Idiopathic pulmonary fibrosis (IPF) is one of the most severe respiratory diseases with median survival 2.5 to 3 years if untreated. In the last 20 years enormous effort was focused to the area of research of pathogenesis and treatment of this disease. Development and launch of the first antifibrotic drug, pirfenidone, in 2011 became a historical milestone, offering a chance to treat IPF for the first time. Nevertheless substantial gaps in knowledge of this mortal disease remain and attempts to achieve cure of this disease fail up to now.
The diagnostic guidelines on IPF underwent a development during time as well and revelation of diversity and variability of the radiological and clinical picture of the disease led to a new radiologic and clinical classification. Despite these achievements we cannot rest self-satisfied since IPF still remains a disease with highly unmet therapeutic needs and should stay in a scope of interest of respiratory physicians, researchers and stakeholders.
Epidemiology and incidence
Epidemiology of IPF is mostly only estimated from health insurance claims and from registries. Its published prevalence ranges from 0.7 to 63 per 100 000 inhabitants and its incidence from 0.6 to 17.4 per 100 000 inhabitants.1 The estimated number of the patients with IPF worldwide is about 5 millions. However, even this high number might be underestimated provided underdiagnosis of interstitial lung diseases (ILDs) in general and due to misdiagnosis for other diseases presenting with chronic breathlessness such as chronic obstructive lung disease (COPD) and cardiac failure. Nevertheless merely these patients who are already diagnosed IPF create substantial burden of costs for medical care, disability, and death. Having IPF is connected with being at high risk of hospital admissions due to respiratory but also non-respiratory conditions, the most severe and deadly being acute exacerbation (AE-IPF). The annual incidence of AE-IPF is 5%–20% with a mortality rate as high as 20–100%. The estimated financial burden of hospitalization for IPF is £16.2 million/year in the UK with the rate of all-cause hospitalization being 0.5 per person/year, a mean 3.1 days of hospital stay per person/year, and an outpatients visit rate of 28 visits per person/ year. Inpatient death rate for IPF-patients is 3-fold higher than for controls.2 Based on a prevalence of 89 000 patients with IPF in the United States the aggregate incremental costs due to this diagnosis was over $1 billion per year.3
Clinical picture and diagnosis
In most cases, IPF has a distinct and typical clinical picture. It is a disease of middle-aged and older people with peak incidence in the 6th to 7th decade. The disease is more prevalent in male, smokers. If younger individuals develop a similar clinical and radiologic/pathologic picture as IPF, interstitial pneumonia/fibrosis should be considered. The typical clinical phenotype of IPF comprises progressive shortness of breath, dry cough, velcro crackles/ rales/crepitation on auscultation and finger clubbing. Lung function impairment might not be present at the time of diagnosis. However, the worsening of vital capacity and transfer factor is typical during follow-up. Due to the 2011 statement on IPF diagnosis the following is required:
- exclusion of other known causes of ILDs
- presence of a usual interstitial pneumonia (UIP) pattern on high resolution computer tomography (HRCT)
- or specific combinations of HRCT and histopathologic patterns in patients lacking typical HRCT features4
The crucial role of HRCT in the diagnosis of IPF is confirmed in the new 2018 statement on IPF diagnosis.5 However, the radiologic classification of IPF changed according to the recommendation of the Fleischner Society from the last year.6 That means that while the subgroup of definite UIP (subpleural predominant reticular abnormality with traction bronchiectasis and honeycombing, with a clear craniocaudal gradient on coronal images) remained the same, the group of possible UIP was subdivided into probable UIP (basal predominant, subpleural predominant reticular abnormality, with peripheral traction bronchiectasis) and indeterminate for UIP. The Fleischner Society then stated based on the probability of a definite diagnosis of IPF related to the HRCT patterns, that a definite diagnosis of IPF can be done in both definite and probable UIP patterns without lung biopsy in the patients with typical clinical signs. However, this recommendation was not reflected in the new 2018 statement on IPF diagnosis. The statement says that in case of appropriate clinical symptoms, provided exogenous origin and connective tissue diseases are excluded, only the HRCT pattern of definite UIP implicates no need for further investigations, neither bronchoalveolar lavage (BAL) nor surgical lung biopsy (SLB). On the other hand, BAL and SLB are recommended not only in cases of indeterminate for IPF diagnosis (like recommended by Fleischner Society) but also in probable UIP (opposed to the Fleischner Society recommendation).5, 6
A multidisciplinary team (MDT) is a proper platform to put together all the clinical, radiologic and pathologic findings and state the final diagnosis. The MDT should involve as regular members at least a pulmonologist/ILD expert, a radiologist and, a pathologist trained in ILDs; a rheumatologist and an occupational physician are usually facultative MDT participants. The MDT should meet regularly at least monthly, and as a result the report with final diagnosis and differential diagnoses should be issued. The meeting is not necessarily in person; the experts could discuss the cases by webex link and/or telephone.7
Problematic is a subgroup of patients with suspect IPF clinically, with probable or indeterminate radiologic UIP patterns who either cannot undergo or are not willing to undergo SLB. This subgroup is quite large, comprising about 40 to 50% of the IPF patients.8 Moreover, the cryobiopsy as a safer alternative to SLB (SLB mortality and morbidity is 4% if TLCO <35% and age >65 years!) stayed with no recommendation in the new 2018 guideline.5, 9 In these cases the MDT can state clinically confident IPF diagnosis in presence of clinical signs typical for IPF and radiologic probable UIP pattern in an individual older than 50 (male) or 60 (female) or in the patient older than 70 with fibrotic radiologic changes of large extent even without traction bronchiectasis, and without lymphocytosis in the BAL fluid.5
Therapy and patient management
Treatment of IPF was already stated in the 2015 clinical practice guideline, where the two antifibrotic drugs, pirfenidone and nintedanib, were recommended for IPF therapy.10 Lung transplantation is to be considered in early course of the disease to identify the candidates suitable for this surgical treatment in case the disease inevitably progresses to respiratory failure. Palliative care should be a part of care for IPF patients from the time of diagnosis to alleviate the symptoms of this incurable disease. Supportive care comprises usually oxygen supplementation if needed and also physiotherapy. The patients either on current antifibrotic treatment or those ineligible for this treatment should be offered participation in the clinical trials with new drugs.10
The 2018 guideline on IPF diagnosis, despite its limitations, has again moved forward the IPF diagnostic process and left enough space for MDT discussion and decision in uncertain cases. The treatment of IPF is evolving; however, we cannot reach cure in the IPF patients to date. Maximum effort should be focused on early diagnosis and treatment of IPF to maximally prolong the lives of the patients. Increasing awareness of IPF with help of the patients’ organizations and media is extremely helpful for this purpose. In the process of increasing knowledge in the field of IPF, not only the basic research and randomized clinical trials, but also the real world registries are of substantial help. The EMPIRE registry, the biggest IPF registry in the world, can offer vast evidence on clinical behavior and the effect of the antifibrotic treatment in real world settings (Tab. 1, Fig. 1-2).