Fatal Graft-Versus-Host Disease After a Small Leukocyte Transfusion in a Patient With Lymphoma and Varicella

(1)

Fatal

Graft-Versus-Host

Disease

After

a Small

Leukocyte

Transfusion

in a Patient

With

Lymphoma

and Varicella

James

Betzhold,

M.D.,

and

Richard

Hong, M.D.

From the Department of Pediatrics and the Iminunobiology Research Center, University of Wisconsin Center

f

or Health Sciences, Madison

ABSTRACT. A child with a poorly differentiated lymphoma developed varicella while being treated with maintenance chemotherapeutic agents. He received a transfusion of nonir-radiated leukocytes from 1 unit of whole blood donated by a healthy volunteer who had recently recovered from varicel-la. The clinical course of varicella was aborted, but a classic graft-versus-host reaction developed and ultimately proved fatal. The host may have presented a large population of antigen-bearing cells to an infusion of presensitized immuno-competent donor cells, leading to an overwhelming

aggres-sor lymphocyte reaction. We speculate that a modified approach using irradiated donor cells could be of benefit in the treatment of varicella infections in the ilnmunosup-pressed host. Pediatrics 62:63-66, 1978, lymphoma, chemo-therapy, varicella, immunosuppression, graft-versus-host

reaction.

Fatal

graft-versus-host

reaction

(GVHR)

is

a

well-described

clinical

entity

following

bone

marrow

transplantation

in

the

totally

immuno-suppressed

host.’

GVHR

also

occurs

as a

conse-quence

of

transfusion

of

blood

products

from

normal

donors

into

children

with

severe

congen-ital

immunodeflciencies.2’3

Despite

the

tremen-dous

number

of

infusions

that

are

necessary

to

provide

hematologic

support

for

leukemic

patients,

fatal

GVHR

has

been

reported

after

leukocyte

transfusions

only

rarely.

In those

cases,

the

complication

was

thought

to occur

because

of

the

close

temporal

relationship

to

immunosup-pressive

therapy

or because

of the

large

numbers

of leukocytes

infused.46

This

report

describes

a

fatal

GVHR

that

occurred

in

a

patient

suffering

from

stem

cell

lymphoma

in

whom

a small

quantity

of

fresh

leukocytes

was

administered

to

treat

an

over-whelming

varicella

infection.

We

believe

that

the

unusual

complication

of

fatal

GVHR

resulted

from

the

presentation

of a target

cell

population

of

generalized

distribution,

i.e.,

virus-infected

host

cells,

to

the

immunocompetent

cell

infu-sion.

CASE

REPORT

A 6-year-old boy was brought to Children’s Hospital in March 1975 with a poorly differentiated lymphoma involv-ing the liver and regional lymph nodes. Initial therapy consisted of prednisone, vincristine, cyclophosphamide, intrathecal methotrexate, and irradiation (3,000 R abdomi-nally and 2,400 R cranially). Maintenance chemotherapy was

begun in July 1975 and consisted of daily 6-mercaptopurine, weekly methotrexate, monthly vincristine, and prednisone, five days per month.

On October 30, seven months after the initial diagnosis, he developed the typical cutaneous lesions of varicella, and all therapy was stopped. In an attempt to provide specific immunotherapy, he received a transfusion the next day with 150 ml of nonirradiated buffy-coat cells derived from 1 unit of blood. Appropriate informed consent was given for the treatment. The donor was a 15-year-old unrelated boy who had had varicella four weeks earlier. The patient’s tempera-ture was 37.9#{176}Cand his chest film was clear. The vesicles did not progress, and he became afebrile in 48 hours. However,

several days later his temperature rose to 40.4#{176}C. He developed a pruritic maculopapular rash over his trunk and extremities and later manifested a markedly positive Nikols-ky sign. Green watery diarrhea developed, and on November 8 (nine days after transfusion) he was admitted to the hospital.

Laboratory values at that time were as follows: hemoglo-bin, 11.8 gm/dl; WBC count, 2,200/gil with 88 lymphocytes per microliter. (The blood count showed a hemoglobin level of 10.2 gm/dl; WBC count, 2,700/il; and 270 lymphocytes per microliter nine days before the infusion.) The ESR was 45 mm/br; platelet count, 102,000/.d; total bilirubin level, 1.23 mg/dl; lactic dehydrogenase level, 1,500 IU; and SGOT level, less than 300 IU. A chest film was clear. Results of

lumbar puncture and blood cultures were negative. Intrave-nous penicillin therapy was started. The next day his total lymphocyte count was 154/jsl and he was slightly irrational. On November 11, intravenous methotrexate therapy, 10 mg/sq m, was started; despite this therapy, he showed

Received September 15; revision accepted for publication November 18, 1977.

Supported by grants HD-07778, AI-10404, and Al-i 1576 from the National Institutes of Health and by the National

Foundation-March of Dimes.

ADDRESS FOR REPRINTS: (RH.) Department of Pediat-rics, University of Wisconsin Hospitals, Madison, WI

(2)

FIG. 1. Periportal necrosis in liver.

64 GRAFT-VERSUS-HOST DISEASE

increasing confusion and liver size. His total WBC count was

300/id; platelet count, 14,000/sl; bilirubin level, 3.2 mg/dl; plasma ammonia level, 86% ammonia N; and SCOT level, 6,380 IU.

Because of the marked lymphopenia, extensive in vitro T cell assessment was not possible. The proliferative response

was 176/368 (stimulated/resting) counts per minute (cpni) to

phytohemagglutinin and the response to tetanus toxoid was 215/665 cpm, i.e., no response. Due to a technical oversight, immunoglobtilin levels were not measured.

on November 12 (13 days after transfusion) the patient died. Postmortem blood cultures yielded pneumococcus and

Escherichia coli. Antibody titers to influenza virus,

parain-fluenza virus, adenovinis, respiratory syncytial vinis,

arbovi-i-us, lymphocytic choriomeningitis, mumps, measles, herpes

simplex, cytomegalovirus, Epstein-Barr virus, and varicella were negative. Postmortem viral cultures of liver, bone

marrow, blood, lung, brain, and lymph node tissue were negative.

At postmortem examination, cerebral edema and pulmo-nary hemorrhage were determined to be the proximate

causes of death. No evidence of residual lymphoma or active

varicella infection was observed. There was generalized depletion of all lymphoid elements and marked hypocellular-ity of the bone marrow. The thymus showed niarked depletion of lymphoid elements but, in general, normal lobular architecture was preserved. Normal vasculature and

. Hassall’s corpuscle formation was noted. The picture was

FIG. 3. Typical crypt lesion of GVHR. Epithelial destruction with aggressor lymphocytes seen in lumen.

FIG. 2. View of skin shows destruction of epidermis with bleb

formation (b), mummified cells (arrows), and obliteration of dermal-epidermal junction.

that of stress involution. Characteristic features of CVHR

were found in the liver, skin, and gastrointestinal tract. The liver showed periportal fibrosis, random areas of necrosis, acidophilic bodies, and bile duct destruction (Fig. 1). In the

skin (Fig. 2), there was vacuolization of the basal layer, mononuclear infiltration in the upper dermis, and “mummi-fled cells.” The intestines (Fig. 3) showed widespread crypt lesions with epithelial necrosis.

DISCUSSION

The

severity

of varicella

infections

in ehildren

who

have

tumors

and

who

are

receiving

immuno-suppressive therapy is

well

documented.

Defec-tive

T lymphocyte

function

would

appear

to be

the

major

factor.’

Feldman

and

his

colleagues

recently

reported

death

in

7%

and

visceral

dissemination

in 32%

of 60 children

who

acquired

varicella

while

receiving

chemotherapy

for

van-ous

malignant

disorders.

The

mortality

did

not

seem

to be

to the

type

of tumor

or status

of the

disease.

In the

patient

in this

report,

the

clinical

course

of the

vanicella

infection

seemed

to be affected

by

the

infusion.

In

the

usual

case

of vanicella,

recur-ring

crops

of vesicles

can

be

expected

for

four

to

five

days.h1

In

patients

with

tumors,

one

sees

a

much

more

severe

and

protracted

course

with

visceral

dissemination;

the

only

other

patients

we

have

encountered

with

this

feature

both

died

of

varicella

pneumonia.

In

the

case

described

here,

all cutaneous

lesions

were

resolved

48 hours

after

the

infusion

and

no

further

progression

of

the

disease

occurred.

The

rationale

for

the

use

of

buffy-coat

cells

from

a normal

individual

who

had

recently

recov-ered

from

vanicella

was

to either

provide

intact

T

killer

cells

that

could

eliminate

the

virus

or

to

“transfer”

to

the

host

cells

the

capability

of

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(3)

immune

reactivity

in a manner

similar

to transfer

factor.’2

A similar

approach

has

been

employed

in

lepromatous

leprosy.’3

Because

fatal

GVHR

was

not

anticipated

on the

basis

of our

past

experience

with

ordinary

hematologic

support

therapy,

cells

were

not

irradiated

before

infusion.

This

case

fulfills

clinical

and

pathological

cnite-na

for

a GVHR.

Clinically

the

first

noticeable

sign

is a generalized

maculopapular

rash.”

In

the

full-blown

case,

this

is followed

rapidly

by

elevation

of

liver

enzyme

and

serum

bilirubin

levels

and

profuse

diarrhea.

Most

patients

devel-op

overwhelming

sepsis

as

the

terminal

event.

This

is precisely

the

clinical

course

that

was

seen

in our

patient.

Pathologically,

one

finds

a

charac-tenistic

aggressor

lymphocyte

attack

of the

skin,

liver,

and

gastrointestinal

tract,

as was

found

in

our

patient

and

as is shown

in

Figures

1 to

3#{149}15

The

organs

involved

and

the

histopathology

confirm

the

clinical

impression

of GVHR.

There

were

no

intracellular

inclusions

suggestive

of

active

vanicella

infection.

A

unique

aspect

of

this

case

was

the

child’s

inability

to

reject

a relatively

small

number

of

immunocompetent

cells.

Although

GVHR

is

a

common

complication

after

allogeneic

bone

marrow

transplantation

or

transfusion

of

blood

products

in

children

with

various

immunodefi-ciencies,

it is not

ordinarily

seen

after

infusions

into

patients

with

malignant

tumors.6”6”7

It has

been

reported

after

repeated

transfusions

of

leukocytes

from

donors

with

chronic

myeloge-nous

leukemia

into

recipients

with

hematologic

malignant

There

is one

report

of

a

fatal

GVHR

in a patient

with

acute

promyelocyt-ic leukemia

who

had

received

ten

transfusions

of

leukocytes

from

three

normal

donors

while

also

receiving

induction

chemotherapy.6

Thus,

under

appropriate

circumstances

and

with

large

infusions,

GVHR

can

be seen.

Experimental

studies

show

the

phenomenon

of

GVHR

to

be

dose-related.

Irradiated

adult

mice

develop

fatal

GVHR

after

receiving

10 lymph

node

cells

per

kilogram

of body

weight,’8

and

Schwarzenberg

et

al.

found

that

the

frequency

of GVHR

in patients

receiving

transfusions

of

chronic

myelogenous

leukemia

cells

was

increased

when

the

number

of

cells

transfused

exceeded

2 x

10k’.

However,

our

patient

received

a maximum

total

of 5

x

10 cells

(2.5

x

10 cells

per

kilogram).

One

might

attribute

the

inability

to reject

the

small

leukocyte

infusion

to the

prior

radiotherapy

and

chemotherapy.

The

immunodeficiency

of

lymphoid

malignant

tumors

has

been

extensively

described.

Immunoglobulin

levels

and

delayed

hypersensitivity

reactions

in patients

with

acute

lymphoblastic

leukemia

have

been

shown

to

be

normal

prior

to

induction

chemotherapy

and

to

become

abnormal

only

after

such

therapy

is

instituted.’9’2#{176} Craniospinal

and

sternal

irradiation

causes

lymphopenia

for

up

to

a

year,

with

a

decrease

in

T cells

and

a relative

increase

in

B

cells.2’

Corticosteroids

decrease

serum

immuno-globulin

levels

for

as

long

as

four

weeks

when

given

in

large

doses,22

and

may

inhibit

host-versus-graft

cytotoxicity.23

Intensive

courses

of

6-mercaptopunine

and

methotrexate

will

lower

phytohemagglutinmn

responsiveness,

but

this

property

returns

to

normal

with

maintenance

chemotherapy.2#{176}’2

6-Mercaptopunine

and

metho-trexate

given

continuously

depress

both

primary

and

secondary

immune

responses,24

however,

and

may

also

cause

a decrease

in levels

of cytotoxic

B

cells.5

None

of

the

above

mechanisms

would

appear

to be a sufficient

explanation

for

a

suscep-tibility

to

GVHR

in

this

patient.

Although

patients

with

lymphomas

are

immunodeficient

to

varying

degrees,

as a result

of either

the

underly-mg

disease

or

the

cytotoxic

treatment

regimens,

infusion

of

blood

products

does

not

ordinarily

result

in fatal

GVHR.6”6”7

In fact,

the

practice

of

irradiating

blood

products

prior

to

transfusion

into

patients

with

congenital

immunodeficiency

to prevent

GVHR26

is not

a routine

procedure

in

cases

of lymphoma.

A most

intriguing

possibility

involves

the

role

of the

varicella

infection.

Viral

infections

in some

animal

species

inhibit

antibody

synthesis,27

and

in

man

varicella

depresses

T

cell

reactions.28

It

is

possible

that

the

active

vanicella

depressed

the

host

sufficiently

to permit

establishment

of

trans-fused T

killer

cells,

allowing

them

to

mount

a

GVHR.

We

believe,

however,

that

a more

likely

explanation

is that

a significant

number

of

the

transfused

cells

were

already

specifically

sensi-tized

against

the

viral

antigen

which

was

widely

distributed

on the

surface

of the

host

cells.

In the

GVHR,

the

histocompatibility

antigens

of

the

host,

distributed

on all cells

of the

recipient,

serve

as the

stimulus

and

target

for

the

attacking

donor

cells.

Thus,

the

mechanism

for

the

unusual

GVHR

and

the

complication

recorded

in

this

case

are

basically

similar.

We

suggest

that

when

immuno-competent

cells

are

infused

in

the

usual

case

of

lymphoid

malignant

tumors,

they

are

eliminated

by

natural

attrition

or

by

the

immune

rejection

mechanisms

of

the

host.

In

the

case

described

here,

the

killer

activity

of

the

infusion

was

enhanced

by

a recall

phenomenon

and

immune

reactivity

against

host

cells

bearing

the

relevant

antigen

(viz.,

vanicella)

was

essentially

immediate.

(4)

66 GRAFT-VERSUS-HOST DISEASE

the

infused

sensitized

lymphocytes,

an

inflamma-tory

reaction

of

major

proportions

was

genen-ated.

The

encouraging

aspect

of

this

case

was

the

rapid

and

complete

resolution

of

the

patient’s

varicella

lesions

after

the

transfusion.

Since

zoster

immune

globulin,

immune

serum

globulin,

and

idoxuridine

are

not

of value

in established

varicel-la infections,

we

believe

that

x-irradiated

leuko-cytes

(3,000

H) obtained

from

normal

donors

who

have

recently

recovered

from

vancella

might

provide

the

benefit

of sensitized

T cells

without

the

danger

of GVHR.

It might

also

be

possible

to

freeze

leukocyte

preparations

for

storage

until

needed.

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1978;62;63

Pediatrics

James Betzhold and Richard Hong

With Lymphoma and Varicella