CHEST
Original Research
INTERSTITIAL LUNG DISEASE
Acute Exacerbation of Interstitial
Pneumonia Other Than Idiopathic
Pulmonary Fibrosis*
I-Nae Park, MD; Dong Soon Kim, MD; Tae Sun Shim, MD;
Chae-Man Lim, MD; Sang Do Lee, MD; Younsuck Koh, MD;
Woo Sung Kim, MD; Won Dong Kim, MD; Se Jin Jang, MD; and
Thomas V. Colby, MD, FCCP
Backgrounds: Acute exacerbation (AE) in idiopathic pulmonary fibrosis (IPF) is increasingly
recognized as a relatively common and highly morbid clinical event. However, clinical data on AE
in non-IPF interstitial pneumonia are sparse. This study was performed to find the frequency,
clinical features, and outcome of AE in non-IPF interstitial pneumonia.
Methods: Retrospective analysis of 10 patients who satisfied the modified Akira criteria for AE
during follow-up of 74 patients with surgical lung biopsy-confirmed idiopathic nonspecific
interstitial pneumonia (I-NSIP) and 93 patients with biopsy-confirmed interstitial pneumonia
associated with collagen vascular disease (CVD-IP).
Results: AE occurred in six patients with I-NSIP (1-year frequency, 4.2%) and in four patients with
CVD-IP (rheumatoid arthritis [RA], n ⴝ 3; scleroderma, n ⴝ 1), with 1-year frequency of 3.3%.
Median age was 58 years (range, 47 to 75); six patients were female. AE occurred in two patients
immediately after surgical biopsy. Median duration of acute symptom before hospital admission
was 10 days (range, 1 to 30). Median ratio of PaO2 to the fraction of inspired oxygen (FIO2) was 172
(range, 107 to 273), and PaO2/FIO2 ratio was < 200 in six patients. Surgical lung biopsy performed
at the time of AE in two patients revealed diffuse alveolar damage superimposed on nonspecific
interstitial pneumonia pattern. Four patients with I-NSIP survived to discharge and were
followed up for 24 months (range, 6 to 121).
Conclusion: AE occurred in the patients with I-NSIP with apparently better prognosis. In patients
with CVD-IP, AE occurred mostly with RA-usual interstitial pneumonia in our small series with
poor outcome.
(CHEST 2007; 132:214 –220)
Key words: acute exacerbation; collagen vascular disease; idiopathic nonspecific interstitial pneumonia; surgical lung
biopsy
Abbreviations: AE ⫽ acute exacerbation; CVD ⫽ collagen vascular disease; CVD-IP ⫽ interstitial pneumonia related
to collagen vascular disease; DAD ⫽ diffuse alveolar damage; Fio2 ⫽ fraction of inspired oxygen; HRCT ⫽ highresolution CT; I-NSIP ⫽ idiopathic nonspecific interstitial pneumonia; IPF ⫽ idiopathic pulmonary fibrosis;
NSIP ⫽ nonspecific interstitial pneumonia; RA ⫽ rheumatoid arthritis; UIP ⫽ usual interstitial pneumonia
idiopathic pulmonary fibrosis (IPF) has
A lthough
typically an insidious, slowly progressive clinical
course, acute exacerbation (AE) is increasingly recognized as a relatively common and highly morbid
clinical event in patients with IPF.1– 8 From autopsy
findings, diffuse alveolar damage (DAD) superimposed on chronic fibrotic lung, a histologic pattern of
AEs, was found in some patients with not only IPF
but also interstitial pneumonia related to collagen
vascular disease (CVD-IP), and on a histologic back214
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ground of both usual interstitial pneumonia (UIP)
and fibrotic nonspecific interstitial pneumonia
(NSIP).9 However, detailed clinical data are not
available, and DAD at autopsy findings may be
complicated with preterminal acute events. Acute
interstitial pneumonia with DAD pattern could occur in patients with collagen vascular disease (CVD)
including polymyositis/dermatomyositis, rheumatoid
arthritis (RA), scleroderma, and systemic lupus erythematosus; however, most of them were the initial
Original Research
presentation of CVD-IP rather than AE of preexisting interstitial pneumonia.9 –17 Recently Parambil et
al18 reviewed nine patients with DAD pattern on
surgical lung biopsy of the patients with CVD, and
six of them had preexisting lung diseases. These
reports suggest that AE can occur in non-IPF interstitial pneumonia; however, there is no more clinical
information on this condition. Therefore, we performed this study to estimate the frequency of AE in
non-IPF interstitial pneumonia, especially surgical
lung biopsy-confirmed idiopathic-NSIP (I-NSIP)
and surgical biopsy-proven CVD-IP in our cohorts,
and to analyze clinical, radiologic, and pathologic
features, and outcome.
Materials and Methods
Diagnostic Criteria
For the diagnosis of I-NSIP and the individual pattern of
interstitial pneumonia, we used the American Thoracic Society/
European Respiratory Society consensus classification, and individual CVDs were diagnosed according to the criteria of each
society.19 –25 For the diagnosis of AE, we used the Akira criteria7:
(1) subjective worsening of dyspnea within the last 1 month; (2)
new ground-glass opacities or consolidation on chest radiograph
or high-resolution CT (HRCT); (3) hypoxemia with decline ⱖ 10
mm Hg in Pao2 from the previous level; (4) no evidence of
infection by negative respiratory culture and serologic test results
for respiratory pathogens; and (5) no clinical evidence of pulmonary embolism, congestive heart failure, or pneumothorax as a
cause of acute worsening. However, two of the subjects did not
have Pao2 data prior to AE because they first presented at the
time of AE, and their surgical lung biopsy performed at that time
showed DAD superimposed on NSIP pattern. For these patients,
we used the criteria of acute lung injury (Pao2/fraction of inspired
oxygen ratio [Fio2] ⬍ 300) in these patients.26
Subjects
From 1993 to April 2006, I-NSIP was diagnosed in 74 patients
and CVD-IP was diagnosed in 93 patients by surgical lung biopsy
*From the Division of Pulmonary and Critical Care Medicine
(Drs. Park, D.S. Kim, Shim, Lim, Lee, Koh, W.S. Kim, and
W.D. Kim) and Department of Pathology (Dr. Jang), College of
Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; and Department of Pathology
(Dr. Colby), Mayo Clinic, Scottsdale, AZ.
This work was performed in the Division of Pulmonary and
Critical Care Medicine, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center.
All of the authors contributed substantially to this work and are
all responsible for the content of the article. The authors have no
conflicts of interest in association with this article to disclose.
Manuscript received February 7, 2007; revision accepted March
9, 2007.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Dong Soon Kim, MD, Division of Pulmonary
and Critical Care Medicine, University of Ulsan College of
Medicine, Asan Medical Center, 388 –1 Pungnap-2dong, Songpagu, Seoul 138 –736, Korea; e-mail: [email protected]
DOI: 10.1378/chest.07-0323
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at Asan Medical Center, Korea, and all of them were included in
the study. Most of the subjects were included in previous
articles.27–29 Among these patients, AE was diagnosed in six
patients with I-NSIP and four patients with CVD-IP.
All clinical and laboratory data were collected retrospectively
from medical records. Spirometry (Vmax22; Sensormedics; Yorba
Linda, CA), lung volumes by plethysmography (6200 Plethysmograph; Sensormedics), and diffusion capacity of the lung for
carbon monoxide (Vmax229D; Sensormedics) were measured,
and the results are expressed as a percentage of normal predicted
values.30 HRCT was performed (HiSpeed Advantage Scanner;
GE Medical Systems; Milwaukee, WI; or Somatom Plus 4;
Siemens Medical Systems; Erlangen, Germany). BAL was performed as previously described.31 Biopsy slides were reviewed
independently by at least two pathologists and reclassified according to the American Thoracic Society/European Respiratory
Society consensus classification of interstitial pneumonia as described in detail in previous report.29 Data are expressed as
median (range). The frequency of AE was obtained from the
Kaplan-Meier survival curve by censoring AE as the “death
variable.” This study was approved by the Institutional Review
Board of Asan Medical Center.
Results
Frequency of AE
Among 74 patients with surgical lung biopsyconfirmed fibrotic I-NSIP, the estimated 1-year
frequency of AE was 4.2%. The estimated 1-year
frequency in surgical lung biopsy-confirmed
CVD-IP (n ⫽ 93) was 3.3% (Fig 1); however, it was
5.6% among the patients with CVD-UIP (n ⫽ 36)
and 11.1% in RA-UIP (n ⫽ 18).
Demographic and Clinical Features
Demographic and clinical characteristics are
shown in Table 1. Median age at the time of AE was
58 years (range, 47 to 75); six patients (60%) were
female. Two patients (I-NSIP, n ⫽ 1;CVD-NSIP,
n ⫽ 1) had AE after surgical lung biopsy (1 day and
11 days, respectively). In the remaining eight patients, the time between the diagnosis of interstitial
pneumonia and the onset of the AE ranged from 2 to
54 months (Fig 1).
Surgical lung biopsy was performed at the time of
AE in two patients with I-NSIP. One patient had
been followed up for 4 years due to abnormal chest
imaging results (interstitial pneumonia pattern) without respiratory symptom or lung function abnormality, and sudden dyspnea developed 3 days prior to
hospital admission. The other patient had dyspnea
and diffuse parenchymal infiltration on chest radiography 7 months prior to hospital admission, and
corticosteroid therapy was administered at other
hospital from 6 weeks before the admission for 1
month. However, 10 days after the discontinuation
of steroid treatment, the dyspnea worsened acutely
and the patient was transferred to our hospital.
CHEST / 132 / 1 / JULY, 2007
215
Figure 1. The 1-year frequency of AE among all the patients with biopsy-proven I-NSIP (n ⫽ 74) and
CVD-IP (n ⫽ 93) at Asan Medical Center.
All subjects presented with rapid worsening of
respiratory symptoms including dyspnea (Medical
Research Council grade 4 –5), cough, and whitish
sputum for median duration of 10 days (range, 1 to
30). Five patients had fever. Inspiratory crackles
were present in all cases. None of the patients had
clinical evidence of heart disease, pneumothorax, or
pulmonary embolism.
Among 10 patients with AE, AE developed in 6
patients during a course of corticosteroid with or
without immunosuppressive therapy (cyclophospha-
mide, n ⫽ 3; azathioprine, n ⫽ 1). The median dose
of prednisolone was 35 mg/d (range, 20 to 40), and
four of the patients (CVD-IP, n ⫽ 3; and I-NSIP,
n ⫽ 1) were undergoing tapering from an initial high
dose of prednisolone. One patient was receiving
home oxygen therapy.
Laboratory and BAL Findings
At the time of AE, all subjects were hypoxemic.
The median ratio of Pao2/Fio2 was 172 (range, 107
Table 1—Clinical Data of 10 Patients With I-NSIP and CVD-IP*
Underlying Disease
I-NSIP
I-NSIP
I-NSIP
I-NSIP
I-NSIP
I-NSIP
RA-UIP
RA-UIP
RA-UIP
Scleroderma
Age, yr/Sex
Smoking
Status
Duration of
Interstitial Pneumonia
Before AE, mo
Pathologic
Pattern
Outcome
57/Male
75/Female
56/Female
51/Female
63/Female
58/Female
68/Male
65/Male
51/Female
47/Male
Never
Never
Never
Past
Never
Never
Current
Past
Never
Never
11 d after SLB
54
3
51
48 (SLB at the time of AE)
7 (SLB at the time of AE)
3
2
39
Next day after SLB
NSIP
NSIP
NSIP
NSIP
NSIP (plus DAD)
NSIP (plus DAD)
UIP
UIP
UIP
NSIP
Died
Died
Survived
Survived
Survived
Survived
Died
Died
Died
Died
*SLB ⫽ surgical lung biopsy.
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Original Research
to 273). Six of 10 patients met the criteria for ARDS
including Pao2/Fio2 ratio ⬍ 200. Six patients presented an increased WBC count, and elevated values
of erythrocyte sedimentation rate or C-reactive protein were found in nine patients. BAL was performed in seven patients at time of AE (Table 2).
Microbiological studies including stains for acid-fast
bacilli and Pneumocystis carinii; cultures for bacteria, mycobacteria, fungus, and virus; and serologic
tests to identify infectious pathogen were performed
on BAL fluid (n ⫽ 7) as well as blood (n ⫽ 10),
sputum (n ⫽ 10), urine (n ⫽ 9), bronchial washing
(n ⫽ 7), and tracheal secretions (n ⫽ 4); and the
results were all negative. The lung tissues (n ⫽ 4)
obtained by surgical lung biopsy were also cultured,
and nothing was found.
Radiologic Features
On chest radiography, all patients displayed newly
developed diffuse bilateral ground-glass opacity
with/without consolidation at time of AE, superimposed on underlying chronic fibrotic changes. The
HRCT films at time of AE were available in eight
patients because two patients were rapidly deteriorating and intubated before undergoing HRCT. The
distribution pattern of new ground-glass opacity was
peripheral in three patients, multifocal in three
patients, and diffuse in two patients (Fig 2).
Pulmonary Function Data
Pulmonary function data prior to AE were available in nine patients. Eight patients had a restrictive
ventilatory defect with a median FVC of 52% of
predicted (range, 34 to 69%), diffusion capacity of
the lung for carbon monoxide of 47% (range, 19 to
59%), and total lung capacity of 61% (range, 39 to
101%). The remaining one patient had normal pulmonary function test results in spite of abnormal
HRCT findings. At the time of AE, only four patients
were able to perform spirometry with a median
decline of FVC of 23% of predicted (range, 15 to
59%).
Table 2—Laboratory Findings at the Time of AE*
Variables
I-NSIP
(n ⫽ 6)
9,500 (4,000–18,800)
WBC, 103/␮L
C-reactive protein, mg/dL
6.9 (0.5–9.6)
Pao2/Fio2
199 (107–273)
BAL findings, %
Macrophages
44.0 (33.0–84.6)
Lymphocytes
44.0 (9.1–66.0)
Neutrophils
6.3 (1.0–12.0)
Eosinophils
0
CVD-IP
(n ⫽ 4)
13,000 (5,900–17,100)
4.8 (2.7–6.9)
146 (121–254)
42.5 (20.9–64.3)
5.9 (4.8–7.0)
51.7 (29.0–74.3)
0
*Data are presented as median (range).
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Pathology Findings
Eight patients had undergone surgical lung biopsy
prior to AE, and AE developed in two of them
immediately after biopsy. The pathologic consensus
diagnosis for these eight patients was NSIP in five
patients (I-NSIP, n ⫽ 4; CVD, n ⫽ 1) and UIP in all
three patients with CVD-RA without acute lung
injury features. The remaining two patients (all with
I-NSIP) underwent surgical lung biopsy at the time
of AE, and both patients showed DAD pattern
(hyaline membrane and organizing DAD without
hyaline membrane, respectively) superimposed on
NSIP pattern (Fig 3).
Treatment and Outcome
Nine patients were treated with broad-spectrum
antibiotics and high-dose systemic corticosteroid
therapy: six patients received IV pulse therapy
(methylprednisolone, 250 mg to 1 g/d for 3 days),
and three patients received 1 mg/kg/d of prednisolone. One patient was treated with broad-spectrum antibiotics with a maintenance dose of methylprednisolone (15 mg/d). Six patients received
mechanical ventilation, and all six died from progressive disease combined with (n ⫽ 2) or without
(n ⫽ 4) ventilator-associated pneumonia after a median of 26 days (range, 11 to 41). Four patients
survived to discharge from the hospital, and the
median duration of follow-up was 24 months (range,
6 to 121). All of survivors had idiopathic NSIP,
whereas all of patients with CVD-IP died.
Discussion
Our experience showed that AE occurred in the
patients with I-NSIP and CVD-IP. The estimated
1-year frequency of AE in our series was 4.2% in
surgical lung biopsy-confirmed I-NSIP, 3.3% in
CVD-IP, 5.6% in surgical biopsy-proven CVD-UIP,
and 11.1% in RA-UIP. The clinical, radiologic, and
pathologic features of our patients were similar to
that of IPF. The exact frequency of AE in IPF is not
known, and the reported numbers vary widely because of the difference in study design, and also due
to the different case definitions.1,32,33 In our previous
report3 on a large cohort of patients with surgical
lung biopsy-confirmed IPF/UIP during the same
period of this study using Akira criteria, the 1-year
frequency of AE was 15.4%. The frequency in our
patients with surgical lung biopsy-confirmed I-NSIP
seems to be lower than that of IPF/UIP. However,
the frequency of AE in our patients with surgical
lung biopsy-confirmed CVD-UIP, especially in RAUIP, may not be lower than that of IPF/UIP.
CHEST / 132 / 1 / JULY, 2007
217
Figure 2. HRCT findings before and at the time of AE in a 63-year-old woman with I-NSIP and AE
showing multifocal patchy type. An initial HRCT (top left, A, and top right, B) shows the minimal
reticular opacity in the subpleural area of the lung. In follow-up HRCT after 16 months (bottom left,
C, and bottom right, D), ground-glass opacities of multifocal patchy distribution have developed in both
lungs.
The etiology of AE in most of the patients in this
study was unknown as in IPF, except for two patients
with AE immediately after surgical lung biopsy. In
IPF, occurrence of AE after the surgical lung biopsy
has been reported before3; Kondoh et al34 observed
that postbiopsy exacerbation occurred in 2.1% of 236
consecutive patients undergoing surgical biopsy for
diffuse lung disease. The finding of our study34
shows that the surgical lung biopsy can induce or
aggravate the rapid worsening of respiratory conditions in patients with idiopathic NSIP as well as
IPF/UIP. RA was the most common underlying
disease among patients with CVD-UIP in our study,
and three of four patients with AE in CVD-IP had
RA. At the time of presentation, they were receiving
oral prednisone with or without a cytotoxic agent;
however, none of these patients was being treated
with lefunomide or methotrexate, which has been
associated with drug-induced lung disease.35–37 Concerning the relationship of activity of CVD with AE,
at the time of surgical biopsy our patients had active
RA. However, at the time of AE, the activity of RA
was stable, suggesting that the activity of CVD may
not be related to the occurrence of AE in our
patients.
The clinical features of our patients were similar to
that of AE in IPF, except slightly younger age and
nonsmoking female predominance in our series,
which may be related to the female and nonsmoker
predominance of the whole group of I-NSIP and
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CVD-IP compared to IPF. Because some of the
subjects did not have arterial blood gas analysis
before the AE, in those patients we used the criteria
of acute lung injury: Pao2/Fio2 ratio ⬍ 300.26 However, Pao2/Fio2 ratio was ⬍ 200 in most of the
patients. All of our patients had newly developed
ground-glass opacities/consolidations in both lungs
on chest radiography and on HRCT, except two
patients who could not tolerate HRCT. The distribution pattern of newly developed ground-glass
opacity or consolidation on HRCT was the same as
AE of IPF: peripheral, multifocal, and diffuse pattern.3,7 Several studies3,4,6 have showed that neutrophils were predominant in BAL fluid of the patients
with AE in IPF. Our patients with CVD-UIP had
similar findings. However, in our AE patients with
I-NSIP, lymphocytes were predominant cell type in
BAL fluid. The reason for this discrepancy is not
known. One possibility is that AE may be just an
exaggerated response of underlying disease process
because many patients with stable NSIP have an
increased number of lymphocytes in BAL fluid.38,39
However, the number of patients in our study is too
small to draw any conclusion.
Because 60% of the patients were receiving steroid therapy at the time of AE, infection, particularly
opportunistic infection, was the most important differential diagnosis; and an extensive workup including BAL studies with exhaustive microbiological tests
was performed with negative results. The pathologic
Original Research
AE was done in only two patients with NSIP;
however, AE is a clinically defined entity rather than
pathologic phenomenon.
In summary, in spite of small number of the
patients, we demonstrated that AE occurred in the
patients with surgical lung biopsy-confirmed I-NSIP
with apparently better prognosis than that of IPF/
UIP. AE occurred also in patients with CVD-IP,
mostly in RA-UIP in our small series with poor
outcome. Further study is required to identify etiology, risk factors, prognostic markers, and effective
treatments.
References
Figure 3. Pathology findings at the time of AE in a 63-year-old
woman undergoing surgical lung biopsy at the time of AE. Top,
A: Typical background pattern of fibrotic NSIP (hematoxylineosin, original ⫻ 200). Bottom, B: The other area of the same
patient shows acute lung injury features manifesting as DAD
pattern with fibrinous exudates (arrows) and inflammatory cell
infiltration in the airspaces (hematoxylin-eosin, original ⫻ 400).
features of two of our patients were almost identical
with that of IPF, except the underlying chronic
disease was NSIP pattern. The outcome of AE in
idiopathic NSIP in this small series seems to be
better than that of IPF, whereas all four of our
patients with AE in CVD-IP died. Actually, the
survival rate of our patients with AE in CVD-IP was
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et al18 reported that in patients with DAD and CVD,
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preexisting chronic CVD-IP compared to those without. Similar to AE of IPF, steroid and/or immunosuppressant agents had little benefit for our patients.
The limitation of our study is that the number of
the subjects was too small for proper evaluation of
the risk factors, prognosis, treatment effect, or prognostic factors. Another limitation is our study was
restricted to surgical lung biopsy-proven cases. However, the confirmation of NSIP requires surgical
biopsy; therefore, it is an inevitable limitation. The
other limitation is that the pathologic confirmation of
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