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Managing atypical manifestations of chronic graft-versus-host disease (cGvHD) in patients who have undergone transplant can be challenging in the context of rare and heterogeneous signs and symptoms.1 Between 2005 and 2020, the United States National Institutes of Health (NIH) held a series of consensus projects considering GvHD. In 2020, as part of the NIH cGvHD Consensus Project, one of the working groups (Working Group IV) focused on atypical features of the disease, considering forms with higher-than-normal morbidity and those that affect unusual systems, such as the skin and eyes.1 Published in Transplantation and Cellular Therapy in May 2022 by Cuvelier at al.1, here we review the formal report from the task force.
cGvHD is a leading cause of late morbidity and non-relapse mortality following allogeneic hematopoietic stem cell transplant (ASCT). Treatment of cGvHD is often ineffective, with incomplete responses and recurrence as common outcomes. In the context of atypical cGvHD, late recognition, paucity of experience in management, and a lack of research mean these features can lead to significant morbidity and frequent treatment failure.
The aims of the NIH cGvHD Consensus Project were as follows:
cGvHD is caused by the systemic failure of immune tolerance to an allogeneic hematopoietic chimera, with immune dysregulation and intolerance of the host by the novel donor immune system. This manifests in cGvHD as both antirecipient alloreactivity and autoreactivity. The study report considers evidence that supports the presence of both processes in cGvHD, including the evidence below:
A major challenge for clinicians is recognizing and therefore diagnosing atypical cGvHD; often a sign or symptom is attributed to an etiology not related to cGvHD. The task force identified that this is especially difficult when atypical features occur in the absence of established cGvHD signs, such as nephritis. The report declares that in this context, atypical features should be described as “possibly” related to cGvHD. This is distinct from referring to atypical features as “definitively” related to cGvHD when they manifest in the presence of a confirmed diagnosis according to established cGvHD criteria (Figure 1).
Figure 1. Typical and atypical manifestations of cGvHD*
AIHA, autoimmune hemolytic anemia; AIN, autoimmune neutropenia; BOS, bronchiolitis obliterans syndrome; cGvHD, chronic graft-versus-host disease; CNS, central nervous system; COP, cryptogenic organizing pneumonia; GI, gastrointestinal; GU, genitourinary; ITP, immune thrombocytopenia purpura; MSK, musculoskeletal system; NIH, National Institutes of Health; PNS, peripheral nervous system; PPFE, pleuroparenchymal pulmonary fibroelastosis.
*Adapted from Cuvelier, et al.1 Created with BioRender.com.
†For the NIH-defined target organs and manifestations, diagnostic features are in italics and distinctive features are in roman text.
A main aim of the task force was to propose provisional diagnostic criteria for atypical GvHD manifestations, which are presented in Figure 2. Though manifestations can occur throughout the body, neurological, renal, pulmonary, musculoskeletal, and hematologic effects predominate.
Figure 2. Proposed diagnostic criteria for atypical manifestations of cGvHD*
Allo-HCT, allogeneic hematopoietic stem cell transplant; CIDP, chronic inflammatory demyelinating polyneuropathy; CNS, central nervous system; DLCO, diffusing capacity for carbon monoxide; FEV-1, forced expiratory volume in 1 second; FVC, forced vital capacity; GBS, Guillain Barré syndrome; MRI, magnetic resonance imaging; SFN, small fiber polyneuropathy; TAM, transplant-associated microangiopathy; TLC, total lung capacity; TMA, thrombotic microangiopathy.
*Adapted from Cuvelier, et al.1
The review also considers current diagnostic challenges and which sequence investigations can be used to guide diagnosis of atypical cGvHD (Figure 3).
Figure 3. Investigations for atypical cGvHD*
ANA, anti-nuclear antibody; cGvHD, chronic graft-versus-host disease; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; CyTOF, cytometry by time of flight; eGFR, estimated glomerular filtration rate; LDH, lactate dehydrogenase; PCR, polymerase chain reaction; PNS, peripheral nervous system; RNA Seq, RNA sequencing; vWF, von Willebrand factor.
*Adapted from Cuvelier, et al.1
†CSF examination: CSF cell count including white blood cell count and differential; CSF lactate, CSF protein; CSF and blood correlation of albumin, IgG, IgA, and IgM; isoelectric focusing; myelin basic protein; and appropriate CSF microbiological and studies (e.g., human herpes virus-6).
Finally, the review discusses where further research is needed given the atypical features that have been described.
Immune-mediated cytopenias (IMCs) are well-recognized sequalae in patients who have received ASCT, with a lack of clearly defined incidence to diagnostic uncertainty and lack of systematic reporting. It is also established that osteoblast injury in either acute GvHD or cGvHD can contribute to decreased hematopoiesis. Numerous immune-mediated mechanisms exist to suggest GvHD drives IMC, including ABO incompatibility, loss of immune tolerance, circulating soluble B cell-activating factors, and ineffective T-cell regulation, with a strong association with HLA-mismatched and unrelated donors.
IMCs can occur in the context of donor–donor reactivity or recipient–donor reactivity, suggesting that either immune-mediated mechanisms or cGvHD can lead to the same result. On this basis, the authors advocate that IMC should not be described as autoimmune or alloimmune, but as a “cGvHD-associated immune-mediated cytopenia.”
Atypical cGvHD symptoms include joint pain, muscle cramps, edema, and restricted joint movement (Figure 2). These can be difficult to distinguish from treatment-related problems, such as steroid- or radiation-induced avascular necrosis or steroid-related myopathy, with heterogeneity and rare forms (e.g., myocarditis) complicating the investigation and diagnosis further. Comprehensive investigation, including blood test, autoimmune screening, radiological investigation, physical examination, clinical history, and muscle biopsy, are required. cGvHD-associated myositis, presenting as peripheral nervous system disease in often heavily pretreated patients, can be particularly challenging, with muscle biopsy described by the consensus review as the “standard of care.”
The atypical endothelial manifestations of cGvHD include avascular areas of skin, neovascularization, and enlarged capillaries. Similar to established GvHD complications, such as thrombotic microangiopathy, these endothelial changes arise from an interplay between proinflammatory cytokines, upregulation of endothelial cell adhesion molecules, migration of lymphocytes, and activation of platelets and coagulation factors. In addition, steroids and other traditional treatments used for cGvHD may cause further endothelium damage. Both coronary and peripheral artery disease related to endothelial injury have been clearly identified in patients with cGvHD, as has organ and tissue injury, including of the skin.
Evaluation of the effects of cGvHD on the central nervous system (CNS) is complicated by pre- and comorbid conditions, as well as medications that affect the CNS and cognitive function. Rare complications, such as cGvHD-associated acute disseminated encephalomyelitis (ADEM), have been described, but the prevalence of true cGvHD-associated CNS impairment remains to be elucidated. While neurocognitive impairment has been clearly described in patients undergoing ASCT, the role of cGvHD is unknown. Putative processes have been described, including cytokine overproduction, T‑cell infiltration, granulomatous changes, and antibody-mediated encephalopathy.
The peripheral nervous system (PNS) manifestations of atypical cGvHD that have been described include immune-mediated Guillain-Barré syndrome, myasthenia gravis, and chronic inflammatory demyelinating polyneuropathy, among others (Figure 2). As with the musculoskeletal manifestations of atypical cGvHD, these can be difficult to distinguish from treatment complications, including drug-related neuropathy, paraneoplastic, and infection-related complications. The PNS symptoms described by patients include positive sensory symptoms (e.g., pain or paresthesia) or negative sensory symptoms (e.g., numbness). They can also include physical symptoms, with autonomic manifestations such as sweating and muscle cramps. A range of investigations exist with the aim of determining the underlying cause of peripheral neuropathy in patients.
Evaluation for possible renal cGvHD requires comparison of current renal function against renal function both before and early after ASCT. Evaluation before transplantation should include consideration of nephrotoxic exposures, such as medications (e.g., aminoglycosides) and pre-existing renal conditions
Polyserositis is rare, manifesting as localized effusions, including pleural and pericardial effusions and ascites. It is a diagnosis of exclusion as it shares this clinical presentation with other transplant-related complications, such as microangiopathic anemia. The pathophysiology of the condition remains poorly understood but it is associated with increased levels of different white cells in effusion fluid and peripheral blood.
The report from the 2020 NIH Consensus Project Task Force clearly proposes provisional diagnostic criteria for the assessment and diagnosis of atypical cGvHD in patients who have undergone transplant. Though rare and heterogenous, these manifestations can carry considerable morbidity risks for patients and treatment challenges for clinicians.
To better manage these patients, large, multicenter, prospective studies, including biobanking and the development of clinical and pathological criteria, are required to improve understanding of the underlying pathological processes.
Impact of ATG on post-allo-HSCT outcomes by pre-transplant MRD status
A retrospective analysis of patients with AML who underwent allo-HSCT in first complete remission (CR1) and received ATG, stratified by MRD status
Key publications selected by the GvHD Hub Steering Committee
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