Management of Pregnancy and Delivery in Patients With Hereditary Angioedema Due to C1 Inhibitor Deficiency.

BACKGROUND AND OBJECTIVE: There is little information on pregnancy and delivery in patients with hereditary angioedema due to C1 inhibitor deficiency (C1INH-HAE). The aim of this study was to describe the effect of pregnancy and deliveries on symptoms of C1INH-HAE and review the need for and safety of treatments available during the study period. METHODS: Retrospective review using a purpose-designed questionnaire of 61 C1INH-HAE patients from 5 hospitals specialized in the management of HAE in Spain. The outcomes measured were number of pregnancies, changes in symptoms during pregnancy and delivery, mode of delivery, type of anesthesia during delivery, treatments received, and tolerance of treatments. RESULTS: We reviewed 125 full-term pregnancies (89 without a prior diagnosis of C1INH-HAE), 14 miscarriages, and 4 induced abortions. Patients reported an increased frequency of C1INH-HAE symptoms in 59.2% of pregnancies (74/125) and the presence of symptoms throughout pregnancy in 40% (50/125). Prophylactic C1INH-HAE therapy was used during 9 (7.2%) of the 125 pregnancies. Nine patients--in 11 pregnancies (8.8 %)--received treatment for acute attacks. Most deliveries (n=110, 88%) were vaginal. A cesarean section was necessary in 15 cases (12%). Short-term prophylaxis with pdhC1INH was administered before 14 deliveries (11.2 %); 111 deliveries (88.8 %) were performed without premedication and were well tolerated. Anesthesia was used in 51 deliveries (40.8%). CONCLUSIONS: Pregnancy has a variable influence on the clinical expression of C1INH-HAE. Attacks tend to occur more frequently but not to increase in severity. Vaginal delivery was mostly well tolerated. pdhC1INH prophylaxis should be administered prior to cesarean delivery and is also recommended before vaginal delivery if there are additional risk factors. pdhC1INH should always be available in the delivery room.

Clinical Pattern and Acute and Long-term Management of Hereditary Angioedema Due to C1-Esterase Inhibitor Deficiency.

BACKGROUND: Hereditary angioedema due to C1-esterase inhibitor deficiency (HAE-C1-INH) is a life-threatening disease. OBJECTIVES: To describe the clinical characteristics and management of patients with HAE-C1-INH during routine clinical practice. METHODS: An observational, retrospective study was performed in patients with HAE-C1-INH. Demographic, clinical, and analytical data were collected from 2 periods: period A (October 2009-September 2010) and period B (October 2007-September 2009). RESULTS: We studied 112 patients with HAE-C1-INH (57.1% females). Age at onset of symptoms was 14.4 years (lower in patients who had experienced attacks in the previous year). In period B (n=87), 62.1% of patients presented at least 1 edema attack (median, 3.5 attacks/patient/2 years), and 19.1% of attacks were treated. In period A (n=77), 58.4% of patients were on maintenance therapy. Stanozolol was the most widely used drug (48.9%), with a mean weekly dose of 6.7 mg. At least 1 attack was recorded in 72.7% of patients (median, 3.0 attacks/patient/year), and 31.5% of the attacks were treated. Treatment of acute attacks increased by 12.4%. CONCLUSION: Age at onset of symptoms is associated with clinical expression of disease. The higher age at onset of symptoms, the fewer number of attacks per patient and year, and the lower dose of attenuated androgens necessary to control the disease than in other series lead us to hypothesize that HAE-C1-INH could have a less severe expression in Spain. Acute attacks seem to be treated increasingly often.

Piperacillin-induced DRESS: distinguishing features observed in a clinical and allergy study of 8 patients.

BACKGROUND: DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome is characterized by fever, rash, eosinophilia, and multiorgan failure. Previous reports have described differences in clinical and laboratory findings of DRESS syndrome depending on the inducing drug. Piperacillin has been reported as the drug responsible for this syndrome in 3 patients. OBJECTIVE: To analyze and describe the clinical, laboratory, and allergy study findings of piperacillin-induced DRESS. PATIENTS AND METHODS: Retrospective case series of patients diagnosed with DRESS associated with piperacillin-tazobactam (Pip/Taz) according to the Kardaun diagnostic score criteria. Assessment of causality was established using the Spanish Pharmacovigilance System and the lymphocyte transformation test (LTT). The allergy study included skin and epicutaneous tests. RESULTS: Eight patients were diagnosed with DRESS due to Pip/Taz (3 probable and 5 definite cases). Skin rash was observed in all cases and facial edema in 50%; the mean latency period was 18 days. Fever was present in 7 patients. Liver and kidney injuries were detected in 6 and 3 patients, respectively. All patients had eosinophilia and a full recovery. The LTT to Pip/Taz was strongly positive in all patients, with a stimulation index of over 6. Three of 3 patients had a positive intradermal test to Pip/Taz, and 1 of 4 had a positive patch test. All patients had a negative LTT to carbapenems. CONCLUSIONS: We have reported on the first case series of piperacillin-induced DRESS. A latency period of 18 days, skin rash, eosinophilia, fever, liver injury, and good prognosis were the most common features. The allergy study, and the LTT in particular, was highly useful for identifying Pip/Taz as the culprit drug and piperacillin as the responsible active ingredient.

Management of dental-oral procedures in patients with hereditary angioedema due to C1 inhibitor deficiency.

BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) has considerable implications for dental health care providers, since dental procedures may trigger severe and even life-threatening episodes. The aim of the present study was to analyze the efficacy and safety of premedication with attenuated androgens (AAs), plasma-derived human C1 esterase inhibitor concentrate (pdhC1INH), or both to prevent the development of upper airway angioedema after dental-oral procedures in patients with HAE-C1-INH. MATERIAL AND METHODS: All dental-oral procedures performed on patients with HAE-C1-INH who were followed up at La Paz University Hospital, Madrid, Spain were reviewed. Demographic data, maintenance treatment, preprocedure prophylaxis, disease severity, and occurrence of upper airway angioedema were recorded. RESULTS: Twenty-four patients (14 male/10 female; mean age, 42.6 years) underwent 66 procedures. Most procedures were performed on patients with severe HAE-C1-INH (20 procedures) or moderate HAE-C1-INH (26 procedures). Only 9 procedures were performed without short-term prophylaxis. Mild upper airway angioedema developed after 3 procedures performed without short-term prophylaxis in patients with minimal or asymptomatic HAE-C1-INH. A statistically significant association was found between development of mild postprocedure upper airway angioedema and lack of maintenance treatment with AA, lack of increased dose of preprocedure AA, and failure to administer preprocedure pdhC1INH (P = .002, Fisher exact test). CONCLUSIONS: Increased doses of prophylactic AA, administration of pdhC1INH, or both were good options for ambulatory management of dental-oral procedures in patients with HAE-C1-INH. Prophylaxis with pdC1INH or increased doses of AA is advisable before dental-oral procedures, even in patients with low disease severity.

Consensus statement on the diagnosis, management, and treatment of angioedema mediated by bradykinin. Part II. Treatment, follow-up, and special situations.

BACKGROUND: There are no previous Spanish guidelines or consensus statements on bradykinin-induced angioedema. AIM: To draft a consensus statement on the management and treatment of angioedema mediated by bradykinin in light of currently available scientific evidence and the experience of experts. This statement will serve as a guideline to health professionals. METHODS: The consensus was led by the Spanish Study Group on Bradykinin-Induced Angioedema, a working group of the Spanish Society of Allergology and Clinical Immunology. A review was conducted of scientific papers on different types of bradykinin-induced angioedema (hereditary and acquired angioedema due to C1 inhibitor deficiency, hereditary angioedema related to estrogens, angioedema induced by angiotensin-converting enzyme inhibitors). Several discussion meetings were held to reach the consensus. RESULTS: Treatment approaches are discussed, and the consensus reached is described. Specific situations are addressed, namely, pregnancy, contraception, travelling, blood donation, and organ transplantation. CONCLUSIONS: A review of and consensus on treatment of bradykinin-induced angioedema is presented.

Consensus statement on the diagnosis, management, and treatment of angioedema mediated by bradykinin. Part I. Classification, epidemiology, pathophysiology, genetics, clinical symptoms, and diagnosis.

BACKGROUND: There are no Spanish guidelines or consensus statement on bradykinin-induced angioedema. AIM: To review the pathophysiology, genetics, and clinical symptoms of the different types of bradykinin-induced angioedema and to draft a consensus statement in light of currently available scientific evidence and the experience of experts. This statement will serve as a guideline to health professionals. METHODS: The consensus was led by the Spanish Study Group on Bradykinin-Induced Angioedema (SGBA), a working group of the Spanish Society of Allergology and Clinical Immunology. A review was conducted of scientific papers on different types of bradykinin-induced angioedema (hereditary and acquired angioedema due to C1 inhibitor deficiency, hereditary angioedema related to estrogens, angioedema induced by angiotensin-converting enzyme inhibitors). Several discussion meetings of the SGBA were held in Madrid to reach the consensus. RESULTS: The pathophysiology, genetics, and clinical symptoms of the different types of angioedema are reviewed. Diagnostic approaches are discussed and the consensus reached is described. CONCLUSIONS: A review of bradykinin-induced angioedema and a consensus on diagnosis are presented.

Multiple acute parasitization by Anisakis simplex.

Hypersensitivity to Anisakis is an increasingly prominent medical problem throughout the world, due to a better understanding of diseases induced by parasites and to modern culinary habits of eating raw or undercooked fish. We describe the case of a patient who presented epigastric pain, wheals, erythema, and pruritus 3 hours after the ingestion of fish. More than 200 larvae were obtained by endoscopy. However, the patient only developed an immune response with specific immunoglobulin E and eosinophilia peaking at day 18 and decreasing during the 17-month follow-up. Only eosinophilia reached normal limits.

Use of the lymphocyte transformation test in the diagnosis of DRESS syndrome induced by ceftriaxone and piperacillin-tazobactam: two case reports.

Drug-related rash with eosinophilia and systemic symptoms (DRESS) syndrome, or drug-induced hypersensitivity syndrome (DIHS), is a life-threatening multiorgan systemic reaction characterized by rash, fever, lymphadenopathy, hepatitis, and leukocytosis with eosinophilia. Aromatic anticonvulsant drugs and allopurinol have been reported to be the most frequent eliciting agents. Our search of the literature revealed only 2 cases induced by piperacillin and 1 case by ceftriaxone.We present 2 cases of DRESS syndrome induced by the beta-lactam drugs ceftriaxone and piperacillin-tazobactam. An allergological workup including skin prick test, intradermal tests, patch tests, and lymphocyte transformation test (LTT) was performed. LTT was shown to be a useful technique in both cases to help to identify the drugs involved.

Diagnosis of aspirin-induced asthma combining the bronchial and the oral challenge tests: a pilot study.

BACKGROUND: We investigated the usefulness of the bronchial challenge (BC) with lysine-acetylsalicylate (L-ASA) in the diagnosis of aspirin-exacerbated respiratory disease (AERD) using a protocol that combined both the oral challenge (OC) and the BC tests. METHODS: Adult asthmatic patients with suspected AERD who underwent BC with L-ASA were included in the study. If the BC result with L-ASA was negative, an OC was carried out to establish the diagnosis. AERD was ruled out if both the BC and the OC results were negative (nonresponders). Both responders and nonresponders were compared for age, gender, a personal or family history of atopy, underlying disease, current asthma treatment, and presence of nasal polyps. Six patients with asthma but no suggestive history of AERD were included as controls. RESULTS: Twenty-two patients completed the study. Ten patients tested positive to the BC and/or OC (responders), whereas 12 did not (nonresponders). Seven out of the 10 responders had a positive BC result and 3 a positive OC result. After BC, 4 patients had an early asthmatic response, 1 had a dual response, and 2 had isolated late responses. No significant differences were observed in the aforementioned variables between responders and nonresponders. The results of both challenges were negative in the 6 controls. CONCLUSIONS: The BC had a high positive predictive value, was safe, and when negative, the subsequent OC did not result in any severe adverse reactions. The BC elicited an isolated late asthmatic response that has not been previously described in the literature.

Associations among pollen sensitizations from different botanical species in patients living in the northern area of Madrid.

OBJECTIVE: To determinate the existence of associations among sensitizations to antigens produced by pollen grains of different botanical species as assessed by skin prick tests in patients with respiratory disorders. METHODS: Six hundred twenty nine consecutive patients living in the northern area of Madrid who underwent clinical evaluation because of rhinoconjunctivitis, and/or asthma were studied. All patients were tested with a skin prick test using a battery of inhalants including pollens, dust mites, molds and danders. The exploratory multivariate technique of Multiple Correspondence Analysis was used to compare the homogeneity of sensitizations between groups. Of the 629 patients, 459 (73.0%) had positive skin prick tests to pollen and were selected as the study group. RESULTS: The most prevalent pollen sensitization was to Gramineae pollen (83.7%) followed by Oleaceae sensitisation (75.8%). Multiple Correspondence Analysis revealed the existence of an association among pollen sensitizations, showing that they clustered two groups: sensitizations to Gramineae, Oleaceae, Cupressaceae, Chenopodiaceae, Plantaginaceae (group I), and sensitizations to Betulaceae, Platanaceae, Compositae (group II). Sensitization to Parietaria was not included in any of the sensitization groups and showed an independent behaviour. CONCLUSION: Pollen sensitizations in our area cluster into two association groups which have not previously been reported.

Booster responses in the study of allergic reactions to beta-lactam antibiotics.

The observation of negative skin and challenge tests to beta-lactams in some patients with prior histories of reactions to these antibiotics led us to develop a protocol ("booster study") which systematically included the performance of skin and challenge tests to beta-lactams ten to thirty days after the study to confirm the negative results. From a total of 430 patients who came to our outpatient clinic because of a reaction to a beta-lactam or unknown antibiotic, 249 completed the study. Out of the patients who completed the second phase, or "booster study," the results were positive in the first phase, or conventional study in 42 patients, and negative in 207. The booster study was negative in 197 patients (95 percent) and positive in ten patients (5 percent). Skin tests were positive in 5 of them (penicilloyl-polylysine: 5; benzylpenicillin: 3; amoxicillin: 2; minor determinant mixture: 1), and 5 patients developed an allergic reaction after rechallenge (benzylpenicillin: 4; amoxicillin: 1). One patient with both negative skin tests and amoxicillin oral challenge in the booster study developed an immediate generalized urticaria with the oral intake of amoxicillin one month later at home; skin tests became positive at that moment. The negative results in the first phase of the study and the development of positive results in the second phase could be due to the existence of an immunological amnestic reaction or to sensitization after reexposure to beta-lactams in the diagnostic procedures.

Erythema multiforme from betalactams with positive cutaneous tests.

We report the case of a woman who after taking ampicillin and amoxicillin developed two severe cutaneous reactions with generalized erythema and maculopapular rash, which later turned into blisters with subsequent desquamation. She was clinically diagnosed with erythema multiforme syndrome after positive delayed cutaneous tests with benzylpenicillin, amoxicillin and ampicillin allowed for a more specific diagnosis. There are very few references to patients with drug reactions to betalactams who have positive skin prick or intradermal test but show delayed hypersensitivity, as was the case in our patient.

Two cases of specific adverse reactions to systemic corticosteroids.

Although true allergic reactions due to systemic corticosteroid therapy are not frequent, they should be kept in mind since allergic reactions to this kind of therapy are possible. We report two cases of specific adverse reactions resulting from systemic corticosteroid therapy which were diagnosed by provocation tests. The corticosteroids involved in each case were paramethasone and betamethasone, and methyl-prednisolone in both of them. Additives and other corticosteroids were studied by skin tests and challenges, with negative results. The structures of paramethasone and betamethasone are similar, with a 16 carbon methyl group in both, and with a fluoride in the alpha position of the 6 carbon in paramethasone, and a fluoride in the beta position of the 9 carbon and a 6 carbon methyl group in betamethasone. Methyl-prednisolone differs from that of other corticosteroids in its 6 carbon methyl group. We report two cases of specific adverse reactions caused by corticosteroids. Positive challenge tests showed a possible immunologic hypersensitivity mechanism in both cases. The patients' reactions demonstrated cross-reactivity between methyl-prednisolone and the corticosteroids having a 16 carbon methyl group, and fluoride or methyl radicals on the 6 carbon.

Delayed hypersensitivity to enoxaparin.

A 65-year-old woman experienced immediate itchy erythematous patches at the subcutaneous injection sites of sodium enoxaparin. An erythematous and infiltrated 40 x 20 mm lesion on the abdominal wall could be observed at the site of enoxaparin injection when she was referred to our clinic 48 h after injection. Lesions subsided spontaneously within 1 week. She had been on this treatment 1 and 3 years before without any adverse reaction. To clarify the nature of the reaction, epicutaneous tests with sodium enoxaparin, calcium nadroparin and calcium heparin were performed, all with negative results. Skin prick test with sodium enoxaparin was also negative. Biopsy of the cutaneous lesion showed spongiotic dermatitis, strongly suggesting a delayed hypersensitivity mechanism. We report here on a new case of delayed hypersensitivity to enoxaparin. Being female, overweight and having prolonged application of the drug were suggested risk factors present in our patient. Biopsy was essential for diagnosis. Although type IV hypersensitivity reactions to enoxaparin are rare, we should start to suspect this condition in order not to underdiagnose it.

Importance of albumin in cross-reactivity among cat, dog and horse allergens.

Different allergenic proteins have been involved in cross-reactivity among animals. Albumins seem to be cross-sensitizing allergenic components. The aim of this study was to assess the importance of albumin as a cross-reactive allergen in patients sensitized to cat, dog and horse. One hundred and seventeen patients sensitized to cat were tested for IgE reactivity using skin prick tests and RAST assays with cat, dog and horse hair/dander extracts and their purified albumin extracts. RAST-inhibition studies were carried out to assess cross-reactivity among cat, dog and horse and among their purified albumins. It was found that 22% of patients exhibited specific IgE to cat albumin; 41% of patients sensitized to cat were also sensitized to dog and horse. Out of these patients, 21% had IgE to three albumins and 17% to two. Reciprocal inhibitions were observed among cat, dog and horse albumins and also among cat, dog and horse hair/dander extracts, using in the latter experiment sera from patients not sensitized to albumins. IgE binding to horse extract was inhibited 30% by its homologous albumin and IgE binding to cat and dog extracts in almost 15% by their respective albumins. It was concluded that albumins from these three animals share some epitopes that account for the cross-reactivity observed in around one-third of patients sensitized to cat, dog and horse. Nevertheless, more than 50% of specific IgE that cross-reacts among these three animals is directed to allergens other than albumin.

A comparison of new nonsedating and classical antihistamines in the treatment of primary acquired cold urticaria (ACU).

The efficacy of the new nonsedating antihistamines loratadine and cetirizine was compared in a randomized, single-blind, crossover, controlled study with that of the classical antihistamines cyproheptadine and ketotifen in seven patients with primary acquired cold urticaria (ACU). The patients received each of the four drugs for 14 consecutive days with a 7-day interval between drugs. We evaluated clinical symptomatology, adverse effects, minimum time of cold contact stimulation required to induce an immediate coalescent wheal (CSTT), and inhibition of histamine-induced wheal response. Both loratadine and cetirizine showed suppression of symptoms with infrequent adverse effects. Important side-effects were observed in patients receiving cyproheptadine. Improvement in CSTT was statistically significant for all drugs compared with baseline values, without differences among them. The histamine-induced skin test was significantly inhibited by all antihistamines. Wheal reductions were 34.6% for loratadine and 50.9% for cetirizine. This study suggests that both loratadine and cetirizine may be effective in the treatment of primary ACU.