The lack of standard treatment for COVID-19 creates the need for investigation of strategies that can either target SARS-CoV-2 to eliminate it or to improve the symptomatology and strengthen the natural defences. We aimed on this second option and evaluated the use of an add-on therapy described previously on literature.17,18 Comparing the two cohorts, a clear difference was seen in the resolution of most symptoms, including fever, dry cough, dyspnoea, headache, diarrhoea, and weakness. Overall, the reduction in time for the resolution of the symptoms indicate a possible positive effect for IF as an add-on therapy for COVID-19.
Robust studies showing the time for recovery of symptoms are still lacking, as most of them focus on the time for symptom onset and in the rate of recovery/complications. The time from exposure to symptom onset is usually reported as is in average 11.5 days, and the time between symptom onset and hospital admission about 7 days.20,21 Usually the first symptoms (Stage I: fever, dry cough, headache, diarrhoea) appear between 0 to 4 days; the Stage II symptoms (hypoxia) in 5-13 days; and Stage III symptoms (ARDS, cardiac failure, shock) after 14 days of infection.1 This is in concordance with what was found by Wang et al, a median 5 days (range 2-8 days) for the progression from mild-moderate cases to severe condition, and a hospital stay range from 14 to 22 days.22
As an attempt for comparison, Carfi et al.23 evaluated a population similar to our IF cohort in sociodemographic terms: patients with mean age of 56.5 (± 14.6) years, and 63% were men; the difference is that they evaluated hospitalized patients. They assessed the patients for a mean of 60.3 days after onset of the first COVID-19 symptom and observed that only 12.6% were completely free of any COVID-19–related symptom, while 32% had 1 or 2 symptoms and 55% had 3 or more. A report from Imperial College of London24 showed that the mean time for recovery after symptom onset is 20.51 (± 6.69) days. In contrast, 90.0% of the IF cohort of the present study recovered during the observational period (30 days), and the most common symptoms were resolved within around 2 to five days (except for loss of taste and smell, which is known to be a long-lasting or irreversible complication of COVID-1925).
A similar population studied was also reported by Chen et al.26: patients with mild cases, a median of 51 years, and a percentage of 50.6% men. In this study, the estimated median duration of fever was 10 days (CI: 8-11 days), after onset of symptoms – in our findings, the duration of fever was 3.35 days after the onset of symptoms and 2.25 days after the start of treatment.
Obtaining fast patient recovery is important, as the persistence of symptoms can reflect the worsening in his prognosis. For example, for severe cases, the symptoms can last for more than 28 days, leading to hyperinflammation/hypercoagulation responses and pulmonary fibrosis formation.27
The improvement in the time needed for recovery of the symptoms in the IF cohort can be related to the multiple mechanisms that the components of the IF theoretically acts on as described earlier by Ferreira et al.17 We will highlight four. First, immune system regulation. This can be related to macrophage activation by Imuno TF®28,29 and spirulina,30,31 to development of neutrophils by Spirulina and Zinc,32 to activation of NK-cells by Imuno TF®, Spirulina, Zinc, Vitamin C, and Resveratrol,31,33–38 to the increase in T-cells functions by Spirulina, Vitamin C and Vitamin D3,32,39–41 and to CD4+ cells activation by Imuno TF® and Selenium, which can regulate the antigenic stimulus triggering CD4+ Th1 cells to produce IFN-𝛾, IL-1 and TNF-𝛼.28,29,32,42–44 In addition, Imuno TF® positively regulates Th1 cytokines, while decreases the release of Th2 cytokines (IL-4, IL-5, IL-6, IL-13).45 This is relevant once there is evidence that the Th2 overresponse are linked to bronchoconstriction, dyspnea and exacerbations of allergic airways diseases.46
Secondly, targeting the virus itself: Resveratrol have demonstrated DPP4R inhibitory effect (also observed with the use of N-acetylcysteine) and potential to block the ACE2’ binding site;47,48 and Zinc (high concentration, intracellular) can inhibit the RNA polymerase.49 In addition, N-acetylcysteine, Selenium, and Glucosamine can amplify the signalling functions of TLR7.50 Recently, U. tomentosa bark extract (one of the components of MiodesinTM) has shown antiviral effect against SARS-CoV-2 on Vero E6 cells.51
Third, the IF effects on the inflammatory process generated by the infection. Vitamin D3 possesses anti-inflammatory properties and can decrease the cytokines storm,52–58 notably decreasing the IL-6 effect, a marker of severity in COVID-19 patients.45,59 Vitamin C is related to an increase in lymphocytes B and T proliferation and differentiation.40,65,66 Resveratrol and Ferulic acid were reported to inhibit the TLR4 signalling pathway50 – Ferulic acid can also diminish the serological concentration of TNF-α and IL-1β.67,68 Another ingredient, MiodesinTM, was shown recently to decrease inflammation through inhibition of the release of cytokines (IL-1β, IL-6, IL-8, and TNF-α) and chemokines (CCL2, CCL3, and CCL5) and the expression of NF-κΒ, inflammatory enzymes (COX-1, COX-2, PLA2, iNOS), and chemokines (CCL2, CCL3, and CCL5).69
Finally, the add-on treatment provided was idealized to also act on the oxidative stress. Phase 2 inductive nutraceuticals as Ferulic acid and Resveratrol induce various peroxidase enzymes and promote synthesis of glutathione. Glutathione production can also be promoted by administration of N-acetylcysteine. Selenium supplementation might also be appropriate in this context.50 Besides, other nutraceuticals with antioxidant properties such as Vitamin C, Spirulina and Astaxanthin can also contribute to reduce the oxidative stress.50,65,66,70–73
As a limitation of our study, we can point out the differences in age of the cohorts. Therefore, we can understand the data as a description of the fast times needed to recover from the most common COVID-19 symptoms, rather than a direct comparison between the cohorts.