Role of antibody and use of respiratory syncytial virus (RSV) immune globulin to prevent severe RSV disease in high-risk children Jessie R. G r o o t h u i s , MD From the Department of Pediatrics, University of Colorado School of Medicine and The Children's Hospital, Denver Infants with cardiac disease or infants born prematurely with or without bronchopulmonary dysplasia are at increased risk of severe respiratory syncytial virus (RSV) disease. A recently d e v e l o p e d RSV immune globulin (R$VIG) was studied in a 3-year multicenter trial to determine safety and efficacy in the prevention of severe RSV disease in children who are at high risk of severe RSVillness. Two hundred forty-nine children were studied; 102 had bronchopulmonary dysplasia, 87 had congenital heart disease, and 60 were born prematurely. RSVIG was given on a monthly basis to 81 children at a high dose of 750 mg/kg (15 ml/ kg) and to 79 children at a low dose of 150 mg/kg (3 ml/kg). The 89 children in the control group did not receive RSVIG. There were 64 episodes of RSV infection: 19 in the high-dose group, 16 in the low-dose group, and 29 in the control group. High-dose recipients had significantly fewer RSV lower respiratory tract infections, hospitalizations, hospital days, intensive care unit days, and less use of ribavirin compared with control subjects. Only 19 adverse events were reported during the 580 infusions administered (3%). No death was attributed to RSV disease or RSVIG therapy. Treated children did not acquire e x a g g e r a t e d RSV illness in a subsequent year. Thus high-dose RSVIG reduced the incidence and severity of RSV lower respiratory tract infection. It is a safe and effective means of RSV prophylaxis in selected high-risk children. (J PEDIATR1994;124:$28-$32) Respiratory syncytial virus, the most important respiratory pathogen in infants and young children worldwide, l-15 produces annual epidemics of bronchiolitis and pneumonia. Morbidity and death from RSV occur predominantly in children less than 2 years of age)' 5, 10, 14, 15 Certain infants Supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases contract No: NO1-A1-82520N; the General Clinical Research Center Program of the Divisionof Research Resources (RR-69), National Institutes of Health; the General Clinical Research Center of the University of Rochester and its computer data Management and Analysis System (M01RR-00044); and MedImmune, Inc., Gaithersburg, Md. Reprint requests: Jessie R. Groothuis, MD, The Children's Hospital, Department of Pediatrics, 1056 E. 19th Ave., B070, Denver, CO 80218. Copyright ® 1994 by Mosby-Year Book, Inc. 0022-3476/94/$3.00 + 0 9/0/53628 $28 and children are at increased risk of serious RSV lower respiratory tract infection. These high-risk infants and children include premature infants who are less than 6 months of age, 16, 17 infants and children with underlying pulmonary 18-2°or cardiac disease, 21 and those with immunodeficiency states. 22, 23 BPD CHD IVIG RSV RSVIG Bronchopulmonarydysplasia Congenital heart disease Intravenously administered immune globulin Respiratory syncytial virus RSV immune globulin During the initial categorization of the clinical and laboratory features of RSV infection, conflicting hypotheses were presented regarding the role of serum antibodies in the protection of the lower airway. The work of several inves- The Journal of Pediatrics Volume 124, Number 5, Part 2 tigators suggested that because primary RSV infections did not prevent reinfection, neutralizing antibodies were of little benefit. 2426 Others believed that neutralizing antibodies played a significant role in the prevention of severe RSV disease and pressed to develop a vaccine for active immunization against RSV. In 1966, trials were initiated with a formalin-inactivated RSV vaccine (lot 100). 27-29 Chin et al. 27 studied 191 children who received injections of RSV vaccine. Vaccinees in whom RSV illness developed in the following year had more serious disease than hospitalized nonvaccinees. Two deaths occurred in the vaccinated group. Complement fixation (not neutralizing) antibody response was marked (titer, 1:128 or greater). It was hypothesized that this antibody interacted with the viral antigens in such a way that an altered antigen-antibody complex produced exaggerated pulmonary disease. Twenty years after this vaccine experience, Murphy et al. 3° measured neutralizing antibody and enzyme-linked immunosorbent titers to the RSV fusion (F) and attachment (G) glycoproteins in the sera of infants and children who were originally immunized with RSV vaccine lot 100. Sera from 21 young infants, 2 to 6 months of age, had high titers of antibody to the F glycoprotein but poor antibody response to the G glycoprotein. Sera from 15 infants and children, 7 to 40 months of age, had high titers of F and G antibodies. However, immunized infants and children had lower levels of neutralizing antibodies than did infants and children of comparable age after a natural RSV infection. Murphy et al. 3° suggested that the treatment of RSV with formalin appeared to alter the epitopes of the F and/or G glycoproteins, with the result that the antibody response consisted largely of "nonfunctional" (i.e., nonneutralizing) antibody. These nonneutralizing antibodies were suspected of being responsible for the exaggerated pulmonary disease in young seronegative infants. This work paved the way for the exploration of a positive role for functional serum neutralizing antibodies. During the past decade, a body of animal and human data was developed that strongly suggests that neutralizing antibody plays an important role in the prevention of severe RSV infection. 1MMUNOPROPHYLAXIS Animal data. Many years passed before the development of an animal model that would permit RSV replication; develop histologic changes in the nasal turbinates, trachea, and lungs; and have an adequate humoral antibody response to RSV infection. The cotton rat model for RSV infection was described in 1978 by Prince et al. 31 In cotton rats, vigorous RSV replication occurs in both the upper and lower respiratory tracts after intranasal inoculation. Although cotton rats acquire the characteristic histologic changes in the lungs, they do not acquire clinical disease. They also Groothuis S 29 have complete resistance to subsequent RSV infection for up to 18 months after inoculation with live RSV virus. In general, this resistance correlates with serum neutralizing antibody levels >_ 1:350. 32 Cotton rats immunized with the formalin-inactivated RSV vaccine, and subsequently challenged with RSV, acquire pulmonary disease that is histologically identical to that observed in children who were treated with the formalin-inactivated RSV vaccine and died of RSV pneumonia. 33 Using this animal model, Prince et al., 34' 35 studied the impact of intravenously administered human immune globulin on the prevention of RSV respiratory tract infection. A commercial intravenous preparation of human immune globulin, Sandoglobulin (titers ranged from l:2707 to 1:3424), was administered intraperitoneally to infant cotton rats (0.5 ml/10 gm body weight) 24 hours before intranasal challenge with 104 plaque-forming units of RSV. The level of virus reduction in the pulmonary tissue was directly proportional to the neutralizing antibody titer in the rat serum. An RSV neutralizing antibody titer of >--1:350 provided almost complete protection for the lower airway. No evidence of enhanced pulmonary damage was observed on rechallenge with RSV. Human data. A body of epidemiologic data emerged that suggested that immunoprophylaxis against RSV infection might be possible. In 1971, Jacobs et al., 36 observed that RSV infection in newborn infants during the first month of life was less severe than that observed in infants older than 4 months. Parrott et al. 14 also observed abatement of infection within the first month of life in term infants. Retrospectively, they correlated neutralizing antibody with RSV disease severity and found protective levels to be between 1:300 and 1:400, a finding similar to those in the cotton rat model. 34 Other investigators reported an inverse correlation between RSV illness severity and RSV neutralizing antibody titers in young children. 17' 24, 37-40 The development of several commercial IVIG preparations provided an opportunity to test the hypothesis that anti-RSV antibody, given in sufficient dosage to produce titers of RSV neutralizing antibodies >_ 1:350, would prevent or ameliorate severe RSV disease in high-risk children. In 1988 the National Institute of Allergy and Infectious Diseases approved funding for a multicenter trial to test the safety and feasibility of administering IVIG to high-risk infants. These children included premature infants less than 6 months of age at study onset, children with BPD (a chronic lung disease associated with prematurity), and children with CHD, particularly those with pulmonary hypertension. Such children have significant morbidity because of RSV illness, even with repeated infections. 4~ A commercial IVIG preparation, Gamimune N (RSV titer of 1:1100), was infused at three different doses (500 mg/kg, S 30 Groothuis The Journal of Pediatrics May 1994 Table. Impact of RSVIG on incidence and outcome of severe lower respiratory tract infections RSVIG dose 750 mg/kg (n = 8 1 ) 150 mg/kg (n = 79) 7* 13 20 6~ 10 18 43t 1~ 63 0§ 128 34 Patients (No.) Severe lower respiratory tract infections Hospitalizations Duration of inpatient care Hospital stay (days) ICU stay (days) Control (n = 8 9 ) *p = 0.01. tP = 0.02. ~p = 0.05. §p = 0.03 versuscontrolsubjects. 600 mg/kg, 750 mg/kg) in 23 infants, monthly (three to five infusions) throughout the RSV season.42 There were few complications; intravenous cannulation was the greatest problem. At 750 mg/kg a mean peak titer of only 1:100 was achieved. A second study, performed by Meissner et al., 43 also used Gamimune N. Children with BPD or severe CHD received either IVIG at 500 mg/kg (n = 25) or no IVIG (n = 24) in a randomized fashion. Immune globulin was given in monthly infusions. No adverse reactions occurred during the study period. Twelve culture-proved RSV illnesses occurred, six in each group. Hospital days were 8.8 + 5 (treated) vs 12.8 + 7.6 (control subjects); this difference was not statistically significant. The average peak RSV titer was only 1:124. The results of these two trials indicated that infusion with commercial IVIG was safe and feasible, although the peak antibody titers achieved were probably too low for protection. 34 Concern regarding low antibody titers and lot-to-lot titer variability of IVIG preparations44 prompted the development of an RSV-enriched immune globulin.45 The method of preparation of RSVIG was identical to that of IVIG except that the plasma used was obtained from donors specifically selected for their high serum RSV neutralizing antibody titers. RSVIG PROPHYLAXIS TRIAL A 3-year multicenter prophylaxis trial of RSVIG was conducted by Groothuis et al. 46 In this blinded, randomized study, 249 infants and children who were born prematurely and were <6 months of age at the start of the study or had BPD or CHD were enrolled during a 3-year period (1989 to 1992). During the RSV season, one group received a high RSVIG dose of 750 mg/kg (15 ml/kg) monthly, a second group received a low dose of 150 mg/kg (3 ml/kg) monthly, and the control group received no RSVIG. A dose of 750 mg/kg proved to be both safe and effective in decreasing the incidence and severity of RSV lower respiratory tract disease, particularly in preterm infants with or without BPD. The group receiving RSVIG, 750 mg/kg, had significantly fewer instances of moderate-to-severe RSV lower respiratory tract infection (72% reduction; p = 0.01), as well as fewer hospitalizations (63% reduction; p = 0.02), fewer hospital days (63% reduction; p = 0.02), fewer days in the intensive care unit (97% reduction; p = 0.05), and less ribavirin use (p = 0.05) than did the group receiving RSVIG, 150 mg/kg, or the control group (Table). The RSVIG preparation had few (3%) adverse effects. These consisted of reversible mild fluid overload, fever, and mildly decreased oxygen saturation. Six deaths occurred, three in the group receiving RSVIG, 150 mg/kg, and three in the group receiving a dose of 750 mg/kg (p = 0.15). No death could be attributed either to RSVIG administration or to RSV illness. Five of the six patients who died had cardiac disease, and three deaths were directly related to cardiac surgery. The safety of RSVIG in children with CHD is currently being studied. All study participants were followed during a subsequent respiratory season. There was no evidence of exaggerated RSV pulmonary illness in RSVIG-treated children compared with control subjects. CONCLUSIONS The successful results of this RSVIG prophylaxis trial justify the evaluation of RSVIG as prophylaxis against severe RSV illness in other high-risk groups of infants, children, and adults. In addition, it should provide the impetus for the development of more efficient means of passive immunoprophylaxis, such as monoclonal antibodies for intramuscular administration. The finding that monthly prophylactic infusions of RSVIG at a dosage of 750 mg/kg reduce both the incidence and severity of RSV illness is clinically important, particularly because active immunization strategies against RSV are proceeding slowly and cautiously in the very young seronegative child, and a vaccine for universal use will not be available for some time. In general, RSVIG should be considered for preterm infants with a gestational age <35 weeks who are younger than 4 months of age in the month of November, infants with a gestational age <32 weeks who are younger than 6 months in the month of November, and infants with a gestational age <28 weeks who are younger than 9 months in the month of November. The results of this trial indicate that RSVIG should be administered at a dosage of 750 mg/kg, delivered intravenously for 2 hours, monthly during the RSV season (November through March or April). This dosage is also appropriate for children with chronic pulmonary disorders who are younger than 18 months of age and The Journal of Pediatrics Volume 124, Number 5, Part 2 m i g h t require mechanical ventilation if they were to contract R S V infection. Therefore R S V I G at a dosage of 750 m g / k g currently offers the only safe and effective m e a n s of protection against serious R S V lower respiratory t r a c t disease in high-risk infants and children. I thank Susan J. King, RN, for manuscript review. REFERENCES 1. Brandt CD, Kim HW, Arrobio JO, et al. Epidemiologyofrespiratory syncytial virus infection in Washington, D.C. III. Composite analysis of eleven consecutive yearly epidemics. Am J Epidemiol 1973;98:355-64. 2. Chanock RM, Parrott RH. Acute respiratory disease in infancy and childhood: present understanding and prospects for prevention. Pediatrics 1965;36:21-39. 3. Glezen WP, Denny FW. Epidemiology of acute lower respiratory disease in children. N Engl J Med 1973~288:498-505. 4. Kim HW, Arrobio JO, Brandt CD, et al. Epidemiology of respiratory syncytial virus infection in Washington, D.C.I. Importance of the virus in different respiratory disease syndromes and temporal distribution of infection. 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