Effect of Infections and Global DNA Methylation on Frailty Trajectories in Hospitalized Older Patients (INFRAGEN)

Aging Clinical Trial

— INFRAGEN  

Official title:

Effect of Infections and Global DNA Methylation on Frailty Trajectories in Hospitalized Older Patients: a Multicenter Observational Study (INFRAGEN)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06430073
• Other study ID #: 83/2023/Oss/AOUFe
• Status: Not yet recruiting
• Start date: May 20, 2024
• Est. completion date: March 1, 2026

Study information

• Verified date: March 2024
• Source: University Hospital of Ferrara
• Contact: Caterina Trevisan, PhD
• Phone: +393896743650
• Email: caterina.trevisan[@]unife.it
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This prospective multicenter study aims at exploring the impact of infections on intra-hospital and 3-month changes in the frailty profile of older inpatients.

To understand the complex pathways under the relationship between infections and frailty, this study will evaluate infection-related clinical and biochemical markers of systemic inflammation and genetics/epigenetics markers at ward admission.

The interplay between clinical, functional, and genetics/epigenetics factors will be evaluated in a subgroup of patients by testing whether 3-month changes in frailty concur with changes in the genomic DNA markers. This study will help characterize the pathophysiological mechanisms of frailty and identify at-risk conditions that may accelerate its course.

Description:

Infectious diseases are among the most common causes of hospitalization in older adults. Indeed, recent data report that more than 15% of hospital admissions in adults 65 years or older are due to infections, mainly in the urinary and respiratory tracts. Frailty is a well-known geriatric syndrome characterized by reduced individual resilience and increased vulnerability to external stressors. The prevalence of frailty ranges from around 10% in the community setting to almost 50% among institutionalized individuals.

Although both infectious diseases and frailty are associated with negative outcomes for the health of older adults and the healthcare system, their interplay has not been largely explored. In particular, it is not clear whether and to which extent acute infectious diseases might affect frailty, fastening its development or hampering its reversion.

The overall goal of the proposed project is to evaluate the impact of acute infections on frailty trajectories in older hospitalized patients from the pre-admission status to 3 months after hospital discharge. Moreover, a comprehensive set of sociodemographic, clinical, functional, and genetic/epigenetic factors will be assessed as possible effect modifiers in the association between infections and frailty trajectories.

This multicenter prospective observational study includes four geriatric wards (Ferrara, Padova, Milano, and Napoli) and involves individuals with no or mild-to-moderate frailty. A novel and interesting aspect will be represented by the analysis of genetic and epigenetic factors, i.e. global DNA methylation and telomere length. This point will make possible exploring the complex pathophysiologic mechanisms of frailty development using a translational approach involving both basic science and clinical researchers.

Overall, this study will help better identify at-risk conditions that may accelerate the course of frailty. Therefore, the project findings may promote the importance of interventions that could counteract frailty development during the hospital stay and should be addressed primarily to the categories of patients at highest risk.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 340
• Est. completion date: March 1, 2026
• Est. primary completion date: September 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 70 Years and older

Eligibility

Inclusion Criteria:

• confirmed diagnosis of acute infection diseases at hospital admission or during the hospital stay, according to specific ICD-9 codes with or without systemic inflammatory reaction;

• pre-admission non-frailty or mild frailty assessed using the Clinical Frailty Scale (CFS < 6).

Exclusion Criteria:

• terminally ill patients with an estimated life expectancy less than 3 months;

• presence of pre-admission frailty (CFS = 6);

• unwillingness to participate in the study or to complete the follow-up assessments

Related Conditions & MeSH terms

• Aging
• Communicable Diseases
• Cross Infection
• Frailty
• Hospital Infection
• Infections
• Inflammation
• Telomere Shortening

Locations

Country	Name	City	State
n/a

Sponsors (4)

Lead Sponsor	Collaborator
University Hospital of Ferrara	Azienda Ospedaliera di Padova, Azienda Ospedaliera Universitaria Policlinico, Fondazione IRCCS San Gerardo dei Tintori

References & Publications (16)

Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014 Jun;69 Suppl 1:S4-9. doi: 10.1093/gerona/glu057. — View Citation

Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, Kop WJ, Burke G, McBurnie MA; Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001 Mar;56(3):M146-56. doi: 10.1093/gerona/56.3.m146. — View Citation

Greco GI, Noale M, Trevisan C, Zatti G, Dalla Pozza M, Lazzarin M, Haxhiaj L, Ramon R, Imoscopi A, Bellon S, Maggi S, Sergi G. Increase in Frailty in Nursing Home Survivors of Coronavirus Disease 2019: Comparison With Noninfected Residents. J Am Med Dir Assoc. 2021 May;22(5):943-947.e3. doi: 10.1016/j.jamda.2021.02.019. Epub 2021 Feb 22. — View Citation

Huoman J, Sayyab S, Apostolou E, Karlsson L, Porcile L, Rizwan M, Sharma S, Das J, Rosen A, Lerm M. Epigenetic rewiring of pathways related to odour perception in immune cells exposed to SARS-CoV-2 in vivo and in vitro. Epigenetics. 2022 Dec;17(13):1875-1891. doi: 10.1080/15592294.2022.2089471. Epub 2022 Jun 26. — View Citation

Iwai-Saito K, Shobugawa Y, Aida J, Kondo K. Frailty is associated with susceptibility and severity of pneumonia in older adults (A JAGES multilevel cross-sectional study). Sci Rep. 2021 Apr 12;11(1):7966. doi: 10.1038/s41598-021-86854-3. — View Citation

Lapham K, Kvale MN, Lin J, Connell S, Croen LA, Dispensa BP, Fang L, Hesselson S, Hoffmann TJ, Iribarren C, Jorgenson E, Kushi LH, Ludwig D, Matsuguchi T, McGuire WB, Miles S, Quesenberry CP Jr, Rowell S, Sadler M, Sakoda LC, Smethurst D, Somkin CP, Van Den Eeden SK, Walter L, Whitmer RA, Kwok PY, Risch N, Schaefer C, Blackburn EH. Automated Assay of Telomere Length Measurement and Informatics for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort. Genetics. 2015 Aug;200(4):1061-72. doi: 10.1534/genetics.115.178624. Epub 2015 Jun 19. — View Citation

Park CM, Kim W, Rhim HC, Lee ES, Kim JH, Cho KH, Kim DH. Frailty and hospitalization-associated disability after pneumonia: A prospective cohort study. BMC Geriatr. 2021 Feb 5;21(1):111. doi: 10.1186/s12877-021-02049-5. — View Citation

Prampart S, Le Gentil S, Bureau ML, Macchi C, Leroux C, Chapelet G, de Decker L, Rouaud A, Boureau AS. Functional decline, long term symptoms and course of frailty at 3-months follow-up in COVID-19 older survivors, a prospective observational cohort study. BMC Geriatr. 2022 Jun 30;22(1):542. doi: 10.1186/s12877-022-03197-y. — View Citation

Rockwood K, Mitnitski A. Frailty in relation to the accumulation of deficits. J Gerontol A Biol Sci Med Sci. 2007 Jul;62(7):722-7. doi: 10.1093/gerona/62.7.722. — View Citation

Schneider CV, Schneider KM, Teumer A, Rudolph KL, Hartmann D, Rader DJ, Strnad P. Association of Telomere Length With Risk of Disease and Mortality. JAMA Intern Med. 2022 Mar 1;182(3):291-300. doi: 10.1001/jamainternmed.2021.7804. — View Citation

Schork NJ, Beaulieu-Jones B, Liang W, Smalley S, Goetz LH. Does Modulation of an Epigenetic Clock Define a Geroprotector? Adv Geriatr Med Res. 2022;4(1):e220002. doi: 10.20900/agmr20220002. Epub 2022 Mar 29. — View Citation

Seligman BJ, Berry SD, Lipsitz LA, Travison TG, Kiel DP. Epigenetic Age Acceleration and Change in Frailty in MOBILIZE Boston. J Gerontol A Biol Sci Med Sci. 2022 Sep 1;77(9):1760-1765. doi: 10.1093/gerona/glac019. — View Citation

Vetter VM, Kalies CH, Sommerer Y, Spira D, Drewelies J, Regitz-Zagrosek V, Bertram L, Gerstorf D, Demuth I. Relationship Between 5 Epigenetic Clocks, Telomere Length, and Functional Capacity Assessed in Older Adults: Cross-Sectional and Longitudinal Analyses. J Gerontol A Biol Sci Med Sci. 2022 Sep 1;77(9):1724-1733. doi: 10.1093/gerona/glab381. — View Citation

Vlachogiannis NI, Baker KF, Georgiopoulos G, Lazaridis C, van der Loeff IS, Hanrath AT, Sopova K, Tual-Chalot S, Gatsiou A, Spyridopoulos I, Stamatelopoulos K, Duncan CJA, Stellos K. Clinical frailty, and not features of acute infection, is associated with late mortality in COVID-19: a retrospective cohort study. J Cachexia Sarcopenia Muscle. 2022 Jun;13(3):1502-1513. doi: 10.1002/jcsm.12966. Epub 2022 Mar 7. — View Citation

Wang J, Maxwell CA, Yu F. Biological Processes and Biomarkers Related to Frailty in Older Adults: A State-of-the-Science Literature Review. Biol Res Nurs. 2019 Jan;21(1):80-106. doi: 10.1177/1099800418798047. Epub 2018 Sep 9. — View Citation

Yoshikawa TT, Norman DC. Geriatric Infectious Diseases: Current Concepts on Diagnosis and Management. J Am Geriatr Soc. 2017 Mar;65(3):631-641. doi: 10.1111/jgs.14731. Epub 2017 Jan 31. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in frailty index from pre-admission to hospital discharge	Frailty will be valuated through the Frailty Index (i.e. score from 0 to 1, with higher values corresponding to higher frailty), considering clinical and functional data. Pre-admission frailty will be retrospectively assessed to reflect the participant's status in the two weeks prior to the hospital admission. Frailty assessment will be repeated within 48h before the hospital discharge.	From 14 days before admission to hospital discharge (up to 60 days)
Secondary	Change in Clinical Frailty Scale from pre-admission to hospital discharge	Frailty will be evaluated through the Clinical Frailty Scale (i.e. score from 1 to 9, with higher values corresponding to higher frailty). Pre-admission frailty will be retrospectively assessed to reflect the participant's status in the two weeks prior to the hospital admission. Frailty assessment will be repeated within 48h before the hospital discharge.	From 14 days before admission to hospital discharge (up to 60 days)
Secondary	Difference in in-hospital mortality between inpatients with vs without infections with systemic inflammation	All-cause mortality will be computed for participants with vs without infections associated with a systemic inflammatory response.	From 14 days before admission to hospital discharge (up to 60 days)
Secondary	Difference in the length of hospital stay between inpatients with vs without infections with systemic inflammation	The length of hospital stay (number of days from hospital admission to hospital discharge) will be computed for participants with vs without infections associated with a systemic inflammatory response.	From 14 days before admission to hospital discharge (up to 60 days)
Secondary	Difference in the global DNA methylation between individuals with stable vs worsened frailty during the hospital stay.	DNA extraction from whole blood will be performed by Automated Genomic DNA Purification EZ1 XL machine (QIAGEN). Global DNA methylation assessment will be performed by "highly quantitative pyrosequencing" technique as genome-wide DNA methylation levels and as gene promoter associated CpG islands utilizing selected age-related methylation marker loci and at LINE-1 repetitive elements (as a surrogate for genome-wide methylation). The patterns of global DNA methylation will be assessed in duplicate for each sample and expressed in percentage as the mean obtained by the two evaluations and considered valuable with a discrepancy <2%. Methylation percentages can be stratified into quartiles, and the middle two quartiles combined will be used as the reference category. The frequencies of individuals belonging to the highest and lowest DNA methylation quartiles will be compared between individuals reporting worsening in FI or CFS during the hospitalization vs those stable in frailty levels.	From 14 days before admission to hospital discharge (up to 60 days)
Secondary	Difference in telomere length between individuals with stable vs worsened frailty during the hospital stay	Telomere length will be compared between individuals with stable vs worsened frailty during the hospital stay. DNA extraction from whole blood will be performed by Automated Genomic DNA Purification EZ1 XL machine (QIAGEN). Leukocyte Telomere Length (LTL) will be assessed by quantitative PCR as previously described as predictors of biological age in frailty and mortality association studies. As a measure of the relative Telomere length, the ratio of the telomere repeat copy number to the number of single-copy gene ratio (T/S ratio) will be determined by quantitative PCR using the single-copy gene 36B4 for reference and a standard curve. Quality controls and assay validation tests will be assessed by official commercial recognized standards (Qiagen, LifeTechnology).	From 14 days before admission to hospital discharge (up to 60 days)
Secondary	Change in frailty index from hospital discharge to 3-month follow-up	Frailty will be valuated through the Frailty Index (i.e. score from 0 to 1, with higher values corresponding to higher frailty), considering clinical and functional data. Frailty assessment will be performed within 48h before the hospital discharge and after 3-month from the hospital discharge.	From hospital discharge until 3 months after hospital discharge (time frame: 3 months)
Secondary	Change in Clinical Frailty Scale from hospital discharge to 3-month follow-up	Frailty will be evaluated through the Clinical Frailty Scale (i.e. score from 1 to 9, with higher values corresponding to higher frailty). Frailty assessment will be performed within 48h before the hospital discharge and after 3-month from the hospital discharge.	From hospital discharge until 3 months after hospital discharge (time frame: 3 months)