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RSV infections: State of the art

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RSV MANAGEMENT

Ribavirin

The life cycle of RSV after the initial infection affects treatment strategies. RSV produces no symptoms for at least 3 to 5 days following infection (“eclipse phase”), during which time it reproduces exponentially and reaches the lungs, causing the first symptoms to be observable after 5 to 7 days. By the time the first symptoms emerge, the virus is already rapidly disappearing from the system.13 If ribavirin is administered at this point, the pediatrician has provided a virostatic agent against a virus that is no longer present, and therapy will not only be ineffective, but it may trigger bronchospasms.

The American Academy of Pediatrics (AAP) Committee on Infectious Diseases supported the use of ribavirin in 1993 guidelines,14 but changed their recommendation to “may be considered” in 1996.15 The only exception for ribavirin use is in the immunocompromised patient with RSV. In this scenario, the virus continues to replicate for months after the initial infection unopposed by the host defense mechanisms; therefore, aerosolized ribavirin therapy should be considered, either alone or in combination with humanized anti-RSV antibody.

Other treatments

Corticosteroids have not been shown to have a significant effect on RSV bronchiolitis.16 Alpha- and beta-adrenergic bronchodilators, such as epinephrine and albuterol, have shown very little or no effect on RSV symptoms in multiple controlled trials. The only effective treatment with proven efficacy is supportive therapy with adequate fluid intake and oxygen. Oral feeding should be withheld in patients with high respiratory rates to prevent aspiration.

PROPHYLAXIS

Vaccines

Vaccines have been ineffective against RSV and can be dangerous in children. RSV is not a strongly cytopathic virus; illness results primarily from the host immune response against the infection rather than from the virus itself.16 Therefore, any vaccine carries the risk of creating a stronger and potentially dangerous immune response to the next infection.

In the 1960s, a formalin-inactivated RSV vaccine was introduced with deleterious outcomes—it was minimally protective and was responsible for infant deaths. Because mortality was not immediate, the vaccine continued to be administered throughout the season. Unfortunately, with their immunity modified, vaccinated children became severely ill when they came in contact with the wild-type virus during the year following vaccination. The withdrawal of the formalin-inactivated vaccine still represents an important precedent that makes investigators and regulatory bodies very cautious about active immunization against this virus.

Palivizumab

Palivizumab is a 96% human monoclonal antibody targeting the RSV F protein, and it offers passive immunity for infants at risk for severe infection. The Impact-RSV clinical trial of palivizumab showed that five monthly intramuscular injections effectively reduced RSV hospitalizations by 78% in premature infants from 32 to 35 weeks gestation without bronchopulmonary dysplasia (BPD). Treatment offered only a 39% reduction in premature infants with BPD.17

The most recent AAP guidelines18 recommend palivizumab prophylaxis with a maximum of five monthly doses only in the first year of life for otherwise healthy infants born before 29 weeks gestation and for infants born before 32 weeks gestation with chronic lung disease of prematurity (CLD) defined as a requirement for supplemental oxygen for at least 28 days after birth. Prophylaxis is no longer recommended in the second year of life, except for infants with CLD still requiring oxygen, corticosteroids, or diuretics. Palivizumab prophylaxis should be discontinued if a breakthrough RSV hospitalization occurs because the likelihood of a second RSV hospitalization in the same season is low.

Palivizumab also should be considered for children with hemodynamically significant congenital heart defects, profound immunodeficiency, and pulmonary or neuromuscular pathologies impairing airway clearance; however, no formal recommendation was made for patients with Down syndrome or cystic fibrosis due to insufficient data.18 The protective effect of palivizumab appears to be cumulative, with almost half of the breakthrough infections observed in the clinical trials occurring after the first injection or immediately following the second.17

A recent randomized, double-blind, placebo-controlled trial has shown that palivizumab given to premature infants during the first year of life provides a 40% to 60% reduction of wheezing episodes.19 This trial confirms the results of previous retrospective studies; however, further large multicenter trials of palivizumab prophylaxis in both premature and full-term infants are needed to assess protection against recurrent wheezing and asthma, and to formulate evidence-based recommendations.

FUTURE DIRECTIONS

Nebulization of 3% saline improves mucociliary clearance and is increasingly being used in airway diseases involving mucus plugging (eg, cystic fibrosis). It also has been reported to reduce length of hospital stay and provide symptomatic relief in patients with bronchiolitis, but its use remains controversial. In particular, it has not been shown to be effective at reducing hospitalization when used in emergency settings. Therefore, based on current evidence, the administration of hypertonic saline for bronchiolitis should be limited to hospitalized infants.

Anti-leukotrienes used during the acute phase of RSV bronchiolitis have been shown to improve post-bronchiolitis respiratory symptoms, especially in younger patients with high urinary leukotriene E4 (LTE4). However, a large, multicenter, randomized, double-blind, placebo-controlled trial with montelukast failed to show statistically significant clinical improvement. A post-hoc data analysis revealed that children with persistent respiratory symptoms after the acute phase of the infection may benefit from montelukast, but the manufacturer (Merck) is no longer pursuing this indication.

There is not enough scientific evidence at present to support the use of DNAse or exogenous surfactant in the setting of acute bronchiolitis. New generations of specific antivirals and vaccines based on immunogens offer hope as new options for prophylaxis and/or management of RSV infection in the not too distant future.

Recent basic science investigations have provided new findings that could influence future therapies. Some of these studies have suggested that the tropism of RSV is not solely for the airway epithelium; rather, this virus can spread hematogenously to infect extrapulmonary targets, particularly the bone marrow stromal cells where RSV finds a sanctuary niche shielding it from immune protection and allowing subclinical latency. In one study, RSV was found in the bone marrow of every child and in about 80% of adults tested.20 Similar findings were replicated with other pathogens like Mycobacterium tuberculosis.21 This discovery could direct future treatment strategies for a number of viral, bacterial, and parasitic infections.

In another study, transplacental transmission of RSV from the mother’s airways to fetal lung tissues was shown for the first time in an animal model of infection. When the virus enters fetal respiratory cells, it persists and induces the expression of neurotrophic factors and receptors resulting in postnatal airways with dramatically increased parasympathetic innervation and methacholine reactivity. These structural and functional changes provide a suitable model to explain the development of long-term bronchial hyperreactivity following re-exposure to RSV in early life.22

In conclusion, the search for a cure for the most common respiratory infection in children has humbled several generations of investigators through the more than 50 years since RSV was discovered. Nevertheless, the rapid evolution in the fields of virology and immunology and recent breakthrough discoveries promise to deliver new strategies that may make a difference in the management of this common infection and its long-term sequelae.

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