Vitamin C
Vitamin C is an antioxidant that plays a role in reducing oxidative stress, improving blood circulation, and protecting cells from disease. The recommended daily intake for vitamin C for adults is 8–16 mg/day, which is equivalent to 8–24 milligrams/day of vitamin A or 0.18–2.6 micrograms/kg/day of vitamin E (1). Although vitamin C may not cause harm if taken as prescribed, your physician may advise you to increase your dose of vitamin C by about 1–2 times if you have any bleeding disorders such as gastrointestinal ulcers and anticoagulant deficiencies (such as thrombocytopenia). It also seems reasonable to increase your dose of vitamin C if severe liver disease, which can lead to scarring and jaundice, occurs, as well as if there are other conditions that can affect absorption, such as autoimmune diseases such as lupus or rheumatoid arthritis ( 2 ). In general, vitamin C should be taken with food, and as directed by your doctor. If you take vitamin C intravenously, you should never exceed the maximum dose you were given. Some people with severe illness may experience nausea or vomiting, diarrhea, and abdominal pain or cramps (3).
Dengue
Dengue is associated with increased coagulation activity and platelet function in susceptible individuals ( 4, 5 ). This is likely due to the direct contact of infected mosquitoes with human immunodeficiency virus (HIV) that leads to changes in the immune system, including decreased levels of T-lymphocytes and B-lymphocytes, increased levels of autoantibodies, increased inflammation, and activation of complement systems ( 6 ). For example, studies have shown that thrombocytopenia may occur if coagulation is inhibited since it reduces platelet response and prevents clotting. Platelets contribute to tissue restoration during acute dengue fever, but platelet dysfunction is also seen in dengue hemorrhagic syndromes ( 7, 8, 9 ). However, it is unclear what specific mechanisms relate to thrombocytopenia and coagulation in patients with dengue virus infection ( 10 ). Data suggest that low and high doses of vitamin C can improve platelet function in healthy subjects, although the effects are similar in humans and monkeys and may be different in children ( 11 ). More research is required on the pharmacokinetics and biologic effects of various doses of vitamin C as well as its clinical use.
Folic Acid in Dengue Complications
Folic acid is important in treating folate deficiency, especially in pregnant women, because folate supplements enhance fetal growth and development. Because of this benefit, some randomized controlled trials have found that supplemental folic acid for up to a year can reduce risk of miscarriage in pregnancies caused by single gene defects ( 12, 13, 14 ). Other randomized controlled trials have also found that folic acid supplementation significantly reduces maternal depression, fetal anomalies, birth weight, and infant mortality ( 15, 16, 17 ). Therefore, taking folic acid for chronic treatment has been proposed as an adjunctive therapy to prevent adverse pregnancy outcomes with adequate folate intake. Supplementation of folic acid to enhance the anti-inflammatory effect associated with COVID-19 treatment might also reduce morbidity and mortality in hospitalized coronavirus infected patients ( 18, 19 ). Additionally, research suggests that supplementation of folic acid in pregnancy may improve maternal health, including a lower incidence of preterm labor, congenital anomalies, preeclampsia, preterm delivery and stillbirth ( 20 ). Finally, research suggests that providing folic acid for approximately 3 months after conception improves neurodevelopmental outcomes in children born to normal mothers ( 21 ). Even though long-term use is safe, there are no definitive reports of serious clinical issues related to folic acid use during pregnancy.
Dengue Virus Infection
The term “dengue” relates to three types of arthropods that cause viral infections with varying severities. According to the World Health Organization, these include West Nile virus, yellow fever virus, Japanese encephalitis virus, and Zika virus ( 22 ). There are four mosquito species associated with dengue virus infection: Anopheles Gambia, Aides Egypt, Andes albopictus, and Andes Egypt ( 23 ). These mosquito species can spread through air and water to humans. Depending on where dengue viruses infect humans, symptoms can range from mild to life-threatening. Dengue can develop in almost all parts of the world, but in Africa and Asia, most cases of dengue virus infections are found among refugees who travel to these regions on work or other economic reasons. In these areas, dengue is frequently transmitted by mosquitoes carrying Andes mosquitoes ( 23 ). Although all three dengue viruses can transmit at least partially by insects, only two viruses — Andes and Andes albopictus — can be carried by both man-made and natural means of vector transmission ( 24 ). Generally, a person becomes infected when they come into physical contact with someone with dengue virus infections, although mosquitoes are not always direct vectors of dengue virus infection. The severity ranges from symptomatic infection to fatal complications such as anemia, seizures, meningitis, shock and death. Of particular note, dengue can often be fatal in infants younger than 6 weeks old and during the childbearing period ( 25 ). At the time of diagnosis, most individuals remain asymptomatic, although it is possible to develop a secondary infection known as relapsing fever. During this re-infection stage, the patient is more likely to suffer from comorbidities, such as cancer or HIV infection. Another potentially lethal complication associated with dengue fever is hemolytic anemia. About one million people die each year in sub-Saharan Africa from this condition. Hemolysis appears to precede every major complication associated with the dengue virus. Approximately 50% of all patients affected develop clinically significant anemia, and this figure rises to 80% when comorbid conditions are present. As dengue affects both adults and children, its management can vary considerably between the two groups. Children are generally more severely affected by the dengue virus than adult individuals, and their treatment needs differ from those of older persons. Nevertheless, early diagnosis of dengue infection, treatment, and antiviral medications significantly decrease the severity of the disease. With proper medication combined with prompt vaccination, however, the prognosis for children may be better than that of adults ( 26 ). Studies have reported that over 40% of dengue patients develop severe complications, and even those with mild disease may develop neurological or cardiovascular problems. Most of the complications that arise from dengue in adults begin within the first 6 weeks after onset of symptoms. Several common conditions that arise in dengue patients are vasculitis, myocardial infarction, pulmonary hypertension, and renal failure, particularly among males, leading to poor outcomes ( 27 ). Overall, the prevalence of dengue fever and dengue disease is increasing worldwide, especially among refugees. Since 1990, around 300 million refugees have crossed borders from endemic countries, and now about 10% of them live in sub-Saharan Africa ( 28 ). Furthermore, in many developing countries, many refugee populations live under very poor conditions, and access to healthcare services can be limited beyond the primary medical care provider. Considering the rising levels of migration and cross-border traffic, many non-traditional medical providers are being used, which raises several questions about vaccine effectiveness and safety for vulnerable populations.
Conclusion and Further Research
As discussed in detail above, dengue virus infection leads to elevated levels of pro-inflammatory molecules produced by inflammatory cells. One aspect of dengue fever is that it produces cytokines, which activate protein kinases that alter key functions of the immune cells, including leukocyte motility, cell adhesion, proliferation and migration. These pro-inflammatory mediators promote the production of toxic substances that damage tissues, organs, and cells. Interleukin-6 (IL-6), which is released by lymphocytes in an attempt to help cells repair damaged cells during dengue virus infection, is involved in mediating the pathogenesis of dengue fever as well as the progression of multiple sequelae. IL-6 is commonly called a cytokine of tumor necrosis factor super family, and researchers have suggested that IL-6 plays a major role in initiating apoptosis, enhancing vascular permeation and endothelial destruction, promoting fibrosis, suppressing the secretion of catharsis L, stimulating monocyte chemotaxis and inducing neutrophil migration ( 29 ). Unfortunately, IL-6 may be a causative agent in the pathogenesis of dengue fever, but this association remains controversial ( 30 ). Many investigators propose that dengue infection initiates the release of pro inflammatory cytokines from activated macrophages and plasma cells, particularly T-lymphocytes, interleukin IL-8 and IL-10, and prostaglandin E-2. Thus, these cytokine mediators trigger the activation of innate and adaptive immune responses against pathogens in response to either the invading virus itself or the host’s own self-antigens. IL-6 is primarily responsible for triggering these pro-inflammatory pathways, which contribute to disease severity. Activation of these pathways promotes activation of additional signaling proteins, including nuclear factor kappa B (NF-κB) and signal transduction and transcription factor p65 (NFΑ). NF-κB and NFΑ are implicated in inflammation, whereas the latter activates p65 to initiate expression of genes associated with immunity.