ID Case ID Case ConferenceConference

7/18/07 – Case #17/18/07 – Case #1

Gretchen Shaughnessy, MDGretchen Shaughnessy, MD

ID Fellow (at last!)ID Fellow (at last!)

The CaseThe Case 56-year-old African-American gentleman with diffuse large T-56-year-old African-American gentleman with diffuse large T-

cell lymphoma. Who developed a follicular rash on day 5 s/p cell lymphoma. Who developed a follicular rash on day 5 s/p BEAM conditioning with autologous stem cell rescue.BEAM conditioning with autologous stem cell rescue.

Presented in the fall of 2006 with three plaque-like lesions on Presented in the fall of 2006 with three plaque-like lesions on the abdominal wall. He had a prior history of eczema. A biopsy the abdominal wall. He had a prior history of eczema. A biopsy of one of these lesions was consistent with a diffuse large T-of one of these lesions was consistent with a diffuse large T-cell lymphoma. Staging studies showed no evidence of visceral cell lymphoma. Staging studies showed no evidence of visceral or marrow involvement. He was treated with hyper CVAD and or marrow involvement. He was treated with hyper CVAD and has to date completed six cycles of therapy. Admitted in late has to date completed six cycles of therapy. Admitted in late June 07 for high dose BEAM conditioning with autologous June 07 for high dose BEAM conditioning with autologous stem cell rescue. stem cell rescue.

Hospitalization complicated by neutropenic colitis, neutropenic Hospitalization complicated by neutropenic colitis, neutropenic fever, anemia, thrombocytopenia, and now new rash. fever, anemia, thrombocytopenia, and now new rash.

He had been treated with topical clindamycin and steroid He had been treated with topical clindamycin and steroid cream without improvement.cream without improvement.

The follicular rash initially started on his torso but progressed The follicular rash initially started on his torso but progressed to involve the abdomen, back, and arms. to involve the abdomen, back, and arms.

ID was consulted day on day 4 of rash.ID was consulted day on day 4 of rash.

PMHPMH Non-Hodgkin's lymphoma Non-Hodgkin's lymphoma

HTN HTN DM Type 2 DM Type 2 MUGA scan showed an ejection fraction of 56%. Pulmonary function MUGA scan showed an ejection fraction of 56%. Pulmonary function shows an FEV1 of 91% predicted, DLCO/VA of 90% predicted. Renal shows an FEV1 of 91% predicted, DLCO/VA of 90% predicted. Renal function is good, creatinine 1.2. Liver function tests reveal bilirubin function is good, creatinine 1.2. Liver function tests reveal bilirubin 0.2, AST 23, ALT 34, alkaline phosphatase 113. Viral serologies show 0.2, AST 23, ALT 34, alkaline phosphatase 113. Viral serologies show hepatitis B surface antigen negative, hepatitis B core antibody hepatitis B surface antigen negative, hepatitis B core antibody negative, hepatitis C antibody negative. CMV IgG positive, EBV IgG negative, hepatitis C antibody negative. CMV IgG positive, EBV IgG positive, HSV type 1 and HSV 2 bothpositive, HSV type 1 and HSV 2 both

Social History: Patient used to work at a recycling plant, processing Social History: Patient used to work at a recycling plant, processing plastic bottles. Prior to that job, he worked for a chicken packaging plastic bottles. Prior to that job, he worked for a chicken packaging factory – did not handle chickens. factory – did not handle chickens. Denies any recent travel or sick contacts. Denies any recent travel or sick contacts. No tobacco, EtOH, IV or other drug use. No tobacco, EtOH, IV or other drug use.

Family History: All siblings (15) w/ DM; mother died of CVA; father Family History: All siblings (15) w/ DM; mother died of CVA; father died of MI.died of MI.

Allergies - NKDAAllergies - NKDA

MedicationsMedications Acyclovir 400 mg IV bid Acyclovir 400 mg IV bid

Imipenem 500 mg IV qid Imipenem 500 mg IV qid Levaquin 750 mg IV q 24 hours Levaquin 750 mg IV q 24 hours Metronidazole 500 mg IV q 8 hours Metronidazole 500 mg IV q 8 hours Vancomycin 1.5 g bid Vancomycin 1.5 g bid micafungin micafungin Famotidine 20 mg IV bid Famotidine 20 mg IV bid Neupogen Neupogen Metoprolol 5 mg IV q6 Metoprolol 5 mg IV q6 Octreotide 200 mg IV q8 Octreotide 200 mg IV q8

For antibiotic coverage, he patient was initally on For antibiotic coverage, he patient was initally on vancomycin and ceftazidime for neutropenic fevers. His vancomycin and ceftazidime for neutropenic fevers. His antibiotics were changed from ceftazidime to impenem, antibiotics were changed from ceftazidime to impenem, then levaquin and fluconazole were added. Fluconazole then levaquin and fluconazole were added. Fluconazole was switched to micafungin prior to consult. was switched to micafungin prior to consult.

ROSROS Constitutional + Fever spikes; no chills or rigors. Weight Constitutional + Fever spikes; no chills or rigors. Weight

stable. stable. Eyes No visual changes or deficits.Eyes No visual changes or deficits. ENT No sore throat, hoarseness, rhinitis, vertigo, tinnitus, ENT No sore throat, hoarseness, rhinitis, vertigo, tinnitus,

neck pain, stiffness, dizziness, or mouth ulcers.neck pain, stiffness, dizziness, or mouth ulcers. Skin/Breast + Eczema, pustules per HPISkin/Breast + Eczema, pustules per HPI Cardiovascular No CP, palpitations, orthopnea.Cardiovascular No CP, palpitations, orthopnea. Pulmonary No cough, wheezing, or dyspnea.Pulmonary No cough, wheezing, or dyspnea. Gastro Intestinal + Diarrhea, + bloody stool, no current Gastro Intestinal + Diarrhea, + bloody stool, no current

abdominal painabdominal pain Genito Urinary No dysuria or hematuria.Genito Urinary No dysuria or hematuria. Neurologic No focal weakness, numbness, or tingling.Neurologic No focal weakness, numbness, or tingling. Heme/Lymph Thrombocytopenia; s/p platelet transfusion Heme/Lymph Thrombocytopenia; s/p platelet transfusion

today.today.

Physical ExamPhysical Exam Vital T max 38.2, Tc 36.6 Vital T max 38.2, Tc 36.6

Pulse 71 Pulse 71 RR 18 RR 18 BP 147-160/ 73-80BP 147-160/ 73-80

Patient resting comfortably, NAD. Patient resting comfortably, NAD. Anicteric, sclera clear; EOMI, PEERLAnicteric, sclera clear; EOMI, PEERL No oral lingual or mucocutaneous lesions; mucosa hydratedNo oral lingual or mucocutaneous lesions; mucosa hydrated Supple; no masses. Supple; no masses. No cervical or axillary adenopathy. No cervical or axillary adenopathy. RRR, no m/r/g; nl S1, S2. No carotid bruits. 2+ radial, DP, PT RRR, no m/r/g; nl S1, S2. No carotid bruits. 2+ radial, DP, PT

pulses. pulses. CTA BCTA B Patient with ovoid 1 cm diameter flat eczematous lesions over Patient with ovoid 1 cm diameter flat eczematous lesions over

abdomen and feet. Multiple pustular lesions over abdomen, R abdomen and feet. Multiple pustular lesions over abdomen, R shoulder, arms, and back measuring about 0.5 cm in diametershoulder, arms, and back measuring about 0.5 cm in diameter

Soft, ND, NT, normoactive BS, no HSM.Soft, ND, NT, normoactive BS, no HSM. No c/c/e. Linear ridges over toenails c/w chronic onychomycosisNo c/c/e. Linear ridges over toenails c/w chronic onychomycosis No focal neurologic deficits.No focal neurologic deficits.

Derm Consult Skin ExamDerm Consult Skin Exam

Discrete vioaceous, edematous, Discrete vioaceous, edematous, non-scaly papules on mid non-scaly papules on mid abdomen proximal upper abdomen proximal upper extremities and lower back. No extremities and lower back. No vesicles, pustules or blisters vesicles, pustules or blisters

Lab ValuesLab Values

WBC 0.3, ANC 0.1, Platelets 74 (post WBC 0.3, ANC 0.1, Platelets 74 (post transfusion) Creatinine 1.3 transfusion) Creatinine 1.3

Blood cultures no growth at 24 hours Blood cultures no growth at 24 hours x 2; no growth at 3 days x 2x 2; no growth at 3 days x 2

Urine cx no growth Urine cx no growth CMV IgG +, EBV IgG +, EBV IgM -, CMV IgG +, EBV IgG +, EBV IgM -,

HSV 1,2 IgG +, Heb Bs -, Hep B core-, HSV 1,2 IgG +, Heb Bs -, Hep B core-, Hep C - CMV viral load negative Hep C - CMV viral load negative

Galactomannan assay negativeGalactomannan assay negative

DiscussionDiscussion

Disseminated Aspergillus Disseminated Aspergillus flavus with Cutaneous flavus with Cutaneous

FindingsFindings

Disseminated AspergillusDisseminated Aspergillus Fungus – genus Fungus – genus AspergillusAspergillus, Family , Family

TrichocomaceaeTrichocomaceae Closely related to genus Closely related to genus PenicilliumPenicillium Named after aspergillum used to sprinkle holy Named after aspergillum used to sprinkle holy

water.water. Changing epidemiology – Changing epidemiology –

72 cases of aspergillosis in hematopoietic stem cell 72 cases of aspergillosis in hematopoietic stem cell transplant recipients 2005transplant recipients 2005

Aspergillus fumigatus (56 percent)Aspergillus fumigatus (56 percent) A. flavus (19 percent)A. flavus (19 percent) A. terreus (16 percent)A. terreus (16 percent) A. niger (8 percent)A. niger (8 percent) A. versicolor (1 percent) A. versicolor (1 percent)

1990s – 90% A. fumigatus 1990s – 90% A. fumigatus Ubiquitous organism – found in soil, water, food, airUbiquitous organism – found in soil, water, food, air

Cutaneous InfectionCutaneous Infection Can represent disseminiated hematogenous Can represent disseminiated hematogenous

infection or local inoculation of infection that infection or local inoculation of infection that may arise around an IV catheter insertion sitemay arise around an IV catheter insertion site Also seen associated with tape or adhesive dressingsAlso seen associated with tape or adhesive dressings

Most lesions occur in patients with neutropenia Most lesions occur in patients with neutropenia or other immunocompromise, can also invade or other immunocompromise, can also invade patients with burns or surgical woundspatients with burns or surgical wounds

Lesion is area of rapidly increasing errythema Lesion is area of rapidly increasing errythema with a necrotic, often ulcerated center.with a necrotic, often ulcerated center.

Resemble pyoderma gangrenosumResemble pyoderma gangrenosum Invasion of blood vessels and cutaneous ulcer Invasion of blood vessels and cutaneous ulcer

occursoccurs

Cutaneous InfectionCutaneous Infection

Usually direct implantation following traumaUsually direct implantation following trauma Less commonly, dissemination from a Less commonly, dissemination from a

primary respiratory tract focus. primary respiratory tract focus. In one series of patients with hematologic In one series of patients with hematologic

malignancies, cutaneous lesions occurred in four malignancies, cutaneous lesions occurred in four percent of patients with documented Aspergillus percent of patients with documented Aspergillus infectioninfection

Lesions rapidly evolve from papular to Lesions rapidly evolve from papular to ulcerative lesions; the ulcers continue to ulcerative lesions; the ulcers continue to enlarge at varying rates depending upon the enlarge at varying rates depending upon the degree of immunosuppressiondegree of immunosuppression

BMT recipient with multiple cutaneous lesions

View image in J Clin Microbiol. 1998 View image in J Clin Microbiol. 1998 November; 36(11): 3115–3121. November; 36(11): 3115–3121.

Aspergillus in BMT Aspergillus in BMT patientspatients

Incidence of invasive aspergillus in Incidence of invasive aspergillus in BMT patients is bimodal – peak BMT patients is bimodal – peak incidence <20 days from transplant incidence <20 days from transplant and then >100 days after transplantand then >100 days after transplant

Associated with a particularly bad Associated with a particularly bad prognosisprognosis

PathogenesisPathogenesis

Usual route of infection is through Usual route of infection is through inhalation of conidia into lungsinhalation of conidia into lungs

Invasive infection can follow local tissue Invasive infection can follow local tissue invasion, but less commoninvasion, but less common

Hydrocortisone significantly increases Hydrocortisone significantly increases the growth rates of the growth rates of AspergillusAspergillus

Vascular invasion and infarction are the Vascular invasion and infarction are the classic features of invasive aspergillosisclassic features of invasive aspergillosis

Pathogenesis – A. flavusPathogenesis – A. flavus

A flavis is known for producing A flavis is known for producing aflatoxinaflatoxin These decrease macrophage and These decrease macrophage and

neutrophil functionneutrophil function Important as a carcinogenic and Important as a carcinogenic and

immunosuppressive agent but does not immunosuppressive agent but does not appear to be important in virulenceappear to be important in virulence

DiagnosisDiagnosis Proven diagnosis requires tissue biopsy showing Proven diagnosis requires tissue biopsy showing

invasion of hyphae and positive culture for invasion of hyphae and positive culture for aspergillusaspergillus

Can be established with needle bx or CSF Can be established with needle bx or CSF Blood cultures rarely positiveBlood cultures rarely positive Hyphae easily seen on common fungal stains Hyphae easily seen on common fungal stains

GMS or PASGMS or PAS Hyaline, septate, acute-angle branched, 3-6uM in widthHyaline, septate, acute-angle branched, 3-6uM in width

Above features can distinguish from other Above features can distinguish from other zygomycosis, but culture necessary to zygomycosis, but culture necessary to differentiate from other opportunistic molds – differentiate from other opportunistic molds – fusarium, scedosporiumfusarium, scedosporium

Aspergillus fumigatus

Macroscopic morphology- showing dichotomously branching hyphae – and histopathology

View slides at Doctor Fungus web site:http://www.doctorfungus.org

Diagnosis - Diagnosis - GalactomannanGalactomannan

Substance released during growth of Substance released during growth of hyphae, major constituent of Aspergillus hyphae, major constituent of Aspergillus cell walls. cell walls.

ELISA for galactomannin FDA approvedELISA for galactomannin FDA approved Permits detection of antigenemia in Permits detection of antigenemia in

some patients an average of five to eight some patients an average of five to eight days before the presence of clinical days before the presence of clinical signs, an abnormal chest x-ray, or signs, an abnormal chest x-ray, or positive cultures. positive cultures.

Galactomannan (cont)Galactomannan (cont) A meta-analysis of patients at risk A meta-analysis of patients at risk

Twenty-seven studies, 4000 patients. Twenty-seven studies, 4000 patients. Sensitivity of test ranged from 61-71%Sensitivity of test ranged from 61-71% Specificity 89-93%Specificity 89-93% NPV 95-98%, PPV 26-53%NPV 95-98%, PPV 26-53%

Galactomannan assay is helpful in ruling out Galactomannan assay is helpful in ruling out the diagnosis of invasive aspergillosis but has the diagnosis of invasive aspergillosis but has only moderate to low sensitivity in confirming only moderate to low sensitivity in confirming disease. disease. Subgroup analyses assay performed better in Subgroup analyses assay performed better in

hematological malignancy patients or hematological malignancy patients or hematological transplant recipients probably hematological transplant recipients probably related to the higher pre-test probability related to the higher pre-test probability compared with solid organ transplant recipientscompared with solid organ transplant recipients

Galactomannan (cont)Galactomannan (cont) Sensitivity and specificity is affected by Sensitivity and specificity is affected by

the administration of other medications. the administration of other medications. False positives in patients onFalse positives in patients on piperacillin/tazobactam /tazobactam amoxicillin-clavulanate

False positive can occur as long as 5 days False positive can occur as long as 5 days after stopping medicationsafter stopping medications

Sensitivity of assay decreased antifungal Sensitivity of assay decreased antifungal therapytherapy

Test performance will vary according to Test performance will vary according to the threshold value used. the threshold value used.

Treatment OptionsTreatment Options Ampho (including lipid formulations)Ampho (including lipid formulations)

We have the most clinical experience with We have the most clinical experience with this medication. Lots of clinical experience this medication. Lots of clinical experience watching 80% of our patients die.watching 80% of our patients die.

Voriconazole – Now First Line Voriconazole – Now First Line TreatmentTreatment c/w ampho in study of 277 pts w/ invasive c/w ampho in study of 277 pts w/ invasive

aspergillosisaspergillosis Better response rate 53% vs 32%Better response rate 53% vs 32% Decreased mortality 29% vs 42%Decreased mortality 29% vs 42% Lower rate of severe adverse reactionsLower rate of severe adverse reactions

Treatment (cont)Treatment (cont)

PosaconazolePosaconazole Similar to Voriconazole in activity against Similar to Voriconazole in activity against

aspergillus aspergillus In open-label non-controlled trial in patients In open-label non-controlled trial in patients

intolerant to prior therapy success rate was intolerant to prior therapy success rate was 42% compared with 26% for controls42% compared with 26% for controls

Initially chosen for this patient because of the Initially chosen for this patient because of the broader spectrum while awaiting culture broader spectrum while awaiting culture resultsresults

CaspofunginCaspofungin Lack of data for primary therapyLack of data for primary therapy Used in patients intolerant to other Used in patients intolerant to other

medicationsmedications

PrognosisPrognosis

Systematic lit review in CID 2001 Systematic lit review in CID 2001 showed overall case fatality rate showed overall case fatality rate 58%58%

86.7% mortality in BMT patients86.7% mortality in BMT patients 88.1% mortality in patients with 88.1% mortality in patients with

disseminated invasive diseasedisseminated invasive disease Favorable responses to ampho was Favorable responses to ampho was

seen in less than 20% of patientsseen in less than 20% of patients

Outcome of Our patientOutcome of Our patient

So far, so good…?So far, so good…? Neutrophils are back, skin lesions Neutrophils are back, skin lesions

appear to be healing. Clinically appear to be healing. Clinically improving. Fever yesterday, repeat improving. Fever yesterday, repeat CXR showed only mild change. CXR showed only mild change.

Planning for lifelong posaconazole Planning for lifelong posaconazole therapy.therapy.

ReferencesReferences Mandell’s Principles and Practices of Infectious Mandell’s Principles and Practices of Infectious

Disease, 6Disease, 6thth Ed. Ed.[Book available online via the [Book available online via the UNC-CH Libraries]]

Pfeiffer CD, Fine JP, Safdar N. Diagnosis of invasive Pfeiffer CD, Fine JP, Safdar N. Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis. 2006 May 15;42(10):1417-analysis. Clin Infect Dis. 2006 May 15;42(10):1417-727.727.

Morgan J, Wannemuehler KA, Marr KA, et al. Incidence Morgan J, Wannemuehler KA, Marr KA, et al. Incidence of invasive aspergillosis following hematopoietic stem of invasive aspergillosis following hematopoietic stem cell and solid organ transplantation: interim results of cell and solid organ transplantation: interim results of a prospective multicenter surveillance program. Med a prospective multicenter surveillance program. Med Mycol 2005 May;43 Suppl 1:S49-58.Mycol 2005 May;43 Suppl 1:S49-58.

D'Antonio D, Pagano L, Girmenia C, et al. Cutaneous D'Antonio D, Pagano L, Girmenia C, et al. Cutaneous aspergillosis in patients with haematological aspergillosis in patients with haematological malignancies. Eur J Clin Microbiol Infect Dis 2000 malignancies. Eur J Clin Microbiol Infect Dis 2000 May;19(5):362-5.May;19(5):362-5.

Isaac M. Cutaneous aspergillosis. Dermatol Clin 1996 Isaac M. Cutaneous aspergillosis. Dermatol Clin 1996 Jan;14(1):137-40.Jan;14(1):137-40.

References (cont’d.) Raad II, Graybill JR, Bustamante AB, et al. Raad II, Graybill JR, Bustamante AB, et al.

Safety of long-term oral posaconazole use in Safety of long-term oral posaconazole use in the treatment of refractory invasive fungal the treatment of refractory invasive fungal infections. Clin Infect Dis. 2006 Jun infections. Clin Infect Dis. 2006 Jun 15;42(12):1726-34. 15;42(12):1726-34.

Walsh TJ; Raad I; Patterson TF. Treatment of Walsh TJ; Raad I; Patterson TF. Treatment of invasive aspergillosis with posaconazole in invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of patients who are refractory to or intolerant of conventional therapy: an externally controlled conventional therapy: an externally controlled trial. Clin Infect Dis 2007 Jan 1;44(1):2-12.  trial. Clin Infect Dis 2007 Jan 1;44(1):2-12.  

Lin SJ, Schranz J, Teutsch SM. Aspergillosis Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the case-fatality rate: systematic review of the literature. Clin Infect Dis 2001 Feb literature. Clin Infect Dis 2001 Feb 1;32(3):358-66. 1;32(3):358-66.

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