Revista Clínica de la Escuela de Medicina UCR – HSJD Año 2015 Vol 5 No II Rev Cl EMed UCR www.revistaclinicahsjd.ucr.ac.cr 27 abril 2015 11 CASO 5-2015: Cryptogenic organizing pneumonia. Hospital San Juan de Dios, San José, Costa Rica. Fundado en 1845 Case Report Recibido: 09/03/2015 Aceptado: 25/03/2015 Mario Sibaja Campos1 Cecilia Monge Bonilla2 1Internal Medicine Department. Hospital San Juan de Dios, C.C.S.S. San José, Costa Rica. 2Internal Medicine Department. Hospital San Juan de Dios, C.C.S.S. San José, Costa Rica. Email: cecili- amonge4@yahoo.com ABSTRACT Cryptogenic organizing pneumonia (COP) is a distinct histopathologic entity characterized by Masson bodies which are intraalveolar buds of granulation tissue; consisting of connective tissue and myofibroblasts. This pathologic pat- tern when present with the characteristic imag- ing and clinical features of COP defines the diagnosis of the disease. A specific etiology is not found. Treatment with corticosteroids re- sults in a rapid clinical and imaging improve- ment but unfortunately relapses are common upon decreasing the dose or stopping the treat- ment. This case report describes a typical case of COP with the characteristic improvement with corticosteroid therapy and relapse upon treatment taper KEY WORDS Cryptogenic organizing pneumonia, intra- alveolar fibrosis, butterfly pattern, bronchiolitis obliterans organizing pneumonia, alveolar wall, Masson bodies. CASE REPORT A 52-year-old otherwise healthy woman is ad- mitted to our hospital due to dry cough, dyspnea on moderate exertion, fever (not quantified) and night sweats for one month and a pulmonary right basal consolidation. Prior to admission the patient received treatment with Levofloxacin 750 mg per day for seven days without im- provement. On physical exam upon admission she was afebrile, tachycardic (heart rate 114 bpm), blood pressure was 130/70 mmHg and not hypoxemic. She was alert and oriented; pulmonary ausculta- tion revealed crackles with diminished breath sounds over the right lower hemi thorax. The rest of the physical exam was unremarkable. The erythrocyte sedimentation rate (ESR) was 65 mm. h-1, C reactive protein (CRP) was 16.8 mg/dl, white blood cell (WBC) count was in- creased at 152.000 with a left shift. The rest of routine laboratory tests including electrolytes, renal and liver function were normal. Tests for collagen vascular disease including RF and ISSN 2215-2741 Revista Clínica de la Escuela de Medicina UCR – HSJD Año 2015 Vol 5 No II Rev Cl EMed UCR www.revistaclinicahsjd.ucr.ac.cr 27 abril 2015 12 ANA were negative. Brain natriuretic peptide (BNP) and procalcitonin were within normal limits. Cultures of bronchial aspirate for myco- bacteria and serology of respiratory viruses was negative, immunoglobulin levels were normal. Figure 1. CT of the lung showed a right posterior segmentary consolidation. You can find a full video of this CT scan in: https://www.youtube.com/channel/UCgRZTxrN cN6zMkw0ih9Rkaw Computed tomography (CT) of the lung showed a right basal posterior segmentary consolidation, a pulmonary embolism was ruled out with an angio-CT (figure 1). Bronchial lavage (BAL) differential cell count revealed lymphocytosis and an increase in polymorphonuclear cells (cell count: 18.3% macrophages, 61.8% lymphocytes, 18.2% polymorphonuclear and 1.8% bronchial cells). The diagnostic impression was an organized pneumonia due to the nonspecific inflammatory lymphoplasmocytic cellularity. Specimens were smear and culture negative. Cytologic analysis was normal. Pulmonary function tests showed a forced vital capacity (FVC) 64% of predicted value, forced expiratory volume in 1 sec. (VEF1) 63% pred. and FEF 25-75% 52% pred. The pathologic review of the lung specimen had revealed Masson bodies; polypoid structures consisting of fibroblasts within the alveolar ducts and bronchioles. A chronic interstitial inflammatory infiltrate was present with promi- nent hyperplasia of type II pneumocytes and intraalveolar macrophages (figure 2). The latter observations were consistent with the diagnosis of cryptogenic organizing pneumonia. Figure 2. Chronic interstitial inflammatory infil- trate was present with prominent hyperplasia of type II pneumocytes and intraalveolar macro- phages. During the hospital stay the patient did not re- ceive antibiotics. The diagnosis of cryptogenic organizing pneumonia was made but steroid treatment was not started pending the tuberculin test result (which was negative). She was dis- charged with ongoing pulmonary clinical symp- toms. The patient was seen in the outpatient clinic two weeks after discharge and treatment with 50 mg of prednisone daily was started. She underwent the six-minute walk test (6MWT) and reached 420 mts. presenting desaturation with a pO2 62 mmHg. The DLco was 75% pred. The plethis- mography showed a VC of 73% pred. with normal TLC and RV values. Pulmonary func- tion tests had a FVC 73% pred. and normal VEF1 and FEF25-75% values. The ESR was 21 mm. h-1 and CRP 0.33 mg/dl. Two months after discharge the patient was seen in the outpatient clinic. On physical exam, pul- Revista Clínica de la Escuela de Medicina UCR – HSJD Año 2015 Vol 5 No II Rev Cl EMed UCR www.revistaclinicahsjd.ucr.ac.cr 27 abril 2015 13 monary auscultation was normal. The chest x- ray showed a significant improvement with radiopaque lines probably due to interstitial fibrosis. CRP was 0.36 mg/dl. Pulmonary func- tion tests were normal and on 6MWT she walked 70 m further without desaturation. Three months after discharge the patient contin- ued asymptomatic and the dose of prednisone was reduced to 25 mg daily. Five months later she presented with a normal pulmonary exam as well as normal chest x-ray and pulmonary func- tion tests. ESR was 65 mm. h-1, the dose of prednisone was decreased at a rate of 5 mg per week until reaching 10 mg daily. In the following year after discharge, the patient continued asymptomatic and with normal pul- monary function tests. During this period of time the dose of prednisone was reduced to 5 mg daily and eventually to 5 mg every 48 hours. One week after the decrease in dose of predni- sone to 5 mg every 48 hours, the patient pre- sents with dyspnea, cough and thoracic pain. On physical exam crackles are present on ausculta- tion of the right upper hemi thorax. Chest x-ray shows an alveolar infiltrate in the right upper lobe (figure 3). The dose of prednisone is in- creased to 25 mg daily. One week later the pa- tient is found to be asymptomatic and pulmo- nary auscultation is normal; ESR is 5 mm. h-1. Figure 3. Chest x-ray: alveolar infiltrate in the right upper lobe. In the following four months the patients con- tinues asymptomatic. Pulmonary exam, chest x- ray and pulmonary function tests are normal; prednisone treatment is decreased to a dose of 5 mg per day. Prophylaxis for Pneumocystis jiro- veci is started with Trimethoprim- sulfamethox- azole (160 mg/800 mg) three times per week. Pulmonary CT shows diffuse laminar atelectasis prominent in the right upper lobe. Currently the patient has been asymptomatic for the last five months on prednisone 5 mg daily and continues follow up in the outpatient clinic. DISCUSSION Cryptogenic organizing pneumonia (COP) is the idiopathic form of organizing pneumonia con- sisting of a diffuse interstitial lung disease af- fecting the alveolar walls as the most important area of injury, alveolar ducts, respiratory bron- chioles and distal bronchioles.(1-3) It is only considered to be cryptogenic when there is not a definite etiology of organizing pneumonia.(4) An incidence of 6 to 7 cases per 100.000 hospi- tal inpatients was found in one study,(5) the annual incidence in other studies has been 1.1 per 100.000.(6) Pathogenesis The most interesting characteristic of COP is that it is not associated with progressive irre- versible fibrosis; the fibrosis seen in COP usual- ly has a marked reversibility with corticoster- oids differentiating COP from usual interstitial pneumonia (UIP). The first stage in the process of organization of the fibrosis seen in COP consists of the for- mation of fibrinoid inflammatory cell clusters, which consist of inflammatory cells including polymorphonuclears, lymphocytes, mast cells and plasma cells with bands of fibrin.(7) The formation of fibroinflammatory buds (Mas- son bodies) is characteristic of the second stage; inflammatory cells are less numerous and fibrin is fragmented. The presence of mitotic figures is proof of the migration and proliferation of fi- broblasts from the interstitium to the basal lami- nae and their colonization of fibrin remnants. A reepithelialisation of the basal laminae takes place because of the proliferation of alveolar cells; this reepithelialisation is vital for the preservation of the integrity of the structure of the alveolar unit.(8) The final stage of the process of organization is characterized by mature fibrotic buds with al- most no inflammatory cells and the fibrin in the alveolar lumen has disappeared; layers of con- nective tissue alternate with concentric rings of fibroblasts.(9) Revista Clínica de la Escuela de Medicina UCR – HSJD Año 2015 Vol 5 No II Rev Cl EMed UCR www.revistaclinicahsjd.ucr.ac.cr 27 abril 2015 14 The intra-alveolar buds in COP are character- ized by prominent capillarisation.(10) Intraalveo- lar buds express basic fibroblast growth factor and vascular endothelial growth factor.(11) These growth factors mediate angiogenesis and are important for the reversal of buds seen in COP with treatment. Clinical Features The mean age of onset of COP is 50-60 years; males and females are affected equally. Clinical manifestations include progressive mild dysp- nea, cough, fever, malaise, anorexia and weight loss. Uncommon manifestations include hemop- tysis, night sweats, mild arthralgia and chest pain.(12,13) Diagnosis is many times delayed because of the nonspecific manifestations. On physical exam the pulmonary exam may present focal sparse crackles or may be normal. Imaging COP has three patterns of presentation on imag- ing studies; solitary opacity (focal COP), multi- ple alveolar opacities (typical COP) and infiltra- tive opacities (infiltrative COP). CT images are characteristic and yield the correct diagnosis in approximately 80% of cases.(14) The most frequent imaging seen in COP con- sists of multiple alveolar opacities, which are mostly peripheral, bilateral and migratory. Their size varies between a complete lobe and a few centimeters; air bronchogram may be present. When patients with COP present with the typi- cal imaging characteristics of the disease on CT scan or HRCT scan the differential diagnosis narrows down to include bronchioalveolar lung carcinoma, idiopathic chronic eosinophilic pneumonias and low-grade lymphoma.(15) Patients presenting with infiltrative or focal COP on imaging are usually diagnosed through histopathology since these patterns are not char- acteristic of the disease. Lung Function Tests On spirometry patients with COP frequently have a moderate to mild restrictive ventilatory defect. Obstructive abnormalities are not char- acteristic of the disease, although they may be seen in patients with underlying chronic ob- structive pulmonary disease or smoking. The reduction of pulmonary restriction is propor- tional to the reduction of the transfer factor of the lung for carbon monoxide. Hypoxemia both with mild exertion and at rest are usually mild.(16,17) Bronchioalveolar lavage (BAL) is indicated in all cases where COP is being considered as a differential diagnosis. BAL may evidence neo- plastic pathologies (bronchioalveolar carcinoma or lymphoma) as well as active infections. Pa- tients with COP characteristically present a BAL with a mixed pattern differential cell count; consisting of an increased percentage of lymphocytes (20-40%), neutrophils (approxi- mately 10%) and eosinophils (approximately 5%); the percentage of eosinophils is character- istically lower than that of lymphocytes. The CD4/ CD8 ratio is usually low.(18,19) Blood tests may present a mild leukocytosis with a mild increase in neutrophils. Eosinophilia is not present. Erythrocyte sedimentation rate and C- reactive protein are characteristically elevated.(20) Diagnosis of COP The diagnosis of COP requires the histopatho- logic diagnosis of organizing pneumonia and the exclusion of any specific cause. Histopatho- logically the typical features of organizing pneumonia are buds of granulation tissue (Mas- son bodies) consisting of myofibroblasts- fibro- blasts embedded in connective tissue. These buds may extend through the interalveolar pores presenting a “butterfly pattern”.(21,22) Foamy alveolar macrophages are present as well as mild interstitial inflammation. Special stains to exclude infection are usually the norm in patients being studied for possible COP. It is imperative to have enough amount of lung tis- sue to be able to perform a meticulous histo- pathologic study; because of this, video assisted thoracoscopy is usually performed in these patients to obtain lung tissue of sufficient size. However in some cases, such as the one pre- sented here, the finding of intra alveolar buds is seen on transbronchial biopsy specimens.(23) Organizing pneumonia within a specific content Organizing pneumonia can be present as a pul- monary manifestation in patients with connec- tive tissue disorders (dermatomyositis- polymiositis, systemic lupus erythematosus, rheumatoid arthritis, CREST, scleroderma and Sjogren syndrome). It may also present with malignancies, hematological diseases and in- flammatory bowel disease. These disorders must be considered and ruled out as appropriate when making the diagnosis of COP. That said, patients with COP have been reported to have articular pain without an underlying disorder.(13) Revista Clínica de la Escuela de Medicina UCR – HSJD Año 2015 Vol 5 No II Rev Cl EMed UCR www.revistaclinicahsjd.ucr.ac.cr 27 abril 2015 15 Treatment of COP Treatment decisions in COP are usually based on practice guidelines since treatment of COP has not been studied in randomized clinical trials.(24) Initiation as well as choice of first line therapy is usually based on pulmonary function on presentation, the severity of clinical symp- toms and the extent and severity of disease on imaging studies as well as the progression of the disease.(25) Patients with COP who have mild symptoms as well as mild abnormalities on pulmonary func- tion tests are usually monitored every 2-3 month intervals without treatment.(26) For symptomatic patients with moderate to severe respiratory impairment glucocorticoid treatment is recommended; the equivalent of 1 mg/kg per day (maximum 100 mg daily) is given as a single dose in the morning. Predni- sone is the drug of choice and the initial dose is given for up to eight weeks, if the patient shows improvement the dose is tapered to 0.5 mg/kg/day for the next six weeks and then gradually tapered to nothing as long as the pa- tient is stable.(26) After the cessation of treatment with prednisone the patient should be followed for the next twelve months and the chest radio- graph is repeated every three months during this period of time.(27) Patients with impending respiratory failure or rapidly progressive COP are treated with high dose intravenous glucocorticoid therapy (methylprednisolone 1.000 mg intravenously for five days) as the treatment of choice.(28,29) Addition of a second immunosuppressant agent is used when patients fail to respond to initial glucocorticoid therapy, have frequent recurrenc- es (more than three) or those who have a fulmi- nant presentation; azathioprine or cyclophos- phamide are the medications of choice in these particular COP cases.(30-32) Patients who are going to receive azathioprine should undergo analysis of the enzyme thiopurine methyltrans- ferase gene since a deficiency of this enzyme predicts those individuals with a higher risk of severe toxic events from this medication.(33) Treatment with glucocorticoids results in clini- cal improvement and normalization of chest imaging in a short period of time (days to weeks) in the majority of patients. 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J Am Geriatr Soc. 2003;51: 433. COMMENTS A special thank you to Alvaro Herrera Alfaro MD for his valuable contribution to the figures in this case report