Respiratory infections in asthma: the role of host defense against infections, allergic inflammation and vitamin D

Morbidity in asthma is strongly determined by disease exacerbations and
associated respiratory infections. Recurrent respiratory infections are one of
the most important risk factors for frequent exacerbations in
difficult-to-treat asthma. Antimicrobial peptides (AMPs) are important effector
molecules in innate immunity that act as endogenous antibiotics in host defense
against respiratory infections. Little is known about the expression and
activity of AMPs in asthma. Recent studies show that both allergic inflammation
and vitamin D are important regulators of production of AMPs. Both human and
mouse studies show that the Th2 cytokines that are a characteristic of allergic
inflammation in asthma, suppress expression of AMPs. Other studies show that
active vitamin D, 1,25 (OH) vitamin D, is an important regulator of AMPs
expression, as demonstrated both in vitro in cell culture and in vivo after
topical application onto the skin.

We hypothesize that local AMPs expression in the airways of patients with
asthma is decreased as a result of allergic inflammation. Furthermore, we
hypothesize that local AMP expression can partly be restored by vitamin D
substitution therapy. We aim to test our hypothesis by investigating AMPs in
sputum and nasal secretions from patients with mild to moderate asthma and
non-atopic controls. In addition, we will study the effects of oral vitamin D
administration in asthma and controls on local expression of AMPs in the
airways. The results from the present study will provide insight into host
defense against respiratory infections in asthma, and will show the feasibility
of using vitamin D treatment to increase this local immunity.

The levels and activity of antimicrobial polypeptides (AMPs) in airway
secretions in patients with mild-to-moderate asthma will be compared to
non-atopic controls.

The subjects will receive 2 microgram 1,25 (OH) vitamin D (calcitriol) or
placebo once daily during seven days (unless discontinued based on assessment
on day 4). The wash out time between the intervention in the cross over design
will be two weeks.

Standardized test as a skin prick test, methacholine challenge, sputum
induction, exhaled NO and spirometry are applied worldwide for the examination
of patients with asthma and are proven to be save.
Nasal secretions will be collected using a narrow-tipped vacuum device to
mildly stimulate nasal secretion. This procedure is safe and non-invasive.
Venous blood for the laboratory assessment will be collected at all visits
using standard procedure. The intervention with 2 microgram 1,25 (OH) vitamin D
(calcitriol) or placebo during seven days is monitored by measuring creatinine
and calcium in venous blood before and at day 4 of the intervention. An
independent physician will check the serum levels and stop treatment if calcium
levels exceed 2.65 mmol/l (albumin-adjusted). In this group of patients no
hypercalcaemia is expected.