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Pulmonary Manifestations and Graft versus Host Disease in Post-BMT Patients

This article discusses the pulmonary manifestations and complications of graft versus host disease (GvHD) in post-bone marrow transplant (BMT) patients. It also includes case studies of two patients with different presentations and outcomes.

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Pulmonary Manifestations and Graft versus Host Disease in Post-BMT Patients

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  1. SpR 1 19/10/2016 Matt Dickson

  2. Patient 1 • 55 year old male • Ex smoker, background emphysema • Multiple myeloma 2006 • Admitted from Haematology clinic hypoxic

  3. Patient 1 continued… • MM 2006 – chemotherapy plus autologous stem cell transplant • Relapse 2009 – second line chemotherapy • Relapse 2011 – unrelated allogeneic stem cell transplant • X5 Donor lymphocyte infusions 2012-2015 • Developed skin and mouth GvHD late 2014/early 2015

  4. Patient 1 continued… • Admitted early May 2015 with 3 week history of increased SOB and cough – found to have pneumomediastinum(severe oropharyngeal GvHD) • Readmitted late May 2015 with worsening SOB – repeat CT thorax revealed multifocal nodular consolidation and ground glass, new bronchial dilatation, treated for fungal infection (posaconazole)

  5. Patient 1 continued… • Gradually worsening breathlessness from June 2015 onwards • FEV1 0.89L (24%), VC 2.38, FEV1/VC 37%, TLC 8.42L, FRC 6.34L, RV 6.04, TLCO 62%, KCO 126% June 2015 • FEV1 3.55L, VC 4.45L in Sept 2012 • Repeat CT July 2015: ground glass/nodular consolidation resolved; bronchial dilatation, most marked at the lung bases, persists • Obliterative bronchiolitis • Referred for extracorporeal photophoresis • Co-trimoxazole switched to Azithromycin • Commenced on budesonide 400mcg BD

  6. Patient 1 continued • Grew Pseudomonas in June 2016 • O2 saturations 87% in clinic July 2016 • Weight loss, lethargy, mouth dryness, dysphagia • Admitted 3/10/16 from clinic as O2 saturations ~80% on RA

  7. Assessment • Ongoing productive cough with green/yellow sputum • Two week history of gradually worsening SOBOE • Minimal crackles in bases • HRCT – progression in bronchial wall dilatation, patchy ground glass changes

  8. Next steps • Bronchoscopy and BAL: Staph aureus and Stenotrophomonasmaltophilia • Commenced on co-trimoxazole and high dose dexamethasone • Discharged on home O2

  9. Graft versus Host Disease • Significantly higher in allogeneic BMT • Minor incompatibility differences between donor and recipient • Immune reaction mediated by donor T-lymphocytes that recognise the recipient's tissue as a foreign body • Acute GvHDaffects 25-75%, affects skin, liver and GI tract (minimal lung involvement) • Chronic GvHD affects 20-45% who survive > 6/12, lung involvement common

  10. Pulmonary manifestations • Symptoms of non-productive cough, breathlessness (fever and sputum uncommon) • Chest radiograph can be normal, focal/diffuse infiltrates • Fall in VC and FEV1 with obstructive picture • Histologically • Diffuse alveolar damage • Lymphocytic interstitial pneumonia • Lymphocytic bronchitis • Obliterative bronchiolitis

  11. Obliterative bronchiolitis • OB reported in 2-14% of allogeneic BMT, rarely in autologous • Low Ig levels and chronic GVHD are at greater risk • Aetiology unclear (viral/autoimmune) • Chronic cough, increased breathlessness • Earliest physiological abnormality is airflow limitation manifested by a decrease in forced expiratory flow at 25% to 75% of the forced vital capacity • Progressive airway obstruction with diffusion impairment eventually leads to respiratory failure • Constrictive bronchiolitis with granulation tissue plugs within the small airways, often extending into the alveolar ducts, or complete destruction of the small airways by fibrosis • 65% mortality three years after transplantation • Inhaled corticosteroids, azithromycin, systemic immunosuppression

  12. Patient 2 • 24 year old male • Bilateral lung transplant for CF 2013 • Excellent lung function, uncomplicated post operative period • Admitted from clinic 12/10/16 • Weight loss • Dyspepsia • Loose stools (3-4x/day) • Intermittent right sided abdominal pain/loin pain • Right testicular swelling • Fever • Decreased appetite • No chest symptoms • Tacrolimus, Azathioprine (stopped 2 weeks), Prednisolone

  13. Patient 2 continued… • Hb 102 • Plts 114 • WCC 4.6 (Neut 1.1) • Urea 13.5 • Creat 247 • ALT 52 • CRP 11 • Tacrolimus 29.7 • MSU NAD • Stool pending • CXR – no acute changes

  14. Patient 2 continued… • USS Testes – Right hydrocele • USS Abdomen – Suspicion of right pyelonephritis • CT Abdo/Pelvis: • Small volume free fluid • Moderate mesenteric lymphadenopathy • Generalised mucosal enhancement/enterocolic inflammatory changes • Two cystic foci ~7mm in right kidney • No soft tissue mass/organ infiltrate • DAT, haptoglobins negative • EBV PCR 1.4 x 10*6 copies/ml • OGD • Generalised oesophagitis, some candida • Erosive duodenitis, biopsies taken

  15. Patient 2 continued… • Commenced on Tazocin • 2 days of fluconazole 200mg for oesophageal candida • PPI continued • Tacrolimus doses reduced, levels normalised • Felt back to normal, E+D, gaining weight, dysphagia and dyspepsia settled, loose stool ongoing • Cryptosporidium grown from stool – Tazocin stopped

  16. Differential diagnoses • Cryptosporidiosis (Tazocin stopped/consider anti-protozoal agent) • Toxic Tacrolimus level side effects (symptoms improved when levels within limits) III) Post Transplant Lymphoproliferative Disorder IV) Combination

  17. Post Transplant Lymphoproliferative Disorder • Lymphoid/plasmacytic proliferations in setting of transplant and immunosuppression • Three types: • Early lesions • Polymorphic PTLD • Monomorphic PTLD • Related to B cell proliferation induced by EBV • Chronic immunosuppression, decreased T cell surveillance • Most common malignancy post solid organ transplant (excluding skin and CIN) • 2-9% incidence over 5 years

  18. Increased risk factors • Degree of immunosuppression • EBV status (EBV –ve recipient, EBV +ve donor) • Concomitant CMV infection • Pre - transplant malignancy • Younger age • Fewer HLA matches • Time after transplant

  19. Signs and Symptoms • Fever, weight loss, malaise • Lymphadenopathy, dysfunction of involved organs, compression of surrounding structures • More than half have extranodal disease • Infiltration of transplant, GI tract, skin, liver, CNS

  20. Lab findings • Unexplained anaemia, thrombocytopenia, or leukopenia • Elevated LDH • Hypercalcaemia • Hyperuricaemia • Monoclonal protein in the serum or urine • Raised EBV PCR

  21. Radiology • Solid organ nodules/infiltration • Bowel wall thickening, ulceration/perforation, obstruction • Lung nodules/infiltrates • Lymphadenopathy, most commonly mediastinum or retroperitoneum

  22. Treatment • Early lesions • taper down immunosuppression • Polymorphic PTLD • decrease immunosuppression + rituximab (if CD20+) • Surgery (if localised)/chemotherapy • Radiotherapy (if localised) • Monomorphic PTLD • decrease immunosuppression + rituximab (if CD20+) • Chemotherapy • Surgery for complications (perforation/obstruction)

  23. Prognosis • Five year survival of ~ 50% • Older age • CKD • Elevated LDH • CNS/serous membrane invasion/BM involvement • Monomorphic/T cell histology (80% mortality)

  24. Questions?

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