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ID Case Conference
7/18/07 – Case #1
Gretchen Shaughnessy, MD
ID Fellow (at last!)
The Case
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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.
PMH
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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
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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.
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Allergies - NKDA
Medications
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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
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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.
ROS
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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.
Physical Exam
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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.
Derm Consult Skin Exam
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Discrete vioaceous, edematous, non-scaly
papules on mid abdomen proximal upper
extremities and lower back. No vesicles,
pustules or blisters
Lab Values
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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
Discussion
Disseminated Aspergillus flavus
with Cutaneous Findings
Disseminated Aspergillus
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Fungus – genus Aspergillus, Family Trichocomaceae
Closely related to genus Penicillium
Named after aspergillum used to sprinkle holy water.
Changing epidemiology –
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72 cases of aspergillosis in hematopoietic stem cell transplant recipients
2005
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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
Cutaneous Infection
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Can represent disseminiated hematogenous infection or
local inoculation of infection that may arise around an
IV catheter insertion site
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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
Cutaneous Infection
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Usually direct implantation following trauma
Less commonly, dissemination from a primary
respiratory tract focus.
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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
BMT recipient with multiple
cutaneous lesions
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View image in J Clin Microbiol. 1998
November; 36(11): 3115–3121.
Aspergillus in BMT patients
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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
Pathogenesis
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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
Pathogenesis – A. flavus
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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
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Diagnosis
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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
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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
Aspergillus fumigatus
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Macroscopic morphology- showing
dichotomously branching hyphae – and
histopathology
View slides at Doctor Fungus web site:
http://www.doctorfungus.org
Diagnosis - Galactomannan
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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.
Galactomannan (cont)
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A meta-analysis of patients at risk
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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.
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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
Galactomannan (cont)
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Sensitivity and specificity is affected by the
administration of other medications. False positives in
patients on
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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.
Treatment Options
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Ampho (including lipid formulations)
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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
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Treatment (cont)
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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
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Caspofungin
Lack of data for primary therapy
 Used in patients intolerant to other medications
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Prognosis
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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
Outcome of Our patient
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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.
References
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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.
References (cont’d.)
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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 casefatality rate: systematic review of the literature. Clin
Infect Dis 2001 Feb 1;32(3):358-66.
Search PubMed
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Cutaneous Aspergillus flavus infections
Case studies
 Reviews
 Differential Diagnosis
 Drug Therapy
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