Low vitamin D levels tied to severe dengue disease

Adults with dengue virus infection are more likely to have a severe disease, including severe bleeding, when they have low levels of vitamin D, according to a single-centre study in Singapore.

“Host immune responses may impact dengue severity in adults,” said lead author Dr Sapna Sadarangani from the Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore. “Vitamin D has multiple immunomodulatory effects on innate and adaptive immunity.”

Sadarangani and colleagues conducted this cohort study at a single, large institution to explore the relationship between systemic 25-hydroxyvitamin D (25[OD]D) and dengue disease severity in adults.

Using stored samples from patients with laboratory-confirmed dengue, they measured plasma for total 25(OD)D levels with an electrochemiluminescence immunoassay. Sixty participants (median age 43 years) had been prospectively enrolled in 2012‒2016 at Tan Tock Seng Hospital.

Of the patients, six had severe dengue based on the World Health Organization (WHO) 1997 criteria (ie, dengue haemorrhagic fever/dengue shock syndrome) and another six had severe dengue based on the WHO 2009 criteria. At the acute phase of the disease, patients had a median 25(OH)D level of 6.175 mcg/L (range, 3.00‒15.29). [Singapore Med J 2024;65:332-339]

After adjusting for age, gender, and ethnicity, an inverse association was seen between 25(OH)D and severe dengue based on the WHO 2009 criteria (adjusted risk ratio [aRR], 0.72, 95 percent confidence interval [CI], 0.57‒0.91; p<0.01).

Serum 25(OH)D also showed a significant association with severe bleeding (aRR, 0.71, 95 percent CI, 0.53‒0.96; p=0.024), but not with severe plasma leakage leading to shock (aRR, 0.73, 95 percent CI, 0.48‒1.114; p=0.142). Notably, thrombocytopenia did not appear to mediate the association between low 25(OH)D and severe bleeding.

“Vitamin D deficiency is not uncommon in Singapore and other tropical dengue-endemic areas despite higher year-round exposure to ultraviolet rays,” Sadarangani said. [Nutrients 2017;9:313; PLoS One 2016;11:e0147616]

“Our study participants had overall low 25(OH)D levels at the acute time point, and lower levels were observed in those of Malay and Indian ethnicity compared to Chinese, as has been reported in other studies,” she added.

Immune mechanism

Few studies have explored the association of 25(OH)D with dengue disease course and severity in greater detail, according to the authors.

In one in vitro study involving human myelomonocytic and hepatic cells lines exposed to various concentrations of 1,25(OH)₂D₃, which were infected with dengue virus serotype-4, researchers observed a significantly reduced percentage of infected cells and production of TNF-α, IL-1B, IL-6, and IL-12p70, with a dose–response relationship observed with 1,25(OH)₂D₃. [Antiviral Res 2012;94:57-61]

The underlying immune mechanisms, however, remain unclear.

“There are many immunological postulations as to how vitamin D may be influencing the susceptibility to infection and inflammatory response,” Sadarangani said. [Clin Chim Acta 2018;478:140-151]

“Studies on the impact of 25(OH)D on the course of dengue infection in terms of underlying immune mechanisms and effects on the vascular endothelium are needed,” she added.