Living with Chronic Spontaneous Urticaria in Italy: A Narrative Medicine Project to Improve the Pathway of Patient Care.

Chronic spontaneous urticaria (CSU) is perceived as a difficult to manage disease with negative impact on quality of life. The aim of this study was to highlight how to improve the care of people with CSU, using the methodology of narrative medicine. From June 2014 to March 2015, CSU-diagnosed patients and their physicians were asked to record their experiences of the condition in writing. Fourteen healthcare teams participated: 41% considered CSU as a challenge to overcome, while 22% experienced CSU as a big commitment. The number of professional involved was evaluated as insufficient in 11 hospitals. Seventy-five percent of the 190 Italian patients had visited 3 or more physicians before receiving a final diagnosis, with a perceived waste of time and resources. The therapeutic pathways were described as unsatisfactory in 83% of cases. As a result, anger and frustration were life-dominant emotions in 92% of patients. The critical points of the care pathway are related to organizational issues and lack of awareness.

Changing of fecal flora and clinical effect of L. salivarius LS01 in adults with atopic dermatitis.

GOAL: To evaluate cytokine stimulation with 3 strains of Lactobacillus salivarius in vitro and to assess changes in intestinal microflora and clinical improvements in adults with atopic dermatitis (AD) induced by the strain showing the best immunomodulatory features. BACKGROUND: AD is a common skin disease in children and adults. It is characterized by chronic inflammation, eczema, and increasing intestinal permeability. Various studies have shown that patients with AD presented some modifications in the intestinal microbiota composition; as a result, intestinal microflora is thought to have a pivotal role in this disease. METHODS: Thirty-eight patients aged from 18 to 46 years with moderate/severe AD were recruited. Subjects were randomized in a double-blind placebo-controlled study to receive active treatment with L. salivarius LS01: probiotic (n=19) or placebo (n=19). Cytokine production was determined by means of specific quantitative enzyme-linked immunosorbent assays. Intestinal bacterial groups were quantified using conventional culture techniques, whereas L. salivarius LS01 was identified using polymerase chain reaction and pulse field gel electrophoresis. RESULTS: L. salivarius LS01 showed the best immunomodulatory features and it was chosen for the second phase of the study. AD subjects showed a reduction in their SCORAD score after probiotic treatment and a significant decrease in the staphylococci load compared with the placebo group. Moreover, L. salivarius LS01 showed the ability to reduce the production of Th2 cytokines, maintaining the production of Th1 cytokines stable. CONCLUSIONS: Treatment with the L. salivarius LS01 strain seems to positively modify clinical and immunologic status and dermatology life quality in a group of adults affected by moderate/severe AD, leading to a rebalancing of altered intestinal microbiota.

Probiotics reduce gut microbial translocation and improve adult atopic dermatitis.

BACKGROUND: It has been suggested that probiotics modulate atopic dermatitis (AD) progression, but no data are actually available on their mechanisms of action and on their ability to act as immunomodulators in this pathology. OBJECTIVE: The aim of this randomized double-blinded active treatment versus placebo study was to evaluate clinical efficacy of an intake of a combination of 2 probiotics (Lactobacillus salivarius LS01 and Bifidobacterium breve BR03) for the treatment of adult AD patients. METHODS: Forty-eight patients were enrolled in the study (randomization ratio 2:1) and treated with a combination (LS01 and BR03) or placebo (maltodextrin) for 12 weeks. Clinical efficacy was assessed from baseline by changes in the SCORAD index and DLQ index improvement. Analysis on the gut permeability barrier, immunologic parameters, and changes in fecal microbiota and recovery of probiotics were performed at baseline, at the end of therapy, and 2 months later. RESULTS: Patients receiving probiotics showed a significant improvement in clinical parameters (SCORAD, P<0.0001 and DLQ index, P=0.021) from baseline. The probiotics reduced microbial translocation (P=0.050), immune activation (P<0.001), improved T-helper cell (Th)17/regulatory T cell (Treg) (P=0.029) and Th1/Th2 (P=0.028) ratios. None of these changes were observed in the placebo group. CONCLUSIONS: Our results suggest that this specific mixture of probiotics (LS01 and BR03 strains) may induce beneficial effects for clinical and immunologic alterations in adult AD. This combination could be considered as adjuvant therapy for the treatment of AD in adult patients.

Immunological effects of sublingual immunotherapy: clinical efficacy is associated with modulation of programmed cell death ligand 1, IL-10, and IgG4.

Sublingual immunotherapy (SLIT) is an alternate route of administration of allergen-specific immunotherapy with an improved safety profile; to clarify the immune mechanisms elicited by this therapy, we analyzed the clinical and immunologic effects of SLIT in patients with a clinical history of ragweed sensitization. To analyze possible difference among immunotherapeutic protocols, we also compared patients receiving preseasonal, seasonal, or prolonged sublingual therapy (≥ 3 y); patients receiving symptomatic therapy alone were enrolled as well in the study. Clinical and immunological parameters were measured twice in and out of the pollination period. Clinical benefits, as measured by the visual analog scale for symptoms and for use of drugs, were evident in all three groups of individuals receiving immunotherapy, but were significantly better in patients undergoing prolonged SLIT. Immunologically, SLIT resulted in increased IL-10 production, programmed cell death ligand 1 expression, and concentration of allergen-specific IgG4, as well as in the reduction of CD80 and CD86 expression and IL-4 production. SLIT, thus, is associated with modulation of programmed cell death ligand 1 expression and IL-10 synthesis and favors the production of allergen-specific IgG4. These effects are evident from the first pollen season, independently from therapeutic regimen (preseasonal or seasonal) even if a prolonged treatment is necessary to obtain full clinical efficacy. A more detailed understanding of the interaction of allergen and APCs within the oral mucosa will allow improved targeting of allergy vaccine.

Alpha-gal syndrome and delayed anaphylaxis after ingestion of red meat: A case report.

α-gal syndrome (AGS) is caused by the intake of products containing α-gal (galactose-α-1,3-galactose) like mammalian meat. Over the last decade, scientific literature about AGS has been increasing, but the true burden of cases is still unknown [1, 2]. In the USA (University of Virginia Allergy Clinic), the number of confirmed cases of AGS was 24 in 2009 [3] and increased to 34,000 in the entire USA by 2019 [4]. As shown in surveys, in Italy AGS is present throughout the country [5]. The literature suggests that a previous tick bite can cause AGS, but in our case it was not possible to demonstrate this association as the patient did not recall any tick bite, even in childhood. After eating red meat, a 56-year-old male patient had developed symptoms such as a generalized urticaria, diarrhea, and faintness, requiring admission to the Emergency Department. The diagnosis was verified using blood CAP-FEIA test and prick-to-prick test. After completing the diagnostic process, we provided the patient with emergency therapy, and auto-injectable adrenaline was prescribed. Despite the diagnosis, the patient ate red meat once again which resulted in severe urticaria 2 hours after the meal, requiring a second visit to the Emergency Room. Now the patient is under follow-up at our Department of Allergy and Clinical Immunology.

Socio-economic burden and resource utilisation in Italian patients with chronic urticaria: 2-year data from the AWARE study.

INTRODUCTION: In Italy, the real-world evidence on the extent of adherence to guidelines and the benefits of recommended therapeutic medications and their impact on the quality of life (QoL) of H1-antihistamines (H1-AH) refractory chronic urticaria (CU) patients is limited. METHODS: AWARE (A World-wide Antihistamine-Refractory chronic urticaria patient Evaluation) was a global prospective, non-interventional study of CU in real-world setting which included patients aged ≥18 years with a medically confirmed diagnosed of CU present for more than 2 months. In this study, the disease characteristics, pharmacological treatments and patient-reported outcomes (PROs) are reported. RESULTS: In total, 159 patients from 24 study centres in Italy completed the study. At baseline, 221 (89.5%) and 8 (3.2%) patients had chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU), respectively, while 18 (7.3%) patients had concomitant CSU and CIndU. For CSU patients, mean dermatology life quality index and CU quality of life questionnaire scores reduced to 3.0 ± 4.9 and 14.6 ± 18.6 at Month 24 from baseline scores of 7.5 ± 6.6 and 33.2 ± 19.5, respectively, indicating an improvement in QoL. This was reflected in their work-life as work productivity impairment reduced considerably after 2 years. Only 71.9% CSU patients had a prior treatment, while during the study, 96.8% of the patients were treated with a medication. At baseline, only 52.9% CSU patients reported nonsedating H1-antihistamines as first-line of treatment in prior medication, this increased to 89.6% during current medication. CONCLUSION: This study shows that CSU has a considerable socio-economic burden and an improvement in QoL can be achieved in CSU patients if an appropriate therapeutic path is followed.

Interleukin-1 receptor antagonist anakinra in association with remdesivir in severe COVID-19: A case report.

We report the first successful treatment with the IL-1 receptor antagonist anakinra, in association with the most promising and available antiviral therapy, of a severe case of novel coronavirus disease 2019 (COVID-19). We describe the diagnosis, clinical course, and management of the case, including the respiratory failure at presentation, the progression to a scenario characterized by profound inflammatory dysregulation similar to that observed during macrophage activation syndrome, and the clinical improvement after treatment with the IL-1 receptor antagonist anakinra. This case highlights the high tolerability and the interesting immunomodulatory profile of the IL-1 receptor antagonist anakinra in the setting of severe COVID-19 associated with remdesivir therapy. Further studies are needed to confirm the safety and efficacy of this combination strategy in the treatment of this emerging infection.

Strain-dependent release of cytokines modulated by Lactobacillus salivarius human isolates in an in vitro model.

BACKGROUND: Oral administration of probiotics is known to modulate cytokines profile not only locally, but also systemically. Four strains of Lactobacillus salivarius, LDR0723, BNL1059, RGS1746 and CRL1528, were evaluated for their ability to modulate release of pro- and anti-inflammatory cytokines. FINDINGS: Strains were assessed for effects on production of Interleukin-12 (IL-12), Interferon-gamma (IFN-gamma), Interleukin-4 (IL-4) and Interleukin-5 (IL-5) by incubating bacterial suspensions with THP-1 macrophage like cells. Cytokines were determined by means of specific quantitative enzyme-linked immunosorbent assays.LDR0723 and CRL1528 led to a sustained increment in production of IL-12 and IFN-gamma and to a decrease in release of IL-4 and IL-5, while BNL1059 and RGS1746 favoured Th2 response, leading to a decrease in Th1/Th2 ratio with respect to unstimulated cells. CONCLUSIONS: In conclusion, capability of L. salivarius to modulate immune response was strictly strain dependent and strains of the same species might have opposite effects. Therefore, a careful evaluation of anti-inflammatory properties of lactobacilli should be performed on single strain, before any consideration on potential probiotic use.

Effects of specific immunotherapy on the B7 family of costimulatory molecules in allergic inflammation.

The effect of allergen-specific immunotherapy (IT) on Ag presentation and T lymphocyte stimulation was evaluated by verifying the expression of costimulatory molecules in allergic patients. Thus, CD28 and CTLA-4, B7, and B7-H molecules on immune cells, as well as cytokine production, were analyzed in and out of the pollination period in 30 patients allergic to Betulaceae that had or had nor undergone specific IT. Results showed that IT attenuated the increase in the percentage of CD28(+)CD4 T cells and the decrease in the percentage of CTLA-4(+)CD4(+) T cells seen in untreated individuals. CD19(+)/CD80, CD19(+)/CD86(+), and CD14(+)/CD80(+) APCs were significantly augmented during pollination in unvaccinated individuals. B7-H1-expressing monocytes (CD14(+)) and B lymphocytes (CD19) as well as CD14 and CD19 B7-H1(+)/IL-10(+) APC were augmented in Betulaceae Ag-stimulated cell cultures of vaccinated patients independently of pollination, and were further increased in these individuals during pollination. As a result, the IL-10-IFN-gamma ratio in CD4(+), CD14(+), and CD19(+) cells increased in vaccinated patients, but decreased in unvaccinated individuals during pollination. These data clarify the cellular and molecular basis underlying the recent observation that peripheral expansion of IL-10-producing cells is associated with successful IT. B7-H1 could be an optimal target for IT of allergic diseases using mAbs.

Immune profiles of patients with chronic idiopathic urticaria.

BACKGROUND: The immunologic characterization of chronic idiopathic urticaria (CIU) is still incomplete. In particular, it is not known if positivity to the intradermal autologous serum skin test (ASST) identifies an immunologic subset of CIU patients. METHODS: Nineteen CIU patients and 15 healthy controls were enrolled in the study. A diagnostic flowchart was designed to select CIU patients, who were then analyzed by ASST. Cytokine and chemokine production and the expression of adhesion molecules was measured in patients and controls. RESULTS: In CIU patients compared to controls, it was found that (1) TNF-alpha, IL-10, MIP-1alpha and RANTES production was augmented and IL-2 and INF-gamma reduced, and (2) CD44, CD11a and CD62L expression on CD4 and CD8 cells was augmented. Additionally, TNF-alpha and chemokine production was significantly increased in CIU patients with a negative ASST (p-; n = 10) compared to patients with a positive response to the test. CONCLUSIONS: The presence of an inflammatory process in CIU patients is suggested by the findings that the production of both TNF-alpha and chemokines as well as the expression of adhesion molecules is increased in these patients. Similarly to what is seen in rheumatoid arthritis, augmented IL-10 production might be secondary to the attempt to hamper the inflammatory milieu. Immune profiles are particularly altered in CIU p- patients, in whom a more aggressive therapeutic strategy might be considered.