IPF

Course of Disease

The natural history of IPF has been described as a progressive decline in subjective and objective pulmonary function until eventual death from respiratory failure or complicating comorbidity. Several retrospective longitudinal studies suggest a median survival time of IPF patients from 2 to 3 years from the time of diagnosis¹. Clinical observations have suggested that IPF patients exhibit variable clinical courses. Patients may suffer ‘‘acute exacerbation’’ of their disease, which is defined as a clinical syndrome characterized by sudden worsening of dyspnea, newly developing diffuse radiographic opacities, worsening hypoxemia, and absence of infectious pneumonia, heart failure, or sepsis. This process is characterized by diffuse alveolar damage on the background of the otherwise typical UIP pattern of injury found in IPF. Pulmonary function tests and HRCT scanning have been proposed to estimate disease severity and monitor disease progression².

IPF patients may be classified as “slow” or “rapid” progressors according to the duration of symptoms before diagnosis. Survival rate determined from the beginning of symptoms was significantly lower in the rapid progressors (Hazard ratio [HR] = 9.0; confidence interval [CI]: 4.48–18.3; p < 0.0001). Mortality determined from the time of diagnosis showed a tendency to be increased in the rapid progressors without reaching statistical significance (HR = 1.5; CI 0.81–2.87; p = 0.18)².

Slowly progressive IPF

Slow progressors are patients who presented with more than 2 years duration of symptoms prior to their diagnosis². Their classic clinical phenotype is slowly progressive decline in lung function and worsening dyspnea leading to death within several years of diagnosis. The mean annual rate of decline in progressive disease, as measured by the forced vital capacity (FVC), ranges from 0.13 L to 0.21 L. A recent population-based cohort study in United States examined 47 incident cases of IPF over a 9-year period and found that only 21% of these patients demonstrated a slowly progressive course without evidence of acute decompensation³.

Rapidly progressive IPF

Rapid progressors are patients who presented within 6 months after the beginning of their symptoms, and are primarily males who smoked². The rapid progressors displayed a gene expression profile that differed from those with slower progression and longer survival despite having similar lung function, chest imaging, and histology findings at the time of diagnosis³.

The genes increased in rapid progressors were adenosine A2B receptor gene, which is involved in the fibrotic remodeling, and prominin-1/CD133, which is found in hematopoietic stem cells and embryonic epithelium. Three genes related to the coagulation pathway were also increased in ‘‘rapid’’ progressors: beta3-endonexin, serine protease inhibitor, Kazal type, and plasminogen activator inhibitor-1. They are antifibrinolytic and may enhance fibrin deposition, a process that has been associated with fibrosis².

Decreased genes in rapid progressors included Smad6, an inhibitor of TGF-β Smad-mediated signal transduction, and the receptor for advanced glycation end-products which is a highly selective differentiation marker of alveolar epithelial type I cells. The down-regulation of Smad6 together with the increase in plasminogen activator inhibitor-1 (a universal TGF-β responsive gene) may signify dysregulated TGF-β-mediated fibrotic response. Rapid progressors also showed higher levels of active human matrix metalloprotease (MMP)-9 in the bronchoalveolar lavage (BAL) fluids. Excessive MMP-9 activity may contribute to the loss of integrity of the basement membranes and subsequently to abnormal tissue repair².

Predictors of survival in IPF

There are many individual clinical variables that have been shown to predict survival in IPF. These may be subdivided into clinical predictors, radiographic predictors, physiologic predictors, pathologic predictors, and biomarker predictors. Factors that are associated with shortened survival time include: older age, smoking history, lower body mass index (BMI), more severe physiologic impairment, greater radiologic extent of disease, and the development of other complications or conditions, in particular, pulmonary hypertension, emphysema, and bronchogenic cancer³.