Otologic manifestations of experimental rhinovirus infection.

Episodes of acute otitis media are commonly associated with viral upper respiratory tract infections. Rhinoviruses account for approximately 40% of these infections, and were previously shown to alter eustachian tube function and middle ear pressures. However, progression to otitis media has not been prospectively documented. In the present study, changes in tympanometric pressures and otoscopic findings resulting from experimental intranasal rhinovirus type-39 inoculation were documented in 60 adult volunteers. Fifty-seven (95%) subjects became infected and 34 (60%) of these had a clinical cold. Prior to viral inoculation, 3 (5%) subjects had middle ear pressures of less than -100 mm H2O and two of these subjects developed middle ear effusions following infection. In all, 22 (39%) subjects developed middle ear pressures of less than -100 mm H2O. No subject with normal middle ear pressures prior to infection developed evidence of effusion. This study extends the otologic manifestations of rhinovirus infection to include otitis media. Furthermore, these results support the hypothesized relationship between upper respiratory tract infections, eustachian tube dysfunction, and otitis media.

Effect of experimental rhinovirus 39 infection on the nasal response to histamine and cold air challenges in allergic and nonallergic subjects.

To determine whether a viral upper respiratory tract infection can alter the responsiveness of the nasal mucosa, paired intranasal histamine and cold air challenge sessions were performed before and after (8 to 13 days) experimental rhinovirus infection in 18 nonallergic subjects and 20 subjects with seasonal allergic rhinitis. The nasal response to the challenges was measured as symptom scores for rhinorrhea and congestion, counts for sneezing, weight for expelled secretions, and inspiratory conductance for nasal patency. For both sessions, a greater response was observed in allergic subjects for sneezing, symptoms of rhinorrhea and congestion, secretion weights provoked by histamine challenge, and secretion weights provoked by cold air challenge when compared with the nonallergic subjects. A comparison of the responses to the paired challenge sessions showed greater responses for sneezing, secretion weight and rhinorrhea to histamine and for secretion weight to cold air challenges performed after rhinovirus infection. No differences were observed between allergic and nonallergic subjects with respect to the degree of enhanced responsiveness secondary to viral infection. These results document an increased responsiveness of the nose to these stimuli during the postsymptomatic period of a rhinovirus infection in both allergic and nonallergic subjects.

Effect of rhinovirus 39 infection on cellular immune parameters in allergic and nonallergic subjects.

Patients with allergic rhinitis (AR), compared with nonallergic persons, have been reported to respond differently to a variety of stimuli, some of which are immunologic in nature. This study compared the systemic cellular immune responses to experimental rhinovirus (RV) 39 challenge in RV-39-seronegative AR (n = 20) and nonallergic (n = 18) subjects. Peripheral blood was obtained before, 4 or 7 days after, and 23 days after RV-39 intranasal challenge and assayed for the number and function of various white blood cells. All subjects were infected, as manifested by viral shedding in nasal secretions or seroconversion. RV-39 induced marked changes from baseline values in both immune cell number and functions. Compared with nonallergic subjects, AR subjects manifested different responses for the following parameters: (1) numbers of total white blood cells and lymphocytes (smaller increases on day 4), (2) helper/suppressor T cell ratio (absence of an increase on day 7 and presence of an increase on day 23), (3) number of IL-2 receptor-positive suppressor T cells (presence of a decrease on day 7), (4) natural killer (NK) cell numbers (absence of an increase on day 4 and presence of increases on days 7 and 23), (5) NK/T cell ratio (absence of an increase on day 4 and a decrease on day 7), (6) NK cell activity (a blunted decrease on day 7 and absence of a decrease on day 23), and (7) RV-39-induced lymphocyte proliferation (exaggerated increase on day 4). The results show that intranasal challenge with RV-39 induced RV-39-specific and nonspecific systemic cellular immune responses and a unique immunologic response pattern in AR subjects.

Eustachian tube function in the ferret.

The role of viral upper respiratory tract infections (URI) in the pathogenesis of otitis media (OM) may be related to Eustachian tube (ET) dysfunction. Preliminary experimental evidence suggests that the ferret may be an appropriate animal for modeling of pathophysiologic process related to URI's and ET dysfunction. In an effort to determine the applicability of this animal model, normal ET function was evaluated in 10 ferrets using the inflation-deflation and forced-response testing protocols. The results indicate that the ET of the ferret functions as a small-scale version of its rhesus monkey and human counterparts. The ET-middle ear (ME) system could maintain applied positive and negative ME pressures in all instances. Nearly complete swallow-induced pressure equilibrations were demonstrated in all ears tested. Elevated passive function parameters suggested a small tubal lumen. The efficiency of the tubal dilatory mechanism as expressed by the normalizing calculation (R0/RA) was shown to be quite similar to that in primates and man. These findings suggest that the ferret's ET functions in a manner similar to humans and is, therefore, an appropriate animal to study the pathogenesis of otitis media in the context of ET dysfunction.

Inhibition of lymphoproliferation by middle ear effusion in experimental otitis media.

In this study, experimental otitis media was created in the chinchilla by direct middle ear challenge with Escherichia coli endotoxin, Streptococcus pneumoniae, Haemophilus influenzae, or Pseudomonas aeruginosa. The effusions recovered from the chinchillas in all four challenge groups were shown to inhibit the lymphoproliferative response of chinchilla peripheral blood lymphocytes to stimulation with phytohemagglutinin. The effect was dose dependent, and for effusions of infectious origin, the degree of inhibition was directly related to the duration of infection. Presence of the inhibitor in plasma was undocumented, suggesting a local production within the middle ear. Lymphocytes from middle ears infected with bacteria but not middle ears challenged with endotoxin were hyporesponsive or nonresponsive to stimulation with phytohemagglutinin. These results confirm the presence of an inhibitor of the lymphoproliferative response in experimental otitis media of different etiologies.

Rhinovirus 39 infection in allergic and nonallergic subjects.

To determine if individuals with allergic rhinitis are hyperresponsive to upper respiratory tract viral infections, 20 allergic and 18 nonallergic, susceptible, adult volunteers were challenged and infected with rhinovirus type 39 before the pollen seasons. Before challenge and on each of 6 days of cloister, all volunteers were interviewed for symptoms and completed a test battery consisting of evaluations of secretion production by weighed tissues, nasal patency by active posterior rhinomanometry, nasal clearance by the dyed saccharin technique, pulmonary function by spirometry, eustachian tube function by sonotubometry, and middle ear status by tympanometry. The symptomatology and pathophysiology resulting from the rhinovirus infection were consistent with those reported in previous studies with this challenge system. Between-group comparisons revealed no differences in symptom presentation, nasal secretion production, or overall pathophysiologic response. However, for decreased mucociliary clearance rate, increased nasal congestion, eustachian tube dysfunction, and symptoms of sneezing, the allergic group demonstrated an earlier onset compared with that of the nonallergic group. The biologic significance of the differences in onset of dysfunction is tempered by the observation that the temporal pattern of responses in the allergic group was similar with that of nonallergic subjects in previous studies. The results of the present study do not support the hypothesis of a physiologic hyperresponsiveness to rhinovirus type 39 infection in allergic subjects during nonallergy seasons.

Third-generation cephalosporins in the treatment of acute pneumococcal otitis media. An animal study.

There is concern that third-generation cephalosporins may not be effective in the treatment of acute otitis media due to Streptococcus pneumoniae. Using the chinchilla animal model, we compared two third-generation cephalosporins, cefixime (Suprax) and ceftibuten (investigational), with ampicillin and saline controls in an investigator-blinded, randomized trial. Whereas the saline controls performed worse than all other groups, no significant differences were detected among the three antibiotics regarding the time required to sterilize the middle ear cleft, or the prevalence of positive cultures after 10 days of therapy. The statistical power of the comparisons of cefixime and ceftibuten with ampicillin were 98% and 67%, respectively. The results of this in vivo animal study fail to support the contention that the two third-generation cephalosporins investigated are not effective in the treatment of pneumococcal acute otitis media. Caution is advised when extrapolating these results to the general clinical setting.

Neonatal conductive hearing loss does not compromise brainstem auditory function and structure in rhesus monkeys.

The effect of conductive hearing loss on the maturation of the auditory pathway was evaluated using the auditory brainstem response (ABR) in rhesus monkeys. Ten newborn rhesus monkeys were assigned to control (N = 4), unilateral hearing loss (N = 3), or bilateral hearing loss (N = 3) groups. Hearing loss was created by surgically excising a 3 mm section of the external auditory canal and suturing the canal. Auditory brainstem responses to click stimuli were recorded prior to and after the surgical procedure and bi-monthly or monthly for a 14 month follow-up period. Results showed that after surgery all ears developed an estimated 30-50 dB conductive hearing loss which was retained throughout the follow-up period. Contrary to expectations, the latencies of the ABR component waves decreased with age in all ears. When adjusted for hearing level, there were no differences between ears in maturation of the component waves of the ABR. These data suggest that, in primates, a conductive hearing loss does not affect the maturation of those aspects of the auditory pathway reflected in the ABR. Furthermore, the conductive losses were not accompanied by any discernible change in the neuronal sizes of brainstem auditory neurons or the volume of the cochlear nuclei.

Experimental paralysis of tensor veli palatini muscle.

In an effort to study the effects of experimental paralysis of tensor veli palatini (TVP) muscle on Eustachian tube (ET) function and middle-ear (ME) status, botulinum toxin A (Oculinum) was injected into the TVP muscles of 8 Rhesus monkeys. Tubal function was tested longitudinally in 2 animals with tympanostomy tubes using the forced-response test, while in the remaining 6 animals; ME condition was documented daily using tympanometry. The postinjection tubal function was characterized by abolished active muscular function and decreased closing pressure. Activity associated with tubal dilations gradually reappeared by the fifth week. The lack of lumen constrictions following injection suggested that the TVP muscle is the cause of constriction as well as normal dilation. In 6 animals with intact tympanic membranes, 10 of the 12 ears developed flat tympanograms associated with otitis media with effusion (OME) within 8-30 days of injection and serous effusions were recovered by tympanocentesis in seven ears. These results show that a non-traumatic reversible functional obstruction of the ET was created by injecting botulinum toxin A into the TVP muscle. This functional obstruction was associated with the development of high negative ME pressure and serous effusion.

Anatomy and physiology of eustachian tube and middle ear related to otitis media.

The middle ear is part of a functional system composed of the nasopharynx and the eustachian tube (anteriorly) and the mastoid air cells (posteriorly). The only active muscle that opens the eustachian tube is the tensor veli palatini, which promotes ventilation of the middle ear. The eustachian tube also functions to protect the middle ear from excessive sound pressure, and nasopharyngeal secretions. The eustachian tube helps drain the middle ear during opening and closing by pumping secretions from the middle ear; clearance of secretions also occurs. An understanding of the anatomy and physiology of the system can aid the clinician in understanding the role of eustachian tube dysfunction in the cause and pathogenesis of middle ear disease and the possible contribution of allergy to this disease.

Microbiology of recurrent and chronic otitis media with effusion.

A study was conducted of 274 children who had recurrent acute or chronic otitis media with effusion. Forty-five percent of the ears with effusion were found to contain bacteria, and 11% contained bacteria that were "probable pathogens" (S. pneumoniae, H. influenzae, and S. pyogenes). Bacteria were also found in 40% of the ears without effusions. The type of organism found did not vary with the age of the patient studied or the season of the year. The significance of these bacteria in the etiology of recurrent acute or chronic otitis media with effusion remains to be demonstrated.