<p>Fatal Dengue in Patients with Sickle Cell Disease or Sickle Cell Anemia in Curaçao: Two Case Reports</p

ACE Andrianarisoa

Albert D. M. E. Osterhaus

BEE Martina

D González

D Limonta

DC Rees

E Teruel-López

Eric C. M. van Gorp

Fleur M. Moesker

Fred D. Muskiet

Isaac Gerstenbluth

Jeanne J. Koeijers

JR Bravo

M Gentilini

MA Ware

Pieter L. A. Fraaij

SB Halstead

Scott B. Halstead

PLoS Neglected Tropical Diseases

PubMed

Moesker, Fleur

Muskiet, FD

Koeijers, JJ

Fraaij, Pieter

Gerstenbluth, I

van Gorp, Eric

Osterhaus, Ab

EUR Research Repository

SymposiumFatal Dengue in Patients with Sickle Cell Disease orSickle Cell Anemia in Curaçao: Two Case ReportsFleur M. Moesker1, Fred D. Muskiet2, Jeanne J. Koeijers2, Pieter L. A. Fraaij1,3*, Isaac Gerstenbluth4,Eric C. M. van Gorp1, Albert D. M. E. Osterhaus11 Department of Viroscience Lab, Erasmus MC, Rotterdam, The Netherlands, 2 St Elisabeth Hospital, Willemstad, Curaçao, 3 Pediatric Infectious Diseases and Immunology,Erasmus MC-Sophia, Rotterdam, The Netherlands, 4 Epidemiology and Research Unit, Medical and Public Health Service of Curaçao, Willemstad, CuraçaoPresentation of CasesCase 1A ten-year-old girl with sickle cell disease(SCD) (combined heterozygosity for theabnormal hemoglobin S and abnormalHbC; HbSC) presented to our clinic witha history of four days fever, malaise, and ageneralized tonic-clonic convulsion. At pre-sentation she was alert, nauseous, andcomplained of headache and retro-orbitalpain. Temperature was 38.0uC, heart rate(HR) 135/min, blood pressure (BP) 94/62 mmHg, respiratory rate (RR) 20/min;minor hepatosplenomegaly and upper-quadrant abdominal tenderness were pres-ent. No further abnormalities were reportedon physical examination. Initial lab resultsrevealed a moderate increase of CRP,anemia, thrombocytopenia, prolonged acti-vated partial thromboplastin time (aPTT)and prothrombin time (PT), increased liverenzymes, and decreased albumin andhematocrit (Ht) (Table S1). On day two,during defervescence she became hypoten-sive and was treated with fluid resuscitationand inotropic agents. Blood products weretransfused to correct anemia and thrombo-cytopenia. Hemolysis and acute hemor-rhage with gastrointestinal, vaginal, andlater on venipuncture sites bleeding devel-oped. Splenic sequestration was also con-sidered as the cause of anemia, but couldnot be confirmed with abdominal ultra-sound. Pleural effusion, gallbladder wallthickening, and ascites were seen. On daythree, she lost vision. A brain CT scanrevealed no abnormalities. Lumbar punc-ture was deferred and antibiotic treatmentwas adjusted to cover possible meningitis.Hereafter she developed acute respiratorydistress syndrome (ARDS) requiring me-chanical ventilation. Dengue serology waspositive for IgM (titer: 3.26) and IgG (3.26)(Focus Diagnostics), and RT-PCR showeddengue virus serotype 2 (DENV-2). Herclinical situation deteriorated with an in-creased hemorrhagic tendency, and blood,clotting products, and clotting factors wereadministered. In time multiorgan dysfunc-tion syndrome (MODS) developed. Bloodcultures remained negative for bacteria, butantibiotics were administered anyway. Can-dida was cultured and antifungals wereinitiated. Despite intensive treatment thepatient did not recover, disseminated intra-vascular coagulation (DIC) progressed andkidney function did not return. Consequent-ly further treatment was discontinued andthe patient died, 28 days after admission.Case 2A 19-year-old female presented to ourclinic with fever, headache, retro-orbitalpain, and muscle ache for two days. Inaddition hematemesis and epistaxis startedon the day of admission. Her medicalhistory revealed sickle cell anemia (SCA)(homozygosity for abnormal HbS; HbSS).On examination she was alert, with atemperature of 37uC, BP 120/80 mmHg,HR 100/min, and RR 15–20/min. Shehad right upper-quadrant abdominal ten-derness. No other abnormalities on physicalexamination were found. Initial lab resultsrevealed moderate increase of CRP, ane-mia, thrombocytopenia, and increased liverenzymes. NS1-antigen tested positive anddengue serology was negative for IgM(0.41) and positive for IgG (5.71), andRT-PCR showed DENV-2. Shortly afteradmittance she became hypotensive, withdistension of her abdomen. Intravenousfluid resuscitation was started and furtherintervention was implemented on the basisof the monitoring of hematocrit, urineoutput, and blood glucose. Profuse abdom-inal bleeding was suspected, with markeddecrease of Hb, low platelets, severedisrupted coagulation parameters, andintra- and retro-abdominal free fluid withfibrin strands on ultrasound. Moreoverextensive capillary leakage and anuriadeveloped. She was intubated due toseizures and following sedation. Althoughin the course of time shock and bleedingstabilized, she continued to develop MODSand both pupils became progressively lessreactive to light until nonreactive. CT brainimaging could not be performed. On dayfour, she died due to cardiac arrest.No autopsies were performed on eitherof the patients. Written informed consentfor publication of the disease histories wasobtained from the direct relatives of bothpatients.Case Discussion: Dengue andCuraçaoDuring the past decades dengue has beenreported to occur in Curaçao. Until nowCitation: Moesker FM, Muskiet FD, Koeijers JJ, Fraaij PLA, Gerstenbluth I, et al. (2013) Fatal Dengue in Patientswith Sickle Cell Disease or Sickle Cell Anemia in Curaçao: Two Case Reports. PLoS Negl Trop Dis 7(8): e2203.doi:10.1371/journal.pntd.0002203Editor: Scott B. Halstead, Pediatric Dengue Vaccine Initiative, United States of AmericaPublished August 8, 2013Copyright:  2013 Moesker et al. This is an open-access article distributed under the terms of the CreativeCommons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,provided the original author and source are credited.Funding: The work was funded by the Erasmus MC Rotterdam and by the Dutch government (project numberFES0908). The funders had no role in study design, data collection and analysis, decision to publish, orpreparation of the manuscript.Competing Interests: We have read the journal’s policy and have the following conflicts: FMM’s, PLAF’s, andADMEO’s scientific work is supported by the Virgo consortium, funded by the Dutch government (projectnumber FES0908). In addition ADMEO has share certificates in ViroClinics Biosciences B.V. The majority of theshares in ViroClinics Biosciences B.V. (.75%) are owned by Erasmus MC through its Erasmus MC Holding B.V.To avoid any possible conflict of interest and to safeguard its employees against the possibility of unethicaldecisions, the Erasmus MC does not allow any of its employees to hold shares in person in any companies thatare (partly) owned by Erasmus MC. As a result thereof, any shares provided by such companies to any ErasmusMC employees are held by a Foundation Administration Office. The board of this foundation is appointed byErasmus MC. The employees receive share certificates of their shares. Apart form those described above theauthors have declared that no competing interests exist.* E-mail: p.fraaij@erasmsumc.nlPLOS Neglected Tropical Diseases | www.plosntds.org 1 August 2013 | Volume 7 | Issue 8 | e2203fatal cases were never documented. Howev-er the 2010–2011 outbreak with 1,822serologically confirmed cases was associatedwith four deaths (personal communication).Two of these patients had been previouslydiagnosed with SCD type HbSC and SCA.SCD is not uncommon in Curaçao, with aprevalence of approximately 0.25% [1].Although chronic diseases such as SCD areconsidered to be a risk factor for develop-ment of severe dengue, few cases of childrenor adolescents have been reported [2].Literature ReviewBoth in the Americas and Asia all fourserotypes of DENV circulate with frequentreports of fatal dengue. Until now no casesof DENV infection in SCD patients havebeen described in Asia, probably due to therelatively low prevalence of SCD [3].Furthermore reports describing patientswith this combination of diseases are scarce,little-detailed, and restricted to a few fatalcases apart from the Cuban study concern-ing adults only (see Table 1) [4–10]. Bravoet al. reported 158 fatal cases during the1981 DENV-2 epidemic in Cuba (72children and 26 adults) [8]. Eight patientswere suffering from sickle cell anemia, ofwhich five presented with hemorrhages andthree with shock. Half of them died within24 hours after admission. The secondarticle from Cuba describes a DENV-3outbreak in 2001 [4]. Two fatal cases withHbSS and HbSC were reported. Bothpatients presented with fever. In onepatient hemorrhage predominated, withplasma leakage leading to shock in theother case. Five or six days after admission,both patients died. In 1999 Ware et al.reported one fatal case of DHF in a SCApatient [6]. She presented with bone painand fever, and she died four days afteradmission. Most cases described are HbSSpatients. However none of the describedcases suggests treatment options or casemanagement, and interaction betweenboth diseases is not described.Presented Cases and TreatmentChallengesThe clinical findings of the two casesdescribed here are difficult to interpretbecause of the apparent complementaryvascular endothelial damage in SCD, SCA,and severe dengue. As proposed in the modelof dengue pathogenesis by Martina et al.,DENV might replicate in selective endothe-liocytes [11]. In SCD, endothelial dysfunc-tion is known to occur [12]. There is nodirect evidence from fatal dengue cases thatdengue virus replicates in endothelial cells.Nonetheless, damage to endothelial cells asreflected by increased vascular permeabilityis central to the dengue vascular permeabilitysyndrome (DHF/DSS). Vascular endothelialcells (VEC) play an important roll ininflammation and coagulation. By damagingthe VEC either through infection of DENVor by sickling of erythrocytes, the permeabil-ity of the vascular endothelial layer canincrease, which may induce plasma leakage,release of cytokines, and cause profoundshock. Based on these findings, we hypoth-esize an essential role for endothelial cells tocontribute to disease severity. The similaritiesbetween the cases are striking: shock, plasmaleakage, hemorrhage, and MODS [2].However plasma leakage predominated incase 1, whereas hemorrhage did in case 2.The onset of vaso-occlusion with SCD andSCA is often triggered by inflammation, as isthe case in a DENV infection [12]. Severebleeding seldom happens in children, butonly in cases of profound shock, and nothrombotic complications are seen [13]. Intreating dengue patients with underlyingSCD or SCA, the treating physician is facinga dilemma. In SCD and SCA, it is preferredto maintain a low Ht to reduce the risk ofvaso-occlusion. Treating physicians may bereluctant to perform blood transfusions inSCD patients because of concerns of exces-sive accumulation of iron, transfusion reac-tions, and alloimmunization. However se-vere anemia as a result of SCD or denguemay necessitate blood transfusion. TheWHO reports an increase of Ht as a signof plasma leakage with subsequently adecrease that may be due to hemorrhage.Both cases showed a continuing decrease ofHt, associated with hemorrhage with plasmaleakage also predominating, suggesting Htshould not be used as a marker in patientswith SCD or SCA. Iatrogenic interstitial fluidoverload in patients with SCD, SCA, andsevere dengue, due to preexisting vascularendothelial damage, is not just a theoreticalhazard. Whether the clinical manifestationswould just have been the result of secondaryDENV infection only, despite SCD or SCA,remains a matter for debate. To furtheraddress this issue, we suggest that a case-control study should be performed to furtherelucidate the proposed association betweensevere dengue and SCD or SCA.This report is based on two fatal cases ofsevere dengue with underlying SCD/SCAin Curaçao during the 2010–2011 epi-demic. Currently no guidelines exist onhow to treat such patients. In populationswith a high prevalence of SCD, SCA, andTable 1. Summary of literature review.Author, year of publication CountryNumber ofpatientsGender/age(years)SCDtype Dengue virus serotype OutcomePresent case 1 Curaçao 1 F/10 HbSC DENV-2 DiedPresent case 2 Curaçao 1 F/19 HbSS DENV-2 DiedLimonta et al., 2009 Cuba 2 M/34M/25HbSCHbSSDENV-3 (s)DENV-3 (s)DiedDiedAndrianarisoa et al., 2007 Madagascar ND ND ND ND NDWare et al., 1999 Jamaica 1 F/19 HbSS ND DiedTeruel-López et al., 1991** Venezuela ND ND ND ND NDBravo et al., 1987 Cuba 44AdultsChildrenHbSSHbSSDENV-2 (ND)DENV-2 (ND)DiedDiedGentilini et al., 1964* Haiti ND ND ND ND NDM, male; F, female; ND, no data available; DENV, dengue virus serotype; (s), secondary; HbSC, heterozygote sickle cell disease; HbSS, homozygote sickle cell anemia;HbAS, sickle cell trait;*no abstract available;**review describing Bravo et al. article.doi:10.1371/journal.pntd.0002203.t001PLOS Neglected Tropical Diseases | www.plosntds.org 2 August 2013 | Volume 7 | Issue 8 | e2203dengue activity, clinicians should be awareof the challenges in clinical management.Supporting InformationTable S1 Detailed laboratory data ofboth patients.(DOC)References1. Dijs FP (2004) Sickle cell disease and a-thalasse-mia in Curaçao: contributors to epidemiology,pathophysiology and supportive care [disserta-tion]. Willemstad.2. World Health Organization (2009) Dengueguidelines: diagnosis, treatment, prevention andcontrol. New edition 2009. Geneva: WorldHealth Organization. pp. 1–160.3. World Health Organization (January 2011)Sickle-cell disease and other haemoglobin disor-ders. Fact sheet Nu308. Available: http://www.who.int/mediacentre/factsheets/fs308/en/index.html. Accessed 5 July 2013.4. Limonta D, González D, Capó V, Torres G, PérezAB, et al. (2009) Fatal severe dengue and cell deathin sickle cell disease during the 2001–2002 Havanadengue epidemic. Int J Infect Dis 13: 77–78.5. Andrianarisoa ACE, Rakotoson J, Randretsa M,Rakotondravelo S, Rakotoarimanana RD, et al.(2007) Madagascar: public health situation on the‘‘Big Island’’ at the beginning of the 21st century.Med Trop (Mars) 67: 19–29.6. Ware MA, Hambleton I, Ochaya I, Serjeant GR(1999) Day-care management of sickle cell painfulcrisis in Jamaica: a model applicable elsewhere?Br J Haematol 104: 93–96.7. Teruel-López E (1991) Dengue. A review. InvestClin 32: 201–217.8. Bravo JR, Guzmán MG, Kouri GP (1987)Why dengue haemorrhagic fever in Cuba? 1.Individual risk factors for dengue haemor-rhagic fever/dengue shock syndrome (DHF/DSS). Trans R Soc Trop Med Hyg 81: 816–820.9. Gentilini M, Laroche V, Degremont A (1964)Aspects of parasitic and infectious tropicalpathology in the Republic of Haiti. Bull SocPathol Exot Filiales 57: 565–570.10. González D, Castro OE, Kourı́ G, Perez J,Martinez E, et al. (2005) Classical denguehemorrhagic fever resulting from two dengueinfections spaced 20 years or more apart:Havana, Dengue 3 epidemic, 2001–2002.Int J Infect Dis 9: 280–285.11. Martina BEE, Koraka P, Osterhaus ADME(2009) Dengue virus pathogenesis: an integratedview. Clin Microbiol Rev 22: 564–581.12. Rees DC, Williams TN, Gladwin MT (2010)Sickle-cell disease. Lancet 376: 2018–2031.13. Halstead SB (2007) Dengue. Lancet 370: 1644–1652.Learning Points1) This case report is suggestive of a fatal interaction between dengue and sicklecell disease or sickle cell anemia.2) Hematocrit values are of limited use for treatment decisions in patients withsevere dengue infection and sickle cell disease or sickle cell anemia.PLOS Neglected Tropical Diseases | www.plosntds.org 3 August 2013 | Volume 7 | Issue 8 | e2203

English

Fatal Dengue in Patients with Sickle Cell Disease or Sickle Cell Anemia in Curacao: Two Case Reports

Fleur M. Moesker (443184)

Fred D. Muskiet (443185)

Jeanne J. Koeijers (443186)

Pieter L. A. Fraaij (364299)

Isaac Gerstenbluth (443187)

Eric C. M. van Gorp (225896)

Albert D. M. E. Osterhaus (138961)

The Francis Crick Institute

Fatal Dengue in Patients with Sickle Cell Disease or Sickle Cell Anemia in Curaçao: Two Case Reports

Crossref

EUR Research Information PortalFatal Dengue in Patients with Sickle Cell Disease or Sickle Cell Anemia in Curacao:Two Case ReportsPublished in:PLoS Neglected Tropical Diseases (print)Publication status and date:Published: 01/01/2013DOI (link to publisher):10.1371/journal.pntd.0002203Document VersionPublisher's PDF, also known as Version of recordCitation for the published version (APA):Moesker, F., Muskiet, FD., Koeijers, JJ., Fraaij, P., Gerstenbluth, I., van Gorp, E., & Osterhaus, A. (2013). Fatal Dengue inPatients with Sickle Cell Disease or Sickle Cell Anemia in Curacao: Two Case Reports. PLoS Neglected Tropical Diseases(print), 7(8). https://doi.org/10.1371/journal.pntd.0002203Link to publication on the EUR Research Information PortalTerms and Conditions of UseExcept as permitted by the applicable copyright law, you may not reproduce or make this material available to any third partywithout the prior written permission from the copyright holder(s). 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In case of a legitimate complaint,we will make the material inaccessible and/or remove it from the website.SymposiumFatal Dengue in Patients with Sickle Cell Disease orSickle Cell Anemia in Curaçao: Two Case ReportsFleur M. Moesker1, Fred D. Muskiet2, Jeanne J. Koeijers2, Pieter L. A. Fraaij1,3*, Isaac Gerstenbluth4,Eric C. M. van Gorp1, Albert D. M. E. Osterhaus11 Department of Viroscience Lab, Erasmus MC, Rotterdam, The Netherlands, 2 St Elisabeth Hospital, Willemstad, Curaçao, 3 Pediatric Infectious Diseases and Immunology,Erasmus MC-Sophia, Rotterdam, The Netherlands, 4 Epidemiology and Research Unit, Medical and Public Health Service of Curaçao, Willemstad, CuraçaoPresentation of CasesCase 1A ten-year-old girl with sickle cell disease(SCD) (combined heterozygosity for theabnormal hemoglobin S and abnormalHbC; HbSC) presented to our clinic witha history of four days fever, malaise, and ageneralized tonic-clonic convulsion. At pre-sentation she was alert, nauseous, andcomplained of headache and retro-orbitalpain. Temperature was 38.0uC, heart rate(HR) 135/min, blood pressure (BP) 94/62 mmHg, respiratory rate (RR) 20/min;minor hepatosplenomegaly and upper-quadrant abdominal tenderness were pres-ent. No further abnormalities were reportedon physical examination. Initial lab resultsrevealed a moderate increase of CRP,anemia, thrombocytopenia, prolonged acti-vated partial thromboplastin time (aPTT)and prothrombin time (PT), increased liverenzymes, and decreased albumin andhematocrit (Ht) (Table S1). On day two,during defervescence she became hypoten-sive and was treated with fluid resuscitationand inotropic agents. Blood products weretransfused to correct anemia and thrombo-cytopenia. Hemolysis and acute hemor-rhage with gastrointestinal, vaginal, andlater on venipuncture sites bleeding devel-oped. Splenic sequestration was also con-sidered as the cause of anemia, but couldnot be confirmed with abdominal ultra-sound. Pleural effusion, gallbladder wallthickening, and ascites were seen. On daythree, she lost vision. A brain CT scanrevealed no abnormalities. Lumbar punc-ture was deferred and antibiotic treatmentwas adjusted to cover possible meningitis.Hereafter she developed acute respiratorydistress syndrome (ARDS) requiring me-chanical ventilation. Dengue serology waspositive for IgM (titer: 3.26) and IgG (3.26)(Focus Diagnostics), and RT-PCR showeddengue virus serotype 2 (DENV-2). Herclinical situation deteriorated with an in-creased hemorrhagic tendency, and blood,clotting products, and clotting factors wereadministered. In time multiorgan dysfunc-tion syndrome (MODS) developed. Bloodcultures remained negative for bacteria, butantibiotics were administered anyway. Can-dida was cultured and antifungals wereinitiated. Despite intensive treatment thepatient did not recover, disseminated intra-vascular coagulation (DIC) progressed andkidney function did not return. Consequent-ly further treatment was discontinued andthe patient died, 28 days after admission.Case 2A 19-year-old female presented to ourclinic with fever, headache, retro-orbitalpain, and muscle ache for two days. Inaddition hematemesis and epistaxis startedon the day of admission. Her medicalhistory revealed sickle cell anemia (SCA)(homozygosity for abnormal HbS; HbSS).On examination she was alert, with atemperature of 37uC, BP 120/80 mmHg,HR 100/min, and RR 15–20/min. Shehad right upper-quadrant abdominal ten-derness. No other abnormalities on physicalexamination were found. Initial lab resultsrevealed moderate increase of CRP, ane-mia, thrombocytopenia, and increased liverenzymes. NS1-antigen tested positive anddengue serology was negative for IgM(0.41) and positive for IgG (5.71), andRT-PCR showed DENV-2. Shortly afteradmittance she became hypotensive, withdistension of her abdomen. Intravenousfluid resuscitation was started and furtherintervention was implemented on the basisof the monitoring of hematocrit, urineoutput, and blood glucose. Profuse abdom-inal bleeding was suspected, with markeddecrease of Hb, low platelets, severedisrupted coagulation parameters, andintra- and retro-abdominal free fluid withfibrin strands on ultrasound. Moreoverextensive capillary leakage and anuriadeveloped. She was intubated due toseizures and following sedation. Althoughin the course of time shock and bleedingstabilized, she continued to develop MODSand both pupils became progressively lessreactive to light until nonreactive. CT brainimaging could not be performed. On dayfour, she died due to cardiac arrest.No autopsies were performed on eitherof the patients. Written informed consentfor publication of the disease histories wasobtained from the direct relatives of bothpatients.Case Discussion: Dengue andCuraçaoDuring the past decades dengue has beenreported to occur in Curaçao. Until nowCitation: Moesker FM, Muskiet FD, Koeijers JJ, Fraaij PLA, Gerstenbluth I, et al. (2013) Fatal Dengue in Patientswith Sickle Cell Disease or Sickle Cell Anemia in Curaçao: Two Case Reports. PLoS Negl Trop Dis 7(8): e2203.doi:10.1371/journal.pntd.0002203Editor: Scott B. Halstead, Pediatric Dengue Vaccine Initiative, United States of AmericaPublished August 8, 2013Copyright:  2013 Moesker et al. This is an open-access article distributed under the terms of the CreativeCommons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,provided the original author and source are credited.Funding: The work was funded by the Erasmus MC Rotterdam and by the Dutch government (project numberFES0908). The funders had no role in study design, data collection and analysis, decision to publish, orpreparation of the manuscript.Competing Interests: We have read the journal’s policy and have the following conflicts: FMM’s, PLAF’s, andADMEO’s scientific work is supported by the Virgo consortium, funded by the Dutch government (projectnumber FES0908). In addition ADMEO has share certificates in ViroClinics Biosciences B.V. The majority of theshares in ViroClinics Biosciences B.V. (.75%) are owned by Erasmus MC through its Erasmus MC Holding B.V.To avoid any possible conflict of interest and to safeguard its employees against the possibility of unethicaldecisions, the Erasmus MC does not allow any of its employees to hold shares in person in any companies thatare (partly) owned by Erasmus MC. As a result thereof, any shares provided by such companies to any ErasmusMC employees are held by a Foundation Administration Office. The board of this foundation is appointed byErasmus MC. The employees receive share certificates of their shares. Apart form those described above theauthors have declared that no competing interests exist.* E-mail: p.fraaij@erasmsumc.nlPLOS Neglected Tropical Diseases | www.plosntds.org 1 August 2013 | Volume 7 | Issue 8 | e2203fatal cases were never documented. Howev-er the 2010–2011 outbreak with 1,822serologically confirmed cases was associatedwith four deaths (personal communication).Two of these patients had been previouslydiagnosed with SCD type HbSC and SCA.SCD is not uncommon in Curaçao, with aprevalence of approximately 0.25% [1].Although chronic diseases such as SCD areconsidered to be a risk factor for develop-ment of severe dengue, few cases of childrenor adolescents have been reported [2].Literature ReviewBoth in the Americas and Asia all fourserotypes of DENV circulate with frequentreports of fatal dengue. Until now no casesof DENV infection in SCD patients havebeen described in Asia, probably due to therelatively low prevalence of SCD [3].Furthermore reports describing patientswith this combination of diseases are scarce,little-detailed, and restricted to a few fatalcases apart from the Cuban study concern-ing adults only (see Table 1) [4–10]. Bravoet al. reported 158 fatal cases during the1981 DENV-2 epidemic in Cuba (72children and 26 adults) [8]. Eight patientswere suffering from sickle cell anemia, ofwhich five presented with hemorrhages andthree with shock. Half of them died within24 hours after admission. The secondarticle from Cuba describes a DENV-3outbreak in 2001 [4]. Two fatal cases withHbSS and HbSC were reported. Bothpatients presented with fever. In onepatient hemorrhage predominated, withplasma leakage leading to shock in theother case. Five or six days after admission,both patients died. In 1999 Ware et al.reported one fatal case of DHF in a SCApatient [6]. She presented with bone painand fever, and she died four days afteradmission. Most cases described are HbSSpatients. However none of the describedcases suggests treatment options or casemanagement, and interaction betweenboth diseases is not described.Presented Cases and TreatmentChallengesThe clinical findings of the two casesdescribed here are difficult to interpretbecause of the apparent complementaryvascular endothelial damage in SCD, SCA,and severe dengue. As proposed in the modelof dengue pathogenesis by Martina et al.,DENV might replicate in selective endothe-liocytes [11]. In SCD, endothelial dysfunc-tion is known to occur [12]. There is nodirect evidence from fatal dengue cases thatdengue virus replicates in endothelial cells.Nonetheless, damage to endothelial cells asreflected by increased vascular permeabilityis central to the dengue vascular permeabilitysyndrome (DHF/DSS). Vascular endothelialcells (VEC) play an important roll ininflammation and coagulation. By damagingthe VEC either through infection of DENVor by sickling of erythrocytes, the permeabil-ity of the vascular endothelial layer canincrease, which may induce plasma leakage,release of cytokines, and cause profoundshock. Based on these findings, we hypoth-esize an essential role for endothelial cells tocontribute to disease severity. The similaritiesbetween the cases are striking: shock, plasmaleakage, hemorrhage, and MODS [2].However plasma leakage predominated incase 1, whereas hemorrhage did in case 2.The onset of vaso-occlusion with SCD andSCA is often triggered by inflammation, as isthe case in a DENV infection [12]. Severebleeding seldom happens in children, butonly in cases of profound shock, and nothrombotic complications are seen [13]. Intreating dengue patients with underlyingSCD or SCA, the treating physician is facinga dilemma. In SCD and SCA, it is preferredto maintain a low Ht to reduce the risk ofvaso-occlusion. Treating physicians may bereluctant to perform blood transfusions inSCD patients because of concerns of exces-sive accumulation of iron, transfusion reac-tions, and alloimmunization. However se-vere anemia as a result of SCD or denguemay necessitate blood transfusion. TheWHO reports an increase of Ht as a signof plasma leakage with subsequently adecrease that may be due to hemorrhage.Both cases showed a continuing decrease ofHt, associated with hemorrhage with plasmaleakage also predominating, suggesting Htshould not be used as a marker in patientswith SCD or SCA. Iatrogenic interstitial fluidoverload in patients with SCD, SCA, andsevere dengue, due to preexisting vascularendothelial damage, is not just a theoreticalhazard. Whether the clinical manifestationswould just have been the result of secondaryDENV infection only, despite SCD or SCA,remains a matter for debate. To furtheraddress this issue, we suggest that a case-control study should be performed to furtherelucidate the proposed association betweensevere dengue and SCD or SCA.This report is based on two fatal cases ofsevere dengue with underlying SCD/SCAin Curaçao during the 2010–2011 epi-demic. Currently no guidelines exist onhow to treat such patients. In populationswith a high prevalence of SCD, SCA, andTable 1. Summary of literature review.Author, year of publication CountryNumber ofpatientsGender/age(years)SCDtype Dengue virus serotype OutcomePresent case 1 Curaçao 1 F/10 HbSC DENV-2 DiedPresent case 2 Curaçao 1 F/19 HbSS DENV-2 DiedLimonta et al., 2009 Cuba 2 M/34M/25HbSCHbSSDENV-3 (s)DENV-3 (s)DiedDiedAndrianarisoa et al., 2007 Madagascar ND ND ND ND NDWare et al., 1999 Jamaica 1 F/19 HbSS ND DiedTeruel-López et al., 1991** Venezuela ND ND ND ND NDBravo et al., 1987 Cuba 44AdultsChildrenHbSSHbSSDENV-2 (ND)DENV-2 (ND)DiedDiedGentilini et al., 1964* Haiti ND ND ND ND NDM, male; F, female; ND, no data available; DENV, dengue virus serotype; (s), secondary; HbSC, heterozygote sickle cell disease; HbSS, homozygote sickle cell anemia;HbAS, sickle cell trait;*no abstract available;**review describing Bravo et al. article.doi:10.1371/journal.pntd.0002203.t001PLOS Neglected Tropical Diseases | www.plosntds.org 2 August 2013 | Volume 7 | Issue 8 | e2203dengue activity, clinicians should be awareof the challenges in clinical management.Supporting InformationTable S1 Detailed laboratory data ofboth patients.(DOC)References1. Dijs FP (2004) Sickle cell disease and a-thalasse-mia in Curaçao: contributors to epidemiology,pathophysiology and supportive care [disserta-tion]. Willemstad.2. World Health Organization (2009) Dengueguidelines: diagnosis, treatment, prevention andcontrol. New edition 2009. Geneva: WorldHealth Organization. pp. 1–160.3. World Health Organization (January 2011)Sickle-cell disease and other haemoglobin disor-ders. Fact sheet Nu308. Available: http://www.who.int/mediacentre/factsheets/fs308/en/index.html. Accessed 5 July 2013.4. Limonta D, González D, Capó V, Torres G, PérezAB, et al. (2009) Fatal severe dengue and cell deathin sickle cell disease during the 2001–2002 Havanadengue epidemic. Int J Infect Dis 13: 77–78.5. Andrianarisoa ACE, Rakotoson J, Randretsa M,Rakotondravelo S, Rakotoarimanana RD, et al.(2007) Madagascar: public health situation on the‘‘Big Island’’ at the beginning of the 21st century.Med Trop (Mars) 67: 19–29.6. Ware MA, Hambleton I, Ochaya I, Serjeant GR(1999) Day-care management of sickle cell painfulcrisis in Jamaica: a model applicable elsewhere?Br J Haematol 104: 93–96.7. Teruel-López E (1991) Dengue. A review. InvestClin 32: 201–217.8. Bravo JR, Guzmán MG, Kouri GP (1987)Why dengue haemorrhagic fever in Cuba? 1.Individual risk factors for dengue haemor-rhagic fever/dengue shock syndrome (DHF/DSS). Trans R Soc Trop Med Hyg 81: 816–820.9. Gentilini M, Laroche V, Degremont A (1964)Aspects of parasitic and infectious tropicalpathology in the Republic of Haiti. Bull SocPathol Exot Filiales 57: 565–570.10. González D, Castro OE, Kourı́ G, Perez J,Martinez E, et al. (2005) Classical denguehemorrhagic fever resulting from two dengueinfections spaced 20 years or more apart:Havana, Dengue 3 epidemic, 2001–2002.Int J Infect Dis 9: 280–285.11. Martina BEE, Koraka P, Osterhaus ADME(2009) Dengue virus pathogenesis: an integratedview. Clin Microbiol Rev 22: 564–581.12. Rees DC, Williams TN, Gladwin MT (2010)Sickle-cell disease. Lancet 376: 2018–2031.13. Halstead SB (2007) Dengue. Lancet 370: 1644–1652.Learning Points1) This case report is suggestive of a fatal interaction between dengue and sicklecell disease or sickle cell anemia.2) Hematocrit values are of limited use for treatment decisions in patients withsevere dengue infection and sickle cell disease or sickle cell anemia.PLOS Neglected Tropical Diseases | www.plosntds.org 3 August 2013 | Volume 7 | Issue 8 | e2203

Undetermined

Fleur M Moesker

Fred D Muskiet

Jeanne J Koeijers

Pieter L A Fraaij

Eric C M van Gorp

Albert D M E Osterhaus

Directory of Open Access Journals

Fatal dengue in patients with sickle cell disease or sickle cell anemia in Curaçao: two case reports.

Moesker, F.M. (Fleur)

Muskiet, F.D. (Fred)

Koeijers, J. (Jeanne)

Fraaij, P.L.A. (Pieter)

Gerstenbluth, I. (Izzy)

Gorp, E.C.M. (Eric) van

Osterhaus, A.D.M.E. (Albert)

Erasmus University Digital Repository

SymposiumFatal Dengue in Patients with Sickle Cell Disease orSickle Cell Anemia in Curac¸ao: Two Case ReportsFleur M. Moesker1, Fred D. Muskiet2, Jeanne J. Koeijers2, Pieter L. A. Fraaij1,3*, Isaac Gerstenbluth4,Eric C. M. van Gorp1, Albert D. M. E. Osterhaus11Department of Viroscience Lab, Erasmus MC, Rotterdam, The Netherlands, 2 St Elisabeth Hospital, Willemstad, Curac¸ao, 3 Pediatric Infectious Diseases and Immunology,Erasmus MC-Sophia, Rotterdam, The Netherlands, 4 Epidemiology and Research Unit, Medical and Public Health Service of Curac¸ao, Willemstad, Curac¸aoPresentation of CasesCase 1A ten-year-old girl with sickle cell disease(SCD) (combined heterozygosity for theabnormal hemoglobin S and abnormalHbC; HbSC) presented to our clinic witha history of four days fever, malaise, and ageneralized tonic-clonic convulsion. At pre-sentation she was alert, nauseous, andcomplained of headache and retro-orbitalpain. Temperature was 38.0uC, heart rate(HR) 135/min, blood pressure (BP) 94/62 mmHg, respiratory rate (RR) 20/min;minor hepatosplenomegaly and upper-quadrant abdominal tenderness were pres-ent. No further abnormalities were reportedon physical examination. Initial lab resultsrevealed a moderate increase of CRP,anemia, thrombocytopenia, prolonged acti-vated partial thromboplastin time (aPTT)and prothrombin time (PT), increased liverenzymes, and decreased albumin andhematocrit (Ht) (Table S1). On day two,during defervescence she became hypoten-sive and was treated with fluid resuscitationand inotropic agents. Blood products weretransfused to correct anemia and thrombo-cytopenia. Hemolysis and acute hemor-rhage with gastrointestinal, vaginal, andlater on venipuncture sites bleeding devel-oped. Splenic sequestration was also con-sidered as the cause of anemia, but couldnot be confirmed with abdominal ultra-sound. Pleural effusion, gallbladder wallthickening, and ascites were seen. On daythree, she lost vision. A brain CT scanrevealed no abnormalities. Lumbar punc-ture was deferred and antibiotic treatmentwas adjusted to cover possible meningitis.Hereafter she developed acute respiratorydistress syndrome (ARDS) requiring me-chanical ventilation. Dengue serology waspositive for IgM (titer: 3.26) and IgG (3.26)(Focus Diagnostics), and RT-PCR showeddengue virus serotype 2 (DENV-2). Herclinical situation deteriorated with an in-creased hemorrhagic tendency, and blood,clotting products, and clotting factors wereadministered. In time multiorgan dysfunc-tion syndrome (MODS) developed. Bloodcultures remained negative for bacteria, butantibiotics were administered anyway. Can-dida was cultured and antifungals wereinitiated. Despite intensive treatment thepatient did not recover, disseminated intra-vascular coagulation (DIC) progressed andkidney function did not return. Consequent-ly further treatment was discontinued andthe patient died, 28 days after admission.Case 2A 19-year-old female presented to ourclinic with fever, headache, retro-orbitalpain, and muscle ache for two days. Inaddition hematemesis and epistaxis startedon the day of admission. Her medicalhistory revealed sickle cell anemia (SCA)(homozygosity for abnormal HbS; HbSS).On examination she was alert, with atemperature of 37uC, BP 120/80 mmHg,HR 100/min, and RR 15–20/min. Shehad right upper-quadrant abdominal ten-derness. No other abnormalities on physicalexamination were found. Initial lab resultsrevealed moderate increase of CRP, ane-mia, thrombocytopenia, and increased liverenzymes. NS1-antigen tested positive anddengue serology was negative for IgM(0.41) and positive for IgG (5.71), andRT-PCR showed DENV-2. Shortly afteradmittance she became hypotensive, withdistension of her abdomen. Intravenousfluid resuscitation was started and furtherintervention was implemented on the basisof the monitoring of hematocrit, urineoutput, and blood glucose. Profuse abdom-inal bleeding was suspected, with markeddecrease of Hb, low platelets, severedisrupted coagulation parameters, andintra- and retro-abdominal free fluid withfibrin strands on ultrasound. Moreoverextensive capillary leakage and anuriadeveloped. She was intubated due toseizures and following sedation. Althoughin the course of time shock and bleedingstabilized, she continued to develop MODSand both pupils became progressively lessreactive to light until nonreactive. CT brainimaging could not be performed. On dayfour, she died due to cardiac arrest.No autopsies were performed on eitherof the patients. Written informed consentfor publication of the disease histories wasobtained from the direct relatives of bothpatients.Case Discussion: Dengue andCurac¸aoDuring the past decades dengue has beenreported to occur in Curac¸ao. Until nowCitation: Moesker FM, Muskiet FD, Koeijers JJ, Fraaij PLA, Gerstenbluth I, et al. (2013) Fatal Dengue in Patientswith Sickle Cell Disease or Sickle Cell Anemia in Curac¸ao: Two Case Reports. PLoS Negl Trop Dis 7(8): e2203.doi:10.1371/journal.pntd.0002203Editor: Scott B. Halstead, Pediatric Dengue Vaccine Initiative, United States of AmericaPublished August 8, 2013Copyright:  2013 Moesker et al. This is an open-access article distributed under the terms of the CreativeCommons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,provided the original author and source are credited.Funding: The work was funded by the Erasmus MC Rotterdam and by the Dutch government (project numberFES0908). The funders had no role in study design, data collection and analysis, decision to publish, orpreparation of the manuscript.Competing Interests: We have read the journal’s policy and have the following conflicts: FMM’s, PLAF’s, andADMEO’s scientific work is supported by the Virgo consortium, funded by the Dutch government (projectnumber FES0908). In addition ADMEO has share certificates in ViroClinics Biosciences B.V. The majority of theshares in ViroClinics Biosciences B.V. (.75%) are owned by Erasmus MC through its Erasmus MC Holding B.V.To avoid any possible conflict of interest and to safeguard its employees against the possibility of unethicaldecisions, the Erasmus MC does not allow any of its employees to hold shares in person in any companies thatare (partly) owned by Erasmus MC. As a result thereof, any shares provided by such companies to any ErasmusMC employees are held by a Foundation Administration Office. The board of this foundation is appointed byErasmus MC. The employees receive share certificates of their shares. Apart form those described above theauthors have declared that no competing interests exist.* E-mail: p.fraaij@erasmsumc.nlPLOS Neglected Tropical Diseases | www.plosntds.org 1 August 2013 | Volume 7 | Issue 8 | e2203fatal cases were never documented. Howev-er the 2010–2011 outbreak with 1,822serologically confirmed cases was associatedwith four deaths (personal communication).Two of these patients had been previouslydiagnosed with SCD type HbSC and SCA.SCD is not uncommon in Curac¸ao, with aprevalence of approximately 0.25% [1].Although chronic diseases such as SCD areconsidered to be a risk factor for develop-ment of severe dengue, few cases of childrenor adolescents have been reported [2].Literature ReviewBoth in the Americas and Asia all fourserotypes of DENV circulate with frequentreports of fatal dengue. Until now no casesof DENV infection in SCD patients havebeen described in Asia, probably due to therelatively low prevalence of SCD [3].Furthermore reports describing patientswith this combination of diseases are scarce,little-detailed, and restricted to a few fatalcases apart from the Cuban study concern-ing adults only (see Table 1) [4–10]. Bravoet al. reported 158 fatal cases during the1981 DENV-2 epidemic in Cuba (72children and 26 adults) [8]. Eight patientswere suffering from sickle cell anemia, ofwhich five presented with hemorrhages andthree with shock. Half of them died within24 hours after admission. The secondarticle from Cuba describes a DENV-3outbreak in 2001 [4]. Two fatal cases withHbSS and HbSC were reported. Bothpatients presented with fever. In onepatient hemorrhage predominated, withplasma leakage leading to shock in theother case. Five or six days after admission,both patients died. In 1999 Ware et al.reported one fatal case of DHF in a SCApatient [6]. She presented with bone painand fever, and she died four days afteradmission. Most cases described are HbSSpatients. However none of the describedcases suggests treatment options or casemanagement, and interaction betweenboth diseases is not described.Presented Cases and TreatmentChallengesThe clinical findings of the two casesdescribed here are difficult to interpretbecause of the apparent complementaryvascular endothelial damage in SCD, SCA,and severe dengue. As proposed in the modelof dengue pathogenesis by Martina et al.,DENV might replicate in selective endothe-liocytes [11]. In SCD, endothelial dysfunc-tion is known to occur [12]. There is nodirect evidence from fatal dengue cases thatdengue virus replicates in endothelial cells.Nonetheless, damage to endothelial cells asreflected by increased vascular permeabilityis central to the dengue vascular permeabilitysyndrome (DHF/DSS). Vascular endothelialcells (VEC) play an important roll ininflammation and coagulation. By damagingthe VEC either through infection of DENVor by sickling of erythrocytes, the permeabil-ity of the vascular endothelial layer canincrease, which may induce plasma leakage,release of cytokines, and cause profoundshock. Based on these findings, we hypoth-esize an essential role for endothelial cells tocontribute to disease severity. The similaritiesbetween the cases are striking: shock, plasmaleakage, hemorrhage, and MODS [2].However plasma leakage predominated incase 1, whereas hemorrhage did in case 2.The onset of vaso-occlusion with SCD andSCA is often triggered by inflammation, as isthe case in a DENV infection [12]. Severebleeding seldom happens in children, butonly in cases of profound shock, and nothrombotic complications are seen [13]. Intreating dengue patients with underlyingSCD or SCA, the treating physician is facinga dilemma. In SCD and SCA, it is preferredto maintain a low Ht to reduce the risk ofvaso-occlusion. Treating physicians may bereluctant to perform blood transfusions inSCD patients because of concerns of exces-sive accumulation of iron, transfusion reac-tions, and alloimmunization. However se-vere anemia as a result of SCD or denguemay necessitate blood transfusion. TheWHO reports an increase of Ht as a signof plasma leakage with subsequently adecrease that may be due to hemorrhage.Both cases showed a continuing decrease ofHt, associated with hemorrhage with plasmaleakage also predominating, suggesting Htshould not be used as a marker in patientswith SCD or SCA. Iatrogenic interstitial fluidoverload in patients with SCD, SCA, andsevere dengue, due to preexisting vascularendothelial damage, is not just a theoreticalhazard. Whether the clinical manifestationswould just have been the result of secondaryDENV infection only, despite SCD or SCA,remains a matter for debate. To furtheraddress this issue, we suggest that a case-control study should be performed to furtherelucidate the proposed association betweensevere dengue and SCD or SCA.This report is based on two fatal cases ofsevere dengue with underlying SCD/SCAin Curac¸ao during the 2010–2011 epi-demic. Currently no guidelines exist onhow to treat such patients. In populationswith a high prevalence of SCD, SCA, andTable 1. Summary of literature review.Author, year of publication CountryNumber ofpatientsGender/age(years)SCDtype Dengue virus serotype OutcomePresent case 1 Curac¸ao 1 F/10 HbSC DENV-2 DiedPresent case 2 Curac¸ao 1 F/19 HbSS DENV-2 DiedLimonta et al., 2009 Cuba 2 M/34M/25HbSCHbSSDENV-3 (s)DENV-3 (s)DiedDiedAndrianarisoa et al., 2007 Madagascar ND ND ND ND NDWare et al., 1999 Jamaica 1 F/19 HbSS ND DiedTeruel-Lo´pez et al., 1991** Venezuela ND ND ND ND NDBravo et al., 1987 Cuba 44AdultsChildrenHbSSHbSSDENV-2 (ND)DENV-2 (ND)DiedDiedGentilini et al., 1964* Haiti ND ND ND ND NDM, male; F, female; ND, no data available; DENV, dengue virus serotype; (s), secondary; HbSC, heterozygote sickle cell disease; HbSS, homozygote sickle cell anemia;HbAS, sickle cell trait;*no abstract available;**review describing Bravo et al. article.doi:10.1371/journal.pntd.0002203.t001PLOS Neglected Tropical Diseases | www.plosntds.org 2 August 2013 | Volume 7 | Issue 8 | e2203dengue activity, clinicians should be awareof the challenges in clinical management.Supporting InformationTable S1 Detailed laboratory data ofboth patients.(DOC)References1. Dijs FP (2004) Sickle cell disease and a-thalasse-mia in Curac¸ao: contributors to epidemiology,pathophysiology and supportive care [disserta-tion]. Willemstad.2. World Health Organization (2009) Dengueguidelines: diagnosis, treatment, prevention andcontrol. New edition 2009. Geneva: WorldHealth Organization. pp. 1–160.3. World Health Organization (January 2011)Sickle-cell disease and other haemoglobin disor-ders. Fact sheet Nu308. Available: http://www.who.int/mediacentre/factsheets/fs308/en/index.html. Accessed 5 July 2013.4. Limonta D, Gonza´lez D, Capo´ V, Torres G, Pe´rezAB, et al. (2009) Fatal severe dengue and cell deathin sickle cell disease during the 2001–2002 Havanadengue epidemic. Int J Infect Dis 13: 77–78.5. Andrianarisoa ACE, Rakotoson J, Randretsa M,Rakotondravelo S, Rakotoarimanana RD, et al.(2007) Madagascar: public health situation on the‘‘Big Island’’ at the beginning of the 21st century.Med Trop (Mars) 67: 19–29.6. Ware MA, Hambleton I, Ochaya I, Serjeant GR(1999) Day-care management of sickle cell painfulcrisis in Jamaica: a model applicable elsewhere?Br J Haematol 104: 93–96.7. Teruel-Lo´pez E (1991) Dengue. A review. InvestClin 32: 201–217.8. Bravo JR, Guzma´n MG, Kouri GP (1987)Why dengue haemorrhagic fever in Cuba? 1.Individual risk factors for dengue haemor-rhagic fever/dengue shock syndrome (DHF/DSS). Trans R Soc Trop Med Hyg 81: 816–820.9. Gentilini M, Laroche V, Degremont A (1964)Aspects of parasitic and infectious tropicalpathology in the Republic of Haiti. Bull SocPathol Exot Filiales 57: 565–570.10. Gonza´lez D, Castro OE, Kourı´ G, Perez J,Martinez E, et al. (2005) Classical denguehemorrhagic fever resulting from two dengueinfections spaced 20 years or more apart:Havana, Dengue 3 epidemic, 2001–2002.Int J Infect Dis 9: 280–285.11. Martina BEE, Koraka P, Osterhaus ADME(2009) Dengue virus pathogenesis: an integratedview. Clin Microbiol Rev 22: 564–581.12. Rees DC, Williams TN, Gladwin MT (2010)Sickle-cell disease. Lancet 376: 2018–2031.13. Halstead SB (2007) Dengue. Lancet 370: 1644–1652.Learning Points1) This case report is suggestive of a fatal interaction between dengue and sicklecell disease or sickle cell anemia.2) Hematocrit values are of limited use for treatment decisions in patients withsevere dengue infection and sickle cell disease or sickle cell anemia.PLOS Neglected Tropical Diseases | www.plosntds.org 3 August 2013 | Volume 7 | Issue 8 | e2203

Fatal Dengue in Patients with Sickle Cell Disease or Sickle Cell Anemia in Curaçao: Two Case Reports

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