| 2021 | Cold Agglutinins and Cryoglobulins Associate With Clinical and Laboratory Parameters of Cold Urticaria. | Front Immunol | Mast cell-activating signals in cold urticaria are not yet well defined and are likely to be heterogeneous. Cold agglutinins and cryoglobulins have been described as factors possibly associated with cold urticaria, but their relevance has not been explained. We performed a single-center prospective cohort study of 35 cold urticaria patients. Cold agglutinin and cryoglobulin test results, demographics, detailed history data, cold stimulation test results, complete blood count values, C-reactive protein, total immunoglobulin E levels, and basal serum tryptase levels were analyzed. Forty six percent ( = 16) of 35 tested patients had a positive cold agglutinin test and 27% ( = 9) of 33 tested patients had a positive cryoglobulin test. Cold agglutinin positive patients, when compared to cold agglutinin negative ones, were mainly female ( = 0.030). No gender-association was found for cryoglobulins. A positive cold agglutinin test, but not a positive cryoglobulin test, was associated with a higher rate of reactions triggered by cold ambient air ( = 0.009) or immersion in cold water ( = 0.041), and aggravated by increased summer humidity ( = 0.007). Additionally, patients with a positive cold agglutinin test had a higher frequency of angioedema triggered by ingestion of cold foods or drinks ( = 0.043), and lower disease control based on Urticaria Control Test ( = 0.023). Cold agglutinin levels correlated with erythrocyte counts (r = -0.372, = 0.028) and monocyte counts (r = -0.425, = 0.011). Cryoglobulin concentrations correlated with basal serum tryptase levels (r = 0.733, = 0.025) and cold urticaria duration (r = 0.683, = 0.042). Results of our study suggest that cold agglutinins and cryoglobulins, in a subpopulation of cold urticaria patients, are linked to the course and possibly the pathogenesis of their disease. |
| 2021 | A Comparative Study of Sex Distribution, Autoimmunity, Blood, and Inflammatory Parameters in Chronic Spontaneous Urticaria with Angioedema and Chronic Histaminergic Angioedema. | J Allergy Clin Immunol Pract | Recurrent idiopathic histaminergic angioedema is currently classified as a subtype of angioedema, as well as a subtype of chronic spontaneous urticaria (CSU), based on the fact that both are mast cell-mediated and respond to the same treatments.In the present work, we sought to verify whether chronic histaminergic angioedema (CHA) is an entity distinct from CSU or represents a CSU subtype that lacks hives.We performed a prospective study comparing 68 CHA patients, angioedema without hives, with 63 CSU patients, with hives and angioedema, from whom we collected demographic and clinical data, as well as blood and serum markers.We found key pathogenic features that differentiate CHA from CSU: gender distribution, basophil number, and antibodies against the IgE receptor. The male/female ratio in CHA was 0.78, whereas in CSU it was 0.36 (P = .0466). Basopenia was more often seen in CSU (n = 13 [20%]) than in CHA (n = 5 [7%]). Finally, 31.15% of CSU sera induced basophil activation, whereas no CHA sera were able to activate normal basophils. By contrast, nonspecific inflammation or immune markers, for example, erythrocyte sedimentation rate, C-reactive protein, or IgG antithyroid antibodies, were very similar between both groups. IgE anti-IL-24 could not be assessed because a control population did not differ from CSU.Inclusion of CHA as part of the spectrum of CSU is an assumption not evidence-based, and when studied separately, important differences were observed. Until there is further evidence, CHA and CSU should not necessarily be considered the same disorder, and it is our opinion that review articles and guidelines should reflect that possibility. |
| 2021 | Clinical Characteristics, Management, and Natural History of Chronic Inducible Urticaria in a Pediatric Cohort. | Int Arch Allergy Immunol | Some forms of chronic urticaria (CU) can be specifically attributed to a response to a definite trigger, referred to as chronic inducible urticaria (CIndU). We aimed to assess the demographics, clinical characteristics, comorbidities, natural history, and management of pediatric patients with CIndU.Over a 6-year period, children presenting to the allergy clinic at the Montreal Children's Hospital (MCH) with CIndU were prospectively recruited. CU was defined as the presence of wheals and/or angioedema, occurring for at least 6 weeks. A standardized diagnostic test was used to establish the presence of a specific form of urticaria. Resolution was defined as the absence of hives for 1 year without treatment.Sixty-four patients presented with CIndU, of which 51.6% were male, with a median age of 12.5 (interquartile range 7.3, 15.9) years. Cold CU and cholinergic CU were the most common subtypes (60.3 and 41.3%, respectively). Basophil counts were undetectable in 48.4% of the cases, and C-reactive protein levels were elevated in 7.8% of patients. Of all cases, 71.4% were controlled with second-generation antihistamines. The resolution rate was of 45.3% (95% confidence interval 33.1-57.5%), based on per-protocol population within the 6-year course of the study. Resolution was more likely in patients who presented with well-controlled urticaria control test scores and elevated CD63 counts and in those suffering from thyroid comorbidity.The natural history of CIndU resolution in pediatric patients was relatively low and was associated with elevated CD63 levels, as well as thyroid comorbidity. |
| Evaluation of serum levels of C-reactive protein, D-Dimer and Autologous Serum Skin Test in patients with Chronic Spontaneous Urticaria in a Brazilian tertiary center : a cross-sectional study. | An Bras Dermatol | The pathophysiology of urticaria is still poorly understood. Recent studies demonstrate that the activation of coagulation is correlated with the clinical activity of Chronic Spontaneous Urticaria. Coagulation and inflammation are strongly linked.To correlate the severity and activity of Chronic Spontaneous Urticaria with the levels of D-dimer, C-reactive protein, and autologous serum test in patients with Chronic Spontaneous Urticaria.The study included 55 patients diagnosed with chronic spontaneous urticaria. D-dimer levels were measured using enzyme-linked fluorescent assay and C-reactive protein levels were measured using the nephelometric method; autologous serum testing was performed on patients who discontinued antihistamine therapy. The severity of the disease was assessed using the urticaria activity score.patients with severe, spontaneous, and difficult-to-control chronic urticaria had elevated serum levels of D-dimer, as well as a positive autologous serum test. Little correlation was demonstrated between the severity of chronic spontaneous urticaria and the levels of C-reactive protein.The authors concluded that patients with severe Chronic Spontaneous Urticaria showed signs of activated fibrinolysis. Most patients with high clinical scores had high D-dimer values. Patients with positive results for the autologous serum test also had more severe Chronic Spontaneous Urticaria and needed more drugs to control the disease. Finally, little correlation was found between C-reactive protein levels and disease severity.The main limitation was the small sample of patients. In the present patients, it was demonstrated that serum D-dimer levels and the autologous serum test can act as predictive markers of severity and activity of Chronic Spontaneous Urticaria. |
| 2021 | D-dimer concentrations in acute urticaria in children. | Allergol Immunopathol (Madr) | Urticaria is a clinical entity presenting as wheals, angioedema, or both simultaneously. Elevated D-dimer levels were reported in the course of chronic spontaneous urticaria. Data regarding D-dimer levels in acute urticaria in children are limited.To assess potential associations between duration of glucocorticosteroid (GCS) therapy and D-dimer concentrations in children with acute urticaria.Hospital records of 106 children (59 females), aged 5.57 ± 4.91 years, hospitalized in 2014-2018 were analyzed retrospectively. The study group consisted of pediatric patients admitted to the hospital due to severe acute urticaria resistant to antihistaminic treatment that was ordered in the ambulatory care (out-patient clinic). Patients were divided into subgroups: no GCS treatment, short-duration treatment (up to 5 days) and long-duration treatment (6 and more days) GCS treatment. Simultaneously, patients received antihistaminic drugs. D-dimer level and other inflammatory factors such as white blood cell (WBC) count, platelet (PLT) count, and C-reactive protein (CRP) in each group were analyzed.The D-dimer level was elevated in 51% of cases. In the subgroup with longer GCS treatment, D-dimer concentration was significantly higher in comparison to patients with a shorter GCS course. There were no differences in the distribution of CRP, PLT, and WBC concentrations between these subgroups.In the studied group of children, there was a tendency for higher D-dimer levels in patients, who required a longer GCS treatment. This finding is hypothesis-generating and requires further investigation to confirm if D-dimers can be used as a prognostic factor in acute urticaria in children. |
| 2020 | Refractory chronic urticaria in adults: clinical characterization and predictors of severity. | Allergy Asthma Clin Immunol | Chronic urticaria (CU) is defined as recurrent urticaria lasting for more than 6 weeks.We aimed to characterize the phenotypes of patients with CU refractory to standard dose anti-H1 antihistamine treatment and search for clinical predictors of poor disease control.Retrospective collection of data regarding clinical characteristics, comorbidities, treatment, and disease control of all adult refractory CU patients presenting to the Allergy and Immunology Department during 1 year.Sixty-one adult patients were included, 74% females, average age 44.5 years (18 to 84 years old). Most patients (78.7%) had initiated CU less than 1 year before enrolment. Chronic spontaneous urticaria (CSU) accounted for 55.7% of the patients, CSU associated with chronic inducible urticaria (CIndU) as a comorbidity for 44.3%, and angioedema was present in 55.7%. Medically-confirmed psychiatric disorders were present in 78.7%. Complementary diagnostic tests were performed in cases with more severe presentation (UAS7 ≥ 28 and/or UCT < 12) or with longer evolution (> 1 year), corresponding to 42 tested patient. Evidence for autoimmunity (positive anti-thyroid peroxidase antibodies, anti-nuclear antibodies or autologous serum test) was found in 45.2% (n = 19/42), and high C-reactive protein was present in 14.3% (n = 6/42), half of these also had positive antinuclear antibodies. Forty-six patients (75.4%) had at least one significant exacerbation, requiring medical appointment, emergency room, hospitalization or job absenteeism. The number of exacerbations correlated with the presence of angioedema (p = 0.022), with a recent diagnosis (< 1 year), and with higher UAS7 severity (p = 0.006). Although ClndU was associated with poor symptom control (p = 0.022), it was also associated with less exacerbations requiring medical observation or hospitalization (p = 0.015). All patients were using antihistamines and 21.3% (n = 13) of them were also under treatment with omalizumab, ciclosporine or montelukast for disease control.Autoimmunity can affect about half of the patients with severe or long-term CU. UAS7 and angioedema are associated with disease exacerbations. UAS7 and UCT presented unequal accuracy, with UAS7 better associating with the occurrence of exacerbations and treatment doses. Patients with refractory CU frequently present psychiatric disorders. Accurate diagnostic tests, namely autoimmune parameters and inflammatory markers, should be recommended in some individual cases. |
| 2019 | Clinical features of angioedema induced by renin-angiotensin-aldosterone system inhibition: a retrospective analysis of 84 patients. | J Community Hosp Intern Med Perspect | : Bradykinin-mediated angioedema (AE) induced by antihypertensive drugs primarily affect the head and neck region and may occur even after several years of uneventful treatment. Many facts about the clinical course remain unknown. Diagnosis is not easy, as the clinical appearance resembles allergic AE. No specific diagnostic markers are known and no officially approved treatment is currently available. : All patients who presented to the ORL department between 2010 and 2016 with acute AE were included. Those with a history of renin-angiotensin-aldosterone system (RAAS) blocker intake were defined as RAE and their pathophysiological characteristics and clinical course of the disease were analyzed. : A total of 84 patients (median age of 71 years) with RAE was identified. The majority (80%) was on ACE inhibition. The oral cavity was most often affected. Nearly 60% were medicated for more than 1 year before AE occurred. RAE occurred more often during the morning hours. The necessity for emergency intubation and/or tracheostomy was nine times higher in patients with acute RAE compared to patients with AE due to other reasons. : Event-free, long-term therapy with an RAAS blocker before the first development of edema does not exclude RAE. RAE is associated with an increased risk for emergency airway management. ACE: Angiotensin Converting Enzyme; ACEi AE: ACE inhibitor-induced angioedema; AE: Angioedema; ARB: Angiotensin II receptor 1 blocker; C1 INH: C1 Inhibitor; CI: Confidence Interval; CRP: C-reactive protein; DPP IV: Dipeptidyl peptidase IV; ENT: Ear, Nose and Throat; HAE: Hereditary Angioedema; ICD 10: International Statistical Classification of Diseases and Related Health Problems, 10th Edition; OR: Odds Ratio; ORL: Otorhinolaryngology; RAAS: Renin-Angiotensin-Aldosterone System; RAE: RAAS-blocker-induced angioedema. |
| 2019 | Chronic Urticaria: An Overview of Treatment and Recent Patents. | Recent Pat Inflamm Allergy Drug Discov | Up to 1% of the general population in the USA and Europe suffer from chronic urticaria (CU) at some point in their lifetime. CU has an adverse effect on the quality of life.This study aims to provide an update on the epidemiology, pathogenesis, clinical manifestations, diagnosis, aggravating factors, complications, treatment and prognosis of CU.The search strategy included meta-analyses, randomized controlled trials, clinical trials, reviews and pertinent references. Patents were searched using the key term "chronic urticaria" at the following links: www.google.com/patents, www.uspto.gov, and www.freepatentsonline.com.CU is a clinical diagnosis, based on the episodic appearance of characteristic urticarial lesions that wax and wane rapidly, with or without angioedema, on most days of the week, for a period of six weeks or longer. Triggers such as medications, physical stimuli, and stress can be identified in 10 to 20% of cases. C-reactive protein/erythrocyte sedimentation rate, and complete blood cell count with differential are the screening tests that may be used to rule out an underlying disorder. The mainstay of therapy is reassurance, patient education, avoidance of known triggers, and pharmacotherapy. Secondgeneration H1 antihistamines are the drugs of choice for initial therapy because of their safety and efficacy profile. If satisfactory improvement does not occur after 2 to 4 weeks or earlier if the symptoms are intolerable, the dose of second-generation H1 antihistamines can be increased up to fourfold the manufacturer's recommended dose (all be it off license). If satisfactory improvement does not occur after 2 to 4 weeks or earlier if the symptoms are intolerable after the fourfold increase in the dosage of second-generation H1 antihistamines, omalizumab should be added. If satisfactory improvement does not occur after 6 months or earlier if the symptoms are intolerable after omalizumab has been added, treatment with cyclosporine and second-generation H1 antihistamines is recommended. Short-term use of systemic corticosteroids may be considered for acute exacerbation of CU and in refractory cases. Recent patents for the management of chronic urticaria are also discussed. Complications of CU may include skin excoriations, adverse effect on quality of life, anxiety, depression, and considerable humanistic and economic impacts. On average, the duration of CU is around two to five years. Disease severity has an association with disease duration.CU is idiopathic in the majority of cases. On average, the duration of CU is around two to five years. Treatment is primarily symptomatic with second generation antihistamines being the first line. Omalizumab has been a remarkable advancement in the management of CU and improves the quality of life beyond symptom control. |
| 2019 | Serum fetuin-A, tumor necrosis factor alpha and C-reactive protein concentrations in patients with hereditary angioedema with C1-inhibitor deficiency. | Orphanet J Rare Dis | Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is characterized by localized, non-pitting, and transient swelling of submucosal or subcutaneous region. Human fetuin-A is a multifunctional glycoprotein that belongs to the proteinase inhibitor cystatin superfamily and has structural similarities to the high molecular weight kininogen. Fetuin-A is also known a negative acute phase reactant with anti-inflammatory characteristics. In this study we aimed to determine serum fetuin-A, C-reactive protein (CRP) and tumor necrosis factor alpha (TNFα) concentrations in patients with C1-INH-HAE during symptom-free period and during attacks and compare them to those of healthy controls. Further we analyzed possible relationship among these parameters as well as D-dimer levels which was known as marker of HAE attacks.Serum samples of 25 C1-INH-HAE patients (8 men, 17 women, age: 33.1 ± 6.9 years, mean ± SD) were compared to 25 healthy controls (15 men, 10 women, age: 32.5 ± 7.8 years). Serum fetuin-A and TNFα concentrations were determined by ELISA, CRP and D-dimer by turbidimetry.Compared to healthy controls patients with C1-INH-HAE in the symptom-free period had significantly decreased serum fetuin-A 258 μg/ml (224-285) vs. 293 μg/ml (263-329), (median (25-75% percentiles, p = 0.035) and TNFα 2.53 ng/ml (1.70-2.83) vs. 3.47 ng/ml (2.92-4.18, p = 0.0008) concentrations. During HAE attacks fetuin-A levels increased from 258 (224-285) μg/ml to 287 (261-317) μg/ml (p = 0.021). TNFα and CRP levels did not change significantly. We found no significant correlation among fetuin-A CRP, TNFα and D-dimer levels in any of these three groups.Patients with C1-INH-HAE have decreased serum fetuin-A concentrations during the symptom-free period. Given the anti-inflammatory properties of fetuin-A, the increase of its levels may contribute to the counter-regulation of edema formation during C1-INH-HAE attacks. |
| 2019 | C-reactive protein (CRP) rs3093059C predicts poor mizolastine response in chronic spontaneous urticaria patients with elevated serum CRP level. | Exp Dermatol | Chronic spontaneous urticaria (CSU) is a frequent disorder with recurrent itchy wheals and/or angioedema, and nearly 35% patients respond poorly to non-sedating H1 antihistamine treatment. CRP gene encodes the C-reactive protein, which is involved in the pathogenesis of CSU. To investigate the impacts of CRP polymorphisms on the susceptibility and therapeutic efficacy in the South Han CSU patients, we enrolled 145 CSU patients in our study. After 4-week non-sedating H1 antihistamine monotherapy treatment, more than 50% reduction of the severity score is considered as effective, or else non-effective. The CRP rs3093059T/C and rs2794521G/A genotypes of patients were determined by Sequenom MassARRAY. Functional studies including relative luciferase assay and β-hexosaminidase assay were conducted in HEK293T cells or RBL-2H3 cells to explore the function of variants. Forty (62.50%) CSU patients were effective when treated with mizolastine, and 55 (72.4%) patients were effective in the desloratadine group. We found that the patients carried with rs3093059TT genotype were significantly associated with good response (OR = 4.20, P = 0.015), had lower serum CRP, IL-6 and TNF-α levels than the CT/CC genotypes. In vitro, the rs3093059C allele exhibited significantly higher luciferase activity than wild allele (P < 0.001). From the β-hexosaminidase assay, we observed the inhibiting degranulation effects by mizolastine and this effect is weakened when with a higher dose CRP in RBL-2H3 cells. Our findings suggested that CSU patients carrying the rs3093059C allele may respond poorly to mizolastine with elevated serum CRP level. |
| 2018 | Acute-phase response and its biomarkers in acute and chronic urticaria. | Postepy Dermatol Alergol | Since urticaria is a persisting inflammatory disease it is important to establish the prognostic factors for the duration and severity of the disease.To evaluate serum concentrations of selected acute-phase proteins (APP) in patients with various forms of urticaria as compared to healthy volunteers and also to analyze these concentrations in different types of urticaria. Additionally, to evaluate the correlation between serum levels of selected APP and disease activity.Serum concentrations of C-reactive protein (CRP), α-acid glycoprotein (AGP), α-antichymotrypsin (ACT), α-antitrypsin (AT), ceruloplasmin (Cp), transferrin (Tf), α-macroglobulin (αM) and haptoglobin (Hp) were measured. Quantitative measurement was conducted using the rocket immunoelectrophoresis. Disease activity was assessed with the use of total symptom score.Analysis of serum APP concentrations revealed statistically higher serum concentrations of CRP, AGP and ACT in the entire group of patients with urticaria in comparison with the control group. In the entire group of patients with urticaria, CRP, AGP, ACT, Cp and Hp correlated positively with disease activity, intensity of pruritus and the number and size of urticarial wheals. Statistically lower serum concentrations of CRP, ACT, Cp and Hp were detected in the group of patients with acute urticaria (AU) and angioedema together, compared to the patients suffering from AU only.Patients with symptoms of various forms of urticaria present a distinct profile of serum APP concentrations. A significant correlation observed between CRP, AGP, ACT, Cp, Hp and clinical activity score points to the potential role of APP as markers of the urticarial activity. |
| 2018 | C-reactive protein is linked to disease activity, impact, and response to treatment in patients with chronic spontaneous urticaria. | Allergy | Elevated levels of C-reactive protein (CRP), a sensitive marker of inflammation, have been consistently reported in chronic spontaneous urticaria (CSU). Here, we retrospectively analyzed data from 1253 CSU patients from 2 centers to answer the following questions: (i) What is the prevalence of elevated levels of CRP in CSU? (ii) Why do CSU patients show elevated levels of CRP? (iii) Are elevated CRP levels relevant?Serum levels of CRP were measured by the nephelometric method. We collected information regarding various laboratory tests including ESR, CBC with differential, D-dimer, fibrinogen, C3, C4, IL-6, etc. For most patients, we also collected data on age, gender, duration of CSU, presence of angioedema, activity (UAS at the time of blood sampling and for 7 days), quality of life (CU-Q2oL and/or DLQI), comorbidities and possible causes of CSU, and autologous serum skin test (ASST) response. The efficacy of second-generation antihistamines was evaluated on the day of blood collecting.One-third of CSU patients had elevated levels of CRP. Higher levels of CRP were associated with ASST positivity (P = .009) and arterial hypertension (P = .005), but not with other possible causes or comorbidities of CSU. C-reactive protein correlated with urticaria activity (P < .001), quality of life impairment (P = .026), and inflammatory and coagulation markers (P < .001). C-reactive protein levels were significantly higher in nonresponders to antihistamines as compared to responders (P < .001).Elevated levels of CRP are common and relevant in CSU patients. The assessment of CRP levels may help to optimize the management of patients with CSU. |
| 2017 | D-Dimer Plasma Levels Parallel the Clinical Response to Omalizumab in Patients with Severe Chronic Spontaneous Urticaria. | Int Arch Allergy Immunol | Omalizumab is very effective in the majority of patients with severe chronic spontaneous urticaria (CSU), but its mechanism of action is still unclear. In CSU the coagulation cascade is activated with an intensity that parallels the disease severity, and elevated plasma D-dimer levels are associated with a poor response to both antihistamines and cyclosporin. We measured D-dimer plasma levels before and after the first administration of omalizumab in 32 patients with severe CSU. A number of clinical and laboratory parameters were recorded, including the urticaria activity score, presence of angioedema, disease duration, C-reactive protein, anti-nuclear, and anti-thyroid antibodies. Baseline D-dimer levels were elevated in 19 (59%) cases. Omalizumab induced a complete response in 25 patients (78%), in most cases already after the first administration. At baseline, 14/25 responders had increased D-dimer plasma levels versus 5/7 non-responders. All responders showed a dramatic decrease of D-dimer plasma levels after the first administration of the drug (from 1,024 ± 248 [mean ± SE] to 251 ± 30 ng/mL; p = 0.003). In contrast, non-responders did not show any reduction in D-dimer levels after omalizumab administration (from 787 ± 206 to 1,230 ± 429 ng/mL; p = ns). In conclusion, plasma levels of D-dimer are frequently elevated in patients with severe CSU before omalizumab administration and decrease according to the clinical response of the disease to the drug, suggesting a possible effect of omalizumab on coagulation activation and fibrin degradation in a subset of CSU patients. |
| 2017 | Potential blood biomarkers in chronic spontaneous urticaria. | Clin Exp Allergy | Chronic spontaneous urticaria (CSU) is a mast cell-driven disease that is defined as the recurrence of weals, angioedema or both for > 6 weeks due to known or unknown causes. As of yet, disease diagnosis is purely clinical. Objective tools are needed to monitor the activity of CSU and the efficacy of treatment. Recently, several reports have suggested that blood parameters may be considered as potential disease-related biomarkers. Here, we reviewed available literature on blood biomarkers for CSU diagnosis, activity monitoring, duration, patient subgroup allocation or response to treatment. We performed a PubMed, Google Scholar and Web of Science search and identified and analysed 151 reports published prior to January 2016. We found strong evidence for significant differences between patients with CSU and healthy controls in blood levels or values of D-dimer, C-reactive protein (CRP), matrix metalloproteinase-9 (MMP-9), mean platelet volume (MPV), factor VIIa, prothrombin fragment 1 + 2 (F1 + 2), tumour necrosis factor, dehydroepiandrosterone sulphate and vitamin D. Also, there is strong evidence for a significant association between CSU activity and blood levels or values of D-dimer, F1 + 2, CRP, IL-6 and MPV. Strong evidence for reduced basophil count and high levels of IgG anti-FcεRI in the subgroup of CSU patients with positive autologous serum skin test was shown. In contrast, the evidence for all reported blood biomarkers for differentiating CSU from other diseases, or a role in prognosis, is weak, inconsistent or non-existent. Taken together, we identified 10 biomarkers that are supported by strong evidence for distinguishing patients with CSU from healthy controls, or for measuring CSU activity. There is a need for further research to identify biomarkers that predict outcome or treatment response in CSU. |
| 2014 | C-reactive protein levels in hereditary angioedema. | Clin Exp Immunol | Hereditary angioedema (HAE) patients experience recurrent episodes of angioedema attacks that can be painful, disfiguring and even life-threatening. The disorder results from a mutation in the gene that controls the synthesis of C1-inhibitor (C1INH). C1INH is a major regulator of activation of the contact system. It is often assumed that attacks results from uncontrolled local activation of the contact system with subsequent formation of bradykinin. To evaluate the involvement of inflammatory reactions in HAE, we analysed C-reactive protein (CRP) levels. HAE patients included in a clinical database of recombinant human C1-inhibitor (rhC1INH) studies were evaluated. For the current study we analysed CRP levels when patients were asymptomatic, during a clinical attack and in a follow-up period, and correlated these with the clinical manifestations of the attack. Data from 68 HAE patients were analysed and included CRP levels on 273 occasions. While asymptomatic, 20% of the patients analysed had increased CRP. At the onset of the attack (P = 0·049) and during the next 24 h CRP rose significantly (P = 0·002) in patients with an abdominal location, and post-attack levels were significantly higher in these patients than in patients with attacks at other locations (P = 0·034). In conclusion, CRP levels are elevated in a substantial proportion of asymptomatic HAE patients. Levels of CRP increase significantly during an abdominal attack. These data suggest low-grade systemic inflammatory reactions in HAE patients as well as a triggering event for attacks that starts prior to symptom onset. |
| 2013 | Leukocytosis and high hematocrit levels during abdominal attacks of hereditary angioedema. | BMC Gastroenterol | The diagnosis of hereditary angioedema (HAE) is often delayed due to the low awareness of this condition. In patients with undiagnosed HAE, abdominal symptoms often create the risk of unnecessary surgical operation and/or drug therapy. To explore the cause of misdiagnosis, we compared the laboratory findings of HAE patients under normal conditions with those during abdominal attacks.Patient medical histories were analyzed and laboratory data at the first consultation with no symptoms and no medication were compared with those at visits to the emergency department during severe attacks.Fourteen HAE patients were enrolled. Initial HAE symptoms occurred at 20.2 ± 9.4 years of age. The correct diagnosis of HAE was made 22.7 ± 14.2 years after the initial symptoms. A common site of angioedema was the extremities. Half of the patients experienced a life-threatening laryngeal attack and/or severe abdominal pain. In the patients with severe abdominal pain, significant leukocytosis with neutrophilia along with increased levels of hematocrit were observed while levels of C-reactive protein (CRP) remained low. All severe attacks were alleviated with an infusion of C1-inhibitor concentrate.Consideration of the likelihood of a HAE attack is important when patients present with acute abdominal pain and leukocytosis without elevation of CRP. |
| 2012 | Eleven cases of angioedema with eosinophilia treated in a single hospital in Japan. | Allergol Int | Angioedema with eosinophilia (AE) is mostly reported in Japanese patients, and only as case reports. In this study, we aimed to determine how prevalent AE cases appear, the characteristic features and the course of AE, and to evaluate whether corticosteroid therapy for AE is necessary or not.The patients whose blood samples showed an eosinophil count of ≥2,000/μL, among the samples tested for blood cell counts and differential counts between January 2006 and December 2010, in Japanese Red Cross Medical Center, were firstly included. Among these, patients with AE were extracted.All of the 11 patients were Japanese young females. One patient with arthralgia showed radioisotope accumulation in the joints by bone scintigraphy. The peak peripheral blood eosinophil count was 7,839 ± 6,008 (2,130-23,170)/μL after visiting our hospital. An increase in white blood cell count was only due to an increase in eosinophil count. Serum C-reactive protein and IgE levels remained almost normal. Peripheral blood eosinophil count decreased steadily for 8 weeks, regardless of corticosteroid use. Edema in all of the patients and arthralgia in 6 patients improved within 12 weeks. As far as followed, none of the patients had a recurrence of AE.AE developed in Japanese young females and likely showed a single course. In AE, the count of eosinophil of 104/μL was observed. Only eosinophil count increased among leukocyte series. Serum C-reactive protein and IgE levels remained almost normal. The eosinophil count in AE patients will return to the normal level within 8 weeks even without corticosteroid therapy. |
| 2013 | Acute phase inflammatory markers in patients with non-steroidal anti-inflammatory drugs (NSAIDs)-induced acute urticaria/angioedema and after aspirin challenge. | J Eur Acad Dermatol Venereol | Active chronic urticaria, identified as a mast cell- and basophil-dependent inflammatory disorder of the skin is able to elicit acute phase response (APR). However, systemic inflammatory response in different types of urticaria is poorly characterized.To determine APR pattern in a clearly defined group of patients with acute urticaria and/or angioedema - induced by NSAIDs.Plasma IL-6 and serum C-reactive protein (CRP) concentrations were studied in 17 patients with NSAIDs-induced acute urticaria/angioedema (NSAIDsAU) and in 20 healthy controls. Eleven patients who used NSAIDs were presented at the emergency room with acute urticaria/angioedema while the remaining six manifested the symptoms during the aspirin challenge test. Patients were examined in a dynamic manner: during the acute phase, and next, after subsidence of the symptoms.CRP and IL-6 concentrations increased significantly in patients with NSAIDsAU as compared with their asymptomatic period and the healthy subjects. In addition, NSAIDsAU patients showed elevated concentration of the biomarkers following aspirin provocation with the baseline values recovered in the asymptomatic period.These results indicate that an acute systemic inflammatory response is activated in patients with NSAIDs-induced urticaria and/or angioedema. The study supports the evidence proving that up-regulation of CRP and IL-6 in urticaria/angioedema does not necessarily reflect any concomitant infection or other inflammatory processes, but may be due to the disease itself. |
| Clinical and laboratory features of antihistamine-resistant chronic idiopathic urticaria. | Allergy Asthma Proc | Chronic idiopathic (spontaneous) urticaria (CIU) is sometimes resistant to the conventional and high doses of antihistamines (AHs). This study compares the clinical and laboratory characteristics of AH responsive and AH-resistant CIU subjects. Clinical and laboratory data were retrospectively collected from 385 CIU patients. Urticaria activity score (UAS), concomitant angioedema, dermatographism, positive autologous serum skin (ASST), and laboratory data were collected. The control group consisted of 44 sex- and age-matched healthy individuals. Two hundred forty-five CIU patients controlled with AH medications were included in the CIU group. Forty-six patients failed to show clinical improvement during 8 weeks of treatment with fourfold AH doses and were included in the resistant CIU (R-CIU) group. The R-CIU group was characterized with a higher incidence (58.7%) of angioedema than the CIU group (28.5%; p < 0.001), more cases concomitant physical urticaria (23.9% in R-CIU versus 12.2% in CIU; p = 0.014), more positive ASST (73.9% in R-CIU versus 45.4% in CIU; p < 0.001), and higher baseline UAS (5.28 ± 0.81 in R-CIU versus 3.32 ± 1.25 in CIU; <0.001). R-CIU was characterized with more severe basopenia (0.04 ± 0.07 cell/mm(3) versus 0.16 ± 0.13 cell/mm(3); p < 0.001), higher mean platelet volume (10.87 ± 2.21 femtoliter (fl) versus 8.65 ± 1.74 fl; p < 0.001), higher levels of C-reactive protein (8.62 ± 3.91 mg/L versus 2.49 ± 1.34 mg/L; <0.001), and higher levels of serum C3 (1.66 ± 0.36 g/L versus 1.19 ± 0.35 g/L; p < 0.001. R-CIU is a clinically more severe disease with laboratory features of low-grade inflammation and platelet activation. |
| 2012 | Endothelial cell function in patients with hereditary angioedema: elevated soluble E-selectin level during inter-attack periods. | J Clin Immunol | The bradykinin pathway in the pathomechanism of hereditary angioedema due to C1-inhibitor deficiency (henceforward "hereditary angioedema") has been thoroughly studied; however, much less is known about endothelial cell function. Enhanced endothelial cell permeability is obvious during edematous attacks, but not during inter-attack periods. Our knowledge about other endothelial characteristics is even more incomplete.Therefore the aim of this study was to characterize endothelial cell function in hereditary angioedema patients during symptom-free, inter-attack periods.We measured the serum levels of soluble E-selectin, endothelin-1, and von Willebrand factor along with collagen-binding activity in 49 hereditary angioedema patients and in 50 healthy controls.Endothelin-1 and von Willebrand factor level, as well as its collagen-binding activity, were similar in hereditary angioedema patients and in controls; however, we found elevated soluble E-selectin levels in the patients. Interestingly, soluble E-selectin concentration did not correlate with any of the inflammatory markers or smoking, and it is not the consequence of the known E-selectin/C1-inhibitor interaction (an analytical phenomenon). In a multiple logistic regression model, the difference in soluble E-selectin between hereditary angioedema patients and controls remained highly significant when adjusted for age, gender, smoking, C-reactive protein, and AB0 blood groups.These results demonstrate that in hereditary angioedema, the majority of endothelial functions are normal during inter-attack periods; however, soluble E-selectin levels are elevated. The higher soluble E-selectin plasma concentration is unlikely to result from inflammation; rather, it reflects enhanced shedding mechanisms. |
| 2010 | Coagulation/fibrinolysis and inflammation markers are associated with disease activity in patients with chronic urticaria. | Allergy | The evaluation of disease severity and activity of chronic urticaria (CU) is essential for the adequate treatment of patients. However, there is no reliable biomarker for such evaluations. Recently, markers of blood coagulation and fibrinolysis have been revealed to be elevated in severe cases of CU. In this article, we studied the coagulation/fibrinolysis and inflammation markers and their relationship to disease activity in patients with CU.Plasma fibrin degradation products (FDP), d-dimer and serum C-reactive protein (CRP) were measured with the assessment of disease severity and skin reaction to autologous serum in 82 patients with CU and 37 patients with acute urticaria, idiopathic angioedema (AE) or inducible types of urticaria (IU).The levels of FDP in patients with CU were significantly higher than those in patients with IU, but no other differences in FDP, d-dimer and CRP were observed among patients with different types of urticaria. These markers of patients with CU were well correlated with each other and significantly associated with disease severity of CU, but not with skin reactions to autologous serum. In 37 patients with CU, levels of all these parameters reduced as their disease condition improved, while they increased when the disease became aggravated. Regarding FDP, this relationship was observed even if FDP concentrations were within normal range throughout the study.The measurement of plasma FDP, d-dimer and serum CRP may be useful for the assessment of disease activity of CU. |
| 2010 | Angioedema: 6 years experience with fourteen cases. | Auris Nasus Larynx | To study the difference in the findings between the causes of angioedema and the characteristics of angioedema induced by angiotensin receptor II blockers (ARBs), and to investigate whether laboratory examinations for acute phase inflammatory markers can aid in diagnosis and predict airway risk.We retrospectively reviewed fourteen cases of patients with angioedema that were treated from 2000 to 2006. Data were collected regarding age, sex, location of the edema, cause, time course of resolution and laboratory examinations (leukocyte counts, serum C-reactive protein (CRP) level, complement function and the activity of C1 esterase inhibitor).The causes of angioedema were ACEIs in six patients (42.9%), candesartan (ARB) in three (21.4%), HAE (types 1 and 2) in two, and unknown in three. Of these patients, 71.4% exhibited edema in the floor of the mouth, irrespective of the cause. Two patients with edema induced by candesartan exhibited both lingual and laryngeal edemas. The remaining one with candesartan-induced edema exhibited edema in the neck and mediastinum and pleural effusion. The average time to resolution was 4.1 days, ranging from one to twelve days. The edema in eleven patients resolved with conservative therapy, while three patients underwent tracheotomy. In two patients with candesartan-induced edema, although the edemas resolved completely after cessation of candesartan administration, the edemas reappeared in the same locations, two and thirty days after the cessation of candesartan for each patient. None of the patients with angioedema induced by ACEIs exhibited elevation of serum CRP levels. No significant differences were found for leukocyte counts and serum CRP levels between patients with angioedemas induced by ACEIs, ARB and those of unknown cause. No significant differences were observed in the above findings between the patients who underwent tracheotomy and those who did not. Two patients exhibited low C4 levels, and one of the two exhibited no activity of C1 esterase inhibitor.Consistent with previous reports, angioedema in the floor of the mouth extending to the tongue should be considered as a possible risk factor for airway compromise. Laboratory examinations for acute phase inflammatory markers are not useful for diagnosis and are not predictive for airway intubation and tracheotomy. Angioedema induced by candesartan can present in anomalous sites and reappear following drug cessation even if the edema has resolved completely. |
| 2005 | Increased C-reactive protein in ACE-inhibitor-induced angioedema. | Br J Clin Pharmacol | This study was designed to identify new factors which may contribute to angiotensin-converting-enzyme-inhibitor (ACEI)-induced angioedema.In a retrospective cohort study we examined 25 patients who used an ACEI and presented at our emergency room with acute angioedema as well as 18 patients with unknown cause of angioedema and a total of 21 patients on ACEI-therapy without previous angioedema. We measured markers of inflammation such as acute-phase proteins (C-reactive protein, fibrinogen), leukocyte count and body temperature.The mean interval between initiation of ACEI treatment and first manifestation of angioedema was 35.8 +/- 5.3 months. During symptomatic angioedema, mean plasma levels of C-reactive protein and fibrinogen were significantly increased by 7.3-fold and 1.5-fold, respectively, while leukocyte count and body temperature were normal. These changes disappeared after successful treatment of angioedema and were not found in patients with angioedema of unknown cause and those receiving ACEI without having experienced angioedema.Our findings demonstrate for the first time that ACEI-induced angioedema is associated with strongly increased plasma levels of CRP. We suggest that CRP is involved in the pathophysiology of ACEI-induced angioedema. |
| 2004 | [ACE inhibitor-induced angioedema in the head and neck region. A matter of time?]. | HNO | Angioedema in the head and neck region is potentially life-threatening and may occur as a side effect of inhibitors of the angiotensin-converting-enzyme (ACEI). So far, little is known about the time between the first application of ACEI and the occurrence of angioedema, or of possible cofactors and laboratory changes.A total of 21 patients with angioedema during the course of ACEI treatment were compared to 11 patients with angioedema of unknown cause. These were retrospectively analysed for the following criteria: (1) duration of ACEI medication, (2) leading and concomitant diseases, (3) history of allergies, (4) co-medication, (5) laboratory changes, (6) treatment success, and (7) manifestation of recurrent episodes.The mean interval between the initiation of ACEI therapy and the first occurrence of angioedema exceeded 2 years. Values for the acute phase proteins C-reactive protein (CRP) and fibrinogen were significantly increased in the ACEI group compared to the control group.In any case of angioedema in the head and neck region, a side effect of ACEI must be taken into consideration even if the medication has been taken for months or years. |
| 2001 | Interleukin 6 and C-reactive protein levels in patients with acute allergic reactions: an emergency department-based study. | Ann Allergy Asthma Immunol | Elevations of interleukin 6 (IL-6) have been described in drug-induced anaphylaxis. Although IL-6 is well known to stimulate an acute phase response, profiling acute phase protein levels, such as C-reactive protein (CRP), has, to our knowledge, never been performed in patients with acute allergic reactions.To examine the pattern of IL-6 and CRP levels in patients with acute allergic reactions and to relate these to relevant clinical and laboratory parameters.Plasma CRP and serum IL-6 levels were determined in 85 adult emergency department patients. These patients had been previously studied with questionnaires, physical examinations, and histamine/tryptase levels. Clinical and historical features were related to CRP and IL-6 levels. CRP and IL-6 levels were also examined for relationships with histamine and tryptase levels.CRP and IL-6 levels were significantly correlated with one another in the study patients (Spearman p = 0.36, P = 0.0008). Similar to histamine levels, IL-6 levels were significantly correlated with the extent of erythema manifested by the study patients. The extent of erythema was independently predicted by both IL-6 and histamine levels. Histamine levels were negatively correlated with CRP levels (Spearman p = -0.32, P = 0.003). Unlike histamine levels, IL-6 and CRP did not show significant relationships with the extent or presence of urticaria/angioedema or the presence of wheezing. IL-6 levels were correlated with the duration of symptoms before serologic sampling. An inverse correlation was observed between IL-6 levels and mean arterial blood pressure. Multivariate modeling showed significant independent effects from mean arterial pressure, duration of symptoms, erythema extent, and age in predicting IL-6 levels. Tryptase levels were higher in patients whose IL-6 levels were >20 pg/mL.CRP and IL-6 levels are not simple surrogate markers for histamine or tryptase release by mast cells or basophils in acute allergic reactions. Increasing IL-6 levels relate to greater erythema extent, lower mean arterial blood pressure, and a longer duration of symptoms. It would be interesting to speculate that CRP and IL-6 increases characterize a late-phase response in immediate hypersensitivity reactions. In this perspective, the inverse relationship between CRP and histamine levels could be explained. As histamine levels are waning, CRP levels are increasing. Timed studies for histamine and CRP/IL-6 levels in allergic reactions are necessary to confirm this hypothesis. |
| 2000 | Protein sgp 120 as a marker of an acquired angioedema. | Eur J Clin Invest | Angioedema is not an event peculiar to an acute-phase response. We registered the appearance of angioedema in four nonatopic patients suffering from diverse inflammatory stimuli.Serum concentrations of C-reactive protein (CRP), haptoglobin, alpha1-antitrypsin, alpha2-macroglobulin, C3, C4, C1INH and protein sgp 120 (classified as a regulatory protein of the complement system) were assessed over 7 consecutive days, beginning with the onset of angioedema in these four patients.Instead of returning to the normal level, CRP peaked again on the 4th day (A-test, P<0.05) and declined significantly by the 7th day (A-test, P<0.05). Serum levels of sgp 120, C3c and C1INH increased gradually up to the 5th day but only sgp 120 was significantly raised in relation to the initial value (P< 0.05).In our patients, we registered four diverse profiles of the acute-phase proteins (Kruskal-Wallis test, P<0.05) probably due to the diverse nature of the pre-existing inflammatory stimuli. According to these results, the unexpected appearance of angioedema implies the contribution of sgp 120 as the main source of fragments with kinin-like properties. |
| 2000 | Acute infectious urticaria: clinical and laboratory analysis in nineteen patients. | J Dermatol | We treated 19 Japanese patients with acute urticaria presumably caused by infection during the five years from 1994 to 1998. The patients' ages ranged from 2 to 66 years (8 males and 11 females). Most of them had urticaria, angioedema, high fever, neutrophilia, and high serum levels of C reactive protein (CRP). The skin rash lasted more than 24 hours. In four patients, a flow cytometric analysis revealed that the percentage of circulating T cells bearing T-cell receptor V beta 3 was decreased during the active stage and that this decrease was sustained for at least 2 to 3 weeks. This suggests that certain T-cell populations were numerically altered in association with the occurrence of the disease. A retrospective review indicated that the combination therapy with corticosteroid and antibiotics was more effective than the single use of either agent. |
| [Round Table: Urticaria in relation to infections]. | Allergol Immunopathol (Madr) | 1) To study the clinical and analytic features of infectious disease associated to urticaria in children. 2) To look into the probable etiology of the infectious disease. 3) To determine atopic predisposition and previous urticarial episodes and to rule out the involvement of antibiotics.Transversal and observational study.Pediatric Allergy Outpatient Clinic of a tertiary Hospital.Forty-four children, aged 1 to 12 years with acute urticaria associated to clinically infectious or febrile illness attending an Emergency Pediatric Department.Symptoms evaluation and physical examination in the seventh first days and follow over 3-6 weeks by the same physician.Clinical features of urticaria (duration, angioedema associated); Clinic diagnosis of illness infectious (acute respiratory infection, gastroenteritis, febrile syndrome); white blood cells count, C-reactive protein, aminotransferases (AST, ALT), L-Y-glutamyl transferase; viral culture and antigen detection: enterovirus (EV), adenovirus, respiratory syncytial virus (RSV), parainfluenza 1, 2 and 3, influenza A y B and cytomegalovirus (CMV); serological assay: CMV, enterovirus, mycoplasma pneumoniae, Epstein-Barr, parvovirus B19.22 children (50%) are between 1-2 years old. 40 patients (90,9%) had symptoms of respiratory tract infection and only four patients had a pneumonia. The other 4 children had a gastroenteritis. The analytic was suggestive of viral infection in 35 (79.5%) and unknown on seven patients. In 20 children (45.4%) was identified a probable infection. The viral detection was positive in 3 patients: CMV, herpes simplex 1 and influenza A. Twenty microbiological findings for seventeen patients was found by serological criterion of probable infection: enterovirus (10); parvovirus B19 (4); Epstein-Barr (3) y mycoplasma (3). Evidence of a double serologic infection was found in three patients. In comparison with a serological control group encountered that acute urticaria during a infectious disease is significantly associated (p = 0.0054) to high titer to enterovirus by complement-fixation. The urticaria was associated with angioedema in 38.6% and 9 children (20.4%) related an previous similar episode. Twenty-one (47.7%) had been treated with antibiotics before development the urticaria. All patients was given the suspected antibiotic and no patient developed any adverse reaction.The clinically infectious associated to urticarial rash in children, usually is a viral respiratory infections. Is more frequent at infant. In spite of antibiotic therapy is often related to development the urticaria, the subsequent challenge with the same antibiotic is good tolerated. |
| 1998 | [Hereditary angioedema. A rare cause of acute abdominal pain with ascites]. | Dtsch Med Wochenschr | Since the age of 16 years a now 25-year-old woman had been known to have C1-inhibitor (C1-INH) deficiency. She presented herself at the emergency department because of acute severe lower abdominal cramps. A urinary infection had been treated with antibiotics for the previous 4 days. There was marked pain on pressure over the lower abdomen, but there were no signs of peritonitis and bowel sound were normal. There had been no nausea or vomiting and the stools had been normal.There was a leukocytosis of 10,200/microliter, moderately elevated C-reactive protein (44.8 mg/l), haemoglobin concentration of 17 g/dl and haematocrit of 51%. Radiology revealed oedema of the duodenum and sonography showed free fluid in the abdomen.After excluding an acute abdomen and in view of the C1-INH deficiency treatment was symptomatic. All symptoms completely disappeared after 2 days.Exclusively gastrointestinal symptoms and ascites are rare in patients with hereditary angioedema. But knowledge of this manifestation of the disease is important because patients are sometimes operated under the false diagnosis of acute abdomen. In severe cases symptomatic treatment may have to be supplemented by C1-INH administration. Prevention with attenuated androgens should be started or modified, respectively. |
| 1998 | A case of episodic angioedema associated with blood eosinophilia: upregulated C5a receptor expression on eosinophils. | Allergy | A 47-year-old woman was admitted to hospital complaining of swelling and pain of the extremities, accompanied by high fever and generalized erythema. Laboratory examination showed marked blood eosinophilia with elevation of IgM, IgE, and C-reactive protein. All autoantibodies examined were negative. The heart and lungs showed no untoward findings. Biopsies of the skin and muscle revealed cellular infiltration of eosinophils around small blood vessels. Quantitation of C5a receptor (C5aR) expression by flow cytometry using anti-C5aR antibody showed upregulated expression of C5aR on blood eosinophils but downregulated expression on neutrophils. The abnormal C5aR expression on eosinophils and neutrophils became normal after spontaneous resolution of symptoms and blood eosinophilia. The possibility that C5aR expression on granulocytes is related to the pathogenesis of this syndrome may be considered. |