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The other effect of intravenously administered respiratory syncytial virus–enriched immune globulin for prophylaxis: Less acute otitis media?
The Journal of Pediatrics Volume 129, Number 2
Editor's column
193
The other effect of intravenously administered respiratory syncytial virus-enriched immune g Iobulln ' for prophylaxis: Less acute otitis media? This issue contains an interesting report by Simoes et al.1 of a corollary effect of intravenously administered respiratory syncytial virus--enriched hyperimmune globulin. The Denver and Buffalo groups (two of the original five sites reporting the direct beneficial effects of RSVIG prophylaxis on RSV disease) report that RSV-at-risk infants receiving high doses of RSVIG at 750 mg/kg monthly from November to April had fewer episodes of acute otitis media during the administration period than did infants receiving low doses (150 mg/kg) of RSVIG or placebo. These results may not be totally surprising. Diseases for which antibody is crucial in protection or outcome are targets for active or passive immunization strategies (e.g., poliomyelitis or Haemophilus influenzae type b disease). Why, then, is there a need for a commentary? In the era of genetically engineered and other "high tech" therapies (read: potentially useful but always expensive), clinicians must ensure that interventions are effective and worth the costs (in money, time, inconvenience, and side effects). Thus further analysis of the Simoes article may put 47 episodes of AOM during a 3-year observation period in perspective--a perspective that is important for an expensive therapy ($4000 to $6000 per season for RSVIG), when today's prime directive seems to be cost containment. Do existing data suggest that polyclonal immune globu: lin, which had been pooled because of high RSV neutralizing titers, might protect infants from AOM? The pathogens most frequently isolated in AOM are bacteria, including Streptococcus pneumoniae (-35%), nontypeable H. influenzae (--25%), BranhamelIa catarrhalis (-15%), and group A streptococci (2% to 5%). Viruses axe increasingly recognized as copathogens. RSV has been estimated as the sole AOM pathogen in up to 7% of AOM episodes during the RSV season, 2-4 and influenza virus has been similarly implicated. Neutralizing antibodies are effective against all these pathogens in vitro. Therefore the beneficial in vivo effect reported in animal studies of disease caused by AOM pathogens, 5-7 particularly pneumococci and RSV, might be expected. Human data reveal that immunodeficient patients have less disease, particularly that caused by pneumoc0cci , with exogenously supplied immune globulin, a, 9 However, immune globulin prophylaxis for AOM in immunocompeJ Pediatr 1996;129:193-6 Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/18/74352
tent patients has been disappointing. Some studies reveal no benefit, whereas others report temporary, marginal, or selected benefits. 1°-13 Why would RSVIG produce better results? The authors' data provide some rationale, showing enhanced antibody titers against some AOM pathogens in comparison with 12 lots of commercial immune globulin from various manufacturers. RSVIG contained higher titers to RSV and P6 (the outer membrane protein shared putatively by all nontypeable H. influenzae organisms) but similar titers to three serotypes of pneumococci. One caveat is that RSV neutralizing antibody should reduce pathogen viability, whereas nontypeable H. influenzae and pneumococcal ELISA antibody may not. Protective neutralizing levels are not defined for these two pathogens, and ELISA antibody contains both neutralizing and nonneutralizing antibodies. An advantage for RSVIG could be expected against RSV but not necessarily against See related article, p. 214.
AOM ELISA OME RSV RSVIG
Acute otitis media Enzyme-linkedimmunosorbentassay Otitis media with effusion Respiratory syncytialvirus Respiratory syncytialvirus-enriched hyperimmune globulin
the other pathogens. For comparison, two monthly intramuscular doses of bacterial polysaccharide immune globulin with high titers of pneumococcal, H. influenzae type b, and meningococcal antibody were administered at the beginning of a 6-month observation period, l° The dose is difficult to compare but appears lower than the high doses of RSVIG used in the current study. However, reduced AOM was observed for the initial 2 months but not the subsequent 4 months when no further injections of bacterial polysaccharide immune globulin were given. The reduction was mostly in pneumococcal AOM, the AOM pathogen for which titers were high. Extrapolating, one could postulate that RSVIG as used by the current study protocol might provide benefits not previously observed because of higher antibody titers, higher doses of immune globulin, and a 6-monthly dosing schedule. Nevertheless, the Simoes study is also an AOM prophylaxis study. How can readers evaluate potential pitfalls in
194
Editor's column
AOM studies? Study design should attempt to ensure that groups differ only by the experimental treatment, so that outcome differences are actually due to the experimental therapy and are not innate differences between study group members. This is accomplished by uniformly applied inclusion and exclusion criteria for enrollment, prospectively collected data, and masking of investigators and subjects. Unfortunately, unexpected imbalances in demographic risk factors despite randomization or inadvertent confounding therapies may be discovered at end-of-study analysis. If so, the original groups should be restratified (subdivided) on the basis of the inadvertent confounding variables to analyze whether results were affected within or between the original groups. Investigators must also define as accurately as possible the end points of the study (i.e., each episode defined as AOM is indeed AOM). The comparative groups also need to be of sufficient size for accurate statistical analysis. Finally, is the therapy for AOM cost-effective? ff we apply this admittedly severe scrutiny to the Simoes report, how clinically useful is RSVIG for AOM prophylaxis? Reassuring factors are masking of investigators and the fact that the number of subjects in each group exceeds the "magic" 30, a minimum to give reasonable power to statistical analysis of group data. The overall data were collected prospectively, but the reported AOM data were retrospectively gathered and analyzed. This retrospective aspect introduced potential weakness in the data and apparently prevented analysis for otitis media with effusion because the data were not set up to track OME. This is unfortunate because reductions in OME episodes and perhaps in the need for pressure-equalizing tubes are also important issues. Nevertheless, retrospective data can be potentially powerful in evaluating accessory phenomena (in this case AOM) to the original main study objective (RSV disease) in these days of shrinking research dollars. Potentially confounding variables are found in the Methods section of the Simoes article. The authors indicate that few subjects had a history of AOM, a few had pressureequalizing tubes, and subjects with OME were placed on a regimen of sulfisoxazole (Gantrisin) prophylaxis. Pressureequalizing tubes or antibiotic prophylaxis would be expected to reduce the number of episodes of AOM, whereas a history of AOM at less than 6 months of age would be a risk factor for being otitis prone. No specific numbers for these variables are available. Are the subjects with an AOM history the same subjects who had pressure-equalizing tubes? Were the subjects with a history of AOM, pressure-equalizing tubes, or use of antibiotic prophylaxis evenly distributed throughout the experimental groups? No stratification is available to ascertain the effects of these potentially confounding variables. One cannot determine whether prophylaxis with sulfisoxazole, use of pressure-equalizing tubes, or a history of AOM affected the differing rates of AOM between groups or within a group. Additionally, passive smoke
The Journal of Pediatrics August 1996
might be an inadvertent variable. The fact that a household member smokes is not sufficiently quantitative in evaluating exposure to passive smoke. For example, if one parent smokes 8 to 10 cigarettes per day, is the exposure the same as if both parents and the babysitter smoke an aggregate of five packs a day? How much of the smoking took place in the infant's immediate environment? Smoking variables are difficult to quantitate but can be important. Overall, the potentially confounding factors need consideration when one is evaluating the power of the study's findings. The end points of analysis (AOM episodes) must be accurate. Stringency in diagnosing AOM ensures that differences in outcome (differences in episodes of AOM) are real. Severn tools have been used to provide reasonably accurate AOM end points. The first is a strict definition of AOM. Simoes et al. used acceptable clinical and tympanic membrane physical findings for this definition. The second tool is the use of validated investigators (i.e., observers whose results with pneumatic otoscopy compared favorably with myringotomy or tympanocentesis results on the s a m e earsl4). Two investigators were predominantly responsible for diagnosing AOM. This lowers the risk of interobserver variation but c o u l d increase the error rate if either observer was not as accurate as the other. Although not stated in the Methods section of the Simoes article, the two predominant masked observers appear to have been AOM-validated in one previous study. 15 The third tool is an objective measure of middle ear dynamics, usually tympanometry. 16 Tympanometry was not used. Tympanometry can be difficult in children less than 6 months of age or even in some former premature infants after 6 months of age. However, the use of a second masked observer as confirmation, if tympanometry was not to be used, could have strengthened confidence in the AOM diagnosis. Last, confirmation of inflammation in the middle ear by tympanocentesis or myringotomy would have been the strongest evidence of AOM. 17 This also would have provided microbiologic data for comparison with other investigations and more complete analysis of the effects of RSVIG in a pathogen-specific manner. Such analysis can be crucial with today's geographic differences in antibiotic resistance and proportions of common AOM pathogens. It" results of this study seem at odds with another, comparisons of culture proven pathogens could clarify why results differ. For immune globulin studies, microbiology is important because the most impact in previous immune globulin studies was on pneumococcal disease. It is possible that the results of the current study were affected by a microbiologic skew. For example, were there inordinate proportions of pneumococci? Or was the high-dose group predominantly afflicted by pneumococci and the low-dose or placebo groups infected with nontypeable H. influenzae? It is hoped that randomization prevents such bias, but nature may not have cooperated. In the absence of microbiologic data, the reader is left to speculate. Pneumococcus is the only
The Journal of Pediatrics Volume 129, Number 2
AOM pathogen with a propensity for invasive life-threatening disease, and the antibiotic choices for drag-resistant pneumococci appear more limited each winter. Additionally, spontaneous remission of pneumococcal AOM is less than that of the gram-negative pathogens that cause AOM (20% vs 50%). Thus data on pneumococcal episodes could sway the decision on clinical importance. Statistics validate differences that may be clinically important, but statistical significance by itself does not ensure clinical importance. Therefore decisions on clinical relevance should take into account both statistics and medical common sense. The overall statistical analysis by Simoes et al. 1 appears sound, but the significance of the analysis of trend for AOM associated with RSV infections seems less notable when one is looking at the raw data. A p value is reported to be 0.033 for data showing 0 of 9 RSV-associated episodes of AOM in high-dose, 2 of 8 in low-dose, and 5 of 19 in placebo recipients. This seems a striking p value for these data. In general, the smaller the numbers per group, the less robust is the statistical conclusion. Even if statistical significance is reached, does a difference of five AOM episodes during a 3-year period seem clinically significant? Presupposing a beneficial effect of RSVIG on AOM, what about pain or inconvenience of administration, the expected side effects, and the known cost? Adverse events appeared to be minimal, although monthly 4- to 5-hour infusions could be considered as adverse events. Placement of an indwelling line could circumvent some of these difficulties and allow home infusions, but is the risk of an indwelling line worth the benefit in regard to AOM? Moreover, RSVIG is a human biologic product. Though it seems safe, recent problems arose with hepatitis C caused by intravenously administered immune globulin, Is so use for nonserious infections should be considered with caution. From a cost perspective, the use of RSVIG is not reasonable AOM prophylaxis. In this study, 27 cases of AOM were prevented during a 3-year period in 11 of the 33 high-dose recipients by administering nearly 200 RSVIG infusions. Dividing the prevented AOM episodes by the 18 months of observation per therapy yields a group reduction rate of 1.5 AOM episodes per observation month. For each subject, AOM was reduced 0.045 episode per infusion. A cost estimate for two office visits and 1.5 antibiotic prescriptions per AOM episode might be $200. The cost savings over traditional care that might otherwise have been used would be approximately $5500 and, when averaged for the 33 subjects, would be $163.63 per subject for a 6-month observation period, or $27.27 saved per month per subject. Thus we could save an estimated $5500 on traditional AOM treatment by using approximately $200,000 worth of RSVIG (estimated cost of about $1000 per infusion). The estimated cost would be $7407 per prevented AOM episode. This is not a resounding economic endorsement for RSVIG use unless recipients receive a major benefit from protection
Editor's column
195
against RSV, the pathogen for which the product was designed. As the authors correctly state, the economics of effects on AOM do not stand alone and can be considered only together with costs related to RSV protection. Should these results direct our efforts to alternative beneficial strategies? The RSVIG data lend credence to humoral protection against AOM, if antibody titers are sufficient. Ideally a low-volume, low-cost, infrequently administered preparation of immune globulin could be developed. Do the monoclonal antibody preparations now under investigation for RSV treatment have potential? Probably not. Because they are not polyclonal and have no antibody to bacterial pathogens, they should affect only RSV-associated AOM (5 episodes in 19 subjects during a 3-year period). More likely, strategies for active immunization against bacterial AOM pathogens such as pneumococcus, nontypeable H. influenzae, and B. catarrhalis, as well as RSV and influenza virus, should be stimulated by these current data. These and other findings regarding the use of passive pneumococcal antibody preparations increase the prospect of reducing AOM caused by pneumococci with the investigational conjugate polyvalent pneumococcal vaccines. Other recent data also raise hope for AOM protection with viral vaccines (e.g., influenza vaccine). 19 The article by Simoes et al.1 is interesting and provocative despite minor design and analysis concerns. The data are useful and informative, giving direction for further investigations and adding knowledge on RSVIG, a new weapon against viral disease in vulnerable populations. However, the bottom line is that current data do not substantiate routine use of immune globulin prophylaxis for AOM in immunocompetent hosts. Nevertheless, fewer episodes of AOM may be a nice side effect of RSVIG prophylaxis for RSV disease. Additionally, we are nudged closer to a true AOM vaccine strategy, which might combine conjugate pneumococcal, influenza, and perhaps RSV vaccines. Until then, we will continue to use breast-feeding, currently available pneumococcal vaccine after 2 years of age, annual influenza vaccine, antibiotic prophylaxis in limited situations, and at times pressure-equalizing tubes to prevent AOM 2°, 21 in otitisprone patients not eligible for RSV prophylaxis.
Christopher J. Harrison, MD Associate Professor of Pediatrics and Medical Microbiology and Immunology Creighton University School of Medicine University of Nebraska Medical Center Omaha, NE 6813I REFERENCES
1. $imoes EAF, Groothuis JR, Tristram DA, Allessi K, Lehr MV, Siber GR, et al. Respiratory syncyfial virus-enriched globulin for the prevention of acute otitis media in high-risk children. J Pediatr 1996;129:214-9. 2. Sarkkinen H, Ruuskanen O, Meurman O, et al. Identification of respiratory virus antigens in middle ear fluids of children with acute otitis media. J Infect Dis 1985;151:444-8.
19 6
Editor's column
3. Chonmaitree T, Owen MJ, Howei VM. Respiratory viruses interfere with bacteriologic response to antibiotic in children with acute otitis media. J Infect Dis 1990;162:546-9. 4. Okamoto Y, Kudo K, Shirotori K, et al. Detection of genomic sequences of respiratory syncytial vires in otitis media with effusion in children. Ann Otol Rhinol Laryngol Suppl 1991;157:7-10. 5. Hermansson A, Prellner K. Effect of gammaglobulin on pneumococcal otitis media in the rat. Acta Otolaryngol Stockh 1990;109:300-6. 6. Shufin PA, Giebink GS, Wegman DL, et al. Prevention of pneumococcal otifis media in chinchillas with human bacterial polysaccharide immune globtflin. J Clin Microbiol 1988;26:755-9. 7. Barenkamp SJ. Protection by serum antibodies in experimental nontypeable Haemophilus influenzae otitis media. Infect Immun 1986;52:572-8. 8. Ishizaka A, Sakiyama Y, Otsu M, et al. Successful intravenous immunoglobulin therapy for recurrent pneumococcal otitis media in young children. Eur J Pediatr 1994;153:174-8. 9. Silk HJ, Ambrosino D, Geha RS. Effect of intravenous gammaglobulin therapy in IgG2 deficient and IgG2 sufficient children with recurrent infections and poor response to immunization with Haemophilus influenzae type b capsular polysaccharide antigen. Ann Allergy 1990;64:21-5. 10. Shurin PA, Rehmus JM, Johnson CE, et al. Bacterial polysaccharide immune globulin for prophylaxis of acute otitis media in high-risk children. J Pediatr 1993;123:801-10. 11. Diamant M, Ek S, Kallos P, et al. Gamma globulin treatment and protection against infections. Acta Otolaryngol 1961;53:317-24. 12. Sih T, Moura R, Caldas S, et al. Prophylaxis for recurrent acute
The Journal of Pediatrics August 1996
13.
14.
15.
16.
17.
18.
19.
20.
21.
otitis media: a Brazilian study. Int J Pediatr Otorhinolaryngol 1993;25:19-24. Kalm O, Prellner K, Christensen P. The effect of intravenous immunoglobulin treatment in recurrent acute otitis media. Int J Pediatr Otorhinolaryngol 1996;22:237-46. Kaleida P, Stool SE. Assessment of otoscopists' accuracy regarding middle ear effusion: otoscopic validation. Arch Pediatr Adolesc Med [Am J Dis Child] 1992;146:433-5. Asmar BI, Dajani AS, Del Belcaro MA, et al. Comparison of cefpodoxime proxetil and cefixime in the treatment of acute otitis media in infants and children. Pediatrics 1994;94:847-52. Marchant CD, McMillan PM, Shutin PA, et al. Objective diagnosis of otitis media in infancy by tympanometry and ipsilateral acoustic reflex thresholds. J Pediatr 1986;109:590-5. Chow AW, Hall CB, Klein JO, et al. Evaluation of new antiinfective drugs for the treatment of respiratory tract infections. Clin Infect Dis 1992;15:$62-88. Bjoro K, Froland SS, Yun Z, et al. Hepatitis C infection in patients with primary hypogammaglobulinemia after treatment with contaminated immune globulin. N Engl J Med 1994;331:1607-11. Clements DA, Langdon L, Bland C, et al. Influenza A vaccine decreases the incidence of otitis media in 6- to 30-month-old children in day care. Arch Pediatr Adolesc Med 1995;149:1113-7. Casselbrant ML, Kaleida PH, Rockett HE, et al. Efficiency of antimicrobial prophylaxis and tympanostomy tube insertion for prevention of recurrent acute otitis media: results of a randomized clinical trial. Pediatr Infect Dis J 1992;11:278-86. Paradise JL. Managing otitis media: a time for change. Pediattics 1995;96:712-5.
Editor's column
193
The other effect of intravenously administered respiratory syncytial virus-enriched immune g Iobulln ' for prophylaxis: Less acute otitis media? This issue contains an interesting report by Simoes et al.1 of a corollary effect of intravenously administered respiratory syncytial virus--enriched hyperimmune globulin. The Denver and Buffalo groups (two of the original five sites reporting the direct beneficial effects of RSVIG prophylaxis on RSV disease) report that RSV-at-risk infants receiving high doses of RSVIG at 750 mg/kg monthly from November to April had fewer episodes of acute otitis media during the administration period than did infants receiving low doses (150 mg/kg) of RSVIG or placebo. These results may not be totally surprising. Diseases for which antibody is crucial in protection or outcome are targets for active or passive immunization strategies (e.g., poliomyelitis or Haemophilus influenzae type b disease). Why, then, is there a need for a commentary? In the era of genetically engineered and other "high tech" therapies (read: potentially useful but always expensive), clinicians must ensure that interventions are effective and worth the costs (in money, time, inconvenience, and side effects). Thus further analysis of the Simoes article may put 47 episodes of AOM during a 3-year observation period in perspective--a perspective that is important for an expensive therapy ($4000 to $6000 per season for RSVIG), when today's prime directive seems to be cost containment. Do existing data suggest that polyclonal immune globu: lin, which had been pooled because of high RSV neutralizing titers, might protect infants from AOM? The pathogens most frequently isolated in AOM are bacteria, including Streptococcus pneumoniae (-35%), nontypeable H. influenzae (--25%), BranhamelIa catarrhalis (-15%), and group A streptococci (2% to 5%). Viruses axe increasingly recognized as copathogens. RSV has been estimated as the sole AOM pathogen in up to 7% of AOM episodes during the RSV season, 2-4 and influenza virus has been similarly implicated. Neutralizing antibodies are effective against all these pathogens in vitro. Therefore the beneficial in vivo effect reported in animal studies of disease caused by AOM pathogens, 5-7 particularly pneumococci and RSV, might be expected. Human data reveal that immunodeficient patients have less disease, particularly that caused by pneumoc0cci , with exogenously supplied immune globulin, a, 9 However, immune globulin prophylaxis for AOM in immunocompeJ Pediatr 1996;129:193-6 Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/18/74352
tent patients has been disappointing. Some studies reveal no benefit, whereas others report temporary, marginal, or selected benefits. 1°-13 Why would RSVIG produce better results? The authors' data provide some rationale, showing enhanced antibody titers against some AOM pathogens in comparison with 12 lots of commercial immune globulin from various manufacturers. RSVIG contained higher titers to RSV and P6 (the outer membrane protein shared putatively by all nontypeable H. influenzae organisms) but similar titers to three serotypes of pneumococci. One caveat is that RSV neutralizing antibody should reduce pathogen viability, whereas nontypeable H. influenzae and pneumococcal ELISA antibody may not. Protective neutralizing levels are not defined for these two pathogens, and ELISA antibody contains both neutralizing and nonneutralizing antibodies. An advantage for RSVIG could be expected against RSV but not necessarily against See related article, p. 214.
AOM ELISA OME RSV RSVIG
Acute otitis media Enzyme-linkedimmunosorbentassay Otitis media with effusion Respiratory syncytialvirus Respiratory syncytialvirus-enriched hyperimmune globulin
the other pathogens. For comparison, two monthly intramuscular doses of bacterial polysaccharide immune globulin with high titers of pneumococcal, H. influenzae type b, and meningococcal antibody were administered at the beginning of a 6-month observation period, l° The dose is difficult to compare but appears lower than the high doses of RSVIG used in the current study. However, reduced AOM was observed for the initial 2 months but not the subsequent 4 months when no further injections of bacterial polysaccharide immune globulin were given. The reduction was mostly in pneumococcal AOM, the AOM pathogen for which titers were high. Extrapolating, one could postulate that RSVIG as used by the current study protocol might provide benefits not previously observed because of higher antibody titers, higher doses of immune globulin, and a 6-monthly dosing schedule. Nevertheless, the Simoes study is also an AOM prophylaxis study. How can readers evaluate potential pitfalls in
194
Editor's column
AOM studies? Study design should attempt to ensure that groups differ only by the experimental treatment, so that outcome differences are actually due to the experimental therapy and are not innate differences between study group members. This is accomplished by uniformly applied inclusion and exclusion criteria for enrollment, prospectively collected data, and masking of investigators and subjects. Unfortunately, unexpected imbalances in demographic risk factors despite randomization or inadvertent confounding therapies may be discovered at end-of-study analysis. If so, the original groups should be restratified (subdivided) on the basis of the inadvertent confounding variables to analyze whether results were affected within or between the original groups. Investigators must also define as accurately as possible the end points of the study (i.e., each episode defined as AOM is indeed AOM). The comparative groups also need to be of sufficient size for accurate statistical analysis. Finally, is the therapy for AOM cost-effective? ff we apply this admittedly severe scrutiny to the Simoes report, how clinically useful is RSVIG for AOM prophylaxis? Reassuring factors are masking of investigators and the fact that the number of subjects in each group exceeds the "magic" 30, a minimum to give reasonable power to statistical analysis of group data. The overall data were collected prospectively, but the reported AOM data were retrospectively gathered and analyzed. This retrospective aspect introduced potential weakness in the data and apparently prevented analysis for otitis media with effusion because the data were not set up to track OME. This is unfortunate because reductions in OME episodes and perhaps in the need for pressure-equalizing tubes are also important issues. Nevertheless, retrospective data can be potentially powerful in evaluating accessory phenomena (in this case AOM) to the original main study objective (RSV disease) in these days of shrinking research dollars. Potentially confounding variables are found in the Methods section of the Simoes article. The authors indicate that few subjects had a history of AOM, a few had pressureequalizing tubes, and subjects with OME were placed on a regimen of sulfisoxazole (Gantrisin) prophylaxis. Pressureequalizing tubes or antibiotic prophylaxis would be expected to reduce the number of episodes of AOM, whereas a history of AOM at less than 6 months of age would be a risk factor for being otitis prone. No specific numbers for these variables are available. Are the subjects with an AOM history the same subjects who had pressure-equalizing tubes? Were the subjects with a history of AOM, pressure-equalizing tubes, or use of antibiotic prophylaxis evenly distributed throughout the experimental groups? No stratification is available to ascertain the effects of these potentially confounding variables. One cannot determine whether prophylaxis with sulfisoxazole, use of pressure-equalizing tubes, or a history of AOM affected the differing rates of AOM between groups or within a group. Additionally, passive smoke
The Journal of Pediatrics August 1996
might be an inadvertent variable. The fact that a household member smokes is not sufficiently quantitative in evaluating exposure to passive smoke. For example, if one parent smokes 8 to 10 cigarettes per day, is the exposure the same as if both parents and the babysitter smoke an aggregate of five packs a day? How much of the smoking took place in the infant's immediate environment? Smoking variables are difficult to quantitate but can be important. Overall, the potentially confounding factors need consideration when one is evaluating the power of the study's findings. The end points of analysis (AOM episodes) must be accurate. Stringency in diagnosing AOM ensures that differences in outcome (differences in episodes of AOM) are real. Severn tools have been used to provide reasonably accurate AOM end points. The first is a strict definition of AOM. Simoes et al. used acceptable clinical and tympanic membrane physical findings for this definition. The second tool is the use of validated investigators (i.e., observers whose results with pneumatic otoscopy compared favorably with myringotomy or tympanocentesis results on the s a m e earsl4). Two investigators were predominantly responsible for diagnosing AOM. This lowers the risk of interobserver variation but c o u l d increase the error rate if either observer was not as accurate as the other. Although not stated in the Methods section of the Simoes article, the two predominant masked observers appear to have been AOM-validated in one previous study. 15 The third tool is an objective measure of middle ear dynamics, usually tympanometry. 16 Tympanometry was not used. Tympanometry can be difficult in children less than 6 months of age or even in some former premature infants after 6 months of age. However, the use of a second masked observer as confirmation, if tympanometry was not to be used, could have strengthened confidence in the AOM diagnosis. Last, confirmation of inflammation in the middle ear by tympanocentesis or myringotomy would have been the strongest evidence of AOM. 17 This also would have provided microbiologic data for comparison with other investigations and more complete analysis of the effects of RSVIG in a pathogen-specific manner. Such analysis can be crucial with today's geographic differences in antibiotic resistance and proportions of common AOM pathogens. It" results of this study seem at odds with another, comparisons of culture proven pathogens could clarify why results differ. For immune globulin studies, microbiology is important because the most impact in previous immune globulin studies was on pneumococcal disease. It is possible that the results of the current study were affected by a microbiologic skew. For example, were there inordinate proportions of pneumococci? Or was the high-dose group predominantly afflicted by pneumococci and the low-dose or placebo groups infected with nontypeable H. influenzae? It is hoped that randomization prevents such bias, but nature may not have cooperated. In the absence of microbiologic data, the reader is left to speculate. Pneumococcus is the only
The Journal of Pediatrics Volume 129, Number 2
AOM pathogen with a propensity for invasive life-threatening disease, and the antibiotic choices for drag-resistant pneumococci appear more limited each winter. Additionally, spontaneous remission of pneumococcal AOM is less than that of the gram-negative pathogens that cause AOM (20% vs 50%). Thus data on pneumococcal episodes could sway the decision on clinical importance. Statistics validate differences that may be clinically important, but statistical significance by itself does not ensure clinical importance. Therefore decisions on clinical relevance should take into account both statistics and medical common sense. The overall statistical analysis by Simoes et al. 1 appears sound, but the significance of the analysis of trend for AOM associated with RSV infections seems less notable when one is looking at the raw data. A p value is reported to be 0.033 for data showing 0 of 9 RSV-associated episodes of AOM in high-dose, 2 of 8 in low-dose, and 5 of 19 in placebo recipients. This seems a striking p value for these data. In general, the smaller the numbers per group, the less robust is the statistical conclusion. Even if statistical significance is reached, does a difference of five AOM episodes during a 3-year period seem clinically significant? Presupposing a beneficial effect of RSVIG on AOM, what about pain or inconvenience of administration, the expected side effects, and the known cost? Adverse events appeared to be minimal, although monthly 4- to 5-hour infusions could be considered as adverse events. Placement of an indwelling line could circumvent some of these difficulties and allow home infusions, but is the risk of an indwelling line worth the benefit in regard to AOM? Moreover, RSVIG is a human biologic product. Though it seems safe, recent problems arose with hepatitis C caused by intravenously administered immune globulin, Is so use for nonserious infections should be considered with caution. From a cost perspective, the use of RSVIG is not reasonable AOM prophylaxis. In this study, 27 cases of AOM were prevented during a 3-year period in 11 of the 33 high-dose recipients by administering nearly 200 RSVIG infusions. Dividing the prevented AOM episodes by the 18 months of observation per therapy yields a group reduction rate of 1.5 AOM episodes per observation month. For each subject, AOM was reduced 0.045 episode per infusion. A cost estimate for two office visits and 1.5 antibiotic prescriptions per AOM episode might be $200. The cost savings over traditional care that might otherwise have been used would be approximately $5500 and, when averaged for the 33 subjects, would be $163.63 per subject for a 6-month observation period, or $27.27 saved per month per subject. Thus we could save an estimated $5500 on traditional AOM treatment by using approximately $200,000 worth of RSVIG (estimated cost of about $1000 per infusion). The estimated cost would be $7407 per prevented AOM episode. This is not a resounding economic endorsement for RSVIG use unless recipients receive a major benefit from protection
Editor's column
195
against RSV, the pathogen for which the product was designed. As the authors correctly state, the economics of effects on AOM do not stand alone and can be considered only together with costs related to RSV protection. Should these results direct our efforts to alternative beneficial strategies? The RSVIG data lend credence to humoral protection against AOM, if antibody titers are sufficient. Ideally a low-volume, low-cost, infrequently administered preparation of immune globulin could be developed. Do the monoclonal antibody preparations now under investigation for RSV treatment have potential? Probably not. Because they are not polyclonal and have no antibody to bacterial pathogens, they should affect only RSV-associated AOM (5 episodes in 19 subjects during a 3-year period). More likely, strategies for active immunization against bacterial AOM pathogens such as pneumococcus, nontypeable H. influenzae, and B. catarrhalis, as well as RSV and influenza virus, should be stimulated by these current data. These and other findings regarding the use of passive pneumococcal antibody preparations increase the prospect of reducing AOM caused by pneumococci with the investigational conjugate polyvalent pneumococcal vaccines. Other recent data also raise hope for AOM protection with viral vaccines (e.g., influenza vaccine). 19 The article by Simoes et al.1 is interesting and provocative despite minor design and analysis concerns. The data are useful and informative, giving direction for further investigations and adding knowledge on RSVIG, a new weapon against viral disease in vulnerable populations. However, the bottom line is that current data do not substantiate routine use of immune globulin prophylaxis for AOM in immunocompetent hosts. Nevertheless, fewer episodes of AOM may be a nice side effect of RSVIG prophylaxis for RSV disease. Additionally, we are nudged closer to a true AOM vaccine strategy, which might combine conjugate pneumococcal, influenza, and perhaps RSV vaccines. Until then, we will continue to use breast-feeding, currently available pneumococcal vaccine after 2 years of age, annual influenza vaccine, antibiotic prophylaxis in limited situations, and at times pressure-equalizing tubes to prevent AOM 2°, 21 in otitisprone patients not eligible for RSV prophylaxis.
Christopher J. Harrison, MD Associate Professor of Pediatrics and Medical Microbiology and Immunology Creighton University School of Medicine University of Nebraska Medical Center Omaha, NE 6813I REFERENCES
1. $imoes EAF, Groothuis JR, Tristram DA, Allessi K, Lehr MV, Siber GR, et al. Respiratory syncyfial virus-enriched globulin for the prevention of acute otitis media in high-risk children. J Pediatr 1996;129:214-9. 2. Sarkkinen H, Ruuskanen O, Meurman O, et al. Identification of respiratory virus antigens in middle ear fluids of children with acute otitis media. J Infect Dis 1985;151:444-8.
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Editor's column
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