An interview with Dr Michael Loebinger conducted by April Cashin-Garbutt, MA (Cantab)
What are nontuberculous mycobacteria (NTM) and where are they found?
Nontuberculous mycobacteria are part of a group of bacteria called mycobacteria. The non-tuberculous mycobacteria are, as the name suggests, mycobacteria that are not tuberculosis. They're also not leprosy, but they are the other members of the bacteria group termed mycobacteria.
NTM are ubiquitous in that they are found throughout the world in the environment; particularly in water and soil.
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Are there different types of NTM? Which are most common?
There are many different types of NTM. The actual number of individual species, or types of NTM, increases continually as the sophistication of our diagnostic and identification techniques increase. At the moment, there are over 170 species that have been identified, although only a relative minority of those cause disease in humans.
The most common types which can affect humans and cause disease are:
- Mycobacterium abscessus
- Mycobacterium avium complex, which contains a few different mycobacteria
- Mycobacterium xenopi
- Mycobacterium malmoense
- Mycobacterium kansasii
There are others which are commonly found but cause disease less often, or not at all, these include Mycobacterium fortuitum and Mycobacterium gordonae.
Often, mycobacteria are classified into fast-growers (i.e. when you culture them in a laboratory they grow up quickly) or slow-growers (i.e. the opposite happens when you grow them in a laboratory and they can take quite a long time to culture them up).
How do NTM affect the body?
NTM normally don't affect the body. NTM are everywhere in the environment and they're not a particularly virulent organism. Most people are exposed to them all the time and don't get affected by them.
Some of the species in some people can cause disease. It can cause disease in a variety of different places, but by far the most common manifestation is pulmonary disease.
How many people are thought to be affected by NTM lung infections?
That's quite a difficult question because we don't know if people are affected by NTM lung infections for certain unless we actually test them for it and that isn't always done. But the published literature suggests that somewhere between 1.4 and 40 per hundred thousand people are infected by NTM pulmonary disease.
This varies with the type of person and is much higher in certain groups. It also varies in different locations as some areas of the world have a much larger problem with NTM pulmonary disease compared to others.
One recent study in the US looked at older patients, patients over 65, and looked at period prevalence (i.e. the amount of patients that had pulmonary NTM over this 11-year period), and in this study they found over 100 per 100,000.
What are the main risk factors and who is most at risk?
As I mentioned, NTM are ubiquitous, they're everywhere and most people aren't affected by them. There needs to be an interaction between the host and the microbe itself in order to cause disease.
Either you have a particularly susceptible host or you have a particularly virulent microbe, or the environment is such that there is quite a high burden of the organism.
In certain areas of the country and of the world, there is an increased risk and these are thought to be places with high humidity, near the sea. In the United States where lots of this work is being done, states such as Hawaii, Florida, California, have particularly high prevalence of nontuberculous mycobacteria.
There was also a study in Europe which suggested that where you lived didn’t just make you more likely to get NTM, but also related to the type or the species of NTM you were more likely to get.
Finally, with regards to the environment, there are some case-control studies which look at environmental exposures comparing people with NTM to people without NTM. In some studies, it was shown that people with NTM have had increased exposures to soil or to water sources.
Another main type of risk factor is the host. Certain aspects of the host make it much more likely to get NTM pulmonary disease. The main risk factor is chronic lung disease, so people that already have a long-standing lung condition and within that group, bronchiectasis and cystic fibrosis are the most common underlying comorbodities. Other underlying causes such as COPD (chronic obstructive pulmonary disease) also make NTM pulmonary disease much more likely.
Also interestingly, there is a group of patients that seem to be at risk and more susceptible to NTM without any obvious long-standing lung conditions and these patients tend to be over represented by post-menopausal women who are taller and thinner on average, commonly with chest wall deformities. The actual reason for this is unknown, but may berelated to mucous clearance
Finally, there has been a lot more research looking into other possible risk factors within the host, including some types of immunodeficiency.
Is it true that NTM lung infections are increasing worldwide in both men and women? What are the likely reasons why?
I think it is true. There has been studies from many different parts of the world and all of them seem to suggest that it is increasing worldwide. Studies that have put numbers on this suggested an annual increase somewhere between 3 to 8 percent per year.
We’ve also found at the Royal Brompton Hospital, a tertiary respiratory hospital in the UK, where I work, a significant increase in the number of patients which have had nontuberculous mycobacteria over the last decade or so.
For example, we recently published that there was an increase in the number of NTM isolates from 137 in the year 2000 to 759 in the year 2013.
Why is it increasing? Well some of that is increased recognition. Exposure at conferences and also the publication of articles have increased the knowledge of NTM and hence, people are testing for it more often. I said back to the beginning, if you don't test for it, then you don't find it and because there is more appreciation of it, people are testing more for it.
However, that's not the whole picture. There was a nice study done a few years ago now, which looked at an American population. They did ahealth survey of civilians both in the early 1970s and also in the turn of the millennium.
As part of this study, they used a small amount of antigen, which is the proteins of one of these NTM compounds, and injected it just under the skin. This is similar to TB testing that many people have had.
The study showed that there was an increase in the number of patients that responded to NTM from the 1970s to 2000s. This shows that there is an increased exposure to these NTMs over this period of time. That is more than just increased recognition. That means that people are being exposed to the NTM more over this period of time.
Why is there more disease? Well, as I keep going to back to, it's an interaction between the host and the bug. The population (host) is getting older. There are an increased number of people with chronic lung disease and underlying diseases. We are getting better at treating other diseases, but we are using drugs which suppress the immune system, which can give bugs more of a chance.
We have also got better at killing other bugs and so NTM have less competition and there is increased chlorination of water supplies and increased hygiene. Also, interestingly, the interaction between the host and the pathogen has changed over the last 20 years. There is an increased amount of showering. We know that these bugs go around in water sources and that they can be around in shower heads.
The increased popularity of showers of the last few decades have also presented mycobacteria to the host in a different manner. Whether that is important again, at the moment it is probably just conjecture. There is also more immigration and environmental contact, so the chance of patients going to areas where NTM are much more prevalent. There are lots of possible reasons.
How is NTM lung infection diagnosed? What are the main challenges with NTM lung infection diagnosis?
The main diagnosis for lung infection is detecting or culturing the mycobacteria or the NTM in the respiratory secretions, so predominantly by sputum tests.
The issue is that they are everywhere and hence finding these microbes in the sputum is not that uncommon. The challenge is deciding on whether it is important or not. Finding it in the sputum may just be an isolated finding, it may be a contaminant from the environment, and not actually represent any problem for the individual.
Additionally, to make things even more difficult, these bugs don't always cause problems. Even if they actually do represent an infection in an individual, sometimes they can live happily in the pulmonary system without actually causing any problems.
Finally, the final group could be that they are actually causing a significant amount of disease and causing problems. The problems with diagnosis are that, an isolate culture of mycobacteria could represent a contaminant, casual isolate, an infection which doesn't cause the individual problem, or actually pulmonary disease.
How these are all sorted out is, is helped by the publication of the American Thoracic Society Diagnostic Criteria which came out in 2007. They stressed that you need two positive cultures of the same species from the same organism.
Additionally, you need symptoms and changes on an x-ray or CT scan which relate to disease, which would separate our infection from the disease. There are various criteria that people follow to actually decide if somebody has NTM lung infection or disease.
How do you decide who to treat?
Firstly, the criteria are obviously important for decisions to treat. Treatment shouldn't be given for casual isolate or contaminant. Most people wouldn't treat an infection that is not causing any damage and that doesn't have any symptoms or radiographic change.
But, still it is not as simple as saying everyone with evidence of NTM disease needs treatments. This is partly because of the fact that it can be quite an indolent infection and actually if you follow patients for some time then often they can remain relatively stable with relatively few symptoms, so the treatment may not be necessary.
Additionally, the situation is further complicated by the fact that, as I mentioned, a lot of these patients have underlying diseases and underlying chronic lung conditions. Since symptoms of the under lung conditions present often very similar to the symptoms of NTM lung disease can cause for example: cough, sputum and exacerbations.
Actually untangling the contribution from the NTM to the underlying chronic lung disease can be quite difficult. It is important to try and do that before determining whether treatment for the NTM is necessary.
This is important because treatment of NTM is difficult. Whereas for a normal lung infection it would just be a short course of antibiotics which would normally get rid of the infection, for NTM lung disease, antibiotics are needed for long periods of time, over a year and additionally multiple different antibiotics at the same time which can cause significant problems with tolerance.
On top of that, cure is not guaranteed and certainly with certain species and certain elements of lung disease a cure may not be possible.
Why is cure not always the aim?
Firstly, you may not want to treat it and that relates back to the previous question. If you decide that treatment is important and you go on and treat, cure may not always be possible.
This is a difficult condition. In some studies, a cure can be anywhere between 13% to 90% depending on the amount of lung disease, the type of species and patient factors as well. Additionally, mortality can be relatively high with these conditions.
Depending on the species and the patient and the amount of lung disease, some studies have shown that all cause of mortality over a 5-year period can be as high as 40%.
When you start treatment in an individual, often you will be trying to cure and get rid of the microbe. In some patients, either due to a lack of tolerance to drugs or a lack of efficacy of drugs, or the fact that the disease is too severe, the aim may be actually to try and control and keep the patient stable with the knowledge that you may not actually get rid of the bug, but you may prevent further lung damage.
What research is currently being conducted on NTM and what more needs to be done to improve understanding of the condition?
There is research that is being done throughout the world looking at all the different facets of NTM disease and trying to improve our understanding in the areas where there are gaps. There is research that is looking at why people are susceptible to NTM.
We ourselves have looked at gene expression analysis to have a look if there are any clues there and also other studies have looked at underlying genetics to see if there are any groups of individuals which are more likely to get nontuberculous mycobacteria.
In addition to that, there is research which is assessing different treatment regimens and modes of treatments and different treatment options. There is presently a Phase III study going on looking into a new inhaled drug for possible future treatment of difficult NTM disease.
What do you think the future holds for patients with NTM?
I think NTM treatments is difficult. I think it is something that is increasing at the moment and we don't have all the tools available to adequately treat these patients. There are issues knowing who to treat, knowing when to treat and knowing what to treat with.
I am encouraged by the fact that there is a significant increase in interest both from academia, but also from the pharmaceutical industry. It is really the combination of the two which is important to really drive through developments in NTM.
I am quite hopeful that over the next ten years or so we will understand a little bit more about it and hopefully have more tools and more drugs available for treatment.
Where can readers find more information?
There are American Thoracic Society guidelines which are published: https://www.thoracic.org/statements/tuberculosis-pneumonia.php
Also about to be published are new British Thoracic Society guidelines of the treatment and management of nontuberculous mycobacteria pulmonary disease, which basically is a critical appraisal of all the available literature, excellentfor interested health care professionals.
They would probably the two main areas of comparative knowledge. There are also lots of different review articles that are available on the internet.
About Dr Michael Loebinger
Dr. Michael Loebinger is a Consultant Respiratory Physician at the Royal Brompton Hospital with a specialist interest in respiratory infections. He chairs the infection special advisory group for the BTS, co-chairs the BTS bronchiectasis guideline committee and is on the steering committee for the BTS non-tuberculous mycobacteria and ERS bronchiectasis guidelines. He is a founding member of the UK and European clinical and research bronchiectasis networks and sits on the ERS Respiratory Infection Education task force. He also holds an honorary senior lecturer position at Imperial College and supervises PhD, MSc and medical students.