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Respiratory syncytial virus (RSV): overview, treatment, and prevention strategies
REVIEW
Abstract Respiratory syncytial virus (RSV) is one of the most common diseases of childhood. Virtually all children have been exposed to this virus by age two. RSV causes common cold symptoms in most patients. In vulnerable children, RSV can progress to bronchiolitis and/ or pneumonia with an increased chance of significant morbidity or death. The nature of the virus and mode of infection protects it from the human immune system. Treatment for RSV is largely supportive. Key elements of treatment are maintenance of hydration, and oxygenation, as well as keeping the airways clear of mucus. Prevention of RSV in vulnerable infants is important because of the increased morbidity and mortality. A modest effort spent identifying vulnerable infants, educating the parents about RSV and its prevention, and providing immunoprophylaxis to those who qualify for it, increases the chances that these vulnerable children get through the first several years of life without RSV bronchiolitis. © 2004 Elsevier Inc. All rights reserved.
Respiratory Syncytial Virus (RSV): Overview, Treatment, and Prevention Strategies By Mark J. Polak, MD
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espiratory syncytial virus (RSV) is one of the most common human pathogens on this planet. By the age of two years, nearly every human child has been exposed to the virus, resulting most often in mild upper respiratory tract illness. But RSV may also be one of the most serious human pathogens on this planet. Worldwide, RSV directly or indirectly contributes to the deaths of between 600,000 and 1,000,000 infants and children under the age of five each year. In the United States, several hundred infants may die directly from the infection, while the deaths of an additional several thousand may be attributed to RSV-related complications. RSV infections account for over 100,000 hospitalizations each year.1– 4 For the neonatal caregiver, an understanding of the virus and how to treat and/or prevent infection is an important part of management of the premature infant.
Background
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From the Department of Pediatrics, West Virginia University School of Medicine, Morgantown, WV. Address reprint requests to Mark J. Polak, Department of Pediatrics, WVU School of Medicine, PO Box 9214, Morgantown, WV 26506-9214 © 2004 Elsevier Inc. All rights reserved. 1527-3369/04/0401-0003$30.00/0 doi:10.1053/j.nainr.2003.12.007
linical descriptions of infantile pneumonias that may have been RSV were noted in the 1840s, and descriptions of seasonal epidemics were made 100 years later. During the 1950s, a curious respiratory illness spread through a colony of chimpanzees in a medical laboratory. The respiratory illness was named “chimpanzee coryza agent.” However, it was later discovered that the origin of the infection was from the human caretakers. In 1963, Robert Chanock and his colleagues were able to isolate and characterize the virus. The name “respiratory syncytial virus” was a descriptive term related to pathological changes of the airway epithelium as a result of the infection. RSV was identified as the agent responsible for seasonal epidemics of upper and lower respiratory infections in infants and children that occur worldwide.5,6 Besides public health awareness and interruption of infection by addressing handling and hygiene issues, RSV has been resistant to efforts to control and eradicate it through a pharmacologic or immunologic approach. Work with a vaccine in the 1960s failed to impart protection. Worse yet, the infants who Newborn and Infant Nursing Reviews, Vol 4, No 1 (March), 2004: pp 15–23
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received the vaccine had more severe infections in the subsequent year.7 During the 1980s, ribavirin, a medication that was effective in decreasing RSV replication in vitro, failed to demonstrate significant clinical utility in several clinical trials.8,9 Throughout this time, research continued into the molecular biology of RSV, and several researchers were able to find a vulnerable aspect of RSV infectivity. Humans do develop antibodies against one of the RSV surface proteins that enable the RSV particle to fuse to the respiratory epithelium. Though the presence of these antibodies did not prevent RSV infection, they were shown to be able to prevent development of lower respiratory tract (LRT) infection, which is the aspect of the disease that has the greatest public health risk.10,11 By the mid-1990s several formulations of these antibodies were commercially available. These antibodies were initially introduced as a polyclonal, pooled RSV-IGIV (RespiGam, MedImmune, Gaithersburg, MD), and later perfected as a monoclonal antibody, palivizumab (Synagis, MedImmune, Gaithersburg, MD). These medications have proven to be highly effective in prevention of LRT infection from RSV in “high-risk” infants.12,13
The RSV Virus
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SV is a medium-sized (between 80 to 350 nm diameter), membrane-bound, RNA virus. (Fig 1) It is classified as a paramyxovirus. RSV is closely related to several other RNA viruses, including measles, mumps, and parainfluenza types 1, 2, and 3. The RNA nucleocapsid of RSV is enclosed in a bylayer lipid sphere. The nucleocapsid genome is a single strand of RNA encoding for 10 viral proteins. Two of these are nonstructural proteins; the remaining eight are structural proteins. The nonstructural proteins direct viral replication within the infected host cell. The structural proteins are divided into three functional groups. The matrix is made up of two membrane-associated proteins, while three proteins make up the viral capsid. In addition there are three transmembrane surface glycoproteins. Two of these, a fusion protein (F) and an attachment protein (G), are responsible for the initiation and propagation of an RSV infection. There are two subtypes of RSV, Types A and B. They differ primarily in the composition of the G protein, while the F protein is conserved between the two strains.14 –16 The surface glycoproteins also evoke a host-derived antibody response following an infection. A primary RSV infection produces a weak humoral antibody response that does not differ with the severity of the disease.17,18 These responses are responsible for ending the infection and eliminating the virus, but do not appear to impart longterm immunity. In fact, it is only with reinfection that the
Fig 1. Cross sectional diagram of RSV virus. The nucleocapsid genome is a single strand of RNA that codes for 10 viral proteins. Two of these are nonstructural proteins. (A) Proteins M and M2 make up the matrix. (B) The viral capsid is made up of 3 proteins, a nucleoprotein, a phosphoprotein, and a polymerase protein. (C) There are 3 transmembrane proteins, a hydrophobic protein, a fusion protein, and an attachment protein.
antibody response is enhanced. If the infection reaches the LRT, a T cell-mediated response is generated.17,19,20
Infection
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SV most often begins as an infection in the nasal epithelial cells. The G protein initiates attachment of the virus to the epithelial cell. The F protein is cleaved by proteolytic enzymes of the infected cell and the virus then fuses with the epithelial cell membrane and enters the cytoplasm. The RSV virus then replicates in the host cell. The host cell is destroyed and the virus particles are released to propagate the infection. In addition to allowing the virion to enter the host cell, the F protein causes the fusion of the host cell to adjacent uninfected cells. The individual cell membranes are broken down, and large multinucleated epithelial cells (syncitia) are formed. The viral RNA can spread without forming complete viral particles. The infection results in the destruction of the epithelial cells of the upper respiratory tract. Exposure to RSV triggers humoral immune responses. Primary RSV infection results in only a weak antibody response with IgM, IgG, and IgA produced. This response is not suffi-
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cient to completely destroy the virus or to prevent upper respiratory tract replication of the virus, thus an upper respiratory tract illness develops. The humoral immune response does not seem to differ with the severity of disease, but is enhanced with reinfection. The degree of resistance to reinfection correlates best with levels of serum versus secretory antibody.14 –18 As noted previously, the RNA from RSV can spread from cell to cell as the epithelial syncitia is produced. Because of this “human shield” aspect of RSV infection, high levels of neutralizing antibodies are required to prevent the progression of infection from the upper respiratory tract to the LRT. By adulthood, most individuals have rather high serum titers from repeated infections throughout childhood. A term infant will usually acquire high titer protection from RSV from his/her mother transplacentally. In this regard, most infants born at term are at least somewhat protected from severe RSV infections within the first three to six months of life.21 In vulnerable individuals (premature infants, immunocompromised hosts), the infection quickly progresses to the LRT. Epithelial damage in terms of syncitia development continues into the bronchioles. As the size of the airways diminishes with each branching, the resultant airway narrowing increases the resistance to airflow. There may be significant respiratory compromise from the epithelial syncitia and excess mucus and debris within the small airways. Also, at this stage of an infection, cellmediated immunity (cytotoxic T lymphocytes) becomes an important factor. As T cells attempt to destroy the virus within the lung, immunopathological responses lead to further lung injury. The infected cells release proinflammatory cytokines and chemokines, including interlukins (IL-1, IL-6, and IL-8) and tumor necrosis factor-alpha (TNF-␣). These proinflammatory mediators activate and recruit inflammatory cells, including macrophages, neutrophils, eosinophils, and T lymphocytes, into the airway wall and surrounding tissues.17,19,21–24 The cell-mediated response originates from CD4⫹ helper T cells, described as Th-1 and Th-2 cell types. Each of these T cell subtypes releases families of cytokines. Th-1 cells produce interferon and interleukins (IL-12R, IL-18R), which are efficient in antiviral destruction without a major inflammatory response. Th-1 cells stimulate macrophages and dendritic cells to produce IL-12, while lung eosinophilia is inhibited. Th-2 cells, on the other hand, release inflammatory mediators, including interleukins (IL-4, IL-5, IL-6, IL-10) and leukotrienes. The Th-2 cells stimulate a proliferation of eosinophils, with the production of IgE. The ratio of Th-1 versus Th-2 cell types may be related to the severity of the disease. Clinically, infants with mild bronchiolitis tend to have increased Th-1–produced cytokines and reduced Th-2–produced cy-
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tokines, whereas infants with severe bronchiolitis are characterized by a higher percentage of Th-2 cells, or even a Th-2–predominant response.17,23–26 Besides severity of the RSV infection, the T cell response may play a role in the development of chronic wheezing.27,28
Clinical RSV
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he incubation period of RSV respiratory disease is estimated to be three to five days. At the beginning of the illness, the virus replicates in the nasopharynx. Common symptoms of an upper respiratory tract infection include a productive cough and mild to moderate nasal congestion with clear rhinorrhea. Often an increase in oral secretions with “drooling” is also noted. A low-grade fever may be present in the early stages of the infection. These symptoms can persist for one to three weeks before complete resolution. In vulnerable patients, the RSV infection will spread into the lower respiratory tract. Compared with infants with upper respiratory tract involvement, patients with lower respiratory tract illness (LTRI) are obviously ill and often appear “toxic.” Symptoms of lower respiratory tract disease include tachypnea (respiratory rate greater than 60 to 70 breaths/min), wheezing, and/or rales, that usually appear one to three days after the onset of rhinorrhea. The occurrence of these symptoms mirrors the viral spreading into the bronchi and bronchioles. Hypoxemia is often apparent, with oxygen saturation measuring below 92% in room air. A chest radiograph demonstrates hyperinflation with flattened diaphragms. If the RSV continues to spread to the alveoli, an interstitial pneumonia may be visible, with middle and upper lobes most likely to be affected. In these unfortunate patients, tachypnea becomes frank respiratory distress, with deep retractions and grunting respirations. Hypoxemia worsens, and the risk for cardiovascular failure secondary to hypoxemia, acidosis, and dehydration increases substantially. Pathologically, proliferation of goblet cells with increased mucus production, necrosis of ciliated bronchiolar epithelial cells, peribronchiolar infiltrate of mononuclear cells, and inflammation and peribronchiolar edema due to local cell-mediated and humoral immune responses mark an LRTI. Premature and young infants, who typically have very narrow bronchioles, are at particularly high risk for complete bronchiolar obstruction. As the respiratory status worsens, the risk for vomiting increases. This is most often related to respiratory distress that may increase the likelihood and/or the severity of gastroesophogeal reflux. As a result of this, decreased oral intake with dehydration may be the most critical factor at presentation.5,14,15,29 Infants younger than six months old (especially if they
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had been born prematurely) may also develop apnea caused by progression of the infection into the lower respiratory tract. Babies with apnea typically have radiographic evidence of LRTI/pneumonia and tend to have higher pCO2 and lower pH on blood gas analysis compared with infants who do not have apnea.30 In addition, studies have suggested that the infants’ ability to produce certain chemokines (ie, IL-1b) and an alteration of laryngoreceptors may increase the likelihood and severity of apnea associated with RSV.31 Although the RSV virus can be cultured from an infected individual, the delay in definitive diagnosis of three to five days decreases the clinical utility. More useful for the ongoing management of the patients are rapid diagnostic methods. RSV antigens can be detected in the scrapings of nasal mucosa. Two rapid diagnostic kits that use either immunofluorescence or enzyme immunoassay are commercially available. Sensitivity and specificity are reasonably high (80 to 95%), they are relatively inexpensive, and provide an answer quickly (15 to 30 min).5
Clinical Management
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he majority of infants infected will present with only upper respiratory tract symptoms. Treatment of these infants is symptomatic: assure proper hydration, monitor and treat fever, and manage nasal congestion conservatively. With the progression of the infection to bronchiolitis, treatment should be more aggressive. The clinical goals should be to return the patient to a normal respiratory status. Therapy is aimed at relief of respiratory distress, improvement in oxygenation, alleviation of airway obstruction, and, if possible, enhancement of mucociliary clearance. Infants with bronchiolitis should be closely monitored for apnea, hypoxemia, and impending respiratory failure. The combined effects of fever and decreased intake may jeopardize normal fluid balance. It is important to monitor and normalize body temperature and maintain proper hydration. In infants with evidence of bronchiolitis, oral intake may be compromised, and the risk of vomiting with aspiration is increased. Discontinuing oral feeds and starting intravenous fluids should be considered (Fig 2).5,32–34 Given the nature of the RSV infection, a major component of RSV bronchiolitis is mucosal edema and inflammation with increased mucus production and deposition of cellular debris that lead to airway obstruction. Numerous therapies, including chest physiotherapy (CPT), administration of mucolytics (Dornase alpha), bronchodilators, and corticosteroids have been used to relieve this problem. CPT has been used empirically in the treatment of cystic fibrosis and occasionally in asthma despite the ab-
sence of solid evidence confirming that this therapy can actually enhance mucus clearance. Similarly, in bronchiolitis, CPT produces no clear improvement in compliance or airway resistance.35 Nasr and coworkers36 evaluated the effect of a mucolytic (recombinant human deoxyribonuclease I) on length of stay and change in the chest radiographs of hospitalized, RSV-infected infants. This was a randomized, double-blind, placebo-controlled trial. Though infants treated with mucolytic did show a more rapid improvement of chest radiograph findings compared with infants from the placebo group, there were no significant differences in clinical measures. Contrary to these negative findings, one very basic therapeutic intervention seems to be very effective. The ongoing removal of mucus and debris by deep, nasopharyngeal suction with or without aerosolized bronchodilators (albuterol) has been shown to significantly improve respiratory status in infants who were hospitalized with RSV bronchiolitis.37 Bronchodilators, specifically 2 adrenergic agonists, are first-line therapy for treatment of acute and chronic asthma. Because of the clinical similarities of status asthmaticus and RSV bronchiolitis, bronchodilators are frequently used to treat severe RSV. 2 Adrenergic agonists work by inhibiting the effects of the early phase of the asthmatic response. Stimulation of adenyl cyclase and activation of cAMP-dependent protein kinase results in a relaxation of bronchial smooth muscles and a corresponding increase in airway caliber. This permits higher flow at lower transthoracic pressure. In RSV bronchiolitis it is airway debris, rather than bronchospasm that precipitates postbronchodilator wheezing. Bronchodilator treatment may relieve resistance properties in large- and mediumsized airways, but not in smaller airways. Clinical studies have given mixed results. Black5 reviewed 24 clinical studies in which albuterol, metaproteronol, ipratropium, or a combination were prescribed for infants with moderate to severe RSV bronchiolitis. Eleven of these studies concluded that these drugs led to improvement in outcome measures. Eight showed no benefit, four showed deterioration in condition, and one study showed improvement with ipratropium and deterioration with albuterol. One problem with the aerosolized vehicle is that the drug cannot reach the small distal airways where a therapeutic effect would be realized. The deposition of nebulized albuterol into the airways of children with acute RSV bronchiolitis has been studied. Less than 2% of the inhaled dose actually reached the lung, with less than 1% penetrating the peripheral lung zone. Approximately 8 to 9% was deposited in the oropharynx and gastrointestinal tract, while 10 to 12% did not get past the patient’s face.38 Several studies have evaluated racemic epinephrine for the treatment of RSV bronchiolitis. The majority of these show improvement in one or more clinical measure. These
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Fig 2. Treatment guidelines for RSV upper respiratory illness (URI) and lower respiratory tract illness (LRTI).
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clinical improvements have included decreased respiratory rate, decreased airway resistance, improved inspiratory/ expiratory volumes, and improvement in oxygen saturations post-treatment. The mechanism of action may be that racemic epinephrine reduces microvascular leak and airway edema.39 – 41 The use of steroids to treat infants with reactive airway disease is a common practice. This therapy is often expanded to infants with severe RSV bronchiolitis.42 Most clinical studies evaluating steroid use with RSV bronchiolitis have been small and therefore underpowered. Garrison and coworkers43 published a metaanalysis of randomized, placebo-controlled trials of systemic corticosteroids in the treatment of infants hospitalized with bronchiolitis. The data for three outcomes: length of stay, duration of symptoms, and clinical scores were evaluated. Of 238 papers reviewed, only six met all criteria. In all three outcomes the pooled data suggested a beneficial effect from steroids in patients with bronchiolitis. The data also suggested that steroids might have a greater effect for infants with severe bronchiolitis. Other studies however have failed to show significant beneficial effects for patients treated with steroids. Black44,45 reviewed 17 double-blind, placebo-controlled trials of the use of corticosteroids for RSV bronchiolitis. Only three of the studies resulted in a favorable outcome for the steroid-treated group, with the remainder reporting no benefit. Because of the paucity of data that demonstrate significant benefits, the use of steroids for mild to moderate RSV bronchiolitis with wheezing is not recommended. The Red Book report of the Committee on Infectious Diseases from the American Academy of Pediatrics (AAP) stated that, “In hospitalized infants with RSV bronchiolitis, corticosteroids are not effective and are not indicated.”46 Similarly, the antiviral agent Ribavirin, which has a strong in vitro activity against RSV virus, has not been proven to have consistent clinical benefit and its use is not recommended by the AAP.46 The use of helium/oxygen (heliox) gas mixture in infants with moderate bronchiolitis has been shown to be beneficial in small studies.47 The low density of the helium aids airflow through the infant’s narrowed, mucus-filled airways. Despite aggressive therapy aimed at maintaining ventilation, some patients will continue to deteriorate and intubation and mechanical ventilation become necessary. The ventilatory strategy should address the reason for respiratory failure, that is, the likely obstruction of small caliber airways. As a result, the patient is at high risk for ongoing air trapping. Managing ventilation requires close monitoring of clinical status, blood gas parameters, and radiograph changes. A reasonable ventilation starting point includes liberal inspired oxygen, modest end expi-
ratory pressure (PEEP ⫽ 5 cm H2O), low rate (10 to 20 breaths/min), adequate tidal volume (6 to 8 mL/kg), and long expiratory time. Depending on the severity of the disease, these settings may be changed considerably. It is not uncommon for infants with severe bronchiolitis or RSV pneumonia to require PEEP in the range of 8 to 20 cm H2O, tidal volume of 10 to 20 mL/kg, and ventilatory rates of 60 or greater.48 Of course, at these extreme levels, the risk of barotrauma and volutrauma are exceedingly high. Sedation and chemical paralysis are frequently employed, though the use of these strategies is not universal.48 Newer modes of patient-triggered, volume- and/or pressure-regulated assist control modes offer some theoretical advantages, though there have been no studies with these techniques. Various high-frequency techniques have also been used, though there is no clear consensus as to the use of this ventilatory mode in RSV. In summary, treatment for RSV is largely supportive. Maintain hydration and oxygenation, and keep airways clear of mucus. Monitor closely for apnea and/or evidence of respiratory failure. Bronchodilators may be helpful, especially racemic epinephrine. Heliox may improve air exchange with few adverse effects. The routine use of corticosteroids is not recommended, though some studies suggest an improvement in infants with pending respiratory failure. If ventilation is required, great care must be taken to avoid hyperinflation and development of pneumothoraces. Other more radical therapies, including use of exogenous surfactant,49 nitric oxide inhalation,50 liquid ventilation with perflubron,51 and ECMO,52 should be reserved for infants with intractable respiratory failure.
RSV Prevention
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s stated previously, most children are exposed to RSV by two years of age. The key is to identify and protect those that have a high risk for severe disease. In terms of efficient management of RSV infections, the old adage that an “ounce of prevention is worth a pound of cure,” certainly is true. A modest effort spent identifying vulnerable infants, educating the parents about RSV and its prevention, and providing immunoprophylaxis to those who qualify for it pays off by increasing the chances that these vulnerable children get through the first several years of life without RSV bronchiolitis. There are several factors that increase the risk of acquiring RSV infection. These include: multiple births, maternal education less than 12th grade level, day care attendance under one year of age (care with two or more unrelated infants), other school age siblings, nonbreastfed infants, crowded living conditions (two or more infants/ children sharing a bedroom), and passive smoke exposure.
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Table 1. Recommendations from the American Academy of Pediatrics, Committee on Infectious Disease (Red Book, 2003) RSV prophylaxis should be initiated at the onset of the RSV season and terminated at the end of the RSV season. Synagis (palivizumab) or RespiGam (RSV-IGIV) prophylaxis should be considered for the following: - Infants and with chronic lung disease (CLD) who have required medical treatment within 6 months or less prior to the RSV season ● Less than 2 years of age at the start of RSV season - Infants without Chronic Lung Disease 䡩 ⱕ28 weeks’ gestation ● Less than 1 year of age at start of RSV season 䡩 29-32 weeks’ gestation ● Less than 6 months of age at start of RSV season 䡩 32-35 weeks’ gestation. With additional risk factors that include: child care attendance, school-age siblings, exposure to environmental air pollutants, congenital abnormalities of the airway, or severe neuromuscular disease ● Less than 6 months of age at start of RSV season - Infants and children with hemodynamically significant cyanotic and acyanotic congenital heart disease ● Less than 2 years of age at the start of RSV season Synagis (palivizumab) is preferred for most high-risk children because of its ease of administration, safety, and efficacy. It also does not interfere with live vaccines.
Other risk factors are related to an increased severity of RSV disease. These include medical factors such as prematurity (less than 35 weeks’ gestation), chronic lung disease (BPD), hemodynamically significant congenital heart disease, immunodeficiency states, and weight less than 2.5 kg, low socioeconomic status, male sex, and white race are also associated with an increased risk of severe RSV disease.53 There are several commonsense practices that can significantly reduce RSV spread. The most important of these is hygiene. Good hand washing before handling an infant, as well as ongoing awareness and maintenance of a clean environment are important.54 Routine cleaning of countertops, tables, toys, etc can significantly decrease live virus that can exist on these surfaces for over 24 hours.55 When possible, these infants should be kept from direct contact with people who have evidence of viral respiratory infections. Limiting day care exposure has also been recommended, but for many families is an impossible task. Infants at high risk for severe RSV disease may be eligible for immunoprophylaxis with palivizumab (Synagis). Palivizumab is a humanized monoclonal antibody directed to the F protein of RSV. Palivizumab is derived from 95% human and 5% murine antibody sequences. The recombinant DNA process grafts the murine complementarily determining regions into the human antibody frameworks. The efficacy of palivizumab in preventing RSV lower respiratory disease was proven in the IMpact-RSV trial conducted in the mid 1990s. This clinical trial was a Phase III study of the safety and effectiveness of palivizumab. Over 1,500 infants were enrolled in this randomized, double-blind, placebo-controlled, trial conducted in the United States, the United Kingdom, and Canada. The
administration of 15 mg/kg palivizumab monthly by IM injection for prophylaxis of RSV in premature infants was shown to be safe and generally well tolerated. Palivizumab prophylaxis was associated with a 55% reduction of RSV hospitalization in all premature infants and an 80% reduction in hospitalization rate for 32 to 35 weeks’ gestational age infants without chronic lung disease (BPD).13 Based on the results of this study, the Food and Drug Administration (FDA) licensed this drug for use. The American Academy of Pediatrics Committee on Infectious Disease recommends palivizumab, “For the prevention of serious LRT disease caused by RSV in pediatric patients at high risk of RSV disease. Safety and efficacy were established in infants with BPD and infants with a history of prematurity (⬍35 weeks’ gestational age).” (Table 1)46 Further clinical studies were conducted to evaluate the safety and efficacy of palivizumab in prevention of RSV lower respiratory disease in infants and children with hemodynamically significant congenital heart disease (CHD). Over 1,200 infants were enrolled in a multicenter, randomized, double-blinded study conducted in the United States, Canada, France, Germany, Poland, Sweden, and the United Kingdom. The infants were all 24 months old or younger, with hemodynamically significant CHD. The results of this trial showed that Palivizumab was safe and well tolerated in this population. Prophylaxis was associated with a 45% reduction of RSV hospitalization in these children.56 Based on this information, the AAP has expanded the indications for use of palivizumab to include children who are 24 months of age or younger with hemodynamically significant cyanotic and acyanotic congenital heart disease. (Table 1)46 From the IM-Pact trial conducted from 1996 to 1997,
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the hospitalization rate for RSV for infants receiving placebo ranged from 8 to 12%, while infants receiving palivizumab had an RSV hospitalization rate of 1.8 to 7.9%.13 In the years following FDA approval and incorporation of palivizumab prophylaxis as standard care for premature infants, RSV hospitalization rates have been tracked and continue to decrease. Between 2001 and 2002, over 5,000 patients were followed in the Synagis outcomes registry. The hospitalization rate for RSV currently ranges between 1.2 and 2.2%. This ongoing follow-up affirms the efficacy of palivizumab as an effective therapy for the prevention of severe RSV in an at risk population.57
Conclusion
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SV is one of the most common diseases of childhood; virtually all children have been exposed to this virus by age two years. Although essentially incurable, it is generally self-limited to common cold symptoms in most patients. In vulnerable infants and those who are immunocompromised, RSV can progress to a bronchiolitis and/or pneumonia, with a resulting high likelihood of hospitalization and an increased chance of significant morbidity or death. Treatment is supportive with few therapies that are certain to make a positive impact. Because of the nature of the virus and mode of infection, the RSV virus is protected from the human immune system, which has made development of an effective vaccine impossible up to this point. Though RSV may never be eradicated, simple public health measures and prophylaxis with palivizumab in high-risk populations can certainly decrease the impact of this disease.
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the hospital course of children with respiratory syncytial virus (RSV) infection? An analysis using the pediatric investigators collaborative network on infections in Canada (PICNIC) RSV database. Pediatrics 99:E7, 1997 10. Welliver RC: Respiratory syncytial virus immunoglobulin and monoclonal antibodies in the prevention and treatment of respiratory syncytial virus infection. Semin Perinatol 22:87–95, 1998 11. Johnson S, Oliver C, Prince GA, et al: Development of a humanized monoclonal antibody (MEDI-493) with potent in vitro and in vivo activity against respiratory syncytial virus. J Infect Dis 176:1215– 1224, 1997 12. The PREVENT Study Group: Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis. Pediatrics 99:93–99, 1997 13. Connor EM and 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 102:531–537, 1998 14. Welliver RC: Respiratory syncytial virus and other respiratory viruses. Pediatr Infect Dis J 22:S6 –S10, 2003 15. Hall CB: Respiratory syncytial virus and parainfluenza virus. N Engl J Med 344:1917–1928, 2001 16. Hacking D, Hull J: Respiratory syncytial virus: Viral biology and the host response. J Infect Dis 45:18 –24, 2002 17. Crowe JE, Williams JV: Immunology of viral respiratory tract infection in infancy. Paediatr Respir Rev 4:112–119, 2003 18. Baumeister EG, Hunicken DS, Savy VL: RSV molecular characterization and specific antibody response in young children with acute lower respiratory infection. J Clin Virol 27:44 –51, 2003 19. de Waal L, Koopman LP, van Benten IJ, et al: Moderate local and systemic respiratory syncytial virus-specific T-cell responses upon mild or subclinical RSV infection. J Med Virol 70:309 –318, 2003 20. Ogilvie MM, Vathenen AS, Radford M, et al: Maternal antibody and respiratory syncytial virus infection in infancy. J Med Virol 7:263– 271, 1981 21. Domachowske JB, Rosenberg HF: Respiratory syncytial virus infection: Immune response, immunopathogenesis, and treatment. Clin Microbiol Rev 12:298 –309, 1999 22. Nadal D, Ogra PL: Development of local immunity: Role in mechanisms of protection against or pathogenesis of respiratory syncytial viral infections. Lung 168S:379 –387, 1990 23. Toms GL, Scott R: Respiratory syncytial virus and the infant immune response. Arch Dis Child 62:544 –546, 1987 24. Welliver RC: Immune response, in Weisman LE, Groothius JR (ed): Contemporary Diagnosis and Management of Respiratory Syncytial Virus. Newton, PA, Handbooks in Health Care, 2000, pp 94 –121 25. Adkins B, Bu Y, Guevara P: Generation of Th memory in neonates versus adults: Prolonged primary Th2 effector function and impaired development of Th1 memory effector function in murine neonates. J Immunol 166:918 –925, 2001 26. Culley FJ, Pollott J, Openshaw PJ: Age at first viral infection determines the pattern of T cell-mediated disease during reinfection in adulthood. J Exp Med 196:1381–1386, 2002 27. Sigurs N: Clinical perspectives on the association between respiratory syncytial virus and reactive airway disease. Respir Res 3:S8 – S14, 2002 28. Martinez FD: Respiratory syncytial virus bronchiolitis and the pathogenesis of childhood asthma. Pediatr Infect Dis J 22:S76 –S82, 2003 29. Greenough A: Respiratory syncytial virus infection: Clinical features, management, and prophylaxis. Curr Opin Pulm Med 8:214 – 217, 2002 30. Kneyber MC, Brandenburg AH, de Groot R, et al: Risk factors for respiratory syncytial virus associated apnoea. Eur J Pediatr 157:331– 335, 1998 31. Lindgren C, Grogaard J: Reflex apnoea response and inflammatory mediators in infants with respiratory tract infection. Acta Paediatr 85:798 – 803, 1996
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32. Hall CB: Respiratory syncytial virus: A continuing culprit and conundrum. J Pediatr 135:2–7, 1999 33. Hodge D, Chetcuti PA: RSV: Management of the acute episode. Paediatr Respir Rev 1:215–220, 2000 34. Buckingham SC, Quasney MW, Bush AJ, et al: Respiratory syncytial virus infections in the pediatric intensive care unit: Clinical characteristics and risk factors for adverse outcomes. Pediatr Crit Care Med 2:318 –323, 2001 35. Quittell L, Wolfson MR, Schidlow D: The effectiveness of chest physical therapy (CPT) in infants with bronchiolitis. Am Rev Respir Dis 137:406, 1988 36. Nasr SZ, Strouse PJ, Soskolne E, et al: Efficacy of recombinant human deoxyribonuclease I in the hospital management of respiratory syncytial virus bronchiolitis. Chest 120:203–208, 2001 37. Wang EE, Milner R, Allen U, et al: Bronchodilators for treatment of mild bronchiolitis: A factorial randomised trial. Arch Dis Child 67:289 –293, 1992 38. Amirav I, Balanov I, Gorenberg M, et al: a´ Agonist aerosol distribution in respiratory syncytial virus bronchiolitis. J Nuclear Med 43:487– 491, 2002 39. Bertrand P, Aranibar H, Castro E, et al: Efficacy of nebulized epinephrine versus salbutamol in hospitalized infants with bronchiolitis. Pediatr Pulmonol 31:284 –288, 2001 40. Sanchez I, De Koster J, Powell RE, et al: Effect of racemic epinephrine and salbutamol on clinical score and pulmonary mechanics in infants with bronchiolitis. J Pediatr 122:145–151, 1993 41. Numa AH, Williams GD, Dakin CJ: The effect of nebulized epinephrine on respiratory mechanics and gas exchange in bronchiolitis. Am J Respir Crit Care Med 164:86 –91, 2001 42. Wright RB, Pomerantz WJ, Luria JW: New approaches to respiratory infections in children: Bronchiolitis and croup. Emerg Med Clin North Am 20:93–114, 2002 43. Garrison MM, Christakis DA, Harvey E, et al: Systemic corticosteroids in infant bronchiolitis: A meta-analysis. Pediatrics 105:E44, 2000 44. Buckingham SC, Jafri HS, Bush AJ, et al: A randomized, doubleblind, placebo-controlled trial of dexamethasone in severe respiratory syncytial virus (RSV) infection: Effects on RSV quantity and clinical outcome. J Infect Dis 185:1222–1228, 2002 45. van Woensel JB, van Aalderen WM, de Weerd W, et al: Dexamethasone for treatment of patients mechanically ventilated for lower respiratory tract infection caused by respiratory syncytial virus. Thorax 58:383–387, 2003
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46. Red Book: Report of the Committee on Infectious Diseases. Pickering LK (ed): American Academy of Pediatrics, Elk Grove Village, IL, 2003 pp. 523–528 47. Hollman G, Shen G, Zeng L, et al: Helium-oxygen improves Clinical Asthma Scores in children with acute bronchiolitis. Crit Care Med 26:1731–1736, 1998 48. Leclerc F, Scalfaro P, Noizet O, et al: Mechanical ventilatory support in infants with respiratory syncytial virus infection. Pediatr Crit Care Med 2:197–204, 2001 49. Tibby SM, Hatherill M, Wright SM, et al: Exogenous surfactant supplementation in infants with respiratory syncytial virus bronchiolitis. Am J Respir Crit Care Med 162:1251–1256, 2000 50. Patel NR, Hammer J, Nichani S, et al: Effect of inhaled nitric oxide on respiratory mechanics in ventilated infants with RSV bronchiolitis. Intensive Care Med 25:81– 87, 1999 51. Haeberle HA, Nesti F, Dieterich HJ, et al: Perflubron reduces lung inflammation in respiratory syncytial virus infection by inhibiting chemokine expression and nuclear factor-kappa B activation. Am J Respir Crit Care Med 165:1433–1438, 2002 52. Meyer TA, Warner BW: Extracorporeal life support for the treatment of viral pneumonia: Collective experience from the ELSO registry. Extracorporeal Life Support Organization. J Pediatr Surg 32: 232–236, 1997 53. Meissner HC, Welliver RC, Chartrand SA, et al: Immunoprophylaxis with palivizumab, a humanized respiratory syncytial virus monoclonal antibody, for prevention of respiratory syncytial virus infection in high risk infants: A consensus opinion. Pediatr Infect Dis J 18:223–231, 1999 54. Teare L, Cookson B, Stone S: Hand hygiene. Br Med J 323:411– 412, 2001 55. Blydt-Hansen T, Subbarao K, Quennec P, et al: Recovery of respiratory syncytial virus from stethoscopes by conventional viral culture and polymerase chain reaction. Pediatr Infect Dis J 18:164 –165, 1999 56. Sondheimer HM: the Cardiac Synagis Study Group: Palivizumab (PV) prevents hospitalization due to respiratory syncytial virus (RSV) in young children with serious congenital heart disease (CHD). Pediatr Cardiol 23:664, 2002 57. Romero JR: Palivizumab prophylaxis of respiratory syncytial virus disease from 1998 to 2002: results from four years of palivizumab usage. Pediatr Infect Dis J 22:S46 –S54, 2003
Abstract Respiratory syncytial virus (RSV) is one of the most common diseases of childhood. Virtually all children have been exposed to this virus by age two. RSV causes common cold symptoms in most patients. In vulnerable children, RSV can progress to bronchiolitis and/ or pneumonia with an increased chance of significant morbidity or death. The nature of the virus and mode of infection protects it from the human immune system. Treatment for RSV is largely supportive. Key elements of treatment are maintenance of hydration, and oxygenation, as well as keeping the airways clear of mucus. Prevention of RSV in vulnerable infants is important because of the increased morbidity and mortality. A modest effort spent identifying vulnerable infants, educating the parents about RSV and its prevention, and providing immunoprophylaxis to those who qualify for it, increases the chances that these vulnerable children get through the first several years of life without RSV bronchiolitis. © 2004 Elsevier Inc. All rights reserved.
Respiratory Syncytial Virus (RSV): Overview, Treatment, and Prevention Strategies By Mark J. Polak, MD
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espiratory syncytial virus (RSV) is one of the most common human pathogens on this planet. By the age of two years, nearly every human child has been exposed to the virus, resulting most often in mild upper respiratory tract illness. But RSV may also be one of the most serious human pathogens on this planet. Worldwide, RSV directly or indirectly contributes to the deaths of between 600,000 and 1,000,000 infants and children under the age of five each year. In the United States, several hundred infants may die directly from the infection, while the deaths of an additional several thousand may be attributed to RSV-related complications. RSV infections account for over 100,000 hospitalizations each year.1– 4 For the neonatal caregiver, an understanding of the virus and how to treat and/or prevent infection is an important part of management of the premature infant.
Background
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From the Department of Pediatrics, West Virginia University School of Medicine, Morgantown, WV. Address reprint requests to Mark J. Polak, Department of Pediatrics, WVU School of Medicine, PO Box 9214, Morgantown, WV 26506-9214 © 2004 Elsevier Inc. All rights reserved. 1527-3369/04/0401-0003$30.00/0 doi:10.1053/j.nainr.2003.12.007
linical descriptions of infantile pneumonias that may have been RSV were noted in the 1840s, and descriptions of seasonal epidemics were made 100 years later. During the 1950s, a curious respiratory illness spread through a colony of chimpanzees in a medical laboratory. The respiratory illness was named “chimpanzee coryza agent.” However, it was later discovered that the origin of the infection was from the human caretakers. In 1963, Robert Chanock and his colleagues were able to isolate and characterize the virus. The name “respiratory syncytial virus” was a descriptive term related to pathological changes of the airway epithelium as a result of the infection. RSV was identified as the agent responsible for seasonal epidemics of upper and lower respiratory infections in infants and children that occur worldwide.5,6 Besides public health awareness and interruption of infection by addressing handling and hygiene issues, RSV has been resistant to efforts to control and eradicate it through a pharmacologic or immunologic approach. Work with a vaccine in the 1960s failed to impart protection. Worse yet, the infants who Newborn and Infant Nursing Reviews, Vol 4, No 1 (March), 2004: pp 15–23
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received the vaccine had more severe infections in the subsequent year.7 During the 1980s, ribavirin, a medication that was effective in decreasing RSV replication in vitro, failed to demonstrate significant clinical utility in several clinical trials.8,9 Throughout this time, research continued into the molecular biology of RSV, and several researchers were able to find a vulnerable aspect of RSV infectivity. Humans do develop antibodies against one of the RSV surface proteins that enable the RSV particle to fuse to the respiratory epithelium. Though the presence of these antibodies did not prevent RSV infection, they were shown to be able to prevent development of lower respiratory tract (LRT) infection, which is the aspect of the disease that has the greatest public health risk.10,11 By the mid-1990s several formulations of these antibodies were commercially available. These antibodies were initially introduced as a polyclonal, pooled RSV-IGIV (RespiGam, MedImmune, Gaithersburg, MD), and later perfected as a monoclonal antibody, palivizumab (Synagis, MedImmune, Gaithersburg, MD). These medications have proven to be highly effective in prevention of LRT infection from RSV in “high-risk” infants.12,13
The RSV Virus
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SV is a medium-sized (between 80 to 350 nm diameter), membrane-bound, RNA virus. (Fig 1) It is classified as a paramyxovirus. RSV is closely related to several other RNA viruses, including measles, mumps, and parainfluenza types 1, 2, and 3. The RNA nucleocapsid of RSV is enclosed in a bylayer lipid sphere. The nucleocapsid genome is a single strand of RNA encoding for 10 viral proteins. Two of these are nonstructural proteins; the remaining eight are structural proteins. The nonstructural proteins direct viral replication within the infected host cell. The structural proteins are divided into three functional groups. The matrix is made up of two membrane-associated proteins, while three proteins make up the viral capsid. In addition there are three transmembrane surface glycoproteins. Two of these, a fusion protein (F) and an attachment protein (G), are responsible for the initiation and propagation of an RSV infection. There are two subtypes of RSV, Types A and B. They differ primarily in the composition of the G protein, while the F protein is conserved between the two strains.14 –16 The surface glycoproteins also evoke a host-derived antibody response following an infection. A primary RSV infection produces a weak humoral antibody response that does not differ with the severity of the disease.17,18 These responses are responsible for ending the infection and eliminating the virus, but do not appear to impart longterm immunity. In fact, it is only with reinfection that the
Fig 1. Cross sectional diagram of RSV virus. The nucleocapsid genome is a single strand of RNA that codes for 10 viral proteins. Two of these are nonstructural proteins. (A) Proteins M and M2 make up the matrix. (B) The viral capsid is made up of 3 proteins, a nucleoprotein, a phosphoprotein, and a polymerase protein. (C) There are 3 transmembrane proteins, a hydrophobic protein, a fusion protein, and an attachment protein.
antibody response is enhanced. If the infection reaches the LRT, a T cell-mediated response is generated.17,19,20
Infection
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SV most often begins as an infection in the nasal epithelial cells. The G protein initiates attachment of the virus to the epithelial cell. The F protein is cleaved by proteolytic enzymes of the infected cell and the virus then fuses with the epithelial cell membrane and enters the cytoplasm. The RSV virus then replicates in the host cell. The host cell is destroyed and the virus particles are released to propagate the infection. In addition to allowing the virion to enter the host cell, the F protein causes the fusion of the host cell to adjacent uninfected cells. The individual cell membranes are broken down, and large multinucleated epithelial cells (syncitia) are formed. The viral RNA can spread without forming complete viral particles. The infection results in the destruction of the epithelial cells of the upper respiratory tract. Exposure to RSV triggers humoral immune responses. Primary RSV infection results in only a weak antibody response with IgM, IgG, and IgA produced. This response is not suffi-
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cient to completely destroy the virus or to prevent upper respiratory tract replication of the virus, thus an upper respiratory tract illness develops. The humoral immune response does not seem to differ with the severity of disease, but is enhanced with reinfection. The degree of resistance to reinfection correlates best with levels of serum versus secretory antibody.14 –18 As noted previously, the RNA from RSV can spread from cell to cell as the epithelial syncitia is produced. Because of this “human shield” aspect of RSV infection, high levels of neutralizing antibodies are required to prevent the progression of infection from the upper respiratory tract to the LRT. By adulthood, most individuals have rather high serum titers from repeated infections throughout childhood. A term infant will usually acquire high titer protection from RSV from his/her mother transplacentally. In this regard, most infants born at term are at least somewhat protected from severe RSV infections within the first three to six months of life.21 In vulnerable individuals (premature infants, immunocompromised hosts), the infection quickly progresses to the LRT. Epithelial damage in terms of syncitia development continues into the bronchioles. As the size of the airways diminishes with each branching, the resultant airway narrowing increases the resistance to airflow. There may be significant respiratory compromise from the epithelial syncitia and excess mucus and debris within the small airways. Also, at this stage of an infection, cellmediated immunity (cytotoxic T lymphocytes) becomes an important factor. As T cells attempt to destroy the virus within the lung, immunopathological responses lead to further lung injury. The infected cells release proinflammatory cytokines and chemokines, including interlukins (IL-1, IL-6, and IL-8) and tumor necrosis factor-alpha (TNF-␣). These proinflammatory mediators activate and recruit inflammatory cells, including macrophages, neutrophils, eosinophils, and T lymphocytes, into the airway wall and surrounding tissues.17,19,21–24 The cell-mediated response originates from CD4⫹ helper T cells, described as Th-1 and Th-2 cell types. Each of these T cell subtypes releases families of cytokines. Th-1 cells produce interferon and interleukins (IL-12R, IL-18R), which are efficient in antiviral destruction without a major inflammatory response. Th-1 cells stimulate macrophages and dendritic cells to produce IL-12, while lung eosinophilia is inhibited. Th-2 cells, on the other hand, release inflammatory mediators, including interleukins (IL-4, IL-5, IL-6, IL-10) and leukotrienes. The Th-2 cells stimulate a proliferation of eosinophils, with the production of IgE. The ratio of Th-1 versus Th-2 cell types may be related to the severity of the disease. Clinically, infants with mild bronchiolitis tend to have increased Th-1–produced cytokines and reduced Th-2–produced cy-
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tokines, whereas infants with severe bronchiolitis are characterized by a higher percentage of Th-2 cells, or even a Th-2–predominant response.17,23–26 Besides severity of the RSV infection, the T cell response may play a role in the development of chronic wheezing.27,28
Clinical RSV
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he incubation period of RSV respiratory disease is estimated to be three to five days. At the beginning of the illness, the virus replicates in the nasopharynx. Common symptoms of an upper respiratory tract infection include a productive cough and mild to moderate nasal congestion with clear rhinorrhea. Often an increase in oral secretions with “drooling” is also noted. A low-grade fever may be present in the early stages of the infection. These symptoms can persist for one to three weeks before complete resolution. In vulnerable patients, the RSV infection will spread into the lower respiratory tract. Compared with infants with upper respiratory tract involvement, patients with lower respiratory tract illness (LTRI) are obviously ill and often appear “toxic.” Symptoms of lower respiratory tract disease include tachypnea (respiratory rate greater than 60 to 70 breaths/min), wheezing, and/or rales, that usually appear one to three days after the onset of rhinorrhea. The occurrence of these symptoms mirrors the viral spreading into the bronchi and bronchioles. Hypoxemia is often apparent, with oxygen saturation measuring below 92% in room air. A chest radiograph demonstrates hyperinflation with flattened diaphragms. If the RSV continues to spread to the alveoli, an interstitial pneumonia may be visible, with middle and upper lobes most likely to be affected. In these unfortunate patients, tachypnea becomes frank respiratory distress, with deep retractions and grunting respirations. Hypoxemia worsens, and the risk for cardiovascular failure secondary to hypoxemia, acidosis, and dehydration increases substantially. Pathologically, proliferation of goblet cells with increased mucus production, necrosis of ciliated bronchiolar epithelial cells, peribronchiolar infiltrate of mononuclear cells, and inflammation and peribronchiolar edema due to local cell-mediated and humoral immune responses mark an LRTI. Premature and young infants, who typically have very narrow bronchioles, are at particularly high risk for complete bronchiolar obstruction. As the respiratory status worsens, the risk for vomiting increases. This is most often related to respiratory distress that may increase the likelihood and/or the severity of gastroesophogeal reflux. As a result of this, decreased oral intake with dehydration may be the most critical factor at presentation.5,14,15,29 Infants younger than six months old (especially if they
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had been born prematurely) may also develop apnea caused by progression of the infection into the lower respiratory tract. Babies with apnea typically have radiographic evidence of LRTI/pneumonia and tend to have higher pCO2 and lower pH on blood gas analysis compared with infants who do not have apnea.30 In addition, studies have suggested that the infants’ ability to produce certain chemokines (ie, IL-1b) and an alteration of laryngoreceptors may increase the likelihood and severity of apnea associated with RSV.31 Although the RSV virus can be cultured from an infected individual, the delay in definitive diagnosis of three to five days decreases the clinical utility. More useful for the ongoing management of the patients are rapid diagnostic methods. RSV antigens can be detected in the scrapings of nasal mucosa. Two rapid diagnostic kits that use either immunofluorescence or enzyme immunoassay are commercially available. Sensitivity and specificity are reasonably high (80 to 95%), they are relatively inexpensive, and provide an answer quickly (15 to 30 min).5
Clinical Management
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he majority of infants infected will present with only upper respiratory tract symptoms. Treatment of these infants is symptomatic: assure proper hydration, monitor and treat fever, and manage nasal congestion conservatively. With the progression of the infection to bronchiolitis, treatment should be more aggressive. The clinical goals should be to return the patient to a normal respiratory status. Therapy is aimed at relief of respiratory distress, improvement in oxygenation, alleviation of airway obstruction, and, if possible, enhancement of mucociliary clearance. Infants with bronchiolitis should be closely monitored for apnea, hypoxemia, and impending respiratory failure. The combined effects of fever and decreased intake may jeopardize normal fluid balance. It is important to monitor and normalize body temperature and maintain proper hydration. In infants with evidence of bronchiolitis, oral intake may be compromised, and the risk of vomiting with aspiration is increased. Discontinuing oral feeds and starting intravenous fluids should be considered (Fig 2).5,32–34 Given the nature of the RSV infection, a major component of RSV bronchiolitis is mucosal edema and inflammation with increased mucus production and deposition of cellular debris that lead to airway obstruction. Numerous therapies, including chest physiotherapy (CPT), administration of mucolytics (Dornase alpha), bronchodilators, and corticosteroids have been used to relieve this problem. CPT has been used empirically in the treatment of cystic fibrosis and occasionally in asthma despite the ab-
sence of solid evidence confirming that this therapy can actually enhance mucus clearance. Similarly, in bronchiolitis, CPT produces no clear improvement in compliance or airway resistance.35 Nasr and coworkers36 evaluated the effect of a mucolytic (recombinant human deoxyribonuclease I) on length of stay and change in the chest radiographs of hospitalized, RSV-infected infants. This was a randomized, double-blind, placebo-controlled trial. Though infants treated with mucolytic did show a more rapid improvement of chest radiograph findings compared with infants from the placebo group, there were no significant differences in clinical measures. Contrary to these negative findings, one very basic therapeutic intervention seems to be very effective. The ongoing removal of mucus and debris by deep, nasopharyngeal suction with or without aerosolized bronchodilators (albuterol) has been shown to significantly improve respiratory status in infants who were hospitalized with RSV bronchiolitis.37 Bronchodilators, specifically 2 adrenergic agonists, are first-line therapy for treatment of acute and chronic asthma. Because of the clinical similarities of status asthmaticus and RSV bronchiolitis, bronchodilators are frequently used to treat severe RSV. 2 Adrenergic agonists work by inhibiting the effects of the early phase of the asthmatic response. Stimulation of adenyl cyclase and activation of cAMP-dependent protein kinase results in a relaxation of bronchial smooth muscles and a corresponding increase in airway caliber. This permits higher flow at lower transthoracic pressure. In RSV bronchiolitis it is airway debris, rather than bronchospasm that precipitates postbronchodilator wheezing. Bronchodilator treatment may relieve resistance properties in large- and mediumsized airways, but not in smaller airways. Clinical studies have given mixed results. Black5 reviewed 24 clinical studies in which albuterol, metaproteronol, ipratropium, or a combination were prescribed for infants with moderate to severe RSV bronchiolitis. Eleven of these studies concluded that these drugs led to improvement in outcome measures. Eight showed no benefit, four showed deterioration in condition, and one study showed improvement with ipratropium and deterioration with albuterol. One problem with the aerosolized vehicle is that the drug cannot reach the small distal airways where a therapeutic effect would be realized. The deposition of nebulized albuterol into the airways of children with acute RSV bronchiolitis has been studied. Less than 2% of the inhaled dose actually reached the lung, with less than 1% penetrating the peripheral lung zone. Approximately 8 to 9% was deposited in the oropharynx and gastrointestinal tract, while 10 to 12% did not get past the patient’s face.38 Several studies have evaluated racemic epinephrine for the treatment of RSV bronchiolitis. The majority of these show improvement in one or more clinical measure. These
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Fig 2. Treatment guidelines for RSV upper respiratory illness (URI) and lower respiratory tract illness (LRTI).
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clinical improvements have included decreased respiratory rate, decreased airway resistance, improved inspiratory/ expiratory volumes, and improvement in oxygen saturations post-treatment. The mechanism of action may be that racemic epinephrine reduces microvascular leak and airway edema.39 – 41 The use of steroids to treat infants with reactive airway disease is a common practice. This therapy is often expanded to infants with severe RSV bronchiolitis.42 Most clinical studies evaluating steroid use with RSV bronchiolitis have been small and therefore underpowered. Garrison and coworkers43 published a metaanalysis of randomized, placebo-controlled trials of systemic corticosteroids in the treatment of infants hospitalized with bronchiolitis. The data for three outcomes: length of stay, duration of symptoms, and clinical scores were evaluated. Of 238 papers reviewed, only six met all criteria. In all three outcomes the pooled data suggested a beneficial effect from steroids in patients with bronchiolitis. The data also suggested that steroids might have a greater effect for infants with severe bronchiolitis. Other studies however have failed to show significant beneficial effects for patients treated with steroids. Black44,45 reviewed 17 double-blind, placebo-controlled trials of the use of corticosteroids for RSV bronchiolitis. Only three of the studies resulted in a favorable outcome for the steroid-treated group, with the remainder reporting no benefit. Because of the paucity of data that demonstrate significant benefits, the use of steroids for mild to moderate RSV bronchiolitis with wheezing is not recommended. The Red Book report of the Committee on Infectious Diseases from the American Academy of Pediatrics (AAP) stated that, “In hospitalized infants with RSV bronchiolitis, corticosteroids are not effective and are not indicated.”46 Similarly, the antiviral agent Ribavirin, which has a strong in vitro activity against RSV virus, has not been proven to have consistent clinical benefit and its use is not recommended by the AAP.46 The use of helium/oxygen (heliox) gas mixture in infants with moderate bronchiolitis has been shown to be beneficial in small studies.47 The low density of the helium aids airflow through the infant’s narrowed, mucus-filled airways. Despite aggressive therapy aimed at maintaining ventilation, some patients will continue to deteriorate and intubation and mechanical ventilation become necessary. The ventilatory strategy should address the reason for respiratory failure, that is, the likely obstruction of small caliber airways. As a result, the patient is at high risk for ongoing air trapping. Managing ventilation requires close monitoring of clinical status, blood gas parameters, and radiograph changes. A reasonable ventilation starting point includes liberal inspired oxygen, modest end expi-
ratory pressure (PEEP ⫽ 5 cm H2O), low rate (10 to 20 breaths/min), adequate tidal volume (6 to 8 mL/kg), and long expiratory time. Depending on the severity of the disease, these settings may be changed considerably. It is not uncommon for infants with severe bronchiolitis or RSV pneumonia to require PEEP in the range of 8 to 20 cm H2O, tidal volume of 10 to 20 mL/kg, and ventilatory rates of 60 or greater.48 Of course, at these extreme levels, the risk of barotrauma and volutrauma are exceedingly high. Sedation and chemical paralysis are frequently employed, though the use of these strategies is not universal.48 Newer modes of patient-triggered, volume- and/or pressure-regulated assist control modes offer some theoretical advantages, though there have been no studies with these techniques. Various high-frequency techniques have also been used, though there is no clear consensus as to the use of this ventilatory mode in RSV. In summary, treatment for RSV is largely supportive. Maintain hydration and oxygenation, and keep airways clear of mucus. Monitor closely for apnea and/or evidence of respiratory failure. Bronchodilators may be helpful, especially racemic epinephrine. Heliox may improve air exchange with few adverse effects. The routine use of corticosteroids is not recommended, though some studies suggest an improvement in infants with pending respiratory failure. If ventilation is required, great care must be taken to avoid hyperinflation and development of pneumothoraces. Other more radical therapies, including use of exogenous surfactant,49 nitric oxide inhalation,50 liquid ventilation with perflubron,51 and ECMO,52 should be reserved for infants with intractable respiratory failure.
RSV Prevention
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s stated previously, most children are exposed to RSV by two years of age. The key is to identify and protect those that have a high risk for severe disease. In terms of efficient management of RSV infections, the old adage that an “ounce of prevention is worth a pound of cure,” certainly is true. A modest effort spent identifying vulnerable infants, educating the parents about RSV and its prevention, and providing immunoprophylaxis to those who qualify for it pays off by increasing the chances that these vulnerable children get through the first several years of life without RSV bronchiolitis. There are several factors that increase the risk of acquiring RSV infection. These include: multiple births, maternal education less than 12th grade level, day care attendance under one year of age (care with two or more unrelated infants), other school age siblings, nonbreastfed infants, crowded living conditions (two or more infants/ children sharing a bedroom), and passive smoke exposure.
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Table 1. Recommendations from the American Academy of Pediatrics, Committee on Infectious Disease (Red Book, 2003) RSV prophylaxis should be initiated at the onset of the RSV season and terminated at the end of the RSV season. Synagis (palivizumab) or RespiGam (RSV-IGIV) prophylaxis should be considered for the following: - Infants and with chronic lung disease (CLD) who have required medical treatment within 6 months or less prior to the RSV season ● Less than 2 years of age at the start of RSV season - Infants without Chronic Lung Disease 䡩 ⱕ28 weeks’ gestation ● Less than 1 year of age at start of RSV season 䡩 29-32 weeks’ gestation ● Less than 6 months of age at start of RSV season 䡩 32-35 weeks’ gestation. With additional risk factors that include: child care attendance, school-age siblings, exposure to environmental air pollutants, congenital abnormalities of the airway, or severe neuromuscular disease ● Less than 6 months of age at start of RSV season - Infants and children with hemodynamically significant cyanotic and acyanotic congenital heart disease ● Less than 2 years of age at the start of RSV season Synagis (palivizumab) is preferred for most high-risk children because of its ease of administration, safety, and efficacy. It also does not interfere with live vaccines.
Other risk factors are related to an increased severity of RSV disease. These include medical factors such as prematurity (less than 35 weeks’ gestation), chronic lung disease (BPD), hemodynamically significant congenital heart disease, immunodeficiency states, and weight less than 2.5 kg, low socioeconomic status, male sex, and white race are also associated with an increased risk of severe RSV disease.53 There are several commonsense practices that can significantly reduce RSV spread. The most important of these is hygiene. Good hand washing before handling an infant, as well as ongoing awareness and maintenance of a clean environment are important.54 Routine cleaning of countertops, tables, toys, etc can significantly decrease live virus that can exist on these surfaces for over 24 hours.55 When possible, these infants should be kept from direct contact with people who have evidence of viral respiratory infections. Limiting day care exposure has also been recommended, but for many families is an impossible task. Infants at high risk for severe RSV disease may be eligible for immunoprophylaxis with palivizumab (Synagis). Palivizumab is a humanized monoclonal antibody directed to the F protein of RSV. Palivizumab is derived from 95% human and 5% murine antibody sequences. The recombinant DNA process grafts the murine complementarily determining regions into the human antibody frameworks. The efficacy of palivizumab in preventing RSV lower respiratory disease was proven in the IMpact-RSV trial conducted in the mid 1990s. This clinical trial was a Phase III study of the safety and effectiveness of palivizumab. Over 1,500 infants were enrolled in this randomized, double-blind, placebo-controlled, trial conducted in the United States, the United Kingdom, and Canada. The
administration of 15 mg/kg palivizumab monthly by IM injection for prophylaxis of RSV in premature infants was shown to be safe and generally well tolerated. Palivizumab prophylaxis was associated with a 55% reduction of RSV hospitalization in all premature infants and an 80% reduction in hospitalization rate for 32 to 35 weeks’ gestational age infants without chronic lung disease (BPD).13 Based on the results of this study, the Food and Drug Administration (FDA) licensed this drug for use. The American Academy of Pediatrics Committee on Infectious Disease recommends palivizumab, “For the prevention of serious LRT disease caused by RSV in pediatric patients at high risk of RSV disease. Safety and efficacy were established in infants with BPD and infants with a history of prematurity (⬍35 weeks’ gestational age).” (Table 1)46 Further clinical studies were conducted to evaluate the safety and efficacy of palivizumab in prevention of RSV lower respiratory disease in infants and children with hemodynamically significant congenital heart disease (CHD). Over 1,200 infants were enrolled in a multicenter, randomized, double-blinded study conducted in the United States, Canada, France, Germany, Poland, Sweden, and the United Kingdom. The infants were all 24 months old or younger, with hemodynamically significant CHD. The results of this trial showed that Palivizumab was safe and well tolerated in this population. Prophylaxis was associated with a 45% reduction of RSV hospitalization in these children.56 Based on this information, the AAP has expanded the indications for use of palivizumab to include children who are 24 months of age or younger with hemodynamically significant cyanotic and acyanotic congenital heart disease. (Table 1)46 From the IM-Pact trial conducted from 1996 to 1997,
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Mark J. Polak
the hospitalization rate for RSV for infants receiving placebo ranged from 8 to 12%, while infants receiving palivizumab had an RSV hospitalization rate of 1.8 to 7.9%.13 In the years following FDA approval and incorporation of palivizumab prophylaxis as standard care for premature infants, RSV hospitalization rates have been tracked and continue to decrease. Between 2001 and 2002, over 5,000 patients were followed in the Synagis outcomes registry. The hospitalization rate for RSV currently ranges between 1.2 and 2.2%. This ongoing follow-up affirms the efficacy of palivizumab as an effective therapy for the prevention of severe RSV in an at risk population.57
Conclusion
R
SV is one of the most common diseases of childhood; virtually all children have been exposed to this virus by age two years. Although essentially incurable, it is generally self-limited to common cold symptoms in most patients. In vulnerable infants and those who are immunocompromised, RSV can progress to a bronchiolitis and/or pneumonia, with a resulting high likelihood of hospitalization and an increased chance of significant morbidity or death. Treatment is supportive with few therapies that are certain to make a positive impact. Because of the nature of the virus and mode of infection, the RSV virus is protected from the human immune system, which has made development of an effective vaccine impossible up to this point. Though RSV may never be eradicated, simple public health measures and prophylaxis with palivizumab in high-risk populations can certainly decrease the impact of this disease.
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