PEDIATRICS Vol. 108 No. 4 October 2001, pp. 1000-1003

COMMENTARY:
Uncertainty in the Management of Viral Lower Respiratory Tract Disease

Approximately 3% of children in the United States will be hospitalized in the first year of life because of a viral infection of the lower respiratory tract.^1,2 Viruses that account for the vast majority of hospitalizations resulting from pneumonia and bronchiolitis include respiratory syncytial virus (RSV), parainfluenza viruses (particularly type 3), influenza viruses, and adenoviruses. A recent report from the Centers for Disease Control and Prevention provides important information on the epidemiology of pediatric viral lower respiratory tract disease in the United States, estimating that 123 000 hospitalizations resulting from bronchiolitis occur each year in children in the first year of life.¹ During the 17 years covered in this report from 1980 to 1996, hospitalization rates for children <12 months with viral infection of the lower respiratory tract increased more than twofold. RSV alone accounts for 50% to 90% of bronchiolitis hospitalizations and 20% to 50% of pediatric hospitalizations for pneumonia. Approximately 500 RSV-associated deaths occur each year in the United States.³ This mortality figure is lower than an estimate made in 1985 by the National Institute of Medicine, at least partly because of improvements in the management of hospitalized infants.⁴ The annual cost of RSV hospitalization for infants in the United States is estimated to be in excess of $300 million to $400 million.⁵

Despite the fact that about 16% of hospital admissions for children in the first year of life are because of viral lower respiratory tract illness, there remains a remarkable lack of consensus on the optimal management of patients.^1,6 Viral infection of the lower airway is generally a self-limited condition. Nonetheless, bronchiolitis is notorious for variation in disease expression based on a number of factors, including the presence of underlying heart or lung disease, gestational age, chronological age, and viral strain.⁷ In this issue of Pediatrics, Willson et al⁸ explore the intriguing issue of differences in resource utilization for infants hospitalized with viral lower respiratory infection at 10 geographically diverse children's medical centers and demonstrate a striking variation in practice patterns. One of the important contributions of this paper is the use of the Pediatric Component of the Comprehensive Severity Index to standardize comparison of patients with similar disease acuity at different institutions. Not surprisingly, hospital costs correlated strongly with intensity of intervention. However, the finding of an inverse correlation between disease severity on admission and institutional average costs suggests an opportunity for cost savings through reduction of inappropriate care without a compromise in quality of care.

Standardizing clinical practice by the use of guidelines-based education has been shown to reduce admissions, reduce resource utilization, and shorten length of stay for hospitalized infants with bronchiolitis without increasing readmission rates or decreasing family satisfaction.^9,10 Ongoing educational efforts can sustain changes in management over time.¹¹ A number of issues regarding optimal management of infants hospitalized with bronchiolitis are yet to be resolved with appropriate placebo-controlled trials. But the challenge raised in the report by Willson et al is to modify practice patterns based on what is currently known and to avoid costly interventions that do not alter the course of disease.⁸

What criteria form the basis for a decision to hospitalize an infant with bronchiolitis? Certain underlying diseases place an infant at increased risk of more severe disease. Congenital heart disease (particularly cardiac lesions associated with increased pulmonary blood flow or pulmonary artery hypertension), prematurity, season of birth, and the requirement for supplemental oxygen in an infant with chronic lung disease are well-recognized markers for more severe disease.⁷ Other conditions may place a child at variable risk of severe disease and may lower the threshold for admission: neuromuscular disease, history of recurrent aspiration, congenital anomaly of the airway, familial dysautonomia, myasthenia gravis, Down syndrome, cystic fibrosis, and an immunodeficiency state. Variation in disease presentation as a function of geographic location has been described but is incompletely understood, perhaps reflecting differences in altitude or differences in air quality in certain urban cities.¹² A report from New York State described a fourfold variation in hospitalization rates for viral lower respiratory infections with the strongest predictor of admission being low socioeconomic status.¹³ Other factors influencing a decision for admission may include reimbursement considerations, bed availability, and referral patterns.

Once admitted, what factors contribute to the dramatic differences in resource utilization noted in this study? Management strategies for children with viral infections of the lower respiratory tract are primarily supportive but the type and frequency of monitoring will add to hospital costs.^14-16 All infants hospitalized with lower respiratory tract disease require careful clinical assessment of respiratory status, including measurement of oxyhemoglobin saturation. Low concentrations of supplemental oxygen are generally sufficient to maintain adequate oxygen saturation. Monitoring of arterial carbon dioxide tension will be needed in a small number of infants. Adequate hydration is important and for tachypneic patients, parenteral therapy may be necessary. Judicious use of the laboratory to confirm a viral etiology by culture or by detection of RSV antigen in nasopharyngeal aspirates generally is appropriate to rule out a bacterial etiology. However, repeat testing of a patient already known to be infected or screening of an asymptomatic contact generally is not appropriate. Numerous studies have confirmed the importance of infection control policies in prevention of nosocomial viral infections.^17,18 A recent report from Children's Hospital of Philadelphia demonstrated that such policies are also cost-effective; each dollar spent on infection control saved an estimated $6 that would have been spent on nosocomial disease.¹⁹ Patients who acquire nosocomial RSV disease are more likely to have underlying cardiopulmonary abnormalities than infants admitted with community acquired RSV disease and, therefore, more likely to have a complicated course. Failure to initiate isolation procedures in a timely manner may add to the cost of RSV disease.

A decision to admit to the intensive care unit (ICU) is generally based on the possible need for intubation because of progressive hypercarbia, increasing hypoxemia despite supplemental oxygen or apnea. Criteria for ICU admission will vary among physicians as noted in the study by Willson et al⁸, which demonstrated a range in ICU utilization of 19% to 56%. Most infants admitted to the hospital with bronchiolitis or pneumonia will not have underlying disease that places them at increased risk of respiratory failure. Among otherwise healthy infants, ICU admission because of respiratory deterioration is an uncommon occurrence. In a study from Children's Hospital at Strong, only 1.8% of 542 previously healthy, full-term infants required transfer to ICU for evolving respiratory distress.²⁰ Some institutions lack a transitional care or step-down unit. This may add to hospital costs when a patient spends extra time in a more expensive ICU bed because of concern that an improving infant requires closer observation than can be provided on the ward.

Bronchodilator therapy is commonly used in the management of hospitalized infants with bronchiolitis although conclusive evidence of efficacy has not been demonstrated. More than 90% of the patients in the report by Willson et al⁸ received this therapy. The results of most prospective, placebo-controlled trials with -2-agonist inhalation fail to demonstrate a significant improvement in oxygen saturation, time to discharge, or reduction in wheezing.^21-23 Similarly, agents with -adrenergic or anticholinergic activity have not conclusively shown a beneficial effect in trials in hospitalized infants with bronchiolitis. Because of concern that reactive airway disease may be misdiagnosed as bronchiolitis, one approach is to assess results of bronchodilator therapy after the initial dose. Repeat doses of an inhaled bronchodilator are then continued only in the small number of infants with well-documented improvement in respiratory function soon after the first dose. Some studies report that inhalation bronchodilator therapy can cause paradoxical bronchospasm with worsening hypoxia.²⁴

Placebo-controlled trials with corticosteroids have failed to demonstrate a beneficial effect on the course of bronchiolitis in hospitalized infants.^25,26 Nonetheless, in the study by Willson et al⁸, between 8% and 61% of patients received corticosteroid therapy. There has been some interest in the possibility that simultaneous administration of an antiviral agent and an antiinflammatory agent such as a steroid might reduce the viral load and shorten the disease process, but there is insufficient clinical experience to support this approach at this time. There is a theoretical concern that steroid therapy during the acute stage of illness could result in higher viral titers and prolonged viral shedding.²⁷

Ribavirin, a synthetic purine nucleoside, is the only antiviral agent which has been licensed by the Food and Drug Administration for the management of RSV bronchiolitis/pneumonia.^28,29 Early trials documented a modest antiviral effect from ribavirin as defined by a reduction in RSV titer in nasopharyngeal secretions relative to controls. However, it has proven more difficult to demonstrate clinically relevant benefit from ribavirin therapy. Well-conducted, placebo-controlled trials with ribavirin have failed to demonstrate a consistent difference between groups in terms of a requirement for mechanical ventilation, duration of stay in the pediatric ICU, or duration of hospitalization. In some placebo-controlled trials, a modest improvement in oxygen saturation has been reported in ribavirin recipients, but this is of uncertain clinical significance. Furthermore, concern has been expressed regarding the choice of placebo in these trials because both water and saline may induce bronchospasm in control patients, introducing bias in favor of ribavirin efficacy. It has been known for some time that infants hospitalized with severe lower respiratory tract disease resulting from RSV are at increased risk of recurrent episodes of wheezing, recurrent lower respiratory tract illness, and abnormal pulmonary function testing later in childhood.³⁰ Long-term follow-up studies of ribavirin-treated patients have been difficult to conduct in a rigorous fashion but they have not provided reproducible data to suggest ribavirin has an effect on pulmonary outcome.^31-33 Use of this antiviral agent has become difficult to justify because of the high cost of ribavirin therapy and inconsistent reports of efficacy.

Antibiotics are unlikely to have therapeutic value in a hospitalized patient with bronchiolitis. Nonetheless, many patients have blood cultures obtained and receive parenteral antibiotic therapy, particularly infants with an abnormal chest radiograph. Approximately 25% of infants will have radiographic evidence of atelectasis or consolidation consistent with a possible bacterial infection.³⁴ However, bacteremia or bacterial pneumonia in hospitalized infants with bronchiolitis is unusual. Otitis media occurs in infants with RSV bronchiolitis, but most patients can be treated orally if antibiotic therapy is necessary.³⁵

In view of the burden placed on patients and on the health care system by viral infections of the lower respiratory tract, what future options may become available for control of viral disease? Despite >35 years of effort, it has proven difficult to develop a safe and effective RSV vaccine for young infants that produces protective immunity but does not enhance natural infection.³⁶ Subunit RSV vaccines consisting of surface glycoproteins F and G, which stimulate neutralizing antibody, seem to be safe and immunogenic in seropositive children as young as 12 months, although efficacy has not been determined. A live-attenuated, temperature-sensitive RSV vaccine for intranasal immunization that elicits both a local mucosal antibody response and systemic immunity is under development.³⁷ Temperature sensitive strains preferentially replicate at the lower temperature of the nasal cavity and less efficiently at core body temperature. Intranasal administration of the vaccine strain results in a subclinical infection that induces immunity by simulating a natural infection of the upper airway. To date, problems encountered with such attenuated vaccines include lack of genetic stability (back-mutation to virulence), overattenuation (does not induce immune response), and underattenuation (causes symptoms in vaccinee). Currently, the only option for prevention of RSV infection in high-risk infants is passive immunoprophylaxis with either a polyclonal hyperimmune globulin, Respigam, or preferentially, with a humanized murine monoclonal anti-F glycoprotein antibody preparation, palivizumab.³⁸ Both preparations have been shown to be safe and efficacious in large, well-designed clinical trials.³⁹ This intervention is restricted to a relatively select number of high-risk infants because of cost. Most infants hospitalized with RSV infection will not fall into a high-risk group and therefore will not satisfy the recommended guidelines for passive immunoprophylaxis. Only a relatively small number of total RSV hospitalizations will be prevented by targeting high-risk infants, although these infants are most likely to experience a complex hospital course.⁴⁰ To dramatically decrease the overall burden of disease and cost associated with RSV, a vaccine will be required.

Inactivated influenza vaccines for use in infants 6 months of age are currently recommended for high-risk infants and children.⁴¹ A promising approach to influenza control is a cold-adapted, live-attenuated influenza vaccine (CAIV) administered via the intranasal route. Phase III studies suggest that CAIV containing 2 attenuated A and 1 B strains is >90% effective in children in preventing cases of influenza resulting from strains included in the vaccine and only slightly less effective against strains that demonstrate antigenic drift.^42,43 Hospitalization rates in children <5 years resulting from influenza infection appear to be equivalent to those in adults over 50 years of age for whom the influenza vaccine is currently recommended.⁴¹ The ease with which CAIV can be administered is likely to result in reconsideration of a recommendation for universal vaccination of children against influenza, once the vaccine is licensed.

After RSV, parainfluenza virus type 3 is the most common cause of hospitalization attributable to bronchiolitis and pneumonia in young children. Vaccines under consideration include subunit vaccines containing surface glycoproteins, as well as live-attenuated vaccines. An attenuated, intranasal parainfluenza 3 vaccine has been shown to be safe, immunogenic, and genetically stable in seropositive as well as seronegative infants as young as a few months of age.⁴⁴ A live, oral adenovirus vaccine consisting of serotypes 4 and 7 for use in military recruits was available for a number of years but has not been studied in civilians and is no longer being produced.⁴⁵

Although most infants with bronchiolitis can be safely managed as outpatients, hospitalization rates for this illness seem to be increasing. Because the optimal course of management of hospitalized infants is not clear and because the course of illness is variable from patient to patient, differences in the use of various interventions and procedures is to be expected. Important advances in the management of patients with bronchiolitis have dramatically reduced mortality rates to <1% among most groups of hospitalized infants. The task now is to carefully define those interventions that are efficacious, those interventions that are unlikely to be effective, and those interventions that need evaluation in controlled clinical trials.

H. Cody Meissner, MD
Floating Hospital for Children at New England Medical Center
Division of Pediatric Infectious Disease
Tufts University School of Medicine
Boston, MA 02111

FOOTNOTES

Received for publication Feb 20, 2001; accepted Feb 22, 2001.

Reprint requests to (H.C.M.) Floating Hospital for Children at New England Medical Center, Division of Pediatric Infectious Disease, Tufts University School of Medicine, 750 Washington St, Boston, MA 02111. E-mail: cmeissner{at}lifespan.org

ABBREVIATIONS

RSV, respiratory syncytial virus; ICU, intensive care unit; CAIV, cold-adapted, live-attenuated influenza vaccine.

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