Association of clinical signs and symptoms with pneumococcal acute otitis media by serotype--implications for vaccine effect.

BACKGROUND: Clinical symptoms and signs in acute otitis media (AOM) may differ depending on the various pneumococcal serotypes causing the disease. Alteration in clinical presentation of AOM could be expected after wide-scale pneumococcal vaccinations if there were considerable differences between vaccine serotypes and nonvaccine serotypes. METHODS: In this study, data from 831 children in the control arm of the Finnish Otitis Media Vaccine Trial were used. The children were followed up prospectively in 8 study clinics from 2 to 24 months of age. If AOM was diagnosed, myringotomy was done, and middle ear fluid was aspirated for bacterial culture. Clinical symptoms and signs of AOM were routinely recorded on structured case report forms. RESULTS: Consistent with previous studies, 60% of pneumococcal episodes were caused by vaccine serotypes. There were no major differences between the clinical presentations of AOM due to different serotypes or serotype categories. However, earache was more often associated with AOM caused by vaccine and cross-reactive serotypes, compared with AOM caused by non-vaccine-related serotypes (42% vs. 29%; odds ratio, 1.66; 95% confidence interval, 1.02-2.70). CONCLUSIONS: Introduction of the currently available pneumococcal conjugate vaccine is unlikely to result in a remarkable alteration in the clinical presentation of pneumococcal AOM in infants.

Salivary antibodies induced by the seven-valent PncOMPC conjugate vaccine in the Finnish Otitis Media Vaccine Trial.

BACKGROUND: Mucosal antibodies have been suggested to have a role in defence against pneumococcal infections. We investigated here the ability of a seven-valent pneumococcal conjugate vaccine, PncOMPC, to induce mucosal immune response. METHODS: Healthy Finnish children (n = 111), a subcohort of the Finnish Otitis Media Vaccine Trial, were recruited and 56 of them were immunised with the PncOMPC at the age of 2, 4, and 6 months. At 12 months of age, 49 of them received the PncOMPC and 7 were vaccinated with the pneumococcal polysaccharide vaccine (PncPS) as a booster. The control group of 55 children received a hepatitis B vaccine at the same ages. Salivary anti-Pnc IgG, IgA, IgA1, and IgA2 antibodies to serotypes 6B, 14, 19F, and 23F were measured in both groups at the age of 7 and 13 months. RESULTS: Salivary anti-Pnc IgG and IgA were detected more often in the PncOMPC than in the control group. However, the difference between groups was significant only for 19F and 23F IgA concentrations at the age of 7 months. At the age of 13 months, antibody concentrations did not differ between PncOMPC and control groups. The rises in IgA concentrations between 7 and 13 months of age were mainly of subclass IgA1. Further, there is a clear trend that PncPS booster induces higher salivary anti-Pnc PS antibody concentrations than the PncOMPC. CONCLUSION: We found that PncOMPC can induce a mucosal IgA response. However, the actual impact of mucosal antibodies in protection against pneumococcal infections is not clear.

Diagnostic value of tympanometry using subject-specific normative values.

OBJECTIVE: Tympanometry has proven valuable in the diagnosis of otitis media in infants. The classification used in the Finnish otitis media studies has resulted in high specificity yet only moderate sensitivity. We aimed to explore the benefit of using each subject's individual previous test results (obtained at previous visits of the children when diagnosed healthy) as normative values. Specific aim was to assess this approach in increasing sensitivity in the diagnosis of otitis media. METHODS: We used tympanometric (GrasonStadler GSI 38) results of children in the Finnish otitis media vaccine trial obtained at pre-scheduled 7-month visits (if ears found healthy) and at the first subsequent sick visit with respiratory infections and potential otitis media within a 90-day period after the 7-month visit. Children with recent otitis media within the previous month and tympanometric tests with documented interfering factors were excluded. Pneumatic otoscopy was used as the reference method for the diagnosis of otitis media. RESULTS: Altogether 2476 children at the 7-month visits were examined; after exclusions data on 1759 children were available for analysis. Of these children, 630 were brought to at least one sick visit defined above. Finally, data on 906 ears were available for analysis. Entirely flat type B tympanograms predicted otitis media accurately; also high-peaked tympanograms were accurate in predicting normal middle ear status. For the moderate-peaked curves in-between, absolute and relative changes in the tympanometric variables from the 7-month visit to the sick visit were explored for accurate prediction of otitis media; decrease in curve height by at least 2/3 was found most valuable. Sensitivity of the type B tympanogram was 61% and specificity 99% at the sick visit. The sensitivity increased to 67% with a specificity of 98%, if results with the ratio of static acoustic admittance (height of the curve) at the sick visit compared to the previous healthy visit <0.35 were also considered abnormal together with type B curve in indicating otitis media. CONCLUSIONS: The subject-specific normative values were not found especially useful, although a slight increase in sensitivity was achieved without compromizing specificity.

Association of clinical signs and symptoms with bacterial findings in acute otitis media.

In acute otitis media (AOM), a means of prediction of the bacterial pathogen based on symptoms and signs would be valuable in selecting appropriate antimicrobial treatment. Children in the control arm (n=831) in the Finnish Otitis Media Vaccine Trial were prospectively observed in a study clinic setting from the age of 2 to 24 months. In patients with AOM, myringotomy with aspiration was performed, and middle ear fluid samples were cultured for bacterial pathogens. Symptoms and signs of respiratory infections were thoroughly recorded. Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae were the most common bacterial pathogens. Pneumococcal AOM was associated with more-severe AOM characterized by fever and earache. AOM due to H. influenzae was associated with eye symptoms and findings. Accurate prediction of a bacterial cause of infection based on symptoms and signs of AOM was not possible, but a specific cause was predicted in some situations, with a high probability of applicability to clinical practice.

No evidence of Mycoplasma pneumoniae in acute myringitis.

Our aim was to discover Mycoplasma pneumoniae in bullous and hemorrhagic myringitis in children <2 years of age. Middle ear fluid samples (n = 37) and samples taken from the blisters of the tympanic membranes (n = 12) studied by polymerase chain reaction for M. pneumoniae were negative. This study does not support an important role for M. pneumoniae as an etiologic agent in acute myringitis.

The seven-valent pneumococcal conjugate vaccine reduces tympanostomy tube placement in children.

BACKGROUND: The novel pneumococcal conjugate vaccine, PncCRM, has been shown to prevent acute otitis media caused by vaccine serotypes and to reduce otitis surgery. Our aim was to assess long term efficacy of the vaccine on tympanostomy tube placements. METHODS: Children with complete follow-up in the Finnish Otitis Media Vaccine Trial up to 24 months of age and still living in the study area (1490 of 1662 randomized at 2 months of age) were invited to a single visit at 4-5 years of age. The children had been vaccinated at 2, 4, 6 and 12 months of age with PncCRM or hepatitis B vaccine (control). Tympanostomy tube placements reported by parents at the visit were verified from hospital and private medical center records. Additionally, tympanostomy tube placements of all children were verified from the hospital discharge registry. Vaccine efficacy (VE) was estimated by comparing all events of tympanostomy tube placement between vaccine groups. RESULTS: During the vaccine trial (2-24 months of age), VE (95% confidence interval) in preventing tympanostomy tube placement was only 4% (-19-23%). Altogether 756 children were enrolled for the follow-up study. After 24 months of age, the rate of surgery was 3.5 per 100 person-years in the PncCRM and 5.7 per 100 person-years in the control children, giving VE of 39% (4-61%). In the hospital-based data of all children (N = 1490), VE of 44% was obtained (19-62%). CONCLUSIONS: Receipt of PncCRM vaccine at infancy was associated with a reduction in tympanostomy tube placement from 2 to 4-5 years of age.

Evaluation of the role of respiratory viruses in acute myringitis in children less than two years of age.

BACKGROUND: The etiology of acute myringitis remains controversial although it is usually encountered in connection with acute otitis media (AOM). In most cases of acute myringitis a bacterial pathogen has been detected in the middle ear fluid, but the role of respiratory viruses has remained unclear. Our objective was to investigate the etiologic role of viruses in the pathogenesis of acute bullous and hemorrhagic myringitis in children <2 years of age. METHODS: A prospective longitudinal cohort study of 2028 children ages 7 to 24 months in primary care in the Finnish Otitis Media Vaccine Trial. Nasopharyngeal aspirate (NPA) and middle ear fluid (MEF) samples taken at the time of the diagnosis were examined by a time-resolved fluoroimmunoassay for antigen detection of adenoviruses; influenza viruses A and B; parainfluenza viruses 1, 2 and 3; and respiratory syncytial virus and by reverse transcription polymerase chain reaction for human rhinovirus and human enterovirus. RESULTS: Eighty-two children with bullous myringitis and 37 children with hemorrhagic myringitis were diagnosed during the 18-month follow-up period. In bullous myringitis a respiratory virus was detected in 70% of NPA samples and in 27% of MEF samples. In hemorrhagic myringitis 57% of NPA samples and 28% of MEF samples were virus-positive. The viral distribution was similar to that of AOM (virus positive 64% of NPA and 37% of MEF). CONCLUSIONS: We could not confirm any specific respiratory virus to be the etiologic agent in acute myringitis. The etiology of acute myringitis is similar to that of AOM in children <2 years of age.

The symptoms and clinical course of acute bullous myringitis in children less than two years of age.

OBJECTIVE: the most characteristic symptom of acute bullous myringitis (inflammation of the tympanic membrane) is a sudden onset of severe ear pain. However, in infants and young children a precise symptom history is more difficult to obtain and the symptoms may be less specific. Our objective was to determine the occurrence of different symptoms, signs and the recovery of symptoms during the course of acute bullous myringitis in children less than 2 years. We also evaluated whether there were any specific features in bullous myringitis in comparison with acute otitis media (AOM). METHODS: 2028 children (aged 7-24 months) at primary care level in a prospective longitudinal cohort study in the Finnish Otitis Media Vaccine Trial. RESULTS: during the follow-up there were 86 office visits with bullous myringitis in 92 ears and 1876 office visits with acute otitis media in 2683 ears. Middle ear fluid developed in 97% of cases of bullous myringitis during the course of disease. Earache was present in 58% and fever (>or=38 degrees C) in 62% of cases of bullous myringitis. The symptoms of upper respiratory tract infection (rhinitis in 93% and cough in 73% of events) were present in a majority of cases. Earache, fever, rubbing of the ear, restless sleeping, excessive crying and poor appetite were present more often in bullous myringitis than in acute otitis media. The symptoms were relieved in 1-2 days in a majority of cases. There were no recognized cases of bullous myringitis in ears with patent tympanostomy tubes. CONCLUSIONS: acute bullous myringitis in children represents a special form of AOM with more severe symptoms. Earache and fever were more common in bullous myringitis than in AOM. However, the condition resolved rapidly and the short-term outcome was good.

The epidemiology of acute bullous myringitis and its relationship to recurrent acute otitis media in children less than 2 years of age.

OBJECTIVE: To evaluate the epidemiological characteristics of acute bullous myringitis (BM), i.e. inflammation of the tympanic membrane with blister(s) in children <2 years and study the relationship between bullous myringitis and recurrent acute otitis media. METHODS: 2028 children aged 7-24 months in a prospective longitudinal cohort study in the Finnish Otitis Media vaccine trial. The main outcome measures were the incidence of bullous myringitis and the incidence of acute otitis media (AOM) before and after the event of bullous myringitis. RESULTS: 82 children had a total of 86 events of acute bullous myringitis. The incidence of bullous myringitis was 5.7 per 100 person years (95% CI, 4.6-7.1 per 100 person years). The number of events with bullous myringitis was 4.6% of the number of all AOM events diagnosed during the follow-up. Recurrent AOM (> or =6 AOM events) occurred in 33% of children with bullous myringitis in comparison with 23% of control children with at least one event of AOM (RR 1.7; 95% CI, 1.01-2.7). The incidence of AOM in children with bullous myringitis was 1.8 per person year (95% CI, 1.4-2.2 per person year) before the event of bullous myringitis and 2.9 per person year (95% CI, 2.3-3.5 per person year) after the event of bullous myringitis. The higher incidence rate of AOM lasted for 2 months after the office visit of bullous myringitis. CONCLUSIONS: Acute bullous myringitis is not a rare disease; it was diagnosed in 5.7% of children <2 years in a 1-year follow-up. It was present in almost 1 of every 20 AOM events. Acute bullous myringitis increases the subsequent risk of recurrent AOM.

Does the presence of pneumococcal DNA in middle-ear fluid indicate pneumococcal etiology in acute otitis media?

Bacterial culture of middle-ear fluid (MEF), the standard for etiologic diagnosis of acute otitis media (AOM), has revealed Streptococcus pneumoniae (Pnc) to be a major pathogen responsible for one-third of AOM cases. In the present study, we compared the results of polymerase chain reaction (PCR) based on the amplification of the pneumolysin gene with the results of pneumococcal culture, for 2595 MEF samples obtained during AOM events in 831 children who were followed from 2-24 months of age in the Finnish Otitis Media Vaccine Trial. PCR results were positive for 47.1% of the MEF samples, and culture results were positive for 27.3% of the samples. PCR-positive, culture-negative samples were associated with previous Pnc AOM in a time-dependent pattern, concurrent antibiotic treatment, low volume of MEF, and concurrent nasopharyngeal carriage. PCR-positive AOM represented a clinically less severe disease, compared with culture-positive Pnc AOM. A positive PCR result seemed to indicate the presence of viable, although often nonculturable, Pnc.