COVID Associated Pulmonary Aspergillosis (CAPA)

Influenza is thought to infect a billion people worldwide each year (WHO figures 2018), which is about 1 in 7 of the total population of the earth! A few million of those cases develop severe symptoms that require them to be treated in hospital. Up to 650 000 cases result in the death of the patient.

Why do so many die? What can we do to reduce that number of deaths?

We know that severe influenza causes significant damage to lung tissue. Such damage may make those patients vulnerable to aspergillosis, so researchers started to look for any such cases as acute invasive aspergillosis is treatable so if that infection is causing some of those deaths, the right treatment could help save lives. The researchers quickly found signs of aspergillosis but what grabbed their attention, even more, where the number of patients that were found. In one of the first studies 44% of influenza patients who had died were identified as having aspergillosis, far more than might be suspected. This was subsequently found to be a high figure and when they started to look for IA other countries found much lower numbers, but still very significant numbers of people who might be helped if treated for aspergillosis.

Since 2019 we have all been experiencing a pandemic from a different type of virus: SARS-CoV-2 that has so far killed over 2 million people globally. This virus also damages the lung tissue of patients experiencing severe symptoms so researchers started to test these new patients for signs of aspergillosis and again high numbers were initially found in some countries, not so high in others. Nevertheless again there is potential to save significant numbers of lives by treating affected patients for aspergillosis.

Exactly how many lives might be helped is difficult to estimate but it is likely that looking for ‘hidden aspergillosis’ in COVID patients will be one way to reduce mortality. Read the consensus document in The Lancet here.

It feels a little like whenever we look for aspergillosis in severely ill respiratory patient groups eg influenza, bronchiectasis, cystic fibrosis, chronic obstructive pulmonary disease, tuberculosis and even occasionally lung cancer, we find aspergillosis sometimes in far higher numbers than we might expect.

World Aspergillosis Day is held to encourage the medical world to pay more attention to aspergillosis, look for it and you may find it in places you don’t expect to find it!

Better diagnostics with minimal equipment

In many parts of the world there is poor diagnosis of fungal infections. Part of the problem is a lack of expertise and equipment in the many diagnostic labs that already exist and in some there is a lack of a reliable electricity supply so sophisticated machines are not going to help the situation. This is a significant barrier to getting the right treatment to many millions of people worldwide.

The Fungal Infection Trust has designed and built a series of online courses that are intended to train people to diagnose all fungal infections using nothing more than a light microscope and a few simple stains.

A microscopy training course for mycologists in 4 key modules. is a series of four modules translated into four languages (English, Spanish, Portuguese and French) with more to come in Chinese. Participating is free of charge and qualifies the participant to receive a certificate accredited by the University of Manchester, UK.

Module 1 – Teaches basic microscopy, stain preparations and staining techniques

Module 2 – How to use basic microscopy methods on wet mounted samples from a wide diversity of human tissues

Module 3 – An introduction to Histology and identification of fungal elements in many human tissues

Module 4 – An advanced course to learn skills in microscopy and histology for the identification of uncommon and very rare fungal pathogens

This course has been available for 18 months and hundreds of people have visited the site and started a course, but much more needs to be done and many more people need to become aware of this resource.
In addition large parts of the world do not speak any of the languages we have mentioned so far, so we need to add more translations to make this valuable resource more widely available.

New Genetics

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The National Aspergillosis Centre and the Manchester Fungal Infection Group (MFIG) are at the forefront of the investigation of why some people get chronic aspergillosis when most of use do not. We are all breathing the same air and the source of the infection can only be the fungal spores in the air as most infection affect the lungs and sinuses!

Genetic studies looking at the entire genome of groups of patients who have chronic aspergillosis have started to reveal a small group of genes that seem to be consistently associated with aspergillosis. Perhaps unsurprisingly many of these appear to play a part in different parts of our defence mechanisms to resist infection. Fungi offer particular challenges for our bodies to solve – they are made up of strong threads that can force their way through membranes that would stop a bacterium for example, and fungal threads (hyphae) are far to large for a single neutrophil to engulf.

A recent study released by MFIG & NAC characterised a single gene named ZNF77 which, when carrying a particular mutation, causes Aspergillus fumigatus spores to stick more easily and strongly to the walls of an airway, and to germinate and grow faster! It isn’t difficult to realise that people carrying such a mutation will be more vulnerable to infection by Aspergillus, however even that change on its own is not thought to be enough to cause CPA or ABPA. There is much more to learn but it could certainly be useful to screen people thought to be at risk of chronic aspergillosis for this mutation. If someone has the mutation doctors could provide increased protection e.g. by giving antifungal drugs prior to and during a planned medical procedure such as a transplant.


New Diagnostics

It is highly important that we are able to diagnose someone with aspergillosis as quickly as possible as the outcome of treatment is improved if we can begin earlier. Currently diagnosis is a complicated process that takes up a lot of time and that has a particular impact on people who have an acute invasive aspergillosis as that infection can progress rapidly, however there is also a large population of people who have chronic forms of aspergillosis such as Chronic Pulmonary Aspergillosis (CPA) and Allergic Pulmonary Aspergillosis (ABPA) and it is likely that many cases of severe asthma (SAFS) are also caused by Aspergillus sensitisation.

People who have chronic forms of aspergillosis are typically very difficult to diagnose. Centres such as the National Aspergillosis Centre (NAC) in Manchester are dedicated to detecting aspergillosis in patients who are struggling to manage severe asthma for example. Doctors throughout the UK send their patients to NAC as there is no local expertise, a situation that is repeated in many countries throughout the world. Only the worst patients tend to be referred, many fewer than predicted numbers of how many people there should be with ABPA/SAFS and other chronic aspergillosis in the UK. A simple test is badly needed to identify the ‘missing patients’, a test that must be sensitive and simple to use.

LD Bio, a company based in Lyon, France have developed a solution that may have far reaching consequences. Using this device doctors at the bedside of a patient who they suspect may have chronic aspergillosis can now simply put a drop of blood into the sample well at the top of the device and wait for a few minutes for the result to develop. If the patient has aspergillosis two bands will appear, if not one band will appear.

The National Aspergillosis Centre in Manchester, UK has tested the device (results to be presented at ECCMID 2019 in April 2019)  and found it to be accurate, identifying 91% of cases of Chronic Pulmonary Aspergillosis in 30min. The manufacturers claim that this test is equally as useful to detect cases of Allergic Bronchopulmonary Aspergillosis (ABPA) and Aspergillus colonisation, suggesting that many more ‘missing’ patients could now be identified quickly and cheaply. If the same technology could be used to detect cases of SAFS then even more patients could receive the correct treatment more quickly.

The test is cheap and accurate enough to use when resources are low (potentially even in developing countries) and a rapid result is desired.


The Impact of Aspergillus Worldwide

Research on Aspergillosis is gradually revealing that the fungus Aspergillus reaches into far more of our lives that we previously thought. Far from earlier assumptions that our airways are usually sterile places that contain no microbes, the latest research suggests that Aspergillus and many other microbes reside in many of our lungs as part of our normal micro/mycobiome and causes no health problems at all.  In fact many bacterial & fungal species found in our microbiome are thought to protect us from infection by pathogens. This harmless growth is sometimes referred to as colonisation.

Paradoxically there are large numbers of people in the world who have serious fungal infections caused by Aspergillus colonisation of their airways and lungs which suggests that either something is different about the fungus or the infected person in each case.

In some cases the cause is clearer for example someone who receives a transplant (solid organ or bone marrow) usually experiences a period of several days when they are less able to fight off infections. People who have an impaired immune system due to having AIDS are similarly affected (estimated 300 000 cases of invasive aspergillosis worldwide). Those people are often kept in sterile rooms until they recover enough of a functional immune system to cope with our normal air which contains many potential pathogens. Despite these precautions some will get an infection such as aspergillosis and it is easy to speculate that such cases may be caused by an Aspergillus pathogen  that had up to that point been harmlessly colonising their lungs.

What then of people with severe asthma with fungal sensitivity (SAFS: 6.5 million cases worldwide) who have a fungus growing in their lungs and they have become sensitive to its allergens, exacerbating their respiratory symptoms? How are they different to other asthmatics and non-asthmatics?

There are also 3 million cases of Aspergillus slowly eroding cavities into the lungs of people who apparently have a normal immune system (Chronic Pulmonary Aspergillosis CPA). Why are they so infected when many more have Aspergillus growing in their lungs with no ill effects?

We need to be able to identify individual at risk from infection as early as possible so that treatment outcomes are the best possible. To do that we need to understand why some people become infected or sensitised when most do not even though they have Aspergillus growing in their lungs.

World Aspergillosis Day is a great time to think about helping the Aspergillosis Trust and the Fungal Infection Trust fund more research into aspergillosis.