An interview with Dr. Rebecca Prevots, PhD, MPH, conducted by April Cashin-Garbutt, MA (Cantab)
Why has nontuberculous mycobacteria (NTM) infection traditionally been associated with immunosuppressed people or those with severe underlying lung damage and how has this changed over recent years?
It is important to keep in mind that nontuberculous mycobacteria are environmental, and so unlike mycobacterial tuberculosis, generally this is not a person to person transmitted disease. The organisms are found universally in water and soil and so most people are exposed on a daily basis.
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People who are immunosuppressed are at a higher risk of infection, but we do not know exactly why this is, and we don't understand all the mechanisms involved. More research is being carried out to answer these questions, but presumably it is related to their reduced ability to fight off the infection.
We know that certain high risk populations, for example persons with cystic fibrosis, mechanistically are unable to clear lung infections. Therefore, this high-risk population has impaired lung clearance mechanisms, and along with immune suppressed people, also has a higher susceptibility to infection.
Another example of a high risk population is persons with rheumatoid arthritis who are taking anti TNF-alpha medicines and again we don't know why this is, but somehow that interferes with their ability to fight these mycobacteria and they are at a much higher risk of infection too.
How has the prevalence of NTM increased globally over the last 20 years?
Before the advent of antiretroviral therapies for persons with AIDS, there was a lot of AIDS associated non-tuberculosis mycobacterial infections, primarily Mycobacteria avium complex or MAC. With the advent of these anti-retrovirual therapies, the frequency of disease associated with AIDS related immunosuppression has gone down and that's made the non-AIDS infections more apparent.
I also think that with increasing the use of rapid diagnostic technology, it has been quicker and cheaper to use those molecular tools to identify NTM in the human population.
I would note first that unlike the disease tuberculosis, which is a reportable condition in most of the world, pulmonary disease from NTM is not generally a reportable condition, which makes it much harder to track. We don't have systematic data globally that would allow us to compare rates and trends across the globe.
However, where we do have data from, we are seeing increases almost everywhere. In the US and Canada, for example, it is mostly not reportable but we do have lab data that allows us to have some insight.
In the US, looking at infections in older adults from the end of the 90's through to 2008, there has been an increase at a rate of 8% per year. In Ontario, Canada, where there has been a lot of work carried out, it has also shown to be increasing, but at a slightly higher rate.
In addition, in one province of Australia, Queensland, NTM non-tuberculosis infections are reportable, and by tracking it, an increase in has been seen.
There appears to be a lot of infections in Asia, such as South Korea and Taiwan. Although the data are not standardized globally, it has come from a variety of systems such as healthcare systems and laboratory systems. These are not typically explosive increases but the rate varies and there seems to be a steady increase over the last 20 years.
What are the main theories for this increase?
There are a few theories as to why we are seeing this increase. I would say first that there is an increased awareness of this condition and so to diagnose it, you have to get the right samples, you have to get a sputum sample, a sample from the lungs.
Unless you're thinking about it and taking the right sample, you can't diagnose it. Therefore, an increased awareness with physicians suspecting it has lead to an increase in taking the right sample, and sending it off for the right testing.
A second theory is that, in the US, in the 70's with the passage of the Clean Water Act, there was increased chlorination of the water system and we know that chlorine doesn't kill these mycobacteria. It kills everything else but leaves the mycobacteria, so they are more concentrated. There is a theory that there's more increasing prevalence of these mycobacteria leading to increased exposure. I’ll get into more detail later, but I would say most people are not at risk. Although it is increasing, it is still a relatively rare disease. Exposure alone is not enough to cause this disease because most people are exposed regularly to water and soil
Another theory is it could be due to changes with human behaviour, for example, people spending more time indoors with more aerosolization from air conditioners or other indoor appliances like humidifiers. Those are the three main theories.
How can these theories be tested?
It is difficult to know or have the data to show the relative contribution of those factors, but in terms of increased awareness, we can look at that by getting data to look at the rate by which physicians are ordering the right tests. We can look at the rate at which samples are sent for acid fast bacilli (AFB) testing, which detects a mycobacteria infection.
Some of the other theories, for example could there be an increase to the susceptible population. We know it is more frequent in older adults and in people with conditions like COPD or immunosuppressive conditions or conditions where there is an underlying structural lung damage.
There are also other special high risk populations, such as people with rheumatoid arthritis or people with CF. This could be due to an increase in the older adult population. We can test that theory by looking at what we call age specific rates, which allows us to adjust for age and we found that it is not due to an increase in older adults.
In terms of COPD we can also look at stratified rates separated within each population to see is it due to that. An example is a study in Canada, showed that the increase in NTM there was not due to the prevalence of people with COPD.
Then, looking at changes in human behavior, we can do some observational studies in people at high risk to see if changes in behavior lead to changes in reinfections and reduced the risk of reinfection. So far, there are no data but that is something that potentially could be done in high risk populations.
What further data is needed?
I think what would really help in tracking this condition and monitoring the effect of interventions, is collecting more standardized data globally both within states in the US and within other countries. The way to do that would be to make pulmonary NTM a notifiable condition, as part of routine disease surveillance.
Making it notifiable ensures that the same information is collected the same way across a state, province, orand country. That in turn would really help with tracking the impact of interventions.
You also need special studies to answer specific questions, like, are physicians looking for it more than previously? I think getting more data from especially large data sets, which is one thing we've been doing would help an answer the unanswered questions, and could also lead to more focused studies.
At NIH, we work a lot on trying to understand the relative role of host and environmental factors. We know clearly there are certain host susceptibilities that play a big role; e want to better understand what genetic factors underlie susceptibility to this condition.
It is important for us to do more studies to better understand the genetics underlying this disease, which I think will help us, in turn, better understand host susceptibility. We're trying to approach it from both angles, both monitoring disease transmission in terms of risk and doing studies and specialized studies to understand the genetics of susceptibility to this condition.
How can we tackle the rise in NTM infections? What challenges will need to be overcome in terms of identifying NTM species?
This is where genetics is especially important. To answer the first part of the question, to tackle the rise, we need to fully understand the risk factors. We can't make progress without understanding the risks.
The main risk is in terms of host susceptibility and moving this research forward is doing the genetic studies that will help us better understand and know how to prevent it. Then in terms of a susceptible host in regards to behaviors and environmental risk factors, doing the studies of the environmental risk would help us further our knowledge of this.
There are also things that we can't control that have an effect, for example, we know that certain environmental factors such as higher humidity, and other factors that relate to increased moisture in the air are associated with an increased risk of disease. These are things that are only controlled by where you live. It would not usually be feasible to suggest that patients move from one area to another, however, there may be household factors that could be modified to reduce risk and some research is being done on that. We know that these mycobacteria concentrate in biofilm on the surfaces of water distribution pipes and some types of piping material may be more predisposed to have biofilms than others.
In addition, we know that these mycobacteria are like legionellae and other opportunistic bacteria, concentrating inside hot water heaters. In the US, we have big hot water tanks and if you increase the temperature, some of the bacteria will be killed. That's the kind of research where you're looking at intervenable risk factors and more work needs to be done on that.
Because we know these are environmental mycobacteria, they have optimum conditions of temperature and pH for growing, and this information can be used to reduce the concentration of them in your household water supply for example. This is something that patients who have been infected and are cured commonly want to know, how they can reduce the risk of exposure. Not a lot has been published on this, but that's the kind of thing that people are looking at.
It is key to look in high risk populations where people have been infected once. We do know that treatment is lengthy and difficult, but even people who have cleared their infection, they are at high risk of getting re-infected by other mycobacteria.
When identifying species, a critical factor is better and more rapid diagnostics, because right now we have to wait 2-6 weeks for these mycobacteria to grow. If you want to get a quicker answer and start treatment, you would need more rapid diagnostics. I think there also needs to be more work done on rapid molecular diagnostics.
When will more effective and more tolerable NTM treatment regimens be available?
A number of investigators are working on developing more tolerable, safe, and effective treatments for NTM, but it is hard to predict when these would be widely available. A recently published study showed promising results for an inhaled formulation of the antibiotic amikacin in high risk populations,
I am most familiar with the process in the US, but I think it is not that different in Europe and other countries. The path to licensing is very lengthy, but there are efforts being made to try to speed up that process. Over the last ten years, I've seen much more interest in trying to develop more effective and well tolerated treatment regimens.
What do you think the future holds for the prevalence of NTM infections – are they likely to continue to rise?
It is very difficult to predict the future. I anticipate at some point, the rate of infection will most likely stabilize. However, in the near future it will continue to increase at the current rate as awareness increases.
One example where the data has shown a stabilizing rate is for among people with cystic fibrosis, about one in five have pulmonary NTM, and in our recent analysis, we've seen that has remained stable.
There will likely be a point at which it stabilizes in other areas too, but I don't know at what point this will happen and in some populations there is currently not sufficient awareness and so, in the near future it will continue to increase. Before it can stabilize, we also need to better understand the risk factors so we can know and better predict the trajectory.
I would like to emphasize that there needs to be increased awareness among physicians, and we need to think of ways to achieve that. We hear stories from patients about taking a really long time to get diagnosed. A huge problem is patients being misdiagnosed and spending several years with a chronic cough, not getting diagnosed until they get sent to the right specialist.
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About Dr. Rebecca Prevots, PhD, MPH
Dr. Prevots began her epidemiology and public health career at the New York City Department of Health in 1985, working as a public health advisor in the AIDS Surveillance and Epidemiology Unit. From there she went to the University of Michigan, where she earned her M.P.H. in 1988 and her Ph.D. in epidemiology in 1991. Upon completing her Ph.D., she joined the Epidemic Intelligence Service at the Centers for Disease Control and Prevention (CDC). During her time at CDC, she worked primarily on the epidemiology of vaccine preventable diseases, as well as on HIV/AIDS. After joining the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health in 2003, she began focusing on studies related to the epidemiology of tuberculosis and nontuberculous mycobacteria. In 2007, she became chief of the newly created Epidemiology Unit in the Division of Intramural Research. Currently the Unit is involved in a range of infectious disease research, including studies of nontuberculous mycobacteria, antibiotic resistance, malaria, and Zika.