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Severe Viral Respiratory Infection in Children

Michael C. Spaeder, MD, MS

In the United States, viral respiratory infections are a leading cause of illness and hospitalization in young children. In 2009, more than 300,000 children were hospitalized as a result of infectious respiratory illness.¹ From 1980 to 1996, rates of hospitalization of infants in the United States with bronchiolitis increased substantially.² The increase was attributed to a number of factors, including (1) trends in childcare practices; (2) changes in criteria for hospitalization; (3) decreasing mortality among premature and medically complex infants at high risk; (4) changes in respiratory syncytial virus (RSV) strain virulence; and (5) alterations in diagnostic coding practices.²

Children with severe viral respiratory illness are often admitted to the pediatric intensive care unit (PICU). Children with risk factors such as chronic lung disease, congenital heart disease, and neuromuscular impairment are at increased risk of morbidity and mortality from viral respiratory infections.^3-11 Hospital acquisition of viral infection, independent of other risk factors, has been associated with increased mortality in children.⁹

The last decade has been witness to the increased availability of highly sensitive and specific methods for the rapid detection of viral pathogens, such as immunochromotography, direct fluorescent antibody, and polymerase chain reaction testing, which have improved our ability to identify and survey infectious agents. Commercially available polymerase chain reaction testing for respiratory viruses has become the standard of care in most pediatric hospitals; this type of testing can detect a variety of respiratory viruses including RSV, influenza, parainfluenza, adenoviruses, coronaviruses, and human metapneumovirus.

In this chapter we review the epidemiological characteristics, outcomes data, and treatment modalities of the major viruses causing severe viral respiratory infection in children. For the purposes of this chapter, the descriptor severe refers to viral respiratory infection necessitating ICU admission. Because variation exists in PICU admission criteria among institutions, published epidemiological and outcomes data can range greatly from study to study. By and large, when discussing severe pediatric viral respiratory infection, this chapter is focused on lower respiratory tract infection and laryngo-tracheobronchitis (croup).

Respiratory Syncytial Virus

Respiratory syncytial virus (RSV) is an RNA virus of the Paramyxoviridae family, which includes a number of other respiratory viruses like parainfluenza, measles, and human metapneumovirus. Globally, RSV is the most common cause of acute lower respiratory infection in children.¹² The presentation of RSV demonstrates a seasonal predominance, with the typical season from November to March in temperate climates.¹³ Seasonal variation from year to year and between communities is common. In tropical climates (eg, South Florida), it is not uncommon for the majority of RSV cases to present during the summer months.

In the United States, bronchiolitis related to RSV is the leading cause of hospitalization in infants under the age of 1 year, with an estimated 120,000 hospital admissions and more than 200 deaths annually.^2,14 In children hospitalized with acute viral respiratory infection, RSV is estimated to be the cause in at least 50% of cases.^3,15 In children admitted to the PICU with severe viral respiratory infection, RSV is implicated in approximately 50% of cases.⁹

Multiple studies have identified certain high-risk groups that are prone to severe complications and increased mortality from RSV, most notably children with congenital heart disease, extreme prematurity, chronic lung disease, and neuromuscular disease.^5-9 Published mortality rates in children admitted to the PICU with RSV infection range from 1.1% to 8.6%.⁵ Hospital acquisition of RSV infection, independent of previous health status, has been demonstrated to increase mortality.⁷

Treatment of severe RSV infection is largely supportive. A number of treatment modalities have been investigated with mixed results. Aerosolized administration of the antiviral ribavirin has US Food and Drug Administration approval for use in RSV infection. In a small number of studies, ribavirin has been associated with a decreased duration of mechanical ventilation and hospital length of stay.¹⁶ In light of the limited evidence of efficacy, the high cost of ribavirin, and the potential for toxic effects among exposed healthcare professionals, the American Academy of Pediatrics (AAP) Committee on Infectious Diseases does not recommend the routine use of ribavirin in the treatment of RSV infection.¹³ The use of ribavirin should be considered on a case-by-case basis.

The routine use of inhaled β-adrenergic agents is not recommended in the treatment of RSV.¹³ A trial of inhaled β-adrenergic agents in patients with wheezing is appropriate, but repeated use should only be considered in patients with a demonstrable improvement in respiratory status following the trial.¹³ Corticosteroids are not effective in the treatment of RSV infection and thus are not recommended.¹⁷

Influenza

Influenza infection is caused by RNA viruses of the Orthomyxoviridae family, of which influenza A and influenza B are the most important causes of illness in humans. Influenza A is more common and virulent than influenza B and is responsible for all influenza pandemics. Similar to RSV, influenza tends to occur in seasonal epidemics during the winter months. We focus our initial discussion on seasonal influenza before briefly touching on pandemic influenza, namely novel 2009 H1N1 influenza A.

Seasonal Influenza

The US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) classifies children with the following conditions at increased risk of severe disease: (1) chronic pulmonary conditions (eg, asthma, cystic fibrosis, chronic lung disease); (2) cardiac disease; (3) pregnancy; (4) immunosuppression; (5) hemoglobinopathies; (6) neurological and neuromuscular disorders; (7) chronic renal dysfunction, and (8) inborn errors of metabolism.¹⁸ Nearly half of all children admitted to the hospital with community-acquired influenza will have at least one ACIP high-risk condition.¹⁰ Young children and those with ACIP high-risk conditions may be at increased risk of influenza-related mortality.¹⁹

Published data suggest that 11% to 19% of children hospitalized with influenza will require intensive care.^10,20 In children admitted to the PICU with influenza, published mortality rates range from 4% to 10%.^9,10 Mechanical ventilation is initiated in 23% to 49% of patients—the broad range most likely reflects variation in PICU admissions criteria among institutions.^9,10,20 In a 6-year single-center study conducted in a large academic PICU, 7% of patients developed acute respiratory distress syndrome and 10% developed multiple-organ dysfunction syndrome.⁹

The role of bacterial pneumonia as a severe complication of influenza-related illness has been implicated in both pandemic and epidemic influenza.^21,22 An analysis by the US National Institute of Allergy and Infectious Diseases of post-mortem samples from the most recent influenza pandemic before antibiotic use, the 1918-1919 “Spanish flu” pandemic, concluded that the majority of deaths likely resulted directly from secondary bacterial pneumonia.²¹ Evidence suggests that although influenza-associated mortality is low in children, the proportion of fatal cases with bacterial co-infection has increased dramatically in recent years.¹¹ The CDC noted a 5-fold increase of Staphylococcus aureus co-infection in fatal cases of pediatric influenza infection from 2003 to 2007.¹¹

Children with ACIP high-risk conditions appear to be at increased risk of developing bacterial pneumonia in the setting of influenza-related illness.¹⁰ In children with community-acquired influenza, co-infection with bacterial pneumonia was associated with increased odds of respiratory failure in both previously healthy children and those with ACIP high-risk conditions.²³

Infection control measures such as hand hygiene, isolation precautions, and immunization of healthcare workers are of paramount importance in the PICU, as hospital acquisition of influenza has been shown to increase mortality.⁹ The AAP now recommends mandatory immunization of all healthcare providers.²⁴

In addition to supportive care, antiviral therapy should be considered in any child with influenza requiring intensive care. Amantadine, rimantadine, oseltamivir, and zanamivir are antiviral therapies approved for use both as treatment and as chemoprophylaxis for influenza infection in children. Recently, influenza strains have demonstrated high levels of resistance to amantadine and rimantadine, and thus these therapies are no longer recommended by the AAP.²⁵ As resistance patterns can potentially change from year to year, the CDC regularly updates its recommendations (www.cdc.gov/flu/profession-als/antivirals/index.htm).

Oseltamivir is approved for use in children over the age of 1 year, although the AAP recommends its use at a dose of 3mg/kg in infants younger than 12 months if the clinical scenario dictates.²⁵ The route of administration of oseltamivir is enteral. Zanamivir, which is administered by inhalation, is approved for use in children aged 7 years and older for the treatment of influenza. Zanamivir is not recommended in patients with chronic respiratory diseases such as asthma or chronic lung disease.²⁵ An intravenous formulation of zanamivir has been developed and is currently in phase 3 testing.

2009 Pandemic Influenza A (H1N1)

The spring of 2009 witnessed the emergence of a novel influenza A (H1N1) virus of swine origin that resulted in the first influenza pandemic since 1968 with circulation outside the usual influenza season in the Northern Hemisphere.²⁶

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