precautions:
a. Avoid handling cut flowers and flowering bulbs from The Netherlands
b. After purchase wash fruit and vegetables prior to storage in the home
c. Dispose of household waste in a timely manner
Action is being proposed and taken nationally and internationally to reduce the risk to aspergillosis patients in particular of inhaling antifungal-resistant spores of A. fumigatus and other fungi (4). Research is ongoing to learn more about what are the causal factors responsible for the increase in resistant spores, which are the main risks to human health and what we can do about it.
In time we should be able to prevent the growth of resistant isolates, ensuring that we have useful antifungal medication for years to come.
1. Effects of Agricultural Fungicide Use on Aspergillus fumigatus Abundance, Antifungal Susceptibility, and Population Structure
Authors: Amelia E. Barber https://orcid.org/0000-0002-3399-1037, Jennifer Riedel, Tongta Sae-Ong, Kang Kang, Werner Brabetz, Gianni Panagiotou, Holger B. Deising, Oliver Kurzai https://orcid.org/0000-0002-7277-2646AUTHORS INFO & AFFILIATIONS
DOI: https://doi.org/10.1128/mbio.02213-20
2. Emerg Infect Dis. 2019 Jul; 25(7): 1347–1353. doi: 10.3201/eid2507.181625
Environmental Hotspots for Azole Resistance Selection of Aspergillus fumigatus, the Netherlands
Sijmen E. Schoustra, Alfons J.M. Debets, Antonius J.M.M. Rijs, 1 Jianhua Zhang, Eveline Snelders, Peter C. Leendertse, Willem J.G. Melchers, Anton G. Rietveld, Bas J. Zwaan, and Paul E. Verweij
3. Azole-resistant Aspergillus fumigatus in the environment by cburks817 · MapHub
4. Nat Rev Microbiol. 2022; 20(9): 557–571.
Published online 2022 Mar 29. doi: 10.1038/s41579-022-00720-1
Tackling the emerging threat of antifungal resistance to human health
Matthew C. Fisher,1 Ana Alastruey-Izquierdo,2 Judith Berman,3 Tihana Bicanic,4 Elaine M. Bignell,5 Paul Bowyer,6 Michael Bromley,6 Roger Brüggemann,7 Gary Garber,8 Oliver A. Cornely,9 Sarah. J. Gurr,10 Thomas S. Harrison,4,5 Ed Kuijper,11 Johanna Rhodes,1 Donald C. Sheppard,12 Adilia Warris,5 P. Lewis White,13 Jianping Xu,14 Bas Zwaan,15 and Paul E. Verweij11,16
Unblocking Airways: New approaches to preventing mucus plugs
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Excess mucus production is a common problem in people with Allergic Bronchopulmonary Aspergillosis (ABPA), and chronic pulmonary aspergillosis (CPA). Mucus is a thick mixture of water, cellular debris, salt, lipids, and proteins. It lines our airways, trapping and removing foreign particles from the lungs. The gel-like thickness of mucus is caused by a family of proteins called mucins. In individuals with asthma, genetic changes to these mucin proteins can thicken the mucus, making it more difficult to clear from the lungs. This thick and dense mucous builds up and can lead to mucus plugs, blocking the airways and causing breathing difficulties, wheezing, coughing, and other respiratory symptoms.
Doctors usually treat these symptoms with inhalable medications such as bronchodilators and corticosteroids to open the airways and reduce inflammation. Mucolytics can also be used to break down mucus plugs, but the only available medication, N-Acetylcysteine (NAC), is not very effective and can cause unwanted side effects. While current treatments can help manage symptoms, there is a need for effective and safe treatments to directly address the issue of mucus plugs.
To address this issue, 3 approaches are being explored:
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- Mucolytics to dissolve mucus plugs
Researchers at the University of Colorado are testing new mucolytics such as tris (2-carboxyethyl) phosphine. They gave this mucolytic to a group of asthmatic mice experiencing inflammation and excess mucus production. After treatment, mucus flow improved, and the asthmatic mice could clear mucus just as effectively as the non-asthmatic mice.
However, mucolytics work by breaking the bonds which hold mucins together, and these bonds are found in other proteins in the body. If the bonds are broken in these proteins, it could lead to unwanted side effects. Therefore, further research is needed to discover a drug that will only target the bonds in mucins, reducing the risk of side effects.
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2. Clearing crystals
In another approach, Helen Aegerter and her team at the University of Belgium are studying protein crystals which they believe drive mucus overproduction in asthma. These crystals, known as Charcot-Leyden crystals (CLC’s) cause mucus to become thicker, therefore harder to clear from the airways.
To address the crystals directly, the team developed antibodies that attack the proteins in the crystals. They tested the antibodies on mucus samples collected from individuals with asthma. They found that the antibodies effectively dissolved the crystals by attaching themselves to the specific regions of the CLC proteins that hold them together. In addition, the antibodies dampened inflammatory reactions in mice. Based on these findings, the researchers are now working on a drug that could have the same effect in humans. Aegerter believes that this approach could be used to treat a variety of inflammatory diseases that involve excessive mucus production, including sinus inflammation and certain allergic reactions to fungal pathogens (such as ABPA).
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- Preventing excess secretion of mucus
In a third approach, pulmonologist Burton Dickey of the University of Texas is working to prevent mucus plugs by reducing the overproduction of mucus. Dickey's team identified a specific gene, Syt2, that is only involved in excessive mucus production and not in normal mucus production. To inhibit excess mucus production, they developed a drug called PEN-SP9-Cy that blocks Syt2's action. This approach is particularly promising as it targets mucus overproduction without interfering with the vital functions of normal mucus. Normal mucus production plays a critical role in protecting and maintaining the health of the respiratory and digestive systems. Although the initial results are promising, further research is necessary to evaluate the efficacy and safety of these drugs in clinical trials.
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In summary, mucus plugs present uncomfortable symptoms in ABPA, CPA and asthma. Current treatments focus on symptom management rather than directly addressing reduction or removal of mucus plugs. However, researchers are exploring 3 potential approaches, involving mucolytics, clearing crystals, and preventing excess mucus secretion. Additional research is required to confirm their effectiveness and safety, but approaches have shown promising results and may in future be one way we can prevent mucus plugs.
Further information:
Phlegm, mucus and asthma | Asthma + Lung UK
How to loosen and clear mucus
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Fungal vaccine developments
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The numbers of people at risk of fungal infections are increasing due to an aging population, increased use of immunosuppressive medications, pre-existing medical conditions, environmental changes, and lifestyle factors. Therefore, there is a growing need for new treatments or preventative options.
Current treatment options for fungal infections often involve the use of antifungal medications, such as azoles, echinocandins, and polyenes. These medications are generally effective in treating fungal infections, but they can have drawbacks. For example, some antifungal drugs can interact with other medications, leading to potentially harmful side effects. Additionally, overuse of antifungal drugs can contribute to the development of antifungal drug resistance, which can make treatment more challenging.
There has been a growing interest in the development of fungal vaccines as an alternative treatment. A fungal vaccine works by stimulating the immune system to produce a specific response against the fungus, which can provide long-term protection against infection. The vaccine could be given to at-risk individuals before exposure to the fungus, preventing infection from occurring in the first place.
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A recent study by researchers from the University of Georgia demonstrated the potential for a pan-fungal vaccine to protect against multiple fungal pathogens, including those that cause aspergillosis, candidiasis, and pneumocystosis. The vaccine, called NXT-2, was designed to stimulate the immune system to recognize and fight against several types of fungi.
The study found that the vaccine was able to induce a strong immune response in mice and additionally protect them from infection with several different fungal pathogens, including Aspergillus fumigatus, which is the main cause of aspergillosis. The vaccine was found to be safe and well-tolerated in the mice, with no adverse effects reported.
This study demonstrates the potential for a pan-fungal vaccine to protect against multiple fungal pathogens. While the study did not specifically address the use of the vaccine in patients with pre-existing aspergillosis infections, the findings suggest that the vaccine has potential to prevent aspergillosis infection in high-risk individuals.
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In summary, while the development of antifungal vaccines offers a promising potential alternative to the challenges posed by current treatment options for fungal infections, further research is needed to determine the safety and efficacy of the vaccine in humans, including those with aspergillosis, before it can be considered as a treatment option.
Original paper: https://academic.oup.com/pnasnexus/article/1/5/pgac248/6798391?login=false
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Developments in Biologic and Inhaled Antifungal medications for ABPA
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ABPA (Allergic Bronchopulmonary Aspergillosis) is a serious allergic disease caused by a fungal infection of the airways. People with ABPA usually have severe asthma and frequent flare-ups that often require long-term use of oral steroids and antibiotics to treat secondary bacterial infections.
The two main treatments for ABPA are antifungal medication and oral steroids. Antifungal medication work by targeting the fungi causing the infection, limiting its growth and spread. This can help reduce the frequency of flare-ups and stabilize the condition but may also cause side effects such as nausea and, more rarely, liver damage. Oral steroids work by reducing inflammation and suppressing the immune system's response to the allergen, which can help control the symptoms of ABPA. However, long-term use can cause significant side effects, including weight gain, mood swings, and adrenal insufficiency.
These side effects can greatly impact quality of life, but both treatments may be necessary to prevent the disease from worsening. Therefore, new or improved treatments are needed.
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Fortunately, there have been recent developments in managing ABPA, and a review by Richard Moss (2023) highlights two promising types of treatment:
- Inhaled antifungal medication treat fungal lung infections by delivering the drug directly to the site of infection. This allows for a higher concentration of the drug to be delivered to the affected area while limiting the exposure of the rest of the body and therefore reduces side effects. For instance, inhaled itraconazole has been shown to reach concentrations high enough to kill or inhibit fungus growth. Further trials will be completed this year (2023) to assess its safety and effectiveness. Although still in development, these drugs offer hope for more effective and better-tolerated treatment options for patients with ABPA.
- Biologic medication is a completely new type of treatment that uses synthetic antibodies to target specific cells or proteins of our immune system instead of using a chemical compound. Omalizumab, a type of biologic, binds to immunoglobulin IgE and deactivates it. IgE is involved in the allergic response our bodies launch against foreign invaders and plays a big role in ABPA symptoms. Deactivation of IgE has been shown to reduce allergic symptoms. In clinical trials omalizumab has been shown to significantly (a) reduced the number of flare-ups compared to pre-treatment, (b) reduced the need for oral steroid use and lowered its necessary dose, (c) increased wean off steroids, (d) improved lung function and (e) improved asthma control. Additionally, other Monoclonal antibodies (Mabs) such as mepolizumab, benralizumab, and dupilumab have shown a reduction in flare-ups, total IgE and a steroid-sparing effect.
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According to Moss (2023), these new treatment approaches are highly effective in reducing hospital visits. Biologics seem highly effective, with up to a 90% reduction in flare-ups for ABPA patients and up to 98% efficacy in reducing the amount of oral steroid needed by the patient. If these new treatments continue to work well, it could potentially offer a new, higher quality of life for individuals with ABPA . Overall, these findings are promising, but further research is needed to confirm the effectiveness of these treatments specifically for ABPA.
Original paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9861760/
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Spring COVID Booster
COVID-19 levels of infection in the UK are far lower than they have been earlier in the pandemic, even while most people have returned to taking fewer precautions against infection. Increased immunity in the UK population caused by vaccination and infection has likely brought us to this better place.
However levels of immunity are not fixed and much like the common cold it gradually declines in each of us, leaving us open to re-infection within a year. Consequently, we must keep 'topping up' immunity in order to avoid severe symptoms should we be infected. For most of us that are now likely to be a natural process of periodic re-infection until the virus stops circulating so widely.
If you are in a highly vulnerable group it is safest to top-up your immunity without being infected by having a booster vaccination. The Uk government will launch a spring booster campaign shortly to address this need.
Those who will be offered this booster will only be the most at risk, so you may or may not be offered it depending on the opinion of your local hospital doctor or GP. The criteria for the spring booster seem to be more restricted than earlier boosters and will only be offered 6 months after your last booster.
Criteria for the spring campaign are:
- adults aged 75 years and over
- residents in a care home for older adults
- individuals aged 5 years and over who are immunosuppressed (Your doctor will get guidelines to decide this for you)
There will likely be a less restricted booster jab in autumn 2023 too.