COVID-19 and chronic rhinosinusitis: management and comorbidity - what have we learned?

INTRODUCTION: Approximately 5%-12% of the population worldwide suffer from chronic rhinosinusitis (CRS). CRS is defined as a chronic respiratory disease and is considered to be a risk factor for COVID-19 patients. AREAS COVERED: A non-systematic literature research was conducted on COVID-19 and treatment options for CRSwNP. The latest international publications in medical databases, international guidelines, and the internet were reviewed. Since there were no publications on all aspects of this topic during the pandemic, we included our own experience in this report. Based on the conducted literature research in addition to our previously reported experience, we discuss the treatment of CRSwNP during the COVID-19 pandemic and what can be taken for future pandemics. EXPERT OPINION: Intranasal corticosteroids remain the standard treatment for CRS in patients with SARS-CoV-2 infection. Indications for surgical treatment of CRS should be critically evaluated and reserved for patients with complications and those with no other treatment options. For this purpose, COVID-19 status should be known if possible and, in case of unclear status (emergency), using appropriate personal protective equipment. Systemic corticosteroids should be avoided were possible. Biological treatment should be continued under careful monitoring in uninfected patients and should be temporarily interrupted during COVID-19 infection.

[Neuroimmunology of allergic rhinitis part 2 : Interactions of neurons and immune cells and neuroimmunological units]. / Neuroimmunologie der allergischen Rhinitis Teil 2 : Interaktionen von Neuronen und Immunzellen und neuroimmunologische Einheiten.

Allergic rhinitis is an IgE-mediated, type­2 inflammatory disease. neuropeptides are released by neurons and interact with immune cells. Via colocalization, neuroimmune cell units such as nerve-mast cell units, nerve-type 2 innate lymphoid cell (ILC2) units, nerve-eosinophil units, and nerve-basophil units are formed. Markedly elevated tryptase levels were found in nasal lavage fluid and were strongly associated with neuropeptide levels. A close anatomical connection allows bidirectional communication between immune and neuronal cells. Transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin repeat 1 (TRPA1) are critically involved in immunological reactions in the setting of allergic rhinitis. Neuroimmunological communication plays an important role in the inflammatory process, so that allergic rhinitis can no longer be considered a purely immunological disease, but rather a combined neuroimmunological disease.

[Neuroimmunology of allergic rhinitis : Part 1: Cellular and humoral basic principles]. / Neuroimmunologie der allergischen Rhinitis : Teil 1: Zelluläre und humorale Grundlagen.

Allergic rhinitis (AR) is a very common disease with a high prevalence worldwide. It is an IgE-mediated type 2 inflammatory disease following exposure to inhalant allergens. A multitude of different neuropeptides including substance P, vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), nerve growth factor (NGF), and neuromedin U (NMU) can be released via peripheral axon or central reflexes, interact with immune cells, and thus contribute to neurogenic inflammation which causes the nasal hyperreactivity (NHR) characteristic of AR. Independent production of neuroendocrine hormones and neuropeptides by immune cells has also been demonstrated. Neuro-immune cell units arise when immune and neuronal cells colocalize, for which typical anatomic regions are, e.g., the mast cell-nerve functional unit. The focus of this review is the elucidation of neuroimmune communication mechanisms in AR.

Empfehlungen zur Überprüfung der Wirksamkeit und Verlaufsdokumentation von Mepolizumab bei chronischer Rhinosinusitis mit Nasenpolypen (CRSwNP) im deutschen Gesundheitssystem ­ Empfehlungen des Ärzteverbandes Deutscher Allergologen (AeDA) und der AGs Klinische Immunologie, Allergologie und Umweltmedizin und Rhinologie und Rhinochirurgie der Deutschen Gesellschaft für HNO-Heilkunde, Kopf- und Halschirurgie (DGHNOKHC).

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the mucous membranes of the nose and sinuses. Eosinophilic inflammation is described as a common endotype. The anti-IL5 antibody mepolizumab was approved in November 2021 as an add-on therapy to intranasal glucocorticosteroids for the treatment of adults with severe chronic rhinosinusitis with nasal polyps when systemic glucocorticosteroids or surgery do not provide adequate disease control. While national and international recommendations exist for the use of mepolizumab in CRSwNP, it has not yet been adequately specified how this therapy is to be monitored, what follow-up documentation is necessary, and when it should be terminated if necessary. METHODS: A literature search was performed to analyze previous data on the treatment of CRSwNP with mepolizumab and to determine the available evidence by searching Medline, Pubmed, the national and international trial and guideline registries and the Cochrane Library. Human studies published in the period up to and including 10/2022 were considered. RESULTS: Based on the international literature and previous experience by an expert panel, recommendations for follow-up, adherence to therapy intervals and possible therapy breaks, as well as termination of therapy when using mepolizumab for the indication CRSwNP in the German health care system are given on the basis of a documentation sheet. CONCLUSIONS: Understanding the immunological basis of CRSwNP opens up new non-surgical therapeutic approaches with biologics for patients with severe, uncontrolled courses. Here, we provide recommendations for follow-up, adherence to therapy intervals, possible therapy pauses, or discontinuation of therapy when mepolizumab is used as add-on therapy with intranasal glucocorticosteroids to treat adult patients with severe CRSwNP that cannot be adequately controlled with systemic glucocorticosteroids and/or surgical intervention.

Symptoms of Long-COVID 1-Year after a COVID-19 outbreak among sailors on a French aircraft carrier.

OBJECTIVES: While persistent symptoms have been reported after the coronavirus disease-2019 (COVID-19), long-term data on outpatients with mild COVID-19 are lacking. The objective was to describe symptoms persisting for 12 months. METHODS: This prospective cohort study on 1767 sailors of an aircraft carrier in which a Covid-19 outbreak occurred during a mission in April 2020 described predefined self-reported symptoms of Long-COVID at 6, 9 and 12 months. Logistic-regression analyses were used to identify correlates for Long-COVID at months 6, 9 and 12. RESULTS: Among the 641 participants, 619 (35%) completed at least one follow-up questionnaire (413 COVID-positive and 206 COVID-negative). Symptoms of Long-COVID were reported by 53.7%, 55.2% and 54.3% of COVID-positive participants vs 31.2%, 23.3% and 40.0% in COVID-negative patients, at 6 (p <.002), 9 (p <.002) and 12 months (p =.13), respectively. The most frequent symptoms reported were concentration and memory difficulties, asthenia and sleep disorders. CONCLUSION: In this study more than half of COVID-positive outpatients reported persistent symptoms up to 12 months post-quarantine. These findings suggests that all patients, including those with mild disease, can be affected by Long-COVID. A lack of difference at 12 months with COVID-negative patienys prompts caution. The symptoms of Long-COVID are so non-specific that they may be viewed as the consequence of multiple intercurrent factors.

Empfehlungen zur Überprüfung der Wirksamkeit und Verlaufsdokumentation von Dupilumab bei chronischer Rhinosinusitis mit Nasenpolypen (CRSwNP) im deutschen Gesundheitssystem.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the nasal and paranasal mucosa. A Type-2 inflammation is described as the most common endotype. Since October 2019 the anti-IL-4/-IL-13 antibody dupilumab has been approved in Germany as an add-on therapy to intranasal corticosteroids for the treatment of adults with severe chronic rhinosinusitis with nasal polyps, when systemic corticosteroids alone or surgery do not provide adequate disease control. While recommendations for the use of dupilumab in CRSwNP exist at both national and international levels, until now it has not been adequately established, how therapy should be monitored and when it should be discontinued in the German Health Care System. METHODS: A literature search was performed analyzing previous data on the treatment of CRSwNP with dupilumab and to determine the available evidence by searching Medline, Pubmed, the national and international trial and guideline registries and the Cochrane Library. Human studies published in the period up to 05/2022 were included. RESULTS: Based on international literature and previous experience, recommendations are given by an expert panel for follow-up and possible therapy breaks, therapy intervals or termination of therapy when using dupilumab for the indication CRSwNP in the German health care system based on a documentation form. CONCLUSIONS: Understanding the immunological basis of CRSwNP opens new non-surgical therapy approaches with biologics for patients with severe courses. The authors give recommendations for follow-up, possible therapy breaks, therapy intervals and a termination for dupilumab treatment as add-on therapy with intranasal corticosteroids for the treatment of adult patients with severe CRSwNP that cannot be adequately controlled with systemic corticosteroids and/or surgical intervention.

Positionspapier: Empfehlungen zur Anwendung von Mepolizumab bei chronischer Rhinosinusitis mit Polyposis nasi (CRSwNP) im deutschen Gesundheitssystem ­ Empfehlungen des Ärzteverbandes Deutscher Allergologen (AeDA) und der AGs Klinische Immunologie, Allergologie und Umweltmedizin und Rhinologie und Rhinochirurgie der Deutschen Gesellschaft für HNO-Heilkunde, Kopf- und Hals-Chirurgie (DGHNO-KHC).

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the paranasal sinus mucosa with eosinophilic inflammation as the most common endotype. The anti-IL5 antibody mepolizumab was approved for the treatment of severe CRSwNP in the EU in November 2021. METHODS: A literature search was performed to analyze the immunology of CRSwNP and determine the available evidence by searching Medline, Pubmed, and the German national and international trial and guideline registries and the Cochrane Library. Human studies published in the period up to and including 12/2021 that investigated the effect of mepolizumab in CRSwNP were considered. RESULTS: Based on the international literature and previous experience, recommendations for the use of mepolizumab in CRSwNP in the German health care system are given by an expert panel on the basis of a documentation form. CONCLUSIONS: Understanding about the immunological basis of CRSwNP opens new non-surgical therapeutic approaches with biologics for patients with severe courses. Mepolizumab is approved since November 2021 for add-on therapy with intranasal corticosteroids for the treatment of adult patients with severe CRSwNP who cannot be adequately controlled with systemic corticosteroids and/or surgical intervention.

Renal cystic diseases during the perinatal and neonatal period.

Renal cystic diseases are a clinically and genetically diverse group of renal diseases that can manifest in utero, infancy, or throughout childhood and adulthood. These diseases may be unilateral or bilateral with a single cyst or multiple cysts, or with increased echogenicity of the renal cortex without macroscopic cysts. Certain cystic renal diseases are life-threatening, with many developing chronic kidney and hepatic disease if not recognized early enough. Therefore, due to the prevalence and life-altering complications of this specific group of diseases in vulnerable populations, it is crucial for clinicians and healthcare providers to have an overall understanding of cystic diseases and how to pre-emptively detect and manage these conditions. In this review, we discuss in detail the epidemiology, genetics and pathophysiology, diagnosis, presentation, and management of numerous genetic and sporadic renal cystic diseases, such as polycystic kidney disease, multicystic dysplastic kidney, and calyceal diverticula, with an emphasis on prenatal care and pregnancy counseling.

AllergoOncology: ultra-low IgE, a potential novel biomarker in cancer-a Position Paper of the European Academy of Allergy and Clinical Immunology (EAACI).

Elevated serum IgE levels are associated with allergic disorders, parasitosis and specific immunologic abnormalities. In addition, epidemiological and mechanistic evidence indicates an association between IgE-mediated immune surveillance and protection from tumour growth. Intriguingly, recent studies reveal a correlation between IgE deficiency and increased malignancy risk. This is the first review discussing IgE levels and links to pathological conditions, with special focus on the potential clinical significance of ultra-low serum IgE levels and risk of malignancy. In this Position Paper we discuss: (a) the utility of measuring total IgE levels in the management of allergies, parasitosis, and immunodeficiencies, (b) factors that may influence serum IgE levels, (c) IgE as a marker of different disorders, and d) the relationship between ultra-low IgE levels and malignancy susceptibility. While elevated serum IgE is generally associated with allergic/atopic conditions, very low or absent IgE may hamper anti-tumour surveillance, indicating the importance of a balanced IgE-mediated immune function. Ultra-low IgE may prove to be an unexpected biomarker for cancer risk. Nevertheless, given the early stage of investigations conducted mostly in patients with diseases that influence IgE levels, in-depth mechanistic studies and stratification of malignancy risk based on associated demographic, immunological and clinical co-factors are warranted.

Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a multifactorial fatal motoneuron disease without a cure. Ten percent of ALS cases can be pointed to a clear genetic cause, while the remaining 90% is classified as sporadic. Our study was aimed to uncover new connections within the ALS network through a bioinformatic approach, by which we identified C13orf18, recently named Pacer, as a new component of the autophagic machinery and potentially involved in ALS pathogenesis. METHODS: Initially, we identified Pacer using a network-based bioinformatic analysis. Expression of Pacer was then investigated in vivo using spinal cord tissue from two ALS mouse models (SOD1G93A and TDP43A315T) and sporadic ALS patients. Mechanistic studies were performed in cell culture using the mouse motoneuron cell line NSC34. Loss of function of Pacer was achieved by knockdown using short-hairpin constructs. The effect of Pacer repression was investigated in the context of autophagy, SOD1 aggregation, and neuronal death. RESULTS: Using an unbiased network-based approach, we integrated all available ALS data to identify new functional interactions involved in ALS pathogenesis. We found that Pacer associates to an ALS-specific subnetwork composed of components of the autophagy pathway, one of the main cellular processes affected in the disease. Interestingly, we found that Pacer levels are significantly reduced in spinal cord tissue from sporadic ALS patients and in tissues from two ALS mouse models. In vitro, Pacer deficiency lead to impaired autophagy and accumulation of ALS-associated protein aggregates, which correlated with the induction of cell death. CONCLUSIONS: This study, therefore, identifies Pacer as a new regulator of proteostasis associated with ALS pathology.

[Hemolytic kidney failure and transient ischemic attack in a 32-year-old female]. / Hämolytisches Nierenversagen mit transitorisch ischämischer Attacke bei einer 32-Jährigen.

We report on the case of a 32-year-old female patient who initially presented with oliguric acute renal failure, hemolytic anemia with moderate thrombocytopenia and subsequently developed a transient ischemic attack in the cerebellum. The kidney biopsy revealed clinically suspected atypical hemolytic-uremic syndrome (aHUS), which was confirmed by intraglomerular thrombotic microangiopathy (TMA). Treatment with plasmapheresis and sustained administration of the C5 inhibitor eculizumab resulted in hematological remission but without improvement of kidney function. Further etiological investigations led to reduced plasma levels of inhibitory complement factor I on the basis of a heterozygous CFI mutation. In patients with aHUS molecular genetic investigations are indicated in order to determine the underlying cause, to regulate the therapeutic regimen and to allow prognostic statements with respect to a potential kidney transplantation.

MKS1 mutations cause Joubert syndrome with agenesis of the corpus callosum.

Joubert syndrome (JS) is a clinically and genetically heterogeneous ciliopathy characterized by episodic hyperpnea and apnea, hypotonia, ataxia, cognitive impairment and ocular motor apraxia. The "molar tooth sign" is pathognomonic of this condition. Mutations in the MKS1 gene are a major cause of Meckel-Gruber syndrome (MKS), the most common form of syndromic neural tube defects, frequently resulting in perinatal lethality. We present the phenotype and genotype of a child with severe JS and agenesis of the corpus callosum (ACC). In our patient, a next generation sequencing (NGS) approach revealed the following two variants of the MKS1 gene: first, a novel missense variant [ c.240G > T (p.Trp80Cys)], which affects a residue that is evolutionarily highly conserved in mammals and ciliates; second, a 29 bp deletion in intron 15 [c.1408-35_1408-7del29], a founder mutation, which in a homozygous state constitutes the major cause of MKS in Finland. We review the MKS1-variants in all of the eleven JS patients reported to date and compare these patients to our case. To our knowledge, this is the first patient with Joubert syndrome and agenesis of the corpus callosum where a potentially causal genotype is provided.

High mobility group box 1 is increased in the sera of psoriatic patients with disease progression.

BACKGROUND: Psoriasis vulgaris (PV) is an autoimmune-related chronic inflammatory disease, which appears mostly in skin, but also affects the vascular and metabolic system. The incidence of PV is 2-3% in the general population and there is still no possibility to cure. Trigger factors have been identified to initiate and maintain inflammation in the skin, which is characterized by Th1-, Th17- and Th22- cells. OBJECTIVE: We hypothesize that the damage-associated molecular pattern (DAMP) molecule high mobility group box 1 (HMGB1) plays a role in the pathogenesis of PV. HMGB1 is a DNA-binding protein located in the nucleus, which acquires cytokine-like properties once released from the cell upon necrotic cell death or actively secreted by immune cells in inflammation and cancer. METHODS: We recruited 90 psoriatic patients under and without therapy with mild, intermediate and severe progression of disease, defined by the Psoriasis Area Severity Index. Serum levels of HMGB1 in patients with PV were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Our results show an increased level of HMGB1 in the sera of patients with PV in comparison to healthy donors. Furthermore, our analyses reveal that HMGB1 levels are significantly increased with disease progression and are downregulated after standard therapies for PV have been conducted. CONCLUSION: Our data provide insights into a possible role of HMGB1 for inflammation in PV.

Syndromic ciliopathies: From single gene to multi gene analysis by SNP arrays and next generation sequencing.

Joubert syndrome (JS) and related disorders (JSRD), Meckel syndrome (MKS) and Bardet-Biedl syndrome (BBS) are autosomal recessive ciliopathies with a broad clinical and genetic overlap. In our multiethnic cohort of 88 MKS, 61 JS/JSRD and 66 BBS families we performed genetic analyses and were able to determine mutation frequencies and detection rates for the most frequently mutated MKS genes. On the basis of determined mutation frequencies, a next generation gene panel for JS/JSRD and MKS was established. Furthermore 35 patients from 26 unrelated consanguineous families were investigated by SNP array-based homozygosity mapping and subsequent DNA sequencing of known candidate genes according to runs of homozygosity size in descending order. This led to the identification of the causative homozygous mutation in 62% of unrelated index cases. Based on our data we discuss various strategies for diagnostic mutation detection in the syndromic ciliopathies JS/JSRD, MKS and BBS.