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334
J. Kim and T. J. Harkin
p
Table 2. (Continued )
Disease Specific Clinical
Features and Summary Radiographic Spectrum Potential Clinical Potential Laboratory
Potential Etiology of Diagnostic Criteria in the Lung Testing Data
lymphangioleiomyoma, or and melanocytic
lymphnode involved by LAM, differentiation, which
and definite or probable tuberous are useful diagnosically
sclerosis complex
Heightened suspicion
Young female with recurrent Thoracocentesis of pleural
pneumothorax or chylous effusion with triglyceride
effusion levels
Pulmonary Young smoker Reticular changes, Lung biopsy: stellate
langerhans micronodules nodules with
cell histiocytosis measuring 2–5 mm, Langerhans cells
(LCH) and diffuse cysts and cysts
measuring up to 1 cm Langerhans cells staining
immunopositive for
CD1a, Langerin,
E-cadherin, and S100
Birbeck granules by
electromicroscopy
335
Evaluation and Treatment of Diffuse Parenchymal Lung Disease
Fig. 3. Radiographic features and extra-pulmonary signs of possible sarcoidosis:
(A) Waxy interscapular skin plaques; (B) lupus pernio; (C) anterior uveitis with synechiae;
(D) enlarged, nodular lacrimal gland; (E) endobronchial cobblestoning; (F) ipsilateral
peripheral facial-nerve and cranial-nerve involvement with hearing loss; (G) spinal cord
mass on a T1-weighted MRI scan (arrow); (H) gallium scan demonstrating nasal, parotid,
lung, liver, spleen, subcutaneous-nodule, and mediastinal and epitrochlear lymph-node
involvement; (I) PET scan demonstrating hypermetabolism in the liver, spleen, and lymph
nodes; (J) a right upper lobe cavity with a gravity-dependent aspergilloma; (K) abdominal
CT scan demonstrating hypodense splenic nodules; (L) involvement of the optic chiasm
seen on a gadolinium-enhanced MRI scan (arrow); (M) T1-weighted MRI scan demonstrating granulomatous involvement of the humerus. (From Reg. 18.)
336
J. Kim and T. J. Harkin
lung biopsy24(see Table 3 and Fig. 6). IPF patients must be considered for
early referral for lung transplantation, because there is no effective treatment and there is a very high risk of death from respiratory failure (mean
survival of about three years).
1,2,26
In addition, they are at risk of presenting with acute exacerbations of IPF, defined as acute, clinically significant
respiratory deteriorations of unidentifiable cause that are associated with
very high inpatient mortality.
25,27
Some DPLDs are also associated with smoking (e.g. IPF, RBILD,
DIP, LCH) or have familial clustering (e.g. IPF, sarcoidosis, Hermansky–
Pudlak syndrome), which should be addressed in the history.
Fig. 4. Lymphangioleiomyomatosis (LAM): A young woman with recurrent pneumoth-
orax, initially diagnosed with emphysema. Chest CT revealed diffuse thin-walled cysts.
She was diagnosed with LAM via surgical lung biopsy. Histopathology: thin-walled cysts
and nodules of LAM cells which stain for melanocyte marker HMB-45.
337
Evaluation and Treatment of Diffuse Parenchymal Lung Disease
Lastly, it is important to note that other respiratory illnesses may share
radiographic and pathologic features of DPLDs and should be excluded
by history at the outset. Most DPLDs have a chronic course, with the
exception of patients with acute interstitial pneumonia (AIP) who
progress rapidly to respiratory failure in a matter of weeks or patients with
IPF presenting with acute IPF exacerbation. Acute and subacute respiratory symptoms with diffuse chest radiographic findings can be caused by
viral pneumonia, opportunistic infections (e.g. pneumocystis or CMV in
an immunocompromised host), adult respiratory distress syndrome
(ARDS), heart failure, transfusion-related acute lung injury, or diffuse
alveolar hemorrhage. These should be expeditiously worked up and eliminated prior to considering a DPLD.
Fig. 5. Pulmonary Langerhans cell histiocytosis (LCH): A 39-year-old female referred for
lung transplantation for progressive DPLD. Chest CT showed innumerable small cystic
structures, reticular lines, coarsened interstitial markings, and diffusely scattered micronodules
typical of LCH. Stellate lung nodules with Langerhans cells were found in her explanted lungs.
338
J. Kim and T. J. Harkin
Clinical Exam
A complete physical exam should be performed to seek classic findings
for ILD, including dry crackles, evidence of pulmonary hypertension and
cor pulmonale, and digital clubbing, but also to obtain subtle findings that
may suggest associated systemic diseases (see Fig. 7).
Radiologic Evaluation
High-resolution chest CT (HRCT) with thin sections of 0.5–2.0 mm
thickness with edge enhancement is the radiologic modality of choice for
the evaluation of the pulmonary interstitium. It is frequently useful to also
obtain images at end expiration and with prone positioning. Various terms
are used by radiologists to describe radiographic findings on HRCTs (see
Table 4).
28
The predominant pattern and distribution of these findings, and
the presence of esophageal disease, lymphadenopathy, pleural/pericardial
Table 3. ATS/ER Criteria for the Diagnosis of Idiopathic Pulmonary Fibrosis in the
Absence of Surgical Lung Biopsy: the “Radiologic Diagnosis” of IPF
Major Criteria (all four Exclusion of other known causes of ILD, such as drug
need to be present) toxicities, environmental exposures, and connective
tissue diseases
Abnormal pulmonary function studies that include
evidence of restriction (reduced VC, often with an
increased FEV1/FVC ratio) and impaired gas
exchange (decreased PaO
2
, increased A-a gradient
with rest or exercise, or decreased DLCO)
Bibasilar reticular abnormalities with minimal ground
glass opacities on HRCT scan
Transbronchial lung biopsy or BAL showing no features
to support an alternative diagnosis
Minor Criteria (at least 3 Age >50 years
of 4 are needed) Insidious onset of otherwise unexplained
dyspnea on exertion
Duration of illness >3 mth
Bibasiliar, inspiratory crackles (dry or
Velcro type)
339
Evaluation and Treatment of Diffuse Parenchymal Lung Disease
Fig. 6. Idiopathic Pulmonary Fibrosis (IPF). A 67-year-old male ex-smoker with IPF.
Chest CT typical for advanced IPF/UIP: traction bronchiectasis (thin arrow), peripheral
honeycombing (thick arrow), and subreticular lines, enlarged pulmonary artery suggestive
of pulmonary hypertension (arrowhead). (B, C): Typical histopathology changes in
IPF/UIP include heterogeneous appearance of lung tissue with alternating areas of normal
lung (arrow head), honeycombing ( black arrow) interstitial inflammation, and fibroblast
foci (yellow arrow). (Pathology courtesy of Kevin Leslie, MD.)
(A)
(B) (C)
340
J. Kim and T. J. Harkin
Fig. 7. Possible clinical manifestations of interstitial lung disease (borrowed from
Dempsey et al.).
disease, or pulmonary artery enlargement can be helpful in the radiographic identification of different DPLDs.
HRCT also helps determine the need for a surgical lung biopsy (see
Fig. 8). After known causes of DPLDs are ruled out, an HRCT that
strongly suggests IPF does not necessarily require a lung biopsy in the
right clinical context.
Pulmonary Function Testing, Echocardiography, Laboratory Data and Ancillary Testing
Baseline pulmonary function tests must be performed in DPLD to evaluate the presence of obstructive and restrictive dysfunction, and repeated to
follow effects of therapeutic interventions. Spirometry with pre- and postbronchodilator testing, lung volumes, and diffusion capacity (DLCO)
should be specifically requested. A very low DLCO is generally a sign
341
Evaluation and Treatment of Diffuse Parenchymal Lung Disease
Table 4. Terminology Frequently Used in Chest CT Radiology
28
Consolidation An increase in lung density that obscures underlying
vessels. This indicates alveolar collapse or
replacement of alveolar air with fluid or cells.
Air bronchograms can be seen amidst the
consolidated lung.
Ground glass A hazy increase in lung density that does not obscure
underlying vessels and is nonspecific. This can
represent partial collapse or partial filling of
alveoli, interstitial inflammation, increased
capillary blood volume, or a combination of these.
It can be nodular, focal/patchy, or diffuse.
Mosaic perfusion Geographic differences in lung attenuation associated
with air trapping or oligemia. This is not to be
confused with ground glass opacity.
Traction bronchiectasis Bronchial dilatation and bronchial irregularity in
patients with pulmonary fibrosis. The traction
of fibrotic lung tissue pulls on the bronchial walls.
Bronchiectasis Bronchial dilatation. This is defined as a bronchial
diameter greater than the diameter of the
neighboring pulmonary arterial branch.
Interlobular septal Abnormal thickening of interlobular septae,
thickening surrounding the secondary pulmonary lobule with
fibrosis, edema, or cell infiltration.
Intralobular septal Fine, meshlike reticulation within the secondary
thickening or intralobular pulmonary lobule. This can be an early sign of
lines fibrosis or lung infiltration.
Macrocysts Cysts greater than 1 cm.
Microcysts Cysts less than 1 cm.
Honeycombing (Fig. 6A) Cystic airspaces with clearly defined
fibrous walls. This results from, or is associated
with, pulmonary fibrosis and loss of lung
architecture.
Subpleural lines / reticulation Thin opacity close to the pleural surface, usually
paralleling the pleurae. This can represent
atelectasis or fibrosis in the nondependent lung.
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J. Kim and T. J. Harkin
that the patient should be evaluated for oxygen supplementation therapy
both at rest and on exertion. The 6 min walk test (6MWT) is helpful in
assessing function and need for supplemental oxygen. Changes in the distance walked in 6 min and the degree of oxygen desaturation during
6MWT add prognostic information.
29
An echocardiogram can help determine the presence of pulmonary
hypertension and other concomitant cardiac factors that can contribute to
respiratory symptoms. Right heart catheterization may be required,
because echocardiography is not a sensitive or specific modality for
detecting pulmonary hypertension.
30
This information is also important
for aiding in a clinician’s decision to refer a patient with DPLD for lung
transplantation.
25
Laboratory data and other ancillary testing should be obtained based
on clinical and radiographic suspicion of disease (see Table 2).
Fig. 8. Role of HRCT in the diagnostic process.
History; Physical exam,
Radiographics; PFTS
DRUGS
Connective
Tissue
Occupation
UIP Pattern
CONSIDER
BRONCHOSCOPY
TREAT UIP
Early
Transp lant
Adapted from ATS/ERS Consensus Statement. Am J Respir Crit Care Med 2002;165:277-304.
AIP NSIP COP RBILD DIP LIP
HRCT
Atypical HRCT or
Clinical Scenario
SURGICAL LUNG BIOPSY
OTHER
Other:
LAM
EG
Eos PNA
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Evaluation and Treatment of Diffuse Parenchymal Lung Disease
Surgical Lung Biopsy
Transbronchial biopsies by bronchoscopy have a limited role in the histologic diagnosis of patients with DPLDs with the exception of sarcoidosis,
hypersensitivity pneumonitis, LCH, and lymphangitic carcinomatosis.
This is because the small amount of tissue obtained is generally insufficient for detecting the architecturally distinct histologic patterns of
DPLDs. For example, transbronchial biopsies were able to detect UIP
changes in only 9.3% of patients who went on to have confirmatory
surgical lung biopsy (SLB).
31
Although it is generally recommended that all patients with diffuse lung
diseases of unknown cause that do not meet criteria for IPF be referred for
SLBs, these are not uniformly performed due to fear of postoperative worsening of respiratory disease, and complications such as bronchopleural fistulas, hemothorax, infection, cardiovascular events, and even death (30-day
risk 5%–7%).
32,33
Preoperative risk factors for postoperative death and complications include a diagnosis of UIP, mechanical ventilation prior to the
operation, and the presence of an immunocompromised state. Preoperative
lung physiology, unfortunately, does not help predict which patients are at
higher risk for postoperative complications.
32,33
These risks have to be
weighed against the benefits of SLB. After SLB, 40%–73% of cases result
in a change in the clinical diagnosis.
32,33
It is recommended that at least two areas in separate lobes of one lung
with varying amounts of damage (area of unaffected and affected lung tissue) be sampled during SLB.
Management of DPLD
Management of DPLDs is disease-specific and generally requires the consultation of specialists familiar with these entities.
For the hospitalist, it is important to note that the mainstay of medical
treatment for DPLDs is immunomodulatory agents that have significant
side effects (e.g. leukopenia, hematuria, hyperglycemia, liver dysfunction,
accelerated atherosclerosis/CAD, and increased risk of certain cancers)