A Prospective, Epidemiological Study to Assess the Disease Burden of Respiratory Syncytial Virus Associated, Suspected Lower Respiratory Tract Infections in Newborns, From 0 to 2 Years of Age and Risk of Development of Wheeze and Asthma From 0 to 6 Years of Age

The incidence rate was calculated by dividing the number of subjects reporting first episode over the follow-up period, to the total person-years. Detection of the RSV-infection was performed by reverse transcription quantitative real time polymerase chain reaction (RT-qPCR ) assay on ribonucleic acids (RNA) extracted from nasal swabs. Number of suspected RSV RTI cases were tabulated.

Healthcare utilization included primary, secondary and tertiary care settings such as self-care with Over-The-Counter [OTC] drugs, general practitioner [GP] visits, emergency room [ER] visits, hospital visits, etc. Note: This outcome measure presents results only for the more severe events of healthcare utilization - RSV hospitalization. Results for other causes (non-RSV) hospitalization and healthcare utilization for other settings were not calculated, as data were not available.

The incidence rate was calculated by dividing the number of subjects reporting first episodes over the follow-up period, to the total person-years. LRTI Case definition by WHO (Modjarrad 2015): LRTI is diagnosed when a child <5 years presents with cough and/or difficulty in breathing has the following symptoms: Fast breathing, (>60 per minute in a child <2 m, >50 per minute in a child 2 to 11 m and >40 per minute in a child 12 to 59 m) or Oxygen saturation <95% by pulse oximetry.

Severe LRTI is diagnosed when an infant with RSV LRTI has oxygen saturation<93% or lower chest wall drawing.

LRTI Case definition by GSK: LRTI is diagnosed when a child <5 years presents with cough or runny or blocked nose and oxygen saturation <95% with a respiratory rate ≥ 60/minute (< 2 months of age); ≥ 50/minute (2 to 11 months of age); ≥ 40/minute (12 to 24 months of age) and has RSV infection, confirmed on nasal swab positive for RSV A or B by quantitative polymerase chain reaction (qPCR).

Severe LRTI case definition by GSK: Child with LRTI and oxygen saturation < 92%, OR Difficulty breathing leading to: Irritability/agitation, or Lethargy/sleepiness, or Severe chest indrawing, or Reduced/no vocalization, or Apnoea > 20 sec, or Cyanosis, or Stop feeding well/dehydration.

LRTI is diagnosed when a child <5 years presents with cough and/or difficulty in breathing has the following symptoms: Fast breathing, (>60 per minute in a child <2 m, >50 per minute in a child 2 to 11 m and >40 per minute in a child 12 to 59 m) or Oxygen saturation <95% by pulse oximetry. Severe LRTI is diagnosed when a child has LRTI and Oxygen saturation <93% by pulse oximetry and/or lower chest wall in-drawing.

LRTI is diagnosed when a child has a history of acute cough or difficulty in breathing and greater than or equal to (≥) 1 of the following: Fast breathing for age (≥ 60 breaths/minimum if the child is < 2 m ≥ 50 breaths/minimum if the child is 2-11 m). Indrawing, or Low oxygen saturation (< 90%) by pulse oximetry or inability to feed (prostration or unconsciousness), when accompanied by a clinical diagnosis of LRTI or bronchiolitis. Severe LRTI is diagnosed when a child has Indrawing, or Low oxygen saturation (< 90%) by pulse oximetry or inability to feed (prostration or unconsciousness), when accompanied by a clinical diagnosis of LRTI or bronchiolitis.

Levels of RSV A and B neutralizing antibodies were expressed as Geometric Mean Titers (GMTs) and the cut off for the neutralization assay was 8 End Point Dilution 60 percent (ED60) for RSV-A antibodies and 6 ED60 for RSV-B antibodies. Infant baseline blood sample serum was tested for detection of RSV neutralizing antibodies level.

Levels of RSV A and B neutralizing antibodies were expressed as GMTs and the cut off for the neutralization assay was 8 End Point Dilution 60 percent (ED60) for RSV-A antibodies and 6 ED60 for RSV-B antibodies. Infant blood sample serum was tested for RSV neutralizing antibodies level detection.

The association between RSV LRTI, RSV severe LRTI and RSV A and B neutralizing antibodies were assessed by calculating the GMTs of RSV A and B neutralizing antibodies in the cord blood by subjects classified according to non-overlapping disease severity categories: Non case (defined as subject not reporting RSV LRTI or RSV severe LRTI), WHO RSV LRTI (excluding WHO RSV severe LRTI) and WHO RSV severe LRTI.

The association between RSV LRTI, RSV severe LRTI and RSV A and B neutralizing antibodies were assessed by calculating the GMTs of RSV A and B neutralizing antibodies by subjects classified according to non-overlapping disease severity categories: Non case (defined as subject not reporting RSV LRTI or RSV severe LRTI), RSV LTRI and RSV severe LRTI.

LRTI refers to Child with RTI AND Blood Oxygen Saturation (SaO2) lower than (<) 95 percent (%), OR respiratory rate (RR) increase: higher than (>) 60/min < 2 months (m) of age; > 50/min 2-11m of age, 40/min 12-24m of age. Severe LRTI refers to Child with LRTI AND SaO2 < 92%, OR Difficulty breathing leading to: Irritability/agitation, OR Lethargy/sleepiness, OR Severe chest indrawing, OR Reduced/no vocalization, OR Apnoea > 20 sec, OR Cyanosis, OR Stop feeding well/dehydration. The number of WHO LRTI cases were assessed for the following age groups: 0-2, 3-5, 6-11 and 12-23 months of age. Occurrence of LRTI/severe LRTI cases as classified by the LRTI case definitions and severity scale, was not limited to the subgroups of subjects recruited from Months 1-6 and 13-18 but was provided for subjects in all age intervals: 0-2 months, 3-5 months, 6-11 months and 12-23 months.

LRTI refers to Child with RTI AND Blood Oxygen Saturation (SaO2) lower than (<) 95 percent (%), OR respiratory rate (RR) increase: higher than (>) 60/min < 2 months (m) of age; > 50/min 2-11m of age, 40/min 12-24m of age. Severe LRTI refers to Child with LRTI AND SaO2 < 92%, OR Difficulty breathing leading to: Irritability/agitation, OR Lethargy/sleepiness, OR Severe chest indrawing, OR Reduced/no vocalization, OR Apnoea > 20 sec, OR Cyanosis, OR Stop feeding well/dehydration. The number of WHO severe LRTI cases were assessed for the following age groups: 0-2, 3-5, 6-11 and 12-23 months of age.

The incidence rate was calculated by dividing the number of subjects reporting first episode of medically attended wheeze over the follow-up period, to the total person-years. Medically attended wheeze = an episode of health care provider confirmed wheeze. Medically attended wheeze, in the extension phase, was collected via a history from parents solicited by contact every 3 months, which was supplemented by the review of routine medical records or contact with health care provider. Incidence rate was assessed for the following categories: All subjects, Non-case (defined as subject not reporting RSV LRTI or RSV severe LRTI) and WHO RSV LRTI.

The incidence rate was calculated by dividing the number of subjects reporting first episode of wheeze or asthma requiring hospital admission over the follow-up period, to the total person-years. Wheeze or asthma requiring hospital admission = an episode of health care provider confirmed wheeze or asthma requiring hospital admission. Wheeze or asthma requiring hospital admission, in the extension phase, was collected via a history from parents, which was supplemented by the review of routine medical records or contact with health care provider. Incidence rate was assessed for the following categories: All subjects, Non-case (defined as subject not reporting RSV LRTI or RSV severe LRTI) and WHO RSV LRTI.

The incidence rate was calculated by dividing the number of subjects reporting first episode of reported wheeze with use of any medication over the follow-up period, to the total person-years. Reported wheeze = parents report a whistling sound associated with labored breathing. Prescription of medications for wheeze, in the extension phase, was collected via a specific request for relevant medication from parents, which was supplemented by the review of routine medical records or contact with health care provider. Incidence rate was assessed for the following categories: All subjects, Non-case (defined as subject not reporting RSV LRTI or RSV severe LRTI) and WHO RSV LRTI.