You probably don’t think about your lungs very often but they do a very useful job – delivering oxygen into your blood stream and removing CO2. Over your lifetime you’ll breathe in and breathe out over half a billion times – that’s enough air to blow up two full sized, inflatable models of the Empire State Building! Not only are your lungs very durable, they somehow manage to expose each lungful to an area bigger than half a tennis court (50m2) so that gas exchange can occur quickly and efficiently between your blood and the air.
If you’ve ever had a chest infection you’ll remember how nasty it felt and how you wished you could give your lungs a rest! Sadly, more than a hundred million people live with chronic lung diseases such as Chronic Obstructive Pulmonary Disease (COPD) and asthma which are not only debilitating for individuals but costly for economies.
The current approach to managing most respiratory diseases involves waiting for lung function to deteriorate until the patient seeks medical help, measuring lung function (how well they can breathe in and out) and providing drugs which can alleviate short-term and long term symptoms. Compared with many other diseases this overall care pathway is still very rudimentary.
Lung damage in COPD is a bit like an area of lush countryside which is occasionally invaded by small numbers of troops from a nearby enemy. On each incursion the local army sends in tanks and troops to quickly expunge the invaders, who aren’t heavily armed. Each incursion doesn’t cause a tremendous amount of damage to the environment but as time goes by, the fighting and continual influx of defensive forces damages the roads, landscape and vegetation.
Thankfully two global trends offer some hope that care for respiratory diseases will be improved. Firstly, the rising costs of healthcare provision is focusing attention on better diagnosis, prevention and management – particularly for chronic diseases such as COPD and asthma. Secondly, biomedical research is shedding new light on the underlying disease mechanisms which cause lung problems.
However, neither COPD or asthma are simple diseases so finding a cure for either won’t be easy. The immune system plays an important role in both diseases, and therein lies a big part of the problem.
Your immune system is extremely clever but also unimaginably complicated. It has to be very sophisticated because it’s constantly fighting off infection from all manner of bacteria and viruses. It also needs to keep watch over your own body’s cells and kill any that show signs of going rogue, multiplying on their own and becoming cancerous.
Most of the time your immune system does a great job – if it didn’t you’d be dead. But sometimes it gets a bit confused and freaks out when it sees things it thinks are a threat but are actually harmless. This can be things in the environment such as a bit of peanut, pollen or dust, but can also be parts of your body such as your joints. Either way the immune system starts fighting what it perceives to be an enemy – with detrimental consequences. Sadly, immune malfunctions aren’t just confined to cases of mistaken identity. Sometimes the communication and coordination systems get muddled and send out spurious messages putting the whole immune system on high alert. Your immune cells will then kick off at the slightest thing, causing all kinds of mayhem. This is one of the things that happens in the airways of an asthma sufferer during an asthma attack.
The trigger can be an allergen such as dust or pollen or even something as benign as a lungful of cold air on a frosty morning. The trigger causes immune cells to start sending out chemical signals, starting a chain reaction which results in the constriction of the smooth muscles in the airways making it very difficult to breathe. Since breathing is an important thing to keep doing, asthma sufferers must be armed with inhaled steroids and bronchodilators to calm down the immune system and relax the smooth muscle in their airways in case of an attack.
COPD also involves the immune system, but unlike asthma it isn’t a rapid problem, it’s a gradual progressive disease. The immune system is aggravated over many years by repeated exposure to irritants like smoke, dust and fumes. This constant assault by irritating particles and caustic chemicals, combined with the aggressive response from the immune system, results in collateral damage to the lung tissue. The lung tissues become scarred, calloused and unable to do their job properly. The problem is a result of both the inhaled irritants themselves and the overreaction which is illicited by the immune system.
Lung damage in COPD is a bit like an area of lush countryside which is occasionally invaded by small numbers of troops from a nearby enemy. On each incursion the local army sends in tanks and troops to quickly expunge the invaders, who aren’t heavily armed. Each incursion doesn’t cause a tremendous amount of damage to the environment but as time goes by, the fighting and continual influx of defensive forces damages the roads, landscape and vegetation. Attempts are made to repair any destruction after each incident but there is always some residual damage to the landscape. To make matters worse, the army decides to retain troops in the area who grow ever more volatile under the constant threat of invasion and shoot at anything or anyone that looks like a potential threat. After several decades, the once-pristine countryside is irreparably scarred. This is similar to the damage which gradually takes place in the lungs of COPD patients.
Thankfully the medical profession now has a variety of new drugs which can specifically dial-down parts of the immune system, and other new drugs are currently in clinical trials. It’s hoped that these highly targeted drugs will help tackle the underlying involvement of the immune system in respiratory diseases, not simply treat symptoms. Scientists are also becoming increasingly aware that complex diseases such as asthma aren’t actually a single disease but are a collection of distinct immune problems which manifest in a similar way. This deeper level of understanding goes some way to explain why not all patients respond to therapy in the same way.
The hope is that by diagnosing disease sub-types more accurately it should be possible to provide more tailored and effective therapy.
All this progress in research makes it more important than ever to accurately identify patients with lung problems, to categorise their particular type of disease and objectively monitor how they are responding to therapy. It is no longer sufficient to simply measure the lung function of wheezy patients every six months. Whole-body imaging modalities such as CT and MRI are very informative but pulmonologists ideally need cheaper, quicker and more accessible diagnostic tools to use on a day-to-day basis. Progress in the diagnostics world means that plenty of sophisticated in-vitro diagnostic technologies are now available.
Unfortunately the lungs and airways aren’t easy to access and take samples from. Several approaches have been adopted over recent years to make cellular and biochemical measurements from the upper airways.
Exhaled breath is the easiest sample to access but it only contains gases and volatile compounds, it doesn’t contain any liquid or cells. That makes it a tricky sample to learn much from. However, that hasn’t dissuaded people from investigating exhaled breath for tell-tale diagnostic compounds. In 1991 scientists discovered that the gas nitric oxide (NO) was an important cell-signalling molecule, involved in immune regulation and found in exhaled breath.
Twenty years, 2,000 academic publications and several diagnostic products later and there is still no unequivocal evidence that nitric oxide measurements have clinical utility. Other than breathalysers for measuring exhaled ethanol, no clinical or commercial products have gained significant traction in this field. Research is continuing and complex gas analysis systems are being successfully miniaturised and applied to clinical breath analysis, so there may yet be breakthroughs in diagnosing and monitoring respiratory disease using exhaled breath over the coming years.
Sputum is useful because it contains cells and biomarkers directly from the respiratory tract, but it’s challenging to access and difficult to physically manage in the lab. Cell samples scraped from the lining of the airways would be good but also can’t be sampled routinely.
Urine isn’t a sample you’d naturally think of as being useful for diagnosing lung disease but, surprisingly, researchershave found a biomarker which appearsin the urine of COPD patients. Healthy lung tissue contains a flexible structural protein called ‘elastin’. One result of COPD is the accelerated breakdown of elastin, causing the lungs to be become hardened and inflexible.
Blood (and plasma) testing is a well established and mature technology but as it only reflects the systemic concentration of cells or biomarkers, it isn’t necessarily very informative about the lungs and airways. Blood testing is useful but is often insufficiently specific to diagnose lung problems from other inflammatory problems.
The overactive immune system of a COPD patient starts attacking the elastin in healthy cells. A by-product of this degradation is a specific group of amino acids called desmosines which aren’t normally found in the body. Desmosines are removed from the body via the kidneys and therefore can be detected in the urine of COPD patients via a simple test. Usefully, when COPD patients experience a worsening or exacerbation in disease, the levels of desmosines in urine jump even higher. This increase occurs because the overactive immune system causes the kidneys to leach more proteins and amino acids than normal into the urine. Thus it makes detection of desmosines in urine even easier during an exacerbation, and therefore it is possible that we may see desmosine urine tests becoming a routine tool for pulmonologists in the coming years.
It’s hoped that management of respiratory disease in the next decade should improve significantly. It needs to, because many millions of patients in an aging population across the developed and developing world will be faced with living for many years with chronic lung disease. It will require respiratory clinicians to embrace new diagnostic tools and technologies as well as new medicines but hopefully the shared goal of improving health for millions of patients will fuel progress.
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