Andrew Husband, MSc, BPharm, MRPharmS
Director of Education (Pharmacy)
Senior Teaching Fellow, Durham University
School of Medicine and Health, UK
Adam Todd, PhD, MPharm, MRPharmS
Senior Lecturer Pharmacy Practice & Clinical Therapeutics, Deparment of Pharmacy, University of Sunderland, UK
Lorna Clark, MSc, BSc (Hons) Pharmacy
Assistant Director of Pharmacy – Clinical Services, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle, UK
Idiopathic pulmonary fibrosis (IPF) is the most common of a group of diseases of the lung parenchyma known as idiopathic interstitial pneumonias (IIPs). IPF is chronic and progressive, and has a very poor prognosis, with a median mortality of three years1 from diagnosis. In recent years, there have been significant advances in diagnosis of the condition, but little progress has been made in terms of overall survival. There is an important challenge in identifying appropriate, evidence-based treatment for IPF due to a relative lack of clinical data.
Classification and epidemiology
IIPs have been subject to a number of classification systems but have been most recently classified by the American Thoracic Society/European Respiratory Society multidisciplinary consensus published in 20022 and the European Respiratory Society.
The statement divides IIPs into seven distinct groups based on histology, radiological findings and clinical presentation.
- Idiopathic pulmonary fibrosis (IPF)
- Non-specific interstitial pneumonia (NSIP)
- Respiratory bronchiolitis interstitial lung disease
- Desquamative interstitial pneumonia
- Acute interstitial pneumonia
- Cryptogenic organising pneumonia
- Lymphoid interstitial pneumonia
IPF is the most common of the IIPs, being responsible for around 60% of all cases, and has the worst prognosis.3 The epidemiology of the condition has been investigated but data lacks precision, possibly as a result of changing disease classification and diagnostic imprecision. Studies conducted on populations in the US suggest IPF has an incidence of 6.8–16.3/100,000/year and a prevalence of 14–42.7/100,000.4 This picture is similar to that in the UK and some recent studies suggest that the incidence is rising, with more than 5000 new cases diagnosed each year and the number of deaths from IPF also continuing to rise.5
The disease appears to be more common in men6 with a median age of onset of 66 years (range 55–75 years).7 There is a familial link; estimates of genetic transmission occur in around 0.5–3.7% of cases in the literature.8 The inevitable link with cigarette smoking exists but is not as clear in terms of clinical outcome as one may expect. Chronic exposure to metal and wood dust are other important environmental risk factors. Infectious agents such as hepatitis C, adenovirus and Epstein–Barr have also been implicated in the pathogenesis of the disease, as have a variety of co-morbid conditions, including diabetes, obesity, gastro-oesophageal reflux, pulmonary hypertension and coronary artery disease. The exact influence of these co-morbid states is still to be established.
Most patients with IPF present for medical attention due to worsening lung function classically observed as exertional dyspnoea and chronic, often non-productive cough. Onset of the disease varies but a chronic insidious course is often observed that eventually leads to death. It is now acknowledged that progression of IPF is variable and some patients can remain stable for a significant period before rapidly worsening or ultimately succumbing to an acute exacerbation. These differences in clinical condition have been related to the existence of potential sub-types of IPF, each of which may have a specific pattern of survival.
On auscultation, patients will typically exhibit inspiratory crackles in the bases of both lungs. These crackles are sometimes described as coarse and ‘Velcro-like’. Other signs such as finger clubbing, pulmonary hypertension and compensated respiratory failure may also be present.
Accurate diagnosis of IPF is essential in terms of providing an effective treatment programme. Other IIPs may present in a similar pattern to IPF but, importantly, show a different course or respond differently to certain therapeutic interventions.
IPF is usually diagnosed and managed in specialist, multi-disciplinary clinics, where clinical, radiological and histopathological information can be combined and placed in the context of the individual patient.
The differential diagnosis of IPF includes:
- non-specific interstitial pneumonia (NSIP) and, less commonly, other IIPs
- other interstitial lung diseases, possibly due to environmental exposure to hazardous materials
- connective tissue disorders
A chest X-ray is taken and it may be normal in a patient with early disease; this will gradually change to show fibrotic changes and reduced lung volumes.
High resolution computed tomography (HRCT) scanning has an important part to play in the diagnosis of the disease. If a patient has a normal HRCT, it is highly unlikely they have IPF. Indeed, in some situations the HRCT is so effective that it reduces the need to undertake a surgical biopsy of the lung. Significant changes are seen in patients with IPF, including typical patterns of destruction of lung tissue and scarring resulting in opacities and ‘honeycombing’. This pattern is reinforced, if necessary, with a surgical biopsy, which will reveal disruption of normal lung architecture with fibrosis mixed with normal lung tissue.
Sprirometry, similar to a chest X-ray, may be normal in an early presentation. On progression, the pattern will demonstrate restriction to the flow of air. This has subsequent effects in terms of reduced gas transfer, which is often reflected in the patient desaturating when undergoing an exercise test. Sprirometry is important in assessing the severity of disease at the point of diagnosis and in monitoring the patient’s condition as the disease progresses.
Unfortunately, there is not a reliable biomarker from serum or bronchoalveolar lavage fluid to help with a definitive diagnosis or predict prognosis.
At present there is no established treatment for IPF that has convincing support from clinical evidence to show a reduction in disease mortality. There are a number of prospective trials being conducted with various agents discussed below in an attempt to address this situation. Other drugs, such as corticosteroids and immunomodulators, have been used for some time but have a relatively poor evidence base from the literature in terms of patient outcomes.
Treatment strategies are based on the patient’s condition at diagnosis. Gas transfer is used as a marker to help stratify treatment decisions. Patients with gas transfer of more than 40% of predicted levels are usually managed via initial watchful waiting or entry into a clinical trial, or, if this is inappropriate, by a ‘standard’ treatment regimen. Patients with gas transfer of less than 40% of predicted levels, or those who progress to this stage, should be referred for a single lung transplant. Clearly this last option is subject to the patient’s ability to tolerate such major surgery.
The efficacy of oral corticosteroids in the management of IIPs has yet to be established but, despite this, these drugs are still used in routine practice – either as monotherapy or in combination with an immunomodulatory agent. There have been various attempts to provide evidence to support the use of corticosteroids in the management of IIP, but, so far, the outcomes have been disappointing. In some IIPs (such as NSIP), the disease is more likely to respond, and this reinforces the importance of a correct initial diagnosis. To complicate the use of corticosteroids further, the long-term adverse effect profile of these agents is a problem and most patients will experience some kind of adverse effect that may ultimately limit dose, affect adherence or require addition of another treatment to manage the adverse effect.
Guidelines suggest that physicians should balance the likelihood of adverse effects occurring with the potential for a favourable response to steroid treatment. This is not a simple decision as, again, there are very few indicators that help with this decision. There is some evidence to suggest that younger patients who have less-established fibrosis, but a significant inflammatory component to their disease, may benefit from a trial of corticosteroids9 and may be able to tolerate any adverse effects. However, this stance is slightly at odds with the typical presentation of IPF in older patients with evidence of fibrosis and may reflect observations in patients who have a different sub-type of IIP. Those with significant co-morbidity may be less appropriate subjects for corticosteroids.
In an attempt to alleviate the inflammation associated with IPF, azathioprine, cyclophosphamide and colchicine have all been used in association with corticosteroids. These agents can also be used for a steroid-sparing effect. In all cases, there is no convincing evidence to suggest that any immunomodulator demonstrates a statistically significant, beneficial effect. To add to this, all three agents have a significant potential to cause severe adverse effects and, as with corticosteroids, the risk-to-benefit ratio should always be considered.
In contrast to the established treatments, the newer therapies focus on the possibility that IPF is a disease of abnormal cell proliferation. The previous premise that IPF is a disease of inflammation is less relevant here.
N-acetylcysteine has been used in IPF in combination with azathioprine and prednisolone. As the precursor of the antioxidant glutathione, administration is thought to replenish levels of depleted pulmonary glutathione and thus reduce oxidative damage to cells. The IFIGENIA study compared high-dose N-acetylcysteine in combination with high-dose corticosteroid and azathioprine to azathioprine and high dose corticosteroid alone.10 The results showed that the N-acetylcysteine group had a lower rate of decline in forced vital capacity and diffusing capacity of carbon monoxide (DLCO) after 12 months. The exact significance of these results is unclear and further work needs to be done to reinforce the place of this agent in therapy.
Another agent that may also have a future role in the management is pirfenidone – a transforming growth factor-β (TGF-β) inhibitor. TGF-β is a protein that can induce apoptosis (programmed cell death) and therefore has an important role in the proliferation of cells and accumulation of extracellular matrix seen in patients with IPF. Trials have shown that pirfenidone appears to slow down progression and stabilise lung function.11,12
Trials of interferon γ1-β, etanercept, bosentan and imatinib have been conducted or are currently being undertaken. None of these agents, however, appears to demonstrate any functional benefit or reduction in the rate of decline. The benefits of anticoagulants have been investigated both in combination with prednisolone and alone versus placebo. These trials resulted in some initial promise but then the warfarin versus placebo trial was stopped due to a low likelihood of warfarin providing any beneficial effect.
Role of the pharmacist
IPF patients have a number of treatment-associated issues, which must not be neglected. Pharmacists in the community and hospital are very well placed to support the management of such issues. Initially, support to help patients to stop smoking is important, as is the provision of domiciliary oxygen and the necessary advice around supply and use. Patients are not allowed to start using oxygen until they have stopped smoking and thus pharmacists could contribute to both these issues. Patients should be reminded to present for appropriate vaccination, including influenza and pneumonia. Indeed, in some settings, pharmacists are already providing vaccination services.
The use of long-term corticosteroids has the potential to cause complications such as osteoporosis, declining renal function and gastrointestinal damage. Clearly pharmacists can help to ensure that patients are prescribed appropriate prophylaxis for osteoporosis, or, if necessary, proton-pump inhibitors for gastrointestinal problems.
The general monitoring around IPF could quite easily be managed by pharmacists as part of multidisciplinary teams, not least those that provide pulmonary rehabilitation.
IPF is a complex disease, the incidence of which appears to be increasing.
At present we have very limited information regarding effective, evidence-based treatment.
1. Fahim A and Hart SP. Idiopathic interstitial pneumonias. Respir Med CME.2009;2:55–62.
2. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This Joint Statement of the American Thoracic Society (ATS) and the European Respiratory Society (ERS) was adopted by the ATS Board of Directors, June 2001 and by The ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002;165:277–304.
3. Dempsey OJ. Clinical review: idiopathic pulmonary fibrosis – past, present and future. Respir Med 2006;100:1871–885.
4. Raghu G et al. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2006;174:810–16.
5. Navaratnam V et al. The rising incidence of idiopathic pulmonary fibrosis in the UK. Thorax 2011;66:462–67.
6. Coultas DB et al. The epidemiology of interstitial lung diseases. Am J Respir Crit Care Med 1994;150:967–72.
7. King TE Jr et al. Idiopathic pulmonary fibrosis. Lancet In Press.
8. Hodgson U et al. Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: evidence of founder effect among multiplex families in Finland. Thorax 2002;57:338–42.
9. laherty KR et al. Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival. Am J Med 2001;110:278–82.
10. Demedts M et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2229–242.
11. Raghu G et al. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label Phase II study. Am J Respir Crit Care Med 1999;159:1061–069.
12. Taniguchi H et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010;35:821–29.