Objective 1: To determine the proportion of children testing positive for a respiratory pathogen when hospitalised with respiratory infection(s)

Objective 2: To estimate the overall proportion of coinfection in children hospitalised for respiratory infection(s)

Objective 3: To determine the impact of specific coinfecting pairs on hospitalisation outcomes (e.g. length of stay)

Searches were conducted in the following databases: EMBASE, Global Health, Biosis Previews, PubMed, MEDLINE, Scopus. Initial searches were run in April and are to be rerun at weekly intervals up until the time of data analysis.

Search terms were divided into five concepts: co-infection, viruses, child, respiratory and hospitalisations. Each concept was searched separately and keywords within a concept were combined with an OR operator. A final search combined all concepts with an AND operator to yield the final results.

No restrictions on language or publication period were specified.

There are no restrictions on the types of study design eligible for inclusion.

Acute respiratory infections refer to chest infections such as bronchiolitis, whooping cough and pneumonia. These infections are the most common cause of death in children worldwide. Children may be infected with one or more pathogens at the time of illness, known as coinfection, and this may contribute to illness severity. Rates of reported coinfection vary greatly between studies and there have been some studies looking at the impact of specific pairs of pathogens on patient outcomes. Synthesis of existing information on coinfections would be of interest to medical practitioners and researchers working in respiratory infections.

The review population is children under five years, living in an OECD country. Studies must meet all of the inclusion criteria and none of the exclusion criteria in order to be included in this review.

Inclusion criteria are studies that:

(1) Report on children aged less than or equal to 5 years and;

(2) Report on children living in an OECD country (as of April 2012) and;

(3) Report on respiratory infections and;

(4) Report on coinfections with one or more viruses.

Exclusion criteria are studies that:

(1) Only report on children with a pre-existing condition (e.g. HIV-positive, organ transplant recipient etc.) or;

(2) Only reports on infections involving non-humans or;

(3) Only reports on the pathways leading to coinfection or;

(4) Only reports on the methods of detecting or treating coinfections or;

(5) Only reports on infections acquired in-hospital (i.e. nosocomial infections).

This review concerns community-acquired coinfections involving one or more viruses that result in a respiratory disease or illness. Community-acquired infections refer to infections acquired while living in the community, rather than infectious acquired while in hospital. Common respiratory illnesses include whooping cough, bronchiolitis, pneumonia and influenza. Potential viral pathogens include adenoviruses, bocaviruses, coronaviruses, human metapneumoviruses, influenza viruses, parainfluenza viruses, respiratory syncytial viruses and rhinoviruses.

The first objective of this review is to determine of the children who were hospitalised for a respiratory infection, how many tested positive for a respiratory pathogen. The second objective of this review is to estimate the overall proportion of children with coinfections who are hospitalised for respiratory infections. As both of these are descriptive, there is no comparison or control group.

The third objective of the study is to determine the impact of specific coinfecting pairs on hospitalisation outcomes. The comparison group for this would be children infected with a single viral pathogen.

Settings for all studies included in the review are likely to be hospitals. Rationale for each of the inclusion and exclusion criteria for this review are given below:

Inclusion criteria 1 - Study reports on children aged less than or equal to 5 years.

Children, in particular young children, are at the highest risk for respiratory infections. Moreover, the patterns for infection for school-aged children and adolescents are different from younger children. As such, this review will focus on respiratory coinfections in children aged <5 years.

Inclusion criteria 2 - Study reports on children living in an OECD country (as of April 2012).

Chronic infections and some pre-existing conditions can increase the risk of respiratory infection in children and certain infections may be endemic in certain countries. In addition, social and environmental factors such as poverty and lack of access to healthcare, will also increase the risk of respiratory infections. Countries that are members of an international group such as the Organisation for Economic Co-operation and Development (OECD) are likely to have less dramatic variability in these areas between them. Moreover, national data on key indicators of health in OECD countries are publicly available, which will aid in interpreting the results of any analysis in this review.

Inclusion criteria 3 - Study reports on respiratory infections.

Pathogens commonly associated with respiratory infections include respiratory syncytial virus, influenza viruses, Streptococcus pneumoniae and Bordetella pertussis. Some respiratory pathogens are also associated with non-respiratory diseases such as otitis media (middle ear infection) and gasteroenteritis, both of which may have different patterns of infection. This review will focus on episodes of respiratory infections.

Inclusion criteria 4 - Study reports on coinfections with one or more viruses.

Respiratory pathogens are commonly viruses or bacteria. Of these, viruses are detected in the majority of episodes of respiratory infections in children. As such, this review will focus on infection episodes associated with one or more viruses.

Exclusion criteria 1: Study reports only on children with a pre-existing condition (e.g. HIV-positive, organ transplant recipient etc.).

Children with pre-existing conditions, particularly those that result in a compromised immune system, are at a higher risk of respiratory infections. To account for this, children with pre-existing conditions would have to be analysed separately to immunocompetent children. As such, studies examining only immunocompromised children will be excluded from this review.

Exclusion criteria 2,3 and 4: Study reports only on infections involving non-humans OR pathways leading to infection OR methods of detecting or treating coinfections. The focus of this review is the proportions of hospitalisations for respiratory infections with a positive identification of one or more respiratory pathogens and the impact of coinfecting pairs on clinical outcomes. As such, studies examining the mechanisms of coinfection or diagnostic methods and treatments of coinfections, are not the focus of this review and will be excluded.

Exclusion criteria 5: Study reports only on infections acquired in-hospital (i.e. nosocomial infections).

Children who are admitted to hospital may subsequently contract a secondary infection whilst in hospital. These are referred to as nosocomial infections. Pathogens causing infections whilst in hospital may not be representative of the pathogens in the community. The focus of this review is on community-acquired infections, as such, studies that report solely on nosocomial infections would be excluded.

Primary outcomes

Of the children who are hospitalised for respiratory infections, what proportion of them have a positive identification of one or more respiratory virus(es) or bacteria?

Secondary outcomes

Of the children with multiple respiratory pathogens identified, how has the specific combination of pathogens affected their clinical outcomes (e.g. length of stay in hospital, attendance at an intensive care unit etc.)?

Titles and/or abstracts of studies retrieved using the search strategy and studies from additional sources will be screened by the first author in the first round of reviews. Studies meeting the exclusion criteria will be tagged as "Exclude". Studies with insufficient information for inclusion or exclusion will be tagged as "Unsure". The second author will review these tags for accuracy. Any disagreement between them over the eligibility of particular studies will be resolved through discussion with a third reviewer.

Full-text copies of studies that may potentially meet the inclusion criteria or were tagged as "Unsure" will be retrieved and assessed in the second round of reviews. Studies meeting the inclusion criteria will be tagged as "Include".

A standardised form will be used to extract data from the included studies for assessment of study quality and evidence synthesis. Extracted information will include: study setting; study population and participant demographics and baseline characteristics; pathogens detected and detection methods; hospitalisation outcomes; information for assessment of the risk of bias. The first author will extract data which will then be reviewed by the second author. Any discrepancies identified will be resolved through discussion (with a third reviewer where necessary).

Both review authors will independently assess the risk of bias in the included studies by assessing the following:

1. Detection bias - were results adjusted for seasonality? Sensitivity and appropriateness of detection methods for each pathogen?

2. Selective outcome reporting - is there evidence of selective outcome reporting and might this have affected the study results?

Disagreements between the review authors over the risk of bias in particular studies will be resolved by discussion, with involvement of a third reviewer where necessary.

Studies will be separated into those with aggregate data and those with individual data. Both groups will be analysed separately using summary statistics.

None planned.

Faye Lim

Telethon Institute for Child Health Research

100 Roberts Road

Subiaco 6008

Western Australia

Australia.

janicelim@ichr.uwa.edu.au

Telethon Institute for Child Health Research

http://www.childhealthresearch.org.au/

Ms Faye Lim, Telethon Institute for Child Health Research
Dr Hannah Moore, Telethon Institute for Child Health Research

Miss Alicia Annamalay, School of Paediatrics and Child Health, University of Western Australia

01 April 2012

31 December 2013

This review was initiated by members of the review team and will be managed by the team. This review is not sponsored or financed by a third party.

None known

English

Australia

Subject indexing assigned by CRD

Child; Coinfection; Hospitalization; Humans; Respiratory Syncytial Viruses; Respiratory Tract Infections

16 August 2012

13 November 2012