Transcript Transplant Infectious Diseases - Vanderbilt University Medical Center

INFECTIONS AFTER
TRANSPLANTATION
Lora Thomas MD, MPH
September 28, 2012
Topics To Be Discussed

How are we doing in transplantation?

Review basic precepts of transplant infections

Discuss some classic transplant pathogens: CMV,
EBV, fungal diseases, pneumocystis, TB
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Emerging transplant problems: polyomaviruses, RSV,
respiratory viruses, arenaviruses

Avoidance of infection
Graft and Patient Survival After Transplantation
by Organ
Type
Renal-LD
Renal-Cad
Pancreas
Heart
Liver
Lung
Heart-Lung
Graft Survival (%)
Patient Survival (%)
1 year
96
91
76
88
84
82
81
1 year
99
96
98
88
88
83
81
3 year
90
80
60
81
74
64
62
Data from SRTR 2009 Annual Report
3 year
95
89
92
82
79
66
62
Decreasing Infectious Mortality in Subsequent
Cardiac Transplant Cohorts 1980-1990
PPID, chapter 304, 2000
Lack of Change in Infectious Mortality
after Cardiac Transplantation: 1990-2000
Infection Related Mortality in
Lung Transplant Recipients
100%
90%
80%
70%
Other
60%
Proportion of All
Deaths Related
to Cause
Cancer
50%
BO/Graft Dys
40%
Infection
30%
20%
10%
0%
1998 1999 2000 2001 2002 2003 2004 2005 2006
VUMC Data
Basic Precepts of Transplant Infections
 Infections occur on a time scale
 Type and frequency of infection vary with transplant type:
lung>liver>heart>kidney
 More surgery  more infection
 More immunosuppression  more infection
 Beware of donor as a source of infection especially early post-
transplant
 Transplantation does not protect from infections “normal”
people get
Time Scale of Infection after Transplantation
Types of Infections vary depending on time posttransplant:

0-30 days: mostly ”surgical” infections,
common bacteria, Candida, HSV

1-6 months: opportunistic pathogens, CMV,
Pneumocystis, Nocardia, Aspergillus

6 months onward: common community infections,
occasional opportunists,
endemic fungi (histo, crypto)
Frequency and Severity of Infections by Organ
Type
N
Inf /Pt.
CMV
Bacteremia
Fungal
Inf. Death
Renal
64
0.98
8%
5%
0%
0%
Heart
119
1.36
16%
13%
8%
15%
Liver
101
1.86
22%
16%
16%
23%
H-Lung 31
3.19
39%
19%
23%
45%
Dummer JS, PPID, 2000, Churchill Livingstone, based on data from early 1980’s in Pittsburgh
Partial List of Organisms Transmitted
by Transplantation

Viruses: CMV and other herpesviruses, HIV, hepatitis A,
B C & D, HTLV-1, WNV, Rabies, LCMV

Fungi: Histoplasma, Coccidioides, Cryptococcus

Protozoa: Toxoplasma, malaria, T. cruzii

Bacteria: TB, nosocomial pneumonia agents (lung),
urinary bacteria (kidney), bacteremic donor

Prions: Creutzfield-Jakob disease (cornea)
Gottesdiener, Ann Int Med 1989;110:1001; Dummer JS, PPID, 2004
Infectious Episodes Related to Total Time Spent in
the Operating Room
Total operative time in hours
Immunosuppression and Infection
- A Summary

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No good marker is available for state of
immunosuppression (unlike CD4 in HIV)
“Net state of immunosuppression” must be
estimated based on clinical status, doses or
levels of drugs, and recent treatment of
rejection
Treatment of rejection increases clinical infection
rates
Patients are treated with a cocktail of oral drugs
with different modes of action; some IV drugs
are also used either for treatment of rejection or
induction early post-transplant
Dummer JS, PPID, 2000; Halloran PF NEJM 2004;351:2715
Immunosuppression and Infection

Infections increase with increased intensity of
immunosuppression

Two major immunosuppressive drugs introduced since 1980,
cyclosporine and tacrolimus, have similar infectious risk but are
associated with less infection than the earlier regimen of
azathioprine/steroids

Two cell cycle inhibiting agents, azathioprine and mycophenylate
mofetil, have similar infectious risk

Risk of post transplant malignancy and CMV may be reduced
with rapamycin
Dummer JS, PPID, 2000
Antibody Therapy and Infection
Antithymocyte Globulin
Rabbit
Equine
Increased risk of CMV, PTLD
Anti-CD25 (IL-2 receptor) antibodies
Basiliximab (Simulect®)
Infection risk not significantly
increased
Anti-CD20 antibody
Rituximab (Rituxan®)
HBV reactivation
Anti-CD52 antibody
Alemtuzumab (Campath®)
Increased risk of CMV, Pneumocystis
jirovecii pneumonia, invasive fungal
infections, immunosuppression effects can
last up to 12 months
Herpesvirus Infections after Transplantation
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Up to 35% of patients develop oral or genital herpes simplex
infection in the first 2-3 weeks after transplantation; rare invasive
or primary infections may be fatal
Herpes zoster or shingles occurs in up to 1/3 of transplant
recipients. Chicken pox can be fatal
Epstein-Barr virus is associated with lymphoma after
transplantation. Risk is 0.3-4%, may be 10 times higher with
primary infection
Human herpes virus 8 associated with Kaposi’s sarcoma after
transplantation
Cytomegalovirus has been the single most important pathogen in
transplant recipients
Labial Herpes
Intraoral Herpes Simplex
Herpes Simplex Esophagitis
Herpes Simplex: Donor Transmitted Disease
Cytomegalovirus and Transplantation
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At one time CMV was the most important serious infection after
transplantation
Now largely controlled by antivirals
Usually occurs 30-90 days after transplantation
Manifestations: Fever most common, but sometimes invasive
infection in bowel, liver, lung or retina
Risk factors for disease are primary infection (usually donor
derived), level of immunosuppression, organ transplanted (lung)
Diagnosis used to be by viral culture, now most often by blood
antigenemia or quant. PCR
Treatment: ganciclovir, foscarnet
Infection and Morbidity due to CMV in Different
Transplant Groups*
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Kidney
Liver
Asymptomatic infection
Heart
Symptomatic infection
Heart-lung
Pneumonia
Data collected in Pittsburgh before the use of antiviral medications
Manifestations of CMV Disease
Following Cardiac Transplantation
Manifestation
No. of Patients
Fever > 38º
Atypical Lymphs > 3%
Interstitial Changes (CXR)
WBC < 4,000
Platelets < 100,000
SGPT > 40 IU
Abdominal Pain
Myalgia
Arthralgia
Data from Dummer, JID, 1985
17
15
8
8
7
7
7
2
2
% of Patients
100%
88%
47%
47%
41%
41%
41%
12%
12%
CMV Pneumonitis
Vogel et al.Br J Radiol 2006 (epub)
CMV Pneumonitis
Horger et al.AJR Am J Roentgenol
2006;187:W636
Cytomegalovirus Pneumonitis: Pathology
Microabscess Caused by CMV in the Liver
CMV Colitis
jmedicalcasereports.com
CMV Retinitis - Early
Management of CMV Infection

Most patients receive preventive regimens, either post-transplant
prophylaxis for 3 or more months or viral monitoring with preemptive
therapy

Valganciclovir is the preferred prophylaxis in the USA; some oral
ganciclovir is also used. High dose valacyclovir is also used but
more outside than inside the USA
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Advantage of prophylaxis is simplicity. Some data supports better
long term outcomes with prophylaxis
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Costs of pre-emptive therapy are potentially lower and late CMV
disease is less likely with pre-emptive therapy
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Treatment of CMV disease is usually with IV ganciclovir or oral
valganciclovir
Epstein-Barr Virus (EBV) and Transplantation
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Epstein-Barr virus can cause lympho-proliferative
disease after transplantation
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Some cases are polyclonal proliferations that respond to
reduction of immunosuppression; others are true
lymphomas

Risk varies by transplant group - lowest in renal
transplants (~0.3%) and highest in lung transplants and
pediatric transplants (~4%)

As with CMV primary infection and level of
immunosuppression are the main risks
Transplant Lymphoma - Case
A 41 year old woman received a heart-lung
transplant for cystic fibrosis in 1993 in North
Carolina. She was EBV seronegative at the time
of transplantation. She converted to EBV after
transplantation possible from the donor
She maintained excellent lung function posttransplant. 13 years later she presented with a
month of headache, low-grade fevers and
malaise. Exam showed only left sided ptosis. An
MRI scan of the head showed numerous
enhancing lesions in the brain.
Initial MRI
Scan of the
Brain
Lymphoproliferative Disease in the
Abdomen related to EBV
Australas Radiol 2006;50:412
Human Herpes Virus – 8 and Kaposi’s
Sarcoma (KS)
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Most recently discovered Herpesvirus
Endemic in Central Africa (50%); also
somewhat in Near East and around
Mediterranean (10%); rare in USA
Strongly associated with KS in AIDS and
transplantation
May respond to reduction of
immunosuppression
Fungal Infection after Transplantation
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Mucocutaneous Candida (Thrush and esophageal candidiasis) once
common but are controlled by topical antifungals such as nystatin
(“swish and swallow”)
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Invasive Candida incidence varies with organ transplanted: bone
marrow = liver>>lung=pancreas>heart=renal
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Cryptococcal infection occurs in 0.5-2.0 % of organ recipients
usually at least 6 months out and often quite late; rare in bone
marrow recipient
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Aspergillus: bone marrow>lung>liver>>heart=renal. Risk factors
high dose steroids, GVHD, renal dysfunction, prolonged neutropenia
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Endemic fungal infections occur sporadically
Esophageal Candidiasis
Candidiasis in Transplantation
Cryptococcal Infection after Transplantation
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Commonly presents either with pulmonary or central nervous
system disease
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Pulmonary: usually presents with lung nodule(s) on CXR with mild
pulmonary or no symptoms
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CNS disease presents as meningitis with gradual evolution of
headache and neurological findings that are often subtle
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Occasionally associated skin lesions
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Diagnosis with invasive procedures (bronchoscopy, lumbar puncture
and cryptococcal antigen)
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Disease can usually be controlled but some patients stay on
antifungals for prolonged durations, even lifelong
Pulmonary Cryptococcosis
Budding Cryptococcus neoformans
Strongly Positive India Ink Smear
Large Ulcer on Arm Caused by Cryptococcus
Skin Lesions Due to Cryptococcus
Mortality of Invasive
Aspergillosis
Organ Transplanted
% Incidence
% Mortality (3 month)
Allo HSCT
12.8%
71%
Auto HSCT
1.1%
42%
Lung
2%
22%
Liver
1.9%
45%
Heart
1.3%
<10%
Kidney
0.4%
25%
Trans Infect Dis 2010
Pulmonary Infiltrates Caused by
Aspergillus in a Neutropenic Host
Hyphae of Aspergillus Invading Tissue
Vascular Invasion by Aspergillus
Pulmonary Nodule due to A. fumigatus
in a Heart transplant Recipient
Aspergillus: Halo Sign
http://radiology.rsna.org
Cerebral Aspergillosis
Transplant Histoplasmosis

Soil fungus seen mostly in south central USA.
Occurs in about 0.5-1% in endemic areas
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Transplant patients often have multisystem
disease with fever, pneumonia, lymph node
enlargement, low blood counts and liver and
spleen enlargement
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Diagnosis by culture (slow), urine or blood
antigen (few days) and in sickest pts by blood
smear
H. Capsulatum
Histoplasmosis: Miliary Pattern
Millet Seeds
Pneumocystis Infection and Transplantation
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Pneumocystis pneumonia once occurred in 5-10% of transplant
patients, now controlled with prophylaxis
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Typically presented with fever, hypoxemia and diffuse
pneumonia 2-6 months after transplantation
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Diagnosis usually required bronchoscopy with lavage of lung
alveoli
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Treatment with sulfa-trimethoprim or pentamadine was usually
successful in clearing the organism but some patients died
during period of hypoxemia
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Two to three sulfa tablets a week prevent it
Radiographic Picture of Pneumocystis Pneumonia
Cysts of Pneumocystis in a Lung Biopsy
Tuberculosis after Transplantation
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Uncommon (< 1%) in developed world compared to
developing world (2-10%)
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2/3 of cases occur in first year; most thought to be
due to reactivation but only 20% in pts with +PPD
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½ of cases disseminated or extra-pulmonary; few
patients have classic upper lobe cavitary changes
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TB can be transmitted by donated organs but this
accounts for <5% of all cases
Singh N, Patterson DL, CID, 1998;27:1266
Polyomaviruses and Transplantation
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Two related small DNA viruses (JC & BK); serology
shows 60-80% of humans infected in childhood
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JC causes progressive multifocal leukoencephalopathy
(PML) in immunosuppressed patients
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Polyomaviruses (esp. BK but also JC) found by culture
in urine of 10-45% of renal and bone marrow transplant
patients; occasionally in normal hosts
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In 1980’s polyomaviruses shown to cause ureteral
stenosis (renal TX) and hemorrhagic cystitis (BM Tx)
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In recent years polyomavirus (mostly BK) shown to
cause severe nephropathy in 2-4% of renal recipients
BK Virus Nephropathy
Polyomavirus Infection of the Transplanted
Kidney: “Decoy” Cells in the Urine
Risk Factors for Polyomavirus Nephropathy after
Renal Transplantation

Generally strongest risk factor is detection of virus;
in one study just finding BKV in urine had an odds
ratio of 68 for nephropathy
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Demographic risk factors are older age, male
gender and caucasian ethnicity
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Polyomavirus nephropathy is associated with level
of immunosuppression, but findings are variable.
BK Virus Nephropathy: Graft Survival
Ramos et al. J Am Soc Nephrol
2002;13:2145-51
Respiratory Syncytial Virus (RSV)
 RNA virus
 Seasonal: Fall-early Spring
 >90% have had primary infection by age 2
 Reinfection common throughout life
 More severe disease seen in stem cell and lung transplant
recipients
 Rhinorrhea, sinus congestion, sore throat usually precede
pneumonia
RSV Pneumonia
Respiratory Viral Infections
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Influenza
Parainfluenza
Adenovirus
Metapneumovirus
Adenovirus
Enterovirus
Rhinovirus
Coronavirus
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Respiratory Viral Panels
increasingly being used
at centers
Nasopharyngeal swab,
wash, BAL
Sensitivity 79%
Specificity 99%
Lymphocytic Choriomeningitis Virus (LCMV)
Transmission by Organ Donation
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Multiple cases reported of LCMV transmission through organ
transplantation
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Fevers in recipients began between 3 and 22 days after
transplantation: other symptoms included peri-incisional rash,
headache, abdominal pain, mental status changes
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Most donors with no evidence of LCMV infection (one donor had
exposure to pet hamster that tested positive)
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Only one known survivor had reduction in immunosuppression
and ribaviron treatment
NEJM 2006;354:2235
LCMV In Transplant Patients
Kidney
Skin
NEJM 2006;354:2235
Prevention of Exposure to Infection

Hospital exposures: usually just standard infection control. Bone
marrow units may HEPA filter air and restrict visitors with colds

Enteric pathogens: avoid raw eggs, unpasteurized milk and
juices, certain soft cheeses, water from streams or lakes

Varicella: if seronegative avoid contact with chickenpox or
shingles

Zoonoses: avoid cat litter, bird cages, avoid jobs with frequent
animal contact
Prevention of Exposure to Infection
Respiratory viruses:
avoid persons with colds,
public places during flu
outbreaks, vaccinate family
members
Prevention of Exposure to InfectionContinued

Airborne molds: avoid barns, silos, chicken coops etc.

STD’s: Practice safer sex
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Exotic infections: Before international travel outside
Canada or W. Europe, confer with infectious disease
expert
Vaccination after Transplantation
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No clear evidence connecting vaccination to rejection episodes
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Inactivated vaccines safe to use starting 3 months after transplant if
at baseline immunosuppression
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Avoid live virus vaccines after transplant (minimum 4 weeks from
live vaccine to transplantation)
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Influenza: inactivated seasonal vaccine recommended, insufficient
data to support use of high dose influenza vaccine, adjuvant, or
booster dose
American Journal of Transplantation 2011;
11: 2020–2030
Questions
?