Usefulness of C1 esterase inhibitor protein concentrate in the management of hereditary angioedema of oropharyngeal tissue.

Hereditary angioedema is an autosomal-dominant disorder caused by mutation of the gene encoding the C1 esterase inhibitor (C1-INH). It manifests as painless, nonpruritic, nonpitting episodic swelling of the subcutaneous tissues, gastrointestinal, and upper respiratory tracts in the absence of urticaria. An attack typically takes 24 h to peak and resolves over 48-72 h. The most serious manifestation is a laryngeal attack associated with upper airway swelling. The aim of this case report is to describe the lifesaving use of a novel C1-INH protein concentrate in a patient with mild-to-moderate dyspnea caused by swelling of the upper airway (larynx) and tongue.

[The morphology of vocal fold polyps and mucosa in Reinke's edema].

OBJECTIVE: To investigate the morphogenesis of vocal fold polyps and Reinke's edema on the basis of clinical and morphological analyses of the histological and immunohistochemical data characterizing the state of the local microcirculatory bed and the mechanisms of its permeability impairment. SUBJECTS AND METHODS: Polyps of the vocal folds and their mucosal tissue samples in Reinke's edema mucosa, which had been obtained after microsurgical treatment of 31 patients (13 men and 18 women) aged 23 to 75 years, were studied using a wide panel of peroxidase-labeled monoclonal and polyclonal antibodies (DAB chromogen), including T and B cell differentiation markers, Toll-like receptors (TLR2, TLR4, and TLR9), the costimulatory molecule CD80 (B7- 1), and markers for angiogenesis (CD34), vascular and tissue permeability (matrix metalloproteinases (MMP-1 and MMP-9)), and vascular cell adhesion molecule-1 (VCAM-1). Results. All types of the examined polypoid hyperplasia were ascertained to realize through the impaired permeability of the wall of microcirculatory vessels in the membranous vocal fold portion called Reinke's space. The expression of molecules, such as CD34, VCAM-1, MMP-1 and MMP-9, as well as TLR4 and TLR9 was revealed on the endothelial cells of microcirculatory vessels. The epithelial lining cells simultaneously expressed the above-mentioned Toll-like receptors and the costimulatory molecule CD80 (B7-1) that modulated T cell lymphocyte activity (through CD28) or attenuation (through CTLA-4), ensuring the interaction of structures of innate and adaptive immunity. CONCLUSION: The morphogenesis of polypoid hyperplasia of the vocal folds is a result of an epithelial stromal interaction under poor etiological factors, such as high vocal loads, exogenic intoxications, and viral infections. The integumentary lining cells carrying Toll-like receptors initiate reactive alterations in Reinke's space.

Pathophysiology of hereditary angioedema.

BACKGROUND: Laryngeal angioedema may be associated with significant morbidity and even mortality. Because of the potential severity of attacks, both allergists and otolaryngologists must be knowledgeable about the recognition and treatment of laryngeal angioedema. This study describes the clinical characteristics and pathophysiology of bradykinin-mediated angioedema. METHODS: A literature review was conducted concerning the clinical characteristics and pathophysiology of types I and II hereditary angioedema (HAE), type III HAE, acquired C1 inhibitor (C1INH) deficiency, and angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. RESULTS: The diagnosis of type I/II HAE is relatively straightforward as long as the clinician maintains a high index of suspicion. Mutations in the SERPING1 gene result in decreased secretion of functional C1INH and episodic activation of plasma kallikrein and Hageman factor (FXII) of the plasma contact system with cleavage of high molecular weight kininogen and generation of bradykinin. In contrast, there are no unequivocal criteria for making a diagnosis of type III HAE, although a minority of these patients may have a mutation in the factor XII gene. Angioedema attacks and mediator of swelling in acquired C1INH deficiency are similar to those in type I or II HAE; however, it occurs on a sporadic basis because of excessive consumption of C1INH in patients who are middle aged or older. ACE inhibitor-associated angioedema should always be considered in any patient taking an ACE inhibitor who experiences angioedema. ACE is a kininase, which when inhibited is thought to result in increased bradykinin levels. Bradykinin acts on vascular endothelial cells to enhance vascular permeability. CONCLUSION: Laryngeal swelling is not infrequently encountered in bradykinin-mediated angioedema. Novel therapies are becoming available that for the first time provide effective treatment for bradykinin-mediated angioedema. Because the characteristics and treatment of these angioedemas are quite distinct from each other and from histamine-mediated angioedema, it is crucial that the physician be able to recognize and distinguish these swelling disorders.

The effects of cigarette smoke condensate on vocal fold transepithelial resistance and inflammatory signaling in vocal fold fibroblasts.

OBJECTIVES/HYPOTHESIS: In response to chronic cigarette smoke exposure, a subset of patients present with edematous vocal folds, characteristically referred to as Reinke's edema. This phenotype differs from the tissue changes associated with prolonged smoke exposure in the lower airway, and the mechanism underlying Reinke's edema remains poorly described. We hypothesize that the effects of smoke are diffuse and involve both the epithelium and mucosa. STUDY DESIGN: In vitro, ex vivo experiment. METHODS: Transepithelial resistance (R(T) ) was quantified in an ex vivo, viable, porcine vocal fold model. Excised tissue was exposed to cigarette smoke condensate (CSC) and R(T) was computed at baseline and 1 and 4 hours after exposure. In vitro, human vocal fold fibroblasts were exposed to CSC. Cyclooxygenase 2 (COX-2), microsomal prostaglandin E synthase-1, and 15-hydroxyprostaglandin dehydrogenase mRNA expression were assessed at 4 hours. Prostaglandin E2 (PGE2) synthesis was quantified via immunoassay following 24 hours of CSC exposure. RESULTS: CSC had no effect on R(T) . CSC did, however, induce COX-2 mRNA expression as well as its downstream lipid mediator PGE2. PGE2 metabolism appears to be regulated via both synthetic and degradative enzymes in response to cigarette smoke. CONCLUSIONS: In vitro, CSC initiates an inflammatory response in vocal fold fibroblasts. However, in isolation, the epithelial resistance is not altered by CSC, at least acutely. These data may suggest a role for the interaction between the inflammatory response in the mucosa and compromised epithelial barrier function, as has been shown in other tissues.

[mRNA expression of extracellular matrix proteins of vocal fold polyps and Reinke edema].

OBJECTIVE: To investigate the pathogenic mechanism of vocal fold polyps and Reinke's edema. METHODS: A reverse-transcriptase polymerase chain reaction (RT-PCR) technique was adopted, mRNA levels of 9 proteins were measured in 12 vocal fold polyps, 2 Reinke's edema and 5 normal vocal folds (from total laryngectomy). RESULTS: The results showed that in the vocal fold polyps, mRNA levels of collagenase and fibromodulin descended and levels of fibronectin increased (P < 0.05). mRNA levels of lysyl oxidase and hyaluronic acid synthase 2 had no statistic difference between lesions and normal vocal folds (P > 0.05). mRNA express of tropoelastin exon, elastase and hyaluronidase was positive in part of lesion tissue and positive in all normal vocal folds. mRNA of procollagen I was negative in both groups. In the Reinke's edema, mRNA express of fibronectin was close to vocal fold polyps and mRNA express of fibromodulin was close to normal vocal folds. CONCLUSIONS: It was speculated phonation trauma and vocal fold restoring to trauma played an important role in pathogenic mechanism. Fibromodulin and fibronectin were two components involved in the disorders.

Differential gene expression profiling of vocal fold polyps and Reinke's edema by complementary DNA microarray.

OBJECTIVES: Our purpose was to determine whether complementary DNA (cDNA) microarray analysis (MA) can establish distinct gene expression profiles for 2 phenotypically similar vocal fold lesions: Reinke's edema (RE) and polyps. Established transcript profiles can provide insight into the molecular and cellular processes involved in these diseases. METHODS: Eleven RE specimens and 17 polyps were analyzed with MA for 8,745 genes. Further MA profiling was attempted within each lesion group to identify molecular markers for reflux exposure and smoking. Prediction analysis was used to predict lesion classification for 2 unclassified samples. A real-time polymerase chain reaction was performed to corroborate MA transcript levels for selected significant genes. RESULTS: Sixty-five genes were found to differentiate RE and polyps (p = .0088). For RE, 19 genes were differentiated for reflux exposure (p = .016). No genes were found to differentiate smokers from nonsmokers. For polyps, no genes were found to differentiate for reflux (p = .16) and smoking (p = .565). Categorization of unclassified lesions was possible with a minimum of 13 genes. CONCLUSIONS: We demonstrate the feasibility of benign lesion classification based on MA. Microarray analysis is useful not only for improving diagnosis and classification of such lesions, but also for potentially generating prognostic indicators and targets for therapy.

Hereditary angioneurotic edema of the larynx.

Hereditary angioneurotic edema (HAE) is an autosomal dominant disease resulting from a deficiency of functional C1-esterase inhibitor. If not recognized promptly and treated properly the disease can result in a fatal outcome as it causes laryngeal edema, which can lead to a life-threatening acute upper airway obstruction. We present the case of a 37-year-old female with HAE of the larynx, who was diagnosed early and treated properly, together with a review of the literature.

Sudden upper airway obstruction in patients with hereditary angioedema.

Hereditary angioedema (HAE) is clinically characterized by recurrent and self-limiting skin, intestinal, and life-threatening laryngeal edema. This study describes the age at which laryngeal edema first occurred, the time between onset and full development, and the effectiveness of therapy and prophylaxis in 123 HAE patients. 61 (49.7%) patients experienced a total of 596 laryngeal edema episodes. The ratio of laryngeal edema episodes to skin swellings and abdominal pain attacks was approximately 1:70:54 in patients who had laryngeal edema. The mean (SD) age at the first laryngeal edema was 26.2 (15.3) years. Nearly 80% of the laryngeal edemas occurred between age 11 and 45. The mean interval between onset and maximum development of laryngeal edema was 8.3 hours. A total of 354 laryngeal edemas cleared spontaneously without treatment and 208 laryngeal edemas were successfully treated with C1 inhibitor concentrate. Despite long-term prophylactic treatment with danazol, 6 patients developed subsequent laryngeal edemas. Laryngeal edema may occur at any age, although young adults are at greatest risk. In adults, the interval between onset of symptoms and acute risk of asphyxiation is usually long enough to allow for use of appropriate emergency procedures. It is essential to instruct patients and their relatives about the first signs of laryngeal edemas and the necessary procedures to follow.

Clinical studies of sudden upper airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor deficiency.

BACKGROUND: Hereditary angioedema due to C1 esterase inhibitor deficiency is clinically characterized by recurrent and self-limiting skin, intestinal, and laryngeal edema. Asphyxiation by laryngeal edema is the main cause of death among patients who die of hereditary angioedema. This study describes the age at which laryngeal edema first occurs, the time between onset and full development, and the effectiveness of therapy and prophylaxis. METHODS: Information on 123 patients with hereditary angioedema was obtained from medical histories and reports by the general practitioners, emergency physicians, and hospitals involved. RESULTS: Sixty-one patients (49.6%) experienced a total of 596 laryngeal edema episodes. The ratio of laryngeal edema episodes to skin swellings and abdominal pain attacks was approximately 1:70:54 in patients who had laryngeal edema. The mean (SD) age at the first laryngeal edema was 26.2 (15.3) years. Nearly 80% of the laryngeal edemas occurred between the ages of 11 and 45 years. The mean interval between onset and maximum development of laryngeal edema was 8.3 hours. A total of 342 laryngeal edemas cleared spontaneously without treatment, and 208 laryngeal edemas were successfully treated with C1 esterase inhibitor concentrate. Despite long-term prophylactic treatment with danazol, 6 patients developed subsequent laryngeal edemas. CONCLUSIONS: Laryngeal edema may occur at any age, although young adults are at greatest risk. In adults, the interval between onset of symptoms and acute risk of asphyxiation is usually long enough to allow for use of appropriate emergency procedures. To prevent a fatal outcome, it is essential to instruct patients and their relatives about the first signs of laryngeal edemas and the necessary procedures to follow.

Fibronectin: an interesting vocal fold protein.

A great deal of information is accruing regarding the function of the extracellular matrix. Once thought to be simply a structural entity to surround cells, it is now known to do much more. Fibronectin in particular has received specific attention. Fibronectin is a ubiquitous glycoprotein found most abundantly in the extracellular matrix of regenerating, healing, and embryonic tissue. Vast evidence supports the fact that fibronectin participates in many diverse functions throughout the body that are relevant to vocal fold biology. This article introduces the structure of fibronectin and its isoforms and provides an introduction to some of the many functions it plays. It also reviews the evidence about fibronectin's place in vocal folds and vocal fold pathology. It discusses fibronectin's presence in vocal nodules, vocal polyps, vocal scarring, and Reinke's edema, and reviews the data on its role in mucosal wave impairment. Lastly, it discusses preliminary microarray data that show gene expression for fibronectin to be upregulated in true vocal folds when compared to false vocal folds.

Genotypic and phenotypic expression of vocal fold polyps and Reinke's edema: a preliminary study.

Although a great deal of research exists regarding lamina propria composition, no report exists that relates gene expression in benign laryngeal lesions to phenotypic markers. In this study, messenger RNA profiles for extracellular matrix proteins--procollagen I, collagenase, elastase, fibronectin, fibromodulin, decorin, hyaluronic acid synthase 2, and hyaluronidase--were completed on 5 polyps and 4 Reinke's edema specimens. These genotypic profiles were correlated to a videostroboscopic parameter of mucosal wave stiffness, which was used as a measurement of phenotypic expression. Polyps, characterized by stiffer mucosal waves, had higher levels of gene expression, whereas stiffer mucosal wave scores for Reinke's edema were associated with lower gene activity levels. This study supports the hypothesis that there is a relationship between genotypic expression found in polyps and Reinke's edema and phenotype as defined by a loss of or a decreased mucosal wave. The study also gives clues as to the proteins responsible for the phenotype.

Treatment of 193 episodes of laryngeal edema with C1 inhibitor concentrate in patients with hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant disease (Mendelian Inheritance in Man 106100) caused by an inherited deficiency of C1 inhibitor (C1-INH) function. The clinical symptoms include skin swelling, abdominal pain, and life-threatening episodes of upper airway obstruction. We evaluated the efficacy of C1-INH concentrate for treating sudden airway compromise. METHODS: A series of 95 patients with HAE and a functional deficiency of C1-INH belonging to 59 families underwent screening for laryngeal edema. Double-blind treatment of randomized patients was not justifiable because of the life-threatening nature of this condition. Efficacy was evaluated by determining the interval from injection of C1-INH concentrate to the beginning of resolution of symptoms. The mean duration of episodes of laryngeal edema was compared in treated and untreated patients. Clinical information was obtained from emergency department physicians, the hospitals involved, reports of the general practitioners, and patients and their relatives. RESULTS: Forty-two patients had 517 episodes of laryngeal edema. Eighteen patients received 500- or 1000-U injections of C1-INH concentrate in 193 episodes. The C1-INH concentrate was effective in all laryngeal edemas. The interval from injection to interruption in progress of symptoms ranged from 10 minutes to 4 hours (mean +/- SD, 42.2 +/- 19.9 minutes). The mean +/- SD duration of laryngeal edema was 15.3 +/- 9.3 hours in patients who received C1-INH concentrate and 100.8 +/- 26.2 hours in those who did not. CONCLUSIONS: Injected C1-INH concentrate is highly and rapidly effective in the treatment of laryngeal edema of HAE. Relief and resolution of symptoms begins 30 to 60 minutes after injection, and duration of the upper airway obstruction is substantially reduced.

[Hereditary or acquired angioedema caused by functional deficiency of C1 inhibitor--a still unfamiliar disease picture]. / Hereditäres oder erworbenes Angioödem durch funktionellen Mangel von C1-Inhibitor--ein immer noch zu wenig bekanntes Krankheitsbild.

Hereditary angioneurotic oedema or hereditary angiooedema (HAE) and acquired angiooedema (AAE) are disorders of the C1-inhibitor (C1-INH) protein, caused by the lack, dysfunction or exhaustion of the C1-INH molecule. Inadequate function of C1-INH results in inappropriate control of various enzymes of the fibrinolytic, complement and kinin systems as well as of factor XII, being the initial enzyme of the kinin and contact coagulation systems. As C1-INH functional deficiency is rare and the clinical manifestation little known, even nowadays the most feared complication of the deficiency may evolve: death from acute airway obstruction. Patients deficient in C1-INH function whose clinical manifestations are misinterpreted as allergic angiooedema are most at risk for fatal laryngeal oedema. The therapy of allergic and C1-INH-related angiooedema is fundamentally different. The background for the hereditary form of inadequate C1-INH function is a gene defect. The predominant primary underlying disease of the acquired form of the deficiency (AAE) is a lymphoproliferative process.

[A fatal case of hereditary angioedema]. / Dødsfall av hereditaert angioødem.

A 27 year old woman suffered from recurrent attacks of laryngeal oedema due to C1-inhibitor deficiency, and was treated with danazol and tranexamic acid. The trachea was intubated with great difficulty, twice on one occasion. Two and a half years later she was admitted to the Intensive Care Unit with dyspnoea and dysphagia. Tranexamic acid, corticosteroids, adrenaline (also inhalated), were administered intravenously, but dyspnoea progressed. During preparation for tracheostomy the patient suffered from sudden airway collapse. Attempts to ventilate by mask, puncture of the cricothyroid membrane and intubation were unsuccessful. A small tube was eventually inserted into the trachea after four minutes. The patient was then severely cyanotic with a pulse of thirty, and had dilated pupils. The next morning convulsions ensued and a CT scan showed cerebral oedema. In spite of treatment with pentothal, mannitol and hyperventilation she died. The authors advocate the use of intravenous infusion of C1-inhibitor concentrate, since traditional treatment is inadequate. Persons with hereditary angio-oedema should have a personal supply of C1-inhibitor at hand.

[Treatment of hereditary angioedema].

Hereditary angioedema is a rare familial disease caused by the defect of complement C1esterase inhibitor (C1-INH). It is characterized by recurrent acute edema of the extremities, the face, the respiratory tract and the gastrointestinal tract. Acute laryngeal edema usually produces laryngeal obstruction. Two cases have been treated since 1986, one of them had been admitted for forty-five times because of recurrent acute laryngeal edema. Investigations showed two families with a high incidence of this disease. Laboratory examination showed a remarkable decrease of C1-INH and C4. Tracheotomy is indicated in patients with laryngeal edema. Great success was achieved in two patients treated with danazol.

[Pathogenesis of hereditary angioedema]. / Pathogenese des hereditären Angioödems (HAE).

The hereditary angioedema (HAE) is an autosomal dominant transduced illness. Patients suffer from severe attacks with circumscribed swellings of the skin, or of the gastro-intestinal mucosa, or of whole organs. Laryngeal edema is responsible for airway obstruction and often for sudden death. Very often the abdominal symptoms are leading to false diagnosis and treatment. The diagnosis is proved by estimation of lowered C1-inhibitor (C1-INH) activity. The defect of C1-INH is responsible for the activation of the start phases of the complement system and of the kinin system. The liberation of vasoactive peptides and kinins induces the edematous swellings and severe pain. The acute symptoms of HAE are promptly resolved by intravenous application of C1-inhibitor concentrate.

Familial angioedema associated with C1 esterase-inhibitor deficiency. A new genetic variant in hereditary angioedema?

In the absence of a positive family history for hereditary angioedema (HAE), both siblings in a family were found to have clinical and laboratory findings similar to those in HAE. Both siblings became symptom free after receiving danazol treatment, accompanied by a subnormal rise in C1 esterase inhibitor and C4 levels. As both siblings and their father share HLA haplotype A2, B7, the influence of other HLA loci on the clinical expression of this disorder should be considered. Although the disorder found in these siblings may be inherited as a recessive disorder, which to our knowledge has never been described before, or may have developed as the result of spontaneous genetic mutation, it is more appropriate to classify these two cases as familial angioedema until proved otherwise.

Hereditary angioneurotic oedema in Finland. Clinical, immunological and genealogical studies.

A total of 7 families with hereditary angioneurotic oedema (HANE) have been found in Finland. Six HANE patients have died from laryngeal oedema, 27 patients with diagnosed HANE are alive and 21 members have a haematological abnormality typical of HANE, i.e. a deficiency of the inhibitor of the activated first component of complement (C1-INH), but no manifest symptoms. The largest family has 363 living members, 303 of whom were investigated for C1-INH, C4 and C3. Fourteen patients had HANE, 18 relatives were symptomless but had C1-INH deficiency, and 3 members of the family had died from laryngeal oedema. In two families only one case of HANE was diagnosed, the parents in both cases being symptomless with normal C1-INH levels. All patients who had died from laryngeal oedema and 10 of the 27 HANE patients still alive had a typical triad of paroxysmal abdominal pain, peripheral oedema and laryngeal oedema. Six patients have had abdominal attacks alone, three peripheral oedema alone and two only laryngeal oedema. The age at onset of symptoms was 1-51 years. Three patients, who have received continuous methyltestosterone therapy, had hardly any symptoms during the treatment. Thirteen patients have received tranexamic acid, either during an attack or continuously, with positive effects in all except two. Cinnarizine treatment was beneficial in three out of four cases, both when given continuously or during an attack.

Angioneurotic edema. A review of modern concepts.

We review the subject of angioneurotic edema with special emphasis on the more clearly defined entity of hereditary angioneurotic edema. The clinical presentations of the various forms of angioneurotic edema are discussed. Attention is directed toward the attempts that have been made to define this group of diseases in terms of their underlying biochemical mechanisms. A simplified schema of the serum complement system is presented. We conclude that only after we understand such biochemical interactions will we able to effect a more definitive form of therapy for the angioneurotic edemas.