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 <front>
  <journal-meta>
   <journal-id journal-id-type="nlm-ta">Ulutas Med J</journal-id>
   <journal-title-group>
    <journal-title>The Ulutas Medical Journal</journal-title>
    <abbrev-journal-title>Ulutas Med J</abbrev-journal-title>
   </journal-title-group>
   <issn pub-type="ppub">2149-0430</issn>
   <issn pub-type="epub">2149-388X</issn>
   <publisher>
    <publisher-name>Hayriye Zehra Ulutaş</publisher-name>
   </publisher>
  </journal-meta>
  <article-meta>
   <article-id pub-id-type="doi">10.5455/umj.20170608022332</article-id>
   <article-id pub-id-type="publisher-id">268883</article-id>
   <article-categories>
    <subj-group subj-group-type="heading">
     <subject>Review Article</subject>
    </subj-group>
    <subj-group subj-group-type="subject">
     <subject>Child Psychiatry</subject>
    </subj-group>
   </article-categories>
   <title-group>
    <article-title>Dengue Viral Infection and Necessity for Screening Patients Having Pyrexia of Unknown Origin</article-title>
   </title-group>
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    <aff id="aff1">
     <label>1</label>
     <institution-wrap>
      <institution-id institution-id-type="ror">https://ror.org/04rmz8121</institution-id>
      <institution>Pathology Consultant Microbiologist, Al Nafees Med College Isra University, Islamabad Campus, Pakistan</institution>
     </institution-wrap>
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    <aff id="aff2">
     <label>2</label>
     <institution-wrap>
      <institution-id institution-id-type="ror">https://ror.org/04rmz8121</institution-id>
      <institution>Pathology Consultant Haematologist, Al Nafees Med College Isra University, Islamabad Campus, Pakistan</institution>
     </institution-wrap>
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    <aff id="aff3">
     <label>3</label>
     <institution-wrap>
      <institution-id institution-id-type="ror">https://ror.org/045f7ep44</institution-id>
      <institution>Rawal Dental College, Rawal Institute of Health Sciences, Islamabad, Pakistan</institution>
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     <label>4</label>
     <institution-wrap>
      <institution-id institution-id-type="ror">https://ror.org/045f7ep44</institution-id>
      <institution>Operative Dentistry, Rawal Dental College Rawal Institute of Health Sciences, Islamabad, Pakistan</institution>
     </institution-wrap>
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    <aff id="aff5">
     <label>5</label>
     <institution-wrap>
      <institution>Pathology Consultant Histopathologist, Al Nafees Med College Isra University, Islamabad Campus, Pakistan</institution>
     </institution-wrap>
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   <pub-date publication-format="electronic" date-type="pub" iso-8601-date="2017-09-27">
    <day>27</day>
    <month>09</month>
    <year>2017</year>
   </pub-date>
   <pub-date publication-format="print" date-type="collection">
    <year>2017</year>
   </pub-date>
   <volume>3</volume>
   <issue>3</issue>
   <fpage>49</fpage>
   <lpage>53</lpage>
   <history>
    <date date-type="received" iso-8601-date="2017-05-25">
     <day>25</day>
     <month>05</month>
     <year>2017</year>
    </date>
    <date date-type="rev-recd" iso-8601-date="2017-07-12">
     <day>12</day>
     <month>07</month>
     <year>2017</year>
    </date>
    <date date-type="accepted" iso-8601-date="2017-08-11">
     <day>11</day>
     <month>08</month>
     <year>2017</year>
    </date>
   </history>
   <permissions>
    <copyright-statement>© 2017 The Author(s)</copyright-statement>
    <copyright-year>2017</copyright-year>
    <license>
     <ali:license_ref>https://creativecommons.org/licenses/by-nc/4.0/</ali:license_ref>
     <license-p>This is an open access article distributed under the CC BY-NC 4.0 licence.</license-p>
    </license>
   </permissions>
   <self-uri xlink:href="https://www.ulutasmedicaljournal.com/?mno=268883"/>
   <self-uri content-type="pdf" xlink:href="https://www.ulutasmedicaljournal.com/pdf/268883.pdf"/>
   <abstract>
    <p>Dengue Viral Infection (DVI) is an emerging global health problem infecting about 50-100 million people annually worldwide. More than 2.5 million people have dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Aedesaegypti is the principal vector for disease transmission while humans are the main reservoir. The clinical manifestations range from self-limited Dengue fever (DF) to complicated and fatal outcomes, DHF and DSS. DF is prevalent in more than 100 countries of the world. More than 2.5 billion people of the World's population are residents of Dengue endemic area. According to one reported study, the prevalence of DF in Pakistan is 29%. Similarly, one study result carried out in India has shown 78% prevalence of DF. In Mexico, the one published seroprevalence study showed 79.6% prevalence of DF. A review/analysis report of the Gynecological and Obstetrical survey from 30 published studies has shown 64% transmission rate of DF from a mother to a child. The study results carried out in Jamaica has shown an increase in the prevalence of DF in seen in less than 1year and more than 60 years. The mortality rate with DHF is 33%. While in less than 15 years of it is 5%. This can be only reduced with early/accurate diagnosis and the prompt management of the condition. The absence of specific vaccine and antiviral is responsible for making this infection as a global health problem. The US government has spent 15 million US dollars for the establishment and discovery of specific DF treatment. The study carried out in India has shown the median cost for treatment per patient about 432.2 US dollars. It is 4 times in case of private health sectors. The proposed review article will highlight the incidence of dengue infection in patients having PUO (pyrexia of unknown origin). It will be a guide for the clinicians to consider DVI in their list of differential diagnosis of PUO. Moreover, it will be helpful in establishing the screening policies for DVI in PUO. The resultant of all of this will improve the life quality of PUO sufferers. It will be useful to reduce the increased financial burden due to PUO missed diagnosis and management in underdeveloped countries like one of ours.</p>
   </abstract>
   <kwd-group kwd-group-type="author">
    <kwd>Dengue viral infection</kwd>
    <kwd>Pyrexia of unknown origin</kwd>
    <kwd>Screeing for PUO</kwd>
   </kwd-group>
   <funding-group>
    <funding-statement>Funding information was not reported in the published version of this article.</funding-statement>
   </funding-group>
  </article-meta>
 </front>
 <body>
  <sec id="sec-1">
   <title>Introduction</title>
   <sec id="sec-2">
    <title>Break Bone Fever</title>
    <p id="b-1">The word dengue has been derived from a Spanish word meaning Fastidious or Careful. An American physician Benjaman Rush first gave Dengue fever a name Break Bone fever or Bone Crush Disease. This is attributed to the major complications of disease i.e. myalgias and arthralgias (     <xref ref-type="bibr" rid="ref1">1</xref>
–     <xref ref-type="bibr" rid="ref3">3</xref>
). Dengue virus belongs to genus flavivirus (     <xref ref-type="bibr" rid="ref4">4</xref>
). According to the WHO report it is amongst the most common causes of arboviral diseases worldwide (     <xref ref-type="bibr" rid="ref5">5</xref>
,     <xref ref-type="bibr" rid="ref6">6</xref>
).</p>
   </sec>
   <sec id="sec-3">
    <title>Vector of Disease</title>
    <p id="b-2">Aedesaegypti is the principle vector in the transmission of disease. This special mosquito is well adapted to humans and prefers to live in clean surroundings in close proximity to humans. Aedesaegypti is the small sized mosquito in comparison to the other mosquitoes. It is black colored with white stripes on head and body. There are specific white rings on the legs. Male Aedesaegypti population is harmless to humans and usually lives on fruits. Female Aedesaegypti are the ones responsible for disease transmission. It sucks blood from one person and transmits to another by biting.The infection develops within 24-30 hours of biting. This pathway between man-vector-man makes a triad of disease (     <xref ref-type="bibr" rid="ref5">5</xref>
). Aedesalbopictus is a lesser vector of dengue viral infection. Few cases with this vector have</p>
   </sec>
   <sec id="sec-4">
    <title>Dengue Virus Genotype And Virulence</title>
    <p id="b-3">In Malaysia DEN 4 serotype is the most common disease causing one (     <xref ref-type="bibr" rid="ref9">9</xref>
). While in Pakistan DEN 2 serotypes predominates followed by DEN 3 serotype (     <xref ref-type="bibr" rid="ref10">10</xref>
). The infection with any one serotype provides the immunity against that specific serotype (     <xref ref-type="bibr" rid="ref11">11</xref>
). Ab produced in result of infection with any serotype usually provides the homotypic immunity (     <xref ref-type="bibr" rid="ref12">12</xref>
).</p>
   </sec>
  </sec>
  <sec id="sec-5">
   <title>LITERATURE REVIEW</title>
   <sec id="sec-6">
    <title>Dengue In Pakistan</title>
    <p id="b-4">In 1994 first outbreak of DHF occurred at Karachi, Pakistan. In 1995, second outbreak occurred in Baluchistan. In 2002, educational programmes for Aedesaegypti mosquitoes were established (     <xref ref-type="bibr" rid="ref13">13</xref>
). In Rawalpindi, from September to November 2008, 49 positive cases were detected. Out of which 23 reported at Benazir Bhutto Hospital and 26 at Holy Family Hospital (     <xref ref-type="bibr" rid="ref14">14</xref>
).</p>
    <p id="b-5">been recorded in Pakistasn and USA (     <xref ref-type="bibr" rid="ref5">5</xref>
).      <bold>
      <italic>Predisposing Factors</italic>
     </bold>
    </p>
   </sec>
   <sec id="sec-7">
    <title>Pathogenesis of Dengue Infection</title>
    <p id="b-6">Dr.Albert Sabin in1944 isolated and detected four serotypes of DV. DEN 1, 2, 3 and 4 are the well known ones for DVI. These serotypes are responsible for the production of serotype specific IgG Ab mediated protective immunity following the first infection(     <xref ref-type="bibr" rid="ref7">7</xref>
). Extrinsic Incubation Period: During these period mosquitoes acquire virus while feeding on the viremic humans. Viral replication starts in the salivary glands of Aedes. This is called as Extrinsic I/P. The mosquitoes remain infected until 65 days of their lifespan. Intrinsic Incubation Period: There are two types of serological responses seen in DVI patient i.e primary and the secondary one. A primary response is seen in those who are not immune to the Flaviviruses. While secondary response is seen in those who had previous flaviviral infection. Thus responsible for pathogenesis of DF, DHF and DSS (     <xref ref-type="bibr" rid="ref5">5</xref>
,     <xref ref-type="bibr" rid="ref8">8</xref>
). The immune status, age of patient, type of virus infecting, climatic change, unplanned urbanization, increase in the international trade and increase in air travel. All of these provide an ideal way of transporting virus to new areas (     <xref ref-type="bibr" rid="ref15">15</xref>
). Moreover lack of awareness and knowledge especially in low socioeconomic class contributes to the spread of disease (     <xref ref-type="bibr" rid="ref16">16</xref>
). The WHO report of the year 2007 had highlighted DF a great threat for travelers (     <xref ref-type="bibr" rid="ref17">17</xref>
). The appropriate education to the travelers can be helpful to reduce arthropod borne diseases (     <xref ref-type="bibr" rid="ref18">18</xref>
).</p>
   </sec>
   <sec id="sec-8">
    <title>Dengue A Global Health Problem</title>
    <p id="b-7">DF is prevalent in more than 100 countries of the world (     <xref ref-type="bibr" rid="ref19">19</xref>
). More than 2.5 billion people of the World     <sup>’</sup>
s population are residents of Dengue endemic area (     <xref ref-type="bibr" rid="ref20">20</xref>
). Currently there is no vaccine or specific anti viral drugs/ injections available for the treatment of DF. Thus, making it a global health problem (     <xref ref-type="bibr" rid="ref21">21</xref>
,     <xref ref-type="bibr" rid="ref22">22</xref>
).</p>
   </sec>
   <sec id="sec-9">
    <title>Commonly Affected Age Groups</title>
    <p id="b-8">A study report on Jamaican population has shown that DF usually affects less than 1 year and more than 60 years of age group (     <xref ref-type="bibr" rid="ref23">23</xref>
). A study in Bangladesh concluded that adults are frequently infected by DV (     <xref ref-type="bibr" rid="ref24">24</xref>
). WHO report has shown that DF is a febrile illness which mostly affects the infants, young children and the adults (     <xref ref-type="bibr" rid="ref25">25</xref>
).</p>
   </sec>
   <sec id="sec-10">
    <title>Vertical Transmission of DVI</title>
    <p id="b-9">A case report in Bangkok has shown that DVI can be vertically transmitted from a mother to 1 day old infant (     <xref ref-type="bibr" rid="ref26">26</xref>
). Another study carried out in Kuala Lumpur has shown that vertical transmission rate of DF is 1.6% (     <xref ref-type="bibr" rid="ref27">27</xref>
). A systematic review report of 30 published studies by gynecological and obstetric survey2010 has shown vertical transmission rate of 64% (     <xref ref-type="bibr" rid="ref28">28</xref>
).</p>
   </sec>
   <sec id="sec-11">
    <title>Clinical Manifestations of DVI</title>
    <p id="b-10">These ranges from self limited DF to DHF and DSS (     <xref ref-type="bibr" rid="ref29">29</xref>
). DF/DHF are amongst important differential diagnosis in an undifferentiated febrile illneses (     <xref ref-type="bibr" rid="ref30">30</xref>
). The fever could be of biphasic pattern (     <xref ref-type="bibr" rid="ref31">31</xref>
). WHO definition of DHF requires filling of criteria: a;fever,bladder problem, constant severe headache, dizziness and loss of appetite. b; Haemorrhagic tendency, i.e. positive tourniquet test, spontaneous bruising, bleeding from mucosa, gingival, injection site etc, menorrhagia, bloody vomiting, malena or bloody diarrhea. c; Thrombocytopenia i.e. less than 100,000/mm3 platelets. d; Hemoconcen-teration i.e. evidence of plasma leakage and hematocrit &gt;20% of expected following I/V fluids, pleural effusion, ascities or hypoproteinemia (     <xref ref-type="bibr" rid="ref32">32</xref>
,     <xref ref-type="bibr" rid="ref33">33</xref>
,     <xref ref-type="bibr" rid="ref35">35</xref>
). DSS is defined as DHF plus weak and rapid pulse, narrow pulse pressure &lt;20 mmHg, cold and clammy skin and restlessness (     <xref ref-type="bibr" rid="ref1">1</xref>
–     <xref ref-type="bibr" rid="ref3">3</xref>
).</p>
   </sec>
   <sec id="sec-12">
    <title>Mortality Rate of DHF/ DSS</title>
    <p id="b-11">It is 5% in less than 15 year of age group (     <xref ref-type="bibr" rid="ref34">34</xref>
). While the estimated overall mortality rate with this infection is 33% (     <xref ref-type="bibr" rid="ref35">35</xref>
). The mortality rates can be decreased by early diagnosis and prompt management of the condition (     <xref ref-type="bibr" rid="ref36">36</xref>
). A study carried out on the citizens residing in Puerto Rico, United States, has shown that the infants and 10 to19 years of age group are amongst those who usually harbor the severe outcomes of DF (     <xref ref-type="bibr" rid="ref37">37</xref>
).</p>
   </sec>
   <sec id="sec-13">
    <title>DVI and PUO</title>
    <p id="b-12">A study result carried out in Singapore on Chinese migrant workers hospitalized due to febrile illness since a month. The serological results have shown the prevalence of acute Dengue in 10% of patients. The most common serotype was DEN 2 (     <xref ref-type="bibr" rid="ref38">38</xref>
). Another study results carried out in United Kingdom had shown that DVI can present as undifferentiated fever (     <xref ref-type="bibr" rid="ref39">39</xref>
). A study carried out on children between 6 months to 12 years in Lucknow, India has shown that DVI can cause undifferentiated febrile illness (     <xref ref-type="bibr" rid="ref40">40</xref>
). The Cuban Government had declared two Dengue outbreaks showing the presence of febrile illness as initial presentation in 3.2% of the total diagnosed cases (     <xref ref-type="bibr" rid="ref41">41</xref>
). In Thailand population the estimated prevalence of DF in patients having PUO is 40.8% (     <xref ref-type="bibr" rid="ref42">42</xref>
).</p>
   </sec>
   <sec id="sec-14">
    <title>Diagnosis of DVI and ELISA</title>
    <p id="b-13">Serologiacal tests, viral isolation and molecular level detection are the three options for DV detection (     <xref ref-type="bibr" rid="ref44">44</xref>
). ELISA is considered to be 99.2% sensitive and 96.2% specific for DF virus IgG detection (     <xref ref-type="bibr" rid="ref45">45</xref>
). The Dengue virus IgG antibodies in the serum are not affected by the duration of storage (     <xref ref-type="bibr" rid="ref46">46</xref>
).</p>
   </sec>
   <sec id="sec-15">
    <title>Cross Reacting Antibodies Formation</title>
    <p id="b-14">The high degree of cross reactivity between flaviviruses can result in false positive serological results. The booster for Yellow fever immunization is 10 years, for Tick borne encephalitis is 3 years and for Japanese encephalitis is 2 years (     <xref ref-type="bibr" rid="ref41">41</xref>
,     <xref ref-type="bibr" rid="ref47">47</xref>
,     <xref ref-type="bibr" rid="ref48">48</xref>
).</p>
   </sec>
   <sec id="sec-16">
    <title>Dengue Prevention</title>
    <p id="b-15">The laboratory based surveillance and daily correspondence between epidemiologists and infectious disease units will provide a proactive approach for the prevention and control of disease in specific regions of the world (     <xref ref-type="bibr" rid="ref49">49</xref>
).</p>
   </sec>
  </sec>
  <sec id="sec-17">
   <title>Conclusion</title>
   <p id="b-16">One of the early presentations of primary dengue viral infection is PUO especially in less than 18 years of age. So that the Government should mainly focus on the particular age group. This study will be helpful for the clinicians to consider DVI in their list of differential diagnosis of PUO.</p>
  </sec>
  <sec id="sec-18">
   <title>Recommendations</title>
   <p id="b-17">Screening of Dengue viral infection should be done in patients having pyrexia of unknown origin.</p>
  </sec>
 </body>
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