Acute otitis media may be defined as the sudden onset of inflammation in the middleear space characterized by ear pain and a bulging, thickened, and immobile tympanic membrane. The middle-ear fluid is typically purulent. A bacterial pathogen is recovered in 75% of the episodes. Streptococcus pneumoniae predominates at 35%, followed by nontypeable Hemophilus influenzae at 25%, and Moraxella catarrhalis at 15%. The remaining 25% of middle-ear fluids are sterile and presumably represent viral infections. Increasing evidence suggests that viruses may participate in more than 50% of all acute otitis media (AOM) episodes; however, pure viral AOM is relatively uncommon.1 The natural course of AOM has not been studied in the past decade. A review of articles concerning treatment of AOM demonstrates a spontaneous self-resolution rate between 30 and 80%.2–6 This rate varies with the specific pathogen from a high rate of 79% with M. catarrhalis to a low rate of 11% with S. pneumoniae.7,8 The mechanisms of eradication appear to involve various host defenses, including phagocytosis and destruction within neutrophils, lysis by host products outside of the cell, immunologic destruction by antibody and complement, and drainage of pus from the middle-ear space through the eustachian tube. Ample evidence has been accumulated that supports the role of serum antibody in protecting the middle-ear space from infection. For example, the incidence of AOM is relatively low during the first six months of life when maternally acquired antibody levels are relatively high in infants. More specifically, antibody concentrations to S. pneumoniae in cord blood correlate to susceptibility to the development of pneumococcal otitis media, as does the level of antibody to nontypeable H. influenzae in older children.9–11 Low levels of antibody can be corrected by passive immunization with serum containing high titers of antibody. By passively raising levels of pneumococcal antibody, the frequency of otitis media is reduced.12 Active immunization with S. pneumoniae has also been associated with a reduced frequency of AOM.13,14 Only pneumococcal types contained in the vaccines were associated with protection, and especially those types that induced a good serologic response.13,14 These data prove that serum antibody is important in the prevention of AOM in humans. Animal studies support the same conclusion. Animals passively immunized with antibody to either S. pneumoniae or nontypeable H. influenzae are protected against the development of AOM.15,16 The protection is type and strain specific.16–18 Animals rechallenged in a previously noninfected ear following resolution of an infection in the contralateral ear are protected against reinfection, presumably by serum antibody that diffused into the challenged ear.17 In contrast to the plethora of studies conducted on bacterial AQM, little information is available on viral disease. Immunization against influenza virus is associated with a reduction in influenzal disease as well as AOM.19 It is not known whether or not the reduction in AOM in immunized children reflects decreased viral AOM or protection against secondary bacterial infection. S. pneumoniae is a gram-positive coccus that most often assumes a diplococcal form. The organism is covered by a large carbohydrate capsule. The capsule is a polymer of repeating oligosaccharides. At present there are more than 84 antigenically different capsular types. Immunity to the pneumococcus is type specific and depends on antibody directed against a short six- or seven-sugar epitope in a particular capsular polysaccharide. Antibody to the capsule is important in opsonophagocytosis. Opsonic activity and IgG and IgM antibody to the capsular polysaccharide highly correlate to protection.20 Once ingested, S. pneumoniae are rapidly destroyed. The specific mechanism of destruction within the neutrophil is unknown. However, it is known that autolysins within S. pneumoniae lead to spontaneous death, while host factors such as lysozyme, which function outside of the neutrophil, hasten the destruction.21,22 In contrast to capsular polysaccharide, the cell (C) wall polysaccharide is homogeneous throughout all strains. Although the cell wall polysaccharide induces an immune response, the specific antibody does not appear to be protective.23 Another antigen that has been shown to be immunogenic and protective is the surface protein A of the pneumococcus.24 This is an approximately 84-kDa protein. Although this protein is present on all clinically important strains, it is serologically highly variable.25 The importance of this antigen in human disease is not known. The natural development of pneumococcal serum antibody is not understood. Gray et al.26 studied a cohort of 82 infants from birth. They were unable to demonstrate consistently the development of serum antibody in response to nasopharyngeal colonization with pneumococci. However, antibody to type 3 pneumococcus was more readily detected after colonization than types 19 or 23. Conversely, serum antibody does not appear to affect colonization. Among children immunized with either an octavalent or 14-valent vaccine, nasopharyngeal colonization remained unaffected regardless of the serum antibody concentration.27 Parenthetically, the children in this immunization study were less than one year of age at the time of immunization. Immunization of children less than two years of age with pneumococcal vaccine is currently contraindicated because of the poor immune response.28 In an animal model of otitis media, immunization produced sufficient serum levels of antibody to protect the middle ear against infection; however, nasopharyngeal colonization remained unaffected.29 The immune response to S. pneumoniae during AOM has been studied in a surprisingly small number of children. In 1974 Sloyer et al.30 used indirect hemaggluti-nation and indirect fluorescence to measure antipneumococcal antibody in acute and convalescent sera as well as middle-ear fluid. Approximately 25% of children developed a systemic immune response that increased with age from 12% for infants less than 1 year of age to 48% for children over 2 years of age. A follow-up study by the same group of investigators demonstrated that middle-ear fluid with pneumococci were cleared more quickly if antibody was present in the middle-ear fluid at the time of diagnosis (75%) than when antibody was absent (18%).31 Almost 10 years later, Koskela et al.32 measured the serum antibody response in children with acute pneumococcal otitis media; however, they employed a technique that used exogenous C polysaccharide to remove noncapsular polysaccharide antibodies. The antibody response was clearly related to the capsular type. For example, capsular types 3 and 18 typically induced specific antibodies, while types 6 and 19 rarely did. Karjalainen et al.33 measured antibody concentrations to all three middle-ear pathogens in middle-ear effusions during AOM, regardless of the inciting agent. They detected antibody to each pathogen in every effusion; however, antibody to the causative agent tended to be more prominent. These data suggest that the antibodies diffuse into the middle-ear space passively due to the acute inflammatory response. Furthermore this study corroborated the findings of Sloyer et al;31 the presence of pneumococcal antibody in middle-ear effusion early in the course of disease was associated with rapid resolution (90%), compared to middle-ear fluid without detectable antibody (57%). We were fortunate enough to study the systemic and local antibody response in seven children with type-19 pneumococcal otitis media. The children ranged in age from 6 to 29 months with a mean of 15.1 months (Table 1). The mean acute serum antibody level of 0.46 μg/mL was not significantly different than the mean convalescent serum antibody level of 0.32 μg/mL. Antibody was concurrently measured in the middle-ear fluids during the acute period. Antibody was detected only in one of six fluids. The one positive middle-ear fluid was recovered from a 29-month-old child who had a relatively high serum antibody concentration. Interestingly, two of the children were unable to resolve their infection despite appropriate antibiotic therapy. Sequential sera and middle-ear fluids demonstrated a failure to develop antibody response in one child and a lack of a local antibody response in the other child (Table 2). These data suggest that eradication of pneumococci from the middle-ear space is dependent on the presence of IgG-specific antibody in the middle-ear space. The antibody appears to come from the systemic circulation. Unfortunately young children generate relatively low levels of serum antibody. Nontypeable H. influenzae is a gram-negative pleomorphic coccobacillus. It is not encapsulated like the pneumococcus; rather, it is enclosed by an outer membrane that contains approximately 20 proteins and a lipooligosaccharide (LOS). The heterogeneity of the outer membrane proteins (OMP) provides a basis for typing the various strains.34 Among the proteins are seven that have been well characterized Pl, 2, 4, 5, 6, high molecular weight (HMW) 1, and HMW 2. Most recently, a second family of HMW proteins has been identified.35 Pl, 2, and 5 are heterogeneous, while P4 and 6 are highly conserved. The two HMW proteins are heterogeneous, and unlike the other proteins are detected on only 70–75% of strains.35 LOS is also fairly heterogeneous.36. P2 is the major OMP. It serves as a porin. Recently our laboratory demonstrated a role for P2 in attachment to mucin.37 P5 and the HMW 1 and 2 proteins have also been shown to play a role in attachment, the former to mucin and the latter to epithelial cells.37–40 Antibody to Pl, 2,4, 6, HMW 1 and 2, and LOS are bactericidal. Since P4 and P6 are antigenically stable and highly conserved, an immune response to either antigen should produce an antibody that recognizes all strains of nontypeable H. influenzae; in contrast, the antibody responses to Pl, 2, HMW1 and 2, and LOS would most likely be strain-specific. In 1988 we began a series of experiments designed to examine the immune response to nontypeable H. influenzae in children with AOM. We first employed an im-munodot assay with a prototypic whole bacterial antigen preparation to describe the seroprevalence in the general population. The assay was specific for H. influenzae, but did not distinguish homologous from heterologous strains. The initial study demonstrated that newborns possessed adult levels of IgG-specific antibody.41,42 These levels dropped to their lowest point between six months and two years. This time period corresponds to the age when the incidence of AOM is the highest. By four to six years adult levels were reached. In an effort to utilize a functional antibody test, we next employed a bactericidal assay Parenthetically, fresh-pooled human serum is able to kill 100% of nontypeable H. influenzae strains. Killing of the organism requires both antibody and complement, A total of 21 infants who experienced 29 episodes of otitis media were evaluated.4,3 Bactericidal antibody was detected in acute serum of 26% with a mean titer of 0.8 (log2) and was observed in convalescent serum of 100% subjects at a mean titer of 4.0 (log2. Unlike the antibody response to S. pneumoniae, the bactericidal antibody response to nontypeable H. influenzae was not age-dependent. The presence of bactericidal antibody correlated with a reduction in the number of bacteria present in the middle-ear fluid. This suggested that serum antibody entered the middle-ear space. Examination of the middle-ear fluids was next performed by an immunodot assay with purified homologous outer membrane antigen. This immunodot assay distinguished homologous from heterologous organisms. Strain-specific IgG predominated.44 It was detected in 91% of the children, compared with IgM in 48%, IgA in 52%, and secretory IgA in 18% (Table 3). The titer of specific IgG, 8.2 (Iog2) exceeded IgM 3.4 (log2), IgA 3.7 (log2), and secretory IgA 1.2 (log2). Antibody was only detected in middle-ear fluids of individuals who possessed complementary serum antibody. Further refining of the antibody assay allowed us to examine the response to the highly conserved protein P6.45 Immunoglobulin G antibody to P6 was detected in 92% of middle-ear fluids compared to 70% for IgM, 78% for IgA, and 45% for secretory IgA. Antibody levels ranged from 249 ng/mL for IgG to a low of 11 ng/mL for IgM. Concentrations of P6-specific IgG in the middle-ear fluid were directly related to the concentration in the serum, r= 0.89, and inversely related to the number of bacteria present, r=−0.62. These data confirm our earlier studies done with serum bactericidal antibody. The mechanism of elimination from the middle-ear fluid of nontypeable H. influenzae is not known. It is possible that the organisms are killed by the action of specific antibody and complement. it is also possible that the bacteria are opsonized, phagocytosed by neutrophils, and destroyed within the cell. Nontypeable H. influenzae are opsonized by antibody directed against surface proteins. At least one report suggests that antibody directed against the P2 protein leads to strain-specific phagocytosis.46 The necessity for complement in the phagocytic process is somewhat controversial. In our experience, phagocytosis can occur in the presence of antibody alone; however, complement augments the process.47 In contrast, studies conducted by Troestra et al.46 and Musher et al.48 attribute greater importance to the role of complement. From our own studies, it is clear that phagocytosis is associated with the release of leukotriene B4, a potent chemoattractant for neutrophils.47 Thus, the inflammatory response is heightened. We suspect that the inflammatory process permits further influx of serum antibody into the middle-ear space. In an effort to delineate the roles of inflammation and local immunity on the appearance of antibody in the middle-ear space, we compared antibody levels in the right and left ears of children with bilateral effusions and in whom the organism was present or absent. The IgG-specific antinontypeable H. influenzae antibody levels in children with bilaterally infected ears were equivalent, while the levels in the infected side of children with bilateral effusions were higher in the infected side.44 These findings suggest local production of antibody in the infected side and only passively acquired antibody in the uninfected side. Another interpretation is greater local inflammation in the infected middle-ear mucosa, allowing more serum antibody to cross into the middle-ear space. Supporting this latter interpretation are data from an earlier study in our laboratory that demonstrated higher levels of mediators of inflammation in middle-ear effusions with viable bacteria.49 We also obtained sequential tympanocenteses from children with AOM. These studies suggested that as an infection resolved, the level of antibody in the effusion decreased, but serum antibody remained stable or increased (Table 4).41,42 We could not distinguish the effect of inflammation or local antibody production. The majority of data suggest that the antibody present in the middle-ear fluid represents serum antibody that has diffused across an inflamed middle-ear mucosa. One intriguing observation from our earlier studies suggested that as the number of episodes of otitis media increased and/or the duration of infection persisted, the likelihood of detecting IgM- and IgA-specific antibody middle-ear effusions increased. We examined middle-ear effusions from children with 1–5 episodes, 6–10 episodes, >10 episodes, and those with persistent effusions (Table 5).41 The serum and middle-ear fluid levels of nontypeable H. influenzae antibody increased as the number of episodes increased. Although specific IgG, M. and A antibodies were detected in the sera of all children in each group, the same was not true for the middleear fluid. IgM- and IgA-specific antibodies were not detected in children with 1–5 episodes. IgA-specific antibodies were absent in the group with 6–10 episodes, while IgM was detected in 25%. In contrast, IgM and IgA antibodies were found in the middle-ear fluids in children with more than 10 episodes, or persistent fluids. Our interpretation of the data is that as the number of episodes increases or the longer the infectious process persists, the more likely a local immune response was responsible for the antibody in the middle-ear fluid. The third pathogen to be considered is M. catarrhalis, formerly called Neisseria catarrhalis and Branhamella catarrhalis. This organism was once thought to be a nonpathogen. However, in 1965, it was first identified as a cause of AOM.50 Gradually, the percent of M. catarrhalis cases rose to 15% of total episodes. The organism is a gram-negative coccus. It typically assumes a diplococcal form. The organism is readily distinguished from other “Neisserial” organisms by the presence of DNAse and butyryl esterase. We have learned much about the antigenic makeup of the organism during the past seven years. For instance, eight major proteins, ranging in molecular weight from 21 kDa to 98 kDa, have been identified in the outer membrane.51 The OMPs have been designated A through H. The OMP patterns are fairly similar between strains. Outer membrane proteins E and G are surface exposed.52 Outer membrane protein C/D contains a highly conserved epitope.53 The OMP designated B actually comprises two separate proteins B1 and B2 B1 is important in iron binding and B2 may be important in attachment of the organism. More recently, an HMW proten has been described with a molecular weight between 350 and 720 kDa.54 Several studies have measured the immune response to M. catarrhalis following respiratory disease.55–58 At least 50% of the subjects demonstrate a rise in antibody of one of the three immunoglobulin classes.55–58 Goldblatt et al.59 indicated that IgG 3 antibody recognizes the majority of outer membrane antigens of M. catarrhalis. Interestingly, children of less than 4 years of age failed to develop an M. catarrhalis- specific IgG 3 antibody response and only manufactured IgGl and IgG2 antibodies to an 82-kDa protein, protein B1 or B2. Antibody to B2 has been associated with increased clearance of organisms from the airway in an animal model.60 Most recently, antibody to the HMW protein of M. catarrhalis has also been shown to hasten clearance from the airway, and, perhaps equally important, the same authors demonstrated the appearance of antibody to this protein in the convalescent sera from patients with M. catarrhalis pneumonia.61 Only three studies have examined the immune response to M. catarrhalis in children with AOM.55,62,63 The first was conducted in 1981 by Leinonen et al.55 in Finland. They detected an antibody rise in 50% of the children using a pool of ten strains of M. catarrhalis as the antigen in an ELISA assay. We studied the systemic and local antibody response in children by utilizing an ELISA assay with homologous outer membrane antigens.62 Fifty-seven percent of the children demonstrated a rise in antibody titer in one or more of the immunoglobulin classes. Local antibody consisted of IgG, 100%, IgM, 29%, and IgA, 71%. Both the IgG- and IgA-specific antibody measured in middle-ear fluids appeared to represent local production rather than passive diffusion from the systemic circulation (TABLES 6 and 7). It is unclear as to how the specific antibodies function to eliminate M. catarrhalis from the middle-ear space. Unlike nontypeable H. influenczae, which is highly susceptible to killing by fresh-pooled human serum, less than 15% of M catarrhalis strains can be killed by fresh-pooled human serum.57 It is possible that convalescent sera incubated with homologous organisms demonstrates greater bactericidal activity. We were able to demonstrate increased opsonic activity in convalescent sera of children with AOM compared to acute sera when using homologous outer membrane antigens.63 It is difficult to hypothesize the mechanism of elimination of M. catarrhalis from the middle-ear space until we learn more about the antigenic structure of the organism. However, we currently know that among the three major middle-ear pathogens, M. catarrhalis is most readily elimiated from the middle-ear space without antibiotic treatment.7,8 This implies that the organism must be very susceptible to destruction by one or more of the host's defense mechanisms. In summary, the majority of evidence suggests that antibody detected in the middle-ear space comes primarily from the systemic circulation, unless the middle-ear process has been persistent. The amount of specific antibody present in the middle-ear space is directly related to the elimination of the organism. Thus, prior exposure to the pathogen through natural means or through immunization should result in prevention of disease.
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HOWARD S. FADEN (1997) studied this question.
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