By Professor Kylie O’Brien PhD and Professor Ian Brighthope MBBS, FACNEM
As the world faces the current COVID-19 pandemic, those with compromised immune systems, including the elderly, are particularly at risk. In addition to recommendations in place regarding prevention of spread of COVID-19, some simple, inexpensive measures could be put in place and reduce the associated morbidity and mortality. The scientiﬁc literature is clear that optimal nutrition is a key factor for a healthy immune system. Vitamin C (ascorbic acid) and vitamin D are essential and eﬀective in supporting and strengthening the immune system. Supplementation with these may help strengthen the immune system and prevent development of the more serious sequelae associated with COVID-19. Treatment with high doses of intravenous Vitamin C may help save lives.
The common cold is typically caused by respiratory viruses (rhino, corona, adeno, parainfluenza, influenza, respiratory syncytial), of which there are around 200 serotypes1. Regular oral supplementation with Vitamin C has been found to reduce the duration of common colds in adults and children, as well as severity, although findings in relation to its therapeutic use are not consistent. A meta-analysis found that cold duration was reduced by 8% in adults (17 RCTs) and 14% in children (14 RCTs) in those who took Vitamin C regularly (in the majority of trials dose was 1000mg/day). In children 1-2g per day of Vitamin C shortened colds by 18%. Severity of colds was also reduced in those who supplemented regularly1. Carr and Maggini’s review of Vitamin C’s role in the immune response concluded: ‘Vitamin C deficiency results in impaired immunity and higher susceptibility to infections. In turn, infections significantly impact on vitamin C levels due to enhanced inflammation and metabolic requirements. Furthermore, supplementation with vitamin C appears to be able to both prevent and treat respiratory and systemic infections’ 2. See their paper for a comprehensive review of its actions.
COVID-19 is associated with much more serious sequelae of pneumonia, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), shock and multiple organ failure3-5 . Chinese data indicates that of 99 patients at a Wuhan hospital, 17% of confirmed cases developed severe illness with ARDS, with 4% needing mechanical ventilation and 4% experiencing septic shock4. Some patients, particularly severely ill ones, had co-infections of bacteria and fungi 4. ARDS is characterised by severe hypoxemia, uncontrolled inflammation, oxidative damage and damage to the alveolar-capillary barrier which can lead to death 6. Viral (and bacterial) infections and sepsis can cause a ‘cytokine storm’. This activates lung capillary endothelial cells, leading to neutrophil infiltration and accumulation (damaging alveolar capillaries), alveolar fluid accumulation and increased oxidative stress3,6. Increased oxidative stress is a key factor in pulmonary injury including ALI and ARDS6.
Vitamin C has pleiotropic functions of relevance to COVID-19 treatment. Animal studies demonstrate that Vitamin C can reduce the incidence and severity of bacterial and viral infections 1. Vitamin C increases neutrophil phagocytosis and chemotaxis, increases macrophage migration, affects replication of viruses, affects production of interferons, enhances T and NK cell proliferation and modulates their functions, and may increase antibody formation1,7. It is a powerful antioxidant that can protect various cells against oxidative stress during infection1. Its anti-viral effects have been demonstrated in influenza type A, herpes simplex type 1 and poliovirus type 18.
What of Vitamin C’s potential in lung pathology? Preclinical research, for example, indicates Vitamin C can ameliorate hyperoxia-induced ALI and attenuate hyperoxia-induced macrophage dysfunction in mice 9. Peng states that early clinical studies have demonstrated that vitamin C can effectively prevent the process by which the cytokine surge damages the lungs3. According to Peng, Vitamin C can help to eliminate alveolar fluid by preventing the activation and accumulation of neutrophils and reducing alveolar epithelial water channel damage, and can also prevent the formation of neutrophil extracellular traps (NETs, associated with damage to alveolar capillaries)3. Case reports of influenza and ARDS have demonstrated IV Vitamin C to be instrumental in recovery6,10,11. Fowler and colleagues reported the treatment of a patient with virus-induced ARDS who was given high dose IV Vitamin C (200mg/kg per 24 h, total daily vitamin C dosage divided equally into four doses and infused every 6 h) initiated on Extra Corporeal Membrane Oxygenation day 1. The authors concluded that: ‘Infusing high dose intravenous vitamin C into this patient with virus-induced ARDS was associated with rapid resolution of lung injury with no evidence of post-ARDS fibroproliferative sequelae. Intravenous vitamin C as a treatment for ARDS may open a new era of therapy for ARDS from many causes’ 10 .
Clinical studies report benefits of IV Vitamin C in septic shock including reduced mortality 12, 13. In a study of 28 ICU patients with sepsis and shock, 25mg/kg Vitamin C intravenously every 6 hours reduced the amount of norepinephrine needed to maintain blood pressure and reduced the 28-day mortality to 14% (compared with 64% in the control group not receiving IV Vitamin C) 13. A meta-analysis reported that Vitamin C reduced the length of ICU stay by almost 8%, and in three of the studies where patients needed mechanical ventilation for over 24 hours, Vitamin C shortened the duration of this intervention by 18.2% 14.
Theoretical risks of IV high-dose Vitamin C such as oxolate nephropathy contrast with data which indicates its safety7, 15. A prospective case series of 157 adults receiving IV Vitamin C therapy found no renal stones occurred and no significant changes in mean serum creatinine or eGFR in those who had follow-up renal function tests 15. However, there are some case reports of high doses of IV Vitamin C causing haemolysis in G6PD-deficient patients. High dose ascorbic acid may promote production of hydrogen peroxide as a byproduct, and since this is a strong oxidizer, can damage G6PD-deficient red blood cells16.
In March 2020, the Shanghai government announced its official recommendation that COVID-19 should be treated with high doses of IV Vitamin C, with amounts varying according to severity of illness17. Details of the Shanghai Medical Association Consensus Statement on treatment of coronavirus can be accessed at: https://mp.weixin.qq.com/s/bF2YhJKiOfe1yimBc4XwOA. An official statement from the Xi’an Jiaotong University Second Hospital, in relation to the COVID-19 outbreak, read: ‘On the afternoon of February 20, 2020, another 4 patients with severe new coronaviral pneumonia recovered from the C10 West Ward of Tongji Hospital. In the past 8 patients have been discharged from hospital…High-dose vitamin C achieved good results in clinical applications. We believe that for patients with severe neonatal pneumonia and critically ill patients, vitamin C treatment should be initiated as soon as possible after admission…Early application of large doses of vitamin C can have a strong antioxidant effect, reduce inflammatory responses, and improve endothelial function…Numerous studies have shown that the dose of vitamin C has a lot to do with the effect of treatment…High-dose vitamin C can not only improve antiviral levels, but more importantly, can prevent and treat acute lung injury (ALI) and acute respiratory distress (ARDS)' 17. Clinical trials are underway in China investigating the effects of high dose IV Vitamin C in ARDS associated with COVID-19.
A recent article by Mathay and colleagues published in the Lancet on treatment of ARDS from COVID-1918 also suggests that rescue therapy with high dose vitamin C can be considered, citing the Fowler et al. (2019)10 study.
A systematic review of 25 RCTs (11,321 participants aged 0-95 years) of Vitamin D supplementation demonstrated a 12% reduction in participants experiencing at least one acute respiratory tract infection (OR 0.88, 95% CI 0.81-0.96). Number needed to treat (NNT) with Vitamin D to prevent one acute respiratory tract infection was 33, comparable with the NNT to prevent one influenza-like illness in adults with parenteral inactivated influenza vaccine (of 40 in adults and 28 in children). The benefit was greater in those receiving daily or weekly vitamin D without additional large bolus doses. Protective effects were greatest in those with severe deficiency (<25mmol/L baseline levels) with only 4 people needing to take supplements to prevent one acute respiratory tract infection19. A Cochrane review also found that Vitamin D supplementation reduces the risk of severe asthma exacerbations which are often precipitated by viral upper respiratory tract infections, further evidence of benefits in respiratory tract infections20.
Former Centre for Disease Control (CDC) Chief Tom Frieden MD has gone on record advising that Vitamin D may strengthen the immune system and may help prevent infection with COVID-19. He states that: ‘Vitamin D supplementation reduces the risk of respiratory infection, regulates cytokine production and can limit the risk of other viruses such as influenza. A respiratory infection can result in cytokine storms – a vicious cycle in which our inflammatory cells damage organs throughout the body – which increase mortality for those with COVID-19. Adequate Vitamin D may potentially provide some modest protection for vulnerable populations’ 21.
What Should Australia Be Doing?
Australia is heading into winter and its traditional cold and flu season. Whilst the focus is firmly on COVID-19 currently, many will simply get colds that are not associated with COVID-19. Current statistics suggest that where COVID-19 is diagnosed, most (but not all) will not be serious. Nonetheless, knowing what we do about Vitamins C and D, recommendations by doctors to patients should include supplementation of Vitamin C and D for prevention and in cases of COVID-19, treatment with high doses of IV Vitamin C should be implemented to help reduce the oxidative stress associated with ARDS.
Regular doses of 1000-2000mg daily of Vitamin C may help reduce the severity and shorten the duration of the common cold. It may also be helpful in reducing the duration and severity of milder cases of COVID-19. Clinical experience indicates that increasing the dose to 10,000 mg per day is required for more severe colds and cases of mild to moderate influenza. This is usually taken orally but is more effective if by IV infusion. The use of IV high-dose vitamin C should be reserved for moderate to severe cases of lower respiratory tract disease such as bronchitis and pneumonia. It should not be stopped suddenly, and it is wise to continue for several weeks.
Professor Kylie O’Brien PhD
Adjunct Professor Torrens University; Director of Education Australasian College of Nutritional & Environmental Medicine
Professor Ian Brighthope MBBS, FACNEM
Founder Australasian College of Nutritional & Environmental Medicine (ACNEM)
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