Bacterial DNA promoting inflammation via the Sgk1/Nedd4L/Syk pathway in mast cells contributes to antihistamine-nonresponsive CSU.

Inflammation centered on non-IgE-mediated mast cell activation characterizes chronic spontaneous urticaria resistant to nonsedating H1-antihistamines. We recently uncovered a strong positive association between inflammation and the fecal Escherichia. To further explore the actions of bacterial DNA derived from Escherichia on mast cells, intestinal permeability of patients with chronic spontaneous urticaria with or without nonsedating H1-antihistamine resistance and healthy controls were determined, and LAD2 cells with knockdown of Syk, Nedd4L, or Sgk1 or with incubation of inhibitors GS9973, GSK650394, and MG132 were posttreated with btDNA. We found that (i) serum intestinal permeability indices and bacterial DNA markedly increased in patients with chronic spontaneous urticaria with nonsedating H1-antihistamine resistance compared with those without (all P < 0.001), and bacterial DNA positively correlated with the degree of inflammation; (ii) IL-6 and TNF-α levels were time- and dose-dependently upregulated in bacterial DNA-stimulated LAD2 cells, which relied on unmethylated CpG in bacterial DNA and Toll-like receptor 9 protein in cells; (iii) Syk knockdown or inhibition of Syk Tyr525/526 phosphorylation blocked bacterial DNA-initiated cytokine production; (iv) Nedd4L interacted with Tyr525/526-phosphorylated Syk, and inhibition of Nedd4L Ser448 phosphorylation induced by bacterial DNA-activated Sgk1 was mandatory for bacterial DNA's proinflammatory property; and (v) Sgk1 suppression showed an inhibitory effect on bacterial DNA-induced inflammation by ensuring Nedd4L-mediated ubiquitination of Tyr525/526-phosphorylated Syk. Collectively, we identified previously unknown contributory roles of bacterial translocation and serum bacterial DNA on the inflammation phenotype in patients with chronic spontaneous urticaria with nonsedating H1-antihistamine resistance and further uncovered a vital negative regulatory role for the Sgk1/Nedd4L/Syk pathway in bacterial DNA-induced inflammation in LAD2 cells.

Identification of gut microbiota signatures in symptomatic dermographism.

Symptomatic dermographism (SD) is a recurrent inflammatory skin disease related to immunity; however, the details remain elusive. In view of the important role of gut microbiota in immune regulation, the purpose of this study is to investigate the alterations of gut microbiota in SD and explore the potential bacterial biomarkers for diagnosis. A case-control study including SD patients and normal controls (NCs) was carried out. Gut microbiota of the participants was analysed by the 16S rDNA sequencing of faecal samples. The linear discriminant analysis effect size and the receiver operating characteristic curve (ROC) analysis were used to identify the bacterial biomarkers. Forty-four participants were included in this study. The alpha-diversity and beta-diversity of gut microbiota differed significantly between SD patients and NCs. The abundance of Verrucomicrobia, Ruminococcaceae and their subordinate taxa were reduced in SD patients, while Enterobacteriales and its subordinate taxon exhibited higher relative abundance compared with NCs. Subdoligranulum and Ruminococcus bromii showed a potential diagnostic value for SD, and Prevotella stercorea was negatively relevant to duration of SD. Furthermore, the pyruvate, butyric acid and histamine metabolism pathway were likely to be involved in the pathogenesis of SD. Our results revealed that the gut microbiota of SD patients experienced obvious changes, and Verrucomicrobia, Ruminococcaceae and Enterobacteriales were microbiota signatures for SD.

Skin and Mucous Membrane Eruptions Associated with Chlamydophila Pneumoniae Respiratory Infections: Literature Review.

BACKGROUND: Mycoplasma pneumoniae pneumonia is sometimes associated with skin or mucous membrane eruptions. Available reviews do not address the association of Chlamydophila pneumoniae pneumonia with skin eruptions. We therefore conducted a systematic review of the literature addressing this issue. The National Library of Medicine, Excerpta Medica, and Web of Science databases were employed. SUMMARY: In two reports, skin lesions and especially urticaria were more common (p < 0.05) in atypical pneumonia caused by C. pneumoniae as compared with M. pneumoniae. We found 47 patients (<18 years, n = 16; ≥18 years, n = 31) affected by a C. pneumoniae atypical pneumonia, which was associated with erythema nodosum, erythema multiforme minus, erythema multiforme majus, isolated mucositis, or cutaneous vasculitis. We also found the case of a boy with C. pneumoniae pneumonia and acute generalized exanthematous pustulosis. We did not find any case of C. pneumoniae respiratory infection associated with either Gianotti-Crosti syndrome, pityriasis lichenoides et varioliformis acuta Mucha-Habermann, or varicella-like skin eruptions.

Impact of mycoplasma pneumonia infection on urticaria: A nationwide, population-based retrospective cohort study in Taiwan.

Mycoplasma pneumonia (MP) infection might be pathogenically closely related to urticaria. This study is a nationwide population-based cohort study from 1997 to 2013, which investigated the association between MP infection and urticaria in Taiwan. A total of 1,175 patients were included for the study group, and 2,350 for the control group. Multivariate Cox regression analysis was performed to estimate the adjusted hazard ratio (aHR) for urticaria. Result showed that 254 patients with new-onset urticaria were involved in the study group and 465 incident cases in the control group. The incidence rates (per 100,000 person-months) of urticaria were 37.2 and 32.5 in the study and control groups, respectively. The relative risk is 1.1 (95% CI = 1.0-1.3) indicating no significant correlation between MP and urticaria. The multivariate analysis revealed that the risk of urticaria with MP infection (aHR = 1.1, P = 0.1058) had no statistically significance difference compared to the control group. However, the risk of urticaria in MP-infected patients aged between 20 and 59 years old was found to have increased (aHR = 1.6, 95% CI = 1.1-2.2) prior to a diagnosis.

Advances in the pathogenesis representing definite outcomes in chronic urticaria.

PURPOSE OF REVIEW: We reviewed in this article, the recent advances in CSU physiopathology and potential clinical and laboratory biomarkers in CSU. RECENT FINDINGS: In addition to the central role of mast cells in urticaria physiopathology, increased interest in basophils has arisen. Recent data corroborate the autoimmunity pathway as one of the main pathways in mast cell activation. The association of inflammatory cytokines, heat shock proteins and staphylococcal infection with CSU are also reviewed. C-reactive protein, D-dimers, autologous serum skin test, IgE levels and FcεRI expression in basophils have shown their potential as biomarkers for disease duration, activity, severity and/or response to treatment. SUMMARY: A comprehensive understanding of chronic spontaneous urticaria mechanisms is essential to find novel biomarkers and treatments. The use of these biomarkers in clinical practice will guide us in choosing the best treatment option for our patients.

Malassezia infection associated with chronic spontaneous urticaria without angioedema: a report on five cases.

INTRODUCTION: Chronic spontaneous urticaria (CSU) is a challenging condition to treat and it significantly affects quality of life. Bacterial, viral, parasitic, and fungal infections have been associated with triggering and/or perpetuating urticaria in certain individuals. There is a paucity of literature on CSU associated with Malassezia infection. METHODS AND RESULTS: We present a case series of five patients with CSU without angioedema in whom we observed temporal association of Malassezia infection with CSU. The presence of Malassezia was confirmed by clinical examination, Wood's lamp, and KOH examination. The patients with CSU experienced improvement after specific antifungal therapy. CONCLUSIONS: Malassezia infection may be associated with recurrent and chronic urticaria in a certain group of susceptible patients and thus specific targeted therapy against it might result in complete remission of urticaria along with clearing of the infection.

Four cases of acute infectious urticaria showing significant elevation of plasma D-dimer level.

D-dimer, a fibrinolytic end-product, has been regarded as a biomarker indicating the severity of urticaria, especially in chronic urticaria. Regarding acute urticaria, D-dimer level is also suggested to be elevated, which may be significant in comparison with chronic urticaria. However, the clinical features of acute urticaria with concomitant significant elevation of D-dimer level have not been investigated in detail so far. We present four cases of acute urticaria fulfilling the proposed diagnostic criterion of acute infectious urticaria, in which significant elevation of D-dimer level and rapid spontaneous normalization in parallel with the resolution of fever and urticaria occurs. No cases had deep vein thrombosis, disseminated intravascular coagulation and malignancy. All cases responded well to antihistaminic treatment in combination with antibiotics, and their fever and urticaria resolved within 10 days. All cases showed severe wheals persistent for several days resolving with hyperpigmentation. Histologically, infiltration into blood vessel walls and interstitial infiltration of lymphocytes and polymorphonuclear cells were marked in the dermis. In our cases, clinical features accorded with acute infectious urticaria, and their histological features were similar to those of neutrophilic urticaria as described previously. In conclusion, there is a certain group of acute urticaria associated with significant elevation of D-dimer level. These common features of our cases may be characteristic in acute urticaria showing the coagulative and fibrinolytic abnormalities.

The protective effect of Lactobacillus and Bifidobacterium as the gut microbiota members against chronic urticaria.

BACKGROUND: Chronic Urticaria is a common disorder which is defined by recurrent occurrence of wheals and sometimes angioedema. It has a notable influence on the patients' quality of life. Regulation of the immune system is one of the important roles of the gut microbiota. The effect of dysbiosis considering some members of gut microbiota in patients with chronic urticaria has been demonstrated in our previous study. OBJECTIVE: Comparing the frequency and bacterial load of Lactobacillus, Bifidobacterium, and Bacteroides between patients with chronic urticaria and healthy controls. METHODS: 20 patients with chronic urticaria and 20 age and sex matched healthy individuals were included in the present study. Stool samples were analyzed for determining the frequency and bacterial load of Lactobacillus, Bifidobacterium, and Bacteroides genera. RESULTS: There were no significant differences among the frequencies of detectable Lactobacillus, Bifidobacterium, or Bacteroides in stool samples of patients with chronic urticaria and healthy controls. The relative amounts of Lactobacillus and Bifidobacterium were significantly higher in fecal samples from controls compared to patients with chronic urticaria (P = 0.038 and 0.039, respectively). CONCLUSION: It is the first study on the implication of Lactobacillus, Bifidobacterium, and Bacteroides genera as gut microbiota members in patients with chronic urticaria.

[Relation between Helicobacter pylori infection and chronic urticaria]. / Relación entre infección por Helicobacter pylori y urticaria crónica.

BACKGROUND: Chronic spontaneous urticaria is a frequent disease that affects the quality of life of patients. Helicobacter pylori infection has increased in the world, linking current studies with a link between both entities. OBJECTIVE: To determine the relationship between chronic urticaria and Helicobacter pylori infection. METHODS: An observational cohort study was conducted with the objective of demonstrating the relationship between chronic urticaria and Helicobacter pylori infection in the allergology clinic of the Hospital Universitario "Manuel Ascunce Domenech" in the province of Camagüey, Cuba, in the period from January 2015 to December of 2016. A universe composed of 93 patients with spontaneous chronic urticaria and the sample by the 43 who met the criteria and formed the case and control group were the 35 apparently healthy patients who gave informed consent for the study. RESULTS: 76.6 % of the women had urticaria and the mean age was 36.10 years. The serological study was positive in 100 % of the cases. CONCLUSIONS: In the present study, the relationship between chronic urticaria and Helicobacter pylori infection was demonstrated. Apparently, the eradicating treatment for Helicobacter pylori was effective as the patients had no symptoms after treatment. Specific immunoglobulin G and urease test together constitute a suitable diagnostic module for the diagnosis of Helicobacter pylori conditions.

Antecedentes: La urticaria crónica espontánea es una enfermedad frecuente que afecta la calidad de vida de los pacientes. La infección por Helicobacter pylori ha aumentado en el mundo; estudios actuales vinculan ambas entidades. Objetivo: determinar la relación entre urticaria crónica e infección por Helicobacter pylori. Métodos: Se realizó un estudio observacional de cohorte en la consulta de alergología del Hospital "Manuel Ascunce Domenech" de la provincia de Camagüey, entre enero de 2015 y diciembre de 2016. El grupo de estudio estuvo integrado por 93 pacientes con urticaria crónica espontánea; la muestra quedó conformada por 43 individuos que reunieron los criterios de inclusión. El grupo control fueron 35 pacientes aparentemente sanos que dieron su consentimiento informado para el estudio. Resultados: 76.6 % de las mujeres padecía urticaria y la media de edad fue de 36.10 años. El estudio serológico fue positivo para Helicobacter pylori en todos los casos. Aparentemente, el tratamiento erradicador fue efectivo, pues los pacientes después no presentaron síntomas. Conclusiones: en la investigación se demostró relación entre urticaria crónica e infección por Helicobacter pylori. La inmunoglobulina G específica y la prueba de ureasa en conjunto constituyen un módulo diagnóstico adecuado para el diagnóstico de afecciones por Helicobacter pylori.

Probiotics and refractory chronic spontaneous urticaria.

Background. In chronic spontaneous urticaria (CSU) first-line therapy with an antihistamine-based regimen may not achieve satisfactory control in patients. Thus, a continuing need exists for effective and safe treatments for refractory CSU. Aim. To evaluate the clinical efficacy and safety of an intake of a combination of 2 probiotics (Lactobacillus salivarius LS01 and Bifidobacterium breve BR03) in patients with CSU who remain symptomatic despite concomitant H1-antihistamine therapy. Methods. This report analyzes the effects of therapy with two probiotic strains on the clinical progress of 52 unselected patients with difficulty to treat CSU underwent to medical examination in two Italian specialist urticaria Clinics between September 2013 and September 2014. A mixture of Lactobacillus LS01 and Bifidobacterium BR03 were administered in each patient twice daily for 8 weeks. To evaluate patients' improvement with probiotics, urticaria activity score over 7 days (UAS7) was used at baseline and at week 8 in addition to a 5-question urticaria quality of life questionnaire. Results. Fifty-two patients with CSU were included in this study (10 male and 42 female, age range 19-72 years). Mean disease duration was 1.5 years. Fourteen patients discontinued treatment, so evaluable population consisted of 38 patients. Nine of the 38 patients experienced mild clinical improvement during probiotic treatment (23.7%); one patient reported significant clinical improvement (2.6%) and one patient had complete remission of urticaria (2.6%). Twenty-seven patients did not have improvement in symptoms (71.1%). No side effects during the course of therapy were reported. Conclusions. A combination of Lactobacillus salivarius LS01 and Bifidobacterium breve BR03 administered twice daily for 8 weeks might reduce the symptoms scores and improve quality of life scores in a part of patients with CSU who remained symptomatic despite treatment with H1 antihistamine mostly in subjects with allergic rhinitis.

Helicobacter pylori: A significant and treatable cause of chronic urticaria and angioedema.

Two outpatient medical offices evaluated 204 patients with chronic urticaria during 2012. This article presents a retrospective study showing that 10% of patients with chronic urticaria may be infected with H. pylori. Furthermore, eradication of infection can be followed by remission of urticaria, reduced morbidity from gastric ulcers, and cancer.

Helicobacter pylori Infection in Pediatrics.

This review includes the main pediatric studies published from April 2014 to March 2015. The host response of Treg cells with increases in FOXP3 and TGF-ß1 combined with a reduction in IFN-γ by Teff cells may contribute to Helicobacter pylori susceptibility in children. Genotypic variability in H. pylori strains influences the clinical manifestation of the infection. Helicobacter pylori infection is associated with variables indicative of a crowded environment and poor living conditions, while breast-feeding has a protective effect. Intrafamilial infection, especially from mother to children and from sibling to sibling, is the dominant transmission route. Studies showed conflicting results regarding the association between H. pylori infection and iron deficiency anemia. One study suggests that H. pylori eradication plays a role in the management of chronic immune thrombocytopenic purpura in H. pylori-infected children and adolescents. The prevalence of H. pylori was higher in chronic urticaria patients than in controls and, following H. pylori eradication, urticarial symptoms disappeared. An inverse relationship between H. pylori infection and allergic disease was reported. Antibiotic resistance and insufficient compliance to treatment limit the efficacy of eradication therapy. Sequential therapy had no advantage over standard triple therapy. In countries where H. pylori infection is prevalent, studies focusing on virulence factors and antibiotic susceptibility may provide anticipation of the prognosis and may be helpful to reduce morbidity and mortality.

Interactions between Cooccurring Lactic Acid Bacteria in Honey Bee Hives.

In contrast to the honey bee gut, which is colonized by a few characteristic bacterial clades, the hive of the honey bee is home to a diverse array of microbes, including many lactic acid bacteria (LAB). In this study, we used culture, combined with sequencing, to sample the LAB communities found across hive environments. Specifically, we sought to use network analysis to identify microbial hubs sharing nearly identical operational taxonomic units, evidence which may indicate cooccurrence of bacteria between environments. In the process, we identified interactions between noncore bacterial members (Fructobacillus and Lactobacillaceae) and honey bee-specific "core" members. Both Fructobacillus and Lactobacillaceae colonize brood cells, bee bread, and nectar and may serve the role of pioneering species, establishing an environment conducive to the inoculation by honey bee core bacteria. Coculture assays showed that these noncore bacterial members promote the growth of honey bee-specific bacterial species. Specifically, Fructobacillus by-products in spent medium supported the growth of the Firm-5 honey bee-specific clade in vitro. Metabolic characterization of Fructobacillus using carbohydrate utilization assays revealed that this strain is capable of utilizing the simple sugars fructose and glucose, as well as the complex plant carbohydrate lignin. We tested Fructobacillus for antibiotic sensitivity and found that this bacterium, which may be important for establishment of the microbiome, is sensitive to the commonly used antibiotic tetracycline. Our results point to the possible significance of "noncore" and environmental microbial community members in the modulation of honey bee microbiome dynamics and suggest that tetracycline use by beekeepers should be limited.

Helicobacter pylori infection and skin disorders.

Helicobacter pylori is a Gram-negative bacterium that has been linked to peptic ulcer disease, gastric lymphoma, and gastric carcinoma. Apart from its well-demonstrated role in gastroduodenal diseases, some authors have suggested a potential role of Helicobacter pylori infection in several extra-intestinal pathologies including haematological, cardiovascular, neurological, metabolic, autoimmune, and dermatological diseases. Some studies suggest an association between Helicobacter pylori infection and skin diseases such as chronic idiopathic urticaria and rosacea. There have also been few case reports documenting association between Helicobacter pylori and psoriasis vulgaris, Behçet's disease, alopecia areata, Henoch-Schönlein purpura, and Sweet's syndrome. However, more systematic studies are required to clarify the proposed association between Helicobacter pylori and skin diseases; most of the studies do not show relevant relationships of these diseases with Helicobacter pylori infections. This review discusses skin diseases that are believed to be associated with Helicobacter pylori.

Helicobacter pylori and skin autoimmune diseases.

Autoimmune skin diseases are characterized by dysregulation of the immune system resulting in a loss of tolerance to skin self-antigen(s). The prolonged interaction between the bacterium and host immune mechanisms makes Helicobacter pylori (H. pylori) a plausible infectious agent for triggering autoimmunity. Epidemiological and experimental data now point to a strong relation of H. pylori infection on the development of many extragastric diseases, including several allergic and autoimmune diseases. H. pylori antigens activate cross-reactive T cells and induce autoantibodies production. Microbial heat shock proteins (HSP) play an important role of in the pathogenesis of autoimmune diseases because of the high level of sequence homology with human HSP. Eradication of H. pylori infection has been shown to be effective in some patients with chronic autoimmune urticaria, psoriasis, alopecia areata and Schoenlein-Henoch purpura. There is conflicting and controversial data regarding the association of H. pylori infection with Behçet's disease, scleroderma and autoimmune bullous diseases. No data are available evaluating the association of H. pylori infection with other skin autoimmune diseases, such as vitiligo, cutaneous lupus erythematosus and dermatomyositis. The epidemiological and experimental evidence for a possible role of H. pylori infection in skin autoimmune diseases are the subject of this review.

Urticaria recurrente asociada a infección por Streptococcus pyogenes / Recurrent urticaria associated with group Streptococcus pyogenes infection

La mayoría de las urticarias crónicas o agudas recidivantes son idiopáticas. Presentamos un caso de urticaria aguda recidivante en una niña de tres años, en la que, tras el estudio realizado, solo se objetivó un valor elevado de anticuerpos antiestreptolisina O (ASLO). La desaparición de la urticaria tras el tratamiento con penicilina G-benzatina intramuscular, junto con la normalización de los ASLO, sugiere que la etiología de esta podría ser las infecciones recurrentes por el Streptococcus pyogenes. Destacar la importancia de incluir en el protocolo diagnóstico de la urticaria la determinación de los ASLO, lo cual permite el diagnóstico y tratamiento precoces de las infecciones por S. pyogenes (AU)

We present a case of relapsing acute urticaria in a three years old girl who after the study only showed a high value of ASLO (antistreptolysin O titer). The disappearance of urticaria after intramuscular penicillin G benzathine treatment, together with the ASLO normalization, suggested that the etiology of this could be recurrent Streptococcal infections. We conclude the importance of including ASLO determination in the diagnostic protocol of urticaria, allowing early diagnosis and treatment of Group A Streptococcus infections (AU)

Recurrence of chronic urticaria caused by reinfection by Helicobacter pylori.

OBJECTIVE: To describe a case of chronic urticaria in a female adolescent associated with Helicobacter pylori infection, confirmed in two different occasions, with improvement of urticaria after the antibacterial treatment. CASE DESCRIPTION: A 13-year-old female patient sought medical care with chronic urticaria and epigastric pain unresponsive to medical treatment. Laboratorial tests for further investigation were normal except for the upper gastrointestinal endoscopy with biopsy showing moderate chronic active gastritis associated with Helicobacter pylori. After specific and appropriate treatment, the patient had remission of the symptoms. A new upper gastrointestinal endoscopy to control the treatment after nine months was normal. After five years, the patient returned with recurrence of urticaria and epigastric pain. She was taking antihistamines, without any improvement. It was again submitted to screening protocol for chronic urticaria with normal results. She was submitted to upper gastrointestinal endoscopy, which showed positive urease test. The patient started a new treatment for Helicobacter pylori with disappearance of chronic urticaria and epigastric pain within seven days. COMMENTS: The reported case suggests a causal relationship between the positive diagnosis of Helicobacter pylori and the occurrence of chronic urticaria, showing the remission of symptoms after the institution of effective therapy for this agent. Chronic urticaria is a disease of complex etiology, and although controversial, there is growing evidence of Helicobacter pylori involvement with extraintestinal diseases, including chronic urticaria.