Prior to around 2000 doctors in the USA and elsewhere used the term idiopathic pulmonary fibrosis as it its name would imply: for patients who had pulmonary fibrosis with no obvious cause or association. In the UK doctors preferred the term cryptogenic fibrosing alveolitis (CFA). By then however there was accumulating evidence that the pattern of disease seen under the microscope if a sample of lung had been removed at an operation (‘surgical lung biopsy’) gave useful information about how a patient was going to fare in the future. Pathologists recognised a number of different ways in which the lung could be affected. Each of these patterns was called a type of interstitial pneumonia (also referred to as interstitial pneumonitis). In this context pneumonia just means involvement of the lung tissue with inflammation or scarring. It does not mean that the conditions are caused by infection as is normally implied by pneumonia in common use (just another potential cause of confusion in interstitial lung disease!). Pathologists found that one particular pattern on interstitial pneumonia occurred more commonly than the others and, because this was what was usually seen, named it Usual Interstitial Pneumonia (UIP). More importantly, patients whose biopsy showed UIP did significantly worse than ones with other patterns of interstitial pneumonia. Because of this data, which was repaeted by a number of centres in different parts of the world, the international specialists decided that the term Idiopathic Pulmonary Fibrosis should only be used for patients with pulmonary fibrosis with no known cause where a biopsy showed the pattern of UIP, or in whom we could predict from their CT scan that they would have UIP without needing a biopsy. The preferred term for all types of pulmonary fibrosis without a known cause (what used to be called IPF prior to 2000) is now idiopathic interstitial pneumonia (IIP).

CT diagnosis of IPF

X ray specialists (radiologists) often try to predict the histopathological pattern based on the CT findings. We know that they can confidently predict UIP based on a CT pattern of basal and peripheral honeycombing: amongst biopsied patients studies show that everone with this pattern has UIP on biopsy. However, even when they feel confident that the pathological diagnosis is something other than UIP radiologists are only as likely to be correct as if they had flipped a coin to decide. Therefore an atypical CT scan can still prove to be UIP if the patient were to have a biopsy. This is perhaps the most common misconception about CT in IPF. We know that IPF is the most common of the IIPs and moreover is increasingly common when the patient is older. Because of these other factors, the gold standard for diagnosis of IVF remains a multidisciplinary team meeting (MDT). A surgical biopsy still remains helpful in my opinion in some situations as it can often secure a diagnosis of IPF when the CT scan is otherwise not typical.

Treatment of IPF

Because we know that IPF has a worse prognosis than other types of IIP and is also more common, recent drug trials have concentrated on this disease alone. This strategy has been rewarded by the finding that two drugs are beneficial in the IPF, pirfenidone (Esbriet™) and nintedanib (Ofev™).

Pirfenidone

Pirfenidone stops the formation of scar tissue, although it’s not entirely clear how it does this. A number of studies have shown the drug to be beneficial in IPF. Following a positive trial in 2011 UK regulators licensed the drug for the treatment of IPF. However American regulators were not as convinced and required a further trial which was positive and was published in 2014. This was known as the ASCEND trial and showed a benefit compared to placebo of slowing the rate of deterioration of breathing tests (a reduction in FVC) but also in survival. The survival benefit was calculated by combining patients from the earlier study and the current study, and some specialists have disputed this finding. Although IPF can prove fatal, fortunately the number of people dying of the disease after year is quite small. Consequently it requires a large number of patients in a trial to show that any change in mortality is certain to have occurred because of the effect of the drug rather than just by chance. Despite some controversy about the survival benefit, specialists agree that pirfenidone reduces the rate of lung function decline by about half compared to placebo. Pirfenidone does however have a number of side effects. The most common is a feeling of sickness and poor appetite. Another common side effect is an abnormal sensitivity to the effects of sunlight (‘photosensitivity’) which can lead to a blistering rash. Preventing this side effect requires people taking the drug to wear an effective sunblock (such as Factor 50) even in the winter and times when sunlight isn’t very strong. There are also a lot of tablets to take which some people find difficult. The full dose of pirfenidone is 3 tablets three times a day (ie 9 tablets a day). With help and advice from doctors and nurses who care for patients with IPF and have experience with the drug, people can often tolerate the side effects quite well. Unfortunately however pirfenione is very expensive (costing around £20,000 a year). Since 2013 it has been recommended by the National Institute for Health and Care Excellence (NICE) for patients with IPF, but only when their breathing tests are within certain limits. These are a Forced Vital Capacity (FVC) of between 50 and 80% predicted. Only certain hospitals in England are able to precribe pirfenidone on the NHS; our unit at Glenfield Hospital in Leicester is one. NICE dictate that the drug should be discontinued if a person’s FVC declies by a certain amount over 12 months. You can see the NICE guidance on the use of pirfenidone in IPF here.

Nintedanib

Nintendanib also inhibits scare tissue formation although the mechanism of action is better understood than pirfenidone. The ‘INPULSIS’ study that showed it to be beneficial was published in the same edition of the journal as the pirfenidone ‘ASCEND’ study in 2014. Nintendanib has now been licensed for IPF and in January 2014 was also recommended by NICE. The criteria for this are identical to that of pirfenidone, namely an FVC of 50 to 80% predicted with the requirement to stop if the FVC drops by a certain amount in 12 months. The criteria may be found here. The price of nintedanib is similar to that of pifenidone but again is available at specialist NHS units to patients fulfilling the NICE criteria. There are also side effects including sickness but also diarrhoea which can range from a minor inconvenience to a problem requiring stopping the drug. Photosensitivity is not seen with nintedanib and there are only 2 tablets to take a day. We cannot be statistically certain that nintedanib improves survival in IPF (although fewer people died on the drug than on placebo in the trial) but it does certainly slow disease progression measured on breathing tests. Many experts think the size of this effect was similar to that shown by pirfenidone.

Why do the NICE criteria specify an FVC of 50-80% predicted for pirfenidone or nintedanib?

This is a very thorny question. Partly it relates to the inclusion criteria of the original drug trials. None of the trials included patients with an FVC of less than 50% predicted, and therefore we cannot be sure the drug is beneficial in patients with lung function worse tan this. However neither of the studies had a upper limit of FVC of 80% predicted. The ASCEND (pirfenidone) study had a top level of FVCof 90% predicted. The INPULSIS study had no FVC upper limit. An unfortunate term of ‘mild to moderate IPF’ has been used by some people to indicate the FVC levels where pirfenidone and nintedanib may be used. Specialists however often see people with IPF with a higher FVC than 80% of predicted particularly when there is some additional emphysema. Many of these patients are badly affected by the disease and we would dearly like to prescribing the drug. Unfortunately the FVC limits for the NICE criteria appear to be based on an apparent health economic argument based on dry statistical concepts such as ‘quality-adjusted life years’. To be a patient with IPF who is not able to receive the drug because of NICE guidance can be frustrating or distressing. Sadly NICE have to make decisions about the provision of expensive drugs somehow and this inevitably affects people who fall outside current criteria. See the section What Should I Do If I Don’t Fulfil NICE Criteria? later on.