Treatable traits in interstitial lung disease: a narrative review

Immune dysregulation and inflammation

Immune dysregulation and inflammation in the lung can reflect the underlying aetiology, including autoimmune diseases or hypersensitivity pneumonitis (HP) where repeated exposures to a wide range of potential antigens trigger an aberrant immune response that results in T cell-mediated inflammation and granuloma formation, with subsequent fibrosis. ³⁸ Identification of pulmonary inflammation is not always straightforward. High-resolution computed tomography (HRCT) imaging patterns most commonly associated with inflammation include ground glass changes, non-specific interstitial pneumonia and organising pneumonia. ³⁹ Bronchoalveolar lavage (BAL) may also be useful in defining inflammation, albeit complex. ⁴⁰ Histopathology may demonstrate significant inflammatory infiltrates and/or a pathological pattern indicating inflammation such as organising pneumonia.

When inflammation is identified, immunosuppressive medications are often utilised to improve patient health outcomes, including lung function and quality of life. ⁴¹ Current treatment guidelines recommend immunosuppression as first line therapy for CTD-ILD and in selected cases of HP. However, when patients have evidence of inflammation without a clear diagnostic label the management approach is less clear.

Connective tissue disease and autoantibodies

Interstitial lung disease can develop in every CTD, ranging from limited disease with innate stability to fulminant and life-threatening disease. The presence of underlying CTD is an important TT to identify and manage. Indeed, CTD-ILD is estimated to represent between 6% and 33% of all ILDs. ⁴² To accurately diagnose CTD-ILD, all patients with ILD should be assessed for subtle features of CTD clinically and serologically. ³⁴ Radiological features that support a CTD include the presence of a NSIP or OP pattern, evidence of serositis or extra-thoracic manifestations of CTD. ³⁹ Once recognised as CTD-ILD, it is appropriate to involve rheumatology or immunology specialist care. Immunosuppression is the cornerstone of first-choice therapy. The decision on when to initiate immunosuppression is often based on delineating whether a patient’s disease is inherently stable or at risk of progression.

Some patients exhibit positive autoantibodies or clinical features suggestive of autoimmunity without meeting the diagnostic criteria for a connective tissue disease (CTD). These individuals have historically been classified as having ‘interstitial pneumonia with autoimmune features’ (IPAF). ⁴³ Although IPAF remains a research definition with management implications that are not fully understood, it underscores the importance of a rheumatology or immunology assessment. ³⁴

Certain autoantibodies have been suggested as a discrete TT, responding to immunosuppression irrespective of the underlying CTD. ² Notably, evidence suggests that antisynthetase antibodies predict a positive response to immunosuppression and favourable outcomes, even in other forms of CTD-ILD. ⁴⁴

Drug exposure

Over 400 drugs have been identified as causative of pulmonary toxicity with many common drugs being culpable including chemotherapeutics, methotrexate, amiodarone and immune checkpoint inhibitors.^45,46 The two main mechanisms of injury are direct cytotoxic pulmonary injury and immune-mediated injury.^45,47 These can occur independently or in combination depending on the drug and host response. Treatment is largely supportive with the mainstay being withdrawal of culprit drug. In some situations, corticosteroids or alternative immunosuppression is advised. ⁴⁵

Environmental exposures

Many environmental exposures are related to the development of ILD, and particularly HP.^38,48 The prevalence of HP in high-risk groups is substantial with estimated prevalence in farmers at 1.2%–12.9%, bird breeders at 3.7%–10.4% and mushroom workers at 3.5%–29%. ³⁸ Identification of environmental exposures is through a targeted patient history, or exposure questionnaire, with one questionnaire recently validated specifically for ILD patients.^40,49 A standardised questionnaire that elicits exposure characteristics further to the absence or presence of exposure may increase diagnostic confidence. ⁴⁹ Central to the management of HP is antigen avoidance, as patients with the removal of a known antigen have improved outcomes.^2,50

There is a growing body of evidence that suggests particulate matter is an aetiological driver of both ILD development and disease progression. ⁴⁸ There is clear evidence from occupational lung disorders including silicosis and asbestosis the significant inflammatory and/or fibrotic response patients can have to inhaled noxious particulate matter. ⁵¹ One meta-analysis confirmed an association between acute exacerbation and PM2.5 (air pollution particles with a diameter of 2.5µm or less) concentrations. ⁴⁸ Management of this TT may involve the change in occupation, mask-wearing, relocation or avoidance of specific exposures (such as wildfires) although this may not be feasible for many patients.

Genetics

It is now understood that genetic variants account for approximately 30% of the risk of development of sporadic and familial IPF.^{52 –55} Rare genetic variants can impact genes involved in telomere maintenance, resulting in shortened telomeres, premature cellular ageing and pulmonary fibrosis. ⁵⁶ Surfactant proteins are essential for lung function with genetic mutations causing disrupted alveolar stability. Common variants of the MUC5B gene including the promoter variant, a single-nucleotide polymorphism rs35705950 which encodes mucin, a key component in macrophage function and mucociliary clearance, are associated with increased risk of IPF.^54,57

Genetic variants come with significant implications for prognosis and management. Shortened telomeres are associated with worse prognosis and heightened risk of immunosuppressive side effects.^56,58 This may be important for patients undergoing lung transplant evaluation.^59,60 Patients with a telomeropathy may also have other clinical features including a family history, young age at diagnosis, nail dystrophy, premature hair greying, personal or family history of blood abnormalities (macrocytosis or thrombocytopenia) or liver disease. ⁶¹

The role of genetic testing in the ILD clinic is not clear and access to testing varies worldwide. Whole genome sequencing involves multigene panels including telomere-maintenance genes (TERT and PARN mutations); surfactant metabolism genes (including ABCA3, and surfactant protein C, SFTPC), MUC5B polymorphism and other genes (e.g., AKAP13).^{62 –65} Telomere length can also be examined using either quantitative PCR or fluorescent in situ hybridisation (flow FISH).^61,64,65

While treatment paradigms guided by genetic variants are yet to be established in ILD, clinical trials stratified by genetic profile are being conducted. The TELO-SCOPE trial (NCT04638517) is assessing the safety and efficacy of danazol in patients with pulmonary fibrosis and short telomeres. ⁶⁶ The PRECISIONS study (NCT04300920) evaluates the role of N-acetylcysteine (NAC) in patients with the TOLLIP rs3750920 TT genotype. ⁶⁷ While it is not yet routine to undertake genetic assessment for ILD patients, genetics, as with many aspects of precision medicine, represents a key future trait in the TT model of care.

Progressive pulmonary fibrosis

PPF refers to a non-IPF progressive phenotype, despite optimal therapy.^3,9 This has now been recognised across many ILD subtypes including CTD-ILD and chronic HP.^3,68,69 In line with ATS/ERS/JRS/ALAT guidelines, PPF involves two or more of (a) worsening respiratory symptoms, (b) physiological deterioration with absolute decline in FVC% predicted ⩾5% or decline in DLCO% predicted of ⩾10% or (c) radiological progression over 1 year with no alternative explanation. ⁷⁰ Understandably, meeting the PPF criteria portrays a poor prognosis both regarding mortality, and further progression. There is now robust evidence that anti-fibrotic medications have similar efficacy as seen in IPF, and nintedanib has now been approved for non-IPF progressive disease in some regions, based on the INBUILD study.^3,5 As a result, all patients regardless of underlying ILD subtype should be closely monitored for progression and, if on optimal therapy for their underlying ILD, adding an anti-fibrotic therapy to their treatment regimen may be considered.

Pulmonary infection

Pulmonary infections are seen frequently in ILD and are often associated with acute exacerbations of ILD.^{71 –73} Acute exacerbations can be devastating, with an in-hospital mortality of over 50%. ⁷³ While identification of the trigger for an acute exacerbation is often futile with minimal change in management, the prevention of exacerbations remains critical. Acute exacerbations can be caused by respiratory viral infections,^74,75 and this is supported by epidemiological data showing exacerbations are seen more commonly in winter, spring and in those taking immunosuppression.^37,73,76 Common pathogens include respiratory viruses (rhinovirus, respiratory syncytial virus, influenza, parainfluenza), Sars-CoV-2 and bacterial infection (H. influenzae, P. aerugonisa, S. pneumoniae).^77,78

Bacterial infection may be a driver of ILD progression.^37,79 In IPF, it has been identified that patients with higher bacterial load have worse progression-free survival. ⁷⁹ Severe COVID-19 infection causes alveolar damage and may result in pulmonary fibrosis ⁸⁰ with 7% of those hospitalised with COVID-19 infection having persisting lung abnormalities on CT within 12 months of infection. ⁸¹

To identify infection, sputum sampling, pan-viral assays, multiplex polymerase chain reaction, and, in some circumstances, bronchoscopy may be required. ⁷⁷ Preventative measures including respiratory hygiene, vaccination and prophylactic antibiotics in those receiving corticosteroids and other immunosuppression are important. The role of prophylactic antibiotics including azithromycin and cotrimoxazole has been investigated with mixed results.^82,83 Rapid treatment of respiratory infection with timely antibiotic initiation is crucial in managing this TT.

Emphysema

IPF and emphysema both share risk factors including increasing age, male gender and smoking. Concomitant emphysema is common in ILD, with the prevalence in current or former smokers with fILD ranging from 8% to 67%. ⁸⁴ Combined pulmonary fibrosis and emphysema (CPFE) is the clinical syndrome of emphysema ⩾10%–15% of total lung volume in the setting of fibrosis. ⁸⁴ CPFE results in a characteristic functional profile with preserved lung volumes, significantly impaired DLCO, exertional hypoxia and increased prevalence of pulmonary hypertension and lung cancer.^{84 –86}

It is important to identify whether patients have CPFE as this will have direct implication on monitoring and treatment. FVC is often preserved in CPFE, with emphysema resulting in the loss of elastic lung recoil, and hyperinflation counteracting the fibrotic reduction in FVC.^84,85 While DLCO may be used in monitoring, DLCO is often disproportionately low in the setting of emphysema, even more so in the setting of pulmonary vasculopathy.^87,88 As a result, CPFE monitoring requires a combination of clinical assessment, regular imaging and multiple function parameters with reduced emphasis on monitoring FVC or DLCO. ⁸⁴

There is evidence that patients with emphysema that demonstrate airflow obstruction have improved outcomes when treated with inhaled bronchodilators.^{89 –91}

Pulmonary hypertension

Pulmonary hypertension (PH) is common in ILD, with a prevalence ranging from 13% to 88%. ⁹² Its presence is associated with right ventricular dysfunction and confers worse survival. ⁹² With the advent of multiple treatments available for pulmonary arterial hypertension, PH is a tantalising TT for ILD patients. PH is often identified on a screening echocardiogram and confirmed at right heart catheterisation (RHC). On echocardiogram, a tricuspid regurgitant jet velocity of >2.8 m/s, corresponding to a pulmonary artery systolic pressure of approximately ⩾35 mmHg, suggests PH.^{93, 94} At RHC, PH is defined as a mean pulmonary artery pressure of ⩾20 mmHg. ⁹³

Effective treatments for PH in ILD have remained elusive until recently, when the INCREASE study evaluated inhaled treprostinil in PH-ILD, demonstrating that treprostinil was associated with increased 6-minute walk distance. ⁹⁵ As a result, treprositinil was fast-tracked for FDA approval for this indication. ⁹⁶ Prior to this, most studies of vasodilator therapies demonstrated no clinical benefit, and some (riociguat and ambrisentan) were associated with disease progression and hospitalisation.^{59,97 –99} There is still equipoise regarding the utility of cyclic guanosine monophosphate specific phosphodiesterase 5 inhibitors (PDE5i, including sildenafil) for PH-ILD. ¹⁰⁰ Some uncontrolled studies have suggested a beneficial effect ¹⁰¹ but this has not been supported in randomised controlled trials.^{102 –104} PH is an ideal TT, with its identification triggering consideration of PH-specific therapy, consideration of palliative care and transplant assessment. For those outside an expert ILD or PH centre, referral is warranted.

Hypoxia

Hypoxia is common in ILD patients and may be considered as resting, nocturnal and/or exertional, all of which are associated with worse outcomes.

Resting hypoxia is present in patients with severe disease and denotes a median survival of less than 1 year. ¹⁰⁵ Identification of hypoxia is through clinical assessment with pulse oximetry and is confirmed through arterial blood gas analysis.^{35,105 –109} Extrapolating from COPD, all ILD guidelines strongly recommend long-term oxygen therapy in patients with severe resting hypoxaemia with a PaO₂ of <56 mmHg or less severe hypoxaemia with PaO₂ 56–59 mmHg and evidence of hypoxic end-organ damage (PH or right heart failure).^{35,105 –110}

Nocturnal hypoxia is common in ILD patients, with reported prevalence of 37% overall, increasing with disease severity. ¹¹¹ There are likely multiple mechanisms driving the pathogenesis of isolated nocturnal hypoxia, including reduced respiratory drive during sleep, particularly with rapid-eye-movement sleep muscle atonia, with co-existent obstructive sleep apnoea (OSA) a common comorbidity. ¹¹¹ Nocturnal hypoxia may be a contributing driver or a marker of PH, a complication that portends poor prognosis in ILD. ¹¹² Furthermore, nocturnal hypoxia can be associated with poor HRQOL with impaired daytime function.^113,114 Nocturnal hypoxia is identified on formal polysomnography or overnight oximetry with most studies defining it as >10% of total sleep time with SpO2 <90% (TST90). ¹¹¹ Polysomnography has the advantage of being able to diagnose co-existent OSA. The treatment of isolated nocturnal hypoxia is less clear. While many regions will prescribe supplemental oxygen for nocturnal hypoxia, the data for this are limited and some regions have recommended against its use.^111,115,116 In a randomised cross-over trial of ILD patients with TST90 ⩾10%, nocturnal supplemental oxygen of 2 L/min improved TST90 compared with medical air, but there were no improvements in sleep architecture, sleep quality, dyspnoea or HRQOL. ¹¹⁷

Exertional hypoxia has a 5-year cumulative incidence of 40.1% in ILD patients overall, with increasing prevalence with disease severity, and is associated with reduced survival.^105,111,118 Traditionally, exertional hypoxia has been assessed on 6-minute walk test (6MWT), defined as pulse oximetry⩽88% during the test.^119,120 Other exercise tests such as the 1-minute sit to stand test are increasingly being used. ¹²¹ The role of supplemental oxygen for those with isolated exercise-induced hypoxia is less clear. The uncontrolled AmbOX study demonstrated improvement in HRQOL for patients using ambulatory oxygen over 2 weeks. ¹²² An RCT currently underway evaluating the impact of ambulatory oxygen versus medical air in fibrotic ILD will likely provide further insights. ¹²³

Hypoxia is an easily identified TT and supplemental oxygen is a readily available therapy in many regions. Ongoing research regarding the impact of oxygen therapy in exertional and nocturnal hypoxaemia is required while titration to reduce the risk of over-oxygenation is an important consideration.

Obstructive sleep apnoea

OSA is one of the most common co-morbidities associated with ILD ¹²⁴ with a prevalence of 61% in ILD patients. ¹²⁴ Reduced lung volumes in ILD lead to upper airway instability and risk of OSA with resulting negative impacts on quality of life. ¹²⁵ OSA is diagnosed on overnight polysomnography which may be performed in a laboratory or at home. ¹²⁶ Screening questionnaires, including the STOP-BANG questionnaire, are useful and easily implemented tools to risk-stratify patients with suspected OSA ¹²⁷ and have high sensitivity in ILD patients. ¹²⁸ Continuous positive airway pressure (C-PAP) is a readily available treatment and with good adherence has been shown to improve HRQOL, fatigue, daytime sleepiness and sleep quality. ¹²⁹ C-PAP may be poorly tolerated in ILD patients. ¹³⁰ Despite this, recent data suggest that auto-set C-PAP with close follow-up results in good adherence with minimal adverse effects reported in an ILD cohort. ¹³¹ Other therapeutic options for OSA in ILD include nocturnal oxygen therapy and mandibular splints. ¹³² Through the identification and management of OSA as a TT, there is potential to improve HRQOL and modify cardiovascular risk.

Lung cancer

The risk of lung cancer in ILD patients is greater than the general aged and sex-matched population.^37,133 Cumulative incidence of lung cancer post diagnosis of IPF is 3.3%, 15.4% and 54.7% at 1, 5 and 10 years, respectively^134,135, greatly impacting survival. ¹³⁶ The drivers of lung cancer in the ILD setting are not clear, ¹³⁷ with lung cancer predominantly occurring within or nearby areas of fibrosis. ¹³⁸ Lung cancer is frequently identified upon CT surveillance for ILD, often prompting further investigation including positron emission tomography scanning and biopsy. ¹³⁹ The management of lung cancer in ILD patients is complex with high risk of treatments including surgery, radiotherapy or chemo-immunotherapy clouding treatment decisions. With early lung cancer identification known to have improved outcomes, consideration of lung cancer screening in ILD patients is important.

Chronic cough

Cough is a common symptom for patients with ILD, with 84% of IPF patients reporting cough. In some studies, cough is more frequent in never smokers and those with advanced disease. ¹⁴⁰ The underlying mechanisms for cough are complex and likely related to chemical or mechanical stimulation of cough receptors. ¹⁴⁰ Patients with cough are more likely to have exercise limitation, disease progression and poorer outcomes.^140,141 Cough can be readily identified through clinical history however cough questionnaires and visual analogue scales can enable more objective assessment. The Leicester Cough Questionnaire (LCQ) is a validated and repeatable self-assessment that can be used to identify and stratify the severity of chronic cough. ¹⁴² Automated cough detection monitors have demonstrated good validity in the identification and severity assessment of cough in clinical settings while small wearable cough detectors may represent a useful tool in the outpatient setting.^143,144

Cough is an important TT with its treatment enabling a significant improvement in patient HRQOL. Cough management strategies include addressing co-contributing drivers such as gastro-oesophageal reflux, post-nasal drip, vocal cord dysfunction and smoking. Non-pharmacological therapies including cough suppressive techniques (cough suppression swallow, controlled breathing, relaxed through breathing) often with the assistance of speech pathology may also be effective. ¹⁴⁵ Other antitussive therapies are neuromodulators (including gabapentin and baclofen), opioids, and in some refractory cases laryngeal botox injection. ¹⁴⁶ Thalidomide is a potent immunomodulator and anti-inflammatory and was associated with improved cough severity in IPF however had substantial adverse event rates (77%). ¹⁴⁷ While there is limited evidence to support these options, a recent small short-term crossover trial of nalbuphine extended release has demonstrated a promising reduction in cough for patients with IPF.^148,149

Chronic dyspnoea

Dyspnoea is one of the cardinal symptoms of ILD, directly impacting functional limitation and quality of life.^150,151 Severity of dyspnoea at time of diagnosis is associated with poorer survival. ¹⁵² Dyspnoea can be identified on clinical history and further characterised through quantified validated questionnaires including the modified Medical Research Council (mMRC) scale or University of California Shortness of Breath Questionnaire. ¹⁵³ Management of dyspnoea is difficult. Increased airflow can be utilised to mitigate breathlessness through either fans (handheld or other) or medical air via nasal prongs. ¹⁴⁹ Pulmonary rehabilitation has been shown to improve dyspnoea and HRQOL in a meta-analysis of 16 studies. ¹² The utility of opioids for dyspnoea is not clear, with recent ERS guidelines having a conditional recommendation against the use of opioids in breathlessness with severe chronic respiratory conditions.^12,149 Management of dyspnoea has been identified as a top research priority for patients living with ILD and as such represents a priority TT. ¹⁵⁴

Exercise intolerance

Physical activity is greatly impacted in IPF patients compared to healthy age-matched controls. ¹⁵⁵ Indeed, exercise intolerance, defined as 6MWT distance <350 m, is associated with both decreased HRQOL and worse survival in patients with ILD.^17,155 Other methods of assessing exercise intolerance include more formal cardiopulmonary exercise testing, pragmatic wearable devices or smartphone applications. ¹⁵⁶ It is now clear that pulmonary rehabilitation improves exercise intolerance, with a meta-analysis showing an increase of 6MW distance of 40m at long-term follow-up (6–11 months). ¹² Most pulmonary rehabilitation studies have been conducted in outpatient settling with a small number being home-based, inpatient or tele-rehabilitation. ¹² Ongoing studies are underway to determine the most efficacious protocol for rehabilitation. ¹⁵⁷

Cardiac disease

Fibrotic lung diseases are associated with increased prevalence of coronary artery disease (CAD) with some studies suggesting that ILD promotes atherogenesis through increased systematic inflammation and chronic hypoxaemia. ¹⁵⁹ In lung transplant candidates, CAD is present in 30% of IPF patients compared to 10% of patients with emphysema, while occult CAD has been identified in up to 53% of ILD patients.^160,161 CAD represents one of the leading causes of death in patients with fibrotic ILD.^161,162 There is some evidence to suggest that moderate-severe coronary artery calcification is identified on HRCT with relatively high sensitivity and specificity, ¹⁶³ prompting further cardiac testing including CT coronary angiography, echocardiogram, stress testing and invasive angiography.^159,163 CAD treatment is important to prevent risk of subsequent cardiovascular events including myocardial infarction, stroke and death from cardiovascular disease. ¹⁶⁴ Risk factor optimisation and cardiology referral should be undertaken to improve survival in patients with ILD. ¹⁶¹

Sarcopenia and frailty

Sarcopenia describes a progressive and generalised skeletal muscle condition with accelerated loss of muscle mass and function. ¹⁶⁵ In ILD patients, reduced physical activity leads to muscle disuse and deconditioning, which, when combined with malnutrition, contributes to sarcopenia. ¹⁶⁶ The rates of sarcopenia in ILD vary across studies from 22.9% to 39.3% of ILD patients.^167,168 Sarcopenia is associated with increased ILD severity and mortality. ¹⁶⁹

To identify sarcopenia, an assessment of both skeletal muscle mass and function is required. Cross-sectional area of thoracoabdominal muscles on CT can be used to identify reduced skeletal muscle mass.^169,170 Further evaluation includes dual-energy X-ray absorptiometry (DEXA). This technique allowed precise, accurate and reproducible differentiation between body fat mass, lean mass and bone mineral content. ¹⁶⁶ Skeletal muscle strength and function can be assessed with quadriceps force which has been demonstrated as an important determinant of exercise capacity.^169,171,172

Evidence-based clinical practice guidelines provide strong recommendations for physical activity as the primary treatment of sarcopenia. ¹⁷³ Exercise programmes have been shown to be efficacious in improving physical performance (gait speed), muscle strength and HRQOL. ¹⁷⁴

There is some overlap between frailty and sarcopenia, with frailty being considered a complex and multidimensional syndrome with reduction of physiological reserves that increase the risk of adverse health outcomes. ¹⁷⁵ While frailty does occur in normal ageing, ¹⁷⁶ data supporting the importance of recognising frailty as a TT in chronic lung diseases is emerging with impacts on both hospitalisations and mortality. ¹⁷⁵

Frailty is more common among people with ILD, and respiratory disease overall, compared to general population. In one study of fibrotic ILD patients, 21% were considered frail. ¹⁷⁷ Frailty is an independent risk factor for early mortality, FVC% decline ¹⁷⁷ and hospital admission. ¹⁷⁶ The clinical frailty scale (CFS) ¹⁷⁷ is a pragmatic tool assessing overall fitness and frailty. Frailty is best addressed in a pulmonary rehabilitation setting. Exercise-based pulmonary rehabilitation programmes can improve exercise performance, muscle strength, dyspnoea and fatigue in patients with chronic lung diseases including ILD, all of which are key determinants of frailty. ¹⁷⁸ Self-management and education are important to further promote independence and reduce frailty. ¹⁷⁸

Osteoporosis and osteopenia

Approximately one third of patients with IPF have been diagnosed with a vertebral fracture. ¹⁷⁹ In ILD, risk factors that promote the development of osteoporosis include steroid use, malnutrition, reduced physical activity and smoking. ⁴⁴ Reduced bone mineral density is associated with significant decrease in FVC and diffusion capacity. ¹⁷⁹ Osteoporosis is diagnosed based on minimal trauma fracture history and DEXA scanning. Once identified, patients should have vitamin D and calcium levels. Treatment involves dietician counselling to ensure adequate nutrient intake, consideration of supplementation and anti-resorptive therapy in accordance with international guidelines. ⁴⁴

Malnutrition

Nutritional abnormalities including malnutrition are increased in ILD patients with reported rates varying between 9% and 55%.^180,181 Malnutrition is likely due to multiple factors, including dyspnoea, increased metabolic rate and the side effect profile of antifibrotics and some immunosuppressive medications.^4,5,180 Malnutrition is independently associated with decreased DLCO and reduced survival. ¹⁸² A body mass index of <18.5 can be used for the identification of malnutrition. ¹⁸³ Dietician assessment can be augmented by the use of the Patient-Generated Subjective Global Assessment Short Form as a screening tool to identify patients at risk of malnutrition. ¹⁸⁴ Targeted dietician input with nutritional plans are effective therapies for malnutrition. Nutritional interventions in other chronic lung diseases improve exercise tolerance, HRQOL, weight and respiratory muscle strength. ¹¹ The identification and treatment of this TT provide an accessible target with significant potential for improved outcomes in ILD.

Gastro-oesophageal reflux disease

The prevalence of gastro-oesophageal reflux disease (GORD) in ILD has primarily been studied in IPF, with hugely variable rates from 0% to 94% ³⁷ depending on the method of assessment and the population studied. GORD may lead to aspiration of gastric content into the airways and alveoli with resulting injury to alveolar epithelium, pneumonitis, fibrotic proliferation and lung fibrosis. ¹⁸⁵ Conversely, pulmonary fibrosis may cause increased negative intrathoracic pressure and traction of the lower oesophageal sphincter and precipitate GORD. ¹⁸⁶ Initial studies demonstrated that GORD was associated with worsened patient outcomes and that anti-reflux medication improved survival. ¹⁸⁷ These findings have not been replicated with some studies showing increased respiratory infections in severe ILD patients receiving anti-reflux therapy. A recent meta-analysis has concluded that there is insufficient evidence to conclude antacid medication improves respiratory outcomes in patients with IPF. ¹⁸⁸

The diagnosis of GORD is made through clinical evaluation with some patients requiring further assessment including gastroscopy, oesophageal manometry and ambulatory oesophageal pH monitoring.^{189 –192} Patients with symptomatic GORD should be managed with guideline-based treatment including anti-acid medications. ¹⁹¹ ILD management guidelines conditionally recommend against the use of anti-reflux medication and surgery for improving respiratory outcomes in patients with ILD. ⁷⁰

Anxiety and depression

Understandably the prevalence of anxiety and depression is high, and likely underestimated in ILD patients. In an Australian IPF cohort, anxiety and depression were 31% and 23%, respectively, ¹⁹³ similar to other cohorts of clinically relevant depression in ILD of >20%.^194,195 Anxiety and depression are associated with worsening symptoms, disease severity, number of comorbidities and worse quality of life.^193,196 However, there is a gap between the need for mental health support that ILD patients report and that which is provided.^2,197,198 Members of the health professional team should be aware of mental health concerns and may use screening tools such as the Hospital Anxiety and Depression Scale, the General Anxiety Disorder-7 (GAD-7) and the Patient Health Questionnaire 9 (PHQ-9) to help in identifying likely cases of anxiety and depression in ILD.^193,196

Treatments for depression and anxiety in ILD are not well studied or understood. Some data support the use of cognitive behaviour therapy to improve depression and anxiety in other chronic lung diseases. ¹⁹⁹ Pulmonary rehabilitation is also associated with a sustained improvement in depressive symptoms. Targeted antidepressant medications and psychology input should be considered for all patients with evidence of clinical depression or anxiety. ¹⁹³

Fatigue

Fatigue is one of the most common symptoms of ILD at the time of presentation and is reported in 60% of patients in some ILD registries.^200,201 Fatigue can lead to reduced HRQOL, impaired social interactions and diminished work capacity. One of the key challenges in understanding fatigue is the absence of a standardised definition. The presence of fatigue can be effectively assessed using a simple, validated fatigue scale.^201,202 Fatigue in ILD is often reflective of the complex interplay between the underlying disease process and contributing comorbidities, treatments and behavioural factors. ²⁰¹ Muscle fatigue results from hypoxia-induced metabolic acidosis, which triggers afferent feedback and the perception of fatigue. In patients with ILD, reduced oxygenation increases acidosis even during light activity, and when combined with dyspnoea and inadequate nutrient supply, can initiate a downward spiral of inactivity and sarcopenia. ²⁰³ Above targeting these individually, there is supportive evidence that a graded exercise therapy programme can be used effectively in the management of fatigue in patients with serious respiratory conditions. ¹⁴⁹

Polypharmacy

Polypharmacy is defined by the World Health Organisation as the concurrent use of five or more regular medications is most frequently seen in the elderly. ²⁰⁴ In one ILD cohort, polypharmacy was seen in 51% of IPF patients and 63% of inflammatory ILD patients. ³⁶ Polypharmacy portends an increased risk for non-adherence, drug-related side effects and drug interactions. ³⁶ The initiation of ILD-specific medications creates further complexity with the side effect burden of anti-fibrotics, medications for symptom management and the often significant pill burden. Non-adherence is further exacerbated by complex drug regimens and difficult to manage side effect profiles. A holistic approach is required to consider and balance the risk–benefit ratio of each medication, and their interplay. Input from pharmacists and medication rationalisation are important therapeutic strategies. ³⁶

Smoking

While smoking is a causative agent in the development of smoking-related ILDs including respiratory bronchiolitis-ILD and desquamative interstitial pneumonia, it is also an important co-factor in the development of other ILDs such as IPF and RA-ILD. ²⁰⁵ Active smoking confers poorer outcomes for survival in ILD. ²⁰⁶ Smoking cessation often requires a multifaceted approach and is frequently inadequately managed by medical teams. ²⁰⁷ A combination of behavioural support such as counselling, mindfulness and group workshops, along with pharmacotherapy maximises the chances of successful long-term smoking cessation. Current pharmacological therapies for smoking cessation are varenicline, nicotine replacement therapy and bupropion. ²⁰⁸