Toward a Better Understanding of the Atypical Features of Chronic Graft-Versus-Host Disease: A Report from the 2020 National Institutes of Health Consensus Project Task Force

Abstract

Alloreactive and autoimmune responses after allogeneic hematopoietic cell transplantation can occur in nonclassical chronic graft-versus-host disease (chronic GVHD) tissues and organ systems or manifest in atypical ways in classical organs commonly affected by chronic GVHD. The National Institutes of Health (NIH) consensus projects were developed to improve understanding and classification of the clinical features and diagnostic criteria for chronic GVHD. Although still speculative whether atypical manifestations are entirely due to chronic GVHD, these manifestations remain poorly captured by the current NIH consensus project criteria. Examples include chronic GVHD impacting the hematopoietic system as immune mediated cytopenias, endothelial dysfunction, or as atypical features in the musculoskeletal system, central and peripheral nervous system, kidneys, and serous membranes. These purported chronic GVHD features may contribute significantly to patient morbidity and mortality. Most of the atypical chronic GVHD features have received little study, particularly within multi-institutional and prospective studies, limiting our understanding of their frequency, pathogenesis, and relation to chronic GVHD. This NIH consensus project task force report provides an update on what is known and not known about the atypical manifestations of chronic GVHD while outlining a research framework for future studies to be undertaken within the next 3 to 7 years. We also provide provisional diagnostic criteria for each atypical manifestation, along with practical investigation strategies for clinicians managing patients with atypical chronic GVHD features.

Keywords: Atypical; Chronic graft-versus-host disease; National Institutes of Health Consensus Project Task Force.

Figure 1.. Comparison of Atypical versus NIH Defined Diagnostic and Distinctive Chronic GVHD Manifestations.

NIH consensus criteria chronic GVHD target organs and manifestations are depicted on the right, with diagnostic features in bold and distinctive features in non-bolded text (modified from Jagasia et al). Suspected atypical chronic GVHD target organs and manifestations are on the left, with asterisks (*) indicating manifestations where endothelial damage likely plays a prominent role in the mechanism of disease. Atypical pulmonary chronic GVHD (#) is not specifically addressed in this manuscript. Abbreviations: Central nervous system (CNS), peripheral nervous system (PNS), musculoskeletal system (MSK), gastroenterology (GI), genitourinary (GU), autoimmune hemolytic anemia (AIHA), immune thrombocytopenia purpura (ITP), autoimmune neutropenia (AIN), pleuroparenchymal pulmonary fibroelastosis (PPFE) cryptogenic organizing pneumonia (COP). Created with BioRender.com.

Figure 2.

Thigh magnetic resonance imaging of chronic GVHD myofasciitis. (A) T1 MRI and (B) STIR thigh MRI in a patient with chronic GVHD myofasciitis showing mild fatty infiltration, a patchy STIR hyperintense signal, and superficial fascial fluid with associated skin thickening and subcutaneous fat edema. (MRI images provided from collection of Dr. Pinal-Fernandez).

Figure 3.. Chronic GVHD myositis.

Patient with progressing sclerotic skin chronic GVHD, tightening of skin and joints, generalized muscle pains and elevations in creatine kinase following tapering of immune suppression. Re-institution of therapeutic levels of tacrolimus and corticosteroids resulted in diminution of muscle pains and normalization of creatine kinase levels over 2-weeks. (A) Hematoxylin and eosin-stained section form right quadriceps muscle biopsy shows two foci of perimysial perivascular inflammatory infiltrate, with no perifascicular atrophy and / or necrotic fibers (×100 magnification). (B) Weigert-Van Gieson stain showing presence of endomysial fibrosis (×100 magnification). (C) Immunostain for MHC class I demonstrates diffuse sarcolemmal labelling (×200 magnification). (D, E, F) The inflammatory infiltrate is mostly composed of CD3+ (CD8+>CD4+) T-lymphocytes, mostly in perimysial distribution with occasional sprinkling in the surrounding endomysium (D: CD3; E: CD4; F: CD8; 200X magnification). (Images from collection of Dr. Namita Sinha).

Figure 4:. CNS and retinal involvement by chronic GVHD.

Patient first developed neurologic signs at day 159 after alloHCT during tapering of immunosuppression. (A). Brain MRI at day 162 after alloHCT to evaluate left-sided hemihypesthesia and hand-tremors during tacrolimus taper. Brain MRI was initially normal (axial-T2 weighted turbo spin echo (TSE), diffusion weighted imaging (DWI), T1-weighted post contrast). (B). Brain MRI at day 1185 after alloHCT showing progressive confluating periventricular lesions without acute changes on DWI and no contrast enhancement (axial T2 TSE, DWI, T1 SE post contrast). Multiple neurologic problems had developed in the interim, including recurrent seizures, changes in personality and cognition, generalized hypersensitivity, and cerebrospinal fluid inflammation without infection that responded to a prolonged course of immune suppression. No other classical chronic GVHD manifestations were present. (C). The patient later developed blurred vision and “floaters”. Fundoscopy revealed whitish, mildly pigmented retinal/chorioretinal scars on the right and left fundus. Optical coherence tomography scan showed retinal/chorioretinal scarring with disorganized retinal layers consistent with progression of CNS chronic GVHD to involve the retina. Classical cutaneous chronic GVHD with sclerosis later developed at 52 months after alloHCT. (Reference: Blecha et al. Onc Res Treat 2015; 38: 532–534. Pictures used with permission)

Figure 5.. Renal thrombotic microangiopathy in a patient with chronic GVHD.

(A) Glomerular microangiopathy with mesangiolysis, entrapment of red blood cells (RBCs) and fragmented RBCs (long arrow), and double contours of the glomerular basement membrane (GBM, short arrow) (HE, 400x). (B) Segmental mesangiolysis (arrow) and capillary microaneurysm (asterisk) (PAS, 400x). (C) Detachment and loss of fenestration in endothelial cells (asterisk) and beginning formation of a second layer of GBM (arrow) (ultrathin section, 5000x) (Images from the collection of Dr. Maike Buettner-Herold).