Download 5-2-Blumberg

Emily A. Blumberg, MD
Perelman School of Medicine at the University of
Pennsylvania
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Research Funding
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Achaogen
Actelion
Ansun
Cubist/Merck
Roche
Viropharma/Shire
DSMB
◦ Bristol Myers Squibb
◦ Pfizer
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American Board of Internal Medicine Test
Development Committee
Deceased donor from India, CMV D-R+
 Progressive weight loss since transplant
 Admitted with CVA
 Incidental finding of newly abnormal chest Xray
 Never had fever and no respiratory symptoms
 Meds: Tacrolimus, prednisone,
mycophenolate (held), tmp sulfa,
valganciclovir, thymoglobulin induction
 Exam unremarkable
 Routine CBC and chemistries unremarkable


Review of exposures revealed extensive
exposure to soil during gardening post
transplantation
LESSONS LEARNED
 Infections occur in the absence of fever and
localizing symptoms
Can be true even months-years post transplant

Detailed history is important in making
diagnoses
Fever, dyspnea, non productive cough
Basiliximab induction, Tacrolimus, Mycophenolate,
Prednisone maintenance
Valganciclovir, Tmp sulfa prophylaxis
Pulmonary rehab – exposed to influenza, started on
oseltamivir

Presented with progressive SOB/DOE for 3-4
weeks
Initial BAL Klebsiella pneumoniae – treated with
cefpodoxime
Persistent dyspnea

BAL
Klebsiella pneumonia
Influenza A
Treated with piperacillin tazobactam,
treatment dose of oseltamivir
 Still symptomatic
 Repeat bronchoscopy


Review of donor chart revealed donor from
the Dominican Republic
Subsequent testing donor serology + for
Strongyloides
LESSONS LEARNED
Recipient history isn’t the only one that matters
Transplant patients can have more than one
diagnosis concurrently
Not always clear which is the most important one
Tacrolimus, azathioprine immunosuppression
 Trimethoprim sulfamethoxazole and acyclovir
for prophylaxis
 Exam – fever, rash
 Labs – pancytopenia
 Normal liver function
tests

Diagnosis by chimerism assay
 All microbiology testing negative initially,
although expired due to persistent bacterial
infection when profoundly neutropenic

LESSONS LEARNED
 Not all fevers are infection
GVHD, Drug fever, rejection, thromboses all may cause
fever
Physical exam and labs can be helpful

Consider all the options and test broadly when
the answer is not obvious
Organ
Donor
Pyogenic
Bacteria
Blood
Donor
Recipient
Hospital
Community
Community Acquired
Viruses
“Opportunistic”
Bacteria
“Opportunistic”
Viruses
Fungi
Parasites
Protozoa

Cultures
Differentiation of colonization from infection

Viral nucleic acid tests
Interpretation of low viral loads and negative results
with high index of suspicion

Fungal assays (e.g., galactomannan, beta D
glucan, histoplasmosis antigen, cryptococcal
antigen)
Variable sensitivity and specificity based on
site/dissemination
Pooled sensitivity and specificity of the galactomannan assay for diagnosis of invasive
aspergillosis (IA).
Christopher D. Pfeiffer et al. Clin Infect Dis. 2006;42:14171727
© 2006 by the Infectious Diseases Society of America
Pooled sensitivity 85% (95% CI 75%-92%), specificity
81% (95% CI 72%-88%)
Yu, et al.Transplant Proc. 2014;46:26-32
Pro-peptide precursor of calcitonin released
by multiple tissues in response to cytokines
and endotoxin
 Biomarker associated with bacterial infection

Also elevated with end stage organ disease
(cirrhosis), pancreatitis, cardiogenic shock, trauma,
ischemic bowel
Levels affected by surgery, immunosuppression
Cytolytics may lead to elevated levels
Viral infections typically associated with lower levels
Co-infections may yield confounding results
Sandkovsky, et al. Clin Transplant 2015: 29: 689–696

Serial measurements can be used
As clue to bacterial infections in the early post
transplant period in patients who did not receive
cytolytics
As indicator of response to treatment
May differentiate infection from rejection
But Procalcitonin alone cannot diagnose infection
 Serial measurements may be important
There is currently no magic set of tests that
will consistently identify who is infected (fever
or no fever)
 Need to incorporate clinical judgment and
physical examination

NOSOCOMIAL, TECHNICAL
Degree of
immunosuppression
Treatment of rejection
1
OPPORTUNIST
IC
CMV
COMMUNITY ACQUIRED
Nocardia
Listeria
Toxoplasmo
sis
Aspergill
us
Cryptococc
PCP
us
Endemic
HSV
mycoses
Tuberculo
VZV
sis
EBV
2
3
4
5
6
7
8
9
Months post-transplant
Courtesy of Dr. Brian Schwartz
10
11
12
Degree of
immunosuppression
CMV
Aspergill
us
Nocardia
Listeria
Toxoplasmo
sis
PCP
HSV
VZV
EBV
1
2
3
4
5
6
7
8
9
Months post-transplant
Courtesy of Dr. Brian Schwartz
10
11
12

Testing should reflect clinical suspicion
Include combination of radiography, non invasive
testing, and biopsy
Extensive diagnostics may be required unless
diagnosis is clear
Step wise testing may result in critical loss of time
(especially since outcomes often linked to timing of
initiation of appropriate antimicrobials)
But is a broad approach cost effective?
Histopathology may ultimately be the quickest reliable
test!
Prompt initiation of
appropriate antimicrobials makes
a difference
All antimicrobials come
at a cost (not purely
financial)
How strong is the suspicion regarding a
specific diagnosis?
 Have I gotten sufficient samples so that
antimicrobials will not affect diagnosis?

What kind of testing will be most helpful?
Will the testing have reduced sensitivity in
transplant patients?
How sick is the patient?
 What is the anticipated toxicity of the
antimicrobials?

Fever usually (but not always) equals infection
 Not all infections are associated with fevers
 Transplant patients may be the exception to
Occam’s Razor (single unifying diagnosis)
