Management

The use of medications for management of interstitial lung disease (ILD) is informed by the cause of the ILD. Not all patients with ILD will need medication, especially if the disease is mild and deemed stable. Establishing the aims of treatment is also important. In patients with ILD who require treatment with medication, the aims include improving or stabilising disease, or slowing disease progression.

Broadly speaking, there are three categories of medications for ILD: (i) immunosuppressant; (ii) antifibrotic; and (iii) those for management of symptoms. All of these medications have potential side effects and patients require monitoring while on medication/s for ILD.

Immunosuppressive therapy is generally used in ILD that is driven by the process of inflammation; for example, in autoimmune diseases or sarcoidosis. High doses of prednisolone (including intravenous methylprednisolone) may be used in conditions which are predominantly inflammatory, in which case, improvement is the aim of treatment. After the initial phase, the aim of immunosuppressive treatment is to halt progression and stabilise disease. A combination of low dose prednisolone (</=10mg/day) and a second line agent, is generally used. Mycophenolate mofetil (MMF) and azathioprine and commonly used second line agents, with cyclophosphamide, methotrexate and rituximab being less common.

Monitoring and side effects

Prednisolone

Prednisolone is an anti-inflammatory agent; it binds to the intracellular glucocorticoid receptor and inhibits cytokine transcription.

Common side effects of prednisolone include dyspepsia, weight gain, mood swings, sleep disturbance, thin skin and easy bruising. Diabetes, hypertension, myopathy, osteoporosis, accelerated atherosclerosis, cataracts and glaucoma are complications seen with prolonged use.

Regular clinical review is vital to treat the significant array of complications. Prednisolone is considered a category A drug for pregnancy risk.

Mycophenolate mofetil (MMF) and Azathioprine (AZA)

MMF inhibits DNA synthesis in T cells and B cells thereby inhibiting their proliferation and suppressing cell-mediated immune responses and antibody formation. AZA inhibits DNA and RNA synthesis in mainly T cells but also B cells, inhibiting their proliferation and immune responses.

Side effects of MMF and AZA are similar and require the same monitoring strategies. Bone marrow suppression and liver toxicity are significant potential complications and require regular blood monitoring. Full blood count and renal and liver function tests should be performed regularly whilst on these medications. Other side effects include gastrointestinal intolerance (diarrhoea and abdominal pains), and in the longer term, increased risk of malignancy – in particular skin cancers and haematological malignancies. MMF is contraindicated in pregnancy. In some situations, AZA may be considered in pregnancy and is used in clinical practice; however, this must be done in consultation with an obstetrician and close monitoring of patients is required.

Anti-fibrotic therapy is currently recommended in mild-to-moderate IPF and PPF; Current anti-fibrotic therapies (Nintedanib (OfevTM) and Pirfenidone (EsbrietTM)) are aimed at slowing disease progression. Nintedanib or Pirfenidone are recommended in the treatment of mild-to-moderate Idiopathic Pulmonary Fibrosis (IPF), whereas only Nintedanib is recommended in the treatment of PPF. In both clinical trials of Idiopathic Pulmonary Fibrosis (IPF) and progressive pulmonary fibrosis (PPF), anti-fibrotic therapy reduced disease progression by approximately 50% (INPULSIS, CAPACITY, ASCEND, INBUILD and SENSCIS).

Nintedanib is a triple kinase inhibitor and interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of extracellular matrix. The exact mechanism of action of Pirfenidone is not unknown but it is thought to have antifibrotic effects by reducing fibroblast proliferation and inhibiting collagen and fibrogenic mediator production via the transforming growth factor (TGF) beta pathway.

In general, a patient on antifibrotic therapy would lose a mean of about 120ml of lung function a year, compared to someone not on treatment who would lose about 240ml of lung function a year. Choice of treatment is largely based on side effect profile rather than efficacy.

Monitoring and side effects

Nintedanib

Side effects of Nintedanib relate to the gastrointestinal tract, with diarrhoea and abdominal discomfort being the most common. Diarrhoea, however, is mostly mild and can be managed with anti-diarrheal medications. Nintedanib is often avoided in patients who are on anticoagulation or have unstable ischaemic heart disease because of the theoretical increased risk of bleeding and clotting (respectively), although this has not been proven.

Pirfenidone

Nausea and a photosensitive rash are common side effects of pirfenidone. The nausea is generally controlled when the medication is taken with food. Patients are reminded of the constant need to wear appropriate clothing and the application of 50+ sunscreen throughout the year to reduce the risk of a photosensitive rash. Weight loss is another common side effect.

Both Nintedanib and Pirfenidone can cause liver toxicity in about 5% of patients. Patients should have monthly liver function tests for the first six months and then every three months afterwards.

Call out box: Whilst the side effects of anti-fibrotic therapies are relatively common, they are not universal and are usually manageable and reversible. Whilst full doses of these medications are ideal, patients still derive benefit from reduced doses. In the face of significant side effects, patients should be encouraged to stay on a reduced dose of the medication if possible. The patient’s respiratory physician or care team should be consulted before stopping these medications. Anti-fibrotic treatment is used in the long term but cessation should be considered if the side effects impact significantly on quality of life.

Symptom control

Breathlessness

In some cases, medications can be prescribed to help manage breathlessness in patients living with ILD. Medications which may help with breathlessness include morphine and anti-anxiety medications.

For more advanced ILD, a patient may be prescribed opiates (such as morphine) to reduce the sensation of breathlessness or benzodiazepines to reduce the feeling of anxiety associated with breathlessness.

Cough

• Medications which may help with cough in ILD include Cough syrups – it is useful to trial both over the counter and prescription syrups to determine whether patients will benefit.
• In severe cases, low-dose opiates such as morphine (shorter-acting Ordine liquid, long-acting MS Contin or Kapanol tablets) or codeine (Pholcodine linctus) can be considered to help suppress cough symptoms. It doesn’t work for everyone, but if it is going to be helpful, it will usually work within 1–2 weeks.
• Immunosuppressive or antifibrotic medication to treat the actual ILD may also help to improve cough symptoms.

There are a number of non-pharmacological treatments that can be considered to help a patient manage ILD and its symptoms, including:

• Pulmonary rehabilitation. A tailored exercise program that can improve a patient’s symptoms and functional capacity. Visit our pulmonary rehabilitation section to find out more information and how to refer your patient.
• Oxygen therapy may be helpful in patients who experience low oxygen levels.
• Lung transplantation may be considered in selected suitable patients. Suitability would need to be evaluated at the specialist transplant centres. The referral pathways for oxygen therapy and lung transplantation vary across different states and institutions, which often involves a close discussion with the treating ILD specialist or team.
• Diet and nutrition. A referral to community dietician may assist with provision of nutritional supplements.
• Palliative care / supportive care.
  Referral Palliative care / supportive careerral to palliative care is encouraged early in a patient’s diagnosis to improve quality of life, help communication, assist in navigating decision-making and provide family support. This integrated, patient-centred medical care is important for people with a debilitating health condition who have evolving care needs during their disease course.
  At all disease stages of ILD, palliative care can be a fundamental management component that provides supportive care for physical and mental wellbeing, in addition to advanced planning of end-of-life needs.
  When discussing palliative care, patients may become emotionally distressed or be reluctant to engage, as many people perceive it as care for terminal patients only. It is valuable to discuss with patients early in their diagnosis the true meaning of palliative care and help demystify concerns for them and their carers/family.
• Vaccinations. Ensure your patients are up to date with their vaccinations (e.g., flu, pneumococcal and COVID).
• Handheld fans can be a useful additional measure for managing breathlessness in ILD. Handheld fans can be purchased via our online shop.
• In addition, smoking cessation is vital. Click on our link and discover more about the importance of lung health with our smoking cessation tools for you and your patients.

People with ILD can develop acute exacerbations with sudden worsening of their symptoms. It is important to exclude the possibility of chest infections as the cause of acute exacerbation for appropriate treatment.

Medications and non-pharmacological treatments for ILD (as described above) can support patients to better manage symptoms and reduce the risk of, and impact of, exacerbations.

People with ILD often have other comorbidities that can contribute to their symptoms and affect their quality of life. Common comorbidities can include gastroesophageal reflux (GORD), cardiovascular conditions, COPD, lung cancer and obstructive sleep apnoea. It is important to consider a holistic care approach to manage a patient’s comorbidities, nutritional status and psychological health, with the potential to improve their overall wellbeing. People with ILD can be at increased risk of developing Pulmonary Hypertension and lung cancer, which are associated with increased mortality.

Appropriate and timely assessments for these conditions are necessary if people with ILD develop relevant symptoms.

Bajwah, S., et al. (2021). “Pharmacological and nonpharmacological interventions to improve symptom control, functional exercise capacity and quality of life in interstitial lung disease: an evidence synthesis.” ERJ Open Res 7(1).

Cottin, V. and L. Richeldi (2014). “Neglected evidence in idiopathic pulmonary fibrosis and the importance of early diagnosis and treatment.” Eur Respir Rev 23(131): 106-110.

Jo*, H. E., et al. (2018). “Diagnosis and management of idiopathic pulmonary fibrosis: Thoracic Society of Australia and New Zealand and Lung Foundation Australia position statements summary.” Medical Journal of Australia 208(2): 82-88.

Margaritopoulos, G. A., et al. (2017). “Comorbidities in interstitial lung diseases.” Eur Respir Rev 26(143).

Wijsenbeek, M. S., et al. (2019). “Comprehensive Supportive Care for Patients with Fibrosing Interstitial Lung Disease.” Am J Respir Crit Care Med 200(2): 152-159.