Elderly long-term care residents (ELTCRs) face considerable burden of infection, especially evident during the COVID-19 pandemic. The nutritional status of the host can influence susceptibility to infection by altering immune system integrity, therefore, nutrition-based interventions may be a viable complement to existing infection prevention measures.
This scoping review sought to identify nutritional interventions and factors that have the strongest evidence to benefit ELTCRs, and thus best poised for rigorous clinical trial evaluation and subsequent implementation.
A database search of OVID-Medline, OVID-Embase, and Web of Science was performed from 2011 to 2021 to identify nutritional intervention studies which attribute to changes in infection in contemporary ELTCR settings. Articles were screened in duplicate and data extraction completed by a single reviewer, while a second reviewer verified the data which was fitted to identify evidence for nutritional interventions related to reducing rates of infection among ELTCRs.
The search identified 1018 studies, of which 11 (nine clinical trials and two observational cohort studies) satisfied screening criteria. Interventions that significantly reduced risk of infection included whey protein (any infection), Black Chokeberry (urinary tract infection), and vitamin D (acute respiratory tract infection, skin and soft tissue infection). Both zinc and a dedicated meal-plan significantly improved lymphocyte parameters. Vitamin D deficiency was associated with the development of respiratory tract infections. Probiotic and soy-based protein interventions did not significantly affect risk of infection or lymphocyte parameters, respectively.
The current scoping review was effective in identifying the use of nutrition-based interventions for infection prevention among ELTCRs. In this study, some nutrition-based interventions were observed to significantly influence the risk of infection among ELTCRs. Nutritional interventions such as vitamin D (preventing deficiency/insufficiency), Black Chokeberry juice, zinc gluconate, whey protein, and varied and nutrient dense meal plans may be suitable for future rigorous clinical trial evaluation.
Citation: Psihogios A, Madampage C, Faught BE (2022) Contemporary nutrition-based interventions to reduce risk of infection among elderly long-term care residents: A scoping review. PLoS ONE 17(8): e0272513. https://doi.org/10.1371/journal.pone.0272513
Editor: Md Nazmul Huda, Western Sydney University and University of New South Wales, AUSTRALIA
Received: January 7, 2022; Accepted: July 20, 2022; Published: August 2, 2022
Copyright: © 2022 Psihogios et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Elderly long-term care residents (ELTCRs) face a considerable burden of infection, including high rates of respiratory tract infections , urinary tract infections , sepsis , and more recently, a disproportionate vulnerability to severe manifestations of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [4–7]. Risk factors for infection among ELTCRs include the presence of numerous comorbidities, functional decline and/or disability, cognitive impairment, dental disease resulting in loss of teeth, use of medical devices to support health-related conditions, and malnutrition . While no internationally accepted standard diagnostic method for identifying malnutrition exists, the assessment often involves a multi-step approach involving different validated tools . Even though some variations exist, most malnutrition definitions and assessments include components of weight loss, BMI measures, and poor food intake . Relative to other risk factors, malnutrition is possibly a viable modifiable option for infection control among ELTCRs [11, 12], as nutritional status directly influences a host’s susceptibility to infection [13–15], and more importantly, can be altered through simple means (e.g., supplementation with vitamins, evaluation of dietary needs, and improving access to nutritional food).
Among ELTCRs, age-associated waning of systemic immunity (known as immunosenescense) may contribute towards increased risk and severity to infectious diseases . An optimally functioning immune system is dependent on both age and adequate and appropriate nutrition. The immune system may progress towards reducing host protection beginning at the sixth decade of life due to decreased microbial immunity, predisposition for atherosclerotic disease, osteoarthritis or many neurodegenerative diseases, and decreased responses to protect against malignancies and wound healing . To predict risk and severity to infectious diseases, the use of immune biomarkers is useful and will further provide opportunities for clinical intervention . Changes in T-cells have been associated with immune biomarkers such as reduction in the number of naïve T-cells, an increase in CD8+ memory T-cells subsets, and an increase in senescent cells (CD8+ CD28-) . Older adults may require additional nutrition due to energy demands, which are further increased during periods of infection necessary for robust immune responses . Nutrient-specific immune system functions have also been identified, such as the need for adequate vitamin A and zinc for effective proliferative immune responses , vitamin E for maintaining and enhancing natural killer (NK) cell cytotoxic activity , and the interaction between vitamin D and its receptors present on most immune cells that broadly effect both the innate and adaptive systems .
In practice, malnutrition, as determined by validated nutritional assessment tools, has been observed to increase the risk of serious infections (lower respiratory tract infection, healthcare-associated infections, and a weakened immune system) [20–22], urinary tract infections , and pneumonia  among malnourished ELTCRs compared to their counterparts who are adequately nourished. Furthermore, specific nutrient deficiencies have also been implicated with infection in this population. The deficiency of zinc is associated with both incidence and duration of pneumonia  and vitamin D deficiency with the risk of developing respiratory tract infections .
These observations are relevant to Canadian ELTCR cohorts, as nutrient intake deficits and/or malnutrition is reported to be widespread and persistent in long-term care facilities across the nation. A 2018 Canadian cross-sectional study conducted in thirty-two long-term care homes (n = 632 randomly selected residents) found that >50% of residents consumed inadequate amounts of vitamin D, E, K, B6, folate, calcium, and magnesium . Another publication by the same authors using the same patient cohort, found 44% of residents were also considered to be malnourished . A similar study in 2008, investigated inadequacies in nutrient intake among five elderly long-term care institutions in Saskatoon (n = 48). The study reported a substantial proportion of residents consumed inadequate folate, magnesium, zinc, vitamin C, E, B6, protein, and thiamine . Calcium, vitamin D, and dietary fibre were also substantially below the recommended intake . A Toronto based cross-sectional study of 11 long-term care facilities (n = 407 residents) found that 30% of residents had low protein intake, >50% had suboptimal calcium, magnesium, zinc, vitamin E, B6, and folate intake, and 15% missed vitamin C, niacin and copper targets . Finally, a small pilot study from Western Canada, assessing the overall nutritional status of veterans living in long-term care facilities (n = 55 residents), found that 58% were considered at risk for malnutrition, while 31% were already malnourished .
To our knowledge, no scoping review encompassing evidence for nutritional interventions in the realm of reducing rates of infection among ELTCRs has been published. A scoping review would facilitate the delineation of data on the effects of nutrition-based interventions to reduce the risk of infection among ELTCRs and facilitate in identifying areas of research to inform future experimental studies and pragmatic approaches to reduce the burden of infection in long-term care facilities. This present scoping review, through a detailed and structured literature search of peer reviewed articles, will attempt to describe the current evidence for the use of nutrition-based interventions to address infections in ELTCRs. The present scoping review is used to identify nutritional interventions and factors that have the strongest evidence to benefit this cohort, and thus, are best suited for rigorous clinical trial evaluation and subsequent implementation.
Objectives of this study
- To methodically map the extent, range, and nature of published, peer-reviewed, research related to nutrition-based interventions to reduce the risk of infection among ELTCRs [32, 33].
- To identify nutrition-based interventions that have demonstrated the capacity to significantly reduce the risk of infection and/or improve clinically relevant immune system parameters (e.g., lymphocyte count) among ELTCRs, which may be suitable for future rigorous clinical trial evaluation.
- To identify nutrition related parameters, evaluated in prospective cohort studies, demonstrating an association between undernutrition and/or nutrient deficiencies, and the risk of infection among ELTCRs.
Materials and methods
The process of a scoping review facilitates identifying existing peer-reviewed literature that provides information that has not been comprehensively reviewed or is complex and diverse in nature . A scoping review of recent academic literature on the current evidence of nutrition-based interventions to address infections in ELTCRs was conducted. Institutional research ethics approval was not required from Brock University as data was obtained from published literature in the public domain. This study was not registered with International Prospective Register of Systematic Reviews (PROSPERO: https://www.crd.york.ac.uk/prospero/) as it is not a systematic review.
The scoping review was conducted using a structured approach presented and informed using guidelines for a preferred reporting of items for systematic reviews and meta-analyses (PRISMA) extension for Scoping Reviews (PRSIMA-ScR) as shown in (S1 Table) . A standard approach was applied to map the literature landscape related to the select topic through a process of: (i) identifying relevant studies; (ii) selection of studies; (iii) data extraction; and (iv) summarisation of results [33, 35].
Studies meeting the following inclusion criteria were included.
- Published between 2011–2021.
- Full-text accessible for review.
- Published in English (to meet the language capabilities of all investigators).
- Peer-reviewed published literature.
- Either experimental/interventional (single-arm trial, randomized controlled trial (RCT), phase I-II clinical trials) or longitudinal epidemiologic study.
- Included a primary intervention that was nutrition based (including dietary supplements, meal plans, special foods, eating schedules, fortified drinks, etc.) or a mixed intervention that included nutritional reporting.
- At least one outcome or measure was infection related, including risk of infection (any type of infection), immune system parameters [T-cell (a type of immune cell), natural killer (NK) cells, etc.], the need for antibiotic use for present infection or other opportunistic infections, length of hospital stay due to infection, other complications due to infection, recovery, and response to vaccination.
- Participants were elderly (≥ 65 years of age). Studies with mixed aged groups were allowed, if the majority (>50%) were ≥ 65 years. The cut off for age (≥ 65 years) was based on the conventional definition of an ‘elderly’ individual to be defined as a chronological age of 65 years .
- Participants resided in any type of long-term care facility, such as nursing homes, throughout the intervention period.
Studies which met the following exclusion criteria were excluded.
- The absence of a peer-review process.
- Unpublished results or literature.
- The following study designs: non-longitudinal observational studies, case reports, review, animal/pre-clinical/in vitro studies, conference abstracts/presentations/posters, editorials, and opinions.
- Did not include nutritional related primary intervention/s.
- Included participants that were primarily of community dwelling, hospitalised, with an acute care setting, in transitional centres, and/or were not within the guidelines of living in long-term care facility.
- Did not include outcome(s) or measure(s) related to infection.
Sources of information
Three databases were searched for published, peer-reviewed, literature, including Web of Science (Core Collection) on May 31st, 2021, and both Ovid-Medline and Ovid-Embase on June 7th, 2021. Grey literature was not included as the intention of this scoping review was to specifically identify possible nutrition-based intervention candidates that can be evaluated and tested in future rigorous clinical trials. Thus, a peer-reviewed process for publication was essential and hence required. The primary reason for choosing 10 years (2011 to 2021) for all three databases was to ensure the collection would most closely reflect contemporary ELTCRs in the population, and thus would be most applicable and relevant to modern and future real-world cohorts. Nevertheless, an initial search with a 20 to 25-year time span (2001–2021 & 1996–2021) with the above-mentioned inclusion and exclusion criteria was implemented. This increased time frame included a very large number of citations. Following removal of duplicates, the remaining studies were not appropriate for nutrition-based interventions. Therefore, the rationale for a 10-year time span was adopted to reflect contemporary nutrition-based interventions among this cohort. Further, there is evidence of updates and revised guidelines pertaining to infection control for long-term and health care institutions in Canada [37–41], and internationally [42–44], that have occurred within the past 10 years, indicating an evolving approach. Thus, we included studies that would be most applicable for a contemporary setting.
Database search terms
Search terms and filters with punctuation and conventions were used to provide a comprehensive landscape of all literature. The use of an asterisk (*) broadened a search by identifying words that begin with the same letters, while the use of combinations of free text keywords, acknowledged as many appropriate records as possible within a search, compared to a single keyword. Conventions such as: (i) exp = “explodes”, controlled vocabulary terms used to expand a search related to specific terms within the vocabulary hierarchy, and (ii) mp. = combined search fields, were incorporated when searching key words in OVID (online bibliographic databases) syntax . The use of three Boolean operators (“AND”, “OR”, and “NOT”) provided a process to combine, narrow down (concentrate), refine, broaden or exclude keywords within the database search. In another vein, Boolean operator “OR” was used in parallel as a filter for key terms searched with the convention of medical subject heading (MeSH) . Finally, after all key search terms were incorporated, Boolean operator “AND” was used to combine these sets . All three databases were searched using search terms: “long-term care resident*”, “nursing care home*”, “nursing home*”, “home for the age*”, “elder*”, “old people*”, “age*”, “infect*”, “sick*”, “ill*”, “clinical nutrition”, “nutrition”, “dietary supplement*”, “vitamin*”, “mineral*”, “nourishment”, “diet*”, “meal*”, and “supplementation”. MeSH terms were then searched, with relevance to both Ovid-Medline and Ovid-Embase databases (Web of Science does not support the use of MeSH terms), including “long-term care”, “aged”, “home(s) for the aged”, “infection”, and “nutrition”. The unique MeSH term “nutrition therapy” was accessible and applied in Ovid-Medline while “geriatric nutrition” was available and applied in Ovid-Embase. All three databases facilitated filters to be applied regarding human population studies.
Selection process and filtering data
The collection of retrieved articles from each individual database were exported to Zotero and duplicate results were removed using appropriate software functions. All deduped records were then uploaded to Rayyan, a free online web based tool used for screening articles encompassing systematic reviews, scoping reviews or environmental scans . All titles, abstracts, and subsequently full texts were reviewed and screened for inclusion and exclusion criteria by the primary investigator (AP) and verified by a second co-investigator (CM). The final list of included studies was reviewed through chain searching to identify additional eligible studies not captured in the original database search. Chain searching, also known as backward reference searching, provides a process to examine studies stated within an article and reference it if applicable .
Once all eligible full text publications were identified, data extraction was performed by the primary investigator (AP) and verified by a second co-investigator (CM) to identify and organise evidence for nutritional interventions related to reducing rates of infection among ELTCRs. A data extraction form was created with the following variables [identified from each study include]: year of publication; study design; data collection period; sample size and characteristics; type of long-term care institution; country of origin; nutrition components details; infection related outcomes; infection related results; study limitations and strengths; and keywords related to the publication.
An annotated bibliography was developed (S1 File) with the following criteria applied to the 11 articles included in this scoping review: summary of source (author, purpose, relevance to our topic, accuracy); the strengths and limitations of the study; affiliation to the purpose of our work and study conclusion(s). The annotated bibliography is intended to provide a brief description or an evaluative paragraph about each article used for data extraction. No formal critical appraisal was conducted as it is beyond the scope of this type of work (a non-systematic, scoping review).
Results from database search
Database searches of Ovid-Medline, Ovid-Embase, and Web of Science identified 1018 articles (after de-duplication). Following inter-database de-duplication (n = 36 articles removed), 982 records were screened by title and abstract for inclusion, resulting in 952 articles being excluded. The remaining 30 records were screened via full text, resulting in 19 exclusions, yielding 11 articles for data extraction. Chain searching of the 30 articles recognized for full text review resulted in no additional eligible studies being identified. Detailed depiction of study identification, screening, eligibility assessment, and inclusion is presented as a PRISMA flow chart (Fig 1).
Characteristics of included studies
All 11 articles selected for data extraction were conducted in high income countries with ten having membership with the organisation for economic co-operation and development (OECD) and one a non-OECD member. Nine of the identified studies were experimental [49–57] and two observational [26, 58] (Table 1). Of the nine experimental, four were randomized, double-blind, placebo controlled clinical trials [50, 51, 54, 55], one was a randomized, double-blind, controlled clinical trial without placebo , one was a randomized, un-blinded, controlled clinical trial , one was a group-randomized, double-blind, placebo controlled, crossover clinical trial , one was a pragmatic participatory evaluation trial , and one was an uncontrolled, pre-post, single-arm clinical trial . Both observational studies applied a prospective cohort design [26, 58]. All study settings were in nursing homes, except for one that recruited residents from long-term care facilities with a mix of skilled nursing homes and assisted living facilities . Intervention administered in the experimental studies included probiotics (n = 3) [49–51], a protein-based product (n = 2) [52, 56], Black Chokeberry (Aronia melanocarpa) juice (n = 1) , dedicated, needs-specific, meal plan (n = 1) , high dose vitamin D (n = 1) , and zinc gluconate n = 1) .
Observed effects of nutritional interventions on risks for infection among ELTCRs
As described in Table 2, some nutrition-based interventions were observed and significantly influenced the risk of infection among ELTCRs, while others failed to do so.
None of the three probiotic-based experimental studies reported a significant benefit of supplementation for any infection related outcome [49–51]. A five-gram multi-strain probiotic (1010 colony forming unit, CFU) product, delivered two times a day, beginning at the onset of antibiotic therapy until one-week post completion, did not reduce the frequency of antibiotic usage/prescriptions throughout the follow-up period .
Compared to placebo, two bottles a day, for 176 days, of a fermented milk product containing Lactobacillus casei Shirota (6.5 x 109 CFU) did not significantly reduce the number of days with respiratory infection symptoms (p = 0. 342), nor the number of participants presenting with respiratory symptoms (p = 0.325), based on univariate analysis . Multiple logistic regression analysis revealed that Lactobacillus casei Shirota did not significantly alter the risk of developing a severe respiratory tract infection, compared to placebo (OR: 0.592; 95% CI: 0.335–1.049) (p = 0.073) . Further, probiotic supplementation did not significantly influence the rates of seroconversion or seroprotection between groups in this cohort who received influenza vaccination at 21 days post-intervention initiation .
Six months of supplementation with two capsules a day of Lactobacillus rhamnosus GG (10 billion CFU/capsule) did not significantly reduce the risk of developing a viral respiratory infection (PCR-confirmed), compared to placebo (HR: 0.65; 95% CI: 0.32–1.31) . There were no significant group differences for any of the secondary outcomes, including influenza-like illness, antimicrobial prescriptions, physician visits for respiratory illness, hospitalization for lower respiratory infections or pneumonia, rate of lower respiratory infections, or pneumonia .
In another vein, while it did not significantly affect an infection related outcome, supplementation with a multi-strain probiotic significantly reduced the number of antibiotic-associated diarrhea episodes (p = 0.022), possibly signalling an option to improve treatment tolerance and compliance .
Twenty grams of whey protein, dissolved in 4.5 deciliter (dL) of juice, consumed in three equal portions a day for 6 months, did not significantly reduce risk of urinary tract infections, compared to control (juice alone) (p = 0.053) . Over a 6 month follow-up, residents in the intervention arm experienced significantly fewer infections overall (not specified), compared to control (p = 0.009) .
At risk residents (BMI ≤ 24 kg/m2 & MNA score ≤ 24) consuming a warm soy drink product (9.5g protein, 250 kcal) once a day, over a 24-week period, did not significantly improve lymphocyte counts, compared to control (p>0.05) .
Black Chokeberry (Aronia melanocarpa).
One intervention trial, with crossover, providing residents with a Black Chokeberry product reported mixed results for different infection related outcomes . Depending on the period of crossover, residents consumed either 300 ml of placebo or Black Chokeberry juice, once a day, for 3 months. Compared to the previous period, Black Chokeberry juice did not significantly alter the frequency of urinary tract infections, or any other infection (p>0.05) . The number of urinary tract infections occurring over the three months following Black Chokeberry juice supplementation significantly decreased (p<0.05). However, no other infection rates were altered (p>0.05) .
Dedicated, needs-specific, meal plan.
One single-arm, pre-post, clinical trial providing dysphagic (difficulty in swallowing) residents with a needs-specific meal plan, which was comprised of food options that included recommended amounts of protein, were textured, more nutrient dense, and varied compared to standard meals, reported positive results . At the end of the 6-month intervention, compared to baseline values, 98.23% of residents achieved normal plasma lymphocyte values, with counts significantly benefiting from the meal plan [analysis of variance test for blood lymphocyte count changes over 12 months: F = 215.39, p<0.001] (Z-score = 19.63, p<0.001) .
One intervention trial supplemented residents with a monthly high dose of vitamin D3 for 12 consecutive months, reporting overall positive results for most infection related outcomes . Residents in the intervention arm received 100,000 international units (IU) of vitamin D3/month, whereas those in the control either received a placebo (if they were already supplementing with 400–1000 IU) or 12,000 IU vitamin D3/month if they were supplementing with <400 IU/day vitamin D. Throughout the study period, at all assessed time points, blood levels of vitamin D were significantly higher in the intervention group compared to control (p<0.001) . The incidence of acute respiratory infections was significantly lower in the intervention arm compared to control (IRR: 0.60; 95% CI: 0.38–0.94, p = 0.02). However, the number of residents having at least one case did not significantly differ between groups (31% vs 46%, respectively) (p = 0.10) . Compared to control, the incidence of specifically upper acute respiratory infection was significantly lower in the intervention arm (IRR: 0.53; 95% CI: 0.31–0.90, p = 0.02), with similar benefits observed for skin and soft tissue infections (IRR: 0.32; 95% CI: 0.13–0.80, p = 0.02) . The incidence of urinary tract infection or any other infection, and hospitalizations for acute respiratory infections, did not differ between groups (p>0.05) .
One small intervention trial, involving residents with low baseline serum zinc concentrations, reported mixed results of zinc gluconate supplementation effects on immunity . Three months of supplementation with a multivitamin (providing ~50% of dietary reference intakes of essential vitamins and minerals) containing 30 mg of zinc gluconate significantly increased T-cell counts (p = 0.03) and improved lymphocyte proliferation (p = 0.02), compared to control (multivitamin with 5 mg of zinc) . Notably, while the mean change in serum zinc levels were significantly higher in the intervention arm (p = 0.007), at the end of the study period, 42% residents still did not reach adequate concentrations.
Association between nutritional deficits/malnutrition and risk of infection
Two observational, prospective cohort, studies were identified; one investigating the association between vitamin D deficiency and the risk of respiratory tract infections, hospitalizations, and any type of infection . The other, focusing on the association between different nutritional assessment tools and development of any type of infection .
The prevalence of vitamin D deficiency was observed to be significantly higher in residents experiencing respiratory tract infections than those with no deficiency . A Kaplan-Meier curve calculation (probability over a period of time of surviving often including a parameter of interest, while accounting for participants departing)  demonstrated that the rate of respiratory tract infection-free survival was significantly lower among those with severe vitamin D deficiency (<10ng/mL) (p<0.001) . Cox proportional hazard analysis indicated that vitamin D deficiency was a significant predictor of developing a respiratory tract infection [HR: 6.755 (95% CI: 3.693–12.358) (p<0.001)] .
Nutritional assessment tools.
Neither the mini-nutritional assessment (MNA) tool, Nutritional Risk Screening 2002 (NRS) tool, or the Malnutrition Universal Screening Tool (MUST) at either the 6-month or 12-month time point was predictive of infection .
In this scoping review, the described literature landscape included interventions that significantly reduced the risk of infection, encompassing whey protein (any infection) , Black Chokeberry (urinary tract infection) , and vitamin D (acute respiratory tract infection, skin infection, and soft tissue infection) . Both zinc and a dedicated meal-plan significantly improved lymphocyte parameters [55, 57]. Vitamin D deficiency was associated with the risk of developing respiratory tract infections .
Vitamin D is a well-documented modulator of both the innate and adaptive immune system with notable influence on antimicrobial peptide production, inflammatory cascade regulation, gene expression, and T-cell activity . Clinically, vitamin D status is associated with the risk of developing infections, such as SARS-CoV-2 , acute respiratory tract infections [63, 64], urinary tract infections , and tuberculosis . In this scoping review, a high dose (100,000 IU/month) of vitamin D3 supplementation within an elderly long-term care setting reduced the risk of developing both general and upper acute respiratory tract infections, as well as skin and soft tissue infections . This dose translates to between 3226 and 3571 IU/day. While a culture of caution exists within the medical community for the use of large bolus doses of vitamin D causing hypervitaminosis toxicity, the totality of evidence indicates that interventions similar to that identified in this review  may be well tolerated [67–70]. This review further identified that the lack of correction of suboptimal vitamin D levels can result in a substantially higher respiratory infection burden among ELTCRs .
Dietary protein supplies necessary organic compounds, termed amino acids , which support vital components of the immune system, including T-cell and B-cell activation, lymphocyte proliferation, gene expression, and antibody production . Protein-malnutrition among ELTCRs is common in Canada [29, 30]. As described by Björkman and colleagues, a supplement of twenty grams of whey protein per day reduced the risk of developing any infection among ELTCRs . The use of whey protein provides a rich source of amino acids involved in immune system activity . Thus, supplementation may be a viable dietary-based addition to infection prevention.
Black Chokeberry (Aronia melanocarpa) fruit is a rich source of bioactive phytochemicals, including anthocyanins, proanthocyanidins, flavonols, flavanols, and phenolic acids . With a similar chemical profile as cranberry, which has been observed to reduce the risk of urinary tract infections [75, 76], our scoping review reports that Black Chokeberry juice reduced the risk of developing a urinary tract infection for up to three months post-intervention .
Lymphocytes, which include T-cells, B-cells, and natural killer cells are involved in essential immune system functions, such as antibody production, cell-mediated (direct) killing of virus-infected cells, and regulating immune responses . Lymphopenia has been associated with an increased risk of infection-related hospitalizations and infection-related mortality for the general population , and more recently, associated with inferior outcomes among the elderly infected with SARS-CoV-2 . Zinc, a trace mineral crucial for a normal functioning immune system , was identified in our scoping review as a possible intervention to increase both T-cell counts and lymphocyte proliferation . So far, the majority of research with reference to zinc supplementation and infection prevention has been focused on children [81–83]. However, this review identified a possible new target population at the opposing end of the age spectrum. A meal plan facilitating consumption of a variety of textured, nutrient dense, foods also increased lymphocyte counts for dysphagic ELTCRs .
In relation to this current scoping review, age-related changes in the human body are associated with a decline in immune system functions, which affect both innate and adaptive immunity and the provision of nutritional interventions may help prevent infectious sequelae . Diet is considered a major influence in the management to prevent the onset of infections . Nutrient deficiencies may cause the immune system to decrease in defences against invading pathogens, as well as increase susceptibility to infection . These deficiencies can be corrected through diets rich in, or supplements containing, essential vitamins and minerals. Infectious agents such as viruses, bacteria, protozoa and parasitic worms can interfere with factors, such as the availability of nutrients on specific components of the immune system related to the host nutritional state, further increasing susceptibility to infection [87, 88]. An example demonstrating the intricate relationship between the immune system and nutrition is exemplified by a component of the intestinal immune system known as the gut-associated lymphoid tissue (GALT) . The GALT becomes impaired in the absence of adequate nutrition which in order to optimally prevent invasion of pathogens requires amino acids, glutamine, arginine; nucleotides; omega-3 fatty acids; and dietary fiber [88, 89]. Furthermore, the process of aging is related to changes in the composite of the gut microbiota that may increase infection among the elderly population . Another example that affects the elderly population is seasonal influenza. Older adults with chronic medical conditions and /or immunological disorders are at greater risk for influenza infection . Vitamin D has been observed to augment cytokine production and lymphocyte proliferation, improve pathogen clearance and possibly improve mucosal and systemic antibody responses when co-administered with influenza vaccine . Thus, maintaining vitamin D levels among the elderly population through diet and supplements may decrease susceptibility to seasonal influenza . In addition to the provision of a balanced diet, vitamins and minerals, other positive lifestyle factors, such as regular low intensity exercise and a routine with adequate hours of sleep will influence the immune system towards infection prevention while promoting health and wellness among an elderly population [92, 93].
Although effective in many ways it is noteworthy that the following limitations were encountered in this scoping review. The protocol used for this scoping review was not registered with PROSPERO and the study included only peer reviewed published articles, while grey literature was not included within the area of interest. This approach was taken to minimize articles which are not a product of peer-review processes. Additionally, the other challenge with grey literature is that many resources may not be retained on an online platform to facilitate searchable solutions. The exclusion of non-longitudinal studies such as cross-sectional studies were a result of the impact of time required for the effectiveness of the nutrition-based intervention or supplement. Our scoping research review describes an elderly cohort living in long-term care facilities that undergo surveillance over time to document the incidence of an outcome (a reduction in infection) among exposed (nutrition-based intervention) and non-exposed participants. The temporality of a prospective or longitudinal study affords the cohort exposure time (nutritional intervention) with each participant observed repeatedly. We believe the time factor in such longitudinal designs is appropriate for this research work as it affords an explanation of causality. Case reports were excluded as they did not fit the designation of a trial as well ranking of validity is lower compared to experimental or prospective cohort studies. This scoping review only included recent studies published within the past 10 years. While this increases the relevance and applicability to modern cohorts, it does not exhaustively describe the overarching research landscape for this topic beyond this time frame.
Review of the current literature was effective in identifying the use of nutrition-based interventions for infection prevention among ELTCRs. In this scoping review, some nutrition-based interventions were observed and significantly influenced the risk of infection among ELTCRs. The nutritional interventions best poised for immediate rigorous clinical trial evaluation and subsequent implementation for ELTCRs are vitamin D (preventing deficiency/insufficiency), Black Chokeberry juice, zinc gluconate, whey protein, and varied and nutrient dense meal plans. Probiotics are unlikely to be of much value for infection prevention/control in this specific at-risk population. Overall, there is minimal research for nutrition-based interventions for infection prevention among ELTCRs, warranting more intervention studies, beginning with the ones identified in this review.
Brock University acknowledges the land on which we gather is the traditional territory of the Haudenosaunee and Anishinaabe peoples, many of whom continue to live and work here today. This territory is covered by the Upper Canada Treaties and is within the land protected by the Dish with One Spoon Wampum Agreement. Today this gathering place is home to many First Nations, Métis and Inuit peoples and acknowledging reminds us that our great standard of living is directly related to the resources and friendship of Indigenous people.
We also take this opportunity to thank Chelsea Humphries from the James A. Gibson Library for their assistance.
- 1. Childs A, Zullo AR, Joyce NR, et al. The burden of respiratory infections among older adults in long-term care: a systematic review. BMC Geriatr. 2019;19(1):210. pmid:31382895
- 2. Genao L, Buhr GT. Urinary Tract Infections in Older Adults Residing in Long-Term Care Facilities. Ann Longterm Care. 2012;20(4):33–38. pmid:23418402
- 3. Yoshikawa TT, Reyes BJ, Ouslander JG. Sepsis in Older Adults in Long-Term Care Facilities: Challenges in Diagnosis and Management. J Am Geriatr Soc. 2019;67(11):2234–2239. pmid:31617944
- 4. Team EPHE, Danis K, Fonteneau L, et al. High impact of COVID-19 in long-term care facilities, suggestion for monitoring in the EU/EEA, May 2020. Euro Surveill. 2020;25(22). pmid:32524949
- 5. Fisman DN, Bogoch I, Lapointe-Shaw L, McCready J, Tuite AR. Risk Factors Associated With Mortality Among Residents With Coronavirus Disease 2019 (COVID-19) in Long-term Care Facilities in Ontario, Canada. JAMA Netw Open. 2020;3(7):e2015957. pmid:32697325
- 6. Webster P. COVID-19 highlights Canada’s care home crisis. Lancet. 2021;397(10270):183. pmid:33453769
- 7. Hashan MR, Smoll N, King C, et al. Epidemiology and clinical features of COVID-19 outbreaks in aged care facilities: A systematic review and meta-analysis. EClinicalMedicine. 2021;33:100771. pmid:33681730
- 8. Juthani-Mehta M, Quagliarello VJ. Infectious diseases in the nursing home setting: challenges and opportunities for clinical investigation. Clin Infect Dis. 2010;51(8):931–936. pmid:20822459
- 9. Sanchez-Rodriguez D, Annweiler C, Ronquillo-Moreno N, et al. Clinical application of the basic definition of malnutrition proposed by the European Society for Clinical Nutrition and Metabolism (ESPEN): Comparison with classical tools in geriatric care. Arch Gerontol Geriatr. 2018;76:210–214. pmid:29558713
- 10. Bell CL, Lee AS, Tamura BK. Malnutrition in the nursing home. Curr Opin Clin Nutr Metab Care. 2015;18(1):17–23. pmid:25394167
- 11. Richardson DP, Lovegrove JA. Nutritional status of micronutrients as a possible and modifiable risk factor for COVID-19: a UK perspective. Br J Nutr. 2021;125(6):678–684. pmid:32815493
- 12. Bencivenga L, Rengo G, Varricchi G. Elderly at time of COronaVIrus disease 2019 (COVID-19): possible role of immunosenescence and malnutrition. Geroscience. 2020;42(4):1089–1092. pmid:32578073
- 13. van Seventer JM, Hochberg NS. Principles of Infectious Diseases: Transmission, Diagnosis, Prevention, and Control. In: Quah SR, ed. International Encyclopedia of Public Health (Second Edition). Oxford: Academic Press; 2017:22–39.
- 14. Childs CE, Calder PC, Miles EA. Diet and Immune Function. Nutrients. 2019;11(8). pmid:31426423
- 15. Wu D, Lewis ED, Pae M, Meydani SN. Nutritional Modulation of Immune Function: Analysis of Evidence, Mechanisms, and Clinical Relevance. Front Immunol. 2018;9:3160. pmid:30697214
- 16. Derhovanessian E, Larbi A, Pawelec G. Biomarkers of human immunosenescence: impact of Cytomegalovirus infection. Curr Opin Immunol. 2009;21(4):440–445. pmid:19535233
- 17. Weyand CM, Goronzy JJ. Aging of the Immune System. Mechanisms and Therapeutic Targets. Ann Am Thorac Soc. 2016;13 Suppl 5:S422–S428. pmid:28005419
- 18. Johnstone J, Millar J, Lelic A, et al. Immunosenescence in the nursing home elderly. BMC Geriatr. 2014;14:50. pmid:24742120
- 19. Gombart AF, Pierre A, Maggini S. A Review of Micronutrients and the Immune System-Working in Harmony to Reduce the Risk of Infection. Nutrients. 2020;12(1).
- 20. Kuikka LK, Salminen S, Ouwehand A, et al. Inflammation markers and malnutrition as risk factors for infections and impaired health-related quality of life among older nursing home residents. J Am Med Dir Assoc. 2009;10(5):348–353. pmid:19497548
- 21. Serra-Prat M, Palomera M, Gomez C, et al. Oropharyngeal dysphagia as a risk factor for malnutrition and lower respiratory tract infection in independently living older persons: a population-based prospective study. Age Ageing. 2012;41(3):376–381. pmid:22311895
- 22. Norman K, Hass U, Pirlich M. Malnutrition in Older Adults-Recent Advances and Remaining Challenges. Nutrients. 2021;13(8). pmid:34444924
- 23. Carlsson M, Haglin L, Rosendahl E, Gustafson Y. Poor nutritional status is associated with urinary tract infection among older people living in residential care facilities. J Nutr Health Aging. 2013;17(2):186–191. pmid:23364500
- 24. Mitani Y, Oki Y, Fujimoto Y, et al. Relationship between functional independence measure and geriatric nutritional risk index in pneumonia patients in long-term nursing care facilities. Geriatr Gerontol Int. 2017;17(10):1617–1622. pmid:28188968
- 25. Meydani SN, Barnett JB, Dallal GE, et al. Serum zinc and pneumonia in nursing home elderly. Am J Clin Nutr. 2007;86(4):1167–1173. pmid:17921398
- 26. Kuwabara A, Tsugawa N, Ao M, Ohta J, Tanaka K. Vitamin D deficiency as the risk of respiratory tract infections in the institutionalized elderly: A prospective 1-year cohort study. Clin Nutr ESPEN. 2020;40:309–313. pmid:33183555
- 27. Keller HH, Lengyel C, Carrier N, et al. Prevalence of inadequate micronutrient intakes of Canadian long-term care residents. Br J Nutr. 2018;119(9):1047–1056. pmid:29444716
- 28. Keller HH, Carrier N, Slaughter SE, et al. Prevalence and Determinants of Poor Food Intake of Residents Living in Long-Term Care. J Am Med Dir Assoc. 2017;18(11):941–947. pmid:28668663
- 29. Lengyel CO, Whiting SJ, Zello GA. Nutrient inadequacies among elderly residents of long-term care facilities. Can J Diet Pract Res. 2008;69(2):82–88. pmid:18538061
- 30. Aghdassi E, McArthur M, Liu B, McGeer A, Simor A, Allard JP. Dietary intake of elderly living in Toronto long-term care facilities: comparison to the dietary reference intake. Rejuvenation Res. 2007;10(3):301–309. pmid:17559335
- 31. Bostrom AM, Van Soest D, Kolewaski B, Milke DL, Estabrooks CA. Nutrition status among residents living in a veterans’ long-term care facility in Western Canada: a pilot study. J Am Med Dir Assoc. 2011;12(3):217–225. pmid:21333925
- 32. Tricco AC, Lillie E, Zarin W, et al. PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. Ann Intern Med. 2018;169(7):467–473. pmid:30178033
- 33. Arksey H, O’Malley L. Scoping studies: towards a methodological framework. International Journal of Social Research Methodology. 2005;8(1):19–32.
- 34. Sucharew H, Macaluso M. Progress Notes: Methods for Research Evidence Synthesis: The Scoping Review Approach. J Hosp Med. 2019;14(7):416–418. pmid:31251164
- 35. Levac D, Colquhoun H, O’Brien KK. Scoping studies: advancing the methodology. Implement Sci. 2010;5:69. pmid:20854677
- 36. Orimo H. [Reviewing the definition of elderly]. Nihon Ronen Igakkai Zasshi. 2006;43(1):27–34. pmid:16521795
- 37. Canada PHAo. Routine Practices and Additional Precautions for Preventing the Transmission of Infection in Healthcare Settings. https://www.canada.ca/content/dam/phac-aspc/documents/services/publications/diseases-conditions/routine-practices-precautions-healthcare-associated-infections/routine-practices-precautions-healthcare-associated-infections-2016-FINAL-eng.pdf. Published 2016. Updated November 2016. Accessed December 9th 2021, 2021.
- 38. PIDAC. Best Practices for Prevention, Surveillance and Infection Control Management of Novel Respiratory Infections in All Health Care Settings Public Health Ontario. https://www.publichealthontario.ca/-/media/documents/b/2020/bp-novel-respiratory-infections.pdf. Published 2020. Updated February 2020. Accessed December 9th 2021, 2021.
- 39. MinistryOfHealthAndLong-TermCare. Control of Respiratory Infection Outbreaks in Long-Term Care Homes, 2018 https://www.health.gov.on.ca/en/pro/programs/publichealth/oph_standards/docs/reference/resp_infectn_ctrl_guide_ltc_2018_en.pdf. Published 2018. Updated November 2018. Accessed December 9th 2021, 2021.
- 40. YorkRegionPublicHealth. INFECTION PREVENTION & CONTROL RESOURCES FOR YORK REGION LONG-TERM CARE HOMES. https://www.york.ca/wps/wcm/connect/yorkpublic/eb0f111c-13cd-405b-8740-ba7e71a6458e/IPAC+Resources+for+LTC+Homes.pdf?MOD=AJPERES&CACHEID=ROOTWORKSPACE.Z18_29D41BG0PGOC70QQGGJK4I0004-eb0f111c-13cd-405b-8740-ba7e71a6458e-mLV-4uu. Published 2019. Updated January 2019. Accessed December 9th 2021, 2021.
- 41. PIDACPublicHealthOntario. Best Practices for Infection Prevention and Control Programs in Ontario. https://www.publichealthontario.ca/-/media/documents/B/2012/bp-ipac-hc-settings.pdf. Published 2012. Updated May 2012. Accessed December 9th 2021, 2021.
- 42. Policies APOoHSa. Japan Health Review. https://apps.who.int/iris/bitstream/handle/10665/259941/9789290226260-eng.pdf. Published 2018. Accessed December 9th 2021, 2021.
- 43. NHS. Infection Prevention and Control Policies and Procedures. https://www.candi.nhs.uk/sites/default/files/Infection%20Prevention%20and%20Control_Policy%20and%20Procedures_CL05_Jan%202018.pdf. Published 2018. Updated January 2018. Accessed December 9th 2021, 2021.
- 44. WorldHealthOrganization. Prevention and control of outbreaks of seasonal influenza in long-term care facilities: a review of the evidence and best-practice guidance. https://www.euro.who.int/__data/assets/pdf_file/0015/330225/LTCF-best-practice-guidance.pdf. Published 2017. Updated January 2017. Accessed December 9th 2021, 2021.
- 45. Tipton KN, Sullivan N, Bruening W, et al. In: Stereotactic Body Radiation Therapy. Rockville (MD)2011.
- 46. Uo Tasmania. Systematic Reviews for Health: 7. Boolean Operators. https://utas.libguides.com/SystematicReviews/Boolean. Published July 8 2021. Accessed July 26 2021.
- 47. Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan-a web and mobile app for systematic reviews. Syst Rev. 2016;5(1):210. pmid:27919275
- 48. Libraries FAU. Guide to Science Information Resources: Backward & Forward Reference Searching. https://libguides.fau.edu/science_resources/reference_searching. Accessed July 26 2021.
- 49. van Wietmarschen HA, Busch M, van Oostveen A, Pot G, Jong MC. Probiotics use for antibiotic-associated diarrhea: a pragmatic participatory evaluation in nursing homes. BMC gastroenterology. 2020;20(1):151. pmid:32404062
- 50. Van Puyenbroeck K, Hens N, Coenen S, et al. Efficacy of daily intake of Lactobacillus casei Shirota on respiratory symptoms and influenza vaccination immune response: a randomized, double-blind, placebo-controlled trial in healthy elderly nursing home residents. Am J Clin Nutr. 2012;95(5):1165–1171. pmid:22440853
- 51. Wang B, Hylwka T, Smieja M, Surrette M, Bowdish DME, Loeb M. Probiotics to Prevent Respiratory Infections in Nursing Homes: A Pilot Randomized Controlled Trial. Journal of the American Geriatrics Society. 2018;66(7):1346–1352. pmid:29741754
- 52. Björkman MP, Finne-Soveri H, Tilvis RS. Whey protein supplementation in nursing home residents. A randomized controlled trial. European Geriatric Medicine. 2012;3(3):161–166.
- 53. Handeland M, Grude N, Torp T, Slimestad R. Black chokeberry juice (Aronia melanocarpa) reduces incidences of urinary tract infection among nursing home residents in the long term—a pilot study. Nutrition research (New York, NY). 2014;34(6):518–525.
- 54. Ginde AA, Blatchford P, Breese K, et al. High-Dose Monthly Vitamin D for Prevention of Acute Respiratory Infection in Older Long-Term Care Residents: A Randomized Clinical Trial. J Am Geriatr Soc. 2017;65(3):496–503. pmid:27861708
- 55. Barnett JB, Dao MC, Hamer DH, et al. Effect of zinc supplementation on serum zinc concentration and T cell proliferation in nursing home elderly: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr. 2016;103(3):942–951. pmid:26817502
- 56. Lee LC, Tsai AC, Wang JY, Hurng BS, Hsu HC, Tsai HJ. Need-based intervention is an effective strategy for improving the nutritional status of older people living in a nursing home: a randomized controlled trial. Int J Nurs Stud. 2013;50(12):1580–1588. pmid:23648392
- 57. Zanini M, Bagnasco A, Catania G, et al. A Dedicated Nutritional Care Program (NUTRICARE) to reduce malnutrition in institutionalised dysphagic older people: A quasi-experimental study. J Clin Nurs. 2017;26(23–24):4446–4455. pmid:28231616
- 58. Diekmann R, Winning K, Uter W, et al. Screening for malnutrition among nursing home residents—a comparative analysis of the mini nutritional assessment, the nutritional risk screening, and the malnutrition universal screening tool. J Nutr Health Aging. 2013;17(4):326–331. pmid:23538654
- 59. Kobus Z, Nadulski R, Wilczynski K, Kozak M, Guz T, Rydzak L. Effect of the black chokeberry (Aronia melanocarpa (Michx.) Elliott) juice acquisition method on the content of polyphenols and antioxidant activity. PLoS One. 2019;14(7):e0219585. pmid:31318882
- 60. Rich JT, Neely JG, Paniello RC, Voelker CC, Nussenbaum B, Wang EW. A practical guide to understanding Kaplan-Meier curves. Otolaryngol Head Neck Surg. 2010;143(3):331–336. pmid:20723767
- 61. Gunville CF, Mourani PM, Ginde AA. The role of vitamin D in prevention and treatment of infection. Inflamm Allergy Drug Targets. 2013;12(4):239–245. pmid:23782205
- 62. Teshome A, Adane A, Girma B, Mekonnen ZA. The Impact of Vitamin D Level on COVID-19 Infection: Systematic Review and Meta-Analysis. Front Public Health. 2021;9:624559. pmid:33748066
- 63. Pham H, Rahman A, Majidi A, Waterhouse M, Neale RE. Acute Respiratory Tract Infection and 25-Hydroxyvitamin D Concentration: A Systematic Review and Meta-Analysis. Int J Environ Res Public Health. 2019;16(17). pmid:31438516
- 64. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. Bmj. 2017;356:i6583. pmid:28202713
- 65. Deng QF, Chu H, Wen Z, Cao YS. Vitamin D and Urinary Tract Infection: A Systematic Review and Meta-Analysis. Ann Clin Lab Sci. 2019;49(1):134–142. pmid:30814089
- 66. Aibana O, Huang CC, Aboud S, et al. Vitamin D status and risk of incident tuberculosis disease: A nested case-control study, systematic review, and individual-participant data meta-analysis. PLoS Med. 2019;16(9):e1002907. pmid:31509529
- 67. Kearns MD, Alvarez JA, Tangpricha V. Large, single-dose, oral vitamin D supplementation in adult populations: a systematic review. Endocr Pract. 2014;20(4):341–351. pmid:24246341
- 68. Malihi Z, Wu Z, Lawes CMM, Scragg R. Adverse events from large dose vitamin D supplementation taken for one year or longer. J Steroid Biochem Mol Biol. 2019;188:29–37. pmid:30529281
- 69. Kearns MD, Binongo JN, Watson D, et al. The effect of a single, large bolus of vitamin D in healthy adults over the winter and following year: a randomized, double-blind, placebo-controlled trial. Eur J Clin Nutr. 2015;69(2):193–197. pmid:25271011
- 70. Billington EO, Burt LA, Rose MS, et al. Safety of High-Dose Vitamin D Supplementation: Secondary Analysis of a Randomized Controlled Trial. J Clin Endocrinol Metab. 2020;105(4). pmid:31746327
- 71. Hou Y, Wu G. Nutritionally Essential Amino Acids. Adv Nutr. 2018;9(6):849–851. pmid:30239556
- 72. Li P, Yin YL, Li D, Kim SW, Wu G. Amino acids and immune function. Br J Nutr. 2007;98(2):237–252. pmid:17403271
- 73. Ha E, Zemel MB. Functional properties of whey, whey components, and essential amino acids: mechanisms underlying health benefits for active people (review). J Nutr Biochem. 2003;14(5):251–258. pmid:12832028
- 74. Sidor A, Gramza-Michalowska A. Black Chokeberry Aronia melanocarpa L.-A Qualitative Composition, Phenolic Profile and Antioxidant Potential. Molecules. 2019;24(20). pmid:31619015
- 75. Fu Z, Liska D, Talan D, Chung M. Cranberry Reduces the Risk of Urinary Tract Infection Recurrence in Otherwise Healthy Women: A Systematic Review and Meta-Analysis. J Nutr. 2017;147(12):2282–2288. pmid:29046404
- 76. Luis A, Domingues F, Pereira L. Can Cranberries Contribute to Reduce the Incidence of Urinary Tract Infections? A Systematic Review with Meta-Analysis and Trial Sequential Analysis of Clinical Trials. J Urol. 2017;198(3):614–621. pmid:28288837
- 77. Larosa DF, Orange JS. 1. Lymphocytes. J Allergy Clin Immunol. 2008;121(2 Suppl):S364–369; quiz S412. pmid:18241683
- 78. Warny M, Helby J, Nordestgaard BG, Birgens H, Bojesen SE. Lymphopenia and risk of infection and infection-related death in 98,344 individuals from a prospective Danish population-based study. PLoS Med. 2018;15(11):e1002685. pmid:30383787
- 79. Gao S, Jiang F, Jin W, et al. Risk factors influencing the prognosis of elderly patients infected with COVID-19: a clinical retrospective study in Wuhan, China. Aging (Albany NY). 2020;12(13):12504–12516. pmid:32651993
- 80. Shankar AH, Prasad AS. Zinc and immune function: the biological basis of altered resistance to infection. Am J Clin Nutr. 1998;68(2 Suppl):447S–463S. pmid:9701160
- 81. Lassi ZS, Moin A, Bhutta ZA. Zinc supplementation for the prevention of pneumonia in children aged 2 months to 59 months. Cochrane Database Syst Rev. 2016;12:CD005978. pmid:27915460
- 82. Lassi ZS, Kurji J, Oliveira CS, Moin A, Bhutta ZA. Zinc supplementation for the promotion of growth and prevention of infections in infants less than six months of age. Cochrane Database Syst Rev. 2020;4:CD010205. pmid:32266964
- 83. Gulani A, Sachdev HS. Zinc supplements for preventing otitis media. Cochrane Database Syst Rev. 2014(6):CD006639. pmid:24974096
- 84. Pae M, Meydani SN, Wu D. The role of nutrition in enhancing immunity in aging. Aging Dis. 2012;3(1):91–129. pmid:22500273
- 85. Cassotta M, Forbes-Hernandez TY, Calderon Iglesias R, et al. Links between Nutrition, Infectious Diseases, and Microbiota: Emerging Technologies and Opportunities for Human-Focused Research. Nutrients. 2020;12(6).
- 86. Gleeson M, Nieman DC, Pedersen BK. Exercise, nutrition and immune function. J Sports Sci. 2004;22(1):115–125. pmid:14971437
- 87. Pereira PCM. Interaction between infection, nutrition and immunity in tropical medicine. The journal of venomous animals and toxins including tropical diseases. 2003;9(2):163–173.
- 88. Saker KE. Nutrition and immune function. Vet Clin North Am Small Anim Pract. 2006;36(6):1199–1224, v. pmid:17085230
- 89. Shikora SA, Blackburn GL. Nutrition Support: Theory and Therapeutics. New York: Springer; 1997.
- 90. Salazar N, Valdes-Varela L, Gonzalez S, Gueimonde M, de Los Reyes-Gavilan CG. Nutrition and the gut microbiome in the elderly. Gut Microbes. 2017;8(2):82–97. pmid:27808595
- 91. Lang PO, Samaras D. Aging adults and seasonal influenza: does the vitamin d status (h)arm the body? J Aging Res. 2012;2012:806198. pmid:22162810
- 92. Vanderlinden J, Boen F, van Uffelen JGZ. Effects of physical activity programs on sleep outcomes in older adults: a systematic review. International Journal of Behavioral Nutrition and Physical Activity. 2020;17(1):11. pmid:32024532
- 93. Harvard T. HChanSchoolofPublicHealth. Nutrition and Immunity. Published n.d. Accessed July 30th 2021, 2021.