According to the Global Burden of Disease Study 2015, lower respiratory tract infection is the leading cause of infectious disease death, and the fifth most common cause of death overall. Vitamin C has a role in modulating resistance to infectious agents, therefore vitamin C supplementation may be important in preventing and treating pneumonia.
To assess the impact of vitamin C supplementation to prevent and treat pneumonia in children and adults.
We searched CENTRAL, MEDLINE, Embase, PubMed, CINAHL, LILACS, Web of Science, and two trials registers to 4 March 2020. We also checked references to identify additional studies. We did not apply any publication status or language filters.
We included randomised controlled trials (RCTs) and quasi‐RCTs (studies using allocation methods that are not random, e.g. date of birth, medical record number) assessing the role of vitamin C supplementation in the prevention and treatment of pneumonia in children and adults compared to control or placebo.
We used standard methodological procedures expected by Cochrane.
We included five studies in the review and identified two ongoing studies. The five included studies involved a total of 2655 participants; two studies were RCTs and three were quasi‐RCTs. The included studies were conducted in one high‐income country (USA) and three lower‐middle‐income countries (Bangladesh and Pakistan). Three studies were conducted in hospital inpatient settings, one in school, and one in a military training centre. Three studies included children under five years of age, one study included school‐aged children, and one study included adult participants. Two studies assessed the effect of vitamin C supplementation for pneumonia prevention; and three studies assessed the effect of vitamin C supplementation as an adjunct to pneumonia treatment. For pneumonia prevention, the included studies provided supplementation in doses of 1 g daily for 14 weeks, 2 g daily for 8 weeks, and 2 g daily for 14 weeks. For pneumonia treatment, the included studies provided vitamin C supplementation in doses of 125 mg daily and 200 mg daily until the symptoms resolved or discharge, as an adjunct to the pneumonia treatment. Overall, the included studies were judged to be at either high or unclear risk of bias for random sequence generation, allocation concealment, and blinding; and the evidence certainty was very low.
Two studies assessed the effect of vitamin C supplementation for pneumonia prevention; we judged the certainty of the evidence as very low. We are uncertain about the effect of vitamin C supplementation on pneumonia incidence and adverse events (urticaria). None of the included studies reported other primary outcomes (pneumonia prevalence and mortality) or any of the secondary outcomes.
Three studies assessed the effect of vitamin C supplementation as an adjunct to pneumonia treatment; we judged the certainty of the evidence as very low. We are uncertain of the effect of vitamin C supplementation on duration of illness and hospitalisation. None of the included studies reported other primary or secondary outcomes.
Due to the small number of included studies and very low certainty of the existing evidence, we are uncertain of the effect of vitamin C supplementation for the prevention and treatment of pneumonia. Further good‐quality studies are required to assess the role of vitamin C supplementation in the prevention and treatment of pneumonia.
Vitamin C supplementation for prevention and treatment of pneumonia
Review question
What is the role of vitamin C supplementation in the prevention and treatment of pneumonia in adults and children compared to no supplementation?
Background
Pneumonia is a chest infection caused by virus, bacteria, and fungi. Vitamin C has a role in the immune system, therefore supplementation could be important in preventing and treating pneumonia amongst children and adults. We assessed the role of vitamin C for the prevention and treatment of pneumonia.
Search date
We searched for evidence up to 4 March 2020.
Study characteristics
We included five studies and two ongoing studies. The five included studies involved a total of 2655 participants and were conducted in one high‐income country (USA) and two lower‐middle‐income countries (Bangladesh and Pakistan). Three studies were conducted in hospital settings, one in schools, and one at a military training centre. Three studies included children under five years of age, one school‐aged children, and one adult participants. Two studies assessed the effect of vitamin C supplementation for pneumonia prevention; and three studies assessed the effect of vitamin C supplementation in pneumonia treatment. The doses of vitamin C supplementation used were 125 mg, 200 mg, 1 g and 2 g.
Study funding sources
Two studies were funded by pharmaceutical companies. Three studies did not report funding sources.
Key results
We assessed the rate of pneumonia (incidence), how common pneumonia is (prevalence), numbers of deaths from pneumonia (mortality), and unintended and harmful outcomes (adverse effects) associated with vitamin C for preventing pneumonia. Only one study (674 participants) reported incidence, and one study reported one adverse effect (hives) associated with vitamin C for preventing pneumonia. No study reported on prevalence or mortality. Evidence was insufficient to determine the effect of vitamin C for preventing pneumonia.
We also assessed how long people were ill (duration of illness), how many people were cured, mortality, and adverse effects associated with the use of vitamin C as a treatment for pneumonia. Only one study reported duration of illness. No studies reported cure rates or adverse effects. Evidence was insufficient to determine the effect of vitamin C for treating pneumonia.
Certainty of the evidence
We judged the included studies to be at overall high or unclear risk of bias. The evidence certainty was very low due to study limitations, variations amongst the studies, small sample sizes and uncertainty of estimates.
Pneumonia is a lower respiratory tract infection characterised by cough, sputum, difficulty in breathing, sharp chest pain during deep breaths, fever, and lung inflammation (WHO 2014). Adults aged 65 years and over, and children aged up to two years, are at high risk of developing pneumonia. According to the Global Burden of Disease Study 2015, lower respiratory tract infection is the leading cause of infectious disease death, and the fifth most common cause of death overall (Troeger 2017). Approximately 2.74 million deaths and 103 million disability‐adjusted life‐years were attributed to lower respiratory tract infections in 2015. There was a disproportionate effect on children aged under five years, and 704,000 deaths occurred in this age group (Troeger 2017). Globally, disease burden has dramatically decreased over the last decade amongst children aged under five years, but in many regions disease burden has increased amongst people aged over 70 years (Whitney 2017).
Pneumonia is caused by viruses, bacteria, and fungi. Streptococcus pneumoniae and Haemophilus influenzae are the most common pathogens responsible for pneumonia in all age groups (Abubakar 2015). Pneumonia can be community acquired (occurs outside the hospital setting) or hospital acquired (occurs during hospital stay).
Pneumonia treatment guidelines recommend therapy according to pneumonia severity. Mild and moderate pneumonia can be treated with appropriate antibiotics and supportive care, including oxygen; severe pneumonia requires hospital treatment (Lim 2009; WHO 2014). In 2009, a Global Action Plan for the Prevention and Control of Pneumonia suggested integrated strategies for preventing and treating childhood pneumonia (WHO/UNICEF 2009). These included improved nutrition, immunisation, healthy environments, and increasing access to appropriate management. Strategies recommended for reducing pneumonia incidence in children include exclusive breastfeeding for the first six months, adequate complementary feeding, micronutrient intake, H influenzae type B (Hib) vaccination, pneumococcal conjugate vaccination, and controlling household air pollution (Niessen 2009; Theodoratou 2010; Webster 2011; WHO/UNICEF 2013). Although pneumonia is largely preventable and treatable, it remains a major cause of death.
Vitamin C is an essential nutrient that cannot be synthesised by the body and plays an important role in the body's immune‐modulating system. Vitamin C donates electrons that protect the body from oxidant damage generated through exposure to toxins and pollutants (Carr 1999; Figueroa‐Méndez 2015). Vitamin C works as a co‐factor for several enzymes involved in the biosynthesis of L‐carnitine, collagen, and neurotransmitters (Himmelreich 1998). Vitamin C stimulates non‐heme iron absorption from the intestine and modulates iron transport and storage, and consequently prevents anaemia (Iannotti 2006).
Vitamin C supplementation has been evaluated for preventing and treating respiratory infections. A review assessing the impact of vitamin C on the incidence, duration, and severity of the common cold suggested no effect on the incidence of cold (Douglas 2005). Older studies in population subgroups have reported some positive effects of vitamin C supplementation on pneumonia, suggesting improved respiratory symptoms amongst hospitalised elderly patients (Hunt 1994), and reduced length of hospital stay (Mochalkin 1970).
Vitamin C is mostly present in the epithelial lining of the respiratory tract, where it functions as an immune‐stimulating agent, helping ameliorate symptoms of upper respiratory tract infections (Maggini 2017). Viral and bacterial infections can potentially decrease vitamin C levels because they generate reactive oxygen and nitrogen species through leukocyte activation that lead to oxidisation of extracellular vitamin C (Akaike 2001). Changes in vitamin C metabolism due to respiratory infections suggest that vitamin C may have a beneficial effect for people with pneumonia (Hemilä 2017).
Vitamin C antioxidant function limits damage from free radicals (oxygen and nitrogen) produced during normal cell metabolism and immune activation of neutrophils in response to bacteria, virus, and toxins (Carr 2017). Vitamin C stimulates neutrophil migration to the infection site in response to chemo‐attractants, enhances phagocytosis and oxidant generation, ultimately killing pathogens (Carr 2017). Phagocytes transfer oxidised vitamin C to cells, where it is converted by reactive oxygen species, altering the chain production of free radicals and preventing the host from cellular damage by products of lipid peroxidation (Nualart 2003). Production of reactive oxygen species during immune response of neutrophils by nicotinamide adenine dinucleotide phosphate helps to kill pathogens (Carr 2017; Winterbourn 2016). The products of lipid peroxidation produced by reactive oxygen species generate a chain reaction of free radicals by altering the structure and function of proteins, carbohydrates, and nucleic acid, which results in oxidative stress. Lipid peroxidation also decreases the immune response of lymphocytes by decreasing membrane fluidity (Ayala 2014). Vitamin C contributes to maintaining the redox integrity of cells and protects against reactive oxygen species (Hemilä 2017).
Vitamin C may have the potential to prevent and treat infections, but the impact of supplementation may differ according to baseline vitamin C deficiency status and other effect modifiers including other micronutrient deficiencies (Blumberg 2018; Smith 2017). The doses of supplementation might also have a potential effect and might differ for prevention and treatment. Prophylactic administration would require vitamin C intake that provides at least adequate intake levels in order to optimise cell and tissue levels. In contrast, treatment would require significantly higher doses to compensate for the increased metabolic demand (Carr 2017).
Vitamin C has a role in modulating resistance to an infectious agent, hence vitamin C deficiency may have a profound effect on the immune system and may increase the risk of respiratory infections. Vitamin C supplementation may therefore be important in preventing and treating pneumonia. This review evaluates the available literature to determine the role of vitamin C to prevent and treat pneumonia in children and adults.
To assess the impact of vitamin C supplementation to prevent and treat pneumonia in children and adults.