Respiratory syncytial virus infection and the primary care physician.

ABSTRACT: Respiratory syncytial virus (RSV) infection is a common viral illness affecting almost all children within their first few years of life. In most young children, RSV results in a mild respiratory infection. It is, however, the single most important cause of bronchiolitis and pneumonitis in infancy and contributes to significant morbidity and even mortality in a subset of high-risk children. There are new developments in the diagnosis, treatment, and prevention of RSV infection in infants and children. Early recognition of young children at high risk for severe RSV infection and apnea can help to minimize the morbidity and mortality.

RESPIRATORY SYNCYTIAL VIRUS (RSV) has been implicated in nearly 75% of bronchiolitis cases and in more than 50% of pneumonia cases. Each year, more than 90,000 infants are hospitalized with RSV infection in the United States at a cost of $300 million. (1,2) From 1988 to 1996, infant hospitalization rates for bronchiolitis increased significantly, while hospitalization rates for lower respiratory tract diseases excluding bronchiolitis did not vary significantly. Sizable outbreaks of RSV occur each year, and virtually all children have RSV infection within their first few years of life. Severe RSV disease, as gauged by the requirement for hospital admission, is most common among infants 1 to 3 months old. (2) Although the frequency and severity of illness decrease with increasing age, repeated infections, usually localized to the upper respiratory tract, occur throughout life. The potential virulence of RSV has generated great concern among parents of young children and in the medical community as well. While t he majority of RSV infections are resolved within 5 to 7 days, there is risk for significant morbidity and even mortality associated with RSV infection. To alleviate much of the anxiety and minimize unexpected complications that include sudden death, primary care physicians need to understand the risk factors for severe RSV infection, the timing of the peak RSV infection season in their practice area, and how to provide early diagnosis and proper management of the RSV infection.

VIROLOGY

Respiratory syncytial virus is a member of the Parmyxoviridae family of RNA viruses in the genus Pneumovirus. The viral envelope has 12 to 15 nm spikes composed of F (fusion) and G (attachment) glycoproteins located on the outer surface at regular intervals (Figure). The virus attaches to the host cell by the G protein, the larger of the two glycoproteins. The F protein provides the means for the viral genome to penetrate into the host cell and mediates cell-to-cell spread leading to the characteristic syncytial formation in tissue culture. Both F and G glycoproteins have the capacity to induce the formation of antibodies that can neutralize RSV. The antibodies induced by the F glycoprotein are the more highly protective ones and are the only antibodies that completely neutralize RSV and inhibit syncytial formation in vitro. These observations have led to the development of monoclonal antibodies against the F glycoprotein. (3)

EPIDEMIOLOGY

Outbreaks of RSV are normally sudden in onset and limited in duration, often lasting from 2 to 5 months. The infection spreads easily and rapidly as infectious material, contacts mucous membranes of the eyes, mouth, or nose, and possibly through the inhalation of droplets generated by a sneeze or cough. It is a seasonal virus. In temperate climates, RSV activity usually peaks in the winter months and extends into the spring.

All age groups are at equal risk for RSV infection, since RSV affects a large segment of the population from infancy to adulthood. Infants from lower socioeconomic environments tend to be younger when they first acquire lower respiratory tract disease from RSV and seem to experience more severe infections. Infants of low-income families with RSV disease are fivefold to tenfold more likely to require hospitalization for treatment of RSV infection than infants from middle-income families.' In large urban populations, the peak age for the incidence of RSV bronchiolitis is 2 months. Epidemics have been reported in newborns' nurseries. The results of most studies looking at children hospitalized with RSV disease indicate that the admission of boys predominates in a ratio of about 2:1. (1) However, in children with milder illness not requiring hospitalization, boys and girls are affected about equally.

PATHOPHYSIOLOGY

The typical abnormalities of the lower respiratory tract in RSV bronchiolitis are necrosis of the respiratory epithelium of the small airways, peribronchiolar mononuclear infiltration, plugging of the lumens, and hyperinflation and atelectasis. Respiratory syncytial virus-specific IgE elevated levels of histamine and leukotriene C4 (the same chemical mediators responsible for inducing bronchospasm and inflammatory reaction in asthma) have been isolated from the secretions of patients with infection accompanied by wheezing. In RSV pneumonia, the epithelial necrosis may extend to both the bronchi and the alveoli. In either case, the pathologic process involving the bronchioles and the production of chemical mediators inducing broncho constriction result in serious alterations in gas exchange. Arterial hypoxemia develops as the result of the mismatching of pulmonary ventilation and perfusion. Some degree of carbon dioxide retention is noted sometime during the course of the disease, especially in young infants. The likely mechanisms for this are severe ventilation/perfusion mismatching and hypoventilation due to the markedly increased work of breathing. (4)

CLINICAL MANIFESTATION

The first signs of infection in an infant with RSV are rhinorrhea, often profuse, and pharyngitis. A cough usually appears after an interval of 1 to 3 days, at which time there may also be sneezing and low-grade fever. Soon after the cough is developed, the child begins to wheeze audibly. When the, disease is mild, the symptoms may not progress beyond this stage. Should the illness progress, cough and wheezing increase along with air hunger and evidence of hyperexpansion of the chest and intercostal and subcostal retraction. There is also an increase in respiratory rate and cyanosis.

Signs of severe, life-threatening illness are central cyanosis, tachypnea (more than 70. breaths per minute), listlessness, and apneic spells. At this stage, the chest may be greatly hyperexpanded and almost silent to auscultadon because of poor air exchange. In some infants, the course of the illness may be more like that of pneumonia. Dyspnea, poor feeding, and listlessness, with a minimum of wheezing and hyperexpansion, follow the prodromal rhinorrhea and cough.

Apnea is more often observed in premature infants, very young infants (usually less than 1 month of age), and those with a history of episodes of apnea. Its mechanisms remain elusive; neither hypoxemia nor obstruction explains most occurrences. Fever is also an inconsistent sign. Hypoxemia is frequent and tends to be more marked than anticipated on the basis of the clinical findings. Hypercapnia is often accompanied by severe hypoxemia and may suggest imminent respiratory failure.

Repeated RSV infections are usually milder and consist of tracheobronchitis or an upper respiratory tract infection. Some children may experience repeated bouts of RSV lower respiratory tract disease.

DIAGNOSIS

Laboratory confirmation of specific RSV etiology is enhanced by the availability of rapid diagnostic tests. Both enzyme-linked immuno-absorbent assay (ELISA) and a direct fluorescent antibody technique provide identification in about 85% of cases. False-positive results are unusual. The sensitivity of antigen detection tests relies on adequate sampling of specimens. Nasal wash by instillation and aspiration of 5 mL of isotonic saline is preferable to nasal smear.

TREATMENT

It is vital that children at high risk for severe illness or apnea that may ultimately lead to prolonged hospitalization and/or intensive care including assisted ventilation be identified. To facilitate early recognition of children at risk, several risk factors have been identified (Table 1). Mild bronchiolitis developing in children without risk factor(s) requires only assurance. In contrast, hospitalization is indicated when there is risk of respiratory failure or apnea or when parenteral hydration is needed.

The treatment of lower respiratory tract disease due to RSV is mainly supportive. The hospitalized patient is commonly placed in an atmosphere of cold, humidified oxygen to relieve hypoxemia and to reduce insensible water loss from tachypnea. Progressive hypercarbia, hypoxemia unresponsive to oxygen administration, and recurrent apnea are potential indications for intubation and mechanical ventilation.

Ribavirin

Recent large cohort studies (5, 6) failed to prove unequivocal benefit from treatment with ribavirin. Given the concerns about benefit, cost, safety, and variable clinical efficacy, decisions about ribavirin aerosol therapy should be based on the particular clinical circumstances and physicians' experience. (7)

Bronchodilators 

Despite only modest short-term improvements in clinical features of mild to moderately severe bronchiolitis, (8) aerosolized bron-chodilators, such as albuterol, have been administered to many infants with bronchiolitis. This should not be part of the routine management of hospitalized infants.

Corticosteroids

Clinical trials provide little evidence to support the use of steroids for bronchiolitis caused by RSV. (7, 9)

Antibiotics

Given that secondary bacterial infection of the lower respiratory tract occurs in only 1.2% of children with infection caused by RSV, (10) routine use of antibiotics should be discouraged.

PROGNOSIS AND COMPLICATIONS

The recent mortality rates reported among patients hospitalized with RSV infection or with bronchiolitis vary between 1% and 3% per year. The variation in mortality depends largely on the population, increasing in those with certain underlying diseases, especially cardiac, pulmonary, and immunocompromised conditions. Besides the previously known risk factors (presence of underlying lung or heart disease, prematurity, age less than 6 weeks at time of admission, and history of apnea), hypoxia on admission (oxygen saturation <90%) and pulmonary consolidation proved to be additional risk factors contributing to severe or fatal RSV infections in hospitalized infants."

Respiratory syncytial virus has been implicated in "cot death" and sudden infant death syndrome in a number of studies, mosdy from the United Kingdom. (12) Some of these unexpected infant deaths associated with RSV may actually have resulted from apnea, which may be the initial sign of RSV infection before respiratory signs are apparent. (13)

Infection with RSV in early infancy has been implicated as a predisposing factor to subsequent chronic lung disease, ie, recurrent wheezing later in life. The reasons for this appear multifactorial. A genetic but not necessarily an atopic predisposition toward hyperreactivity of the lung has been suggested as a selective factor. Whether genetic airway overresponsiveness is the cause of chronic airway abnormalities, or whether the viral infection is synergistic or primary in causing these lung abnormalities in a previously normal host, the cause remains elusive. In a recently published epidemiologic study, Martinez et al (14) observed a significantly higher total serum IgE level during the acute phase when compared with the convalescent phase of the lower respiratory tract infection in persistent wheezers. This response was not observed in transient wheezers. The authors concluded that subjects who will continue to have persistent wheezing later in life may have had an altered immune response to viral infecti on during the acute phase of their first lower respiratory tract infection.

PREVENTION

Numerous obstacles to the development of a safe and effective RSV vaccine have shifted the focus of research and development to passive immunization. A strategy of maternal immunization also has been proposed to allow early infant protection through maternal antibody transfer. Initial clinical studies of this strategy are currently under way.

The use of RSV immune globulin (RSVIG) to impart passive prophylaxis has been effective. This form of passive immunity requires recurrent monthly injections of immune globulin throughout the RSV season and is targeted at groups identified as being at high risk for severe illness. The effectiveness of passive immunity has been shown by reducing the rates of hospitalization, length of hospital stay, and duration of oxygen supplementation in the recipients. (15)

Respiratory syncytial virus-IGIV (RespiGam), a hyperimmune polyclonal globulin, was licensed by the Food and Drug Administration in 1996 as the first intervention with proven safety and efficacy in prevention of RSV infections in high-risk preterm infants. Some concerns that restrict the use of RSV-IGIV include (1) monthly IV infusions lasting several hours each, (2) increased fluid volume and protein loads necessitating occasional use of diuretics, (3) theoretical concerns for transmission of blood-borne pathogens, and (4) the potential for polyclonal immunoglobulin interference with the immune response to vaccination. These concerns led to the development of another class of RSVIG-humanized monoclonal antibody--Palivizumab (MEDI-493, Synagis). Palivizumab (Synagis), a monoclonal IgG antibody preparation directed against the F glycoprotein of RSV, has the following advantages over RSV-IGIV: (1) the small required dose of palivizumab (15 mg/kg/dose) permits intramuscular injection, (2) the immunization schedule need not be altered after administration, (3) no fluid overload occurs, and (4) there is no possibility of transmission of blood-borne pathogens. A large placebo-controlled trial conducted at 139 centers in the United States, United Kingdom, and Canada revealed that palivizumab prophylactic therapy, consisting of five monthly injections administered during the RSV season, resulted in a 55% reduction in RSV infection-related hospitalization. (15) M oreover, RSV-attributed hospitalizations of premature children without bronchopulmonary dysplasia (BPD) were reduced by 78% and for those with BPD, by 39%. The current indications for palivizumab are listed in Table 2.

CONCLUSION

The majority of infants and older children infected by RSV have mild disease and do not require any therapeutic interventions. For children at high risk for severe RSV infection, passive immunization with palivizumab (Synagis) and early aggressive management when they do become infected with RSV should reduce morbidity and mortality. Despite the availability of prophylactic antibody preparations to reduce RSV-associated hospitalizations among children with conditions placing them at high risk for serious disease, the majority of infants hospitalized with bronchiolitis are not the ones with risk factors. A safe and effective RSV vaccine is needed to reduce hospitalizations for treatment of bronchiolitis.

TABLE 1

Factors Placing Infants at High Risk for Severe Respiratory Syncytial
Virus Infection (1, 13)

Prematurity

Young age (less than 6 weeks)

Cyanotic or complicated congenital heart disease

Underlying pulmonary disease, especially bronchopulmonary dysplasia

Immunocompromised infants and children
TABLE 2

Current indications for Palivizumab Therapy for Respiratory Syncytial
Virus (RSV) Infection (7)

Infants less than 24 months of age with chronic lung disease (CLD) who
have required medical therapy within the past 6 months.

Neonates born at 28 weeks gestation or less without CLD and who are <12
months of age at the start of the RSV season.

Neonates born at >28 weeks' and <32 weeks' gestation without CLD who are
<6 months of age at the start of RSV season.

Neonates born between 32 and 35 weeks' gestation without CLD who are <6
months of age and who have additional risk factors, inclutling
school-aged siblings, crowding in the home, clay-care attendance,
exposure to tobacco smoke in the home, and multiple births.

Infants with hemodynamically insignificant congenital heart disease who
qualify because of prematurity or CLD.

References

(1.) Hall GB: Respiratory syncytial virus. Textbook of Pediatric Infectious Diseases. Feigin RD, Cherry JD (eds). Philadelphia, WB Saunders Go, 4th Ed, 1998, pp 2084-2102

(2.) Shay DK, Holman RC, Newman RD, et al: Bronchiolitis-associated hospitalizations among US children, 1980-1996. JAMA 1999; 282:1440-1446

(3.) Prober GG, Sullender WM: Advances in prevention of respiratory syncytial virus infections. J Pediatr 1999; 135:546-558

(4.) Wohl MEB: Bronchiolitis. Kendig's Disorders of the Respiratory Tract in Children. Chernick V, Boat TF (eds). Philadelphia, WB Saunders Co, 1998, pp 473-476

(5.) Wheeler JG, Wofford J, Turner RB: Historical cohort evaluation of ribavirin efficacy in respiratory syncytial virus infection. Pediatr Infect Dis J 1993;12:209-213

(6.) Moler FW, Steinhart CM, Ohmit SE, et al: Effectiveness of ribavirin in otherwise well infants with respiratory syncytial virus associated respiratory failure. J Pediatr 1996;128:422-428

(7.) Report of the Committee on Infectious Diseases. Pickering LK (ed). Elk Grove Village, Ill, American Academy of Pediatrics, 2000, p 485

(8.) Kellner JD, Ohlsson A, Gadomski AM, et al: Efficacy of bronchodilator therapy in bronchiolitis: a meta-analysis. Arch Pediatr Adolesc Med 1996;150:116-117

(9.) Springer C, Bar-Yishay E, Umayyed K, et al: Corticosteroids do not affect the clinical or physiological status of infants with bronchiolitis. Pediatr Pulmonol 1990;9:181-185

(10.) Hall CB, Powell KR, Schnabel KG, et al: Risk of secondary bacterial infection in infants hospitalized with respiratory syncytial viral infection. J Pediatr 1988;113:266-271

(11.) Wang EEL, Law BJ, Stephens D: Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) prospective study of risk factors and outcomes in patients hospitalized with respiratory syncytical viral lower respiratory tract infection. J Pediatr 1995;126:212-219

(12.) Williams AL, Ureh EC, Bretherton L: Respiratory viruses and sudden infant death. BMJ 1984;288:1491-1493

(13.) Church NR, Anas NG, Hall GB, et al: Respiratory syncytial virus related apnea in infants: demographics and outcome. Am J Dis Child 1984;138:247-250

(14.) Martinez FD, Stem DA, Taussig LM, et al: Differential immune responses to acute lower respiratory illness in early life and subsequent development of persisent wheezing and asthma. J Allergy Gun Immunol 1998;102:915-920

(15.) The IMpact-RSV Study Group: Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998;102:531-537

RELATED ARTICLE: KEY POINTS

* To alleviate much of the anxiety and minimize unexpected complications that include sudden death, primary care physicians need to understand the risk factors for severe RSV infection, the timing of the peak RSV infection season in their practice area, and how to provide early diagnosis and proper management of the RSV infection.

* It is vital that children at high risk for severe illness or apnea that may ultimately lead to prolonged hospitalization and/or intensive care including assisted ventilation be identified. To facilitate early recognition of children at risk, several risk factors have been identified. Mild bronchiolitis developing in children without risk factor(s) requires only assurance.

* The treatment of lower respiratory tract disease due to RSV is mainly supportive. The hospitalized patient is commonly placed in an atmosphere of cold, humidified oxygen to relieve hypoxemia and to reduce insensible water loss from tachypnea.

From the Department of Pediatrics, Texas Tech University Health Sciences Center, Odessa.

Reprint requests to Jay W. Park, MD, Texas Tech University Health Sciences Center, Department of Pediatrics, 701 W Fifth St, Suite 3174, Odessa, TX 79763.