Modulating toll-like receptor 7 and 9 responses as therapy for allergy and autoimmunity.

Type I allergic diseases, such as allergic rhinitis and asthma, depend on allergen-induced T-helper type 2 (Th2) cells and IgE-secreting plasma cells. Fortunately, this harmful immune response can be modified by engaging Toll-like receptor (TLR)7 and TLR9, offering hopes to allergy sufferers. While clinical trials employing synthetic ligands for TLR7 or TLR9 are under way, one can wonder whether TLR7 or TLR9 engagements may trigger inadvertent autoreactivity and/or Th1-/Th17-mediated tissue pathology. To neutralize such danger, we have pioneered the development of potent TLR9 pathway antagonists, inhibitory oligonucleotides (INH-ODNs), which work in a sequence-specific manner. Interestingly, INH-ODNs also have TLR7-inhibitory properties; however, these effects appear to be sequence independent and phosphorothioate backbone dependent. In B cells, co-engagement of the B-cell receptor for antigen and TLR7 or TLR9 may influence how INH-ODNs impose their regulatory effects. INH-ODNs block TLR9 activation by competitively antagonizing ligand binding to proteolytically cleaved C-terminal TLR9 fragment. One may envision future use of INH-ODNs in systemic autoimmune diseases, DNA-mediated sepsis, or other situations in which chronic inflammation results from abnormal TLR7- and/or TLR9-mediated immune activation.

Female sex as a risk factor for penicillin allergy.

BACKGROUND: Identification of risk factors is an integral part of a physician's evaluation of a patient. OBJECTIVE: To determine whether female sex is an independent risk factor for penicillin allergy. METHODS: Rates of positive penicillin skin test (PST) results, according to sex, were determined in patients with a history of penicillin allergy undergoing penicillin allergy evaluation with major and minor determinants of penicillin between June 1, 2002, and June 30, 2004. Univariate and multivariate logistic regression analyses were used to calculate unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for sex differences in the rates of positive PST results. RESULTS: Of the 1,921 patients, 1,759 underwent PST and 157 did not; 5 medical records were not available for review. The mean patient age was 60 years. Sixty-four patients (4%) had a positive PST reaction; of these, 53 (83%) were females and 11 (17%) were males (OR, 3.6; 95% CI, 1.9-7.2; P < .001). In a multivariate logistic regression analysis adjusted for age, history of multiple drug allergies, and elapsed time from the initial penicillin adverse drug reaction to PST, female sex again had a significant risk of a positive PST reaction (OR, 3.2; 95% CI, 1.6-6.7; P = .001). CONCLUSION: A greater risk of penicillin allergy exists in association with female sex in patients with a history of penicillin allergy.

Acute pancreatitis due to hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is an infrequent disorder characterized by abnormalities in the levels and/or function of complement C1 esterase inhibitor. Clinical manifestations of HAE are due to recurrent episodic swelling of the subcutaneous or submucosal tissue. When swelling involves the gastrointestinal mucosa, patients may present with nausea, vomiting, diarrhea, and severe abdominal pain. However, HAE is almost never suspected as a potential cause of acute pancreatitis. OBJECTIVE: To describe a patient with HAE-associated pancreatitis requiring intensive medical care that responded favorably to conservative and supportive measures. METHODS: Various tests were performed, including abdominal imaging, measurement of pancreatic enzymes levels, liver function tests, measurement of complement levels, and endoscopic retrograde cholangiopancreatography. RESULTS: The results of these tests confirmed the diagnosis of HAE-associated acute pancreatitis. No other obvious origin, such as gallstones or alcohol use, was identified. CONCLUSION: This case illustrates the need for a high clinical suspicion of acute pancreatitis when caring for patients with HAE who present with abdominal symptoms. There continues to be an urgent need for better and additional therapeutic options for HAE patients, including those to prevent and abort ongoing attacks.

Safety and effectiveness of a preoperative allergy clinic in decreasing vancomycin use in patients with a history of penicillin allergy.

BACKGROUND: We developed a clinical pathway to optimize the use of antimicrobials by decreasing vancomycin use in preoperative patients with a history of penicillin allergy. OBJECTIVE: To decrease the use of vancomycin in surgical patients with a self-reported penicillin allergy. METHODS: In June 2002, same-day allergy consultation and penicillin skin testing were made available for preoperative patients with self-reported penicillin allergy at the preoperative evaluation (POE) clinic. We reviewed the penicillin allergy skin test results, recommendations, and beta-lactam antibiotic administration outcomes from July 1, 2002, to September 16, 2003. RESULTS: A total of 1,204 of 11,819 patients were evaluated for beta-lactam allergy at the POE clinic. Of these, 1,120 were approved by the institutional review board for inclusion in the study and 9 were excluded from the study. Of the remaining 1,111 patients, 1,030 (93%) underwent skin testing for penicillin allergy. Forty-three (4%) had a positive skin test result to penicillin. A total of 947 (85%) of the 1,111 patients with a history of beta-lactam allergy were advised to use a beta-lactam antibiotic, and 164 (15%) were advised to avoid beta-lactams. A total of 955 patients (86%) actually received preoperative antibiotics. Of these 955 patients, 716 (75%) received cefazolin, and only 149 (16%) received vancomycin compared with 30% historical controls (P < .01). Among the patients with a negative penicillin skin test result who received a cephalosporin, 5 (0.7%) of 675 experienced an adverse drug reaction to a cephalosporin. CONCLUSIONS: Establishment of a clinical pathway in a preoperative clinic that includes allergy consultation and penicillin skin testing reduced vancomycin use to only 16% in surgical patients with a history of beta-lactam allergy.

Case report: intraoperative anaphylactoid reaction and hydroxyethyl starch in balanced electrolyte solution (Hextend).

PURPOSE: To report a first case of probable anaphylactoid reaction to 6% hydroxyethyl starch reconstituted in balanced electrolyte and glucose solution (Hextend). CLINICAL FEATURES: A 22-yr-old man was admitted for a partial nephrectomy. Near the end of the four-hour operation, an infusion of Hextend was initiated. Shortly thereafter, mechanical ventilation became difficult, peak inspiratory pressure increased to 55 cm H2O with audible wheezing over the patient's lungs. Blood pressure suddenly decreased to 68/46 mmHg. Multiple doses of phenylephrine, ephedrine and epinephrine were required to restore the patient's blood pressure. Postoperatively, a diffuse urticarial rash was apparent on his upper torso. The patient recovered uneventfully. His postoperative serum tryptase was 26.3 ng x mL(-1) (reference range, < 11.5 ng x mL(-1)) and the urine N-methyl-histamine was 2448 microg x g(-1) creatinine (reference range, 30-200 microg x g(-1) creatinine). Two months after the event, skin testing was conducted to test for possible allergy to latex, lidocaine, propofol, cisatracurium, succinylcholine, vecuronium, midazolam, fentanyl, ondansetron, neostigmine, and cephazolin, and all were negative. Hextend was also tested, starting with a 1:100,000 dilution and the results were negative. CONCLUSIONS: The temporal relationship of severe hypotension, bronchospasm and skin rash within ten minutes from administration of Hextend in this patient suggests an immediate hypersensitivity reaction to hetastarch. The elevated levels of serum tryptase and urinary N-methyl-histamine suggest that this hypersensitivity was mediated from mast cell degranulation. Negative skin testing suggests that the reaction was anaphylactoid.