Ecchymotic angioedema revealing childhood systemic lupus erythematosus with anti-C1q antibodies

BACKGROUND: Hypocomplement urticarial vasculitis syndrome may be the presenting sign of systemic lupus erythematosus. Hypocomplement urticarial vasculitis presents as atypical urticaria associated in 50% of cases with angioedema. On laboratory investigation, hypocomplementaemia is the characteristic feature, with reduced C3, C4 and C1q. This disease is very rare in children. PATIENTS AND METHODS: An eight-year-old girl was hospitalised for relapsing urticaria with ecchymotic angioedema present for one year, in a setting of impaired general health and fever. Screening for native anti-DNA and antinuclear antibodies was positive. Analysis of complement revealed activation of the classical pathway with reduced CH50, C4 and C3. These anomalies persisted outside active episodes. The C1q fraction was completely depressed and screening for anti-C1q was positive. There was no quantitative or qualitative deficit in C1-esterase inhibitor. Direct immunofluorescence of skin lesions demonstrated deposits of immunoglobulin and complement. These episodes of angioedema persisted despite long-term systemic corticosteroid therapy (1mg/kg per day). DISCUSSION: This is the first reported case of hypocomplement urticarial vasculitis syndrome arising from systemic lupus erythematosus in a child exhibiting anti-C1q antibodies. Furthermore, this case is original because of the highly ecchymotic nature of the lesions. In the presence of angioedema with ecchymotic progression associated with atypical chronic urticaria, a diagnosis of hypocomplement urticarial vasculitis syndrome should be considered.     

Gleich's syndrome

BACKGROUND: Episodic angioedema with eosinophilia is a new syndrome associating hypereosinophilia, episodic angioedema and elevation of immunoglobulin M. This syndrome, first described by Gerald Gleich, has a good prognosis and no organ involvement. CASE REPORT: A 39-year old woman developed for 10 years, recurrent episodes of swelling, weight gain of 4 to 6 kg, hypereosinophilia and hyperimmunoglobulinemia M and G. All symptoms disappeared spontaneously within a few days. Numerous investigations (cutaneous, cardiac, pulmonary, immunologic, parasitologic) were negative. The patient was recently hospitalized because of increased recurrence of episodes and major discomfort. We noted hypereosinophilia up to 30. 731 eosinophils/mm(3), elevated lactate dehydrogenase to 902 U/l (N: 204-412), elevated eosinophile cationic protein to 371 microg/l (N<12) and elevated immunoglobulin E to 140 U/l (N<100). Renal, pulmonary and cardiac functions were normal. Bone marrow biopsy showed no abnormality. DISCUSSION: Gleich's syndrome is a benign but often incapacitating disease of unknown etiology. Systemic glucocorticoids may control flare-ups.     

Controlled clinical assessment of astemizole in the treatment of chronic idiopathic urticaria and angioedema

Astemizole, one of the newer generation of nonsedating antihistamines, was evaluated in a double-blind study of forty-six patients who had chronic idiopathic urticaria with or without angioedema; most had severe disease. Nineteen of twenty-three patients who were on placebo discontinued treatment because of lack of response compared to only five of twenty-three astemizole-treated patients (p less than 0.0001). Fourteen of twenty-two astemizole-treated patients and two of twenty-two placebo-treated patients considered the results to be good or excellent (p less than 0.0001). Blinded assessment by the investigators yielded similar results (p less than 0.0001). Therapeutic response was the same in patients with and without angioedema in addition to urticaria and in those requiring corticosteroids. Duration of urticaria also did not influence the results. Increased appetite and weight gain were the main side effects reported more frequently in the astemizole-treated than in the placebo-treated group, and no significant toxicity was noted. Follow-up after terminating the drug study indicated a high frequency of remissions during the subsequent year.     

Management of urticaria in COVID‐19 patients: A systematic review

The global pandemic COVID‐19 has resulted in significant global morbidity, mortality and increased healthcare demands. There is now emerging evidence of patients experiencing urticaria. We sought to systematically review current evidence, critique the literature, and present our findings. Allowing PRISMA guidelines, a comprehensive literature search was carried out with Medline, EMBASE, Scopus, Cochrane, and Google Scholar, using key MeSH words, which include “COVID‐19,” “Coronavirus,” “SARS‐Cov‐2,” “Urticaria,” “Angioedema,” and “Skin rash” up to 01 August 2020. The key inclusion criteria were articles that reported on urticaria and/or angioedema due to COVID‐19 infection and reported management and outcome. Studies were excluded if no case or cohort outcomes were observed. Our search returned 169 articles, 25 of which met inclusion criteria. All studies were case reports, reporting 26 patients with urticaria and/or angioedema, COVID‐19 infection and their management and/or response. ajority of patients (n = 16, 69%) were over 50 years old. However, urticaria in the younger ages was not uncommon, with reported case of 2 months old infant. Skin lesions resolved from less than 24 hours to up to 2 weeks following treatment with antihistamines and/or steroids. There have been no cases of recurrent urticaria or cases nonresponsive to steroids. Management of urticarial in COVID‐19 patients should involve antihistamines. Low dose prednisolone should be considered on an individualized basis. Further research is required in understanding urticarial pathogenesis in COVID‐19. This will aid early diagnostic assessment in patients with high index of suspicion and subsequent management in the acute phase.     

Urticarial venulitis

ABSTRACT: Episodes of recurrent urticaria and angioedema may be a clinical manifestation of cutaneous necrotizing venulitis. Known as urticarial vasculitis, this edematous form of necrotizing venulitis occurs in patients with serum sickness, connective tissue disorders, hematologic malignant conditions, an IgM_KM component, infections, or physical urticarias after the administration of therapeutic agents, and as an idiopathic disorder. The skin lesions appear as erythematous, occasionally indurated wheals which may contain foci of purpura. Although the individual urticarial lesions may last for less than 24 hours, they often persist up to 3–5 days. The episodes of urticaria are chronic; approximately 70% of the afflicted individuals are women. General features include fever, malaise, and myalgia. Specific organ involvement includes enlargement of the lymph nodes, liver, and spleen and involvement of the synovia, kidneys, gastrointestinal tract, respiratory tract, eyes, and central nervous system. In the treatment of urticarial vasculitis there are no double-blind, placebo-controlled trials. Reports exist of the treatment of patients with H₁ antihistamines, nonsteroidal anti-inflammatory agents, colchicine, hydroxychloroquine, dapsone, prednisone, azathioprine, methotrexate, cyclophosphamide, and intramuscular gold therapy.     

Cutaneous findings in five cases of malaria

Malaria is an infectious disease caused by protozoa of the genus Plasmodium. Cutaneous lesions in malaria are rarely reported and include urticaria, angioedema, petechiae, purpura, and disseminated intravascular coagulation (DIC). Here, five malaria cases associated with cutaneous lesions have been described. Out of the five cases of malaria, two were associated with urticaria and angioedema, one case was associated with urticaria, and other two were associated with reticulated blotchy erythema with petechiae. Most of the cutaneous lesions in malaria were nonspecific and reflected the different immunopathological mechanism in malarial infection.     

Chronic urticaria,arthralgia, raised erythrocyte sedimentation rate and IgG paraproteinaemia: a variant of Schnitzler's syndrome?

Schnitzler's syndrome is a distinct disease entity characterized by the association of chronic urticaria, intermittent fever, arthralgia, elevated erythrocyte sedimentation rate and IgM macroglobulin-aemia. We report a patient with the same symptoms, but a monoclonal IgG instead of IgM gammopathy. Histological examination of the urticarial lesions showed signs of mild leucocyto-clastic vasculitis. Except for the different class of the monoclonal immunoglobulin, the clinical symptoms, laboratory findings and histology in this patient were identical with those in classical Schnitzler's syndrome. IgG and IgM paraproteins may be equivalent with regard to the putative pathophysiology of the disease process in Schnitzler's syndrome. We therefore suggest that the spectrum of Schnitzler's syndrome is expanded to include patients with chronic urticaria and monoclonal IgG gammopathy, as a closely related variant.     

Solar angioedema: an uncommonly recognized condition?

Solar urticaria is a well defined although uncommon photosensitivity disorder, and is said to be the underlying cause of chronic urticaria in approximately 0.5% cases. In contrast, solar angioedema is seldom reported. We describe two patients with postulated solar angioedema, associated with clinical and/or phototest features of solar urticaria. Recognition of solar provocation of angioedema has important consequences for patient management.     

Urticaria

Urticaria is a very common skin disease which was already described in the ancient world. Questions still remain about its pathogenesis and management remain open. Compared to other common skin diseases, the published evidence is rather low. The clinical symptoms with pruritic transient wheals and/or angioedema are caused by mediators (particularly histamine) released by activated mast cells and basophils. The mechanism of target cell activation has not been clarified in detail for most urticaria subtypes. Different urticaria subtypes should be distinguished. Spontaneous forms are more common than inducible forms. Chronic urticaria and urticaria in certain age groups (children, pregnancy) can be difficult to manage. Therefore, international consensus resulting in the regular update of urticaria guidelines can be very helpful. Currently, these updated guidelines include a three‐step treatment algorithm for chronic spontaneous urticaria. Only the first step of this algorithm, second generation H1‐antihistamine in standard dose, utilized approved drugs. However after omalizumab was established as a third line choice in the guideline algorithm, it has approved in many countries for chronic spontaneous urticaria without response to H1‐antihistamines. The exact mechanism of action of omalizumab in urticaria has not been fully elucidated. Unrevealing this mechanism might result in a deeper understanding of urticaria pathogenesis and the development of further therapeutic strategies.     

Exacerbation of skin lesions during fever in a patient with chronic infantile neurologic cutaneous articular (CINCA) syndrome

Chronic infantile neurologic cutaneous articular (CINCA) syndrome is a serious chronic systemic inflammatory disease that presents at a young age and that is characterized by skin, joint, and central nervous system disease. Skin symptoms are the first to appear, in the form of a longstanding nonpruritic urticarial rash, with exacerbations coinciding with episodes of fever, arthritis, and enlarged lymph nodes. The findings of biopsy of skin lesions are extremely variable but characterized by perivascular neutrophilic infiltrate. With the discovery of mutations in the CIAS1 gene, which encodes a protein known as cryopyrin, this entity has been classified as one of the cryopyrin-associated autoinflammatory diseases, along with familial cold urticaria and Muckle-Wells syndrome. This discovery has also made available new therapeutic options. We present the case of a boy diagnosed with CINCA syndrome who presented with an outbreak of painful skin lesions and fever. These lesions were thought to be an exacerbation of underlying lesions during an episode of fever.     

Chronic urticaria: a role for newer immunomodulatory drugs?

Chronic urticaria is now recognized as an autoreactive disorder in a substantial fraction of patients. A serologic mediator of whealing has been demonstrated in 50-60% of patients with chronic urticaria, and autoantibodies against the high affinity IgE receptor or IgE have been detected in about half of these patients. The demonstration that chronic urticaria is frequently autoimmune has encouraged a more aggressive therapeutic approach, with the use of immunomodulatory drugs.A step-by-step approach to the management of chronic urticaria is proposed, based on our personal experience and review of current medical literature, identified through Medline research and hand searching in medical journals. The non- or low-sedating H(1) receptor antagonists (antihistamines), such as cetirizine, fexofenadine, loratadine, mizolastine and, more recently, levocetirizine, desloratadine and ebastine, represent the basic therapy for all chronic urticaria patients. Older sedating antihistamines, such as hydroxyzine and diphenhydramine, may be indicated if symptoms are severe, are associated with angioedema, and if the patient is anxious and disturbed at night.Corticosteroid therapy with prednisone or methylprednisolone can be administered for a few days (7-14) if urticarial symptoms are not controlled by antihistamines and a rapid clinical response is needed. In cases of relapse after corticosteroid suspension, leukotriene receptor antagonists, such as montelukast and zafirlukast, should be tried. In our experience, remission of urticarial symptoms can be achieved in 20-50% of chronic urticaria patients unresponsive to antihistamines alone. When urticaria is unremitting and is not controlled by combined therapy with antihistamines and leukotriene receptor antagonists, prolonged corticosteroid therapy may be needed. Long-term corticosteroid therapy should be administered at the lowest dose able to control urticarial symptoms, in order to minimize adverse effects. In a few patients, however, high-dose corticosteroid therapy may have to be administered for long periods. In these patients, immunosuppressive treatment with low-dose cyclosporine can be started. This type of treatment has a corticosteroid-sparing effect and is also generally effective in patients with severe, unremitting urticaria, but requires careful monitoring of cyclosporine plasma concentration and possible adverse effects. Other immunomodulating drugs that have been tried in chronic urticaria patients include hydroxychloroquine, dapsone, sulfasalazine and methotrexate, but their efficacy has not been proven in large controlled studies. Warfarin therapy may also be considered in some patients with chronic urticaria and angioedema unresponsive to antihistamines.     

Delayed pressure urticaria syndrome: a clinical expression of interleukin 1

Study of a patient with the bullous delayed pressure urticaria syndrome showed remarkable congruence of the extra-cutaneous findings and the known effects of interleukin 1: malaise, fever, myalgia, arthralgia, leukocytosis, increased sedimentation rate, and circulating acute phase reactants. As a result of this "clinical assay" for interleukin 1, we conclude that the delayed pressure urticaria syndrome is the clinical expression of interleukin 1, synthesized in the skin as a result of pressure and released into the circulation. Delayed urticaria, mediated by interleukin 1, is to be contrasted with immediate type urticaria, long known to be histamine mediated.     

Kälteinduzierte Quaddeln und Angioödeme

The onset of wheals and/or angioedema following the exposure to cold may be associated with a number of different diseases. Most frequently this occurs in cold contact urticaria, a type of physical urticaria, which is characterized by a positive cold stimulation test. The clinical symptoms are based on cold-dependent mast cell activation with subsequent release of proinflammatory mediators. In cases of negative or atypical reaction to cold stimulation testing rare acquired atypical or familiar cold urticaria forms may be suspected. Strict avoidance of cold should be recommended as far as possible. As the underlying causes of cold contact urticaria are widely unknown, the symptomatic use of non-sedating antihistamines is the treatment of first choice. The very rare familiar cold auto-inflammatory syndrome (FCAS) is based on CIAS1/NLRP3 mutations and may be treated effectively by neutralization of pathogenic interleukin 1β.     

Neutrophilic urticaria

Eight patients with neutrophilic urticaria were identified in a 5-year biopsy experience (1980-1984). All patients had a neutrophilic venulitis without fibrinoid necrosis, hemorrhage, or leukocytoclasia. Four patients had a history of angioedema, and two had a personal history of atopic disease. Results of laboratory studies, including complement and protein values and antibody serologic tests, were normal. All patients responded to antihistamine agents. Despite occasional clinical or histologic diagnoses of vasculitis for such cases in the past, the clinical, laboratory, and histologic features and the therapeutic course of these patients are compatible with a phase or type of chronic urticaria.     

Drug‐induced angioedema without urticaria: prevalence and clinical features

Background Angioedema without urticaria can be caused by drugs. The purpose of our study was to assess the prevalence and clinical features of patients with drug‐induced angioedema without urticaria. Methods This study retrospectively reviewed case records at Siriraj Hospital, between January 2007 and December 2008. Patients aged at least 15 years were included. Results The prevalence of drug‐induced angioedema without urticaria among patients with adverse drug reactions was 2.3%/year. Non‐steroidal anti‐inflammatory drugs (NSAID) were the most common cause (50%), followed by antibiotics (20%). The commonest NSAID which induced angioedema were ibuprofen and diclofenac. The common sites were periorbital area (67.3%) and lips (27.6%). The median duration of suspected drug therapy before the development of angioedema was 1 day with the range of 10 min to 23 days. Conclusions Non‐steroidal anti‐inflammatory drugs and antibiotics were the most common drugs causing angioedema without urticaria. The duration of onset ranged from minutes to days. After stopping the suspected drugs, symptoms disappeared within 2–5 days in most patients.     

What lessons can we learn? Clinical and epidemiological retrospective analysis of 267 patients with urticaria in a Brazilian tertiary center

BackgroundThere are few epidemiological studies of urticaria, published in the indexed literature (PubMed/Medline).ObjectiveThe study aimed to evaluate the epidemiological and clinical data among patients with urticaria/angioedema attending a reference clinic in Brazil.MethodsTwo hundred sixty-seven patients were evaluated retrospectively considering demographic data, time course of the disease, triggering symptoms, the presence of angioedema, complementary laboratory tests including total blood count, reactive-C protein, erythrocyte sedimentation rate, IgE serum levels, and other, as necessary.ResultsThe most commonly diagnosed type of urticaria was chronic spontaneous urticaria (56.93%). Angioedema was associated with chronic urticaria in 108 patients (40.08%).Study limitationsUnicentered and retrospective.ConclusionSome relevant findings in this study are the observation of a female prevalence of cases (4-females: 1-man), a result more elevated than demonstrated in previous studies in Europe and Asia, the median age was 43-years old and the delay of time between the diagnosis of urticaria and the admission for treatment in a specialized center was approximately 2-years. Other multicenter studies can better establish these differences in Brazilian patients.     

Vaccine allergy and pseudo-allergy

Allergic and pseudo-allergic reactions to vaccines frequently involve the skin, and can be generalized systemic symptoms (urticaria/angioedema, serum sickness, flares of eczema) or localized at the sites of vaccination (persistent nodules, abcesses, granulomas). Diagnosis of Arthus-type reactions is based on clinical history and specific IgM/IgG anti-toxoid determination. For other local reactions, diagnostic value of non-immediate responses in skin tests varies with clinical symptoms and substances involved. Immediate responses in skin tests and specific IgE determination have good diagnostic and/or predictive value in anaphylaxis and immediate/accelerated urticaria/angioedema to toxoid-, pneumococcus-, and egg- and gelatin-containing vaccines. Diagnosis of reactions to dextran in BCG is based on specific IgM/IgG determination. Most non-immediate generalized reactions result from non-specific inflammation, except for gelatin-containing vaccines, but the diagnostic value of immuno-allergological tests with the vaccines and gelatin are controversial. Withholding booster injections is advised if specific IgM/IgG levels are high. If the levels are low, sequential injections of vaccines containing a single vaccinating agent are usually tolerated. However, injections of the vaccine should be performed using a " desensitization " procedure in patients reporting anaphylaxis and immediate/accelerated urticaria/angioedema.     

Angioedema

Although first described more than 130 years ago, the pathophysiology, origin, and management of the several types of angioedema are poorly understood by most dermatologists. Although clinically similar, angioedema can be caused by either mast cell degranulation or activation of kinin formation. In the former category, allergic and nonsteroidal anti-inflammatory drug-induced angioedema are frequently accompanied by urticaria. Idiopathic chronic angioedema is also usually accompanied by urticaria, but can occur without hives. In either case, an autoimmune process leading to dermal mast cell degranulation occurs in some patients. In these patients, histamine-releasing IgG anti-FcepsilonR1 autoantibodies are believed to be the cause of the disease, removal or suppression by immunomodulation being followed by remission. Angiotensin-converting enzyme inhibitor-induced angioedema is unaccompanied by hives, and is caused by the inhibition of enzymatic degradation of tissue bradykinin. Hereditary angioedema, caused by unchecked tissue bradykinin formation, is recognized biochemically by a low plasma C'4 and low quantitative or functional C'1 inhibitor. Progress has now been made in understanding the molecular genetic basis of the two isoforms of this dominantly inherited disease. Recently, a third type of hereditary angioedema has been defined by several groups. Occurring exclusively in women, it is not associated with detectable abnormalities of the complement system. Angioedema caused by a C'1 esterase inhibitor deficiency can also be acquired in several clinical settings, including lymphoma and autoimmune connective tissue disease. It can also occur as a consequence of specific anti-C'1 esterase autoantibodies in some patients. We have reviewed the clinical features, diagnosis, and management of these different subtypes of angioedema. LEARNING OBJECTIVE: After completing this learning activity, participants should be aware of the classification, causes, and differential diagnosis of angioedema, the molecular basis of hereditary and non-hereditary forms of angioedema, and be able to formulate a pathophysiology-based treatment strategy for each of the subtypes of angioedema.     

Kutane Symptome nach Genuss pollenassoziierter Nahrungsmittel

The molecular basis of pollen-related food allergy is the marked similarity in sequence and structure of allergenic proteins in pollens and food plants. In affected patients, specific IgE antibodies are primarily directed against pollen allergens but then recognize homologous allergens in plant food. In Central and Northern Europe up to 80% of birch pollen allergic subjects suffer from a food allergy, in particular to stone- and pip fruits, nuts and vegetables. The main clinical manifestation of pollen-related food allergy is the oral allergy syndrome (OAS), a contact urticaria of the oral mucosa. Other features include contact urticaria of the hands in those handling the foods, as well as generalized urticaria and angioedema following ingestion. The impact of pollen-related food allergy on the severity and course of atopic eczema remain to be elucidated.     

Urticaria

Urticaria and angioedema are common and, if chronic, often persist for years with significant impact on quality of life and occupational ability. To achieve a better understanding of disease etiology and pathogenesis and to compare clinical trials, there is a clear need for cross‐specialty and international agreement of the nomenclature and diagnostic classification of urticaria and angioedema. At least in part this has been achieved by two recently published European guidelines. After the urticaria subtype is defined, potential triggers should be sought including persistent bacterial infections (Helicobacter pylori, streptococci, staphylococci, Yersinia, parasites) pseudoallergic reactions (acetylsalicylic acid, rarely food additives) and/or autoreactive mechanisms (autologous serum test). Identified trigger factors should be avoided or eradicated, as this is the most successful therapeutic approach. Treatment of most urticaria subtypes is difficult and besides H1 antihistamines neither standardized nor evidence‐based. Low‐sedating H1 antihistamines represent the mainstay of treatment, as they have a better therapeutic index and pharmacodynamic properties than older agents. In severe cases their dose has to be increased which is off‐label use. The evidence base for treatment alternatives is totally insufficient and the risk‐benefit profile of each off‐label used drug should be carefully considered.