About Idiopathic Pulmonary Fibrosis

What is Idiopathic Fibrosis (IPF)?

Idiopathic Pulmonary Fibrosis, or IPF, is a serious condition that affects the delicate tissues of the lungs. Normally the lung tissue is soft and flexible which means it is easy to breathe, but in someone with IPF the lung tissue stiffens and damaged from scarring. The process of the scarring of the lungs is called fibrosis, and once it has occurred the tissue does not recover.

  • Idiopathic (means a condition without any known cause)
  • Pulmonary (relating to the lungs or respiratory system)
  • Fibrosis (a rapid increase of fibrous connective tissue – this process occurs naturally in the formation of scar tissue to replace normal tissue lost through injury or infection, but in this instance causes irreversible damage of the lung tissue)

There is no known cause for IPF, however:

  • It is not an infection
  • It is not infectious (caught from other people)
  • It is not a form of cancer
  • It is nothing to do with cystic fibrosis

Click here to learn more about what IPF is and how it is related to other Interstitial Lung Disease's.

Symptoms

Most people develop their symptoms after the age of 60 years and the disease is uncommon below the age of 50 years. Men are affected more commonly than women. However, occasionally more than one family member develops IPF, suggesting that genes may be involved in causing the disease.

The most common symptoms are

  • Breathlessness, especially when taking exercise, such as walking up hills or stairs
  • A chronic dry or hacking cough
  • Discomfort in the chest
  • Finger “clubbing”, which is a change in the shape of the fingernails
  • Fatigue and weakness
  • Loss of appetiteRapid loss of weight

These symptoms are not specific to IPF. They can become more evident when the disease has already caused considerable damage to the lungs.

Symptoms

Most people develop their IPF symptoms after the age of 60 years and the disease is uncommon in people below the age of 50 years. Men are affected more commonly than women.

The most common symptoms are:

  • Breathlessness, especially when exercising, such as walking up hills or stairs
  • A chronic dry or hacking cough
  • Discomfort in the chest, although rarely is this described as severe pain
  • Finger “clubbing”, which is a change in the shape of the fingernails
  • Fatigue and weakness
  • Loss of appetite
  • Rapid loss of weight

These symptoms are not specific to IPF, meaning that there are many other conditions which can have the same symptoms. In particular, heart failure or chest infection can cause many of the above symptoms. This means IPF can be difficult to diagnose in the early stages of the disease. The symptoms often only become more evident when the disease has already caused considerable damage to the lungs. Other symptoms may be found in other ILDs, such as joint or muscle pain.

Causes

Although the cause of IPF is not known, a number of factors are thought to trigger it:

  • Viral infections
  • Gastric-oesophageal reflux (‘heartburn”, with stomach acid entering the lungs in small quantities)
  • Exposure to a variety of occupational dusts and chemical fumes
  • Smoking

Occasionally more than one family member develops IPF, suggesting that genes may be involved in causing the disease.

Diagnosis

A limited awareness of the cause and progress of the disease has often made diagnosis difficult and it is common for the condition to be incorrectly diagnosed initially. A diagnosis is usually made by a specialist, after a referral by a general practitioner (GP). How commonly IPF occurs is not clearly known, but a reasonable estimate would be around 5 cases per 10,000 individuals – which means most GPs may encounter a new case about once per decade of full time work.

Most people will have the following investigations:

  • History and physical examination: Talking to the patient and often their family to find any factors in the home or work environment, any medical illnesses that run through the family, any medications, treatments (such as radiotherapy) or any other medical conditions that might make a person at risk of getting ILD. When listening to the lungs with a stethoscope, a doctor may hear crackles (often referred to as “velcro crackles”). However as mentioned above, other conditions can also cause crackles, so they cannot be relied upon for a definite diagnosis.
  • Chest x-ray: This may show signs of the scarring, even early on, so some people will be diagnosed by an abnormal chest x-ray before they develop symptoms.
  • Lung function tests: These are breathing tests to show how well your lungs are working. They are used later to monitor both how bad the disease is, and assess rate of worsening.
  • Pulse oximeter: This test indicates the amount of oxygen carried in the blood.
  • Arterial blood gases: A direct measurement is made of both oxygen and carbon dioxide levels in blood, by taking a sample with a needle and syringe from an artery, usually in the wrist.
  • Blood tests: These are usually done to exclude other causes of ILD (such as rheumatological diseases).
  • CT scan (HRCT): This is a special type of x-ray scan which produces very high resolution pictures of the inside of the lungs.
  • Bronchoscopy: Some people may also require a bronchoscopy, which involves passing a small flexible telescope down into the lungs to collect samples.
  • Surgical lung biopsy: Some patients may also need to have a surgical lung biopsy under general anaesthetic, to make a firm diagnosis of IPF.

Click here to view more detailed information about each of the above investigations.

IPF treatment options

This is a complex area. A good working relationship with your healthcare team is key for getting the right treatment advice. Before getting in to the particular treatments, it is useful to look quickly at how drug treatments are assessed for how well they work.

How do we know that a treatment actually works?

When a drug is developed, it goes through a series of trials to see if it might work. These trials usually start with animals or other ‘models’ of the disease, before moving on to humans if the treatment appears safe and potentially effective. Early (Phase 1) trials come first to look at safety and tolerability of the drug, and then as more experience and knowledge builds up, Phase 2 and Phase 3 studies are performed to assess if it is effective. Phase 3 studies are needed to get approval from various regulatory authorities such as the US Food and Drug Administration (FDA) for a treatment. These drug trials are often performed with a “placebo arm” – a trial patient receives either the active drug or a dummy drug, and this choice is made randomly with neither the patient nor the treating doctor knowing which treatment “arm” a patient is on. This is because we are all familiar with the ‘placebo effect’ – sometimes even totally inactive drugs can make people feel better, and patient health can improve just by being in a study and “being looked after”. If neither the patient not the doctor knows if the “real” treatment is being used, there reduces the risk of accidentally getting a biased view of effectiveness. This may seem unfair, but as we will see it can be a good thing… The progression through the stages of clinical trials can be slow and frustrating for people keen to access the latest treatments. However, these clinical trials have often been performed in NZ and there may be trials of new drugs available (such as the current PRAISE study looking at the use of pamrevlumab in IPF, which recruited patients with IPF in Dunedin, Christchurch and Tauranga).

Drug Therapy

Pirfenidone, also known under the trade name Esbriet, is a drug funded for the treatment of IPF in New Zealand from January 2017. It was developed by Intermune, who are now part of Roche Pharmaceuticals. The American FDA approved it for use in the US from late 2014.  Pirfenidone acts on multiple pathways that may be involved in the scarring of lung tissue. Its safety and effectiveness were established in three clinical trials of 1,247 patients with IPF, including the ASCEND study of 555 patients which also enrolled here in NZ. Click here to view the ASCEND study. The decline in forced vital capacity (FVC)– the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible, and so a measure of the effective ‘size’ of the lungs – was significantly more reduced in patients receiving pirfenidone compared to patients receiving placebo (this means lung function tests fell more slowly in patients on pirfenidone, compared to patients on the dummy medication).

There are several requirements to getting pirfenidone funded by Pharmac in NZ: (1) IPF diagnosed by CT or biopsy, (2) FVC between 50% and 80% of predicted values (for the patient’s age and height), and (3) that pirfenidone should be discontinued if the FVC falls by 10% or more within any 12 month period.

Only a respiratory specialist can apply for pirfenidone funding (i.e. someone registered with the NZ Medical Council as being accredited in Respiratory Medicine). The FVC criteria relate to the trials performed to show the drug was effective, which recruited people who had an FVC neither ‘too good” – in who it would be tough to show benefit - nor “too bad”, at a stage where pirfenidone may not make much difference. As pirfenidone is an expensive drug, Pharmac probably wished to keep the funding of the drug to those they would have confidence would benefit. However, this has led to some controversy as many doctors feel that there is potential benefit to using the drug early in the disease.

Patients taking pirfenidone need to be careful about sunlight exposure, as it causes photosensitivity – floppy sun hats and sunblock are needed outdoors even on cloudy days, and sun damage can still occur behind glass (for instance while driving). It also causes tummy upsets (usually diarrhoea) and can cause liver damage. The dose is started low with 1x 267mg tablet three times a day for a week, then 2 tablets three times a day, building up to the full dose of 3 tablets three times a day. Blood tests (looking at liver function) are needed monthly for the first 6 months of treatment; if no problems these tests can be dropped down to once every 3 months thereafter. While the potential side effects sound daunting, only about 1 in 20 patients has to discontinue the drug treatment permanently. Studies show that when a proactive effort is made to manage potential side effects, with education and support, patients tend to be able to achieve better drug use than without.

Nintedanib is the other drug licensed for use in IPF with reasonable evidence for use. It is again a very expensive drug at GBP40,000/year, or about NZ$80,000 annually. It was developed by Boehringer Ingelheim and is also called Ofev. Although it is licensed in NZ it has not been approved for funding by Pharmac. It was approved for use in the US by the FDA in late 2014. The results of the INPULSIS-1 and INPULSIS-2 clinical trials are published here.

It became available in the UK in April 2015. Like pirfenidone, nintedanib may slow progression and decline of FVC. Studies have shown it reduces fall in lung function by 50% in broad ranges of IPF patients and reduces risk of acute exacerbations by 68%. However, it has a worse reputation for causing diarrhoea. This is underlined by the fact that in the UK the drug comes packaged with tablets of the anti-diarrhoea drug loperamide (Imodium) in the same packet. Studies show 2 out of 3 people on nintedanib experience diarrhoea to an extent that it interferes with their lifestyle. However, again real world experience shows that it is still rare for patients to have to permanently discontinue nintedanib treatment, as the diarrhoea can usually be managed by changes in diet and the use of loperamide.

There are no studies yet reported of using both pirfenidone and nintedanib at the same time. It is possible that the two drugs together may be better than one, but we just don’t have the data to know at present.

Other drugs have been tried: particularly the combination of prednisone, azathioprine, and N-acetylcysteine which showed some promise in the early studies. However, the PANTHER-IPF study had to be stopped early in 2012 as patients on the Pred/Aza/NAC combination therapy were more likely to die or be admitted to hospital than those taking placebo. Clearly, in the PANTHER-IPF trial, the patients who were assigned to placebo were perhaps the fortunate ones. Click here to view this trial.

Subsequent research has shown that NAC alone has no benefit over placebo in mild-to-moderate IPF, and had a higher rate of heart disorders (6.8% in the NAC arm but only 1.5% in the placebo arm). However, these are small numbers and may be just occurring by chance. Click here to view this study.

Other drugs that have been shown not to work either by themselves or in combination include ambrisentanazathioprinebosentancotrimoxazolemycophenolateprednisonesildenafil and warfarin (although the latter may still be used for other reasons than fibrosis, such as venous thrombosis).

The Internet has many other suggestions for treatments. It is easy to see how in a desperate situation these might be ‘worth a go’. Sadly, it is also the case that there are people out there happy to exploit fear and uncertainty for their own financial gain. If something is too good to be true then it usually is. Be careful.

Serracor-NK is a commercial preparation of enzymes that has been suggested (by the manufacturers) for IPF. There are no placebo controlled clinical trials for Serracor-NK, and so there is no good evidence for it being useful. It would be helpful for a high quality trial to be performed with a placebo arm and independent monitoring. From a scientific perspective, none of the long list of studies cited on the company website are relevant to IPF, and many are of marginal or no scientific merit. However, there does appear to be an increased risk of bleeding as well interactions with other drugs, such as warfarin. The manufacturer’s website has many testimonials from happy customers, who tell us that it has been effective for them for many different conditions from chilblains to pulmonary fibrosis. We know some treatments that can work and these must be the first line therapies - but in the unlikely event you are unable to tolerate them then it is understandable the desire to try something else, even if unproven. If this is the case, talk to your healthcare team and maybe use something measurable to see if the drug helps – a 6 minute walk test or changes in lung function would be the most obvious medical tests that allow us to see a trend. The Serracor-NK tablets are expensive, so if you wish to go down this route you may want to make sure that you are seeing some benefit.

Do I need additional oxygen therapy?

This is a harder question than at first it might appear – oxygen, to the surprise of many, is not that good at relieving breathlessness. Many studies have shown no difference between bottled (100%) oxygen and room air (21% oxygen) in terms of breathlessness – opening the window, using a handheld fan etc may be just as effective, and considerably safer, cheaper and easier than noisy oxygen concentrators or heavy bottles that run out at awkward moments. It can also have quite a profound psychological effect, and some patients can become very much psychologically dependent on it at a stage when they might otherwise still be able to get out and about. On the other hand, oxygen is extremely good at increasing oxygen levels as measured by a pulse oximeter – the red glowing “sats probe” used to measure blood oxygen saturation, and there is some evidence that when oxygen levels are very low the use of oxygen for at least 16 hours a day reduces the risk of dying or being admitted to hospital. There are fairly strict criteria for starting long term oxygen therapy (LTOT) set down by the Ministry of Health, including a strict no smoking policy (it doesn’t work in smokers and can be very dangerous because of the fire risk) and clear cut-offs for oxygen levels measured by an arterial blood gas test (ABG). Using oxygen for less than 16 hours a day doesn’t seem to make any difference in terms of prolonging life or avoiding admission to hospital. Portable oxygen concentrators can be helpful for helping people with IPF and low oxygen levels get out of the home, and can be particularly helpful when flying.

What other treatments might make me feel better?

Palliative treatments are ones aimed at relieving distressing symptoms, rather than treating the underlying disease. One of the more effective drug groups for cough and/or breathlessness are the opiates – drugs related to morphine. Morphine for many people comes with concerns about addiction or about inadvertent overdosage causing death, which is unfortunate because for most people morphine is a very safe drug. The most common side effect is constipation, which can be controlled with careful use of laxatives, although some people may also experience nausea. Occasionally confusion or even hallucinations may occur within the first few days of use, but these generally settle within a day or two. Opiates are good at suppressing cough, and especially if they make you sleepier may be a good choice before going to bed at night if you are struggling with cough. Although in large doses morphine can reduce breathing drive, in the smaller doses used for breathlessness it is much more effective at relieving the distressing feelings that go with breathlessness. It can also help reduce breathlessness on exertion. Addiction to morphine used in this setting is vanishingly rare, and there is evidence from other lung disease (including COPD) to suggest that it is safe for the management of breathlessness – in a large study from Scandinavia patients starting on LTOT who took up to 30mg of morphine per day were no more likely to die than those with the same condition managed without morphine. Again, discuss with your healthcare team the pros and cons of treatment.

What about lung transplantation?

Lung transplantation can be an effective treatment for IPF in the right circumstances. It is a very major undertaking – there is only one lung transplant centre in NZ (Auckland City Hospital), which can be a challenge for travel even with support, and there are risks during and after transplant. However transplant can improve both length of life and quality of life in certain people.

Overall, the most recent figures show half of NZ lung transplant recipients are alive 5.8 years after their operation – but these are transplants for any reason, not just for IPF. As IPF patients tend to be older, they have a higher chance of having other medical illnesses (diabetes, heart disease etc) which may become more problematic after transplant.

The operation often needs to be done at quite short notice and may last over 8 hours, with a small chance of dying during the procedure or on ICU afterwards. The patient needs to be neither too ill (and therefore likely to die during the procedure) nor too well (too soon to get a benefit from transplant), be neither too fat nor too thin nor too tall or too short, have a good donor match (rare blood groups are hard to match, as are lungs at the extremes of size), be extremely motivated and committed to taking a cocktail of anti-rejection drugs for the rest of their lives. On the whole after transplant most people are home about three months later. In addition, transplant becomes much more difficult in patients older than 60 years and it is highly unlikely that a patient over the age of 65 would be offered transplantation for IPF,  as it is very unlikely to be successful.

In New Zealand with our low number of organ donors (only 46 in 2014), there is a long waiting list for donor organs. NZ is very lucky to have an excellent transplant service (our survival figures are significantly better than the global average, despite being a small centre with limited funding). Again, if you are wondering about transplant this should be discussed with your healthcare team early.

What can I do to help myself?

If you smoke, it is extremely important to stop immediately. Old theories that smoking may help IPF are proven to be wrong. Exercise remains important, and studies show that pulmonary rehabilitation makes a difference to quality of life and ability to do everyday tasks.