Respiratory Syncytial Virus: Diagnosis, Prevention, and Management of Complications

ABSTRACT: Respiratory syncytial virus (RSV) is a highly contagious virus that causes pediatric respiratory infections. Most children will contract RSV multiple times throughout childhood, beginning before their first birthday. In many patients RSV infections are minor and self-limiting, but in certain patient populations they can lead to serious complications. Prevention techniques can minimize the spread of RSV. In addition to nonpharmacologic prevention methods, one pharmacologic prevention option, palivizumab, is available for certain patient populations at high risk for complications. Currently, there is a strong need for more preventive and treatment options for RSV.

Epidemiology

RSV is an RNA virus in the family Paramyxoviridae. It is transmitted by inoculation of mucous membranes after contact with secretions or surfaces contaminated with the virus. RSV is usually transmitted by direct contact, but transmission can also take place through airborne droplets, as with influenza. Because there are multiple genotypes of RSV, patients can be reinfected multiple times.¹

Typically a mild, self-limiting infection, RSV has the potential to cause severe and life-threatening symptoms in certain patient populations. The American Academy of Pediatrics (AAP) reports that, each year, RSV is responsible for the hospitalization of approximately 57,500 children aged <5 years and accounts for an estimated 1 of every 334 hospitalizations in this age group.¹ Hospitalizations are mainly attributed to patients who are at high risk for complications. High-risk patients include premature infants, neonates, very young infants (<12 weeks old during RSV season), and those born with heart or lung impairments, such as bronchopulmonary dysplasia and congenital heart diseases. Infants exposed to environmental triggers and twins, triplets, and other multiples also are at high risk.² Refer to TABLE 1 for a summary of high-risk patients.

RSV is also a health concern for non–high-risk (referred to as low risk for the purposes of this article) children. This infection is the most common cause of bronchiolitis (inflammation of the bronchioles resulting in wheezing, shortness of breath, cough, fever, and fatigue) in children aged <1 year.³ The CDC reports that approximately 25% to 40% of RSV infections in infants and young children will progress to bronchiolitis or pneumonia.² RSV patients who develop bronchiolitis or pneumonia have higher rates of hospitalization than those without complications.³

Signs and Symptoms

In low-risk patients, RSV infections generally present with mild, nondescript respiratory manifestations. Symptoms start after a brief incubation period, with patients typically developing upper respiratory symptoms around days 4 to 6 of the infection. The most common initial symptoms in these patients include loss of appetite and runny nose. Immediately afterward, most patients will exhibit coughing, wheezing, and sneezing and may become febrile.² Supportive care aimed at alleviating and minimizing symptoms may be administered during this time. Most patients are contagious for 3 to 8 days and fully clear the infection in 1 to 2 weeks; however, immunosuppressed patients may be contagious for up to 3 weeks.² In order to limit the spread of the virus to high-risk patients, most pediatric and neonatal ICUs do not allow elementary school–aged children, who may be infected and contagious prior to developing symptoms, to visit during RSV season.

In high-risk patients, the course of infection can be much different. These patients have a much greater risk of developing complications such as lower respiratory infections, bronchiolitis, and pneumonia.² Patients in this category may develop early symptoms similar to those of low-risk patients, but are much more likely to progress to manifestations such as significant shortness of breath, severe coughing or wheezing, and cyanosis.⁴ If the illness is severe enough to require inpatient admission, oxygen administration and intubation may be considered.²

Diagnosis

Diagnosis of RSV is based on clinical presentation, patient history, and environment. Since bacterial infections are usually not found concurrently with RSV, the only therapy available to RSV-infected patients is symptomatic treatment. Although rapid antigen tests to detect RSV exist, they are not commonly used. Typically, these tests are not warranted for low-risk patients because the course of therapy would be the same (symptom-based) even if the patient were negative for RSV. In the inpatient setting, diagnostic tests (including the rapid antigen test and reverse transcriptase polymerase chain reaction analysis) may be used to differentiate high-risk noninfected patients from RSV positive patients.⁵

Nonpharmacologic Prevention

The most important prevention methods for low-risk patients are nonpharmacologic in nature. Pharmacists can counsel patients and their caretakers on proper hand-washing techniques, containment of secretions when sneezing or coughing, and sanitization of home surfaces.² This is especially important in households with small children, who are more likely to put items in their mouths and touch mucous membranes. Parents and caregivers should be advised to refrain from kissing their child when either they or the child is ill in order to prevent the infection from spreading.² Pharmacists are in a unique position to counsel about the spread of RSV through oral and nasal secretions.

Environmental factors are a source of exposure to RSV and may render children at higher risk. When a child is exposed to two or more children who are not immediate relatives in day care, school, or other places, his or her chance of contracting RSV increases dramatically. In addition, patients who live in crowded home environments, were not breastfed, or are exposed to cigarette smoke are at higher risk for infection and complications.¹

Pharmacologic Prevention

High-risk patients require more dedicated preventive therapy than low-risk patients. In 1998, the FDA approved the first pharmacologic therapy for prevention of RSV in certain high-risk patient groups. Synagis ( palivizumab) is a humanized monoclonal antibody that is approved to prevent contraction of RSV during RSV season in high-risk patients ( TABLE 1).⁶

Palivizumab is injected IM into the thigh at a dose of 15 mg/kg. It must be given once a month during RSV season and should be continued throughout the season even if the patient develops RSV.⁶ According to the most recent AAP guidelines, most patients should receive no more than five doses over the course of the season. Infants born prematurely between the start of week 32 and the end of week 34 who do not have significant congenital heart defects or chronic lung disease are at lower risk than other high-risk patients and therefore should receive only three doses.¹

Reports of anaphylaxis from palivizumab have been documented in some patients. Such occurrences should be treated by using suitable supportive therapy, including epinephrine, and discontinuing the medication. Patients and their parents or caregivers should be advised of the risk of anaphylaxis and hypersensitivity reactions.¹

Cost is an important consideration for patients requiring palivizumab therapy. The average wholesale price of a 50 mg/0.5 mL vial of Synagis is approximately $1,000.⁷ A 100 mg/1 mL vial is also available. Depending upon the child’s weight, a dose could require multiple-vial administration. For this reason, MedImmune—the manufacturer of Synagis—provides a copayment assistance program for qualified patients. This program, called Access 360, is available through the Synagis website and may lower the patient’s copayments to as little as $30. The MedImmune Assistance Program, also available through the Synagis website, may cover the full cost of the medication for certain low-income, uninsured families.⁸

Treatment

Therapy for low-risk patients presenting with mild upper respiratory tract infection (URTI) manifestations is mainly symptom-based. These patients can be treated with OTC products (mainly nonpharmacologic) or with prescription products. One of the most important factors to consider in these patients is adequate hydration.⁴ A patient’s hydration status may be assessed by testing skin turgor (pinching the skin and noting its elasticity), observing the moisture of mucous membranes, or evaluating the child’s urine output. Normal hydration methods such as routine eating and drinking can be supplemented with oral rehydration products. Patients aged >4 years may be able to take noncombination cold and cough products as needed to overcome more irritating symptoms, but these products are not recommended for RSV patients unless under direct supervision of a physician.¹ For RSV-infected children, pharmacists can suggest symptom management with saline nasal drops, humidifier therapy, and bulb syringes to remove excess mucus. Most patients may also take weight-dosed acetaminophen. See TABLE 2 for a chart of available symptom-relief products.

Therapy for high-risk RSV patients depends upon infection severity and complications. Practitioners should consider many factors in order to develop an individualized therapy plan for the patient. For mild infections, high-risk patients may be treated similarly to low-risk patients with OTC products. In cases of moderate-to-severe infection, hospitalization may be required. In the hospital, therapy will be tailored to the patient’s needs. Depending on the situation, patients may receive respiratory therapy (including supplemental oxygen, intubation, mechanical ventilation, or rehydration therapy with IV fluids) and/or nutritional therapy, which may include parenteral nutrition.⁴ Previously, ribavirin—a nucleoside analogue used to treat some viral infections, such as hepatitis C—was often used in high-risk patients, but the AAP no longer recommends it for RSV treatment.⁴ The most important therapy difference between high-risk and low-risk patients is the continuation of the specialized preventive therapy palivizumab in high-risk patients for the remainder of the RSV season (discussed in more detail earlier in this article).¹

New and Emergent Therapy

The creation of a vaccine to prevent RSV has been hampered by the immune systems of the patients requiring it most. In general, children aged <6 months have an underdeveloped immune system, owing to their age and the presence of maternal antibodies.⁸ Maternal antibodies may suppress the infant’s normal, necessary response to vaccines that would enable the development of immunity.

In the future, live vaccines that can be given intranasally and vector vaccines may be used to avoid the maternal-antibody effect.⁹ Currently, several medications and vaccines are being investigated for RSV prevention and treatment. RSV cps2 and RSV MEDI ∆M2-2 are pipeline vaccines currently in recruitment for phase I trials. RSV cps2 will be studied in seropositive children; RSV MEDI ∆M2-2 will be studied in seropositive and seronegative children, adults, and seronegative infants. These live attenuated vaccines, both of which are being sponsored by the National Institute of Allergy and Infectious Diseases, are designed to be delivered intranasally.^10,11

Another drug, tentatively named ALX-0171, is an inhaled nanobody (an antibody-derived therapeutic protein) that is being studied for the treatment of RSV. ALX-0171, which is designed to bind to and neutralize RSV, was studied previously in lamb models for stimulation of neonatal respiratory systems. Recently, ALX-0171 successfully completed an initial phase I trial and is now moving into a second phase I trial.¹² Given the great need for therapeutic options for patients who have or are at risk for RSV, there is room in the market for the development of new products. To that end, many laboratories and pharmaceutical companies are working to create new and better products for the future treatment of RSV.

The Pharmacist’s Role in Prevention and Care

Pharmacists are in a prime position to help care for patients affected by RSV and to educate such patients and their families. In an outpatient setting, this can achieved through a variety of means, including explaining the concepts of antibiotic stewardship with regard to viral infections, discussing the importance of proper preventive measures, and advising whether the patient may qualify for pharmacologic therapy with palivizumab. Pharmacists can also assist in the selection of appropriate products for symptom control. Pharmacists can counsel patients and caregivers on how to prevent the spread of RSV to high-risk children, especially in families with more than one child. Early identification of high-risk patients, in conjunction with the rest of the medical team, may help families more quickly connect to available resources for their child. Pharmacists should remain up-to-date on RSV information, including current trends and RSV seasonality, through resources such as the CDC. TABLE 3 lists online resources for tracking RSV seasonality in all geographic regions.

Conclusion

RSV is often the offending culprit in upper respiratory infections in children of all ages. RSV infections are usually mild and self-limiting, but there is the potential for very serious complications necessitating hospitalization. Because of the high number of RSV cases, the ease of spread, and the likelihood of complications, it is imperative that proper preventive measures be taken. Palivizumab remains the only FDA-approved preventive modality. The development of new preventive and treatment modalities and adequate patient education are vital to improving the outcomes of patients with RSV.

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