Outcome of Extracorporeal Photopheresis as an Add-On Therapy for Antibody-Mediated Rejection in Lung Transplant Recipients.

INTRODUCTION: The diagnosis and treatment of antibody-mediated rejection (AMR) after lung transplantation has recently gained recognition within the transplant community. Extracorporeal photopheresis (ECP), currently used to treat chronic lung allograft dysfunction, modulates various pathways of the immune system known to be involved in AMR. We hypothesize that adding ECP to established AMR treatments could prevent the rebound of donor-specific antibodies (DSA). OBJECTIVES: This study aimed to analyze the role of ECP as an add-on therapy to prevent the rebound of DSA. METHODS: Lung transplant recipients who received ECP as an add-on therapy for pulmonary AMR between January 2010 and January 2019 were included in this single-center retrospective analysis. Baseline demographics of the patients, as well as their immunological characteristics and long-term transplant outcomes, were analyzed. RESULTS: A total of 41 patients developed clinical AMR during the study period. Sixteen patients received ECP as an add-on therapy after first-line AMR treatment. Among the 16 patients, 2 (13%) had pretransplant DSA, both against human leukocyte antigen (HLA) class I (B38, B13, and C06). Fifteen patients (94%) developed de novo DSA (dnDSA), i.e., 10 (63%) against class I and 14 (88%) against class II. The median time to dnDSA after lung transplantation was 361 days (range 25-2,548). According to the most recent International Society of Heart and Lung Transplantation (ISHLT) consensus report, 2 (13%) patients had definite clinical AMR, 6 (38%) had probable AMR, and 7 (44%) had possible AMR. The median mean fluorescence intensity (MFI) of dnDSA at the time of clinical diagnosis was 4,220 (range 1,319-10,552) for anti-HLA class I and 10,953 (range 1,969-27,501) for anti-HLA class II antibodies. ECP was performed for a median of 14 cycles (range 1-64). MFI values of dnDSA against HLA classes I and II were significantly reduced over the treatment period (for anti-class I: 752; range 70-2,066; for anti-class II: 5,612; range 1,689-21,858). The 1-year survival rate was 55%. No adverse events related to ECP were reported in any of the patients. CONCLUSIONS: ECP is associated with a reduction of dnDSA in lung transplant recipients affected by AMR. Prospective studies are warranted to confirm the beneficial effects of ECP in the setting of AMR.

A potassium-titanyl-phosphate laser is an efficacious tool in the treatment of pyogenic granulomas. A retrospective study in 28 patients.

BACKGROUND AND OBJECTIVE: Pyogenic granuloma is a common benign vascular lesion of the skin and mucosa prone to ulceration and bleeding. Current therapeutic approaches include surgical excision, removal by means of electro caustic therapy, cryotherapy, and ablation with CO2 or vascular lasers. The purpose of this study was to investigate the efficacy of a 532 nm potassium-titanyl-phosphate laser (KTP-laser) for the treatment of pyogenic granulomas in terms of efficacy, advantages in clinical outcome, technique and associated side effects. METHODS: In this retrospective study we report on the response of 28 consecutive patients with pyogenic granulomas at multiple locations on the skin after having been treated with a 532 nm KTP laser (532 nm AuraTM Star Pulse laser, Laserscope, CA, USA). Treatment was performed with a 2 mm handpiece and energy fluences of 35-60 J cm-2 and a laser pulse width of 50 ms or with a 1 mm handpiece and energy fluences of 200-240 J cm-2 and a laser pulse width of 50 ms. All patients were treated on an outpatient basis at the department of dermatology, Medical University of Vienna, Austria. RESULTS: In all of the 28 patients treated, we were able to demonstrate both symptomatic and clinical clearing of the lesions with excellent cosmetic results after the treatment. In 25 of the 28 patients a single treatment was sufficient to obtain optimal results. In three patients a second treatment session was required due to the recurrence of the lesion. The procedure required only local anesthesia, and postoperative care was limited to the application of a topical antibiotic ointment. No postoperative complications such as increased pain or wound infection and only minimal scarring were observed. CONCLUSIONS: This experience with excellent patient satisfaction suggests that treatment of pyogenic granulomas with the KTP laser is a safe, effective, and reasonable alternative to conventional therapy. As with many other limited interventions with this laser technology, the advantages include minimal postoperative pain, conservative site-specific minimally invasive surgeries and a very satisfactory cosmetic result with a high acceptance rate on the side of the patients.

Incidence of lung cancer in patients with systemic sclerosis treated with extracorporeal photopheresis.

BACKGROUND: Extracorporeal photopheresis (ECP) improves skin sclerosis in systemic sclerosis (SSc) patients. SSc is associated with an increased risk of lung cancer. As ECP is supposed to exert immunomodulatory effects, a possible impact of ECP on the incidence of lung cancer in SSc patients was evaluated. METHODS: Seventy-one SSc patients treated with ECP at the Photopheresis Unit of the Department of Dermatology at the Medical University of Vienna between 1991 and 2013 were analyzed retrospectively. RESULTS: We calculated a standardized incidence ratio (SIR) for lung cancer in ECP-treated SSc patients of 2.34 [95% confidence interval (CI) 1.63-2.49]. This is in accordance with recent meta-analyses demonstrating a significantly enhanced risk of lung carcinoma in SSc patients. Comparison of the lung cancer risks of these patients with our ECP-treated patients revealed that ECP has no influence. Each patient with lung carcinoma had previously been diagnosed with lung involvement of the non-specific interstitial pneumonitis (NSIP) type. CONCLUSION: We confirm that SSc patients are at significantly increased risk for lung cancer. However, ECP does not influence this risk. NSIP may be a risk factor for lung cancer in SSc patients.

Extracorporeal photopheresis in acute and chronic graft-versus-host disease.

Graft-versus-host disease (GvHD) is a serious complication of allogeneic hematopoietic cell transplantation causing significant morbidity and mortality. Corticosteroids are the established first-line treatment of GvHD. Patients not responding to corticosteroids have a dismal prognosis. Extracorporeal photopheresis (ECP) has objective activity in the treatment of both acute and chronic corticosteroid-refractory GvHD patients, has an excellent safety profile and is internationally well-established. ECP has been recommended by a significant number of renowned scientific organizations as an efficient treatment option for patients with GvHD. ECP has a proven corticosteroid-sparing effect and favourably impacts on survival and quality of life of responding patients.

Photopheresis (extracorporeal photochemotherapy).

Photopheresis is a form of phototherapy where specialized equipment is used to isolate a leukocyte fraction from the peripheral blood which is then exposed to photoactivated 8-methoxypsoralen and reinfused into the patient. At the time of its invention the treatment was conceptually based on the hypothesis of T cell vaccination, i.e. the observation in experimental studies that exposure of the immune system to physically modified T cell clones leads to a specific inhibition of T cell mediated autoimmunity. Consequently, photopheresis has been tried in a variety of conditions where T cells are thought to have a critical role and has shown clinical efficacy mainly in variants of cutaneous T cell lymphomas, graft-versus-host disease, systemic sclerosis, in solid organ transplant rejection and Crohn's disease. Evidence has accumulated that alterations in antigen presentation and the generation of regulatory T cells are induced by photopheresis and might be related to the observed clinical effects. Summarizing what has been published in the 25 years since its introduction into the clinic, photopheresis to date has found its place in the treatment of the above mentioned conditions as a well tolerated treatment option that can safely be combined with other established modalities. It can be expected that further research will help refine its clinical indications and close the gaps that still exist in our knowledge on when, how, and why photopheresis works.

Leucocyte scintigraphy with 111In-oxine for assessment of cell trafficking after extracorporeal photopheresis.

Extracorporeal photopheresis (ECP) is an established therapy for transplant rejection, graft-versus-host disease (GvHD) after allogeneic stem cell transplantation, cutaneous T-cell lymphoma and systemic autoimmune disorders such as systemic sclerosis. Knowledge regarding the in vivo behaviour of the cells after reinfusion is very limited. The aim of this prospective study was to investigate the path of 8-MOP-/UVA-exposed radiolabelled cells after ECP treatment and reinfusion. In this prospective single-centre study, peripheral blood mononuclear cells (PBMC) and neutrophils of 10 patients undergoing ECP as part of their regular treatment were labelled separately with (111) In-oxine after exposure to 8-MOP/UVA and prior to reinfusion. The fate of the labelled leucocytes was monitored at 10 min, 3.5 and 24 h following reinfusion with whole-body scintigraphy. Comparison of distribution patterns showed that PBMC and neutrophils have different kinetic patterns after intravenous reinjection. The most prominent difference was immediate retention of PBMC but not of neutrophils in the lungs corresponding to a signal three times more intense. After 24 h, more than 80% of both cell populations could be detected in liver and spleen. By means of a novel tool allowing for tracking of 8-MOP-/UVA-exposed leucocytes in ECP, we could show that organ-specific homing of leucocytes after ECP can be visualized in vivo and that migration patterns differ between PBMC and neutrophils. Based on our results, further studies should (i) extend the morphometric studies described here to specific ECP-responsive conditions and (ii) functionally address the interaction of ECP-modified PBMC with pulmonary tissue in experimental models.

Cutaneous manifestations of acute and chronic graft-versus-host disease.

Graft-versus-host disease (GvHD) is a commonly occurring immunological reaction and frequent complication following allogeneic hematopoietic stem cell transplantation. Its highly diverse manifestations including skin involvement as the most common appearance of GvHD, can dramatically influence patient's quality of life, in particular in the chronic stage, in addition to patient's decreased survival outcome. Hence, the role of the dermatologist has become very crucial in an interdisciplinary setting, particularly since appearances of GvHD in the skin can be multifaceted and challenging. Clinical manifestation of the acute GvHD (aGvHD) is limited to erythematous maculopapular rash and oral mucosal lesions while the chronic form manifests in a wider range in a localized area or disseminated including involvement of nail, scalp and genital area. This article aims to provide a comprehensive overview on the variable cutaneous presentations of acute and chronic GvHD for a proper and early diagnosis on the one hand, and to discuss updated therapeutic options for both acute and chronic GvHD on the other hand, to initiate an adequate treatment to obtain the most beneficial clinical outcome.

Challenge of diagnosing pyoderma gangrenosum after caesarean section.

Pyoderma gangrenosum is a neutrophilic skin disease that leads to extensive, painful, necrotic ulcerations, particularly at surgical sites. As obstetric cases with pyoderma gangrenosum are rare and, therefore, often misdiagnosed initially, it is important to raise awareness about this rare complication. Here, we describe a patient who presented with pyoderma gangrenosum at the surgical site 4 days after undergoing a caesarean section. The erythema was initially misdiagnosed as wound infection, and the patient, who was experiencing pain, underwent antibiotic treatment and surgical wound debridement. When the wound was unresponsive to these treatments, a dermatologist was consulted who suspected pyoderma gangrenosum and began a high-dose corticosteroids therapy, which led to a fulminant improvement of the local wound. In conclusion, the rare diagnosis of pyoderma gangrenosum should be considered in the differential diagnosis of a suspected surgical wound infection. Early interdisciplinary treatment is essential to avoid further complications.

Pattern-reversal visual-evoked potentials in children with migraine and other primary headache: evidence for maturation disorder?

Recently, evidence for a disturbed maturation of cerebral information processing in migraine came from studies investigating the auditory-evoked contingent negative variation and the auditory-evoked potential from childhood to adulthood. This study is to clarify whether age-dependent development is altered also for the processing of visual stimuli in migraine. Components of pattern-reversal visual-evoked potentials at four different spatial frequencies (which can preferentially activate the magno- and the parvocellular visual system) were compared between children aged 6 and 18 years with primary headache (N = 123; 67 migraine without aura, MO; 32 migraine with aura, MA; 24 tension-type headache, TH) in the headache-free interval and healthy controls (N = 82). Children were divided into two age groups: 6-11 years (pre- and early puberty) and 12-18 years (late and post-puberty). Age-dependent development was normal for N80 and P100 latency in children with primary headache, but altered for N135 latency as indicated by a significant interaction among the factors diagnosis, spatial frequency and age group (P < 0.01). In headache-free controls, N135 latency reduction between pre- and post-puberty age was most pronounced at high spatial frequency. The main 'decline' of N135 latency with increasing age was shifted to lower spatial frequencies in the headache subgroups. The results give evidence that maturation of visual processing is partly disturbed in migraineurs.

A prospective interventional study on the use of extracorporeal photopheresis in patients with bronchiolitis obliterans syndrome after lung transplantation.

BACKGROUND: The aim of this prospective study was to evaluate the efficacy and safety of extracorporeal photopheresis (ECP) in patients with bronchiolitis obliterans syndrome (BOS) after lung transplantation and to identify factors predicting treatment response. METHODS: The study was performed at a single center and consisted of a cohort of 1,012 lung transplant recipients (November 1989-June 2010). A total of 194 patients developed BOS after a mean of 1,293 ± 1,008 days (range, 99-4,949 days) and received established treatment, and 51 patients received additional ECP. RESULTS: Thirty-one (61%) of the ECP-treated patients responded to the therapy and showed sustained stabilization (forced expiratory volume in 1 second range, -5% to 5% vs baseline at start of ECP) of lung function over 6 months. Responders to ECP showed significantly greater survival and less need for retransplantation (p = 0.001) than non-responders. Factors associated with an inferior treatment response were cystic fibrosis as underlying lung disease and a longer time between transplantation and development of BOS. No side effects were observed after ECP. Compared with BOS patients not treated with ECP, the ECP responders showed an improved graft survival (p = 0.05). CONCLUSIONS: These results confirm and suggest that early use of ECP could be an effective adjunct treatment for patients who develop BOS after lung transplantation.

cis-Urocanic acid initiates gene transcription in primary human keratinocytes.

It is well established that solar UV radiation (UVR) suppresses cutaneous cell-mediated immunity in humans. trans-Urocanic acid (trans-UCA) is a major UVR-absorbing skin molecule that undergoes a photoisomerization to its cis-isomer following UVR exposure. Animal studies have demonstrated that cis-UCA plays a role in UVR-induced immune suppression, but the molecular mechanisms of action of cis-UCA are not fully understood. In this study, we examined changes in gene expression and synthesis of cytokines and PGE2 following UCA treatment of primary human keratinocytes. A limited microarray analysis of keratinocytes from two donors indicated that approximately 400 genes were induced by solar-simulated radiation (SSR), 16 of which were also up-regulated by cis-UCA. In contrast, trans-UCA had little or no effect on gene expression. The genes up-regulated by both cis-UCA and SSR were associated with apoptosis, cell growth arrest, cytokines, and oxidative stress. Further studies using primary keratinocytes from four new donors showed that PG-endoperoxide synthase-2 was dramatically induced by cis-UCA, resulting in an enhanced secretion of PGE2 into the cell culture supernatant. cis-UCA also increased cytokine protein production such as that of TNF-alpha, IL-6, and IL-8 in a dose-dependent manner. SSR had the same effect as cis-UCA, but trans-UCA had no effect. In addition, activation of NF-kappaB and lipid peroxidation were induced by cis-UCA and SSR, but not trans-UCA, suggesting possible upstream events of the gene expression changes. The data suggest that the induction of immune suppression by cis-UCA may involve the initiation of gene transcription of immunomodulatory mediators in primary human keratinocytes.