Respiratory syncytial virus–enriched globulin for the prevention of acute otitis media in high-risk children

Respiratory syncytial virus-enriched globulin for the prevention of acute otitis media in high-risk children E. A. F. Simoes, MD, DCh, J, R. Groothuis, MD, D. A. Tristram, MD, K. Allessi, RN, M. V. Lehr, RN, G. R, Siber, MD, a n d R. C. Welliver, MD From the Department of Pediatrics, Divisionsof Infectious Diseasesand Neonatology, the Universityof Colorado School of Medicine and Children's Hospital, Denver; the Department of Pediatrics, Division of Infectious Diseases,State Universityof New York Medical Centers Hospital, Buffalo; the Divisionof Infectious Diseases,Dana Farber Cancer Institute, Harvard Medical School and the Massachuseffs Public Health Biologic Laboratories, Boston. Acute otitis media (AOM) has been associated with respiratory syncytial virus (RSV) infection; AOM develops in up to one third of children with RSV illness. A masked multicenter trial used an immune globulin enriched with RSV-neutralizing antibodies (RSVIG) to prevent RSV infection of the lower respiratory tract in 249 children with either bronchopulmonary dysplasia, congenital heart disease, or prematurity. To determine whether monthly RSVIG therapy might decrease the incidence of AOM, we retrospectively analyzed the records of 109 children in two of the centers. RSVIG was administered during RSV season at a high dose of 750 m g / k g monthly or a low dose of 150 m g / k g monthly; control children received no RSVIG. Children were examined for AOM by masked observers using pneumatic otoscopy. No difference in sex, race, underlying diagnosis, number of persons in the home, exposure to smoking, or atopy was found between groups studied. In recipients of high doses of RSVIG, significantly less AOM developed per season than in control children (mean episodes, 0.15 vs 0.78; p = 0.003), and fewer episodes of RSV-related AOM occurred (0 vs 5; p = 0.047). Low doses of RSVIG did not have a clinically significant impact. High doses of RSVIG appeared to have a significant impact on preventing AOM (both RSV- and non-RSV-related AOM) in these-high risk populations. This finding may have important implications in the development of improved preventive modalities for AOM. (J Pediatr 1996;

129:214-9) It has been estimated that children in the United States have 9.3 million episodes of acute otitis media in the first 2 years Supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases Contract No. 1A182520; General Clinical Research Center Program No. 5 MO1 RR00069, of the Division of Research Resources, National Institutes of Health (RR69); and MedImmune, Inc. Presented in part at the Society for Pediatric Research, May 1994, Seattle, Wash. Submitted for publication Nov. 29, 1995; accepted March 9, 1996. Reprint requests: Eric A.F. Simoes, MD, Children's Hospital, 1056 E. 19th Ave., B070, Denver, CO 80218. Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/20/73293

214

of life. 1 The cost of medical and surgical treatment of A O M has been estimated at $3 to $4 billion per year. 2 A recent metaanalysis of the clinical efficacy of antibiotics in the See c o m m e n t a r y , p. 193. AOM BPIG IVIG RSV RSVIG

Acute otitis media Bacterial polysaccharide immune globulin Intravenously administered immune globulin Respiratory syncytial vims RSV antibody-enriched immune globulin

treatment of acute otitis media has shown only a 13.7% benefit (95% confidence interval: 8.2% to 19.2%) compared with no treatment)' 4 Entry into these studies was not well

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controlled, which may have skewed results toward placebo. Nonetheless, effective measures to prevent AOM could result in significant reductions in morbidity and expense. Efforts to prevent AOM thus far have been primarily directed against bacterial pathogens. Active immunization with a 23-valent pneumococcal vaccine reduced the frequency of pneumococcal AOM caused by those types that induced an adequate immune response but did not reduce the overall incidence of AOM. 57 Passive immunoprophylaxis against AOM by means of immune globulin has also been examined.81° Shurin et al.v studied the prevention of recurrent AOM in children less than 24 months of age, using a bacterial polysaccharide immune globulin. In this randomized, stratified, double-blind, placebo-controlled trial, the BPIG group had significantly fewer individual episodes of AOM caused by Streptococcus pneumoniae. However, the overall incidence of episodes of AOM during the 4-month period of study was similar for BPIG and placebo recipients. The absence of an effect on AOM incidence was thought to be due to the fact that S. pneumoniae AOM accounted for only 20% of all AOM episodes in this population of children. We postulated that an immune globulin that contained antibody against respiratory viruses as well as bacterial pathogens might be an effective means of prevention of AOM. The dramatic increase of AOM episodes concomitant with the season for viral upper respiratory tract infection has been well documented. 12-15 AOM has been observed in conjunctionwith respiratory syncytial virus, adenovirus, and influenza virusJ 5 RSV, in particular, is an important pathogen; up to 30% of children who have RSV also have AOM.16, 17A recently concluded masked multicenter trial to determine the efficacy of RSV antibody-enriched immune globulin against lower respiratory tract infection in high-risk children18 allowed us the opportunity to assess whether RSVIG therapy might also decrease the incidence of AOM.

METHODS This study was part of a prospective, masked multicenter trial using RSVIG to prevent severe RSV lower respiratory tract infection in children with underlying bronchopulmonary dysplasia, prematnrity, or congenital heart disease. Details of this trial have been published elsewhereJ 8 The RSVIG preparation was developed and produced by the Massachusetts Public Health Biologic Laboratories) 9 It is currently distributed by MedImmune, Inc. (Gaithersburg, Md.), under the trade name Respigam. Subjects included preterm infants less than 35 weeks of postconceptional age with or without bronchopulmonary dysplasia, and children with severe congenital heart disease. Children were randomly placed into three groups: a "high-dose group" receiving RSVIG at a dose of 750 mg/kg monthly, a"low-dose group" receiving 150 mg/kg monthly,

Simoes et al.

2 15

Table I. Patient demographics High-dose Low-dose Control group* groupt group (n = 33) (n = 35) (n = 41)

Female gender: No. (%) 15 (45) 23 (66) Median gestationalage (wk) at 29 32 enrollment (Range) (24-44) (24-42) Median age (yr) at enrollment 0.6 0.5 (Range) (0.1-2.4) 0.2-3.3) Underlyingdisease Bronchopulmonarydysplasia 21 18 Congenitalheart disease 9 13 Preterrn 3 4 Either parent smoked: No. (%) 15 (46) 15 (43) Persons in home ->4: No. (%) 16 (48) 12 (34) 1

17 (42) 32 (24-41) 0.4 0.1-4.0) 20 14 7 19 (46) 19 (46)

p Value>0.05 (not significant)for all variables. *High dose of RSVIG= 750 mg/kg. ?Low dose of RSVIG= 150 mg/kg. and a "control group" of children who received no RSVIG infusions. Infusions were given on a monthly basis from November through April through thi'ee respiratory seasons. Children in all groups, including control children, were examined at least monthly as well as at the time any acute respiratory illness developed. Children were examined at all monthly well visits and at ill visits. If the acute respiratory illness was associated with RSV, patients were seen daily (for hospitalized children) and every alternate day as outpatients if ambulatory until their respiratory status returned to baseline. Children with non-RSV-associated AOM were examined up to 2 to 3 weeks after completion of treatment. A new episode of AOM was diagnosed only if the previously affected eardrum(s) had been documented as having returned to baseline status. Children with otitis media with effusion were given antibiotic prophylaxis with sulfisoxazole (Gantrisin). A two-team approach was used to maintain masking and avoid bias. A nonmasked team randomly assigned patients and conducted all monthly well visits. These visits included an interim history, baseline physical examination, and RSVIG infusions for those in infusion groups. A masked team was kept unaware of the infusion status of patients. This team performed surveillance for acute respiratory illness by means of weekly telephone calls and also examined all children at the time of each episode of acute respiratory illness. The examination included an illness history, a physical examination, and a nasal wash for viral culture and rapid RSV antigen detection. The masked investigators also determined the severity of illness at the time of each RSV infection and determined the presence of otitis media in all children. The RSVIG study was approved by the human subjects committees at all sites, and parents or guardians signed an informed consent form on enrollment.

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Simoes et al.

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T a b l e II. Frequency of acute ofitis media in high-risk children treated with monthly infusions of high and low doses of RSVIG and in control children

Patients: No. AOM episodes during study period Mean No. of AOM episodes per (Range) Children with 1 or more AOM episodes Children with 2 or more AOM episodes RSV respiratory infection RSV-associated AOM episodes

HD RSVIG group

LD RSVIG group

Control group

33 5 0.15 (0-1) 5 0 9 0

35 12 0.34 (0-3) 8 3 8 2

41 32 0.78 (0-6) 19 7 19 5

HD vs Control

LD vs Control

p

(p)

(p)

0.62*

0.35*

0.49*

0.008"~

0.003"~

0.06:)

0.008§ 0.042§ 0.09* 0.033*

0.005§ 0.013§ 0.21" 0.084#

0.03§ 0.28§ 0.06* 0.44#

HD, High dose;LD, low dose. *Chi-squaretest. tOne-way analysisof variance. :~tTest for independentsamples. §Chi-squareapproximation(Goodmanand Kruskal). #Fisher Exact Test.

The otitis media study was conducted at two of the five clinical sites, Buffalo Children's Hospital and Children's Hospital, Denver, Colo. These sites were selected because the majority of examinations (>90%) were performed by one individual at each site who had previously validated the accuracy of clinical examinations with tympanocentesis in prior studies,z° Examination of the ear was performed by pneumatic otoscopy; tympanocentesis and tympanometry were not performed. AOM was diagnosed by the presence of a bulging, immobile eardrum with no visible bony landmarks or by the presence of purulent drainage from the ear if there was a perforated eardrum, tympanotomy tube, or both. Levels of antibody to various bacterial and viral pathogens were determined for the eight lots of RSVIG used in this trial. RSV neutralization antibody titers were determined by a microneutralizationassay. 21 Antibodies to polyribosylribitol phosphate, the capsular polysaccharide of Haemophilus influenzae type b, were determined by a radioactive antigenbinding assay using a standard serum (U.S. Food and Drug Administration No. 1983) containing 70 ~tg anti-polyribosylribitol phosphate as a control,zz Assays for antibodies to S. pneumoniae polysaccharides23 and nontypeable H. influenzae outer membrane proteins were performed with an enzyme-linked immunosorbent assay. 24 Pneumococcal antibody concentrations were assigned by means of a standard serum (FS 89) obtained from Dr. Carl Frash, Center for Biologics Evaluation and Research, Bethesda, Md. Data were double-entered in Epi-Info version 5.01Az5 and analyzed with Epi-Info and SPSS version 6.1 for Windows (SPSS, Inc., Chicago, Ill.). A chi-square test was used to test for independence of variables in comparisons of demographic descriptors in study groups. The Yates correction for

continuity was used, and the Fischer Exact Test was used if expected cell values in a 2 x 2 table were less than 5. Oneway analysis of variance was used to test for trends across categories. The Student t statistic was used for testing the significance of a difference in means for independent samples. The Goodman-Kruskal test was used to test for association between variables,a6

RESULTS One hundred nine children were studied at the two sites. Table I presents demographic data for the high-dose, lowdose, and control recipients. Race and day care were comparable between groups. A small number of children had tympanostomy tubes, and this was not taken into account for stratification of patients. The frequency of episodes of AOM in subjects in each treatment group during the study period is shown in Table II. Children receiving the high dose of RSVIG had one sixth as many episodes of AOM, and children receiving the low dose had half as many overall episodes, as control children had. The mean number of episodes of AOM per patient was significantly lower in the high-dose group (p = 0.003). The number of patients who had one or more episodes of AOM per season were also significantly lower in the high-dose group than in the control group (p =0.005 and 0.013, respectively). The Figure shows the number of episodes of AOM in each study group. The total number of respiratory infections caused by RSV and the total number of RSV-related AOM episodes are shown in Table II. In the control group, AOM was diagnosed during 5 (26.3%) of the 19 RSV infections, a frequency similar to that reported in previous studies of RSV infection.15' 18 In contrast, AOM did not occur at the time of any of the nine RSV infections in subjects

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Simoes et al.

2 17

14 12 10 8 6 4

0 HIGH DOSE

LOW DOSE

CONTROL

NUMBERS OF EPISODES OF AOM 11 B2 D3 ~4 ~5 ~6 Figure. Number of episodes of AOM in each study group. receiving the high dose of RSVIG; AOM did occur at the time of 2 (25%) of the 8 RSV infections in recipients of the low RSVIG dose (p = 0.033 for trend). Table III compares concentrations of antibody to selected bacterial and viral pathogens standardized for a 1% solution of 12 lots of conventional intravenously administered immune globulin obtained from various commercial manufacturers, 19 and eight lots of RSVIG. The RSV-neutralizing antibody titer was fourfold higher in RSVIG than in IVIG (p <0.001). Antibody to the P6 outer membrane protein of nontypeable H. influenzae (which is presumed to be protective against AOM infection)23 was twofold higher in the RSVIG than in IVIG group. However, antibody titers to H. influenzae type b (polyribosylribitolphosphate) and to three pneumococcal serotypes were comparable for both types of immune globulin. DISCUSSION The results of this study demonstrate that administration of RSVIG at a dose of 750 mg/kg at monthly intervals reduced the overall incidence of AOM and the mean number of AOM episodes in the high-risk population studied. Two previous otitis media trials using pooled hyperimmune globulin derived from healthy pediatric populations have

Table III. IVIG and RSVIG antibody titers standardized for 1% solution

PRP (pg/ml) by RABA P6 (gg/ml) by ELISA S. pneumoniae 6B (lag/ml)by ELISA S. pneumoniae 14 (pg/rnl)by ELISA S. pneumoniae 19 (pg/ml) by ELISA Microneutralizationto RSV A Long (titer)$

IGIV*

RSVIGt

1.75 13 2.82 3.45 3.67 5605

1.21 25.7 3.05 3.56 4.27 20,505

PRP, Polyribosylribitolphosphate;RABA, radioactiveantigen-bindingassay; ELISA, enzyme-linkedimmunosorbentassay.

*Mean of 12 lots. #Mean of 8 lots. :)Fromreference 19.

been published. 9, 10 In each of these studies the patient base consisted of healthy but "otitis prone" children who had had between three and six previous episodes of AOM. Slight but "clinically insignificant" reductions in the total incidence of AOM were observed in recipients of hyperimmune globulin preparations. One possible explanation for the more positive outcome in the present study is that our patient population consisted of infants and young children, who received rela-

2 18

Simoes et al.

tively high doses of IVIG. Few of these children had a history of AOM. It is also conceivable that comparable doses of IVIG might have had a small similar impact on non-RSV A O M if given in more optimal doses. In two previous studies, only conventional immune globulin at a dose of 165 mg/kg 9 or 200 mg/kg 1° was administered every 3 to 4 weeks, or hyperimmune BPIG, 80 mg/kg, was given every 4 weeks. H In the present study, the most significant effect in prevention of A O M was observed when an R S V I G dose of 750 mg/kg was infused monthly. Only a marginal effect was noted when a low dose (150 mg/kg) of R S V I G was given. In addition, prevention of RSV infection (a known precipitant of A O M ) might have prevented the development of persistent eustachian tube dysfunction and therefore further episodes of A O M . Shurin et al.H evaluated an immune globulin preparation that was enriched for antibody to S. pneumoniae, Neisseria meningitidis, and H. influenzae type b. Use of this preparation resulted in an approximately 50% reduction in A O M episodes caused by S. pneumoniae but no reduction of A O M caused by other bacterial or viral pathogens. The reduction in the overall incidence of A O M observed in this study suggests that the administration of relatively high doses of antibody specific to A O M pathogens are necessary for the prevention of AOM. In our study, five episodes of RSV-related A O M occurred in the control group, whereas no A O M occurred in the highdose recipients. Therefore the positive effect of R S V I G in reducing the frequency of A O M may be partially explained by the reduction of A O M episodes occurring simultaneously with RSV infection. However, even when specific RSV episodes were excluded, there remained a substantial decrease in A O M episodes (5 in high-dose group vs 10 in the low-dose and 27 in the control groups). Because the overall incidence of acute respiratory illnesses from all infectious agents was comparable in the three treatment groups, ~8 the effects of R S V I G cannot simply be attributed to a reduction in the total number of viral infections. This suggests that the principal effect of R S V I G in the prevention of A O M lies in its content of specific RSV and antibacterial antibodies. The results of this study strongly suggest that monthly infusions of high doses of R S V I G may prevent A O M in certain infants and young children. Preventing very early episodes of A O M may have an added benefit in preventing multiple episodes of A O M in the "otitis prone" child. The use of this product for prevention of severe RSV-related lower respiratory tract illness in susceptible infants will be expensive in terms of both the cost of drug and the cost of administration. It is also somewhat cumbersome and timeconsuming to administer. However, the reduction in the expense of office visits and of treatment of A O M episodes, as well as the reduction in severe RSV-related lower respiratory

The Journal of Pediatrics August 1996

tract infection, 18 should be considered in determining the cost/benefit ratio for the use of R S V I G in selected high-risk infants. REFERENCES

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