A Historical Perspective and Modern Techniques in Pulmonary Pathology
Moderators: Dr. Henry D. Tazelaar, Dr. Ming S. Tsao and Dr. Brendan Mullen
Section 3 -
Curing Idiopathic Pulmonary Fibrosis: Beyond Interferon Gamma
Kevin O. Leslie
Mayo Clinic Arizona
Idiopathic pulmonary fibrosis (IPF) is a specific form of progressive fibrosing interstitial pneumonia
of unknown etiology, occurring most frequently in older men, and confined to the lungs.  The prognosis
historically for this disorder is dismal, with median survival estimates at less than 3.5 years from
diagnosis. No therapy has proven effective in the treatment of IPF but many have been tried over the
years.  In this presentation, we will explore data from prior experiments in therapy for IPF and
review ongoing/proposed clinical trials aimed at improving survival and quality of life in this
universally fatal condition.
Idiopathic Pulmonary Fibrosis and Usual Interstitial Pneumonia
The pathology of IPF is usual interstitial pneumonia (UIP).  This progressive fibrosing interstitial
pneumonia was originally described by Liebow as the most common or "usual" form of idiopathic
interstitial pneumonia occurring in adults.  UIP has a distinctive appearance in surgical lung
biopsies and resected lung material, with "temporally heterogeneous" structural remodeling including
fibrosis, fibroblast foci at the interface between fibrosis and uninvolved lung, and microscopic
honeycombing in the classical example.  This morphologic pattern of usual interstitial pneumonia can
occur as a manifestation of other lung diseases such as rheumatoid arthritis and chronic hypersensitivity
pneumonitis, but when UIP is clinically idiopathic, IPF is nearly always the correct diagnosis.
Diagnosis of IPF
Patients with IPF are typically over 50 at the time of their clinical presentation, although the age
distribution at presentation is quite wide.  Slowly progressive breathlessness, especially with
exertion, is the most common clinical complaint. Nonproductive cough is typically present and can be a
difficult component of the disease to manage. Laboratory studies may show mild nonspecific elevation of
antinuclear antibodies (ANA), but serologic studies for defined rheumatic disease are by definition
absent. Pulmonary function testing reveals restrictive physiology with decreased total lung capacity,
forced vital capacity, and diffusing capacity for carbon monoxide (DLco). Oxygen desaturation with
exercise is commonly present and the degree of desaturation during the six minute walk test has been
shown to have prognostic value for the individual patient.  The high resolution CT scan is a major
cornerstone in the diagnostic work up and typically shows bibasilar reticular abnormalities, frequently
accompanied by subpleural honeycombing.  Subpleural disease is variable in distribution along the
pleura and some asymmetry from side to side is expected. Increased reticular lines are nearly always
present in the upper lung zones when subpleural honeycombing is identified at the bases. A gradient
towards the apex occurs with abnormalities accruing from base toward the apex as the disease progresses.
Today, a characteristic HRCT in the appropriate clinical and physiologic presentation obviates the need
for a surgical lung biopsy in most practice settings,
with the caveat that when IPF is a clinical
concern, a less than diagnostic HRCT scan will be frequently overridden by usual interstitial pneumonia
in the surgical lung biopsy. 
Past, Present, and Future Therapies for IPF
After critically reviewing 3,500 published reports on IPF including physiologic, radiologic, and
pathologic findings; pathogenesis, epidemiology, clinical presentation, staging, inheritance or familial
occurrence, treatment, and prognosis, a 2000 international consensus statement from the American Thoracic
Society concluded that "There is no supportive evidence [for therapy] from well-conducted randomized
control trials. The best evidence is from well-conducted cohort studies from case-control studies. Even
in these instances the diagnosis of IPF was frequently not well established and the series often included
patients with other diseases as potential causes of lung fibrosis".  That document went on to say
"until adequate studies are conducted that define the best treatment for patients with IPF, this
committee suggests the following combined therapy (corticosteroid and either azathioprine or
cyclophosphamide) for those patients who have been given adequate information regarding the merits and
pitfalls of treatment and who possess features consistent with a more likely favorable outcome". A
recent review article also reached this consensus for combined therapy for those patients who cannot
enroll in clinical trials.  The major milestones in IPF therapy are presented here with analysis and
Corticosteroid Therapy for IPF
Systemic corticosteroid therapy for patients with IPF began with the notion that inflammatory diseases
that result in fibrosis might be controlled or cured with immunosuppression.  This notion was not
misguided, as pulmonary practice experience and the published literature have clearly documented the
effectiveness of anti-inflammatory therapies in a number of inflammatory lung diseases (e.g. eosinophilic
pneumonia, rheumatic diseases manifesting in the lung, drug reactions, hypersensitivity reactions).
While it is generally agreed that systemic corticosteroids have no proven benefit for patients with IPF,
many anecdotal experiences would suggest that some patients who appear to have IPF clinically can rarely
derive a benefit from this therapy. Unfortunately, agreed-upon criteria for the pathologic diagnosis of
IPF only recently became available from a 2002 international consensus conference based on clinical
radiologic and pathologic correlation and available literature  and retrospective review of biopsy
material from prior cohorts of IPF reveal significant heterogeneity of diagnosis. This variability has
been blamed for a false sense that a subset of patients with IPF will respond to corticosteroids or
combined immunosuppressive therapies.
Corticosteroids and Azathioprine for IPF
The most cited early study of combined corticosteroid and cytotoxic therapy for IPF was a 1991
randomized control trial published by Raghu et al. describing the results of 27 patients randomized to
prednisone alone (n= 13) or combined prednisone with azathioprine (n=14).  The initial results did
not reach statistical significance (p= 0.16). A recent reanalysis (after two patients were discovered to
have switched therapy arms from prednisone to combined prednisone with azathioprine, one patient in the
azathioprine arm had switched to prednisone, a death was discovered in the prednisone arm at year 6, and
age adjustment), showed significant differences in these two therapies (p= 0.02).
N-acetyl-cysteine in IPF
N-acetyl-cysteine is an antioxidant and is proposed as a useful therapy given evidence that oxidative
stress may play a role in pulmonary fibrosis.  A recent European clinical trial (Ifigenia) in which
combined therapy with prednisone and azathioprine was compared with the same regimen plus N-acetyl-cysteine (n=155) showed statistically less decline in FVC and DLco in the
Pred-Aza-Nac arm compared to Pred-Aza alone over the year of study. No difference in survival was
detected between the groups however. 
Prednisone and Cyclophosphamide in IPF
While no randomized control trials have been evaluated for this therapy, a study by Collard et al. in
2004 compared two historical groups of patients treated at two different medical centers, one where all
patients with IPF received prednisone and cyclophosphamide and the other where patients received no
therapy. After matching patients by age and FVC at baseline across the two populations, no difference
in survival (p=0.58) was detected between the two groups as compared to expected mortality. 
Colchicine and IPF
Colchicine was used for many years in the therapy of IPF, especially by clinicians at the Mayo
Clinic. Colchicine is reported to have anti-fibrotic properties, but several studies have shown no
efficacy for colchicine in the treatment of IPF.
Interferon Gamma and IPF
In 1999 a study appeared in the New England Journal of Medicine by Ziesche et al. describing the
results of a randomized clinical trial using human recombinant interferon gamma 1b in 18 patients with
IPF (9 in each arm). The control group received low dose prednisone while the treatment arm received
combined low-dose prednisone with interferon gamma 1b by subcutaneous injection (200 µg) three times a
week. At the end of one year, a significant improvement in pulmonary function was detected for the
treatment arm compared to the "placebo arm". 
Based on these results, a large randomized double-blind placebo controlled clinical trial of
interferon gamma 1b was designed and implemented. Three hundred and thirty (330) patients were recruited
and the primary end points selected for the 48-week period study were a 10% decrement in forced vital
capacity or an upward change in A-a gradient of greater than 15%. Mortality was chosen as a secondary
endpoint. At the end of the study no difference was identified between the placebo and treatment arms
regarding the primary end points, but an unexpected trend was identified with decreased mortality for the
interferon-treated group (p = 0.08).  When the patients were examined using baseline FVC of greater
than or equal to 55% of predicted, the interferon treated arm showed a statistically significant improved
survival compared to FVC matched controls. 
In April of 2006, a second large randomized placebo-controlled trial (2:1 randomization) closed
enrollment with 800 + patients accrued and survival as the primary endpoint (GIPF-007). The results of
this second clinical trial of interferon gamma 1b in IPF will be available at the end of 2007.
Enrollment criteria for this study required on FVC of greater than 55% of predicted and a DLCo of greater
than 35% of predicted (baseline physiologic parameters associated with 100% survival in the treatment arm
compared controls in the GIPF-001 trial).
A recent publication from the Mayo Clinic examined all of the available clinical trial data on
interferon gamma in the treatment of IPF.  Their comparison of mortality at different time points
revealed that IFN-gamma1b therapy was associated with significantly reduced mortality at 1 year (0.0861;
95% CI, 0.0244 to 0.1478; p = 0.0063), 18 months (0.1682; 95% CI, 0.1065 to 0.2299; p < 0.0001), 650
days (0.1939; 95% CI, 0.1386 to 0.2492; p < 0.0001), and 2 years (0.2652; 95% CI, 0.1652 to 0.3652; p
< 0.0001). They concluded that the use of interferon gamma 1b in patients with IPF was associated
with reduced mortality.
Anti-TNF Alpha and IPF
Tumor necrosis factor alpha (TNF alpha) is a pleotropic cytokine thought to be involved with
regulation of fibroblast proliferation and collagen expression modulated through TGF-beta and/or PDGF.
Enhanced expression of TNF alpha has been shown in both experimental models and patients with
A clinical trial assessing the safety and efficacy of anti-TNF alpha in IPF patients
enrolled 87 patients. At the end of 48 weeks, a favorable trend (p=0.05) relative to death or a 10%
decrement of FVC was identified in the treatment group compared to controls. (Presented at Chest in
abstract form 2005;128:496S)
Anti-Endothelin 1 and IPF
Endothelin-1 (ET-1) is instrumental in regulating fibroblast proliferation, migration, and conversion
to the myofibroblastic phenotype.  ET-1 increases collagen synthesis and decreases collagen
breakdown. ET-1 also plays a primary role in smooth muscle/ endothelial cell regulation through ETa and
ETb receptors.  A phase II study has been completed and results are pending.
Pirfenidone and IPF
Pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone) has proven anti-fibrotic activity both in vitro and in
This agent has been shown to inhibit TNF alpha at the translational level  and inhibits
TGF-b- induced collagen synthesis in fibroblasts derived from patients with IPF. Pirfenidone also
inhibits mitogenic effects of profibrotic cytokines on lung fibroblasts.
trials of pirfenidone in IPF [34-36] have been completed and have shown this agent to be safe and
reasonably well tolerated (oral) in patients with IPF. The most recent of these  was a 2:1
randomization with 107 patients. Reduced numbers of acute exacerbation episodes in the treatment arm
forced premature closure of the study and the primary endpoints were not met. Some interesting trends
were noted between the perfenidone and placebo arms with a statistically significant (p=0.003) smaller
decline in FVC over the period of study for the perfenidone treated group. A larger randomized,
placebo-controlled trial is currently underway and enrolling patients (PIPF-001).
Imatinib Mesylate and IPF
Imatinib mesylate is an anticancer drug targeting the c-Abl gene, thought to initiate the destructive
and abnormal growth of tissue. Imatinib mesylate also is known to inhibit the profibrotic growth factors
to TGF-b and PDGF  and has been shown to reduce fibrosis in a mouse experimental model of
bleomycin-induced pulmonary fibrosis.  A phase II randomized, double-blind placebo-controlled trial
has enrolled 100 patients, is currently closed, and the results are under analysis.
FG-3019 and IPF
FG-3019 is a human monoclonal antibody directed against connective tissue growth factor (CTGF). CTGF
and TGFb are felt to play critical roles in the accrual of fibrosis and FG 3019 has been shown to reduce
scarring and excess deposition of extracellular matrix following injury in preclinical models.  A
phase I clinical trial has shown that FG-3019 is well-tolerated and safe for IPF patients. A phase II
trial is in the planning stages. 
Lung Transplant and IPF
Lung transplant is a viable therapeutic option for some patients with IPF. New allocation guidelines
favor IPF patients and lungs are more available than ever for the treatment of IPF patients. Recent
studies have shown that IPF is the most common indication (17%) for adult lung transplantation following
COPD/emphysema (39%). 79% survival at one year, 63% survival at two years and 39% survival at five years
have been reported. 
Single lung transplant may be more effective than bilateral lung transplants. 
Drugs Aimed at Treating Pulmonary Hypertension in IPF
Recent data suggest that a subset of patients with IPF develop significant pulmonary hypertension
during the course of their disease and there is growing expert consensus that this comorbidity may play a
significant role in overall (and possibly sudden unexpected) mortality.
Survival for patients
stratified by mean arterial pressure (MAP) show significant median survival differences as MAP increases
(MAP of 0-35mm/hg = 4.8 yrs, MAP of 35-50 mm/hg = 4.1 yrs, MAP greater than 50mm/hg = 7mos). 
National Institutes of Health-Sponsored Idiopathic Pulmonary Fibrosis Clinical Research Network
Ongoing multi-institutional grant to study novel combined therapies in IPF. No data.
Future Drug Therapies Being Considered for Trials:
Statins: Lovastatin induces a poptosis in normal and fibrotic lung
fibroblasts in vitro, reduces granulation tissue formation and induces
fibroblast apoptosis in vivo in rodent wound chamber models. 
Angiotensin converting enzyme inhibitors: Angiotensin II stimulates
expression of TGF-beta gene and proteins expression and induces proliferation of human lung fibroblasts,
increasing extracellular matrix production. Blockade of ACE inhibitors has been shown to abrogate
fibrosis in experimental models. No human efficacy has been demonstrated. 
Lipoxygenase: Lipoxygenase increases pro-inflammatory leukotrienes which
are likely to play a role in IPF. Leukotrienes may promote fibrosis by influencing fibroblast migration,
proliferation, and extracellular matrix protein synthesis. Mice deficient in leukotrienes show
attenuated fibrosis following bleomycin administration. 
Stem cell transplant: Evidence has shown that tissue specific stem cells
can differentiate into multiple cell lineages. Mesenchymal stem cells have been shown to home-in on lung
tissue after bleomycin injury and help reduce fibrosis in this model. Research avenues hope to be able
to reconstitute damaged tissue in the lungs of IPF patients. 
Anticoagulants: Coagulation events are consistently involved in cell
injury and repair and increased procoagulant activity has been shown to be elevated in BAL fluid from IPF
patients.  A recent clinical study evaluated the effects of anticoagulant therapy, combined with
corticosteroids, for acute exacerbations of IPF. The authors demonstrated a significant difference
between survival curves of the non-anticoagulant control group and the experimental group, with a 2.9
hazard ratio (p=0.04). They postulated that combined therapy with low molecular weight heparin and
prednisolone during the acute exacerbation was responsible for decreased plasma D-dimer levels in the
treated survivors and that anticoagualant therapy has a beneficial effect on survival in patients with
Non-pharmacologic Therapies in IPF
Supplemental oxygen-educate patients to use oxygen as prescribed (home, travel, exercise)
- Smoking cessation
- Eat and sleep issues
- Positive attitude and support issues
Manage gastroesophageal reflux (GERD)
End of life and palliative care discussions.
- Improvement in general and disease specific health status
- Increase exercise tolerance
- Maximize functional ability
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