1. A Case of IRIS Edward L. Goodman, MD October 8, 2003

2. First Admission 36 year old gay man with two weeks fatigue, dyspnea, mild cough and fever. He was first seen in ER 7/3/03 four days prior to admission where a CXR was interpreted as normal

3. Film in ER 7/03/03

4. First admission He returned 7/7/03 with worsening symptoms and was admitted Therapy for CAP was started with Levaquin and TMP/SMX plus prednisone. ID consult 7/10/03

5. Film on Admission 7/7/03

6. First Admission Exam revealed harsh breath sounds with possible consolidation in LLL. Lab revealed mildly elevated LDH and transaminases. HIV EIA was positive Bronchoscopy was performed: PCP was identified CD 48, viral load 220,000

7. Course in Hospital 7/16/03 a florid rash developed –Bactrim was stopped –Dapsone and Trimethoprim were substituted Hypoxemia persisted. CXR slowly improved Discharged 7/21 to complete final week of anti PCP therapy with Dap/TMP and tapering prednisone

8. Film prior to discharge 7/16/03

9. First Office Visit 7/28/2003 Feeling well Completed “induction therapy” for PCP Exam normal except for resolving rash PCP prophylaxis: Dapsone daily MAI prophylaxis: Azithromycin weekly HAART : once daily Tenofovir, Lamivudine and Efavirenz

10. Second Admission 8/04/03 Within four days of starting HAART, he had headache, followed by chills, fever and orthostatic dizziness No respiratory or GI symptoms On exam: BP 84/56, HR 128 rising to 156 on sitting Otherwise negative exam

11. Film on second admission

12. Differential Diagnosis Relapse of PCP? New opportunistic infection? –CMV? –MAI? –Histo? Drug Reaction? Adrenal Insufficiency? Immune Reconstitution Inflammatory Syndrome?

13. Hospital Evaluation Fluid resuscitation successful Normal ACTH stimulation Negative marrow biopsy Negative gallium scan Tolerated rechallenge with HAART Bronchoscopy 8/5/03

14. Second Bronchoscopy

23. Pneumocystis Carini (PCP) Pneumocystis Pneumonia Usual/typical Pathology Untreated Changes confined to alveoli/terminal airways Alveoli filled with “foamy” pink material - proliferating organisms (trophozoites, cysts) - cellular debris - +/- fibrin, red cells

24. Pneumocystis Carini (PCP) Pneumocystis Pneumonia Usual/typical Pathology Untreated Inconsistent findings - pneumocyte proliferation - mild interstitial edema - interstitial lymphocyte/plasma cell infiltrate

29. PCP Pneumonia Atypical Pathology Diffuse alveolar damage (DAD) Granulomas Multifocal giant cells Desquamative interstitial pneumonitis-like Interstitial fibrosis

30. PCP Pneumonia Atypical Pathology PCP induced Treated PCP Coincident injury - chemo/radiation therapy - infection - oxygen toxicity

31. PCP Pneumonia Diagnosis Optimal specimens -bronchial lavage -induced bronchial secretions -biopsy * NOT sputum Special stains required to detect cyst -silver stains (i.e. GMS) -immunostain

32. How do we interpret the bronchoscopy? Relapse of PCP? Expected response after successful therapy for PCP? What about the granuloma?

33. Natural History of Treated PCP O’Donnell et al, Chest 114; Nov 1998, 1264 Induced sputum at 2,3,4,6 weeks and year At two weeks: 88% + Three weeks: 76%+ Four weeks: 29%+ Six weeks: 24%+ Persisting cysts did not predict relapse. THUS, THIS IS NOT A FAILURE OF RX

34. Immune Reconstitution Inflammatory Syndrome (IRIS) Shelburne et al. Medicine 2002; 81:213 Define: a paradoxical deterioration in clinical status attributable to the recovery of the immune system during HAART Pathophysiology –Rapid fall in viral load –Increase in immune effector cells –Functional T cell immunity return

35. IRIS: clinical features Inflammatory process at site of previous infection, known or unknown Lymphadenitis Cutaneous Vitreitis Pneumonitis

36. IRIS: pathogens MAI, Mycobacterium tuberculosis Cryptococcus neoformans CMV, HSV, VZV PCP Hepatitis C and B

37. IRIS: non infectious Kaposi’s Sarcoma (HHV 8) Castleman’s Disease (HHV 8) Sarcoid Graves Disease

38. Features of IRIS PCP Five cases reported in detail Pathology –Few organisms –Granuloma around the cysts Immune reconstitution demonstrated in all Outcomes were good

39. Treatment of IRIS None: self limited Adding steroids Stopping HAART Retreat the infection?

40. Case Under Discussion: response to HAART CD 4Viral Load 7/9/0348220,000 7/28/0344661,000 8/13/03120921

41. Management Resume steroids Start new therapy for PCP –Clindamycin and Primaquine for 21 days Patient doing very well 8/21/03