Christoph Spiekermann

Transcriptome Assessment Reveals a Dominant Role for TLR4 in the Activation of Human Monocytes by the Alarmin MRP8

The alarmins myeloid-related protein (MRP)8 and MRP14 are the most prevalent cytoplasmic proteins in phagocytes. When released from activated or necrotic phagocytes, extracellular MRP8/MRP14 promote inflammation in many diseases, including infections, allergies, autoimmune diseases, rheumatoid arthritis, and inflammatory bowel disease. The involvement of TLR4 and the multiligand receptor for advanced glycation end products as receptors during MRP8-mediated effects on inflammation remains controversial. By comparative bioinformatic analysis of genome-wide response patterns of human monocytes to MRP8, endotoxins, and various cytokines, we have developed a model in which TLR4 is the dominant receptor for MRP8-mediated phagocyte activation. The relevance of the TLR4 signaling pathway was experimentally validated using human and murine models of TLR4- and receptor for advanced glycation end products–dependent signaling. Furthermore, our systems biology approach has uncovered an antiapoptotic role for MRP8 in monocytes, which was corroborated by independent functional experiments. Our data confirm the primary importance of the TLR4/MRP8 axis in the activation of human monocytes, representing a novel and attractive target for modulation of the overwhelming innate immune response.

Highly pathogenic influenza viruses inhibit inflammatory response in monocytes via activation of rar-related orphan receptor RORα

Infections with highly pathogenic avian influenza viruses (HPAIV) in humans lead to systemic disease associated with cytokine storm and multiorgan failure. In this study we aimed to identify the role of monocytes for the host response to HPAIV infection. Using genome-wide microarray analysis, we surprisingly demonstrate a reduced immune response of human monocytes to HPAIV H5N1 compared to human influenza A viruses. In bioinformatic analyses we could reveal a potential role of the Rar-related orphan receptor alpha (RORa) for the gene expression pattern induced by H5N1. RORa is known as an inhibitor of NF-κB signaling. We provide evidence that in monocytes RORa is activated by H5N1, resulting in inhibited NF-κB signaling. Using murine Hoxb8-immortalized RORa-/-, monocytes rescued NF-κB signaling upon H5N1 infection, confirming the biological relevance of RORa as an H5N1-induced mediator of monocytic immunosuppression. In summary, our study reveals a novel RORa-dependent escape mechanism by which H5N1 prevents an effective inflammatory response of monocytes blocking NF-κB-dependent gene expression.

Increased Levels of S100A8/A9 in Patients with Peritonsillar Abscess: A New Promising Diagnostic Marker to Differentiate between Peritonsillar Abscess and Peritonsillitis

Peritonsillar abscess (PTA) is a very frequent reason for urgent outpatient consultation and otolaryngological hospital admission. Early, correct diagnosis and therapy of peritonsillar abscess are important to prevent possible life-threatening complications. Based on physical examinations, a reliable differentiation between peritonsillar cellulitis and peritonsillar abscess is restricted. A heterodimeric complex called calprotectin consists of the S100 proteins A8 and A9 (S100A8/A9) and is predominantly expressed not only in monocytes and neutrophils but also in epithelial cells. Due to its release by activated phagocytes at local sites of inflammation, we assumed S100A8/A9 to be a potential biomarker for peritonsillar abscess. We examined serum and saliva of patients with peritonsillitis, acute tonsillitis, peritonsillar abscess, and healthy controls and found significantly increased levels of S100A8/A9 in patients with PTA. Furthermore, we could identify halitosis, trismus, uvula edema, and unilateral swelling of the arched palate to be characteristic symptoms for PTA. Using a combination of these characteristic symptoms and S100A8/A9 levels, we developed a PTA score as an objective and appropriate tool to differentiate between peritonsillitis and peritonsillar abscess with a sensitivity of 92% and specificity of 93%.

Adaption and validation of the nasal obstruction symptom evaluation scale in German language (D-NOSE)

BackgroundQuestionnaires have proven their worth in detecting changes in quality of life after medical interventions. The Nasal Obstruction Symptom Evaluation scale (NOSE) is a reliable and valid tool to identify restrictions of quality of life in patients with nasal problems. The aim of this prospective study was the validation of the German version of the NOSE scale (D-NOSE).MethodsAdaption of the NOSE in German language was performed by forward and backward translation process. Patients undergoing functional septorhinoplasty were asked to complete the D-NOSE preoperatively, one, three or twelve months after surgery. Healthy volunteers served as controls. Reliability, validity and responsiveness of the D-NOSE were determined.ResultsThe D-NOSE showed a good internal consistency as well as good inter-item, item-total correlation and a satisfactory test-retest reliability. The convincing validity of the adapted NOSE scale was approved by good construct validity and an excellent discriminant validity. Furthermore, a high sensitivity to identify clinical changes due to an intervention indicates a good responsiveness of the D-NOSE.ConclusionsThe adapted German version of the NOSE questionnaire (D-NOSE) is an appropriate and validated tool to assess the influence of nasal obstruction in quality of life in German speaking patients.

Development and Validation of a Brief Four-Component Questionnaire to Identify Patient's Motivation to Undergo Functional Rhinoplasty

Abstract Outcome of functional rhinoplasty depends on different domains such as functional and aesthetic improvement. The aim of this study was to develop a brief and comprehensible questionnaire to identify patient motivation to undergo rhinoplasty and to measure the outcome of an intervention within a short time during outpatient consultation. Patients undergoing rhinoplasty were asked to complete the Rhinoplasty Outcome Evaluation (ROE) questionnaire, the Nasal Obstruction Symptom Evaluation (NOSE) scale, and the Utrecht Questionnaire for Outcome Assessment in Aesthetic Rhinoplasty (OAR) preoperatively, as well as one, three, and twelve months postoperatively. Patient satisfaction after surgery was assessed at postoperative consultations using a five‐point Likert scale. Principle component analysis was performed to reveal the main domains, which were detected by the different questionnaires. Items with the strongest loading on a factor were identified by correlation matrix. Influence of the nasal appearance on the quality of life, troubles with nasal breathing, subjective perception of nasal appearance, and the wish for modification or alteration were found to be the four important domains of the questionnaires. The questions with the strongest loading on these domains were compiled and the four‐component questionnaire (4CQ) was developed. The 4CQ is a very effective instrument to obtain a comprehensive impression of the varied determinants representing the major motifs to undergo functional rhinoplasty within a short time. The preoperative assessment of the 4CQ allows an estimation concerning the expected outcome.

Potential of the Novel PTA Score to Identify Patients with Peritonsillar Inflammation Profiting from Medical Treatment

Peritonsillar inflammation is a common characteristic of both peritonsillar abscess (PTA) and peritonsillitis (PC). The aim of the present study was to apply the PTA score as an objective criterion to identify patients with peritonsillar inflammation (PI) who might profit from medical treatment. Hence, the recently developed PTA score was applied retrospectively on patients suffering from acute tonsillitis, peritonsillitis, and peritonsillar abscess. Analysis of the clinical data, the follow-up, and the initial PTA score was performed. Patients with peritonsillar inflammation show significant higher PTA score values compared to patients with acute tonsillitis without peritonsillar inflammation and healthy controls. Patients with a PTA score ≤ 2 profited from medical treatment consisting of antibiotics in 92.3% of the cases. In 89.2% of the patients with a PTA score > 2, pus was detected during abscess relief. Patients with peritonsillar inflammation who profited from medical treatment had significantly reduced PTA score values and a reduced duration of hospitalization compared to the patients with abscess relief. Thus, the PTA score has the potential as an objective criterion to identify patients with peritonsillar inflammation profiting from medical treatment. Hence, application of the PTA score helps to determine an optimal, individualized treatment approach and might reduce utilization of medical resources.

The Visual Analog Scale as a Comprehensible Patient-Reported Outcome Measure (PROM) in Septorhinoplasty

The patient’s satisfaction with the esthetic result is a major criterion of success in septorhinoplasty. However, the idea of esthetic perfection varies greatly and primarily depends on subjective perception. Hence, patient-reported instruments are important and necessary to assess the outcome in septorhinoplasty. To analyze the potential of the visual analog scale (VAS) as a patient-reported outcome measure in septorhinoplasty, the perception of the nasal appearance was assessed by a VAS pre- and postoperatively in 213 patients undergoing septorhinoplasty. Furthermore, in this prospective study, the patients’ satisfaction concerning the procedure’s result was analyzed using a five-point Likert scale. Females had lower preoperative VAS scores but a higher increase compared to males. Patients with lower initial VAS scores showed a higher improvement in the VAS score postoperatively compared to patients with higher initial VAS scores. Satisfaction with the result depends on the increase in the VAS score value. The VAS scale is a short and comprehensible tool to assess patients’ perception of nasal appearance preoperatively and represents an appropriate instrument to assess the esthetic patient-reported outcome in septorhinoplasty.Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Coexistence of sarcoidosis and metastatic lesions: A diagnostic and therapeutic dilemma (Review)

Sarcoidosis, a chronic, inflammatory disease that affects various different organs, is characterized by noncaseating epitheloid granulomas. This systemic inflammatory process is associated with an increased risk of cancer. Several cases of sarcoidosis that mimic metastatic tumor progression in radiological findings have been reported so far. However, there are also cases that have presented a coexistence of sarcoidosis and metastasis, which have caused a diagnostic and therapeutic dilemma. Due to inadequate current therapies, a reliable differentiation between benign and malignant lesions is crucial. This review focuses on the residual risk of the coexistence of metastases within radiological suspicious lesions in patients with a history of solid tumors and sarcoidosis, as well as immunological findings, in order to explain the potential associations. Sarcoidosis has the potential to promote metastasis as it includes tumor-promoting and immune-regulating cell subsets. Notably, myeloid derived suppressor cells may serve a pivotal role in metastatic progression in patients with sarcoidosis. In addition, the present review also evaluates the potential novel diagnostic approaches, which may be able to differentiate between metastatic lesions and sarcoidosis. The risk of coexistent metastasis in sarcoidosis lesions must be considered by clinical practitioners, and a multidisciplinary approach may be required to avoid misdiagnosis and the subsequent unnecessary surgery or insufficient treatments.