Solid-organ transplant graft-versus-host disease (SOT-GVHD) is a rare complication of organ transplant that is associated with high mortality. The initial signs and symptoms are vague, so this disease is easily confused with other posttransplant complications. A case of SOT-GVHD occurred after orthotopic liver transplant for liver failure due to hepatitis C in a patient in a Veterans Affairs intensive care unit. The patient had dehydration, acute kidney injuries, rashes, diarrhea, and pancytopenia. Results of skin biopsy, bone marrow biopsy, and cytogenetic studies were consistent with SOT-GVHD. Despite supportive care including antibiotics, antiviral and antifungal therapy, high-dose steroids, antithymoglobulin and neupogen, the patient died of overwhelming sepsis. Owing to the rarity of SOT-GVHD, no evidence-based guidelines or recommendations for treatment exist. Treatment includes high-dose corticosteroids and antibiotic, antifungal, and antiviral prophylaxis. Treatment of liver transplant–related GVHD with anti–tumor necrosis factor a agents has been successful.

Solid-organ transplant graft-versus-host disease (SOT-GVHD) occurs in 2 forms. The more common type is antibody mediated.1  In this form, antibodies from cells from a donor with blood type O attack recipients’ red blood cells in recipients with blood type A, B, or AB, leading to mild transient, hemolytic anemias.1  The second form of SOT-GVHD is a cellular type.1  Cellular SOT-GVHD is a rare complication following organ transplant.25  In this condition, donor-derived T cells have a reaction to histoincompatible cells in the skin, liver, gastrointestinal tract, and bone marrow, leading to complications in these organs.6  This particular form of SOT-GVHD occurs through a multistep process. First, allograft-associated lymphocytes engraft and proliferate in the recipient’s bone marrow. Next, donor-origin effector cells produce an immunological attack against immunologically disparate host tissue.2  Unfortunately, this diagnosis carries a high mortality, partly because of delays in diagnosis, as it typically has signs and symptoms similar to those of more common diseases such as infection.6  GVHD is an important disease about which intensive care nurses must be aware. Treatment must be rapidly instituted. This disease should be considered in patients with transplants in the past and vague signs and symptoms. We present a case of a patient who had SOT-GVHD develop after orthotopic liver transplant.

CASE REPORT

CASE REPORT

A 65-year-old man initially underwent orthotopic liver transplant in our facility for end-stage liver failure due to infection with hepatitis C virus with resultant stage T3b Nx hepatocellular carcinoma. He is noted to have type O Rh+ blood. Donor liver was from a female patient of blood group type O Rh+. A total of 4 units of O Rh− packed red blood cells and 8 units of fresh frozen plasma were administered. No blood products were leukoreduced or irradiated.

His initial posttransplant course was notable for cytomegalovirus-positive conversion within the subsequent month. He had several other hospital admissions for dehydration, acute kidney injuries, rashes, and diarrhea. These symptoms are vague and not uncommon in transplant recipients, leading to uncertainty of diagnosis. GVHD, however, must be considered in such patients. At 3 months after transplant, he went to an outside hospital where he was found to have a white blood cell count of 0.1 × 109/L with neutrophils of 0.04 × 109/L, prompting his transfer to our transplant center. He had started treatment with filgrastin with discontinuation of dapsone and valgancyclovir. With his ongoing rash, he had a skin biopsy. His biopsy showed basal vacuolar changes with multiple ectopic keratinocytes, in association with a superficial perivascular and interstitial mixed infiltrate with prominent melanophages. These findings were consistent with graft-versus-host disease grade 2. Bone marrow biopsy showed aplastic anemia with overall pancytopenia. The biopsy was negative for cytomegalovirus, Epstein-Barr virus, and parvovirus. Cytogenetic studies, however, were significant for evidence of chimerization with the finding of a 46,XX karyotype. This female karyotype in a male patient demonstrates complete graft-versus-host disease with infiltration of bone marrow with female cells most likely from the donor liver, leading to immunological attack of the graft bone marrow on our patient. Further testing was not performed as it would not change the patient’s management and it was considered unethical to charge the patient for testing to verify the origin of the graft-versus-host disease (less likely blood products vs more likely liver transplant because of the larger lymphoid tissue).

The hematology/oncology and infectious disease services were consulted and the patient was cared for in the ICU. Throughout his hospital course, he was maintained on neutropenic precautions. He received supportive therapy with irradiated, leukocyte-reduced blood products as needed. Additionally, he was treated with high-dose methylprednisolone (1 mg/kg intravenously daily) as well as cyclosporine (10 mg/kg daily divided into every-12-hour dosing with target levels of 200-400 ng/mL). Filgrastin was discontinued as the patient was not responsive to it. He was treated with a 4-day course of antithymoglobulin. For anti-infectious prophylaxis, he was treated with caspofungin and piperacillin/tazobactam. A potential bone marrow transplant had been discussed but was ultimately decided against, given the high risk of inducing rejection of his orthotopic liver and low certainty of successful treatment.

Unfortunately, his course was complicated by infection with vancomycin-resistant Enterococcus, noted on blood cultures, and the patient was treated with daptomycin. He was initially receiving linezolid, but changed to daptomycin to reduce further pancytopenia. The patient continued to have severe protein malnutrition with ongoing diarrhea and gastrointestinal losses. Eventually the patient had septic shock develop, requiring mechanical ventilation for respiratory failure and multiple pressors. At that time, the patient’s family elected to change his goals of care to comfort measures only, leading to his death.

Discussion

SOT-GVHD is a rare and lethal complication of transplant.2  Published incidence rates for SOT-GVHD in liver transplant recipients are between 0.1% and 2%.2,4  Mortality rates are documented at 75% or greater in liver transplant recipients.3,5  There are 2 forms of SOT-GVHD.6  In the first and more common form, group O donor antibodies form against cells in patients with disparate blood group types.6  The second form is cell mediated.6  In this form, donor-derived T cells have a reaction to histoincompatible cells in the skin, liver, gastrointestinal tract, and bone marrow, leading to complications in these organs.6  This particular form occurs through a multistep process. First, allograft-associated lymphocytes engraft and proliferate in the recipient’s bone marrow. Next, donor-origin effector cells produce an immunological attack against immunologically disparate host tissue.2 

SOT-GVHD has an acute phase and a chronic phase. The acute phase is defined as occurring within the first 100 days after transplant.7  It typically occurs 1 to 11 weeks after transplant,6  with a median onset of 33 days.8  Chronic GVHD is defined as occurring more than 100 days after transplant.7 

SOT-GVHD more commonly occurs after small-bowel and liver transplant, whereas lung and kidney transplants are rarer3,5  causes (Table 1). It is hypothesized that the risk factor for SOT-GVHD is related to the amount of lymphoid tissue in the donor organ. Other risk factors include greater HLA match between donor and recipient3  and age greater than 65 years.2,4 

SOT-GVHD typically is manifested by fever, diarrhea, rash, and multilineage cytopenia or pancytopenia.2  The signs and symptoms are usually quite subtle6  and are often confused with early infection in the immunocompromised state. GVHD most likely has many contributing factors. African Americans, for instance, have higher rates than do whites, Hispanics, and persons of Far-Eastern origin.10  Additionally, cytomegalovirus infection is associated with chronic GVHD development in bone marrow recipients.11  Diagnosis of SOT-GVHD is implied by biopsy-proven histologic features.2  Confirmation is made by showing greater than 1%12  lymphocyte macrochimerism in peripheral blood.2  Of note, diagnosis of SOT-GVHD is commonly delayed as the early signs and symptoms mirror those of more common problems such as viral illnesses. Donor chimerism studies should be obtained and GVHD diagnosis should be considered in all solid-organ transplant recipients with rash, diarrhea, liver dysfunction, and/or pancytopenias. The prognosis for patients with SOT-GVHD is poor. Death is usually due to infections associated with marrow suppression and multiorgan failure. Mortality rates for SOT-GVHD depend on the transplanted organ. Liver transplant patients have a mortality rate of 75%.24  Lung transplant recipients have a mortality rate of 100%. Other solid-organ transplant patients are reported to have a 30% mortality.2 

Treatment of SOT-GVHD is controversial, with the limited evidence given the rarity and high mortality of cases precluding a strong evidence-based consensus on therapy. Several therapies have been proposed in published case reports and series (Table 2). Treatment is usually initialized with high-dose corticosteroids.2  It is likely that a second agent is necessary (second-line therapy) in addition to steroids, owing to the poor response to steroids alone. Additionally, antibiotic, antifungal, and antiviral prophylaxis should be started for potential septic complications in immunosuppressed patients.14  In patients who do not respond to increasing immunosuppression, reduction of immunosuppressive agents to allow the recipient’s immunological recovery and rejection of allograft donor T cells may be tried. Case reports have described successful therapies for GVHD related to liver transplant, including infliximab,15  etarnercept,16  and alefacept.17  Ultimately, because of the rarity of the disease, no evidence-based guidelines for therapies exist. However, it is possible that earlier diagnosis of SOT-GVHD may allow improved treatment response. For this reason, lymphocyte macrochimerism should be pursued in solid-organ transplant recipients in whom pancytopenia develops at any time, in particular, within the first 2 months after transplant.

Conclusions

SOT-GVHD is a rare condition with subtle signs and symptoms, which often lead to delays in care and increased mortality rate. We describe a case of this particular condition. This diagnosis should be considered in all transplant patients, particularly in patients with pancytopenia or fever and rash within the first 2 months of transplant. Diagnosis is made with biopsy of tissue and lymphocyte macrochimerism. Treatment of this condition is controversial and should include high-dose corticosteroids, broad-spectrum antibiotics, antiviral agents, and antifungal agents. One should further consider reducing the patient’s immunosuppressive agents and use of biological agents such as infliximab. GVHD is an important disease of which intensive care nurses should be aware. Treatment must be instituted rapidly. This disease should be considered as a potential diagnosis in patients who have received transplants in the past and have vague signs and symptoms.

References

References
1
Gulbahce
HE
,
Brown
CA
,
Wick
M
,
Segall
M
,
Jessurun
J
.
Graft-vs-host disease after solid organ transplant
.
Am J Clin Pathol
.
2003
;
119
(
4
):
568
573
.
2
Smith
EP
.
Hematologic disorders after solid organ transplantation
.
Hematology Am Soc Hematol Educ Program
.
2010
;
2010
:
281
286
.
3
Kato
T
,
Yazawa
K
,
Madono
K
, et al
.
Acute graft-vs-host disease in kidney transplantation: case report and review of literature
.
Transplant Proc
.
2009
;
41
(
9
):
3949
3952
.
4
Smith
DM
,
Agura
E
,
Netto
G
, et al
.
Liver transplant-associated graft-versus-host disease
.
Transplantation
.
2003
;
75
:
118
126
.
5
Pavenski
K
,
Kamel-Reid
S
,
Wei
C
,
Cserti-Gazdewich
CM
.
Lung transplantation complicated by graft-versus-host disease and confounded by incidental transfusion-asociated macrochimerism
.
Transfusion
.
2008
;
48
(
10
):
2190
2196
.
6
Zacharias
N
,
Gallichio
MH
,
Conti
DJ
.
Graft-versus-host disease after living-unrelated kidney transplantation
.
Case Rep Transplant
.
2014
;
2014
:
971426
.
7
Sharma
A
,
Armstrong
AE
,
Posner
MP
, et al
.
Graft-versus-host disease after solid organ transplantation: a single center experience and review of literature
.
Ann Transplant
.
2012
;
17
(
4
):
133
139
.
8
Assi
MA
,
Pulido
JS
,
Peters
SG
,
McCannel
CA
,
Razonable
RR
.
Graft-vs.-host disease in lung and other solid organ transplantation recipients
.
Clin Transplant
.
2007
;
21
(
1
):
1
6
.
9
Worel
N
,
Bojic
A
,
Binder
M
, et al
.
Catastrophic graft-versus-host disease after lung transplantation proven by PCR-based chimerism analysis
.
Transpl Int
.
2008
;
21
(
11
):
1098
1101
.
10
Bortin
MM
.
Acute graft-versus-host disease following bone marrow transplantation in humans: prognostic factors. Advisory Committee of the International Bone Marrow Transplant Registry
.
Transplant Proc
.
1987
;
19
(
1 pt 3
):
2655
2657
.
11
Soderberg
C
,
Larsson
S
,
Rozell
BL
,
Sumitran-Karuppan
S
,
Ljungman
P
,
Moller
E
.
Cytomegalovirus-induced CD13-specific autoimmunity: a possible cause of chronic graft-vs-host disease
.
Transplantation
.
1996
;
61
(
4
):
600
609
.
12
Taylor
Al
,
Gibbs
P
,
Sudhindran
S
, et al
.
Monitoring systemic donor lymphocyte macrochimerism to aide the diagnosis of graft-versus-host disease after liver transplantation
.
Transplantation
.
2004
;
77
(
3
):
441
446
.
13
Chao
NJ
.
Treatment of acute graft-versus-host disease
.
UpToDate website
. . Accessed March 28, 2016.
14
Deeg
HJ
.
Graft-versus-host disease and the development of late complications
.
Transfus Sci
.
1994
;
15
(
3
):
243
254
.
15
Piton
G
,
Larosa
F
,
Minello
A
, et al
.
Infliximab treatment for steroid-refractory acute graft-versus-host disease after orthotopic liver transplantation: a case report
.
Liver Transpl
.
2009
;
15
(
7
):
682
685
.
16
Thin
L
,
MacQuillan
G
,
Adams
L
, et al
.
Acute graft-versus-host disease after liver transplant: novel use of etanercept and the role of tumor necrosis factor alpha inhibitors
.
Liver Transpl
.
2009
;
15
(
4
):
421
426
.
17
Stotler
CJ
,
Eghtesad
B
,
Hsi
E
,
Silver
B
.
Rapid resolution of GVHD after orthotopic liver transplantation in a patient treated with alefacept [letter to the editor]
.
Blood
.
2009
;
113
(
21
):
5365
5366
.

Footnotes

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Financial Disclosures

None reported.

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