The Immu-KNEE-ty Study

Study Overview
=================
Brief Summary
-----------------
The goal of this observational study is to determine changes in immune functioning after total knee replacement surgery in elderly. The study population consists of 14 patients aged 65 years or over undergoing primary total knee replacement surgery. Immune functioning will be assessed at multiple timepoints before and after surgery (i.e., ± 6 weeks before, and 1 day, 1 week, ± 2 weeks, and ± 6 weeks after surgery). Each patient will serve as his/her own control. Immune functioning will primarily be assessed by determining the change from baseline in monocyte-derived TNFα production at 1 week after surgery. Changes in monocyte responsiveness are considered indicative for changes in immune functioning. As secondary objective, additional parameters of immune functioning will be assessed. In addition, the course of immune functioning following total knee replacement surgery will be investigated. Burden and potential risks for the patient are estimated to be minor. During the study, 5 blood samples of 20 mL will be collected over a period of ± 12 weeks, resulting in a total blood draw of 100 mL. During surgery a sample of synovial fluid (± 2 mL) will be taken from surgical waste. Before and after surgery patients will report their pain medication intake and the presence of cold and flu-like symptoms in a diary. Patients do not directly benefit from the study.

Detailed Description
-----------------
The world population is progressively aging. As humans age, their immune system becomes weaker through a process called immunosenescence. This age-related decline in immune functioning results in an increased susceptibility to infections. Elderly with chronic diseases or elderly who have experienced an incident, such as fall-related trauma or surgery, are particularly vulnerable to these infections, likely due to immunosuppression resulting from such an immune challenge. Currently, there are no standard interventions used to improve immune functioning in these immune-suppressed elderly. However, before the potential of such interventions can be explored, postoperative immune suppression in elderly first needs to be demonstrated. The goal of this prospective ex vivo study is therefore to determine changes in immune functioning after total knee replacement surgery in elderly. The study population consists of 14 patients (classified as ASA II or ASA III) aged 65 years or over, diagnosed with osteoarthritis, undergoing primary total knee replacement surgery under general anesthesia. Immune functioning will be assessed at multiple timepoints before and after surgery (i.e., ± 6 weeks before, and 1 day, 1 week, ± 2 weeks, and ± 6 weeks after surgery). Each patient will serve as his/her own control. Immune functioning will primarily be assessed by determining the change from baseline in monocyte-derived TNFα production at 1 week after surgery. TNFα production will be measured after ex vivo stimulation of whole blood with inflammatory stimuli and normalized for monocyte count. Changes in monocyte responsiveness are considered indicative for changes in immune functioning. As secondary objective, additional parameters of immune functioning will be assessed. In addition, the course of immune functioning following total knee replacement surgery will be investigated. Burden and potential risks for the patient are estimated to be minor. During the study, 5 blood samples of 20 mL will be collected over a period of ± 12 weeks, resulting in a total blood draw of 100 mL. Blood sampling will be combined with regular care visits, with the exception of one occasion where blood sampling will be performed at home. Patients could experience mild pain by the venipuncture, which occasionally leads to lightheadedness, fainting and hematoma. During surgery a sample of synovial fluid (± 2 mL) will be taken from surgical waste. Before and after surgery patients will report their pain medication intake and the presence of cold and flu-like symptoms in a diary. Patients do not directly benefit from the study.

Official Title
-----------------
The Effect of Total Knee Replacement Surgery on Immune Functioning in Elderly

Conditions
-----------------
Immunosenescence, Aging

Intervention / Treatment
-----------------
* Procedure: Knee arthroplasty


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Planned for primary total knee replacement surgery Aged 65 years or over Diagnosed with osteoarthritis ASA Physical Status Classification of II or III Scheduled for general anesthesia Willing to donate a blood sample at 5 different timepoints Able to give written informed consent Exclusion Criteria: Daily use of high doses NSAIDs within the 14 days before inclusion: Defined as higher than maintenance dose in the farmacotherapeutisch kompas. For example: acetylsalicylic acid > 4 g/day; diclofenac > 75 mg/day; naproxen > 500 mg/day; ibuprofen> 1600 mg/day; celecoxib > 200 mg/day Use of systemic corticosteroids Use of antibiotics within the 14 days before inclusion Current diagnosis of cancer Diagnosed with a primary immunodeficiency disorder (e.g., Severe Combined Immunodeficiency (SCID), Common Variable Immune Deficiency (CVID), X-linked agammaglobulinemia, selective immunoglobulin A deficiency, chronic granulomatous disease) Vaccination (e.g., immunization against COVID-19, influenza, pneumonia, and travel-related infections) within the 14 days before inclusion and during the study period Current participation in other scientific research

Ages Eligible for Study
-----------------
Minimum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Elderly<br> | Procedure: Knee arthroplasty<br>* At multiple timepoints (i.e., ± 6 weeks before, and 1 day, 1 week, ± 2 weeks, and ± 6 weeks after surgery) before and after total knee replacement surgery blood will be collected to assess immune functioning<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Monocyte-derived TNFa production | TNFα production after ex vivo stimulation of whole blood with inflammatory stimuli corrected for monocyte count | Change from baseline at 1 week after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Monocyte-derived cytokine production | Cytokine production after ex vivo stimulation of whole blood with inflammatory stimuli and corrected for monocyte count | Change from baseline at 1 day after surgery | 
| Monocyte-derived cytokine production | Cytokine production after ex vivo stimulation of whole blood with inflammatory stimuli and corrected for monocyte count | Change from baseline at 1 week after surgery | 
| Monocyte-derived cytokine production | Cytokine production after ex vivo stimulation of whole blood with inflammatory stimuli and corrected for monocyte count | Change from baseline at ± 2 weeks after surgery | 
| Monocyte-derived cytokine production | Cytokine production after ex vivo stimulation of whole blood with inflammatory stimuli and corrected for monocyte count | Change from baseline at ± 6 weeks after surgery | 
| Monocyte-derived cytokine production | Cytokine production after ex vivo stimulation of isolated monocytes with inflammatory stimuli | Change from baseline at 1 day after surgery | 
| Monocyte-derived cytokine production | Cytokine production after ex vivo stimulation of isolated monocytes with inflammatory stimuli | Change from baseline at 1 week after surgery | 
| Monocyte-derived cytokine production | Cytokine production after ex vivo stimulation of isolated monocytes with inflammatory stimuli | Change from baseline at ± 2 weeks after surgery | 
| Monocyte-derived cytokine production | Cytokine production after ex vivo stimulation of isolated monocytes with inflammatory stimuli | Change from baseline at ± 6 weeks after surgery | 
| PBMC (peripheral blood mononuclear cell)-derived cytokine production | Cytokine production after ex vivo stimulation of PBMCs with inflammatory stimuli | Change from baseline at 1 day after surgery | 
| PBMC-derived cytokine production | Cytokine production after ex vivo stimulation of PBMCs with inflammatory stimuli | Change from baseline at 1 week after surgery | 
| PBMC-derived cytokine production | Cytokine production after ex vivo stimulation of PBMCs with inflammatory stimuli | Change from baseline at ± 2 weeks after surgery | 
| PBMC-derived cytokine production | Cytokine production after ex vivo stimulation of PBMCs with inflammatory stimuli | Change from baseline at ± 6 weeks after surgery | 
| Composition of immune cell populations | Composition of immune cell populations (white blood cell count and differential) in whole blood | Change from baseline at 1 day after surgery | 
| Composition of immune cell populations | Composition of immune cell populations (white blood cell count and differential) in whole blood | Change from baseline at 1 week after surgery | 
| Composition of immune cell populations | Composition of immune cell populations (white blood cell count and differential) in whole blood | Change from baseline at ± 2 weeks after surgery | 
| Composition of immune cell populations | Composition of immune cell populations (white blood cell count and differential) in whole blood | Change from baseline at ± 6 weeks after surgery | 
| Systemic inflammation | Systemic inflammation as measured by circulating cytokines, chemokines, acute phase proteins, oxylipins, and markers of intestinal function | Change from baseline at 1 day after surgery | 
| Systemic inflammation | Systemic inflammation as measured by circulating cytokines, chemokines, acute phase proteins, oxylipins, and markers of intestinal function | Change from baseline at 1 week after surgery | 
| Systemic inflammation | Systemic inflammation as measured by circulating cytokines, chemokines, acute phase proteins, oxylipins, and markers of intestinal function | Change from baseline at ± 2 weeks after surgery | 
| Systemic inflammation | Systemic inflammation as measured by circulating cytokines, chemokines, acute phase proteins, oxylipins, and markers of intestinal function | Change from baseline at ± 6 weeks after surgery | 
| Phagocytic function of monocytes | Phagocytic function of monocytes as measured by the uptake of fluorescent particles | Change from baseline at 1 day after surgery | 
| Phagocytic function of monocytes | Phagocytic function of monocytes as measured by the uptake of fluorescent particles | Change from baseline at 1 week after surgery | 
| Phagocytic function of monocytes | Phagocytic function of monocytes as measured by the uptake of fluorescent particles | Change from baseline at ± 2 weeks after surgery | 
| Phagocytic function of monocytes | Phagocytic function of monocytes as measured by the uptake of fluorescent particles | Change from baseline at ± 6 weeks after surgery | 
| Monocyte HLA-DR expression | Monocyte HLA-DR expression as measured with fluorescent antibodies | Change from baseline at 1 day after surgery | 
| Monocyte HLA-DR expression | Monocyte HLA-DR expression as measured with fluorescent antibodies | Change from baseline at 1 week after surgery | 
| Monocyte HLA-DR expression | Monocyte HLA-DR expression as measured with fluorescent antibodies | Change from baseline at ± 2 weeks after surgery | 
| Monocyte HLA-DR expression | Monocyte HLA-DR expression as measured with fluorescent antibodies | Change from baseline at ± 6 weeks after surgery | 
| Synovial inflammation | Synovial inflammation as scored by the surgeon (yes/no) | During surgery | 
| Synovial inflammation | Synovial inflammation as measured by cytokine and chemokine levels in synovial fluid | During surgery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Knee arthroplasty, Elderly, Immune functioning, Monocytes