This document presents a case of a 74-year-old man with COPD who presents with worsening dyspnea. Examinations reveal diffuse crackles, an elevated WBC count and inflammatory markers. A chest CT shows bilateral consolidations and ground glass opacities. A lung biopsy reveals a uniform temporal appearance with fibrosis within the airspaces, consistent with cryptogenic organizing pneumonia (COP). The diagnosis, treatment, typical presentation and pathology of COP are discussed. COP is characterized by organizing pneumonia seen on biopsy without an identifiable cause.

2. Case Presentations
Gamal Rabie Agmy ,MD ,FCCP
Professor of Chest Diseases, Assiut University

3. Case No. 4

4. • A 48-year-old woman is referred to
you with chest heaviness and
shortness of breath on exertion.
• She was recently investigated by a
cardiologist who concluded her
symptoms were noncardiac in origin
after a normal angiogram.

5. • She has also noticed increasing fatigue for the
past 6 months. She mentions she works in a
stressful environment as a critical care nurse.
She denies any associated wheezing, cough,
nocturnal symptoms, radiation of chest
discomfort, palpitations, or syncope.
• Her symptoms were not relieved with
nitroglycerin spray. Her history is otherwise
negative, she is a lifelong nonsmoker, and she
is on no medications.
• Physical examination results are normal.

6. Pulmonary Function Test Results

7. • A methacholine challenge test:
Demonstrates a PC20 (percent concentration
associated with a 20% fall in the FEV1) of 6.00
mg/mL.
Her symptoms were not reproduced during
the methacholine challenge test.
• The patient underwent cardiopulmonary
exercise testing, revealing the following data:

8. Cardiopulmonary Exercise Test Results

9. • There were no arrhythmias, significant ST
segment, or T-wave changes.
• The patient reported discontinuing exercise
because of shortness of breath.
• Spirometry performed immediately following
exercise was done.

10. Results of Spirometry After Exercise

12. The results from these investigations are most
consistent with which of the following?
•
•
•
•
A. Exercise-induced bronchoconstriction (EIB).
B. Deconditioning.
C. Vocal cord dysfunction.
D. Primary hyperventilation syndrome

13. • This patient has shortness of breath and chest
discomfort with exertion in the setting of
normal pulmonary function and a negative
result of a methacholine challenge test.
• Cardiopulmonary exercise testing reveals
normal performance and values, except for a
15% decrease in the FEV1 immediately
following exercise, consistent with a diagnosis
of EIB (choice A is correct).

14. • Exercise testing shows normal aerobic and work
capacity with no significantly abnormal cardiac or
respiratory responses (choice B is incorrect).
• While the patient works in a stressful occupation,
there are no findings consistent with primary
hyperventilation syndrome such as an erratic
breathing pattern and hyperventilation, which is
excessive for the simultaneous metabolic load
(choice D is incorrect).
• Examination of the exercise tidal flow-volume
curves, both at rest and with exercise, does not
reveal any changes consistent with central airway
obstruction (choice C is incorrect).

15. • Exercise associated airway narrowing occurs in
the majority of patients with asthma. Although
patients often deny or do not recognize other
symptoms of asthma, these symptoms can often
be detected with a careful clinical history.
• It is important to understand the diagnosis of EIB
is not excluded by a negative result of a
methacholine challenge test, although it is most
commonly positive in this clinical setting. In this
instance, the patient underwent cardiopulmonary
exercise testing to objectively understand the
patient’s symptoms of activity limitation, which
was normal, as the patient demonstrated normal
work and aerobic capacity.

16. • However, spirometry following exercise did
reveal a significant decrement in the FEV1,
which responded to the administration of a
bronchodilator. Not mentioned is that the
patient’s symptoms were also reproduced
immediately following exercise. These findings
confirm the diagnosis of EIB, although if these
results were not demonstrated and clinical
suspicion for EIB remained, a more specific EIB
exercise protocol would have been indicated

17. • This typically consists of high intensity exercise on a
treadmill or bicycle ergometer of 6 to 8 min duration
intended to rapidly achieve the highest possible level
of ventilation for 4 to 6 min. There should not be a
significant warm-up period, which may lead to
tolerance or refractoriness to EIB. This can also occur if
exercise duration exceeds 12 min.
• A fall in the FEV1 of 10% or more is interpreted as
abnormal, while a 15% or more fall is considered to be
diagnostic. An appropriate post exercise testing
schedule is 1, 3, 5, 10, 15, 20, and 30 min after
cessation of exercise, although if the FEV1 has returned
from its nadir to the baseline level or greater,
spirometry testing may be terminated at 20 min post
exercise.

18. • These bronchoconstriction responses may also
occasionally be demonstrated with eucapnic
voluntary hyperventilation or cold air
challenge. While a positive response (ie, a fall
in the FEV1) may also be seen in patients with
upper airway obstruction or vocal cord
dysfunction, the cases can be readily
distinguished from EIB by examination of the
exercise tidal flow-volume curves

19. So the finial diagnosis is
•
•
•
•
A. Exercise-induced bronchoconstriction (EIB).
B. Deconditioning.
C. Vocal cord dysfunction.
D. Primary hyperventilation syndrome

20. • Exercise testing shows normal aerobic and work
capacity with no significantly abnormal cardiac or
respiratory responses (choice B is incorrect).
• While the patient works in a stressful occupation,
there are no findings consistent with primary
hyperventilation syndrome such as an erratic
breathing pattern and hyperventilation, which is
excessive for the simultaneous metabolic load
(choice D is incorrect).
• Examination of the exercise tidal flow-volume
curves, both at rest and with exercise, does not
reveal any changes consistent with central airway
obstruction (choice C is incorrect).

21. Case No. 5

22. • A 74-year-old man with a history of mild COPD
has a 3-month history of worsening dyspnea
on exertion.
• He was seen by his primary care provider 3
weeks ago, diagnosed with a COPD
exacerbation, and received a 5-day course of
azithromycin that did not provide much relief.
• He now notes a nonproductive cough and
intermittent low-grade fevers.

23. • He has no other medical problems and takes
no regular medications. He smoked 1 pack of
cigarettes a day for 30 years but quit 25 years
ago.
• He denies taking any over-the-counter
medications or supplements.
• He has no pets or other unusual exposures,
and he has not travelled out of the United
States

24. • Vital signs on admission are only
remarkable for a temperature of 37.9C
and an oxygen saturation of 89% on 4
L/min nasal cannula.
• Physical examination is notable for
diffuse inspiratory crackles.
• There is no clubbing, cyanosis, or
edema.

25. His chest radiograph:

26. • A CBC reveals a WBC count of 12,300/L (12.3
× 109/L) with 55% neutrophils, 3% bands, 30%
lymphocytes, 4% monos, and 8% eosinophils;
hemoglobin level of 14.2 g/dL (142 g/L); and a
platelet count of 223 × 103/L (223 × 109/L).
His electrolyte levels are normal.
• His erythrocyte sedimentation rate (ESR) is 52
mm/h.
• C-reactive protein level is 8.2 mg/L (78.1
nmol/L)

27. • Serum IgE level is not markedly elevated.
• Total eosinophil count is 400/L (0.400 ×
109/L).
• Cytoplasmic
antineutrophil
cytoplasmic
antibodies (c-ANCA) findings are negative.
• Perinuclear
antineutrophil
cytoplasmic
antibodies (p-ANCA) findings are positive at
1:80.

28. • He is admitted to the hospital and started
on a regimen of broad-spectrum
antibiotics.
• Over the next 3 days, his symptoms and
radiograph
worsen,
and
IV
methylprednisolone, 60 mg tid is added.

29. A CT scan of the chest is obtained

30. • A bronchoscopy is performed and is
nondiagnostic; no organisms are seen
and there are no eosinophils on cell
count.
• His oxygen requirement remains high
and a thoracoscopic lung biopsy is
performed

31. What is your diagnosis?
•
•
•
•
A. Acute interstitial pneumonia (AIP).
B. Cryptogenic organizing pneumonia (COP).
C. Nonspecific interstitial pneumonia (NSIP).
D. Chronic eosinophilic pneumonia (CEP).

32. • This patient’s clinical history and imaging could be
consistent with any of the diagnoses listed above.
• The lung biopsy specimen,
however, reveals a uniform
temporal appearance with
preservation of the lung
architecture.
• There is fibroblastic tissue within the alveolar airspace
and the lumina of the respiratory bronchioles without
evidence of vasculitis or granuloma formation. These
changes are classic for COP (choice B is correct).

33. • This organizing pneumonia pattern can be
secondary to collagen vascular disease,
infection, or drug reactions.
• When the cause is not known, the term
cryptogenic organizing pneumonia is used.
Although this patient may have had an
infection early in his course, nothing could be
identified after thorough evaluation in the
hospital

34. • Patients with COP often present with a
subacute illness, typically complaining of
cough and dyspnea.
• Systemic symptoms such as fever, night
sweats, and weight loss are common.
• Examination of the lungs will typically reveal
crackles. Laboratory findings include an
elevated ESR and C-reactive protein.

35. • Chest radiographs will reveal diffuse, patchy
opacities, typically in the subpleural or lower
lung fields.
• CT scan features include ground-glass
attenuation and consolidation, which is either
peribronchial or subpleural, as in this patient.
Although relapses and chronic fibrosis can
occur, most patients will recover after receiving
a course of oral corticosteroids

36. • As mentioned above, the radiographic features of this
case are not specific, and the pattern seen could also
be consistent with AIP, NSIP, and given the subpleural
predominance, CEP.
• The pathologic features, however, are distinctive. The
hallmark pathologic finding in AIP is diffuse alveolar
damage, with alveolar wall thickening, airspacem filling
with proteinaceous exudates, and hyaline membranes
along the airways. None of these features is present in
this patient (choice A is incorrect).
• Classic features of CEP (interstitial and alveolar
eosinophils, interstitial fibrosis, and eosinophilic
microabscesses) are also absent (choice D is incorrect).

37. • NSIP is histologically characterized by interstitial
inflammation and fibrosis that is temporally
uniform without specific features that allow the
identification of other idiopathic pneumonias,
such as the temporal heterogeneity and
prominent honeycombing of usual interstitial
pneumonia
or
the
numerous
alveolar
macrophages of desquamative interstitial
pneumonitis and respiratory bronchiolitisassociated interstitial lung disease. Although
small foci of organizing pneumonia can be seen,
this is not the dominant feature (choice C is
incorrect).

38. Idiopathic Interstitial Pneumonias
Gamal Rabie Agmy ,MD ,FCCP
Professor of Chest Diseases, Assiut University

39. Idiopathic Interstitial
Pneumonias

40. 7 histological categories
•
•
•
•
•
•
•
Usual interstitial pneumonia (UIP)
Nonspecific interstitial pneumonia (NSIP)
Organising pneumonia (OP)*
Diffuse alveolar damage (DAD)
Desquamative interstitial pneumonia (DIP)**
Respiratory bronchiolitis (RB)
Lymphocytic interstitial pneumonia (LIP)
* previously BOOP
** previously AMP

41. Correlation with HRCT patterns
UIP
+
NSIP
+
OP
+
DAD
+
DIP
+
RB
+
LIP
+
=
IPF
=
NSIP
=
COP
=
AIP
=
DIP
=
RB-ILD
=
LIP
 7 clinical-radiological-pathological categories
ATS/ERS International Multidisciplinary Consensus Classification of the
Idiopathic Interstitial Pneumonias, AJRCCM Vol 165. pp 277-304, 2002

42. IPF/UIP
„disease status‟
Histology:
• Heterogeneous appearance
ü(hardly any inflammation)
• Temporal heterogeneity
Old + new fibrosis (fibroblastic foci)

43. Non-specific interstitial pneumonia
‟IIP-NSIP cellular / fibrotic variant‟
• fine reticulation
• ground glass
• temporal uniformity on biopsy
• no / few fibroblastic foci

44. Cryptogenic organising
pneumonia
(BOOP)
• patchy consolidations (95%)
• perilobular opacity (50%)
Ujita, Radiology 2004; 232: 757-61

45. Acute interstitial
pneumonia
Congestion & oedema
Exudative phase
acute onset, with systemic features: idiopathic ARDS
 granulocytes + occasional lymphocytes; debris
 survival from diagnosis often days despite mechanical support


46. Desquamative interstitial pneumonia
(AMP)

smoker
 BAL: AM+++N+E+L

47. Respiratory bronchiolitis
associated interstitial lung disease

cigarette smoker
 obstructive or restrictive lung function
 AM with smoker’s inclusions on BAL

48. Lymphocytic interstitial
LIP
pneumonia
 AIDS
lymphoproliferative
 rheumatological
 idiopathic (rare)
 lymphocytes on BAL


49. Scenario 1: HRCT appearances are
pathognomonic

50. To be useful in the routine
diagnosis of IIP, a test MUST be
good at diagnosing IPF

51. IPF/usual interstitial pneumonia

54. Key conclusion
• Typical HRCT features of IPF in
association with a compatible clinical
profile obviate surgical biopsy
BUT
• Atypical features on HRCT for IPF do NOT
exclude the diagnosis

55. Scenario 2: HRCT and clinical features
are, together, diagnostic

56. RBILD
• Exaggerated form of smoking-related
respiratory bronchiolitis
• Generally benign/self limited vs survival
• Significant symptoms/functional
impairment
• Is a thoracoscopic biopsy necessary to
make the diagnosis?

58. RBILD vs HP
Ask the patient!
BAL: lymphocytosis vs
pigmented macrophages

59. Key conclusion
The combination of HRCT, smoking
and exposure history and BAL allows
most RBILD patients to be diagnosed
non-invasively

60. Scenario 3: Diagnoses in which a
biopsy is required

63. Is an HRCT diagnosis of NSIP
inherently invalid?
The key concept of NSIP sub-groups
“If my pathologist tells me the biopsy shows
NSIP, then my job has only just begun”

64. Scenario 4: Clinico-radiologic subgroups
• Clinical features of IPF, HRCT overlap….
• Organizing pneumonia variant
• HP variant
• Connective tissue disease
• Post diffuse alveolar damage
• Smoking related?

65. The OP variant of NSIP
Nagai S. Eur Respir J 1998; 12:1010-1019
Kim TS. AJR 1998; 171:1645-1650.
Consolidation a prominent feature on CT
(admixed with ground-glass/reticular
elements)
A component of organizing pneumonia (<10%)
often present at biopsy

67. The concept of “fibrosing organizing
pneumonia”
Does this equate with the “OP
variant” of NSIP?

68. NSIP presenting with the clinical
features of IPF
• A rather different HRCT profile (compared
to the organizing pneumonia variant)
• Organizing pneumonia, nodules not
present on HRCT
• Predominant findings are ground-glass
attenuation, fine reticulation, traction
bronchiectasis

69. NSIP presenting with the clinical
features of IPF
• A rather different HRCT profile (compared
to the organizing pneumonia variant)
• Organizing pneumonia, nodules not
present on HRCT
• Predominant findings are ground-glass
attenuation, fine reticulation, traction
bronchiectasis

72. Key conclusion
NSIP should be separated into clinicoradiologic sub-groups.

73. Typical COP
• HRCT is often less discriminatory (vis a
vis diagnosis) than serial chest
radiography
• Evanescent (“immunological disorders”)
versus fixed consolidation (alveolar cell
cancer, non-bacterial infection)
• HRCT valuable in disclosing fibrosing
variants

74. Lee JS. JCAT 2003; 27:260-265.
• 26 patients with histopathologic diagnosis
of organizing pneumonia (“BOOP”)
• Persistent or progressive disease on
HRCT despite treatment in 35%
• Predominant consolidation/nodules =
good outcome
• Reticular abnormalities on HRCT = bad
outcome

75. 11-99

76. 08-00

77. 02-2001

78. Key conclusion
The greatest utility of HRCT in COP is
to identify patients progressing or more
likely to progress to fibrosis

79. Scenario 5: Prognosis based on
reconciling HRCT and biopsy

80. Fibrotic NSIP

81. UIP
NSIP…. or is it really UIP?

82. Scenario 6: Prognosis based on
reconciling baseline data and disease
behaviour

83. Essentially, biopsy and HRCT are
“silver standards” against the true
clinical “gold standard” of disease
behaviour/ outcome

84. The real utility of the ATS/ERS
classification……….

85. What clinicians need from a
classification….
• Captures clusters of disease behaviour
• Articulates logical therapeutic goals
• Makes approach to monitoring obvious

86. This can be achieved

87. A classification based on pragmatic
management ...
• Cause
• Predominant morphologic abnormality
• Severity
• Longitudinal behaviour
Integrate these

88. Self-limited inflammation
• Examples: hypersensitivity pneumonitis,
sarcoidosis, drug-induced lung disease
• Outcome good
• Avoidance of antigen, where applicable,
crucial
• Repeated attempts to limit treatment
justified
• Monitor to confirm disease regression

89. Stable/indolent fibrotic disease
• Diagnosis often incidental: CTD,
hypersensitivity pneumonitis, sarcoidosis
• Key is not to over-react
• Management: MICO therapy…..
• Monitor to confirm disease stability

90. “Indolent disease”
MICO:
Masterful Inactivity
with Cat-like Observation
The role of the doctor is to amuse the patient
while nature takes its course
(Voltaire)

91. Major inflammation with variable
fibrosis
• Severe sarcoidosis, hypersensitivity
pneumonitis, drug-induced lung disease
• Key is distinguishing these cases from
extensive irreversible fibrotic disease
• Essential to treat vigorously
• Monitor early to establish best treated PFT
and later to exclude relapse

92. Inexorably progressive fibrosis
• Sarcoidosis, hypersensitivity pneumonitis
• Key to management is to find the right
balance between slowing progression and
poisoning the patient
• Monitor to evaluate rate of progression

93. Explosive ILD
• Sudden onset of disease. Idiopathic,
“cryptogenic fibrosing alveolitis”
• Often life-threatening
• Exact diagnosis usually uncertain
• Key issue: biopsy on ventilator?
• Policy of “treat the treatable”
• Very stressful for doctors, patients and
relatives

94. We investigate to distinguish between…….
• Self-limited inflammation
• Stable fibrotic disease
• Major inflammation with variable
fibrosis
• Inexorably progressive fibrosis
• Explosive ILD

95. What clinicians need from a
classification….
• Captures clusters of disease behaviour
• Articulates logical therapeutic goals
• Makes approach to monitoring obvious

96. Self-limited inflammation
RBILD

97. Stable/indolent fibrotic disease
Fibrotic NSIP

98. Major inflammation with
variable fibrosis
DIP
COP

99. Inexorably progressive fibrosis
UIP

100. Explosive ILD
AIP, accelerated UIP

101. Conclusions: useful points for
clinicians (1)
• Biopsy is no longer the diagnostic gold
standard
• Diagnosis of IIP is now multidisciplinary
• IPF can be diagnosed on HRCT in the
majority of cases but a crucial sub-group
have very atypical HRCT appearances
• RBILD can be diagnosed using a
combination of clinical and HRCT data
• DIP and NSIP require a biopsy for diagnosis

102. Conclusions : useful points for
clinicians (2)
• NSIP should be classified according to the
disease it most closely represents
• In a small OP subset, there is progression to
inexorable fibrosis
• Prognosis is based upon the reconciliation
of HRCT, biopsy and clinical data
• A simple pragmatic clinical classification
underlies best management
• Biopsy when these key clinical distinctions
are blurred

103. Case No. 6

104. • You are called to suggest additional
therapeutic options after a patient just
underwent a diagnostic and therapeutic
thoracentesis.
• The patient is a 65-year-old man with a longstanding left pleural effusion.
• The patient has had thoracentesis for the
effusion on several occasions over the last
year.

105. • The most recent pleural fluid values from 6
weeks ago include:
 A protein level of 2.9 g/dL (29.0 g/L),
Lactate dehydrogenase (LDH) level of 124 U/L
(2.1 kat/L) (serum: 220 U/L, 3.7 kat/L), and
pH of 7.34.
All culture results and cytologic evaluations
have been negative

106. • The patient notes that he is able to perform
his daily activities without difficulty.
• He notes only a mild increase in dyspnea on
exertion over the last year while climbing
stairs; he notes no other respiratory
symptoms.
• His past medical history includes hypertension
and dyslipidemia, both well controlled with
medications.

107. • He had three-vessel coronary artery bypass
grafting 2½ years ago and currently has no
anginal symptoms.
• His most recent echocardiogram 4 months ago
shows good left ventricular function, with an
ejection fraction of 50%.
• After today’s thoracentesis, he notes no new
symptoms specifically, also noting that he has
no shortness of breath or chest discomfort.

108. • The consulting physician has obtained a
postthoracentesis chest radiograph

109. CT scan of the chest

110. • Upon review of prior chest radiographs
postthoracentesis, findings are similar to the
current radiograph; similarly, a prior CT scan
postthoracentesis 4 months ago has findings
similar to the current CT scan.
• Pleural fluid values now available include a
WBC count of 986/mm3 (0.986 × 109/L),
protein level of 2.8 g/dL (28.0 g/L), and LDH
level of 80 U/L (1.3 kat/L) (serum: 140 U/L [2.3
kat/L]).

111. Which is the most appropriate
therapeutic approach for this patient?
• Place two 32F chest tubes, apply 20 cm of
water suction to each.
• B. Consult surgery to perform a decortication.
• C. Start indomethacin.
• D. No specific treatment, monitor.

112. • This patient has a chronic stable and nearly
asymptomatic pleural effusion with a thickened
visceral pleural surface seen both on the chest
radiograph (best seen at the apex) and the CT scan,
compatible with a diagnosis of a trapped lung.
• The space between the thickened visceral pleural
surface and the parietal pleura (chest wall) could
represent a pneumothorax ex vacuo, but does not
reflect lung injury during thoracentesis with
consequent air entry into the pleural space
(iatrogenic pneumothorax).

113. • Given the patient’s nearly asymptomatic state,
no specific treatment is warranted (choice D is
correct). The incidence of trapped lung is
unknown but likely higher than recognized.
• Events producing initial pleural inflammation
such as pneumonia, including with empyema;
hemothorax; or prior thoracic surgery,
including coronary artery bypass grafting
(CABG), as in this patient, precede the
development of a trapped lung and usually
have an accompanying exudative effusion.
•

114. • The lung may first become “entrapped,”
demonstrating limited reexpansion and an
active pleural inflammatory process.
• At this stage, therapy is directed at the active
process. As the inflammatory process
becomes temporally remote, if the visceral
pleural fibrosis (fibrous pleural peel) does not
resolve, the lung becomes trapped and will
not fully re-expand.

115. • Pleural fluid fills the space between the lung
and parietal pleura.
• In one series, the most common cause out of
11 cases of trapped lung was coronary artery
bypass graft (CABG), with the other causes
found to be uremia, thoracic radiation,
pericardiectomy,
and
complicated
parapneumonic effusion

116. • Pleural fluid analysis from patients with a trapped
lung often reveals borderline exudative values,
with one series noting a mean pleural fluid pH of
7.30, LDH level of 124 U/L (2.1 kat/L), and protein
level of 2.9 g/dL (29 g/L).
• The fluid is paucicellular with a mononuclear cell
predominance, including an elevated lymphocyte
percentage ( 50%) in most patients.
• Pleural manometry usually shows an initial
negative pleural pressure with a rapid and steep
decline in pleural pressure as fluid is removed,
reflecting the inability of the lung to re-expand.

117. • However, most clinicians do not perform
manometry, and the diagnosis can be made by
a chest radiograph or CT chest after
thoracentesis, demonstrating a thickened
pleural surface and an unexpanded lung, as in
this patient.
• The time between the inciting pleural event
(eg, CABG), chronic nature of the effusion,
pleural fluid findings, and all the radiographic
findings are compatible with a trapped lung,
and not an entrapped lung, in this patient.

118. • Placement of chest tubes with application of
negative pressure will not cause reexpansion of a
trapped lung (choice A is incorrect).
• Indomethacin may be useful in the management
of postcardiac injury syndrome (PCIS), but the
clinical picture in this patient, which includes the
chronic nature of this patient’s effusion and
limited clinical symptoms, including no fever,
make PCIS very unlikely (choice C is incorrect).
• The definitive therapy for a trapped lung is
decortication to allow lung reexpansion.
However, this is major surgery and should only be
employed in patients with significant symptoms
arising from the trapped lung (choice B is
incorrect).

119. So the best management of this
patient is
• Place two 32F chest tubes, apply 20 cm of
water suction to each.
• B. Consult surgery to perform a decortication.
• C. Start indomethacin.
• D. No specific treatment, monitor.