Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose.

BACKGROUND: Cetuximab, a chimeric mouse-human IgG1 monoclonal antibody against the epidermal growth factor receptor, is approved for use in colorectal cancer and squamous-cell carcinoma of the head and neck. A high prevalence of hypersensitivity reactions to cetuximab has been reported in some areas of the United States. METHODS: We analyzed serum samples from four groups of subjects for IgE antibodies against cetuximab: pretreatment samples from 76 case subjects who had been treated with cetuximab at multiple centers, predominantly in Tennessee, Arkansas, and North Carolina; samples from 72 control subjects in Tennessee; samples from 49 control subjects with cancer in northern California; and samples from 341 female control subjects in Boston. RESULTS: Among 76 cetuximab-treated subjects, 25 had a hypersensitivity reaction to the drug. IgE antibodies against cetuximab were found in pretreatment samples from 17 of these subjects; only 1 of 51 subjects who did not have a hypersensitivity reaction had such antibodies (P<0.001). IgE antibodies against cetuximab were found in 15 of 72 samples (20.8%) from control subjects in Tennessee, in 3 of 49 samples (6.1%) from northern California, and in 2 of 341 samples (0.6%) from Boston. The IgE antibodies were shown to be specific for an oligosaccharide, galactose-alpha-1,3-galactose, which is present on the Fab portion of the cetuximab heavy chain. CONCLUSIONS: In most subjects who had a hypersensitivity reaction to cetuximab, IgE antibodies against cetuximab were present in serum before therapy. The antibodies were specific for galactose-alpha-1,3-galactose.

Sinus computed tomography scan and markers of inflammation in vocal cord dysfunction and asthma.

BACKGROUND: The inappropriate closure of the vocal cords is characteristic of vocal cord dysfunction (VCD). These patients present with wheezing and frequently receive a misdiagnosis of asthma. OBJECTIVE: To demonstrate the ability of computed tomography (CT) scored for the presence and extent of sinus disease and markers of inflammation to distinguish patients with VCD from patients with asthma. METHODS: Comparisons of 13 patients with VCD were made to 77 patients presenting to the emergency room with acute asthma, 31 non-acute asthmatic patients, and 65 nonasthmatic controls. Evaluation consisted of exhaled nitric oxide gas (eNO), circulating eosinophils, and total serum immunoglobulin (Ig)E, as well as the sinus CT scan. RESULTS: Extensive sinus CT changes were present in 23 of 74 acute asthmatic patients, 5 of 29 non-acute asthmatic patients, and 2 of 59 nonasthmatic controls. In addition, absolute eosinophil counts, eNO, and total IgE were significantly elevated among the asthmatic patients. Sinus symptoms reported by questionnaire did not predict sinus CT findings. Among the patients with VCD, none had extensive sinus disease. They also had normal eNO, low IgE, and normal eosinophil count. Five of the patients presenting to the emergency room who were identified as acute asthmatic were identified with VCD by laryngoscopy and were all characterized by the absence of significant inflammation on their sinus CT scan, low IgE, and normal eosinophil count. CONCLUSIONS: Among patients presenting with intermittent or reversible airway obstruction, patients with VCD can be distinguished from asthma by minimum or absence of inflammation in their sinuses as shown by CT scan. Clinical symptom scores are not predictive of presence or extent of sinus disease in most cases.

Experimental rhinovirus challenges in adults with mild asthma: response to infection in relation to IgE.

BACKGROUND: Although most children and young adults with asthma are atopic, exacerbations of asthma are frequently associated with viral respiratory tract infections, especially those caused by rhinovirus (HRV). OBJECTIVE: Young atopic adults with mild asthma were evaluated before and during an experimental HRV infection to test the hypothesis that airway inflammation before virus inoculation may be a risk factor for an adverse response to HRV. METHODS: Experimental HRV infections were evaluated in 16 allergic volunteers with mild asthma and 9 nonatopic control patients (age, 18 to 30 years). Before virus inoculation, each participant was screened with tests for lung function, prick skin tests for sensitization to common aeroallergens, measurements of total serum IgE, and serum neutralizing antibody to rhinovirus-16 (the serotype used for inoculation). The response to infection was monitored for 21 days by using symptom diary cards, tests for lung function, and markers of airway inflammation in nasal washes, blood, and expired air. RESULTS: During the infection, asthmatic patients had cumulative upper and lower respiratory tract symptom scores that were significantly greater over the course of 21 days than scores from the control patients. At baseline, the asthmatic patients also had increased sensitivity to methacholine and significantly lower values for FEV(1) (percent predicted) than the control patients (geometric mean and intraquartile values: 87% [79% to 91%] for the asthmatic patients and 101% [90% to 104%] for the control patients, P <.03). Among the patients with mild asthma, 6 had levels of total serum IgE that were substantially elevated (range, 371 to 820 IU/mL) compared with 10 who had lower levels (range, 29 to 124 IU/mL). Those with high levels of IgE had significantly greater lower respiratory tract symptom scores during the initial 4 days of the infection than the low IgE group. They also had higher total blood eosinophil counts at baseline, increased eosinophil cationic protein in their nasal washes (>200 ng/mL), and augmented levels of expired nitric oxide at baseline and during peak cold symptoms. In contrast, levels of soluble intracellular adhesion molecule-1 in nasal wash supernatants from the asthmatic patients with high IgE were diminished, both at baseline and during the infection. CONCLUSIONS: The reduced lung function and increased markers of inflammation observed before virus inoculation in the asthmatic patients who had high levels of total serum IgE may be risk factors for an adverse response to infections with HRV.

Viral infections in relation to age, atopy, and season of admission among children hospitalized for wheezing.

BACKGROUND: Viral respiratory tract infections and atopy are associated with attacks of wheezing during childhood. However, information about the relationship between viral infections and atopy among children whose attacks of wheezing lead to hospitalization is unclear. OBJECTIVE: To evaluate the prevalence of viral respiratory tract pathogens among infants and children hospitalized for wheezing and to analyze the results in relation to the patient's age, atopic characteristics, and season of admission. METHODS: This was a case-control study of children (age 2 months to 18 years) admitted for wheezing to the University of Virginia Medical Center over a period of 12 months. Children without wheezing were enrolled as controls. Nasal secretions were evaluated for viral pathogens by using cultures, PCR tests, and antigen detection. Total IgE and specific IgE antibody to common aeroallergens was measured in serum. RESULTS: Seventy percent of children hospitalized for wheezing before age 3 years (n=79) were admitted between December and March, whereas 46% of children age 3 to 18 years (n=54) were hospitalized between September and November. Among children younger than 3 years, viral pathogens were detected in 84% (66/79) of wheezing children and 55% (42/77) of controls (P <.001). Respiratory syncytial virus was the dominant pathogen during the winter months, but rhinovirus was more common during other months. Total serum IgE levels were generally low, and values from wheezing and control subjects overlapped considerably. Among children 3 years and older, 61% (33/54) of subjects admitted for wheezing tested positive for virus (predominantly rhinovirus), compared with 21% (12/56) of controls (P <.001). The total serum IgE values among wheezing children (geometric mean, 386 IU/mL; 95% CI, 259-573) were substantially elevated compared with those of controls (geometric mean, 38 IU/mL; 95% CI, 26-56; P <.001). A significantly higher percentage of wheezing children compared with controls was sensitized to at least 1 of the inhaled allergens tested: 84% (36/43) compared with 33% (15/45; P <.001). The atopic characteristics of wheezing children who tested positive or negative for virus were similar. CONCLUSIONS: Viral infections were the dominant risk factor for wheezing among children hospitalized before 3 years of age. By comparison, a large majority of the wheezing children age 3 to 18 years had striking atopic characteristics that may be critical as a risk factor for hospitalization and an adverse response to viral infections, especially infections caused by rhinovirus.