Recurrent respiratory tract infections (RRTI) in the elderly: from phenotypic and immunological characterizaton to a mechanistic unravelling of a potential primary immunodeficiency (PID).

Primary immunodeficiencies (PID) are generally associated with children and
treated within the field of
paediatric specialists. We know fairly well when to start the diagnostic and
treatment processes. We also know that immunity weakens with age, a process
that was coined *immunosenescence*. In addition, there is an upregulation of
inflammatory responses, so-called *inflammaging*. These two processes culminate
into a higher incidence of infections in seniors. However, research has yet to
account for the incidence of recurrent infections at advanced age, and in
particular for the role of defects in host immune responses in these
infections. In our academic medical center, we identified over a period of 4
years, 22 elderly patients (median age 57 years) with late-onset recurrent
respiratory tract infections (RRTI) of whom 45% displayed a weak response to
unconjugated pneumococcal polysaccharide (PnPs) antigens (Pneumovax23
vaccination). These patients had low antibody titers despite normal
concentrations of total IgG. It appears that normal immunosenescence and
inflammaging cannot account for these occurrences of RRTI, and that these mild
and previously concealed defects in immune responses of an ageing individual
may be categorized as PID.

We hypothesise:
1) that there are mild PID in elderly patients with RRTI.
2) that the loss of adequate responses to PnPs antigens in a large proportion
of these elderly is either due to a B cell intrinsic problem or to a regression
in T cell independent (TI) co-stimulation of B cells affecting antibody
production.
3) that PID in RRTI patients with normal responses to Pneumovax23 is due to
(an)other still unknown mechanism(s).

The overall aim of the proposed project is to identify mild PID in elderly
patients that distinguish patients with RRTI from individuals with a healthy
ageing innate and adaptive immune system. In innate immunity, normal
immunosenescence is characterized by, among others, the accumulation of
neutrophils with impaired antimicrobial functions. In adaptive immunity, an
individual*s decreased B-cell response is correlated with changes in function
and proportion of his T-cell population. A typical, known example of a mild PID
is Mannose Binding Lectin (MBL) deficiency. In our pilotstudy
identifying patients with inadequate responses to PnPs antigens, an unexpected
high percentage (40% vs 5% in the general population) exhibited complete MBL
deficiency.
Goals
I. Describe clinical disorder in elderly patients with RRTI.
II. Assess immune responses within this clinical phenotypes, both innate and
adaptive.
III. Determine T cell independent condition of B cells in patients with RRTI
and inadequate responses to PnPs antigens.

To identify clinical phenotypes and perform immunological assays in search for
PID in elderly RRTI patients, we will recruit patients from the outpatient
clinic of our two academic centers (LUMC and Erasmus Medical Center). We aim to
admit 30 patients each (total of 60 patients). We will assess the innate and
adaptive function of the immune system in all of them and analyse factors that
are in some cases known to decay with age. For control purposes, we will sample
60 gender- and age-matched seniors from the population register, excluding
those with RRTI or known immunodeficiency. In addition, in collaboration with
the department of Geriatrics of the LUMC, we will randomly select 10 very old
(90+) healthy individuals who are genetically enriched for longevity from the
Leiden Longevity study to serve as extreme controls in our immunological
studies.
Furthermore, we will collect DNA from all patients for future genetic studies
investigating the association between recurrent respiratory tract infections
with genetic variations in genes encoding pattern recognition receptors, their
adapters and downstream signalling molecules that are involved in the
recognition of common pathogens found in RRTI (e.g., TLR1-4/6-9, NOD1, MDA5,
MYD88, TIRAP, TICAM1/2), or associated with CF and CVID (CFTR, CARD11, TACI and
POU2AF1). . In the current setting, the number of cases required for the
association of genetic differences with mild effect and disease is unrealistic.
Informed consent will be obtained from all patients and controls.

We will use a health questionnaires to assess the frequency and course of RRTI
and possibly other infections in the 60 patients. Furthermore we will acquire
bloodsamples by vena punction and perform several immunologic tests.

The burden and risks associated with participation in this study are small, and
related to the venapunction only. The group of patients as a whole will benefit
from the outcome of the study as it will help their treating phycisians to
identify those patients with recurrent respiratory tract infections due to a
primary immunedeficiency who are in need of a more rigorious antibiotic regime
or IVIG.