kathi

Bronchoscopy in Sarcoidosis: Diagnostic and Therapeutic Interventions
Posted 10/01/2003
Jeffrey T. Chapman, MD, Atul C. Mehta, MD
Abstract and Introduction
Abstract

Flexible bronchoscopy has revolutionized the evaluation of patients with
suspected sarcoidosis and the treatment of sarcoid patients with
significant endobronchial disease. The authors explore the diagnostic
and therapeutic utility of flexible bronchoscopy by reviewing the
pertinent literature with a special interest in recent studies.
Bronchoscopy allows multiple diagnostic modalities in suspected
sarcoidosis. Recent studies show sometimes surprising results, and the
authors review the additive contributions of transbronchial lung biopsy,
endobronchial biopsy, transbronchial needle aspiration, and
bronchoalveolar lavage to diagnose sarcoidosis. New data specifically
show the additive benefit of routine endobronchial biopsy and
transbronchial needle aspiration to traditional transbronchial biopsy
specimens. In addition, the techniques have been optimized via recent
studies and these results are discussed. Endobronchial therapy is
reviewed with the recent findings of the superiority of balloon
bronchoplasty. Flexible bronchoscopy has a very high diagnostic yield in
all stages of suspected sarcoidosis. Transbronchial lung biopsy and
endobronchial biopsy should be used routinely, and transbronchial needle
aspiration should be considered in cases of significant adenopathy.
Bronchoalveolar lavage should be used routinely to exclude alternative
diagnoses. Therapeutic bronchoscopy is rarely needed, but when necessary
the authors' procedure of choice is bronchoscopic balloon dilatation.
Introduction

Flexible bronchoscopy (FB) has revolutionized the evaluation of patients
with sarcoidosis. We explore the utility of several bronchoscopic
modalities in diagnosing sarcoidosis. FB has become an accepted
therapeutic modality in patients with significant obstruction. We also
review the indications and techniques for therapeutic bronchoscopy in
sarcoidosis.

Diagnostic Bronchoscopy in Sarcoidosis

Flexible bronchoscopy has revolutionized the evaluation of patients with
suspected sarcoidosis. Before FB, patients underwent rigid bronchoscopy,
mediastinoscopy, surgical lung biopsy, scalene node biopsy, skin biopsy,
or the Kveim-Siltzbach test (where available), or the diagnosis was
established "clinically," without tissue. Many patients were reluctant
to undergo invasive biopsies but were also hesitant to take medications
with known side effects without a secure diagnosis. Since its
introduction by Ikeda et al.[1] in 1968, FB has enabled the
pulmonologist to diagnose patients with a well-tolerated procedure. We
explore the evolution of FB in diagnosing sarcoidosis by reviewing the
pertinent literature with a special interest in recent studies.

Flexible bronchoscopy allows tissue sampling from several different
anatomic sources. We explore each modality, including transbronchial
biopsy (TBLB), endobronchial biopsy (EBB), transbronchial needle
aspiration (TBNA), and bronchoalveolar lavage (BAL). TBLB is discussed
first because it is the most widely used. We then discuss the utility of
performing EBB and TBNA. Lastly, BAL is evaluated for its diagnostic and
prognostic efficacy. Transbronchial Biopsy

Transbronchial biopsy was developed to diagnose diffuse lung diseases
soon after the fiberoptic bronchoscope became available,[2] and its
utility for diagnosing sarcoidosis was recognized early as well.[3]
Nonnecrotizing granulomas, in the absence of exposure to antigens known
to cause hypersensitivity pneumonitis or acid-fast bacilli or fungi on
special stains, is the pathologic pattern seen on TBLB.

More advanced stages of disease have a higher rate of diagnostic TBLB
(stage I, 55% versus stages II to III, 70%).[4] Somewhat surprisingly,
stage I disease can yield diagnostic granulomas on TBLB. Even patients
with normal plain chest radiographs or high-resolution chest CT, with
stage 0 disease can have parenchymal granuloma on TBLB.[5, 6]

Perhaps even more surprising, prebiopsy disease activity does not
influence diagnostic yield of TBLBs. Thus, TBLB has become the accepted
standard of care in all patients with suspected sarcoidosis despite
variances in radiographic stage and disease activity. Comparing TBLB
with more invasive diagnostic techniques is difficult, but it is equal
to scalene node biopsy in patients with stage II disease.[7]

Variations in the technique used to perform TBLB have been investigated
to determine the optimum method for diagnosing sarcoidosis. Most
important, biopsy number has been shown to affect diagnostic yield. The
probability of making a diagnosis is the same for each TBLB specimen,
thus diagnostic yield follows a logarithmic curve, increasing with each
successive specimen until a plateau is reached.[8] The plateau varies in
different studies, but most investigators think four to six specimens
are adequate for stage II disease, but more (perhaps 10) are needed for
stage I disease.[8-10] The location of each biopsy is also important,
with higher yield seen when biopsies are taken from more than one lobe
in all patients and taken from the area of most affected tissue in stage
II or stage III disease.[10] Race is also a factor, with blacks more
likely to have a positive TBLB than whites (74% versus 50%, P =
0.0038).[11]

Other determinants of biopsy yield have been investigated. Larger
forceps secure bigger specimens that have a higher diagnostic yield, but
do not lead to increased risk of bleeding or pneumothorax.[12] Specimen
pieces that float when placed in fixative are more likely to contain
alveolar tissue and have a higher diagnostic yield than pieces that
sink, and are unlikely to contain alveoli.[13] However, pieces that
contain only bronchial wall may still contain granuloma and should not
be discarded. Endobronchial Biopsy

Sarcoid granulomas can involve any aspect of the respiratory tract.
Being aware of mucosal abnormalities can lead to a correct diagnosis,
such as when Mariotta et al.[14] confirmed sarcoidosis by sampling a
patient's abnormal arytenoids during bronchoscopy.

In unusual cases the endobronchial mucosa is markedly abnormal, such as
in Figure 1, and EBB is performed by most bronchoscopists. However, in
many instances the respiratory mucosa appears normal, but EBB may be
diagnostic in these cases as well. Several case series using rigid
bronchoscopy demonstrate positive biopsies in 24% to 44% of
patients.[15-17] Introduction of FB opened this diagnostic modality to
nonsurgeons.


Figure 1. (click image to zoom) Severe endobronchial sarcoidosis that
demonstrated granuloma on biopsy

The utility of EBB has been reported in several studies. Armstrong et
al.[18] published a case series report describing 101 patients. Most of
their patients had abnormal mucosa, with either mucosal nodularity (64%)
and/or bronchostenosis (26%). This led to a very high diagnostic yield
of 58% for stage I, 62% for stage II, and 46% for stage III. Yield was
highest in those with abnormal mucosa (91%) compared with normal mucosa
(37%). Another series of consecutive patients reported in 1999 that half
of patients with stage I or stage II disease had mucosal abnormalities,
whereas those with stage III disease had higher rates of abnormal mucosa
at 83%.[19] As would be expected in this patient population, EBB had a
high diagnostic yield of 49% in all patients and increased the
diagnostic yield of TBLB alone from 52 to 64% when both types of
biopsies were used.

A recent case series of consecutive patients reported diagnostic utility
in a setting of less frequent mucosal abnormalities.[20] Abnormal mucosa
was seen in only one third of patients, but EBB was still useful, being
positive in 54% of patients with abnormal mucosa and 20% of patients
with normal mucosa. EBB increased the diagnostic yield of TBLB by 10%,
from 76 to 86% for the combined procedures.

The Walter Reed Army Medical Center recently reported a prospective
study attempting to define the benefit of adding EBB to TBLB in routine
clinical practice.[21] A total of 34 patients were enrolled and
underwent TBLB, EBB, and mediastinoscopy, if needed. Mucosal erythema or
thickening was seen in 70% of patients and was associated with a higher
frequency of positive biopsy than normal mucosa (75% versus 30%). The
likelihood ratio of a positive biopsy for abnormal mucosa compared with
normal was 7.0 (95% CI, 1.4 to 36.1).

Somewhat surprisingly, EBB had a higher overall diagnostic yield than
TBLB alone. The yield for EBB was 62% whereas TBLB demonstrated
nonnecrotizing granulomas in 59% of participants. Many patients had
positive biopsies from both modalities, but seven patients had positive
biopsies only on EBB. Diagnostic yield increased by 21% with EBB.

Further refinements of the benefit and meaning of EBB have been
performed by this same group. Racial differences were examined in
relation to EBB because other aspects of the disease have racial
variation.[11] Black and white patients both had abnormal mucosa in
approximately half the patients, but biopsies were positive in 85% of
blacks but in only 38% of whites.

We recommend the use of EBB either routinely or when mucosal
abnormalities are present. For normal mucosa we recommend six specimens,
two from the main carina and two each from bilateral secondary carinae.
When an abnormality is present we obtain four biopsies from this area
and two from the contralateral secondary carina. Transbronchial Needle
Aspiration

Patients with sarcoidosis very frequently have enlarged mediastinal and
hilar lymph nodes. They are tempting targets for biopsy via FB given the
incomplete sensitivity described earlier. TBNA was first developed by
surgeons for use during rigid bronchoscopy.[22] French surgeons reported
a diagnostic yield of 66% in stage I or stage II patients when a 1.5-mm
diameter aspiration needle was used to obtain specimens during rigid
bronchoscopy.[23] There was no difference in yield between samples from
the paratracheal or hilar nodes.

Wang et al.[24] introduced the technique to FB and reported early
results in sarcoidosis. When using an 18-gauge needle, the diagnostic
yield of TBNA was 90% in the 20 patients reported. Members of our group
confirmed this observation, when we reported that the 18-gauge TBNA
needle could diagnose sarcoidosis.[25] This is in contrast to the
22-gauge needle that delivers only cytologic specimens that are
inadequate to diagnose granulomatous inflammation.

The addition of TBNA to standard TBLB has been delineated. Morales et
al.[26] reported TBNA specimens in 51 patients. The diagnostic yield for
TBNA in stage I and stage II disease was 50%, and most important added
10 to 20% to the yield of TBLB alone. A recent prospective study
reported 13 patients with suspected sarcoidosis who underwent TBNA and
TBLB.[27] Seven of 13 patients had positive TBNA specimens. Although
most patients had diagnostic TBLB, four patients had negative TBLB but
diagnostic TBNA tissue, demonstrating a clinically important diagnostic
yield. Another recent study demonstrated that seven of eight patients
with sarcoidosis had positive TBNA specimens.[28*] These numbers are too
small to suggest when to perform TBNA, although they highlight its
utility in situations in which the other forms of biopsy may be expected
to have a lower yield.

At our center we routinely use TBNA when the main diagnostic
consideration is sarcoidosis, and mediastinal or hilar lymphadenopathy
is present and malignancy is a strong possibility. Our technique has
been described previously and we refer the reader there in the interest
of conserving space.[29] Bronchoalveolar Lavage

Given that sarcoidosis is a diffuse disease and can involve the alveoli
and respiratory bronchioles, one would expect BAL to be a window into
the disease. In fact, soon after the application of the technique a key
question was answered. It had long been known that patients with
sarcoidosis were frequently anergic to common antigens, could convert a
previous positive reaction to a negative one, and could have peripheral
lymphopenia.[30, 31] This was thought to represent decreased immune
function and possibly be the cause of the disease. However, BAL fluid
analysis demonstrated an increase compared with normal controls in total
lung lymphocytes and immune system activation with elevated helper T
lymphocytes.[32, 33] This revolutionized thinking about the disease and
led to BAL as a research and diagnostic tool.

Bronchoalveolar lavage differential cell analysis as a diagnostic tool
has been well studied. The location of BAL sampling is not important in
this diffuse disease.[34, 35] Many investigators have described the
classic sarcoidosis BAL fluid cell differential: elevated lymphocytes
with a specific increase in helper T cells leading to an elevated
CD4-to-CD8 ratio.[36] The positive predictive value of a CD4-to-CD8
ratio of 4:1 is only 50% for separating sarcoidosis from all other lung
diseases, but the value increases to 94% when only patients with
interstitial lung disease are considered.[37] Unfortunately the
sensitivity is low, at 59%. When a ratio greater than 4:1 is coupled
with BAL fluid neutrophils and eosinophils less than 1% each, the
diagnostic utility is equal to TBLB. Given the variability in
differentials, especially in smokers, and the chance of spurious 1% or
2% neutrophils or eosinophils, we do not recommend using this combined
differential technique in lieu of TBLB or EBB.[38] Thus, as a diagnostic
tool, analysis of differential cell counts function as an adjunct test.

This lack of diagnostic utility contrasts to the sarcoid mimic beryllium
lung disease, in which lymphocytes obtained via BAL can be diagnostic
for berylliosis if they are reactive to beryllium in vitro.[39, 40]
Because the antigens involved in sarcoidosis are unproved, we cannot use
this simple test.

Perhaps an even more difficult task than diagnosing sarcoidosis is
predicting who will progress or respond to steroids. BAL fluid
differential analysis has been investigated toward this end. Studies
have shown that initial BAL fluid lymphocyte counts do not predict
disease progression or remission.[41, 42] BAL fluid CD4 cell analysis
shows, contrary to popular belief, that elevated CD4 lymphocyte counts
predict future disease remission.[43] More recently, BAL fluid
neutrophilia has been investigated.[42] A total BAL fluid neutrophil
count of more than 0.2 × 104 cells mL-1 was shown to predict significant
worsening in lung function and chest radiographs. However, one needs to
note that patients with elevated BAL fluid neutrophils had significantly
more advanced disease as assessed by chest radiograph and lung function
at study entry than those with low neutrophils. Thus, other tests such
as baseline chest radiograph and pulmonary function tests would likely
have predicted this group to worsen.

Although BAL fluid differential cell analysis is of questionable use as
a clinical tool, BAL cytokine analysis has provided great insights into
the pathogenesis of the disease. Although many of these discoveries are
beyond the scope of this article, some tests show promise and may one
day prove clinically useful and will be described. Two notable
cytokines, which are important in granulomatous inflammation, have been
found in BAL fluid. Both tumor necrosis factor- and interferon- are
present in elevated levels in patients with worsening disease compared
with normal control subjects and patients with inactive sarcoidosis.[44]
Other BAL fluid cytokine markers (KL-6, tumor necrosis factor-,
granulocyte-macrophage colony stimulating factor, transforming growth
factor-1) have been shown to correlate with disease severity and
activity.[45-48] However promising, these markers have not become the
standard of care for making the diagnosis of sarcoidosis or assessing
disease activity, but research is ongoing.

Therapeutic Bronchoscopy

Significant tracheobronchial obstruction from sarcoidosis is relatively
rare and is thought to occur in 2 to 8% of patients with sarcoidosis
[49, 50], although this percentage is likely an overestimate because far
more persons are now diagnosed with early, nonobstructive disease than
when these cohorts were reported. Obstruction can occur in relatively
advanced stage III and stage IV disease, but has also been reported in
stage II disease.[51]

The mechanism of stenosis is typically from one of two causes: segmental
or lobar obstruction from accumulation of endobronchial granulomas.[50]
This occurs most frequently in the right middle lobe and both upper lobe
bronchi, but obstruction can occur in all bronchi and even rarely in the
trachea.[52] Endobronchial obstruction can improve with corticosteroid
therapy and may not require bronchoscopic intervention. However, if
obstruction persists, bronchoscopic intervention should be considered.

The other mechanism of obstruction is extrinsic compression of the large
airways from enlarged lymph nodes.[53] Systemic corticosteroids can
improve this type of obstruction as well, but when it persists,
bronchoscopic intervention should be considered.

Several modalities for bronchoscopic intervention exist today. However,
laser ablation, electrocautery, and cryotherapy have no utility because
of either the diffuse submucosal nature of endobronchial occlusions, or
because the compression is from extrinsic nodal compression of the
bronchus. Thus, mechanical dilatation with balloons, and stenting are
the procedures of choice.
Balloon Dilatation

Mechanical dilatation was first performed with bougie catheters via
rigid bronchoscopy.[54] This was successful in reducing segmental and
lobar intrinsic obstruction in two patients with sarcoidosis. On
follow-up examination, one patient had recurrence of obstruction at 10
years, which was redilated with good results. Unfortunately the other
patient had frequent restenosis requiring frequent repeat dilatation and
oral corticosteroids.[55] Balloon angioplasty catheters applied during
rigid bronchoscopy were first used in 1984 to dilate tracheal stenosis,
and in 1988 were used to remedy left main bronchus obstruction from
sarcoidosis.[56, 57]

Successful balloon dilatation via FB was initially reported in 1994,
when Fouty et al.[58] used 5-Fr Fogarty embolectomy catheters to dilate
segmental and lobar stenoses in six patients with sarcoidosis. All
patients improved subjectively and there were no complications.

Bronchoscopic balloon dilatation (BBD) is our procedure of choice in
patients with stenosis. However, BBD can be performed only if the airway
is not occluded completely. Our technique has been described recently
elsewhere and entails placing the balloon catheter in the stenosed
airway either under direct visualization with the bronchoscope or using
fluoroscopy and a guidewire if the catheter cannot be placed through the
bronchoscope.[59] The various complications of BBD include chest pain,
bronchospasm, atelectasis, hemorrhage, bronchial rupture, pneumothorax,
pneumomediastinum, or mediastinitis.
Tracheobronchial Stents

Placing a prosthetic stent in obstructed airways is an option few
patients with sarcoidosis require, but can be very beneficial in select
patients. A stent is a cylindrical, hollow prosthesis used to maintain
airway patency by opposing extrinsic compressive forces. Two general
categories are available: expandable metal and silicone tube. Silicone
tube stents require placement via rigid bronchoscopy under general
anesthesia and are not discussed further.

The decision to place a stent for sarcoidosis is generally difficult and
arrived at after previous treatment failure and recurrence of stenosis.
We reserve this technique for when stenosis recurs despite aggressive
oral corticosteroid and BBD fails to achieve satisfactory results, when
previous inflammation leads to destruction of bronchial cartilaginous
architecture, and when extrabronchial compression via enlarged lymph
nodes occludes the airway despite oral corticosteroid therapy. We
recommend stenting only in these situations because of the possibility
of stent-induced granulation, and the relative difficulty of stent
removal if complications occur.

There has been significant development of covered and uncovered stents.
Our choice in these patients is to use a covered metallic prosthesis if
granulation recurrence is expected, and to use an uncovered device if
compression is extrinsic or if reestablishment of cartilage architecture
is desired. Our group has previously described the technique for stent
deployment.[60]
Conclusions

Flexible bronchoscopy is an important tool in sarcoidosis for the
pulmonary physician. The procedure is safe, well tolerated, and less
invasive than alternatives. The diagnostic utility is maximized when EBB
and TBLB are used routinely. TBNA and BAL fluid analysis can be helpful
in special cases. Bronchoscopic therapy is reserved for patients who
have endobronchial obstruction despite corticosteroid therapy. We favor
BBD for patients who have significant segmental, lobar, or tracheal
stenosis. Stent placement is reserved for recalcitrant cases, or when
there is significant destruction of supporting architecture.

Reprint Address

Correspondence to Jeffrey T. Chapman, MD, Department of Pulmonary and
Critical Care Medicine, Cleveland Clinic Foundation, Desk A/90, 9500
Euclid Ave., Cleveland, OH 44195, USA; e-mail: chapmaj@ccf.org


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icemaidenz

Kathi I had such a long post about this and hit a button and it went.
I wish someone that knew something about these buttons would help me.
I can post or type and lose a whole page somehow.

I type and my cursor flies to another area and types until I find it.
Anyone know what my problem is, I am on AOL.

Duh, of course you know this.

Kathi there is one thing I want to repeat if I can.

I had no Idea how serious this was, I just got out of the hospital was
in for a week. Both lungs full of fluid and thought I had congestive
heart failure.
I had the surgery about nine months ago, cut me in about four places
and also used the scope down the throat.

Kathi we have been thru a lot together, our illness so much alike, do
we have the same think Kati, I remember you struggling for air and I
could not stand the thought of you going thru this. You have been a
true sister to me, and I am sorry that years ago I could not show you
how Ilena was, I did try my best Hun.
She may have been and may be kind to some people, but I wonder why. It
is not n her nature. And we have seen enough lately haven't we. And we
know what the Lord tells us in his word about people that afflict pain
on others and go against the Lords teachings, harming, hurting,
causing continued pain, stress, to his children. I know he hears us
and answers our prayers. I pray that more sisters will start coming
here and sharing. A lot of us have many of the conditions listed by
the manufacturers in their little laughable grid.

We have so much to give. That does not mean we don't need also. I need
my sisters now more than I have never needed my friends in my whole
life. It is hard to deal with all that is in my body and mind. It is
so hard to see my caretaker Phil, my precious husband continue to
waste his life on me, when he should be at his time of life enjoying
things, without worry. I want to go home to Jesus, but afraid to leave
him, I just pray that the Lord will use me in some way to help those
that need me.

It would be great to see more inspirational postings.

Do you realize that many many of our sisters are in the late or worse
stages of their illnesses. Look how long we have been fighting.

I wish I had the other post back Kathi, I love you dear. Thanks for
the post,

Oh Sarcoidosis can enter any organ of the body..nasty sick thing to
pop up in ones life.

God Bless You and God Bless all of those that read.