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REVIEW ARTICLE
Year : 2014  |  Volume : 4  |  Issue : 4  |  Page : 314-316

Dengue and Calcium


1 University Medical Unit, National Hospital of Sri Lanka, Colombo, Sri Lanka
2 Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka

Date of Web Publication23-Dec-2014

Correspondence Address:
Dr. Mitrakrishnan C Shivanthan
University Medical Unit, National Hospital of Sri Lanka, Regent Street, Colombo 08, Sri Lanka
Sri Lanka
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2229-5151.147538

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   Abstract 

Dengue is potentially fatal unless managed appropriately. No specific treatment is available and the mainstay of treatment is fluid management with careful monitoring, organ support, and correction of metabolic derangement. Evidence with regards to the role of calcium homeostasis in dengue is limited. Low blood calcium levels have been demonstrated in dengue infection and hypocalcemia maybe more pronounced in more severe forms. The cause of hypocalcemia is likely to be multifactorial. Calcium has been also implicated in the immuopathogenesis of dengue; however, the precise clinical implications of these interactions are yet not clearly defined. Derangements of calcium homeostasis are likely to be associated with myocardial dysfunction and cardiac arrhythmias observed in dengue as suggested by in vitro studies. Calcium also plays a role in platelet aggregation. Studies evaluating the therapeutic use of calcium in dengue have been underpowered and poorly designed to make any firm recommendations. Further studies are needed to explore the role and usefulness of maintenance of calcium homeostasis in modulating cardiac dysfunction, immunopathogenesis, and platelet abnormalities related to dengue.

Keywords: Calcium, dengue, hypocalcemia, myocarditis


How to cite this article:
Shivanthan MC, Rajapakse S. Dengue and Calcium. Int J Crit Illn Inj Sci 2014;4:314-6

How to cite this URL:
Shivanthan MC, Rajapakse S. Dengue and Calcium. Int J Crit Illn Inj Sci [serial online] 2014 [cited 2020 Feb 24];4:314-6. Available from: http://www.ijciis.org/text.asp?2014/4/4/314/147538


   Introduction Top


Dengue is endemic in over 100 countries. Infection with the dengue virus may be asymptomatic or may give rise to a spectrum of clinical illness, ranging from undifferentiated fever to a severe life threatening hemorrhagic/shock syndrome with multiple organ failure and fatality. Early recognition of dengue with prompt and appropriate treatment is vital to limit morbidity and mortality. [1] Recent guidelines, [2] which have built on the wealth of experience in managing these patients over recent years have made management strategies more well defined. In brief, the mainstay of management of dengue is based on careful fluid management and monitoring, together with provision of organ support and correction of metabolic derangement where necessary. No specific treatment is available, although steroids and immunoglobulins have been used in the past with little evidence-based benefit.

Hypocalcemia has been documented in dengue infection [3],[4],[5] and is seen more frequently in patients with severe dengue. [4] Nonetheless, evidence with regards to the role of calcium homeostasis in dengue is limited, and current recommendations do not mention the need to monitor or correct blood calcium levels in dengue. In this paper, we discuss the key issues in relation to calcium and dengue infection, focusing on the current evidence on the role of calcium, both intracellular and extracellular, in the pathophysiology and complications of dengue; the causes and effects of low blood calcium levels and the potential place for correction of low calcium levels as well as calcium supplementation as a treatment for dengue infection. Further, we attempt to identify gaps in the understanding of the relationship between calcium homeostasis and dengue infection and suggest key target areas for future basic sciences and clinical research.


   Materials and Methods Top


Pubmed was searched for papers containing the keywords 'dengue' with any of the following: 'Calcium', 'hypocalcemia', and 'hypocalcaemia' in any combination in the title, abstract, or medical subject headings (MeSH) terms. The search was not time restricted. There were 37 abstracts found during the search. Endnote X5 ® was used to filter the papers. All authors read through all 37 papers; the full text was read through in these. Related references were also included. Twenty papers provided relevant information regarding the role of calcium pertaining to calcium homeostasis, immunopathogenesis, cardiac dysfunction, and treatment of dengue.

Hypocalcemia in dengue

Hypocalcemia has been demonstrated in other tropical diseases, such as leptospirosis and malaria, and is more commonly seen in severe infection; however, the clinical effects of low blood calcium levels in these conditions are unclear. [6] Several causes for low blood calcium levels have been suggested, including reduced Na+-K adenosine triphosphatase (ATPase) activity, reduced Ca 2+ -ATPase activity, acquired parathyroid hormone deficiency, renal one-alpha hydroxylase insufficiency, reduced dietary vitamin D intake, and reduced dietary calcium intake. [7] Low blood calcium levels have been demonstrated in dengue infection [3],[4],[5],[8] and maybe present in over 80% of patients. [3] It is often underrecognized but can present with tetany. [8] There is little information on the other effects of hypocalcemia, e.g., effects on cardiac rhythm and contractility. There is some evidence that hypocalcemia maybe more pronounced in more severe forms of dengue, [4] although lower calcium levels have not shown an association with mortality. [3]

The possible role of calcium in the immuopathogenesis of dengue

In in vitro studies, depletion of Mg 2+ and Ca 2+ has been shown to enhance binding of dengue virus to monocyte macrophages and cells of T cell and B cell lineages. [9] Ca 2+ has been shown to be essential for cytotoxic activity of the dengue type 2 virus (DV)-induced macrophage cytotoxin (CF2); cell death has been shown to be associated with increased intracellular Ca 2+ . [10],[11] Ca 2+ appears to play a role in the induction of dengue-specific T-helper cells. Dengue antigen has been shown to increase the influx of Ca 2+ into T-cells. The proliferation of dengue-specific T-helper cells appears to be dependent on Ca 2+ and is inhibited in the absence of Ca 2+ and by calcium channel antagonist drugs. [12] In another in vitro study, production of DV-induced suppressor cytokine (SF) by cultured spleen cells was inhibited when the medium was depleted of calcium; production was restored by addition of calcium to the medium. Both the production of SF and transmission of the suppressor signal via syngeneic macrophage (M phi) to recruit the second subpopulation of suppressor T (TS2) cell were inhibited in a dose-dependent manner by the calcium channel antagonists verapamil and nifedipine. [13] There is some evidence that the production of nitrite in response to dengue virus infection is also calcium dependent and can be inhibited by calcium channel blocking drugs. [14],[15] Thus, calcium appears to play a role in the immune response in dengue, although the interactions are complex, and the precise clinical implications of these interactions are yet not clearly defined.

Calcium and the myocardium in dengue

Calcium plays a key role in the functioning of myocardial tissue. Cardiac involvement in dengue has been documented in many studies, although little is known about its actual pathogenesis. [16],[17] Dengue myocarditis may present with a variety of features including electrocardiographic changes (sinus bradycardia, tachycardia, T-wave inversions of electrocardiography (ECG)), pericardial effusion, impairment of diastolic function, and pathologically elevated levels of creatine phosphokinase myocardial band (CPK-MB). It has been proposed that the derangements of Ca 2+ storage in the infected myocardial cells may directly contribute to the development of myocarditis. Salgado et al., [18] attempted to test the hypothesis that striated muscle is a target of dengue infection and that alterations in calcium homeostasis was associated with myocardial dysfunction in dengue infection. In this in vitro study, human skeletal myotubes were exposed to dengue virus in vitro and intracellular Ca 2+ changes were assayed. Dengue virus capsid proteins were demonstrated in myotubes by confocal immunofluorescence microscopy, confirming virus infection and replication in myotubes. An increase in resting intracellular Ca 2+ was demonstrated in infected skeletal myotubes when compared with non-exposed controls. The authors suggested that this increase in resting (i.e. diastolic) Ca 2+ levels in infected myocardium may be responsible for arrhythmias and altered contractile function.

The potential role of calcium in treatment of dengue

Calcium is needed for platelet aggregation, although its precise role is not known. [19],[20] In a case series of just five patients suffering from dengue fever, the administration of oral calcium carbonate and vitamin D3 were reported to result in improvement in clinical condition and platelet counts. However, there was no control group. Platelet counts and clinical features improve spontaneously in dengue; thus these findings are insufficient to conclude that improvement was a result of the intervention. [21] In a case controlled study of 10 patients with clinical features of dengue in each arm, a significant increase in the platelet counts was observed following oral administration of calcium carbonate. Significant clinical improvement, with shorter time to defervescence and clinical recovery was also seen in the treatment arm. [22] Overall, there is no hard evidence of benefit that calcium supplementation is beneficial in dengue, although the limited evidence suggests that it is an area needing further study.


   Conclusions Top


Hypocalcemia is seen in cases with severe dengue and has been purported to be associated with increased mortality. In vitro studies on animals and human tissue link calcium with the infectivity of dengue virus and the immune response to dengue. Intracellular calcium derangements have been linked with myocarditis and dengue-related cardiac dysfunction. Nonetheless, there is a paucity of clinical evidence on the role of calcium disequilibrium in dengue, the clinical effects of hypocalcemia in dengue and on the interactions between blood calcium ions and the immunopathogenesis of the disease. Although hypocalcemia has been observed in dengue, there is no evidence currently that this hypocalcemia has significant clinical implications. There is little evidence on the role, if any, of calcium replacement in patients with dengue who are hypocalcemic. The potential role of calcium as therapy to modulate the immune system, in either hypocalcemic or normocalcemic patients with dengue is unknown. Though the routine use of calcium in patients with dengue fever cannot be routinely recommended, maintenance of calcium homeostasis in critical dengue patients should be decided on a case by case basis by experienced clinicians. Further well-designed studies are needed in this area that has not been adequately addressed to date. We suggest the following target areas for research:

  1. Clinical studies to identify the incidence and clinical effects of hypocalcemia, in particular, effects on skeletal and cardiac muscle
  2. Basic sciences research aimed at understanding the effects of hypocalcemia on the immune response in dengue
  3. Adequately powered randomized controlled trials of calcium, given intravenously or orally, in patients with dengue associated with hypocalcemia and normocalcemia, with clinical recovery, prevention of shock, and improvement in thrombocytopenia as outcome measures.


 
   References Top

1.
Malavige GN, Fernando S, Fernando DJ, Seneviratne SL. Dengue viral infections. Postgrad Med J 2004;80:588-601.  Back to cited text no. 1
    
2.
WHO. Handbook for the clinical management of dengue. Available from: http://apps.who.int/iris/bitstream/10665/76887/1/9789241504713_eng.pdf [Last accessed on 2012 Dec 26].  Back to cited text no. 2
    
3.
Bunnag T, Kalayanarooj S; Dengue shock syndrome at the emergency room of Queen Sirikit National Institute of Child Health, Bangkok, Thailand. J Med Assoc Thai 2011;94:S57-63.  Back to cited text no. 3
    
4.
Uddin KN, Musa AKM, Haque WMM, Sarker RSC, Ahmed AKMS. A follow up on biochemical parameters in dengue patients attending BIRDEM hospital. Ibrahim Med Coll J 2008;2:25-7.  Back to cited text no. 4
    
5.
Kapoor S, Singh A. Hypocalcemic tetany: An infrequently recognized association with acute dengue infection. Indian J Pediatr 2012;79:1673.  Back to cited text no. 5
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6.
Sitprija V. Altered fluid, electrolyte and mineral status in tropical disease, with an emphasis on malaria and leptospirosis. Nat Clin Pract Nephrol 2008;4:91-101.  Back to cited text no. 6
    
7.
Zaloga GP, Chernow B. The multifactorial basis for hypocalcemia during sepsis. Studies of the parathyroid hormone-vitamin D axis. Ann Intern Med 1987;107:36-41.  Back to cited text no. 7
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8.
Wiwanitkit S, Wiwanitkit V. Hypocalcemia, tetany and dengue. Indian J Pediatr 2012;80:618.  Back to cited text no. 8
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9.
Bielefeldt-Ohmann H, Meyer M, Fitzpatrick DR, Mackenzie JS. Dengue virus binding to human leukocyte cell lines: Receptor usage differs between cell types and virus strains. Virus Res 2001;73:81-9.  Back to cited text no. 9
    
10.
Dhawan R, Chaturvedi UC, Khanna M, Mathur A, Tekwani BL, Pandey VC. Obligatory role of Ca2+in the cytotoxic activity of dengue virus-induced cytotoxin. Int J Exp Pathol 1991;72:31-9.  Back to cited text no. 10
    
11.
Khanna M, Chaturvedi UC, Dhawan R, Tekwani BL, Pandey VC. Presence of Ca 2+ is obligatory for the cytotoxic activity of dengue virus-induced cytotoxic factor. Immunology 1991;72:73-8.  Back to cited text no. 11
    
12.
Chaturvedi P, Saxena V, Dhawan R, Chaturvedi UC. Role of calcium in induction of dengue virus-specific helper T cells. Indian J Exp Biol 1995;33:809-15.  Back to cited text no. 12
    
13.
Khare M, Chaturvedi UC. Transmission of dengue virus-specific suppressor signal depends on the presence of calcium. Indian J Med Res 1995;102:1-8.  Back to cited text no. 13
    
14.
Misra A, Mukerjee R, Chaturvedi UC. Production of nitrite by dengue virus-induced cytotoxic factor. Clin Exp Immunol 1996;104:406-11.  Back to cited text no. 14
    
15.
Mukerjee R, Misra A, Chaturvedi UC. Dengue virus-induced cytotoxin releases nitrite by spleen cells. Int J Exp Pathol 1996;77:45-51.  Back to cited text no. 15
    
16.
Wichmann D, Kularatne S, Ehrhardt S, Wijesinghe S, Brattig NW, Abel W, et al. Cardiac involvement in dengue virus infections during the 2004/2005 dengue fever season in Sri Lanka. Southeast Asian J Trop Med Public Health 2009;40:727-30.  Back to cited text no. 16
    
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Kularatne SA, Pathirage MM, Kumarasiri PV, Gunasena S, Mahindawanse SI. Cardiac complications of a dengue fever outbreak in Sri Lanka, 2005. Trans R Soc Trop Med Hyg 2007;101:804-8.  Back to cited text no. 17
    
18.
Salgado DM, Eltit JM, Mansfield K, Panqueba C, Castro D, Vega MR, et al. Heart and skeletal muscle are targets of dengue virus infection. Pediatr Infect Dis J 2010;29:238-42.  Back to cited text no. 18
    
19.
Authi KS. TRP channels in platelet function. Handb Exp Pharmacol 2007:425-43.  Back to cited text no. 19
    
20.
Colomer J, Means AR. Physiological roles of the Ca 2+ /CaM-dependent protein kinase cascade in health and disease. Subcell Biochem 2007;45:169-214.  Back to cited text no. 20
    
21.
Sanchez-Valdez E, Delgado-Aradillas M, Torres-Martinez JA, Torres-Benítez JM. Clinical response in patients with dengue fever to oral calcium plus vitamin D administration: Study of 5 cases. Proc West Pharmacol Soc 2009;52:14-7.  Back to cited text no. 21
    
22.
Cabrera-Cortina JI, Sanchez-Valdez E, Cedas-DeLezama D, Ramírez-González MD. Oral calcium administration attenuates thrombocytopenia in patients with dengue fever. Report of a pilot study. Proc West Pharmacol Soc 2008;51:38-41.  Back to cited text no. 22
    



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