Acute Exacerbation of Idiopathic Pulmonary Fibrosis: Unrecognized Other Conditions?

Acute Exacerbation of Idiopathic Pulmonary Fibrosis: An Acceleration of Idiopathic Pulmonary Fibrosis process?

The next possibility is that AEx-IPF may be an acceleration of an underlying disease process, enhanced fibroproliferation. Although research is ongoing, the molecular mechanisms underlying AEx-IPF remain poorly understood. Activation of the immune system, disordered coagulation/fibrinolysis, and oxidative stress may all contribute to the pathophysiology of AEx-IPF. Because AEx-IPF is similar to acute respiratory distress syndrome (ARDS) clinically, radiologically, and pathologically, the pathobiology may also be similar. To investigate this possibility, Collard et al. compared the biomarker profile of stable IPF, AEx-IPF, and ARDS. In ARDS, the levels of the receptor for advanced glycation end-products (RAGE), a marker of type I alveolar epithelial cell (AEC) injury/proliferation, proinflammatory cytokines, markers of endothelial dysfunction, activated coagulation, and inhibited fibrinolysis were all elevated, whereas the AEx-IPF group had lower levels of RAGE and higher levels of Krebs von Lungen-6 (KL-6) and surfactant protein-D (markers of type II AEC proliferation and/or injury), which was similar to stable IPF but in greater degree. The absence of a type I cell injury signature combined with an exuberant elevation of type II cell markers provides support for the hypothesis that AEx-IPF is predominantly a manifestation of the acceleration of an underlying disease process, rather than the result of a second, different kind of injury.

This hypothesis was also supported by a gene expression study by Konishi et al. They found that the global gene expression patterns of AEx-IPF were almost identical to those of stable IPF. AEx-IPF exhibited a fibrosis signature that was identical to stable IPF, no dramatic shift indicating a new process, and no dramatic shift in cellular phenotype. Only 579 genes related to stress response were significantly differentially expressed. There was no indication of any infectious etiology or overwhelming inflammatory response.

These results suggest that the basic pathologic process of AEx-IPF is the same as or similar to that of stable IPF, but more enhanced in degree.

Then what triggers the acute acceleration of IPF disease process?

Triggering Factors

As discussed previously, infection or aspiration can be triggering factors, although they cannot be the main pathobiologic process of AEx-IPF itself.

• 1.
  

  Infection

  
  
• 2.
  

  Aspiration of gastric content

  
  
• 3.
  

  Surgery and other procedures

There are many reports about the development of AEx-IPF after the surgery, not only lung resection, but also extrathoracic, and even surgical lung biopsy, or BAL. The mechanism is not certain, but a surgical procedure or mechanical stress by high tidal volume, high oxygen flow, or intraoperative fluid imbalance may trigger AEx-IPF.

• 4.
  

  Air pollution

The relationship between ambient air pollution and exacerbation of respiratory diseases such as asthma and chronic obstructive pulmonary disease is well established, and AEx-IPF may be caused by air pollution. Johansen et al. studied the relationship between the development of AEx-IPF and exposure to air pollution using the data collected by a fixed telemonitoring system situated throughout Korea since 2000 in 505 patients with IPF. They found a significant relationship between AEx-IPF and exposure to ozone and NO ₂ during 42 days prior to AE-IPF but not to other pollutants, suggesting that increased exposure to ozone and NO ₂ contributes to the development of AEx in some patients.

• 5.
  

  Drugs

Many biologic (etanercept and infliximab) and nonbiologic (ambrisentan) agents, immunomodulatory agents (interferon α/β, everolimus, and leflunomide), and antineoplastic therapies can provoke interstitial pneumonia and may mimic AEx in the patients with preexisting IPF. Minegishi and colleagues reported that the incidence of acute respiratory deterioration related to anticancer treatment was 22.7% among 120 patients with lung cancer accompanied by idiopathic interstitial pneumonia.

Therefore, it seems that AEx-IPF may be the acute acceleration of an underlying fibroproliferative process triggered by these extrinsic or unknown insults in patients with IPF, who already have a predisposition of exaggerated fibrosis secondary to abnormal wound healing. Several studies reported increased incidence of AEx-IPF and/or higher mortality in patients with IPF after lung cancer surgery or major thoracic surgery compared with the patients without IPF, which suggests the increased susceptibility of IPF patients to extrinsic insults. Voltolini et al. reported that patients with interstitial lung disease (ILD), mostly IPF, had a higher incidence of postoperative ARDS (presumable AEx-IPF) compared with patients without ILD (13% vs. 1.8%, P < .01).

Risk Factors

Most of the studies showed that AEx-IPF is more common in patients with advanced disease, low FVC, low diffusing capacity for carbon monoxide, low 6-min walk distance, pulmonary hypertension, poor baseline oxygenation, increased dyspnea score, and recent decline in FVC. Younger age, comorbid coronary artery disease, higher body mass index, a history of AEx, and elevated serum level of KL-6 at baseline have been reported to be associated with increased risk for AEx-IPF.

Biomarkers

In addition to serum KL-6, neutrophil elastase, and lactate dehydrogenase levels, which have been suggested as markers of AEx-IPF, there are several new possible biomarkers. The levels of α-defensins, circulating fibrocytes, high-mobility group box-1, monocyte chemotactic protein-1, soluble ST2 protein, annexin-1, markers of oxidative stress, heat shock protein 47, heat shock protein 70, galectin-3, a mediator of fibrosis induced by TGF-β, and intercellular adhesion molecule-1 were reported to be elevated in the peripheral blood of patients with AEx-IPF. Tachibana et al. demonstrated in 19 patients with AEx-IPF that increased serum IL-7, an inhibitor of transforming growth factor-β production and fibroblast signaling, was associated with better prognosis in AEx-IPF.

New Definition for Acute Respiratory Deterioration in Idiopathic Pulmonary Fibrosis

The consensus opinion of the international working group was that the definition should include any acute respiratory event characterized by new bilateral ground-glass opacification/consolidation not fully explained by cardiac failure or fluid overload, because there is little clinical or biologic support for distinguishing idiopathic from nonidiopathic respiratory events. However, cardiogenic pulmonary edema is believed to have a distinct pathobiology and favorable prognosis compared with other causes of acute respiratory deterioration with bilateral radiologic involvement, which parallels the Berlin criteria for ARDS and excludes isolated congestive heart failure. Therefore the revised definition of AEx of IPF is: an acute, clinically significant, respiratory deterioration characterized by evidence of new, widespread alveolar abnormality in patients with IPF. It is more inclusive and results in diagnostic criteria that are more feasible for clinicians and clinical trialists, who have had difficulty in the requirement for invasive microbiologic evaluation of the 2007 criteria.

New Diagnostic Criteria

There are two changes from the previous 2007 consensus diagnostic criteria.

• 1.
  

  Removing “idiopathic” from the diagnostic criteria of acute exacerbation

Because of the changing definition of AEx-IPF, the exclusion of infection or other potential triggers is no longer required. However, the committee stated that this change should not discount the clinical relevance of identifying infection when present, because its treatment may be important to the overall management of the patient. In addition, they suggested that future studies are needed to test whether aggressive investigation (e.g., BAL, bronchoscopic cryobiopsy, surgical lung biopsy) of patients with AEx-IPF improves outcomes.

• 2.
  

  Changing the time interval from 30 days to “typically less than 1 month”

There was a majority opinion that the 30-day time period was arbitrary and should be made more flexible to allow for cases that fall outside the time window by a few days to weeks. The phrase “typically less than 1 month” seems to retain precision but allow for the inclusion of exceptions that physicians feel clinically represent acute exacerbations. A more flexible time interval than this may lead to heterogeneity among clinical trial endpoint definitions for AEx and that this could complicate comparisons between trials.

The new consensus report emphasized the importance of HRCT in the diagnosis of AEx-IPF and stated that HRCT of the chest should be obtained in all patients in whom it can be safely performed. Transbronchial biopsy is of limited utility, and surgical lung biopsy should generally be avoided because of its high morbidity in the nonelective setting.

Although the new consensus criteria excluded the workup for infection for the diagnosis, it is still important to exclude the possibility of the presence of active infection, not as a triggering factor, because the treatment is different. Considering that corticosteroid is still widely used for AEx-IPF and also one therapeutic candidate for future clinical trial, misdiagnosis of infection as AEx-IPF can be a big mistake. Furthermore, clinical and radiologic features of infection, especially viral infection, are similar to AEx-IPF, and actually Song et al. reported that almost half of the patients with acute respiratory deterioration among those with IPF had infection. Recently Moua et al. also reported the high frequency of infection (20%) among the patients admitted because of acute respiratory worsening.

Management

Supportive care remains the mainstay of treatment for AEx-IPF, focused on palliation of symptoms and correction of hypoxemia with supplemental oxygen. Because of high in-hospital mortality (90%) of the patients with respiratory failure, the international guidelines on the management of IPF made a weak recommendation against the use of mechanical ventilation in these patients, although it is “a value-laden decision that is best made by the patient, clinician, and family ahead of time” based on a firm understanding of the patient’s goals of care.

The guidelines also give a weak recommendation of corticosteroids for the majority of patients with AEx-IPF, based on a high value on anecdotal reports of benefit and the high mortality associated with AEx-IPF. There are some data suggesting that response to high-dose corticosteroid treatment may depend on the type of HRCT lesion, with better responses achieved in those with a peripheral pattern and the organizing pneumonia pattern of pathology compared with the DAD pattern. Because of the difficulty in exclusion of infection, especially in the early phase, broad-spectrum antibiotics are commonly used.

Kubo et al. reported better survival in the anticoagulation group, mostly due to reduced mortality associated with AEx-IPF, suggesting the efficacy of anticoagulation in the treatment of AEx-IPF ; however, because of the small sample size and methodologic limitations of this study, the benefit of anticoagulation therapy is controversial and a recent clinical trial of anticoagulation in patients with IPF showed, actually, increased mortality in the warfarin-treated group.

There are several innovative treatments for AEx-IPF mostly tried in Japan, including polymyxin B–immobilized fiber column (PMX) hemoperfusion and tacrolimus, intravenous thrombomodulin, rituximab combined with plasma exchange, and intravenous immunoglobulin, usually administered in addition to corticosteroids. However, these studies are mostly small and uncontrolled, using historical data or a parallel, untreated control arm.