Accepted Manuscript Submission Date: 2025-08-15

Accepted Date: 2025-09-16

Accepted Manuscript online: 2025-09-18

Seminars in Respiratory and Critical Care Medicine

Cryptogenic Organizing Pneumonia
Michael Z Root, Joyce S Lee.

Affiliations below.

DOI: 10.1055/a-2703-4537
This article is protected by copyright. All rights reserved.

Please cite this article as: Root M Z, Lee J S. Cryptogenic Organizing Pneumonia. Seminars in Respiratory and Critical Care Medicine
2025. doi: 10.1055/a-2703-4537

Conflict of Interest: Michael Root

None

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Joyce Lee
I have received grants from the NIH and Boehringer Ingelheim, outside the submitted work.

Accepted Manuscript
I have received an unrestricted research gift from Pliant, outside the submitted work.

I have received consulting fees from Blade, Boehringer Ingelheim, Astra Zeneca, Elima, Gatehouse Bio, Mannkind, Syndax, Mediar
Therapeutics, Abbvie, BMS, Avalyn and Eleven P15, outside the submitted work.

I am/have been a DSMB member for United Therapeutics and Pulmovant, outside the submitted work

I am an advisor for the Pulmonary Fibrosis Foundation, outside the submitted work.

I am a section editor for UpToDate and Merck, outside the submitted work.

Abstract:
Cryptogenic organizing pneumonia (COP), formerly called bronchiolitis obliterans organizing pneumonia (BOOP), was first
described in the 1980s and is classified as a rare idiopathic interstitial pneumonia (IIP). COP classically presents in a subacu-
te fashion following a flu-like illness with fever, non-productive cough, and fatigue. Imaging often reveals diffuse, bilateral,
peribronchovascular and peripheral consolidative and ground glass opacities although various imaging subtypes also exist.
Physical exam may be normal or reveal inspiratory crackles. Hypoxemia, when present, is commonly identified with exertion
but can also occur at rest. Diagnostic evaluation relies on excluding secondary causes of organizing pneumonia and includes
a thorough history including medications, exposures, and signs or symptoms of underlying rheumatologic disease. Invasive
diagnostic testing including tissue sampling allows for histopathologic confirmation of COP while excluding secondary causes
including infection and malignancy. While video-assisted thorascopic surgery (VATS) lung biopsy is often the preferred method
of obtaining sufficient tissue, less invasive means may be employed based on patient-specific factors. A defining feature of COP
is steroid-responsiveness, and most experts recommend prolonged corticosteroid courses (6-12 months). Response to corti-
costeroids and prognosis is typically excellent. Relapse rates range from 25-50% and occur most often during steroid taper or
complete withdrawal necessitating additional therapy. Steroid-sparing immunosuppression may be used in select circumstan-
ces. Further study is needed to define optimal corticosteroid dose and duration.

Corresponding Author:
Dr. Michael Z Root, University of Colorado Anschutz Medical Campus, Division of Pulmonary, Allergy, and Critical Care Medicine, Auro-

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service
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 ra, United States, michael.root@cuanschutz.edu

Contributors‘ Statement: Michael Z Root: Conceptualization, Visualization, Writing - original draft, Writing - review & editing. Joyce S.
Lee: Conceptualization, Project administration, Supervision, Writing - review & editing.

Affiliations:
Michael Z Root, University of Colorado Anschutz Medical Campus, Division of Pulmonary, Allergy, and Critical Care Medicine, Aurora,
United States
Joyce S Lee, University of Colorado Anschutz Medical Campus, Division of Pulmonary, Allergy, and Critical Care Medicine, Aurora, United
States
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Accepted Manuscript

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service
to our customers we are providing this early version of the manuscript. The manuscript will
undergo copyediting, typesetting, and review of the resulting proof before it is published in its
final form. Please note that during the production process errors may be discovered which could
affect the content, and all legal disclaimers that apply to the journal pertain.
 Cryptogenic Organizing Pneumonia

Michael Z. Root, MD
Assistant Professor of Medicine
Division of Pulmonary, Allergy, and Critical Care Medicine

Joyce S. Lee, MD
Professor of Medicine
Division of Pulmonary, Allergy, and Critical Care Medicine
This article is protected by copyright. All rights reserved.

University of Colorado Anschutz Medical Center

Department of Medicine
Division of Pulmonary, Allergy, and Critical Care Medicine
Aurora, CO, USA, 80045

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Key Words:

Accepted Manuscript
Cryptogenic Organizing Pneumonia (COP)
Organizing Pneumonia (OP)
Idiopathic Interstitial Pneumonia (IIP)
Bronchiolitis Obliterans Organizing Pneumonia (BOOP)
Interstitial Lung Disease (ILD)

Abstract

Cryptogenic organizing pneumonia (COP), formerly called bronchiolitis obliterans organizing

pneumonia (BOOP), was first described in the 1980s and is classified as a rare idiopathic

interstitial pneumonia (IIP). COP classically presents in a subacute fashion following a flu-like

illness with fever, non-productive cough, and fatigue. Imaging often reveals diffuse, bilateral,

peribronchovascular and peripheral consolidative and ground glass opacities although various

imaging subtypes also exist. Physical exam may be normal or reveal inspiratory crackles.

Hypoxemia, when present, is commonly identified with exertion but can also occur at rest.

Diagnostic evaluation relies on excluding secondary causes of organizing pneumonia and

 includes a thorough history including medications, exposures, and signs or symptoms of

underlying rheumatologic disease. Invasive diagnostic testing including tissue sampling allows

for histopathologic confirmation of COP while excluding secondary causes including infection

and malignancy. While video-assisted thorascopic surgery (VATS) lung biopsy is often the

preferred method of obtaining sufficient tissue, less invasive means may be employed based on

patient-specific factors. A defining feature of COP is steroid-responsiveness, and most experts

This article is protected by copyright. All rights reserved.

recommend prolonged corticosteroid courses (6-12 months). Response to corticosteroids and

prognosis is typically excellent. Relapse rates range from 25-50% and occur most often during

steroid taper or complete withdrawal necessitating additional therapy. Steroid-sparing

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immunosuppression may be used in select circumstances. Further study is needed to define

Accepted Manuscript
optimal corticosteroid dose and duration.

History and Terminology:

Cryptogenic organizing pneumonia (COP) was first described in 1983 by Davison et al in a case

series of eight patients with a steroid-responsive but potentially relapsing, non-infectious

pneumonia without a clear underlying cause (1). Then, Epler et al in 1985 described a larger

cohort of patients with bronchiolitis obliterans of which about half (50/94) had no identifiable

underlying cause or disease. Patients presented after a flu-like illness with radiographic patchy

ground glass and histopathologic organizing pneumonia. They described the steroid-

responsiveness as a crucial distinguishing factor compared to bronchiolitis obliterans with

irreversible obstruction. The term BOOP – bronchiolitis obliterans organizing pneumonia – was
 coined and became increasingly popular to describe this disease entity, despite fundamental

differences between OP and bronchiolitis (2). It wasn’t until 2002 that the American Thoracic

Society (ATS) and the European Respiratory Society (ERS) developed an updated taxonomy of

terms for the idiopathic interstitial pneumonias (IIPs), of which COP became the preferred term

and BOOP was no longer recommended to avoid confusion and misclassification for distinct

entities such as constrictive bronchiolitis (3).

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COP remains a rare IIP and requires a thorough evaluation to exclude secondary causes of

organizing pneumonia given the impact it has on treatment and prognosis. This review will

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outline the clinical presentation including radiographic and histopathologic findings, discuss the

Accepted Manuscript
diagnostic evaluation and major differential, and present a treatment approach for COP.

Epidemiology:

The mean age of diagnosis is often in the fifth or sixth decade of life with a wide age range (15

to 87 years). The exact incidence and prevalence of disease may vary by geographic location and

is difficult to measure as most studies are small and include both COP and secondary organizing

pneumonia. A retrospective study in Iceland reported annual incidence of COP to be 1.10 per

100,000 (4). The incidence is roughly similar between men and women. In some small studies,

COP may be more common in non-smokers than smokers (2:1) which differs from many other

interstitial lung diseases where smoking is considered a major risk factor (4-6).

Clinical Presentation:
 Clinical History:

The initial workup for patients with suspected COP includes a thorough history encompassing

time course and description of symptoms, recent sick contacts or illnesses, presence or absence

of pre-existing pulmonary disease, and evaluation of prior empiric therapies and their efficacy.
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COP typically presents in a subacute fashion (weeks to less than 2-3 months) following a flu-like

illness with fever, non-productive cough, fatigue, and weight loss. Hemoptysis is a rare finding.

A history of non-resolving pneumonia despite standard of care antimicrobial therapy is common

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and points to the non-infectious yet inflammatory nature of COP.

Accepted Manuscript
Patients should also undergo a full rheumatologic review of systems to evaluate for underlying

connective tissue disease, a detailed exposure history evaluating for risk factors for

hypersensitivity pneumonitis, and a review of their medication list for culprit drugs that can

cause pulmonary toxicity, which can present with similar symptoms and radiographic

abnormalities.

The physical exam may be normal but can demonstrate inspiratory crackles and the notable

absence of extra-pulmonary findings of a systemic autoimmune disease. Wheezing and digital

clubbing are rare clinical manifestations. Patients with substantial parenchymal disease will

present with exertional and sometimes resting hypoxemia. Rarely does COP present with a

rapidly progressive phenotype with respiratory failure requiring hospitalization.

 Laboratory Testing:

Laboratory analysis reveals non-specific elevation in inflammatory markers (C-reactive protein

(CRP) and erythrocyte sedimentation rate (ESR)). A basic evaluation for infection may yield a

peripheral leukocytosis, often with increased neutrophils. Serologic evaluation for connective

tissue disease is often normal or negative and is an important distinction to rule out underlying

rheumatologic disease which can first present with organizing pneumonia. A basic serologic
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evaluation encompasses antinuclear antibodies (ANA) with titer, rheumatoid factor (RF), anti-

cyclic citrullinated peptide (CCP), anti-topoisomerase I antibodies (Scl-70), centromere

antibodies, and an extended myositis panel. Patients who have gas exchange abnormalities

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and/or require hospital admission often undergo a more thorough evaluation for infectious

Accepted Manuscript
etiologies including community or hospital acquired pneumonia with sputum gram stain and

cultures as well as ancillary testing such as respiratory viral panel and urine antigen testing for

Legionella pneumophila and Streptococcus pneumoniae. Evaluation for underlying

immunodeficiency with HIV testing and quantitative immunoglobulins should be considered in

the right clinical context, particularly if evidence of recurrent or non-resolving pneumonias.

Pulmonary Function Testing:

Pulmonary function testing most commonly demonstrates an isolated diffusing capacity

impairment. A restrictive ventilatory defect may be present but spirometry and lung volumes are

often normal in mild disease. Serial spirometry and DLCO can provide non-invasive and

objective measures to monitor disease course and response to therapy over time (6).

Radiology:
 All patients should undergo a formal high-resolution computed tomography (HRCT) scan to

evaluate the underlying lung parenchyma, as plain chest radiographs may underestimate the

parenchymal abnormalities. Serial imaging is also useful for monitoring clinical response to

therapy over time. Typical radiographic patterns include focal or multi-focal areas of

consolidation and ground glass (Figure 1). Chest x-ray most often reveals a diffuse, bilateral

alveolar filling process. Opacities are often peripheral and peribronchovascular with mid and
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lower lung predominance although upper lobe disease can occur (7). Air bronchograms are often

present with consolidation reflecting the alveolar filling process. Infiltrates may also be

migratory in nature, waxing and waning spontaneously over time on serial imaging which can

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also be seen in other diseases such as eosinophilic pneumonia or vasculitis (8). Focal

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consolidations and/or nodular disease are less common and can be mistaken for malignancy. A

characteristic and specific imaging pattern of a “reversed halo sign” or “atoll sign” can be seen in

about 20% of patients with COP. This is defined as an ovoid or circular area of consolidation

with internal ground glass (9, 10). In one study, HRCT findings of patchy parenchymal

consolidation without interlobular septal thickening or honeycombing had a specificity of 99%

but a sensitivity of only 38% (11). Predominant reticulation on imaging is less common and has

been associated with incomplete resolution on follow-up (12).

Bronchoscopy:

Bronchoalveolar lavage (BAL) cellular analysis often reveals a non-specific inflammatory

pattern of cells. Poletti et al evaluated the performance of BAL and transbronchial biopsies

(TBLB) in diagnosing COP. BAL criteria for the diagnosis of COP were: >25% lymphocytosis,

CD4/CD8 < 0.9, foamy macrophages >20%, neutrophils > 5%, and eosinophils >2% but < 25%.
 TBLB were diagnostic if there was evidence of granulation tissue in the air spaces, chronic

inflammation in alveolar walls, and preservation of alveolar architecture. BAL alone was

reported to have a sensitivity of 63% and a specificity of 57%. TBLB had a sensitivity of 64%

and specificity of 86% (13).

Perhaps most importantly, BAL allows for exonerating infectious causes for presenting
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symptoms and pulmonary infiltrates, but also provides reassurance prior to initiation of

prolonged corticosteroids in the treatment for COP. Bronchoscopy can also rule-out common

radiographic mimics including eosinophilic pneumonia (typically >25% eosinophils) and diffuse

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alveolar hemorrhage (serially bloody lavage samples). BAL cytology can assist in evaluating for

Accepted Manuscript
underlying malignancy, including pulmonary lymphoma and adenocarcinoma, which can present

similarly.

Pathogenesis and Histopathology:

It is hypothesized that COP develops after an acute lung injury event, whether occult infection,

micro or macro aspiration, or other environmental exposures. Following lung injury, there is

accumulation of loose fibromyxoid granulation tissue containing collagen and fibrin within the

small airspaces (alveoli, alveolar ducts, and terminal bronchioles) which produces the

histopathologic characteristic finding of Masson bodies (Figure 2). Granulation tissue may

extend to adjacent alveolar spaces through pores of Kohn. There is notably preserved

background lung architecture without significant fibrosis and absent or only mild interstitial

inflammation. There may be increased alveolar foamy macrophages. Histopathologic diagnosis

 of COP also relies on the absence of findings to suggest secondary OP such as granulomas,

infection, malignancy, or vasculitis. There are no specific features on histopathology alone that

differentiate COP from secondary OP requiring clinical investigation.

Video-assisted thorascopic surgery (VATS) lung biopsy is often the preferred method of

obtaining sufficient lung tissue for histopathologic diagnosis of COP given the need to exclude
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other types of parenchymal lung disease. However, less invasive methods such as transbronchial

lung biopsy (TBLB), percutaneous CT-guided core biopsy, or transbronchial cryobiopsy are

alternatives in certain cases and may provide sufficient diagnostic information in patients who

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cannot safely undergo surgical lung biopsy or would prefer to avoid surgical interventions.

Accepted Manuscript
TBLB provide much smaller tissue samples which can limit diagnostic accuracy and provide a

provisional rather than definitive diagnosis. Core needle biopsies are larger than TBLB and may

be more appropriate for patients with focal lesions who do not undergo surgical resection. In one

retrospective study, CT-guided biopsies had a diagnostic accuracy of 88% for OP (14). The

method of tissue sampling, when feasible, should be patient specific.

Differential Diagnosis:

When considering a diagnosis of COP, secondary causes of organizing pneumonia must be

excluded. While not exhaustive, Table 1 outlines common causes of secondary organizing

pneumonia. As discussed previously, a thorough history, physical exam, and laboratory

evaluation should be undertaken to evaluate for and exclude these secondary causes prior to
 making a diagnosis of COP. Based on radiographic appearance, the differential diagnosis also

includes chronic eosinophilic pneumonia, malignancy, and systemic vasculitis.

Treatment: corticosteroids

Corticosteroids are the cornerstone of treatment for COP although in some cases, the radiologic
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opacities will spontaneously resolve. One observational study reported that 16/40 patients had

spontaneous resolution and clinical improvement within 2 weeks. Spontaneous resolution was

associated with lower CRP levels, a higher BAL lymphocyte ratio, and a longer duration from

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symptoms to diagnosis compared to those treated with corticosteroids (15).

Accepted Manuscript
There are no randomized controlled trials studying the most effective dose or duration of

therapy. Most experts recommend prolonged treatment for 6-12 months of corticosteroid therapy

(Figure 3) (16). Corticosteroids are typically started at 0.5-1.0 mg/kg of Prednisone using ideal

body weight (IBW), depending on disease severity. This dose is continued for 2-4 weeks of

therapy while monitoring for clinical response which tends to occur rapidly, within days, of

starting therapy. A lack of clinical response to corticosteroids should prompt reconsideration for

an alternative diagnosis. If patients demonstrate clinical response based on a combination of

symptomatic, radiographic, and physiologic improvement, this initial dose is tapered down to

about 0.5 mg/kg at 2-3 months then tapered further to 0.25 mg/kg at 4-6 months. Corticosteroids

are then tapered off more gradually over the following 6 months for a total duration of therapy

between 6 and 12 months. Prophylaxis against Pneumocystis jirovecii is recommended when on

corticosteroid doses of 20 mg daily or more of prednisone equivalent for over 2-4 weeks.
 The rationale for a slower taper at the end of therapy is related to the risk of COP relapse.

Relapse rates have ranged from 25-50% depending on the study and definition. Relapse most

commonly occurs when corticosteroids are tapered below 10-15 mg/d or stopped entirely (6, 17-

19). Relapse is most often treated with re-initiation of corticosteroids with a slower taper,

although corticosteroid-sparing immunosuppressing agents (see below) are sometimes used if

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relapse recurs, or significant side effects of corticosteroid therapy develop.

Other Treatments:

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Accepted Manuscript
Macrolides

Macrolides, most commonly Azithromycin and Clarithromycin, have a variety of anti-

inflammatory properties that target cytokines which are up regulated in patients with COP. These

agents have been shown to decrease cytokine levels in both the serum and BAL fluid (20, 21). In

clinical practice, macrolide therapy has been described in case reports and small case series as

effective treatment for patients with COP especially those who are unable to tolerate

corticosteroids (22-24).

Immunosuppression: corticosteroid-sparing

There are case reports of using corticosteroid-sparing immunosuppressing agents to treat COP,

often in the setting of corticosteroid-refractory disease or when patients suffer significant side

effects from long-term corticosteroid use. Described agents used as monotherapy or in

 combination include azathioprine (25), mycophenolate mofetil or mycophenolic acid (26, 27),

IVIg (28), cyclosporin (29), cyclophosphamide (30), and rituximab (31).

COP Variants:

Cicatricial Variant:
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Rarely, COP can develop into a progressive disease where loose connective tissue filling the

airspaces is replaced by dense eosinophilic scar tissue with preservation of background lung

architecture. Patients may present with reticulonodular disease which is less responsive to

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corticosteroids and can develop into fibrotic interstitial pneumonia (32).

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Focal OP:

OP that presents with a focal consolidation may be radiographically mistaken for malignancy.

Focal OP can be mildly PET avid further increasing concern over malignancy (33). Focal OP can

regress spontaneously or with corticosteroids, although many patients undergo surgical resection

given concerns for malignancy, which is also curative. In two small case series where patients

presented with a focal imaging opacity, most were asymptomatic and were treated with surgical

resection. Among unifocal OP patients, only two had a recurrence that required additional

corticosteroids (34, 35). With the advent of less invasive tissue sampling techniques,

bronchoscopic or CT-guided biopsies may be obtained demonstrating characteristic OP

histopathology and potentially sparing surgical resection.

Acute Fibrinous Organizing Pneumonia (AFOP):

 A rare subtype of OP that can present with a subacute clinical course or a more rapidly

progressive course with acute respiratory failure. AFOP can be idiopathic or secondary to

another underlying disease process. Biopsy samples demonstrate organized intra-alveolar fibrous

tissue with pneumocyte hyperplasia, patchy organizing pneumonia, and absence of hyaline

membrane formation. Response to immunosuppression is preserved but more variable, relapse

rates are higher, and prognosis is worse overall (36-40).

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Conclusion and Future Directions:

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Cryptogenic organizing pneumonia remains a rare idiopathic interstitial pneumonia that relies on

Accepted Manuscript
integration of clinical, radiographic, and histopathologic data for accurate diagnosis. Additional

studies are needed to better characterize the incidence and prevalence of this disease and how to

more accurately differentiate COP from secondary organizing pneumonia. While COP is

characteristically a corticosteroids-responsive condition, further study is warranted to define the

optimal dose and duration of corticosteroids to ensure resolution while limiting treatment side

effects and relapse rates.

Conflicts of Interests:

Dr. Root has no conflicts of interest to disclose.

Dr. Lee has received grants from the NIH and Boehringer Ingelheim, has received an
unrestricted research gift from Pliant, consulting fees from Blade, Boehringer Ingelheim, Astra
Zeneca, Elima, Gatehouse Bio, Mannkind, Syndax, Mediar Therapeutics, Abbvie, BMS, Avalyn
and Eleven P15, is and has been a DSMB member for United Therapeutics and Pulmovant, is an
advisor for the Pulmonary Fibrosis Foundation and a section editor for UpToDate and Merck, all
outside the submitted work.
This article is protected by copyright. All rights reserved.

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Table 1: Causes of Secondary Organizing Pneumonia Accepted Manuscript

Figure 1 – Radiographic Patterns in COP

Figure 1: Radiographic Patterns in COP

Panel A) Cross-sectional CT image from a patient with focal organizing pneumonia presenting
with a peribronchovascular right lower lobe consolidation initially considered infectious or
malignant. Panel B) CT image depicting the reversed halo or “atoll sign” with a rim of
consolidation with central clearing or ground glass. Panel C and D) High-resolution CT (HRCT)
images from the same patient taken two months apart with no intervening treatment
demonstrating migratory, patchy, peribronchovascular ground glass opacities.
 Figure 2 – Histopathologic Features of COP

Figure 2: Histopathologic Features of COP

Panel A) High-magnification hematoxylin and eosin (H&E) demonstrating intraluminal plugs of
loose connective tissue with preserved background lung architecture. Panel B) Another high-
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magnification H&E stain demonstrating the “butterfly pattern” of loose connective tissue
extending between alveoli through pores of Kohn. Note background mild inflammatory infiltrate
with preserved lung architecture. Panel C) Pentachrome stain highlighting a focus of organizing
pneumonia in green. Panel D) Low-magnification H&E stain showing acute fibrinous and
organizing pneumonia (AFOP) characterized by intra-alveolar fibrin (asterisk).
Images courtesy of Dr. Carlyne Cool, MD. University of Colorado and National Jewish Health.

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Accepted Manuscript
Figure 3 – COP Corticosteroid Treatment Approach

Figure 3: COP Corticosteroid Treatment Approach

Corticosteroids dosing, typically with Prednisone, is performed using ideal body weight (IBW).
Steroids are tapered based on clinical response and tolerance of therapy for total duration of 6-
12 months. Clinical assessments occur throughout treatment course often at time points denoted
by arrows but adjusted for patient-specific monitoring. Prophylaxis against Pneumocystis
jirovecii is recommended when on corticosteroid doses of 20 mg daily or more of prednisone
equivalent for over 2-4 weeks.

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Table 1: Causes of Secondary Organizing Pneumonia

Infections Bacterial, viral, fungal, tuberculosis and non-tuberculous

mycobacterium

Medications * Antibiotics: cephalosporins, daptomycin, nitrofurantoin

Antifungals: amphotericin
Biologics: adalimumab, rituximab
Chemotherapy
Immunotherapy: trastuzumab, pembrolizumab
Immunosuppressants: azathioprine
Antidepressants
Cardiac: amiodarone, bleomycin, beta blockers, hydralazine

Connective Tissue Diseases Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis

(RA), Sjogren’s Syndrome, Dermatomyositis/Myositis

Systemic vasculitis Granulomatosis with polyangiitis (GPA), Microscopic

polyangiitis (MPA), Eosinophilic granulomatosis with
polyangiitis (EGPA)

Radiation Exposure Particularly breast cancer

Malignancy Primary pulmonary malignancy, lymphoma

 Post-transplant Bone marrow, stem cell, solid organ

Hypersensitivity pneumonitis

Inflammatory Bowel Disease Ulcerative colitis (UC), Crohn’s Disease (CD)

Exposures including inhalational Drugs, toxins

* See pneumotox.com for a complete list of medications associated with OP

Sources (16, 41-43)
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Accepted Manuscript
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Accepted Manuscript
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This article is protected by copyright. All rights reserved.

Accepted Manuscript
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