key: cord-0824281-iwsijmpf
authors: Kitko, Carrie L.; Pidala, Joseph; Schoemans, Hélène M.; Lawitschka, Anita; Flowers, Mary E.; Cowen, Edward W.; Tkaczyk, Eric; Farhadfar, Nosha; Jain, Sandeep; Steven, Philipp; Luo, Zhonghui K.; Ogawa, Yoko; Stern, Michael; Yanik, Greg A.; Cuvelier, Geoffrey D.E.; Cheng, Guang-Shing; Holtan, Shernan G.; Schultz, Kirk R.; Martin, Paul J.; Lee, Stephanie J.; Pavletic, Steven Z.; Wolff, Daniel; Paczesny, Sophie; Blazar, Bruce R.; Sarantopoulos, Stephanie; Socie, Gerard; Greinix, Hildegard; Cutler, Corey
title: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IIa. The 2020 Clinical Implementation and Early Diagnosis Working Group Report
date: 2021-04-09
journal: Transplant Cell Ther
DOI: 10.1016/j.jtct.2021.03.033
sha: 108bd2c0df3b6a0b619e584c6189187292c86f57
doc_id: 824281
cord_uid: iwsijmpf

Recognition of the earliest signs and symptoms of chronic graft-versus-host disease (GVHD) that lead to severe manifestations remains a challenge. The standardization provided by the National Institutes of Health (NIH) 2005 and 2014 consensus projects has helped improve diagnostic accuracy and severity scoring for clinical trials, but utilization of these tools in routine clinical practice is variable. Additionally, when patients meet the NIH diagnostic criteria, many already have significant morbidity and possibly irreversible organ damage. The goals of this early diagnosis project are 2-fold. First, we provide consensus recommendations regarding implementation of the current NIH diagnostic guidelines into routine transplant care, outside of clinical trials, aiming to enhance early clinical recognition of chronic GVHD. Second, we propose directions for future research efforts to enable discovery of new, early laboratory as well as clinical indicators of chronic GVHD, both globally and for highly morbid organ-specific manifestations. Identification of early features of chronic GVHD that have high positive predictive value for progression to more severe manifestations of the disease could potentially allow for future pre-emptive clinical trials.

providers. Additionally, patient education regarding early signs and symptoms, increased education of primary health care providers, and utilization of better communication practices from patient and local clinicians to the transplant center could enhance timely diagnosis of chronic GVHD according to current NIH criteria. The second goal of this working group was to review approaches allowing earlier diagnosis of chronic GVHD before meeting NIH criteria when irreversible changes in organ function have occurred. As examples, we discuss 3 organs associated with a high incidence of irreversibility and morbidity: skin/fascia, eyes, and lungs. We outline future research efforts to identify new early diagnostic criteria or reproducible early markers of severe disease, to allow for the development of earlier interventions or even pre-emptive treatments. Future clinical trials could use these early diagnostic tools as eligibility criteria testing feasibility and efficacy of pre-emptive treatment strategies.

Earlier clinical recognition of chronic GVHD is needed and requires greater involvement of all HCT stakeholders, including nontransplant providers as well as patients and caregivers, and could be facilitated by eHealth technology such as telehealth (remote physician and patient assessment), teleconferences (remote multidisciplinary conferences), and electronic applications and reporting tools.

Early signs, symptoms, or other diagnostic determinants of chronic GVHD that are reliably associated with later progression to highly morbid forms of chronic GVHD need to be identified. Early detection of chronic GVHD requires careful and repetitive assessments, including physical examinations by providers with expertise in transplantation, starting before transplantation and continuing through post-transplant follow-up to allow formal diagnosis and assessment of disease trajectory.

Research into prognostic markers in blood, tissue, fluid, imaging, and functional testing is needed to identify actionable early indicators for potential pre-emptive therapy.

Four working groups were created to encourage global engagement in the topic [29] . Groups worked individually beginning in February 2020 to review the relevant literature and create the initial draft of the paper. The Steering Committee reviewed and discussed the initial draft and offered recommendations for revisions. Two iterative rounds of comments and revisions were collected before the November 18 to 20, 2020, Consensus Conference. The manuscript was further revised for submission after additional suggestions from external reviewers, the Steering Committee, and virtual conference participants, which included patient and caregiver representatives, and a 30-day public comment period. 

Timely recognition of chronic GVHD could potentially be improved by (1) better education of health care providers about the diagnostic criteria or early indicators for chronic GVHD, potentially supported by the use of eHealth tools; (2) delineation of essential chronic GVHD documentation needed in clinical practice; and (3) empowering patients to participate actively in symptom monitoring.

Many health care providers, including transplant providers, have difficulty recognizing very early signs and symptoms of chronic GVHD. Application of the current NIH criteria to diagnose chronic GVHD can be challenging [24, 27, 30] , and early signs may not be diagnostic. It is important to recognize that there is no global model of care post-HCT, and geographic and center-specific practices often dictate whether the patient continues to receive most clinical care in a transplant center versus transfer of care back to a local physician with limited transplant and GVHD-specific knowledge.

For transplant providers, knowledge and confidence can be improved by targeted training sessions [28] . Several online training platforms are available, although several encompass topics beyond chronic GVHD diagnosis (Supplementary Table S1 ). Development of shorter, more targeted training would be helpful. Similarly, eHealth tools can be used to educate and facilitate the implementation of the NIH criteria in clinical practice. Recently, the eGVHD app (www.uzleuven.be/egvhd) was shown to improve the accuracy of GVHD assessment among health care professionals [23, 25, 26] . The app has received CE Marking Type I approval, indicating compliance with European quality standards for medical devices, and has been used by providers worldwide, with the United Sttaes, China, France, and the United Kingdom being the top downloaders. The use of low-cost, ubiquitously available eHealth tools allows clinicians to access the GVHD criteria at the bedside, encourages systematic physical evaluation of patients, and decreases diagnosis and scoring errors. Ideally, such tools would be integrated in the electronic health record, although this requires a number of functionalities that could prove very costly (need for user identification mechanisms, data protection, interoperability and compatibility with other software, medical device regulation compliance, and availability of maintenance systems). Integration will therefore require partnership with funding agencies or the private sector. Epic, one of the largest electronic medical record systems in the United STates, has collaborated with the Center for International Blood and Marrow Transplant Research (CIBMTR) and a group of transplant physicians to develop specialized flowsheets to document both acute and chronic GVHD data. Approximately 100 US-based transplant centers are using Epic, and approximately 40% of these centers routinely use the flowsheets. While important and useful to educate the community about the NIH diagnostic criteria, it is important to note that these criteria were meant for chronic GVHD clinical trials, and some patients who do not meet NIH criteria may still have chronic GVHD that requires treatment, particularly when the disease presents with rare manifestations such as serositis, nephrotic syndrome, or autoimmune cytopenias. 

For patients followed locally by health care providers with less chronic GVHD expertise, teleconferences may also help support and educate community providers by facilitating consultation with experts at transplant centers. It is critical to establish this relationship before the patient is referred back to the community partner so that a proactive (rather than reactive) approach to chronic GVHD can be implemented. The COVID-19 pandemic has resulted in the development of more teleconferencing platforms, including many with appropriate security measures to allow Health Insurance Portability and Accountability Act compliance. The ability to show pictures of physical findings and ask experts questions about new signs and symptoms could facilitate accurate diagnosis of remote patients while also educating local providers about chronic GVHD.

Early recognition of chronic GVHD may offer an opportunity to prevent evolution to more severe disease with irreversible damage [31] , although this hypothesis should be formally tested. The 2014 NIH recommendations for clinical trials advocate use of a form that captures diagnostic signs and organ severity scoring [17] . Such evaluations were developed for use in clinical trials and likely lack the granularity required to adjust treatments for individual patients. However, completion of the form does ensure that the main organs involved with chronic GVHD are assessed at each visit. The form is brief and available online at https://doi.org/10.1007/978-3-030-02278-5_44, appendix 1. [32] . One recommended modification to the 2014 form is the addition of a checkbox for "Abnormality thought to represent chronic GVHD plus other causes (specify)," since organ dysfunction can have multiple contributing causes, thereby allowing capture of both chronic GVHD and known non-GVHD causes.

Members of this working group unanimously agreed that it is crucial to properly document the pretransplant baseline status of multiple organ systems in patients in order to correctly identify new abnormalities developing after HCT. With the input of disease and organ experts, we propose the use of a checklist to be completed before HCT to document the presence of signs and symptoms (e.g., dry eyes, restrictions to joint range of motion, lung function tests) that could be subsequently confused with chronic GVHD if not documented before HCT (Table 1 ) [33] . Post-transplant evaluation for possible chronic GVHD is standard of care in many centers starting around 100 days after HCT, recognizing that chronic GVHD is diagnosed earlier in 5% to 10% of patients [34] . Thereafter, clinical evaluation is required every 1 to 3 months to screen for signs and symptoms of active chronic GVHD until the patient has discontinued immunosuppressive therapy for at least 6 months [35, 36] . If abnormalities are detected, prompt referral to a specialized transplantation team for a detailed evaluation and therapy should be considered if the primary provider lacks expertise in diagnosing and managing chronic GVHD (Table 2) .

Empowering patients to actively participate in monitoring and reporting their symptoms can facilitate early diagnosis and help monitor treatment response with the potential for improved outcomes. In several other settings, frequent patient symptom reporting was effective in improving survival [37] and lowering hospital readmission rates [38] . For chronic GVHD and other post-HCT complications, research tools are being developed to determine whether patient education and recognition of sentinel symptoms could help guide appropriate patient reporting [39] [40] [41] [42] [43] [44] [45] . For now, patients should be encouraged to use available information platforms (Supplement 2) [46] , with particular attention to educating patients about the signs and symptoms of chronic GVHD around day 100 (D100) or when patients are discharged back to their referring physicians. Targeted outreach to patients from the transplant center at regular intervals should be considered as well. Future studies should evaluate the timing and content of educational tools as well as the value of self-monitoring in the post-HCT setting. Care should also be taken to ensure that patients do not feel overly responsible for monitoring themselves. Additionally, it is important to recognize that as many as 17% to 26% of adult long-term HCT survivors have possible or probable limited health literacy [47] , which could potentially impact compliance as well as the reliability of self-monitoring practices.

Telemedicine represents an attractive option for patients who have difficulty accessing chronic GVHD monitoring by their providers due to distance from the transplant center, limited resources, inconvenience, or restrictions on travel, such as in the COVID-19 pandemic [48] [49] [50] . The pandemic allowed very rapid advancement of telehealth capabilities, but issues that will need to be considered moving forward are the requirement for medical licensure where the patient resides, obtaining e-consent prior to the visit, variable coverage based on patient insurance and ability to collect copays for services rendered, and lack of access for some patients who do not have electronic devices or Internet. In addition, it will be important to ensure consistent provider-patient engagement, as inconsistent provider interactions may discourage patients from discussing new subtle signs or symptoms. Importantly, proper evaluation for chronic GVHD is incomplete without a thorough physical exam, which will be limited by the nature of the telemedicine platform that emphasizes the additional need for a qualified clinician to perform a clinical exam in collaboration with the transplant center as part of the telemedicine evaluation.

Better integration of the 2014 NIH diagnostic criteria into routine clinical practice at transplant centers as described above may allow for earlier recognition of chronic GVHD and implementation of effective interventions. However, our current diagnostic strategies have limitations, and even with early diagnosis per the 2014 criteria, outcomes might not be improved. Patients meeting current NIH diagnostic criteria have low rates of responding to current best available initial therapies, as demonstrated in a prospective observational study that enrolled patients within 3 months of chronic GVHD diagnosis. In this study, 91% of patients had moderate to severe chronic GVHD, and less than 20% had a complete or partial response without additional systemic therapy at 1 year [51] . Therefore, identification of early systemic or organ-specific features that are highly correlated with later development of moderate to severe disease should be a goal for the next 5 years. Successful identification of these features may offer an opportunity to explore the efficacy of very early or even preemptive therapy. If new technology proves useful for early diagnosis, it will have to be highly portable, not cost-prohibitive unless high value is demonstrated, and easily standardized across multiple centers; have high test-retest and intra-and interobserver reliability; require minimal training for operation; and provide easily interpretable data.

Development of prospective observational studies that monitor patients closely for the earliest changes associated with subsequent development of chronic GVHD is needed. Studies should enroll patients at the time of transplant or shortly after and follow them closely in order to detect early signs of disease before meeting current NIH diagnostic criteria. Patients will need to be followed for at least 1 to 2 years post-transplant in order to best correlate early findings with important late outcomes ( Figure 1 , Table 3 ). At least 2 current trials are attempting to identify diagnostic and prognostic signs of chronic GVHD, including both clinical characteristics and biomarkers, one in pediatric patients and one in adult patients (NCT04372524 and NCT04188912, respectively). More specifically, future research efforts should attempt to:

Validate that patient-reported symptoms can predate the development of current NIH diagnostic criteria and determine whether some of these symptoms are closely associated with later development of moderate or severe chronic GVHD. Assessment tools that capture common symptoms (pruritus, muscle cramps, etc.), such as the Lee Chronic GVHD Symptom Scale, already exist and would be easy to study [52, 53] . Additional common symptoms not currently captured should be explored as well. Deploying these tools via telemedicine, diaries, or electronically (eg, wearable technology) should be studied to enable future dissemination to patients who are not actively followed at a transplant center on a regular basis.

Describe the clinical evolution of chronic GVHD, including the emergence of diagnostic, distinctive, other or unclassified, and common features as previously published in the 2014 NIH Consensus Criteria on Diagnosis and Staging to understand their true prevalence and prognostic value [17] . These studies could also better document and follow less common manifestations, such as serositis, nephrotic syndrome, immune-mediated cytopenias, polymyositis, and peripheral neuropathy, and provide a framework to study hypothesized chronic GVHD target tissues such as the central nervous system and the endothelium.

Collect clinically characterized blood and tissue samples for both discovery and validation of risk assignment, predictive, prognostic, and diagnostic biomarkers [54] .

Application of machine learning (ML) could help identify risk factors or features or biomarker profiles that are highly associated with the development of chronic GVHD requiring systemic treatment. ML techniques have the advantage 

VA Author Manuscript of potentially identifying previously unknown associations that do not rely on a priori hypotheses based on currently known risk factors or patterns of disease. This approach has been applied to better identify survival patterns in patients with chronic GVHD based on multiple factors, including individual organ involvement and severity [55] . Future efforts using ML should focus on combining known risk factors, provisional early signs and symptoms of disease, biomarkers, patient-reported outcomes (PROs), and other data hypothesized to be associated with chronic GVHD or its outcome (eg, laboratory data, infectious history) to help identify patients at highest risk for morbidity and mortality (Table 3) . It is important to note the limitations to ML such as lack of standard ML techniques for challenges such as data quality issues and methods for integration of high-dimensional data [56] . A planned CIBMTR study will investigate patient-, disease-, and transplant-specific factors available within the CIBMTR database with predictive ML models to develop a prototype clinical decision support tool to help identify patients at high risk for developing acute and chronic GVHD (GV20-01) [57] .

Another strategy to facilitate earlier diagnosis of chronic GVHD focuses on specific organs associated with high morbidity or mortality: skin and fascia, eyes, and lungs. Our working group included disease experts in each of these areas to help develop both screening recommendations and potential research approaches. These experts have provided a recommended schedule for screening that at times would involve examinations by a subspecialist or specialized testing, such as pulmonary function tests (PFTs). It is acknowledged that these recommendations might not always be feasible outside of a clinical trial due to need for insurance coverage or proximity to appropriate providers and facilities. Additionally, these experts have also provided alternative screening recommendations with triggers signaling the need to involve subspecialists ( Table 2) .

Skin fibrosis and fasciitis affect up to 20% of patients with chronic GVHD and are associated with high morbidity, disability, and prolonged immunosuppression [58, 59] . New assessment techniques, including imaging and other biomarkers to diagnose prodromal or early sclerotic disease and reliably assess disease activity, are needed. Biomarkers based on skin biopsy materials could also be explored for their potential early diagnostic value for prodromal chronic GVHD in other organs.

A comprehensive skin evaluation at every clinic visit is essential, with special attention to palpation of anatomic sites with propensity for the development of sclerotic features, particularly the lower legs and sites of repetitive skin friction and injury such as the waist [60, 61] . The measurement of sclerotic skin and fascial disease is challenging, and no validated methods are available for precise quantification; thus, semiquantitative markers of severity, including skin 

Photographic range of motion (P-ROM) [62] has been refined [63] for response assessment of fasciitis and should be assessed at each clinic visit. Decreased range of motion in patients with chronic GVHD is usually related to deep sclerosis affecting the fasciae and may not be detectable by palpation. Arthralgias, arthritis, and prior injury can cause anatomic distortion, making the pre-HCT evaluation critical.

Biomarkers for patients at risk for or with early disease:

Systemic prognostic biomarkers: At present, no skin-specific chronic GVHD biomarkers have been identified, although elafin has previously been identified as a biomarker of cutaneous acute GVHD [64] . A proteomic analysis of patients with systemic sclerosis identified elevated levels of CXCL4 compared to other autoimmune diseases, and levels were associated with the presence of skin fibrosis and progression of disease [65, 66] . Therefore, serial and unbiased -omic analyses of HCT patients prior to the onset of chronic GVHD skin fibrosis or fasciitis may be able to identify similar high-risk biomarkers in our patient population.

Tissue specific: Skin is one of the most accessible organs from which to develop tissue-based chronic GVHD biomarkers, but such biomarkers are lacking. Novel immunohistochemistry markers, especially those studied in connective tissue diseases or acute GVHD [67, 68] , and other means of adding specificity should be explored. Despite the skin being readily accessible, multiple biopsies may be too invasive to serve as a source of serial biomarkers. Improvements in tissue microsampling may enable serial biomarker assessment in a minimally invasive manner [69, 70] . Studies should explore the use of multiplexed ion beam imaging based on time of flight that can detect in situ expression of up to 40 proteins in tissue samples [71] or other techniques that evaluate single-cell profiles together with noninvasive microscopic imaging technologies, such as bedside confocal microscopy [72, 73] and photoacoustic microscopy [74] .

Validation of early signs of disease:

Symptoms: Prodromal features suggestive of evolving chronic GVHD fibrosis include muscle cramping, edema [75] , new subcutaneous pain, and eosinophilia [58, 76] . These signs and symptoms should be assessed serially and prospectively to determine sensitivity and specificity for future development of sclerotic disease.

Diagnostic assessment: Early detection of subclinical sclerotic chronic GVHD remains an urgent need, and technologies such as magnetic resonance imaging (MRI) [77] , variants of ultrasound [78, 79] , and the Myoton device (Myoton AS, Tallinn, Estonia) [80, 81] are being studied.

Patient engagement: Self-assessment at regular intervals between clinic visits using the P-ROM scale could be performed and recorded in a logbook or app. The P-ROM scale has previously been reported as a sensitive marker of disease progression [62] , but its utility in early diagnosis is unknown, especially since joint limitation is a late sign. Similarly, app-based patient-reported symptom assessment (eg, leg swelling, loss of flexibility, skin tightness) could provide information that triggers prompt evaluation of new-onset fibrosis.

Ocular chronic GVHD can have a severe adverse impact on quality of life [82, 83] . Therefore, early diagnosis and targeted therapy for ocular chronic GVHD could have significant clinical benefits. Ocular chronic GVHD should not be viewed as a severe form of dry-eye disease but rather as a rapidly progressive immune-mediated inflammatory and destructive process of the eye, but clinical distinction between the two remains a challenge. Current diagnostic criteria, which require an exam by an eye care provider, are not designed to detect preclinical ocular chronic GVHD. One clinical trial demonstrated that patients had detectable exam changes as early as 14 to 28 days post-HCT that were associated with an increased risk of later ocular chronic GVHD, but these changes were not associated with patient-reported ocular symptoms at the time of assessment [84] . These findings suggest that evaluation by an ophthalmologist may be required to detect early preclinical signs of ocular chronic GVHD, regardless of patient-reported symptoms.

Comprehensive eye examination conducted by an eye care provider within a month prior to HCT or within 3 months afterward is necessary to identify baseline abnormal tissue function [85] (Table 4 ). During the same visit, patients should be educated about the incidence and potential serious sequelae of ocular GVHD and the warning signs such as dryness, light sensitivity, excessive tearing, foreign body sensation, pain, redness, swelling, mucoid aggregates, or change in vision.

Follow-up eye examination should be performed at the onset of any concerning eye symptoms post-HCT. Prompt referral to a specialist with experience in ocular GVHD is encouraged to confirm the diagnosis and begin treatment. Due to a high level of concern from ophthalmology experts that symptom onset may be too late in the disease course, an alternative strategy would include assessments by ophthalmology every 3 months during the first year post-transplant and at longer intervals afterward. This recommendation requires access to ophthalmology care that may impose a burden on patients due to travel or cost. Future longitudinal chronic GVHD studies are strongly encouraged to investigate whether regularly scheduled ophthalmology care post-HCT is feasible, results in earlier diagnosis, and is associated with improved clinical outcomes.

Biomarkers for subclinical/early disease:

Tissue specific: Validated biomarkers for imminent ocular GVHD are needed using tears or impression cytology. Tear fluid osmolarity change does not differentiate ocular GVHD from other ocular surface diseases [86, 87] . However, IL-6, IL-8, lactoferrin, and other neutrophil-related biomarkers may be useful [88] [89] [90] . EGFR, IL-1Ra, and fractalkine measured at time of HCT are associated with future development of ocular GVHD [91, 92] . Noninvasive imaging such as optical coherence tomography [93] or confocal microscopy [94] [95] [96] [97] are also being studied.

Validation of early clinical signs of disease:

Symptoms: An ocular GVHD-specific and validated questionnaire for early symptoms should be developed. Current instruments such as the modified Ocular Surface Disease Index [98] and Change in Dry Eye Symptoms-Questionnaire [99] emphasize late symptoms. In patients with established chronic GVHD, the patient-reported version of the NIH eye score and the 3 eye-specific questions of the Lee Chronic GVHD Symptom Scale were both strongly correlated with eye involvement [100] . Whether earlier utilization of the PROs would result in earlier referral to ophthalmology and diagnosis is not known but should be studied.

Serial exams: Early signs of ocular chronic GVHD may include changes in the eyelid margin, new conjunctival subepithelial fibrosis if present under the upper or lower palpebral conjunctiva, and hypervascularity and punctate staining of the superior bulbar conjunctiva and punctate staining of the superior cornea. The timing of these findings and their association with ocular chronic GVHD should be studied through frequent evaluations by an ophthalmologist to define the evolution of the disease.

Bronchiolitis obliterans syndrome (BOS) is the primary diagnostic manifestation of pulmonary chronic GVHD. The 2014 NIH chronic GVHD diagnostic criteria for BOS emphasize the presence of new-onset airflow obstruction on PFTs, plus supportive clinical and radiographic features [17] . When the NIH criteria are strictly applied, many patients already have severe obstructive lung disease, missing an opportunity for early recognition of the disorder. At present, the diagnostic workup for BOS is often initiated based on symptoms, at which time, the forced expiratory volume in 1 second (FEV 1 ) may already be 30% to 50% of predicted normal values [101, 102] . A randomized double-blind study of patients with newly diagnosed BOS (respiratory symptoms for <6 months) showed that patients receiving inhaled budesonide/formoterol had a statistically significant increase in FEV 1 after 1 month of therapy, and the improvement was maintained after 6 months of therapy [103] , supporting the concept that earlier recognition of disease and intervention may improve outcomes.

Earlier recognition of BOS requires routine screening of asymptomatic patients to detect a decline in lung function. The threshold of FEV 1 <75% predicted as a criterion for significant airflow decline misleadingly implies that BOS is a binary condition present only when lung function is clearly below normal limits. The requirement for an FEV 1 /forced vital capacity (FVC) (or slow vital capacity if it is greater) ratio less than 0.70 or the fifth percentile of predicted (the lower limit of the 90% confidence interval) in children could also result in missed diagnoses. In patients with BOS, it is not uncommon for the FVC to decline concurrently with a decline in FEV 1 , resulting in an FEV 1 /FVC ratio greater than 0.7. This would imply that a mixed restrictive/obstructive lung process may be present [104] [105] [106] .

The criteria for BOS in the 2014 NIH guidelines provide other diagnostic challenges. The diagnostic requirement for "absence of infection in the respiratory tract" does not account for the clear association between respiratory viral infections and chronic GVHD of the lung [107] [108] [109] [110] and can falsely reassure clinicians that declines in lung function are reversible and solely linked to an infectious event. Newer molecular methods of testing for viruses may detect nucleic acid remnants for months after initial infection, further complicating the application of current NIH-defined criteria. In addition, spirometric-based criteria cannot be used in children less than 6 to 8 years of age due to the inherent difficulties of performing PFTs in this age group.

Routine PFTs for all HCT recipients (even asymptomatic) should be performed pretransplant and then every 3 months for at least 1 year after HCT. Full PFTs, which include spirometry, lung volumes, and diffusing capacity of carbon monoxide, should be obtained when feasible at preHCT baseline, D100, and 1 year. Limited spirometry can be substituted for full PFTs at 6 and 9 months post-HCT. For patients with newly diagnosed chronic GVHD, it is recommended that spirometry be obtained every 3 months [33, 111] . Alternative approaches to lung function are needed for evaluation of younger patients unable to perform PFTs to provide equivalent screening functionality.

Patients with documented respiratory viral infections and concomitant FEV 1 decline should be considered high risk for BOS and followed with serial PFTs (or spirometry) at short time intervals.

Asymptomatic decline in FEV 1 may be indicative of early BOS or other pulmonary disease. A decline in FEV 1 of 10% from preHCT baseline, or the immediate prior spirometry, in an asymptomatic patient should be followed up clinically with close interval spirometry or further workup. In lung allograft 

VA Author Manuscript VA Author Manuscript recipients, changes in absolute values (in liters) for FEV 1 have been followed and are associated with the development of BOS and poor outcomes [112, 113] .

Identification and validation of biomarkers:

Systemic: Aberrant populations of circulating B cell pre-cursors and dysregulation of B cell homeostasis have been seen in BOS [114] . Potential cytokine and cellular injury markers such as endothelial markers, extracellular matrix proteins, and lung surfactant/lung proteins have all been reported [115] [116] [117] [118] . Replication and validation studies should be performed.

Tissue specific: Novel radiographic techniques, including parametric response mapping and hyperpolarized Xenon-129 MRI, should be tested for their ability to distinguish BOS from other pulmonary conditions [119] [120] [121] .

Validation of early clinical signs of disease:

Diagnostic assessments:

Define a "pre-BOS" stage that identifies airflow obstruction in patients prior to the development of clinical symptoms. BOS-0p is spirometric-based parameter that has been used in lung allograft recipients to identify patients at high risk of developing BOS [122, 123] . In HCT recipients, application of similar spirometric criteria that includes a 10% decline in FEV 1 and/or a 25% decline in FEF 25-75% compared to pre-HCT baseline has been shown to be sensitive for the prediction of BOS (85%) with a high negative predictive value (98%) [124] . FEF 25-75% measures airflow in distal small airways and has known utility as an early marker of airflow obstruction following lung transplantation [125] [126] [127] . Early post-transplant declines in FEF 25-75% are strongly associated with the development of BOS after HCT and may be more important than FEV 1 ; therefore, both should be monitored and compared when developing an early diagnostic strategy [128, 129] .

The clinical evolution of BOS after HCT needs to be defined. The trajectory of decline of FEV 1 (ie, rate of change) in patients is heterogeneous, and the optimal testing interval for detection of subclinical changes, and in which high-risk patients, remains to be determined. It is clear that early diagnosis of BOS is more likely with a routine monitoring strategy than with a symptombased testing approach [130] . Yet, frequent monitoring may be physically and economically challenging, particularly for children and patients living far from a PFT laboratory. Home spirometry with portable handheld devices is feasible in HCT recipients and can be coupled with Cloud-based telemonitoring solutions [131, 132] to solve the practical concern of frequent spirometric monitoring of high-risk individuals [133] . 

VA Author Manuscript

Studies are needed to clarify the role of respiratory infections in the development of BOS and to update their consideration in BOS diagnostic criteria. Several studies have shown an increased risk of pulmonary impairment following respiratory viral infections and an associated increased risk of non-relapse mortality [107, 108, 110] . Currently, the diagnosis of BOS requires absence of infection in the respiratory tract documented with clinical investigations, including microbiologic testing, but patients with chronic GVHD often have persistent viral shedding and frequent recurrent infections. Therefore, some modification or clarification to the diagnostic criteria should be explored to allow for the diagnosis of BOS in patients who have a persistent decline in FEV 1 and a persistent respiratory pathogen.

Alternatives to PFTs in children are needed. Noninvasive pulmonary testing that is safe, feasible, and reproducible in children, such as the nitrogen multiple breath washout test that measures ventilation inhomogeneity as a measure of airway obstruction, has been successfully applied to infants with cystic fibrosis [134] and in children with early airway pathology following lung transplant [135] . This test is highly sensitive for detecting early lung chronic GVHD in adults after HCT [136] . Other approaches such as high-resolution computed tomography or Xenon MRI also need to be explored.

Redefining how we recognize chronic GVHD earlier in its clinical evolution will be a major undertaking but has the potential to improve outcomes for patients given the limitations of our current diagnostic criteria, particularly the concern of irreversible organ damage prior to meeting the current criteria. Validation of earlier prediagnostic signs and symptoms should enable the development of pre-emptive intervention strategies with the goal of preventing much of the morbidity and mortality that patients with moderate to severe chronic GVHD currently face. Discovery and validation of early features of chronic GVHD will involve patients and caregivers, transplant providers, and our subspecialty colleagues. Longitudinal studies should enroll patients before chronic GVHD has developed. These observational studies should include serial sample collections, including blood and tissue, for biomarker assessments, patient involvement to assess symptom burden, the use of handheld spirometry, and standardized documentation of physical exam findings, recognizing that screening tests may have variable performance in different populations. These studies should begin during the next 3 years because they will take years to yield definitive data. Diagnosis of ocular and genital involvement is a particular challenge because current diagnostic criteria require assessment by a subspecialist. Engagement with these subspecialists will be essential to help develop early assessment tools and patient symptom measures that could be used to prompt early referral for specialty evaluation. In the next 3 to 7 years, the ability to recognize subclinical chronic GVHD will allow studies of interventions targeted to underlying pathophysiology and delivered preemptively to test whether this approach leads to better transplant outcomes with less chronic GVHD morbidity and no increase in underlying risks of disease relapse or infectious complications. These approaches would be greatly facilitated by development of validated biomarker-based risk assignment strategies. Design of studies to improve early chronic GVHD diagnosis. Studies may be designed to detect any manifestation of chronic GVHD or focus on specific organs that require subspecialty involvement, such as ocular or genital involvement. Patients should be enrolled prior to or shortly after HCT and followed serially every 2 to 3 months for clinical assessments and data collection. year, and yearly. Spirometry is recommended at 6 and 9 months post-HCT, and every 3 months in patients with chronic GVHD. Lung volumes and DLCO can be performed more frequently if clinically indicated.

Decline in the FEV 1 of 10% or greater from the patient's baseline or D100 assessment; recommend short interval repeat testing (within 2-4 weeks)

Obtain bilirubin, AST, ALT, alkaline phosphatase Rise of bilirubin or liver enzymes above 2014 NIH consensus conference thresholds Gastrointestinal tract Assess for nausea, anorexia, dysphagia, diarrhea, or weight loss New onset of signs/symptoms suggestive for chronic GVHD per 2014 NIH consensus conference guidelines Fascia/joint Conduct functional and P-ROM assessment; for the pediatric adaption of P-ROM, see EBMT handbook/ chronic GVHD [32] .

In clinical trials, a 2-point difference in total P-ROM is considered clinically relevant [63] , but as a screening measure, any change from baseline, even by 1 point, may be significant.

Evaluate for any evidence of lichen-planus-like lesions, erythema, ulcers, fibrosis, or phimosis in males (ideally women would be evaluated by a gynecologist). Ask about any change in appearance, pain, or dryness. 

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Employment, insurance, and financial experiences of patients with chronic graft-versus-host disease in North America

Patient-reported outcomes and health status associated with chronic graft-versus-host disease

Comparison of patient-reported outcomes in 5-year survivors who received bone marrow vs peripheral blood unrelated donor transplantation: long-term followup of a randomized clinical trial

National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report

Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria Working Group report

National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 Diagnosis and Staging Working Group report

Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group report

Validation of National Institutes of Health global scoring system for chronic graft-versus-host disease (GVHD) according to overall and GVHD-specific survival

Impact of the 2014 NIH chronic graft-versus-host disease scoring criteria modifications assessed in a large cohort of severely affected patients

Classification systems for chronic graft-versus-host disease

Ibrutinib for chronic graft-versus-host disease after failure of prior therapy

The eGVHD App has the potential to improve the accuracy of graft-versus-host disease assessment: a multicenter randomized controlled trial

A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801

Development, preliminary usability and accuracy testing of the EBMT 'eGVHD App' to support GvHD assessment according to NIH criteria-a proof of concept

Accuracy and usability of the eGVHD app in assessing the severity of graft-versus-host disease at the 2017 EBMT annual congress

Uptake and use of recommendations for the diagnosis, severity scoring and management of chronic GVHD: an international survey of the EBMT-NCI Chronic GVHD Task Force

A multicenter pilot evaluation of the National Institutes of Health chronic graft-versus-host disease (cGVHD) therapeutic response measures: feasibility, interrater reliability, and minimum detectable change

The future of chronic graft-versus-host disease: introduction to the 2020 National Institutes of Health Consensus Development Project Reports

Benefits and challenges with diagnosing chronic and late acute GVHD in children using the NIH consensus criteria

The biology of chronic graft-versus-host disease: a task force report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease

The EBMT Handbook: Hematopoietic Stem Cell Transplantation and Cellular Therapies

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease

Ancillary Therapy and Supportive Care Working Group Report

Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria

Success of immunosuppressive treatments in patients with chronic graft-versus-host disease

EBMT-NIH-CIBMTR Task Force position statement on standardized terminology & guidance for graft-versus-host disease assessment

Two-year survival comparing web-based symptom monitoring vs routine surveillance following treatment for lung cancer

A complex health services intervention to improve medical care in long-term care homes: study protocol of the controlled coordinated medical care (CoCare) study.BMC

Patient interest in and feasibility of a mobile health app to support patients undergoing hematopoietic stem cell transplantation

Clinicians and patients perspectives on follow-up care and eHealth support after allogeneic hematopoietic stem cell transplantation: a mixed-methods contextual analysis as part of the SMILe study

Impact of a health information technology tool addressing information needs of caregivers of adult and pediatric hematopoietic stem cell transplantation patients

Pilot randomized trial of an electronic symptom monitoring and reporting intervention for hospitalized adults undergoing hematopoietic stem cell transplantation

Engagement with INSPIRE, an online program for hematopoietic cell transplantation survivors

Cytokine mediators of chronic graft-versus-host disease

Development and evaluation of a specifically designed website for haematopoietic stem cell transplant patients in Leeds

A conceptual framework and key research questions in educational needs of blood and marrow transplantation patients, caregivers, and families

Randomized controlled trial of individualized treatment summary and survivorship care plans for hematopoietic cell transplantation survivors

Providing access to oncology care for rural patients via telemedicine

Telemedicine in cancer care

Telemedicine for cancer patients during COVID-19 pandemic: between threats and opportunities

An endpoint associated with clinical benefit after initial treatment of chronic graft-versus-host disease

Development and validation of a scale to measure symptoms of chronic graft-versus-host disease

Systematic review of patient-reported outcome measures in graft-versus-host disease

NLM Citation: FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource

Food and Drug Administration (US)

Machine learning reveals chronic graft-versus-host disease phenotypes and stratifies survival after stem cell transplant for hematologic malignancies

A systematic review of machine learning techniques in hematopoietic stem cell transplantation (HSCT)

Committee CG. 2020 Working Committee Meetings Materials

Incidence, risk factors, and outcomes of sclerosis in patients with chronic graft-versus-host disease

A call for more dermatologic input into chronic graft-vs-host disease clinical trials

The isomorphic response in morphealike chronic graft-vs-host disease

The anatomic distribution of skin involvement in patients with incident chronic graft-versus-host disease

Assessment of joint and fascia manifestations in chronic graft-versus-host disease

Refined National Institutes of Health response algorithm for chronic graft-versus-host disease in joints and fascia

Elafin is a biomarker of graft-versus-host disease of the skin

Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis

A proteome-derived longitudinal pharmacodynamic biomarker for diffuse systemic sclerosis skin

Acute cutaneous graft-vs.-host disease compared to drug hypersensitivity reaction with vacuolar interface changes: a blinded study of microscopic and immunohistochemical features

CD47 prevents the elimination of diseased fibroblasts in scleroderma

Mechanisms of sampling interstitial fluid from skin using a microneedle patch

A review of microsampling techniques and their social impact

A structured tumor-immune microenvironment in triple negative breast cancer revealed by multiplexed ion beam imaging

Features of cutaneous acute graft-versus-host disease by reflectance confocal microscopy

Optical coherence tomography for quantifying human cutaneous chronic graft-versus-host disease

Innovations and developments in dermatologic non-invasive optical imaging and potential clinical applications

Localized edema with sclerodermatous evolution: a possible form of skin chronic graft-versus-host disease associated with endothelial activation

Nail dystrophy, edema, and eosinophilia: harbingers of severe chronic GVHD of the skin in children

Magnetic resonance imaging in sclerotic-type chronic graft-vshost disease

Preliminary results on the feasibility of using ARFI/SWEI to assess cutaneous sclerotic diseases

Quantifying skin stiffness in graft-versus-host disease, morphea, and systemic sclerosis using acoustic radiation force impulse imaging and shear wave elastography

Noninvasive measurement of sclerosis in cutaneous cGVHD patients with the handheld device Myoton: a cross-sectional study

Longitudinal tracking of skin dynamic stiffness to quantify evolution of sclerosis in chronic graft-versus-host disease

Impact of ocular chronic graft-versus-host disease on quality of life

Vision-related quality of life in patients with ocular graft-versus-host disease

Adverse environmental conditions are a risk factor for ocular GvHD after allogeneic hematopoietic stem cell transplantation

Dry eye after haematopoietic stem cell transplantation

Tear osmolarity in ocular graftversus-host disease

Correlation between tear film osmolarity and the disease score of the International Chronic Ocular Graft-Versus-Host-Disease Consensus Group in hematopoietic stem cell transplantation patients

Neutrophil extracellular traps (NETs) contribute to pathological changes of ocular graft-vs.-host disease (oGVHD) dry eye: implications for novel biomarkers and therapeutic strategies

Pathological consequences of anti-citrullinated protein antibodies in tear fluid and therapeutic potential of pooled human immune globulin-eye drops in dry eye disease

A novel and innovative paper-based analytical device for assessing tear lactoferrin of dry eye patients

Biomarkers in ocular chronic graft versus host disease: tear cytokine-and chemokine-based predictive model

Prehematopoietic stem cell transplantation tear cytokines as potential susceptibility biomarkers for ocular chronic graft-versus-host disease

Corneal higher-order aberrations in eyes with chronic ocular graft-versus-host disease

Morphologic evaluation of meibomian glands in chronic graft-versus-host disease using in vivo laser confocal microscopy

In vivo confocal microscopy evaluation of ocular surface with graft-versus-host disease-related dry eye disease

In vivo confocal microscopic characterisation of the cornea in chronic graft-versus-host disease related severe dry eye disease

Correlation between corneal innervation and inflammation evaluated with confocal microscopy and symptomatology in patients with dry eye syndromes: a preliminary study

Reliability and validity of the Ocular Surface Disease Index

Development of a questionnaire for detecting changes in dry eye disease-related symptoms

Predictive models for ocular chronic graftversus-host disease diagnosis and disease activity in transplant clinical practice

Prognostic role of FEV1 for survival in bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation

Lung function trajectory in bronchiolitis obliterans syndrome after allogeneic hematopoietic cell transplant

Budesonide/formoterol for bronchiolitis obliterans after hematopoietic stem cell transplantation

Interpretative strategies for lung function tests

Bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation

Bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: phenotypes and prognosis

Pulmonary impairment after respiratory viral infections is associated with high mortality in allogeneic hematopoietic cell transplant recipients

Strong association between respiratory viral infection early after hematopoietic stem cell transplantation and the development of life-threatening acute and chronic alloimmune lung syndromes

Infection with a respiratory virus before hematopoietic cell transplantation is associated with alloimmune-mediated lung syndromes

Airflow decline after myeloablative allogeneic hematopoietic cell transplantation: the role of community respiratory viruses

Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation

Bronchiolitis obliterans syndrome 2001:an update of the diagnostic criteria

An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome

CD19(+)CD21(low) B cells and patients at risk for NIH-defined chronic graft-versus-host disease with bronchiolitis obliterans syndrome

Prognostic value of serum surfactant protein D level prior to transplant for the development of bronchiolitis obliterans syndrome and idiopathic pneumonia syndrome following allogeneic hematopoietic stem cell transplantation

Decreased serum levels of clara cell secretory protein (CC16) are associated with bronchiolitis obliterans and may permit early diagnosis in patients after allogeneic stem-cell transplantation

Serum Krebs Von Den Lungen-6 as a biomarker for early detection of bronchiolitis obliterans syndrome in children undergoing allogeneic stem cell transplantation

Soluble tumor necrosis factor receptor: enbrel (etanercept) for subacute pulmonary dysfunction following allogeneic stem cell transplantation

Multicenter evaluation of parametric response mapping as an indicator of bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation

Parametric response mapping as an indicator of bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation

Xenon-129 MRI detects ventilation deficits in paediatric stem cell transplant patients unable to perform spirometry

Prognostic value of bronchiolitis obliterans syndrome stage 0-p in single-lung transplant recipients

The predictive value of bronchiolitis obliterans syndrome stage 0-p

Predictive value of bronchiolitis obliterans syndrome stage 0p in chronic graft-versus-host disease of the lung

Decline in 25% to 75%forced expiratory flow as an early predictor of chronic airway rejection in pediatric lung transplant recipients

Physiologic definitions of obliterative bronchiolitis in heart-lung and double lung transplantation: a comparison of the forced expiratory flow between 25%and 75%of the forced vital capacity and forced expiratory volume in one second

Bronchiolitis obliterans syndrome: utility of the new guidelines in single lung transplant recipients

Early post-transplantation spirometry is associated with the development of bronchiolitis obliterans syndrome after allogeneic hematopoietic cell transplantation

Noninfectious lung complications after allogeneic haematopoietic stem cell transplantation

Spirometry states the obvious: recognizing bronchiolitis obliterans syndrome early after hematopoietic cell transplantation

Correlation and agreement of handheld spirometry with laboratory spirometry in allogeneic hematopoietic cell transplant recipients

Telemetric monitoring of pulmonary function after allogeneic hematopoietic stem cell transplantation

Feasibility and reliability of home-based spirometry telemonitoring in allogeneic hematopoietic cell transplant recipients

Nitrogen multiple breath washout test for infants with cysticfibrosis

Multiple breath washout in pediatric patients after lung transplantation

Inert gas washout in bronchiolitis obliterans following hematopoietic cell transplantation

Home spirometry telemonitoring for early detection of bronchiolitis obliterans syndrome in patients with chronic graft-versus-host disease