Broncho-alveolar Lavage Matrix Metalloproteases as a Sensitive Measure of Bronchiolitis Obliterans

Bronchiolitis obliterans (BO) is a survival-limiting factor in lung transplantation. There are no common BO markers in use. Since BO is associated with extracellular matrix remodeling, we asked whether matrix metalloproteases (MMPs) and their tissue inhibitors (TIMPs) could serve as BO markers. In 72 lung transplant patients (34 BO syndrome (BOS) 0, 15 BOS 0-p, and 23 BOS 1) serum and broncho-alveolar lavage (BAL) MMP and TIMP levels were examined by ELISA. The BAL cell counts were additionally analyzed. The serum MMP-2, MMP-8, MMP-9 and TIMP-2 levels were not different in all groups. In contrast, the BAL MMP-8, -9 and TIMP-1 levels were significantly elevated in BOS 0-p (p = 0.003; p = 0.007; p = 0.0003, respectively) and BOS 1 (p = 0.003; p = 0.001; p = 0.0004, respectively) as compared to BOS 0 patients. The BAL MMP-8, -9 and TIMP-1 levels were significant predictors of BOS 0-p (p = 0.01; p = 0.01; p = 0.01, respectively) and BOS-1 (p = 0.007; p = 0.01; p = 0.006, respectively) in receiver operating characteristic analysis. Except for BAL macrophages that were significantly decreased in BOS 0-p versus BOS 0 patients; other cell counts were not different between the groups. BAL MMP-8, -9 and TIMP-1 might be useful markers to detect BO in lung transplant patients.     

The effect of oral anticoagulation on clotting during hemodialysis

BACKGROUND: Between 5% and 10% of hemodialysis patients are treated with oral anticoagulants. It is currently unknown whether additional anticoagulation with heparin or low-molecular-weight heparin (LMWH) is needed to prevent clotting during hemodialysis. METHODS: In this prospective, randomized, cross-over study 10 patients treated with oral anticoagulants (phenprocoumon) received either no additional anticoagulation or low dose dalteparin (bolus of 40 IU/kg body weight) before dialysis. Efficacy of hemodialysis was measured by normalized weekly Kt/V and urea reduction rate (URR). Thrombus formation was evaluated by measurement of D-dimer and inspection of air traps and dialyser. RESULTS: The median international normalized ratio (INR) did not differ between both observation periods (phenprocoumon 2.2(2 to 3) vs. dalteparin 2.1(2 to 2.9). The anti-Xa level in dalteparin patients was 0.33 (0.27 to 0.38) IU/mL after 2 hours and 0.16 (0.03 to 0.23) IU/mL after 4 hours of hemodialysis. The median increase of D-dimer was significantly higher in patients without additional dalteparin therapy during hemodialysis (DeltaD-dimer 0.23 microg/mL vs. 0.03 mug/mL) (P= 0.0004). Complete thrombosis of the dialyser membrane occurred in one patient in the phenprocoumon group but in none with combined treatment. The extent of thrombosis in the arterial and venous air trap and dialyser was significantly less in patients with additional dalteparin therapy (P= 0.0014, P= 0.0002, and P= 0.0005, respectively). Weekly Kt/V and URR was similar in both groups. CONCLUSION: Standard oral anticoagulation with an INR between 2 and 3 is insufficient to prevent clotting during hemodialysis. Additional low dose anticoagulation with a LMWH or heparin is necessary to facilitate treatment.     

Emergence of West Nile virus lineage 2 in Europe: Characteristics of the first seven cases of West Nile neuroinvasive disease in horses in Austria

We report details of the first seven equine cases of confirmed West Nile neuroinvasive disease in Austria. The cases presented during summer and autumn of 2016 (n = 2), 2017 (n = 3) and 2018 (n = 2). All horses showed gait abnormalities and 6 of 7 horses exhibited fasciculations and/or tremors, and we provide video recordings of these. Three horses also showed cranial nerve involvement. Following rapid improvement, three horses were discharged. Four horses were euthanized due to the severity of clinical signs and subjected to neuropathological examination. West Nile virus (WNV) lineage 2 nucleic acid was detected in 5 of 7 horses, and WNV‐specific neutralizing antibodies in all 7 horses. In addition, serologic evidence of WNV infection was found in two out of fourteen in‐contact horses. Horses may be considered a sentinel species for human WNV infections, integrating human and veterinary medicine and thus contributing to the one health concept.     

Side effect management during immune checkpoint blockade using CTLA‐4 and PD‐1 antibodies for metastatic melanoma – an update

CTLA‐4 and PD‐1 play a key role in tumor‐induced downregulation of lymphocytic immune responses. Immune checkpoint inhibitors have been shown to alter the immune response to various cancer types. Anti‐CTLA‐4 and anti‐PD‐1 antibodies affect the interaction between tumor, antigen‐presenting cells and T lymphocytes. Clinical studies of the anti‐CTLA‐4 antibody ipilimumab and the anti‐PD‐1 antibodies nivolumab and pembrolizumab have provided evidence of their positive effects on overall survival in melanoma patients. Combined treatment using ipilimumab and nivolumab has been shown to achieve five‐year survival rates of 52 %. Such enhancement of the immune response is inevitably associated with adverse events. Knowledge of the spectrum of side effects is essential, both in terms of prevention and management. Adverse events include colitis, dermatitis, hypophysitis, thyroiditis, hepatitis and other, less common autoimmune phenomena. In recent years, considerable progress has been made in the detection and treatment of the aforementioned immune‐related adverse events. However, early diagnosis of rare neurological or cardiac side effects, which may be associated with increased mortality, frequently pose a challenge. The present update highlights our current understanding as well as new insights into the spectrum of side effects associated with checkpoint inhibitors and their management.     

Effectiveness of dupilumab for the treatment of nummular eczema phenotype of atopic dermatitis in adults

Nummular eczema (NE) is currently considered as one of the clinical phenotypes of atopic dermatitis (AD) of the adult. In this multicentre study, 30 adult patients (age ≥ 18 years) affected with nummular‐like AD were treated with dupilumab, a monoclonal antibody against the receptor for interleukin(IL)‐4 and IL‐13. The evaluation of the results after 16 weeks of treatment showed a significant improvement of the disease, as demonstrated by reduction in Eczema Area Severity Score (EASI), visual analogue score (VAS) of pruritus, and Dermatology Life Quality Index (DLQI) scores. Conjunctivitis in one patient was the only side effect. In conclusion, dupilumab seems to be an effective and safe treatment in NE phenotype of AD of the adult.     

Fatal paraneoplastic pemphigus associated with a mediastinal tumor

Paraneoplastic pemphigus (PNP) is a rare life‐threatening autoimmune bullous skin disease which is an obligate paraneoplasma. A 34‐year‐old woman presented with recalcitrant stomatitis and a generalized lichenoid rash. A diagnosis of PNP was established based on clinical findings, immunofluorescence, histopathology and biochemistry. A localized mediastinal mass was found with CT imaging and excised. The histologic diagnosis was dendritic cell sarcoma. Despite removal of tumor and immunosuppressive therapy, the PNP progressed rapidly and the patient died of septic multiorgan failure.     

Effects of the chemokine MIP-1alpha on anemia and inflammation in rheumatoid arthritis

Macrophage inflammatory protein-1alpha (MIP-1alpha) is an interesting chemokine because in addition to its variety proinflammatory activities including chemotaxis and immunomodulation, it is a potent inhibitor of hematopoetic stem cell proliferation. Inhibition of erythroid progenitor cells due to MIP-1alpha or other cytokines can play a role in the pathogenesis of anemia which is one of the most common extra-articular features of active rheumatoid arthritis (RA). In 84 patients with RA, serological and immunological parameters were assessed to detect inflammatory mechanisms and anemia in relation to the serum concentrations of MIP-1alpha. All patients fulfilled the ACR criteria for the diagnosis of a definite or classic RA. We used a quantitative enzyme immuno assay for the detection of MIP-1alpha as well as for the measurement of the acute phase protein serum amyloid A (SAA), the erythropoiesis inducer erythropoietin (EPO) and the transferrin receptor (TfR). The immune activation marker neopterin was measured radioimmunologically. Half of the patients with RA were anemic with hemoglobin values below 12 g/dl. MIP-1alpha was found to be elevated significantly in serum of patients with active rheumatoid arthritis and in patients with anemia. Most of the anemic patients with markedly elevated acute phase reactions had an anemia with chronic diseases and not a functional iron deficiency alone. TfR correlated with EPO. The results show that enhanced expression of MIP-1alpha is indicative of systemic inflammation in RA. Moreover, besides the regulation of inflammatory processes, this chemokine may influence the pathogenesis of anemia in RA patients.     

Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses

The tyrosine kinase inhibitors sorafenib and sunitinib are approved for the treatment of patients with malignant diseases. To analyze the possible use of these compounds in combination with immunotherapeutic approaches, we analyzed the effects of both inhibitors on the immunostimulatory capacity of human dendritic cells (DCs) and the induction of primary immune responses in vivo. Sorafenib, but not sunitinib, inhibits function of DCs, characterized by reduced secretion of cytokines and expression of CD1a, major histocompatibility complex, and costimulatory molecules in response to TLR ligands as well as by their impaired ability to migrate and stimulate T-cell responses. These inhibitory effects are mediated by inhibition of PI3 and MAP kinases and NFB signaling. In contrast, sorafenib had no influence on the phenotype and proliferation of T cells. To analyze the effects of both TKIs on cytotoxic T-cell induction in vivo, C57BL/6 mice were pretreated with sorafenib or sunitinib and immunized with OVA_257-264 peptide. Sorafenib, but not sunitinib, application significantly reduced the induction of antigen-specific T cells. Numbers of regulatory T cells were reduced in peripheral blood mononuclear cells from mice treated with sunitinib. These results indicate that sunitinib, but not sorafenib, is suitable for combination with immunotherapeutic approaches for treatment of cancer patients.