Question: 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: 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.

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Question: 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: 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.

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Question: 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: 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.

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Question: Is Agent Orange exposure a risk factor for IPF?

Answer: 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.

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Question: 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: 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.

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Question: 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: 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.

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Question: 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: 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)