A 19-year-old female presented to our clinic with fever, headache, retro-orbital pain, and muscle ache for two days. In addition hematemesis and epistaxis started on the day of admission. Her medical history revealed sickle cell anemia (SCA) (homozygosity for abnormal HbS; HbSS). On examination she was alert, with a temperature of 37 C, BP 120/80 mmHg, HR 100/min, and RR 15-20/min. She had right upper-quadrant abdominal tenderness. No other abnormalities on physical examination were found. Initial lab results revealed moderate increase of CRP, anemia, thrombocytopenia, and increased liver enzymes. NS1-antigen tested positive and dengue serology was negative for IgM (0.41) and positive for IgG (5.71), and RT-PCR showed DENV-2. Shortly after admittance she became hypotensive, with distension of her abdomen. Intravenous fluid resuscitation was started and further intervention was implemented on the basis of the monitoring of hematocrit, urine output, and blood glucose. Profuse abdominal bleeding was suspected, with marked decrease of Hb, low platelets, severe disrupted coagulation parameters, and intra- and retro-abdominal free fluid with fibrin strands on ultrasound. Moreover extensive capillary leakage and anuria developed. She was intubated due to seizures and following sedation. Although in the course of time shock and bleeding stabilized, she continued to develop MODS and both pupils became progressively less reactive to light until nonreactive. CT brain imaging could not be performed. On day four, she died due to cardiac arrest.
No autopsies were performed on either of the patients. Written informed consent for publication of the disease histories was obtained from the direct relatives of both patients.
During the past decades dengue has been reported to occur in Curacao. Until now fatal cases were never documented. However the 2010-2011 outbreak with 1,822 serologically confirmed cases was associated with four deaths (personal communication). Two of these patients had been previously diagnosed with SCD type HbSC and SCA. SCD is not uncommon in Curacao, with a prevalence of approximately 0.25%. Although chronic diseases such as SCD are considered to be a risk factor for development of severe dengue, few cases of children or adolescents have been reported.
The clinical findings of the two cases described here are difficult to interpret because of the apparent complementary vascular endothelial damage in SCD, SCA, and severe dengue. As proposed in the model of dengue pathogenesis by Martina et al., DENV might replicate in selective endotheliocytes. In SCD, endothelial dysfunction is known to occur. There is no direct evidence from fatal dengue cases that dengue virus replicates in endothelial cells. Nonetheless, damage to endothelial cells as reflected by increased vascular permeability is central to the dengue vascular permeability syndrome (DHF/DSS). Vascular endothelial cells (VEC) play an important roll in inflammation and coagulation. By damaging the VEC either through infection of DENV or by sickling of erythrocytes, the permeability of the vascular endothelial layer can increase, which may induce plasma leakage, release of cytokines, and cause profound shock. Based on these findings, we hypothesize an essential role for endothelial cells to contribute to disease severity. The similarities between the cases are striking: shock, plasma leakage, hemorrhage, and MODS. However plasma leakage predominated in case 1, whereas hemorrhage did in case 2. The onset of vaso-occlusion with SCD and SCA is often triggered by inflammation, as is the case in a DENV infection. Severe bleeding seldom happens in children, but only in cases of profound shock, and no thrombotic complications are seen. In treating dengue patients with underlying SCD or SCA, the treating physician is facing a dilemma. In SCD and SCA, it is preferred to maintain a low Ht to reduce the risk of vaso-occlusion. Treating physicians may be reluctant to perform blood transfusions in SCD patients because of concerns of excessive accumulation of iron, transfusion reactions, and alloimmunization. However severe anemia as a result of SCD or dengue may necessitate blood transfusion. The WHO reports an increase of Ht as a sign of plasma leakage with subsequently a decrease that may be due to hemorrhage. Both cases showed a continuing decrease of Ht, associated with hemorrhage with plasma leakage also predominating, suggesting Ht should not be used as a marker in patients with SCD or SCA. Iatrogenic interstitial fluid overload in patients with SCD, SCA, and severe dengue, due to preexisting vascular endothelial damage, is not just a theoretical hazard. Whether the clinical manifestations would just have been the result of secondary DENV infection only, despite SCD or SCA, remains a matter for debate. To further address this issue, we suggest that a case-control study should be performed to further elucidate the proposed association between severe dengue and SCD or SCA.
This report is based on two fatal cases of severe dengue with underlying SCD/SCA in Curacao during the 2010-2011 epidemic. Currently no guidelines exist on how to treat such patients. In populations with a high prevalence of SCD, SCA, and dengue activity, clinicians should be aware of the challenges in clinical management.