Diagnosis and management of idiopathic pulmonary fibrosis

Interstitial lung disease (ILD) describes a diverse group of lung diseases that result in the impairment or fibrosis of the alveolar interstitium. They can be classified according to clinical, radiological, physiological or pathological criteria (see Figure 1)^[1]
. Around two-thirds of ILDs have no known cause; the remainder are caused by environmental or occupational factors, infection or drug toxicity. The management of the ILD subtypes differs; therefore, accurate diagnosis and therapy often requires specialist input from a multidisciplinary team, which may include a chest physician, rheumatologist, radiologist and histopathologist, as well as a specialist nurse and pharmacist^[2],[3],[4]
.

Idiopathic interstitial pneumonias are the most common ILDs and idiopathic pulmonary fibrosis (IPF) has the greatest prevalence within this cohort of patients. IPF is defined by The American Thoracic Society/European Respiratory Society as “a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring in adults”, and is characterised by progressive worsening of breathlessness and lung function decline, associated with a poor prognosis. IPF is defined by the radiological and/or histopathological pattern of usual interstitial pneumonia (UIP)^[1]
.

The increasing rate of hospital admissions and deaths owing to IPF suggests the burden of disease is rising. Around 5 million people worldwide are reported as having IPF and it is estimated that a further 5,000 patients will be diagnosed with IPF each year. In the UK, the median survival time is three years after diagnosis^[4]
; however, 20% of people with IPF survive for more than five years^[2],[3]
,[4]
. IPF is often initially misdiagnosed as COPD or congestive heart failure and disease progression varies over time and between patients. There is currently no cure for IPF; therefore, early recognition and accurate diagnosis are likely to improve outcomes through avoidance of potentially harmful therapies and by prompting initiation of effective medicines and supportive care^[2],[3]
,[4]
.

This article describes the evidence base for IPF diagnosis and management, and the role that pharmacists can play as part of a multidisciplinary team.

Pathogenesis

The exact pathogenesis of IPF is unknown; it is currently thought to involve repetitive injury and abnormal wound healing in alveolar epithelium, which results in the deposition of interstitial fibrosis by myofibroblasts, leading to progressive lung injury, scarring and irreversible loss of function (see Figure 2)^[5]
. Injury can lead to the activation of coagulation cascades, oxidant pathways, fibrocytes and circulating cells, as well as macrophage stimulation.

Epithelial tissue usually responds to injury through a sequence of highly regulated, overlapping events for successful tissue repair and barrier integrity. When the normal responses to tissue injury become dysregulated (e.g. shortened telomeres, oxidative injury, proteostatic dysregulation and mitochondrial dysfunction), the imbalance of profibrotic mediators (e.g. transforming growth factor beta-1, vascular endothelial growth factor [VEGF], fibroblast growth factor [FGF] and platelet-derived growth factor [PDGF]) and antifibrotic mediators (e.g. prostaglandin E2) may contribute to the replacement of functional tissue with fibrous scar tissue^[2],[3]
,[6]
.

Risk factors

Although it is not known what factors directly cause IPF, there are several inherited and environmental factors that have been linked with an increased risk of developing IPF. These include:

• A family history of ILD;
• Cigarette smoking;
• Exposure to certain types of dust (e.g. metal and wood dust)^[7]
  ;
• Comorbidities, such as gastro-oesophageal reflux disease (GORD)^[7]
  .

Abnormal gastro-oesophageal reflux has been observed in 90% of patients with IPF and it has been suggested that GORD can cause or worsen IPF.

In addition, a genetic risk factor has been identified. Mucin 5B (MUC5B) is a glycoprotein required for airway clearance and innate immune responses to bacteria; it is now thought a polymorphism in MUC5B substantially increases the risk of IPF.

Furthermore, IPF is more common in male patients aged over 60 years^{[2],[3]
,[4]
,[6]}
.

Signs and symptoms

Symptoms of IPF include persistent, dry and irritating cough; dyspnoea that can affect the ability to eat or talk; fatigue; rounded and swollen fingertips (known as ‘finger clubbing’); and loss of appetite and subsequent gradual weight loss. Symptoms of IPF often affect the patient’s quality of life (QOL); continuous coughing can be painful and disruptive, and fatigue and dyspnoea can limit daily activities. As a result, IPF can lead to feelings of fear, anxiety, isolation, depression and anger^[2],[3]
,[4]
.

A small number of patients with IPF — around 5–10% per year — may experience unpredictable and substantial worsening of the disease, known as an acute exacerbation. Acute exacerbations can increase the burden of disease, reduce QOL and contribute to disease progression. They can also be fatal; 50% of patients hospitalised for acute exacerbation of IPF die during hospitalisation. The diagnosis and management of acute exacerbations varies widely owing to limited evidence upon which to base recommendations. This continues to be an area of active research^{[1]
,[8],[9],[10]}
.

Diagnosis

Accurate diagnosis of IPF is challenging owing to its complex, heterogeneous nature, as well as the difficulty in differentiating it from other diseases with similar clinical symptoms, and radiological and histopathological patterns.

In patients aged over 45 years, IPF should be considered in those who present with the following criteria: unexplained chronic dyspnoea on exertion; persistent cough; bibasilar inspiratory crackles on auscultation (often described as ‘Velcro-like’); and/or finger clubbing. Spirometry results can appear normal or impaired with a restrictive pattern, which sometimes can be obstructive.

The National Institute for Health and Care Excellence (NICE) recommends that people with suspected IPF should be assessed with all of the following^[4]
:

• Taking a detailed history, clinical examination and blood tests to help exclude alternative diagnoses;
• Spirometry and gas transfer;
• Chest x-ray;
• High-resolution computed tomography scan.

Diagnosis can only be made using these clinical features, lung function and radiological findings, with the consensus of the multidisplinary team^[4]
. These features are sufficient to allow a confident diagnosis of IPF in more than 50% of suspected cases. If the multidisciplinary team cannot make a confident diagnosis from these findings, a biopsy can be considered^[4]
. However, biopsy is associated with mortality within 30 days after the procedure, with a reported frequency of 3–17%. This mortality risk is increased in patients with idiopathic UIP who present with atypical features (any computed tomography features and/or distribution of lung fibrosis that do not suggest any specific aetiology)^[2]
.

Table 1 summarises the potential investigations recommended in national and international guidelines that may be undertaken to arrive at a diagnosis of IPF.

The timely and accurate diagnosis of IPF is important to ensure that patients gain access to appropriate clinical services and therapy for better relief of symptoms, which will help slow disease progression and improve clinical outcomes. As a result, if suspected, the patient should be referred for specialist assessments and diagnosis as soon as possible^{[2],[3]
,[12]}
.

Management

IPF is a chronic, progressive and irreversible condition. The major goal of IPF management is to slow the decline in lung function and to reduce the frequency and severity of acute exacerbations.

Pharmacological therapy

There are currently two antifibrotic medicines, pirfenidone^[13]
and nintedanib^[14]
, licensed for use in the UK and approved by NICE in patients with forced vital capacity (FVC) between 50% and 80% predicted.

Drug selection

Although the mechanism of action is not fully understood, it is thought that pirfenidone attenuates fibroblast proliferation and inhibits the synthesis and activity of TGF-α and -β, which are potent mediators that promote the formation of fibrotic tissues.

Nintedanib is a potent intracellular inhibitor of tyrosine kinases that targets multiple growth receptors (e.g. PDGF-α and -β; VEGF 1, 2 and 3; and FGF 1, 2 and 3) to slow down disease progression^[3]
,[4]
.

Pirfenidone and nintedanib have been evaluated in multiple clinical trials. A summary of a selection of these trials are described in Table 2 and Table 3, respectively. As yet, there are little data on the comparison of these medicines and which, if any, should be first line.

Cautions and contraindications

Pirfenidone is cautioned for use in mild-to-moderate hepatic impairment (i.e. patients graded as Child-Pugh A and B) and contraindicated in severe hepatic impairment and end-stage disease. It is also cautioned in moderate renal impairment (creatinine clearance 30–50ml/min) and contraindicated in severe renal impairment and end-stage kidney disease. Other contraindications include hypersensitivity to pirfenidone, history of angioedema with pirfenidone and concomitant use of fluvoxamine.

Nintedanib is cautioned for use in mild hepatic impairment (i.e. patients graded as Child-Pugh A), with a recommendation to prescribe a lower dose of 100mg twice daily. It is not recommended for use in moderate-to-severe (i.e. patients graded as Child-Pugh B and C) hepatic impairment. Nintedanib is contraindicated for use in patients with hypersensitivity to the drug, peanuts, soya or any of the excipients. It should be used with caution, if at all, in patients with higher bleeding or cardiovascular risk (including coronary artery disease); higher rates of bleeding and myocardial infarction were observed in the treatment arms of the INPULSIS studies. In addition, the concomitant use with anticoagulant and prothrombotic drugs was not studied in the INPULSIS trials and should be avoided where possible^[18],[19]
.

Cautions and contraindications should be considered carefully and, where possible, patients should be given the opportunity to make an informed decision about antifibrotic therapy.

Dosage

Pirfenidone should be titrated up over 14 days: 267mg three times daily for 7 days, followed by an increase to 534mg three times daily after 7 days, if tolerated. This is then further increased to a target dose of 801mg three times daily after 7 days, if tolerated.

Nintedanib should be prescribed at a dose of 150mg twice daily and the doses should be taken 12 hours apart.

Pirfenidone and nintedanib should be taken with food^{[18],[19]
,[20],[21]}
.

Adverse effects

As drug treatment can delay disease progression and reduce mortality risk, it is important that any adverse effects are prevented and/or managed effectively so patients can continue on therapy (see Table 4 and Table 5). When necessary, dose reductions or treatment interruption can be considered to manage adverse effects and, once symptoms have resolved or become tolerable, the recommended daily dose can be re-introduced, if tolerated.

Nintedanib is listed as a black triangle; therefore, any incidence of adverse effects need to be assessed for severity and reported via the Yellow Card Scheme^[20],[21]
.

Current guidelines advise against the use of warfarin, sildenafil, co-trimoxazole, imatinib, N-acetylcysteine monotherapy or in combination with azathioprine and prednisolone, ambrisentan, bosentan and macitentan in patients with IPF who do not have a known alternative indication for its use^[2]
.

Supportive care from healthcare professionals

The rate of disease progression and associated symptoms in IPF is variable. Antifibrotics can modify the course of disease, and slow the decline in lung function and exercise capacity, but are unlikely to improve symptoms, such as breathlessness, cough and fatigue. NICE has made recommendations about supportive care for patients with IPF (see Box)^[4]
.

Antifibrotics are high-cost, high-risk specialist medicines that require in-depth prescriber knowledge. If prescribed incorrectly, the patient could experience avoidable adverse effects that could lead to serious harm or fatality. For this reason, prescribing of antifibrotics is limited to specialist ILD settings and, at present, cannot be shared with primary or secondary care providers.

Role of the pharmacist

Pharmacists working in a specialist setting with routine contact with IPF patients are likely to be involved in supporting patients to make decisions on treatment, providing advice on preventing and managing potential adverse effects, and overseeing the prescribing and supply of antifibrotic therapy, where appropriate. In this setting, the pharmacist may also undertake a personalised medicine review to elicit a full medicine history, rationalise and optimise prescribed therapies, and deprescribe inappropriate or harmful therapies.

Comorbidities that contribute to breathlessness may alter patient perception on the effectiveness of antifibrotic therapy. Therefore, it is important that patients with co-existing asthma and/or COPD have effective therapy for those conditions to improve QOL and clinical outcomes. It is equally important that patients misdiagnosed with asthma and/or COPD have this diagnosis reviewed and related therapy deprescribed where there is no evidence of airway disease. Other comorbidities include lung cancer, GORD, pulmonary hypertension, sleep apnoea and coronary artery disease^[1]
; these conditions should be managed by specialists and/or GPs in primary care.

When selecting antifibrotic therapy, all cautions and contraindications should be carefully considered, including hypersensitivity, hepatic impairment, renal impairment and cardiovascular history. Pirfenidone is primarily metabolised by Cytochrome P enzymes in the liver (including CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP2E1) and, therefore, interacts with inhibitors and inducers, such as omeprazole, smoking, grapefruit juice and rifampicin.

Nintedanib is a substrate of P-glycoprotein (efflux pump). Co-administration with P-glycoprotein inhibitors or inducers can increase or decrease exposure to nintedanib, respectively. Patients can be educated by specialist pharmacists on avoiding interactions where possible and recommendations made to the GP for potential alternative medicines.

It has been suggested that around a third of patients feel inadequately informed, making specialist pharmacists well-placed to counsel patients on their diagnosis, offer them a choice of therapy where appropriate, and educate them on disease course, treatment strategies and prognosis from onset of disease. At ongoing review, pharmacists can help to assess tolerability and adherence to therapy, and alleviate any concerns patients may have about their condition and/or medicines.

Although pharmacists in primary and secondary care settings may not be directly involved in the initiation, monitoring and supply of antifibrotics, they may have a role in the identification and management of patients with IPF in certain situations. This includes referring patients for further investigations if they present with progressive breathlessness, a dry persistent cough and/or finger clubbing. Non-specialist pharmacists may be asked for advice and support on concomitant therapy, to check for drug interactions with newly prescribed medications or potential adverse effects. They should offer the advice and support that is appropriate or refer the patient to their specialist team, when necessary. In addition, patients diagnosed with IPF can be signposted to the British Lung Foundation website for further information (see useful resources box), local IPF support groups, smoking cessation clinics, vaccination clinics and pulmonary rehabilitation, where appropriate.

Summary

As patient numbers increase and the complex management of IPF is considered, pharmacists will need to work within multidisciplinary teams in their organisation and across the interface to offer integrated care. Sharing care may provide the best outcomes for patients and increase their access to medicines. Appropriate identification and management of acute exacerbations may prevent hospitalisation, adverse outcomes for patients and untimely death. Pharmacists have a role in helping patients understand more about IPF, the management of symptoms and disease progression. This is an area of interest and more resources are being utilised in research and development; therefore, it is expected that the identification, diagnosis and management of IPF will evolve.

• This article was amended on 2 March 2020 to change “Pirfenidone is cautioned for use in mild-to-moderate renal impairment (i.e. patients graded as Child-Pugh A and B)…” to “Pirfenidone is cautioned for use in mild-to-moderate hepatic impairment (i.e. patients graded as Child-Pugh A and B)”.