Besifloxacin is a novel fluoroquinolone that, like other fluoroquinolones, acts by inhibiting the essential bacterial enzymes DNA gyrase and topoisomerase IV. Topical besifloxacin ophthalmic suspension 0.6% is indicated for use in patients with bacterial conjunctivitis caused by susceptible bacteria. Besifloxacin had in vitro activity against a broad spectrum of Gram-positive and -negative bacteria that commonly cause ocular infections (e.g. Haemophilus influenzae, Staphylococcus aureus, S. epidermidis and Streptococcus pneumoniae), including drug-resistant strains. In two randomized, double-blind, multicentre trials, besifloxacin ophthalmic suspension 0.6% administered at the recommended dose for 5 days in patients aged >/=1 year with bacterial conjunctivitis was significantly (p < 0.01) more effective than vehicle in terms of clinical resolution and microbial eradication rates (coprimary endpoints) at study visit two (day 5+/-1) or three (day 8 or 9)[primary timepoints]. Besifloxacin ophthalmic suspension 0.6% was noninferior to moxifloxacin ophthalmic solution 0.5% in patients aged >/=1 year with bacterial conjunctivitis with regard to clinical resolution (58.3% vs 59.4%) and microbial eradication (93.3% vs 91.1%) rates on day 5 +/- 1 of treatment (coprimary endpoints) in a randomized, double-blind, multicentre trial; both drugs were administered at a dosage of one drop in the affected eye(s) three times daily for 5 days. Besifloxacin ophthalmic suspension 0.6% was generally well tolerated in clinical trials, with most adverse events being mild in severity. The tolerability profile of besifloxacin ophthalmic suspension 0.6% was similar to that of moxifloxacin ophthalmic solution 0.5%.

Icatibant is a selective antagonist of the bradykinin type 2 receptor. In the randomized, double-blind, multicentre, FAST-1 trial, the difference in the median time to the onset of symptom relief (primary endpoint) did not reach statistical significance between a single dose of subcutaneous icatibant 30 mg and placebo in adults with moderate to very severe acute abdominal or cutaneous episodes of hereditary angioedema. However, icatibant was effective with regard to several other endpoints, providing significantly greater reductions from baseline in symptom severity scores 4 and 12 hours after administration, and eliciting significantly shorter times to both first symptom improvement and overall patient improvement than placebo. In the similarly designed, active comparator-controlled, FAST-2 trial, a single dose of subcutaneous icatibant 30 mg was associated with a significantly shorter median time to onset of symptom relief (primary endpoint) than oral tranexamic acid in adults with acute abdominal or cutaneous episodes of hereditary angioedema, and was also more effective than tranexamic acid in terms of most other endpoints. Across both FAST-1 and -2, the efficacy of subcutaneous icatibant 30 mg in the treatment of laryngeal episodes of hereditary angioedema was generally consistent with that seen for abdominal and cutaneous episodes, with a median time to first symptom improvement of 0.6-1.0 hours. Subcutaneous icatibant was generally well tolerated in adult patients with hereditary angioedema in the FAST trials, with the most common adverse events being injection-site reactions that were generally of mild severity, transient in nature and resolved spontaneously without treatment.

PURPOSE OF REVIEW: The purpose of the present review is to outline the clinical aspects and management of the upper airway involvement in the patients suffering from hereditary angioedema. RECENT FINDINGS: Molecular mechanisms of hereditary angioedema reviewed in the literature conclude that it is an autosomal dominant disorder, characterized by the deficiency of C1 inhibitor due to mutations of its gene (SERPING). Hereditary angioedema manifests as episodes of localized swelling in any site of the body from skin, gastrointestinal tract to the upper airway, where it is severe and life-threatening. The age of onset, frequency of attacks and the factors triggering upper airway swelling in hereditary angioedema are variable among different patients. Acute laryngeal edema should be managed in emergency with monitoring of airway patency. To avoid airway obstruction, therapy should begin early either with current treatment (C1 inhibitor concentrate) or with new drugs developed recently. In patients with recurrent upper airway swelling attacks, long-term prophylaxis is recommended. CONCLUSION: The use of old and new treatment in acute attacks as well as in prophylaxis (long and short-term) has changed the outcome of patients with hereditary angioedema who present upper airway swelling.

BACKGROUND: Activation of bradykinin-mediated B2 receptor has been shown to play an important role in the onset of angioedema associated with C1 inhibitor deficiency. This finding has led to the development of novel therapeutic drugs such as the B2 receptor antagonist icatibant. However, it is unclear whether other receptors expressed on endothelial cells contribute to the release of kinins and vascular leakage in these patients. The recognition of their role may have obvious therapeutic implications. OBJECTIVE: Our aim was to investigate the involvement of B1 and gC1q receptors in in vitro and in vivo models of vascular leakage induced by plasma samples obtained from patients with C1 inhibitor deficiency. METHODS: The vascular leakage was evaluated in vitro on endothelial cells by a transwell model system and in vivo on rat mesentery microvessels by intravital microscopy. RESULTS: We observed that the attack phase plasma from C1 inhibitor-deficient patients caused a delayed fluorescein-labeled albumin leakage as opposed to the rapid effect of bradykinin, whereas remission plasma elicited a modest effect compared with control plasma. The plasma permeabilizing effect was prevented by blocking the gC1q receptor-high-molecular-weight kininogen interaction, was partially inhibited by B2 receptor or B1 receptor antagonists, and was totally prevented by the mixture of the 2 antagonists. Involvement of B1 receptor was supported by the finding that albumin leakage caused by attack phase plasma was enhanced by IL-1beta and was markedly reduced by brefeldin A. CONCLUSION: Our data suggest that both B1 receptor and gC1q receptor are involved in the vascular leakage induced by hereditary and acquired angioedema plasma.

Summary Background Hereditary angio-oedema (HAE) is a rare disease caused by deficiency of complement C1 inhibitor (C1 inhibitor). The diagnosis is challenging as the disease can have a variety of clinical manifestations. In 2001 a national HAE comprehensive care centre was established and a search for these patients was initiated. Objectives To identify and characterize all patients with HAE in Denmark and increase awareness of the disease. Methods Patients were recruited from hospital departments, dermatologists in private practice, Centres for Rare Diseases, the Danish patient organization and the national reference laboratory. Family interviews were conducted and medical records were evaluated. Information was spread through lectures, articles in popular magazines and via television. National guidelines for diagnosis and treatment were published. Results Eighty-two patients were identified. The mean diagnostic delay was 16.3 years. Five patients had HAE type II. Forty-five patients reported a characteristic serpiginous rash (erythema marginatum). More than 90% of patients had noticed precipitating factors before skin and mucosal swellings. Four patients underwent a total of eight tracheotomies and five families recalled 11 relatives who died of HAE. Conclusions The minimal prevalence of HAE in Denmark is approximately 1.41 per 100 000 inhabitants. The risk of upper airway obstruction underlines the importance of diagnosing these patients. Precipitating factors, a preceding or concomitant serpiginous erythema and cutaneous swelling and/or abdominal pain attack and/or laryngeal oedema are clues to the diagnosis. As a consequence of this survey, information has been spread to patients, families and physicians.

C1 inhibitor deficiency (hereditary angioedema [HAE]) is a rare disorder for which there is a lack of consensus concerning diagnosis, therapy, and management, particularly in Canada. European initiatives have driven the approach to managing HAE with 3 C1-INH Deficiency Workshops held every 2 years in Hungary starting in 1999, with the third Workshop having recently been held in May 2003. The European Contact Board has established a European HAE Registry that will hopefully advance our knowledge of this disorder. The Canadian Hereditary Angioedema Society/Société d'Angioédème Héréditaire du Canada organized a Canadian International Consensus Conference held in Toronto, Ontario, Canada, on October 24 to 26, 2003, to foster consensus between major European and North American HAE treatment centers. Papers were presented by investigators from Europe and North America, and this consensus algorithm approach was discussed. There is a paucity of double-blind placebo-controlled trials in the treatment of HAE, making levels of evidence to support the algorithm less than optimal. Enclosed is the consensus algorithm approach recommended for the diagnosis, therapy, and management of HAE and agreed to by the authors of this article. This document is only a consensus algorithm approach and requires validation. As such, participants agreed to make this a living 2003 algorithm (ie, a work in progress) and agreed to review its content at future international HAE meetings. The consensus, however, has strength in that it was arrived at by the meeting of patient-care providers along with patient group representatives and individual patients reviewing information available to date and reaching agreement on how to approach the diagnosis, therapy, and management of HAE circa 2003. Hopefully evidence to support approaches to the management of HAE will approach the level of meta-analysis of randomized controlled trials in the near future.

In 2009, reports on basic and clinical immunology had an increased focus on human disease mechanisms and management. The molecular pathogenesis of familial angioedema associated with estrogen was further explored to find possible factors affecting severity, including polymorphisms in enzymes and receptors related to bradykinin pathways. A placebo-controlled clinical trial of C1 esterase inhibitor concentrate in patients with hereditary angioedema demonstrated the safety of its use and its efficacy to reduce the duration of angioedema attacks. The interaction of innate immunity and adaptive responses was further examined in several reports, establishing the significant role of Toll-like receptor stimulation for the development of optimal specific antibody responses. The 2009 update of the classification of primary immunodeficiencies introduced more than 15 new genetic defects related to the immune response, including of dedicator of cytokinesis 8 (DOCK8) mutations, which are responsible for the autosomal recessive form of the hyper-IgE syndrome. Other reports expanded the clinical spectrum of disease and improved the characterization of conditions such as warts, hypogammaglobulinemia, and myelokathexis syndrome or the occurrence of mucormycosis and Serratia species infections in patients with chronic granulomatous disease. The frequent presentation of gastrointestinal disorders in patients with humoral immunodeficiencies was recognized, and recommendations for management were reviewed. Clinical research focused on severe combined immunodeficiency included the development and implementation of a state-wide newborn screening program for this condition, a desired goal considering the significant reduction of mortality rate when the diagnosis is made early before opportunistic infections occur.

BACKGROUND: Danazol is a drug most widely used for the prophylaxis of hereditary angioedema resulting from the deficiency of the C1-inhibitor. Potential hepatotoxic or liver tumor-inducing side effects of long-term danazol prophylaxis have been investigated during the follow-up of hereditary angioedema patients. METHODS: Characteristic parameters of liver function (including bilirubin, GOT, GPT, gammaGT, total protein, ALP, LDH), as well as findings of viral serology screens and abdominal ultrasonography-determined during years 0 and 5 of follow-up of patient groups taking/not taking danazol-have been reviewed and analyzed comparatively. RESULTS: From a population of 126 hereditary angioedema patients, 46 subjects taking danazol and another 46 not taking danazol fulfilled the inclusion criteria. Longitudinal follow-up did not reveal any clinically relevant difference between the liver function parameters determined in years 0 and 5 in the two groups. Abdominal ultrasound did not detect neoplastic or other potentially treatment-related alterations of the liver parenchyma. There were no discontinuations of treatment during the study. CONCLUSIONS: Our results clearly suggest that, administered at the lowest effective dose, danazol does not induce liver injury in hereditary angioedema patients.

Hereditary angioedema (HAE) is a rare genetic disorder, manifested by recurrent bouts of swelling in various tissues. The biochemical basis leading to HAE manifestations is either a quantitative or qualitative deficiency in plasma C1 esterase inhibitor (C1-INH). Its proposed physiological role is regulation of vascular permeability, by inhibiting certain steps in the complement, coagulation and the fibrinolytic pathways. Recent evidence implies that bradykinin, a plasma kinin, is the main mediator of HAE, Leading to vasodilatation and hyperpermeability of small vessels. Bradykinin receptors have been recently identified, Leading to significant progress in our understanding of the physiologic mechanisms leading to edema. HAE is characterized by edema of the extremities, face, tongue, Larynx, genitalia and severe abdominal pains. Edema of the tongue and Larynx are life-threatening, and fataloutcomes have been described. Diagnosis of HAE is frequently missed, due to the rarity, non-specific symptoms and lack of awareness of physicians to the diagnosis and treatment. In this review, the authors describe the mechanisms of HAE and the clinical approach to diagnosis and management, according to accepted international guidelines. Furthermore, new treatment modalities that have recently been developed are presented: novel molecules targeting bradykinin, either by inhibiting its generation from plasma kininogens or by direct inhibition of its specific receptors on blood vessels, replacement therapy with human recombinant C1-INH produced in transgenic rabbits. HAE is a chronic disabling diseasewith serious consequences for the patients and their families, severely affecting the quality of life. Recently, new clinical guidelines were published and treatment centers, specializing in the management of HAE were established. The authors are convinced that the increased awareness of the medical staff, in addition to new data and novel treatments, will reduce the burden of the disease, improve its grim prognosis and enable a better quality of life for HAE patients.

It has been found that although there is some parallelism between the quantity of tubercle bacilli demonstrable histologically and the number of colonies that can be isolated from a given tissue, the culture method is far the more efficient in indicating quantitative relations. Tubercle bacilli were not perceived in the organs of rabbits 1 day after infection with the modified BCG although as many as 1,500 colonies were isolated from one of them. This may be solely because it is difficult to see widely dispersed single minute acid-fast rods in the diffuse infiltrations of mononuclears with their hyperchromatic nuclei and sparse cytoplasm. Later, with the formation of tubercle, the parallelism is much closer. The culture method gives evidence concerning the number of living tubercle bacilli in the tissue. The significance of the accumulation of acid-fast particles in the tissues has been discussed. It has been seen that from the beginning this accumulation is greater in the Kupffer cells of the liver, in the macrophages of the spleen and in the reticular cells of the bone marrow than within the mononuclears of the lung, the organ where the bacilli grow with the greatest rapidity and are destroyed with the greatest difficulty. Acid-fast particles are more prominent with the bovine than with the human bacillus or the BCG, the microorganism that is destroyed with the greatest difficulty thus leaving more incompletely digested bacillary debris at a given time within the cells. Thus it seems permissible to conclude from the presence of acid-fast material that some tubercle bacilli are undergoing destruction even 24 hours after infection. The initial accumulation of polynuclear leucocytes corresponds with the subsequent severity of the infection. Despite the greater primary localization of bacilli in the liver, this initial inflammatory reaction with all three infections is much greater in the lung than in the liver. In each organ it is more intense with the bovine than with the less virulent strains. The multiplication of the bacillus and its accumulation within large mononuclear and young epithelioid cells is accompanied by an intense formation of new mononuclears by mitosis. The more rapid the growth of the bacillus, the more conspicuous the regeneration of these cells. Thus with all strains mitosis is more intense in the more susceptible organ, as in the lung compared with the liver; with the most virulent strain the most extensive and diffuse accumulation of these new cells corresponds with the greater rise in the numbers of bovine bacilli after the lag of the 1st week. With the maturation of the epithelioid cells and the formation of tubercles the bacilli have already been greatly reduced numerically and the speed of this process diminishes with the virulence of the three strains used. The faster the development of tubercle the faster the destruction of the bacillus and the earlier the resorption of the tubercle. Tubercle bacilli never accumulate in such large numbers in the mononuclears of the liver as they do in the lung. Though at first the tubercles in the liver may be more numerous than those in the lung they never attain the same size. The formation of new mononuclears by mitosis is restricted and Langhans' giant cells appear very early (1st and 2nd weeks). In the lung, giant cells are not found until much later with the BCG and the human bacillus (4th week); they were not noted in the interstitial tubercles with the bovine type, but the extension of these tubercles was accompanied by an unabated mitosis of mononuclears until the death of the animal. The liver tubercles are resorbed early even with the bovine infection. Associated with these histological differences are the slow initial growth and the early and complete destruction of the tubercle bacilli even of bovine type in the liver, and the more rapid initial growth in the lung, with the later destruction of the BCG and the human bacillus and the unabated growth of the bovine bacillus. Similar differences were observed between the splenic pulp and corpuscle. In the former the accumulation of acid-fast particles was much greater and the tubercles developed earlier. Mitosis of mononuclears was less frequent and giant cells appeared earlier. Tubercle bacilli, always intracellular, disappeared from the tubercles in the pulp sooner than from those in the corpuscle, and the tubercles themselves first disappeared from the pulp. Consequently with the persistence of bacilli mitosis continued in the tubercles of the corpuscle and these attained a much larger size. Moreover individual resistance is linked with the ability to form mature tubercles early. In two animals simultaneously infected with the same strain and killed at the same time, the destruction or retardation of the bacillus is greater in that rabbit in which maturation of the tubercle and of epithelioid cells has proceeded further (Figs. 15 and 16). These observations indicate that the mononuclears of different organs or even of the same organ, as in the different parts of the spleen, have a different capacity to destroy the tubercle bacillus, and that the transformation of the mononuclear into the mature epithelioid cell follows its destruction of the tubercle bacilli. In the lung the more virulent types of bacillus are destroyed within the epithelioid cells of interstitial tubercles but persist in foci of tuberculous pneumonia. In this organ in rabbits infected with the human strain and to a lesser degree in rabbits infected with the bovine strain, the parasite largely disappears from the epithelioid cells of interstitial tubercles. But with both strains tubercle bacilli in large numbers may accumulate within epithelioid cells lying free in the alveoli. With the human type they are numerous within the cells and free in caseous material in the localized foci of caseous pneumonia. With the bovine infection, this caseous pneumonia is more often widespread and in the areas of caseous pneumonia the greater part of the vast accumulation of bovine bacilli in the lungs is found; as many as 200,000 colonies have been isolated from 10 mg. of tissue (Fig. 11). Flooding of the respiratory passages by the caseation of tuberculous lesions into the bronchi plays an important rôle in dissemination of tubercle bacilli through the lung. The process on the contrary is predominantly interstitial when the bovine bacillus is held in check (Fig. 12). Thus there is apparently some factor acting in the alveoli that favors the growth of the parasite. The accumulation of tubercle bacilli is seen especially in the peripheral epithelioid cells in immediate contact with the alveolar space. In the same lung the bacilli are much fewer in the interstitial tubercles. The accumulation in human tuberculosis of large numbers of tubercle bacilli in the tissues lining cavities is well known. Novy and Soule (20) have shown that within certain limits the growth of the bacillus in vitro is proportional to the oxygen tension of its environment. Corper, Lurie and Uyei (21) have confirmed these observations and have noted further that a difference in the gaseous environment of the bacilli equal to the difference between the conditions existing in the alveolar air and the venous blood is sufficient to cause a considerable increase in the growth of the microorganism in vitro. Loebel, Shorr and Richardson (22) by the use of Warburg's manometer have found that the oxygen consumption of tuberculous tissue is such that a tubercle 0.5 mm. thick would completely exhaust the oxygen of the air before it reached the center. These observations suggest that a factor responsible for the greater multiplication of the bacillus in the cells of the alveoli may be the greater oxygen tension of the alveolar air. In the liver, spleen and bone marrow even with the bovine infection many instances were found of the effective destruction of the parasite synchronously with the maturation of epithelioid cells and the formation of tubercle. On the other hand, in the spleen and bone marrow of some rabbits, living bacilli persisted within the epithelioid cells of isolated tubercles even 2 months after infection, a condition never found with the human type or BCG infection. Thus the epithelioid cell is the means of defense for the rabbit against the bovine type bacillus, and as such it is usually adequate in the liver, spleen and bone marrow though ineffective in the lung and kidney. In the latter, descending infection, and the occasional colony-like multiplication of bacilli in unorganized material, tubular casts, determine the long persistence of large numbers of bacilli in this organ. In differentiating the mononuclear phagocyte of the connective tissues into the monocyte and clasmatocyte Sabin and her coworkers (23) have maintained that the clasmatocyte can efficiently destroy the tubercle bacillus but that the monocyte and its derivatives, the epithelioid and Langhans' giant cells, cannot. With the progress of the disease they have noted that the monocytes accumulate in great numbers in the foci of infection and overflow into general circulation (4). White (24) and Sabin and her coworkers have concluded that tuberculosis is specifically a disease of the monocyte, and that this cell and its derivatives act as incubators for the tubercle bacillus. Doan and Sabin (25) have therefore sought, with indecisive results, to protect the body against tuberculosis by an antimonocytic serum. However it has been shown here that although an intense multiplication of mononuclears is associated with the growth of the tubercle bacillus, their transformation into mature epithelioid cells is constantly associated with its destruction, and the rapidity of the destruction varies with the rapidity of the maturation of tubercle. Even in the bovine infection the epithelioid cells destroy the bacilli in the liver, spleen and bone marrow as a rule, and even in the lung, keep them in check in the interstitial tubercles. The appearance of giant cells is associated with cessation or diminution of mononuclear regeneration by mitosis, and is coincident with cessation of multiplication or marked reduction in the number of living bacilli. They therefore appear earlier and in larger numbers in these organs or parts of organs that first destroy the bacillus (Figs. 16 and 17). They were not observed even 2 months after the bovine infection in the interstitial tubercles in the lung. Their absence and the continued mitosis of mononuclears, which accounts for the massive pneumonic and interstitial consolidation of the lung with this infection, were associated with the failure of the lung to destroy effectively the bovine parasite. The formation of giant cells in the pneumonic foci in the bovine infection would seem to be an exception to this rule. The Langhans giant cells have often been considered an indication of the chronicity of the pathological process. It would appear that they are formed from existing epithelioid cells when the multiplication of the bacillus has ceased and the stimulus for the formation of new cells has decreased or stopped. Giant cells were most conspicuous in the liver and splenic pulp where, with the BCG infection, no caseation ever developed, and in the liver before caseation was seen anywhere in the body. In the human and bovine infections, giant cells formed in the liver before caseation appeared. Hence caseation is not a necessary requirement for giant cell formation, as maintained by Medlar (26), though these cells frequently form about caseous material. Lymphocytes and granulation tissue do not cause the destruction of tubercle bacilli, these being destroyed in their absence. They usually appear about tubercles due to all strains and in all organs, after the greater part of the microorganisms have been destroyed (Fig. 18). The bacilli are not destroyed in the lung with bovine infection where the tubercles are usually little permeated by lymphocytes and granulation tissue. There is however, no constant relation between granulation tissue and destruction of tubercle bacilli, for in the lung after the human infection and even in other organs after the bovine infection isolated tubercles may be surrounded and penetrated by lymphocytes and granulation tissue at a time when considerable numbers of living bacilli are still histologically demonstrable within the epithelioid cells. Caseation is usually not caused by the local accumulation of tubercle bacilli. At first, when the BCG (after 1 week) and the human microorganism (after 2 weeks) are present in the cells in very large numbers as demonstrated both histologically and by culture (Figs. 4 and 13) there is no necrosis of these cells. An exception to this rule found in the lung with the bovine infection is considered below. Later, after the bacilli have been destroyed to a great extent and even though the number of bacilli is small, caseation appears (Fig. 14). After this preliminary destruction the extent of caseation apparently varies with the number of residual bacilli. With the least virulent microorganism, the BCG, few bacilli remained in the liver in the 4th week and no caseation was seen. In the tubercles of the splenic corpuscle at the same time bacilli were somewhat more numerous and there was scant caseation. On the other hand with the human bacillus after 4 weeks more bacilli survived and caseation was more extensive in both organs; with the bovine microorganism tubercle bacilli were much more numerous and caseation was far advanced. In the lung, however, caseation appeared with the first considerable accumulation of the bovine bacilli present 2 weeks after inoculation. That the bovine bacillus is primarily more injurious to the lung of rabbits than the BCG or the human bacillus is suggested by the greater intensity of the initial inflammation and by the more conspicuous accumulation of cells in the alveoli evident from the very beginning of infection. Maximow (27) showed that bovine bacilli even in small numbers cause the death of cells in tissue cultures of rabbit lymph nodes whereas the BCG or the human bacillus may accumulate within the cells in tremendous numbers without injuring them. Nevertheless in the liver, spleen and bone marrow of the living animal, caseation does not appear at the time when bovine bacilli are most abundant, but after they have been greatly reduced in numbers. Large numbers of the less virulent types of tubercle bacilli accumulated in different organs a short time after infection do not cause caseation, and with the bovine infection caseation under the same conditions occurs only in the lung. Later when the animal is sensitized caseation occurs in various organs in the presence of the small numbers of tubercle bacilli that remain in the tissues after most of them have been destroyed, and the extent of this caseation varies with the numbers of residual bacilli. These observations suggest that a large number of bacilli fail to cause necrosis soon after infection whereas a few bacilli produce caseation in the animal that is sensitized. Many investigators have held that caseation is due to sensitization. Krause (28), Huebschman (29) and Pagel (30) think that caseation is caused by the action of tuberculin-like substances on the sensitized tissues of the allergic animal. Rich and McCordock (31) view the process in essentially the same light. Recently Schleussing (32) has suggested that caseation is a coagulation necrosis in Weigert's sense of an allergically inflamed tissue, and is similar to the necrosis of the Arthus phenomenon.

Summary Hereditary angioedema is a rare genetic disorder resulting from an inherited deficiency or dysfunction of the C1-esterase inhibitor of the classic complement pathway. It is characterised by recurrent episodes of angioedema, without urticaria or pruritus, most often affecting the skin or the mucosal tissues of the upper respiratory and gastrointestinal tracts. We describe the peri-operative care of a woman with hereditary angioedema undergoing laparoscopic cholecystectomy with emphasis on the role of anaesthetists as peri-operative physicians.

BACKGROUND: Activation of bradykinin-mediated B2 receptor has been shown to play an important role in the onset of angioedema associated with C1 inhibitor deficiency. This finding has led to the development of novel therapeutic drugs such as the B2 receptor antagonist icatibant. However, it is unclear whether other receptors expressed on endothelial cells contribute to the release of kinins and vascular leakage in these patients. The recognition of their role may have obvious therapeutic implications. OBJECTIVE: Our aim was to investigate the involvement of B1 and gC1q receptors in in vitro and in vivo models of vascular leakage induced by plasma samples obtained from patients with C1 inhibitor deficiency. METHODS: The vascular leakage was evaluated in vitro on endothelial cells by a transwell model system and in vivo on rat mesentery microvessels by intravital microscopy. RESULTS: We observed that the attack phase plasma from C1 inhibitor-deficient patients caused a delayed fluorescein-labeled albumin leakage as opposed to the rapid effect of bradykinin, whereas remission plasma elicited a modest effect compared with control plasma. The plasma permeabilizing effect was prevented by blocking the gC1q receptor-high-molecular-weight kininogen interaction, was partially inhibited by B2 receptor or B1 receptor antagonists, and was totally prevented by the mixture of the 2 antagonists. Involvement of B1 receptor was supported by the finding that albumin leakage caused by attack phase plasma was enhanced by IL-1beta and was markedly reduced by brefeldin A. CONCLUSION: Our data suggest that both B1 receptor and gC1q receptor are involved in the vascular leakage induced by hereditary and acquired angioedema plasma.