RSV InfectionDisease overview

DR/ AHMED OKASHAJAHRA NICU

RSV Overview

RSV- Definition

Respiratory syncytial (sin-SISH-uhl) virus, or RSV, is a member of the Pneumovirus genus, of the family Paramyxoviridae . The virus is an enveloped, non-segmented virus containing a single negative-strand of RNA. The viral genome encodes ten proteins including two envelope proteins, F and G. The G protein mediates the attachment of the virus to the host cells and the F protein is involved in cell penetration and promotes cell to cell transmission through the formation of syncytia. 1,2,3

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RSV- Clinical Features

• RSV is the most common virus causing respiratory infections in children and almost all will have been infected with RSV by the age of 2 years. 1

• Primary RSV symptoms include fever, runny nose, cough and wheezing. In 25-40% of cases symptoms progress to bronchiolitis or pneumonia. 2

• Risk factors for RSV include premature birth, CHD, BPD/CLD and a compromised immune system and RSV poses greater risk to children with underlying vulnerability 3

• Severe RSV infection can lead to long-term complications including the development of wheezing and asthma later in life.3

• RSV is also associated with a high mortality rate, and in infants under 1 year it is the most common cause of viral death . 4

Diagnosis

When suspected, infection with RSV may be confirmed using a number of diagnostic methods such as viral culture, rapid antigen detection tests (enzyme immunoassay, EIA) and reverse-transcriptase polymerase chain reaction (RT-PCR).1,2

EPIDEMIOLOGY OF SEVERE RSV INFECTIONDiagnosis & Transmission

Transmission

Severe RSV infection is easily spread, particularly in environments such as hospitals, day care, schools and large families. 3RSV is spread via direct contact with contaminated hands, surfaces, and respiratory secretions, as well as unprotected coughing and sneezing. 4

Annual outbreaks are consistent and seasonal The RSV season occurs in the winter months. However, the overall length of the season varies greatly between countries. 1 Overview of RSV annual seasons in different countries. 2,3,4,5

EPIDEMIOLOGY OF SEVERE RSV INFECTIONSeasonality

RSV-infection in (almost) all children

It has been estimated that RSV causes as much as 90% of all childhood bronchiolitis and up to 40% of all paediatric pneumonias.

Approximately two thirds of all infants are infected with RSV during their first year; about one third of those infected develop LRTI, 2.5% are hospitalised and 0.1% die.

By 2 years, 95% of infants have been infected with RSV at least once and 36% at least twice.27, 77 Peak rates of severe RSV infection occur in infants aged 6 weeks to 6 months.

Re-infection is common

re-infection occurs because infection does not provide complete long-lasting immunity: between 40% and 70% of preschool-age children are re-infected with RSV, and approximately 20% of school-age children, adolescents and adults are re-infected.1

RSV is the only pathogen of its kind to have such a high rate of re-infection and a high viral load is thought to be related to risk of recurrence . 2

Severe RSV infection does not provide complete immunity that may lead to re-infection 1

However, RSV re-infection can be severe in high-risk patients such as those born prematurely, those with chronic lung disease (CLD) and those with congenital heart disease (CHD) . 3

EPIDEMIOLOGY OF SEVERE RSV INFECTIONRe-Infection

RSV Overview

RSV infection in preterm infants

Preterm infants with immature lungs will suffer greater damage to their airways and respiratory system compared to full term infants.1

POPULATION AT HIGH RISK

<29 Weeks Gestational Age

29 – 32 Weeks Gestational Age

32 – 35 Weeks Gestational Age

Congenital Heart Disease (<2years at the beginning of the season)

Chronic Lung Disease (<2years at the beginning of the season)

The highest between the high risk

RSV Overview

The risk factors listed in Below Table have been shown to increase the risk and severity of severe RSV infection.1,2,3,4,5,6,7,8,9

GROUPS AT HIGHEST RISK OF SEVERE RSV DISEASE

RSV Overview

Multiple risk factors associated with severe RSV infection

There are several risk factors for severe RSV infection and premature infants or infants with BPD/CLD or CHD are particularly vulnerable. 1

Risk factors associated with severe RSV infection in late preterms

These include inadequate housing, socioeconomic status and a poor standard of hospital care.2

Other social factors such as teenage mothers and unmarried mothers of infants are also considered to be potential factors in RSV hospitalisation, as well as medical factors including a NICU stay and/or ventilator assistance at birth.3

Tobacco smoke has also been linked to an increased risk of RSV hospitalisation but is also seen as a factor that can be controlled in the home.1

GROUPS AT HIGHEST RISK OF SEVERE RSV DISEASE

RSV Overview

• Retrospective cohort study from the Tennessee Medicaid program (USA) collected between 1989 and 1993

• 47% of all RSV hospitalizations occurred in babies born prematurely

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562

1. Boyce et al. J Pediatr 2000;

High Risk Infants Have a Greater Risk of RSV Hospitalization Relative to Healthy, Term infants

Once Hospitalized, RSV Disease Tends to be more Severe in High Risk Infant Populations

Patients hospitalized with RSV LRTIs at seven centres in Canada were prospectively followed (n=689)

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Wang EEL, et al. J Peds. 1995:126(2):212–219.

RSV Overview

RSV Hospitalized CLD Babies Incur Significant Resource-Use During the First 2 Years of Life

A retrospective chart review in CLD babies <32wGA. Infants that were re-admitted for a proven RSV infection were compared with infants with non-respiratory re-admission or no re-admission

Greenough et al. Arch Dis Child. 2001 (UK study)

Mean health resource utilization

*

**

**** *

*P<0.001**P<0.01***P<0.05

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BPD/CLD infants have a reduced response to severe RSV infection due to reduced oxygenation and a poor response to inflammation 2

The burden of RSV in children with BPD/CLD was initially described prospectively in a cohort of 30 infants <2 years of age at the onset of RSV season who were receiving home oxygen therapy. During the 4-month study, 27 children had one or more acute respiratory illnesses and RSV was responsible for 16/27 (59%). Of the 16 children with RSV, 11 (69%) required hospitalisation. The hospital course was prolonged and complicated. Seven of the 11 children were hospitalised for more than 1 week; four were admitted to the intensive care unit and two needed mechanical ventilation. No

children died.3

1.Baraldi E, Flippone M. Chronic Lung Disease after premature birth. N Engl J Med. 2007;357:1946-552.Stenmark K. International Congress on Respiratory Viruses 2003. (CONFERENCE PRESENTATION) . 3.Groothuis JR, Gutierrez KM, Lauer BA. Respiratory syncytial virus infection in children with bronchopulmonary dysplasia. Pediatrics. 1988;82(2):199-203.

Chronic lung disease and severe RSV infection

RSV Overview

Congenital heart disease (CHD): CHD refers to heart defects present from birth. Physical signs of heart disease include tachypnea, hyperpnea and tachycardia. There are many types of heart defects, e.g. stenotic valve lesions 1

Cyanotic heart disease patients have lower than normal oxygen saturation levels 1

Acyanotic heart disease patients have normal oxygen levels but blood is abnormally pumped around the body1

CHD patients have increased hospitalisation rates for RSV due to a compromised cardiovascular function.2

Congenital heart disease and RSV infection

RSV Overview

Outcomes in CHD children with RSV compared to children without CHD

Acute Bronchiolitis is one of the major causes of morbidity in infants under 12 months who have severe RSV infection with up to 80 percent of acute bronchiolitis cases are associated with RSV infection.1

BURDEN OF DISEASE

RSV and global rates of acute lower respiratory infections (ALRI) This equates to 22% of all ALRIs. At least 3.4 million of these were severe cases requiring hospital admission. 2

RSV burden compared to influenza In children <1 year, deaths associated with RSV are higher than those caused by influenza 1

Severe RSV infection is still the leading cause of bronchiolitis associated hospitalisation

42-45% of LRTI hospitalisations in children under 2 years of age are caused by RSV . 1

67% of children under 2 years hospitalised for bronchiolitis in the US in 2007 were RSV positive . 2

Percentage of bronchiolitis hospitalisations which are RSV-related . 2

BURDEN OF DISEASEBronchiolitis Associated Hospitalisation

Rate of emergency department visits per 1000 patients for infants with Influenza or RSV.

Bourgeois F, Valim C, McAdam A, Mandl K. Relative impact of influenza and respiratory syncytial virus in young children. Pediatrics. 2009;124(6):e1072-e80.

BURDEN OF DISEASERSV Vs Influenza

Rate of RSV emergency department visits and office visits per 1000 patients for infants 0-59 months.

all C, et al. The Burden of Respiratory Syncytial Virus Infection in Young Children. N Engl J Med. 2009;360(6):588-98.

BURDEN OF DISEASEEmergency and Clinic Visits

Healthcare resource utilization in RSV-bronchiolitus hospitalisations versus non-RSV bronchiolitis hospitalisations.

Garcia JJ et al. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) and the Infectious Disease Society of America (IDSA). Washington DC, USA; October 2008.

BURDEN OF DISEASERSV Resource Utilization

RSV Overview

Resource intensive and complex hospitalisations in high-risk infants

Hospitalisation rates, length of stay and rates of mechanical ventilation are higher in infants with risk factors for RSV infection, especially in infants with 3+ risk factors 1

A US study of 684 infants (≤1 year) hospitalised with bronchiolitis or RSV pneumonia states that 76% of high-risk patients are managed in PICU due to the increased risk of respiratory complications once hospitalised. Complications are associated with a longer length of stay and increased costs.2

1.Thorburn K. Pre-existing disease is associated with a significantly higher risk of death in severe respiratory syncytial virus infection. ArchDisChild. 2009;94(2):99-103. 2.Willson DF, Landrigan CP, Horn SD, Smout RJ. Complications in infants hospitalized for bronchiolitis or respiratory syncytial virus pneumonia. J Pediatr. 2003;143(5):142-9

BURDEN OF DISEASERSV Intensive/Complex Resource Utilization

RSV Overview

Long-term outcomes of severe RSV disease

Greater severity of RSV bronchiolitis is associated with an increased risk of developing childhood asthma .

Proportion of patients in each severity group diagnosed with asthma.

Carroll K, Wu P, Gebretsadik T, Griffin M, Dupont W, Mitchel E, et al. Season of infant bronchiolitis and estimates of subsequent risk and burden of early childhood asthma. J Allergy Clin Immunol. 2009;123(4):964-6.

BURDEN OF DISEASEIncreased risk of Childhood Asthma

RSV Overview

Severe RSV bronchiolitis is associated with asthma and wheezing throughout childhood.

RSV LRTI in early childhood is an independent risk factor for the subsequent development of wheezing up to age 18 years .

Current prevalence (%) of asthma in RSV-infected children and controls by age at follow-up .

Sigurs N, Aljassim F, Kjellmann B. Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life. THORAX. 2010.

BURDEN OF DISEASEIncreased risk of Childhood Asthma/Wheezing

RSV Overview

Quality of life in high-risk infants and parents

According to a prospective study conducted in the US, RSV-related hospitalisation causes significant distress for children.Children’s health and functional status during hospitalisation for severe RSV infection as assessed by the caregiver was significantly poorer than that of age-matched controls (the control group were hospitalisations of premature infants who had no history of RSV, RSV-related illness or RSV prophylaxis). Caregivers continued to report significantly poorer child health in the RSV group as long as 60 days after hospital discharge.

Leidy N, Margolis M, Marcin J, Flynn J, Frankel L, Johnson S, et al. The impact of severe respiratory syncytial virus on the child, caregiver, and family during hospitalization and recovery. Pediatrics. 2005;115(6):1536-46.

BURDEN OF DISEASEQuality of Life

Hospitalisation for severe RSV infection results in significant, lasting consequences for the child

RSV Overview

Severe RSV disease may be fatal

Using US mortality data from the National Center for Health Statistics, Thompson and colleagues developed a statistical model to estimate the age-specific number of deaths attributable to RSV and influenza. The results show that, during the period 1990–1999, RSV was the leading cause of viral death in infants, (mean mortality rates for underlying respiratory and circulatory deaths) with nearly nine times the mortality associated with influenza in infants less than 1 year old (5.3 deaths per 100,000 person-years vs 0.6 attributed to influenza).

Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289(2):179-86.

BURDEN OF DISEASE

RSV Overview

High-Risk Infants are at Greater Risk of RSV-Related DeathCo morbidity RSV Case-Fatality Rate Range

Chronic Lung Disease (CLD) 3.5%–23%

Congenital Heart Disease (CHD) 2%–37%

Preterm (≤36 wGA) 0%–6.1%

Nosocomial RSV Infection 0%–12.2%

No Comorbidity or Risk Factors <1%

Welliver, et al. Curr Med Res Opin. 2010

Mortality specifically attributed to RSV can be difficult to determine as most pediatric patients do not undergo postmortem

examination to determine cause of death

Table: review of literature identified from a structured literature search (1966–2009)

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BURDEN OF DISEASECo Morbidity Leading to Fatality

RSV Overview

Mortality in high-risk infants

Hospitalisation for RSV is associated with greater mortality risk in the two years following discharge

Sampalis JS. Morbidity and mortality after RSV-associated hospitalizations among premature Canadian infants. J Pediatr. 2003;143(5 Suppl):S150-S6.

BURDEN OF DISEASEMortality

RSV Overview

Treatment for Severe RSV Infection is Limited to Supportive Care

Severe RSV disease can be managed using:

• Hospitalization

• Oxygen supplementation

• Mechanical ventilation

• Pediatric intensive care

Other treatment options include:• Antibiotics – given for suspected bacterial

infection; NOT for Tx of RSV

• Bronchodilators

• Nebulized hypertonic saline

• Ribavirin is the only approved drug for the treatment of severe RSV.However, due to conflicting data and limitations of the drug, use of ribavirin is controversial.

1. Krilow, Expert Rev. Anti Infect. Ther, 2011

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CURRENT CLINICAL PRACTICETreatment

RSV Overview

Synagis® (palivizumab)1 Is the Only Available Effective Option for Prevention of Severe RSV Infection

• Humanized monoclonal antibody that provides effective prophylaxis against severe disease caused by RSV infection

• Injected intramuscularly once monthly during periods of active RSV circulation

• Binds the F protein of the RS virus

• Blocks fusion of RSV to host cell membrane and fusion of infected host cells (“syncytial formation”)

• The F protein does not change in RSV subtypes; palivizumab provide protection against subtypes of RSV2,3

1.Synagis® (palivizumab) [package insert], Abbott Laboratories2.Johnson S, et al. J Infect Dis. 1997;176:1215–1224. 3.Williams JV, et al. In: Richman DD, et al, eds.Clinical Virology. 3rd ed

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CURRENT CLINICAL PRACTICEPrevention

RSV Overview

Prevention Is the Only Viable Strategy to Reduce the Risk of Acquiring an RSV Infection1

- Routine hand washing

- Careful handling of contaminated materials

- Cohort infected individuals

- Limit contact with hospital visitors, especially young children

- Passive immunization with Synagis® (palivizumab)2

1.Hall et al. J Pediatr. 19812.Allen et al. Am J Infect Control. 1990.

• RSV transmission can be minimized through a number of dif ferent ways:

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CURRENT CLINICAL PRACTICEPrevention

RSV Overview