Disease Review: Understanding Incidence of Idiopathic pulmonary fibrosis (IPF) in India, Diagnosis and Treatment
Idiopathic pulmonary fibrosis (IPF), previously known as "Hamman Rich syndrome", "cryptogenic fibrosing alveolitis", and "cirrhosis of the lung", is a chronic, debilitating lung disorder. The most noticed symptoms are dyspnoea and cough, occurring alongside progressive deterioration of lung function that ultimately results in death. (1) IPF is a type of idiopathic interstitial pneumonia that shows chronic lung fibrosis and is associated with increased morbidity and mortality. This chronic fibrosis replaces the healthy lung tissue with a modified extracellular matrix (ECM) leading to the destruction of the alveolar structure. This further disrupts the gas exchange, alters lung compliance, and ultimately results in death, mainly due to respiratory system failure. (2)
Increasing incidence and awareness of IPF
Recently, IPF has raised attention due to the disease's increasing incidence, prevalence, and severity. Globally, the prevalence data varies as there are non-standardized differences in diagnostic criteria. IPF is the most common of the fibrosing lung diseases and accounts for between 17% and 86% of all cases of interstitial lung diseases, the incidence of which has doubled over the last two decades. ( 3,4)
Findings from the ILD India Registry Report
From a recent interstitial lung disease (ILD) India registry report, that enrolled 1084 patients, the prevalence rate of IPF was found to be 13.7%. (1) Although the prevalence rates are lower as compared to other respiratory conditions, IPF continues to remain a challenging condition that poses a significant burden on healthcare resources.
Age and its association with IPF
With the growing attention towards the disease, it has been observed that incidence and severity of IPF noticeably increase with age (age-imparted changes and the mechanism of disease appearance and progression). IPF is usually not found in the younger generation (<50 years), but a significant increase in morbidity is found with increasing age (>75 years). The estimated prevalence of IPF in this age group is around 0.2%. (2)
Typical disease course in IPF
The disease progression of IPF includes a wide array of rapid progressors (A), usual decline with periods of acute exacerbations (B), typical progression (C) (Fig. 1). (3)
Figure 1. Disease course of IPF.
Know the recent diagnostic approaches in IPF
IPF is considered a diagnosis of exclusion, and it requires a comprehensive clinical evaluation. The guidelines for diagnosing IPF are updated over time and offer substantial clarity in approaching a patient with suspected IPF (figure 2). A detailed history taking, thorough physical examination, chest imaging studies, laboratory testing, and tissue evaluation together form the background of evaluating a patient with suspected IPF. Interactions within multiple medical disciplines such as pulmonary, radiology, and pathology are needed to confirm the diagnosis, including an active clinical discussion of the patient's condition. (3)
Figure 2. Schematic representation of diagnostic process as per American Thoracic Society 2019 guidelines.(3) BAL: bronchoalveolar lavage; HRCT: high resolution computed tomography; MDD: multidisciplinary discussion; UIP: usual interstitial pneumonia.
Therapies in managing IPF
IPF is a chronic, relentless, and insidious progressive disease, thereby making it difficult to manage. The treatment approaches are based on the perception that inflammation results in injury and fibrosis in the lungs and thus, the focus has been on eliminating or suppressing the agents causing inflammatory response. IPF treatment strategies largely rely on a combinatorial approach of pharmacologic and non-pharmacologic regimens and are focused on interfering with disease progression and prevention of acute exacerbations. (2)
The older therapeutic regimens included multiple combinations of cytotoxic, immunosuppressive, and anti-inflammatory agents such as corticosteroids, cyclophosphamide, colchicine, azathioprine + N-acetylcysteine + prednisone, N-acetylcysteine, interferon-gamma, warfarin, sildenafil, endothelin receptor antagonists, and imatinib. As therapeutic trials with these agents failed to find any significant reductions in mortality, they have been replaced by newer treatment regimens that target the signaling pathways and thereby alter disease progression. (2)
Disease-modifying agents (tyrosine-kinase inhibitors) in IPF
Currently approved therapies in IPF consist of two drugs Pirfenidone and Nintedanib. The latter is a tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR). Nintedanib exerts both anti-inflammatory and anti-fibrotic activity by competitively binding with the ATP binding pocket of these receptors. This binding interferes in migration, fibroblast proliferation, differentiation, and collagen secretion; all of which are key processes in lung fibrosis. (2)
Three large-scale international trials TOMORROW, INPULSIS-1, and INPULSIS-2 have found that Nintedanib is both safe and effective in patients with IPF. There was a significant reduction in the rate of annual FVC decline found in the patients treated with Nintedanib as compared to placebo intervention. The INPULSIS-ON trial was an extension of the INPULSIS trial which found that the benefit on the rate of FVC decline persisted up to 3 years in patients receiving Nintedanib regimen post 52 weeks of the INPULSIS trial intervention. (1)
A retrospective study conducted by Cameli et al. (2020) confirmed the efficacy of antifibrotic therapy with Nintedanib in terms of mortality and functional disease progression in long-term follow-up of IPF patients. Nintedanib was well tolerated in the study group with lesser side effects compared to Pirfenidone. (5)
Nintedanib in early and advanced IPF
There have been apprehensions regarding Nintedanib therapy in patients with preserved lung function in the early stages of IPF. Studies have found that irrespective of the baseline FVC, the Nintedanib regimen caused a reduction in FVC decline, thereby leading to the recommendation of the use of Nintedanib early in the course of the disease, at the time of diagnosis itself. (1)
Similarly, there have been concerns about the use of Nintedanib in patients with advanced stages of the disease. A post hoc analysis conducted in patients enrolled for INPULSIS-ON having FVC ≤ 50% and FVC > 50% predicted at baseline found that the rate of FVC decline in both groups was similar, but the adverse effect profile was more severe in patients with advanced disease. (1)
Nintedanib is approved by both USFDA and EC for the treatment of IPF. With Nintedanib receiving approvals for IPF treatment in India and several other countries, there is now a glimmer of hope for patients who were otherwise battling a grim disease with a paucity of effective treatments.
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1. Singh A, Kishore K, Verma AK, Singh A. Nintedanib for the treatment of idiopathic pulmonary fibrosis: An Indian perspective. The Journal of Association of Chest Physicians. 2020 Jul 1;8(2):48.
2. Suri, G. S., Kaur, G., Jha, C. K., & Tiwari, M. (2021). Understanding idiopathic pulmonary fibrosis - Clinical features, molecular mechanism, and therapies. Experimental Gerontology, 153, 111473.
3. Wakwaya, Y., & Brown, K. K. (2019). Idiopathic Pulmonary Fibrosis: Epidemiology, Diagnosis and Outcomes. The American Journal of the Medical Sciences.
4. Xie, M., Liu, X., Cao, X. et al. Trends in prevalence and incidence of chronic respiratory diseases from 1990 to 2017. Respir Res 21, 49 (2020).
5. Cameli P, Refini RM, Bergantini L, d'Alessandro M, Alonzi V, Magnoni C, Rottoli P, Sestini P, Bargagli E. Long-term follow-up of patients with idiopathic pulmonary fibrosis treated with pirfenidone or nintedanib: A real-life comparison study. Frontiers in Molecular Biosciences. 2020 Sep 4;7:230.