Microbiome and lower respiratory tract infections in children

Lower respiratory tract infections (LRTI) are a major cause of morbidity in
young children in high- income countries and the major cause of mortality in
developing countries. The etiology of LRTI is often polymicrobial involving
well-known viral or bacterial pathogens and also combinations of both.

LRTI pathogens all originate from the nasopharynx . Most of the time these
bacteria are regular residents of the nasopharynx of asymptomatic individuals
and live there together with other presumed harmless commensals, without
causing disease. Together they are a complex bacterial community, called the
nasopharyngeal (NP) bacterial microbiome. Next to bacteria, viral presence is
also found in the nasopharynx during respiratory tract infection and in
asymptomatic individuals.

Studies of the microbiome have only recently become feasible with the
development of molecular methods, since 40-80% of microbiome bacteria cannot be
detected by conventional culture techniques. Novel molecular techniques as 454
pyrosequencing
enable us to measure in detail the composition of complex microbial communities
in various states of health and disease.

The reason for progression from nasopharyngeal bacterial or viral carriage
towards invasive or symptomatic respiratory infectious disease is unknown. The
composition of the NP microbiome may be highly relevant for health or
susceptibility to disease. For instance, acquisition of a viral common cold may
alter bacterial outgrowth of common colonizers of the nasopharynx like S.
pneumoniae. Subsequently these bacteria may spread and cause pneumonia. This
development towards infectious disease by commensals like S. pneumoniae may
however not only depend on viral acquisition, but also on the total NP
microbiome of which S. Pneumoniae is part. A well- balanced composition may
play a role in the containment of potential pathogens by preventing outgrowth.
LRTI may occur as the balance is disturbed and host defense is insufficient.

The intestinal microbiome is important for its presumed correlation to several
diseases. Also respiratory immunity seems to be affected by the intestinal
microbiome. In addition the digestive system is believed to function as the
largest reservoir for exchanging antibiotic resistance genes between commensals
and bacteria passing through the gastro-intestinal tract. Antibiotic
consumption may also have influence on the equilibrium of the microbiome on the
other various body sides, like the nasopharynx, which will render a child more
susceptible for a new infection.

In this study we will focus on the microbiome composition of the nasopharynx,
the oral cavity and intestines during health and LRTI. This may lead to new
insights in the pathogenesis of LRTI and create possibilities for future
preventive strategies.

Primary objective:
To compare the NP microbiome composition and the presence of viruses in
children hospitalized for a LRTI to the NP microbiome composition and the
presence of viruses in healthy age- and gender-matched controls.

Secondary objectives:
1.To study the differences in composition of the NP microbiome in children
hospitalized for a LRTI during disease and after recovery.
2.To study the correlation between clinical, radiological and laboratory
findings and the bacterial and viral presence as well as their density in the
nasopharynx during LRTI.
3.To study the relation between the NP- and oral- and intestinal microbiome
during health and LRTI.

Exploratory Objectives:
To explore the influence of host and environmental factors such as age and use
of antibiotics on the composition of the NP-, lower respiratory tract-, oral-
and intestinal microbiome.
To explore the relation between the NP microbiome in to the bacteria and
viruses present in the lungs of children with severe LRTI

Case control study. The NP-, oral- and intestinal microbiome of children
hospitalized for a LRTI will be compared with the NP-, oral- and intestinal
microbiome of healthy age- and gender-matched children within the same period
of time.

Participation in this study holds no more risks than negligible risk and no
benefits. We believe that the risk of this study is no more than negligible for
the participants since all sampling methods are non-invasive and generally
accepted as fully save. Sampling moments will take place during hospitalization
and on regular visits to the outpatient department or "consultatiebureau" to
minimize burden and time spent for the study participants. There is no personal
benefit for the child or the parents.
We will follow the code of conduct relating to expressions of objection by
minors participating in medical research, as stated by the CCMO.
The sampling moments including signing of the informed consent will take about
30 minutes of participant*s time.