A 46-year-old male patient presented to his primary care provider for screening. The latter detected a perfused mass in the right renal pelvis on routine ultrasound. Blood pressure levels had been normal when previously measured at the medical office and were 128/78 mmHg at diagnosis. No auscultatory gap was found at the respective renal location. Ultrasound examination (Figure a) revealed an arteriovenous fistula in the renal parenchyma (arrows) draining into a large, parapelvic venous aneurysm. The volume of the fistula was determined on ultrasound to be approximately 1000 mL/min. Following computed tomography verification (Figure b) of the findings, the fistula was catheterized during the angiography and occluded by means of coil and onyx-based embolization. No changes in blood pressure were observed following the intervention. Kidney biopsy, which is the most frequent cause of renal AV fistulas, had not been performed in this patient. In terms of medical history, the patient had suffered a motorcycle accident 20 years previously and sustained bruising to the abdominal area, making a traumatic etiology appear likely.

BACKGROUNDThe prevalence of chronic kidney disease (CKD) requiring dialysis therapy is increasing globally. Survival and mortality data of these patients in Germany are fragmentary since the nationwide registry was terminated in 2006.OBJECTIVEThe objective of this study was to analyze the survival, causes of death, and co-morbidities of dialysis patients in a German population cohort as well as to assess the factors influencing mortality in these patients.MATERIALS AND METHODSWe included adult, prevalent chronic dialysis patients from the German population who underwent hemodialysis and peritoneal dialysis at our centers between 2014 and 2018. We compared the characteristics of living and deceased patients and assessed survival. Patients with and without diabetes mellitus were also examined, and their co-morbidities were analyzed.RESULTSOf the 425 patients included in our study (m/f: 235/190), 182 died within the observation period. Mean survival of patients with coronary artery disease (CAD) (n = 217), peripheral artery disease (PAD) (n = 128), and cardiorenal syndrome (CRS) (n = 99) was significantly reduced compared to patients without the disease (CAD: 4.2 vs. 6.4 years; PAD: 4.3 vs. 6.5 years; CRS: 3.7 vs. 7.3 years, p < 0.001, respectively). Patients with diabetes mellitus (n = 110) showed no reduced survival compared to patients without the disease (n = 315) (4.8 vs. 4.9 years, p = 0.421). Diastolic blood pressure (DBP) and C-reactive protein (CRP) levels were associated with dialysis time in linear regression analysis (DBP: R = 0.029, p < 0,001; CRP: R = 0.085, p < 0.001).CONCLUSIONOur results provide novel data regarding German CKD patients requiring dialysis and factors influencing mortality, which could serve as a useful reference for further studies.

Elevated immunoglobulin (Ig) E levels may interfere with skin inflammation in atopic dermatitis (AD) at different levels. One hypothesis is that IgE binding to dendritic cells via the high-affinity IgE receptor, FcεRI, activates the release of pro-inflammatory mediators and facilitates stimulation of allergen-specific cutaneous T-cell responses (Reich et al., 2001; Werfel et al., 2015). In a pilot trial, extracorporeal immunoadsorption (IA) with columns that bind all Ig classes reduced parameters of cutaneous inflammation and improved the clinical phenotype of AD (Kasperkiewicz et al., 2011).

Purpose: Human infection with Dobrava-Belgrade virus (DOBV) in Northern Germany causes a mild form of hantavirus disease predominantly characterized by acute kidney injury due to interstitial nephritis. We evaluated the largest number of DOBV-infected patients so far regarding clinical course, proteinuria, and prognostic markers. Patients and Methods: Patients with DOBV-associated hantavirus disease admitted to the Renal Division of the University of Lübeck (Germany) between 1997 and 2012 were included in this study. Symptoms, clinical course, laboratory parameters, and urinary protein analysis were investigated at admission (baseline, t0), 3–5 days (t3–5), 10–17 days (t10–17), and after 1 year of follow-up (t365). Results: Of the 34 patients (male/female ratio: 23/11; age: 41 ± 14 years) included in the study, 4 underwent hemodialysis (HD). Glomerular filtration rate was 17 ± 14 mL/min at t0 and increased to 27 ± 26 mL/min (t3–5), 57 ± 20 mL/min (t10–17), and 84 ± 16 mL/min (t365). Albuminuria and tubular proteinuria (α1- and β2-microglobulin) decreased during follow-up; the urinary α1-microglobulin concentration in patients who required HD was significantly higher than that in patients not requiring HD (t0: 186 ± 51 vs. 45 ± 26 mg/g creatinine; t3–5: 87 ± 14 vs. 32 ± 16 mg/g creatinine; t10–17: 63 ± 18 vs. 28 ± 12 mg/g creatinine; p < 0.001). Conclusions: DOBV infection of inpatients in Northern Germany is associated with severe kidney injury that recovers within a few weeks and normalizes within 1 year. Tubular proteinuria is associated with the severity of kidney injury and the necessity of renal replacement therapy in these DOBV-infected patients.

OBJECTIVES:Renal duplex sonography represents a standard noninvasive diagnostic procedure to demonstrate morphologic changes in acute kidney transplant dysfunction. We investigated whether a newly developed serial duplex index (SDI) can differentiate between acute cellular rejection and acute vascular rejection more effectively than the established Doppler parameters of the resistive index (RI) and pulsatility index (PI) in recently transplanted patients. METHODS:Serial duplex scans of patients with histologically proven acute tubular necrosis (n = 25), acute cellular rejection (n = 28), acute vascular rejection (n = 18), and normal graft function (n = 50, partially protocol biopsied) were retrospectively analyzed. For each patient, the RI, PI, and cortex-pelvis proportion (CPP) were included from the day of biopsy (t0) and 3 to 7 days before biopsy (t-1). The sequential CPP ratio (CPPt0 /CPPt-1 ), RI ratio (RIt0 /RIt-1 ), and PI ratio (PIt0 /Pit-1 ) were determined. The SDI was calculated as: RI ratio × PI ratio/CPP ratio. The diagnostic accuracy of the SDI was compared with that of the RI and PI ratios. RESULTS:Selected groups were statistically comparable in all routinely determined transplant parameters. The SDI was significantly different between patients with normal graft function, acute cellular rejection, and acute vascular rejection (P < .01, analysis of variance on ranks), whereas the RI and PI ratios were only significantly different between patients with normal graft function and acute vascular rejection (P < .05, analysis of variance on ranks). The indices' ranges were defined by the 95% confidence intervals between the allograft functions. CONCLUSIONS:The developed SDI was able to detect acute renal transplant rejection with greater sensitivity and specificity than the RI and PI ratios. Since the SDI distinguishes between acute tubular necrosis, acute cellular rejection, and acute vascular rejection, it might be a supportive tool to indicate renal biopsy.

INTRODUCTION: Complications after renal transplants are frequent. A well-known but less frequent complication is arteriovenous fistula formation, which can remain asymptomatic or present with hematuria, hypertension, or renal insufficiency.PRESENTATION OF CASE: We present the case of a young, male kidney transplant recipient with newly developed hypertension due to the formation of an arteriovenous fistula a long period after the last renal biopsy.DISCUSSION: In our case, the sonographic evaluation showed the aliasing phenomenon, which was useful in the detection of the AVF. Superselective transcatheter embolization is considered to be the treatment of choice in such cases and has been proven to be safe and effective, even in long-term evaluations.CONCLUSION: Our findings in this case highlight a rarely reported clinical presentation which physicians should be aware of when evaluating patients who have received a renal transplant. (C) 2016 The Author(s). Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.

Background: Determination of cyclosporine A (CsA) and tacrolimus (Tac) in dried blood spots (DBS) could enable drug monitoring in transplanted patients without the necessity of having to take venous blood samples. Therefore, we have developed a method for quantitative determination of calcineurin inhibitors (CNI) by liquid-chromatography-tandem mass spectrometry (LCMS). Methods: In a study with 68 kidney transplant recipients (KTR, 34 CsA, 34 Tac), we tested the clinical application of LCMS monitoring in DBS in comparison to LCMS in whole blood. Results: The measuring range is proven for 27.33 to 1345 ng/ml for CsA and for 1.63 to 39.7 ng/ml for Tac. The requirements for clinical chemical analyses for precision and accuracy are complied with. Stability is documented for a period of 14 days. The study showed the following deviations from LCMS in whole blood for determination of CsA and Tac in DBS after introducing a correction factor by the haematocrit (Hct) value (CsA trough level: mean = 4.7%, ±1.96 standard deviation (SD) －52.1% to 61.4%, N = 96; CsA peak level: mean = 7.3%, ±1.96 SD －39.7% to 54.4%, N = 95; Tac trough level: mean = －0.5%, ±1.96 SD －76.4% to 75.3%, N = 88; Tac peak level: mean = 3.9%, ±1.96 SD －80.1% to 88.7%, N = 92). Conclusions: Our data show comparable results with the reference method by means of LCMS in whole blood. Therefore, DBS of KTR for determination of CNI levels could be transported on filter cards by mail to the respective laboratory resistant to breakage and the hazard of infection.

Mesenchymal stromal cells (MSC) have been introduced into the field of tissue-engineered airway transplantation. Since patients with extensive tracheal defects often require an open tracheotomy, this study investigated if MSC could be obtained from the adipose tissue of the neck during this procedure. Cells were isolated by plastic adherence from the adipose tissue of 8 patients. Cell isolates were analyzed for (i) proliferation, (ii) the expression of CD marker molecules and (iii) multilineage differentiation. The isolated spindle-shaped cells showed a high proliferation capacity and the flow cytometric analysis revealed a distinct population meeting the criteria for MSC. Using classical MSC cultivation protocols the characterized cells showed adipogenic, chondrogenic and osteogenic differentiation for all analyzed cell isolates. This study was able to demonstrate that sufficient amounts of stem/progenitor cells can be easily isolated from adipose tissue of the neck obtained during open tracheotomy. These cells may be a source for future tracheal replacement therapies.

Background: Hantavirus infection in humans usually occurs via inhalation of infectious aerosolized excreta of rodents. Horizontal human-to-human transmission was reported only for the highly virulent Andes virus. The likelihood of vertical transmission and the clinical outcome of hantavirus infections in pregnancy is still unpredictable.Objectives: Very few data were published about the impact of hantaviruses in pregnancy. Here we present four cases of pregnant women infected by European hantaviruses. The risk of vertical virus transmission was investigated.Study design: Four pregnant women with clinical signs of acute hantavirus disease were investigated for hantavirus IgM and IgG after onset of clinical symptoms. Furthermore, the newborns were tested for presence of viral RNA and antibodies in cord blood and, if any parameter was found positive, 8-12 months after delivery.Results: Four women suffered from a hantavirus infection, two of them due to infection by Puumala virus and two by Dobrava-Belgrade virus. Three women delivered healthy babies by vaginal route and one woman by Caesarean section (week 28). In no case hantavirus RNA was detected in cord blood after delivery or in the 8-12 month old babies. Hantavirus IgG was detectable in the cord blood of 3 babies (but not in the preterm child); these antibodies disappeared after 8-12 months indicating a passive transfer of immunoglobulins. No child had any clinical sign of hantavirus infection.Conclusions: In this study, the absence of vertical hantavirus transmission was demonstrated for pregnant women with onset of hantavirus disease between gestation weeks 14 and 28. (C) 2012 Elsevier B.V. All rights reserved.

A 40-year old prima para presented with multiple urticaria-like plaques and severe pruritus 2 weeks prior to giving birth by cesarean section. Three days after birth, the disease flared up and tense blisters appeared on hands, lower arms and feet. Based on the clinical presentation, direct immunofluorescence microscopy, complement binding test and detection of high levels of circulating anti-BP180 antibodies, the diagnosis of pemphigoid gestationis was established. Despite treatment with class IV topical corticosteroid and prednisolone p.o. up to 60 mg/day, both skin lesions and severe pruritus progressed accompanied by increasing anti-BP180 antibody serum levels. In order to continue breast feeding, the prednisolone dose could not be further increased and 10 immunoadsorptions over 4 weeks were performed. During this period, skin lesions cleared rapidly, pruritus subsided and BP180-specific serum autoantibodies decreased by 99.5% allowing the reduction of prednisolone to 7.5 mg/day. We conclude that immunoadsorption is an effective and safe adjuvant therapeutic option for severe pemphigoid gestationis.

Background: C-reactive protein (CRP) is a key molecule in inflammation and tissue homeostasis and is produced locally by renal tubular epithelial cells. Its significance of expression in contrast to expression of cytotoxic T cell (CTL) markers remains to be elucidated. Methods: By means of real-time PCR, we determined mRNA levels of CRP in 66 renal allograft biopsies with acute allograft failure and in 34 biopsies with chronic dysfunction. Results were compared to expression of CTL components (perforin, granzyme B) and were correlated with histologic diagnoses and outcome. Results: CTL markers were found in most biopsies, and thus were not specific for particular histologies, although expression levels increased significantly with Banff rejection grades. Expression of CRP was highly specific for rejection episodes in acute failure (p < 0.0001) as well as for transplant glomerulopathy or de novo/recurrent glomerulonephritis in chronic failure (p < 0.005). Finally, the presence of CRP expression in renal allografts was associated with a deteriorating 1-year graft function in acute (p < 0.01) as well as chronic allograft dysfunction (p = 0.077). Conclusions: Our data suggest local CRP expression of kidney transplants as an indicator for pathologic entities associated with unfavorable outcomes in the early and late course of kidney transplants.

Background: The aim of our one year prospective multicenter randomized controlled trial was to compare the effects of low dose tacrolimus (LD-Tac) and mycophenolate-mofetil (MMF) in elderly kidney transplant recipients (KTR) within the Eurotransplant Senior Program (ESP). Methods: Ninety kidney transplant recipients (KTR) were enrolled. All received baseline immunosuppression (IS) with daclizumab induction (2mg/kg), LD-Tac (trough level 5-8ng/ml), MMF (2g/d) and steroids. After three months, patients were randomized to receive either MMF (1-2g/d) and steroids or LD-Tac and steroids. Results: Of the 90 KTR enrolled, 38 patients (P) dropped out prior to randomization due to severe rejection (5P), intolerance of MMF dose (3P), out of target Tac level (3P), or other protocol violations (27P). Prior to randomization, delayed graft function occurred in 41%, and acute rejections in 58% of the KTR. Creatinine clearance in the MMF group was superior compared to the LD-Tac group after 6 months (p<0.05) and 12 months (p<0.05), whereas rejection and infection rates were not different. Conclusion: Unfortunately, the high dropout rate led to underpowerment of the study. However, the high incidence of early rejection demonstrates that low dose IS in this phase after transplantation is not sufficient for older patients. (ClinicalTrials.gov Identifier: NCT00912678).

Linear IgA disease (LAD) is an autoimmune subepidermal blistering disorder characterized by IgA autoantibodies at the dermal-epidermal junction. Conventional first-line treatments include dapsone with or without oral glucocorticosteroids. Various other therapeutic approaches have been used in refractory patients. Immunoadsorption (IA) has been previously successfully applied in severe and/or otherwise treatment-resistant IgG-mediated immunobullous disorders. Here, we report a patient with a severe generalized LAD in whom adjuvant tryptophan IA was associated with rapid healing of skin lesions. Our observation suggests that IA may also be a helpful adjuvant treatment option for severe LAD.

To the Editor: Therapy with the anti-IgE antibody omalizumab has been shown to be effective in case series of patients with recalcitrant atopic dermatitis (AD), but extremely high total serum IgE levels may present a limitation for this treatment.1Krathen R.A. Hsu S. Failure of omalizumab for treatment of severe adult atopic dermatitis.J Am Acad Dermatol. 2005; 53: 338-340Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 2Lane J.E. Cheyney J.M. Lane T.N. Kent D.E. Cohen D.J. Treatment of recalcitrant atopic dermatitis with omalizumab.J Am Acad Dermatol. 2006; 54: 68-72Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 3Vigo P.G. Girgis K.R. Pfuetze B.L. Critchlow M.E. Fisher J. Hussain I. Efficacy of anti-IgE therapy in patients with atopic dermatitis.J Am Acad Dermatol. 2006; 55: 168-170Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 4Belloni B. Ziai M. Lim A. Lemercier B. Sbornik M. Weidinger S. et al.Low-dose anti-IgE therapy in patients with atopic eczema with high serum IgE levels.J Allergy Clin Immunol. 2007; 120: 1223-1225Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 5Sheinkopf L.E. Rafi A.W. Do L.T. Katz R.M. Klaustermeyer W.B. Efficacy of omalizumab in the treatment of atopic dermatitis: a pilot study.Allergy Asthma Proc. 2008; 29: 530-537Crossref PubMed Scopus (125) Google Scholar On the basis of the concept of a pathophysiological relevance of high IgE serum levels in AD and the known capacity of immunoadsorption to effectively reduce high titers of circulating antibodies,6Schmidt E. Zillikens D. Immunoadsorption in dermatology.Arch Dermatol Res. 2010; 302: 241-253Crossref PubMed Scopus (66) Google Scholar we initiated a pilot study to investigate clinical efficacy, safety, and immunologic effects of immunoadsorption in severe AD with high serum IgE levels. In this investigator-initiated, open-label pilot study, 12 patients with severe AD were enrolled. All patients displayed (1) total serum IgE levels >4500 kU/L, (2) an Investigators Global Assessment score ≥3, and (3) a history of no significant or long-term Scoring Atopic Dermatitis (SCORAD) reduction after treatment with topical corticosteroids/calcineurin inhibitors, ultraviolet light therapy (at least 4 weeks of therapy), systemic corticosteroids, and cyclosporine A (at least 8 weeks of therapy) or contraindications to use any of these therapeutic options. Patients were treated with a total of 10 immunoadsorptions on days 1 to 5 (week 1) and days 29 to 33 (week 5) by using adsorption columns that contained polyclonal sheep antihuman immunoglobulin antibodies binding the different human immunoglobulins with similar affinity (Ig-Therasorb; Miltenyi Biotec, Teterow, Germany). The patients' medications, including cyclosporine A, oral antihistamines, topical corticosteroids, and/or topical calcineurin inhibitors, were initially continued without change of frequency and/or dosage and later reduced or discontinued according to disease activity (except cyclosporine A). Clinical (SCORAD,7Kunz B. Oranje A.P. Labrèze L. Stalder J.F. Ring J. Taïeb A. Clinical validation and guidelines for the SCORAD index: consensus report of the European Task Force on Atopic Dermatitis.Dermatology. 1997; 195: 10-19Crossref PubMed Google Scholar Eczema Area and Severity Index,8Hanifin J.M. Thurston M. Omoto M. Cherill R. Tofte S.J. Graeber M. The Eczema Area and Severity Index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group.Exp Dermatol. 2001; 10: 11-18Crossref PubMed Scopus (288) Google Scholar visual analog scale assessing pruritus), blood (immunoglobulins, lymphocyte subsets, FcεRI expression on leukocytes) and histologic (total IgE in the skin, hyperkeratosis, acanthosis, spongiosis, dermal infiltration) parameters were monitored before, during, and up to 13 weeks after initiation of therapy (see this article’s Table E1 in the Online Repository at www.jacionline.org). For additional information regarding selection criteria, materials and methods, and statistical analyses, see this article’s Methods in the Online Repository at www.jacionline.org. Of the 12 patients enrolled, 2 patients did not complete the study because of a severe adverse event (central venous catheter–related Staphylococcus aureus septicemia) or a coping problem, respectively. Otherwise, treatment was well tolerated. Before immunoadsorption was initiated, the mean SCORAD was 78.6 ± 3.9. Significant improvements of the mean SCORAD were observed at week 3 (by 38% to a score of 49.2 ± 7.1), at week 5 (by 46% to a score of 42.5 ± 3.6), at week 9 (by 56% to a score of 35.0 ± 2.6), and at the end of the study at week 13 (by 59% to a score of 32.4 ± 3.5; Fig 1, A and B). In all patients, a 24% to 82% individual SCORAD reduction was observed between week 1 and 13 (see this article’s Table E2 in the Online Repository at www.jacionline.org). In parallel with the SCORAD, the mean Eczema Area and Severity Index and the pruritus score decreased significantly between week 1 and 13 (by 72%, P < .001, and by 52%, P < .001, respectively; details not shown). Of note, a pruritus reduction of 45% (P < .003) was already observed after 3 weeks of treatment. Previous concomitant medication with antihistamines, topical corticosteroids, and/or calcineurin inhibitors could be reduced or discontinued in 4 of 5, 4 of 9, and 5 of 5 patients, respectively. Pretreatment serum IgE levels ranged from 4666 to 86,119 kU/L (mean, 22,034 ± 7796 kU/L; see this article’s Table E3 in the Online Repository at www.jacionline.org). Each immunoadsorption cycle induced an average reduction of total IgE levels of >90%. IgE levels started to rise again approximately 12 hours after each immunoadsorption, but with repetitive aphereses continuously decreased in a sawtooth-like manner. Within 3 weeks after discontinuation of immunoadsorption, levels of IgE returned to initial concentrations. Similar patterns were seen for circulating total IgG, IgM, and IgA (data not shown). No changes in red and total white blood cell counts as well as blood levels of eosinophil cationic protein were found. Phenotypic characterization by flow cytometry showed no significant change in the percentages of peripheral CD3+, CD4+, CD8+, or CD20+ cells, and no changes in the pattern of their surface expression of HLA-DR, CD69, CLA, ICAM1, or the high-affinity IgE receptor FcεRI on leukocytes. Strikingly, in contrast to serum IgE, immunoadsorption induced a sustained reduction of mainly membrane-bound and cytoplasmatic IgE of histiocytic cells in the dermis and epidermis as well as of Langerhans cells in the epidermis (Fig 2, A and B). Histologic alterations such as hyperkeratosis, spongiosis, acanthosis, and dermal infiltrate, including CD3+, CD4+, CD1a+, HLA-DR+, and MIB1+ cell numbers also dramatically decreased (see this article’s Figs E1, A and B, and E2, A and B, in the Online Repository at www.jacionline.org). In the past few years, a number of case series have shown efficacy of omalizumab in the treatment of AD,2Lane J.E. Cheyney J.M. Lane T.N. Kent D.E. Cohen D.J. Treatment of recalcitrant atopic dermatitis with omalizumab.J Am Acad Dermatol. 2006; 54: 68-72Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 3Vigo P.G. Girgis K.R. Pfuetze B.L. Critchlow M.E. Fisher J. Hussain I. Efficacy of anti-IgE therapy in patients with atopic dermatitis.J Am Acad Dermatol. 2006; 55: 168-170Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 4Belloni B. Ziai M. Lim A. Lemercier B. Sbornik M. Weidinger S. et al.Low-dose anti-IgE therapy in patients with atopic eczema with high serum IgE levels.J Allergy Clin Immunol. 2007; 120: 1223-1225Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 5Sheinkopf L.E. Rafi A.W. Do L.T. Katz R.M. Klaustermeyer W.B. Efficacy of omalizumab in the treatment of atopic dermatitis: a pilot study.Allergy Asthma Proc. 2008; 29: 530-537Crossref PubMed Scopus (125) Google Scholar although no controlled trial has yet been performed to corroborate this efficacy. Our current study extends previously published reports on anti-IgE treatment in AD by presenting, for the first time, immunoadsorption as an alternative and effective IgE depletion method. Clinical improvement was achieved in all our patients presenting with a mean serum IgE level of 22,034, a range that has been previously shown to limit efficacy of omalizumab in patients with AD.1Krathen R.A. Hsu S. Failure of omalizumab for treatment of severe adult atopic dermatitis.J Am Acad Dermatol. 2005; 53: 338-340Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 4Belloni B. Ziai M. Lim A. Lemercier B. Sbornik M. Weidinger S. et al.Low-dose anti-IgE therapy in patients with atopic eczema with high serum IgE levels.J Allergy Clin Immunol. 2007; 120: 1223-1225Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar Of note, immunoadsorption was associated with disease amelioration in all our patients with previously therapy-refractory disease, including patients under current long-term treatment with cyclosporine A. Although we found immunoadsorption to be associated with continuous clinical improvement of AD, only a short-term depletion of serum IgE, followed by fast recovery, was observed. Because neosynthesis of IgE within this short period appears unlikely, the rapid recovery of serum IgE levels may rather be a result of a redistribution of IgE from the interstitial into the intravascular compartment. In line, intensity of IgE deposits in the skin almost halved after immunoadsorption. Interestingly, this effect continued to the end of the study. In parallel with reduction of skin-bound IgE, decreased skin infiltration by inflammatory cells, including antigen-presenting and T cells, and normalization of altered epidermal morphology were observed after immunoadsorption. By downregulating FcεRI expression on dendritic cells, omalizumab has been previously shown to inhibit antigen processing and presentation to T cells.9Prussin C. Griffith D.T. Boesel K.M. Lin H. Foster B. Casale T.B. Omalizumab treatment downregulates dendritic cell FcepsilonRI expression.J Allergy Clin Immunol. 2003; 112: 1147-1154Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar Similarly, it may be speculated that immunoadsorption, by decreasing the amount of IgE in the skin, alters IgE-mediated allergen presentation in AD, thereby preventing the development of long-term consequences of allergen exposure, such as inflammatory cell recruitment and changes in skin architecture. Overall, this case series suggests that immunoadsorption is effective in treatment-refractory AD characterized by excessively high serum IgE levels. Further studies will aim at (1) confirming efficacy and safety of this novel treatment in a prospective randomized controlled trial, (2) studying the long-term effects of immunoadsorption in AD, and (3) better characterizing the mode of action of immunoadsorption in AD. In this investigator-initiated, open-label pilot study, 12 patients with severe AD according to the criteria of Hanifin and RajkaE1Hanifin J.M. Rajka G. Diagnostic features of atopic dermatitis.Acta Derm Venerol (Stockh). 1980; 92: S44-S47Google Scholar (9 men, 3 women; age, 24-66 years; average, 42 years) were consecutively identified and recruited between January 2008 and September 2009. In all patients, AD had been present since early childhood. Study participants had to meet all of the following inclusion and none of the exclusion criteria. The inclusion criteria were (1) AD, (2) 18 years of age or above, (3) total serum IgE level >4500 kU/L, (4) Investigators Global Assessment score 3 or above, and (5) no significant or long-term SCORAD reduction after treatment with topical corticosteroids/calcineurin inhibitors, ultraviolet light therapy (at least 4 weeks of therapy), systemic corticosteroids, and cyclosporine A (at least 8 weeks of therapy) or no possibility of a prolonged use of this therapy because of adverse events or contraindications. The exclusion criteria were (1) known hypersensitivity or allergy to materials used in the adsorber columns, (2) no possibility of an adequate anticoagulation (eg, multiple allergies to various anticoagulants), (3) bleeding disorders including hypocoagulabilities and hypercoagulabilities, (4) severe cardiovascular disease (cardiac failure, NYHA III and IV), (5) severe systemic infections extending beyond skin, (6) serum IgG level below 250 mg/dL, (7) severe immunodeficiency (eg, AIDS), (8) treatment with an ACE inhibitor that could not be omitted 72 hours before immunoadsorption, and (9) pregnancy. Written informed consent was obtained from all patients before participation in the study. The study was approved by the ethics committee of the University of Lübeck (identification no. 07-111) and followed the Declaration of Helsinki. The study is registered with ClinicalTrials.gov (identification number NCT00616096). The study design is shown in Table E1. Immunoadsorption treatment was performed in a 2-step approach: first, plasma was separated by using rotating disc-filtration technique (Life-18 Apheresis Unit; Miltenyi Biotec, Teterow, Germany). Two patient plasma volumes were then applied alternately to 2 adsorption columns (48-52 cycles of 200 mL separated plasma) that contained polyclonal sheep antihuman immunoglobulin antibodies binding human IgG (IgG1-4), IgA, IgM, and IgE with similar affinity (Ig-Therasorb; Miltenyi Biotec). The duration of each treatment session was approximately 5 hours. In 10 patients, a peripheral venous catheter was used, and in 2 patients, a central venous access was required. A total of 10 immunoadsorptions were applied on days 1 to 5 (week 1) and days 29 to 33 (week 5). Initially, the preceding medication including oral antihistamines, topical corticosteroids, and/or topical calcineurin inhibitors was continued without change of frequency and/or dosage and subsequently reduced or discontinued according to disease activity. Reduction or discontinuation of oral cyclosporine A, applied at doses between 100 and 250 mg per day, was not included in the study protocol because a relapse rate of 55% within weeks after cessation of cyclosporine A has been reported in patients with AD.E2Hijnen D.J. ten Berge O. Timmer-de Mik L. Bruijnzeel-Koomen C.A. de Bruin-Weller M.S. Efficacy and safety of long-term treatment with cyclosporin A for atopic dermatitis.J Eur Acad Dermatol Venereol. 2007; 21: 85-89Crossref PubMed Scopus (62) Google Scholar This would have interfered with the evaluation of the clinical outcome parameters. Punch biopsies were taken from lesional skin before initiating immunoadsorption. From the same areas, additional biopsies were obtained 3 weeks after the first (week 5) and 7 weeks after the second immunoadsorption cycle (week 13). To evaluate the clinical efficacy of immunoadsorption, SCORAD,E3Kunz B. Oranje A.P. Labrèze L. Stalder J.F. Ring J. Taïeb A. Clinical validation and guidelines for the SCORAD index: consensus report of the European Task Force on Atopic Dermatitis.Dermatology. 1997; 195: 10-19Crossref PubMed Scopus (846) Google Scholar Eczema Area and Severity Index,E4Hanifin J.M. Thurston M. Omoto M. Cherill R. Tofte S.J. Graeber M. The Eczema Area and Severity Index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group.Exp Dermatol. 2001; 10: 11-18Crossref PubMed Scopus (762) Google Scholar and a visual analog scale assessing pruritus (0-10: 0, no pruritus; 10, maximal experienced pruritus) were applied. In addition, the use of concomitant therapy for AD (frequency of topical corticosteroids and/or calcineurin inhibitors, doses of cyclosporine A and antihistamines) was evaluated. Adverse events were recorded at each visit. To monitor complete blood count, an automatic blood count analysis system (LH750; Beckman Coulter, Krefeld, Germany) was used. Levels of eosinophil cationic protein in blood were determined by the Immuno CAP 250 system (Phadia, Freiburg, Germany). Lymphocyte subsets and FcεRI expression on leucocytes were analyzed by standard flow cytometry by using a FACS Calibur (BD Bioscience, Basel, Switzerland). Total serum IgE levels were measured with the UniCAP system (Phadia) and total IgG, IgM, and IgA serum levels with the BN Prospec Nephelometer system (Siemens, Munich, Germany). Sections of 6 μm of the paraformaldehyde-fixed, paraffin-embedded punch biopsies were stained with hematoxylin and eosin and examined by light microscopy (BX40F; Olympus, Tokyo, Japan). To assess the extent of hyperkeratosis, acanthosis, spongiosis, and dermal infiltration, a semiquantitative score (0, none; 1, mild; 2, moderate; 3, severe) was applied.E5Simon D. Hösli S. Kostylina G. Yawalkar N. Simon H.U. Anti-CD20 (rituximab) treatment improves atopic eczema.J Allergy Clin Immunol. 2008; 121: 122-128Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar Sections were evaluated by 2 independent investigators. Immunohistochemical staining was performed on 4-μm sections of paraformaldehyde-fixed and paraffin-embedded punch biopsies. Total IgE amount in the skin was determined by a polyclonal rabbit antibody against the ε chains of IgE (Dako, Glostrup, Denmark). To characterize inflammatory cell patterns, sections were treated with monoclonal murine antibodies against CD3 (TH cells), CD4 (TH cells), CD8 (T effector cells), and CD20 (B cells; all from LAB Vision, Fremont, Calif) as well as against CD1a (epidermal dendritic cells), HLA-DR (antigen-presenting cells), and tryptase and c-kit (mast cells; all from Dako). Eosinophils were visualized by the naphthol AD-D chloroacetate (Leder) stain (Sigma, St Louis, Mo). For detection of proliferating cells, a mAb to MIB1 was used (Dako). Intensity of immunohistochemical staining was evaluated by using a semiquantitative score (0, none; 1, mild; 2, moderate; 3, severe).E5Simon D. Hösli S. Kostylina G. Yawalkar N. Simon H.U. Anti-CD20 (rituximab) treatment improves atopic eczema.J Allergy Clin Immunol. 2008; 121: 122-128Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar Data are presented as means ± SEMs. To compare the data before and after therapy, the t test was applied. In cases of repeated measurements, the 1-way ANOVA or 1-way ANOVA on ranks was used. A P value <.05 was considered statistically significant. Tabled 1Study designProceduresTime (wk)135913Immunoadsorption (5×)xxClinical monitoringxxxxxHematology, assays for IgE, IgG, IgM, and IgAxxxxxImmunophenotypingxxxSkin biopsyxxx Open table in a new tab Tabled 1SCORAD during the course of the studyPatient no.†Order according to consecutive identification and recruitment of study patients.SCORADWeek 1 (before first IA cycle)Week 3Week 5 (before second IA cycle)Week 9Week 131Dropout2555048334237127353326470333352295Dropout68031363123791433434358837058455397254472413109898503132118958583939127729263032Mean ± SEM78.6 ± 3.949.2 ± 7.1∗Statistically significant difference from SCORAD values at week 1 (P < .001).42.5 ± 3.6∗Statistically significant difference from SCORAD values at week 1 (P < .001).35.0 ± 2.6∗Statistically significant difference from SCORAD values at week 1 (P < .001).32.4 ± 3.5∗Statistically significant difference from SCORAD values at week 1 (P < .001).IA, Immunoadsorption.∗ Statistically significant difference from SCORAD values at week 1 (P < .001).† Order according to consecutive identification and recruitment of study patients. Open table in a new tab IA, Immunoadsorption. Tabled 1Serum IgE levels during the course of the studyPatient no.Total serum IgE (kU/L)Week 1, day 1 (before first IA cycle)Week 1, day 5 (after first IA cycle)Week 3Week 5, day 1 (before second IA cycle)Week 5, day 5 (after second IA cycle)Week 9Week 131Dropout214,4061,47111,64310,5042,213ND12,553324,3581,39912,34722,6861,40629,08726,97444,6664104,8734,8654274,7065,9425Dropout637,7684,96643,90539,8433,15377,54878,21779,9132,4638,8397,7849876,4686,143819,0951,14712,36913,5251,56216,77717,22699,4587078,3307,0885647,4678,8151086,1197,18499,150117,33811,001126,990127,660116,6634903,9726,4617907,2107,275127,8914667,1117,6244736,6398,750Mean ± SEM22,033.7 ± 7,795.82,070.3 ± 715.221,253.9 ± 9,380.723,771.8 ± 10,927.52,257.6 ± 1,009.031,432.4 ± 14,235.929,955.5 ± 12,868.5IA, Immunoadsorption; ND, not done. Open table in a new tab IA, Immunoadsorption; ND, not done.