Idiopathic Pulmonary Fibrosis (IPF)


Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by chronically progressing lung fibrosis. The most common symptoms of IPF include exertional dyspnea and chronic, nonproductive cough. As the disease progresses, patients experience loss of lung function that can eventually lead to death.

Disease Course

IPF has a variable clinical course, with some patients surviving only weeks after a diagnosis and others surviving more than a decade.1 However, the median untreated survival is estimated between 3 and 5 years after diagnosis.1 The course of progression can vary from slow to rapidly deteriorating. All patients may also be susceptible to acute exacerbations, discrete episodes of rapid deterioration of respiratory function coinciding with new alveolar abnormalities.1 These acute exacerbations usually result in hospitalization and are associated with high rates of mortality.2

The exact cause of IPF is unknown, but experts suggest it begins with repeated injury to the alveolar epithelial cells combined with abnormal wound healing leading to excessive fibrosis.3,4 The disease progresses through an asymptomatic period but with radiographic evidence of fibrosis.1 As scarring progresses, patients develop nonproductive cough and dyspnea.1 Symptoms are usually present for 1 to 2 years prior to diagnosis.1 As the disease progresses, forced vital capacity (FVC), exercise capacity, and health-related quality of life decline, along with worsening of dyspnea and cough.5 Most patients eventually die from respiratory failure, with death rates being highest during the winter.1

Factors Affecting IPF Prognosis

Many factors have been associated with poorer prognosis in patients with IPF. Studies have shown the presence of several comorbidities may reduce survival.6 For example, patients diagnosed with cardiovascular disease during follow-up for IPF have been shown to have a higher mortality rate.6 Diabetes mellitus and anticoagulant treatment have also been associated with higher mortality.6 Patients with IPF in combination with pulmonary hypertension and emphysema also tend to have a poor prognosis.7 

Gastroesophageal reflux (GERD) may also be associated with poorer prognosis.7 The reason for this is not fully understood but is hypothesized to be related to microaspirations of gastric contents contributing to the fibrosis seen in IPF patients.7 Data shows that patients taking antacids had reduced rates of decline in FVC and fewer acute exacerbations, which potentially support this hypothesis.7 Older age, as well as smoking status, may also be related to poorer prognosis but study results have been inconsistent.7 Male patients appear to have worse survival than female patients, even after adjusting for age, smoking history, maximum desaturation area, and diffusion capacity of carbon monoxide (DLCO).7 There also appears to be an association between body mass index (BMI) and survival, with higher BMIs leading to increased survival.7 The link between these two is unclear but may be linked to lower BMIs being related to higher levels of malnutrition and greater basal energy expenditure.7 The presence of lung cancer has also shown to have a negative effect on survival.1

One of the most significant factors affecting survival in IPF patients is acute exacerbations. These significant deteriorations affect roughly 10% to 20% of patients each year.8 The exacerbations of symptoms are believed to be caused by physical insults such as infection, aspiration, surgery, or simply an intrinsic acceleration of the disease.1 Acute exacerbations often require hospitalization, with mortality rates at least 50%. The mortality rate is higher in patients requiring mechanical ventilation due to their loss of respiratory function.1

A few treatment options are available that may prolong survival in some patients. The antifibrotic drugs pirfenidone and nintedanib have been shown to slow the decline in FVC for these patients. Pirfenidone has also demonstrated a reduction in all-cause mortality versus placebo over a 120-week trial period using pooled data from three clinical trials.1 A decrease in respiratory-related hospitalizations compared to placebo has also been demonstrated for pirfenidone.1 Both pirfenidone and nintedanib may impact acute exacerbations by reducing their number or increasing the time until occurrence.1 Lung transplantation is another treatment that can prolong survival in patients, especially when combined with pulmonary rehabilitation.1,9

Predictors of Outcome

The variability in the clinical course of IPF can make outcome predictions difficult for patients with IPF. A number of predictors have been investigated for their prognostic value.7 Studies have shown that worse baseline values in pulmonary function tests including FVC, total lung capacity, and DLCO are associated with shorter survival times.7 Changes over time in pulmonary function tests may have an even better predictive power.7 Decreases in the 6-minute walk test distance (6MWD) have also been shown to have predictive value.7 Baseline 6MWD values less than 250 meters and a 24-week decline greater than 50 meters were associated with a 2.1- and 2.7-fold increase, respectively, in mortality during the following year.7 Changes in cough and dyspnea, as well as the extent of fibrosis on high-resolution computed tomography (HRCT) scans, have also been linked to poorer prognosis.5 Several models have sought to use multiple variables for better predictions including the Gender-Age-Physiology (GAP) index and staging system, the composite physiologic index, and the risk of stratification score, but none of these systems are widely used due to their inability to provide accurate predictions of the disease course.5

A number of new potential predictors have also been proposed. One study investigated changes in biomarkers including the plasma proteins CCL13, CCL17, CCL18, CXCL13, CXCL14, COMP, interleukin 13, MMP3, MMP7, osteopontin, periostin, and YKL40 in the placebo arm of two pirfenidone clinical trials. The researchers found that CCL13, CCL18, COMP, CXCL13, CXCL14, periostin, and YKL40 showed correlations with declines in FVC but only CCL18 was consistently useful for prognostic value.10 Several genetic variants including mutations of the MUC5B and TOLLIP genes, as well as those affecting telomere length, have also been proposed as predictive factors for IPF survival.11 These genetic and plasma biomarkers require more research to validate their utility.

References

  1. Wakwaya Y, Brown KK. Idiopathic pulmonary fibrosis: epidemiology, diagnosis andOutcomes. Am J Med Sci. 2019;357(5):359-369. doi.org/10.1016/j.amjms.2019.02.013
  2. Quinn C, Wisse A, Manns ST. Clinical course and management of idiopathic pulmonary fibrosis. Multidiscip Respir Med. 2019;14(1):35. doi.org/10.1186/s40248-019-0197-0
  3. Sgalla G, Iovene B, Calvello M, Ori M, Varone F, Richeldi L. Idiopathic pulmonary fibrosis: pathogenesis and management. Respir Res. 2018;19(1):32. doi:10.1186/s12931-018-0730-2 
  4. Hadjicharalambous MR, Lindsay MA. Idiopathic pulmonary fibrosis: pathogenesis and the emerging role of long non-coding RNAs. Int J Mol Sci. 2020;21(2):524. doi.org/10.3390/ijms21020524
  5. Wuyts WA, Wijsenbeek M, Bondue B, et al. Idiopathic pulmonary fibrosis: Best practice in monitoring and managing a relentless fibrotic disease. Respiration. 2020;99(1):73-82. doi.org/10.1159/000504763
  6. Hyldgaard C, Hilberg O, Bendstrup E. How does comorbidity influence survival in idiopathic pulmonary fibrosis? Respir Med. 2014;108(4):647-53. doi: 10.1016/j.rmed.2014.01.008
  7. Kim HJ, Perlman D, Tomic R. Natural history of idiopathic pulmonary fibrosis. Respir Med. 2015;109(6):661-70. doi: 10.1016/j.rmed.2015.02.002
  8. Sauleda J, Núñez B, Sala E, Soriano JB. Idiopathic pulmonary fibrosis: epidemiology, natural history, phenotypes. Med Sci (Basel). 2018;6(4):110. doi:10.3390/medsci6040110
  9. Florian J, Watte G, Teixeira PJZ, et al. Pulmonary rehabilitation improves survival in patients with idiopathic pulmonary fibrosis undergoing lung transplantation. Sci Rep. 2019; 9: 9347. doi:10.1038/s41598-019-45828-2
  10. Neighbors M, Cabanski CR, Ramalingam TR, et al. Prognostic and predictive biomarkers for patients with idiopathic pulmonary fibrosis treated with pirfenidone: post-hoc assessment of the CAPACITY and ASCEND trials. Lancet Respir Med. 2018;6(8):615-626. doi:10.1016/S2213-2600(18)30185-1.
  11. Kaur A, Mathai SK, Schwartz DA. Genetics in idiopathic pulmonary fibrosis pathogenesis, prognosis, and treatment. Front Med (Lausanne). 2017;4. doi:10.3389/fmed.2017.00154

Reviewed by Harshi Dhingra, MD, on 7/1/2021.

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