1. Introduction

Dengue (fever) is an acute viral infection that encompasses a wide spectrum of systemic manifestations ranging from self-limiting febrile episodes to features of severe dengue (SD), dengue hemorrhagic fever (DHF) and dengue hemorrhagic shock (DHS) that may lead to rapid deterioration and invariably death ^[1]. The World Health Organization (WHO) estimates 50 million cases of dengue infection yearly, of which 500,000 of them are cases of DHF and 22,000 mortalities from complications of the disease, while recent cartographic estimates suggest that more accurate figures may reach almost 400 million ^{[2, 3]}. This flavivirus which is spread exclusively by the vectors Aedes aegypti and Aedes albopictus comprises of four antigenically distinct serotypes (DEN1,2,3,4) and confers lifelong serotype-specific immunity ^{[1, 4, 5]}. However, secondary heterotypic dengue infection may still occur and has been commonly linked to severe dengue by epidemiological studies ^{[2, 5]}. The fact that plasma leakage in DHF occurs during the defervescence and viral clearance phase has given rise to the hypothesis that severe dengue is caused by a heightened immune response rather than being a direct effect of dengue ^{[5, 7]}. More specifically, it has been theorized that secondary dengue infection leads to “serotype-cross-reactivation” among memory T cells, contributing to a sub-optimal immune response responsible for the pathology behind severe dengue disease ^[5]. With the rise in global travels, this tropical disease has widely expanded its natural ranges and has re-emerged as a global issue, which is reflected by the increase in incidence by approximately 30-folds worldwide over the past 50 years ^[6]. Given its geographic expansion, clinicians in non-endemic countries should have a high index of clinical suspicion for this disease when treating patients with a recent history of travel. This case series illustrates the non-specific nature and unpredictability of dengue fever, and attempts to clarify the management dilemma when dealing with presentations on both ends of the spectrum.

2. Case Presentation

A 19 year-old Malaysian Indian male presented to the emergency department with two days of high fever associated with myalgia, arthralgia and malaise. He was previously well with no history of recent travel or sick contact. He had no abdominal pain, anorexia or vomiting, nor did he experience any mucosal bleed. Despite his lethargy, he was still able to maintain good oral intake and urine output. Physical examination revealed a temperature of 38°C with otherwise stable vital signs. All systemic examinations were unremarkable. The tourniquet test was negative. His full blood count, renal profile, liver function tests and electrolytes are as shown in Table 1. The NS1 (non structural protein-1) test was reactive, leading to a diagnosis of dengue fever, second day of illness in febrile phase without warning signs. He was discharged home with oral antipyretics and encouraged to maintain adequate oral hydration, as well as to seek immediate treatment if he noticed the presence of any warning signs. He was followed up daily at the outpatient clinic for a week with repeat of daily full blood count to observe the blood parameter trends. His fever subsided on day 5 and on day 7 of his illness, his total white cell and platelet counts began to normalize. He then recovered from his illness without any serious sequelae.

Ms. N, a 26 year old pregnant female of Malay descent 39 weeks gestation presented to us with a two day duration of fever. She had a past obstetric history of gestational diabetes mellitus in which she was on diet control. Her fever was associated with episodic vomiting, epigastric pain, anorexia, malaise, myalgia and arthalgia. Although, she does stay in a dengue prone area, she does not report of being bitten by mosquitos, no history of recent travel, swimming in lakes or sick contact within the family. She had no obvious per vaginal bleed or any other bleeding tendency. She is a non-smoker and a teetotaler. On physical examination, she has good perfusion with warm peripheries. Her blood pressure was 112/68 mmHg with a pulse rate of 112 beats per minute, good pulse volume. Her oral temperature was 39.5 C. She had good oxygen saturation.The tourniquet test was negative. Cardiovascular examination revealed normal heart sounds with no audible murmurs. Lungs were clear on auscultation. Examination of the abdomen revealed a gravid uterus, a singleton pregnancy with an estimated fetal weight (EFW) of 2.8-3kg .There was obvious epigastric tenderness. No features of ascites noted . Her full blood count, renal profile, liver function tests and electrolytes are as shown in Table 1. Transthoracic ultrasonography revealed a singleton pregnancy with normal fetal biometry. There were no signs of retroplacental clot or placental abnormalities. The fetal cardiotocography revealed a baseline heart rate of 165bpm with a variability of 5-15bpm and no deceleration. The non structural protein 1 (NS 1) was reactive leading to the diagnosis of primary dengue fever, first day of illness in febrile phase with warning signs. She was started on intravenous normal saline at a rate of 1.2ml/kg/hr. She was given antipyretics for temperature control and placed on strict input-output charting. Her vital signs were monitored four hourly. On day three of illness, the fetal cardiotocography tracing was less reactive. This lead to the decision to induce labour using prostaglandin E2 by the attending obstetrician. Within six hours of induction, she had an uneventful spontaneous vaginal delivery. She was still in febrile phase post delivery. Her vital signs remained stable post delivery. She entered defervescence phase on day 6 and subsequently she recovered from her dengue fever on day 8 with her blood counts normalizing.

A 86 years old Malaysian Chinese female presented to the hospital with a 4 day history of high fever associated with chills, myalgia, arthralgia, nausea and diarrhea. There was no history of contact with dirty water and no recent travel to the jungle. She is a non smoker and a teetotaler. Her past medical history includes essential hypertension, congestive cardiac failure and chronic kidney disease. On admission, she was alert, pink and febrile to touch. She was not jaundiced. Her oral temperature was 38.5 C. The blood pressure was 100/84 mmHg with a pulse rate of 110 beats per minute. The pulse volume was weak. Her oxygen saturation was 97% on room air. She had a positive tourniquet test. The heart sounds were normal. Lungs revealed bibasal crepitations. Abdominal examination was unremarkable. There was no central nervous system deficit. The blood parameters are as shown in Table 1. Ultrasonography of the kidneys showed bilateral renal parenchymal disease with no evidence of obstructive uropathy. Her arterial blood gas showed moderate metabolic acidosis with respiratory compensation. Her viral hepatitis and retroviral screening were all not reactive. She was given an intravenous fluid bolus of 5 ml/kg/hour (275 ml) of isotonic saline over an hour. Post fluid resuscitation, her capillary perfusion and radial pulse volume improved. Her pulse pressure increased to 30 mmHg. Her fluid balance was carefully monitored by assessing the caval index of the inferior vena cava. She was then maintained on isotonic saline fluid at a rate of 1.2 ml/kg/hour for the first 6 hours. She was anuric for the first three hours followed by good urine output at 0.7 ml/kg/hour. Following her improvement in metabolic acidosis, good urine output and stable vital signs, the rate of the intravenous fluids was reduced by half to 0.6ml/kg/hour and subsequently ceased.

A 40 year old male of Malay descent with a past history of a dengue infection presented to our department with fever for 4 days in duration (day four of illness). This was associated with persistent vomiting of food content, arthralgia, myalgia and right hypochondriac pain. He also had a 4 day history of anorexia for solids but he was able to tolerate liquids. He had no retro-orbital pain or bleeding tendencies. He denied swimming in pools or dirty water but admitted to a few cases of dengue around his neighborhood with a recent history of fogging 3 days ago. He had no significant family history. He works as technician in a local textile factory. He was an otherwise relatively stable patient when he presented to our Emergency Department on day 4 of illness with an admission blood pressure of 115/88 with a heart rate of 110 beats per minute, inadequate pulse volume. He had an oral temperature of 37 C. His peripheral examination was unremarkable. He had a positive tourniquet test. Cardiovascular and respiratory examinations were normal. He had obvious right hypochondriac tenderness with no palpable liver. There was no palpable spleen or ascites. The non structural protein 1 (NS-1) and dengue IgG were positive on day 4 of his illness. He had good urine output. He was diagnosed with dengue fever, day 4 of illness in defervescence phase with warning signs. He was immediately started on 5ml/kg/hr of intravenous normal saline which was subsequently tapered down to 3ml/kg/hr, 2 ml/kg/hr and then single maintenance. However on day 5 of illness, he had worsening vomiting and diarrhea which led him to develop acute kidney injury and metabolic acidosis. His liver enzymes began to worsen. Respiratory and abdominal examination revealed pleural effusion and ascites. He was referred to the anesthetist and transferred to the intensive care unit. He was carefully hydrated with intravenous fluids to avoid over-hydration. Hours later, he complained of frank hematemesis which subsequently lead to generalized hemorrhage from all mucosal cavities. Due to worsening metabolic acidosis and Kussmaul breathing, he was intubated for airway protection on day 6 of illness. His inflammatory marker, the serum ferritin showed an extremely high value of 100 000 with low serum fibrinogen and high serum triglyceride leading to a suspected diagnosis of hemophagocytic syndrome. There was no bone marrow aspiration/trephine biopsy done as family refused consent. Following this, a trial of intravenous methylprednisolone 15 mg/kg daily was administered. His liver and kidney function continued to worsen. Due to the massive hemorrhage, transfusion of whole blood, platelets and fresh frozen plasma were administered. Severe hypotension ensued necessitating multiple vasopressor support. The patient succumbed to death on day 7 of illness due to severe metabolic acidosis and multi-organ failure. His blood parameters are summarised as in Table 2 below.

Table 1.

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Table 2.

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3. Discussion

Dengue is a dynamic disease characterized by three phases, namely a febrile phase, critical phase and recovery phase. As with the scenario in Case 1, most patients seek medical attention during the febrile phase of their illness with symptoms similar to most febrile viral conditions such as pyrexia, headache, arthralgia, myalgia, retro-orbital pain and rashes ^{[2, 4]}. In dengue endemic areas, dengue NS1 and IgM tests are routinely done for surveillance purposes ^{[1, 2, 3, 4]}. The need for admission with or without close monitoring and astute management depends on the group category that a patient falls under. Group A patients are those who do not present with warning signs and are found to be hemodynamically stable. They must meet the following criteria before a decision is made to allow outpatient management. The criteria to be adhered strictly to are the patient’s ability to gain adequate volume of oral fluids, passing urine at least once every 4 to 6 hours, do not have any warning signs, have stable hematocrit, hemodynamically stable and do not have any co-existing conditions ^{[2, 4]}. Such patients can be monitored daily in an outpatient setting with serial complete blood counts and close assessment for any development of new warning signs. Proper guidance is essential to educate them about the warning signs that warrant attention ^{[2, 4]}. Besides that, the tourniquet test is also used to determine capillary fragility in a dengue patient. It is a diagnostic method used to determine hemorrhagic tendency. A blood pressure cuff is applied and it is inflated midway between the systolic and diastolic blood pressure for five minutes. The test is considered positive if there are more than 10-20 petechiae per square inch. This test is no longer used as a classification test in the WHO guidelines for treatment, prevention and control of dengue fever 2009 due to the many interfering factors such as pre/postmenstruation and sun damaged skin which have increased capillary fragility ^[24]. Meanwhile, Group B patients require in-hospital management as they are either present with warning signs or belong to high-risk categories such as pregnant mothers, infants, elderly, or those with co-morbidities like diabetes mellitus ^{[2, 4]}. Patients should be monitored closely to ensure hemodynamic stability and oral fluid intake should still be encouraged ^{[2, 4]}. Conversely, intravenous fluids are to be used judiciously, especially in the critical phase of illness to prevent fluid overload. A patient presenting with features of severe plasma leakage, severe hemorrhage or severe organ impairment should be admitted as a dengue Group C patient who requires emergency treatment. In the case of dengue fever in pregnancy, much attention needs to be given to a few key differences in respect to dengue fever, primarily due to the increased risk of hemorrhage in the mother as well as the fetus ^{[8, 9, 10, 11]}. On the whole, the clinical presentation of dengue fever and the subsequent progress follow similarly to their non-pregnant counterparts ^{[9, 10, 11]}. However, dengue as previously mentioned above tends to present with a multitude of symptoms that are considered warning signs such as vomiting and abdominal pain which can easily be confused with common obstetric illnesses such as abruptio placentae, hyperemesis gravidarum, toxemia or even life-threatening diseases such as HELLP syndrome ^{[9, 10, 11]}. Great index of suspicion coupled with epidemiological context to incidence of dengue endemic areas are invaluable tools for the treating obstetrician for this situation ^[10]. Furthermore, there are plenty of normal physiological changes that occur within the pregnant woman that provide great challenges for diagnosis and detection/monitoring of complications of dengue. During pregnancy, the following changes occur with respects to dengue ^{[8, 9]}.

Table 3.

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In terms of maternal outcome in dengue fever, a retrospective study by Chitra and Panicker illustrated that extremes of gestational age appeared to be a significant risk factor of bad outcomes such as bleeding tendencies and thrombocytopenia requiring platelet transfusion in the mother, multiple myocardial infarctions and Hypoxic Ischemic Encephalopathy ^[11]. Pouliot and Xiong et al had only recently published a systematic review that perused through 19 case reports, 9 case series and 2 comparison studies. Amongst the case reports, there were higher rates of cesarean deliveries (44%) and pre-eclampsia (12%) and amongst the case series there were higher rates of cesarean deliveries (20.4%) and rates of preterm deliveries (16.1%) ^[12]. In addition to that, the comparative studies reported an increase in low birth weight pregnancies as compared to non-dengue infected mothers ^[12]. A newer and more established cohort retrospective study by Friendman and Dallah et al that studied a similar endpoints had collected patient data of 86 patients and their children from the years 1992-2010 seemed to echo the findings of the previous studies, adjusted for confounders such as concurrent illnesses and preterm births of other causes ^[13]. Results of the study highlighted that unadjusted point estimates for odds ratio that “ranged from 2.06 for all infants regardless of gestational age to 1.62 for models restricted to infants of 22 or more weeks of gestational age and their strata” and thus the odds ratio including all gestational ages ended up being statistically significant to support the claim that there is a risk of low birthweight infants and preterm birth in symptomatic dengue mothers ^[13]. There are implications of various pathophysiological changes in dengue to a pregnant woman such as trophoblastic apoptosis, production of pro-inflammatory cytokines, fever and placental irritation that could lead to early labour ^[13]. Some studies have shown that the presence of IL-6, IL-8 and IL-18 in high titers which are manufactured in a febrile illness such as dengue, are present in preterm deliveries as well ^[14]. However all the authors of the studies mentioned concluded that more comparative studies are required to firmly measure poor pregnancy outcomes in the mother and fetus as there were many limitations such as a small sample size and not investigating effects of asymptomatic dengue in pregnancy ^{[12, 13]}. An interesting phenomenon reported in many journal articles is the presence of vertical transmission of the dengue virus ^{[12, 13, 15, 16]}. It would appear that various studies confirm this finding as transplacental crossing of maternal antibodies IgG subclass 1 as high as 96% in a sample of 250 infants via the hemagluttination inhibition technique with around 75% and 100% of these patients with maternally derived antibodies becoming seronegative by 7 and 12 months of age respectively ^[15]. The same study also showed that the titer was actually higher in infants than the mother and that only 10% of the immunoglobulins were created in the infant, suggesting a possible active process of transport of the antibodies through the placenta^[15]. It is also possible to detect IgM dengue virus antibodies and even its serotypes by other methods such as PCR ^{[15, 16]}. These children if retain their immunoglobulins are at a higher risk of dengue hemorrhagic fever ^[22]. It is of utmost importance to take a proper history especially in the dilemma of diagnosis dengue patient in an elderly as the signs of dengue can be very subtle in the elderly group ^[17]. Gastrointestinal bleed and microhematuria can be the only sign present for the elderly dengue patient ^[18]. Therefore is important to monitor the full blood count in this group of patients. As a clinician, holistic management of a patient’s co-morbidities is imperative in determining the overall outcome of a patient who presents with severe dengue. Fluid management is vital as hypervolaemia could be detrimental for a patient with chronic renal disease or heart failure ^[18]. In this patient, the caval index was used to determine the volume status. The caval index can be measured by the following formula ^[19]:

Caval index of more than 50% will suggest volume depletion meanwhile a caval index of less than 50% will signify hypervolaemia^[20].Using this caval index, attending clinicians are able to predict accurately the amount of fluid to be administered to the given patient and hence reduce the risk of hypervolaemia. It is imperative for physicians practicing in dengue endemic areas to have a sound understanding on the underlying process that lead to dengue hemorrhagic fever and dengue shock syndrome and 2 very important pathophysiological constructs come to mind: Plasma Leakage and Bleeding Tendencies ^{[1, 2]}. In the last half century devoted to research, we have strong evidence to state that the pathogenesis of Dengue Hemorrhagic Fever and Dengue Shock Syndrome involves the following ^[1]:

•  Host cell and tissue tropism for monocytes and mononuclear cells,

•  Viral virulence factors in between the four strains and

•  Detrimental and exaggerated host reactions.

These three processes often lead to the well-known knowledge of abnormal hemostasis, bleeding tendencies and capillary permeability ^[21]. However, in spite of this huge body of research the actual mechanism still alludes the minds of researches ^[21]. All we know is that plasma leakage is specific to pleural and peritoneal surfaces and that a host of various cytokine secretions lead to vascular permeability. Wills and Oragui in 2004 drew conclusions that only little destruction of the sieving mechanism was present but more interestingly, a selective restriction based on negative charge proteins was dysfunctional as the normally negatively charged albumin was demonstrated to have the same clearance pattern as transferrin, a known neutral molecule of similar size ^[23]. However, we have recently focused our attention on the damage of glycocalyx, a gelatinous layer lining the vascular endothelium in which albumin adheres to being an important pathophysiological process ^[22]. Furthermore, dengue hepatitis is a known pathological entity in the pathogenesis of dengue with deranged liver function tests and coagulation profile being the indicators of choice. It has been observed in terminal dengue hepatitis, the virus was demonstrable in over 90% hepatocytes and kupfer cells ^[24]. Dengue in Haemorrhage or Shock can sometimes require much more than just simple fluid resuscitation ^{[21, 22, 25]}. Crystalloids are used to rapidly replace volumes loss due to plasma leakage. Colloid solutions known for being “plasma expanders” can be administered in hypotensive shock ^[25]. Fluid replacement for these instances should continue for about 24-48 hours and for those who are overweight or obese, the Ideal body weight should be calculated as follows ^[25]:

The following management plans were adapted from the WHO Guidelines on Dengue, Diagnosis, Treatment, Prevention and Control 2009. The Goals of fluid resuscitation is to recover central and peripheral circulations by stabilizing vital signs and improving end organ perfusion evidenced by clear conscious level with adequate urine output and resolving metabolic acidosis ^[25]. Essentially, if the patient is in compensated shock, the action goes as follows; Beginning intravenous fluid resuscitation with isotonic crystalloid solutions dosed at 5-10ml/kg/hours over one hour followed by vital signs reassessment, if there is improvement, a tapered down fluid regime should ensue using hemodynamic status as a guide. If hemodynamic instability persists and the hematocrit is raised a repeated second bolus of 10-20ml/kg/hr for one hour should be carried out followed by tapering down fluid prescription. However if the hematocrit remains low, then bleeding has occurred and planning for transfusion via cross-matching should be the next step ^[25]. Hypotensive or decompensated shock requires more rigorous attention. The following are the recommended guidelines to achieve fluid resuscitation; The first and most important step for this algorithm is to get the patient out of the hypotension as quickly as possible by either rigorous crystalloid or colloid solutions at 20ml/kg as bolus in 15 minutes. Following that, if the patient improves again, a tapering regime continues down until a certain fluid prescription can be used to maintain vital signs for 24-48 hours. However, if vital signs remain unstable, proceed to review the hematocrit before resuscitation. If the value was low, there is bleeding and the steps follow similar to compensated shock above. If it remains high, it implies that plasma leakage has occurred with reduced intravascular volume and therefore colloid solution at 10-20ml/kg should be given as a second bolus over 30 minutes to an hour. If the vital signs stabilizes, tapering of fluids should occur. If the vital signs remain unstable, a low repeated hematocrit indicates bleeding and a repeated high hematocrit requires another bolus. Repeated amount of boluses are permissible for the next 24 hours with considerations into rate and titrations ^[25].

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Figure 1. Adapted from World Health Organization: Dengue: Guidelines for diagnosis, treatment, prevention and control. Geneva: World Health Organization; 2009

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Figure 2. Adapted from World Health Organization: Dengue: Guidelines for diagnosis, treatment, prevention and control. Geneva: World Health Organization; 2009

4. Conclusion

Dengue virus is currently a problematic global infection. Presumptive clinical diagnosis of dengue is useful in reducing the mortality and morbidity associated with it. The ongoing research on anti-viral drugs may be the clue to better treatment.

Acknowledgement

None.

Statement of Competing Interest

The authors have no competing interests.

List of Abbreviations

None.

Informed Consent

Informed consent was obtained for publication of this case series.

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