Diffuse Lung Disease II/Pulmonary Board Review

Joseph P.
Lynch, III, MD
Professor of Clinical Medicine, Step VIII
Division of Pulmonary & Critical Care Medicine
The David Geffen School of Medicine at UCLA
Diffuse Lung Disease-II (Lynch)
Joseph P. Lynch, III, MD
Sarcoidosis
Sarcoidosis
Etiology unknown
Prevalence 10-20/100,000 (USA)
(higher in blacks, Scandinavians)
Lung involved > 90%
Sarcoidosis
Lung involvement predominates
Can involve virtually any organ
Natural history heterogeneous
Sarcoidosis: prognosis
Spontaneous remissions (50-60%)
Chronic or progressive (10-30%)
Fatalities (1-4%)
Sarcoidosis
Pulmonary involvement dominates
Lung parenchyma
Endobronchial
Intrathoracic lymph nodes (hilar,
paratracheal, mediastinal)
Extrapulmonary Sarcoidosis
Common Sites (symptomatic)
Lymph nodes
Skin (erythema nodosum; chronic)
Eyes (conjunctivitis, uveitis)
Joints (acute polyarthritis)
Uncommon Sites (symptomatic)
Liver, spleen
Heart, central nervous system
Kidneys, bone, muscle, misc.
Involvement of heart or CNS
uncommon (2-7%), but can be
devastating
Sarcoidosis: Laboratory tests
Hypercalcemia 2-4%
Hypercalciuria 15-40%
Leukopenia 5-15%
Serum ACE 30-80%
Serum ACE in Sarcoidosis
Elevated in 30 to 80%
Prognostic value limited
May mirror course disease
Refects total granuloma burden
Sarcoidosis: Chest X-rays
Bilateral hilar lymphadenopathy
Parenchymal infltrates
Upper/mid lung zone
predominance
Distortion, fbrosis
Sarcoidosis: PFTs
Restrictive ( VC, TLC) in 30-60%
Obstruction ( FEV
1
) in 9-40%
DL
CO
(not as severe as IPF)
Hypoxemia uncommon (late)
Sarcoidosis
Q5. Which statement is correct?
a) BAL demonstrates high CD8/CD4
ratio
b) Pleural effusions occur in < 5 %
c) BAL cell profles should direct therapy
d) Elevated serum ACE should prompt
treatment with corticosteroids
BAL in Sarcoidosis
Increased CD
4
, CD
4
/CD
8
ratio
Prognostic value limited
Disease may wax and wane
Expensive, not necessary

Spontaneous remissions
(50-60%)
Chronic or progressive (10-30%)
Fatalities (1-4%)
Heterogeneous clinical expression
Who and when to treat controversial
? Role of ancillary tests (SACE,
HRCT)
Sarcoidosis: tissue conrmation
Transbronchial lung Bx advised
Lymph nodes
(mediastinoscopy)
Cutaneous lesions
Surgical lung Bx not required
Spontaneous remissions (SR)
Radiographic stage I (60-85%)
Lfgrens syndrome (> 85%)
Stage III (< 20% SR)
Sarcoidosis
Lfgrens syndrome:
Bilateral hilar lymphadenopathy
Fever
Erythema nodosum
Polyarthritis
Sarcoidosis: X-ray Staging
Radiographic Stage
0 Normal
I BHL without infltrates
II BHL + infltrates
III parenchymal infltrates
Sarcoidosis
Q6. Which statement is correct?
a) Persistent infltrates > 2 years predicts spontaneous
resolution in < 20%
b) Stage II or III sarcoidosis: chest X-rays have a
predilection for the bases
c) Stage III sarcoidosis resolves spontaneously in
30-40% of patients.
d) Ga-67 scans are useful to stage sarcoidosis.

136 pts > 5 yrs (both Rx and unRxd)
X-ray stage # asymptomatic
I 32 31 (97%)
II 40 23 (58%)
III 64 16 (25%)
Scadding, Br Med J 1961:2;1165
(both treated and untreated pts)
Stage # CR Deaths
I 110 54% 0
II 94 31% 11%
III 40 10% 18%
SiItzbach, Med Clin N Am 1967:51;483
(210 pts, both treated and untreated)
Stage # Improved
I 116 70%
II 83 67%
III 10 30%
Romer, Danish Med Bull 1982:29;27
First 2 yrs predicts outcome:
85% of all remissions occur by 2 yrs
Remissions unlikely if stage II at 2 yrs
Romer, Danish Med Bull 1982:29;27
Favorable prognosis if:
Spontaneous (as opposed to
induced) remissions
Sarcoidosis: NaturaI History
British Thoracic Society Study
Stage II or III
39% improved spontaneously (SR)
Only 1 of 58 SR ever required Rx
for late relapse
Gibson, Thorax 1996:51;238
Sarcoidosis: NaturaI History
357 pts (Philadelphia)
Spontaneous remissions (SR) in
35%
If SR, only 10 (8%) later relapsed
GottIieb, Chest 1997:111;623
Sarcoidosis
Favorable prognostic factors:
Lfgrens syndrome
Radiograph Stage I
Certain HLA marker (DQB1*0201)
Sarcoidosis
Adverse prognostic factors:
Chronic hypercalcemia
Lupus pernio; nasal
Osseous
Chronic uveitis
Certain HLA markers
HRCT in Sarcoidosis
Upper lobe predominance
Central bronchovascular bundles
Nodules
Confuent alveolar opacities
Distortion, fbrosis, cysts
Sarcoidosis: HRCT
Potentially reversible if:
Nodules
Alveolar consolidation
Ground glass opacities
Sarcoidosis: HRCT
Adverse prognostic factors:
Honeycomb cysts
Traction bronchiectasis
Broad septal bands
Distortion
Sarcoidosis
Heterogeneous clinical expression
Spontaneous remissions common
Progressive damage, fbrosis can
occur
When to treat controversial
Corticosteroids in sarcoidosis
Spontaneous remissions common
(interpretation effcacy of Rx
diffcult)
Short term responses but long
term effcacy less clear
Interpretation effcacy of Rx diffcult
due to:
Natural history of disease
Objective staging of disease
Timing of intervention critical
(early or late in the course)
Effcacious in some patients
Indications for Rx controversial
Chronic stage II or III
Extrapulmonary sites
Treatment of sarcoidosis
Corticosteroids
Favorable responses: 50-90%
Relapses in 20-70%
Toxicities cumulative
Dose (and duration) appropriate#
(for site and severity)
Avoid futile Rx for end-stage disease
(irreversible brosis)
Lack of beneft may refect:
Inadequate dose or duration
Irreversible fbrosis or damage
Non-compliance
Intrinsic steroid resistance
Corticosteroids in Sarcoidosis
Prospective studies failed to show beneft
Israel, Am Rev Respir Dis 1973:110:609
Yamamoto, Sarc Granul Dis (Paris) 1980; 470-474
Eule, Ann NY Acad Sci 1986:465;695
Zaki, NY State J Med 1987:87;496
Selroos, Scand J Respir Dis 1979:60;215
Corticosteroids for sarcoidosis
Controlled, randomized trials
Lack of beneft may refect:
High spontaneous remission rates
Minimal disease (normal PFTs, no Sx)
Corticosteroids for Sarcoidosis
Stage I or II, asymptomatic, normal PFTs
(n=172)
Randomized for 6 or 12 months:
prednisone placebo
Normal CXR 83% 77%
DL
CO
< 70% 11% 6%
Eule, Ann NY Acad Sci 1986:465;695
Sarcoidosis: controversies
Who to treat?
? Optimal dose, duration
What to do if steroids fail?

Indications should be circumscribed
Routine Rx for mild sx not
appropriate
Steroids effective in some patients
Rx if severe or progressive
symptoms or dysfunction
Multicenter, randomized (BTS) (n=149)
At 6 month evaluation:
Rxd steroids for sx 33 (22%)
Improved spontaneously 58 (39%)
Persistent infltrates CXR 58 (39%)
Sarcoidosis: Natural History
British Thoracic Society Study
Stage II or III
By 6 months, 58 (39%) had
improved spontaneously (SR)
58 (39%) with persistent infltrates
Persistent infltrates at 6 mo (n=58)
Randomized to:
Long term prednisolone (n=27)
Selective* prednisolone (n=31) (*only
if worsening symptoms or PFTs)
Spontaneous remission (n=58)
Mild or stable sx (n=116)
Prednisolone for stage II or III sarcoidosis
Persistent inItrates (n=58)
Steroids prn only (n=31) PrednisoIone (n=27)
Severe or worsening sx (n=33)
No treatment
6 month observation period
Immediate
steroid Rx

Final PFTs (% pred) FEV
1
FVC
Prednisolone Rx 96% 99%
Selective Rx 86% 92%
PFTs improved in steroid-
cohort
Treat if chronic stage II or III#
(after initial observation period)
When to treat sarcoidosis
Pulmonary: progressive or severe
Critical organ involvement
(CNS, Heart, Eye)
Hypercalcemia, hypercalciuria
(nephrolithiasis)
Individualize prednisone dose:
Initial: 40 mg/day
For CNS or cardiac, 1 mg/kg/d
Taper to 40 mg q.o.d < 3
months
Sarcoidosis failing steroids
Cytotoxic Rx (methotrexate, azathioprine)
Antimalarials (hydroxychloroquine)
TNF antagonists (infiximab)
Transplantation (lung, heart, liver)
Immunosuppressive agents
Role for:
Corticosteroid failures
Corticosteroid side effects
Risk for steroid side effects
Immunosuppressive drugs
Limited data in sarcoidosis:
No randomized trials
Comparative data lacking
(e.g., methotrexate vs azathioprine)
Immunosuppressive agents
Optimal Rx not studied
Long term Rx may be required
Late toxicities a concern
Azathoprine (Imuran)
Alone or combined with prednisone:
100-150/day (2-3 mg/kg/d)
Bone marrow toxicity
Monitor CBC, diff, platelets
Methotrexate
Alone or combined with prednisone
10-20 mg once weekly (p.o. or i.m.)
Concomitant folic acid (1 mg/d)
Monitor AST, ALT q 4-6 wks
Cyclophosphamide (Cytoxan)
Oral daily or IV pulse (monthly)
Oncogenic
Bladder, marrow toxicities
Reserve for CNS sarcoid failing
other agents
Hydroxychloroquine (Plaquenil)
Dose 200 mg once or twice daily
Effects delayed (3-6 mos)
Retinal toxicity rarely severe
Steroid-sparing effect
Iniximab (Remicade) for sarcoidosis
Anecdotal responses with infiximab
(case reports; small series)
Primarily extrapulmonary
(osseous, lupus pernio)
Lung TranspIant for Sarcoidosis
Criteria:
Severity, rate of progression (PFTs)
Irreversible disease (HRCT)
Failed aggressive medical Rx
When to list for transplant?
? Parameters to predict survival
Course more indolent than IPF
Objective data lacking
Lung transpIant (LT) for
sarcoidosis
UNOS, 1995-2000, 405 sarcoid pts listed
for LT
111 (27%) died while awaiting LT
PFTs did not predict mortality

Shorr, Chest 2003:124;922
Prognosis of sarcoidosis
Pulmonary function tests did not
discriminate survivors for survivors
Sarcoidosis awaiting Iung Tx
43
36
41
37
32
34
36
38
40
42
44
FVC FEV1
survivors
non-survivors
p
e
r
c
e
n
t

405 pts (UNOS, 1995-2000)
Sarcoidosis: Prognosis
Risk factors for mortality:
Pulmonary hypertension
Amount supplemental 02
Black race
PAH Increases Mortality
31.7
41.4
0
5
10
15
20
25
30
35
40
45
survivors non-survivors
m
e
a
n

P
A
P

405 pts (UNOS, 1995-2000)
mPAP
Sarcoidosis: Prognostic Factors
Pulmonary arterial hypertension
markedly worsens prognosis
Predicting mortality (sarcoidosis)
Awaiting lung transplant (n=43)
23 died (53%) while on transplant list
Mortality most closely linked to:
Mean right atrial pressure > 15 torr
Arcasoy, Chest 2001:120;873
Risk for mortality (sarcoidosis)
(univariate analysis) Relative risk
pa0
2
< 60 mm Hg 3.4
Cardiac index < 2 2.8
Mean PAP > 35 mm Hg 3.2
RAP > 15 mm Hg 7.6
Arcasoy, Chest 2001:120;873
Sarcoidosis: lung transplant
Post lung transplant:
2-3 y survival post Tx 70-80%
Recurrent NCG in allograft
Joseph P. Lynch, III, MD
LCH and LAM (ACCP-IV)
Langerhans cell histiocytosis
Formerly termed:
Pulmonary eosinophilic granuloma
Histiocytosis X
Langerhans cell granulomatosis
Langerhans Cell Histiocytosis
Pulmonary LCH
> 95% smokers; age 20-50 y
Cough, dyspnea; pneumothorax
Extrapulmonary (15-20%)
Pulmonary LCH
Epidemiology of LCH:
Prevalence 2-5 cases/million
Almost exclusively Causasians
Pulmonary LCH
Restrictive defect on PFTs
Reticulonodular, cysts lesions
CXR
HRCT highly characteristic
LCH: HRCT features
Upper lobe predominance
Numerous cysts
Peribronchiolar nodules
Pulmonary LCH
Q7. Which features are not typical ?
a) SteIIate pattern of brosis
b) Numerous peribronchioIar noduIes
c) Immature smooth muscle cells
d) Extensive cysts
LCH: Histopathology
Langerhans histocytes (HX cells)
Stellate pattern fbrosis (low
power)
Infammation; cysts, nodules
Q8. Which is not seen in pulmonary LCH?

a) Infammatory cells in alveolar septae
b) (+) S-100 protein
c) (+) HMB-45
d) (+) CD1a (OKT6) antigen
Immunohistochemical stains
S-100 protein
OKT6 (CD1a antigen)
Pulmonary LCH
Clinical course variable:
Resolves or stabilizes 60-70%
Worse or severe 15-30%
Fatalities 6-25%
Pulmonary LCH
Natural history variable:
Cessation smoking paramount
No proven therapy
Lung transplantation (end-stage)
Pulmonary LCH
Prospective, Germany, 1994-2002 (n=77):
Only 1 non-smoker
Only 3 deaths (mean observation 38.2 mos)
Smoking cessation: no effect clinical course
SchonfeId, Sarcoid Vasc Diff Lung Dis 2012:29;132
Relapsing LCH
Lung transplantation (n=7):
Recurrent LCH in 2 within 12 mos
Both had resumed smoking
Etienne, AJRCCM 1998:157;288
Lymphangioleiomyomatosis (LAM)
Exclusively affects women
Cystic lung disease
LymphangioIeiomyomatosis (LAM)
Atypical smooth muscle (HMB-45+)
Progressive dyspnea (FEV
1
)
Pneumothoraces
Chylothorax
Lymphangioleiomyomatosis
Mean age onset 30-36 y
Pre-menopausal women > 95%
Prevalence 2-6 per million
PuImonary LAM
Progressive airfow obstruction
Pneumothoraces (rupture of cysts)
Chylothorax (rupture of lymphatics)
Hemoptysis (rupture of venules)
Course indolent, but progressive
Pace of disease highly variable
Deaths due to respiratory failure
10-yr survival variable (> 80%)
PuImonary LAM
Sporadic
Tuberous sclerosis
LAM: chest X-ray ndings
Features at presentation
Pneumothoraces 39-53%
Cysts or bullae 41-58%
Pleural effusions 7-39%
HRCT Features of LAM
Numerous thin-walled cysts
Diffuse, no predominance
No nodules or fbrosis
Involvement outside lung > 40%
(principally uterus, ovaries,
kidneys)
Angiomyolipomas (AMLs)
Proliferation of blood vessels,
abnormal smooth muscle, fat
Kidney or abdominal/pelvic AMLs
LAM: Extrapulmonary involvement
Angiomyolipomas or cysts
Uterus, ovaries 41%
Kidneys 15-54%
Lymph nodes 39%
Liver, spleen < 5%
Histology of LAM
Proliferating atypical smooth m.
HMB-45 (+) smooth muscle cells
Extensive cysts
Diagnosis of Pulmonary LAM
Transbronchial lung biopsies (+) in
36/63 (56%)
Given extensive cysts, ? risk
Meraj, Front Med 2012:6;395
Pulmonary LAM: Condent Diagnosis
Typical cysts on HRCT
Tuberous sclerosis complex
Chylous ascites or pleural effusion
Lymphangioleiomyomas
Serum VEGF-D > 800 pg/ml
Young, Chest 2010:138;674
Pathogenesis:
Smooth muscle proliferation
Estrogens likely play major role
? Chromosome 12 involved
Genetic Mutations in LAM
Mutations in tumor suppressor
genes (TSC-1 and TSC-2) in LAM
Identical mutations in Tuberous
Sclerosis Complex (TSC)
Tuberous Sclerosis
Inherited (usually autosomal
dominant; 60% sporadic)
Pulmonary LAM < 30%
Share features with LAM:
Extrapulmonary angiomyolipomas
Pulmonary LAM (1-26%)
Express HMB-45
Chromosomal abnormalities
(13q14, 14q24 in both TSC and LAM)
Mental retardation
Cranial calcifcations
Sebaceous adenomas
75% died by age 20 yrs
Pulmonary LAM
Progressive airfow obstruction
(FEV
1
surrogate marker)
Rate of decline highly variable
Pulmonary LAM
-106
-118
-140
-120
-100
-80
-60
-40
-20
0
20
m
e
a
n

a
n
n
u
a
l

f
a
l
l

F
E
V
1

(
c
c
)

Urban, Medicine 1999:78;321
Mean annual fall FEV
1
Johnson, AJRCCM 1999:160;628
UK (n=43) France (n=69)
Pulmonary LAM
-1.7
-2.4
-5
0
5
m
e
a
n

a
n
n
u
a
I

f
a
I
I

(
%

p
r
e
d
)

Taveria-Dasilva, Chest 2004:126;1867
Mean annual FEV
1
and DL
CO
% pred
USA, NIH (n=275)
FEV
1
DL
CO
Pulmonary LAM
Natural history variable
Early studies antedated CT
(likely more severe cases)
Current 10-yr survival > 90%
Pulmonary LAM
79
91
0
20
40
60
80
100
France 1999 (n=69) UK 2004 (n=57)
%

1
0
-
y
r

s
u
r
v
i
v
a
l

Urban, Medicine 1999:78;321
10-y survival
Johnson, Thorax 2004:59;800
Pulmonary LAM
91.3
92
0
20
40
60
80
100
pneumothorax no pneumothorax
%

1
5
-
y
r

s
u
r
v
i
v
a
l

Steagall, Am J Physiol Lung Cell Mol Biol 2007:293;L800
15-y survival, USA NIH (n=227)
Optimal therapy uncertain:
Avoid estrogens or pregnancy
Medroxyprogesterone acetate
Sirolimus (Rapamycin)
Treatment of LAM
Sirolimus (rapamycin):
Suppresses:
Smooth muscle proliferation
DNA synthesis LAM cells in vitro
Treatment of LAM
Angiomyolipomas (AMLs) (n=25)
Open label: sirolimus x 12 months
Primary end point; AML volume at 12 mos
Observed for 12 mos after stopping
sirolimus
Bissler, N Engl M Med 2008:358;140
Angiomyolipomas (TSC or LAM)
54
86
0
20
40
60
80
100
12 months 24 months
%

b
a
s
e
l
i
n
e

v
o
l
u
m
e

25 pts (18 LAM; 7 TSC only)
Bissler, N Engl J Med Jan 10, 2008
AML volume
Pulmonary function (LAM)
118
390
0
50
100
150
200
250
300
350
400
450
FEV1 FVC
FEV1
FVC
I
n
c
r
e
a
s
e

a
b
o
v
e

b
a
s
e
l
i
n
e

(
c
c
)

11 pts (sirolimus for 12 mos)
Bissler, N Engl J Med 2008:358;140
PFTs (n=11)
Treatment of LAM
LAM, moderate lung impairment (n=89)
RDBPC: sirolimus vs placebo for 12 mos
Drug stopped at 12 mo; observed to 24 mo
McCormack, N Engl J Med 2011:364;1595
Sirolimus for LAM
Primary End Point: FEV
1
McCormack, N Engl M Med Apr 28, 2011
Sirolimus for LAM
-129
-134
97
19
-150
-100
-50
0
50
100
150
placebo
sirolimus
c
h
a
n
g
e

(
c
c
)

(
1
2

m
o
)

McCormack, N Engl J Med Apr 28, 2011
12 months
FEV1
FVC
Sirolimus for LAM
At 12 mos, sirolimus improved:
FVC, FEV
1
, VEGF-D, QOL
No difference DL
CO
or 6-MWT
McCormack, N Engl M Med Apr 28, 2011
Sirolimus for LAM
Benefcial effect (stabilization)
but not sustained
Given need for long-term use, and
side effect profle, indications not
defned

VEGF-D as Biomarker for LAM
Miles Trial (n=87)
Serum VEGF-D time 0, 6 mo, 12 mo
Higher VEGF-D: worse airfow
obstruction
Decreased VEGF-D in sirolimus cohort
assoc with improved FEV
1
Young, Lancet Respiratory June 2013
LAM: Lung Transplantation

SHY #363-71-11
Lung Transplant (LT) for LAM
5-year survival 55% post LT
LAM recurs in < 10% post LT

Diffuse Lung Disease II/Pulmonary Board Review

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