Wilkins L, Lewis RA, Klein R, Rosemberg E. Suppression of adrenal andro- Lee PA, Plotnick LP, Kowarski AA, Migeon CJ, eds. Congenital Adrenal gen secretion by cortisone in a case of congenital adrenal hyperplasia. Bull Hyperplasia. Baltimore, MD: University Park Press; 1977:1–532 Johns Hopkins Hosp. 1950;86:249–252 Miller WL. Genetics, diagnosis and management of 21-hydroxylase defi- Wilkins L, Lewis RA, Klein R, Gardner L, Crigler JF, Rosemberg E, Migeon ciency. J Clin Endocrinol Metab. 1994;78:241–246 CJ. Treatment of congenital adrenal hyperplasia with cortisone. J Clin Miller WL. Pathophysiology, genetics, and treatment of hyperandrogenism. Endocrinol. 1951;11:1–25 Pediatr Clin North Am. 1997;44:375–395 Morel Y, Miller WL. Clinical and molecular genetics of congenital adrenal REVIEW ARTICLES AND MONOGRAPHS WHICH hyperplasia due to 21-hydroxylase deficiency. Adv Hum Genet. 1991;20:1–68 INCLUDE CITATIONS NOT LISTED ABOVE New MI, ed. Congenital adrenal hyperplasia. Ann NY Acad Sci. 1985;458: 1–287 Donahoue PA, Parker K, Migeon CJ. Congenital adrenal hyperplasia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular New MI. Congenital adrenal hyperplasia. In: DeGroot LJ, Besser M, Burger Bases of Inherited Disease. 7th ed. New York, NY: McGraw-Hill, 1995: HG, et al, eds. Endocrinology. 3rd ed, vol 2. Philadelphia, PA: WB 2929–2966 Saunders; 1995:1813–1835 Grumbach MM, Conte FA. Disorders of sex differentiation. In: Wilson JD, White PC, New MI. Genetic basis of endocrine disease 2: congenital adrenal Foster DW, Kronenberg HM, Larsen PR, eds. Williams’ Textbook of Endo- hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab. crinology. 9th ed. Philadelphia, PA: WB Saunders; 1998:1303–1425 1992;74:6–11

COMMENTARY

The Rational Use of Antimicrobials in Acute Otitis Media: A Bacteriologic Investigation of Otitis Media in Infancy, by E. A. Mortimer Jr, and R. L. Watterson Jr, Pediatrics, 1956;17:359–366; Otitis Media in the Practice of Pediatrics: Bacteriological and Clinical Observations, by J. D. Coffey Jr, Pediatrics, 1966;38:25–32; Acute Otitis Media: Treatment Results in Relation to Bacterial Etiology, by B. W. Nilson, et al, Pediatrics, 1969;43: 351–358; The “In Vivo Sensitivity Test”—Bacteriology of Middle Ear Exudate During Antimicrobial Therapy in Otitis Media, by V. M. Howie and J. H. Ploussard, Pediatrics, 1969;44:940–944; and Otitis Media: A Clinical and Bacteriological Correlation, by V. M. Howie, et al, Pediatrics, 1970;45:29–35

Comments by Jack L. Paradise, MD

he most common reason for antimicrobial use over a 14-year period beginning in 1956. Each of the in United States children is treatment of otitis reports concerned the bacteriology of AOM as deter- Tmedia.1 Of 44.5 million office-based prescrip- mined from aspiration and culture of middle ear tions for antimicrobials in 1986 for children younger exudate. Taken as a group, these reports in my judg- than than 10 years of age, 42% were for otitis media,2 ment constitute the most important contribution of and of the estimated 20 million visits in 1990 for otitis an otolaryngologic nature to appear in the 50-year media by children younger than 14 years of age, history of Pediatrics. Today, when otitis media con- antimicrobials were prescribed at Ͼ80%.3,4 In a recent stitutes the most common reason for office visits by prospective study, antimicrobial treatment of otitis children,3 it seems remarkable that during the 8 years media accounted for Ͼ90% of all antimicrobial use of publication of Pediatrics before 1956, only two during the first 2 years of life.5 reports in any way involving otitis media were pub- Foundations for rational use of antimicrobials for lished: one, a case report describing chronic suppu- acute otitis media (AOM) were first laid down in the rative otitis media as one element of what came to be 6–10 United States in a series of five reports in Pediatrics termed the Wiskott–Aldrich syndrome,11 and the other, a brief discussion of the diagnosis and man- agement of secretory otitis media (otitis media with From the Department of Pediatrics, University of Pittsburgh School of 12 Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania. effusion [OME]). Received for publication Mar 19, 1998; accepted Mar 19, 1998. An additional bit of historical perspective is nec- Address correspondence to: Jack L. Paradise, MD, University of Pittsburgh essary as preface to a discussion of the five selected School of Medicine, Children’s Hospital of Pittsburgh, 3705 Fifth Ave, reports. Early in the 20th century, the organisms Pittsburgh, PA 15213-2583. PEDIATRICS (ISSN 0031 4005). Copyright © 1998 by the American Acad- implicated most commonly in AOM were the group emy of Pediatrics. A ␤-hemolytic streptococcus (Streptococcus pyogenes)

Downloaded from www.aappublications.org/news by guest on September 29, 2021 SUPPLEMENT 221 and the pneumococcus (Streptococcus pneumoniae); be the cause of a substantial number of cases. Rela- other frequently encountered organisms considered tively few cases were attributable to S pyogenes. Cof- pathogenic included staphylococci, other varieties of fey made a number of important observations in- streptococci, Haemophilus influenzae, and coliform ba- cluding 1) that a majority of the children had cilli.13,14 Treatment consisted primarily of measures apparently been free of ear pain; 2) that a number of to relieve pain, and in cases that seemed severe, children—primarily those in whom H influenzae was myringotomy.13 By the late 1930s, sulfanilamide had cultured from the middle ear—had associated con- been shown to be effective in treating streptococcal junctival discharge; 3) that those with bullous myr- AOM—in one study,15 reducing the proportion of ingitis, an entity thought previously to be attribut- cases requiring mastoidectomy from 69% to 8%— able to viral infection, in fact had positive cultures for and sulfapyridine had shown promise in treating S pneumoniae and/or H influenzae; 4) that none of the pneumococcal AOM.14 Nonetheless, in the discus- children from whose aspirates M catarrhalis was iso- sion of the treatment of AOM in a standard pediatric lated were acutely ill or febrile; and 5) that of the textbook of the time, almost two pages were devoted children whose cultures showed no growth, most to myringotomy but only a single paragraph to sul- had a history of recurrent otitis media, many had fonamide therapy.14 Sulfonamides remained the only received antimicrobial treatment, and many had vis- antimicrobial drugs available for treating AOM until cid middle ear effusions characteristic of OME. In the mid-1940s, when penicillin first became avail- instances of relapse or recurrence of otitis media, able. By the time volume 1 of Pediatrics was Coffey often found middle ear pathogens other than published in 1948, antibacterial therapy with sulfon- those recovered originally. Finally, he gently re- amides or penicillin had become, among pediatri- minded readers that “the number of cases found cians, the predominant mode of treating AOM. A varies directly with the diligence with which they are standard pediatric textbook of that time stated that sought.” The observation that M catarrhalis was a such therapy had “reduced materially the incidence middle ear pathogen had been made previously in of suppurative otitis media and also of mastoiditis,” Finland by Gro¨nroos,21 but Coffey appears to have and it also noted “a growing tendency toward con- been the first anywhere to report the presence of the servatism” regarding the use of myringotomy.16 organisms intracellularly in middle ear exudate. However, only in connection with myringotomy was The connection between initial bacteriologic find- bacterial culture of middle ear contents mentioned. ings in AOM and the outcome of specific treatments In 1956, in “A Bacteriologic Investigation of Otitis was first made in 1969 by Bjorn Nilson and col- Media in Infancy,”6 Edward Mortimer and Reich leagues at Johns Hopkins, in “Acute Otitis Media: Watterson at Cleveland City Hospital reported find- Treatment Results in Relation to Bacterial Etiology.”8 ings of the first study in the United States to use In a double-blind, randomized trial, they assigned tympanocentesis for diagnostic purposes in children 306 children younger than 3 years of age with AOM with AOM. Previous such studies had been under- to receive either penicillin V, penicillin V plus a taken only in Scandinavia.17–20 Mortimer and Watter- sulfonamide, or ampicillin. Clinical response was son found, as did the the Scandinavian investigators, correlated with the type of organism isolated from that in children younger than 2 years of age, the most the initial middle ear aspirate. Patients with otitis commonly recovered pathogen was S pneumoniae, generally, irrespective of culture results, and patients and the next most common, nontypeable H influen- with pneumococcal otitis fared equally well with zae. They considered staphylococci, diphtheroids, each of the three regimens. However, patients in and other miscellaneous organisms recovered from whom the infecting organism was H influenzae fared the aspirates to be contaminants because they were better with either the penicillin-sulfa combination or cultured also from the surface of the tympanic mem- ampicillin than with penicillin V alone. Correspond- brane before aspiration. Not infrequently as well, ingly, most patients receiving ampicillin achieved cultures of middle ear exudate were sterile. Clini- bacteriostatic serum levels for the strains of H influ- cally, Mortimer and Watterson pointed out that the enzae initially isolated, whereas most patients receiv- relative severity of the otitis, as judged by the ap- ing penicillin V did not. This report by Nilson and pearance of the eardrum, did not correlate well with colleagues appears to have offered the first reported the presence or absence of organisms on culture. evidence of the superiority of one antimicrobial over They also noted that “it was unusual to find an another in treating otitis media caused by a specific organism in the middle ear that was not also present pathogen. in the nose and/or the throat.” Their report included Later in 1969 came the next development in the use a figure showing the type of otoscope and the aspi- of information derived from tympanocentesis to ra- ration equipment they used. tionalize antimicrobial therapy for otitis media. In Ten years later, in “Otitis Media in the Practice of “The ‘In Vivo Sensitivity Test’—Bacteriology of Mid- Pediatrics: Bacteriological and Clinical Observa- dle Ear Exudate During Antimicrobial Therapy in tions,”7 John Coffey reported findings gathered over Otitis Media,”9 Virgil Howie and John Ploussard re- a 1-year period in his private pediatric practice in ported data derived from initial and repeat tympa- Natchez, MS. Coffey collected middle ear specimens nocentesis in patients with otitis media in their pri- by tympanocentesis from 267 infants and children vate practices in Huntsville, AL. Starting from the with purulent otitis media, and found that in addi- premise that “the ultimate test of the efficacy of tion to S pneumoniae and H influenzae, Moraxella ca- antibiotic therapy is its ability to eradicate the organ- tarrhalis (then called Neisseria catarrhalis) appeared to ism at the site of infection,” Howie and Ploussard

222 SUPPLEMENT Downloaded from www.aappublications.org/news by guest on September 29, 2021 undertook to evaluate response to treatment accord- treating children with AOM, we currently confront a ingly. In the course of 858 episodes treated on an major problem of antimicrobial resistance, particu- individual basis with a variety of antimicrobials, they larly on the part of S pneumoniae.22 In especially re- performed a total of 1233 tympanocenteses and cul- fractory cases, there is no reasonable substitute for tures. In 271 of the episodes, they were able not only diagnostic tympanocentesis (or myringotomy) to en- to perform initial tympanocentesis and culture, but able identification of the offending organism (if any) also to repeat the procedure 1 to 12 days after insti- and determination of its antimicrobial sensitivities, tuting antimicrobial therapy. Importantly, they per- so that treatment can be directed accordingly. Incis- formed the repeat tympanocenteses whenever feasi- ing the tympanic membrane in children with AOM ble, without regard to patients’ degree of clinical to relieve pressure and accomplish drainage became improvement. They found that both S pneumoniae a lost art for most pediatricians trained after the and H influenzae were eradicated most effectively advent of the antimicrobial era, and few currently from middle ear exudate by ampicillin or by sulfon- practicing primary care clinicians perform the proce- amides combined with either penicillin V or eryth- dure. Even fewer, in my experience, feel comfortable romycin. Sulfonamides alone and tetracycline were undertaking diagnostic tympanocentesis. That is a both relatively ineffective in eradicating S pneu- limitation that cries out for remedying. If treatment is moniae, whereas penicillin and erythromycin were to be rationalized maximally, pediatricians must in- both relatively ineffective in eradicating H influenzae. corporate tympanocentesis into their armamentar- Clinical outcomes, as distinct from bacteriologic out- ium. To do so, they will need at minimum to acquire comes, were not reported by Howie and Ploussard. a surgical head for their otoscopes, no different from Accordingly, they were careful to qualify their infer- the type pictured 42 years ago in the report by Mor- ences about the effectiveness of therapy by prefacing timer and Watterson6 and pictured again in another the inferences with phrases such as “using only our report in Pediatrics 25 years later.23 A more recent data presented . . . ” and “ . . . by the ‘In Vivo Sensi- report had as its goal improving general familiarity tivity Test . . . ,’” and they cautioned that “the effec- with a convenient tympanocentesis apparatus and tiveness of a drug in sterilizing the middle ear may with appropriate technique for performing the pro- not mean that it is the best drug for the patient.” cedure.24 Finally, in 1970, in “Otitis Media: A Clinical and An unanswered research question involving tym- Bacteriological Correlation,”10 Howie and Ploussard, panocentesis concerns the optimal design for com- together with Richard Lester, provided additional parative trials of antimicrobials in treating AOM. clinical details about the same 858 episodes in rela- Most experts would agree that children entering tion to the initial bacteriologic findings. In contrast to such trials should undergo initial tympanocentesis previous reports suggesting that H influenzae caused and aspiration of middle ear contents so that the AOM in children older than 3 years of age only infecting organism(s) can be identified. Experts do infrequently, Howie and colleagues found no corre- not agree, however, on whether such trials should be lation between patient age and the type of infecting designed to measure primarily clinical outcomes or organism. Notably, however, although symptoms whether, instead, they should focus primarily on were variable and inconsistent, the cases in their bacteriologic outcomes as determined by the results series attributable to S pneumoniae were significantly of repeat tympanocentesis 3 to 5 days after therapy more often associated with severe pain and with has been instituted, much as originally described by high fever than were the cases attributable to H Howie and Ploussard.9 Marchant and colleagues influenzae. Correspondingly, most of the cases attrib- have called attention to three interrelated factors that utable to H influenzae were associated with little or no argue for a primary focus on bacteriologic outcomes: fever and with mild or no pain. 1) the well known fact that some patients with AOM Among the noteworthy aspects of these studies fail to improve clinically despite treatment with an that collectively have contributed so much to our antimicrobial effective against the infecting organ- understanding of AOM, perhaps the most notewor- ism, whereas others improve despite treatment with thy is the fact that major elements of the work were an ineffective antimicrobial; 2) limited correlations contributed by pediatric practitioners. These individ- between clinical efficacy (measured by the presence uals recognized the need for new knowledge; they or absence of symptoms as noted at a visit 3 to 6 days brought to bear keen clinical skills to make important after the onset of therapy) and bacteriologic efficacy observations; and they had the initiative and the (measured at the same visit by tympanocentesis and courage, and took the time in the course of their culture in the comparative trials of antimicrobials practices, to perform the necessary investigative pro- that they conducted); and 3) in the same trials, cedures and to record, analyze, and report their find- greater differences between drugs in bacteriologic ings. This is not to depreciate the contributions of efficacy than in clinical efficacy. Accordingly, March- those working in academic settings, but rather to ant and colleagues concluded that between-drug dif- acknowledge not only the practitioners’ contribu- ferences can be demonstrated more readily with bac- tions to our understanding, but also the exceptional teriologic than with clinical outcome measures, and effort required to overcome the obstacles to research therefore that tests of differences between bacterio- inherent in pediatric practice. logic outcomes would require smaller sample sizes A timely lesson to be derived from these studies is than would tests of differences between clinical out- that tympanocentesis is a procedure well within the comes.25 purview of everyday pediatric practice. As clinicians The proposition appears to be persuasive, but the

Downloaded from www.aappublications.org/news by guest on September 29, 2021 SUPPLEMENT 223 validity of its evidential basis depends on a number cial groundwork not only for rational antimicrobial of assumptions including 1) that symptomatic re- treatment of AOM, but also for continuing efforts by sponse at 3 to 6 days is a consistently valid indicator otitis media researchers in this complex era of evolv- of concurrent middle ear status and also a valid ing antimicrobial resistance. predictor of middle ear status that is obtained at the REFERENCES termination of therapy or at any given point there- after; 2) that in any individual episode of AOM 1. McCaig LF, Hughes JM. Trends in antimicrobial drug prescribing among office-based physicians in the United States. JAMA. 1995;273: treated with a given antimicrobial drug, symptom- 214–219 atic status on each of days 3 to 6 is invariably the 2. Nelson WL, Kuritsky JN, Kennedy DL, Lao CS. Outpatient pediatric same (My clinical experience would suggest other- antibiotic use in the US: trends and therapy for otitis media, 1977–1986. American Society for Microbiology Program and Abstracts of the 27th wise); 3) that in any such episode, middle ear bacte- Interscience Conference on Antimicrobial Agents and Chemotherapy; riologic status on each of days 3 to 6 also is invariably October 4–7, 1987; Washington, DC the same; 4) that the time between the repeat tym- 3. Schappert SM. Office Visits for Otitis Media: United States, 1975–90. panocentesis and the most recent preceding dose of Hyattsville, MD: National Center for Health Statistics; Vital and Health Statistics; No 214; 1992 antimicrobial has no influence on the culture results; 4. Nelson CR. Drug Utilization in Office Practice, National Ambulatory Med- 5) that the recovery of any bacterial pathogens from ical Care Survey, 1990. Hyattsville, MD: National Center for Health middle ear exudate, irrespective of their concentra- Statistics; Vital and Health Statistics; No 232; 1993 tion, is indicative of inadequate antibacterial efficacy; 5. Paradise JL, Rockette HE, Colborn DK, et al. Otitis media in 2253 Pittsburgh-area infants: prevalence and risk factors during the first two 6) that whatever the antimicrobial drug used, the rate years of life. Pediatrics. 1997;99:318–333 of bacterial killing is a consistent indicator of even- 6. Mortimer EA Jr, Watterson RL Jr. A bacteriologic investigation of otitis tual antibacterial efficacy; and 7) that performing media in infancy. Pediatrics. 1956;17:359–366 7. Coffey JD Jr. Otitis media in the practice of pediatrics: bacteriological tympanocentesis twice within 6 days does not affect and clinical observations. Pediatrics. 1966;38:25–32 clinical outcomes favorably, and, therefore, does not 8. Nilson BW, Poland RL, Thompson RS, Morehead D, Baghdassarian A, obscure differences in such outcomes that might oth- Carver DH. Acute otitis media: treatment results in relation to bacterial erwise have been observable. None of these assump- etiology. Pediatrics. 1969;43:351–358 9. Howie VM, Ploussard JH. The “in vivo sensitivity test”—bacteriology tions has, to my knowledge, been tested. of middle ear exudate during antimicrobial therapy in otitis media. Currently, some experts favor a trial design that Pediatrics. 1969;44:940–944 would involve relatively small numbers of subjects 10. Howie VM, Ploussard JH, Lester RL Jr. Otitis media: a clinical and bacteriological correlation. Pediatrics. 1970;45:29–35 and would require both initial and repeat tympano- 11. Aldrich RA, Steinberg AG, Campbell DC. Pedigree demonstrating a centesis routinely. Others, however, favor a design sex-linked recessive condition characterized by draining ears, eczema- that would involve, in combination with in vitro toid dermatitis and bloody diarrhea. Pediatrics. 1954;13:133–139 studies of efficacy of the drugs in question, some- 12. Samuels SS. Secretory otitis media in children. Pediatrics. 1955;15: 334–336 what larger numbers of subjects, stratification by 13. Politzer A. A Textbook of the Diseases of the Ear, 5th ed. Philadelphia, PA: initial clinical severity, outcome measures that in- Lea & Febiger; 1909:722 clude otoscopic findings as well as symptomatic re- 14. Holt LE Jr, McIntosh R. Holt’s Diseases of Infancy and Childhood. New sponse, and repeat tympanocentesis only in subjects York, NY: D Appleton–Century Company; 1940:382–396 15. Fisher GE. Sulfanilamide in the treatment of otitis media. JAMA. 1939; with clinically defined treatment failure (M. L. Co- 112:2271 hen, MD, personal communication, July 1997; letter 16. Nelson WE. The Ear. 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Clinico-bacteriologic studies on acute otitis media: as- piration of tympanum as a diagnostic and therapeutic method. Acta 5, even though by then most will have become Otolaryngol (Stockh). 1953;(suppl 107):1–82 asymptomatic, or whether it would be preferable 21. Gro¨nroos JA, Kortekangas AE, Ojala L, Vuori M. The aetiology of acute to enroll a larger number of subjects, all of whom middle ear infection. Acta Otolaryngol (Stockh). 1964;:58:149–158 would undergo initial tympanocentesis but few of 22. Paradise JL. Managing otitis media: a time for change. Pediatrics. 1995; 96:712–715 whom would undergo repeat tympanocentesis be- 23. Paradise JL. Otitis media in infants and children. Pediatrics. 1980;65: cause few would have an unfavorable clinical 917–943 course. The issue involves both practical and eth- 24. Hoberman A, Paradise JL, Wald ER. Tympanocentesis technique revis- ical considerations. ited. Pediatr Infect Dis J. 1997;16:S25–S26 25. Marchant CD, Carlin SA, Johnson CE, Shurin PA. Measuring the com- Plainly, the reports over the past half-century in parative efficacy of antibacterial agents for acute otitis media: the “Pol- Pediatrics involving tympanocentesis have laid cru- lyanna phenomenon.” J Pediatr. 1992;120:72–77

224 SUPPLEMENT Downloaded from www.aappublications.org/news by guest on September 29, 2021 The Rational Use of Antimicrobials in Acute Otitis Media: A Bacteriologic Investigation of Otitis Media in Infancy , by E. A. Mortimer Jr, and R. L. Watterson Jr, Pediatrics, 1956;17:359−366; Otitis Media in the Practice of Pediatrics: Bacteriological and Clinical Observations , by J. D. Coffey Jr,Pediatrics, 1966;38:25−32; Acute Otitis Media: Treatment Results in Relation to Bacterial Etiology , by B. W. Nilson, et al, Pediatrics, 1969;43:351−358; The ''In Vivo Sensitivity Test''−−Bacteriology of Middle Ear Exudate During Antimicrobial Therapy in Otitis Media , by V. M. Howie and J. H. Ploussard, Pediatrics, 1969;44:940−944; andOtitis Media: A Clinical and Bacteriological Correlation, by V. M. Howie, et al, Pediatrics, 1970;45:29−35 Jack L. Paradise Pediatrics 1998;102;221

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/102/Supplement_1/221 References This article cites 17 articles, 10 of which you can access for free at: http://pediatrics.aappublications.org/content/102/Supplement_1/221# BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Otitis Media http://www.aappublications.org/cgi/collection/otitis_media_sub Infectious Disease http://www.aappublications.org/cgi/collection/infectious_diseases_su b Pharmacology http://www.aappublications.org/cgi/collection/pharmacology_sub Therapeutics http://www.aappublications.org/cgi/collection/therapeutics_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 29, 2021 The Rational Use of Antimicrobials in Acute Otitis Media: A Bacteriologic Investigation of Otitis Media in Infancy , by E. A. Mortimer Jr, and R. L. Watterson Jr, Pediatrics, 1956;17:359−366; Otitis Media in the Practice of Pediatrics: Bacteriological and Clinical Observations , by J. D. Coffey Jr,Pediatrics, 1966;38:25−32; Acute Otitis Media: Treatment Results in Relation to Bacterial Etiology , by B. W. Nilson, et al, Pediatrics, 1969;43:351−358; The ''In Vivo Sensitivity Test''−−Bacteriology of Middle Ear Exudate During Antimicrobial Therapy in Otitis Media , by V. M. Howie and J. H. Ploussard, Pediatrics, 1969;44:940−944; andOtitis Media: A Clinical and Bacteriological Correlation, by V. M. Howie, et al, Pediatrics, 1970;45:29−35 Jack L. Paradise Pediatrics 1998;102;221

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1998 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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