ArchClinInfectDis.2017July;12(3):e62221.                                                                   doi: 10.5812/archcid.62221.
                Publishedonline2017July30.                                                                                          ResearchArticle
                ChangingTrendsinClinicalPresentationandBiochemicalSpectrum
                of DengueFever:AnObservationofaTertiaryCareCentre
                                 1,*                   2                      3                    4                      5
                DeepakJain, RajeshRajput, VaibhavPathak, AshimaMittal, andPromilJain
                1AssociateProfessor,Departmentof Medicine,PtBDSharmaUniversityofHealthSciences,Rohtak,Haryana,India
                2SeniorProfessorandHeadEndocrinologyandDepartmentofMedicineVI,PtBDSharmaUniversityofHealthSciences,Rohtak,Haryana,India
                3Resident,DepartmentofMedicine,PtBDSharmaUniversityofHealthSciences,Rohtak,Haryana,India
                4SeniorResident,DepartmentofMedicine,PtBDSharmaUniversityofHealthSciences,Rohtak,Haryana,India
                5AssistantProfessor,Departmentof Pathology,SPtBDSharmaUniversityofHealthSciences,Rohtak,Haryana,India
                *Correspondingauthor:DeepakJain,DepartmentofMedicine,PtBDSharmaUniversityofHealthSciences,Rohtak,Haryana,India.Tel:+91-9416147887,E-mail:
                jaindeepakdr@gmail.com
                Received2016April15;Revised2017March04;Accepted2017March14.
                  Abstract
                  Objectives: Casesof dengueareontheriseandIndiaexperienceditsworstepidemicduring2015. Therewasalmosta2timesrise
                  inthenumberofcases. Thisstudywasdonetounderstandthevariedpresentationandmanifestationof dengueatatertiarycare
                  centreof Haryana,India.
                  Methods: ThiswasanobservationalcrosssectionalstudyundertakenatPGIMSRohtak,Haryana,India. Onehundredandonepa-
                  tients aged ≥ 14 years, who had positive test results for dengue, as NS1/IgM, were included in the study. Clinical presentations,
                  haematological,andbiochemicalmarkerswerestudiedandanalyzed.
                  Results: Out of 101 patients, 63.3% were males. Overall, 95% had fever followed by headache (62.3%), rash (53.4%), retrorbital pain
                  (43.5%), and abdomenal pain (43.5%). Furthermore, 31.8% of patients had bleeding manifestation, of which the commonest was
                  petechiae (12.8%) followed by malena (7.9%) and bleeding gum (6.9%). All patients had raised liver enzymes. Platelet count of <
                  50,000/mm3waspresentin79.2%.Leucopeniawasfoundin43.5% ofpatients.Ultrasonographysuggestiveoffreefluidwasfoundin
                  44.5%. Hypokalemiawasseenin21.7% ofpatients.Complications,suchasacuterespiratorydistresssyndrome(ARDS)andDIC,were
                  seenin2.9% and5.9% cases.Overallmortalityratewas2.97%.
                  Conclusions:Denguecouldhavevariedpresentationsrangingfromasimplefebrileillnesstofatalmultiorganfailure.Itiscrucial
                  tounderstandthefeatures,whichpredicttheprogressofdenguefever(DF)todenguehaemorrhagicfever(DHF)anddengueshock
                  syndrome(DSS).Consideringthatthetreatmentof dengueisrelativelysimple,earlyinstitutionof appropriatetherapywithclose
                  monitoringofvitalsignsandlaboratoryparameterscouldhelppreventmorbidityandmortalityrelatedtodengue.
                  Keywords:DengueFever,Hypokalemia,Petechiae,Leukopenia
                1. Background                                                         (NVBDCP),intheyear2015therewasatotalof 99913cases
                     Dengue is a mosquito-borne viral disease, which is               of dengue with 220 deaths, which was double that of the
                causedbydenguevirusthatbelongstothefamilyFlavivir-                    previous years (2). Dengue has diverse clinical presenta-
                dae and has 4 serotypes. Mosquitoes of the genus Aedes,               tions, often with unpredictable clinical progression and
                principally Aedes aegypti, are responsible for its spread.            outcome. Symptomatic dengue virus infections could be
                Duringthelast3decades,incidencehasrisendramatically                   grouped into undifferentiated fever, dengue fever (DF),
                withincreasinggeographicexpansiontonewareasandin                      and dengue haemorrhagic fever (DHF). Dengue haemor-
                thepresentdecade,fromurbantoruralsettings. Approxi-                   rhagic fever is further classified to 4 severity grades, with
                mately50milliondengueinfectionsoccureveryyearand                      gradesIIIandIVbeingdefinedasdengueshocksyndrome
                around 2.5 billion people live in dengue endemic coun-                (DSS) and expanded dengue syndrome (3). While the ma-
                tries (1). While cyclic epidemics are on the rise through-            jorityofpatientsrecoverwellfromaminorclinicalcourse,
                out the globe, there is in-country geographic expansion               afewprogresstoseveredisease,whichischaracterizedby
                occurring as well within countries like India with multi-             plasmaleakagewithorwithouthaemorrhage.Itisdifficult
                ple serotypes of virus in circulation. In India, according            topredicttheprogressionofnon-severecasestoseveredis-
                to the national vector borne disease control programme                ease. However,thisisofutmostimportancesinceapttreat-
                Copyright© 2017,ArchivesofClinicalInfectiousDiseases.Thisisanopen-accessarticledistributedunderthetermsof theCreativeCommonsAttribution-NonCommercial
                4.0InternationalLicense(http://creativecommons.org/licenses/by-nc/4.0/)whichpermitscopyandredistributethematerialjustinnoncommercialusages,providedthe
                originalworkisproperlycited.
                                                                           JainDetal.
                  mentmayavertthesepatientsfromdevelopmentofsevere               2.1. Ethics Statement
                  disease. Foradiseasethatisperplexinginitspresentation,             The study was analyzed and approved by the ethics
                  managementisrelativelyeasyandveryeffectiveinsaving              committeereviewboardof PGIMSRohtak. Informedcon-
                  livesaslongasitisprovidedontime.Thekeyisawareness              sentwasobtainedfromeachpatient.
                  and understanding of the clinical features of the differ-
                  entphasesof thedisease, whichwouldenableabalanced              2.2. Statistical Analysis
                  approach to case management and good outcome. For a
                  countrylikeIndiathattacklestheepidemicof dengueev-                 AnalyseswereperformedusingtheSPSSsoftware,Ver-
                  ery year, there is a large financial burden on the govern-      sion 20. Total numbers and percentages were calculated
                  mentaswellaspatients.Therefore,understandingthevar-            fordifferentcategoricalvariables,suchasclinicalfeatures
                  iedpresentationanddiseaseburdenof dengueinIndiais              andbiochemicalparameters.
                  essential to assist policy makers and public health man-
                  agers to prepare for control of outbreaks. With the back-      3. Results
                  groundofthisveryfactanddramaticincreaseinthenum-
                  berofcasesfrompreviousyearwithmoreatypicalpresen-                  Outof 101 confirmedcases, 63.3% weremales. Mostof
                  tation,thereisaneedtorelookatclinicalandbiochemical            thepatientsinstudygroupwerefromthedistrictRohtak
                  spectrumof denguefever. Hence, this study was planned          anditssurroundingdistrictsi.e. JhajjarandBahadurgarh.
                  to demonstrate the clinical and laboratory parameters of       Themajorityof cases were from the age group of 21 to 60
                  serologicallyconfirmedcasesofdenguefever.                       yearsold(Table1). AsshowninTable2,feverwasthecom-
                                                                                 monestpresentationbeingpresentin95% ofpatientsand
                  2. Methods                                                     average duration of fever was 3 to 5 days. The next com-
                                                                                 monsymptomatpresentation was headache, which was
                      This observational cross sectional study was per-          present in around 63%. Other common clinical features
                  formedfrom20thof May2015to20thof October2015at                 wererashes(54%), painintheabdomen(42.5%),andretro
                  a governmenteducationalhospital. This hospital catered         orbital pain (43.5%). Around 35.6% of patients had pruri-
                  mostly referral cases from all across Haryana and adjoin-      tus,whichwasobservedtooccurduringthelaterstagesof
                  ing states of the country. Rohtak city, in which the study     febrile period along with improvement of platelet count.
                  wasconducted, has a population of 10 lacs with a gender        Atotalof32(31.6%)patientshadbleedingmanifestation,of
                  ratio of 868 females for every 1000 males. The climate is      which petechiae (12.8%) and malena (7.9%) were the most
                  hotsemiaridandtheeconomyofthecityismainlybased                 commen(Table3).Furthermore,DFwasobservedin40.9%
                  onagriculture. Patients aged ≥ 14 years, who referred to       while DHF (grade I and II) and DSS (DHF grade III and IV)
                  the emergency department with symptoms suggestive              wereobservedin51.4% and7.7% ofcases,respectively.Clin-
                  of tropical fever were screened. A total of 710 patients       ically, hepatomegaly was present in 25.7% of patients and
                  were screened and 110 patients were confirmed to have           splenomegaly in 20.7%. Free fluid could be demonstrated
                  dengue with NS1 antigen and/or IgM dengue antibody             in12.8% andpleuraleffusionin9.9%. Atotalof 7(6.9%)pa-
                  positivity by using the dengue diagnostic kit (SD BIOLINE      tients had SBP < 90 mmHg and they responded with ad-
                  Dengue Duo combo device). Nine cases with other con-           equate oral and intravenous fluids. A total of 6 (5.9%) pa-
                  comitantillnesses,suchasmalaria,typhoid,leptospirosis,         tients had features suggestive of DIC and 3 (2.9%) patients
                  scrub typhus, and tuberculosis, which was confirmed by          werediagnosedtohaveARDS.Totalmortalitywas3(2.9%).
                  laboratory tests, were excluded from the study. Finally,       Theremainingpatientshadgoodrecoverywithtime.
                  statistical analysis was performed on 101 patients.     De-        AsshowninTable4,themajorityofthepatients(79.2%)
                  tailedhistoryregardingsymptomswasobtained.Subjects             hadplateletof< 50,000cells/mm3atpresentation.Atpre-
                  were thoroughly examined and clinical variables were           sentation haemoglobin of > 16 gm% was present in 25.7%
                  measured by the same resident and senior resident un-          and haematocrit > 45% in 23.4%. Overall, 43.56% of pa-
                  der the supervision of a faculty member to avoid bias.         tientshadevidenceofleucopeniaTLCbeinglessthan4000
                                                                                          3
                  Serologically confirmed dengue patients were subjected          cells/mm .Liverfunctiontestderangementwasuniversal.
                  to clinical case definition and disease severity was classi-    Hypokalemiawasfoundinatotalof22patients(18.8%),out
                  fied to DF, DHF, and DSS, according to the world health         of which 3 patients had symptomatic hypokalemia with
                  organization (WHO) criteria (3). A complete haemogram,         weaknessofbilaterallowerlimbsandabsentdeeptendon
                  renal/liver function tests, chest X-ray, electrocardiogram     reflexes. Onultrasonographyof abdomenandthoraxand
                  (ECG), abdominalUltrasound(USG),andthoraxwerealso              chest X-ray, more than one-third of cases had evidence of
                  done.                                                          serositis.
                  2                                                                                   ArchClinInfectDis.2017;12(3):e62221.
                                                                                 JainDetal.
                 Table1.GenderandAgeCharacteristics
                  Variables                                                                             Value
                  Age                                              14-20                     21-40                    41-60                   > 60
                  Male                                               12                       25                        21                      6
                  Female                                             9                        12                        11                      4
                  Total                                              21                       37                        33                     10
                 Table2.ClinicalFeatures
                  ClinicalFeatures                   NoofPatients       Percentage,%          ClinicalFeatures         NoofPatients        Percentage,%
                  Fever                                   96                 95                Pleuraleffusion               10                  9.9
                  Headache                                63                 62.3              SBP< 90mmHg                   7                  6.9
                  Rash                                    54                 53.4               Breathlessness               6                  5.9
                  Retroorbitalpain                        44                 43.5                   DIC                      6                  5.9
                  Painabdomen                             44                 43.5                   ARDS                     3                  2.9
                  Conjunctivalsuffusion                   40                  39.6                 Pruritus                  36                  35.6
                  Positivetourniquettest                  33                 32.6            Nauseaandvomiting              29                  28.7
                  Hepatomegaly                            26                 25.7               Splenomegaly                 21                 20.7
                  Ascitis                                 13                 12.8
                 Table3.BleedingManifestations                                          outwarningsigns(4). Earlydangersignsof dengue,such
                                                                                        asabdominalpain,recurrentvomiting,hepatomegaly,in-
                  BleedingTendencies              NoofPatients        Percentage        creasedhaematocrit,andclueoffluidleakshouldbemon-
                  Petechiae                            13                12.8           itoredcarefullyfortimelyactiontopreventseverecompli-
                                                                                        cations.
                  Epistaxis                            6                 5.9                 Thecurrentstudydemonstratesthevariedclinicalpro-
                  Haemtemesis                          5                 4.9            fileandlaboratoryparametersof denguefever. Therewas
                  Malena                               8                 7.9            a greater number of male patients in the current study
                  Bleedinggum                          7                 6.9            (63.3%) as compared to females, which may be because of
                  Haemptysis                           2                  1.9           the proportion of male population being higher in the
                                                                                        studyarea.Onanalysisofcollecteddata,itwasshownthat
                  Haematuria                           1                 0.9            fever (95%) was the most common presenting symptom,
                  Menorrhagia                          3                 2.9            whichwassimilartootherstudiesinIndia(5-7).Headache
                                                                                        and retrorbital pain were seen in the majority of cases.
                                                                                        Conjunctivalinjectionwasfoundin39.6% andrashin53.4%
                 4. Discussion                                                          of cases. Patients in the group with rash and conjucti-
                                                                                        val injection were the ones with features of DHF. Kumar
                     Dengue has become a major public health concern                    et al. (8) in their study documented that headache was
                 acrosstheglobewiththevirusexpandingitspresenceatan                     present in 47.6% and rash in 21.7% of patients. Other than
                 alarmingrate. Duetoclimaticchangesandfailuretocon-                     the above-mentioned symptoms, gastrointestinal symp-
                 trol mosquito vector, there is increased frequency of epi-             tomsweremoreprevalent,of whichabdominalpainwas
                 demics.Easyavailabilityofdiagnostickitsalongwithalert-                 presentin42.5% andnausea/vomitingin28.7% ofthestudy
                 ness among medical fraternity has led to increased num-                population. Liver injury due to dengue virus could be re-
                 ber of cases being detected. There is also a rise in various           sponsibleforsuchsymptoms. Nimmagaddaetal. (9)also
                 atypical manifestations and severity of dengue fever. As               demonstrated similar findings in their study. Fever pre-
                 per new classification of WHO, dengue is classified to se-               sentedwithgastrointestinalsymptomsisacommonfind-
                 veredengue,denguewithwarningsigns,anddenguewith-                       ing of various other febrile illnesses like typhoid and lep-
                 ArchClinInfectDis.2017;12(3):e62221.                                                                                                     3
                                                                                     JainDetal.
                     Table4.LabParameters                                                    itive tourniquet test and bleeding tendency, which was in
                                                                                             contrary to the other previous studies (11). Eight patients
                       Parameters                         NoofPatients      Percentage       (7.9%) had spontaneous bleeding as their initial present-
                       AST> 40U/L                              100             99            ing complaint in the current study group. Therefore, in
                                                                                             case of outbreak of dengue fever, one should be careful
                       ALT> 40U/L                              101             100           that bleeding could only be the sole presentation with-
                       ASTT> 3timesnormal                       48             47.5          outotherassociatedtypicalfeaturesof denguefever. Dur-
                       ALT> 3timesnormal                        78             77.2          ing the current study, patients who had bleeding mani-
                       ALP> 117U/L                              23             22.7          festation were not universally found to have platelet of <
                                                                                                                3
                       Thrombocytopenia,cells/mm3                                            20,000cells/mm .Evenpatients,whohadplateletcountof
                                                                                                                   3
                                                                                             > 50,000cells/mm werefoundtohavebleedingmanifes-
                             < 50,000                          80              79.2          tations. Various other studies across India showed that al-
                             > 50,000-1lac                      21             20.7          thoughthrombocytopeniaisacommonfindingindengue
                       Haemoglobin> 16gm%                       26             25.7          patients, there is poor correlation between bleeding ten-
                       TLC< 4000mm3                            44              43.5          dencies and platelet count (10, 12-14). Virus-induced inhi-
                       HCT> 45%                                 22             23.4          bition and destruction of myeloid progenitor cells could
                                                                                             lead to low leukocyte count. The researchers found that
                       Hypokalemia,mEq/L                                                     only 43.5% of cases had a leukocyte count below 4000
                             3.5 - 2.5                          19             18.8                    3
                                                                                             cells/mm .However,inthestudyofItodaetal.(11),leucope-
                             < 2.5                              3              2.9           niawasdetectedin71% of cases,whileAgeepAKetal. (15),
                       Creatnine> 1.5mg/dL                      3              2.9           reported leucopenia in 90%. However, Mittal H et al. (14)
                       Urea> 40mg/dL                            10             9.9           foundleucopeniaonlyin19.2% of cases. Patientswithleu-
                                                                                             copeniaalongwithseverethrombocytopeniainthestudy
                       GBthickwalled                            30             29.7          groupweretheones,whohadmajorepisodeof bleeding
                       USGfreefuid                              45             44.5          andshock.
                       BluntedCPangleonChestX-ray               15             14.8              Hypokalemiaisawell-knownelectrolyteimbalanceof
                                                                                             dengue fever. Overall, 21.7% of patients had hypokalemia
                                                                                             inthecurrentstudygroupand3(2.97%)hadsymptomatic
                     tospirosis,whichareprevalentinIndiaandtheymaydelay                      hypokalemia with bilateral weakness of lower limbs and
                     the diagnosis of dengue. The current study suggests that                absent deep tendon reflexes. These findings are consis-
                     dengue must be included in the differential diagnosis of                 tent with other studies (16). The proposed mechanisms
                     patientswithfeverandgastrointestinalsymptoms.                           areentryof potassiumtothecellsortransientrenaltubu-
                         Hypotension was recorded in 6.9%, they responded                    lar disturbance, which causes increased urinary potas-
                     well to fluids. Itching was noticed in 35.6% of the cases,               siumwasting. Stress of infection causes adrenergic surge
                     mostly during the period in which platelets were on the                 and secondary insulin release could result in intracellu-
                     rise, this is in contrary to other studies barring a few.               lar shift of potassiumandhypokalemia(17). Therefore,pa-
                     Rachel et al. (6) from their study in Kollam, Kerala doc-               tients presenting absent tendon reflexes and weakness of
                     umented pruritis in 10.4% of their patients and Deshwal                 lower limbs mimicking Guillain-Barre syndrome, before
                     et al, (10) showed this disease in 13.4% of patients. This is           proceedingfurtherdengue,shouldberuledout.
                     thoughttobeduetotheinteractionof theviruswiththe                            Denguevirusviainteractionwithhostcellscausesre-
                     hostcells causing release of different chemical mediators                lease of various cytokines and stimulates immunologic
                     andinitiationof immunologicalmechanisms.                                mechanism, vascular endothelial changes, infiltration of
                         Bleeding manifestations have been a known feature                   mononuclear cells, and perivascular edema (18). Ascites,
                     of DF and currently a common manifestation because of                   pleural effusion, and gall bladder edema from capillary
                     low platelet count and efflux from blood vessels. Other                   leak syndrome are one of those features. The researchers
                     factors, which may be responsible, are immune mediated                  found that clinically free fluid was demonstrated in 12.8%
                     disorders, bone marrow suppression, and aggregation of                  andpleuraleffusionin9.9%,yetonultrasonography,44.5%
                     plateletstoendotheliumcells. Inthecurrentstudy,there-                   patienthadfreefluidintheabdomen,29.7% hadgallblad-
                     searchers found that 32.6% of patients had positive torni-              deredema,and14.8% hadevidenceofpleuraleffusion. Ul-
                     quet test while 31.6% of patients had bleeding episodes                 trasonography is highly sensitive in detecting even small
                     in the form of petechiae (12.8%) and malena (7.9%). The                 amounts of pleural effusion and ascites. Ultrasonogra-
                     current study showed a positive correlation between pos-                phycoulddetectplasmaleakageinvariousbodycompart-
                     4                                                                                              ArchClinInfectDis.2017;12(3):e62221.