(Chest. 2000;118:788-794.)
© 2000
American College of Chest Physicians
Idiopathic Pulmonary Fibrosis*
A Practical Approach for Diagnosis and Management
Jeffrey E. Michaelson, MD;
Samuel M. Aguayo, MD, FCCP and
Jesse Roman, MD
*
From the Division of Pulmonary and Critical Care Medicine (Drs. Michaelson and Roman), Departments of Medicine, Atlanta Veterans Affairs Medical Center, Emory University School of Medicine; and Morehouse School of Medicine (Dr. Aguayo), Atlanta, GA.
Correspondence to: Jesse Roman, MD, Atlanta VA Medical Center, Pulmonary Section, Rm 12C191, 1670 Clairmont Rd, Decatur, GA 30033; e-mail: ROMAN-RODRIGUEZ.JESSE{at}ATLANTA.VA.GOV
Key Words: high-resolution CT • idiopathic interstitial pneumonias • idiopathic pulmonary fibrosis • interstitial lung disease
 |
Introduction
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Idiopathic
pulmonary fibrosis (IPF) is a challenging clinical entity because
virtually every aspect of the disease (ie, pathogenesis,
diagnosis, management) remains controversial. While the resolution of
these controversies will require further investigations, the purpose of
this clinical commentary is to integrate recent advances described in
the literature in an effort to delineate a practical clinical approach
for the diagnosis and management of IPF. As such, our commentary is not
meant to be an exhaustive review, but rather a focused discussion
dealing specifically with terminology, diagnosis, and treatment of this
condition.
Our clinical commentary on IPF is timely because recent epidemiologic
data suggest that IPF may be more common than originally suspected. For
instance, Coultas and colleagues,1
studied all diagnoses
of interstitial lung disease (ILD) from 1988 to 1990 in a population of
almost 500,000 in Bernadillo County, NM. In that study, IPF was the
most common form of ILD, accounting for 39% of all ILD cases. Of note,
only a minority of such diagnoses were proven by open lung biopsy
specimens, and this may contribute to the relatively high prevalence,
compared to previous estimates. At any rate, among male subjects, the
prevalence of IPF was 30.3/100,000 and the incidence was
27.5/100,000/yr. Rates among female subjects were approximately half
that of male subjects, with a prevalence and incidence of 14.6/100,000
and 11.5/100,000/yr, respectively. IPF rates increased with advancing
age, such that for those > 75 years old, the prevalence was
250/100,000, with an incidence of 160/100,000/yr. Another limitation of
the study by Coultas and colleagues1
is that, compared to
the general population of North America, the disproportionate
representations of African Americans (reduced) and Hispanics
(increased) in New Mexico may have partly accounted for the increased
rates of IPF relative to other forms of ILD such as sarcoidosis.
Nevertheless, the results suggest that IPF is indeed a clinical entity
of considerable impact. Along those same lines, Mannino and
coworkers2
have observed that in the United States,
disease-related mortality for IPF increased from 1979 to 1991. Again,
although increased awareness and, perhaps, misdiagnoses may have
contributed to this observation, the work of Mannino and
coworkers2
underscores how little progress has been made
in the treatment of this complex disorder.
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What Is IPF?
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Diagnostic uncertainties created in part by the multiple
different ways in which physicians have approached IPF (ie,
the availability of appropriate lung biopsy specimens and accurate
medical histories) and the variability in the natural history and
response to therapy of IPF have contributed to the confusion inherent
in this topic. Historically, IPF (or cryptogenic fibrosing alveolitis,
as it has been known in Europe) was originally presumed to be a single
clinical entity distinguished by a constellation of symptoms and signs
that include cough, dyspnea, and inspiratory rales on physical
examination; evidence of restrictive physiology with reduced diffusion
capacity for carbon monoxide and abnormal gas exchange; and the
appearance of diffuse interstitial infiltrates on chest imaging.
Unfortunately, there is nothing specific about this
clinical-radiographic syndrome that would distinguish an idiopathic
form of pulmonary fibrosis from other forms of ILD (eg,
asbestosis, collagen vascular disease-associated lung disease, chronic
hypersensitivity pneumonitis, bronchiolitis obliterans and organizing
pneumonia), for which we may have more specific information about
etiology, pathogenesis, and course of the illness. It is critical then
to remember that, when reviewing and integrating the medical
literature, some confusion is likely to be generated by many of the
early clinical studies of IPF because of the inclusion of patients with
ILD secondary to other illnesses (eg, collagen vascular
disease), in which the clinical course has been demonstrated more
recently to be more benign than that of IPF. Furthermore, it should be
recognized that in patients in whom other causes of ILD have been
carefully considered and discarded, histologic analysis of their lungs
may still reveal several patterns that differ in the distribution,
intensity, and nature of their fibrosis and inflammation.
Liebow3
was the first to classify these patterns of
idiopathic interstitial pneumonias based on morphologic criteria.
Katzenstein and Myers4
revised this scheme and
described the following four major histologic patterns of idiopathic
interstitial pneumonia: usual interstitial pneumonitis (UIP),
desquamative interstitial pneumonitis (DIP), acute interstitial
pneumonitis (AIP), and nonspecific interstitial pneumonitis (NSIP;
Table 1
). Of these four patterns, UIP appears to be the most common, followed
by NSIP, DIP, and AIP.5
The existence of these different
histologic subsets is perhaps what best explains the variable clinical
manifestations of the clinical-radiographic syndrome of IPF (see
below). Accordingly, the clinical diagnosis of idiopathic interstitial
pneumonia without an open lung biopsy specimen may include any of these
histologic patterns, with a probability that is determined by the
prevalence of each condition (Table 1)
. However, the firm
diagnosis of IPF should be reserved only for the idiopathic
interstitial pneumonia that has been classified as UIP by histology or
other means (see below).
|
Is Histology Necessary in All Patients Suspected of Having IPF?
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One of the most difficult decisions in the evaluation of a patient
suspected of suffering from IPF is whether a lung biopsy should be
performed to confirm the diagnosis.6
Our short answer is
that histologic confirmation is not necessary in every single patient
with suspected IPF, but that it is desirable to have histologic
confirmation whenever possible. However, this is a very complicated
decision that needs to incorporate factors such as the desire for
diagnostic and prognostic certainty, both from the patient’s and the
physician’s perspective; the overall health status and age of the
patient, as these relate to possible complications and expected
outcomes; the availability of surgical and pathology expertise that
would minimize complications and maximize the usefulness of the biopsy,
respectively; and the disposition of the patient to adhere to the
available therapeutic regimens after considering the prognosis and
other issues, like side effects and quality of life.
Those who strongly advocate for histologic confirmation have done so
based on the assumption that, under most circumstances, it provides
clinically useful information about prognosis that can affect patient
management. This assumption is for the most part supported by the
literature. The review by Carrington and colleagues7
was
one of the first to clearly demonstrate the differences in prognosis
and survival of separate histologic diagnoses in a group of patients
suspected of having IPF. They evaluated mortality and response to
therapy in 53 patients with UIP, compared to 40 patients with DIP.
After an observation period of 24 years, they found that those with UIP
had a 66% mortality rate, as opposed to a 27.5% mortality rate in
patients with DIP. More recently, Katzenstein and Myers4
evaluated all such trials that have adequate histologic data, and have
defined those clinical characteristics that accompany the various
histologic patterns (Table 2
). Of note, UIP is still associated with having a poor response to
corticosteroids and a high mortality rate. This is in contrast to DIP
and NSIP, which are more likely to respond to corticosteroids and have
lower mortality rates. Furthermore, DIP, AIP, and NSIP all tend to
occur in patients at a younger age than does UIP.
In addition to the qualitative methodology of Katzenstein and
Myers,4
in which an overall histologic pattern is specific
for a diagnosis, another method of relating histology to prognosis and
survival among patients with the clinical-radiographic syndrome of IPF
is the semiquantitative histologic analysis.8
9
Semiquantitative analysis utilizes a scoring system that takes into
account the extent and severity of four factors (fibrosis, cellularity,
desquamation, and granulation/connective tissue) and does not rely on
the overall pattern. Results from studies using this method have
demonstrated an improved survival and response to therapy in those
patients with greater cellularity and less fibrosis.10
11
12
13
14
15
The earliest of these studies were limited by lack of sufficient biopsy
material and the lack of standard methods of histologic analysis.
However, more recent and rigorous studies using this technique continue
to demonstrate that those with greater cellularity respond better to
corticosteroids and survive longer.7
16
17
Survival rates
related to qualitative vs semiquantitative methods of histologic
analyses have not been compared.
Regardless of the method of analysis, the available data suggest that
histologic review of lung biopsy specimens may indeed provide distinct
information regarding prognosis, survival, and response to therapy,
information that could affect management. And, because transbronchial
biopsies do not provide sufficient amount of tissue for this type of
analysis, an open or thoracoscopic lung biopsy is still the procedure
of choice for obtaining tissue from patients suspected of having IPF.
Unfortunately, open or thoracoscopic lung biopsies can be expensive and
have associated morbidity and, very rarely, mortality. Consequently,
many have searched for a less invasive means of obtaining the same type
of diagnostic and prognostic information. Among the many unsuccessful
attempts to validate less invasive diagnostic techniques, those that
have proved unreliable, impractical, or not consistent with histology
include sophisticated pulmonary function testing,16
18
19
20
BAL analysis,15
21
gallium scanning,7
and the
use of a combined clinical-radiologic-physiologic scoring
system.22
More recently, high-resolution CT (HRCT) has
shown some promise as a noninvasive test that could obviate the need
for lung biopsy in many patients suspected of suffering from IPF.
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What Is the Role of HRCT?
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Diagnostically, HRCT scanning is too nonspecific, not only for ILD
in general, but also for IPF in particular.23
24
Some
would argue that even its sensitivity is questionable. Orens and
colleagues25
prospectively found HRCT scanning to be only
88% sensitive in detecting IPF that was proven by open lung biopsy in
25 patients. The specificity of HRCT is raised only in conjunction with
clinical information, but once the ILD diagnoses that are more easily
identified on clinical grounds are eliminated from the differential,
one is left simply with a descriptive modality. Investigators have used
such descriptive findings to correlate the HRCT appearance with
pathology.26
27
Overall, these studies suggest that a
ground-glass appearance correlates with "cellular inflammation" or
"active alveolitis," whereas a reticular pattern reflects fibrosis.
Although these types of correlations seem enticing, they continue to be
challenged.28
29
For instance, Remy-Jardin and
colleagues29
retrospectively demonstrated that
ground-glass attenuation by HRCT corresponded to actual histologic
inflammation only 65% of the time, with fibrosis being the
predominating pattern seen in the biopsy specimen in the rest.
Furthermore, many studies that have attempted to correlate HRCT
appearance with histologic appearance and prognosis are biased by their
retrospective nature, usually have small number of subjects, may lack
consistent histologic diagnoses, and have variable therapy and
follow-up.30
31
A study published in 1998 by Gay and colleagues16
may have
overcome some of these limitations. They prospectively demonstrated in
38 patients with biopsy-proven IPF, all of whom were treated with 1
mg/kg/d of corticosteroids, that a patient with a pretreatment HRCT
showing an "interstitial score" 
2 had a decreased survival. An
interstitial score of 2 was defined as honeycombing involving at most
25% of the lung (Table 3
). At a mean follow-up of 34 months, 60% of patients with a score > 2
had died, compared to 15% of those patients with a score 
2. Such a
pattern predicted death with 80% sensitivity and 85% specificity, as
determined by receiver operating characteristics analysis.
Interestingly, the HRCT ground-glass score was not found to be an
independent predictor of death during follow-up, consistent with the
findings of Remy-Jardin and colleagues29
described above,
reaffirming the inaccuracy of the ground-glass appearance to correlate
with pathology.
In summary, the best literature on the use of HRCT to date suggests
that it is the predominantly fibrotic appearance, rather than the
ground-glass attenuation, that provides the most useful information
regarding prognosis. Patients with fibrosis involving > 25% of the
lungs, as determined by HRCT, have the worst prognosis and will likely
progress despite treatment.32
In these patients, an open
lung biopsy is unlikely to provide further useful information. In
contrast, in those patients with a predominantly ground-glass-appearing
HRCT, any of the four idiopathic interstitial pneumonias could be
present, suggesting that such patients could benefit the most from the
information provided by an open lung biopsy.
|
Should All Patients Suspected of Having IPF Be Treated With
Corticosteroids?
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The early reviews that evaluated response to corticosteroids found
that < 30% of patients with IPF responded to
treatment.7
11
12
13
14
33
As alluded to earlier, these trials
were limited by the small number of cases or by their lack of
consistent histologic and clinical criteria for diagnosis of
IPF.7
12
13
14
33
Hence, many of those who responded could
have been patients with ILD of secondary causes, such as
hypersensitivity pneumonitis or collagen vascular disease; therefore,
the true rate of response to steroids was probably much < 30%.
Additionally, Bjoraker and colleagues5
demonstrated that
when current histologic criteria were used to retrospectively review
open lung biopsy specimens of patients with diagnosed IPF, various
lesions other than UIP were found, including NSIP, DIP, and
bronchiolitis—histologic patterns that are associated with a better
response to corticosteroids and improved survival.
Carrington et al7
noted the relative amounts of histologic
fibrosis in all of their patients with UIP and DIP, and compared the
two groups depending on whether they were treated with high-dose
corticosteroids or untreated. Two interesting findings resulted. First,
those patients who responded to therapy, regardless of diagnosis, had
only mild to moderate amounts of fibrosis. When UIP patients in
particular were scrutinized, however, only three patients responded:
one with nitrofurantoin toxicity, another with systemic sclerosis, and
still another with polymyositis—entities that are not classified as
idiopathic interstitial pneumonitis. If these patients are excluded
from the analysis, one finds that none of the patients with UIP
responded to treatment. Second, those patients with severe amounts of
fibrosis, regardless of diagnosis, did not have improved conditions.
These findings are consistent with the observation of Gay et al
(1998),16
described above, which demonstrated the value of
a fibrotic-appearing HRCT in predicting death and lack of long-term
response to therapy in patients with UIP. Based on this information,
one would predict that patients with UIP (as determined by histology)
or a picture consistent with IPF associated with a predominant fibrotic
pattern on HRCT would not benefit from corticosteroids.
To date and to our knowledge, only three trials have ever attempted to
evaluate the treatment of UIP prospectively.34
35
36
The
first trial, by Johnson and colleagues34
in 1989, compared
the effect of prednisolone and cyclophosphamide vs prednisolone alone.
Biases and limitations of earlier reports also apply to this study.
Limited by the inclusion of patients with collagen vascular disease,
inadequate numbers of open lung biopsies, a histologic grading system
based on needle biopsies, and dissimilar baseline characteristics, this
study did not find any significant difference in survival between the
two groups. Nor was there a significant long-term response to either
treatment in those who did survive, as measured by pulmonary function
testing.
The next trial, by Raghu and colleagues35
in 1991,
evaluated the efficacy of azathioprine and prednisone vs prednisone and
placebo in 27 patients, 23 of whom had IPF diagnosed by open lung
biopsy specimens, graded only in terms of the severity of fibrosis.
This study was somewhat limited by its ill-defined histologic criteria,
since the investigators did not use either semiquantitative analysis or
the histologic subsetting proposed by Katzenstein and
Myers.4
They did, however, exclude patients with
associated collagen vascular diseases. This study also found no
significant difference in overall survival between the two groups.
Furthermore, no patient in either group experienced a significant
improvement with any treatment.
The third trial, by Douglas and colleagues36
in 1998,
evaluated the efficacy of colchicine vs prednisone in 26 patients with
UIP diagnosed by clinical criteria, supported by HRCT and/or open lung
biopsy. Prior retrospective evaluations of colchicine by the same
investigators37
38
did not show any significant advantage
over prednisone. Only one patient had an open lung biopsy. This fact,
however, is not necessarily a limitation to the study, since they based
their HRCT criteria of UIP on a predominantly fibrotic appearance. As
noted previously, a predominantly fibrotic-appearing HRCT carries the
worst prognosis, and is an independent predictor of death in these
patients.16
Likewise, biopsy-proven UIP had been shown not
to respond long-term to therapy with high-dose
corticosteroids.7
As would be expected, no difference in
survival was seen between the two groups in their prospective
evaluation. In fact, not one patient responded to either treatment.
Of note, Douglas and colleagues36
observed that
those patients receiving prednisone experienced significantly more
serious side effects than those receiving colchicine. This last finding
complements results from a preliminary report39
that
prospectively assessed adverse effects associated with corticosteroids
therapy in patients with biopsy-proven IPF. Only 1 of 16 patients
treated with high-dose corticosteroids (prednisone, 1 mg/kg/d)
experienced an improvement in clinicoradiologic physiologic
score after 4 months of treatment. However, virtually all patients were
noted to have significant side effects, including diabetes mellitus
requiring insulin therapy, avascular necrosis, corticosteroid myopathy,
insomnia, irritability, fatigue, cushingoid features, blurred vision,
depression, acne, and peptic ulcer disease. These results suggest that
the host of side effects associated with high-dose corticosteroid
therapy may cause more harm than good for many of these patients.
Furthermore, it should be emphasized that each of the trials used
prednisone as the "standard therapy," but only the last trial
evaluated prednisone against an alternate drug alone (rather than a
combination of prednisone and the alternate drug), and none compared
prednisone vs placebo. With the lack of randomized placebo-controlled
trials of corticosteroids in a population-based sample of patients with
UIP, we cannot definitively say whether corticosteroids truly have a
beneficial effect in these patients.40
None of these drugs
have shown an unequivocal advantage in survival. In fact, based on
historical data, one might even conclude that they are as effective as
no treatment at all. In view of these findings, one has to wonder why
corticosteroids remain the standard of care for patients with UIP. We
argue that indiscriminate long-term treatment with high-dose
corticosteroids (> 10 mg/d of prednisone for > 3 months) in IPF
should be discouraged, and that corticosteroids should be used mainly
when a more corticosteroid-responsive lesion (eg, DIP or
NSIP) is identified histologically. Beyond lung transplantation, which
should be considered early in those patients who are eligible, the
results of these trials indicate that there is currently no treatment
available that will unequivocally benefit patients with UIP. We suggest
that when confronted with such a patient, perhaps the most appropriate
action to take is to explain the pros and cons of available agents, in
view of the limited data, and help each patient decide what is best for
him or her.
|
Summary
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In summary, the term IPF should be reserved for the
clinical syndrome associated with the histologic pattern of UIP, the
most common of the idiopathic interstitial pneumonias. Several reviews
detail the distinguishing histologic features of these
pneumonitides.4
41
A recently published consensus
statement provides detailed recommendations about diagnosis and
management of IPF.42
We propose that when evaluating a
patient with suspected IPF, the physician must consider the risks and
benefits of histologic confirmation of the diagnosis. Figure 1
depicts a suggested algorithm for decision making regarding open lung
biopsy in patients presenting with the clinical syndrome of ILD.
Histologic confirmation should be pursued in all patients with
progressive disease who show a predominantly ground-glass appearance by
HRCT. Conversely, those immunocompetent patients with a predominantly
fibrotic-appearing HRCT and, hence, likely to have UIP, are less likely
to benefit from an open lung biopsy, since this may not provide any
additional prognostic information. Such patients have been shown not to
respond well to corticosteroid therapy. In fact, if these patients are
treated with high-dose corticosteroids indiscriminately, there are data
to suggest that not only will they not respond, but that they may also
do worse than if they had not been treated at all. Thus, by succumbing
to the argument that "no patient with IPF should be denied a trial of
corticosteroids," clinicians run the risk of doing their patients a
disservice. When appropriate, transplantation should be an early
consideration. Educating the patient regarding the risks and benefits
of treatment is paramount. Communication is of the essence when dealing
with a disease with limited therapeutic options.
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Acknowledgements
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We are indebted to Dr. Jeffrey L. Myers (Mayo
Clinic, Rochester, MN), Dr. Talmadge E. King, Jr. (University of
California at San Francisco, San Francisco, CA), and Dr. Roland H.
Ingram, Jr. (Emory University School of Medicine, Atlanta, GA) for
their helpful discussions and for their critical review of this
article.
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Footnotes
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Abbreviations: AIP = acute interstitial
pneumonitis; DIP = desquamative interstitial pneumonitis;
HRCT = high-resolution CT; ILD = interstitial lung disease;
IPF = idiopathic pulmonary fibrosis; NSIP = nonspecific
interstitial pneumonitis; UIP = usual interstitial
pneumonitis
Dr. Aguayo is recipient of a Career Investigator Award from the
American Lung Association, and Dr. Roman is recipient of an Established
Investigator Award from the American Heart Association. This work was
also supported in part by Merit Review Grants from the Department of
Veterans Affairs (S.M.A. and J.R.) and by grant NHLBI UO1-HL60263
(S.M.A.).
Received for publication March 10, 1999.
Accepted for publication March 17, 2000.
|
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TOP
Introduction
What Is IPF?
