Short-term penicillin-V prophylaxis did not prevent acute otitis media in infants.

OBJECTIVE: To determine whether prophylactic, short-term penicillin V treatment during upper respiratory tract infections can prevent the occurrence of recurrent acute otitis media in young children. METHODS: Seventy children were studied in a prospective, double-blind, placebo-controlled study. All children had suffered their first episode of acute otitis media before the age of 6 months. After inclusion in the study group, administration of penicillin V or placebo was initiated by the parents at subsequent upper respiratory tract infections. The children were examined by otomicroscopy within 3 days after treatment was initiated. The children were scheduled for a total follow-up period of 12 months, including bimonthly visits for check-up irrespective of treatment periods. RESULTS: There were 304 treated episodes of upper respiratory tract infection. There was no significant difference in the number of acute otitis episodes between groups. CONCLUSION: Initiation of penicillin V prophylaxis at upper respiratory tract infection in small children did not prevent recurrent acute otitis media in this study.

Goblet cell density in acute otitis media caused by Moraxella catarrhalis.

HYPOTHESIS AND BACKGROUND: Secretory otitis media is associated with a highly increased goblet cell density, confirming the secretory pathogenesis of this disease. Previous studies have shown that the middle ear goblet cell density, and thus the secretory capacity, are massively increased during experimental acute otitis media and at least 6 months thereafter, conceivably predisposing to the subsequent development of secretory otitis media. These studies used middle ear inoculation of either Streptococcus pneumoniae, nontypeable Haemophilus influenzae, or H. influenzae type b. The present study aimed at determining the goblet cell density during and after acute otitis media caused by Moraxella catarrhalis to clarify whether this bacterium induces an equivalently enhanced secretory capacity. METHODS: Twenty-five 25 rat middle ears were inoculated with M. catarrhalis. Five rats were killed on days 4, 8, 16, 60, and 180 after inoculation, followed by staining, dissection, and whole-mount embedding of the middle ear mucosae. The goblet cell density was determined by counting in 24 fields, covering the entire middle ear. RESULTS: In comparison with 25 normal middle ears, the goblet cell density was significantly increased in almost all counting localities, from day 4 and < or = 2 months after inoculation. The goblet cell density peaked on day 16, subsided thereafter, and in some areas reached a normal level 6 months after the acute incident. Mucosal areas containing goblet cells were consistently enlarged, thus leaving the middle ear with an increased secretory capacity during and 6 months after inoculation. CONCLUSION: The goblet cell density of the middle ear mucosa is increased during acute otitis media caused by M. catarrhalis and up to several months thereafter. This may predispose to the subsequent development of secretory otitis media. However, in comparison with acute otitis media caused by other bacteria, M. catarrhalis induced only modest changes in goblet cell density.

Middle ear secretory capacity after acute otitis media caused by Streptococcus pneumoniae, Moraxella catarrhalis, non-typeable or type B Haemophilus influenzae. A comparative analysis based on goblet cell density.

To investigate whether the type of bacteria is correlated with an increase in goblet cell density during and after acute otitis media, we inoculated the middle ear of 25 rats with either Streptococcus pneumoniae, Moraxella catarrhalis, non-typeable or type b Haemophilus influenzae. Mucosal goblet cell density was determined by a whole-mount method on days 4, 8, 16, 60 and 180 post-inoculation. The goblet cell density was increased on all days of sacrifice, employing either bacteria, except M. catarrhalis 6 months after the acute incident. Type b H. influenzae induced the highest increase, followed by non-typeable H. influenzae, S. pneumoniae and M. catarrhalis. The mucosal area containing goblet cells was enlarged on all examination days, employing either bacteria. We conclude, that mucosal secretory capacity is highly increased during and up to 6 months after acute middle ear infection caused by either bacteria, conceivably predisposing a subsequent development of secretory otitis media. The results indicate that type b H. influenzae seems to be the bacteria most likely to induce a subsequent secretory condition.

Effect of penicillin on experimental acute otitis media. A histopathological study of goblet cell density, bone modelling dynamics, polyp and adhesion formation.

Clinical studies have shown that the effect of antibiotic treatment on acute otitis media is modest. Experimental acute otitis media induces a number of histopathological changes in the middle ear mucosa. Among these are increased goblet cell density, polyp and adhesion formation, as well as massive osteoneogenesis. To investigate the effect of penicillin administration on these histopathological features, we employed a rat model of acute pneumococcal otitis media. Five of 25 rats were sacrificed on days 4, 8, 16, 90 and 180 post-inoculation, preceded by oral administration of penicillin V 100 mg/kg/day, initiated on day 2 and lasting 5 days. Using a light microscope, qualitative and quantitative histopathology of middle ear goblet cell density, bone-modelling dynamics, polyp and adhesion formation was registered and compared with previous studies of untreated animals. Increase in goblet cell density and new bone formation was reduced significantly by treatment, whereas polyp and adhesion formation was unaffected by penicillin administration. It is concluded that penicillin reduces middle ear secretory capacity and new bone formation during and following acute otitis media, conceivably preventing subsequent development of secretory otitis media, leaving polyp and adhesion formation unchanged.

Update of microbial problems in pediatric otorhinolaryngology: plenary session.

The bacteria to consider in upper respiratory tract infections in children are pneumococci, Haemophilus influenzae, group A streptococci and Moraxella catarrhalis.

Effects of active immunization with a pneumococcal surface protein (PspA) and of locally applied antibodies in experimental otitis media.

An experimental rat model for Streptococcus pneumoniae otitis media was used to investigate passive protection by anti-type 3 capsular antibodies and effects of immunization with pneumococcal surface protein A (PspA). Anti-type 3 antibodies instilled into the middle ear reduced purulent otitis media as compared to control animals (p = 0.015). Secondly, after immunization with PspA, the right middle ear was inoculated with S. pneumoniae type 6A in a dose calibrated to induce purulent otitis media. There was an anti-PspA antibody response in all rats immunized and a reduction in signs of purulent otitis media as compared to control animals (p = 0.026). Thus, purulent (acute) otitis media can be reduced by local application of antibodies in the middle ear and also by immunization with a non-type-specific pneumococcal protein, PspA.

Immunization and protection in pneumococcal otitis media studied in a rat model.

The recent and growing problem of bacterial resistance to common antibiotics has generated great interest in different methods for prevention of infections. The treatment of the pathogens causing upper airway infections and especially acute otitis media (AOM) is especially interesting in this context because these infections are a common cause of prescription of antibiotics all over the world. Both in AOM and recurrent AOM, Streptococcus pneumoniae, the most frequently occurring bacterium is isolated in 30-50% of all AOM attacks. In the last decade, multiresistant S. pneumoniae have emerged as a major problem. Thus, it is important to explore possibilities that immunization may protect against pneumococcal OM. In a well-defined animal model using Sprague-Dawley rats, we have investigated the effects of different routes of immunization with different antigens and whole cells. Together with otomicroscopical evaluation of middle ear (ME) status, samples for bacterial cultivation as well as for studies of histopathological changes have been collected. Antibody titers have been followed during and after pneumococcal AOM by an enzyme-linked immunosorbent assay (ELISA) method.

Bone modeling dynamics in acute otitis media.

OBJECTIVE: A number of middle ear diseases are associated with pathologic bone modeling, either formative or resorptive. As such, the pathogenesis of a sclerotic mastoid has been controversial for decades. Experimental studies on acute middle ear infection have shown varying degrees of both osteoresorption and osteoneogenesis. This study presents data on the dynamics of bone modeling in a rat model of acute pneumococcal otitis media, studied longitudinally from day 1 through 6 months after inoculation. RESULTS: Qualitative, as well as quantitative histopathology revealed initial osteoresorption, followed by increasing apposition of new bone in the middle ear cavity, initiated at the outer periosteum. Measured bone thickness in four anatomically distinct locations peaked 3 months after inoculation, followed by some degree of normalization. However, bone thickness was still massively increased 6 months after the acute incident. Except in perilymphatic spaces of the otic capsule, resorptive and formative activity were found in all bone tissue structures surrounding the middle ear cavity, including the bony external auditory canal and the ossicles. CONCLUSION: These findings may support the existence of a perilymphatic barrier of specialized bone and suggest that even a single episode of acute infection may alter properties of ossicular chain conduction. The authors conclude that acute otitis media is accompanied by massive and progressing net osteoneogenesis, already evident at 3 days and peaking 3 months after inoculation, followed by some degree of normalization. This is conceivably in support of the environmental theory of mastoid pneumatization, claiming inflammatory disease as the cause of a sclerotic mastoid.

Intra- and interstrain differences of virulence among nontypeable Haemophilus influenzae strains.

Nontypeable Haemophilus influenzae (NTHi) is sometimes the causative agent of invasive diseases, and it has been suggested that there may be differences in virulence among NTHi strains. Whilst studying clinical isolates of NTHi in a rat model of acute otitis media, intra- and interstrain differences in virulence were observed. Two strains with suddenly reduced capacity to cause middle ear infections and one highly virulent strain with dose requirements comparable only to encapsulated H. influenzae strains were further investigated, together with 15 other H. influenzae strains. The strains were characterized by analyzing the lipopolysaccharide, the outer membrane proteins, the hemagglutinating ability, and the polymerase chain reaction products after amplification of a gene sequence associated with encapsulation. The pathogenic capacity was assessed in two different in vivo models. It was found that the two strains with reduced pathogenic capacity could regain their virulence after animal passage. The LPS analysis and the results from the chicken embryo model suggested that the observed change in virulence might be associated with the lipopolysaccharide. For the non-animal-passaged strain 3655 there were indications that an undefined factor(s) contributed to its relatively potent virulence. As all three strains lacked genes necessary for encapsulation, in no case could any part of the increased virulence be attributed to the expression of small amounts of capsule.

Aetiology of acute epiglottitis in adults.

In order to determine the aetiology of acute epiglottitis in adults, blood cultures, paired sera and a urine sample were obtained from 54 patients with fever and epiglottitis visualized by indirect laryngoscopy or by direct fibreoptic nasolaryngoscopy. Antibodies were determined against the capsular polysaccharide of Haemophilus influenzae type b (Hib), 3 pneumococcal antigens (a mixture of 23 capsular polysaccharides, C-polysaccharide and pneumolysin) and antistreptolysin O. Acute sera were examined by the polymerase chain reaction (PCR) for DNA of Hib and pneumococci. The urine samples were examined for Hib capsular antigen. Blood cultures were positive in 15 patients. In another 16, serology and/or PCR verified the aetiology. Hib was the cause in 14, pneumococci in 12 and group A streptococci in 5 patients. The aetiology remained unknown in 23/54 patients (43%). In conclusion, the addition of serology and PCR to blood cultures doubled the possibilities of verifying the aetiology of acute epiglottitis in adults.

Changes in mucosal goblet cell density in acute otitis media caused by non-typeable Haemophilus influenzae.

The correlation between secretory otitis media and increased goblet cell density in the middle ear mucosa is well established. Previous studies have shown that a single episode of acute otitis media caused by Streptococcus pneumoniae is followed by increased goblet cell density for a period of at least 6 months, conceivably predisposing a subsequent development of secretory otitis media. In this study, 25 rat middle ears were inoculated with non-typeable Haemophilus influenzae in order to determine the effect on mucosal goblet cell density. Five rats were killed on days 4, 8, 16, 60 and 180 postinoculation, followed by dissection, staining and whole-mount embedding of the middle ear mucosae. The goblet cell density was determined in 24 well-defined localities. Compared with 25 normal middle ears, the goblet cell density was significantly increased in almost all localities, at all days on which the animals were killed. Thus, increased goblet cell density and enlargement of mucosal areas containing goblet cells persisted 6 months after the acute incident. The induced increase of goblet cell density was higher than the increase following inoculation of S. pneumoniae. We conclude that acute otitis media caused by non-typeable H. influenzae is followed by a longstanding increase in mucosal secretory capacity, likely to predispose a subsequent development of secretory otitis media.

Sequelae of recurrent acute otitis media. Ten-year follow-up of a prospectively studied cohort of children.

In a cohort of 113 children prospectively followed from birth to the age of 3, two subgroups were discerned: one with recurrent acute otitis media (rAOM), the other subgroup with no AOM at all ("healthy" children). At further follow-up at the age of 10, no child had AOM or secretory otitis media (SOM), but between 3 and 7 y of age the rAOM subgroup was characterized by a significantly higher incidence of AOM as well as protracted secretory otitis media (SOM) episodes than was the "healthy" subgroup. The two subgroups did not differ significantly in hearing-thresholds at pure tone audiometry. After the age of 7, the incidence of AOM was the same in both groups. It is concluded that children with frequent AOM episodes before the age of 3 need long-term follow-up to school age, but seem not be predisposed to chronic SOM.

Increased secretory capacity of the middle ear mucosa after acute otitis media caused by Haemophilus influenzae type B.

Secretory otitis media is associated with a highly increased goblet cell density of the middle ear mucosa. Previous studies have shown that a single episode of experimental acute otitis media caused by Streptococcus pneumoniae or nontypeable Haemophilus influenzae is followed by increased goblet cell density for a period of at least 6 months. This condition may create a predisposition for subsequent development of secretory otitis media. We inoculated the middle ears of 25 rats with type B H. influenzae to determine the effect of the bacteria on mucosal secretory capacity. Five rats were euthanized 4, 8, 16, 60, and 180 days after inoculation, followed by dissection, staining, and whole-mount embedding of the middle ear mucosa. The goblet cell density was determined in 24 well-defined localities. Compared with that of 25 normal middle ears, the goblet cell density was significantly increased in almost all counting localities on all days of euthanasia. Thus increased goblet cell density and enlargement of mucosal areas containing goblet cells persisted for 6 months after the acute incident. Inoculation of type B H. influenzae induced an increase of goblet cell density that was higher than the increase after inoculation of S. pneumoniae or nontypeable H. influenzae. We conclude that experimental acute otitis media caused by type B H. influenzae is followed by a longstanding increase of mucosal secretory capacity, which is likely to induce a subsequent development of secretory otitis media.

Amoxicillin treatment of experimental acute otitis media caused by Haemophilus influenzae with non-beta-lactamase-mediated resistance to beta-lactams: aspects of virulence and treatment.

Through alterations primarily in the penicillin-binding proteins, a non-beta-lactamase-mediated resistance to beta-lactams has evolved in Haemophilus influenzae. The virulence of these chromosomally changed strains has been questioned. To ascertain whether these alterations involve a reduction in virulence of H. influenzae and whether they could be advantageous for the bacterium during amoxicillin treatment of acute otitis media, a total of 70 Sprague-Dawley rats were challenged with a susceptible recipient strain or a genetically similar resistant transformant strain. Antibiotic therapy was started on day 3 after inoculation, and the animals were monitored by daily otomicroscopy and analysis of bacterial samples from middle ear effusions obtained on day 8, the last day of observation. The animals were also sacrificed on days 4 and 8 and after 2 months for morphological examination. Compared with the susceptible recipient strain, recovery from infections caused by the resistant transformant strain was delayed, and the late structural changes were more severe in the animals challenged with the latter strain. The results of the study indicate that chromosomal alterations mediating a relatively low level of resistance to beta-lactams may be advantageous for H. influenzae during antibiotic treatment of a local infection in the rat, and the alterations may occur without any significant loss of virulence.

A resolved pneumococcal infection protects against nontypeable Haemophilus influenzae: an evaluation of different routes of whole cell immunization in protection against experimental acute otitis media.

A conferred cross-protection between Haemophilus influenzae type b (Hib) and nontypeable H. influenzae (NTHi) was demonstrated in a previous study of experimental recurrent otitis media. To explore cross-protection further, and to compare oral administration of whole cells with two more conventional routes for vaccination against acute otitis media (AOM), a total number of 79 rats were immunized perorally, subcutaneously and intrabullarly with H. influenzae or pneumococci and thereafter challenged in the middle ear with NTHi or Hib 4 or 9 weeks later. Otomicroscopic changes, bacterial cultures, and serum IgG antibody levels were monitored. The study demonstrated that while peroral administration did not elicit any protection, a resolved pneumococcal AOM could reduce the susceptibility to reinfection with NTHi. In the latter case no cross-reacting antibodies were detected, but the protective rate was 50% or more, and it was comparable with that found after subcutaneous or intrabullar immunization with homologous NTHi or Hib strains. The results suggest that the protection of the rat middle ear mucosa may involve unspecific responses.