Pulmonary Manifestations of GVHD Jonathan Douds August 23,

Pulmonary Manifestations of GVHD Jonathan Douds August 23,

Pulmonary Manifestations of GVHD Jonathan Douds August 23, 2013 Outline Introduction and Background Graft versus Host Disease Pulmonary Disease Associated with GVHD Research and Literature

Graft versus Host Disease Acute and chronic forms of the disease have been described Historical definitions Acute occurs within the first 100 days post allotransplant Chronic occurs from 3 m post allotransplant onwards

Acute GVHD Inflammatory process which finally leads to the target organ being damaged Chronic GVHD Resemble autoimmune disease and may affect any recipients organ Risk increases with recipient age and donor age Associated with loss of self-tolerance Graft versus Host Disease Acute vs. Chronic GVHD (Table 2 from Filipovich, et al., BB&MT 11:945-955 (2005)) Category

Time of Symptoms after HCT or DLI Presence of Acute GVHD Features Presence of Chronic GVHD Features LE 100 d

Yes No Yes No No Yes Acute GVHD Classic acute

GVHD Persistent, > 100 d recurrent, or late-onset acute GVHD Chronic GVHD Classic, chronic GVHD No time limit Graft versus Host Disease

In the past, any manifestation of GVHD still present at 100 days was arbitrarily considered chronic GVHD Chronic GVHD requires the following: Distinction from acute GVHD Presence of at least 1 diagnostic clinical sign of chronic GVHD OR 1 manifestation confirmed by biopsy Exclusion of other diagnoses Chronic GVHD can have many manifestations including:

Bronchiolitis Keratoconjunctivitis sicca Esophageal stricture Review of Pulmonary Function Tests Barrerio TJ and Perillo I. Am Fam Physician. 2004 Mar 1;69(5):1107-14. Complications of Stem Cell Transplantation Late complications defined as occurring beyond 3 months Separated into delayed (3m-2y), late (2y10y), and very late (>10y)

Delayed pulmonary complications involve airway and lung parenchyma Complications of Stem Cell Transplantation Common non-infectious late complications include Bronchiolitis obliterans

BOOP Idiopathic pneumonia syndrome Appear within 3m to 2y after HSCT In auto-transplants, pulmonary complications are unusual after 3m In allo-transplants, the incidence of delayed onset pulmonary complications is higher, with a worse clinical outcome and delayed onset Bronchiolitis Obliterans Organizing Pneumonia Clinical symptoms Acute, dry cough, dyspnea, fever

Radiology CXR demonstrates patchy consolidation, ground glass attenuation and nodular opacities Pulmonary function tests Restrictive pattern with decreased TLC and DLCO but normal FEV

Incidence <2% Bronchiolitis Obliterans Organizing Pneumonia Clinicopathological syndrome involving bronchioles, alveolar ducts, and alveoli Lumens of alveoli become filled with buds of

granulation tissue In setting of HSCT, presents as an interstitial pneumonia rather than an airway disease Compared to BO, occurs earlier in the course of HSCT, mainly between 1 and 12 months post transplant Bronchiolitis Obliterans Organizing Pneumonia Definitive diagnosis based on histopathology Systemic corticosteroids or inhaled corticosteroids are first line therapy for BOOP/COP Poor prognosis associated with progressive disease

Idiopathic Pneumonia Syndrome Occurs within 120 days after transplantation and is related to TBI, pretransplant chemo, GVHD and older age at HSCT

Presentation and radiographic findings are nonspecific and do not differ from infection pneumonia PFTs show a restrictive pattern with decreased TLC but normal FEV1 It is rare for delayed onset IPS to progress to respiratory failure Bronchiolitis Obliterans Clinical characteristics Chronic cough, dyspnea, limitation of airflow,

and lack of response to bronchodilators Once the nonspecific symptoms develop, the airflow obstruction is already significant and irreversible Clinical diagnosis made when the following criteria are met: FEV1/FVC ratio <0.7 and FEV1 <75% of predicted Air trapping or small airway thickening or bronchiectasis on CT Absence of infection Bronchiolitis Obliterans

Histology Thickened, fibrotic hypocellular walls Contain mononuclear inflammatory cell infiltrate including lymphocytes and plasma cells Luminal narrowing; progression of disease causes obliteration of lumen Irreversible mural and luminal fibrotic scarring of bronchioles Narrowing or obliteration of airway lumens Major site of airway narrowing is in the terminal and respiratory bronchioles less than 2 mm in internal diameter BO

Bronchiolitis Obliterans Etiologies Complication of lung or bone marrow transplantation Estimates suggest that it develops after allo-HSCT among 1-2% of transplanted population Inhalation of toxic agents such as nitrogen dioxide, sulfur dioxide, ammonia, chlorine Use of drugs such as gold, penicillamine Sequel of infections such as adenovirus Systemic disorders including rheumatoid arthritis, lupus, ulcerative colitis, among others

Important to distinguish from other processes with may worsen with the use of immunosuppressive agents Bronchiolitis Obliterans Pathogenesis Not well understood May involve the role of lymphocytes, fibroblasts, and growth mediators Pulmonary function testing Obstructive ventilatory defects

No response to bronchodilators Progressive destruction with decreasing FEV1 (bronchiolitis obliterans syndrome) Bronchiolitis Obliterans Radiology Chest radiographs may be normal in early stages In more advanced stages, radiographs show hyperinflation, peripheral attenuation of vascular margins, and nodular or reticulonodular opacities High resolution CT with inspiratory and

expiratory images is the procedure of choice to assess changes Characteristic mosaic image seen in bronchiolitis obliterans Bronchiolitis Obliterans Alloimmunity postulated to be involved Usually associated with concurrent involvement of other organs such as skin, gut, liver, or eyes with GVHD Involvement of donor T cells is thought to be central in the development of BOS Because GVHD develops despite

immunomodulation of T cells in all-HSCT, other pathways are likely involved Bronchiolitis Obliterans Commonly used therapies High dose corticosteroids used in cGVHD with standard dosing usually at 1 mg/kg/day Many complications Inhaled corticosteroids Lack of systemic risks Local therapy

Other immunosuppressives Calcineurin inhibitors, mTOR inhibitors, and mycophenolate mofetil have been shown to be efficacious in BOS Bronchiolitis Obliterans Azithromycin Modulates cytokine production and impairs neutrophil function Has been shown to improve FEV1 or slow progression of BOS Also effective macrolide antibiotic against encapsulated organisms

Leukotriene receptor antagonists Imatinib Most reported data are small case series but has shown to be effective Bronchiolitis Obliterans Scoring Filipovich et al., BB&MT 11:945-955 (2005) Bronchiolitis Obliterans

Scoring A variety of organ systems are scored Each is scored according to a 4 point scale 0-3 0 represents no involvement 3 is severe impairment Performance status is noted on a 0-3 point scale Check boxes also note the presence of other symptoms

Bronchiolitis Obliterans Bronchiolitis Obliterans Bronchiolitis Obliterans Jaksch, et al. (2012)

Efficacy and safety of extracorporeal photopheresis in patients with BOS after lung transplantation Study performed in a cohort of 1,012 lung transplant patients from November 1989 to June 2010. Standard maintenance immunosuppression were given to all patients BOS staging was performed according to the ISHLT classification system throughout the study along with baseline FEV1 Jaksch, et al. (2012)

ECP performed using UVAR XTS system Performed on 2 successive days every 2 weeks during the first 3 months and every 4 weeks thereafter until the end of therapy Primary end point in study was the rate of change in lung function before and after the initiation of ECP. A positive response to ECP was defined as stabilization in FEV1

Lung function patterns were compared with BOS patients who did not receive ECP as an add-on therapy Jaksch, et al. (2012) Of 1,012 lung allograft patients, 194 developed at least BOS stage 1 between January 2001 and June 2010 and 51 received ECP treatment Treatment was administered to 51 for 3 months and was continued in 25 patients for 12 months The FEV1 improved in 18% of patients for more than 1 year after the initiation of ECP and 12% showed an improvement for just 3 to 6 months

FEV1 stabilized in 31% and showed a progressive decline in 39% Jaksch, et al. (2012) Factors affecting response to ECP Patient who developed BOS more quickly after transplantation (within the first 3 years) showed a better response to ECP than patients who developed BOS as a late complication A more rapid decline in lung function at start of BOS was also a significant risk factor for poor ECP response (p=0.048) Grade of BOS also influenced the response with

better response when the BOS stage was lower (p=0.05) Jaksch, et al. (2012) Comparison with BOS patients without ECP The ECP treated cohort had a longer long term survival (p=0.046) The ECP patients underwent 18 retransplantations compared with 21 in the non-ECP group (p=0.04) Discussion

Showed promising results as 61% showed improvement or stabilization of FEV1 after 3, 6, or 12 months of therapy Morrell, et al. Retrospective analysis of efficacy and safety of

ECP for progressive BOS Between 2000 and 2007, 60 lung allograft patients were treated with ECP Mean difference in rate of decline in FEV1 from 6 months before to 6 months after initiation of ECP was 87.1 ml/month (P<0.0001) FEV1 improved in 25% of patients after initiation of ECP Mean increase was 20.1 ml/month Summary Graft versus host disease has acute and chronic forms and is a serious side effect of transplantation Pulmonary manifestations include

bronchiolitis obliterans Photopheresis is an effective therapy for these patients References

Barrerio TJ, Perillo I. An approach to Interpreting Spirometry. Am Fam Physician 69(5). 2004. Tichelli A, Rovo A, Gratwohl A. Late pulmonary, cardiovascular, and renal complications after hematopoietic stem cell transplantation and recommended screening practices. Hematology. 2008. Kaloyannidis P, Mallouri D. The role of the extracorporeal photopheresis in the management of the graft-versushost disease. Transfusion and Apheresis Science 46 (2012) 211-219. Bacigalupo A, Chien J, Barisione G, Pavletic S. Late pulmonary complications after allogeneic hematopoietic

stem cell transplantation: Diagnosis, monitoring, prevention, and treatment. Seminars in Hematology, Vol 49, No 1, January 2012, pp 15-24. Hildebrandt GC, Fazekas T, Lawitschka A, Bertz H, Greinix H, Halter J, Pavletic SZ, Holler E, Wolff D. Diagnosis and treatment of pulmonary chronic GVHD: report from the consensus conference on clinical practice in chronic GVHD. Bone Marrow Transplantation (2011) 46, 1283-1295. Jaksch P, et al. A prospective interventional study on the use of extracorporeal photopheresis in patients with bronchiolitis obliterans syndrome after lung transplantation. Journal of Heart and Lung Transplantation, Vol 31, No 9, September 2012. Sengsayadeth SM, Srivastava S, Jagasia M, Savani BN. Time to explore preventive and novel therapies for bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation. ASBMT 18:14791487, 2012. Filipovich, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. Diagnosis and Staging Working Group Report. ASBMT 11:945-055 (2005). Trulock EP, Christie JD, Edwards LB, Boucek MM, Aurora P, Taylor DO, Dobbels F, Rahmel AO, Keck BM, Hertz MI. Registry of the International Society for Heart and Lung Transplantation: twenty-fourth official adult lung and heart-lung transplantation report -2007. J Heart Lung Transplant. 2007 Aug;26(8)782-95

Morrell MR, Despotis GJ, Lublin DM, Patterson GA, Trulock EP, Hachem RR. The effiacy of photopheresis for bronchiolitis obliterans syndrome after lung transplantation. J Heart Transplant. 2010 Apr;29(4):424-31.

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