Download Graft vs. Host Disease

Graft vs. Host Disease
What is GVHD?
• An cell mediated reaction of donor origin
against recipient tissues
• It requires:
– a donor graft with immunologically competent
cells
– a recipient unable to mount immune response
– recipient expresses tissue antigens that are not
present in the donor.
Clinical Features of Acute
GVHD
• Risk Factors
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Age
HLA mismatch
CMV positive
multiparous
female male
Tissue injury
• Signs/Symptoms
– Liver
• Cholestasis
– Skin
• inflammatory rash
– Gut
• Secretory diarrhea
Very Basic Immunology
• Auditors - responsible for sifting thru all
available info to find evidence of intrusion.
Shows data to Regulators and Enforcers.
• Regulators - Reviews data presented by
Auditor and contacts Enforcers. (includes
prosecutors and defenders)
• Enforcers - Kill things.
Auditors
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Dendritic cells
B cells
Macrophages
Endothelial Cells
Kupffer cells
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Sample Outside
Sample Inside
Process Specimen
Present Data
Auditor
(Sampling surroundings)
Degraded in peptides
Combined with HLA molecules
Displayed with HLA molecule
Exogenous substance
Auditor
(Sampling inside)
Viral or intracellular protein
Nucleus
Virus
Displayed with HLA molecule
Communicating Trouble
HLA Class II - i.e. HLA - DR, DQ, DP
“Regulator”
“Trouble”
signal
CD4
Dendritic cell
B cell
Macrophage
“Meaning of Life”
“Enforcer”
CD8
HLA Class I - i.e. HLA-A, B, C
Why do we have to match?
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BMT = immune system transplant
HLA molecules act as T cell “superantigens”
All somatic tissues express HLA class I
Transferred T cell could “over-react”
Transferred T cells won’t work if they can’t
bind their own HLA molecule
If there is a “match”, why
GVHD?
• HLA molecules “show” what’s inside
• We are all different inside
• GVHD results from T cell reactivity toward
polymorphisms between donor and host.
– This can be a good thing
• or
– This can be a bad thing
Polymorphisms can help rid
disease or cause GVHD
• H -Y
– antigen from Y
chromosome
– expressed ubiquitously
– target for CTL
responses
– CTL response leads to
less relapse, more
GVHD
• HA-1
– polymorphic
– unknown function
– expressed only on
hematopoietic cells
– target for CTL
responses
– CTL response leads to
less relapse, no GVHD
GVHD Prophylaxis - How much?
Aggressive Prophylaxis
Minimal Prophylaxis
•LESS GVHD
•MORE infection
•MORE relapse
•MORE GVHD
•LESS infection
•LESS relapse
SURVIVAL
Graft vs. Lymphoma
1.0
Proportion Progression-free
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
0
1000
2000
3000
Days after BMT
Figure 3
Juckett, et al BMT 21:893, 1998
Myeloablative SCT
High dose radiation
High dose chemo
Stem cells
Watch and wait
Non-myeloablative SCT
Immuno
suppression
Stem cells
Manipulate the Immune response to
maximize G vs. disease
Infection after SCT
Infection after SCT
• Infection is the most common cause of nonrelapse death
• Risk increases with:
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previous treatment
history of infection (especially fungal)
tissue injury (especially mucositis)
duration of neutropenia
GVHD and treatment thereof (prednisone)
mismatched/unrelated vs. matched/related
Infection of SCT patients
Phase I - first month
• Host immune system defect
– skin, mucous membrane, neutropenia
• Pathogens
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staph epidermidis
facultative gram neg bacilli
oropharyngeal streptococci
all candida, aspergillus
respiratory and enteric viruses
Infection of SCT patients
Phase II - 30 to 100 days
• Host immune system defect
– Impaired cellular immunity, GVHD
• Pathogens
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CMV
all candida, aspergillus
staph epidermidis
respiratory and enteric viruses
EBV (for T cell depleted SCT)
Infection of SCT patients
Phase III - > 100 days
• Host immune system defect
– Impaired cellular and humoral immunity
• Pathogens
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CMV
Encapsulated bacteria
Aspergillus species
varicella-zoster, EBV
PCP, Toxoplasma
Invasive Fungal Infection
•
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Incidence 10 - 20%
Mortality 70%
Autopsy 10 - 30%
Candida sp.
– Krusei, glabrata
• Aspergillus sp.
• Diagnosis difficult
Risk Factors for Invasive Fungal
Infection
• Strong Association
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Acute GVHD
ATG treatment
Age
Fungal colonization
Long neutropenia
Dx: AML
HLA mismatched
• Weak Association
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Splenectormy
CMV Pos
TBI
low BM dose
HSV positive donor
Available at
http://www.cdc.gov/mmwr/
preview/mmwrhtml/
rr4910a1.htm
Systemic Fungal Infections Diagnosed in
HSCT Recipients, by Prophylaxis Used
Yes
No
Total
Fluconazole
5 (3%)
174
179
Placebo
28 (16%)
149
177
Total
33
323
356
OR = 0.15, 95% C.I. (0.05, 0.42), P < 0.001
Goodman JL, et al. N Engl J Med 1992;326(13):845-851.
Ventilation Recommendations
Allogeneic HSCT recipients
• Rooms with >12 air exchanges/hour [AIII]
• Point-of-use high efficiency (>99%) particulate
air (HEPA) filters that are capable of removing
particles >0.3 µm in diameter [AIII]
Autologous HSCT recipients
• Use of HEPA-filtered rooms should be
considered for autologous HSCT recipients if
they develop prolonged neutropenia [CIII]
Positive Room Air Pressure
• Hospital rooms for HSCT recipients should have
positive room air pressure
• HSCT units should maintain consistent pressure
differentials between the patient’s room and the
hallway or anteroom at >2.5 Pascals or 0.01 inch
by water gauge [BIII]
Equipment and Supplies
• All HSCT units should sterilize or disinfect and
maintain equipment and devices using only FDAor EPA-registered compounds as directed by
established guidelines [AIII]
• HSCT units should monitor opened and unopened
wound dressing supplies [BIII]
• Monitoring should consist of discarding all bandages
and wound dressings that are out of date, have
damaged packaging, or are visually contaminated by
construction debris or moisture [BIII]
HSCT Hospital Surveillance
NO
• Routine bacterial and fungal patient surveillance
cultures [DII]
YES
• Routine fungal environmental surveillance
cultures [CIII]
• Routine surveillance for the number of
aspergillosis cases in HSCT recipients [BIII]
Viral Infections after SCT
• Common
– CMV, HSV, VZV
• Less common
– Adenovirus,
influenza A,
parainfluenza, RSV,
Rhinovirus
• Rare
– Rotavirus,
Coxsackie, polyoma
virus
• Prophylaxis/Treatment
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Acyclovir
Ganciclovir
Foscarnet
Avoidance
• Possible Treatments
– RSV Ig, ribavirin
neuraminidase inhibitor,
rimantadine
Community-Acquired Respiratory Virus
Infections After Marrow Transplant:
Fred Hutchinson Cancer Research Center (1990-1996)
Respiratory syncytial virus
Parainfluenza
Type 1
Type 2
Type 3
Rhinovirus
Influenza
Type A
Type B
Bowden R. Am J Med 1997;102(3A):27-30.
44 (35%)
38 (30%)
18
4
16
31 (25%)
14 (11%)
12
2
Number of patients diagnosed
Respiratory Syncytial Virus Infection in
Bone Marrow Transplant Patients
Fred Hutchinson Cancer Research Center,1990
9
8
7
6
5
4
3
2
1
0
2
January
4
6
8
February
Harrington et al. J Infect Dis 1992;165:987-93.
Week
10
March
12
14
April
16
1991 Community Influenza Outbreak
Houston, TX
• 27% of 15 HSCT outpatients and 29% of 28
HSCT inpatients with acute respiratory infections
had documented influenza - mortality 17%.
• 75% of all HSCT influenza cases during this
outbreak were associated with pneumonia.
• Risk factors for severe influenza disease include
infection early after transplant just before
engraftment of chronic GVHD.
• Many acquired the infection while hospitalized
Whimbey E. Bone Marrow Transplant 1994;13:437-40.
Viral Shedding for CRV Infections
in HSCT Recipients
Duration
up to 4 months
up to 2 years
up to 22 days
Infection
influenza
adenovirus
RSV
Note: RSV viral shedding has been reported to
last 112 days in a child with SCID.
URI Recommendations
HCWs and visitors with URI symptoms should be
restricted from contact with HSCT recipients and
candidates under-going conditioning therapy to
minimize the risk for CRV transmission (AIII).
Visitors with URI symptoms should be asked to
defer their visit to the HSCT center until their URI
symptoms resolve (BIII).
All HCWs with URI symptoms should be restricted
from patient contact and reassigned to non-patient
care duties until their symptoms resolve (BIII).