Graft-versus-host disease differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2] M. Khurram Afzal, MD [3]

Overview

The differential diagnosis of GvHD is broad given the complexity of post-transplant patients. Infectious etiologies must be considered in persons who under stem cell transplant. A skin rash in the post-transplant setting, for example, could reflect infectious dermatitis or skin GvHD. Liver dysfunction in the post-transplant setting, for example, can reflect an infectious hepatitis of liver GvHD. Gastrointestinal symptoms in the post-transplant setting, for example, could reflect infectious enteritis/colitis or GI GvHD. Chronic graft-versus-host disease must be differentiated from other diseases that cause skin thickening such as scleredema, scleromyxedema, eosinophilic fasciitis, scleroderma, drug induced scleroderma, scleroderma overlap syndromes, diabetic cheiroarthropathy, myxedema, and nephrogenic systemic fibrosis.

Differential Diagnosis

The differential diagnosis for GvHD can be categorized into the specific organs involved. When a post-transplant patient develops skin, liver, or [Gastrointestinal tract|GI,]] symptoms, there are numerous possibilities regarding the etiology, as post-transplant patients are immunocompromised and at risk for infections. The clinical manifestations of infection in the skin, liver, or GI tract can mimic symptoms of GvHD.

For skin signs and symptoms, differential diagnosis includes:

• Varicella zoster (shingles)
• Bacterial cellulitis
• Fungal skin infection (tinea corporis)
• Toxic erythema of chemotherapy
• Drug eruption

For liver signs and symptoms, differential diagnosis includes:

• CMV hepatitis
• Sinusoidal obstruction syndrome (hepatic veno-occlusive disease)
• Viral hepatitis
• Cholelithiasis
• Choledocholithiasis

For gastrointestinal signs and symptoms, differential diagnosis includes:

• Typhilitis (neutropenic enterocolitis)
• Clostridium difficile colitis
• Viral gastroenteritis
• Ischemic colitis

Differentiating Chronic graft-versus-host disease from other Diseases

• Chronic graft-versus-host disease must be differentiated from other diseases that cause skin thickening such as scleredema, scleromyxedema, eosinophilic fasciitis, scleroderma, drug induced scleroderma, scleroderma overlap syndromes, diabetic cheiroarthropathy, myxedema, and nephrogenic systemic fibrosis.

Differentiating Chronic graft-versus-host disease from other Diseases

Diseases		Clinical manifestations							Para-clinical findings				Gold standard	Additional findings
		Symptoms			Physical examination
									Lab Findings		Imaging	Histopathology
		Skin thickening	Raynaud phenomenon	Heart burn	Edema (swelling)	Sclerodactyly	Telangiectasia	Impaired mobility	Autoantibodies	Blood indices
Scleroderma	Chronic graft-versus-host disease	+ (induration)	-	-	-	-	-	+	Antinuclear antibody (ANA) Anti-mitochondrial antibody	Increased serum bilirubin concentration	N/A	Thick collagen bundles in the dermis Normal appearing epidermis	Skin biopsy	Occurs after allogeneic hematopoietic transplantation Pulmonary fibrosis Esophageal sclerosis
	Limited cutaneous systemic sclerosis (CREST syndrome)	+ (induration)	+	+	+/-	+	+	+/-	Anti-centromere antibody Antinuclear antibody (ANA)	Anemia Elevated creatinine level	Nailfold microvascular changes on nailfold video capillaroscopy (NVC) Chest HRCT scan showing evidence of pulmonary fibrosis	Nailfold microvascular changes Dilated capillary loops Microhemmorhages	American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) classification criteria	Interstitial lung disease Pulmonary hypertension Calcinosis Dyspnea
	Scleredema (Buschke's disease)	+	-	-	+	-	-	+	N/A	Fasting blood sugar HbA1C	N/A	Normal epidermis Thickened dermis with swelling of collagen Fibroblast proliferation is absent in the dermis	Skin biopsy	Symmetrical skin thickening Trunk, shoulders, upper back, face Fingers are spared Immobility of shoulders and chest Associated with viral URTI and diabetes mellitus type 1, monoclonal gammopathy
	Scleromyxedema (lichen myxedematosus)	+ (waxy yellow-red papules)	+/-	+/-	+	-	-	-	N/A	Monoclonal gammopathy (IgG-lambda) Normal TSH	N/A	Fibroblast proliferation in the dermis Mucin deposition in the dermis	Skin biopsy	Associated with malignancies AL amyloidosis Normal thyroid function Scalp and head are affected
	Eosinophilic fasciitis	+ (orange peel-peau d'orange appearance)	-	-	+	-	-	-	N/A	Eosinophilia (peripheral blood smear)	Normal appearance on nailfold video capillaroscopy (NVC)	Fascia is edematous and infiltrated by eosinophils	Skin biopsy	Fasciitis present on the trunk sparing extremities Visible collapse of superficial veins when the limb is elevated Hands and feet are not involved
	Drug-induced scleroderma	+	+	+/-	+/-	+	+/-	-	N/A	N/A	N/A	IgG and complement deposits on epidermal keratinocytes	Skin biopsy	Bleomycin Cancer chemotherapeutic drugs Skin changes present on trunk and extremities
	Diffuse cutaneous systemic sclerosis	+ (induration)	+	+	+/-	+	+	+/-	Anti-topoisomerase-I (Scl-70) antibody Anti-RNA polymerase III antibody Antinuclear antibody (ANA)	Anemia Elevated creatinine level	Nailfold microvascular changes on nailfold video capillaroscopy (NVC) Chest HRCT scan showing evidence of pulmonary fibrosis	Nailfold microvascular changes Dilated capillary loops Microhemmorhages	American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) classification criteria	Interstitial lung disease Pulmonary hypertension Scleroderma renal crisis Dyspnea
Scleroderma overlap syndromes	Scleroderma-systemic lupus erythematosus overlap	+ (rash)	+	+	+/-	+	+	+/-	Anti-Ro52 antibody Antinuclear antibody (ANA) Anti-Smith antibody Anti-dsDNA antibody Antiphospholipid antibody Anti-centromere antibody (ACA) Anti-topoisomerase-I (Scl-70) antibody Anti-RNA polymerase III antibody	Decreased C3, C4 and CH50 Anemia	N/A	Inflammation at the dermal-epidermal junction	Anti-Ro52 antibody Anti-dsDNA antibody	Malar (butterfly) rash Arthritis
	Scleroderma-polymyositis overlap	+ (rash)	+	+	+/-	+	+	+/-	Anti-Ro52 antibody Antinuclear antibody (ANA) Anti-Jo-1 antibody Anti-SRP antibody Anti-Mi-2 antibody Anti-centromere antibody (ACA) Anti-topoisomerase-I (Scl-70) antibody Anti-RNA polymerase III antibody	Elevated creatine kinase Aldolase Anemia	N/A	Inflammation at the dermal-epidermal junction Atrophy of the epidermis Perivascular infiltrate in the dermis Necrosis and atrophy of endomysial connective tissue on muscle biopsy	Anti-Ro52 antibody Muscle biopsy	Symmetric proximal muscle weakness
	Scleroderma-rheumatoid arthritis overlap	+ (rash)	+	+	+/-	+	+	+/-	Anti-Ro52 antibody Antinuclear antibody (ANA) Rheumatoid factor (RF) +ve Anti-CCP antibody Anti-centromere antibody (ACA) Anti-topoisomerase-I (Scl-70) antibody Anti-RNA polymerase III antibody	Elevated ESR Anemia	N/A	Inflammation at the dermal-epidermal junction	Anti-Ro52 antibody Anti-CCP antibody	Clinical findings that suggest rheumatoid arthritis (RA) but do not fulfill the ACR criteria for RA
Endocrine disorders	Diabetic cheiroarthropathy	+ (waxy skin)	-	-	-	+	-	+	N/A	Fasting blood sugar ≥126 mg/dL HbA1C ≥ 6.5%	N/A	N/A	Fasting blood sugar ≥126 mg/dL HbA1C ≥ 6.5%	Long standing type I diabetes mellitus Skin thickening of fingers Flexion contractures on fingers
	Myxedema	+ (coarse skin)	-	-	+	-	-	-	Anti-TPO antibody Anti-Tg antibody	Anemia Serum TSH elevated	N/A	Atrophied epidermis Hyperkeratosis	Serum TSH	Hypothyroidism Nonpitting edema present
Renal diseases	Nephrogenic systemic fibrosis	+ (induration)	-	-	+	+	-	-	N/A	Elevated C-reactive protein Elevated ESR Decreased serum albumin Decreased creatinine clearance	N/A	Fibrosis of dermis Accumulation of CD34 positive fibroblasts	Skin biopsy	Skin changes on extremities and trunk (involves hand and feet) Affects patients with advanced dialysis dependent renal failure Gadolinium containing contrast exposure is a risk factor Internal organ fibrosis can occur