ID Case Conference

1. ID Case Conference 7/18/07 – Case #1 Gretchen Shaughnessy, MD ID Fellow (at last!)

2. The Case • 56-year-old African-American gentleman with diffuse large T-cell lymphoma. Who developed a follicular rash on day 5 s/p BEAM conditioning with autologous stem cell rescue. • Presented in the fall of 2006 with three plaque-like lesions on the abdominal wall. He had a prior history of eczema. A biopsy of one of these lesions was consistent with a diffuse large T-cell lymphoma. Staging studies showed no evidence of visceral or marrow involvement. He was treated with hyper CVAD and has to date completed six cycles of therapy. Admitted in late June 07 for high dose BEAM conditioning with autologous stem cell rescue. • Hospitalization complicated by neutropenic colitis, neutropenic fever, anemia, thrombocytopenia, and now new rash. • He had been treated with topical clindamycin and steroid cream without improvement. • The follicular rash initially started on his torso but progressed to involve the abdomen, back, and arms. • ID was consulted day on day 4 of rash.

3. PMH • Non-Hodgkin's lymphoma HTN DM Type 2 MUGA scan showed an ejection fraction of 56%. Pulmonary function shows an FEV1 of 91% predicted, DLCO/VA of 90% predicted. Renal function is good, creatinine 1.2. Liver function tests reveal bilirubin 0.2, AST 23, ALT 34, alkaline phosphatase 113. Viral serologies show hepatitis B surface antigen negative, hepatitis B core antibody negative, hepatitis C antibody negative. CMV IgG positive, EBV IgG positive, HSV type 1 and HSV 2 both • Social History: Patient used to work at a recycling plant, processing plastic bottles. Prior to that job, he worked for a chicken packaging factory – did not handle chickens. Denies any recent travel or sick contacts. No tobacco, EtOH, IV or other drug use. Family History: All siblings (15) w/ DM; mother died of CVA; father died of MI. • Allergies - NKDA

4. Medications • Acyclovir 400 mg IV bid Imipenem 500 mg IV qid Levaquin 750 mg IV q 24 hours Metronidazole 500 mg IV q 8 hours Vancomycin 1.5 g bid micafungin Famotidine 20 mg IV bid Neupogen Metoprolol 5 mg IV q6 Octreotide 200 mg IV q8 • For antibiotic coverage, he patient was initally on vancomycin and ceftazidime for neutropenic fevers. His antibiotics were changed from ceftazidime to impenem, then levaquin and fluconazole were added. Fluconazole was switched to micafungin prior to consult.

5. ROS • Constitutional + Fever spikes; no chills or rigors. Weight stable. • Eyes No visual changes or deficits. • ENT No sore throat, hoarseness, rhinitis, vertigo, tinnitus, neck pain, stiffness, dizziness, or mouth ulcers. • Skin/Breast + Eczema, pustules per HPI • Cardiovascular No CP, palpitations, orthopnea. • Pulmonary No cough, wheezing, or dyspnea. • Gastro Intestinal + Diarrhea, + bloody stool, no current abdominal pain • Genito Urinary No dysuria or hematuria. • Neurologic No focal weakness, numbness, or tingling. • Heme/Lymph Thrombocytopenia; s/p platelet transfusion today.

6. Physical Exam • Vital T max 38.2, Tc 36.6 Pulse 71 RR 18 BP 147-160/ 73-80 • Patient resting comfortably, NAD. • Anicteric, sclera clear; EOMI, PEERL • No oral lingual or mucocutaneous lesions; mucosa hydrated • Supple; no masses. • No cervical or axillary adenopathy. • RRR, no m/r/g; nl S1, S2. No carotid bruits. 2+ radial, DP, PT pulses. • CTA B • Patient with ovoid 1 cm diameter flat eczematous lesions over abdomen and feet. Multiple pustular lesions over abdomen, R shoulder, arms, and back measuring about 0.5 cm in diameter • Soft, ND, NT, normoactive BS, no HSM. • No c/c/e. Linear ridges over toenails c/w chronic onychomycosis • No focal neurologic deficits.

7. Derm Consult Skin Exam • Discrete vioaceous, edematous, non-scaly papules on mid abdomen proximal upper extremities and lower back. No vesicles, pustules or blisters

9. Lab Values • WBC 0.3, ANC 0.1, Platelets 74 (post transfusion) Creatinine 1.3 • Blood cultures no growth at 24 hours x 2; no growth at 3 days x 2 • Urine cx no growth • CMV IgG +, EBV IgG +, EBV IgM -, HSV 1,2 IgG +, Heb Bs -, Hep B core-, Hep C - CMV viral load negative • Galactomannan assay negative

22. Discussion

27. Disseminated Aspergillus flavus with Cutaneous Findings

28. Disseminated Aspergillus • Fungus – genus Aspergillus, Family Trichocomaceae • Closely related to genus Penicillium • Named after aspergillum used to sprinkle holy water. • Changing epidemiology – • 72 cases of aspergillosis in hematopoietic stem cell transplant recipients 2005 • Aspergillus fumigatus (56 percent) • A. flavus (19 percent) • A. terreus (16 percent) • A. niger (8 percent) • A. versicolor (1 percent) • 1990s – 90% A. fumigatus • Ubiquitous organism – found in soil, water, food, air

29. Cutaneous Infection • Can represent disseminiated hematogenous infection or local inoculation of infection that may arise around an IV catheter insertion site • Also seen associated with tape or adhesive dressings • Most lesions occur in patients with neutropenia or other immunocompromise, can also invade patients with burns or surgical wounds • Lesion is area of rapidly increasing errythema with a necrotic, often ulcerated center. • Resemble pyoderma gangrenosum • Invasion of blood vessels and cutaneous ulcer occurs

30. Cutaneous Infection • Usually direct implantation following trauma • Less commonly, dissemination from a primary respiratory tract focus. • In one series of patients with hematologic malignancies, cutaneous lesions occurred in four percent of patients with documented Aspergillus infection • Lesions rapidly evolve from papular to ulcerative lesions; the ulcers continue to enlarge at varying rates depending upon the degree of immunosuppression

31. BMT recipient with multiple cutaneous lesions • View image in J Clin Microbiol. 1998 November; 36(11): 3115–3121.

32. Aspergillus in BMT patients • Incidence of invasive aspergillus in BMT patients is bimodal – peak incidence <20 days from transplant and then >100 days after transplant • Associated with a particularly bad prognosis

33. Pathogenesis • Usual route of infection is through inhalation of conidia into lungs • Invasive infection can follow local tissue invasion, but less common • Hydrocortisone significantly increases the growth rates of Aspergillus • Vascular invasion and infarction are the classic features of invasive aspergillosis

34. Pathogenesis – A. flavus • A flavis is known for producing aflatoxin • These decrease macrophage and neutrophil function • Important as a carcinogenic and immunosuppressive agent but does not appear to be important in virulence

35. Diagnosis • Proven diagnosis requires tissue biopsy showing invasion of hyphae and positive culture for aspergillus • Can be established with needle bx or CSF • Blood cultures rarely positive • Hyphae easily seen on common fungal stains GMS or PAS • Hyaline, septate, acute-angle branched, 3-6uM in width • Above features can distinguish from other zygomycosis, but culture necessary to differentiate from other opportunistic molds – fusarium, scedosporium

36. Aspergillus fumigatus • Macroscopic morphology- showing dichotomously branching hyphae – and histopathology • View slides at Doctor Fungus web site: http://www.doctorfungus.org

37. Diagnosis - Galactomannan • Substance released during growth of hyphae, major constituent of Aspergillus cell walls. • ELISA for galactomannin FDA approved • Permits detection of antigenemia in some patients an average of five to eight days before the presence of clinical signs, an abnormal chest x-ray, or positive cultures.

38. Galactomannan (cont) • A meta-analysis of patients at risk • Twenty-seven studies, 4000 patients. • Sensitivity of test ranged from 61-71% • Specificity 89-93% • NPV 95-98%, PPV 26-53% • Galactomannan assay is helpful in ruling out the diagnosis of invasive aspergillosis but has only moderate to low sensitivity in confirming disease. • Subgroup analyses assay performed better in hematological malignancy patients or hematological transplant recipients probably related to the higher pre-test probability compared with solid organ transplant recipients

39. Galactomannan (cont) • Sensitivity and specificity is affected by the administration of other medications. False positives in patients on • piperacillin/tazobactam • amoxicillin-clavulanate • False positive can occur as long as 5 days after stopping medications • Sensitivity of assay decreased antifungal therapy • Test performance will vary according to the threshold value used.

40. Treatment Options • Ampho (including lipid formulations) • We have the most clinical experience with this medication. Lots of clinical experience watching 80% of our patients die. • Voriconazole – Now First Line Treatment • c/w ampho in study of 277 pts w/ invasive aspergillosis • Better response rate 53% vs 32% • Decreased mortality 29% vs 42% • Lower rate of severe adverse reactions

41. Treatment (cont) • Posaconazole • Similar to Voriconazole in activity against aspergillus • In open-label non-controlled trial in patients intolerant to prior therapy success rate was 42% compared with 26% for controls • Initially chosen for this patient because of the broader spectrum while awaiting culture results • Caspofungin • Lack of data for primary therapy • Used in patients intolerant to other medications

42. Prognosis • Systematic lit review in CID 2001 showed overall case fatality rate 58% • 86.7% mortality in BMT patients • 88.1% mortality in patients with disseminated invasive disease • Favorable responses to ampho was seen in less than 20% of patients

43. Outcome of Our patient • So far, so good…? • Neutrophils are back, skin lesions appear to be healing. Clinically improving. Fever yesterday, repeat CXR showed only mild change. • Planning for lifelong posaconazole therapy.

46. References • Mandell’s Principles and Practices of Infectious Disease, 6th Ed. [Book available online via the UNC-CH Libraries] • Pfeiffer CD, Fine JP, Safdar N. Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis. 2006 May 15;42(10):1417-727. • Morgan J, Wannemuehler KA, Marr KA, et al. Incidence of invasive aspergillosis following hematopoietic stem cell and solid organ transplantation: interim results of a prospective multicenter surveillance program. Med Mycol 2005 May;43 Suppl 1:S49-58. • D'Antonio D, Pagano L, Girmenia C, et al. Cutaneous aspergillosis in patients with haematological malignancies. Eur J Clin Microbiol Infect Dis 2000 May;19(5):362-5. • Isaac M. Cutaneous aspergillosis. Dermatol Clin 1996 Jan;14(1):137-40.

47. References (cont’d.) • Raad II, Graybill JR, Bustamante AB, et al. Safety of long-term oral posaconazole use in the treatment of refractory invasive fungal infections. Clin Infect Dis. 2006 Jun 15;42(12):1726-34. • Walsh TJ; Raad I; Patterson TF. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis 2007 Jan 1;44(1):2-12.   • Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis 2001 Feb 1;32(3):358-66.

48. Search PubMed • Cutaneous Aspergillus flavus infections • Case studies • Reviews • Differential Diagnosis • Drug Therapy