ESCMID Online Lecture Library. by author. CASE PRESENTATION ECCMID clinical grand round May Anat Stern, MD Rambam medical center Haifa, Israel

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1 CASE PRESENTATION ECCMID clinical grand round May 2014 Anat Stern, MD Rambam medical center Haifa, Israel

2 An 18 years old Female, from Ukraine, diagnosed with acute lymphoblastic leukemia (ALL) in Multiple courses of chemotherapy, 3 relapses. May 2013 July Sep 2013 Stem cell transplantation from a matched unrelated donor in Germany followed by complete remission. ALL relapse: extra-medullary and lepto-meningial. No evidence of active graft versus host disease. Salvage chemotherapy initiation through a port-acath central vein catheter.

3 Day 0 16/9/13 Day 7 23/9/13 Admission with fever and severe neutropenia one week after salvage chemotherapy. Peri-anal infection and E. coli bacteremia. Treatment with piperacillin-tazobactam with good local and systemic response. Persistent neutropenia. Acute clinical deterioration. Hypotension requiring vasopressor therapy and respiratory distress, without fever.

4 Day 7 23/9/13 Chest CT scan revealed multiple nodular lesions in both lungs; some cavitary. Abdominal CT scan was normal.

5 What would you do next? Treatment was escalated to meropenem, vancomycin and voriconazole. A few month old port-a-cath was removed.

6 Day 8 24/9/13 Day 9 25/9/13 A maculo-papular rash starting on the neck and chest, later spreading all over the body, including scalp, ears, hands and feet. Part of the lesions became vesicular. Acyclovir added for suspected disseminated cutaneous varicella zoster infection. Negative PCR to VZV from a lesion smear. What is the differential diagnosis?

7 Day 12 28/9/13 A single blood culture positive for yeasts. The culture was drawn from a new Hickman catheter. Should the voriconazole be switched to a different drug? Antifungal treatment changed empirically from voriconazole to caspofungin

8 Day 13 29/9/13 A further deterioration in the patient's clinical state with need for mechanical ventilation. Patient still severely neutropenic. Chest X-ray showed bilateral diffuse opacities.

9 Day 13 29/9/13 Positive blood galactomannan with 2.81 index. Bronchoalveolar lavage: Negative bacterial culture. Negative Legionella PCR and culture. Negative Aspergillus PCR. PCR for Pneumocystis jirovecii weakly positive. What would you do next? TMP-SMX added. Hickman cathter removed.

10 Day 15 1/10/13 The yeast was identified as Candida tropicalis. Antifungal therapy was mainstreamed to voriconazole targeting candidemia and probable invasive pulmonary aspergillosis (host criteria, radiography and positive galactomannan).

11 Day 24 10/10/13 Resolution of neutropenia. Gradual clinical improvement permitting extubation and discontinuation of vasopressors. Persistent fever. But

12 Day 28 14/10/13 The result of a punch biopsy from a skin lesion showed large groups of fungal spores in the dermis. Funduscopic examination which was previously normal revealed bilateral sub-retinal exudates consistent with candida chorioretinitis. Day 41 27/10/13 Follow up ophthalmologic examination: worsening of retinal exudates. left vitreous body involvement. Treatment with intra-ocular amphotericin B inject

13 Day 41 27/10/13 Abdominal CT scan: multiple hypo-dense lesions in the spleen and kidneys not apparent on previous CT scans chest CT: worsening of the known lesions with development of a halo sign. Bilateral pleural effusion.

14 Patient continues to deteriorate with persistent fever. Erratic voriconazole blood levels. Hepatic enzyme elevation, mainly cholestatic with γ- glutamyl transferase up to 1375 U/L and alkaline phosphatase up to 531 U/L. Date Voriconazole dose and route What would you do next? Antifungal therapy switched to anidulafungin. Voriconazole Level (mg/l) (TR 2-6) 25/9/13 PO 400 mg/d /10/13 IV 400 mg/d /10/13 IV 600 mg/d /10/13 IV 400 mg/d /11/13 PO 600 mg/d /12/13 PO 600 mg/d /12/13 PO 800 mg/d 4.69

15 Day 54 9/11/13 Neutrophil count in the normal range. תרשים מעורבות סיסטמית? no evidence of ALL relapse according to bone marrow examination and PET-CT. Clinical deterioration, re-intubation due to respiratory insufficiency. High grade fever. Antifungal treatment with anidulafungin and fluconazole. Differential diagnosis?

16 Differential diagnosis Uncontrolled active candida infection Uncontrolled invasive pulmonary aspergillosis Inflammatory reaction secondary to immune reconstitution What would you do next?

17 J Antimicrob Chemother 2012; 67: Clinical Infectious Diseases 2008; 46:

18 Day 77 5/12/13 Treatment with prednisone 30 mg X1/D /1/2013 Temperature (Celsius degrees) 11/3/ /5/ /7/ /9/ /11/ /13/ /15/ /17/ /19/ /21/ /23/ /25/ /27/ /29/ /1/ /3/ /5/ /7/ /9/ /11/ /13/ /15/ /17/ /19/ /21/ /23/2013

19 Alkaline GGT prednisone phosphatase prednisone Gradual clinical improvement. Withdrawal from mechanical ventilation.

20 Day 91 19/12/13 Day 89 17/12/13 Day 95 23/12/13 Ophthalmologic examination: bilateral retinal scars with no active exudates. Clear vitreous bodies. Decreased vision acuity on the left side. Chest CT: a few lesions with cavitation. A significant improvement with thinning of the cavitations wall and disappearance of the ground glass opacities. Discharge from the hospital.

21 An 18 years old ALL patient after salvage chemotherapy with severe chronic disseminated candidiasis with multiorgan involvement + probable invasive aspergillosis. Dramatic response to glucocorticosteroid therapy? Qs remaining: Preferred antifungal regimen for concomitant infection with Candida and probable invasive aspergillosis? Factors affecting voriconazole levels? The role of glucocorticosteroid therapy in invasive candidiasis?

22 THANK YOU!