The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) or COVID-19, as was named by the World Health Organization (WHO) , is a novel coronavirus that has resulted in a pandemic. The first record of the disease was on 31 December 2019 in Wuhan, a city in Mainland China  and is currently rapidly spreading to the rest of the world. Owing to its rate of spread and fatality with a case fatality rate estimated at 2–5% , the WHO pronounced the outbreak a global health emergency on 30 January 2020. As of 14 August 2020, 10:42 AM Central European Summer Time, 20,687,815 cases and 750,400 deaths have been reported globally . Among other reported symptoms resulting from this virus, respiratory disorders such as respiratory failure, acute respiratory distress syndrome, and pneumonia are significant symptoms associated with fatality [5, 6, 7]. In moderate to severe cases, COVID-19 attacks the respiratory system [8, 9], which progresses to a respiratory failure resulting from a damage to the alveoli, which could be fatal or leave the patients not only in critical need for supplemental oxygen and mechanical ventilator but also with residual lung damage that may require extended recovery time .
Globally, the mortality rate as a result of COVID-19 is on a steady increase. Although all population groups are at risk of contracting COVID-19, some individuals with specific comorbidities are more susceptible than others. A meta-analysis of 6 studies involving 1527 confirmed cases reported that hypertension (17.1%), cardio-cerebrovascular conditions (16.4%), and diabetes mellitus (9.7%) were the most prevalent cardiovascular and metabolic conditions associated with COVID-19 . Zeng et al. , Paroh et al.  and Tian et al.  conducted a systematic review and included 13, 14 and 14 studies, respectively. The studies reported that men aged 60 years and above with conditions such as hypertension, diabetes, cancer, cardiovascular and respiratory diseases were at higher risk of contracting, developing serious symptoms and dying from COVID-19.
Similarly, Jain and Yuan  reviewed seven articles that evaluated the characteristics of COVID-19 patients admitted in an intensive care unit and reported that patients with chronic obstructive pulmonary disease (COPD) were the most vulnerable, followed by patients with cardiovascular disease and hypertension. Furthermore, the World Health Organization has also identified hypertension, cardiovascular disease, diabetes, chronic respiratory disease such as COPD, and cancer as risk factors for contracting and developing serious illness from COVID-19 . Summarily, people with comorbidities such as hypertension, diabetes, cardiovascular disease, chronic respiratory disease and cancer have been identified as the high-risk individuals that are the most vulnerable, susceptible to COVID-19 with a high mortality rate . In this study, we refer to these comorbidities as proxy conditions prone to developing COVID-19.
Notably, individuals with these proxy conditions by default have lower immunity, and these make them more susceptible to developing COVID-19. For instance, diabetes mellitus (DM) increases patients’ susceptibility to viral infections due to its negative impact on both the innate and adaptive immune parameters [18, 19, 20]. Besides, more than 80% of individuals with type-2 DM have hypertension . Compromised immunity has also been reported in patients with cancer, which increases their susceptibility to opportunistic infections . Worthy to note, a decrease in adaptive immunity marked by a significant reduction in CD4 and CD8 cells have been reported among individuals with COVID-19 [23, 24]. Similarly, a study reported that there is usually a significant reduction in the total T cells, CD4 and CD8 T cell counts, which is a reliable marker of disease severity in patients with COVID-19 . Recent studies showed that 82.1% of patients with COVID-19 have decreased circulating lymphocytes (a constituent of both innate and adaptive immunity) [7, 26, 27]. The combined impact of the comorbidities and SARS-CoV-2 on immunity results in a very poor clinical outcome in these population groups.
Also, individuals with hypertension, diabetes, cardiovascular (e.g. congestive heart failure) and cardio-pulmonary conditions (e.g. COPD) have an increased plasma level of inflammatory biomarkers, for example C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) [28, 29, 30, 31, 32, 33, 34]. Elevated inflammatory responses have also been reported among patients with cancer. A study reported an increased serum concentration of IL-6, IL-1β, TNF-α, and CRP in patients with cancer as compared with healthy individuals . Notably, increase in the inflammatory response (cytokine release syndrome), marked by an elevated concentration of inflammatory cytokines (Interleukin-6, Interleukin-10, Interleukin-2, Tumor necrosis factor-α, Interferon-γ) is one of the significant causes of disease severity and mortality in patients with COVID-19 . An elevation in inflammatory biomarkers results to an increased vascular permeability, which causes an influx of a large amount of fluid and blood cells into the alveoli, consequently causing dyspnea and respiratory failure [37, 38, 39]. Interestingly, studies have reported that immune parameters, T-cells (CD8 and CD4) counts have a negative correlation with inflammatory markers (IL-6, IL-10, and TNF-α), with COVID-19 disease resolution marked by a reduced concentration of IL-6, IL-10, and TNF-α, and increased T-cell counts . The phenomenon is an indication that the reduction of T-cells noted in patients with COVID-19 could be a consequence of the increased concentration of TNF-α, IL-6, and IL-10, which negatively regulates T-cell survival or proliferation .
Exercise improves both innate and adaptive immunity. Aerobic exercise of moderate to high intensity performed for 30 minutes, 3–5 times per week, enhances the antipathogen functions of tissue macrophages with an associated increase in recirculation of immunoglobulins, natural killer cells, cytotoxic T cells, anti-inflammatory cytokines, neutrophils, and immature B cells [40, 41, 42, 43, 44]. All of these immune-markers play critical roles in metabolic health and immune defense activity .
Similarly, physical activity/exercise has a negative correlation with inflammatory biomarkers . Several studies have reported that exercises reduce inflammatory biomarkers including the serum concentration of CRP, IL-6, IL-18, TNF-α, and IL-1α, in individuals at risk of cardiovascular diseases [46, 47, 48, 49, 50], and type 2 DM . Previous studies have reported that exercise reduces the concentration of CRP and TNF-α among individuals with hypertension  and cancer , respectively.
Given that there is no treatment for COVID-19, the emphasis is placed on prevention, among other means, improving the body’s immunity against the virus is a crucial factor. Exercise is a reliable and most accessible form of prevention strategy; however, the impact of exercise on COVID-19 is still at its testing stage. Since studies have identified comorbidities that predispose individuals to developing COVID-19, we believed that reviewing the impact of exercises on the immune parameters of these proxy conditions is warranted. Because improving the body’s immunity and reducing the concentration of inflammatory biomarkers in those identified vulnerable groups would be useful in the preventive approach, thus, reducing the risk of contracting COVID-19, and reducing the risk of mortality due to COVID-19. Besides, this review will provide a comprehensive exercise Frequency-intensity-time-type that interventionists can use in developing randomized control trials to test the impact of exercise on the course of the disease, chances of hospitalization, landing on ICU and surviving from COVID-19.
This study aims to investigate the effectiveness of physical activity/exercise in improving the immune parameters and reducing the inflammatory biomarkers in proxy conditions that make individuals susceptible to COVID-19. Specifically, this study will aim to answer two research questions: (a) What are the exercise FITT parameters that increase the immune outcomes and reduce inflammatory biomarkers for proxy conditions that make individuals susceptible to COVID-19?; (b) What are the specific exercise regimen suitable for each of the proxy conditions i.e. what specific exercise regimen is beneficial per proxy group?