Lana Grković

Clinical laboratory markers of inflammation as determinants of chronic graft-versus-host disease activity and NIH global severity

Chronic graft-versus-host disease (cGVHD) remains a major cause of non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Currently there are no accepted measures of cGVHD activity to aid in clinical management and disease staging. We analyzed clinical markers of inflammation in the sera of patients with established cGVHD and correlated those with definitions of disease activity. In all, 189 adults with cGVHD (33% moderate and 66% severe according to National Institutes of Health (NIH) global scoring) were consecutively enrolled onto a cross-sectional prospective cGVHD natural history study. At the time of evaluation, 80% were receiving systemic immunosuppression and failed a median of four prior systemic therapies (PST) for their cGVHD. Lower albumin (P<0.0001), higher C-reactive protein (P=0.043), higher platelets (P=0.030) and higher number of PST (P<0.0001) were associated with active disease defined as clinicians intention to intensify or alter systemic therapy due to the lack of response. Higher platelet count (P=0.021) and higher number of PST (P<0.0001) were associated with more severe diseased defined by NIH global score. This study identified common laboratory indicators of inflammation that can serve as markers of cGVHD activity and severity.

Malnutrition in patients with chronic GVHD.

Malnutrition is a known complication of chronic GVHD (cGVHD), but has not been well described in the context of organ-specific manifestations and the recent National Institutes of Health (NIH) criteria. Here, 210 cGVHD patients were analyzed, in a cross-sectional study design, for demographics, transplant-related history, clinical assessments, symptoms, function, quality-of-life, laboratory values and survival in order to determine their associations with nutritional status. Most patients had long-standing, moderate or severe cGVHD and had failed many lines of therapy. Twenty-nine percent (60/210) of subjects were malnourished, using the subjective Patient-Generated Subjective Global Assessment (PG-SGA) questionnaire and evaluation. No demographic or transplant characteristics were associated with malnutrition; cGVHD of the lungs, gastrointestinal (GI) tract and mouth, NIH global score, cGVHD symptoms, worse functioning, low albumin, poorer survival and low BMI were associated with malnutrition. A predictive model was developed from all variables of significance: cGVHD of the lungs, GI tract, mouth and BMI accurately predicted 84.2% of malnourished patients as well as 87.2% of well-nourished patients. The PG-SGA questionnaire may be a useful tool in diagnosing nutritional deficits in cGVHD patients undergoing one-time evaluations. Longitudinal prospective studies should assess the utility of nutritional support interventions in cGVHD.

Validation of the National Institutes of Health chronic GVHD Oral Mucosal Score using component-specific measures

Oral chronic GVHD (cGVHD) is a common, late complication of alloSCT that is associated with significant patient morbidity. The NIH Oral Mucosal Score (NIH OMS) was developed to assess oral cGVHD therapeutic response, but has not been fully validated. This study’s purpose was to conduct a rigorous construct validity and internal consistency analysis of this score and its components (erythema, lichenoid, ulcers, mucoceles) using established measures of oral pain, oral function, oral-related quality-of-life, nutrition and laboratory parameters in 198 patients with cGVHD. The construct validity of the NIH OMS was supported: a moderate correlation was observed between NIH OMS and mouth pain (rho=0.43), while a weaker correlation was observed with low albumin (rho=−0.26). Total NIH OMS, erythema and lichenoid components were associated with malnutrition, oral pain and impaired oral QOL, while ulcers were only associated with oral pain. No associations were found between mucoceles and any indicator evaluated, including salivary function or xerostomia. Kappa determined between scale components was low overall (all ⩽0.35), supporting a conclusion that each component measures a distinct manifestation of oral cGVHD. This study supports the use of the NIH OMS and its components (erythema, lichenoid and ulcerations) to measure clinician-reported severity of oral cGVHD.

NIH response criteria measures are associated with important parameters of disease severity in patients with chronic GVHD

Lack of standardized criteria measuring therapeutic response remains an obstacle to the development of better treatments for chronic GVHD (cGVHD). This cross-sectional prospective study examined the concurrent and predictive validity of 18 clinician-reported (‘Form A’) and 8 patient-reported (‘Form B’) response measures proposed by NIH criteria. Concurrent parameters of interest were NIH global score, cGVHD activity, Lee symptom score and SF36 PCS. Patient cohort included 193 adults with moderate-to-severe cGVHD. Measures associated with the highest number of outcomes were lung function score (LFS), 2-min walk, grip strength, 4-point health-care provider (HCP) and patient global scores, 11-point clinician- and patient-reported global symptom severity scores, and Karnofsky performance score (KPS). Measures associated with survival in univariate analyses led to a Cox model containing skin erythema, LFS, KPS, eosinophil count and interval from cGVHD diagnosis to enrollment as jointly associated with survival. In conclusion, 4-point HCP and patient global scores and 11-point clinician- and patient-reported global symptom severity scores are associated with the majority of concurrent outcomes. Skin erythema is a potentially reversible sign of cGVHD that is associated with survival. These results define a subset of measures that should be prioritized for evaluation in future studies.

NHANES III equations enhance early detection and mortality prediction of bronchiolitis obliterans syndrome after hematopoietic SCT

Bronchiolitis obliterans syndrome (BOS) is a serious complication of chronic GVHD (cGVHD) following HSCT (hematopoietic SCT). The clinical diagnosis of BOS is based on pulmonary function test (PFT) abnormalities including: FEV1<75% predicted and obstructive FEV1/VC ratio, calculated using reference equations. We sought to determine if the frequency of clinical diagnoses and severity of BOS would be altered by using the recommended NHANES III vs older equations (Morris/Goldman/Bates, MGB) in 166 cGVHD patients, median age 48 (range: 12–67). We found that NHANES III equations significantly increased the prevalence of BOS, with an additional 11% (18/166) meeting diagnostic criteria by revealing low FEV1 (<75%) (P<0.0001), and six additional patients by obstructive ratio (vs MBG). Collectively, this led to an increase of BOS incidence from 17 (29/166) to 29% (41/166). For patients with severe BOS, (FEV1<35%), NHANES III equations correctly predicted death 71.4% vs 50% using MGB. In conclusion, the use of NHANES III equations markedly increases the proportion of cases meeting diagnostic criteria for BOS and improves prediction of survival.