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 • Signs/Symptoms
– Age – Liver
– HLA mismatch • Cholestasis
– CMV positive – Skin
• inflammatory rash
– multiparous
– female male – Gut
• Secretory diarrhea
– Tissue injury
 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
• Sample Outside
• Dendritic cells • Sample Inside
• B cells • Process Specimen
• Macrophages • Present Data
• Endothelial Cells
• Kupffer cells
 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 “Meaning of Life”
B cell
Macrophage
“Enforcer”

CD8
HLA Class I - i.e. HLA-A, B, C
 Why do we have to match?
• 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 • HA-1
– antigen from Y – polymorphic
chromosome – unknown function
– expressed ubiquitously – expressed only on
– target for CTL hematopoietic cells
responses – target for CTL
– CTL response leads to responses
less relapse, more – CTL response leads to
GVHD less relapse, no GVHD
GVHD Prophylaxis - How much?
Aggressive Prophylaxis Minimal Prophylaxis
•LESS GVHD •MORE GVHD
•MORE infection •LESS infection
•MORE relapse •LESS relapse

SURVIVAL
 Graft vs. Lymphoma
1.0

.9

.8
Proportion Progression-free

.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 Stem cells

suppression

Manipulate the Immune response to

maximize G vs. disease
Infection after SCT
 Infection after SCT
• Infection is the most common cause of non-
relapse death
• Risk increases with:
– 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
– 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
– 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
– CMV
– Encapsulated bacteria
– Aspergillus species
– varicella-zoster, EBV
– PCP, Toxoplasma
 Invasive Fungal Infection

• Incidence 10 - 20%
• Mortality 70%
• Autopsy 10 - 30%
• Candida sp.
– Krusei, glabrata
• Aspergillus sp.
• Diagnosis difficult
Risk Factors for Invasive Fungal
Infection
• Strong Association • Weak Association
– Acute GVHD – Splenectormy
– ATG treatment – CMV Pos
– Age – TBI
– Fungal colonization – low BM dose
– Long neutropenia – HSV positive donor
– Dx: AML
– HLA mismatched
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 FDA-
or 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 • Prophylaxis/Treatment
– CMV, HSV, VZV – Acyclovir
• Less common – Ganciclovir
– Adenovirus, – Foscarnet
influenza A, – Avoidance
parainfluenza, RSV, • Possible Treatments
Rhinovirus
– RSV Ig, ribavirin
• Rare neuraminidase inhibitor,
– Rotavirus, rimantadine
Coxsackie, polyoma
virus
 Community-Acquired Respiratory Virus
Infections After Marrow Transplant:
Fred Hutchinson Cancer Research Center (1990-1996)
Respiratory syncytial virus 44 (35%)
Parainfluenza 38 (30%)
Type 1 18
Type 2 4
Type 3 16
Rhinovirus 31 (25%)
Influenza 14 (11%)
Type A 12
Type B 2
Bowden R. Am J Med 1997;102(3A):27-30.
 Respiratory Syncytial Virus Infection in
Bone Marrow Transplant Patients
Fred Hutchinson Cancer Research Center,1990
9
Number of patients diagnosed

8
7
6
5
4
3
2
1
0
2 4 6 8 10 12 14 16
January February March April
Week
Harrington et al. J Infect Dis 1992;165:987-93.
 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 Infection
up to 4 months influenza
up to 2 years adenovirus
up to 22 days 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).