roberts & thompson-2005

http://ncp.sagepub.com/Nutrition in Clinical Practice

http://ncp.sagepub.com/content/20/4/440The online version of this article can be found at:

DOI: 10.1177/0115426505020004440 2005 20: 440Nutr Clin Pract

Susan Roberts and Jennifer Thompson-Host Disease: Nutrition Therapy in a Challenging ConditionvsGraft-

Published by:

http://www.sagepublications.com

On behalf of:

The American Society for Parenteral & Enteral Nutrition

can be found at:Nutrition in Clinical PracticeAdditional services and information for

http://ncp.sagepub.com/cgi/alertsEmail Alerts:

http://ncp.sagepub.com/subscriptionsSubscriptions:

http://www.sagepub.com/journalsReprints.navReprints:

http://www.sagepub.com/journalsPermissions.navPermissions:

What is This?

- Aug 1, 2005Version of Record >>

at OhioLink on June 25, 2014ncp.sagepub.comDownloaded from at OhioLink on June 25, 2014ncp.sagepub.comDownloaded from

Clinical Observations

Graft-vs-Host Disease: Nutrition Therapy in a ChallengingCondition

Susan Roberts, MS, RD, LD, CNSD; and Jennifer Thompson, RD, LD, CNSDBaylor University Medical Center, Dallas, Texas

ABSTRACT: Graft-vs-host disease (GVHD) is a majorcomplication after allogeneic hematopoietic stem celltransplantation. Both acute and chronic forms of GVHDare challenging to manage medically and nutritionally.Patients with advanced GVHD commonly becomedepleted nutritionally, with loss of lean body mass (LBM)and functional status. We present 2 case reports ofpatients who developed GVHD and subsequent nutritiondecline. Although both patients were candidates for spe-cialized nutrition support (SNS), only 1 was able to receiveenteral and parenteral nutrition due to GVHD complica-tions preventing access for provision of SNS. Fortunately,the patients have remained in remission from their hema-tologic malignancy, but they continue to cope with chronicGVHD and its consequences. These cases exhibit thecomplexity of managing a patient with extensive GVHDand nutrition interventions for clinicians to consider tooptimize outcomes.

Hematopoietic stem cell transplantation (HSCT)has become a standard of care for a number ofmalignant and nonmalignant hematologic diseases.1

It is also used in certain congenital and geneticdisorders and some solid tumors and is being inves-tigated for treatment of selected autoimmune disor-ders2,3 (Figures 1 and 2). HSCT involves high-dosechemotherapy with or without total body irradiation(TBI) to eradicate the nonfunctioning or malignantcells and immunocompetent cells in allogeneicHSCT. Then, the recipient receives an IV infusion ofhematopoietic stem cells (collected either from theperipheral blood, marrow, or umbilical cord blood) torepopulate the marrow. Allogeneic HSCT involvestransplanting cells from a human leukocyte antigen

(HLA)matched donor. The donor is a relative, typ-ically a sibling, or an unrelated donor. It is esti-mated over 15,000 allogeneic HSCTs are performedworldwide each year.3 The source of hematopoieticstem cells and type of transplant varies and isdependent on factors such as disease, donor avail-ability, the patients age, and the presence of othermedical complications. Nonmyeloablative HSCT is arelatively recent form of transplant in which lessintensive chemotherapy TBI is used. Nonmyelo-ablative or minitransplants are being used forolder patients and those with a lower performancestatus or suboptimal organ function who areunlikely to tolerate toxicities associated with a con-

Correspondence: Susan Roberts, MS, RD, LD, CNSD, BaylorUniversity Medical Center Nutrition Services, 3500 Gaston Ave-nue, Dallas, TX 75246. Electronic mail may be sent [email protected].

0884-5336/05/2004-0440$03.00/0Nutrition in Clinical Practice 20:440450, August 2005Copyright 2005 American Society for Parenteral and Enteral Nutrition

Figure 1. Diseases (and percentages) treated withautologous HSCT in North America in 2002. AML,acute myelogenous leukemia; NHL, Non-Hodgkinslymphoma; MM, multiple myeloma; HD, Hodgkinsdisease; CA, cancer; NB, neuroblastoma; HSCT,hematopoietic stem cell transplant.3

440 at OhioLink on June 25, 2014ncp.sagepub.comDownloaded from

ventional transplant. Because the cytotoxic therapyis not myeloablative, the patients hematopoieticand the malignant cells are not completely eradi-cated as with a traditional transplant. The goal ofthe minitransplant is to establish immune toleranceand for the donor cells to destroy remaining malig-nant cells through the graft-vs-tumor effect (GVT).Our experience is that graft-vs-host disease (GVHD)is anticipated and prevalent in minitransplants.4

GVHD: Etiology, Incidence, and GradingGVHD is a major complication associated with

allogeneic (related and unrelated) HSCT and resultsin significant morbidity and mortality. GVHD occurs

when the immunocompetent donor T cells recognizethe recipient (or host) as foreign and mount animmune response. GVHD sets in motion a cascade ofevents designed to eradicate the foreign bodies ortissues of the recipient, resulting in tissue destruc-tion. Two forms of GVHD, acute (onset within thefirst 100 days posttransplant) and chronic (onset100 days posttransplant), can develop. Researchsuggests the GVHD process ensues through 2 differ-ent pathways, depending on which form of GVHD ispresent: T-helper (TH)1-type cytokines are seen pri-marily in acute GVHD and TH2-type cytokinesdominate in chronic GVHD (cGVHD).5 The 3 targettissues (skin, gastrointestinal tract, and liver) inacute GVHD may also be targeted in cGVHD andother tissues. However, the expression by eachaffected tissue changes between the 2 stages, result-ing in 2 different grading scales (see Tables 1 and2).69

A number of factors influence the development ofGVHD, including donor compatibility, source ofdonor (related vs unrelated), age of the patient, andimmunosuppressive therapy (IST). In the presenceof an HLA-identical sibling transplant, the incidenceof acute GVHD is 30%60% and cGVHD develops in35%50% of HSCT recipients.10 IST, along with awell-matched donor, is the foundation for preventionof GVHD. Once GVHD has developed, IST is usuallyaltered with increased doses of some medicationsand the addition of other agents when GVHD failsto respond to initial corticosteroid-based therapy(see Table 3 for a list of common ISTs used inHSCT).1113 Multiple options exist for patients whodo not respond to standard IST, but which second-line treatment qualifies as optimal remains undeter-mined. A definitive answer on optimal GVHD treat-ment is not apparent at this time because mostresearch studies have included small numbers and

Figure 2. Diseases (and percentages) treated with alloge-neic HSCT worldwide in 2002. ALL, acute lymphoblasticleukemia; AML, acute myelogenous leukemia; CML,chronic myelogenous leukemia; MDS, myelodysplasticsyndrome; HSCT, hematopoietic stem cell transplant.3

Table 1Acute graft-vs-host disease (GVHD)

Onset/incidenceOnset: Within the first 100 days posttransplant.Incidence: 25%60% in human leukocyte antigen (HLA)-matchedtransplants.

Common target tissuesSkin: Maculopapular rash, may progress to generalized

erythroderma with desquamation and bullae, much like a burn injury.

Gastrointestinal (GI): Diarrhea (often L/day), nausea, vomiting,abdominal cramping/pain, protein-losing enteropathy.

Liver: Elevated liver function tests (LFTs) and bilirubin, cholestasis,malabsorption.

ClassicationStage ISkin: Rash on 25% of body surfaceGI: Diarrhea, 5001000 mL/dayLiver: Bilirubin 23 mg/dL

Stage IISkin: Rash on 25%50% of body surfaceGI: Diarrhea, 10001500 mL/dayLiver: Bilirubin 36 mg/dL

Stage IIISkin: Generalized erythrodermaGI: Diarrhea, 1500 mL/dayLiver: Bilirubin 615 mg/dL

Stage IVSkin: Desquamation and bullaeGI: Pain or ileusLiver: Bilirubin 15 mg/dL

Source: Reprinted with permission from Roberts S, Vanzee J. Nonmyeloablative stem cell transplantation (NMSCT) and its nutritionalconsequences. Support Line. 2003;25:39.

August 2005 441GRAFT-VS-HOST DISEASE

at OhioLink on June 25, 2014ncp.sagepub.comDownloaded from

have been retrospective in nature instead of ran-domized, prospective trials.11 Larger prospective tri-als are needed, but only after consensus is reachedon issues such as the definition of steroid-refrac-tory cGVHD and quantification of response to ther-apy.11 IST possesses the potential to cause a numberof side effects, adding complexity to the care of analready complicated patient population. Patientswith GVHD, who are burdened with more than justmedical complications, require a multidisciplinaryteam to manage the medical, nutrition, economic,and psychosocial issues surrounding this condition.

GVT is the silver lining in the dark cloud ofGVHD. Research suggests whereas the immuno-competent donor cells are causing damage to normaltissues of the recipient, they are also destroyingresidual malignant cells.14 Therefore, patients whodevelop GVHD are less likely to have diseaserelapse.15 As the understanding of GVHD increases,researchers are challenged with the task of findingnovel ways to harness the essential GVT effect whilepreventing or controlling the devastating conse-quences of GVHD.

Case Report 1A 38-year-old man was admitted for an HLA-

matched unrelated donor (MUD) transplant due tochronic myelogenous leukemia (CML). The patientwas in a near-remission second chronic-phase CMLwhen admitted for a transplant. When initiallydiagnosed with CML, he was treated with hydroxyu-rea, interferon, and then imatinib mesylate. Afterfailing these treatments, he received weekly vincris-tine and daily prednisone (200 mg per day) forapproximately 2 months before being admitted forHSCT. On admission, the patient was well nour-ished, with a body mass index (BMI) of 32 kg/m2 and

was above his usual body weight (UBW). He was notexperiencing any GI symptoms, and his oral intakewas adequate. Table 4 outlines the patients medicalcourse, complications, and associated nutritioninformation from transplant to day 936.

The patient was assessed and monitored through-out his hospitalization by a registered dietitian (RD)to ensure adequate nutrient intake and to avoidnutrition depletion. During the immediate post-transplant course, the patient experienced minimalcomplications and required no specialized nutritionintervention beyond providing food according topreferences; encouraging intake of small, frequentmeals and high-calorie, high-protein foods; andoffering oral nutrition supplements. His nutritiondecline began after discharge with the developmentof skin and oral cGVHD (see Figures 3 and 4). Thelatter caused intermittent mouth sores requiring thepatient to alter his diet consistency for short periodsof time. He willingly consumed oral nutrition sup-plements in an attempt to meet his nutrition needs.His skin GVHD continued to worsen and severelylimited his physical activity due to sclerodermatouschanges. It also affected his ability to eat because ofskin tightening around the mouth.

By day 100 (after transplant), the patient was90% of his UBW, and over the course of the next 10months, his weight fluctuated between 80% and 90%of UBW. From that point until approximately 2.5years posttransplant, the patient continued to loseweight to a status of 60% pretransplant weight, 64%of UBW, and 81% of ideal body weight (IBW). TheRD followed the patient consistently in the outpa-tient clinic and counseled him on nutrition interven-tions related to cGVHD complications and weight-gain strategies. The patient consumed various oralnutrition supplements during that time, selectingdifferent supplements as his taste preferences

Table 2Chronic graft-vs-host disease (GVHD)

Onset/incidence ClassicationOnset:100 Days posttransplant

Incidence:33% In HLA-identical sibling transplants64% In matched unrelated transplantsUp to 80% in 1 antigen-mismatched transplants

LimitedEither or both:Localized skin involvementLiver dysfunction due to chronic GVHD

ExtensiveEither:Generalized skin involvement orLocalized skin involvement and/or liver dysfunction dueto chronic GVHD

Plusa. Liver biopsy demonstrating chronic hepatitis,

necrosis, or cirrhosisb. Eye involvementc. Oral mucosa or salivary gland involvementd. Involvement of any other target tissue

Common target tissuesSkinLiverUpper gastrointestinal tract (mouth, esophagus)EyesLungs

Source: Reprinted with permission from Roberts S, Vanzee J. Nonmyeloablative stem cell transplantation (NMSCT) and its nutritionalconsequences. Support Line. 2003;25:39.

442 Vol. 20, No. 4ROBERTS AND THOMPSON


changed. Besides taste alterations, the patient alsowas confronted with financial constraints, whichsometimes prevented him from purchasing the

needed oral supplements. Free samples of oral sup-plements were provided to the patient as often aspossible.

Table 3Immunosuppressive medications and treatments used in graft-vs-host disease (GVHD)1115

Medicine or treatment Mechanism of action Nutrition-related side effects

Corticosteroids (systemic, topical,and mouthwash)

Anti-inflammatory response at arterial siteinhibits IL-1 and decreases IL-2, whichsuppresses lymphocyte proliferationand decreases circulating lymphocytes

Fluid and sodium retention, hyperglycemia,hypertriglyceridemia,hypercholesterolemia, increased appetite,weight gain, muscle wasting, bonedemineralization

Cyclosporine Inhibits response of cytotoxic T cells toIL-2 and prevents T helper lymphocytesfrom producing IL-2

HTN, hyperglycemia, hyperkalemia,hypomagnesemia, hyperlipidemia,gingival hyperplasia, nephrotoxic,neurotoxic

Tacrolimus Inhibits proliferation of cytotoxic T cellsand synthesis of IL-2

HTN, hyperglycemia, hyperkalemia, N/V/D,hypomagnesemia, nephrotoxicity,neurotoxicity

Methotrexate Antimetabolite, antineoplastic,immunosuppressant

Anorexia, N/V/D, stomatitis, mucositis,elevated liver function tests, renal failure,cirrhosis

Mycophenolate mofetil Decreases lymphocyte activation andreplication by suppressing enzymes inthe purine salvage pathway, creatinga purine deficiency and thus inhibitingT and B cell proliferation; suppressesantibody formation

N/V/D/C, GI bleeding, peripheral edema,sepsis

Sirolimus Inhibits T and B cell proliferation whilenot affecting IL-2 production

Hypercholesterolemia, hypertriglyceridemia,HTN, peripheral edema

Thalidomide Anti-inflammatory andimmunosuppressive properties

Neuropathy, C, neutropenia

Antithymocyte globulin (ATG) Decreases circulating lymphocytes Abdominal pain, N/V/D, hyperkalemia,HTN, peripheral edema, sepsis

Etanercept TNF- antagonist or binder Abdominal pain, V, rhinitisUrsodeoxycholic acid Replaces native human bile acids,

reduces class I HLA expression onhepatocytes

N/V/D, abdominal pain

Daclizumab Humanized anti-IL-2 receptor antibody V, edema, HTN, hypotension, fever,dyspnea, infection

Azathioprine Inhibits RNA and DNA synthesis toprevent cytotoxic T and B cellproliferation and antibody production

GI hypersensitivity, hepatotoxicity,megaloblastic anemia, pancreatitis,infection, bone marrow suppression

Hydroxychloroquine Interferes with antigen processing andpresentation, proliferation, TNF-production, and cytotoxicity,synergistic with cyclosporine andtacrolimus in vitro

N/V/D

Infliximab Humanized chimeric antibody againstTNF-, IgG monoclonal antibody

Abdominal pain, N/V, worsening CHF

Psoralen and PUVA Interferes with antigen presentation andinflammatory cytokine production byLangerhans cells, increases IL-10production by keratinocytes

Increase in skin cancer, phototoxicity, N,hepatotoxicity

Extracorporeal photopheresis Induces apoptosis in alloreactive T cells,normalization of CD4/CD8 ratios bydecreasing CD8 cells, increasesnatural killer cells, decreases dendriticcells, photoinactivation of antigenpresenting cells and T lymphocytes

GI upset, hypocalcemia (if citrateanticoagulant used)

N, nausea; V, vomiting; D, diarrhea, C, constipation; HTN, hypertension; Abd, abdominal; CHF, congestive heart failure; GI, gastrointestinal;TNF, tumor necrosis factor; IL, interleukin; HLA, human leukocyte antigen; IgG, immunoglobulin G.



Due to the significant weight loss, the healthcareteam considered placement of a percutaneous endo-scopic gastrostomy (PEG) tube for enteral feedingsand promotion of weight gain. However, the condi-tion of his skin with cGVHD and his immunocom-promised status discouraged the team from proceed-ing with PEG placement. His ability to heal at theinsertion site was questionable, and the physicianwanted to minimize possible sites of infection, theleading cause of death in cGVHD.11

Throughout his posttransplant course, thepatient experienced multiple bouts of bacteremia,

with his indwelling catheter considered the likelysource. Three of his hospital readmissions were dueto episodes of bacteremia (Table 4). Therefore, theteam and patient persisted with more conserva-tive medical and pharmacologic interventions inattempts to improve the skin cGHVD. Table 3 liststhe recognized and experimental treatments used inGVHD. His consistent immunosuppressive regimenincluded corticosteroids and tacrolimus or mycophe-nolate mofetil. Other treatments were used butstopped for a variety of reasons, including lack ofinsurance coverage for experimental treatments.

Table 4Case report 1

Time posttransplant Event or complication Associated nutrition information

Day 0 Transplant received after preparative regimen ofetoposide, cyclophosphamide, and TBI.

Minimal GI side effects in the early posttransplantphase; no nutrition support required; weightloss minimal at 3%.

Day 9 Grade 3 Acute GVHD of the skin; overall GVHDgrade 2. High-dose corticosteroids wereinitiated (100 mg every 12 h).

Pt experienced mild hyperglycemia withmaximum blood glucose level of 244 on day18.

Day 14 Discharged from the hospital. Pt able to tolerate oral diet with minimal GIsymptoms except dysgeusia.

Day 33 to Day 71 Corticosteroid taper in process. Experiencing some nausea, early satiety,xerostomia and continued dysgeusia. Drinkingoral nutrition supplements.

Day 113 Corticosteroids restarted and tacrolimusdiscontinued.

Day 120 Chronic GVHD (cGVHD) evolved involving skinand oropharynx; oral Decadron rinse tried for1 month.

Mouth sores present so patient avoiding saltyand spicy foods but otherwise eating regularfoods.

Day 159 MMF started as part of IST. Progressive weight loss of 16%.Day 180(Oct 2002)

Readmitted due to a fall complicated bystreptococcal pneumonia and septic shock.Question of liver GVHD; IVIG andoxandrolone started (latter given 6 months).

Mouth healed; only complaint is xerostomia.

2003 Seen in outpatient clinic; skin cGVHD worsening(sclerodermatous); tacrolimus restarted (day349).

Mouth sores occurred intermittently; difficultyeating because of tightness of skin aroundmouth.

Day 657(Feb 2004)

Acute on chronic flare of skin GVHD andbacteremia. Transferred to rehabilitation due toextensive cGVHD of skin; corticosteroids held.

Day 690(Mar 2004)

Readmitted with sepsis. Corticosteroids restartedat 20 mg twice daily. Diagnosed with steroid-induced diabetes. cGVHD persists anddaclizumab initiated (total of 18 cycles given,last dose given 8/04).

Diabetes management education provided(insulin therapy with the glucometer).

Day 777(June 2004)

Readmitted for neuromuscular weakness, openwounds on legs and buttocks (moderate tosevere), SICCA syndrome, and chronicdysphagia. Tacrolimus held.

Insulin stopped because of several episodes ofhypoglycemia and an episode of loss ofconsciousness.

Still with xerostomia. Drinking a variety ofnutrition supplements. Also taking B-complex,folate, and zinc supplements.

Day 936 to current Continues to receive IST (MMF and prednisone)with monthly IVIG; continues rehab includingwhirlpool treatment of wounds on lowerextremities; able to walk with assistance ofcane only.

Taking oral multivitamin, vitamin C, folate and-3 fatty acid nutrition supplements.

GI, gastrointestinal; BG, blood glucose; TBI, total body irradiation; GVHD, graft-vs-host disease; IST, immunosuppressive therapy; MMF,Mycophenolate mofetil; IVIG, IV immunoglobulin.



The following nutrition supplements were con-sumed by the patient at various times throughouthis posttransplant course: multivitamin with miner-als, vitamin C, folic acid, zinc, B-complex and -3fatty acid supplements. Calcium supplements werenot recommended to the patient, because repeateddiet recalls suggested he was consuming adequatedietary calcium. Table 5 details the rationale behindthe use of various dietary supplements in the GVHDpopulation.12,1620

The patient participates in the cGVHD clinicconducted at the Baylor University Medical Center

(BUMC) Blood & Marrow Ambulatory Clinic, wherehe is followed up by a multidisciplinary team,including a social worker, RD, registered nurse,occupational and physical therapists, transplantphysician, and dermatologist. Patients attendingthe clinic are referred to other specialists, as needed,such as an ophthalmologist if ocular cGVHD ispresent.

The patients wounds are now showing signs ofhealing, and the oral cGVHD has been stable, allow-ing the patient to consume a large variety of foodswithout difficulty. His weight remains a concernbecause he is at 81% IBW and 64% UBW; thus, hewill continued to be monitored closely.

Case Report 2The second case is similar to the first in several

ways, including continual nutrition assessment andmonitoring by an RD, but provides a different per-spective due to the nutrition support (NS) providedto this patient. The patient was a 52-year-old man

Figure 4. Oral chronic GVHD.

Figure 3. Case report 1: chronic GVHD of the skin.

Table 5Nutrition supplements recommended to HSCT recipients with GVHD at Baylor University Medical Center12,1620

Supplements Reason for consumption

Multivitamin with minerals (no iron for minimum offirst year posttransplant)

To ensure adequate resources of vitamins and minerals formetabolism and anabolism especially if patient is known tobe consuming inadequate oral intake

Vitamin C (500 mg twice daily) To help with wound healingZinc (220 mg zinc sulfate daily for 2 weeks) To help with wound healing; to replete patients stores lost

from chronic diarrheaFolic acid (1 mg once daily) To meet elevated needs for adequate red blood cell

production; certain medications cause increasedmetabolism or wasting of this vitamin, and thus it needs tobe supplemented

Calcium with vitamin D (dose depends on patient) To minimize bone demineralization with chronic steroid useB-complex (dose depends on physicians prescription) Tried as treatment of peripheral neuropathy by the physicians

although unlikely to work unless Pt has B12 deficiency-3 fatty acids (2 g daily) Possible interaction at cellular level to modify cytokine

production and thus reduce inflammatory process of GVHD



with CML in chronic phase at time of HSCT. Hispreparative regimen included etoposide, cyclophos-phamide, and TBI, followed by a full HLA-matchedMUD transplant and GVHD prophylaxis therapyusing methotrexate (days1,3, and6 posttrans-plant) and tacrolimus. He was well nourished(height, 5 feet 11 inches; weight, 81.8 kg; BMI, 25kg/m2; UBW, 79.5 kg; IBW, 75.5 kg) at admission,with no history of weight loss or eating problems.His early posttransplant course was complicated bysevere mucositis, diarrhea, acute GVHD of the skin,and staphylococcal bacteremia. The severe mucosi-tis and diarrhea were attributed not only to thepreparative regimen but also to the methotrexategiven to prevent GVHD. Because of these gastroin-testinal toxicities, parenteral nutrition (PN) wasinitiated on day 3 posttransplant. The PN pre-

scription was a 3-in-1 admixture (7.5% amino acids,21% dextrose, 4% lipids, final concentration) andprovided 30 kcal/kg and protein at a dose of 1.5g/kg/day. Despite optimal GVHD prophylaxis withmethotrexate and tacrolimus in the early posttrans-plant period, on day 10, as his donor white bloodcells (WBCs) engrafted, the patient developed asevere skin rash identified as stage III acute GVHDof the skin (overall GVHD grade II). The patientcontinued to receive tacrolimus; solumedrol wasadded at a dose of 2 mg/kg to treat the skin GVHD.By day 15, the patients mucositis had resolvedsignificantly, and he was able to begin oral intake offluids and soft foods. At this point, a positive bloodculture was noted, and the patient began a course ofIV vancomycin infusions. PN was discontinued onday 17, and the patient was discharged from the

Table 6Case report 2

Day posttransplant Event or complication Associated nutrition information Weight

Day 29 Persistent skin GVHD (grade III),prednisone 40 mg 2 timesper day tacrolimus 2 mg 2times per day, no other targettissues involved

Oral intake improving gradually 83.8 kg

Day 47 Skin rash resolving (grade IGVHD), prednisone 20 mg 2times per day tacrolimus1 mg 2 times per day

Appetite good but weight loss hasoccurred, edema resolved

76.1 kg

Day 78Limited* cGVHDdiagnosed

Oropharyngeal erythema,prednisone 10 mg/day tacrolimus 1 mg/day

Multivitamin addedAnorexia and weight loss,oxandrolone initiated at 10 mg2 times per day

74.5 kg

Day 92 Dry skin and oral mucosa, mildincrease in liver function tests,prednisone discontinued,tacrolimus maintained

Stable nutritionally, continues onoxandrolone

74.6 kg

Day 99 GI GVHD developed; excessiveabdominal cramping anddiarrhea; prednisone startedagain 20 mg/day

Oral intake poor at 1000 kcal/day (50% of estimatedcalorie needs); still takingoxandrolone

73.7 kg

Day 125Extensive* cGVHDdiagnosed

Mental status changes present,patient discontinuedoxandrolone; prednisone 10mg every other day

Stable nutrition status,improvement in energy andappetite noted

74.4 kg

Days 140183 Readmission due to bilateralpneumonia, mechanicalventilation required for ARDS

PN provided initially; PEG placedon day 173 due tomalnourished, debilitated state

74.3 kg (Admit)69.4 kg (Day 173)

Days 183300 Extensive cGVHD persists withskin, mouth, eyes, liver, andlung involvement; patientnoncompliant withimmunosuppressivemedication regimen

Patient relies almost completely onPEG feedings for nutrient intakedue to anorexia and nausea

71.5 kg (Day 183)

Day 300 Good control of GVHD but stillpresent

Patient eating 34 meals per day,PEG discontinued

79 kg

Day 365 Continues with extensivecGVHD; using a Decadronmouth rinse

Increased oral sensitivity 81.6 kg

* See Table 2.ARDS, acute respiratory distress syndrome; PEG, percutaneous endoscopic gastrostomy.



hospital on day 21. He tolerated the course of PNwell, except for mild hyperglycemia once the high-dose solumedrol was initiated. His weight at dis-charge was 81.2 kg, which was stable compared withadmission, but the patient had edema. He requiredclose monitoring in the outpatient clinic and wasprescribed many medications, including tacrolimus,prednisone (40 mg twice daily), magnesium oxide,famotidine, itraconazole, sulfamethoxazole tri-methoprim, and IV immunoglobulin. Table 6 out-lines the patients course over his first year post-transplant. In this case, the patients acute GVHDevolved into cGVHD, resulting in the need for con-tinual and prolonged use of immunosuppressivemedications. The patient attributed side effects suchas tremors and irritability to his medications andconsistently modified his regimen or discontinuedmedications on his own. The patient experienced aninfectious complication (a common occurrence incGVHD) and a period of critical illness, which wors-ened his nutrition depletion and resulted in PEGplacement for enteral NS. The placement of a PEGfeeding tube was successful in several ways. The sitehealed well, there were no infectious complicationsrelated to the tube, and the patient was able to toleratean adequate volume of feedings using a standardpolymeric, high-nitrogen formula to promote weightgain. The patient continues to have extensive cGVHD(skin and esophageal involvement) at 6 years post-transplant but currently is not receiving any IST.

Nutrition Requirements in GVHDThe impact of GVHD on nutrition status is fre-

quently significant. The nutrition needs of the HSCTpopulation are elevated and estimated at 3050kcal/kg/day, with most centers using 3035 kcal/kg/day as a goal.12 However, when GVHD is present,calorie requirements are often 35 kcal/kg/day. TheHSCT patient needs 1.52 g/kg of protein per day,and the higher end of the range is usually needed incases of severe GVHD.21,22 After HSCT, extra pro-tein is used to repair damaged tissue from chemo-therapy or radiation in the early posttransplantperiod, for growth of new tissue and cells (whiteblood cells, red blood cells, platelets), and to meetthe further demands on the body such as infection,wound healing, and hypermetabolism. The presenceof GVHD and its common treatment of high-dosecorticosteroids contribute to the increased need forprotein. As with any medical condition, each patientresponds differently, and interventions that are suc-cessful in one patient may not be for another. If apatient is consistently meeting the estimated nutri-tion needs but continues to exhibit signs of musclewasting and malnutrition, an increase in calories orprotein should be considered. If available, measur-ing energy expenditure via indirect calorimetry canbe valuable. A multivitamin/mineral supplement iscommonly prescribed to HSCT patients posttrans-plant because of inconsistent intake of a normal

healthy diet and the added stress related to recov-ery. Although research related to micronutrientneeds specific to GVHD patients is not available, theincreased nutrient needs present in patients withwounds (vitamin C and zinc) are extrapolated to theGVHD patient as well. Our physicians often pre-scribe folic acid supplementation (1 mg daily) in theposttransplant period also due to its importance inred blood cell formation. The use of -3 fatty acids isrelatively new, and the benefits are unproven in theGVHD arena. Research using -3 fatty acid supple-ments in the treatment of GVHD is limited, but theresults are promising. Takatsuka and colleagues20

performed a single-center, randomized, controlledstudy with 16 patients undergoing MUD trans-plants. The 7 patients who received -3 fatty acidsupplementation (1.8 g per day from day 21 to day180) all survived, and 2 had grade III GVHD. Ofthe 9 patients in the control group, 3 developedgrade III or IV GVHD and 5 died. Because thesurvival curves between the 2 groups revealed sig-nificantly better outcomes in the -3 fatty acidsupplement group, the study results were publishedearly. The -3 fatty acidsupplement group alsoshowed significantly lower serum levels of cytokines(TNF-, IFN-, and IL-10).20 More research in alarger number of patients is needed to validate theseresults.-3 fatty acids have been shown to modulatecytokine production and therefore, in theory, havethe potential to modulate GVHD, a cytokine-relateddisease.10 Table 7 summarizes nutrition interven-tions to consider in GVHD patients.

Table 7Nutrition interventions in HSCT patients with GVHD12,16,17

Nutrition assessment and monitoring by nutrition professional. Calorie and needs are usually 3050 kcal/kg and proteinneeds are usually 1.52 g/kg.

Monitoring of weight, nutrient intake, and laboratory data for1 year posttransplant; longer monitoring required for patientswith active GVHD.

Nutrition counseling on management of gastrointestinalcomplications, medication side effects, and methods forimproving nutrient intake.

Multivitamin/mineral supplement (iron-free) posttransplant.Iron-free supplements are recommended due to frequency ofblood product support and risk of hemochromatosis.

Other supplements, such as vitamin C, zinc, folic acid, and-3 fatty acids, may be beneficial.

Initiation of specialized nutrition support in patients withsignificant gastrointestinal dysfunction and prolongedanorexia who are unable to maintain weight and lean bodymass.

Nutrition counseling on food safety and diet guidelines toavoid food-borne illness while immunosuppressed. Low-bacteria diets are commonly used in the early posttransplantperiod to avoid food as a potential source of infection. Manytransplant centers, including ours, have liberalized the HSCTdiet and allow well-washed raw fruits and vegetables andrestrict only those foods commonly associated with food-borneillness or containing mold or fungi.



Clinical Issues in Nutrition Management ofGVHD

The core of the nutrition problems in this popu-lation continues to be difficulty in providing ade-quate calories and protein. Nutrition needs can becalculated or measured, but if a patient is unable toreceive and properly process the nutrients, the num-bers become inconsequential. The degree to whichnutrition needs are properly met depends on multi-ple factors related to GVHD, such as status (acute orchronic), severity (stages I-IV or extensive/limited),tissues affected, and the length of time GVHD per-sists. These issues influence the patients ability toconsume or tolerate oral nutrition and NS. Table 8summarizes common nutrition problems experi-enced in GVHD and recommended interventions.

The prevalence of nutrition-related symptoms canbe difficult to quantify because specific nutritionproblems are not part of the GVHD diagnosis andgrading criteria. Weight loss, which is often gradualand subtle with frequent fluctuations, is a challengeto monitor and treat. In the long term, persistentweight loss is detrimental to the patient because

often by the time the physician, patient, and care-givers recognize the extent of the problem, thepatient has already lost a significant amount of leanbody mass (LBM), and quality of life has beenaffected. Lenssen et al23 studied the incidence ofweight loss in allogeneic patients 1 year posttrans-plant and found 33% of patients with extensivecGVHD and 19% of patients with limited cGHVDexperienced weight loss. More recently, Jacobsohnand colleagues24 retrospectively reviewed 93patients with cGVHD and reported 43% had a BMI21.9 kg/m2 and 14% had a BMI 18.5 kg/m2, theformer designated as malnutrition and the latter assevere malnutrition. Beyond investigating the inci-dence of malnutrition in the cGVHD population, theinvestigators also wanted to explore the etiology ofthe weight loss. Their results suggest dysphagia,abdominal pain, and active cGVHD are importantplayers in the etiology of weight loss. A statisticallysignificant relationship between weight loss andsymptoms such as nausea, anorexia, and oral sensi-tivity was not found, which led the researchers toconclude that unknown factors exist that contribute

Table 8Interventions recommended with various eating problems in GVHD

Problems Recommended interventions

Nausea/Vomiting/Diarrhea Control of GI symptoms with proper medications (antiemetics, antidiarrheals)Adequate hydration (IV or oral, if able)Nutrition support if bowel rest indicatedIntroduction of bland diet and isotonic liquidsMinimize smells of food by focusing on colder foods over hot foods

Oral mouth sores Avoid salty, spicy, and acidic foodsAvoid rough-textured foodsAvoid alcohol and carbonated beveragesAvoid extreme temperatures in food

Anorexia Oral nutrition supplementsEat small amounts to stimulate the appetite throughout the dayTrial of appetite stimulant

Early satiety Small frequent mealsServe meals in small portions on a smaller plateEat solids before drinking liquids at mealtime

Dysgeusia Trial of different flavors and spices to find acceptable onesTrial of supplemental zinc (if patient has chronic losses from diarrhea)Meats problematic and may require alternate flavoring or preparationAdd lemon or lime slices to water if tastes offDilute juices or other fluids if too sweet

Xerostomia Trial of available products to keep mouth moistPush fluidsTrial of sour foods to stimulate saliva productionAvoid bread products and meats unless served with gravy or in soup

Nonhealing wounds Adequate caloric and protein intakeMultivitamin and mineral supplement (without iron); consider additional vitamin C and zincsupplementation

Weight loss Work to resolve any of the above issues that may be impairing patients ability to consumeadequate amount of calories for weight gain

Assess intake by calorie count to determine level of intakePerform indirect calorimetry to assess resting metabolic rate (use as base for determining needswith activity factor and stress factor added in)

Add nutrition supplements to eating regimenConsider anabolic steroid to facilitate weight and lean body mass gain



to the weight loss in patients with cGVHD. Theytheorize that the presence of elevated energy expen-diture and increased serum levels of TNF- arepossible causes and need further study.24

Identifying Patients Who Need NSIn broad terms, the goal of NS in the patient with

GVHD includes providing the patient with theresources necessary to achieve an optimal nutritionstatus by gaining or maintaining LBM. The applica-tion of NS must be individualized, as each patientssituation is unique and constantly changing. Thetype of NS given can range from oral nutritionsupplements as in the case report 1 to specializedenteral or parenteral NS as provided in case report2. The specialized forms of NS are indicated when apatient is unable to maintain nutrition needs bytheir own efforts. See Table 9 for enteral and PNindications and special considerations in GVHDpatients.

Often a patient with GVHD presents with anobvious need for specialized NS (enteral or PN) tomeet nutrient needs. An episode of acute GI GVHDis a prime example. Because of the severe diarrhea,malabsorption of nutrients, fluids, and electrolytesin acute GI GVHD, PN is a common adjunctivetherapy. A patient who is unable to tolerate an oraldiet because of persistent vomiting or diarrhea qual-ifies for PN support until the GI symptoms areunder control. Unfortunately in some cases, theneed for NS is recognized but extenuating circum-stances exist to prevent the patient from receivingNS. Case report 1 exemplifies a situation in whichNS was appropriate and indicated, but the individ-ual circumstances of the case precluded access forprovision of NS. In theory, at the time the patientwould have benefited from long-term enteral NS, thepresence of extensive skin cGVHD did not allowplacement of a PEG. In contrast, case report 2, whohad a PEG placed relatively early in the posttrans-plant course, had no complications related to PEG

placement and had an improved nutrition statusand quality of life as a result of enteral NS.

ConclusionHSCT recipients with acute or cGVHD are a

unique and challenging population to manage. Gas-trointestinal and organ dysfunction, skin manifesta-tions, medication side effects, and psychosocial andeconomic issues merge into a very complex scenario,which can result in poor outcomes. A multidisci-plinary approach is needed to effectively treatGVHD patients. Early intervention using a range ofnutrition interventions is important to preventextensive loss of LBM and to preserve the ability toperform basic activities of daily living, and ulti-mately, quality of life.

References1. Baron F, Storb R, Little M. Hematopoietic cell transplantation:

five decades of progress. Arch Med Res. 2003;34:528544.2. Tabbara IA, Zimmerman K, Morgan C, Nahleh Z. Allogeneic

hematopoietic stem cell transplantation. Arch Intern Med. 2002;162:15581566.

3. International Bone Marrow Transplant Registry. Internationalbone marrow transplant registry. Available at: http://www.ibmtr.org. Accessed January 10, 2005.

4. Roberts S, Vanzee J. Nonmyeloablative stem cell transplantationand its nutritional consequences. Support Line. 2003;25:39.

5. Ratanatharathorn V, Ayash L, Lazarus HM, Fu J, Uberti JP.Chronic graft-versus-host disease: clinical manifestation andtherapy. Bone Marrow Transplant. 2001;28:121129.

6. Klingebiel T, Schlegel PG. GVHD: overview on pathophysiology,incidence, clinical, and biological features. Bone Marrow Trans-plant. 1998;21(suppl):S45S49.

7. Sullivan KM. Graft-versus-host disease. In: Blume KG, FormanSJ, Appelbaum F, eds. Thomas Hematopoietic Cell Transplanta-tion. Boston, MA: Blackwell Scientific; 2004:635664.

8. Vogelsang GB, Lee L, Bensen-Kennedy DM. Pathogenesis andtreatment of graft-versus-host disease after bone marrow trans-plant. Annu Rev Med. 2003;54:2952.

9. Shulman HM, Sullivan KM, Weiden PI, et al. Chronic graft-versus-host syndrome in man: a long-term clinicopathologic studyof 20 Seattle patients. Am J Med. 1980;69:204217.

10. Arai S, Vogelsang GB. Management of graft-versus-host disease.Blood Rev. 2000;14:190204.

Table 9Indications and considerations for nutrition support (NS) in patients with graft-vs-host disease (GVHD)

Enteral NS Parenteral NS

Functioning GI tract with inability to maintain nutrition statusvia oral intake. The presence of oral esophagealGVHD or overall failure to thrive can result in need forenteral feedings.

Presence of mucositis esophagitis eliminating the optionof enteral access during early posttransplant phase.

Stable chronic gastrointestinal GVHD with inability tomaintain nutrition status despite attempts to meet needsvia oral intake.

Intractable vomiting or diarrhea from acute gastrointestinalGVHD requiring prolonged bowel rest.

Parenteral NS is contraindicated due to fluid retention organ failure and gastrointestinal function is adequate toinitiate enteral NS.

Severe thrombocytopenia prohibiting enteral access.Consider platelet transfusion before placement offeeding tube when platelet count 50,000.

Central IV access not possible but temporary enteral accessis possible and gastrointestinal function is acceptable.

History of nonhealing wounds or extensive skin cGVHDpreventing permanent enteral access (ie, gastricfeeding tube).



11. Farag SS. Chronic graft-versus-host disease: where do we go fromhere? Bone Marrow Transplant. 2004;33:569577.

12. Hasse J, Roberts S. Transplantation. In: Rombeau JL, RolandelliRH, eds. Clinical Nutrition: Parenteral Nutrition. Philadelphia,PA: W.B. Saunders Company; 2001:529561.

13. Higman MA, Vogelsang GB. Chronic graft versus host disease.Br J Haematol. 2004;125:435454.

14. Bacigalupo A, Palandri R. Management of acute graft versus hostdisease. Hematol J. 2004;5:189196.

15. Nordlander A, Mattsson J, Ringden O, et al. Graft-versus-hostdisease is associated with a lower relapse incidence after hema-topoietic stem cell transplantation in patients with acute lympho-blastic leukemia. Biol Blood Marrow Transplant. 2004;10:195203.

16. Muscaritoli M, Grieco G, Capria S, Iori AP, Rossi FF. Nutritionaland metabolic support in patients undergoing bone marrow trans-plantation. Am J Clin Nutr. 2002;75:183190.

17. Lenssen P, Bruemmer B, Aker SN, McDonald GB. Nutrientsupport in hematopoietic cell transplantation. JPEN J ParenterEnteral Nutr. 2001;25:219228.

18. Ross V. Micronutrient recommendations for wound healing. Sup-port Line. 2002;24:39.

19. Scholl D, Langkamp-Henken B. Nutrient recommendations forwound healing. J IV Nurs. 2001;24:124132.

20. Takatsuka H, Takemoto Y, Iwata N, et al. Oral eicosapentaenoicacid for complications of bone marrow transplantation. BoneMarrow Transplant. 2001;28:769774.

21. Lenssen P. Hematopoietic cell transplantation. In: Matarese LE,Gottschlich MM, eds. Contemporary Nutrition Support Practice.St. Louis, MO: W.B. Saunders Co: 2003:574594.

22. Lenssen P, Aker SN. Adult hematopoietic stem cell transplanta-tion. In: Hasse JM, Blue LS, eds. Comprehensive Guide to Trans-plant Nutrition. Chicago, IL: American Dietetic Association; 2002:123152.

23. Lenssen P, Sherry ME, Cheney CL, et al. Prevalence of nutrition-related problems among long-term survivors of allogeneic marrowtransplantation. J Am Diet Assoc. 1990;90:835842.

24. Jacobsohn DA, Margolis J, Doherty J, Anders V, Vogelsang GB.Weight loss and malnutrition in patients with chronic graft-versus-host disease. Bone Marrow Transplant. 2002;29:231236.



roberts & thompson-2005

Documents