Biomedical subjects
Publications and source records attributed to P Fireman.
Sinusitis has been considered to be a possible causal factor for asthma. Reflex has also been postulated between the upper and lower airway. Data for and against the existence of such a reflex are presented, together with the diagnosis and management of sinusitis.
To assess the immunologic differences related to histocompatibility leukocyte antigen (HLA) haplotypes in patients with type 1 diabetes, trivalent killed influenza virus vaccine was given in the fall, when no influenza occurred, to 59 patients with diabetes (mean age 16 years) and 64 siblings without diabetes (mean age 36 years). All subjects had normal hemagglutination inhibition antibody responses at days 14 and 42 after vaccination, with no significant differences noted between patients with diabetes and those without diabetes. However, subjects with HLA haplotypes DR 3, DR 4, or both had lower antibody responses to influenza A/Chile and B/USSR at 14 days after vaccination (p less than 0.02) than DR x/x controls (who lacked 3 or 4). Lymphocyte transformation (LT) responses before and after vaccination were similar for patients with diabetes and those without diabetes. Of significance was that subjects with HLA haplotypes DR 3, DR 4, or both had 41.1% LT responders at 42 days after vaccination, compared with subjects with HLA-DR x/x (lacking 3 or 4) who had 22.6% responders (p less than 0.03), when influenza A/Chile was used as an antigen. Although not significant, influenza antigens A/Philippines and B/USSR each showed similar trends with increased postvaccine LT responses. The HLA associations were independent of sex, age, and the presence of diabetes. These studies suggest that HLA haplotypes DR 3 and DR 4, which were clearly linked to type 1 diabetes mellitus, were also associated with altered immune responsiveness to influenza viral proteins.
Eustachian tube obstruction (ETO) has been reported to develop more frequently in subjects with allergic rhinitis (AR) than in subjects without AR after a single intranasal histamine challenge. The present double-blind crossover study was designed to confirm and extend this observation. In a pilot study, nebulization was demonstrated to be superior to insufflation in provoking ETO. Five subjects with AR and five subjects without AR were repeatedly challenged intranasally with nebulized normal saline or increasing doses of histamine (0.01, 0.1, 0.5, 1.0, 5, and 10 mg per nostril). Subjects with AR were selected on the basis of AR symptoms and IgE antibodies to allergens and were challenged in their nonallergy seasons. ETO was assessed by nine-step tympanometry and nasal airway resistance by anterior rhinomanometry before and after each challenge. Of nine ears in subjects with AR, ETO developed in five ears at 0.1 mg and in four ears at 0.5 mg. In contrast, in 10 ears of subjects without AR, ETO developed in two ears at 5 mg but did not develop in eight ears at doses as large as 10 mg. This test effectively discriminated subjects with AR from subjects without AR, groups that could not be similarly differentiated by nasal or skin responsiveness to histamine challenge. Saline challenges provoked ETO in three of nine ears of subjects with AR and in one of 10 ears of subjects without AR. These data suggest a hyperresponsiveness of the nasopharyngeal and/or tubal mucosa to histamine in subjects with AR that may predispose these patients to otitis media with effusion.
Ten adult subjects with documented ragweed allergic rhinitis underwent progressive intranasal allergen challenge following pretreatment with either an antihistamine/decongestant or placebo in a double-blind crossover fashion. Objective measurements of nasal and Eustachian tube (ET) function were made following each challenge dose using posterior rhinomanometry and sonotubometry. The percent decrease in nasal airway function, expressed as a change in conductance, was significantly less in the drug pretreatment tests when compared with placebo pretreatment. Eustachian tube function was also significantly improved by antihistamine/decongestant pretreatment as 13 of the 20 ET were obstructed at a higher antigen dose following drug pretreatment when compared with placebo. These results demonstrate a role for antihistamine/decongestant preparations in the treatment of allergic rhinitis as well as for potential allergen-induced ET dysfunction.
Studies of the efficacy of antihistamines in treating human upper airway pathology are difficult to design and conduct. In part, this is the result of a lack of objective measures of the nasal response. The purpose of this study was to develop a monkey model for the objective evaluation of antihistamine effectiveness and, using this model, to study the efficacy of cetirizine. Computer-assisted active anterior rhinomanometry was used to assess nasal airway resistance (NAR) before and after a nasal histamine provocation in conscious rhesus monkeys (Macaca mulatta). To establish dose-response relationships for oral antihistamines in monkeys, we measured the suppression of wheal-and-flare reactions by two such agents, oral cetirizine (CET) 0.1 to 1 mg/kg and chlorpheniramine (CHL) 0.07 to 0.2 mg/kg. The decreases in wheal sizes were maximal 60 to 120 minutes after CET 1.0 mg/kg (90%), and after CHL 0.2 mg/kg (70%). The four monkeys were challenged intranasally with increasing histamine doses (0.5, 1, 5, and 10 mg). The NAR was measured 15 minutes after each dose. At least three days later and 90 minutes after oral pretreatment with either CET 1 mg/kg or CHL 0.2 mg/kg, the intranasal challenges were repeated. Postchallenge NAR data are given as the percent increase from the baseline NAR values. The four monkeys studied had coefficients of variation of 13%, 15%, 16%, and 26% respectively for baseline studies. Mean percent increases in NAR +/- standard deviation were 14% +/- 0.4%, 47% +/- 10.0%, 45% +/- 3.0%, and 72% +/- 6.0% after intranasal challenge with 0.5, 1, 5, and 10 mg of histamine, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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Past studies have shown that provocative intranasal pollen challenge in allergic subjects results in signs and symptoms of allergic rhinitis, nasal obstruction, and eustachian tube obstruction. The study presented herein extends these observations to challenges with a perennial antigen, house dust mite. Twenty-three adult volunteers with confirmed sensitivity to Dermatophagoides farinae were challenged by intranasal inhalation of antigen in doses that were incremented from 0.5 to 10.0 mg. Eustachian tube function by the nine-step pressure-swallow test and nasal airway resistance by anterior rhinomanometry were evaluated before and after challenge. Twenty-two of the 40 ears showing normal tubal function before challenge were abnormal after challenge. Sixteen of the 23 subjects developed a nasal obstruction after challenge. The median specific serum IgE antibody titer for those individuals responding to the challenge was significantly greater than that of the individuals exhibiting no response. These results show that intranasal challenge with D farinae can provoke immune-mediated nasal obstruction and eustachian tube dysfunction in sensitized subjects.
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To explain an allergic basis for the development of otitis media with effusion (OME), it was suggested that the middle ear mucosa can act as an allergic "shock organ." To evaluate this possibility, 16 juvenile rhesus monkeys were passively sensitized to pollen by intravenous injection of allergic human serum. All ears were then challenged by insufflation of pollen via the nose and eustachian tube (ET), twice daily, for four to five days. Daily tympanometry and otomicroscopy were performed, and on the last day of challenge, tympanocentesis was done to recover effusions. Five animals were killed and the middle ears were processed for histologic study. The results showed that none of the ears developed a middle ear effusion or OME. It is concluded that middle ear challenge with an appropriate pollen antigen in passively sensitized rhesus monkeys does not initiate an inflammatory reaction in the middle ear or induce OME.
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Eustachian tube (ET) function was evaluated bilaterally by use of the inflation-deflation and forced-response test before and after nasal challenge with various doses of histamine in five adult and 10 infant rhesus monkeys (Macaca mulatta). Of the 20 experiments conducted on the infant and juvenile monkeys, functional ET obstruction resulted in six ears after a dose of 0.5 mg of histamine, in 10 ears after a dose of 1 mg, and in four ears after a dose of 2 mg. In contrast, of the 10 experiments conducted on the adult monkeys, functional ET obstruction developed in two ears after a dose of 1 mg of histamine and in two ears after a dose of 4 mg. Six ears failed to respond at doses of 8 mg of histamine. The ET obstruction was characterized by increases in the values of the passive function parameters and an abolition of the ability to equilibrate applied middle ear pressures by muscular activity. ET obstruction was not observed in any ears after challenge with a saline control. The severity of the induced ET obstruction was lessened within 60 minutes after challenge. These data are similar to those reported for intranasal pollen challenges in sensitized rhesus monkeys and human volunteers and suggest that type I allergic reactions at the site of the nasopharyngeal mucosa disrupts the normal functioning of the ET by a mechanism potentially mediated by histamine release.
Perception of respiratory function may be an important factor in self-management of asthma. Previous research has suggested that asthmatics may not accurately perceive pulmonary functioning. The perception of normal and asthmatic individuals was assessed using a magnitude production procedure in a series of three studies, proceeding from normal individuals during rest, then submaximal exercise, to a comparison of normal and asthmatic adolescents during rest and submaximal exercise. At rest there were no differences between males and females, adults and adolescents, or asthmatics and non-asthmatics. However, there were significant differences in perception between rest and exercise for all groups. These findings suggest that a breakdown in perception does not occur during submaximal exercise in patients with asthma.
A small group of children with various types of immunodeficiency disorders, examined on a battery of neuropsychological and intellectual tests, was found to be impaired on perceptual speed, visuospatial sequencing, and visual attention span capacities when compared to a control group of closest aged siblings and normal children matched for age, education, and IQ. The results suggest that cerebral dysfunction may be associated with immunodeficiency disorders in children, although these findings are tentative since other factors, such as the effects of chronic illness, could not be excluded in this small cohort of patients.
To test if allergic rhinitis is associated with abnormal eustachian tube function (ET), juvenile rhesus monkeys were passively sensitized with serum samples from patients allergic to timothy grass or ragweed pollen. Tympanostomy tubes were inserted for direct measurement of ET function by inflation-deflation and forced-response testing before and after provocative intranasal challenge. Intranasal challenge with pollen (antigen) resulted in rhinorrhea and nasal obstruction. Slight increases in passive ET function values and significantly impaired active ET function were observed after antigen challenge. No changes in nasal airway patency or active ET function resulted from control nonantigen pollen challenges. These data complement our studies in man and support the use of this model to evaluate the relationships among allergic rhinitis, ET function and middle ear disease.
Signs, symptoms, and radiographic abnormalities of sinusitis are frequent in children with asthma; it is not known whether sinus inflammation is associated with bacterial infection or other mechanisms. Eight asthmatic patients with exacerbation of asthma despite bronchodilator therapy were studied after maxillary sinusitis was confirmed by radiographs. All had cough, wheezing, nasal stuffiness, rhinorrhea and were afebrile. Four patients had headaches, and two had facial pain. Maxillary sinus aspirates were obtained, and bacterial cultures were positive in five: Branhamella catarrhalis (2), nontypeable Hemophilus influenzae (2), Streptococcus pneumoniae (1). Nose and throat cultures did not correlate with sinus cultures. All patients received bronchodilators, and four of eight patients received steroids. All were treated for 14 to 28 days with antibiotics during which seven of the eight patients improved clinically including all with positive sinus cultures. Asthma-symptoms diary scores were kept by five; all demonstrated improvement. Pulmonary-function tests improved in five of seven patients after the antibiotic and asthma therapy including the four patients with positive cultures. Sinus radiographs cleared in three, improved in three, and were unchanged in two patients after antibiotic therapy.
ETO and symptoms of AR have been demonstrated to develop after an intranasal provocative antigen-challenge test. To determine the antigen dose required to produce ETO, intranasal insufflations of increasing amounts of pollen (ragweed or timothy) from 0.1 to 100 mg were delivered to 29 patients, ages 20 to 31 yr with AR who were skin test positive or had elevated serum-IgE antibodies to ragweed or timothy but not pine pollen. Our results demonstrated ETO developed in four ears at 0.05 mg of pollen, in one at 0.5 mg, in four at 1 mg, in 28 at 10 mg, in 15 at 50 mg, and in two at 100 mg of pollen. ETO persisted from 2 to 120 hr. Dose responses and duration of ETO were compared to patients' serum-IgE antibodies that ranged from 3% to 36% B/T (median 26.4%). The patients with the highest serum-IgE antibody values (greater than or equal to 26.4%) required lower antigen-dose challenges (less than or equal to 10 mg) to develop ETO (p less than or equal to 0.01) that also persisted longer (less than or equal to 48 hr) p less than or equal to 0.05. Symptoms of AR developed with an antigen dose that was less than the antigen dose that resulted in the development of ETO in 22 patients and at the same antigen dose in the other seven subjects. At a later date, these same subjects were also challenged intranasally with 50 mg of pine pollen after which no symptoms of AR or development of ETO were noted. In summary, the expression of ETO after provocative intranasal pollen challenge in AR patients is an immune-mediated reaction that is antigen-dose dependent and related to serum-IgE antibody titer.