INFECTIOUS DISEASES IN CHILDREN September 2007
Clinical Case Challenges in Respiratory Syncytial Virus

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Introduction Six-month-old with rhinitis John J. LaBella, MD Lethargic, febrile 28-day-old Gary Goodman, MD Preterm 8-week-old with wheezing Michael Forbes, MD

Introduction

Respiratory syncytial virus is one of the leading causes of severe lower respiratory tract disease in infants, accounting for a significant percentage of cases of bronchiolitis and pneumonia during the RSV season, generally from November to April. Patients at greatest risk for infection are those in day care, those with school-age siblings and those with underlying heart or pulmonary disease or comprised immune systems, problems often arising following premature birth.

There is no cure or vaccine for RSV; however, for high-risk infants, immunoprophylaxis has been shown to be effective in preventing infection. In addition, lifestyle modifications, such as avoiding contact with those with respiratory disease and frequent hand washing during the RSV season, can reduce the incidence of the viral infection as well.

In a series of interviews, Michael Forbes, MD, Gary Goodman, MD, and John LaBella, MD, developed case studies to enable clinicians to better identify patients at risk for developing RSV, to illustrate the normal case presentation and to discuss steps that should be taken to prevent the contraction of RSV. In addition, important concepts in understanding the nature of the virus, the concurrence with apnea and identifying candidates for prophylaxis, were discussed.

Leonard Krilov, MD, Course Director
Chief of Pediatric Infectious Diseases
Vice Chair, Department of Pediatrics
Winthrop University Hospital
Mineola, N.Y.

Six-month-old with rhinitis
John J. LaBella, MD

Case Study 1 Presentation/history A 6-month-old boy presented with symptoms of rhinitis for 3 to 4 days, followed by a low-grade fever (100.5°F) that developed on day 5. The patient’s mother reported rapid, noisy breathing in the infant with poor feeding and decreased bottle endurance, but attributed the infant’s symptoms to a cold. Twelve hours prior to presentation at the pediatric clinic, the patient displayed louder wheezing, which prompted his mother to bring him in for assessment. The infant was delivered full-term with no complications; he had no history of respiratory illness but has had mild eczema since birth; lived with both parents (father smoked cigarettes outside the home); had one sibling, age 3 years; patient was enrolled in day care at the time of presentation (late January). The patient’s family history was otherwise non-contributory. Vital signs at presentation included a temperature of 100.5°F, heart rate of 110 beats per minute, respiratory rate of 50 breaths per minute, blood pressure of 77/48 mm Hg, and oxygen saturation by pulse oximetry (SpO2) of 92%. One hour later, the patient’s vital signs were unchanged, the patient appeared alert and slightly prolonged expiratory phase breathing was noted on auscultation, but no wheezes were appreciated. Nasal irrigation with saline, followed by bulb suctioning, was performed, and the patient was released from clinic after successfully feeding 6 oz of formula without distress. Prior to release, the patient’s mother was instructed to monitor the infant and to call the clinic if his condition appeared to worsen. Increasing Symptoms Six hours after discharge, the mother reported the infant’s breathing was noisier and appeared to be more labored, especially during an attempt at feeding. The mother was instructed to return to the clinic with her son. Upon re-examination, the respiratory rate had increased to 80 breaths per minute, the heart rate was 135 beats per minute, and the oxygen saturation level on re-presentation was 89%; chest x-ray revealed right middle lobe atelectasis and hyperlucency of the right lung field. The patient was referred to ED, where IV fluids were administered due to poor feeding, and supplemental oxygen was provided to maintain saturations >90%. Rapid RSV testing was positive. The patient was subsequently admitted to the pediatric ward for observation with a clinical diagnosis of RSV bronchiolitis. Frequent reassessments were performed by the hospital staff, but no other interventions were required. Resolution Over the next 36 hours, supplemental oxygen was discontinued as oxygen saturation on room air, as measured by pulse oximetry, was consistently >93%. The patient resumed oral feedings, with nasal suctioning performed before each feeding. The patient’s vital signs stabilized, with a reduction of the respiratory rate to 30 to 45 breaths per minute, and the patient was discharged. Prior to discharge, the patient’s mother was re-instructed on proper suctioning techniques for home care and informed that the child may cough for the next 2 to 3 weeks. She was instructed to call the clinic, however, if the patient’s feedings decreased, difficulty breathing returned or if fever recurred. Phone follow-up over the next few days was encouraged. At a clinic visit scheduled 3 weeks later, the patient was asymptomatic and appeared fully recovered. No recurrent wheezing or other respiratory sequelae were noted. © 2007, iStockphoto.com / PhotoDisc,Getty Images / Creatas, JupiterImages Corporation

Epidemiology of RSV
John J. LaBella, MD

Respiratory syncytial virus affects people of all ages but is most prevalent in infants and young children. By age 2, 80% to 90% of children experience at least one episode of RSV infection, with approximately 40% resulting in a lower respiratory tract infection (LRTI).¹ Multiple RSV infections can occur in infants younger than 1 year. In a 3-year study conducted at Baylor University, 69% of infants were infected by RSV in their first year of life, a third of whom developed LRTI. In the second year of the study, 83% of children were infected and 16% reported LRTI. During the third and fourth years, 30% to 50% of the children were infected, with LRTI occurring in 25% of cases.²

RSV infections account for >120,000 hospital admissions in the United States annually.³ Over the past several decades, the hospitalization rate for RSV-associated bronchiolitis has increased, with data demonstrating a 2.4-fold increase in incidence of infection from 1980 to 1996 (12.9 children per 1,000 vs. 31.2 per 1,000, respectively).⁴ Of these RSV-related hospital admissions, 7% to 21% of pediatric patients will require assisted ventilatory support due to respiratory insufficiency.^5-8 Combining direct and indirect costs of an RSV hospitalization, Robbins and colleagues determined the cost of hospitalization for RSV infection to be between $16,325 and $33,700.⁹ Case-controlled studies have demonstrated that severe RSV bronchiolitis in infancy is associated with a nearly 12-fold increase in the risk of subsequent wheezing episodes over the next 10 to 12 years.¹⁰ Although the majority of RSV infections resolve uneventfully in otherwise healthy children, LRTIs in high-risk populations such as premature infants may be much more severe.^1,11

Geography and Seasonality of RSV infection

RSV is distributed globally and is the only respiratory virus that predictably produces a sizable outbreak of infection each year. In the northern hemisphere, RSV outbreaks usually occur from November to April, with a peak infection rate in January and February.¹¹ In the southern hemisphere, wintertime epidemics occur from May to September, peaking in May, June or July. In tropical and semitropical climates, the seasonal outbreaks are usually associated with the rainy season. The epidemic peaks are not as sharp as in temperate climates and, in some settings, RSV can be isolated in as many as 8 months of the year.^12-14 Although 91% of 2005 to 2006 RSV cases were reported to the CDC’s National Respiratory and Enteric Virus Surveillance System (NREVSS) between November and April, sporadic detections were reported throughout the year. During mid-April through September 2006, 36 states and the District of Columbia reported 1,072 RSV cases; of these, 48% were located in Florida.¹¹ Although the magnitude of RSV outbreaks may fluctuate, the number of hospital admissions for children with RSV-associated LRTIs is fairly constant. For example, admissions for LRTIs associated with RSV in a Washington, DC, study did not vary more than 2.7-fold over an 11-year period.¹⁵

Reducing the burden of RSV disease

Health care providers should consider RSV infection in the differential diagnosis of persons of all ages with RTIs (particularly during the annual seasonal RSV peak), and implement appropriate isolation precautions to prevent nosocomial transmission from RSV-infected patients.¹⁶ Although rapid antigen can detect RSV infection in young children, sensitive reverse transcription–polymerase chain reaction (RT-PCR) assays are more reliable to detect RSV in older children and adults.¹⁷ Prevention of community-acquired disease is particularly difficult as RSV is a nearly ubiquitous virus during the winter months, and transmission between household, day care, school and work contacts is very high, and re-infections in the same season are common. No successful vaccine against RSV exists and no clinically useful anti-viral treatments are effective against RSV. For infants and young children considered at highest risk for complications from RSV infection, passive immunoprophylaxis with the anti-RSV monoclonal antibody palivizumab given as monthly injections during the RSV season should be considered.¹⁸

The American Academy of Pediatrics has identified infants and children at highest risk for RSV including those aged <24 months with chronic lung disease who have required medical therapy within 6 months of RSV season onset, those with hemodynamically significant congenital heart disease and preterm infants born at <32 weeks’ gestation or preterm infants born at 32 to 35 weeks’ gestation having at least two additional risk factors (eg, day care attendance, exposure to environmental pollutants, school-aged siblings, congenital abnormalities of the airways or neuromuscular disease) during their first RSV season.¹⁸

Significant reductions in hospitalization rates in these high-risk populations were observed during the clinical trials which led to the FDA licensure of palivizumab. More recently, a naturalistic, population-based study of the impact of palivizumab on confirmed hospitalizations over a 7-year period between two similar regions in Canada (ie, Calgary and Edmonton) was recently conducted. Clinicians in Calgary implemented palivizumab prophylaxis for high-risk infants during the last four RSV seasons, but clinicians in Edmonton did not. In Calgary, hospitalization was significantly reduced: 7.3% before palivizumab prophylaxis vs. 3.0% after its introduction (odds ratio: 2.53; 95% confidence interval: 1.34 to 4.76). No reduction in hospitalization of high-risk infants during the RSV season was observed in Edmonton, where palivizumab prophylaxis was not offered.^19,20 A similar observation was noted in rural Alaska where hospitalizations due to RSV were observed to decline following the clinical availability of palivizumab.

References

1. Hall CB. In: Feign RD, eds. Textbook of Pediatric Infectious Diseases. 5th ed. Philadelphia, PA: WB Saunders Co; 2003.
2. Kasel JA, Walsh EE, Frank AL, et al. Viral Immunol. 1987-1988;1:199-205.
3. Moler F, Ohmit S. Am J Respir Crit Care Med. 1999;159:1234-1240.
4. Kimpen JL. Respir Res. 2002;3(suppl 1):S40-S45.
5. Sigurs N, Bjarnason R, Sigurbergsson F, et al. Am J Respir Crit Care Med. 2000;161:1501-1507.
6. Frankel L, Lewiston N, Stevenson D. Pediatr Pulmonol. 1986;2:307-311.
7. Everard M, Milner A. Eur J Pediatr. 1992;151:638-650.
8. Tissing W, van Steensel-Moll H, Offringa M. Eur J Pediatr. 1993;152:125-127.
9. Robbins JM, et al. Arch Pediatr Adolesc Med 1998;152:358-366.
10. Falsey AR. Semin Respir Crit Care Med. 2007;28:171-181.
11. Fowlkes AL, et al. MMWR. 2006;55:1277-1279.
12. Spence L, Barratt N. Am J Epidemiol. 1968;88:257.
13. Sung RYT, et al. J Infect Dis 1987;156:527.
14. Cane PA. Rev Med Virol. 2001;11:103-116.
15. Kim HW, et al. Am J Epidemiol. 1973;98:216-225.
16. CDC. MMWR. 2004;53(No. RR-3).
17. Weinberg GA, et al. J Infect Dis. 2004;189:706-710.
18. Meissner HC, Long SS, American Academy of Pediatrics Committee on Infectious Diseases and Committee on Fetus and Newborn. Pediatrics. 2003;112:1447-1452.
19. Mitchell I, et al. Pediatr Pulmonol. 2006;41:1167-1174.
20. Simoes EA, Groothuis JR. J Pediatr. 2007;151:34-42.

DISCUSSION Q. What kind of parent questions are useful for getting valid patient history and environmental information? Gary Goodman, MD: A routine checklist in the office is useful to assess the risk of exposure to RSV infections. I routinely assess three topics: environment, exposure and chronic medical conditions. Environmental risk factors include home living conditions/crowding and exposure to second hand smoke; the potential for exposure to ill people (siblings, day care, school attendance); and chronic medical conditions (respiratory, cardiac, neurologic, immune system). Leonard Krilov, MD: I inquire about adults/children who live with the baby, caregivers, siblings in day care, possible exposure to virus and birth and nursery history. John J. LaBella, MD: Open-ended, non-threatening questions about where and with whom the infant spends his/her time is an essential part of the history. It is essential to know all of the infants’ contacts and caregivers, as well as their smoking history. Explaining to parents the importance of understanding these exposure risk factors often yields additional information not often offered voluntarily on checklists. Q. What symptoms distinguish RSV from a common cold? Goodman: The hallmark of significant RSV infection and that which distinguishes RSV from the common cold is wheezing. Wheezing represents the small airway obstruction that is characteristic of RSV lower respiratory infection and is seen in the majority of patients who are admitted to the hospital. Apnea, especially in young infants and in infants with a history of prematurity, can also occur with RSV infection. Krilov: Initially, there is an overlap, but the progression to LRTI, wheezing and retractions is the standard factor. The cough, frequently brassy, is suggestive, as well. LaBella: The progression from a runny nose with a “wet” cough to audible wheezing with an increase in respiratory rate and prolonged expiratory phase is a classic sign, along with decreased feeding endurance. Q. What are the patient criteria for observation? For a physician visit? For ED admittance? Goodman: Any infant with labored respirations, poor feeding, cyanosis or respiratory distress with nasal flaring, grunting, retractions or tachypnea should be evaluated. Krilov: I evaluate the comfort of breathing, respiratory effort, color or duskiness, activity level, feeding ability or volume primarily. Q. Are any OTC medications appropriate for use in these patients? Goodman: Saline nose drops are probably the most useful OTC treatment. Infants younger than 2 months are generally unable to breathe through their mouths and relieving their nasal congestion will often dramatically improve the infant’s breathing and feeding. Q. What role do atopic dermatitis and allergies play in RSV risk? Goodman: There is no doubt that a complex relationship exists between pre-existing allergies and the host response to RSV infection. Exactly how much atopy contributes to RSV risk specifically, though, is unclear. It is generally not considered a strong enough risk factor to independently qualify an infant for RSV prophylaxis. Krilov: Atopic dermatitis suggests an increased risk for RSV-LRTI. Q. Does a history of asthma impact treatment of RSV? Goodman: I consider the use of corticosteroid medications in patients who have had previous episodes of wheezing. I will also routinely add inhaled ipratropium bromide (Atrovent, Boehringer Ingelheim) to the bronchodilator regimen for children diagnosed with asthma. We know that RSV infection can be a trigger for older children with bronchial asthma and we encourage RSV testing in older children admitted to the hospital with acute asthma with obvious cold symptoms. Q. How important is parent education in the prevention and treatment of RSV? Goodman: Since treatment for RSV infection is so limited and the short- and long-term consequences are so significant, and since there currently is no vaccine for RSV, prevention is the cornerstone of RSV disease management. Each year, 4 million children are born in the United States and at least half of them will get RSV their first winter season. Education of new parents about the risks for RSV, its mode of transmission and the risk factors that can be modified is essential to minimize exposure, especially in infants at risk. Unfortunately, even in clinical trials with palivizumab where both treatment and placebo patients received intensive RSV education, there was a significant background rate of infection. Only treatment with monthly doses of palivizumab was effective in reducing the hospitalization risk from RSV infection. Only by intensive education of parents about RSV and identifying infants at risk can we optimize our prophylaxis efforts. Krilov: Parent education is very important — in terms of prevention issues and management of secretions and feeding. But, given the ubiquity of the virus, it will still occur and still lead to hospitalizations. Remember, although there are high-risk groups as outlined above, the majority of newborns are otherwise normal and most hospitalizations are in otherwise normal, full-term babies.

Risk factors for the development of RSV infection
John J. LaBella, MD

The public health impact of respiratory syncytial virus infection is significant. Approximately two-thirds of infants are infected with RSV in their first year of life, and one-third of those develop a lower respiratory tract infection (LRTI).^1-5 A strong association between severe RSV disease in infancy and long-term pulmonary sequelae has been observed. Studies suggest that RSV-LRTI during infancy is a contributory factor to wheezing and additional lower respiratory tract problems in childhood.^6-8 Sigurs and colleagues found a close association between hospitalized infants with RSV-induced bronchiolitis and the subsequent development of asthma.⁸ The financial burden of children hospitalized with RSV infection is also a concern, with an estimated $300 million spent for this purpose each year in the United States.⁹

Those at highest risk

The most serious RSV infections are found in infants and toddlers, especially those born prematurely, with lung disease, with complicated heart disease at birth or with a compromised immune system.¹⁰ Premature infants comprise the largest population at risk for severe complications from RSV infection.¹¹ Their smaller, more easily obstructed airways can result in poor gas exchange and increased respiratory effort¹²; because they have less energy reserve, premature infants can quickly progress to respiratory failure. Being born before the complete transmission of maternal IgG antibodies in the final weeks of pregnancy, premature infants lack an immune system capable of preventing or limiting the progression of RSV infection in the first year of life. The Tucson Children’s Respiratory Study found that those with lower cord serum RSV antibody (who were also minimally breast fed) were at especially high risk for RSV-induced LRTIs in the first 5 months of life.¹³

RSV transmission

RSV is easily spread with infectious virus shed from the mucous membranes of the eyes, mouth or nose. RSV-induced bronchiolitis is typically associated with profuse secretions that facilitate viral spread through the inhalation of droplets generated by recurrent sneezing and coughing.² RSV can easily be transmitted through direct contact with respiratory secretions or indirectly from contaminated surfaces. RSV can survive on surfaces such as counter tops for up to 30 hours and on clothes or hands for up to 1 hour.^9,10 The most common method of transmission is inhalation of the RSV-infected droplets after someone has sneezed or coughed. However, simply touching, kissing or shaking hands with an infected person can spread RSV. Thus, homes or day care centers can become vectors of infection, contributing to the annual RSV epidemics observed each November to April.^9,14

Much effort has been put forth to better identify who is at greatest risk of exposure to RSV, and also who might be most susceptible to developing severe disease. Several epidemiologic risk factors including children who attend day care, have school-age siblings, live in crowded conditions, are exposed to high levels of air pollution or have family members who smoke elevate the risk for the development of RSV infection.¹⁰ Children from lower socioeconomic environments tend to be younger when they first acquire an RSV-induced LRTI; they are also prone to a more intense clinical course, with a 5- to 10-fold greater likelihood of hospitalization.² A genetic contribution to the risk for severe RSV infection recently has been identified. The common polymorphisms of SP-A2 and SP-D may increase both the risk for and severity of RSV infection.¹⁵ Understanding how the interactions among combinations of these risk factors may further increase risk requires additional epidemiologic study.

Lowering the risk for RSV infection

No effective curative treatments and no clinically available vaccine for severe RSV disease are available. Frequent hand washing and regularly disinfecting household surfaces are effective methods of lowering risk. Other preventive measures include avoiding contact with adults and children with symptoms of upper respiratory infections and preventing sick children from attending day care or school until respiratory symptoms have resolved. Limiting an infant’s exposure to crowds is also advisable.²

Passive immunoprophylaxis is another method of reducing the risk of severe RSV infection in the most vulnerable infants and children. Respiratory syncytial virus-immune globulin intravenous (RSV-IGIV) was the first agent clinically approved for the prophylaxis of severe RSV infections in children younger than 24 months with chronic lung disease or premature birth (ie, <35 weeks’ gestation).¹⁶ A study of RSV-IGIV in such children found a 41% reduction in hospitalization rates, a 53% decrease in days of hospitalization due to RSV and a 60% decrease in the number of days requiring supplemental oxygen.¹⁷ The need for an IV and the large fluid volume for infusion needed per treatment limited the use of RSV-IGIV. Additionally, a possible increase in adverse events in children with congenital heart disease limited the product’s use. In 1998, palivizumab, a humanized RSV neutralizing monoclonal antibody, received FDA approval for the prevention of LRTIs in infants at high risk for developing severe RSV disease.¹⁸ The Impact-RSV trial found that monthly injections of palivizumab reduced RSV hospitalizations by 55% for all children enrolled.^18,19 An additional study in children with congenital heart disease demonstrated safety and efficacy of palivizumab in this high-risk group of children. Palivizumab is not a human blood product and, therefore, does not have the risks associated with blood products, as does RSV-IGIV. Palivizumab is also easier to administer than RSV-IGIV (one intramuscular injection/month vs. a 4-hour IV infusion), does not interfere with concomitant vaccine administration and can be administered in an outpatient setting.¹⁶

Parents and caregivers of infants must be made aware of the importance of reducing exposure and transmission of the disease, especially when the infant is considered at high risk. More effective prevention strategies are needed to decrease the burden of acute RSV disease, in all age groups and populations, worldwide. Reducing the risk of RSV infection may also lead to a reduction in recurrent wheezing, asthma and persistent pulmonary function abnormalities associated with RSV-LRTIs in infancy.

References

1. Moler F, Ohmit S. Am J Respir Crit Care Med. 1999;159:1234-1240.
2. Hall CB. In: Feign RD, et al, eds. Textbook of Pediatric Infectious Diseases. 5th ed. Philadelphia, PA: WB Saunders Co; 2003.
3. Holberg CJ, et al. Am J Epidemiol. 1991;133:1135-1151.
4. Parrot RH, et al. Am J Epidemiol. 1973;98:289-300.
5. Kim HW, et al. Am J Epidemiol. 1973;98:216-225.
6. Eriksson M, et al. Pediatr Allergy Immunol. 2000;11:193-197.
7. Openshaw PJM, Hewitt C. Am J Resp Crit Care Med. 2000;162:S40-S43.
8. Sigurs N, et al. Am J Resp Crit Care Med. 2000;161:1501-1507.
9. CDC. Respiratory Syncytial Virus. Available at: www.cdc.gov/ncidod/dvrd/revb/respiratory/rsvfeat.htm.
10. Linzer JF, Guthrie CC. Emerg Med Rep. 2003;8:13-22.
11. Boyce TG, et al. J Pediatrics. 2000;137:865-870.
12. Greenough A. Acta Paed Supp. 2001;436:11-14.
13. Holberg CJ, et al. Am J Epidemiol. 1991;133:1135-1151.
14. Fowlkes AL, et al. MMWR. 2006;55:1277-1279.
15. Hallman M, Haataja R. Semin Perinatol. 2006;30:350-361.
16. Meissner HC, Long SS, Pediatrics. 2003;112:1447-1452.
17. The PREVENT Study Group. Pediatrics. 1997;99:93-99.
18. Sorrentino M, Powers T. Pediatr Infect Dis J. 2000;19:1068-1071.
19. The Impact-RSV Study Group. Pediatrics. 1998;102:531-537.

Lethargic, febrile 28-day-old
Gary Goodman, MD

Case Study 2 Presentation/history A 28-day-old male infant presented to his family physician in January with decreased activity, trouble feeding and a temperature of 102°F (38.8°C). On physical examination, chest sounds were normal with no evidence of wheezing or respiratory distress; the patient appeared to be irritable and had a moderate amount of rhinorrhea and otorrhea. Pneumatic otoscopy and tympanometry found evidence of middle-ear effusion. The patient, who was delivered full-term with no complications, lives with both parents and one female sibling, aged 38 months. Both parents smoke cigarettes, but deny smoking indoors or near the patient; no pets. The patient was visited by grandmother 5 days prior to presentation; she had complained to family members of having a cough. The patient was admitted to a community hospital and was placed in isolation. Nasopharyngeal secretions were obtained from the patient with the use of a DeLee mucus trap and a portable suction machine. A CBC with differential and serum concentration of CRP were determined; a sepsis workup, which included blood and urine cultures, was performed. A chest radiograph was also taken. Rapid viral testing for RSV, influenza type A and B, parainfluenza and adenovirus was performed on the specimens using a direct fluorescent antibody respiratory panel. Lab results The radiograph was unremarkable, with no evidence of acute infectious changes or hyperinflation. CBC was normal, with white blood cells of 9.4 thou/µL (reference range, 4.5-13.5), red blood cells of 5 thou/µL (4.2-5.4), hemoglobin of 13.9 g/dL (11.5-15.5) and platelets of 406 thou/µL (133-450) with the following differential: 10% bands (0%-11%), 22% segmented neutrophils (34%-64%), 38% lymphocytes (27%-47%), 5% monocytes (2%-12%), and 1% eosinophils (0%-4%). Urinalysis revealed specific gravity of 1.012; urine culture was negative. Serum CRP level was normal (0.41 mg/dL). Bacterial cultures of blood, urine and CSF were subsequently reported as negative. Diagnosis Nasopharyngeal washing was both culture- and immunofluorescence (FA)-positive for RSV. On hospital day 2, the patient was diagnosed with concomitant acute otitis media infection. Treatment When the results of the viral testing became available, the child was placed on contact precautions. He was monitored for sleep apnea and hypoxemia with a bedside cardiorespiratory monitor and pulse oximeter for 48 hours. Supplemental oxygen was supplied by nasal cannula when SpO2 was <90%. IV fluids (5% dextrose w/ 0.25% sodium chloride plus 20 mEq KCl/L) were infused, and ceftriaxone (50 mg/kg) was administered IV. No instances of apnea were observed and the child was discharged in stable condition after 48 hours when the bacterial cultures were reported as negative. Outcome The patient responded well to therapy and was discharged 5 days after hospital admission. At 1-year follow-up, the patient had no evidence of reactive airway disease or pulmonary function deficits; recurrent wheezing or coughing was neither evident nor reported. © 2007, iStockphoto.com / PhotoDisc,Getty Images

Management of apnea in RSV
Gary Goodman, MD

Respiratory syncytial virus is the most important cause of viral lower respiratory tract illness in infants and children worldwide, is responsible for >120,000 annual hospitalizations of infants in the United States alone, and ranks as the leading viral cause of death in children younger than 2 years in the United States.^1,2 Symptoms of RSV infection may range from a simple runny nose and occasional cough that can be treated at home, to severe difficulty breathing that may require hospitalization. Younger children are most at risk for more severe symptoms, such as high fever, wheezing, persistent cough or apnea.^3,4

Apnea is a known complication of RSV infection, with some studies showing an incidence as high as 25% in hospitalized neonates and infants.⁵ Apnea resulting from RSV infection most commonly presents in the first 1 to 2 months of age in premature infants or in infants exhibiting moderate to severe hypoxemia. Apnea may be the only initial symptom in an infant having no other respiratory symptoms of RSV infection and, in addition to hypercarbia and respiratory failure, is a major factor leading to assisted ventilation in infants with RSV.⁶

Although the association between RSV and central apnea has been well documented,^7-9 the mechanisms responsible are complex and remain poorly understood. In the 1970s, Steinschneider and colleagues first implicated prolonged apnea occurring in conjunction with upper respiratory tract infection in cases of sudden infant death syndrome (SIDS).¹⁰ Later sleep studies by the same investigator on large groups of infants confirmed the presence of apnea during upper respiratory illnesses, and further characterized the properties of the phenomenon: the apnea resolved when the infants were illness-free and ceased to occur as the infants grew older.^11,12 Anas and colleagues reported that all prolonged apneic events are central.⁵ Isolated central apnea seems consistent with other reports of cases in which apnea occurred in the absence of the respiratory symptoms that would seem necessary for obstructive apnea.¹³ However, Pickens and colleagues, based upon polysomnography of two RSV-infected infants, reported mixed apnea, having both obstructive and central events.¹⁴ Nonetheless, obstructive apnea may not be independent of central processes and may exist or be more notable in the presence of diminished central nervous system (CNS) arousal mechanisms.¹⁵

Without supportive care, an infant with severe RSV infection may experience apneic spells that can rapidly progress to cyanosis and respiratory failure.¹⁶ Ventilatory assistance (ie, intubation) should be considered for all RSV-infected infants with recurrent apnea or severe oxygen desaturation.¹⁷ Other treatment options include external stimulation, supplemental oxygen, continuous positive airway pressure, mechanical ventilation and pharmacologic management with xanthine derivatives.⁴ The xanthines have been shown to be effective in the treatment of apnea of prematurity.^18-20 Options for xanthine use include aminophylline, theophylline and caffeine, given orally or intravenously. Larsen and colleagues compared the efficacy of caffeine and aminophylline in the treatment of apnea of prematurity. Although the efficacy of the two agents was similar, fewer cardiovascular and gastrointestinal side effects with caffeine were noted.²¹ Davis and colleagues showed that caffeine was effective in 11 neonates whose apnea had been unresponsive to therapeutic theophylline levels.²² A recent retrospective review concluded that caffeine should be considered in the treatment of apnea related to RSV infections in neonates and infants. The number of apneic episodes during the 2 hours before the use of caffeine and the number of episodes after the administration of caffeine were compared in seven infants having RSV-associated apnea, ranging in age from 14 to 64 days. The number of apneic episodes per hour for the 2 to 3 hours before the administration of caffeine ranged from seven to 12, and the number of episodes during the 3 hours after administration of the first dose of caffeine ranged from zero to two. Apneic episodes after caffeine administration responded to external stimulation.²³

Apnea is a common complication of RSV infection in young infants. Prolonged apnea can be the first sign of RSV infection in young infants in the absence of other respiratory symptoms and without any previous observation of apnea by caregivers.^4,5,24 As such, it may pose a diagnostic challenge to the physician and be extremely frightening for the parent.

References

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22. Davis JM, et al. Pediatr Pulmon. 1987;3:90-93.
23. Tobias JD. South Med J. 2000;93:294-296.
24. Rayyan M, et al. Acta Paediatr. 2004;93:847-849.

DISCUSSION Q. When treating a patient with potential RSV, at what point should antibiotics be administered? At what point should they be halted? Gary Goodman, MD: In an infant younger than 2 months with documented fever, our practice is to treat empirically with IV antibiotics until bacterial cultures are negative for at least 48 hours. We will re-evaluate antibiotic therapy if we have confirmation of a documented viral infection such as RSV and stop antibiotics earlier if there is no evidence of a secondary bacterial infection. Leonard Krilov, MD: I administer antibiotics when a patient is “severely ill” pending cultures (subjective) and possibly when the patient has otitis media. John J. LaBella, MD: Antibiotic treatment should be initiated whenever bacterial disease is suspected (concurrent otitis media, lobar pneumonia or shock), but can often be discontinued after surveillance blood, urine and CSF cultures are negative and the patient is responding without signs of on-going clinical decompensation. Transitioning to oral antibiotics for the treatment of otitis is an appropriate alternative to prolonged parenteral administration in the case of the hospitalized infant who has stabilized. Q. Under what conditions should a neonate be isolated? Goodman: Any child admitted to the hospital with respiratory symptoms (runny nose, cough, congestion) should be isolated. It is our practice not to admit any infant to the NICU if the infant could have a community-acquired infection. We will cohort infants with confirmed infections in the same room. Krilov: A neonate should be isolated when RSV or other respiratory viral infection is strongly suspected or confirmed. Precautions including hand washing should be applied universally. LaBella: Isolation policies and, in particular, the practice of cohorting RSV-infected patients, may vary between institutions and even within a given hospital depending on the number of infected patients at any given time. Consultation with local Infection Control Personnel prior to the onset of RSV and influenza seasons can help establish appropriate guidelines and criteria to help minimize the risk of nosocomial outbreaks. Q. How much of an issue is RSV exposure to neonates admitted to the NICU for an unrelated illness? Goodman: Nosocomial RSV is a serious concern during the winter months. We do not admit any infant to the NICU with a community-acquired infection. We also carefully screen staff, visitors and siblings for respiratory symptoms before entering the NICU. And we emphasize the importance of hand washing before and after patient contact. Krilov: It can vary based on unit policy (eg, visitor policy, season, crowding, readmission of discharged babies), but, in general, vigilance is warranted. LaBella: Nosocomial outbreaks of RSV in the NICU continue to occur each season, regardless of the cause for the initial admission. Strict adherence to infection control policies by the staff, as well as restriction of visitation by pre-school and school-age children with mild respiratory illnesses, is absolutely critical to minimize these risks. Q. Please discuss the value of a rapid-acting RSV test. Krilov: Debate exists with this issue. One argument is that all acute respiratory illnesses should be treated and isolated regardless of RSV status, so why bother. I believe it is helpful based on: (1) Education. RSV means more to health care workers and families than “just a virus”; (2) Prevention or cessation of unnecessary antibiotic therapy; (3) Epidemiologic data to understand community illnesses. If available promptly, I believe testing in the hospital setting can at least be cost-effective. LaBella: Rapid RSV testing in the primary care setting may not prove to be cost-effective for the individual patient being tested, as it may not affect treatment strategies. However, it is important to help determine the onset and offset of the RSV season in the community and aids clinicians in the determination of when RSV prophylaxis should begin and end. Q. Does a positive diagnosis of RSV impact patient management? Goodman: Definitely. Although we traditionally think of viral infections as self-limited, RSV infections specifically can have significant morbidity and mortality which can be anticipated and monitored. Confirmation of RSV (or other viral infections) often allows us to limit antibiotic treatment. Appropriate isolation and infection control are also important. And there are long-term implications of hospitalization for RSV disease (such as a 30% risk of recurrent wheezing). Krilov: I may stop antibiotics. LaBella: A positive diagnosis of RSV may play a role in limiting the use of antibiotics and in infection control in the hospital. Q. Are chest x-rays useful or necessary when diagnosing RSV? Should a first-time wheezer receive a chest x-ray? Goodman: It is my opinion that any child being admitted to the hospital for the first time with respiratory symptoms deserves a chest x-ray. Not only will a chest x-ray help rule out other noninfectious causes of wheezing such as congestive heart failure or foreign body aspiration but, in children with confirmed RSV, a chest x-ray can demonstrate pulmonary complications such as atelectatic air leaks (pneumothorax or pneumomediastinum) or secondary bacterial pneumonia. Krilov: This is debatable, but I believe a chest x-ray is not always necessary in typical RSV disease. With severe disease, a chest x-ray may be of some value to assess aeration or focal infiltrates. LaBella: Infants with signs of impending respiratory failure would always warrant a chest x-ray, even in the context of a positive rapid RSV test. But for the patients with an RSV-URTI and a self-limited LRTI, the clinical impression of the managing physician should be considered the priority factor in additional testing. Q. Are inhaled steroids appropriate for wheezing RSV patients? Goodman: To my knowledge, there are no controlled studies demonstrating the efficacy of inhaled (or for that matter oral or parenteral) steroids for RSV bronchiolitis. It is my practice to reserve the use of steroids for patients with previous episodes of wheezing or patients with chronic lung disease. Krilov: Inhaled steroids are not appropriate—at least not in a young infant with typical RSV disease. LaBella: Patients with underlying asthma who subsequently develop an RSV infection may benefit from inhaled corticosteroids, but the previously healthy, first-time wheezer without other atopic risk factors probably would not. Q. Should all children of this age group with RSV be monitored for sleep apnea? If not, what symptoms necessitate monitoring? Goodman: All infants hospitalized for RSV bronchiolitis should be monitored with pulse oximetry. Infants younger than 2 months, especially if they were born prematurely, should also be on an apnea monitor for 48 to 72 hours. Krilov: We monitor patients younger than 1 to 2 months, if admitted; but, possibly, a patient with mild URTI without apnea can be managed at home without monitoring. Q. Under what conditions should the patient be discharged from the ED or NICU? Goodman: Discharge criteria include: maintenance of arterial oxygen saturations (SpO2) 90% or above in room air while awake, asleep and during feedings; minimal respiratory distress clinically; an adequate oral feeding pattern with a normal state of hydration; and appropriate follow-up with a medical professional. Krilov: The patient should be discharged when clinically stable, that is, without oxygen requirement and feeding adequately orally. LaBella: Ongoing hypoxemia, poor feeding and respiratory fatigue in any infant with RSV require additional monitoring, whereas the otherwise healthy full-term infant who is able to feed without distress or hypoxemia can be followed closely as an outpatient as long as follow-up is assured.

RSV: Special considerations for infections in neonates
Gary Goodman, MD

Respiratory syncytial virus is the most common cause of bronchiolitis and pneumonia among children younger than 1 year and approximately 80% of cases occur during the first year of life.^1,2 In developed countries, RSV infection is the most frequent reason for hospitalization of infants, the majority being younger than 6 months.¹ Classically, RSV bronchiolitis manifests as cough, wheezing and respiratory distress. In neonates, however, the disease may have an atypical presentation and may be overlooked. An early prospective study of infection in a neonatal unit during a community outbreak of RSV found that 66 of 82 neonates studied were hospitalized for 6 days or longer and 23 (35%) acquired the virus. Four infants died, two unexpectedly. Illness was often atypical with nonspecific signs, especially in infants younger than 3 weeks. Neonates had significantly less involvement of the lower respiratory tract and lower quantities of virus in their nasal washes.³

Conditions placing young infants at high risk for severe infection with RSV include premature birth (particularly those with chronic lung disease of prematurity), bronchopulmonary dysplasia, cystic fibrosis, congenital heart disease, immunodeficiency, neurologic disease, nephrotic syndrome and low birth weight.⁴ Incomplete development of the airway, damage to the airway and airway hyperreactivity underlie the increased morbidity of RSV infection in prematurely born infants.⁵ Male sex, young age, birth in the first half of the RSV season and crowding/siblings are independent risk factors for the development of severe RSV lower respiratory tract infection (LRTI).⁶ RSV spreads through close contact, direct inoculation of droplets of the secretions from an infected person and indirect transmission from hands that touch infectious secretions that contaminate environmental surfaces. Although prevention of infection through interruption of transmission of the virus is difficult in the home and community, preventing transmission in the hospital setting is essential. The Centers for Diseases Control and Prevention (CDC) recommend the use of droplet precautions for patients with RSV. In addition, these precautions require that gloves must be worn when entering the room of someone infected.⁷

Acute complications of RSV in infants include apnea and respiratory failure. Apnea as a result of RSV infection most commonly presents in the first 1 to 2 months of age, in premature infants and in infants exhibiting moderate to severe hypoxemia. There is limited evidence that RSV contributes to the occurrence of sudden infant death syndrome (SIDS) in infants >3 months. Hypercarbia, respiratory failure, and apnea are the major factors leading to assisted ventilation.⁴ Although most infants recover from RSV-LRTI (the mortality rate is <1%),² they have an increased risk of recurrent wheezing and asthma later in life. Infants hospitalized with bronchiolitis subsequent to RSV infection are at significantly increased risk for both recurrent wheezing and childhood asthma.^8,9

Commonly employed palliative and supportive treatments for symptomatic RSV infection include oxygen, hydration, inhaled beta-2 agonists, racemic epinephrine, systemic and inhaled corticosteroids, inhaled ribavirin and nasopharyngeal suctioning. Infants suffering severe lower airway disease may require mechanical ventilation.¹⁰ High-risk children who should be hospitalized include those <3 months and those with a preterm birth, cardiopulmonary disease, immunodeficiency, respiratory distress or inadequate oxygenation.¹¹ Antibiotic treatment should be reserved for cases in which bacterial infection is proven to be concomitant with RSV infection.⁴ Otitis media is a frequent complication of RSV infection and antibiotics may be used if this diagnosis is confirmed. A single dose of parenteral ceftriaxone may be adequate for uncomplicated otitis media. Ribavirin is approved for treatment of RSV infection, but questions about its efficacy, concerns about occupational exposure and its high cost make its use controversial.¹²

Despite significant gains in the survival of infants born at lower gestational ages, prematurity, low birth weight and/or underlying chronic pulmonary disease put the pediatric patient at risk for increased frequency and severity of RSV lower respiratory tract illness and the potential for its long-term sequelae.¹³ Immunoprophylaxis to prevent severe RSV disease in groups of high-risk infants has received greater attention. Passive immunization with the monoclonal antibody palivizumab is an option for high-risk infants. Monthly injections of palivizumab, given just before and during the RSV season, have been shown to significantly reduce hospitalization in the first 6 months in premature infants born at <35 weeks, infants <24 months of age with chronic lung disease and requiring treatment in the last 6 months, and in children <24 months with hemodynamically significant heart disease.¹⁴ Impact-RSV, a double-blind, placebo-controlled, randomized study, showed that palivizumab was safe and decreased hospital admissions related to RSV in infants at high risk.¹⁵ The American Academy of Pediatrics first published its guidelines for passive immunization against RSV in 2000, with recent revisions in 2003 and 2006. Current recommendations are that palivizumab be considered for high-risk premature infants born at <35 weeks’ gestation or infants <2 years, with either chronic lung disease or symptomatic congenital heart disease. In the United States, approximately 100,000 infants receive palivizumab immunization against RSV infection each year.¹⁶

References

1. Mejías A, et al. Pediatr Infect Dis J. 2005;24(11 Suppl):S189-196.
2. Leung AK, et al. J Natl Med Assoc. 2005;97:1708-1713.
3. Hall CB, et al. N Engl J Med. 1979;300:393-396.
4. Hall CB, McCarthy CA. In Mandell GL, et al, eds. Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, PA: Churchill Livingstone; 2000:782-1801.
5. Welliver RC. J Pediatr. 2003;143(5 Suppl):S112-S117.
6. Simoes EA. J Pediatr. 2003;143(5 Suppl):S118-S126.
7. National Center for Infectious Diseases Respiratory and Enteric Viruses Branch. Respiratory Syncytial Virus. Available at www.cdc.gov/ncidod/dvrd/revb/respiratory/rsvfeat.htm.
8. Smyth RL, Openshaw PJ. Lancet. 2006;368:312-322.
9. Singh AM, et al. Am J Respir Crit Care Med. 2007;175:108-119.
10. Black CP. Respir Care. 2003;48:209-231.
11. Steiner RW. Am Fam Physician. 2004;69:325-330.
12. Ventre K, Randolph AG. Cochrane Database Syst Rev. 2007;24:CD000181.
13. Weisman LE. Pediatr Infect Dis J. 2003;22(2 suppl):S33-S37.
14. Venkatesh MP, Weisman LE. Expert Rev Vaccines. 2006;5:261-268.
15. The Impact-RSV Study Group. Pediatrics. 1998;102: 531-537.
16. American Academy of Pediatrics. In: Pickering LK, ed. Red Book: 2006 Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006:560-566.

Preterm 8-week-old with wheezing
Michael Forbes, MD

Case Study 3 Presentation Eight-week old female patient, at 34 weeks gestational age, presented at her pediatrician’s office in mid-February with her mother, who reported that the patient was unwell for the previous 24 hours. Signs included irritability, a fever (103.5°F), poor feeding and lower respiratory tract symptoms (ie, cough, wheezing). Relevant history at the time of the visit revealed that the patient had 5- and 7-year-old siblings, both of whom had symptoms of a lower respiratory tract infection. Neither parent smoked. The patient’s family lives in close proximity to a major truck route, and there is a city bus garage/depot on the same block as their apartment. The patient’s father had well-controlled asthma and the mother had a history of hay fever, which she treated with OTC medications. Examination On physical examination, the child appeared irritable and inconsolable. Blood pressure was 77/48 mm Hg; she had tachycardia (165 bpm) and tachypnea (85/min). She had clear rhinorrhea, moist mucous membranes, marked increased work of breathing with sub-sternal and intercostal retractions and bilateral wheeze and rhonchi on auscultation, no hepatomegaly or splenomegaly and a soft abdomen; the patient’s perfusion was normal. Oxygen saturation (SpO2) was 89% in room air. The patient was referred to the emergency department of the local community hospital. On admission to the ED, differential diagnosis included sepsis, meningitis and urinary tract or other bacterial infection. A nasopharyngeal wash for RSV screening was performed, as well as a respiratory viral panel that included screening for influenza A and B, parainfluenza and adenovirus. A lumbar puncture was done to rule out meningitis. Nebulized albuterol was administered in the ED, but no change in the patient’s SpO2 (89%) was noted. Albuterol was discontinued and the patient was admitted to the hospital’s pediatric ward under contact isolation, where IV ampicillin and cefotaxime were begun empirically. The patient’s WBC count (14.1x103/µL), with an absolute neutrophil count of 4x103/ µL and bands noted on smear, was considered inconclusive. Diagnosis Forty-eight hours after admission, bacterial cultures of cerebrospinal fluid, blood and urine were negative, and antibiotics were discontinued; a chest x-ray taken on admission revealed hyperinfiltration with diffuse increased interstitial markings. RSV was detected in the patient’s nasopharyngeal sample and supportive and symptomatic treatment was continued. Treatment Bulb suctioning with saline was performed. Supplemental oxygen (0.5 L/min) was begun and the patient’s oxygen saturation was monitored. The patient’s respiration rate during the first 24 hours averaged 65/min; feeding was withheld and the head of the patient’s bed was elevated 30· to decrease the risk for aspiration of gastric contents. Outcome The patient’s symptoms steadily improved. On day 5 of her hospital stay, the patient was weaned off oxygen and gradually began to feed and sleep normally again. The patient’s energy and work of breathing improved; continuous pulse oximetry was changed to every 8-hour measurements. The patient was discharged later on day 8, when the baby was on adequate oral feeds and without distress in room air. The baby remained improved at a follow-up visit to the patient’s pediatrician 2 days after discharge, and resolution of this illness was confirmed at a 4-week follow-up visit. © 2007, iStockphoto.com / PhotoDisc,Getty Images / PhotoDisc

RSV: Immunoprophylaxis and prevention techniques
Michael Forbes, MD

Respiratory syncytial virus is the most important pathogen in lower respiratory tract infections (LRTI) in infants and young children.¹ The RSV pathogen is unusual in that primary infection does not confer protective immunity and repeated infections are common. Risk for severe RSV infection is higher in male infants, infants born within 10 weeks of the RSV season, infants with low birth weight, infants breast fed <2 months, infants living in crowded conditions with siblings, and infants having family members with atopy, day care exposure or exposure to secondhand smoke or environmental pollutants.² Although the majority of RSV infections resolve in otherwise healthy children, high-risk populations may develop severe and sometimes fatal LRTIs.¹ In addition, infants hospitalized with bronchiolitis subsequent to RSV infection are at significantly increased risk for both recurrent wheezing and childhood asthma.^3-5

While practicing scrupulous hygiene and avoiding preventable risk factors can reduce the incidence of RSV infection in the home and infection control measures can limit the spread of nosocomial RSV infection, there is no cure. Respiratory syncytial virus-immune globulin intravenous (RSV-IGIV), a polyclonal globulin prepared from donors selected for having high serum titers of RSV neutralizing antibody, was the first product demonstrated to be efficacious in preventing severe RSV disease in high-risk premature infants. Palivizumab, a humanized monoclonal antibody with neutralizing and inhibitory activity against RSV was approved in 1998 for prevention of RSV disease in selected infants and children <24 months with chronic lung disease or a history of preterm birth (<35 weeks’ gestation).⁶ Palivizumab is also approved for prevention of serious RSV-LRTIs in infants <2 years with hemodynamically significant congenital heart disease.

RSV-IGIV

In two randomized, controlled clinical trials, monthly RSV-IGIV infusions in high-risk infants resulted in a 41% to 63% decrease in the rate of hospitalization.^7,8 In one trial, 81 infants received RSV-IGIV at a dosage of 750 mg/kg per infusion, 79 infants received 150 mg/kg and 89 infants received no infusions. Participants received monthly RSV-IGIV infusions from mid-November through March or April. Infants receiving RSV-IGIV at a dosage of 750 mg/kg had statistically significantly decreased RSV-associated lower respiratory tract disease severity, lower frequency of hospital admissions and fewer days in the hospital or ICU. Monthly RSV-IGIV infusions were reasonably well tolerated, with adverse reactions (eg, mild decreases in oxygen saturation, fever and mild fluid overload) occurring in 3% of 580 infusions.⁷

Results of a second multicenter, randomized study in infants <24 months with chronic lung disease and/or premature birth showed that RSV-IGIV decreased the frequency and severity of RSV-associated illness by 41% to 60%. Children receiving RSV-IGIV had a 50% decrease in the rate of hospitalization for respiratory illness of any cause (P =.005), with a greater decrease in RSV-related hospitalizations among infants with chronic lung disease than for premature infants (49% vs. 20%, respectively). Moderate to severe adverse events (ie, fever, increased respiratory distress, rash) were no more frequent in patients receiving RSV-IGIV than in control patients.⁸

RSV-IGIV is contraindicated for use in children with hemodynamically significant heart disease, particularly cyanotic heart disease, because of safety concerns. RSV-IGIV prophylaxis requires IV access with a 4-hour infusion each month during the RSV season, which may lead to volume overload. RSV-IGIV is also known to interfere with immune response to some live virus vaccines and, although no issues of contamination have been raised, this is a constant theoretical concern for all products derived from human donors.⁹ Due to the large fluid volume and need for IV infusion and the variability in selecting high titer donors, RSV-IGIV has been replaced by palivizumab for RSV prophylaxis of high-risk infants.

Palivizumab

The safety and efficacy of palivizumab in infants and children at high risk for RSV infection have been demonstrated in two randomized, placebo-controlled trials.^10,11 The Impact-RSV trial enrolled 1,502 infants who were randomized to receive either placebo or five intramuscular injections of palivizumab (15 mg/kg) administered at 30-day intervals. Participants included those <24 months with chronic lung disease who required continuing medical therapy within the previous 6 months and children born at <35 weeks’ gestation who were <6 months at the start of the RSV season. Prophylaxis with palivizumab resulted in a 55% overall decrease in the rate of RSV-related hospitalization compared with placebo (10.6% vs. 4.8%, respectively [P < .001]). The number of days of hospitalization for RSV infection per 100 children was decreased from 62.6 for patients receiving placebo to 36.4 for those receiving palivizumab (P <.001). Subgroup analyses demonstrated statistical benefit for all groups: premature <32 weeks gestational age, 32 to 35 weeks gestational age, without chronic lung disease, with lung disease. There was no significant difference in the rate of adverse events. Erythema, pain and induration at the site of intramuscular injection occurred in 1.8% of placebo recipients and in 2.7% of infants receiving palivizumab.¹⁰ In a trial that enrolled infants and children with hemodynamically significant congenital heart disease, palivizumab administration resulted in a 45% decrease in the rate of RSV-associated hospitalizations compared with placebo recipients. Serious adverse events occurred in 55.4% of palivizumab recipients and 63.1% of placebo recipients (P <.005); none of the events were related to palivizumab. Twenty-one children (3.3%) in the palivizumab group and 27 (4.2%) in the placebo group died; no deaths were attributed to palivizumab.¹¹

A recently published clinical trial conducted by the Palivizumab Long-Term Respiratory Outcomes Study Group assessed the effect of palivizumab on the rate of later recurrent wheezing in preterm infants.¹² A cohort of preterm infants who had received palivizumab and were not hospitalized for RSV (n = 191) or who never received palivizumab (n = 230) were prospectively followed for 24 months beginning at a mean age of 19 months. Seventy-six of the infants who had never received palivizumab were hospitalized for RSV and 154 were not. The incidences of recurrent wheezing and physician-diagnosed recurrent wheezing were significantly lower in the 191 palivizumab-treated patients (13% and 8%, respectively) compared with all 230 untreated patients (26% [P = .001] and 16%, [P = .011] respectively) and with the 154 patients in the subgroup not hospitalized for RSV (23% [P = .022] and 16% [P = .027], respectively). The effect of palivizumab treatment in this trial remained significant after adjustment for potential confounding variables.¹²

Motavizumab

A new, more potent humanized mAb derived from palivizumab—motavizumab—binds to RSV F protein 70-fold better than palivizumab and exhibits an approximate 20-fold improvement in neutralization of RSV in vitro.¹³ At-risk infants who received either motavizumab or palivizumab experienced lowered rates of RSV-related hospitalization, according to results from a recently reported multicenter, multinational phase 3 trial.¹⁴ The study enrolled 6,635 preterm infants over two consecutive RSV seasons. Infants were randomized to either palivizumab (n = 3,326) or motavizumab (n = 3,329) to assess the safety and efficacy of motavizumab and its effect on hospitalizations and medically attended LRTIs. Infants in the motavizumab group experienced a 26% relative reduction in RSV hospitalizations (P <.01 for noninferiority compared with palivizumab). The motavizumab group also experienced a 50% relative reduction in medically attended LRTIs, which was significantly superior to the palivizumab group (2% vs. 3.9%, [P <.01]). Adverse events, serious adverse events and mortality between the two groups were similar.¹⁴

Summary

Palivizumab is indicated for the prevention of serious lower respiratory tract disease caused by RSV in pediatric patients at high risk for RSV disease. Safety and efficacy were established in infants with bronchopulmonary dysplasia, infants with a history of premature birth (<35 weeks gestational age) and children with hemodynamically significant congenital heart disease. Palivizumab does not interfere with immune response to any vaccine in the immunization schedule.

Updated recommendations for RSV prophylaxis, from the American Academy of Pediatrics' Committee on Infectious Diseases and Committee on Fetus and Newborn,⁶ are summarized in the Table.

AAP Recommendations for Prophylaxis Against RSV Infections6 Palivizumab or RSV-IGIV prophylaxis should be considered for infants and children younger than 2 years with chronic lung disease (CLD) who have required medical therapy for CLD within 6 months before the anticipated start of the RSV season or hemodynamically significant congenital heart disease (CHD). Patients with more severe CLD or CHD may benefit from prophylaxis during a second RSV season if they continue to require medical therapy for pulmonary or cardiac dysfunction. For premature infants without CLD or CHD palivizumab prophylaxis may be considered based on a combination of gestational age (GA) and chronological age (CA) at the start of RSV season. Infants born at 28 weeks’ gestation or earlier may benefit from prophylaxis during their first RSV season, whenever that occurs during the first 12 months of life. Infants born at 29 to 32 weeks’ gestation may benefit most from prophylaxis up to <6 months of age. Infants born at 32 to 35 weeks GA may benefit from prophylaxis if they are 6 months CA at start of RSV season and have >2 risk factors (child care attendance, school aged siblings, exposure to environmental pollutants, congenital abnormality of the airway or severe neuromuscular disease). In most seasons and in most regions of the Northern Hemisphere, the first dose of palivizumab should be administered at the beginning of November and the last dose should be administered at the beginning of March, which will provide protection into April. The monthly dose of palivizumab is 15 mg/kg IM.

References

1. Hall CB. In: Feign RD, et al, eds. Textbook of Pediatric Infectious Diseases. 5th ed. Philadelphia, Pa: WB Saunders Co; 2003.
2. Simoes EAF. J Pediatrics. 2003;243:S118-S126.
3. Smyth RL, Openshaw PJ. Lancet. 2006;368:312-322.
4. Singh AM, et al. Am J Respir Crit Care Med. 2007;175:108-119.
5. Sigurs N, et al. Am J Resp Crit Care Med. 2000;161:1501-1507.
6. American Academy of Pediatrics. In: Pickering LK, ed. Red Book: 2006 Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006:560-566.
7. Groothuis JR, et al. N Engl J Med 1993;329:1524-1530.
8. The PREVENT Study Group. Pediatrics 1997;99:93-99.
9. Meissner HC, Long SS, and the Committee on Infectious Diseases and Committee on Fetus and Newborn. Pediatrics. 2003;112;1447-1452.
10. The IMpact-RSV Study Group. Pediatrics 1998;102:531-537.
11. Feltes TM, et al. J Pediatr. 2003;143:532-540.
12. Simoes EA, Groothuis JR, Carbonell-Estrany X, for the Palivizumab Long-Term Respiratory Outcomes Study Group. J Pediatr. 2007;151:34-42.
13. Wu H, et al. J Mol Biol. 2007;368:652-665.
14. Carbonell X, et al. Presented at: The Pediatric Academic Societies’ Annual Meeting. May 5-8, 2007; Toronto. Abstract 8220.9.

DISCUSSION Q. Is the risk for RSV different in infants born at 28, 32 and 34 weeks? Gary Goodman, MD: Data from numerous studies emphasizes that all premature infants regardless of gestational age are at increased risk of RSV infection. A recent study showed a prolonged hospital stay in infants with RSV who were born between 32 and 35 weeks, exceeding that for infants born <32 weeks. The risk group with the highest rate of hospitalization is premature infants with chronic lung disease (bronchopulmonary dysplasia). Every premature infant should be considered a candidate for RSV prophylaxis and evaluated appropriately. Michael Forbes, MD: The risk for RSV-related disease is higher in preterm infants than term-born infants. Of note, the mortality risk is approximately five times higher in infants born between 32 and 35 weeks (Holman RC, et al Pediatr Infect Dis J. 2003;22:483-489). This mortality risk appears graduated and increases with lower gestational age. The risk of hospitalization and nosocomial morbidity, however, does not appear as graduated. Length of stay, ICU admission and need for mechanical ventilation appear comparably elevated in 32- to 35-week vs. term infants (Horn SD, Smout RJ. J Pediatr. 2003;143:S133-S141). Q. What is the impact of RSV on long-term health? Goodman: RSV is such a ubiquitous infection that the long-term impact can be difficult to fully evaluate. All children will have universally been infected with RSV at least once by their third birthday. There is no doubt of the impact acute RSV infections have on emergency departments and pediatric units across the United States; the long-term consequences that result are more difficult to document. In patients hospitalized with RSV, there is a 35% chance of having future episodes of wheezing. While RSV infection is ultimately unavoidable, there may be great long-term benefit to postponing RSV lower respiratory infection to a child’s second or third year, especially if they are premature. In fact, we are currently only able to prophylax a relatively modest number of children. Krilov: I agree. This is still an unanswered question. There is increased wheezing for years after RSV-LRTI in infancy, but this does not prove causality from RSV. It Is possible that the reason they get severe RSV disease is that their airways are “abnormal” and they were destined to get reactive airway disease, as well. The preliminary data that prevention of severe RSV in small numbers of infants leads to less subsequent pulmonary involvement are intriguing. Forbes: This is unknown. The prevailing impression from published data suggests RSV infection is associated with long-term pulmonary morbidity and increased resource utilization. It remains unclear, however, whether RSV infection simply identifies infants who are otherwise vulnerable. The infection would, therefore, represent an opportunistic infection in uniquely vulnerable hosts. Q. Would prophylaxis with palivizumab have been appropriate in this patient? Goodman: Yes. Currently, palivizumab prophylaxis is recommended only for high-risk infants such as those born at <35 weeks’ gestation. The drug is equally effective in all premature infants and is the most effective in infants without chronic lung disease or congenital heart disease with an 80% reduction in RSV hospitalizations in the clinical trial. All premature infants will benefit from palivizumab, only financial constraints limit those who can receive prophylaxis. For most premature infants, though, RSV prophylaxis is the standard of care for the first winter after hospital discharge. Krilov: I agree. This patient was born at 34 weeks gestational age, <6 months of age and had two or more risk factors (siblings, environmental pollution). Q. What is the risk of contracting RSV in the NICU? Should immunoprophylaxis be administered to any patient admitted to the NICU regardless of diagnosis? Goodman: The risk of contracting RSV in the NICU should be zero. Unfortunately, infection control and isolation measures sometimes fall short. Any infant in the NICU during the RSV season who has an unexpected clinical deterioration should be immediately isolated and tested for RSV. There are a number of case reports of the use of palivizumab for prophylaxis of premature infants in an NICU during a nosocomial RSV outbreak after standard measures have failed. No infant who has been discharged to home should be readmitted to the NICU if they should become ill. Krilov: There is some debate on this. Some NICUs prophylax infants during their NICU stay. We do not, preferring to emphasize infection control, hand washing, restriction of visits by siblings. We provide the first dose of palivizumab within 1 week of anticipated discharge to eligible infants. In the event of a case or outbreak of RSV in an NICU, prophylaxis of other exposed high-risk infants might be considered along with cohorting measures. John J. LaBella, MD: Currently, there are no well-controlled studies to support the routine use of palivizumab in every patient in every NICU, just as there is no evidence that palivizumab has a role in the treatment of active RSV disease. While RSV often is a nosocomial disease in many NICUs, case-by-case decisions still remain the recommendation at this time. Forbes: During the RSV season, the risk is elevated. The question remains unanswered, however, regarding the propriety of universal immunoprophylaxis of all NICU patients. It likely would represent over treatment at this time. Q. Does RSV ever occur as epidemic? If so, do prophylaxis protocols change? Goodman: In reality, we have an epidemic of RSV each winter (in North America). While the exact timing of onset and the duration of the RSV season may vary, there has never been a winter without RSV. In fact, over the last two decades, the number of infants hospitalized for RSV has steadily increased, a phenomenon that has never been adequately explained. Prophylaxis is important every year and planning needs to start in the summer, identifying infants at risk and beginning prophylaxis well in advance of the RSV season to ensure optimum efficacy. Krilov: RSV generally occurs as an annual winter epidemic. This is the basis of palivizumab recommendations. Again, a NICU outbreak may be a possible time to use extra prophylaxis. Forbes: Each season, the CDC defines an epidemic. The only notable matter vis a vis the epidemic would be that, due to RSV’s ability to create immune-amnesia, immunoprophylaxis must continue throughout the epidemic in infected infants. Q. When should immunoprophylaxis with palivizumab be administered (in appropriate patients)? Goodman: The timing of RSV prophylaxis needs to be based on two important pieces of information: knowledge of the pharmacokinetics of palivizumab and the historical timing of the local RSV season. Palivizumab levels in the blood increase progressively with each subsequent dose and there is evidence that the frequency of hospitalizations for RSV decreases with cumulative doses. Thus, it makes pharmacologic sense to start prophylaxis well in advance of the start of the RSV season, when possible. This should best be determined by local or regional epidemiologic data. The Centers for Disease Control National Respiratory and Enteric Virus Surveillance System (NREVSS) tracks national and regional epidemiology which is posted on the Internet with updates throughout the winter. Ideally, two doses of palivizumab should have been received before the RSV season peaks. Prophylaxis should also be individualized with respect to discontinuation. Ongoing assessment of the current RSV season, in real time, and a re-evaluation of the patient and the risk factors should inform the decision to continue or discontinue prophylaxis. Krilov: Immunoprophylaxis with palivizumab typically should be administered monthly from November to April. Whether local epidemiology might suggest an earlier start or later continuation based on local RSV activity is debatable. Forbes: Ideally, palivizumab should be administered 1 month prior to the start of the season to provide “in-season” protection. The current epidemic can be predicted based on last year’s season. Data for your region are published on the CDC Web site, or local ID/Pediatric pulmonologist input can advise your decision. Q. What is the regional impact of palivizumab prophylaxis? Goodman: Since RSV prophylaxis is limited to premature infants and infants with chronic lung disease and congenital heart disease, the clinical impact of prophylaxis may be subtle. The majority of infants hospitalized with RSV are and always have been healthy. In the ICU, though, we have seen a dramatic shift in RSV epidemiology with very few infants who received prophylaxis requiring PICU care. The infants who do stand out are those who were candidates for palivizumab, but for a variety of reasons did not receive prophylaxis. There is no doubt that prophylaxis is extremely beneficial in infants who qualify. Krilov: One issue might be south Florida or parts of Texas where the virus might be present for more than 6 months per year.

RSV: The burden of disease
Michael Forbes, MD

Respiratory syncytial virus is the leading cause of lower respiratory tract infections (LRTIs) in infants and young children.¹ The clinical burden of disease associated with RSV has been found to be as great as, if not greater than, that of influenza.² A recent study compared the burden of illness due to a spectrum of respiratory diagnostic categories among patients in a general practice network during periods of influenza and RSV activity. Excess rates of acute bronchiolitis were greater in children <1 year and in children aged 1 to 4 years during RSV active periods rather than influenza. For the common cold, estimates of median excess rates were significantly higher in RSV-active periods for the age groups younger than 1 year and 5 to 14 years.²

Viral LRTIs are particularly serious during infancy, when the lungs are adapting to extrauterine life. Although the burden of LRTIs affects children in developing regions disproportionately (where it is the cause of death for an estimated 4.3 million children<5 years old each year),^3,4 these infections are also associated with substantial childhood mortality in more developed countries, including those in the western hemisphere.⁵ An increasing proportion of childhood LRTI morbidity in the United States, as reflected by hospital admissions, is associated with bronchiolitis. From 1980 through 1996, the proportion of all hospitalizations associated with LRTI bronchiolitis among U.S. children <1 year increased from 22% to 47%.⁶ RSV is the pathogen most commonly recovered from children with bronchiolitis,^7,8 with as many as 50% to 90% of children hospitalized during the winter with this diagnosis infected with RSV.^1,8 Among infants hospitalized for bronchiolitis, mechanical ventilation is needed in 2% to 5%.⁹ RSV and parainfluenza virus are together estimated to cause 91,000 hospital admissions per year in the United States, with associated costs of $300 million per year.^10,11 The cost of RSV, including ambulatory care, increased child care requirements and loss of workplace productivity, adds to this financial burden.

Sequelae of RSV infection

Severe RSV infection in the first 6 months of life is often followed by recurrent childhood wheezing.^12-15 Although RSV bronchiolitis and recurrent childhood wheeze are associated, direct interventional studies demonstrating a causal relationship have not been published. However, administration of anti-RSV immune globulin to children at high risk for RSV disease seems to improve asthma scores and reduce atopy.¹⁶ It is also possible that an anti-RSV neutralizing monoclonal antibody (ie, palivizumab) has long-term beneficial effects. Whatever the role of RSV in the pathogenesis of asthma, RSV is known to cause asthma exacerbations in older children and adults.¹¹

RSV infection in adults

The burden of RSV re-infection in adults on the health care system has been underappreciated. While pediatricians are aware of the likelihood of RSV among their patient populations, most internists rarely consider RSV in adult patients. RSV causes significant disease in healthy adults (especially those in contact with children) and generally goes undiagnosed.¹¹ An estimated 14,000 elderly and high-risk adults die annually from an RSV infection, and RSV infections account for more than 177,500 hospitalizations of adults each year, at a cost that exceeds $1 billion. RSV causes high morbidity and mortality in patients with underlying cardiopulmonary illnesses,¹⁷ the elderly¹⁸ and the immunosuppressed, particularly bone marrow transplant patients.^19,20

A 2005 study analyzed epidemiologic and clinical data related to RSV infection over four consecutive winters. Those enrolled in the study included 1,388 hospitalized patients, 608 healthy people >65 years of age and 540 adults (>21 years of age) who were considered at elevated risk because of a diagnosis of congestive heart failure or chronic pulmonary disease. Among the 2,514 illnesses evaluated, the impact of RSV infection on both the healthy elderly and the high-risk group was significant. RSV infection accounted for 10.6% of hospitalizations for pneumonia, 11.4% for those with chronic obstructive pulmonary disease, 5.4% for congestive heart failure and 7.2% for asthma. These results suggest a disease burden of RSV among adults equal to that of nonpandemic influenza.²¹

All people, regardless of age, should be informed of the importance of reducing exposure and transmission of RSV, particularly those at high risk themselves or in contact with persons at high risk. The most effective method for reducing the transmission of RSV and other infectious diseases is frequent hand washing. This is particularly true for those caring for children who are at high risk for RSV.^1,22 Additional preventative measures to reduce the incidence of RSV infection in infants and children include eliminating cigarette smoke from the environment and limiting exposure to crowds and other children (eg, day care attendance) when possible.²²

References

1. Hall CB. In: Feign RD, et al, eds. Textbook of Pediatric Infectious Diseases. 5th ed. Philadelphia, Pa: WB Saunders Co; 2003.
2. Fleming DM, et al. Epidemiol Infect. 2007;Feb:1-10.
3. Murray CJL, Lopez AD. In: Murray CJL, eds. The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020. Boston: Harvard School of Public Health, 1996:247-293.
4. Garenne M, et al. World Health Stat Q. 1992;45:180-191.
5. Pan American Health Organization. Health statistics from the Americas, 1995.Washington, DC: Pan American Health Organization, 1995:148–154.
6. Shay DK, et al. JAMA. 1999;282:1440-1446.
7. Parrott RH, et al. Am J Epidemiol. 1973;98:289-300.
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14. Stein RT, et al. Lancet. 1999;354:541-545.
15. Sigurs N. Am J Respir Crit Care Med. 2001;163:S2-S6.
16. Wenzel SE, et al. Am J Med. 2002;112:627-633.
17. Walsh EE, et al. Am J Respir Crit Care Med. 1999;160:791-795.
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19. Hassan IA, et al. Bone Marrow Transplant. 2003;32:73-77.
20. Raboni SM, et al. Transplantation. 2003;76:142-146.
21. Falsey AR, et al. N Engl J Med. 2005;352:1749-1759.
22. Meissner HC, Long SS, and the Committee on Infectious Diseases and Committee on Fetus and Newborn. Pediatrics. 2003;112;1447-1452.