Aging is a biological process with high susceptibility to several infections. This risk increases in older patients in residential care facilities (RCF). Thus, there is a clear demand for developing preventive interventions with new therapeutic compounds that combine efficacy and safety. This could be the case of compounds derived from plants of the genus Allium spp. The purpose of this study was to evaluate the impact of a combination of a garlic and onion extract concentrate standardized in organosulfur compounds derived from propiin on the incidence of respiratory tract infections in elderly patients of RCF. Sixty-five volunteers were selected at random to receive a placebo or a single daily dose of the extract for thirty-six weeks. Different clinical visits were performed to evaluate the main respiratory diseases with an infectious origin, as well as the associated symptoms and their duration. The extract showed a clinical safety profile and significantly reduced the incidence of respiratory infections. Moreover, the treatment decreased the number and duration of the associated symptoms compared with the placebo group. For the first time, we demonstrated the protective effect of Alliaceae extract in respiratory infectious diseases in elderly healthy volunteers, which could be used prophylactically against the most common infectious respiratory diseases.
1. Introduction
Aging is a natural process that impairs several physiological systems, including the immune system, resulting in increased susceptibility to infectious, auto-immune, and neoplastic diseases. The world population over the age of 65 is expected to reach 1.5 billion in 2050 . Therefore, emphasis on the overall quality of life of the older person represents a major global public health challenge. Most older adults would prefer to age at home; however, unfortunately, this goal is frequently complicated due to the loss of cognitive and physical abilities, autonomy, and independence. Furthermore, the traditional family structure and socialization have changed, and consequently, home-based care for older adults is declining, and the demand for residential care facilities (RCFs) is rapidly increasing.
RCFs have become receptors of patients with a high risk of acquiring infections, which are mainly related to their underlying conditions and the invasive procedures they may undergo. In fact, it is well known that older adults who reside in RCFs are highly vulnerable to respiratory tract infections. Among them, pneumonia, influenza, and recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are common and can endanger their life. Although vaccination against these pathogens in this population is widespread, outbreaks persist, resulting in continued morbidity and mortality. Moreover, it has been reported that once infected, the residents are more likely to develop complications, such as lower respiratory tract illness, which is the most important cause of death in elderly residents, and one of the most common reasons for transfer to the hospital . Therefore, there is clearly an urgent need to develop potential and preventive therapeutic strategies that reduce the incidence and/or the severity of respiratory infections. In this context, different plant-based natural herbal formulations and related compounds, which have been traditionally used for the protection against infections and for the improvement of the immune response, are being assayed for the discovery and development of novel antiviral drugs. Since most of these plant-derived products have been reported to be safe after their administration, they could become a high-value therapeutic approach for these conditions in this vulnerable population.
In this context, plants of the genus Allium spp. such as garlic (Allium sativum L.) and onion (Allium cepa L.), which are rich in organosulfur compounds, including allicin, propyl-propane thiosulfinate (PTS), and propyl-propane thiosulfonate (PTSO), have been traditionally used against conditions such as joint inflammation, constipation, infectious diseases, and parasitic infestations . Most of these beneficial effects have been confirmed experimentally in vivo and in vitro. Additionally, in vitro studies have reported that the supplementation of a formula that includes concentrated garlic and onion shows broad-spectrum antimicrobial activity against multidrug-resistant bacteria isolated from human samples, and is also effective against porcine reproductive and respiratory syndrome virus (PRRS), as reported in experimental and human studies .
Therefore, the aim of this study was to evaluate the impact of daily consumption of a combination of garlic and onion extract concentrate rich in organosulfur compounds, severity, and duration of respiratory tract infections in healthy elderly volunteers who live in a nursing home.
2. Materials and Methods
2.1. Ethics, Approval, and Consent
This study was performed in compliance with the Declaration of Helsinki Ethical Principles for Medical Research involving human subjects and its amendment, and the Guidelines on Good Clinical Practice standards of CPMP/ICH/135/95 and ISO 14155 and all relevant Spanish guidelines. The study protocol was reviewed and approved by the Regional Ethical Committee (Granada, Spain) and registered in the US Library of Medicine.
Before the start of the study, the medical team of the residence selected the participants due to their characteristics, and they were invited to participate in the study. If they agreed, their relatives were informed so that they could also give their consent. All subjects provided written informed consent prior to their inclusion in the study.
2.2. Subjects and Study Design
The study enrolled 65 healthy older volunteers of both sexes who lived in the nursing home Residencia de Mayores Claret in Granada (Spain), aged more than 65 years and were vaccinated against flu according to the inclusion criteria. Exclusion criteria were, before the study, having any disease that affects the development and results of the study, being unable to understand the study and sign voluntarily and freely the informed consent, and having a low expectation of compliance with the study protocol; during the study, and always according to the opinion of the researchers, failure to comply with the study protocol, suffering some adverse event not tolerated by the subject, suffering changes in health status incompatible with continued participation in the study, and wish to withdraw from the study voluntarily. Finally, during the development of the study, the residence offered all volunteers the opportunity to be vaccinated against the SARS-CoV-2 virus. Agreeing to be vaccinated was a mandatory condition to continue in the study.
2.3. Intervention
Participants were randomized to receive either the active or a placebo product. The active product (Aliocare®, DOMCA SAU., Granada, Spain) contained concentrated onion extract (86 mg) standardized in organosulfur compounds derived from propiin (10 mg per capsule), garlic powder (14 mg), and microcrystalline cellulose (9892-Capsucel®, Laboratorios Guinama, La Pobla de Vallbona, Valencia, Spain) up to 450 mg, whereas the placebo product only contained 450 mg of microcrystalline cellulose. Both were delivered in hydroxypropyl methylcellulose capsules (Solchem®, Solchem, Barcelona, Spain). The medical team at the nursing home was in charge of administering one capsule a day to each volunteer during lunch for the 36 weeks, ensuring that they ingested it.
Participating subjects were instructed not to deviate from their regular habits during the intervention. Moreover, the participants’ diet was controlled throughout the study (the volunteers had to maintain their menu type).
Neither the researchers (intervention and statistical analysis) nor the participants knew which treatment sequence the subjects had been assigned to; the researchers were unblinded only at the end of the study. The odor of the product was masked to ensure blindness.
2.4. Clinical Parameters
The study’s primary outcome was the incidence of respiratory diseases of infectious origin (RDIO), mainly influenza-like illness (ILI), the common cold, and COVID-19. The diagnosis of ILI was made following the guidelines of the European Center for Disease Prevention and Control (Influenza case definitions (2017)) as follows: sudden onset of symptoms with one or more respiratory symptoms (cough, sore throat and/or nasal congestion) plus one or more systemic symptoms (fever, headache, myalgia and/or malaise). The common cold was determined by the sudden onset of one or more respiratory symptoms (cough, sore throat, and/or nasal congestion) without systemic symptoms . Since many of these symptoms coincide with those of infection by the SARS-CoV-2 virus, all those suspected of infectious respiratory disease underwent a PCR (polymerase chain reaction) test. In the case of a negative result, ILI or a common cold was diagnosed.
For this reason, every 28 days during the study, 14 clinical parameters related to these illnesses were monitored. The chosen symptoms were cough, fever, nasal congestion, throat pain, headache, bone pain, fatigue, chest pain, difficulty breathing, loss of smell/taste, nausea, diarrhea, lack of appetite, and sleeping problems. Moreover, medication intake and total illnesses were followed during the intervention. The events were recorded daily by the medical team in the residence files and collected every four weeks in the study database.
The severity of the events was analyzed by studying the number of symptoms experienced by the volunteers and their duration.
Finally, product safety was monitored daily by asking volunteers if they felt bad when taking the product and by weighing and measuring blood pressure every 28 days. Medicine intake was also followed.
2.5. Statistical Analysis
The calculation of the sample size, as well as the statistical analysis, was carried out by the company SEPLIN Soluciones Estadisticas, S.L. (Granada, Spain). The blind of the study was only opened by the principal investigator upon receipt of the statistical report.
A study was proposed with a sample size necessary to determine a difference in the reduction of incidences of respiratory symptoms of 35% and determining a statistical power of 80% and a significance level of 5%. Based on these considerations, 31 patients per group would be necessary, making a total of 62. In any case, in anticipation of possible losses during the study, 69 volunteers were recruited.
The results of the primary variable “Incidence of respiratory symptoms associated with infections” were analyzed longitudinally at different times (every four weeks of the study) and according to the treatment groups. Descriptive measures of the incidences (IRR Incidence rate ratio/OR-odds ratio), 95% confidence interval for the IRR/OR by study group, and time were studied, depending on the number of respiratory events or the occurrence of at least one case of respiratory symptom.
Generalized Mixed Models or repeated measures were used to compare the groups over time, adjusted for the baseline variables and the characteristics of the person both for the occurrence of some symptom at each measurement moment and the response of the number of events that occurred (longitudinal analysis of the response; mixed logistic model in the case of occurrence and mixed Poisson model in the case of the number of observed events).
To analyze the duration of the symptoms (number of days with symptoms associated with each event), these quantities have been described considering means, median, deviation, and range of values. The results have been compared between groups at each moment as well as the global measurement of total days of symptoms at the end of the study. A Poisson model has been applied to analyze the number of days with symptoms over time, comparing the mean number of days with symptoms by group.