HONOLULU – Acute worsening is an important part of the natural history of many interstitial lung diseases, especially idiopathic pulmonary fibrosis.

But the roots of acute worsening in interstitial lung disease (ILD) are not fully understood, Dr. Harold R. Collard said at the annual meeting of the American College of Chest Physicians.

"A lot of what’s known in the medical literature comes from patients with idiopathic pulmonary fibrosis [IPF]," said Dr. Collard, who directs the interstitial lung disease program at the University of California, San Francisco. "I think it’s an open question whether that can be extrapolated to patients with other forms of ILD or not. The course of many ILDs – certainly IPF – is unpredictable; it’s not always a linear decline," he continued. "This is an important shift in how we think about the disease – to recognize that this is the case for many patients."

According to a survey of academic pulmonologists, 88% of respondents reported that acute exacerbations in ILD patients occur "sometimes" or "frequently," while 92% of respondents reported that exacerbations were "sometimes" or "frequently" fatal (Respir. Med. 2007;101:2011-6).

If these are not fatal, they often leave patients significantly worse than they were before, unlike exacerbations in other forms of lung disease, said Dr. Collard, who was the survey’s lead investigator.

Potential causes of acute worsening include infection, aspiration, myocardial infarction, pulmonary embolism, pneumothorax, and heart failure, as well as idiopathic causes. Acute worsening has not been studied in all ILDs, but it has been most closely studied in IPF. In Dr. Collard’s opinion, the best data on acute worsening in IPF come from a Korean cohort study of 461 patients with IPF who were followed longitudinally (Eur. Resp. J. 2011;37:356-63). The researchers divided patients into two groups: those with respiratory deterioration (defined as acute worsening with radiographic abnormalities) and those with acute exacerbation (defined as acute worsening in the absence of an identifiable etiology).

The researchers found that the 1-year incidence of respiratory deterioration was 23%, "which is higher than a lot of us have taken from clinical trials," Dr. Collard said. Of these cases, 55% were idiopathic, while the remainder had known causes that included infection and heart failure.

"These idiopathic acute worsenings, as defined in this study, are what we call acute exacerbation," Dr. Collard noted. "In IPF, acute exacerbation has a specific connotation compared with asthma or [chronic obstructive pulmonary disease]. It’s an idiopathic acute worsening."

The median survival among patients with acute exacerbation of IPF was 2.2 months from the onset of exacerbation. "This is a highly morbid and fatal condition," he said.

Dr. Collard led a panel of experts that established criteria for acute exacerbations of IPF (Am. J. Respir. Crit. Care Med. 2007;176:636-43). The criteria include previous or concurrent diagnosis of IPF, unexplained worsening or development of dyspnea over a period of 30 days or less, new bilateral ground glass and/or consolidation superimposed on a usual interstitial pneumonitis pattern on high-resolution CT, no microbiologic evidence of respiratory infection by endotracheal aspirate or bronchoalveolar lavage, and exclusion of other known causes of acute worsening.

According to the Korean IPF cohort study, significant risk factors for acute exacerbation include never having smoked tobacco and having a low forced vital capacity (FVC). "The higher your FVC, the lower your risk of acute exacerbation," Dr. Collard said. "That makes sense, [but] the protective effect of smoking is hard to explain."

He acknowledged that certain aspects of acute exacerbation remain elusive. "Does exacerbation actually represent an abrupt acceleration of the underlying disease process, or is it a manifestation of an occult secondary complication such as an infection that we’re missing because of the limitations of our clinical assessment?" he asked.

Researchers who conducted a test of gene expression profiling in this patient population found no differences in the global expression pattern between patients with stable IPF and those with acute exacerbation (Am. J. Respir. Crit. Care Med. 2009;180:167-75). "They did find evidence of enhanced alveolar epithelial cell activity," Dr. Collard said. "That was the main predominant pattern."

A study of biomarkers conducted by Dr. Collard and his associates yielded similar findings (Am. J. Physiol. Lung Cell Mol. Physiol. 2010;299:L3-7).

Dr. Collard hypothesized that acute exacerbation of IPF represents a primary acceleration of IPF in the setting of acute lung stress. "This stress may be minor, at a level that would not cause clinical disease in a normal lung," he said. Potential sources of stress include infection, occult aspiration, interventions, and drugs.

Dr. Collard disclosed that he receives research funding from the National Institutes of Health, the University of California, Boehringer Ingelheim, and Genentech. He also receives consulting fees from Fibrogen, Gilead, InterMune, and Onyx.

Roots of Acute Worsening in ILD Elusive