BACKGROUND:

Hereditary Angioedema due to C1-Inhibitor deficiency (HAE types I and II) is a monogenic disease characterized by sudden, self-limited episodes of cutaneous and mucosal swelling due to local deregulation of vascular permeability. Despite its monogenic pattern of inheritance, HAE exhibits great clinical variability and low genotype/phenotype correlation among those affected, which ultimately hinders therapeutic approach and probably underlies yet unknown genetic and environmental factors.

METHODS:

We studied whole-genome RNA expression of PBMCs in three HAE type-I families (accounting for 40 individuals), 24 of which carry the same R472X mutation in the C1-Inhibitor gene and show large variability in terms of disease expression. Those included in this study were analyzed according to the presence of mutation and/or clinical symptoms.

RESULTS:

Instead of a single, common disease-associated expression pattern, we found different transcriptome signatures in two of the families studied. In one of them (referred to as DR family), symptoms correlate with the upregulation of 35 genes associated to the biological response to viral infections (including RSADs, OAS, MX and ISG pathway members) and immune response. In another pedigree (Q family), disease manifestation is linked to the upregulation of 43 genes with diverse functions, including transcription and protein folding. Moreover, symptoms-free members of the Q pedigree display relatively higher expression of 394 genes with a wide diversity of functions.

CONCLUSION:

We found no evidence for a common altered PBMC expression pattern linked to HAE symptoms in the three families analyzed. All the data considered, differential gene expression in PBMCs do not seem to play a significant role in the predisposition or protection against HAE in the basal -between crises- conditions analyzed. Although the RNA expression pattern associated to the response to viral infections observed in the DR family supports the idea of infectious diseases as a modifying factor for HAE severity, large-scale studies would be needed to statistically associate such expression pattern to the development of this rare disease.

Hereditary angioedema (HAE) is a rare type of angioedema caused by a quantitative or functional deficit of C1 inhibitor (C1 INH) that leads to excess production of bradykinin, which can result in acute localized swelling attacks in the skin or mucous membranes of the mouth, head and neck, extremities, gastrointestinal (GI) tract, genitals, trunk, and larynx. Angioedema in the respiratorytract maycause airway obstruction; severe abdominal pain, vomiting, or diarrhea may occur in the GI tract. Patients with HAE may be diagnosed and managed by HAE specialists or by primary care physicians depending on individual circumstances. Proper treatment requires differentiation from other forms of angioedema. Patients with HAE who are managed appropriately with medications that treat and prevent atttacks may have a lower risk of death from laryngeal edema and a better quality of life. Less frequent attacks may allow them to attend work, school, and leisure activities more regularlyand be free of the pain and disfigurement of HAE attacks moreoften.

Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1-INH) is a rare, autosomal-dominant disease. HAE-C1-INH is characterized by recurrent attacks of marked, diffuse, nonpitting and nonpruritic skin swellings, painful abdominal attacks, and laryngeal edema. The extremities and the gastrointestinal tract are most commonly affected. Swelling of the upper respiratory mucosa poses the greatest risk because death from asphyxiation can result from laryngealedema. HAE-C1-INH attacks are variable, unpredictable, and may be induced by a variety of stimuli, including stress or physical trauma. Because the clinical presentation of HAE-C1-INH is similar to other types of angioedema, the condition may be a challenge to diagnose. Accurate identification of HAE-C1-INH is critical in order to avoid asphyxiation by laryngeal edema and to improve the burden of disease. Based on an understanding of the underlying pathophysiology of IHAE-C1-INH, drugs targeted specifically to the disease, such as C1-inhibitor therapy, bradykinin B2-receptor antagonists, and kallikrein-inhibitors, have become available for both treatment and prevention of angioedema attacks. This article reviews the clinical features, differential diagnosis, and current approaches to management of HAE-C1-INH.

Introduction: Patients who have an adverse drug reaction are frequently labelled drug allergic without undergoing proper evaluation and confirmatory testing. These drug allergy labels may be inaccurate, leading to unnecessary lifelong avoidance. The aim of this study was to review the patients that underwent drug provocation tests (DPTs) in our centre and examine the usefulness of DPTs in confirming or rejecting a diagnosis of drug hypersensitivity. Materials and

Methods:

The study design was a retrospective chart review of all adult patients who underwent drug provocation in the allergy unit at the National University Hospital, Singapore, for single or multiple suspected drug allergies from the period January 2009 to June 2011.

Results:

Eighty-seven patients underwent 123 DPTs (median age 41; interquartile range 28 to 50). Twenty-one patients underwent multiple DPTs. The most common culprit drugs reported were antibiotics (43.9%) of which beta-lactams were implicated in 75.9% of the cases. This was followed by non-steroidal anti-inflammatory drugs (NSAIDS) in 15.4%, paracetamol in 7.3% and both NSAIDs and paracetamol in 3.3%. Rash was the most commonly reported symptom (41.5%), followed by angioedema (32.5%), anaphylaxis (9.8%), and other symptoms including respiratory (2.4%), gastrointestinal (0.8%) and others (13.0%). The majority of DPTs were performed to antibiotics (43.9%), NSAIDs (19.5%) and paracetamol (6.5%). DPTs were negative in 93.5% of subjects and positive in 6.5%. Of the 8 positive DPTs, none had a serious reaction, with 5 patients requiring rescue therapy, which comprised solely of oral antihistamines.

Conclusion:

Suspected drug hypersensitivity is common but true drug allergy is rare. DPTs remain the gold standard and should be included as part of an investigative protocol. DPTs are a safe and valuable diagnostic tool in the hands of the experienced clinician.

Angiotensin-converting enzyme inhibitor (ACE-I)-induced angioedema can be life-threatening without emergent intervention. The putative mediator is believed to be bradykinin, similar to hereditary angioedema, so these patients respond poorly to corticosteroids and antihistamines. This study was designed to determine characteristics and clinical outcomes of patients presenting to an emergency department (ED) with ACE-I angioedema. This was a retrospective chart review of 100 patients presenting to the ED from 2007 to 2008 with an ICD-9 code of 995.1 (angioedema) or 995.2 (drug-induced angioedema). Two hundred fifty-two patients with these ICD-9 codes were identified and placed in random order, and the first 100 meeting inclusion criteria were included. Statistical analysis was primarily descriptive. All 100 patients had an ICD-9 code of 995.1 (angioedema). Patients presented in every month, with spring months (April-June) having the most presentations (32%). The median age was 59 years, 75% were African American, and 66% were admitted to the hospital. Two patients (2%) required endotracheal intubation. Lisinopril was the most commonly prescribed ACE-I (84%). The most common symptom was moderate lip and tongue swelling (89%) followed by mild difficulty breathing (12%). Tongue swelling was significantly associated with admission. Time from symptom onset to ED presentation was not associated with need for admission. Concomitant medications did not differ between admitted and discharged patients. ACE-I angioedema is associated with significant morbidity and health care use because many patients require hospitalization, suggesting an unmet need for novel therapies targeted to treat this condition.

In patients with hereditary angioedema (HAE), premonitory symptoms ("prodromes") may appear hours to days before attack onset. It remains to be determined if prodromes could be useful indicators for early treatment initiation. Most published reports of prodromes have been limited to case reports or small case series. The common objective of several recent survey-based studies was to collect information relevant to prodromal patterns in patients with HAE. Three separate surveys solicited prodromal data from HAE patients. Although differences in survey methodologies permit only descriptive analysis of data, responses to the surveys provide the largest compilation of observational data on this topic to date. Prodromes were reported by 82.5-95.7% of patients surveyed. In one survey, about two-thirds of subjects reported experiencing prodromes before all or most acute HAE attacks, and only 6% of subjects noted the appearance of prodromes in <10% of all attacks. The most common types of prodromal symptoms were related to skin/soft tissue and gastrointestinal tract. Most prodromes were experienced hours to days before the onset of angioedema. A large percentage of surveyed subjects indicated being able to predict an impending HAE attack all or most of the time; <10% reported being rarely or never able to predict an attack. Although insufficient to establish the clinical role of prodromal symptoms, results of these surveys provide additional data on the scope of prodromes and could stimulate further research into the potential efficacy and cost-effectiveness of HAE attack prediction and prodrome-triggered interventions.

BACKGROUND:

We have previously reported that prekallikrein expresses an active site when it is bound to high-molecular-weight kininogen (HK) and can digest HK to produce bradykinin. The reaction is stoichiometric and inhibited by C1 inhibitor (C1-INH) or corn trypsin inhibitor. Addition of heat shock protein 90 leads to conversion of prekallikrein to kallikrein in a zinc-dependent reaction.

OBJECTIVE:

Our goal was to determine whether these reactions are demonstrable in plasma and distinguish them from activation through factor XII.

METHODS:

Plasma was incubated in polystyrene plates and assayed for kallikrein formation. C1-INH was removed from factor XII-deficient plasma by means of immunoadsorption.

RESULTS:

We demonstrate that prekallikrein-HK will activate to kallikrein in phosphate-containing buffers and that the rate is further accelerated on addition of heat shock protein 90. Prolonged incubation of plasma deficient in both factor XII and C1-INH led to conversion of prekallikrein to kallikrein and cleavage of HK, as was seen in plasma from patients with hereditary angioedema but not plasma from healthy subjects.

CONCLUSIONS:

These results indicate that C1-INH stabilizes the prekallikrein-HK complex to prevent HK cleavage either by prekallikrein or by prekallikrein-HK autoactivation to generate kallikrein. In patients with hereditary angioedema, kallikrein and bradykinin formation can occur without invoking factor XII activation, although the kallikrein formed can rapidly activate factor XII if it is surface bound.

Red ants sting anaphylaxis was rarely reported from India. But angioedema due to ingestion of fried flying red fire ants in children is almost never reported from India and also very rarely reported from outside India. We report a case of recurrent non allergic angioedema following ingestion of fried flying red ants.