Next Article in Journal
Evaluation of Two Different Strategies for Schistosomiasis Screening in High-Risk Groups in a Non-Endemic Setting
Next Article in Special Issue
Serum Cortisol as a Biomarker of Severe Dengue
Previous Article in Journal
Population Genetics of Oncomelania hupensis Snails from New-Emerging Snail Habitats in a Currently Schistosoma japonicum Non-Endemic Area
Previous Article in Special Issue
Assessment of Post-Dengue Rheumatic Symptoms Using the WOMAC and DAS-28 Questionnaires in a Honduran Population after a Four-Month Follow-Up
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
TropicalMed
Volume 8
Issue 1
10.3390/tropicalmed8010043
tropicalmed-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Vitamin D Deficiency (VDD) and Susceptibility towards Severe Dengue Fever—A Prospective Cross-Sectional Study of Hospitalized Dengue Fever Patients from Lahore, Pakistan

by
Somia Iqtadar
1,
Amjad Khan
2,*,
Sami Ullah Mumtaz
1,
Shona Livingstone
3,
Muhammad Nabeel Akbar Chaudhry
4,
Nauman Raza
1,
Mehreen Zahra
1 and
Sajid Abaidullah
1
1
Department of Medicine, King Edward Medical University, Lahore 54000, Pakistan
2
Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford OX3 9DU, UK
3
School of Medicine, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK
4
Cath Laboratory, Punjab Institute of Cardiology, Lahore 54000, Pakistan
*
Author to whom correspondence should be addressed.
Trop. Med. Infect. Dis. 2023, 8(1), 43; https://doi.org/10.3390/tropicalmed8010043
Submission received: 23 November 2022 / Revised: 19 December 2022 / Accepted: 30 December 2022 / Published: 5 January 2023
(This article belongs to the Special Issue Recent Advances in Dengue)
Browse Figure
Versions Notes

Abstract

:
Dengue is a mosquito-borne flaviviral serious febrile illness, most common in the tropical and subtropical regions including Pakistan. Vitamin D is a strong immunomodulator affecting both the innate and adaptive immune responses and plays a pivotal role in pathogen-defense mechanisms. There has been considerable interest in the possible role of vitamin D in dengue viral (DENV) infection. In the present prospective cross-sectional study, we assessed a possible association between serum vitamin D deficiency (VDD) and susceptibility towards severe dengue fever (DF) illness. Serum vitamin D levels were measured at the time of hospitalization in 97 patients diagnosed with dengue fever (DF), dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) at Mayo Hospital, King Edward Medical University, Lahore, PK, from 16 November 2021 to 15 January 2022. In terms of disease severity, 37 (38.1%) patients were DF, 52 (53.6%) were DHF grade 1 and 2, and 8 (8.2%) were DSS. The results revealed that most patients (75 (77.3%)) were vitamin-D-deficient (i.e., serum level < 20 ng/mL), including 27 (73.0%) in DF, 41 (78.8%) in DHF grade 1 and 2, and 7 (87.5%) in DSS. The degree of VDD was somewhat higher in DSS patients as compared to DF and DHF grade 1 and 2 patients. Overall, serum vitamin D levels ranged from 4.2 to 109.7 ng/mL, and the median (IQR) was in the VDD range, i.e., 12.2 (9.1, 17.8) ng/mL. Our results suggest that there may be a possible association between VDD and susceptibility towards severe dengue illness. Hence, maintaining sufficient vitamin D levels in the body either through diet or supplementation may help provide adequate immune protection against severe dengue fever illness. Further research is warranted.

1. Introduction

Dengue is a mosquito-borne flaviviral serious febrile illness, most common in the tropical and subtropical regions, especially in Southeast Asia, Latin America, the Caribbean, and the Pacific Islands. Dengue virus (DENV) has four serotypes (DENV1, DENV2, DENV3 and DENV4), and the first infection with one of the four serotypes is usually mild or asymptomatic, while a second infection with one of other serotypes may cause severe dengue manifestations. Each year, an estimated 50 million people are affected by DENV infection in dengue-endemic countries, with 70% of cases reported in Asia [1]. Each year, Pakistan also experiences large dengue outbreak that affect the healthcare system. Although the global fatality rate from dengue is very low, i.e., 1% [2], without timely management it can increase up to 20% [3]. The clinical manifestation of dengue infection ranges from asymptomatic to a wide range of symptoms, known as “dengue fever (DF)”. Symptoms of DF range from a mild flu-like syndrome to a severe form, dengue hemorrhagic fever (DHF). DHF is characterized by hemorrhagic manifestations such as spontaneous bleeding, significant decrease in platelet count and increased vascular permeability noted as increased hemo-concentration or pleural effusion or ascites [4]. DHF, if not timely managed, may progress to the life-threatening stage of hypovolemic shock, known as dengue shock syndrome (DSS) [5]. DSS occurs at the time of or shortly after blood pressure drop, and is characterized by a rapid, weak pulse, narrow pulse pressure (≤20 mm Hg) or hypotension with cold, clammy skin in the early stage of shock. In the absence of a prompt and appropriate treatment, this may soon progress to more serious form of shock in which pulse and blood pressure become undetectable, resulting in death within 12 to 36 h after the onset of shock.
A dengue virus vaccine named Dengvaxia® (CYD-TDV) [6] has been recently developed and is licensed in 20 countries, but with limited use. In the EU and the United States, Dengvaxia® has been approved for use by individuals living in endemic areas, aged 9–45 years and who had a previous dengue virus infection, i.e., prevention of secondary dengue infection [7,8]. In Pakistan, there is currently no dengue vaccine available to help provide protection against DENV infection. In the absence of a specific antiviral treatment, the present management of dengue fever illness is primarily supportive. Currently, the standard care is limited to rest, and administration of antipyretics such as paracetamol when fever is too high. In addition, crystalloid fluids, for maintaining fluid electrolyte balance and colloids to increase intravascular volume along with blood and blood products in case of bleeding are used in the management of dengue infection.
The reason why some patients progress to severe and potentially fatal forms of dengue illness remains unknown. Several host-associated risk factors including prior exposure to DENV, co-morbidity, and genetic predisposition are believed to influence the likelihood of developing severe dengue illness [9]. In the absence of DENV specific antiviral therapy, and limited therapeutic arsenal, identifying host’s new potentially modifiable risk factors that can prevent progression to severe illness, is currently under investigation.
The host’s nutritional status has been suggested as a potentially relevant predictor of disease progression in dengue patients [10] because some nutrients possess strong immunomodulatory activity. There is a growing body of evidence to suggest vitamin D deficiency (VDD), i.e., serum level < 20 ng/mL, as possible risk factor for developing severe dengue illness. Though, limited studies have evaluated the possible association between VDD and dengue disease severity [11,12,13,14,15,16,17], but the available evidence is scanty and inconsistent. Elucidating the possible link between VDD and severity of dengue symptoms would constitute a critical first step to investigate supplementation of this nutrient as a preventive against susceptibility of developing severe dengue illness. In the present study, we evaluated systemic vitamin D, i.e., serum 25-(OH) D levels in adults hospitalized with DF, DHF and DSS [18] prospectively upon admission at our institution, the largest tertiary teaching hospital in Lahore, Pakistan. We aimed to assess a possible association between low systemic 25-(OH) D levels and susceptibility towards severe dengue fever.

2. Materials and Methods

2.1. Study Design

This was a prospective, single-center, single-group, cross-sectional study conducted at the Department of Medicine, King Edward Medical University (KEMU), Lahore, PK. The study aimed to assess possible association between VDD and susceptibility toward severe DENV illness, evaluated at the time of admission, in hospitalized patients diagnosed with DF, DHF or DSS.

2.2. Eligibility Criteria

NS1/IgM dengue positive patients with platelet count < 100,000/µL of blood, of either gender who were admitted to the dengue wards, High-dependency Units (HDUs) and Intensive Care Units (ICUs) of Mayo Hospital, King Edward Medical University, from 16 November 2021 to 15 January 2022 for diagnosis of DENV fever, were included in the study. Participants gave informed written consent to participate in the study. The study was approved by the Institution Review Board, King Edward Medical University, Lahore, PK via Ref. number 351/RC/KEMU.

2.3. Treatment

Upon hospitalization, acetaminophen was used to relieve fever and body pain, while antiemetics including dompdridone and ondansetron were used to treat nausea and vomiting. Patients were treated with 2.5 L/24 h of oral fluid or intravenous normal saline as maintenance fluid. Severe disease was managed in HDUs and ICUs with judicious fluid administration calculated according to weight of the patient, with a maximum of 4.6 L in entire 48 h of critical phase. Crystalloids were mainstay of treatment to maintain adequate hydration to avoid both shock and fluid overload and ensure organ perfusion. Fluids were administered as oral or intravenous (IV) infusion (depending on the oral tolerance of patient), aiming for a pulse pressure of more than 30 and urine output of 0.5 mL/kg/hour while carefully monitoring vital statistics and hematocrit. In selective cases of DHF or DSS, colloids, blood and blood products were also used.

2.4. NS1/IgM and Vitamin D/25-(OH)D Assays

NS1/IgM dengue detection was carried out by enzyme-linked immunosorbent assay (ELISA) (International Immuno-Diagnostics Inc, Foster City, CA, USA). Serum levels of vitamin D were also evaluated by ELISA (Roche Diagnostics, Indianapolis, IN, USA).

2.5. Statistical Analysis

Median and interquartile range are shown for continuous variables and counts and percentage for categorical variables. Categorical and continuous variables were compared by vitamin D group. p-values are unadjusted for multiple comparisons.

3. Results

A total of 97 patients were enrolled in the study. Assessment of the patient’s clinical characteristics, overall, and by VDD, evaluated at the time of hospitalization, revealed the following (Table 1). Patient’s median (IQR) for age was 30.0 (22.0, 42.0) years and include 55 (56.7%) males. Serologically, most patients were either NS1+ or IgM+. All patients were within five days of dengue infection symptoms. The most prevalent symptoms were fever, body aches, vomiting, arthralgia, epistaxis, while less common symptoms include hematemesis, gum bleed, melena, hemoptysis, loose stools, hematuria, nausea, rectal and Per Vaginal (PV) bleed. In terms of disease severity, 37 (38.1%) patients were DF, 18 (18.5%) were DHF grade 1, 34 (35.0%) were DHF grade 2, seven (7.2%) were DHF grade 3 and one (1.0%) was DHF grade 4. Overall, 2 (2.1%) patients had a previous dengue infection (self-reporting), and 6 (6.2%) patients had a history of previous intake of vitamin D supplementation.
Overall, the patient’s serum vitamin D level ranged from 4.2 to 109.7 ng/mL, and the median (IQR) was in the VDD range, i.e., 12.2 (9.1, 17.8) ng/mL (Table 1 and Table 2). Serum vitamin D median IQR in all the three dengue severity groups (DF, DHF, DSS) was in VDD range. The degree of VDD was relatively higher in the DSS patients as compared to DF and DHF grade 1 and 2 patients. In terms of VDD prevalence, majority of the patients in all the three dengue severity groups, i.e., 75 out of 97 (77.3%), were vitamin-D-deficient at the time of hospitalization, i.e., DF: 27 (73.0%), DHF grade 1 and 2: 41 (78.8%), and DHF grade 3 and 4 (DSS): 7 (87.5%) (Figure 1).
In laboratory biochemistry (Table 3), evaluated at the time of hospitalization, 49 (86.0%) patients had markedly elevated serum levels of aspartate aminotransferase (AST), and alanine transaminase (ALT) liver enzymes, and the overall patients’ platelets count median (IQR) was also significantly low. In radiological examinations (Table 4), overall, 42 (43.2%) patients showed pericholecystic fluid and/or ascites in ultrasound, with more patients affected in VDD group. In circulatory system, 41 (43.2%) patients had a postural drop of ≥10 (mm Hg), with more patients in the vitamin D deficiency group. Patients’ hospitalization period was just under a week, i.e., median (IQR) 6.0 (3.0, 8.0) days, and in outcome, 96 (99%) were safely discharged from the hospital, and 1 (1.0%) patient (DHF grade 2, serum vitamin D level 11.02 ng/mL) was referred to nephrology for dialysis.

4. Discussion

In this cohort of 97 patients hospitalized for dengue fever, most patients, i.e., 75 (77.3%) were vitamin-D-deficient at the time of hospitalization. We speculate that one potential cause of DF progression to severe illness in these patients could be their serum VDD which could not provide them adequate immune protection against the development of disease severe condition. Although due to small sample size, we could find a statistically significant difference in the dengue clinical manifestations between vitamin-D-deficient patients and those with vitamin D levels above the deficiency threshold (i.e., ≥20 ng/mL), some of the severe symptoms such as pericholecystic fluid/ascites were more prevalent in patients with VDD. It is possible that the severity of these symptoms may be linked with VDD. In this cohort analysis, consistent with the previously reported studies [18,19,20,21,22,23], 49 (86.0%) patients presented markedly elevated serum levels of both AST and ALT liver enzymes at admission. Acute phase of DENV infection is also associated with varying degrees of liver involvement, believed to result from hepatocyte apoptosis directly by the virus, hypoxic damage due to impaired liver perfusion resulting from fluid leakage, oxidative stress, or immune mediated injury [24,25,26]. Study by Hass et al. [27] has shown that vitamin D can inhibit endoplasmic oxidative stress, a pathophysiological condition reportedly activated during DENV infection, and is believed to be essential for DENV replication [28,29]. The authors had shown that vitamin D could down regulate the endoplasmic stress induced up-regulation of glucose-regulated protein 78 (GRP78), a protein that is essential for DENV replication. To date, no specific study has evaluated a possible link between VDD and markedly elevated liver enzymes levels in patients with DENV infection. In the present study, patients also had significantly low platelets count at admission. A rapid decline in platelet count is one of the indicators of clinical worsening and one of the warning signs of plasma leakage in dengue patients. The study also showed a postural drop of ≥10 mm Hg in 41 (42.2%) patients, which indicates compensated shock (pre-shock) which if not timely indicated and addressed can lead to frank shock with poor outcome.
The possible role of vitamin D in DENV infection has been suggested by several studies [12,13,14,15,17,30], both in terms of its deficiency as a potential risk factor for developing severe dengue illness [31,32,33] and as possible adjuvant in the treatment of dengue patients [12,13,15,34,35]. Acute high dose vitamin D is believed to help in DF symptoms improvement and reduce the likelihood of progression to DHF/DSS. Some studies have shown contrasting results, i.e., higher serum 25-(OH) D is associated with more severe dengue (DHF/DSS) condition [11,16]. In the presence of limited studies, the available evidence on the possible association between VDD and susceptibility towards severe dengue illness is scanty and inconsistent. Though, VDD has been shown to induce increased susceptibility to viral infections including hepatitis C virus, influenza virus and human immunodeficiency virus (HIV) [36,37,38]. Few studies have shown the association of the vitamin D receptor (VDR) gene polymorphisms with susceptibility towards dengue virus infection [14,39].
The possible association of VDD and susceptibility towards severe DENV infection could be explained in several ways [40]. Vitamin D is a powerful immunomodulator affecting both the innate and adaptive immune responses [41] and plays a pivotal role in the pathogen-defense mechanisms [42]. Vitamin D activates both innate and adaptive immune response through several mechanisms including T-cells activation, macrophage differentiation and the production of anti-microbial peptides such as cathelicidin (LL-37) and β-Defensin [43,44,45]. Vitamin D also influences the expression of DENV entry receptor, dendritic cell specific intercellular adhesion molecule-grabbing non integrin (DC-SIGN) and FCγRIIA in immune cells [12,46,47]. Studies have also shown vitamin D antiviral activity against flaviviruses including hepatitis C virus [37,38,48,49] and DENV [11,12,13,15,50].
Our study is not free from limitations, which could be addressed in future studies. We did not have a control group of non-dengue febrile patients or healthy volunteers. Additionally, our study involved small sample size, as this was an exploratory study, hence, our study was not sufficiently powered to examine the effects of 25-(OH) D on different subgroups of patients and severity indicators of dengue illness. Nevertheless, we have carried out a pragmatic study which suggest that VDD may be a possible risk factor towards susceptibility of severe DENV illness. The results of this study are generalized, widely applicable and can help raise public awareness in people living in endemic areas against severe DENV infection.

5. Conclusions

Our study suggests a possible association between low systemic 25-(OH) D levels and increased risk of severe dengue illness in people living in the endemic areas. Regular testing of serum vitamin D levels is highly encouraged, and in case of VDD, medical advice should be sought, and followed. Overcoming VDD can possibly help in protection against severe DENV illness.

Author Contributions

Conceptualization, A.K. and S.I.; methodology, S.I.; software, S.L.; validation, A.K., S.I. and S.A.; formal analysis, S.L.; investigation, S.I.; resources, S.I.; data curation, S.U.M., N.R. and M.Z.; writing—original draft preparation, A.K; writing—review and editing, S.I.; M.N.A.C. and A.K.; visualization, A.K.; supervision, S.I., M.N.A.C. and S.A.; project administration, S.I.; funding acquisition, S.I. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of King Edward Medical University via Ref number 351/RC/KEMU.

Informed Consent Statement

All subjects gave their informed consent for inclusion before they participated in the study.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Acknowledgments

We thank PharmEvo for facilitating the patient’s vitamin D laboratory evaluation.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Bhatt, S.; Gething, P.W.; Brady, O.J.; Messina, J.P.; Farlow, A.W.; Moyes, C.L.; Drake, J.M.; Brownstein, J.S.; Hoen, A.G.; Sankoh, O.; et al. The global distribution and burden of dengue. Nature 2013, 496, 504–507. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Simmons, C.P.; Farrar, J.J.; van Vinh Chau, N.; Wills, B. Dengue. N. Engl. J. Med. 2012, 366, 1423–1432. [Google Scholar] [CrossRef] [PubMed]
  3. Guo, C.; Zhou, Z.; Wen, Z.; Liu, Y.; Zeng, C.; Xiao, D.; Ou, M.; Han, Y.; Huang, S.; Liu, D.; et al. Global Epidemiology of Dengue Outbreaks in 1990–2015: A Systematic Review and Meta-Analysis. Front. Cell. Infect. Microbiol. 2017, 7, 317. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Weaver, S.C.; Vasilakis, N. Molecular evolution of dengue viruses: Contributions of phylogenetics to understanding the history and epidemiology of the preeminent arboviral disease. Infect. Genet. Evol. 2009, 9, 523–540. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Prommalikit, O.; Thisyakorn, U. Dengue virus virulence and diseases severity. Southeast Asian J. Trop. Med. Public Health 2015, 46 (Suppl. 1), 35–42. [Google Scholar] [PubMed]
  6. Tully, D.; Griffiths, C.L. Dengvaxia: The world’s first vaccine for prevention of secondary dengue. Ther. Adv. Vaccines Immunother. 2021, 9, 1–8. [Google Scholar] [CrossRef]
  7. FDA News Release: First FDA-Approved Vaccine for the Prevention of Dengue Disease in Endemic Regions. 2019. Available online: https://www.fda.gov/news-events/press-announcements/first-fda-approved-vaccine-prevention-dengue-disease-endemic-regions (accessed on 22 October 2022).
  8. Sanofi—Aventis Press Release: Dengvaxia® Vaccine Approved for Prevention of Dengue in Europe. 2018. Available online: https://www.sanofi.com/en/media-room/press-releases/2018/2018-12-19-12-00-00-1669374 (accessed on 22 October 2022).
  9. Rathore, A.P.; Farouk, F.S.; John, A.L.S. Risk factors and biomarkers of severe dengue. Curr. Opin. Virol. 2020, 43, 1–8. [Google Scholar] [CrossRef]
  10. Ahmed, S.; Finkelstein, J.L.; Stewart, A.M.; Kenneth, J.; Polhemus, M.E.; Endy, T.P.; Cardenas, W.; Mehta, S. Micronutrients and dengue. Am. J. Trop. Med. Hyg. 2014, 91, 1049–1056. [Google Scholar] [CrossRef] [Green Version]
  11. Alagarasu, K.; Bachal, R.V.; Bhagat, A.B.; Shah, P.S.; Dayaraj, C. Elevated levels of vitamin D and deficiency of mannose binding lectin in dengue hemorrhagic fever. Virol. J. 2012, 9, 86. [Google Scholar] [CrossRef] [Green Version]
  12. Arboleda Alzate, J.F.; Rodenhuis-Zybert, I.A.; Hernández, J.C.; Smit, J.M.; Urcuqui-Inchima, S. Human macrophages differentiated in the presence of vitamin D3 restrict dengue virus infection and innate responses by downregulating mannose receptor expression. PLoS Negl. Trop. Dis. 2017, 11, e0005904. [Google Scholar] [CrossRef]
  13. Giraldo, D.M.; Cardona, A.; Urcuqui-Inchima, S. High-dose of vitamin D supplement is associated with reduced susceptibility of monocyte-derived macrophages to dengue virus infection and pro-inflammatory cytokine production: An exploratory study. Clin. Chim. Acta 2018, 478, 140–151. [Google Scholar] [CrossRef] [PubMed]
  14. Loke, H.; Bethell, D.; Farrar, J.; Day, N.; Phuong, C.X.T.; Hill, A.; White, N. Susceptibility to dengue hemorrhagic fever in vietnam: Evidence of an association with variation in the vitamin d receptor and Fc gamma receptor IIa genes. Am. J. Trop. Med. Hyg. 2002, 67, 102–106. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Puerta-Guardo, H.; Medina, F.; De la Cruz Hernández, S.I.; Rosales, V.H.; Ludert, J.E.; del Angel, R.M. The 1α,25-dihydroxy-vitamin D3 reduces dengue virus infection in human myelomonocyte (U937) and hepatic (Huh-7) cell lines and cytokine production in the infected monocytes. Antivir. Res. 2012, 94, 57–61. [Google Scholar] [CrossRef] [PubMed]
  16. Villamor, E.; Villar, L.A.; Lozano, A.; Herrera, V.M.; Herrán, O.F. Vitamin D serostatus and dengue fever progression to dengue hemorrhagic fever/dengue shock syndrome. Epidemiology Infect. 2017, 145, 2961–2970. [Google Scholar] [CrossRef] [Green Version]
  17. Voge, N.V.; Perera, R.; Mahapatra, S.; Gresh, L.; Balmaseda, A.; Loroño-Pino, M.A.; Hopf-Jannasch, A.S.; Belisle, J.T.; Harris, E.; Blair, C.D.; et al. Metabolomics-Based Discovery of Small Molecule Biomarkers in Serum Associated with Dengue Virus Infections and Disease Outcomes. PLOS Negl. Trop. Dis. 2016, 10, e0004449. [Google Scholar] [CrossRef]
  18. Iqtadar, S.; Akbar, N.; Huma, N.; Randhawa, F.A. Profile of hepatic involvement in dengue infections in adult Pakistani population. Pak. J. Med. Sci. 2017, 33, 963–967. [Google Scholar] [CrossRef]
  19. de Souza, L.J.; Nogueira, R.M.; Soares, L.C.; Soares, C.E.; Ribas, B.F.; Alves, F.P.; Vieira, F.R.; Pessanha, F.E.B. The impact of dengue on liver function as evaluated by aminotransferase levels. Braz. J. Infect. Dis. 2007, 11, 407–410. [Google Scholar] [CrossRef] [Green Version]
  20. Fernando, S.; Wijewickrama, A.; Gomes, L.; Punchihewa, C.T.; Madusanka, S.D.P.; Dissanayake, H.; Jeewandara, C.; Peiris, H.; Ogg, G.S.; Malavige, G.N. Patterns and causes of liver involvement in acute dengue infection. BMC Infect. Dis. 2016, 16, 319. [Google Scholar] [CrossRef] [Green Version]
  21. Leowattana, W.; Leowattana, T. Dengue hemorrhagic fever and the liver. World J. Hepatol. 2021, 13, 1968–1976. [Google Scholar] [CrossRef]
  22. Mahmuduzzaman, M.; Chowdhury, A.S.; Ghosh, D.K.; Kabir, I.M.; Rahman, M.A.; Ali, M.S. Serum transaminase level changes in dengue fever and its correlation with disease severity. Mymensingh Med. J. 2011, 20, 349–355. [Google Scholar]
  23. Md Sani, S.S.; Han, W.H.; Bujang, M.A.; Ding, H.J.; Ng, K.L.; Amir Shariffuddin, M.A. Evaluation of creatine kinase and liver enzymes in identification of severe dengue. BMC Infect. Dis. 2017, 17, 505. [Google Scholar] [CrossRef] [PubMed]
  24. Diamond, M.S.; Edgil, D.; Roberts, T.G.; Lu, B.; Harris, E. Infection of Human Cells by Dengue Virus Is Modulated by Different Cell Types and Viral Strains. J. Virol. 2000, 74, 7814–7823. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Gil, L.; Martínez, G.; Tápanes, R.; Castro, O.; González, D.; Bernardo, L.; Vázquez, S.; Kourí, G.; Guzmán, M. Oxidative stress in adult dengue patients. Am. J. Trop. Med. Hyg. 2004, 71, 652–657. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Martina, B.E.E.; Koraka, P.; Osterhaus, A.D.M.E. Dengue Virus Pathogenesis: An Integrated View. Clin. Microbiol. Rev. 2009, 22, 564–581. [Google Scholar] [CrossRef] [Green Version]
  27. Haas, M.J.; Jafri, M.; Wehmeier, K.R.; Onstead-Haas, L.M.; Mooradian, A.D. Inhibition of endoplasmic reticulum stress and oxidative stress by vitamin D in endothelial cells. Free. Radic. Biol. Med. 2016, 99, 1–10. [Google Scholar] [CrossRef]
  28. Datan, E.; Roy, S.G.; Germain, G.; Zali, N.; McLean, J.E.; Golshan, G.; Harbajan, S.; Lockshin, R.A.; Zakeri, Z. Dengue-induced autophagy, virus replication and protection from cell death require ER stress (PERK) pathway activation. Cell Death Dis. 2016, 7, e2127. [Google Scholar] [CrossRef] [Green Version]
  29. Lee, Y.-R.; Kuo, S.-H.; Lin, C.-Y.; Fu, P.-J.; Lin, Y.-S.; Yeh, T.-M.; Liu, H.-S. Dengue virus-induced ER stress is required for autophagy activation, viral replication, and pathogenesis both in vitro and in vivo. Sci. Rep. 2018, 8, 489. [Google Scholar] [CrossRef] [Green Version]
  30. Langerman, S.D.; Ververs, M. Micronutrient Supplementation and Clinical Outcomes in Patients with Dengue Fever. Am. J. Trop. Med. Hyg. 2021, 104, 45–51. [Google Scholar] [CrossRef]
  31. Dissanayake, S.; Tennekoon, S.; Gaffoor, S.; Liyanage, G. Vitamin D Deficiency in Dengue Hemorrhagic Fever and Dengue Shock Syndrome among Sri Lankan Children: A Case-Control Study. J. Trop. Med. 2021, 2021, 4173303. [Google Scholar] [CrossRef]
  32. Fatima, H.; Riaz, M.; Mahmood, Z.; Yousaf, F.; Shahid, M. Dengue viral infection deteriorates vitamin D3, K, thrombopoietin, and angiotensinogen levels in humans. Eur. J. Inflamm. 2018, 16, 1–5. [Google Scholar] [CrossRef] [Green Version]
  33. Sadarangani, S.; Htun, H.; Ling, W.; Hawkins, R.; Yeo, T.; Rivino, L.; MacAry, P.; Leo, Y. Association of systemic vitamin D on the course of dengue virus infection in adults: A single-centre dengue cohort study at a large institution in Singapore. Singap. Med. J. 2022. published ahead of print. [Google Scholar] [CrossRef] [PubMed]
  34. Sánchez-Valdéz, E.; Delgado-Aradillas, M.; Torres-Martínez, J.A.; Torres-Benítez, J.M. Clinical response in patients with dengue fever to oral calcium plus vitamin D administration: Study of 5 cases. Proc. West. Pharmacol. Soc. 2009, 52, 14–17. [Google Scholar] [PubMed]
  35. Zaman, S.; Mahmud, M.R.; Ali, M.A.; Zahid, A.; Khalid, S.; Kabir, I.; Manzoor, S.; Zaman, H.Z.; Mahmud, M.R.; Khalid, M.A.; et al. Effectiveness of Vitamin D in Prevention of Dengue Haemorrhagic Fever and Dengue Shock Syndrome. JRMC 2017, 21, 205–207. [Google Scholar]
  36. Alvarez, N.; Aguilar-Jimenez, W.; Rugeles, M.T. The Potential Protective Role of Vitamin D Supplementation on HIV-1 Infection. Front. Immunol. 2019, 10, 2291. [Google Scholar] [CrossRef] [PubMed]
  37. Gal-Tanamy, M.; Bachmetov, L.; Ravid, A.; Koren, R.; Erman, A.; Tur-Kaspa, R.; Zemel, R. Vitamin D: An innate antiviral agent suppressing hepatitis C virus in human hepatocytes. Hepatology 2011, 54, 1570–1579. [Google Scholar] [CrossRef] [PubMed]
  38. Gupta, S.; Read, S.A.; Shackel, N.A.; Hebbard, L.; George, J.; Ahlenstiel, G. The Role of Micronutrients in the Infection and Subsequent Response to Hepatitis C Virus. Cells 2019, 8, 603. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Alagarasu, K.; Honap, T.; Mulay, A.P.; Bachal, R.V.; Shah, P.S.; Cecilia, D. Association of vitamin D receptor gene polymorphisms with clinical outcomes of dengue virus infection. Hum. Immunol. 2012, 73, 1194–1199. [Google Scholar] [CrossRef] [PubMed]
  40. Alagarasu, K. Immunomodulatory effect of vitamin D on immune response to dengue virus infection. Vitam. Horm. 2021, 117, 239–252. [Google Scholar] [CrossRef]
  41. Arboleda, J.F.; Urcuqui-Inchima, S. Vitamin D-Regulated MicroRNAs: Are They Protective Factors against Dengue Virus Infection? Adv. Virol. 2016, 2016, 1016840. [Google Scholar] [CrossRef] [Green Version]
  42. Nagpal, S.; Na, S.; Rathnachalam, R. Noncalcemic Actions of Vitamin D Receptor Ligands. Endocr. Rev. 2005, 26, 662–687. [Google Scholar] [CrossRef]
  43. Alagarasu, K.; Patil, P.S.; Shil, P.; Seervi, M.; Kakade, M.; Tillu, H.; Salunke, A. In-vitro effect of human cathelicidin antimicrobial peptide LL-37 on dengue virus type 2. Peptides 2017, 92, 23–30. [Google Scholar] [CrossRef] [PubMed]
  44. Aranow, C. Vitamin D and the immune system. J. Investig. Med. 2011, 59, 881–886. [Google Scholar] [CrossRef] [PubMed]
  45. Kongsbak, M.; Levring, T.B.; Geisler, C.; von Essen, M.R. The vitamin d receptor and T cell function. Front. Immunol. 2013, 4, 148. [Google Scholar] [CrossRef] [Green Version]
  46. Rigby, W.F.; Shen, L.; Ball, E.D.; Guyre, P.M.; Fanger, M.W. Differentiation of a human monocytic cell line by 1,25-dihydroxyvitamin D3 (calcitriol): A morphologic, phenotypic, and functional analysis. Blood 1984, 64, 1110–1115. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Torres, C.; Sanchez-De-La-Torre, M.; Garcia-Moruja, C.; Carrero, A.J.; Trujillo, M.D.M.; Fibla, J.; Caruz, A. Immunophenotype of Vitamin D Receptor Polymorphism Associated to Risk of HIV-1 Infection and Rate of Disease Progression. Curr. HIV Res. 2010, 8, 487–492. [Google Scholar] [CrossRef]
  48. Bitetto, D.; Fabris, C.; Fornasiere, E.; Pipan, C.; Fumolo, E.; Cussigh, A.; Bignulin, S.; Cmet, S.; Fontanini, E.; Falleti, E.; et al. Vitamin D supplementation improves response to antiviral treatment for recurrent hepatitis C. Transpl. Int. 2010, 24, 43–50. [Google Scholar] [CrossRef] [PubMed]
  49. Ravid, A.; Rapaport, N.; Issachar, A.; Erman, A.; Bachmetov, L.; Tur-Kaspa, R.; Zemel, R. 25-Hydroxyvitamin D Inhibits Hepatitis C Virus Production in Hepatocellular Carcinoma Cell Line by a Vitamin D Receptor-Independent Mechanism. Int. J. Mol. Sci. 2019, 20, 2367. [Google Scholar] [CrossRef] [Green Version]
  50. Jadhav, N.J.; Gokhale, S.; Seervi, M.; Patil, P.S.; Alagarasu, K. Immunomodulatory effect of 1, 25 dihydroxy vitamin D3 on the expression of RNA sensing pattern recognition receptor genes and cytokine response in dengue virus infected U937-DC-SIGN cells and THP-1 macrophages. Int. Immunopharmacol. 2018, 62, 237–243. [Google Scholar] [CrossRef]
Tropicalmed 08 00043 g001 550
Figure 1. Prevalence of VDD by dengue stage on admission to hospital. Fisher’s exact p-value = 0.705.
Figure 1. Prevalence of VDD by dengue stage on admission to hospital. Fisher’s exact p-value = 0.705.
Tropicalmed 08 00043 g001
Table
Table 1. Patients’ demographic and clinical characteristics, overall and by vitamin D levels, at the time of hospitalisation.
Table 1. Patients’ demographic and clinical characteristics, overall and by vitamin D levels, at the time of hospitalisation.
Clinical SymptomOverall (n = 97)Patients with Vit D
<20 ng/mL (n = 75)		Patients with Vit D
≥20 ng/mL (n = 22)		p-Value
Age, median (IQR), years30.0 (22.0, 42.0)30.0 (21.5, 39.0)35.0 (30.0, 50.0)0.026
Gender, male, n%55 (56.7)43 (57.3)12 (54.5)0.812
Serology (n%)
NS1+28 (28.9)21 (28.0)7 (31.8)0.617
NS1+, IgM+8 (8.2)8 (10.7)0 (0.0)
IgM+44 (45.4)33 (44.0)11 (50.0)
IgM+, IgG+16 (16.5)12 (16.0)4 (18.2)
NS1+, IgM+, IgG+1 (1)1 (1.3)0 (0.0)
Dengue presentations, median (IQR) days5.0 (5.0, 6.0)5.0 (5.0, 6.0)5.0 (5.0, 5.0)0.293
Dengue Symptoms (n%)
Fever97 (100.0)75 (100.0)22 (100.0)>0.99
Bodyaches84 (86.6)64 (85.3)20 (90.9)0.726
Abdominal pain18 (18.6)14 (18.7)4 (18.2)>0.99
Headache20 (20.6)16 (21.3)4 (18.2)>0.99
Epistaxis15 (15.5)13 (17.3)2 (9.1)0.508
Vomiting14 (14.4)11 (14.7)3 (13.6)>0.99
Arthralgia10 (10.3)5 (6.7)5 (22.7)0.044
Hematemesis5 (5.2)3 (4.0)2 (9.1)0.317
Gum bleed4 (4.1)3 (4.0)1 (4.5)>0.99
Malena3 (3.1)3 (4.0)0 (0.0)>0.99
Haemoptysis3 (3.1)3 (4.0)0 (0.0)>0.99
Loose stools3 (3.1)2 (2.7)1 (4.5)0.542
Hematuria1 (1.0)1 (1.3)0 (0.0)>0.99
Nausea2 (2.1)1 (1.3)1 (4.5)0.403
Rectal bleeding2 (2.1)2 (2.7)0 (0.0)>0.99
PV Bleeding2 (2.1)2 (2.7)0 (0.0)>0.99
Others3 (3.1)3 (4.0)0 (0.0)>0.99
Previous Dengue infection, n%2 (2.1)2 (2.7)0 (0.0)>0.99
Previous vitamin D intake, n%6 (6.2)2 (2.7)4 (18.2)0.022
Vitamin D level, median (IQR), ng/mL12.2 (9.1, 17.8)10.6 (8.4, 12.7)28.9 (25.7, 42.5)
n: numbers of patients. n (%) and median (IQR) are shown for categorical and continuous measures, respectively.
Table
Table 2. Serum vitamin D levels at the time of hospitalization.
Table 2. Serum vitamin D levels at the time of hospitalization.
Dengue Fever SeveritySerum Vitamin D Level, Median (IQR) ng/mL
Overall (n = 97)12.2 (9.1, 17.8)
DF (n = 37)12.5 (8.1, 20.2)
DHF grade 1 and 2 (n = 52)12.4 (10.3, 17.7)
DHF grade 3 and 4 (DSS) (n = 8)9.5 (7.9, 11.9)
n: numbers of patients.
Table
Table 3. Patient’s laboratory biochemistry.
Table 3. Patient’s laboratory biochemistry.
BiochemistryOverall (n = 97)Patients with Vit D
<20 ng/mL (n = 75)		Patients with Vit D
≥20 ng/mL (n = 22)		p-Value
Liver enzymesn = 57n = 47n = 10
Abnormal Bilirubin, n%13 (22.8)11 (23.4)2 (20.0)>0.99
Median (IQR), mg/dL0.6 (0.4, 0.9)0.7 (0.4, 0.9)0.6 (0.5, 1.1)0.723
Abnormal AST, n%49 (86.0)40 (85.1)9 (90.0)>0.99
Median (IQR), IU/L132.0 (73.0, 194.0)131.0 (73.0, 186.5)143.0 (124.8, 385.2)0.341
Abnormal ALT, n%49 (86.0)40 (85.1)9 (90.0)>0.99
Median (IQR), IU/L73.0 (47.0, 139.0)70.0 (46.0, 132.5)80.0 (54.5, 211.5)0.393
Complete blood count
Haemoglobin, median (IQR), g/dL13.2 (12.0, 14.5)13.1 (12.0, 14.5)13.7 (12.3, 14.7)0.725
Total leukocyte count, median (IQR) × 109/L4.7 (3.8, 6.2)4.6 (3.8, 6.0)5.8 (4.0, 7.4)0.470
Haematocrit, median (IQR) %43.0 (41.0, 47.0)43.6 (41.0, 47.5)43.0 (41.0, 46.2)0.285
Platelets, median (IQR) × 109/L30.5 (20.0, 53.0)30.5 (20.0, 51.5)30.5 (21.0, 55.0)0.681
Neutrophil, median (IQR) %54.1 (43.0, 68.0)54.0 (43.5, 68.0)58.8 (43.2, 67.0)0.963
Lymphocyte, median (IQR) %31.5 (24.0, 39.0)31.6 (24.0, 39.0)30.4 (24.2, 41.5)0.724
n: numbers of patients. Reference range: Bilirubin: 0.2–1.2 mg/dL; AST: 1–45 IU/L; ALT: 0–40 IU/L, Haemoglobin: 13.6–16.2; Leukocyte count: 4.5–11 × 109; haematocrit: 41–50%; platelets count: 150–450 × 109/L; Neutrophile: 50–70%; Lymphocyte: 20–40%.
Table
Table 4. Radiology and circulatory disease parameters by vitamin D deficiency status.
Table 4. Radiology and circulatory disease parameters by vitamin D deficiency status.
Clinical CharacteristicOverall
(n = 97)		Vitamin D
<20 ng/mL
(n = 75)		Vitamin D
≥20 ng/mL
(n = 22)		p-Value
Chest x-ray (n%)
Right-side fleural effusion6 (6.2)4 (5.3)2 (9.1)-
Bilateral fleural effusion2 (2.1)1 (1.3)1 (4.5)-
Unremarkable89 (91.8)70 (93.3)19 (86.4)0.346
Ultrasound (n%)
Pericholecystic fluid16 (16.5)12 (16.0)4 (18.2)-
Ascites9 (9.3)8 (10.7)1 (4.5)-
Pericholecystic fluid + Ascites26 (26.8)23 (30.7)3 (13.6)-
Hepatomegaly/hepatosplenomegaly2 (2.1)2 (2.7)0 (0.0)-
Unremarkable43 (44.3)29 (38.7)14 (63.6)0.357
Circulatory system
Pulse rate, BPM, median (IQR)90.0 (90.0, 100.0)92.0 (90.0, 100.0)90.0 (81.8, 100.0)0.309
Systolic BP, median (IQR) (mm Hg)110.0 (100.0, 120.0)110.0 (100.0, 117.5)110.0 (101.2, 120.0)0.728
Diastolic BP, median (IQR) (mm Hg)70.0 (60.0, 80.0)70.0 (60.0, 80.0)70.0 (61.2, 80.0)0.765
Postural drop ≥ 10 (mm Hg)41 (42.2)36 (48.6)5 (23.8)0.049
CRT ≥ 2 s n%10 (10.3)9 (12.0)1 (4.5)0.447
n: numbers of patients.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Iqtadar, S.; Khan, A.; Mumtaz, S.U.; Livingstone, S.; Chaudhry, M.N.A.; Raza, N.; Zahra, M.; Abaidullah, S. Vitamin D Deficiency (VDD) and Susceptibility towards Severe Dengue Fever—A Prospective Cross-Sectional Study of Hospitalized Dengue Fever Patients from Lahore, Pakistan. Trop. Med. Infect. Dis. 2023, 8, 43. https://doi.org/10.3390/tropicalmed8010043

AMA Style

Iqtadar S, Khan A, Mumtaz SU, Livingstone S, Chaudhry MNA, Raza N, Zahra M, Abaidullah S. Vitamin D Deficiency (VDD) and Susceptibility towards Severe Dengue Fever—A Prospective Cross-Sectional Study of Hospitalized Dengue Fever Patients from Lahore, Pakistan. Tropical Medicine and Infectious Disease. 2023; 8(1):43. https://doi.org/10.3390/tropicalmed8010043

Chicago/Turabian Style

Iqtadar, Somia, Amjad Khan, Sami Ullah Mumtaz, Shona Livingstone, Muhammad Nabeel Akbar Chaudhry, Nauman Raza, Mehreen Zahra, and Sajid Abaidullah. 2023. "Vitamin D Deficiency (VDD) and Susceptibility towards Severe Dengue Fever—A Prospective Cross-Sectional Study of Hospitalized Dengue Fever Patients from Lahore, Pakistan" Tropical Medicine and Infectious Disease 8, no. 1: 43. https://doi.org/10.3390/tropicalmed8010043

APA Style

Iqtadar, S., Khan, A., Mumtaz, S. U., Livingstone, S., Chaudhry, M. N. A., Raza, N., Zahra, M., & Abaidullah, S. (2023). Vitamin D Deficiency (VDD) and Susceptibility towards Severe Dengue Fever—A Prospective Cross-Sectional Study of Hospitalized Dengue Fever Patients from Lahore, Pakistan. Tropical Medicine and Infectious Disease, 8(1), 43. https://doi.org/10.3390/tropicalmed8010043

Article Metrics

Back to TopTop