1. MD Anderson case Citiwide Oct 7/2009 Nabil Khoury MD UT ID fellow Bacterias Fungi Viruses Parasites

2. History First admit to MDA: 10/06/08-10/13/2008 A 21 year-old Caucasian male, college student, from Oklahoma without any prior medical history was admitted because of Fever, anemia, thrombocytopenia. Found to have pre-B ALL. ANC 800 at that time Received antibiotics and chemotherapy Microbiological w/u was negative

3. Antibiotics During his hospital stay:  Cefepime and Linezolid  Oral valtrex and Itraconazole as prophylaxis On discharge:  Cefepime 2 g IV q 8 x 5 days, then cefpodoxime 200 mg po bid  Bactrim DS one tab bid 3 times/week  Valtrex 500 mg po qd  Itraconazole 20 cc bid

4. Chemotherapy Daunorubicin Vincristine PEG-L-asparaginase Prednisone 110 mg/day Intrathecal MTX

5. Second admit to MDA: 11/21-11/24/08 Admit for Fever, diarrhea His ANC 200 at that time He was given Cefepime and Vancomycin He became afebrile Work-up: C difficile, Blood and urine C: neg

6. Discharged on:  Levaquin 500 mg po qd  Continue: Bactrim Valtrex Itraconazole

7. Admit on 12/11/2008 Fever 39 C Chills Fatigue Sore throat Anorexia, nausea and vomiting No cough, no dyspnea

8. Physical Exam:  Temp 39 C, BP 107/59, HR 120  Cachectic looking  Eyes: pale, anicteric sclerae  ENMT: no exudate, no ulceration  Neck: no goiter, no adenopathies  C-V: S1S2 regular, tachy  Lungs: decrease breath sound bilaterally, no wheezing or rhonchi  Abdomen: Soft, non tender  Skin: pale, warm and dry, petechiae appreciated, mac les!!  Neuro: AOx3, no evident deficits  Picc line RUE: no erythema, no tenderness

9. Work-up WBC 0.2 – Neutropenic since 11/25 Hb 7.5 Plt 16,000 Alb 2.8 Glucose 125 Uric acid 1.9 Bil 1.4 AP 228 LDH 302

10. Neutropenia Graph

11. Chest X-ray on 12/11/2008 12/11/2008

12. Admit on 12/11/2008 He was admitted and started on:  Meropenem  Vancomycin  Micafungin  Voriconazole 12/13/2008: Not doing well, febrile. Blood cultures: no growth. GM: negative CMV: negative CT Scan Chest was ordered

13. 12/13/2008

16. CT Scan report Mixed interstitial alveolar infiltrate in the upper lobe of the left lung with some minimal superimposed consolidative changes Minimal adjacent infiltrate in the left lower lobe superiorly. Small left pleural effusion Findings are compatible with a pneumonic process and can be clinically correlated.

17. ID consult 12/14 ID note: Fever, dry cough, no dyspnea Exposure to tick bites Temp max 39C

18. Differential Diagnosis and Work-up?

19. ID recommendations ID recommended to add doxycycline and Amikacin Work-up with Rickettsia, Ehlrichia, anaplasmosis, Crypto and histo atigen Nasal wash for viral cultures Bronchoscopy and BAL to send for:  Cultures  PCP  AFB Skin biopsy for some macular skin lesion

20. 12/15/09

21. Meanwhile all the prior work-up including:  BAL: negative for AFB, fungi, bacteria, PCP  Crypto, Histo negative  GM: still negative On sunday 12/19: Still not doing well, febrile on a daily basis!  What do you want to do now?  It is almost X-mas!

22. 12/19/2009 on Sunday Another ID attending re-evaluating Decision was made to add:  Ambisome and Bactrim  d/c doxycycline

23. 12/20: Getting better, Fever trending down 12/21: Afebrile 12/22: Add posaconazole and d/c Vori, Caspofungin 12/23: Discharged home on Ambisome, posaconazole, Bactrim, Linezolid and Cipro

24. 1/21 1/21/2009

25. Not being compliant with Posaconazole 2/18/2009: Admit for severe hemoptysis Required urgent embolization 2/23: Wedge resection of left upper lobe

27. Pathology Lung parenchyma with fungal organism, morphologically consistent with: Zygomyces And associated extensive granulomatous inflammation and necrosis.

28. Mucormycosis Rare and rapidly progressive opportunistic fungal infection Rhizopus>Rhizomucor>Cunninghamella species Many other species to name Ubiquitous fungi: common inhabitants of decaying matter Characterized by: fast-growing fibrous mycelium and thin-walled aseptate or hyposeptate hyphae. Right angle branching is seen.

30. Pathogenesis Knowing the pathogenesis helps understand risk factors, manifestations and later on therapeutic implications

31. Pathogenesis

32. Risk Factors Prolonged neutropenia Hyperglycemia and acidosis (DKA) Steroids Immunosuppressive therapy Burns, trauma (skin form) Excess iron Deferoxamine (not iron chelators in general) Voriconazole use?

33. Clinical forms Rhino-cerebral or cranio-facial (1/3-1/2 of the cases) Pulmonary Cutaneous Gastro-intestinal: rare Disseminated>90% mortality Others: endocarditis, kidneys, etc..

34. Pulmonary form High resolution CT Scan may demonstrate evidence of infection before the Chest X-ray Sputum culture is unreliable This Mold is difficult to culture Hematogenous dissemination frequent but blood cultures are negatives Death may occur before respiratory failure! Mortality 50-70%

35. Diagnosis Final diagnosis: Biopsy or Autopsy No blood markers available such GM, Histo or Crypto antigen

36. Classic radiological signs for ‘fungal’ Dense well circumscribed lesion with or without halo sign Air-crescent sign Cavity

37. Radiological findings that favors Mucor v/s Aspergillosis Multiple nodules >=10 (>1 cm each) Sinusitis Pleural effusion Reverse halo sign:  Focal area of ground-glass attenuation surrounded by a ring of consolidation

38. Reverse halo sign

39. Treatment Early therapy is crucial: need for high index of suspicion Reversal of the underlying predisposing factors if possible Surgical debridement: urgent basis Appropriate anti-fungal therapy: before definite diagnosis Other adjunctive therapy

40. Anti-fungal therapy Amphotericin B:++  Liposomal/lipid form: seems better? More tolerated, high doses, long time Echinocandin: has no efficacy by themselves Combination: Ampho B and echinocandin  Current trend in MDA

41. CID Jun 16, 2008

45. Azoles Voriconazole: no activity, Mucorales is a major hole in the spectrum Itraconazole: Absidia species only(4%) Posaconazole: has good activity  Second line  Only po form available  Takes 1 week to get to steady state  Success as salvage therapy  Combination with polyene: no benefit in animal models.

46. Adjunctive therapy Iron chelation: deferasirox po x 2-4 wks Hyperbaric oxygen Granulocyte transfusions Cytokine therapy: INF-gamma, G-CSF or GM-CSF

47. Duration of therapy? Long enough!  Resolution of clinical signs and symptoms  Resolution or stabilization of residual radiographic signs of disease  Resolution of underlying immunosuppression  Posaconazole may be used as chronic suppressive therapy such in SOT, Chemo

48. Hopefully I did not get you bored References:  Recent Advances in the Management of Mucormycosis. CID 12 May 2009  Novel prospectives on Mucormycosis. Clinical microbiology review July 2005  Zygomycosis: the re-emerging fungal infection. Eur J Clin Microbiol Infect dis 2006  Mucormycosis in hematologic patients hematologica 2004  Revised Definition of Invasive Fungal Disease CID 20 Feb 2008  Treatment of Zygomycosis: current and new options. Journal of antimicrobial chemo 2008