Vitamin D supplements
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Between about late March and September each year in the UK most of us are able to generate enough vitamin D from sunlight exposure, but from the months of October to March our bodies do not get enough vitamin D from sunlight. A lack of vitamin D affects teeth, muscles and can lead to bone deformities. Whilst there isn't specific evidence that vitamin D affects aspergillosis, deficiency has been linked with other chronic illnesses.
Vitamin D can be found in foods such as oily fish, red meat and egg yolks but the NHS recommends that everyone takes vitamin D supplements between October to March to ensure we have sufficiently high levels. The recommended dose for adults and children over 1 is 10 micrograms (or 400 IU) per day.
Vitamin D supplements can be bought from most pharmacies or supermarkets.[/et_pb_text][/et_pb_column][/et_pb_row][/et_pb_section]
Antifungal Drug Pipeline
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Many of our patients already know of the increasing need for new antifungal drugs; treatments for fungal diseases like aspergillosis have significant limitations. Toxicities, drug-drug interactions, resistance, and dosing are all issues that can complicate therapy; therefore, the more treatment options we have, the more likely we are to find an optimal therapeutic option for patients.
Developing antifungal drugs is difficult because of the biological similarities between people and fungi; we share many of the same biological pathways as fungi, creating issues in developing safe antifungals. To develop new antifungal drugs, researchers must look at how they can exploit some of the differences we do have.
Below is a layman’s breakdown of a recently published review that looked at seven antifungal drugs currently in various stages of development. The majority of new antifungals have been new versions of old drugs, but the ones discussed in this review have new mechanisms of action and different dosing regimens, so, if approved, these drugs could provide a ray of hope in the not so distant future in terms of treatment.
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Rezafungin
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Rezafungin is currently in phase 3 of development. It is a member of the echinocandin class of drugs, including micafungin and caspofungin; Echinocandins work by inhibiting a fungal cell wall component essential to homeostasis.
Rezafungin has been developed to retain the safety benefits of its echinocandin predecessors; while enhancing its pharmacokinetic and pharmacodynamic properties to create a unique, longer-acting, more stable treatment that allows for weekly intravenous rather than daily administration, potentially expanding treatment options in the setting of echinocandin resistance.
Fosmanogepix
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Fosmanogepix is known as a first-in-class drug (so first of its kind antifungal) that blocks the production of an essential compound that is important for the construction of the cell wall and self-regulation. Blocking the production of this compound weakens the cell’s wall enough that the cell can no longer infect other cells or evade the immune system. It is currently in Phase 2 clinical trials and is showing promising results in the oral and intravenous treatment of multiple invasive fungal infections, demonstrating efficacy in multi-drug resistant and other difficult-to-treat infections.
Olorifim
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Olorifim falls under an entirely new class of antifungal drugs called orotomides. The orotomides have a distinct mechanism of action, selectively targeting a key enzyme in pyrimidine biosynthesis. Pyrimidine is an essential molecule in DNA, RNA, cell wall and phospholipid synthesis, cell regulation, and protein production, so when Olorofim targets this enzyme, it profoundly affects the fungi. Unfortunately, Olorifim isn’t broad spectrum, and it only kills a few fungi – pertinently, Aspergillus, and the fungus that causes valley fever (which affects the brain), Coccidioides. Since its discovery, it has progressed through pre-clinical studies and phase 1 human trials and is currently an ongoing phase 2 clinical trial testing its use orally and intravenously.
Ibrexafungerp
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Ibrexafungerp is the first of a new class of antifungals called Triterpenoids. Ibrexafungerp targets the same essential component of the fungal cell wall that the echinocandins do, but it has an entirely different structure, making it stabler and meaning it can be given orally; differentiating Ibrexafungerp from the three currently available echinocandins (caspofungin, micafungin, andulafungin), which can only be given intravenously limiting their use to hospitalised patients and those with indwelling venous access.
There are two ongoing phase 3 trials of ibrexafungerp. The most extensive enrolling study to date is the FURI study, which evaluates the efficacy and safety of Ibrexafungerp among patients with severe fungal infection and who are unresponsive or intolerant of standard antifungal agents. The oral formulation was recently approved by the USA’s Food and Drug Administration (FDA) for the treatment of vulvovaginal candidiasis (VVC).
Oteseconazole
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Oteseconazole is the first of several tetrazole agents designed with the goal of greater selectivity, fewer side effects, and improved efficacy compared to currently available azoles. Oteseconazole has been designed to tightly bind to an enzyme called cytochrome P450. When we discussed earlier fungi and humans being similar, cytochrome P450 is one of those similarities. Human cells contain various species of cytochrome P450, which are responsible for many important metabolic functions. Therefore, if azole antifungal agents inhibit the human cytochrome P450, the result can be adverse reactions. But, unlike other azole antifungals, Oteseconazole only inhibits the fungal cytochrome p450- not the human one because of its affinity for the target enzyme (cytochrome P450) is greater. This should mean fewer drug-drug interactions and less direct toxicity.
Oteseconazole is in phase 3 of development and is currently under FDA consideration for approval to treat recurrent vulvovaginal candidiasis.
Encochleated Amphotericin B
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Many of our patients will already be aware of Amphotericin B, which has been around since the 1950s. Amphotericin B falls under the class of drugs called Polyenes- the oldest class of antifungal drugs available. They kill fungi by binding to ergosterol which acts to maintain cell membrane integrity. The drug works by stripping away the ergosterol, causing holes in the cell membrane, making it leaky enough to fail. But, polyenes also interact with cholesterol in human cell membranes, meaning they have significant toxicities. Encochleated Amphotericin B has been developed to avoid these significant toxicities – its novel lipid nanocrystal design allows for drug delivery directly to the infected tissues, shielding the body from unnecessary exposure – and it can be given orally, potentially reducing hospital stays.
Encochleated Amphotericin B is currently in phases 1 & 2 of development, so a little way off. Still, it promises the potential of an oral drug with little, if any, of the typical toxicities of amphotericin B.
ATI-2307
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ATI-2307 is in the very early stages of development and is a new antifungal drug with a unique mechanism of action. ATI-2307 inhibits mitochondrial function (mitochondria are structures within cells that convert food to energy), decreasing the production of ATP (adenosine triphosphate), which is the molecule that carries energy, leading to growth inhibition.
As mentioned earlier, ATI-2307 is still in the early stages. Still, researchers have completed three Phase 1 clinical studies that demonstrated it was well tolerated in humans at anticipated therapeutic dose levels. Thus, the clinical role for ATI–2307 is unclear; however, its broad in vitro activity against a host of important fungal pathogens, including multi-drug resistant organisms, could translate into a critical role for this compound, especially for fungal infections due to drug-resistant organisms such as azole-resistant Aspergillus species.
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When will there be a vaccine for aspergillosis?
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[et_pb_column type="4_4"][et_pb_text admin_label="Text"]Why are there no vaccines for fungal infections?
Unfortunately, our understanding of immunity to fungi lags far behind our understanding of bacterial or viral infections. There are currently no vaccines available for any fungal infection, but several groups around the world are working towards designing and getting them approved for use in clinics.
The fungal vaccine currently nearest to the finish line is called NDV-3A. It is designed to boost immunity against Candida and prevent vaginal thrush (yeast infection), which will be of great comfort to people suffering from recurrent thrush (4+ infections per year).
Current efforts to produce an Aspergillus vaccine are mainly aimed at preventing invasive aspergillosis, which kills around 200,000 people per year worldwide. Many of these infections could be prevented if we had a way to vaccinate high-risk patients before starting medical treatments that lower their immunity (for example chemotherapy, transplants, strong steroids). However, it is very difficult for a person who already has an existing immunodeficiency to mount an effective immune response.
Efforts are also being made to develop a 'pan-fungal' vaccine, which would protect against many fungal pathogens at once.
What aspergillosis vaccines are in the pipeline?
Several approaches to designing an Aspergillus vaccine have been tried and are starting to achieve promising results in mice. Some researchers have tried injecting purified (recombinant) single proteins, while others have tried using complex mixtures made by fragmenting Aspergillus cell wall matter.
Earlier this year, staff at the Center for Vaccines and Immunology (University of Georgia, USA) tried using a recombinant protein called AF.KEX1, which is naturally found on the surface of Aspergillus cells. Vaccinated mice showed a good antibody response and grew smaller amounts of Aspergillus in their lungs. Importantly, they were less likely to die even if their immune systems were suppressed using corticosteroids.
- Read the research paper: Rayens et al (2021)
- Read an in-depth article about Aspergillus vaccines development: Levitz (2017)
• Read about how the same group used their microbiology skills to help during the COVID-19 pandemic
Will they be used to prevent CPA / ABPA in future?
Even after a vaccine for invasive aspergillosis has been approved, more work will be needed to find out whether it is also effective in preventing CPA and/or ABPA. It is much harder to predict who is at risk of developing chronic forms of aspergillosis because they are so rare even among people who have a known risk factor – most people with COPD do not develop CPA, and most people with asthma do not develop ABPA. This make it very hard to decide who should be vaccinated. It also makes it difficult to recruit enough of the right patients to run a meaningful clinical trial.
So how long?
As with many medical conditions, a prevention is better than a cure. But this is a long-term goal and it is impossible to predict with any accuracy when an Aspergillus vaccine will be available to patients.
We might hope to see some early-stage trials in humans in the next 3-5 years, but there is no guarantee that any of the current candidates will be effective or safe enough in humans to justify larger trials or be rolled out in clinics.
On the other hand, the COVID-19 pandemic has generated an enormous amount of public interest and new technologies for vaccination. Multiple COVID-19 vaccines were developed and brought to the public on a timescale that could scarcely be imagined even just 5 years ago. We may find that the vaccine development landscape changes beyond recognition in the near future and brings the prospect of an Aspergillus vaccine closer than we thought.
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COVID Vaccination Side Effects
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Most people suffer few or no side effects from either vaccine other than having a slightly sore arm for a day or two or feeling a few aches. Doctors are recommending that we take paracetamol to relieve those symptoms.
The UK government has now published more detailed information on side effects and all three vaccinations currently in use in the UK (a third vaccine named Moderna has recently started to be used). You can read this information at the links below:
You can also report any suspected side effect.
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How to manage breathlessness
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Recording from 15 April 2021, when our specialist physiotherapist Phil Langridge gave a talk to our aspergillosis patient and carers support group on breathlessness.
-----Contents of video----
- 00:00 Intro
- 01:05 Meaning of breathlessness
- 03:19 When to seek help (Safety net)
- 04:09 Causes of breahlessness
- 06:53 Things that can be done to help with breathlessness
- 17:19 Techniques to help with breathlessness - Mechanics
- 21:44 Techniques to help with breathlessness - Positions for recovery
- 24:09 Techniques to help with breathlessness - Timing
- 29:27 Techniques to help with breathlessness - Worry
- 32:09 Techniques to help with breathlessness - Other
- 41:04 Take home points
- 43:16 Q&A
You can read more about managing breathlessness here.
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Aspergillosis monthly patient & carer meeting
????Don't forget that 1pm this Friday (9 April) is our monthly patient & carer meeting.
Hosted by NAC staff, we will present an update on Covid-19, discuss any changes to our service and give a talk/presentation on an aspergillosis related topic.
Discussion and questions are actively encouraged, and this is another great opportunity to meet other patients and carers with aspergillosis.
There are 3 ways to watch:
2) Watch live on Facebook:
COVID Vaccination - hesitating?
What is an MDT?
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I have been told I am to be discussed at MDT, what does this mean?
Don't panic! Most patients with complex conditions like aspergillosis will hear the term 'MDT' at some point in their journey to diagnosis or afterwards.
But what does it mean?
MDT stands for Multidisciplinary Team and is often associated with the care of patients with cancer or suspected cancer; however, MDTs are also used to inform the decision-making process in the care of patients with other conditions, particularly those that are complex.
Okay, so who is in this team, and what do they do?
This team is far more impressive than any sporting team out there. A Multidisciplinary Team brings together a range of clinicians and specialists, all of whom bring their professional expertise in diagnosis, treatment options, and individual patients' overall care - ensuring a joint approach to care.
In the context of the aspergillosis MDT, the team meet once a week, and the core members are:
- Doctors
- Nurses
- Physiotherapists
- Pharmacists
- Laboratory staff
One of the doctors or nurses in attendance will always be the referring clinician. This ensures a patient-centred approach as there is an advocate for the patient who knows their personal circumstances and wishes.
What do they discuss?
This is dependent on the individual case. The team will review (and where possible compare) CT scans, X-rays, laboratory results and medications. They will discuss referral letters, look at the patient history and take into account discussions with the patient.
Does this delay my treatment or diagnosis?
In short, no.
Being told you need to be discussed at MDT may feel like it is delaying treatment or answers; however, MDTs are held weekly and are an essential element in managing complex conditions to ensure the best possible care and treatment in line with national guidance and best practice.
Will I get to know the outcome?
Yes, the team's conclusions and recommendations will be fed back to you at your next appointment, or earlier if necessary, for example, if you need to change medication or have more tests.
When will I be discussed at MDT?
Patients can be referred to the MDT at any point in their journey, be it while a diagnosis of aspergillosis is being considered, or if changes occur and alternative treatment options need to be discussed.
You can find more detailed information produced by the NHS on MDTs here.
If you want to access additional support materials about aspergillosis, click here.
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Aspergillosis Monthly Patient & Carer Meeting
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Aspergillosis patient and carers meeting, today (Friday, 5 February) at 1 pm.
We understand how difficult it is at the moment with the ongoing national lockdown and this is part of the National Aspergillosis Centre's efforts to provide ongoing support for all patients (not just those of the National Aspergillosis Centre) and carers with aspergillosis.
This month we will be talking about:
- Sars-cov-2 (Covid-19) vaccines and the recent developments
- Immunodeficiency
- Recapping on the global success of World Aspergillosis Day which took place on Monday 1 February
- The importance of getting any new lumps, bumps or ongoing symptoms checked in support of World Cancer Day
- There will also be time for general chat and questions.
The meeting is run by the National Aspergillosis Centre (NAC) staff. It is a great opportunity for any patients and their carers, family or friends to come along, ask questions and talk to other patients and NAC staff.
You can join the meeting for free on Zoom by clicking here, or using the meeting ID: 811 3773 5608.
The code to join is 784131.
If you want to know more about aspergillosis, the symptoms and who is at risk, click here:[/et_pb_text][/et_pb_column]
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