Idiopathic pulmonary fibrosis (IPF), the most severe form of pulmonary fibrosis, is a progressive lung disease, which, despite the advent of antifibrotic agents, remains a debilitating and lethal condition. Acute and chronic infection, gastroesophageal reflux (GER), pulmonary hypertension (PH), lung cancer, cardiovascular diseases, obstructive sleep apnoea (OSA) and depression are comorbidities that can either precede or follow the development of IPF. If these comorbidities are undiagnosed and untreated, they may negatively affect the patient’s functional status, quality of life, and survival.1
Acute and chronic respiratory infections
In IPF, acute pulmonary infection is second only to acute exacerbation (AE) as a cause of rapid progression. In the past, the use of immunosuppressive agents was the major predisposing factor for acute infections but recent observations led to a strong negative recommendation against the use of these agents in IPF.2 Until recently, the exclusion of an infection was a requirement for the definition of AE of IPF.3 However, it is now recognised that infection can trigger diffuse alveolar damage (DAD) with the same clinical and HRCT features seen in AE and the same poor outcome. AE and respiratory infections have the same seasonal incidence (that is, winter). Therefore, the term ‘triggered AEIPF’ has been introduced in order to describe AE of IPF associated with acute respiratory infection.4 Thus, it is imperative to treat acute lower respiratory tract infections as early as possible in IPF. Furthermore, although no randomised control data exist, patients who experience recurrent chest infections could benefit from the introduction of antibiotics on a prophylactic dose as a preventive measurement.
In the past, patients with IPF were more susceptible to chronic pulmonary infections mainly from Mycobacterium species because of the chronic use of immunosuppressive therapies. Importantly, the radiological manifestations of pulmonary TB in patients with IPF may be atypical and more frequently are characterised by peripheral mass-like lesions.5 The comparison with previous imaging is warranted as pre-existing fibrotic changes may mask typical imaging appearances of infection.
There is a strong association between GER and pulmonary fibrosis, mainly IPF. In large series, the prevalence of distal and proximal GER varies from 67% to 88% and from 30% to 74% respectively.1 Although there is uncertainty regarding the pathogenetic role of GER, the current view is that GER is likely to contribute to the development and progression of IPF.1 This view was recently strengthened by the acknowledgement that chronic microaspiration could lead to ‘triggered AEIPF’.4 It is worth noting that in experimental models, chronic aspiration-related lung injury may occur without a significant reduction in pH, implying that non acid reflux may also be relevant.6
In symptomatic GER, lifestyle changes such as small frequent meals, elevating the head of the bed on blocks, avoiding lying supine for three to four hours after eating, avoiding garlic, onions, and heavily spiced food, and excessive tea, coffee or alcohol are recommended. Laparoscopic fundoplication may be required for severe symptomatic reflux resistant to high dosage protein pump inhibitors, H2 receptor antagonists and prokinetic agents. In a recent update of an IPF treatment guideline, a weak positive treatment recommendation for the routine use of anti-acid therapy was made.2 However, in this regard, the absence of controlled data establishing efficacy is a major concern. Indeed, in a recent pharmaceutical cohort, the rate of pulmonary infection was increased in prevalence in patients with moderate to severe disease (FVC<70%) receiving anti-acid treatment.7 This finding, possibly representing an adverse antacid effect on the composition of the respiratory microbiome, has added to reservations about the use of anti-acid therapy in IPF patients without symptomatic GER.
It is strongly recommend that patients with suspected PH, mainly when associated with early disease and when disproportionate to the underlying ILD, should be referred to specialist PH centres. PH is considered a predictor of poor survival and an indication for immediate listing for lung transplantation.8 The prevalence of PH in IPF, varies from 32% to 85%.1
Clinical signs such as presyncope or syncope and dyspnoea out of proportion to imaging raise the suspicion of PH. Right heart catheterisation (RHC) is still considered to be the diagnostic reference standard. However, in severe cases, the procedure may not be recommended because of increased risk. In these cases, a combination of non-invasive tests is used to reach a working diagnosis of PH, including:1
- Echocardiography: Elevated right ventricular systolic pressure, dilatation of the right atrium or right ventricle, and right ventricular dysfunction are all predictive of findings at RHC
- Lung function tests at rest: PH is characterised by disproportionate reductions in diffusing capacity for carbon monoxide (DLco) and diffusing capacity adjusted for VA (Kco), compared to lung volumes, in combination with a reduced PaO2 and widened alveolar–arterial oxygen gradient
- Exercise data: PH is associated with prominent six-minute walk test abnormalities including reductions in distance walked, desaturation to <85% and impaired heart rate recovery after the test
- Biomarker data: Currently this is confined to elevation of brain natriuretic protein
- High resolution CT (HRCT) data: PH is more likely to be present when there is enlargement of the main pulmonary artery or when the ratio of pulmonary artery diameter : aorta diameter exceeds 1.0.
Patients with PH should be screened for reversible causes including OSA, pulmonary embolism and left heart failure.
Vasodilators have been used cautiously in IPF patients, due to the potential risk of worsened gas exchange and hypoxaemia. There has been little support from clinical and trial data for the use of targeted PH therapies in IPF. The only encouraging result emerged from a trial of sildenafil in patients with advanced IPF. In this trial, active treatment was associated with improved dyspnoea, quality of life, and oxygenation, with greater benefits observed in patients with evidence of right ventricular strain on echocardiography.9 The combination of an anti-fibrotic drug with sildenafil in moderate to severe PH is attractive in principle as it targets both the interstitial and vascular compartments.10
IPF is associated with several comorbid cardiac conditions, including atrial fibrillation, other arrhythmias, congestive heart failure and coronary artery disease.1 In patients with breathlessness disproportionate to the extent of the underlying ILD, proactive cardiac evaluation with HRCT and an echocardiogram is warranted. 24-hour Holter monitoring is appropriate if there is reason to suspect cardiac arrhythmias, triggered by exertional hypoxia. HRCT gives clinicians a means of diagnosing cardiac failure (profuse septal thickening, ground glass opacities with patchy distribution and pleural effusions) and screening for coronary artery disease without additional tests.11 In IPF, the identification of moderate to severe coronary calcification on HRCT can predict the presence of underlying significant coronary artery disease with a sensitivity and sensibility of more than 80%.11 Aggressive medical treatment of coronary artery disease in IPF is appropriate.2
Pulmonary embolism (PE)
There is an increased incidence of venous thromboembolism in patients with IPF compared with the general population.1 Contributing factors could include the decreased mobility of patients with IPF and the possibility of shared pathogenetic mechanisms between venous thromboembolism and IPF (with activation of the coagulation cascade observed in fibrotic lung disease). The diagnosis of PE requires the performance of CT-pulmonary angiography. Ventilation/perfusion (V/Q) scanning is highly non-specific for pulmonary embolism (PE) in IPF because perfusion defects in ventilated lung are a recognised feature of honeycombing cysts.12 The use of warfarin in the treatment of PE in IPF has been debated. A recent placebo-controlled trial of warfarin was stopped early after an interim analysis showed an increase in mortality in patients receiving warfarin13 A post-hoc analysis of patients in the placebo arms of the three major randomised controlled trials of antifibrotic therapy for IPF found that the use of warfarin was an independent predictor of IPF-related death.14 It is uncertain whether this adverse effect also applies to new oral anticoagulants such as factor Xa inhibitors. If there is an absolute requirement for anticoagulation in an IPF patient (for example, PE, paroxysmal atrial fibrillation), it can be argued that low molecular weight heparin is preferable to warfarin.15
The prevalence of lung cancer in IPF varies from 4.4% to 9.8%.1 Lung cancers in IPF tend to be peripheral and located in the lower lobes, which is in accordance with the distribution of the fibrotic lesions in IPF. The distinction between malignancy and areas of confluent fibrosis on HRCT may be difficult, especially when previous imaging is unavailable. Advancing age, male sex, and smoking history are all associated with an increased risk for the development of lung cancer in patients with IPF. The optimal treatment remains unknown as chemotherapy, radiotherapy and surgical resection are all associated with a high risk of AEIPF.1 Therefore, risk and benefits should be weighed and detailed discussion with the patient is required.
OSA affects patients with IPF and the reported incidence varies from 59% to 90%.1 OSA is not screened routinely but tends to be investigated when there is a high likelihood based on clinical symptoms (daytime somnolence) and validated scales (such as the Epworth score). However, the Epworth sleepiness score did not reflect the severity of OSA at nocturnal polysomnography (NPSG) and less than 25% of IPF patients with sleep disordered breathing had an OSA clinical syndrome (with compatible Epworth sleepiness scores).16,17 Thus, it has not been established that routine NSPG in all IPF patients adds value to clinical evaluation. However, the routine performance of overnight oximetry can be justified by the observation that nocturnal desaturation is associated with increased mortality in fibrotic idiopathic interstitial pneumonia.18 The test is easy to perform and can be used to select IPF patients to undergo NSPG.
Symptomatic OSA in IPF requires treatment. The unresolved question is whether asymptomatic OSA should also be treated. There are several underpowered studies suggesting survival benefits in IPF patients receiving OSA treatment. However, these inconclusive observations do not establish that the treatment of asymptomatic OSA is beneficial. It is believed that nocturnal desaturation may be associated with the development of pulmonary hypertension but there are no data to indicate which patients would benefit from the routine institution of continuous positive airways pressure or from the addition of nocturnal oxygen supplementation alone. When treatment with CPAP is instituted, correction of factors that reduce patient compliance, such as nocturnal dry and irritating cough and claustrophobia, is very important.
In IPF, the prevalence of depression varies from 11% to 50% according to the tools used for assessment. Depression is associated with dyspnoea, loss of independence, feelings of social isolation, and inadequate sleep.1 Studies supporting early referral to specialised ILD centres with access to expert psychiatric advice showed a high prevalence of clinically significant depression, often undiagnosed prior to referral.19 Pulmonary rehabilitation and palliative care intervention for patients with advanced fibrotic lung disease is associated with improvements in both anxiety and depression but studies in less severe patients are lacking.20
1 Margaritopoulos GA et al. Comorbidities in interstitial lung diseases. Eur Respir Rev 2017;26(143).
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4 Collard HR et al. Acute exacerbation of idiopathic pulmonary fibrosis. An International Working Group Report. Am J Respir Crit Care Med 2016;194(3):
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6 Downing TE et al. Pulmonary histopathology in an experimental model of chronic aspiration is independent of acidity. Exp Biol Med (Maywood) 2008;233:1202–12.
7 Kreuter M et al. Antacid therapy and disease outcomes in idiopathic pulmonary fibrosis: a pooled analysis. Lancet Respir Med 2016;4(5):381–9.
8 Caminati A et al. Pulmonary hypertension in chronic interstitial lung diseases. Eur Respir Rev 2013;22:292–301.
9 Idiopathic Pulmonary Fibrosis Clinical Research Network. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med 2010;12;363:620–8.
10 Wuyts WA et al. Combination therapy: the future of management for idiopathic pulmonary fibrosis? Lancet Respir Med 2014;2:933–42.
11 Nathan SD et al. The value of computed tomography scanning for the detection of coronary artery disease in patients with idiopathic pulmonary fibrosis. Respirology 2011;16:481–6.
12 Strickland NH et al. Cause of regional ventilation-perfusion mismatching in patients with idiopathic pulmonary fibrosis: a combined CT and scintigraphic study. AJR Am J Roentgenol 1993;161:719–25.
13 Noth I et al. The Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet). A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2012;186:88–95.
14 Kreuter M et al. Unfavourable effects of medically indicated oral anticoagulants on survival in idiopathic pulmonary fibrosis. Eur Respir J 2016;47:1776–84.
15 Margaritopoulos GA et al. Can warfarin be used in the treatment of pulmonary embolism in idiopathic pulmonary fibrosis? Am J Respir Crit Care Med 2016;193:810–11.
16 Lancaster LH et al. Obstructive sleep apnea is common in idiopathic pulmonary fibrosis. Chest 2009;136:772–8.
17 Milioli G et al. Sleep and respiratory sleep disorders in idiopathic pulmonary fibrosis. Sleep Med Rev 2015;26:57–63.
18 Corte TJ et al. Elevated nocturnal desaturation index predicts mortality in interstitial lung disease. Sarcoidosis Vasc Diffuse Lung Dis 2012;29:41–50.
19 Holland A et al. Dyspnoea and comorbidity contribute to anxiety and depression in interstitial lung disease. Respirology 2014;19:1215–21.
20 Bajwah S et al. Palliative care for patients with advanced fibrotic lung disease: a randomised controlled phase II and feasibility trial of a community case conference intervention. Thorax 2015;70:830–9.