Questions and Expert Responses: (Click + to expand answers)

 How accurate is HRCT in distinguishing usual interstitial pneumonia and idiopathic pulmonary fibrosis (UIP/IPF) from fibrotic nonspecific interstitial pneumonia (NSIP)?

Answer:
Dr. Webb: Classic examples of UIP/IPF show findings of reticulation, traction bronchiectasis, and honeycombing with little, if any, ground-glass opacity, with a basal and subpleural distribution. Classic examples of fibrotic NSIP show a preponderance of reticulation and traction bronchiectasis with a basal predominance, and with a peripheral or diffuse distribution. Honeycombing is uncommon and, when present, is not as extensive as seen with UIP/IPF. A finding highly suggestive of NSIP is sparing of the immediate subpleural lung, seen in 20-50% of cases. Ground-glass opacity is more common than with UIP/IPF. Such classic or advanced cases can be distinguished with a high degree of accuracy. However, there is considerable overlap between the appearances of early UIP/IPF and that of fibrotic NSIP, with reticulation and traction bronchiectasis being the predominant findings in both. Unless the subpleural sparing or considerable ground-glass opacity is present, thus suggesting the diagnosis of NSIP, an accurate distinction between these diseases using HRCT may be impossible. Considering all cases of suspected UIP/IPF or fibrotic NSIP, the diagnostic accuracy of HRCT is about 70%. It is important to emphasize that a distinction between these diseases is difficult in patients with early disease.

Travis WD, Hunninghake G, King TE, Jr, et al. Idiopathic nonspecific interstitial pneumonia: report of an American thoracic society project. Am J Respir Crit Care Med. 2008;177:1338-1347.

 I have a patient with progressive shortness of breath and no obvious exposures or predisposing diseases. His HRCT shows honeycombing. What is the differential diagnosis? Does the honeycombing mean he has IPF?

Answer:
Dr. Webb: A basal, subpleural, and posterior predominance of honeycombing, with less severe abnormalities in the upper lobes, is typical of patients with usual interstitial pneumonia (UIP) on pathology. In the absence of any exposures or clinical findings of associated diseases, this appearance strongly suggests the diagnosis of IPF. However, the differential diagnosis of honeycombing on HRCT includes fibrotic nonspecific interstitial pneumonia (NSIP), collagen-vascular diseases, chronic hypersensitivity pneumonitis, and even sarcoidosis. Asbestosis and fibrosis associated with drug treatment can also result in this HRCT appearance, but an appropriate history is often available. It should be kept in mind that although fibrotic NSIP can result in honeycombing, other findings of fibrosis (eg, reticulation and traction bronchiectasis) and ground-glass opacity usually predominate in patients with NSIP. Honeycombing is less common in NSIP than in UIP/IPF and tends to be less extensive.

 What is the best HRCT technique to use in a patient with possible idiopathic pulmonary fibrosis?

Answer:
Dr. Webb: Proper HRCT technique requires the use of thin slices (1 mm) and reconstruction of the scan data using a high-resolution algorithm, with scans obtained at full inspiration. However, there are many different ways of imaging the patient that can provide scans adequate for diagnosis of IPF or the other interstitial pneumonias.

Scans can be obtained with a multi-detector CT scanner using thin detectors (eg, 1.25 mm or 0.625 mm) and spiral technique. This allows volumetric acquisition and reconstruction in any plane. It has not been shown however, that multiplanar reconstructions add much to diagnostic accuracy.

Scans can be obtained with single axial slices being obtained at spaced intervals, either 1 or 2 cm. This technique has the advantage of low radiation dose, when compared to spiral scanning, and the accuracy of spaced scanning has been validated in numerous papers over the years.

Regardless of which scanning technique is chosen, it is prudent to obtain scans in both the supine and prone positions. In the supine position, dependent atelectasis can mimic early interstitial lung disease. Scans in the prone position obviate this problem. Since early IPF and nonspecific interstitial pneumonia predominate in the posterior and subpleural lung, diagnosis may be difficult if only supine scans are available.

Volpe J, Storto ML, Lee K, Webb WR. High-resolution CT of the lung: determination of the usefulness of CT scans obtained with the patient prone based on plain radiographic findings. AJR Am J Roentgenol. 1997;169:369-374.

 What is the risk of a nonsmoking IPF patient getting lung cancer?

Answer:
Dr. Sahn: There are a number of manuscripts in the literature that report an increased frequency of lung cancer in patients with IPF. The reported frequency is highest in Japan (48%) and lowest in the United States (5%). The large discrepancy may include both criteria for establishing the diagnosis of IPF and distinguishing adenocarcinoma from squamous metaplasia often seen with IPF. The literature confirms that most IPF patients with lung cancer are men with a history of cigarette smoking; additionally, unknown occupational or environmental exposure may increase the risk of both IPF and lung cancer. Approximately 80% of lung cancers in IPF are located in peripheral fibrotic sites in the lower lobes, tending to implicate the inflammatory process and bronchiolar squamous metaplasia in the pathogenesis of lung cancer. Squamous cell cancer has been found to be most common in men and adenocarcinomas most common in women in IPF, although all cell types have been found in both sexes.

The pathogenesis of the apparent association of IPF and lung cancer is unclear; however, investigators have found apoptosis in IPF tissue of tumor suppressor proteins that may play a role.

While one series reported that the relative risk of developing lung cancer is 14.2 for male smokers and 6.7 for female smokers, the incidence in nonsmoking IPF patients was much lower when compared to the general population of comparable age and sex. This suggests that cigarette smoke may be an added risk factor for the development of lung cancer in IPF patients.

 I have a 62 y/o female patient who was recently diagnosed with bird fancier's lung disease. She had 3 parakeets in her home for approximately 5 years, before she began to develop shortness of breath, cough, and chest discomfort. She and her husband moved out of their home and had it thoroughly cleaned, with removal of carpets and draperies, and her symptoms improved with a short course of prednisone. The birds were given to relatives. Approximately 2 months after moving back into her home, she began to experience similar symptoms. How should I treat her?

Answer:
Dr. Sahn: In most patients, removing bird antigens from the home will result in resolution of symptoms. However, in some instances, removal of all of the avian antigens from the home is problematic, as these antigens find their way into cracks in wood floors and other places. In this situation, I suggest that you advise your patient to move out of the home to determine the effect on her disease. If improvement occurs, she should strongly consider a permanent move. Corticosteroids may be effective in acute, severe, and progressive disease; however, their long-term efficacy has not been determined.

 Do I need to do a bronchoscopic biopsy in the workup of IPF if the chest CT scan is classic with peripheral honeycombing?

Answer:
Dr. Strange: The ATS/ERS statement on the diagnosis of IPF suggests that a bronchoscopy with transbronchial lung biopsy or bronchoalveolar lavage (BAL) be performed to exclude alternative diagnoses to IPF. Some have questioned whether this test is necessary in an older patient with insidious onset of dyspnea and a classic CT scan.

I find the BAL more helpful than the biopsy in this situation, provided the CT has no features to suggest sarcoidosis (significant adenopathy or fibrosis that conforms to bronchovascular distribution). The BAL should show excesses of polymorphonuclear leukocytes (> 3% of total nucleated cells), but should not show large excesses of lymphocytes or eosinophils (> 30%) that would suggest alternative diagnoses such as hypersensitivity pneumonitis (HP) or chronic eosinophilic pneumonia (CEP), respectively. It should be noted that both HP and CEP can produce a UIP pattern on the CT scan; therefore, I support the ATS/ERS statement.

 I have a 68 y/o female patient with systemic mastocytosis. HRCT scan reveals diffuse reticulation with traction bronchiectasies, scanty ground glass. On biopsy, there is heterogeneous interstitial fibrosis with moderate-severe chronic inflammation with eosinophils and some mastocytes. No alveolar occupation. Pattern is similar in lower and upper lobes. Pulmonary fibrosis was previous to treatment (cromoglicate and antihystaminic). Is there any relation between systemic mastocytosis and pulmonary fibrosis?

Answer:
Dr. Sahn: Systemic mast cell disease is an idiopathic disorder characterized by the proliferation of mast cells in a variety of organs including the bone marrow, liver, spleen, and lymph nodes. The skin may or may not have lesions of urticaria pigmentosa. The literature does not contain any cases of clinical lung involvement from mastocytosis, including interstitial lung disease, and more specifically IPF.

However, it is not rare to see a 70 y/o individual with a preexisting chronic disease who develops IPF. On a number of occasions, I have seen patients with a known history of a chronic disease, such as sarcoidosis, who years later presented with IPF.

 My doctor tells me that my construction job has contributed to my pulmonary fibrosis. Is this true? Should I change jobs?

Answer:
Dr. Strange: First of all, this is a complicated question that depends on many aspects of the job and what kind of "pulmonary fibrosis" is present. The best way to answer the question is to explore some of the occupational interstitial lung diseases. For starters, we know that some kinds of dust can cause pulmonary fibrosis.

One common cause is asbestos, which is being systematically removed from many old buildings. An exposure to asbestos sufficient to cause pulmonary fibrosis comes with daily exposure for many years to a significant dust burden. This can be seen in automobile brake workers, plumbers, and demolition experts who do not wear masks. The lung disease is called "asbestosis." If an x-ray shows calcium deposits along the pleura (the outside lining of the lung), asbestosis is suspected.

Another mineral that can cause lung disease is silica, which is different from silicone. Silica is a hard rock that is the principle component of sand and quartz. Therefore, quarry workers, sandblasters, and others with exposure to rock dust have a risk for this disease. The disease "silicosis" is characterized by small nodules that are most common in the upper parts of the lung.

Other minerals can also cause lung disease. Found in hardened metals, cobalt causes giant cell interstitial pneumonitis, a disease with a characteristic biopsy. Coal causes coal worker's pneumoconiosis, a disease that is much more symptomatic when mixed with silicosis.

Last, it has been noted that idiopathic pulmonary fibrosis (IPF) is seen more commonly in some occupations that have contact with dust. Whether there is some particular component of dust that scars the lungs, or whether IPF is the result of a more generalized response to a dusty environment remains unknown. Unfortunately, there is no information on whether removal from a dusty environment is beneficial to an established IPF patient. The general recommendation of working in a clean air environment makes some common sense, but has never been subjected to study.

  I never know when to order an antinuclear antibody (ANA) or rheumatoid factor (RF) test on my interstitial lung disease (ILD) patients or what to do with a positive test. Please help!

Answer:
Dr. Strange: Many pulmonary physicians choose to screen for occult connective tissue disease (CTD) with a variety of laboratory tests. The practice has evolved from the knowledge that 10% to 25% of ILD patients will eventually be diagnosed with a CTD; however, the frequency with which ILD is the only manifestation of a CTD remains unknown. Usually a CTD will evolve in the first 2 years following ILD presentation in these patients.

Older data has suggested that the frequency of ANA and RF positivity in idiopathic pulmonary fibrosis (IPF) is approximately 40%. More recent case series have suggested that many of these patients do not meet high resolution computed tomography (HRCT) or open lung biopsy criteria for usual interstitial pneumonitis (UIP), the pathologic correlate of IPF, and more typically have nonspecific interstitial pneumonitis (NSIP) in which lung fibrosis is more diffuse but less progressive.

Therefore, when a patient has a positive RF, particularly if arthritis is present, then further work must be done. A new test for anticyclic citrullinated peptide antibodies (Anti-CCP) is both more sensitive and specific for rheumatoid arthritis. Hand films and films of affected joints are obtained to solidify diagnosis. Importantly, if RA can be confirmed, anti-inflammatory therapy will be begin with a goal of reducing joint (and lung) inflammation. Most commonly, this will require a tumor necrosis factor (TNF) inhibitor when RA is advanced sufficiently to have ILD.

The utility of ANA is less well studied. ANA is almost always positive in systemic lupus erythematosis, scleroderma, CTD-associated Sjögren's syndrome, and often positive in polymyositis/dermatomyositis. If ANA is positive in ILD at a titer of 1:160 or higher, further characterization of an extractable nuclear antigen (ENA) panel is recommended. This panel can further characterize the disease and suggest the most appropriate anti-inflammatory therapy.

Although these laboratory tests are inexpensive and felt to be helpful, no prospective study has ever determined if the tests truly make a difference independent of a good history and physical exam.

  I am a PCP with a 72 y/o patient. The pulmonologist made a diagnosis of IPF based on radiologic findings. She stressed the extensive honeycombing of the lungs. What is honeycombing and what is the underlying physiology?

Answer:
Dr. Strange:This is the million dollar question to the pathogenesis of Idiopathic Pulmonary Fibrosis (IPF). Briefly, honeycombing is a word applied to the appearance on the computed tomography (CT) scan that applies to the development of adjacent cystic airspace enlargement, usually in a subpleural location. As pulmonary specialists and radiologists, we use many words that do not have formal definitions and "honeycombing" is one of these words. In brief, it looks like a "honeycomb."

Airspace enlargement is common to many diseases. The best known of these is emphysema in which airspace enlargement (holes in the lung) is not associated with any surrounding fibrosis. A lung bullous is a large (> 3 cm diameter) area of emphysema. Lung cysts, in contrast, are areas of airspace enlargement with surrounding fibrosis. Cysts are seen in a variety of infectious lung diseases (eg, tuberculosis), cystic fibrosis, and some of the rarer diffuse parenchymal lung diseases such as lymphangioleiomyomatosis (LAM) or pulmonary Langerhans cell histiocytosis (PLCH).

When cystic lung disease is adjacent to the pleura and surrounded by areas of fibrosis, open lung biopsies have suggested that these cystic airspaces are the result of interstitial lung fibrosis that is pulling the lung apart. The holes that are left have distorted architecture and excess mucus inspisation; however, the pathology is not the hole, but the scarring in the lung characterized by excesses of fibroblasts. Therefore, if a novel therapy for IPF were found tomorrow, the impact of that drug on honeycomb fibrosis is not likely to be the mechanism of improvement. However, if milder degrees of fibrosis are present elsewhere in the lung before lung distortion occurs, then such a medication would have a better opportunity to work.

When radiologists are asked to define "honeycombing" they often do not agree, particularly in mild disease. However, your consultant is impressed with the amount of honeycombing, and large amounts of honeycombing are almost universally associated with a lung biopsy finding of usual interstitial fibrosis (UIP), the pathologic entity associated with IPF.

I would make the point that some diseases can have honeycombing (UIP) and not be IPF. Interstitial lung disease due to rheumatoid arthritis, radiation fibrosis, asbestosis, and some forms of chronic hypersensitivity pneumonitis (bird fancier's disease, hot tub lung, or farmer's lung, for example) will also have this appearance. Therefore, patients with extensive honeycombing should still be asked about connective tissue disease symptoms, and exposures to organic antigens (eg, birds, hot tubs, moldy hay) in their evaluation, since control of these may prevent progression of lung disease.

In summary, I agree that extensive honeycombing suggests the probable diagnosis of IPF and is usually sufficient for entry into a treatment trial for this disease. We all hope that new therapies will soon be available for IPF.

  I am treating a 32 y/o Hispanic man with pulmonary fibrosis and a pathology result consistent with UIP with lymphoid hyperplasia. His tests for connective tissue diseases have all been negative. He has worked in construction in the past. He has no insurance and no medical coverage. I placed him on prednisone 30 mg po qd and TMP-SMX mwf for pcp prophylaxis because this is an atypical case (young, lymphoid hyperplasia) on the off chance that he has an atypically steroid responsive process (though UIP usually isn't). Do you know of any data regarding treatment of cases like this?

Answer:
Dr. Leslie: The diagnosis of "UIP" in a 32 y/o is unlikely to correspond to idiopathic pulmonary fibrosis, as we understand that condition today. Clearly he must have advanced fibrosis on biopsy, and this has resulted in the pathological diagnosis of "UIP."

UIP-pattern lung fibrosis accompanied by lymphoid hyperplasia in a 32 y/o raises a differential diagnosis to include: 1) clinically occult systemic autoimmune disease manifesting as pulmonary fibrosis; 2) chronic medication toxicity (most often to very specific drugs such as nitrofurantoin); and 3) "familial" forms of pulmonary fibrosis.

The distribution on HRCT will be very important in establishing prognosis, especially in conjunction with his baseline pulmonary function (including data on desaturation with exercise). I would make sure that a broad panel of serologic studies has been performed, even if a rheumatic condition is not clinically apparent (ANA, RF, ANCA, SCL70, SSA, SSB, aldolase, Jo-1, sed rate, CRP).

Many pulmonologists who are experts in the care of patients with ILD would agree with your approach to therapy in this patient, in fact some would strongly advocate the use of a combined therapy approach with the addition of a cytotoxic agent such as azathioprine (see ATS/ERS consensus statement on IPF for dosage and administration), with or without N-acetylcysteine (NAC). It is doubtful that any therapy will reverse existing fibrosis in this patient, but by modifying or eliminating an immunologically mediated mechanism, the overall prognosis may be changed favorably.

  I have a 58 y/o male patient who has Sjögren's syndrome, factor V Leiden, IPF from a biopsy in 2005, and positive LAC. How commonly is IPF associated with autoimmune diseases (and is there a pathological connection)? This patient has a history of PE and clotting. Is lung transplant a viable option?

Answer:
Dr. Leslie: There is a definite pathological connection. Pulmonary fibrosis can occur in patients with Sjögren's syndrome and also in the context of many other "named" connective tissue diseases, with incidence varying according to diagnosis (eg, up to 40% of patients with scleroderma will develop interstitial lung disease). In this situation, a patient's pulmonary fibrosis would not be "idiopathic," however.

Lung transplantation may be an option, and will likely depend on the severity of any co-morbidities, the patient's performance status, the extent of lung disease radiologically, and the degree of pulmonary function deficit. The patient's Lupus anticoagulant status may play a role in this decision, as well.

  Can you comment on the clinical trials using the drug pirfenidone for patients with IPF? Do we know if these patients have mild, moderate, or advanced disease? From what I have read, it looks like this drug may help slow the progression of IPF.

Answer:
Dr. Leslie: Currently, there is a large, randomized, double-blind, clinical trial ongoing (no longer enrolling patients) using pirfenidone in IPF patients (CAPACITY trial). The enrollment criteria were designed to recruit patients with less advanced disease and are as follows (from www.ClinicalTrials.gov):
Primary Inclusion criteria:

• Diagnosis of IPF
• 40 to 80 years of age
• FVC ≥ 50% predicted value
• DL_CO ≥ 35% predicted value
• Either FVC or DL_CO ≤ 90% predicted value
• No improvement in past year
• Able to walk 150 meters in 6 minutes and maintain saturation ≥ 83% while on no more than 6 L/min supplemental oxygen

Primary Exclusion criteria:

• Unable to undergo pulmonary function testing
• Evidence of significant obstructive lung disease or airway hyper-responsiveness
• In the clinical opinion of the investigator, the patient is expected to need and be eligible for a lung transplant within 72 weeks of randomization
• Active infection
• Liver disease
• Cancer or other medical condition likely to result in death within 2 years
• Diabetes
• Pregnancy or lactation
• Substance abuse
• Personal or family history of long QT syndrome
• Other IPF treatment
• Unable to take study medication
• Withdrawal from other IPF trials

Prior studies have suggested a benefit (see abstract below):
Azuma A, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2005:1;171(9):1040-1047.

  Is Agent Orange exposure a risk factor for IPF?

Answer:
Dr. Leslie: There are no available data directly linking exposure to Agent Orange with IPF. The etiology for IPF remains unknown. Epidemiologic studies suggest increased risk associated with metal and wood dust exposure, but even this is not evidence of causation.

  I have a patient with exposure to high levels (50+ ppm) of bromine vapor from a whirlpool. Patient experienced dermal burns (healed) and ongoing seizure, hallucination, memory problems, tremors, loss of taste, lumps under tongue and fissures on tongue, difficulty swallowing, shortness of breath, headaches, blood/oxygen level of 91, and rapid heart rate of up to 118 bpm at sitting. Patient cannot walk more than 100 ft. Is bromine exposure associated with an increased rate of IPF?

Answer:
Dr. Leslie: Acute bromine inhalation can result in acute toxic lung injury with chemical airway damage. It is conceivable that pulmonary injury in this setting could result in scar formation and compromised lung function. No data link toxic exposure to bromine and the idiopathic form of pulmonary fibrosis referred to as “IPF.” Lung damage from any toxic exposure can result in permanent damage, including pulmonary fibrosis. This would not be “idiopathic” pulmonary fibrosis, but fibrosis related to acute bromine inhalation.

See abstract below:
Inagaki N, et al. Case with bromine exposure leading to respiratory insufficiency. Chudoku Kenyu. 2005 Apr;18(2):141-147.

  Our local pathologists are really excellent, but when one of my patients has suspected ILD and requires a surgical lung biopsy, they tend to send these out for expert review. Why is this the case?

Answer:
Dr. Leslie: The pathology of diffuse parenchymal lung disease is nearly always a manifestation of inflammatory/immune mechanisms. Diagnosing these conditions requires considerable experience. Several factors contribute to the diagnostic difficulty. First, the "images" of inflammatory diseases seen through the microscope are not specific for a single diagnostic entity and there is considerable overlap between inflammatory injuries. For example, the histopathology of sarcoidosis is one of the easiest to recognize by surgical pathologists. But other conditions such as those of berylliosis and granulomatous infection can exactly mimic sarcoidosis. Second, repetition is essential for histopathology patterns to be learned, even by the greatest surgical pathologists. In even the busiest of general practices, surgical lung biopsies come infrequently and it may take many years for a pathologist to see enough of these patterns to accurately distinguish them. Finally, a basic knowledge of chest radiology and pulmonary medicine are absolute prerequisites for the interpretation of lung histopathology. Without such knowledge, the most experienced pathologist may misguide the clinician. A nice example of this is the often dramatic pathology of "middle lobe syndrome," where intense inflammation, advanced fibrosis, and even necrotizing granulomas all may be present in the same biopsy. The condition results from chronic obstruction of the long and narrow middle lobe (and lingula) bronchus and in most patients is not a reflection of ILD. In this setting, without radiologic knowledge of the localization of disease, the interpretation might range from "granulomatous infection" to "IPF." Even the experienced pulmonologist may miss the clinical diagnosis of middle lobe syndrome when such extensive microscopic pathology is detailed in the pathology report.

  Has the 5-year survival rate improved for patients undergoing single lung transplantation for IPF? Also, what determines if the patient qualifies for a single vs double lung transplant?

Answer:
Dr. Leslie: The answer to the first question is yes, 5-year survival rates have improved when different periods are compared. According to the ISHLT:


Figure 1

The choice of single lung transplant (SLT) versus bilateral lung transplant (BLT) is controversial in IPF. Some publications suggest no survival differences, while other data suggest that BLT may improve survival for IPF patients specifically as illustrated in Fig. 1 and in a recent abstract (Click here for the abstract) presented below. The most recent ISHLT BLT group (2000-2004) has significantly higher survival than earlier transplant groups. (Mason 2007)

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

Answer:
Dr. Golden: 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.

  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:
Dr. Golden: 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.

  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:
Dr. Golden: 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.

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

Answer:
Dr. Golden: 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.

  What is the role of genetic testing in patients with IPF?

Answer:
Dr. Collard: There have been some recent discoveries in patients with familial pulmonary fibrosis, a condition with varying phenotype and defined by the presence of pulmonary fibrosis in two or more family members. Mutations in genes related to telomerase function have been identified in families manifesting clinical and histopathological evidence of IPF (Tsakiri et al. Proc Natl Acad Sci USA. 2007;104:7552, Armanios et al. N Engl J Med. 2007;356:1317). Telomerase length is important to cellular proliferation and response to injury. Mutations in surfactant protein C have also been associated with ILD (Thomas et al. Am J Respir Crit Care. 2002;165:1322). Given these findings, many patients and their family members are understandably interested in finding out whether or not they carry similar mutations. In my opinion, however, genetic testing in ILD is not yet ready for clinical use. For patients, we have no idea how the presence of one of these mutations should affect prognosis and management. For family members or other unaffected individuals, we do not know the risk these mutations confer for developing ILD later in life. While there is arguably inherent value for some patients in knowing whether or not they may carry a mutation known to be associated with ILD, our inability to translate this knowledge into prognostic or therapeutic recommendations makes the costs associated with such testing (psychological in particular, but also financial) hard to justify.

  What is the role for bronchoscopy in patients with presumed idiopathic pulmonary fibrosis (IPF)?

Answer:
Dr. Collard: There is general consensus (although not universal) that transbronchial biopsy serves little role in the diagnosis of IPF. Although a recent publication suggests otherwise in selected cases (Berbescu et al. Chest. 2006;129:1126), it is generally believed that the accurate diagnosis of IPF (ie, the demonstration of usual interstitial pneumonia pattern on lung biopsy) requires a surgical technique. Bronchoscopy can aid in the clinical diagnosis of IPF, and has been included as one of the major diagnostic criteria, as published by the American Thoracic Society/European Respiratory Society (Am J Respir Crit Care Med. 2000;161:646). It is most useful in reducing the likelihood of alternative diagnoses (eg, chronic eosinophilic pneumonia, hypersensitivity pneumonitis) which would demonstrate striking elevations of particular cell types on the differential cell count of bronchoalveolar lavage fluid. There is some debate about whether or not bronchoscopy and bronchoalveolar lavage should be required for the clinical diagnosis of IPF and many practicing clinicians do not routinely perform this test as part of their diagnostic evaluation (Collard et al. Respir Med. 2007;101:2011).

  How should I follow patients with ILD over time?

Answer:
Dr. Collard: The strongest data exist for serial pulmonary function measurements, in particular forced vital capacity (Flaherty et al. Am J Respir Crit Care Med. 2003;168:543). Additional data exist for dyspnea and diffusion capacity, although the data are not as strong. There are no compelling data for serial high resolution CT scanning. My practice is to follow patients every 6 months (unless clinical events dictate a shorter interval) with an assessment of dyspnea, spirometry, and diffusion capacity measurement. I do not, as a general rule, perform serial CT scanning. There are several metrics for dyspnea; my favorite is the baseline/transitional dyspnea index (Witek and Mahler. Eur Respir J. 2003;21:267) although data using this scale in IPF are limited. The only tested measure is the CRP Dyspnea scale (Watters et al. Am Rev Respir Dis. 1986;133:97); a change of 2 points or greater is prognostic (Collard et al. Am J Respir Crit Care Med. 2003;168:538). Changes in 10% or greater in forced vital capacity and 15% in diffusion capacity are considered significant and prognostic. Stability or improvement in these measures should suggest that the disease is stable and/or the therapy is working. Worsening of these measures should prompt a change in therapy, including evaluation for lung transplantation.

  What alternatives are there to prednisone for the treatment of interstitial lung disease?

Answer:
Dr. Collard: Corticosteroids are still first-line therapy for most forms of interstitial lung disease (ILD), but many patients experience significant morbidity (eg, hyperglycemia, weight gain, agitation, mood disturbance) and require an alternative medication. While the choice varies somewhat based on the diagnosis, a few general comments can be made. There are three drugs that are routinely used in combination with, or in place of, corticosteroids for the treatment of ILD. These are cyclophosphamide, azathioprine, and mycophenolate. All three drugs work to suppress the immune system. There are significant potential toxicities associated with each, and unlike prednisone, regular blood work is required. These medications should be prescribed by a physician expert in the care of ILD.

  What are PFT, SpO₂, ABG, and other relevant criteria for allowing airplane travel for patients with advanced IPF?

Answer:
Dr. Rosen: There are no strict PFT criteria for airplane travel but there are some clues which would indicate the need for oxygen during travel. For example, desaturation during a 6-minute walk test and a diffusing capacity < 35% of predicted suggest the need for oxygen during flight. Neither the resting SpO₂ nor resting ABG is useful unless the patient is hypoxemic at rest, quite unusual even in patients with severe IPF. We do altitude simulation studies in most or all patients who we think may need oxygen during flight. To accomplish this, the patient is placed in a reduced FiO₂ chamber (16%) which corresponds to a plane pressurized to 8,000 ft (all planes are now pressurized to 7,000-8,000 ft). SpO₂ is monitored for 25 minutes followed by ABG at the end of the test. If PaO₂ is less than 55 mm Hg or 88%, we recommend O₂ during flight.

  Currently, what is the best line of management for IPF? How accurate is the histopathological diagnosis of the condition, keeping in mind the grave prognosis of the irreversible condition?

Answer:
Dr. Rosen: Since there are currently no approved drugs for the treatment of IPF, the best approach is to enter a patient into a clinical trial. However, the pirfenidone trial is closed and the bosentan trial is closing imminently so the only active trials are those sponsored by the NIH (IPF Network). One trial is for patients with mild to moderate disease who will be randomized to placebo vs NAC (N-acetylcysteine) vs Prednisone/Azathioprine/NAC. This trial follows a study by Demedts M, High-dose acetylcysteine in idiopathic pulmonary fibrosis (N Engl J Med. 2005;353:2229-2242), which showed Pred/Aza/NAC preserved FVC and DL_CO in IPF patients compared to placebo treatment. The second IPFnet trial is looking at whether sildenafil will abate pulmonary hypertension in patients with advanced IPF and improve 6-minute walk test performance. The histopathologic diagnosis is still the “gold standard” but should be looked at in the clinical context. We have seen several cases where the biopsy analysis shows UIP but the HRCT has more ground glass than usual and only minimal or no honeycombing. This may be a sampling problem if the biopsy specimen is from a scar area, but it also may reveal comorbid NSIP and IPF, which may be more responsive to prednisone and immunosuppressive therapy than IPF alone. If there is honeycombing on HRCT there is a greater than 85% likelihood that the patient has IPF, so biopsy is not necessary.

  What nonpharmacologic treatments can help IPF patients and what are some important comorbidities that need to be addressed?

Answer:
Dr. Rosen: The two major challenges in patients with IPF are control of cough and maintaining an adequate level of exercise and physical activity in the face of profound dyspnea. We treat cough aggressively with low dose prednisone and control GERD (all patients should be on a PPI even if though do not have symptoms because over 70% of patients with IPF have reflux). Codeine-containing narcotics, tessalon perles, and occasionally, inhaled corticosteroids and bronchodilators are of benefit. Still, cough can be crippling and novel suppressors of cough are being sought. Also, ALL patients with IPF should enter a formal pulmonary rehabilitation program for 6–8 weeks, followed by maintenance. These programs are proving to be critically important for increasing exercise tolerance, well-being, muscle strength, and may improve survival. Learning to exercise with or without oxygen, learning how to regulate and control breathing, and the support network all make rehabilitation a key nonpharmacologic therapy for IPF patients. Comorbidities, such as GERD, sleep apnea, and pulmonary hypertension (PH), also need to be addressed. The diagnosis, significance, and treatment of PH will be addressed in other PILOT features.

  When should a patient with IPF be referred for a workup for lung transplant and when is the best time to transplant?

Answer:
Dr. Rosen: A patient who is eligible should be referred for lung transplant upon diagnosis of IPF. Since the course of IPF is unpredictable with possible acute exacerbations and rapid deterioration, the patient should be evaluated for treatment and workup completed early in the disease. We don’t know the “perfect” time for transplant in large part because only 50% of patients are alive 5 years after transplant. Clinicians and transplant physicians should jointly pick the optimal time, generally when functional status is good but there is clear evidence of progression. Also, when FVC < 40–50% and DLCO < 30–35% of predicted, waiting may entail high risk. Patients at some centers are considered for transplant up to 70 years of age, so age alone is not a barrier anymore.

  Who with interstitial lung disease should undergo a surgical lung biopsy?

Answer:
Dr. Rosen: This is somewhat controversial but our rule-of-thumb is that anyone with ILD who is less than 40 years of age should undergo a surgical lung biopsy. IPF is less common in this age group but still occurs. Even with an HRCT that is classic for IPF, ie, honeycombing with minimal ground glass, traction bronchiectasis, and reticular abnormalities, we recommend biopsy in younger patients. In those over 40 with a classic HRCT and clinical presentation (insidious onset, crackles on exam, no known exposure or evidence of autoimmune disease) biopsy is not necessary.

  The EPA has recognized that exposure to diesel exhaust can lead to pulmonary fibrosis. Using the American Thoracic Society (or any other reliable qualifiers), how does one refer to that disease? Is it still idiopathic, if causation is known, or is “idiopathic” dropped once cause is determined? Please refer to published articles, if possible.

Answer:
Dr. Rosen: The EPA has shown that exposure to diesel exhaust can lead to pulmonary fibrosis, but it has been confirmed only in animal models. There are no human studies that corroborate the animal work. It is a potential but unproven cause of pulmonary fibrosis. A nice review by JC Bonner, “Lung fibrotic responses to particle exposure,” recently appeared in Toxicologic Pathology. 2007;35:148-153. (Click here for abstract) On the other hand, exposure to asbestos is a known cause of pulmonary fibrosis. Therefore, if a patient reports exposure to high concentrations of diesel exhaust alone and has fibrosis, the diagnosis would still be IPF.

  What is your approach to patients who have focal areas of honeycombing or fibrosis in the absence of history of pneumonia? Is there an approach to seeing if they’re developing IPF? How often would one repeat a CT or PFTs in this situation?

Answer:
Dr. Rosen: In patients with focal honeycombing or fibrosis, we adopt a watchful waiting approach. Even if the patient does not have a history of pneumonia, focal scar is not uncommon with previous infection or a possible environmental insult. We recommend following PFTs every 6 months for approximately 2 years and if there is any significant reduction in FVC (> 5%) or DL_CO (> 5-10%), I would follow-up with a repeat HRCT. Even though HRCT is almost 5X less radiation than a conventional CT, we still need to be cautious prior to recommending its use on a frequent basis.

  What is Burkholdi?

Answer:
Dr. Rosen: Burkholdi species are gram negative organisms with the most common being Burkholderia cepacia, which is common in patients with cystic fibrosis. It can also be found in patients with severe bronchiectasis such as IPF patients. It is difficult to treat and frequently resistant to antibiotics but carbapenems (eg, meropenem) and aminoglycosides (eg, tobramycin) are the preferred antibiotics. Infection with this organism is associated with decreased survival.