The prevalence of anxiety disorders in dermatology outpatients: A systematic review and meta-analysis.

Anxiety is common in those with medical conditions and has significant impacts on mental well-being as well as physical health outcomes. While several systematic reviews have examined the prevalence of anxiety in specific dermatological conditions, no reviews have examined the prevalence across the entire dermatology outpatient setting. This systematic review aims to provide an overview to dermatologists of the prevalence of, and trends in, anxiety in their outpatient clinics. As such, prevalence of anxiety in dermatology outpatient clinics was examined, and variations across type of anxiety and dermatological conditions were assessed. A search of PubMed, Embase, Cochrane and PsycINFO was conducted for studies that assessed anxiety prevalence in dermatology outpatients, with the last search conducted on 7 September 2022. Results underwent title/abstract and full-text screening, followed by data extraction. Studies of patients 16 years and older and representative of dermatology clinics were included. Risk of bias was assessed using Joanna Briggs Institute Critical Appraisal Checklist. Meta-analysis was conducted using CMA software, and subgroup analysis was conducted on relevant variables. 5423 studies were identified, and 32 included, with a total n = 12,812 participants. Under the random effects model, prevalence was estimated at 26.7% (95%CI 22.4-31.4; 95%PI 9.7-55.4). Subgroup analysis revealed a higher prevalence among studies of psoriasis patients than general dermatology studies. Estimates of prevalence were higher when assessed via self-report screening than diagnostic interview. Anxiety occurred frequently among dermatology outpatients, especially psoriasis outpatients, at a higher rate than common estimates of prevalence in the general population. Given the effect of anxiety on patient outcomes and well-being, dermatologists are encouraged to consider how anxiety may impact patients in their clinic, and how they can best identify patients with anxiety and subsequently support them.

Marrow grafts from HLA-identical siblings for severe aplastic anemia: does limiting the number of transplanted marrow cells reduce the risk of chronic GvHD?

A total of 21 patients with severe aplastic anemia (SAA) underwent marrow transplantation from HLA-identical siblings following a standard conditioning regimen with cyclophosphamide (50 mg/kg/day × 4 days) and horse antithymocyte globulin (30 mg/kg/day × 3 days). Post-grafting immunosuppression consisted of a short course of methotrexate (MTX) combined with cyclosporine (CSP). The transplant protocol tested the hypothesis that the incidence of chronic GvHD could be reduced by limiting the marrow grafts to ⩽2.5 × 108 nucleated marrow cells/kg. None of the patients rejected the graft, all had sustained engraftment and all are surviving at a median of 4 (range 1-8) years after transplantation. Chronic GvHD developed in 16% of patients given ⩽2.5 × 108 nucleated marrow cells/kg. Post-grafting immunosuppression has been discontinued in 20 of the 21 patients. In conclusion, limiting the number of transplanted marrow cells may have resulted in minimal improvement in the incidence and severity of chronic GvHD.

Confounding factors affecting the National Institutes of Health (NIH) chronic Graft-Versus-Host Disease Organ-Specific Score and global severity.

The 2005 NIH chronic GVHD (cGVHD) organ severity is based on the assessment of current status regardless of whether abnormalities are due to GVHD. The score assignment does not require knowledge of past manifestations, attribution or whether cGVHD is still active. The aim of this study is to describe confounding factors affecting organ scores in patients with cGVHD. The study included 189 consecutive cGVHD patients evaluated at our center in 2013. Providers completed the NIH 0-3 organ-specific scoring evaluation with two questions added for each organ to identify abnormalities that were (i) not attributed to cGVHD or (ii) attributed to cGVHD plus other causes. Abnormalities attributed to causes other than GVHD were recorded. Eighty (14%) abnormalities were not attributed to cGVHD in at least one organ, and 41 (7%) abnormalities were attributed to cGVHD plus other causes in at least one organ. A total of 436 (78%) abnormalities were attributed only to cGVHD. Abnormalities not attributed to cGVHD were observed most frequently in the lung, gastrointestinal tract and skin. Most common abnormalities included pre-transplant condition, sequelae from GVHD, deconditioning, infections and medications. Our results support the 2014 NIH consensus recommendation to consider attribution when scoring organ abnormalities.

The association between donor and recipient statin use and infections after allogeneic hematopoietic cell transplantation.

Recent studies have reported that statin use may be associated with improved outcomes in patients with sepsis or respiratory viral infections. In the setting of allogeneic hematopoietic cell transplantation (HCT), it has been shown that donor and recipient statin use is associated with reduced risks of GVHD. We assessed in retrospective analysis whether donor or recipient statin use impacts infection risk after allogeneic HCT (n=1191). Although recipient statin use was associated with the increased incidence of Gram-negative bacteremia (adjusted hazard ratio (aHR) 2.22, (95% confidence interval (CI) 1.2-4.2), P=0.01) without affecting mortality, donor statin use was associated with an increased incidence of respiratory viral infections in recipients (aHR 2.84 (95% CI 1.3-6.0), P=0.007). The overall incidence of invasive fungal infections and CMV reactivation and CMV disease were not impacted by recipient or donor statin use. In conclusion, this study suggests that recipient or donor statin use may be associated with an increased incidence of some infections without adversely affecting mortality.

Comparison of minimal residual disease as outcome predictor for AML patients in first complete remission undergoing myeloablative or nonmyeloablative allogeneic hematopoietic cell transplantation.

Minimal residual disease (MRD) is associated with adverse outcome in acute myeloid leukemia (AML) after myeloablative (MA) hematopoietic cell transplantation (HCT). We compared this association with that seen after nonmyeloablative (NMA) conditioning in 241 adults receiving NMA (n=86) or MA (n=155) HCT for AML in first remission with pre-HCT bone marrow aspirates assessed by flow cytometry. NMA patients were older and had more comorbidities and secondary leukemias. Three-year relapse estimates were 28% and 57% for MRD(neg) and MRD(pos) NMA patients, and 22% and 63% for MA patients. Three-year overall survival (OS) estimates were 48% and 41% for MRD(neg) and MRD(pos) NMA patients and 76% and 25% for MA patients. This similar OS after NMA conditioning was largely accounted for by higher non-relapse mortality (NRM) in MRD(neg) (30%) compared with MRD(pos) (10%) patients, whereas the reverse was found for MRD(neg) (7%) and MRD(pos) (23%) MA patients. A statistically significant difference between MA and NMA patients in the association of MRD with OS (P<0.001) and NRM (P=0.002) but not relapse (P=0.17) was confirmed. After adjustment, the risk of relapse was 4.51 times (P<0.001) higher for MRD(pos) patients. These data indicate that the negative impact of MRD on relapse risk is similar after NMA and MA conditioning.

Prognostic factors and outcomes of severe gastrointestinal GVHD after allogeneic hematopoietic cell transplantation.

We hypothesized that clinical risk factors could be identified within 2 weeks of onset of severe (stage 3 or 4) acute gut GVHD for identifying a patient population with a very poor outcome. Among 1462 patients who had allogeneic hematopoietic cell transplantation (HCT) between January 2000 and December 2005, 116 (7.9%) developed stage 3-4 gut GVHD. The median time for onset of stage 3-4 gut GVHD was 35 (4-135) days after allogeneic HCT. Eighty-five of the 116 patients (73%) had corticosteroid resistance before or within 2 weeks after the onset of stage 3-4 gut GVHD. Significant risk factors for mortality included corticosteroid resistance (hazards ratio (HR)=2.93; P=0.0005), age >18 years (HR=4.95; P=0.0004), increased serum bilirubin (HR 2.53; P=0.0001) and overt gastrointestinal bleeding (HR 2.88; P=0.0004). Among patients with stage 3-4 gut GVHD, the subgroup with 0, 1 or 2 risk factors had a favorable prognosis, whereas the subgroup with 3 or 4 risk factors had a dismal prognosis. This information should be considered in designing future studies of severe gut GVHD and in counseling patients about prognosis.

Comorbidity burden in patients with chronic GVHD.

Chronic GVHD (cGVHD) is associated with mortality, disability and impaired quality of life. Understanding the role of comorbidity in patients with cGVHD is important both for prognostication and potentially for tailoring treatments based on mortality risks. In a prospective cohort study of patients with cGVHD (n=239), we examined the performance of two comorbidity scales, the Functional Comorbidity Index (FCI) and the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI). Both scales detected a higher number of comorbidities at cGVHD cohort enrollment than pre-hematopoietic cell transplant (HCT) (P<0.001). Higher HCT-CI scores at the time of cGVHD cohort enrollment were associated with higher non-relapse mortality (HR: 1.21:1.04-1.42, P=0.01). For overall mortality, we detected an interaction with platelet count. Higher HCT-CI scores at enrollment were associated with an increased risk of overall mortality when the platelet count was ≤ 100,000/µL (HR: 2.01:1.20-3.35, P=0.01), but not when it was >100,000/µL (HR: 1.05:0.90-1.22, P=0.53). Comorbidity scoring may help better to predict survival outcomes in patients with cGVHD. Further studies to understand vulnerability unrelated to cGVHD activity in this patient population are needed.

Canine DLA-79 gene: an improved typing method, identification of new alleles and its role in graft rejection and graft-versus-host disease.

Developing a preclinical canine model that predicts outcomes for hematopoietic cell transplantation in humans requires a model that mimics the degree of matching between human donor and recipient major histocompatibility complex (MHC) genes. The polymorphic class I and class II genes in mammals are typically located in a single chromosome as part of the MHC complex. However, a divergent class I gene in dogs, designated dog leukocyte antigen-79 (DLA-79), is located on chromosome 18 while other MHC genes are on chromosome 12. This gene is not taken into account while DLA matching for transplantation. Though divergent, this gene shares significant similarity in sequence and exon-intron architecture with other class I genes, and is transcribed. Little is known about the polymorphisms of DLA-79 and their potential role in transplantation. This study was aimed at exploring the reason for high rate of rejection seen in DLA-matched dogs given reduced intensity conditioning, in particular, the possibility that DLA-79 allele mismatches may be the cause. We found that about 82% of 407 dogs typed were homozygous for a single, reference allele. Owing to the high prevalence of a single allele, 87 of the 108 dogs (∼80%) transplanted were matched for DLA-79 with their donor. In conclusion, we have developed an efficient method to type alleles of a divergent MHC gene in dogs and identified two new alleles. We did not find any statistical correlation between DLA-79 allele disparity and graft rejection or graft-versus-host disease, among our transplant dogs.

Allo-SCT for multiple myeloma: a review of outcomes at a single transplant center.

Allogeneic stem cell transplant for multiple myeloma (MM) is one treatment associated with long-term disease-free survival. The high incidence of treatment-related mortality and relapses, however, are important reasons for controversy about the role of allografting in the management of MM. We reviewed our results of allografting for MM spanning a period of 34 years in order to better define long-term outcomes and identify areas of progress as well as areas requiring improvement. A total of 278 patients received allogeneic marrow or PBSCs after high-dose myeloablative (N=144) or reduced intensity, non-myeloablative (N=134) regimens. In multivariable analysis, adjusting for differences in patient groups, reduced intensity/non-myeloablative transplants were associated with significantly less acute GVHD, lower transplant mortality, better PFS and overall survival. There were no significant differences in relapse, progression or chronic GVHD, when adjusted. In multivariable analysis of patients receiving only non-myeloablative transplants, decreased overall survival and PFS were associated with relapse after a prior autograft and a ß2 microglobulin >4.0. Transplant mortality was reduced and only influenced by a prior tandem autograft.

The quality of life of adult survivors of childhood hematopoietic cell transplant.

Survival rates after myeloablative hematopoietic cell transplantation (HCT) in childhood have improved. We conducted a cross-sectional study evaluating the quality of life (QOL) of 214 adult survivors of a childhood HCT compared with controls using standardized self-report measures with strong psychometric properties to evaluate physical function, psychological function and cognitive symptoms. From these results we conducted a multivariate analysis of risk factors. This analysis for physical functioning showed poorer function among myeloid disease survivors compared with patients with all other diagnoses (P=0.02), men functioned better than women (P=0.05) and those >18 years after transplant functioned more poorly than those <18 years after transplant (P=0.05). Psychological functioning showed that those who received more therapy and females were more likely to be depressed (P=0.03) and (P=0.005). Perceived cognitive symptoms showed that female survivors had more symptoms than male survivors (P=0.01), and those receiving more preceding therapy compared with those with less preceding therapy (P=0.001) or cranial irradiation compared with those without cranial irradiation (P=0.002) had more perceived cognitive symptoms. Overall, these data indicate that the majority of adult survivors of a childhood transplant are functioning well, but some have problems that need to be addressed.

Immunomodulatory effects of mixed hematopoietic chimerism: immune tolerance in canine model of lung transplantation.

Long-term survival after lung transplantation is limited by acute and chronic graft rejection. Induction of immune tolerance by first establishing mixed hematopoietic chimerism (MC) is a promising strategy to improve outcomes. In a preclinical canine model, stable MC was established in recipients after reduced-intensity conditioning and hematopoietic cell transplantation from a DLA-identical donor. Delayed lung transplantation was performed from the stem cell donor without pharmacological immunosuppression. Lung graft survival without loss of function was prolonged in chimeric (n = 5) vs. nonchimeric (n = 7) recipients (p < or = 0.05, Fisher's test). There were histological changes consistent with low-grade rejection in 3/5 of the lung grafts in chimeric recipients at > or =1 year. Chimeric recipients after lung transplantation had a normal immune response to a T-dependent antigen. Compared to normal dogs, there were significant increases of CD4+INFgamma+, CD4+IL-4+ and CD8+ INFgamma+ T-cell subsets in the blood (p < 0.0001 for each of the three T-cell subsets). Markers for regulatory T-cell subsets including foxP3, IL10 and TGFbeta were also increased in CD3+ T cells from the blood and peripheral tissues of chimeric recipients after lung transplantation. Establishing MC is immunomodulatory and observed changes were consistent with activation of both the effector and regulatory immune response.

Therapy with mycophenolate mofetil for refractory acute and chronic GVHD.

We evaluated the pharmacokinetics and efficacy of oral mycophenolate mofetil (MMF) for treatment of refractory GVHD. In a prospective study of acute GVHD, 9 of 19 patients (47%) had a response and 10 (53%) had no improvement. Survival at 6 and 12 months after the start of MMF was 37 and 16%, respectively. In a retrospective study of acute GVHD, 14 of 29 patients (48%) had a response and 15 (52%) had no improvement. Survival at 6 and 12 months was 55 and 52%, respectively. In a prospective study of chronic GVHD, the cumulative incidence of disease resolution and withdrawal of all systemic immunosuppressive treatment was 9, 17 and 26% at 12, 24 and 36 months, respectively, after starting MMF. Thirteen patients (59%) required additional systemic immunosuppressive treatment for chronic GVHD. Nine of the 42 patients (21%) in the prospective studies discontinued MMF treatment because of toxicity. The area under the curve plasma concentrations of mycophenolic acid seemed to be suboptimal among patients with acute GVHD but not among those with chronic GVHD. MMF can be used effectively for treatment of GVHD.

Serious acute or chronic graft-versus-host disease after hematopoietic cell transplantation: a comparison of myeloablative and nonmyeloablative conditioning regimens.

We previously reported a 25% incidence of serious graft-versus-host disease (GVHD) (that is, acute or chronic GVHD that caused death, lengthy hospitalization or disability, or resulted in recurrent major infections) among 171 hematopoietic cell transplantation (HCT) recipients after nonmyeloablative (NMA) regimen. Here we present a retrospective study applying the same criteria to 264 recipients of peripheral blood HCT after myeloablative (MA) regimen, and compare the results with the previous study after additional follow-up. The MA group was younger and had lower comorbidity scores at HCT than those in the NMA group. The overall incidence of serious GVHD was 17% (44/264) in the MA group versus 28% (48/171) in the NMA group. The adjusted hazard ratio (HR) of serious GVHD in the MA group compared to the NMA group was 0.65 (95% CI, 0.4-1.1); P=0.13, and if follow-up was censored at the onset of recurrent or progressive malignancy, HR was 0.67 (95% CI, 0.4-1.3), P=0.22. We conclude that the choice between MA and NMA regimens does not greatly affect the risk of serious GVHD as an overall indicator of outcomes related to either acute or chronic GVHD. Serious GVHD may be considered as an endpoint in clinical trials with GVHD-related outcomes.

Prolonged anorexia and elevated plasma cytokine levels following myeloablative allogeneic hematopoietic cell transplant.

Myeloablative conditioning regimens commonly lead to prolonged anorexia and poor oral intake. In a prospective study of 147 patients receiving CY, total body irradiation and allogeneic hematopoietic cells, we determined the extent of decline in oral intake and assessed plasma cytokine levels and development of acute GVHD as explanations for protracted anorexia. For each patient, daily oral caloric intake was expressed as a percent of estimated basal requirements, calculated as basal energy expenditure, through day 20. Oral caloric intake was significantly reduced in 92% of patients and remained low. The nadir in oral intake occurred at days 10-12, when median oral caloric intake was 3% of basal energy requirements. Plasma cytokines known to affect appetite (IL2, IL6, tumor necrosis factor-alpha) were significantly elevated above normal following conditioning therapy (P<0.001 for each cytokine). Acute GVHD did not appear to affect oral intake to transplant day 20 in this cohort of patients; however, plasma levels of IL6 rose steeply before the clinical onset of GVHD. Persistent fever occurred with the greatest frequency in patients with most profound reduction in oral intake. We conclude that prolonged alterations in oral intake following this myeloablative regimen may be related to circulating cytokines known to alter eating behavior.

Chronic kidney disease following non-myeloablative hematopoietic cell transplantation.

Chronic kidney disease (CKD) following myeloablative allogeneic hematopoietic cell transplantation (HCT) occurs in 20% of survivors at 1 year and is believed to be due to radiation nephritis. Non-myeloablative allogeneic HCT is a recent procedure that employs significantly lower doses of chemoradiotherapy, however, incidence and risk factors for CKD following non-myleoablative HCT have not been defined. We performed a retrospective cohort study of 122 patients from three institutions who were available for analysis at 6 months following non-myeloablative HCT. Patients received two Gy of radiation; 62% received fludarabine as preconditioning. CKD was defined as at least a 25% reduction in glomerular filtration rate (GFR) from baseline using the abbreviated modified diet in renal disease (MDRD) equation. Eighty-one of 122 patients (66%) showed evidence of CKD at follow-up. Multivariate analysis revealed that acute renal failure (ARF) during the first 100 days post-transplant was associated with development of CKD (Adjusted OR 32.8 with 95% CI 4.3-250) after controlling for other variables. Previous autologous HCT, long-term calcineurin inhibitor use and extensive chronic GVHD were independently associated with CKD. CKD following non-myeloablative HCT appears to be a distinct clinical entity and likely not related to radiation nephritis. Future research should focus on possible mechanisms for alleviating chronic injury and decreasing use of calcineurin inhibitors.

Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: a retrospective analysis.

Transplant outcome was analyzed in 150 patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia transformed from MDS (tAML) conditioned with nonmyeloablative or myeloablative regimens. A total of 38 patients received nonmyeloablative regimens of 2 Gy total body irradiation alone (n=2) or with fludarabine (n=36), 90mg/m2. A total of 112 patients received a myeloablative regimen of busulfan, 16mg/ kg (targeted to 800-900 ng/ml), and cyclophosphamide 120 mg/ kg. Nonmyeloablative patients were older (median age 62 vs 52 years, P<0.001), more frequently had progressed to tAML (53 vs 31%, P=0.06), had higher risk disease by the International Prognostic Scoring System (53 vs 30%, P=0.004), had higher transplant specific comorbidity indices (68 vs 42%, P=0.01) and more frequently had durable complete responses to induction chemotherapy (58 vs 14%). Three-year overall survival (27%/48% (P=0.56)), progression-free survival (28%/4 44%, (P=0.60)), and nonrelapse mortality (41%/34%, (P=0.94)) did not differ significantly between nonmyeloblative/myeloablative conditioning. Overall (HR=0.9, P=0.84) and progression-free survivals (HR=1, P=0.93) were similar for patients with chemotherapy-induced remissions irrespective of conditioning intensity. Graft vs leukemia effects may be more important than conditioning intensity in preventing progression in patients in chemotherapy-induced remissions at the time of transplantation. Randomized prospective studies are needed to further address the optimal choice of transplant conditioning intensity in myeloid neoplasms.