An unusual neurological presentation in a patient with primary hypereosinophilic syndrome.

Hypereosinophilic syndromes are characterized by an increased number of blood eosinophils (usually more than 1.5 × 109) infiltrating tissues and causing organ damage through over-production of pro-inflammatory cytokines with heterogeneous clinical presentation. Here we present a case of a 47 years old male, with an unremarkable previous medical history, with a sudden onset of subungual hemorrhage and low back pain. Admitted for right arm weakness and vomiting, was raised the suspicion of acute cerebrovascular syndrome, but a brain CT scan with angiogram and perfusion sequences did not show any signs of early ischaemic lesions; conversely, lab tests revealed an increased peripheral eosinophil blood count. Clinical conditions rapidly worsened and a brain MRI showed multiple sub-acute ischaemic lesions compatible with vasculitis while EEG was in favor of widespread cortical distress. Diagnosis of the hypereosinophilic syndrome was made through peripheral blood smear and osteo-medullar biopsy, which showed a rich prevalence of eosinophils. The molecular biology testing showed FIP1L1-PDGRA gene mutation. Despite the prompt therapy beginning with intravenous corticosteroids and tyrosine-kinase inhibitors with normalization of cell blood count in a few days, the patient remained in minimal consciousness. When facing unusual symptoms onset (low back pain with weakness in one limb) and a highly impaired WBC not consistent with other courses (such as infections, vasculitis, allergies, and other diseases involving the immune system) clinicians should take into account the possibility of a hematological disorder and treat it as soon as possible to avoid a poor prognosis.

Nailfold Videocapillaroscopy Findings in Bradykinin-Mediated Angioedema.

BACKGROUND AND OBJECTIVE: Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) and acquired angioedema related to angiotensin-converting enzyme (ACE) inhibitors (ACEI-AAE) are types of bradykinin-mediated angioedema without wheals characterized by recurrent swelling episodes. Recent evidence suggests that a state of "vascular preconditioning" predisposes individuals to attacks, although no data are available on possible structural alterations of the vessels. Objective: This study aims to compare the features of nailfold capillaries to highlight possible structural anomalies between patients affected by C1-INH-HAE and controls and between patients with ACEI-AAE and hypertensive controls. METHODS: We used nailfold videocapillaroscopy (NVC) to assess the following: apical, internal, and external diameter; loop length; intercapillary distance; and capillary density, distribution, and morphology. Plasma levels of vascular endothelial growth factor (VEGF) A, VEGF-C, angiopoietin (Ang) 1, and Ang2 were also measured. RESULTS: Compared with healthy controls (n=28), C1-INH-HAE patients (n = 34) were characterized by significant structural alterations of the capillaries, such as greater intercapillary distance (216 vs 190 µm), increased apical, internal, and external diameter (28 vs 22 µm; 22 vs 20 µm; and 81 vs 65 µm, respectively), decreased density (4 vs 5 capillaries/mm2), more irregular capillary distribution, and more tortuous morphology. Apical diameter was enlarged in patients with ≥12 attacks per year. In ACEI-AAE patients, NVC showed no alterations with respect to hypertensive controls. NVC performed in 2 C1-INH-HAE patients during attacks showed no changes compared with the remission phase. CONCLUSIONS: We detected major structural capillary alterations in C1-INH-HAE patients, thus confirming the involvement of microcirculation in the pathogenesis of angioedema.

Angiotensin-Converting Enzyme Inhibitor-Associated Angioedema: From Bed to Bench.

BACKGROUND AND OBJECTIVE: Angiotensin-converting enzyme inhibitor-associated angioedema (ACEI-AAE) affects 0.1%-0.7% of patients treated with ACEIs. While previous research suggests that angioedema attacks result from increased vascular permeability, the pathogenesis is not completely understood. Objective: This study aimed to describe the clinical, genetic, and laboratory parameters of ACEI-AAE patients and to investigate the role of vascular endothelial growth factors A and C (VEGF-A and VEGF-C), angiopoietins 1 and 2 (Ang1/Ang2), and secretory phospholipase A2 (sPLA2) in the pathogenesis of ACEI-AAE. METHODS: The clinical and laboratory data of ACEI-AAE patients were collected from 2 angioedema reference centers. Healthy volunteers and ACEI-treated patients without angioedema were enrolled to compare laboratory parameters. Genetic analyses to detect mutations in the genes SERPING1, ANGPT1, PLG, and F12 were performed in a subset of patients. RESULTS: A total of 51 patients (57% male) were diagnosed with ACEI-AAE. The average time to onset of symptoms from the start of ACEI therapy was 3 years (range, 30 days-20 years). The most commonly affected sites were the lips (74.5%), tongue (51.9%), and face (41.2%). Switching from ACEIs to sartans was not associated with an increased risk of angioedema in patients with a history of ACEIAAE. VEGF-A, VEGF-C, and sPLA2 plasma levels were higher in ACEI-AAE patients than in the controls. Ang1/2 concentrations remained unchanged. No mutations were detected in the genes analyzed. CONCLUSIONS: Our data suggest that sartans are a safe therapeutic alternative in ACEI-AAE patients. Increased concentrations of VEGF-A, VEGF-C, and sPLA2 in ACEI-AAE patients suggest a possible role of these mediators in the pathogenesis of ACEI-AAE.

Elevated plasma levels of vascular permeability factors in C1 inhibitor-deficient hereditary angioedema.

BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare inherited genetic disease characterized by recurrent swelling episodes of the skin, gastrointestinal tract, and upper airways. Angioedema attacks result from increased vascular permeability due to the release of bradykinin from high molecular weight kininogen. Currently, there are no biomarkers predicting the frequency of angioedema attacks. Vascular permeability is modulated by several factors, including vascular endothelial growth factors (VEGFs) and angiopoietins (Angs). As increased circulating levels of VEGFs and Angs have been observed in diseases associated with higher vascular permeability (e.g., systemic capillary leak syndrome and sepsis), we sought to analyze plasma concentrations of VEGFs and Angs in patients with C1-INH-HAE. METHODS: Sixty-eight healthy controls and 128 patients with C1-INH-HAE were studied. Concentrations of angiogenic (VEGF-A, Ang1, Ang2), anti-angiogenic (VEGF-A165b ) and lymphangiogenic (VEGF-C) factors were evaluated by ELISA. C1-INH functional activity was assessed by EIA. RESULTS: Plasma concentrations of VEGF-A, VEGF-C, Ang1, and Ang2 were higher in patients with C1-INH-HAE in remission than in healthy controls. Concentration of VEGF-A was further increased in patients with lower C1-INH functional activity. Patients with C1-INH-HAE experiencing more than 12 angioedema attacks per year were characterized by higher plasma levels of VEGF-A, VEGF-C, and Ang2 compared with the other patients. CONCLUSIONS: We hypothesize that VEGFs and Angs induce a state of 'vascular preconditioning' that may predispose to angioedema attacks. In addition, the identification of increased plasma levels of VEGFs and Angs in patients with C1-INH-HAE may prompt the investigation of VEGFs and Angs as biomarkers of C1-INH-HAE severity.

Icatibant treatment for acquired C1-inhibitor deficiency: a real-world observational study.

Icatibant, a bradykinin B2 receptor antagonist, is an established treatment for acute attacks of hereditary angioedema (HAE) with C1-inhibitor (C1-INH) deficiency. We describe our experience with icatibant in eight patients with angioedema because of acquired C1-INH deficiency (AAE). Forty-eight moderate-to-severe attacks were treated with subcutaneous icatibant 30 mg; two moderate attacks resolved without treatment. The median (range) duration of treated attacks (onset to complete resolution) was 9.33 (1.67-39.00) h; durations of the untreated attacks were 72 and 96 h. Symptom improvement following icatibant treatment occurred in 0.5 (0.25-2.10) h and complete resolution in 6.75 (0.50-30.75) h. A single icatibant injection achieved complete symptom resolution in 47 attacks; one facial attack required a second injection. One peripheral attack responded less quickly than other treated attacks. Five patients reported transient injection site reactions. Icatibant appeared to provide effective symptom relief and was generally well tolerated.

Placental cortisol and cord serum IGFBP-2 concentrations are important determinants of postnatal weight gain.

There is a need to identify simple biochemical markers at birth that may predict subjects at risk of growth failure and metabolic complications in later life. Limited research to date has been performed on relationships of specific biochemical determinants at birth with postnatal weight gain and growth. We proposed to establish whether placental cortisol and IL-6 concentrations and cord serum IGF-II and IGFBP-2 concentrations influenced postnatal growth. We followed up from pregnancy 23 IUGR and 37 AGA subjects, and determined placental cortisol and IL-6 concentrations, and cord serum IGF-II, and IGFBP-2 concentrations at birth. We obtained height and weight measurements at 3, 6, 12, 24 months and 5 years of age in 20 IUGR and 15 AGA subjects of comparable gestational age. A multiple linear regression model was designed to establish the effect of the placental and cord serum peptides on postnatal linear growth and weight gain. All IUGR subjects had catch-up growth before 2 years of age. Placental cortisol concentration correlated positively with weight gain during the first 5 years of postnatal growth (P<0.05). Subjects with the highest placental cortisol concentrations were those who showed a greater increase in weight. Cord serum IGFBP-2 concentrations correlated positively with weight gain throughout the 5 year observation period (P:0.003). The subjects with the highest concentrations showed a greater weight gain. Placental cortisol and cord serum IGFBP-2 concentrations were related to postnatal weight gain, suggesting that the fetal environment has long-term effects on growth.

Pregnancy in women with Hereditary Angioedema due to C1-inhibitor deficiency: Results from the ITACA cohort study on outcome of mothers and children with in utero exposure to plasma-derived C1-inhibitor.

Background: In women with Hereditary Angioedema (HAE) due to C1-inhibitor (C1INH) deficiency (C1INH-HAE), pregnancy counseling and treatment can be challenging. Despite the evidence of the immediate favorable outcome and safety of plasma-derived (pd)C1INH concentrate, there are no data regarding any difference among women who underwent or not pdC1INH during pregnancy or on children with in utero exposure to pdC1INH. The present interview study aimed at analyzing outcome of C1INH-HAE mothers and children according to pdC1INH-exposure during pregnancies. Methods: C1INH-HAE women who experienced at least 1 pregnancy were included from seven centers of the Italian Network for Hereditary and Acquired Angioedema (ITACA). The interview study retrospectively analyzed pregnancies who underwent (group 1) or not (group 2) pdC1INH. The overall goals of the study included immediate and long-term outcomes, in terms of outcomes in the time interval between pregnancy and survey. Results: A total of 168 pregnancies from 87 included women were analyzed. At term delivery (>37 gestation-week, GW) has been registered in 73.8% of cases, while spontaneous abortion (SA) occurred in 14.2% of cases with a mean GW 7 ± 2. The group 1 including pdC1INH-treated pregnancies comprised a third of the cohort (51/168, time interval 1.5 ± 10.4 yrs), while the group 2 represented 69.6% (117/168, time interval 32.8 ± 14 yrs). The same prevalence of SA occurred when comparing group 1 (11.7%) with group 2 (15.4%) with a similar GW at SA. The group 1 was older at the pregnancy time and younger at the interview than the group 2 (P < 0.01 for both); moreover, the group 1 showed a higher prevalence of cesarean delivery (P < 0.0001). The overall prevalence of obstetrical syndromes was similar between two groups: however, gestational diabetes was described only in pdC1INH-untreated pregnancies. In utero pdC1INH-exposed children (n = 45) did not show differences compared with unexposed ones (n = 99) in neonatal short-term outcomes. Conclusion: Through appropriate management and counseling, most of C1INH-HAE women undergo successful pregnancy and delivery. For pregnant C1INH-HAE women being treated with pdC1INH, our findings are reassuring and might lead to an improvement of both the knowledge about treatments and the experience of HAE itself.

Quantitative analysis of movements in facial nerve palsy with surface electromyography and kinematic analysis.

Facial nerve paralysis (FNP) has a significant effect on a person's quality of life. In individuals with FNP undergoing facial rehabilitation, methods to analyze the loss of function are useful in diagnosis, treatment and follow up. To propose a protocol with kinematic analysis coupled with sEMG to evaluate the outcomes of FNP, quantifying the excursion degrees of the facial muscles and symmetry of voluntary movements. 10 patients (Group A) were followed by diagnosis until the end of the rehabilitation program. Kinematic analysis of 20 healthy adults (group B) was performed as a starting point to have a normality range and to test intra-subject and inter- intra rater reliability. An optoelectronic system and sEMG wireless electrodes were used. In Group A, a significant improvement in the movement of frontalis muscle (P = 0.0118) after 4-week treatment from the beginning (T0) 9.8 ± 4.5 mm to the end of rehabilitation (T1) 16.3 ± 5.8 mm and orbicularis oris (P = 0.0143) from T0 14.8 ± 5.5 mm to T1 20.3 ± 3.3 mm and, a reduction of % of maximum voluntary contractions (MVC) at T1 for frontalis and orbicularis compared to T0. This protocol provides meaningful data in a simple, reliable and objective way for the functional assessment of patients with PNF.

Rehabilitation of patients post-COVID-19 infection: a literature review.

Rehabilitation is important for patients with coronavirus disease 2019 (COVID-19) infection. Given the lack of guidelines in English on the rehabilitation of these patients, we conducted a review of the most recent reports. We performed this literature review using the principal research databases and included randomized trials, recommendations, quasi-randomized or prospective controlled clinical trials, reports, guidelines, field updates, and letters to the editor. We identified 107 studies in the database search, among which 85 were excluded after screening the full text or abstract. In total, 22 studies were finally included. The complexity of the clinical setting and the speed of spread of the severe acute respiratory syndrome coronavirus 2, which leads to rapid occupation of beds in the intensive care unit, make it necessary to discharge patients with COVID-19 who have mild symptoms as soon as possible. For these reasons, it is necessary to formulate rehabilitation programs for these patients, to help them restore physical and respiratory function and to reduce anxiety and depression, particularly patients with comorbidities and those who live alone or in rural settings, to restore a good quality of life.

Mechanisms of IgE elevation in HIV-1 infection.

Serum IgE levels are high in adults and children with HIV-1 infection and could be a marker of poor prognosis. Allergic reactions and adverse reactions to drugs also tend to increase in HIV-1-infected individuals. An imbalance between a "T(H)1-like" and a "T(H)2-like" cytokine profile has been documented in HIV-1 infection. We have demonstrated that HIV-1 gp 120 from different clades is a stimulus for histamine and cytokine (IL-4 and IL-13) release from basophils. Gp 120 acts as a viral superantigen, interacting with the V(H)3 region of IgE to induce mediator release from human Fc epsilonRI+ cells. Human basophils and mast cells express the chemokine receptor CCR3, which binds the chemokines eotaxin and RANTES. By interacting with the CCR3 receptor on Fc epsilonRI+ cells, HIV-I Tat protein is a potent chemoattractant for human basophils and lung mast cells. Preincubation of basophils with Tat protein upregulates mRNA CCR3 and the surface expression of this chemokine receptor. Tat also induces IL-4 and IL-13 release from basophils. Extracellular Tat can influence the directional migration of human Fc epsilonRI+ cells, the expression of chemokine receptor CCR3, and the release of T(H)2 cytokines. Our results indicate two novel mechanisms by which two HIV-1 proteins, gp120 and Tat, trigger the release of cytokines critical for T(H)2 polarization from human Fc epsilonRI+ cells.

The immunoglobulin superantigen-binding site of HIV-1 gp120 activates human basophils.

OBJECTIVE: To investigate the mechanism whereby HIV-1 envelope glycoprotein gp120 from four different isolates obtained in three different countries induces proinflammatory mediator release from normal human basophils. METHODS: Histamine, cysteinyl leukotriene C4 (LTC4) and interleukin 4 (IL-4) release into the supernatant was measured in gp120-stimulated peripheral blood basophils from HIV-1 and HIV-2 negative subjects. RESULTS: The HIV glycoprotein was a potent stimulus for release of these mediators in basophils purified from donors negative for HIV-1 and HIV-2. There was also a correlation (r = 0.58; P < 0.01) between the maximum IL-4 release from basophils induced by gp120 and by anti-IgE. Basophils from which IgE had been dissociated by brief exposure to lactic acid no longer released histamine in response to gp120 and anti-IgE. Anti-IgE specifically desensitized basophils to a subsequent challenge with anti-IgE and gp120. Human monoclonal IgM carrying the VH3 domain, but not that carrying the VH6 domain, inhibited gp120-induced secretion of histamine from basophils in a concentration-dependent manner. Synthetic peptides identical to regions distant from the N- and C-termini of gp120MN inhibited its activating capacity. CONCLUSIONS: gp120 acts as a viral superantigen interacting with the VH3 domain of IgE to induce the release of preformed and de novo synthesized mediators from human cells carrying the Fc fragment Fc epsilonRI receptor.

[Clinical observations on the treatment of obese patients with dexfenfluramine]. / Osservazioni cliniche sul trattamento di pazienti obesi con dexfenfluramina.

In a 12-months double-blind study 42 obese patients (5 males, 37 females) were treated either with d-fenfluramine (30 mg daily) or with placebo plus low-calorie diet (1500-1200 kcal daily). Evaluation of treatment efficacy was based on evolution of the initial cohort, weight loss, number of subjects completing treatment, tolerability and events leading to dropout. Patients receiving d-fenfluramine had statistically significant greater weight loss than the placebo group; 30 mg daily proved to be an effective and well tolerated dose of d-fenfluramine with the best long-term activity/acceptability ratio.

Dysregulation of the IgE/Fc epsilon RI network in HIV-1 infection.

Serum IgE levels are increased in adults and children with HIV-1 infection and could be a marker of poor prognosis. Allergic reactions and adverse reactions to drugs are also increased in HIV-1-infected individuals. An imbalance between a T(H)1-like and a T(H)2-like cytokine profile has been documented in HIV-1 infection. We have found that HIV-1 gp120 from different clades is a potent stimulus for histamine and cytokine (IL-4 and IL-13) release from basophils. Gp120 acts as a viral superantigen, interacting with the V(H)3 region of IgE to induce mediator release from human Fc epsilon RI(+) cells. Human basophils and mast cells express the chemokine receptor CCR3, which binds the chemokines eotaxin and RANTES. By interacting with the CCR3 receptor on Fc epsilon RI(+) cells, HIV-1 Tat protein is a potent chemoattractant for human basophils and lung mast cells. Tat protein also induced IL-4 and IL-13 release from basophils. Preincubation of basophils with Tat protein upregulated the surface expression of the CCR3 receptor. Extracellular Tat can influence the directional migration of human Fc epsilon RI(+) cells, the expression of chemokine receptor CCR3, and the release of T(H)2 cytokines. Because Tat protein is actively released by HIV-1-infected cells, our results indicate a novel mechanism by which Fc epsilon RI(+) cells are rendered more susceptible to infection with CCR3-tropic HIV-1 isolates; that is, two HIV-1 proteins, gp120 and Tat, trigger the release of cytokines critical for T(H)2 polarization from Fc epsilon RI(+) cells, and Tat upregulates beta-chemokine receptor CCR3 on these cells.

HIV-1 gp120 induces IL-4 and IL-13 release from human Fc epsilon RI+ cells through interaction with the VH3 region of IgE.

HIV-1 glycoprotein (gp) 120 from different clades is a potent stimulus for IL-4 and IL-13 release from basophils purified from healthy individuals seronegative for Abs to HIV-1 and HIV-2. IL-4 mRNA, constitutively present in basophils, was increased after stimulation by gp120 and was inhibited cyclosporin A and tacrolimus. IL-4 and IL-13 secretion from basophils activated by gp120 was not correlated. There was a correlation between the maximum gp120- and anti-IgE-induced IL-4 release from basophils. The average t1/2 gp120-induced IL-4 release was lower than for IL-13 release. Basophils from which IgE had been dissociated by brief exposure to lactic acid no longer released IL-4 in response to gp120 or to anti-IgE. The response to a mAb cross-linking the alpha-chain of high-affinity receptor for IgE (Fc epsilon RI) was unaffected by this treatment. Three human VH3+ monoclonal IgM inhibited gp120-induced secretion of IL-4 from basophils. In contrast, VH6+ monoclonal IgM did not inhibit the release of IL-4 induced by gp120. Synthetic peptides distant from the NH2 and COOH termini of gp120MN inhibited the activating property of gp120MN. These results indicate that gp120, which acts as a viral superantigen, interacts with the VH3 region of IgE to induce the release of IL-4 and IL-13 from human Fc epsilon RI+ cells.

Human mast cells and basophils in HIV-1 infection.

Mast cells and basophils (FcvarepsilonRI(+) cells) are classically involved in allergic disorders. HIV-1 glycoprotein gp120 acts as a viral superantigen by interacting with the heavy chain, variable 3 (V(H)3) region of IgE to induce cytokine release from FcvarepsilonRI(+) cells. The chemokine receptors CCR3 and CXCR4, co-receptors for HIV-1, are expressed by FcvarepsilonRI(+) cells. Via its interaction with CCR3, HIV-1 transactivation (Tat) protein is a potent chemoattractant for FcvarepsilonRI(+) cells. Incubation of basophils with Tat protein upregulates the surface expression of the CCR3 receptor. There is some evidence that human FcvarepsilonRI(+) cells could be infected in vitro by M-tropic HIV-1 strains.

Are mast cells MASTers in HIV-1 infection?

HIV-1 gp120 interacts with IgE V(H)3(+) on the surface of human basophils and mast cells (Fc epsilon RI(+) cells), acting as a viral immunoglobulin superantigen. gp120 from different clades induces mediator release from Fc epsilon RI(+) cells. gp120 also induces IL-4 and IL-13 synthesis in human basophils. The chemokine receptors CCR3 and CXCR4, which are coreceptors of HIV-1 infection, are expressed by human Fc epsilon RI(+) cells. HIV-1 Tat protein is a potent chemoattractant for basophils and lung mast cells, interacting with CCR3. Incubation of basophils with Tat protein upregulates the surface expression of the CCR3 receptor. There is evidence that human Fc epsilon RI(+) cells could be infected in vitro by M-tropic HIV-1 strains.

Histamine-induced activation of human lung macrophages.

BACKGROUND: Histamine plays a central role in the pathogenesis of allergic and inflammatory diseases by modulating vascular and airway responses. Increasing evidence suggests that histamine also regulates the function of inflammatory and immune cells. Macrophages are primarily involved in inflammatory diseases of the lung. We explored the ability of low concentrations of histamine to induce the release of proinflammatory mediators from human lung macrophages. METHODS: Macrophages purified (> 95%) from lung parenchyma by Percoll density gradients and adherence to polystyrene dishes were incubated (37 degrees C, 2-24 h) with histamine (10(-9)-10(-6) M). At the end of incubation, the release of beta-glucuronidase and IL-6 was determined. RESULTS: Histamine induced a concentration-dependent release of beta-glucuronidase and IL-6 with a maximum release after 2 and 6 h of incubation, respectively. Exocytosis induced by histamine was noncytotoxic and was Ca(2+)- and temperature-dependent. The effect of histamine was inhibited by the H(1) receptor antagonist fexofenadine but not by the H(2) antagonist ranitidine. CONCLUSIONS: These data indicate that histamine is an effective stimulus for exocytosis and cytokine production from human lung macrophages. These effects are inhibited by pharmacological concentrations of fexofenadine. Our results suggest that histamine may contribute to the long-term evolution of lung inflammation and tissue remodelling in allergic diseases by modulating the production of proinflammatory and immunoregulatory mediators by macrophages.