Question: What is your approach to IPF patients in whom you detect GERD?

Answer: Although there is accumulating published experience suggesting that GERD is important in the development of IPF, there is no consensus. There is evidence that 67% of IPF patients have esophageal reflux in whom 65% have symptoms (Sweet 2007). Of patients with GERD, 70% were being treated with proton pump inhibitors, suggesting that they are still at risk of aspiration despite this medication. It may be that acid is not the culprit and new evidence suggests that bile salts, pepsin and other potentially aspirated substances cause injury which is not avoided by acid-reducing therapy (D'Ovidio 2005).

IPF may represent a confluence of factors that include increased fibroblast response to serial injury and recurrent aspiration. Studies with small numbers of patients suggest that fundoplication can stabilize the course of IPF (Linden 2006; Raghu 2006). There is also emerging information that the post lung transplant course is negatively affected by reflux (Davis 2003; Cantu 2004). In fact, patients with documented esophageal dysfunction before lung transplantation get worse after transplantation (Young 2003).

What is needed is a systematic assessment of esophageal dysfunction in IPF patients including a controlled trial of medical versus surgical intervention. In the absence of such information, what should a physician recommend to patients with IPF? All patients with IPF should undergo esophageal assessment. Patients at risk for aspiration should avoid recumbency soon after eating and elevate the head of their bed by 6 inches. Some physicians suggest esophageal wrap procedures. The benefit of such interventions should be subjected to rigorous analysis.

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Question: A recently diagnosed patient with IPF is being treated with steroids. What is the medically appropriate time to begin evaluation for lung transplantation? The patient has modest income and high-deductible insurance; if the steroids are effective, when is the expense of the lung transplant evaluation justifiable?

Answer: If the patient has a clear diagnosis of IPF there is little reason to employ steroids. In some cases, steroids may alleviate the symptoms of cough but the dose should eventually be reduced to about 10 mg/day.

Given that there is no effective pharmacotherapy for IPF and the natural history is not predictable, the patient should be evaluated for lung transplantation at the time of diagnosis unless the patient is too old or has significant comorbidities that would make transplantation unlikely. It should be remembered that the upper age limit for lung transplantation is not fixed. Lung transplantation is sometimes considered for patients who are more than 65 years old. Reversible comorbidities such as being overweight and lack of physical conditioning can also be addressed if the referral is timely.

Early referral allows the patient and family to become familiar with the concept of lung transplantation. This preparation is preferable to waiting for an acute or subacute deterioration.

Finally, most insurance policies cover both the pretransplant evaluation and the lung transplantation.

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Question: Why should patients who have had a surgical lung biopsy and a discordant CT respond better to bosentan than patients with definite IPF, diagnosed by CT?

Answer: This question derives from the results of a recent study of a randomized placebo-controlled trial of bosentan in patients with idiopathic pulmonary fibrosis (IPF) (King 2008). In that study, the subset of patients who had surgical lung biopsy and bosentan treatment had significantly less progression of disease (FVC and DL_CO) than the placebo group.

There are two possible explanations. First, it is possible that patients who required lung biopsy because their CT scan did not suggest "definite" IPF are different from the IPF patients with classic CT changes. Perhaps there are different mechanisms of disease in the alveolar microenvironment despite similar usual interstitial pneumonia (UIP) histologic patterns.

The second possibilitiy is that the reported benefit of bosentan in the patients with "atypical" CT scans who underwent lung biopsy will not be confirmed by further testing. Progression of disease was a secondary endpoint; the authors note that this study was not sufficiently powered to test such secondary endpoints.

For entry into this study, the biopsies that were used to qualify patients were read locally and there was no central pathology laboratory certification. After the study, 86 of 100 biopsies underwent central laboratory analysis. Of note, 26% of those patients entered in the study did not have UIP.

Patients with "definite" versus "atypical" CT scans may be in different stages of the same IPF process. Although the authors say the duration of symptoms and lung function were the same between the patients who underwent lung biopsy compared to the "all-treated set," there is no data available in this report to compare those with a biopsy to those without a biopsy. The biopsy patients were younger than the patients with a definitive CT diagnosis of UIP who did not undergo biopsy. It is possible that the patients who underwent biopsy because of an "atypical", ie not "definite," CT scan are at an earlier stage of IPF.

In a prior paper that compared survival in patients with a histologic diagnosis of UIP/IPF and a definitive or probable diagnosis of IPF by CT scan, the patients with "atypical" (not "definite" or "probable") CT scans were younger with shorter duration of symptoms and more preserved DL_CO. IPF patients with this "atypical" CT pattern survived longer than IPF patients with a classic CT scan (Flaherty, 2003). The paper by King et al suggests that bosentan may be more effective when applied earlier in the disease when an "atypical" CT scan necessitates a lung biopsy for diagnosis.

Resolution of the question will come with the results of the Build 3 trial. In this ongoing study of bosentan, the primary endpoint will be morbidity/mortality. One inclusion criterion is a UIP diagnosis that is certified by a central pathology laboratory.

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Question: How are donated lungs allocated for transplantation and what does this mean for patients with Idiopathic Pulmonary Fibrosis (IPF)?

Answer: In May 2005, the Lung Allocation Score (LAS) was initiated. It gives priority to patients on the waiting list who are most severely ill (medical urgency) and who have the best expected outcome during the first year after transplantation. Of these two parameters, medical urgency is given more weight than post transplantation survival. Survival is considered so that futile procedures in particularly impaired patients are not performed. Prior to the LAS system, potential recipients were prioritized only by accrued time on the waiting list. The impetus for LAS was the scarcity of donor lungs and consequent deaths of patients on the waiting list. Before the LAS system, IPF patients had the highest percentage of waiting list deaths (33%) of all diagnostic categories (Egan, 2006).

The LAS is based on a series of parameters including FVC, use of oxygen, 6-minute walk test, pulmonary artery systolic pressure, specific diagnosis, and other indices. The LAS will be evaluated every 6 months following the first three years and the parameters of the score will be adjusted.

Early analysis suggests that the LAS favors IPF patients both in increased numbers of transplants and decreased mortality on the waiting list. In a review of the Organ Procurement and Transplantation Network data base to be presented at the 2008 ATS Annual Meeting in Toronto (May 16 – 21, 2008), the percentage of IPF patients listed who get transplants has increased by 40% and death on the waiting list has decreased by about 40% (Chen, 2008).

Since illness severity is emphasized in the LAS system, it was expected that more patients with advanced IPF would undergo transplantation. Although patients are more ill pre-transplantation and have more primary graft dysfunction (PGD) and increased ICU stay after the procedure, the 1-year mortality is the same before and after LAS initiation (90%). Adjusting this LAS analysis for specific diagnosis, there is no difference for lung fibrosis in terms of PGD and ICU stay (Kozower, 2007).

Of particular relevance to IPF patients, the LAS can be updated if a patient worsens, which shortens the waiting time. Allocating by severity of illness will permit more ill IPF patients to obtain lungs. Finally, the LAS system should be adapted to include parameters of right heart failure, which would enhance the ability of patients with IPF to get organs.