Idiopathic Pulmonary Fibrosis (IPF)


Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease (ILD), characterized by progressive fibrosis with an unknown cause.1 Symptoms of ILD commonly include chronic cough, exertional dyspnea, “velcro” crackles on lung auscultation, and sometimes “finger clubbing.”2 The progression of IPF may be slow, rapid, or relatively stable with periods of sudden deterioration called acute exacerbations.3 Despite the variability in the natural course of the disease, the median untreated survival time is 3 to 4 years after diagnosis.4 As the disease progresses, forced vital capacity (FVC) declines, exercise capacity drops, and health-related quality of life (HRQL) decreases and patients become more at risk for developing life-threatening complications.5 

Acute Exacerbations

Acute exacerbations are defined as acute, clinically significant, respiratory deteriorations of an unidentifiable cause. The exacerbations can play a major role in the course of IPF for patients, with an estimated 46% of IPF deaths being preceded by an acute exacerbation. The median survival of patients who have experienced an acute exacerbation is estimated at 3 to 4 months.6 Acute exacerbations are commonly experienced in patients with more severe disease signs such as lower FVC, diffusion of lung carbon monoxide (DLCO), 6-minute walk distance, and baseline oxygenation, as well as increased dyspnea, elevated levels of Krebs von Lungen-6 (KL-6), higher body mass index, and a history of pulmonary hypertension.7

The exact cause of acute exacerbations is unknown but several hypotheses have been proposed, including a further manifestation of a pathobiological process that underlies IPF such as dysfunction in the wound healing process,8 a symptom of another condition such as undiagnosed infection or aspiration of gastric contents due to gastroesophageal reflux, or an acceleration of the abnormal fibroproliferative process following acute stress to the lungs.7

There are currently no proven effective treatments for acute exacerbations, and therapy is mostly supportive and palliative care to help alleviate symptoms.6 The American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society (ATS/ERS/JRS/ALAT) gave a weak recommendation for the use of corticosteroids for acute exacerbations in their 2011 guidelines for IPF management.9 Supplemental oxygen should also be given to patients with hypoxemia.6,9 The ATS/ERS/JRS/ALAT also made a weak recommendation against the use of mechanical ventilation for acute exacerbation patients, however, given that in-hospital mortality was as high as 90% in these patients. The use of mechanical ventilation should be decided ahead of time by the patient, family, and clinician based on the patient’s goals.6

Lung Cancer

Lung cancer is another potential life-threatening complication faced by patients with IPF. Patients with IPF are almost 5 times more likely to be diagnosed with lung cancer than the general population. It is unclear whether lung cancer is a direct consequence of IPF or if they are merely comorbidities that share common risk factors. Both diseases are associated with advanced age, smoking, and male sex. Both diseases also have similar pathophysiologies, such as irregular signaling pathways, uncontrolled mechanisms of cell proliferation, epigenetic and genetic abnormalities, and abnormal microRNA expression. Histological evidence has shown that most cancers arise in peripheral basal positions that have more severe fibrosis or at the junction between fibrosis and normal lung tissue. Some studies have found conflicting results, however.7

Treatment of lung cancer in patients with IPF can pose challenges. Surgical resection, radiation, and chemotherapy, while possibly curative for the cancer, may increase the patient’s risk for acute exacerbations. Some studies have found that the use of chemotherapy in conjunction with pirfenidone or nintedanib, anti-fibrotic agents approved for IPF, may improve clinical outcomes.7

Pulmonary Hypertension

Another frequently occurring disorder in patients with IPF is pulmonary hypertension, which is defined as a mean pulmonary arterial pressure (mPAP) greater than 25 mmHg in the presence of normal left atrial pressure, a pulmonary arterial wedge pressure of less than or equal to 15 mmHg, and elevated pulmonary vascular resistance above 3 wood units with a cardiac index of less than 2.5 L/min/m2. Pulmonary hypertension often occurs in more advanced stages of IPF or in conjunction with emphysema.7

Pulmonary hypertension in IPF is believed to be due to several factors, including hypoxemic vasoconstriction and destruction of the pulmonary vascular bed due to increasing fibrosis. Dysfunction of endothelial cells, irregular angiogenesis, and vasoactive properties of profibrogenic cytokines may also play roles in the development of pulmonary hypertension.10 There is no specific treatment for pulmonary hypertension, and the 2011 guidelines from the ATS/ERS/JRS/ALAT give a weak recommendation against treatment.9 Long-term supplemental oxygen may be recommended in patients with hypoxemia, however.7

Pneumothorax

Sudden cases of pneumothorax may also occur in patients with IPF due to the rupture of a subpleural honeycomb cyst into the pleural space.11 The prognosis for IPF patients with pneumothorax is poor, with an overall survival of around 13 months.7 Treatment for pneumothorax with a blood-patch or chemical pleurodesis is often performed, but pneumothorax is often refractory to treatment and can recur. Despite the risk of acute exacerbations or post-operative infection, surgical correction is the preferred treatment.7

Respiratory Infection

Diffuse fibrosis of the lungs can increase the risk of developing pulmonary infections in patients with IPF. These infections are usually caused by species of Mycobacterium, Aspergillus, or Pneumocystis jirovecii pneumonia (PJP). Patients with IPF are also at risk of reactivation of prior tuberculosis (TB). The increased risk of these pulmonary infections is related to several factors, including chronic hypoxemia and the use of immunosuppressants in patients with IPF.7 

References

  1. Mohning MP, Richards JC, Huie TJ. Idiopathic pulmonary fibrosis: the radiologist’s role in making the diagnosis. Br J Radiol. 2019;92(1099):20181003. doi:10.1259/bjr.20181003
  2. Raghu G, Remy-Jardin M, Myers JL, et al.; American Thoracic Society; European Respiratory Society; Japanese Respiratory Society; Latin American Thoracic Society. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018;198(5):e44-e68. doi:10.1164/rccm.201807-1255ST
  3. 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
  4. Quinn C, Wisse A, Manns ST. Clinical course and management of idiopathic pulmonary fibrosis. Multidiscip Respir Med. 2019;14:35. doi:10.1186/s40248-019-0197-0
  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:10.1159/000504763
  6. Collard HR, Ryerson CJ, Corte TJ, et al. Acute exacerbation of idiopathic pulmonary fibrosis. An international working group report. Am J Respir Crit Care Med. 2016;194(3):265-275. doi:10.1164/rccm.201604-0801CI
  7. Galioto F, Palmucci S, Astuti GM, et al. Complications in idiopathic pulmonary fibrosis: focus on their clinical and radiological features. Diagnostics (Basel). 2020;10(7):450. doi:10.3390/diagnostics10070450
  8. 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
  9. Raghu G, Collard HR, Egan JJ, et al.; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824. doi:10.1164/rccm.2009-040GL
  10. van Cleemput J, Sonaglioni A, Wuyts WA, Bengus M, Stauffer JL, Harari S. Idiopathic pulmonary fibrosis for cardiologists: differential diagnosis, cardiovascular comorbidities, and patient management. Adv Ther. 2019;36(2):298-317. doi:10.1007/s12325-018-0857-z
  11. Aburto M, Herráez I, Iturbe D, Jiménez-Romero A. Diagnosis of idiopathic pulmonary fibrosis: differential diagnosis. Med Sci (Basel). 2018;6(3)73. doi:10.3390/medsci6030073

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