PULMONARY GRAND ROUNDS Eduardo Santiago March 08,2012

HPI 65 year old woman, no PMH. Subjective fever, chills, malaise and mild cough 1 month ago. Progressive shortness of breath. Dry cough.

HPI Seen by her PCP: Diagnosis of CAP. Azithromycin for 1 week. Started on oxygen.

PMH: Unremarkable. SH: ½ pack per day for 20 years. Denies any occupational or recreational exposure. Denies any prior use of medications. ROS: Unremarkable.

PE HR 70, BP 126/80, RR 14, T 100, O2 SAT 90% on 2 LPM Weight: CHEST EXAM: Decreased breath sound at both bases. Diffuse inspiratory crackles at both lower lungs. CARDIAC EXAM: RRR, S1 and S2 within normal limits. No S3 or S4. EXTREMITIES: No edema. No clubbing or cyanosis. SKIN: No skin rash.

WBC9.8 HB14.4 HT44 Platelets366 ESR44 ANANone detected RF<7 Jo-1 IgG0 ANCA<1/20 Scl 700

FVC: 1.36L (46%) FEV1: 0.91 (40%) FEV1/FVC: 87% DLCO:5.89 (25%)

BAL Macrophages :46% Lymphocytes:7% Neutrophils:43% Bronchial lining cells:4%

Pathology Patchy organizing pneumonia, fibroblastic intra alveolar infiltrate, scattered lymphocytes within the interstitium. No significant acute inflammation. No granulation tissue. No evidence of vasculitis.

DateFEV1FVCFEV1/FVCDLCO Aug (40%)1.36L (46%)87%5.89 (25%) Nov (60%)1.64 (56%)82%9.46(40%)

COP

J.M Charcot 1877–1878. Milne: Type of pneumonia where the usual process of resolution has failed and organization of the inflammatory exudate in the air alveoli of the lung by fibrous tissue has resulted.

COP Organizing pneumonia: Endobronchial connective tissue masses composed of myxoid fibroblastic tissue resembling granulation tissue. Central cluster of mononuclear inflammatory cells. Chronic inflammation in the walls of the surrounding alveoli. Preserve lung architecture.

COP Organizing pneumonia pathologic pattern is a nonspecific reaction that results from alveolar damage with intra-alveolar leakage of plasma protein with alveolar organization.

COP Clinical, radiological and pathological diagnosis. Pattern of organizing pneumonia must be prominent.

Pathogenesis The intra alveolar fibrosis is its usual dramatic reversibility with corticosteroids and not associated with progressive irreversible fibrosis.

Pathogenesis/ First Stage Alveolar epithelial injury with necrosis and sloughing of pneumocytes resulting in the denudation of the epithelial basal lamina. The endothelial cells are only mildly damaged. Infiltration of the alveolar interstitium by inflammatory cells: lymphocytes, neutrophils and eosinophils.

Pathogenesis/ Second Satge Intra alveolar stage: formation of fibrinoid inflammatory cell clusters with prominent bands of fibrin and inflammatory cells. Formation of fibro inflammatory buds, fibrin is fragmented and reduction of inflammatory cells. Migration of fibroblast from the interstitium and proliferation.

Pathogenesis/Second Stage Myofibroblast. Proliferation of the alveolar cells and re epithelialization of the basal lamina.

Pathogenesis/Third stage Inflammatory cells have disappeared. There is no fibrin within the alveolar lumen. Concentric rings of fibroblasts alternate with layers of connective tissue.

Connective Matrix Loose connective matrix with high type III collagen content which is more susceptible to degradation and reversal of fibrosis.

Angiogenesis Prominent capillarization of the intra alveolar buds. Vascular endothelial growth factor and basic fibroblast growth factor. Angiogenesis could contribute to the reversal of buds in OP.

Pathogenesis The opposing mechanisms of reversibility of fibrosis in COP and ongoing fibrosis in UIP are not yet established.

Radiology

Multiple alveolar opacities: typical COP. Solitary opacity: focal COP. Infiltrative opacities: infiltrative COP.

Diagnosis Diagnosis of organizing pneumonia. Exclusion of any possible cause. Histopathology: Buds of granulation tissue consisting of fibroblasts myofibroblasts embedded in connective tissue.

Diagnosis Definite: compatible clinicoradiologic manifestations and typical pathologic pattern on a pulmonary biopsy of sufficient size. Probable: findings of organizing pneumonia on transbronchial biopsy and a typical clinicoradiologic presentation without pathologic confirmation. Possible: typical clinicoradiologic presentation without biopsy confirmation.

Treatment Rapid clinical improvement and clearing of the opacities. The precise dose and duration of treatment have not been established. Prednisone 0.75–1.5 mg/kg/day mg/kg/day during 4 weeks, followed by 0.5 mg/kg for 4 weeks, then 20 mg for 4 weeks, 10 mg for 6 weeks, and then 5mg for 6 weeks.

Treatment Complete clinical and physiologic recovery in 65 % of patients. Gary Epler. Bronchiolitis Obliterans Organizing Pneumonia. NEJM; 1985:152-8

Treatment Predictors of relapse: delayed treatment and mildly increased gammaglutamyltransferase and alkaline phosphatase levels.

Treatment Severe cases: prednisolone 2mg/kg/day for the first 3-5 days.

Treatment Spontaneous improvement. Macrolides: Patients with minimal symptoms and/or minimal physiologic impairment. Adjuvant therapy in patients receiving steroids. Patients who cannot tolerate steroids. 3 to 6 months or longer. Diane E. Stover.Macrolides: A Treatment Alternative for Bronchiolitis Obliterans Organizing Pneumonia?. CHEST 2005; 128:3611–3617

Reference American Thoracic Society/European Respiratory Society. Classification of the idiopathic interstitial pneumonias: international multidisciplinary consensus. American Thoracic Society/European Respiratory Society. Am J Respir Crit Care Med 2002;165: 277–304. J.-F. Cordier. Cryptogenic organizing pneumonia. Clinics in Chest Medicine 2004;25 : 727– 738. J.-F. Cordier. Organising pneumonia. Thorax 2000;55:318–328. J.-F. Cordier. Cryptogenic organizing pneumonia. Eur Respir J 2006; 28: 422–446.