We were not able to recruit sufficient older adults with frailty and therefore stopped the study prematurely

Rationale: Individuals with advanced age are at a progressively increasing risk of acquiring lower respiratory tract infections. Besides calendar age, the degree of frailty also associates with increased susceptibility to pneumonia requiring hospitalization. How alterations in the mucosal immune system with advanced age predispose to infections remains unclear as access to relevant tissue samples is limited. With minimally-invasive nasal sampling methods, it was recently observed that in vital older adults, both CD4+ T cells and CD8+ T cells are selectively lost from the nasal mucosa. However, the exact phenotype, underlying mechanisms, key molecules and consequences of this have not yet been investigated.

Objective:

Elucidate the mechanisms underlying the loss of nasal T cells and characterize in depth the differences of T cells in young and older adults and associate this loss with susceptibility to infections.

Study design: Prospective cohort study

Study population: Participants will be recruited from 3 groups:

• healthy young adults (18-30 years, n=50)
• vital older adults (>65 years, n=60)
• frail elderly (>65 years, n=60). This group includes individuals without a history of recurrent respiratory infections or with >2 self-reported episodes of respiratory infection in the past year.

Main study parameters/endpoints: Frequency of nasal CD8+ T cells in young adults and frail older adults.

Secondary study parameters/endpoints:

• Phenotype (subsets, activation status), functionality, transcriptomic state, clonality and frequency of nasal and blood T cell populations
• Stability of T cells and other immune parameters, as described for main study parameter, during a second sample after 3 months.
• Analysis of other immune populations as for main study parameter
• Concentration of nasal and systemic factors (e.g. cytokines and metabolites) and their association with T cells and other immune populations
• Respiratory tract microbiota profiles and presence of asymptomatic viral infections and their association with T cells and other immune parameters
• Chronological and biological age, sex, and other immunologically relevant parameters with T cell populations and other immune parameters
• Alteration of T cell phenotype, during and following respiratory tract infections. Levels of antigen-specific T cells and other immune parameters in nose and blood post infection.

Inclusion Criteria:

•Adults able and willing to provide informed consent.

Specific inclusion criteria per group:

• Young adults aged 18-30 years old
• Healthy elderly aged >65 years old
• Frail elderly >65 years old
• Clinical Frailty score healthy elderly 1-3
• Clinical Frailty score frail elderly >3
• Self-reported respiratory tract infection in previous year healthy elderly 0-1
• Self-reported respiratory tract infection in previous year frail elderly 0-1 or >1

Exclusion Criteria:

• Incompetence to provide informed consent prior or during study
• Current smoker or >40 pack year history
• History of severe nose bleedings
• Diagnosed with asthma, COPD or chronic rhinosinusitis
• Use of inhalation corticosteroids or antibiotics in the past 6 weeks
• Current use of anti-coagulants (to prevent nosebleeds). Platelet inhibitors like acetylsalicylzuur (Ascal) are allowed.
• Respiratory tract infection or common cold in the past 2 weeks
• Immunocompromised individuals (with primary immune deficiency or secondary immune deficiency)
• Life expectancy <28 days in the opinion of study physician
• Vaccination in the 2 months prior to study start. A potential subject that is only excluded from participation based on a recent vaccination will be asked to re-participate 2 months post vaccination.

Study population: Investigators will recruit participants from 3 groups:

• healthy young adults (18-30 years, n=50)
• vital older adults (>65 years, n=60)
• frail elderly (>65 years, n=60). These will be consist of individuals without a history of recurrent respiratory infections or with >2 self-reported episodes of respiratory infection in the past year.

Frailty will be determined by a clinical frailty score. The Clinical Frailty Scale (CFS) is a scale that caretakers can use to identify level of frailty in older patients from 1 (very fit) through 9 (terminally ill). For the present study, "vital older patients" are defined as those with a CFS of 1-3 and "older patients living with frailty with a CFS of 4 or higher".

As even pseudonymized data is considered personal data as these can sometimes be traced back to an individual, data can be requested from the PI. If requests fall within the scope of the informed consent and study protocol, an MTA/DTA can be shared. Data will be posted on repositories with restricted access.