Assessment of inflammatory response of bronchial cells to gastric juice from hospitalized infants on and off proton pump inhibitor (PPI) therapy, PICU admitted children and long term users (0-18 years) of PPIs and controls off PPI

Gastro esophageal reflux (GER) is the passive movement of gastric contents into
the esophagus. This is present in children in all age groups. Only when GER
causes symptoms and complications it is referred to as GER disease (GERD).
These symptoms may include: regurgitation, heartburn and unexplained crying.
Extra esophageal symptoms and complications may include respiratory symptoms,
such as chronic cough, apnea, wheezing, pulmonary fibrosis and pneumonia.
It has now become well accepted that not only acid, but also weakly acid and
alkaline GER can cause significant symptoms and complaints of GERD and
micro-aspiration of gastric contents is one putative mechanism behind the
respiratory symptoms associated with GER. Micro-aspiration may cause an
inflammatory response, which can ultimately lead to clinically relevant
bronchitis and/or pneumonia. It is commonly thought that gastric contents are
increasingly deleterious to bronchial tissue with increasing acidity and
especially when pH drops below 4. However, recent evidence in animals and in
adults, show that weakly acid and alkaline aspirated reflux might be able to
provoke a significant greater inflammatory response compared to acid GER. This
suggests that the acidity of gastric contents, presumably by its antibacterial
qualities, could in fact play a role in the prevention of bronchial damage
resulting from micro-aspiration following GER.
Proton pump inhibitors (PPI*s), a therapy focused on reducing the acidity, but
not the number of GER episodes, are more and more used to treat GERD and
prevent GER related respiratory symptoms in infants and children with
increased risk of aspiration and/or the suspicion of impaired pulmonary
clearance mechanisms. This is striking given the evidence available. Five out
of five randomized controlled placebo controlled trials show no clinical effect
of PPI treatment on GERD symptoms in infants and children. Moreover, PPIs might
not be as safe as previously presumed. Studies report a number of adverse
events such as gastric bacterial overgrowth of the upper gastrointestinal
tract. With regards to respiratory adverse events, the following are described
in literature in children and adults: community-acquired pneumonia an increase
of respiratory tract infections in critically ill children and hospital
acquired pneumonias. All of the above are attributed to the acid suppressing
ability of PPIs.
The possible causal relationship between PPI use and respiratory tract
infections would be especially relevant for hospitalized infants, in whom an
increase in the prescription of PPI is seen to treat and prevent respiratory
symptoms which are clinically expected to be GER related (e.g. apnea), and in
ventilated PICU admitted children, who receive PPI on a prophylactic base.
Currently, it is unclear how gastric juice from hospitalized infants, PICU
admitted children and children on long term PPI treatment influences
inflammatory responses in bronchial epithelium.

Quantify inflammatory response (through IL-8 production) of bronchial (both
commercial available cells and cultivated brushed infant cells) when exposing
these to gastric juice from: hospitalized Infants, before and during PPI
treatment and age matched controls who do not receive PPI therapy, mechanically
ventilated infants and children admitted to the pediatric intensive care unit
(PICU) before and during PPI treatment and children who have received and
currently receive PPI treatment for at least six weeks and controls not
recieving anti-reflux treatment.

Prospective, observational, laboratory study.

With regards to gastric juice collection, two samples will be taken from
patients admitted at the PICU wards and one from children who are on long term
PPI treatment. In hospitalized infants, both GERD patients and controls,
gastric juice samples will be taken 4 times: prior and after feeding, both
prior and after start of PPI therapy. This is to analyse the effect of feeding
on the composition of the gastric juice and the possible effects on the
inflammatory response of bronchial cells. All samples will be taken through a
catheter which is already in place and should therefore cause no additional
discomfort or risk. One exception is the group of patients with long term PPI
use. If these patients are not routinely fed through a nasogastric tube, the
gastric juice will be taken during a routine pH or pH-impedance investigation A
combined catheter will be used for this purpose and although the diameter of
this catheter is slightly larger than that of the pH or pH-impedance catheter
used for clinical purposes (6F compared to 4F), in our experience this
procedure is well tolerated and should cause no or minor additional discomfort.
No side effects are to be expected. In control patients, we will only collect
gastric juice through an already existing nasogastric tube or PEG tube.
Also with regards to collecting primary bronchial cells through a blind brush
procedure, which we will perform in 3 patients, minimal additional side effects
are expected, since infants or children are intubated for either a surgical
procedure or a broncho-alveolar lavage (BAL) procedure they need to undergo for
other medical reasons besides respiratory tract infections. No side effects of
the brush procedure are foreseen.