Survival and Causes of Death
The earliest signs and symptoms of IPF may be nonspecific, and as a result, patients commonly present with advanced disease, years after the onset of initial symptoms.4
Historically, the prognosis of IPF has been very poor, with a median survival time after diagnosis from 2 to 3 years based on several longitudinal studies.5678 While this may be an underestimate of survival based on more recent data from clinical trials that included patients with preserved pulmonary function,1 the prognosis of IPF remains poor for many patients.
A significant challenge in defining the natural history of IPF lies in the various different time points from which survival can be calculated:
- Time of first radiologic abnormality
- Time of onset of symptoms, or
- Time of diagnosis2
Demonstrating the impact of the time point chosen on survival estimates, a prospective analysis of 238 patients with IPF in the United States found that median survival time from first clinic visit was 35.2 months, compared to a median survival of 80.8 months from first onset of symptoms (Figure 1).9
Comparison of IPF Survival to Other Serious Diseases
As noted above, IPF carries a poor prognosis – 5-year survival in IPF is only 20 to 40%,5681011 which is lower than that of other well-known, serious diseases such as breast cancer,12 colorectal cancer,12 ovarian cancer,12 and pulmonary arterial hypertension (Figure 2).13 Among the most common malignancies, only lung cancer has a lower 5-year survival rate compared with IPF.12
Causes of Death
Most patients with idiopathic pulmonary fibrosis die of respiratory failure due to their lung disease. Epidemiologic data from the United States Multiple Cause-of-Death (MCOD) mortality database indicate that from 1992-2003, among patients with pulmonary fibrosis (94% of whom had IPF), the cause of death was attributed to the disease itself in 60% of cases (Figure 3).14 In the remaining cases, the underlying cause of death was attributed to ischemic heart disease, lung cancer, pneumonia, congestive heart failure, cerebrovascular disease, or “other” (Figure 3).14 Notably, the proportion of patients with PF dying from the disease itself appears to have increased over time.14 This may be explained in part by changes in the classification schema for idiopathic interstitial pneumonias, as well as advances in the treatment of other conditions that commonly affect patients with PF.14
More recently, IPF-related deaths that were prospectively recorded in 6 published clinical trials were examined.15 The vast majority of deaths (77%) were due to respiratory causes (Figure 4).15 Acute deterioration leading to death (defined as sudden worsening less than 4 weeks in duration) was observed in 30% of patients, while subacute deterioration (defined as worsening over a period of greater than 4 weeks to months) was observed in 47%.15
Cumulatively, these data indicate that the prognosis for patients with IPF remains poor, and that their survival is closely tied to IPF progression.
Overview of the Clinical Course of IPF
The disease course of IPF is heterogeneous – clinical forms demonstrating different rates of decline and patterns of survival are now being recognized15 (ie, several natural histories for patients with IPF may be possible) (Figure 5).1 Whether these different natural histories represent distinct types of IPF or if the natural history is influenced by geographic, ethnic, cultural, racial, or other factors is not known.1
The disease course of IPF is heterogeneous and difficult to predict but typically involves progressive deterioration.15 However, even stable patients can experience sudden deteriorations without warning.115
As noted, the clinical course of IPF may take several forms: slow physiologic worsening with increasing severity of dyspnea (slowly progressive course), rapid worsening and progression to death (rapidly progressive course), or periods of general stability interspersed with periods of acute respiratory decline (acute exacerbations of IPF) (Figure 5).115 Prior to the onset of symptoms there is a period of subclinical disease.15 This asymptomatic period may extend from years to decades.15 When the severity of lung lesions reaches a threshold that is enough to provoke symptoms, patients seek treatment and a diagnosis is made.15
Slowly Progressive Course
The clinical course for many patients is relatively slow.1 Months or years may pass from the time of initial symptoms, which typically include nonproductive cough and increasing dyspnea,2 until they first seek care from a physician.15 Data from the placebo arms of clinical trials in patients with IPF demonstrate that the rate of decline in forced vital capacity (FVC) is about 0.15 L to 0.20 L per year.15161718192021 These data suggest that, on average, more than 10 years would be required to lose 50% of original FVC. Based on the discordance between the rate of decline in pulmonary function and mortality, current thought is that the clinical course of IPF is less a gradual decline and more a step-like process (Figure 5).2 There may be periods of relative stability interspersed with periods of acute decompensation (associated with high mortality).2
Rapidly Progressive (Accelerated Variant)
A subgroup of patients exhibit a rapidly progressive course with shortened survival compared with the slowly progressive clinical course (Figure 5).1522 Patients in this subgroup tend to be male and cigarette smokers.22 At the time of diagnosis, patients with the accelerated variant of IPF have similar lung function, chest imaging, and histological findings as patients with the typical slowly progressive form, but have a different gene expression profile. In one study, gene expression profiling suggesting accelerated disease was associated with upregulation of genes related to morphogenesis, cancer, oxidative stress, apoptosis, cell migration/proliferation, and genes from fibroblasts/smooth muscle cells along with downregulation of genes related to signal transducer activity, and epithelial receptors along with others.22 The significance of these gene expression patterns has yet to be established.
Acute Exacerbations of IPF (AE-IPF)
In 2007, an international group of experts in IPF along with the Idiopathic Pulmonary Fibrosis Clinical Research Network developed a consensus definition of AE-IPF as well as diagnostic criteria. They defined AE-IPF as “acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF.”23
Although patients with IPF may experience abrupt and unexpected worsening of their lung disease secondary to infections, pulmonary embolism, pneumothorax, or heart failure, none of these identifiable causes of acute deterioration are present in episodes of acute exacerbations.24 Patients with IPF may experience acute exacerbations at any time during the course of their disease. Further, there is no link to the level of pulmonary function derangement.23
Acute exacerbations of IPF occur without warning or cause and all patients are susceptible, regardless of disease severity.23
AE-IPF seem to be more common in men, but there does not appear to be a link to age or smoking history.23 Extensive efforts have not demonstrated an infectious etiology in most patients with AE-IPF.25
The diagnostic criteria for AE- IPF can be found in Table 2.23 Generally, new or worsening dyspnea occurs within 30 days, and many patients with acute exacerbations have severe hypoxemia and respiratory failure requiring mechanical ventilation.23 Cough, fever, and flu-like symptoms may also be present despite the absence of evidence for an infectious cause.223
|Previous or concurrent diagnosis of idiopathic pulmonary fibrosis*|
|Unexplained worsening or development of dyspnea within 30 days|
|High-resolution computed tomography with new bilateral ground-glass abnormality and/or consolidation superimposed on a background reticular or honeycomb pattern consistent with usual interstitial pneumonia pattern†|
|No evidence of pulmonary infection by endotracheal aspirate or bronchoalveolar lavage‡|
Exclusion of alternative causes, including the following:
*If the diagnosis of idiopathic pulmonary fibrosis is not previously established according to American Thoracic Society/European Respiratory Society consensus criteria,1 this criterion can be met by the presence of radiologic and/or histopathologic changes consistent with a pattern of usual interstitial pneumonia on the current evaluation.
†If no previous high-resolution computed tomography is available, the qualifier “new” can be dropped.
‡Evaluation of samples should include studies for routine bacterial organisms, opportunistic pathogens, and common viral pathogens.
§Causes of acute lung injury include sepsis, aspiration, trauma, reperfusion pulmonary edema, pulmonary contusion, fat embolization, inhalational injury, cardiopulmonary bypass, drug toxicity, acute pancreatitis, transfusion of blood products, and stem cell transplantation.
Key to a diagnosis of AE-IPF is new abnormalities on high-resolution computed tomography (HRCT).23 The new, extensive ground-glass abnormality overlaid on a background of lung fibrosis can be seen on the HRCT of a patient with acute exacerbation of IPF in Figure 6.23 The degree of CT involvement may predict survival in patients with acute exacerbations of IPF.23
At present, there is not a role for plasma biomarkers in diagnosing or predicting acute exacerbations of IPF; however, a single center study reported promising results suggesting different plasma biomarker profiles in patients with AE-IPF compared to stable patients with IPF or acute lung injury.26
AE-IPF are relatively common clinical events. One recent retrospective review of 461 patients with IPF found 1-year and 3-year acute exacerbation incidences of 14.2% and 20.7%, respectively.27 Similarly, another retrospective study of 74 patients with IPF found 1-year and 3-year acute exacerbation incidences of 8.6% and 23.9%, respectively.28
Acute exacerbations can significantly impact the course of disease progression and often result in death.27
Acute exacerbations are associated with a very poor prognosis. Among 461 patients with IPF examined retrospectively, the median survival from onset of acute exacerbation was just 2.2 months and 50% of patients expired while in the hospital. Exacerbations leading to an ICU admission are associated with very poor survival; in one recent study about 80% of these patients died in the hospital.27
Content contributed by:
Jonathan A. Kropski, MD