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An Interesting Case of Bilateral Lung Consolidation

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Organising pneumonia is a histopathological entity characterised by intra-alveolar buds of granulation tissue, intermixed myofibroblasts and connective tissue. Cryptogenic organising pneumonia (COP) is characterised by this particular histopathological pattern, along with typical clinical and imaging features, when no other underlying aetiology is found. COP (previously known as bronchiolitis obliterans organising pneumonia [BOOP]) is one of the rare variants of interstitial pneumonias. This condition is characterised by a rapid clinical and radiological improvement with steroid treatment. Here we are reporting a case of COP in adult female with discussion on approach and basic pathophysiology of this type of pneumonia.
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54 Journal of The Association of Physicians of India Vol. 63 July 2015
Case and Discussion
A 55-year-old housewife, a
known diabetic, presented to
the outpatient department of All
India Institute of Medical Sciences
(AIIMS) hospital, New Delhi
with 4 month history of cough
and high grade fever. The cough
was dry in nature, no diurnal or
postural variation and without any
significant aggravating or relieving
factors. Patient had complaints
of weight loss of about 4 kgs
over last one month. She also had
progressive shortness of breath for
last 1 month, which had progressed
from mMRC (modified medical
research council) grade 1 to grade
4 over 1 month. She was a known
diabetic since last 7 years and was
on oral hypoglycemic agents. She
had history of exposure to passive
An Interesting Case of Bilateral Lung
Consolidation
Satyajit Pawar1, Animesh Sharma2, R Ragesh1, Neeraj Nischal1, Saket Jha1,
Chandan J Das3, MC Sharma4, SK Sharma1
smoking and exposure to chulha
for 20 years in the past. There was
no history suggestive of connective
tissue disease, exposure to fumes,
dust or working in the farm. At
the same time her husband was
diagnosed to have extra-pulmonary
TB (tubercular pleural effusion).
At admission, she was febrile
with temperature of 100°F. Blood
pressure was 110/70 mmHg with
pulse rate of 110/min. Respiratory
rate was 30/min with use of
accessory respiratory muscles and
visible intercostal recession. The
SpO2 was 80% on room air and
96% on oxygen (O2) at 6 litres/
minute via face mask. Patient
was pale, however, there was
no icterus, clubbing, cyanosis,
lymphadenopathy, skin rash or
pedal edema. The ocular and
fundus examination was normal.
Examination of upper respiratory
tract, oral cavity, tonsils and
posterior pharyngeal wall was
normal. Examination of respiratory
system reveled bilateral coarse
mid-inspiratory crepitation were
heard in infra-axillary and infra-
scapular area. Examination of
cardiovascular, abdominal and
central nervous system revealed no
abnormality.
Laboratory investigations
revealed haemoglobin – 12.6 g/dl,
total leucocyte count – 14.6 x 103/
mm3, platelet count – 490 x 103/mm3
and erythrocyte sedimentation rate
Departments of 1Internal Medicine, 3Radio-diagnosis, 4Pathology, All India Institute of Medical Sciences,
New Delhi; 2Intern, Sir Ganga Ram Hospital, New Delhi
Received: 20.05.2015; Accepted: 27.05.2015
CASE OF THE MONTH
Abstract
Organising pneumonia is a histopathological entity characterised by
intra-alveolar buds of granulation tissue, intermixed myofibroblasts
and connective tissue. Cryptogenic organising pneumonia (COP) is
characterised by this particular histopathological pattern, along with
typical clinical and imaging features, when no other underlying aetiology
is found. COP (previously known as bronchiolitis obliterans organising
pneumonia [BOOP]) is one of the rare variants of interstitial pneumonias.
This condition is characterised by a rapid clinical and radiological
improvement with steroid treatment. Here we are reporting a case of COP
in adult female with discussion on approach and basic pathophysiology
of this type of pneumonia.
Introduction
Organising pneumonias (OP)
usually present with non-
specific symptoms, radiographic
and pulmonary function test (PFT)
findings. The cause can be primary
(cryptogenic organising pneumonia
[COP]) or secondary (secondary
OP). Cryptogenic organising
pneumonia is classified under
idiopathic interstitial pneumonia.
Secondary causes of OP include
infections, connective tissue
diseases, drugs, malignancies,
organ transplantation, aspiration
and radiation injury. It is important
to make such distinction as
the management of secondary
organising pneumonia involves
treatment of the underlying
disease or potential avoidance of
the offending agent. It is often
associated with poor prognosis and
is less responsive to treatment as
compared to COP.
55
Journal of The Association of Physicians of India Vol. 63 July 2015
– 102 mm at the end of 1st hour.
Chest X-ray revealed bilateral
lower and mid zone air-space
opacities (Figure 1). Differential
diagnosis considered were
pulmonary tuberculosis, bacterial/
fungal pneumonia, lung carcinoma
(bronchoalveolar variant),
hypersensitivity pneumonitis and
sarcoidosis were considered.
Liver and renal functions were
in normal range with exception
of reversal of albumin:globulin
ratio. Electrocardiogram (ECG)
and 2D-echocardiography (ECHO)
were within normal limits. Arterial
blood gas (ABG) analysis revealed
pH – 7.40, PaCO2 – 30.8 mmHg,
PaO2 - 55.6 mmHg, HCO3 – 20.3
mmol/L with FiO2 – 0.4. Alveolar
(A) to arterial (a) oxygen gradient
was 196 mmHg (normal value - 5 –
20 mmHg) suggestive of pulmonary
parenchymal pathology. Normal
(A-a) gradient adjusted for age
can be calculated as estimated
(A-a) gradient which is (4 + age
in years/4).1 (A-a) gradient helps
in differentiating the extra-
pulmonary causes of respiratory
failure from those involving
parenchymal lung disease. In
extra-pulmonary failure, the (A-a)
gradient remains normal. In cases
of shunt, diffusion impairment
or ventilation-perfusion (V-Q)
mismatch, the gradient is usually
elevated. Hypoxemia due to V-Q
mismatch or diffusion impairment
can be corrected with supplemental
oxygen while that due to right-left
shunt cannot. (A-a) gradient is also
a measure of the severity of gas
exchange impairment and is used
as guide for steroid therapy in cases
of Pneumocystis carinii pneumonia.
HIV ELISA was negative.
Autoimmune work-up in the
form of rheumatoid factor (RF),
p-ANCA and c-ANCA and double
stranded (ds) -DNA was negative.
Anti-nuclear antibody (ANA) was
positive in 1:40 titer with speckled
pattern. Positive titres of less than
1:160 can be present in up to 20%
of the healthy elderly population.
Titres more than 1:160 are seen in up
to 5% of normal adult individuals.
Serology for Aspergillus and
Histoplasma was negative. Serum
lactate dehydrogenase (LDH) and
angiotensin converting enzyme
(ACE) levels were within normal
limits. Serum C - reactive protein
(CRP) was elevated. Sputum smear
examination with Gram stain
and acid-fast bacilli (AFB) stain
was negative. High resolution
computed tomography (HRCT) of
the chest (Figure 2) revealed areas of
bilateral lower zone consolidation
mainly involving peri-hilar areas,
without any surrounding ground-
glassing with presence of reverse-
halo sign suggesting organizing
pneumonia. Reverse halo sign is
characterized by presence of central
ground-glass opacity surrounded
by area of consolidation. It was
first described as a specific sign
for COP, however it has been
reported in a variety of pulmonary
diseases including invasive
fungal pneumonias, tuberculosis,
granulomatous polyangiitis,
lymphomatoid granulomatosis
and sarcoidosis.2 Based on this
revised differentials of pulmonary
tuberculosis (spouse diagnosed as
TB, systemic symptoms, elevated
ESR, imaging compatible), bacterial
pneumonia (sick, elevated total
peripheral blood counts, imaging
compatible), sarcoidosis (though
serum ACE was normal and HRCT
was not typical, alveolar sarcoid still
a possibility), limited Wegener’s
(ANCA can be negative), and
cryptogenic organizing pneumonia
(age group compatible, subacute
presentation, imaging compatible)
were kept.
CT-guided lung biopsy was
Fig. 1: Chest radiograph showing
air space consolidation in
bilateral mid and lower
zone. Note a round opacity
with central lucency in left
mid zone (arrow)
Fig. 2: HRCT axial image showing
symmetrical bronchocentric
consolidation in both lungs.
Note consolidation in left
lung with central lucency
(arrow) ---reversed halo or
Atoll sign suggesting COP
Fig. 3: CT-guided lung biopsy specimen under haematoxylin-eosin stain
(original magnication x 100). (A) Biopsy shows thickening of inter-
alveolar septae along with chronic inammatory cell inltrate. (B) Type
II pneumocytes proliferation with intra-alveolar smooth muscle bundle
proliferation forming a ball-like structure (Masson body) (arrow)
56 Journal of The Association of Physicians of India Vol. 63 July 2015
radiological and histopathological
features with no other secondary
cause.
The term ‘cryptogenic organizing
pneumonia’ (COP) was introduced
by Davison et al in 1983.3 It was
later supplanted in the American
literature by the term ‘BOOP.’
In 2002, the American Thoracic
Society/European Respiratory
Society International Consensus
Panel for the Classification of
Idiopathic Interstitial Pneumonia
(ATS/ERS) recommended the
term ‘COP’ be used as preferred
clinical term for idiopathic cases,
emphasising the cryptogenic
nature of the process.4 COP is
characterised by insidious onset,
non-specific physiologic findings,
and variable radiographic patterns,
but with typical histopathologic
findings that are sine qua non
for diagnosis. It is important to
remember that COP is a diagnosis
of exclusion and secondary causes
(Table 1) should be ruled out before
making final diagnosis. Patients
usually experience a 2–10 week
prodrome prior to seeking medical
attention. The disease has no sex
predilection and occurs usually
in 6th decade, although paediatric
cases have been reported. No
predisposing factors have been
identified and, in particular,
organising pneumonia is not related
to smoking in comparison to other
ILDs like respiratory bronchiolitis-
associated interstitial lung
disease, desquamative interstitial
pneumonia, and pulmonary
Langerhans cell histiocytosis.
COP should be included in the
differential diagnosis in any patient
with bilateral airspace disease that
is unresponsive to antibiotics.
The typical imaging
characteristic of COP is of
multiple patchy alveolar opacities
with a peripheral and bilateral
distribution. These opacities may
migrate spontaneously. Their size
is often variable and can range from
a few centimetres to a whole lobe.
Two other patterns include solitary
opacity (focal COP), and infiltrative
opacities (infiltrative COP). This
imaging pattern, although highly
suggestive of COP, is not specific
and the differential diagnosis on
imaging include conditions such as
the primary-low grade pulmonary
lymphomas, chronic eosinophilic
pneumonias (which can occur
with COP), and bronchioloalveolar
carcinoma. Pulmonary functions
reveal mild to moderate restrictive
defect, with minimal or no airflow
obstruction and reduced carbon
monoxide diffusion capacity. No
specific lab findings are observed in
COP. Patients usually have raised
ESR and CRP with neutrophilic
leucocytosis more so in secondary
OP. The gold standard for diagnosis
is video-assisted thoracoscopic
lung biopsy, as it provides large
lung specimens allowing diagnosis
to be made with confidence and
other pathological features can also
be searched. Trans-bronchial lung
biopsy specimens are inadequate
for excluding secondary causes.
Treatment decisions are based on
clinical experience and observations
from case series because of lack of
randomized trials. The decision
to initiate treatment and choice
of initial therapy depends on
severity of symptoms, extent of
disease on imaging and rapidity
of progression. In patients with
minimal symptoms and mild
radiographic involvement it is
reasonable to monitor abnormalities
at 8 to 12 weeks interval. In patients
with mild to moderate symptoms
treatment with macrolides is an
option, particularly for those
Table 1: Various aetiologies for
organizing pneumonia
Infections
1. Bacterial
Chlamydia pneumoniae
Coxiella burnetii
Legionella pneumophila
Mycoplasma pneumoniae
Nocardia asteroides
Pseudomonas aeruginosa
Serratia marcescens
Staphylococcus aureus
Streptococcus
2. Viral
Herpes virus
 Humanimmunodeciencyvirus
 Inuenzavirus
 Parainuenzavirus
3. Fungal
Cryptococcus neoformans
Pneumocystis carinii
Drugs
Amiodarone
Bleomycin
Carbamazepine
Cocaine
Interferon alpha
Minocycline
Phenytoin
Sulfasalazine
Tacrolimus
Sotalol
Systemic inammatory diseases
Rheumatoid arthritis
Polymyositis/dermatomyositis
Polymyalgia rheumatic
Solid organ malignancies
Colon
Breast
Haematological malignancies
Non- Hodgkin lymphoma
Renal transplant
Post-radiation
Aspiration pneumonia
Table 2 : Comparison of pre-treatment
and post-treatment lab
parameters and arterial blood
gas values
Parameter Pre-
treatment
Post-
treatment
pH
PaO2 (mmHg)
PaCO2 (mmHg)
FiO2
7.40
55.6
30.8
0.4
7.42
66.5
32.5
0.21
ESR (mm/hr) 102 40
D(A-a)O2 (mmHg) 194 44
D (A-a) O2 – Alveolar to arterial oxygen
gradient
done. Biopsy revealed thickening
of inter-alveolar septae along
with chronic inflammatory cell
infiltrate (Figure 3A) and type II
pneumocytes proliferation with
intra-alveolar smooth muscle
bundles proliferation forming a
ball-like structure (Masson body)
(Figure 3B) which is a characteristic
finding of organizing pneumonia.
A final diagnosis of COP was made
in view of characteristic clinical,
57
Journal of The Association of Physicians of India Vol. 63 July 2015
who chose to avoid steroids.5
Clarithromycin 250 to 500 mg twice
a day has been used in few cases.
Corticosteroids is the treatment of
choice in patients with persistent
or progressive disease. The ideal
dose and duration of steroids in
COP is not well-defined. Clinical
improvement is seen within 48 hrs,
while radiological resolution takes
several months. The recommended
daily dose of steroids is 0.75 – 1 mg/
kg of prednisone and usual duration
is six to twelve weeks.6 COP is
associated with frequent relapses
involving initial or different
sites and some patients require
prolonged treatment with steroids.
In such cases steroid-sparing
agents in from of azathioprine and
cyclophosphamide can be used.
The prognosis of typical COP with
patchy alveolar involvement is
usually good.
Our patient was started on 60 mg
(1 mg/kg) prednisone initially which
was tapered over next 3 months.
Subsequently, she was shifted to
steroid-sparing agent in the form of
azathioprine due to development of
side effects of steroids. At the end
of 6 months, she was doing well
with remarkable relief in fever,
weight loss, shortness of breath
and cough. Her diabetic status is
also well controlled. Investigations
showed normalization of ESR,
CRP and albumin:globulin ratio.
Arterial blood gas (ABG) analysis
on room air revealed pH – 7.42,
PaCO2 – 32.5 mmHg, PaO2 - 66.5
mmHg. D (A-a) O2 was 44 mmHg
compared to 194 mmHg at the time
of presentation (Table 2). Both chest
X-ray and HRCT (Figure 4) showed
significant resolution. The patient
is currently on follow-up in the
outpatient department.
Conclusion
COP is one of the rare idiopathic
interstitial pneumonias and
remains as diagnosis of exclusion.
Patient is labelled to have a COP
based on clinical, radiological
and characteristic histological
findings only after excluding
secondary causes. A careful history
of occupation, exposure to dusts,
fumes, therapeutic radiation and
history suggestive of connective
tissue diseases should be elicited as
other pulmonary pathologies such
as chronic eosinophilic pneumonia,
hypersensitivity pneumonitis
or diffuse alveolar damage can
have similar radiological and
histopathological findings.
References
1. Harris EA, Kenyon AM, Nisbet HD, et al. The
normal alveolar-arterial oxygen tension
gradient in man. Clin Sci Mol Med 1974;
46:89-104.
2. Godoy MCB, Viswanathan C, Marchiori E,
et al. The reversed halo sign: update and
dierential diagnosis.Brit J Radiol 2012;
85:1226-1235.
3. Davison AG, Heard BE, McAllister WA, et al.
Cryptogenic organizing pneumonitis. QJ
Med 1983; 52:382—394.
4. Travis WD, Colby T, Bateman ED, et al.
ATS/ERS international multidisciplinary
consensus classification of idiopathic
interstitial pneumonia. Am J Respir Crit Care
Med 2002; 165:277-304.
5. Stover DE, Mangino D et al. Macrolides:
a treatment alternative for bronchiolitis
obliterans organizing pneumonia?
Chest2005; 128:3611-7.
6. Bradley B, Branley HM, Egan JJ, Greaves
MS, Hansell DM, Harrison NK, Hirani N et al.
Interstitial lung disease guidelines. Thorax
2008; 63:1029.
Fig. 4: Chest radiograph (A) and HRCT thorax (B) showing marked clearing of
bilateral lung consolidation after treatment
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Article
Full-text available
The reversed halo sign is characterised by a central ground-glass opacity surrounded by denser air-space consolidation in the shape of a crescent or a ring. It was first described on high-resolution CT as being specific for cryptogenic organising pneumonia. Since then, the reversed halo sign has been reported in association with a wide range of pulmonary diseases, including invasive pulmonary fungal infections, paracoccidioidomycosis, pneumocystis pneumonia, tuberculosis, community-acquired pneumonia, lymphomatoid granulomatosis, Wegener granulomatosis, lipoid pneumonia and sarcoidosis. It is also seen in pulmonary neoplasms and infarction, and following radiation therapy and radiofrequency ablation of pulmonary malignancies. In this article, we present the spectrum of neoplastic and non-neoplastic diseases that may show the reversed halo sign and offer helpful clues for assisting in the differential diagnosis. By integrating the patient's clinical history with the presence of the reversed halo sign and other accompanying radiological findings, the radiologist should be able to narrow the differential diagnosis substantially, and may be able to provide a presumptive final diagnosis, which may obviate the need for biopsy in selected cases, especially in the immunosuppressed population.
Article
1. The alveolar-arterial oxygen-tension gradient was measured in duplicate, in forty-eight healthy subjects (twenty-four men and twenty-four women) aged from 20 to 74 years, while breathing oxygen concentrations of approximately 14, 21, 40, 60 and 100%. 2. The gradient increased with age and with inspired O2 concentration up to 60%. Above 60%, during normal breathing, there was no significant change in gradient. 3. Breathing 100% O2 in deep breaths decreased the gradient in all age-groups, significantly so in subjects of 50 years and younger. The remaining gradient was due to anatomical venous shunt. 4. When this anatomical shunt was allowed for, the differences in gradient between age-groups were largely abolished at all inspired O2 concentrations. The gradient which was not due to anatomical shunt, when breathing air, remained higher in subjects over 60 years than in the younger subjects. 5. The results can be interpreted to mean that three components contribute to the normal gradient: (a) irreversible anatomical shunt; (b) closed, unventilated alveoli which can only be inflated by deep breaths; and (c) cyclical airway closure during normal breathing in subjects over 60 years. Diffusion disequilibrium may contribute a gradient of up to 3 mmHg during the breathing of low O2 concentrations.
Article
Eight patients with histological intra-alveolar organization, but no evidence of an infective or other aetiological agent, are reported. They characteristically presented with a short history of severe dyspnoea, cough, malaise, weight loss, bilateral radiographic shadowing and a raised ESR. There was a dramatic response clinically and radiologically to prednisolone but relapse occurred quickly as the dose was reduced. Control was re-established with an increased dose of prednisolone. In order to avoid confusion with post-infective organizing pneumonia the term cryptogenic organizing pneumonitis is suggested.
Article
Some macrolides have been found to exert anti-inflammatory effects. Lung diseases such as asthma, panbronchiolitis, cystic fibrosis, and bronchiectasis are thought to respond to the immunomodulatory properties of macrolides. We report three cases of idiopathic bronchiolitis obliterans organizing pneumonia, now called cryptogenic organizing pneumonia, and three cases of radiation-related bronchiolitis obliterans organizing pneumonia that responded to macrolide therapy. An explanation of why macrolides may have anti-inflammatory effects in patients with these syndromes is discussed. These cases help to reinforce accumulating data that macrolides are beneficial as anti-inflammatory agents and organizing pneumonia may be another pulmonary disease that can benefit from such therapy.
ATS/ERS international multidisciplinary consensus classification of idiopathic interstitial pneumonia
ATS/ERS international multidisciplinary consensus classification of idiopathic interstitial pneumonia. Am J Respir Crit Care Med 2002; 165:277-304.
Macrolides: a treatment alternative for bronchiolitis obliterans organizing pneumonia?
  • D E Stover
  • D Mangino
Stover DE, Mangino D et al. Macrolides: a treatment alternative for bronchiolitis obliterans organizing pneumonia? Chest 2005; 128:3611-7.