The Immu-KNEE-ty Study

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

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.

Study Overview

• Status: Completed
• Conditions: Aging; Immunosenescence
• Intervention / Treatment: Procedure: Knee arthroplasty

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.

• Study Type: Observational
• Enrollment (Actual): 14

Contacts and Locations

Study Locations

• Netherlands
  • Ede, Netherlands, 6716 RP
    • Gelderse Vallei Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

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.

Description

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
• 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

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Elderly	Procedure: Knee arthroplasty; 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

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of surgery	Duration of surgery	During surgery
Body Mass Index	Body Mass Index	Baseline
American Society of Anesthesiologists (ASA) classification	ASA classification	Baseline
Kellgren-Lawrence classification	Kellgren-Lawrence classification	Baseline
Knee function and pain	Knee function and pain as measured by the Oxford Knee Score (OKS)	Baseline
Physical function	Physical function as measure by the Knee injury and Osteoarthritis Outcome Score - Physical Function Short Form (KOOS-PS)	Baseline
Quality of Life (QoL)	QoL as measured by EQ-5D	Baseline
Pain as measured by the Numeric Pain Rating Scale (NPRS)	Pain as measured by the NPRS	Baseline
Mobility	Timed Up and Go (TUG) test	Baseline
Mobility	Sit to Stand (STS) test	Baseline
Mobility	10 Meter Walk Test (10MWT)	Baseline
Amount of blood loss	Amount of blood loss	During surgery
Analgesic therapies	Amount of analgesic therapies recorded in a pain medication diary	1 week before surgery
Analgesic therapies	Amount of analgesic therapies recorded in a pain medication diary	During hospitalization
Analgesic therapies	Amount of analgesic therapies recorded in a pain medication diary	In the 6 weeks after surgery
Cold and flu-like symptoms	Cold and flu-like symptoms in a diary	In the 6 weeks after surgery

Collaborators and Investigators

• Sponsor: Wageningen University
• Collaborators: Wageningen University and Research; Gelderse Vallei Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2024
• Primary Completion (Actual): December 11, 2024
• Study Completion (Actual): December 11, 2024

Study Registration Dates

• First Submitted: June 15, 2023
• First Submitted That Met QC Criteria: June 15, 2023
• First Posted (Actual): June 27, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 27, 2025
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Elderly; Knee arthroplasty; Monocytes; Immune functioning
• Other Study ID Numbers: NL84069.091.23

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No