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Organizing pneumonia is a particular type of inflammatory and reparative reaction of the lung parenchyma characterized by fibroblast proliferation in the distal airspaces with overall preservation of the lung architecture. When microscopic, it is an asymptomatic and nonspecific reaction of little clinical significance accompanying many pathological processes. When macroscopic and affecting large portions of the lung parenchyma, it manifests by restrictive ventilatory defect and gas exchange impairment leading to dyspnea, cough, hypoxemia, alveolar opacities at chest imaging, and symptoms of systemic inflammation such as fever, malaise, and weight loss. This picture constitutes the clinico-pathological syndrome of organizing pneumonia, which has been recognized and characterized as a distinct entity in the past 30 years. Although the classical features of organizing pneumonia are increasingly familiar to chest physicians, and the efficacy of corticosteroid treatment makes it appear at first sight as an easy problem to resolve, atypical clinical presentations, similarities with other diseases, severe forms, histological variants, side effects of therapy, and relapses can make the management more difficult than initially expected. This chapter will address the classical and less common features of organizing pneumonia, and will provide practical clues to the diagnosis and management of this disorder.
KeywordsCryptogenic organizing pneumonia Bronchiolitis obliterans organizing pneumonia Idiopathic interstitial pneumonias Treatment Recurrence Acute fibrinous organizing pneumonia
Acute fibrinous organizing pneumonia
Bronchiolitis obliterans organizing pneumonia
Cryptogenic organizing pneumonia
Chronic obstructive pulmonary disease
Diffuse alveolar damage
Granulomatosis with polyangiitis
Nonspecific interstitial pneumonia
New York Heart Association
Secondary organizing pneumonia
Definition and Terminology
Organizing pneumonia is a particular type of inflammatory and fibroproliferative process of the lung leading to a clinico-pathological syndrome. It is characterized clinically by symptoms and signs resulting from inflammation and consolidation of the lung parenchyma, and histologically by the presence of buds of granulation tissue filling the distal airspaces as a reparative process following damage to the alveolar epithelium. Although its histological features were known since the beginning of the twentieth century, the clinico-pathological syndrome of organizing pneumonia has only been described in the early 1980s [1, 2].
Although the term bronchiolitis obliterans with organizing pneumonia (BOOP) used in the original description  became rapidly popular, it led to confusion with bronchiolitis obliterans (BO), a clinically and histologically distinct entity characterized by bronchiolar involvement and airflow obstruction, whereas BOOP mainly affects the alveolar spaces and bronchiolitis, if present, is only an ancillary feature. To clarify this issue, the term BOOP has now been replaced by the more accurate term of organizing pneumonia (OP) . If OP occurs in association with an identified cause or clinical condition, it is called secondary organizing pneumonia (SOP). If no cause is identified, OP is termed cryptogenic organizing pneumonia (COP). COP has been integrated in the international classification of idiopathic interstitial pneumonias in 2002 , and further confirmed in the 2013 update of this classification . The term “organizing pneumonia” has been used both by pathologists to designate a particular but otherwise unspecific histopathological lesion, and by clinicians to describe a specific clinico-pathological syndrome. To clearly identify these two distinct but overlapping concepts, the term organizing pneumonia is now used for the clinico-pathological syndrome, whereas the term organizing pneumonia pattern designates the histopathological lesion .
OP represents 2–10 % of all interstitial lung diseases [5, 6, 7]. In the only epidemiological study available so far, performed in Iceland, the mean annual incidence of OP was 1.97/100,000, with 1.10/100,000 for COP and 0.87/100,000 for secondary OP , meaning that more than half of cases of OP were idiopathic. Men and women were equally affected, at a mean age of 60–70 years. Smoking has not been found a risk factor for OP occurrence.
OP is initiated by an injury to the alveolar epithelium leading to necrosis and shedding of epithelial cells. Denudation and formation of gaps in the basal membranes lead to increased alveolar permeability, and exudation of plasma proteins and coagulation factors into the alveoli [9, 10]. In contrast with diffuse alveolar damage (DAD), there are no hyaline membranes. The endothelium appears only mildly damaged.
Intraalveolar fibrosis resulting from organization of inflammatory exsudates in OP is characterized by dramatic reversibility with corticosteroids, in sharp contrast with fibrosis in the other fibrosing idiopathic interstitial pneumonias, especially usual interstitial pneumonia (UIP), which is irreversible. The mechanisms governing the disappearance of myofibroblasts and fibroblasts from alveolar spaces in OP (spontaneously or with corticosteroids) are poorly understood. Apoptosis may play a role, as apoptotic activity is increased in the newly formed connective tissue in OP . Intraalveolar buds in OP are also characterized by prominent capillarization resembling granulation tissue in cutaneous wound healing . Vascular endothelial growth factor and basic fibroblast growth factor are widely expressed in intraalveolar buds, and angiogenesis mediated by these growth factors could contribute to the reversal of buds in OP .
A 77-year old woman presented because of progressive dyspnea stage NYHA II, cough, fatigue, night sweats, anorexia, and loss of 10 kg over 1 year. A chest X-ray showed a left basal infiltrate. A course of antibiotic therapy had no effect, and the patient was referred to a respiratory physician. A chest CT-scan revealed multiple alveolar opacities with air bronchogram in the lingula, middle lobe, and left lower lobe. Bilateral crackles were present. The patient had never smoked, did not take any medication, had no symptoms of connective tissue disease, and no environmental exposure. C-reactive protein was 38 mg/dL. Hemoglobin was 114 g/L. Leucocytes differential count was normal. Antinuclear antibodies were positive at 1/320 but rheumatoid factor, anti-cyclic citrullinated peptide, anti-double strand DNA and anti-nucleoprotein antibodies were negative. BAL differential count showed 52 % lymphocytes, 6 % neutrophils, and 4 % eosinophils. Cultures were negative. Transbronchial biopsies showed mild chronic interstitial inflammation and intraalveolar fibroblastic buds. Cryptogenic organizing pneumonia was diagnosed. Because of old age, prednisone was started at only 0.5 mg/kg/day (25 mg/day). After 3 days, cough and general symptoms had completely resolved, and dyspnea was markedly reduced. After 2 weeks, chest X-ray was improved. Prednisone was well tolerated and maintained at the same dose for 2 more weeks then tapered over 6 months. The patient was informed about the risk of relapse.
The clinical features of OP are unspecific and mimic other pulmonary diseases especially infections and malignancies. Many patients initially receive one or more courses of empirical antibiotic therapy, and it is only when this treatment proves ineffective that further investigations are performed. The diagnosis of OP is thus frequently delayed by weeks or even months [2, 14, 18, 19, 20, 21, 22, 23].
Frequency of symptoms and signs in organizing pneumonia
No symptoms (incidental finding at chest X-ray)
At pulmonary function testing, OP is characterized by mild to moderate restrictive ventilatory defect. Airflow obstruction is found in only a minority of patients, usually smokers , and probably reflects preexisting chronic obstructive pulmonary disease unrelated to the OP pathologic process. Carbon monoxide diffusion capacity is usually moderately reduced. Mild to moderate hypoxemia is common [2, 13, 14, 18, 19]. Severe hypoxemia is rare and may result from right-to-left blood shunting through densely consolidated lung parenchyma .
Blood cell count usually discloses moderate leucocytosis and neutrophilia [22, 26, 27]. C-reactive protein level and erythrocyte sedimentation rate are usually increased [14, 26, 27, 30]. Bronchoalveolar lavage (BAL) typically shows a mixed pattern alveolitis [14, 20, 21, 23, 24, 31], with predominance of lymphocytes (20–40 %), and a moderate increase of neutrophils (~10 %) and eosinophils (~5 %). Mast cells (~2 %) may be found in one fourth of cases and plasma cells are occasionally present . The lymphocyte CD4/CD8 ratio is usually decreased [14, 21, 23, 24, 31], but it has no specific diagnostic value for OP and is therefore not useful in the diagnostic process. Predominance of eosinophils over lymphocytes is uncommon  and suggests the diagnosis of eosinophilic pneumonia rather than OP (cases with overlapping features of eosinophilic pneumonia and OP have occasionally been reported).
The imaging characteristics of OP are variable, but can be broadly classified into four patterns: (1) multifocal alveolar opacities, (2) isolated nodule, (3) diffuse infiltrative opacities, and (4) others.
Differential diagnosis of migratory pulmonary infiltrates
Organizing pneumonia (cryptogenic or secondary)
Chronic idiopathic eosinophilic pneumonia
Secondary eosinophilic pneumonias due to parasitic infections, drug toxicity, etc.
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
Allergic bronchopulmonary aspergillosis
Granulomatosis with polyangiitis (Wegener’s)
Others (thromboembolic pulmonary manifestations, psittacosis)
Isolated Nodular Form
In pooled data from five series of nodular OP totalizing 105 cases [39, 40, 41, 42, 43], 69 % were men (range across series 56–100 %) and 74 % were smokers or ex-smokers (range 57–72 %, n = 87). Only 47 % were symptomatic (range 17–77 %). A history of recent infection was found in 29 % (range 12–57 %). The upper lobes were affected in 45 % of cases (range 29–58 %, n = 47). The mean size of the nodular opacity was 21 mm (range 6–68 mm). Irregular, lobulated or spiculated margins were present in 72 % (range 54–94 %). An air bronchogram was found in 18 % of cases (n = 47). Satellite nodules were found in 40 % (range 29–56 %, n = 65) and mediastinal lymphadenopathy in 7 % (range 0–19 %, n = 73).
Isolated nodular OP presents with contrast enhancement on CT and positive tracer uptake on positron emission tomography [40, 41], and cannot be confidently distinguished from primary or metastatic malignancy at imaging. This tumor-like appearance frequently leads to surgical resection, and the diagnosis of OP is made retrospectively at pathological examination. In one report, lung resections for isolated nodular OP represented 0.8 % of 1,612 thoracic surgical procedures performed in a 3-year period at one institution . In 105 patients with nodular OP from five series, preoperative transthoracic or transbronchial biopsy was performed in only 23 % of patients (range 0–83 %), whereas 70 % underwent a wedge resection or a segmentectomy (range 17–100), and 7 % had a lobectomy (range 0–24 %). The surgical procedure was curative in most cases without the need for subsequent corticosteroid therapy [40, 41]. Of note, in all of 17 non-operated cases, a spontaneous improvement of the opacity was observed [39, 43]. One practical difficulty in the management of nodular OP is thus to avoid unnecessary lobectomy in this benign disorder mimicking lung cancer. The causes of nodular OP are discussed later in this chapter.
Diffuse Infiltrative Form
A diffuse infiltrative imaging pattern has been reported to occur in 10–40 % of cases in several series of OP [2, 10, 22, 26, 33, 44], some presenting with severe, rapidly progressive disease and respiratory failure [23, 45, 46, 47, 48, 49, 50, 51]. Some cases were associated with drugs, connective tissue diseases, or toxic exposure [50, 51, 52], whereas other appeared cryptogenic [23, 46, 47, 52].
Diffuse infiltrative OP probably represents a heterogeneous group. It has mainly been reported in early series of OP, suggesting misclassification or overlap with other entities which were unknown at that time. Some early descriptions of diffuse infiltrative OP would probably be now better classified as nonspecific interstitial pneumonia (NSIP), an idiopathic interstitial pneumonia described in the 1990s and characterized histologically by homogeneous chronic interstitial inflammation and/or fibrosis with preserved lung architecture, in which intra-alveolar buds of granulation tissue are a common ancillary finding. Hence, OP pattern representing usually less than 10 % (but sometimes up to 20 %) of the total abnormalities is found in half of cases of NSIP at surgical lung biopsy [53, 54]. Sampling of such focal OP lesions by transbronchial biopsies might thus have led to misdiagnose NSIP as diffuse infiltrative OP. It has also been suggested that a continuum exists between OP and NSIP , and that OP/NSIP overlap might explain part of the diffuse infiltrative cases of OP . Hence, patients presenting at imaging with both interstitial changes (histologically corresponding to NSIP) and consolidations (histologically corresponding to OP) have been reported . In a large series of NSIP, the distinction between OP and NSIP has been based upon whether OP pattern represents more or less than 10 or 20 % of the total abnormalities at surgical lung biopsy, an arbitrary criterion . In support of the concept of overlap between OP and NSIP, one study of 22 patients with OP proven by surgical lung biopsy and prolonged CT follow-up reported the evolution of OP consolidations into reticular changes resembling NSIP pattern in a subset of patients . The coexistence of OP and NSIP histological patterns at surgical lung biopsy has been especially observed in idiopathic inflammatory myopathies, in contrast with other autoimmune diseases , but more histological data are needed to support the concept of OP/NSIP overlap as a distinct entity.
Other cases diagnosed as diffuse infiltrative OP may actually have had acute interstitial pneumonia, with OP being only a minor histopathological feature or overlapping with DAD at the organizing stage. Other cases could correspond to “acute fibrinous and organizing pneumonia” (AFOP), a recently described entity combining clinical and pathological features of DAD and OP  (see below).
Finally, other cases initially reported as diffuse OP may have had acute exacerbation of interstitial lung disease, a recently described acute event occurring in the natural history of idiopathic pulmonary fibrosis, NSIP and other fibrotic interstitial disorders . Acute exacerbations of interstitial lung disease have been associated with histological patterns of either OP or DAD at lung biopsy, the former being associated with a much better short term prognosis .
Although genuine diffuse infiltrative OP probably exists, it still awaits better characterization and distinction from similarly appearing entities. Meanwhile, the above-mentioned disorders need to be considered in the differential diagnosis.
Other Imaging Patterns
Rarely, OP may present as multiple, sometimes cavitary nodules [62, 63, 64, 65], a micronodular pattern, with multiple small well- or poorly- defined nodules, or nodules with an air bronchogram . Other variants include a bronchocentric pattern, a perilobular pattern resembling thickened interlobular septas, circumferential subpleural linear opacities, and radial opacities [32, 62, 66, 67, 68, 69]. A “ring-like”, “reversed halo” or “atoll” pattern has rarely been reported in OP, consisting of a focal round area of ground glass surrounded by a crescent or ring of consolidation (Fig. 24.4b) . Contrary to early beliefs, this sign is not specific to OP and may also be found in Churg-Strauss syndrome, granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis), chronic eosinophilic pneumonia, lymphomatoid granulomatosis, tuberculosis, and various fungal infections .
Histopathological Diagnosis of OP Pattern
Disorders in which organizing pneumonia pattern may be found as an ancillary histopathological feature
Organization distal to airway obstruction
Nonspecific interstitial pneumonia
Desquamative interstitial pneumonia
Chronic idiopathic eosinophilic pneumonia
Secondary eosinophilic pneumonias
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
Granulomatosis with polyangiitis (Wegener’s)
Primary pulmonary lymphoma
Diffuse alveolar damage
Drug reactions and toxic exposures
Compatible clinical picture, imaging and bronchoalveolar lavage (see text)
- B.OP pattern at histopathology obtained by transbronchial, transthoracic, or surgical lung biopsy*, showing:
Presence of intraluminal organizing fibrosis in distal airspaces (bronchioles, alveolar ducts, and alveoli) as the predominant feature, patchy distribution of lesions, uniform temporal appearance, mild chronic interstitial inflammation, and overall preservation of lung architecture
Absence of other significant abnormalities such as interstitial fibrosis, granulomas, neutrophilic infiltration or abscesses, necrosis, hyaline membranes, prominent airspace fibrin, prominent eosinophilic infiltration, and vasculitis
A diagnosis of OP without biopsy is acceptable if a typical clinico-radiological picture and a well-identified cause are present, and if an infectious process has been ruled out
If the patient is too frail or too old for a biopsy, an empirical treatment of corticosteroids may be acceptable, but the risk-benefit ratio of empirical therapy should be carefully weighted in individual cases. Mimics of OP should be ruled out by history and clinical examination, blood and/or urine analyses, and BAL, especially pulmonary infection, drug toxicity, environmental exposure, granulomatosis with polyangiitis (Wegener’s), and lymphoproliferative disorder
If corticosteroids are administered empirically, a critical re-assessment of the diagnosis should be performed after 2–4 weeks. A rapid and complete response to corticosteroids provides an additional argument in favor of OP, although disorders mimicking OP may also initially respond to corticosteroids (see text). Lack of response to corticosteroids after 2–4 weeks should lead to reconsider the initial diagnosis of OP
Adapted from Ref. 
Clinicopathological Diagnosis of OP Syndrome
The clinicopathological diagnosis of OP requires the combination of clinical, imaging and histopathological features. Thus, OP is essentially a multidisciplinary diagnosis. BAL is recommended in virtually all cases presenting with multiple or diffuse opacities at imaging in which a diagnosis of OP is suspected. It allows to exclude an active infectious process and to differentiate OP from other inflammatory disorders having a similar picture such as eosinophilic pneumonias. A histological proof of OP should be obtained whenever possible . Transbronchial lung biopsy (TBB) is the most commonly used method, whereas surgical lung biopsy is now performed in a minority of cases, although it can be considered as the gold standard for histological diagnosis of OP.
The diagnostic value of BAL and TBB to diagnose COP has been analyzed in one study . In 37 consecutive patients presenting with clinical features suggestive of COP and bilateral patchy infiltrates at chest X-ray, BAL with >25 % lymphocytes combined with 2 out of 3 other criteria (foamy macrophages >20 %, neutrophils >5 %, or eosinophils >2 % and <25 %) had a sensitivity of 63 % and a specificity of 57 % to diagnose COP . A sensitivity of 20 % and a specificity of 89 % were found in another study using the same criteria . Transbronchial biopsies showing buds of granulation tissue in distal airspaces, chronic inflammation of the alveolar walls, and preserved lung architecture were 64 % sensitive and 86 % specific for the diagnosis of COP . Although generalization of these data is questionable, expert opinion-based current international guidelines consider that if the clinical and imaging picture is typical with multifocal opacities, a TBB showing also typical intraalveolar buds of granulation tissue is sufficient to confidently diagnose OP [3, 55].
Transthoracic CT-guided needle biopsy has been recently reported as a useful minimally invasive diagnostic method for OP with a high diagnostic yield [75, 76]. Most patients studied had unilateral or bilateral consolidations or tumor-like lesions, and only a few had a diffuse infiltrative pattern [75, 76]. The most frequent complications were subclinical pneumothorax and minor hemoptysis, occurring in around 30 % of cases. As transthoracic needle biopsy usually provides larger tissue samples than transbronchial biopsy, it may constitute an alternative to surgical lung biopsy in some cases (Fig. 24.5b). However, experience with this technique for the diagnosis of OP is currently insufficient to recommend it for routine clinical use.
Biopsy may be omitted in a minority of cases with typical clinico-radiological and BAL features, and a clearly identified causal agent of OP such as radiotherapy for breast cancer within the past year, recent documented infectious pneumonia, or obvious drug toxicity. In COP, a combination of typical BAL and multiple patchy parenchymal consolidations at imaging has been found diagnostic in half of cases in one series in the absence of a biopsy, and this strategy deserves further studies . If the risk/benefit ratio of lung biopsy is considered unfavorable due to old age, frail patient or significant comorbidities, a presumptive diagnosis of OP and an empirical treatment of prednisone may be an acceptable strategy. However, the disadvantages of prolonged empirical corticosteroid therapy in the absence of a clear diagnosis, and the risk of false diagnosis of OP, should also been kept in mind. Hence, disorders mimicking the clinical and imaging features of OP may initially respond to corticosteroid treatment, including GPA (Wegener’s), primary pulmonary lymphoma, NSIP, or hypersensitivity pneumonitis. Therefore, if the disease follows an unusual course or the response to therapy is inadequate, the diagnosis of OP should be reconsidered, especially if the initial diagnosis was made without biopsy or with transbronchial biopsy only.
After having assessed the clinical, imaging and histopathological features which make OP a likely diagnostic hypothesis, one must consider other disorders presenting with similar features such as infections, tumors and other inflammatory lung diseases. Imaging could be a starting point to address the differential diagnosis.
In cases presenting with single or multiple areas of parenchymal consolidation, the main differential diagnosis includes infections, minimally invasive or invasive adenocarcinoma (formerly bronchoalveolar carcinoma), eosinophilic pneumonias (either idiopathic or secondary to a known cause), GPA (Wegener’s), Churg-Strauss syndrome, and primary pulmonary lymphoma. The distinction between OP and GPA may be challenging in some cases, as GPA may present with clinical, imaging, and even histological features of OP pattern [11, 71]. Although the latter usually consist of small foci of OP at the vicinity of otherwise typical granulomatous lesions, OP pattern may occasionally be a prominent histological finding in GPA [11, 71].
In patients presenting with a solitary nodule or mass, lung cancer is the main working hypothesis until proven otherwise. When multiple nodules are present, the differential diagnosis includes metastatic tumors, lymphomas, and pulmonary infections including septic emboli.
If OP presents as a diffuse infiltrative disorder at imaging, the differential diagnosis mainly includes hypersensitivity pneumonitis, NSIP, acute interstitial pneumonia, other idiopathic interstitial pneumonias, and acute exacerbation of preexisting interstitial lung disease.
Etiological Diagnosis of OP
The next step in the diagnostic process of OP is to distinguish between SOP and COP. The search for a cause or associated condition should not be overlooked, as removal of an offending agent, such as a drug, is an essential part of therapy. Since there is no clinical, radiological, or histological characteristic allowing to confidently distinguish COP from secondary OP , the diagnosis of COP is made by exclusion, when the search for a cause remains negative.
Causes of secondary organizing pneumonia, with relative frequencies of main categories
Bacteria (Chlamydia pneumoniae, Coxiella burnetii, Legionella pneumophila, Mycoplasma pneumoniae, Nocardia asteroides, Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus aureus, Streptococcus group B, Streptococcus pneumoniae), virus (herpes virus, human immunodeficiency virus, influenza, parainfluenza, adenovirus, cytomegalovirus, hepatitis C), parasites (Plasmodium vivax), fungi (Cryptococcus neoformans, Penicillium janthinellum, Pneumocystis jiroveci)
5-Aminosalicylic acid, amiodarone, amphotericin, azathioprine, barbiturates, beta blockers, bleomycin, busulphan, carbamazepine, cephalosporin, clomipramine, cocaine, erlotinib, everolimus, gold salts, interferon, L-tryptophan, mesalazine, minocycline, nitrofurantoin, nilutamide, oxaliplatin, phenytoin, rituximab, sulfasalazine, tacrolimus, thalidomide, temozolomide, ticlopidine, transtuzumab. See also www.pneumotox.com
Solid tumors and hematologic malignancies
Systemic lupus erythematosus, Behçet disease, rheumatoid arthritis, polymyalgia rheumatica, polymyositis and dermatomyositis, systemic sclerosis, mixed connective-tissue disease, Sjögren syndrome, ankylosing spondylitis
Radiation therapy for breast carcinoma
Allografts (lung, bone marrow, kidney, liver)
Inflammatory bowel diseases
Toxic exposures (acramin FWN – an aerosolized textile dye, paraquat, sulfur dioxide, house fire, paraffinic mineral oil)
Post-obstructive pneumonia and aspiration pneumonia
IgA nephropathy, thyroiditis, primary biliary cirrhosis, mesangiocapillary glomerulonephropathy, Sweet’s syndrome, common variable immunodeficiency, essential mixed cryoglobulinemia, coronary artery bypass graft surgery
OP may occur in women receiving radiation therapy for breast cancer [82, 83, 84, 85, 86, 87], with a reported incidence of 1.8 % among 2,056 patients followed by chest-X-ray every 3 months for 1 year . Affected patients are women treated by tumorectomy or mastectomy followed by chemotherapy or hormonal therapy, and radiation therapy of approximately 50 Gy on the tumoral site and homolateral lymph nodes. The clinical picture is identical to COP and starts on average 14 weeks after the irradiation, although it can occur up to 1 year later . In contrast to classical radiation pneumonitis, which is limited to the radiation field, radiation-induced OP also affects the lung outside the radiation field and frequently involves the controlateral lung. Opacities may be migratory. BAL shows a typical mixed pattern alveolitis. The outcome is favorable under corticosteroid treatment . Despite the frequent occurrence of relapses, a complete cure is usually observed. In milder cases, spontaneous disappearance without corticosteroids has been reported . Interestingly, this variant of OP has been almost exclusively described in women irradiated for breast carcinoma, and only rarely in individuals of both genders irradiated for other types of tumors, especially lung cancer. The particular tangential irradiation fields used for breast cancer could play a role. A bilateral lymphocytic alveolitis has been reported to occur in 85 % of women receiving unilateral irradiation for breast cancer and, despite being asymptomatic in most cases, could be an early event in the occurrence of OP . Hormonal factors could also be involved. Hence, in one study, age >50 and anti-estrogen therapy were significantly correlated with the occurrence of OP, with odd ratios of respectively 8.88 and 3.05 . However, given the importance of hormonal therapy for tumor control in these patients, avoidance or interruption of hormonal therapy to prevent or cure OP cannot be recommended at the present time.
The cause and mechanisms of focal OP are probably different from the other forms of OP. Although some authors found focal OP to be idiopathic in most cases , others have reported underlying COPD in up to 67 % of cases, and recurrent respiratory infections in up to 57 % , suggesting that focal OP may be triggered and preceded by an infectious process. In support of this hypothesis, one study reported the occurrence of small neutrophil aggregates in the vicinity of localized OP (with otherwise typical OP pattern at histopathology) in 73 % of cases . Aspiration of food particles may be another cause of focal OP . In one retrospective study of 59 cases of aspiration pneumonia, OP pattern was the predominant histopathological pattern in 88 %, usually associated with particulate foreign material, multinucleated giant cells, acute pneumonia, bronchiolitis, or suppurative granulomas . Twenty-two percent of these cases presented as solitary nodules suspect of lung cancer, whereas food aspiration was clinically suspected in less than 10 % . Infraclinical particulate matter aspiration pneumonia may thus be a relatively common cause of lung nodules presenting with OP pattern at histopathology. Interestingly, the prevalence of active or former smoking appears high in series of isolated nodular OP (57–93 %) [39, 40, 41, 42, 43]. It is currently unknown whether smokers are more prone to develop this presentation of OP, or are simply more likely to undergo a surgical procedure for such nodular lesions resembling lung cancer.
In the majority of cases, OP has no recognizable cause  and is termed cryptogenic OP (COP). COP has been integrated in 2002 in the classification of idiopathic interstitial pneumonias , and maintained in the 2013 update of this classification in the category of major idiopathic interstitial pneumonias (acute/subacute disorders) .
Corticosteroids are the current standard treatment of OP [2, 14, 20, 22, 26, 31, 34], although spontaneous improvement has occasionally been reported [2, 88]. Clinical improvement usually occurs within 2–3 days after treatment onset. Pulmonary infiltrates at chest X-ray usually markedly improve within a few days. On average, a >50 % improvement at imaging usually occurs within 3 weeks of treatment, and complete cure is observed after around 3 months [21, 22]. The spectacular and reproducible response to corticosteroids can even be considered as an additional diagnostic feature of the clinical syndrome of OP, and if this response is poor, the initial diagnosis should be reconsidered. Besides corticosteroids, removal of the causing agent should be done whenever possible in secondary OP.
Proposed therapeutic regimen for typical COP
Doses of prednisone for the initial episode
Doses of prednisone for the first relapse (mg/day)
Whether SOP should be treated differently from COP is currently unclear. Some data suggest that SOP is associated with less frequent resolution of symptoms and higher mortality than COP , but no such difference was found in another recent large series . In a recent comparison of COP and OP secondary to connective tissue disease, treatment modalities, improvement rate and mortality rate were similar, although complete recovery was slightly more frequent in COP . Thus, at the present time, no data support the use of different treatment regimens for SOP and COP.
Not all cases of OP require treatment. In six large series totalizing 418 cases [2, 23, 27, 31, 52, 93], 12 % of patients (range across series 3–23 %) did not receive corticosteroids. Among 26 of these cases with reported outcome, spontaneous improvement was noted in 8/26 and complete cure in 16/26 [23, 52, 93]. In another study of 12 women with OP after radiation therapy for breast cancer detected by systematic chest X-ray, only 6 were symptomatic. Hormonal treatment was temporarily withheld in 9, and complete cure was observed in all without corticosteroids . Thus, in asymptomatic patients with mild OP, corticosteroids may not be necessary, and careful clinical and chest-X-ray follow-up may be the best initial strategy.
Several macrolide antibiotics (erythromycin, clarithromycin, azithromycin) have been found to have anti-inflammatory properties, which have been first observed in Japanese panbronchiolitis. A significant clinical benefit of azithromycin has now been demonstrated by randomized controlled trials in several other airway diseases including cystic fibrosis, bronchiolitis obliterans syndrome after lung transplantation, bronchiectasis, and more recently COPD. A beneficial effect of erythromycin and clarithromycin has also been reported in small uncontrolled series of COP and OP secondary to radiation therapy for breast cancer [94, 95, 96, 97]. In a retrospective series of 12 patients with mild or moderate OP, the administration of clarithromycin 1,000 mg/day for 3–4 months led to complete cure in 7 cases, and an improvement in 2, whereas 3 other patients did not respond and required prednisone as a rescue therapy [97, 95]. Altogether, in the cases reported so far, onset of clinical improvement with macrolides appeared much slower than with corticosteroids (weeks instead of days) and therapeutic response was less constant [94, 95, 96, 97]. Given the current paucity of evidence, the use of macrolides for the treatment of OP is currently not recommended in the usual clinical setting.
Clinical Course and Outcome
In typical multifocal COP, the outcome is usually excellent with disappearance of symptoms and normalization of imaging in more than 80 % of cases . In a minority of cases, some minor fibrous sequellae can persist at imaging. Overall mortality in COP is reported to be <5 % [22, 23]. It has been suggested that the prognosis could be less favorable in SOP than in COP [2, 13, 26, 50], but a recent formal comparison did not find any significant difference between COP and SOP in clinical features, response to therapy, relapses and outcome .
COP is characterized by the frequent occurrence of relapses when corticosteroid treatment is tapered or stopped [1, 2, 14, 22]. Single or multiple relapses have been reported in up to 58 % of cases . Most relapses occur within the first year, while patients are still taking low-dose prednisone (usually <10 mg/day) for the initial episode. A relapse occurring under higher doses (>20 mg/day) or >18 months after the initial episode is unusual and should prompt to carefully re-assess the diagnosis. The cause of relapses is unknown, but the initial episode of COP and the subsequent relapses may be viewed as a single pathological process, which progressively abates over time . Relapses are not due to insufficient prednisone dose for the initial episode, but delayed treatment onset could be a risk factor . Other factors associated with the occurrence of relapses include more severe hypoxemia at first examination , elevation of serum gamma-glutamyl-transferase and alkaline phosphatase , and the multifocal form of OP . Importantly, relapses did not affect morbidity and mortality . Therefore, preventing relapses by extending treatment duration appears unnecessary in most cases, and the strategy should rather aim at minimizing the adverse effects of corticosteroids. To avoid unnecessary concerns, the possible occurrence of relapses, and even multiple relapses, should be explained to the patient during tapering of prednisone for the initial episode. The occurrence of a relapse in OP should prompt to reconsider the hypothesis of a persisting causal agent, such as a drug, which has not been removed initially.
Aggressive treatment of relapses was initially recommended, but they now appear as a relatively benign phenomenon, which can usually be controlled with a moderate increase of corticosteroid treatment. Accordingly, a low-dose regimen of 6-month duration to treat relapses of COP has been proposed (Table 24.5), starting at 20 mg/day of prednisone . In localized OP, relapses are less common [40, 41], but also respond to corticosteroids. Mild asymptomatic relapses detected at chest X-ray may be observed without treatment.
Severe Forms of OP with Respiratory Failure
Patients with severe OP have been reported in several small series and isolated cases [23, 46, 47, 50, 51, 52]. Some of these cases were secondary to collagen vascular diseases, drugs, or toxic exposure to an aerosol textile dye [50, 51, 52] and others were idiopathic [23, 46, 47, 52]. In the 44 cases from five series with available data [46, 47, 50, 51, 52], nearly all patients received high-dose corticosteroids, 32 % received immunosuppressive drugs (mostly cyclophosphamide), and 43 % required mechanical ventilation. Twenty-seven percent recovered, 9 % evolved to chronic respiratory insufficiency or required lung transplantation, and 64 % died. Factors which have been associated with a poorer outcome in OP include presence of collagen vascular disease , diffuse infiltrative pattern at imaging [14, 100], absence of lymphocytosis at BAL [14, 50], and interstitial fibrosis with architecture remodeling of lung parenchyma at histopathology . As several of these characteristics are atypical in OP, it is possible that some of these cases had in fact other disorders in which OP pattern was only an ancillary histological finding, such acute interstitial pneumonia, acute respiratory distress syndrome, acute exacerbation of interstitial lung disease, or acute fibrinous and organizing pneumonia (see below). Alternatively, some cases may have had a true overlap between OP and one of these entities. Hence, among ten patients with severe OP and characteristic OP pattern at lung biopsy, seven died and five of them had associated UIP pattern, honeycombing or DAD at autopsy . In other cases, OP may have been the initial pathologic process, but lung injury may have occurred as a secondary event due to superimposed infection or drug toxicity. Both multifocal and diffuse infiltrative imaging patterns have been described in severe OP .
Acute Fibrinous and Organizing Pneumonia
Acute fibrinous and organizing pneumonia (AFOP) has been first described in 2002 as an entity with overlapping features of DAD and OP . Two very different clinical courses have been observed with the same histological picture, and the imaging characteristics have not been fully characterized. Therefore, in contrast with OP, AFOP cannot be currently viewed as a clinico-pathological syndrome but rather as a particular and uncommon histopathological pattern, which clinical significance needs to be further clarified. AFOP has been integrated in the 2013 classification of idiopathic interstitial pneumonias in the category of rare histopathological patterns .
Conditions associated with acute fibrinous and organizing pneumonia
Haemophilus influenzae, Acinetobacter baumanii, severe acute respiratory syndrome coronavirus, Pneumocystis jiroveci, human immunodeficiency virus
Abacavir, amiodarone, busulfan, decitabine
Polymyositis, dermatomyositis, ankylosing spondylitis, systemic lupus erythematosus, primary biliary cirrhosis
Lymphoma, acute lymphocytic leukemia
Construction worker, animal exposure (zoologist), excessive hair-spray use, coalminer
Hematopoetic stem cell transplantation
Histopathological features of acute fibrinous and organizing pneumonia
Organizing intra-alveolar fibrin “balls” as dominant finding
Organizing pneumonia pattern, less prominent than fibrin balls
Patchy distribution of lesions
Mild to moderate acute and/or chronic interstitial inflammation
Alveolar septal expansion by myxoid connective tissue
Type 2 pneumocyte hyperplasia
Interstitial changes co-localized with patchy intra-alveolar fibrin lesions, with only minimal changes in the intervening parenchyma
Prominent eosinophilic inflammation
Prominent neutrophilic inflammation or abcesses
In its original description, AFOP was classified as a fibrinous variant of DAD, which however differs from classical DAD by several aspects: (1) organizing intra-alveolar fibrin was the dominant feature, whereas it is less prominent in classical DAD, (2) fibrin was organized into “balls” with a patchy distribution, as opposed to the widespread changes found in DAD, (3) intervening lung parenchyma appeared relatively normal in most cases, and (4) hyaline membranes were absent. AFOP differed from typical acute infectious pneumonia by the absence of significant neutrophilic inflammation. AFOP also markedly differed from classical OP by the predominance of intra-alveolar fibrin over intra-alveolar buds of granulation tissue. Besides histopathological differences, AFOP and classical OP were characterized by different disease course . However, one cannot rule out that AFOP corresponds to a particular variant of severe OP, with lung biopsy performed at an early stage of the OP pathogenic process when fibrin fills the alveolar spaces before being colonized by proliferating fibroblasts to constitute the classical buds of granulation tissue. Further studies are needed to clarify this issue.
Similarly to the OP pattern, the histological AFOP pattern has been found as a minor nonspecific reaction in the vicinity of abcesses, necrotizing granulomas, GPA (Wegener’s) lesions, and lung carcinomas . For this reason, and until more data become available, transbronchial biopsies should not be considered adequate to diagnose AFOP, and this pattern can currently be identified only by surgical lung biopsy.
Treatment of AFOP is not codified. In the original report, most patients received antibiotics and/or corticosteroids, but no correlation was found between treatment modalities and outcome . However, more than half of the patients did not receive corticosteroids, or received them late in the disease course. It therefore cannot be concluded that steroids are not effective in AFOP. Furthermore, significant and even dramatic improvement with corticosteroids has been reported by some authors . The usefulness of cyclophosphamide and mycophenolate mofetil in addition to corticosteroids has been occasionally reported [102, 103]. Similarly to classical COP, relapses have been reported in AFOP .
Until the clinical significance of the AFOP pattern is further clarified, this histopathological finding should lead the clinician to consider the disease course as potentially more severe and life-threatening than classical OP. Similarly to OP, a cause or associated condition should be looked for in AFOP, and removed whenever possible. Corticosteroids seem effective in a number of cases and a steroid treatment should be attempted after having ruled out or treated an infectious process.
The author acknowledges Dr Samuel Rotman and Dr Igor Letovanec, Institute of Pathology, Lausanne University Hospital, for providing several of the histological pictures.
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