Dengue Hemorrhagic fever causes a decrease in platelets because of leak from the blood vessels. Dengue shock syndrome may be fatal if not diagnosed timely.

Dengue Hemorrhagic Fever / Dengue Shock Syndrome

Humza Khizer

Overview

Dengue is a mosquito-borne viral disease that is transmitted by the female vector mosquitoes of the species Aedes aegypti and Aedes albopictus. According to the WHO, the disease has rapidly spread to all regions in recent years.&nbsp;

<a href="https://merisehat.pk/disease/dengue">Dengue</a> causes a wide spectrum of diseases that can range from subclinical disease (asymptomatic disease) to severe flu-like symptoms in those infected with the dengue virus. Additionally, some people may also develop a severe form of the disease called dengue hemorrhagic fever which can cause several complications including plasma leakage, severe bleeding, and organ impairment.&nbsp; 
&nbsp;

If severe dengue is not managed appropriately, the risk of death is higher. The patient may develop warning signs of severe form disease typically around the time the fever begins to subside. These warning signs include a change in mental status, irritability, obtundation, confusion, hemorrhagic manifestations, a marked change in temperature, vomiting, and severe abdominal pain. The patient may also present with early signs of shock such as narrowing of pulse pressure, rapid weak pulse, cold clammy skin, and restlessness.&nbsp;

The first case of dengue hemorrhagic fever or severe dengue was recognized in the 1950s during dengue epidemics in the Philippines and Thailand<a href="#accordion">[1]</a>.&nbsp;Severe dengue has now become a common cause of hospitalization and death of children and adults in most Asian and Latin American countries<a href="#accordion">[1]</a>.&nbsp;

Dengue virus belongs to the Flaviviridae family and four serotypes of the virus can cause dengue: DENV-1, DENV-2 DENV-3, and DENV-4. Studies have shown that recovery from the infection provides lifelong immunity against the serotype causing the infection, however, cross-immunity to the other serotypes is only temporary. Thus, reinfection can occur.&nbsp; 
&nbsp;

Furthermore, secondary infection by other serotypes increases the risk of developing dengue hemorrhagic fever. Dengue&rsquo;s epidemiological patterns are quite distinct. An estimated 50 to 100 million cases of dengue are reported each year<a href="#accordian">[2]</a>.&nbsp;Whereas hundreds and thousands of cases of dengue hemorrhagic fever occur yearly, and the virus has an alarming impact on both human health and the economy<a href="#accordian">[2]</a>. The dengue virus is easily transmitted from one place to another due to increased air travel. The virus is a public health problem worldwide, especially in low-income areas and cities particularly impacted by climate warming. Dengue fever and dengue hemorrhagic fever are endemic in the eastern Mediterranean, Africa, the western Pacific, the Americas, and Southeast Asia.&nbsp; 
&nbsp;

WHO highlights that the increase in the number of cases and geographic distribution of the virus, other than transmission from travelers, is also a consequence of poor solid waste disposal and unreliable water supply systems. The WHO further estimated that the rise in global temperatures may shorten the incubation period of the viruses and add more fatality cases annually.&nbsp;

Dengue is endemic in Pakistan and from September to December 2019, 53,498 cases and 95 deaths were reported<a href="#accordion">[3]</a>. In addition, from January 1 to November 25, 2021, a total of 48,906 cases were reported in Pakistan with 183 deaths. Whereas in November, the Punjab province reported 24,146 cases and 127 deaths, which was the highest number of cases reported in the region to date. Most deaths were reported in Lahore.&nbsp; 
&nbsp;

The global burden of dengue has also grown dramatically over the past few decades. Moreover, since most cases of dengue are asymptomatic, mild, or self-managed, the actual number of cases may be underreported. Some cases are also misdiagnosed as febrile illnesses<a href="#accordion">[4]</a>. A study on the prevalence of dengue estimated that 390 million cases of dengue virus infections are reported per year<a href="#accordion">[5]</a>. However, 70% of the burden of dengue is in Asia<a href="#accordion">[5]</a>.&nbsp;

Unfortunately, the number of dengue cases reported by the WHO&nbsp; has increased by 8 times over the last 20 years, affecting mostly the younger age group<a href="#accordion">[1]</a>. Whereas 3.1 million cases were reported in the United States with more than 25,000 classified as dengue hemorrhagic fever.<a href="#accordion">[1]</a> The total number of cases decreased considerably during the years 2020 and 2021, though, the data is not yet elucidated because of the <a href="https://merisehat.pk/disease/covid-19">COVID-19</a> pandemic.

&nbsp;

The dengue virus is divided into 4 serotypes DENV-1, DENV-2, DENV-3, and DENV-4. All the viruses are transmitted from the bite of certain species of Aedes mosquitoes.&nbsp;

The incubation period of dengue is 4 to 10 days, and most cases are asymptomatic or cause mild systemic illness.&nbsp;

Dengue was earlier classified into three overlapping types, classic dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. However, recently, the World Health Organization has classified it into two categories:

<ul>
	<li>Severe dengue&nbsp;</li>
	<li>Non-severe dengue&nbsp;</li>
</ul>

Non-severe dengue is self-limiting and usually resolves without any presenting symptoms. Whereas severe dengue is reported in less than 1% of all cases and presents with the following symptoms: severe organ dysfunction, severe hemorrhage, extravascular fluid accumulation, plasma leakage, and vascular permeability. Severe dengue has a high fatality rate if not treated appropriately. Severe dengue occurs secondary to a primary dengue virus infection, though, may also occur following a secondary infection.&nbsp;

Rarer presentations of the dengue virus may include neurologic symptoms, myocarditis, and hepatitis.&nbsp;

&nbsp;

The World Health Organization further classifies dengue into three phases:

&nbsp;

<ul>
	<li>Acute Or Febrile Phase: The acute phase of dengue typically presents with fever and headache. The symptoms may also include body pain, joint pain, and maculopapular rash (a flat reddened area of skin present in a rash). The acute phase of dengue may also present with thrombocytopenia, leukopenia, sudden unilateral neuralgiform conjunctival injection tearing headache, vomiting, and anorexia. Some patients with dengue also have mild hemorrhagic presentations such as epistaxis (nose bleeding) or gum bleeding.&nbsp; 
	&nbsp;</li>
	<li>Critical Phase: The critical phase of dengue begins 2 to 7 days after the onset of illness and in this phase, the illness generally resolves. Although the illness may resolve after a recurrence of fever. Some patients may also develop increased capillary permeability which is linked with severe dengue, rising hematocrit (the percentage by volume of the red blood cells), thrombocytopenia (low platelet count), and progressive leukopenia (low white blood cell count). The clinical warning signs of dengue include decreased platelet count, increased hematocrit levels, hepatomegaly, restlessness, lethargy, severe mucosal bleeding, extravascular fluid accumulation, persistent vomiting, and abdominal pain.&nbsp; 
	&nbsp;</li>
	<li>Recovery Or Convalescent Phase: The recovery phase is the phase of dengue after the 6th day of illness. However, a sizable number of patients take longer to recover. In this phase, the plasma leakage subsides, and patients enter the convalescent phase and begin to reabsorb extravasated intravenous fluids hence, the patient&rsquo;s hemodynamic status and hematocrit stabilize. The white cell count also usually begins to rise in this phase.</li>
</ul>

&nbsp;

Signs And Symptoms

Dengue becomes asymptomatic after 4 to 10 days of the incubation period. The symptoms typically last for 2 to 7 days, though many individuals may remain asymptomatic throughout.&nbsp;

Common symptoms of dengue include a prodrome of chills, rash, erythematous mottling of the skin, and a 2- to 3-day history of facial flushing. Children younger than 15 years present with nonspecific febrile syndrome and a maculopapular rash. Individuals who present with high fever, nausea, vomiting, joint pain, muscle pain, retro-orbital headache, rash, or have traveled to an area where dengue is endemic, within 2 weeks of the onset of symptoms should be tested for dengue.&nbsp;

&nbsp;

Other accompanying symptoms of patients with dengue include:&nbsp;

<ul>
	<li>Fever&nbsp;</li>
	<li><a href="https://merisehat.pk/disease/migraines-73">Headache</a>&nbsp;</li>
	<li>Retro-orbital pain&nbsp;</li>
	<li>Muscle aches and pain&nbsp;</li>
	<li>Joint pain usually in the knees and shoulders&nbsp;</li>
	<li>Nausea and vomiting&nbsp;</li>
	<li>Rarely diarrhea</li>
	<li>A maculopapular or macular rash over the face, flexor surfaces, thorax, or islands of skin&nbsp;</li>
	<li>Weakness, lethargy, and malaise&nbsp;</li>
	<li>Restlessness&nbsp;</li>
	<li>Altered taste&nbsp;</li>
	<li>Loss of weight&nbsp;</li>
	<li>Sore throat&nbsp;</li>
	<li>Mild hemorrhagic presentations, for example, hematuria (blood in urine), menorrhagia (menstrual bleeding that lasts more than 7 days), epistaxis, bleeding gums, and petechiae.&nbsp;</li>
	<li>Lymphadenopathy&nbsp;</li>
	<li>Liver enlargement&nbsp;</li>
</ul>

<h5>&nbsp;</h5>

<h5>Dengue Hemorrhagic Fever&nbsp;</h5>

The initial phase of dengue hemorrhagic fever is similar to dengue fever or other fever-causing illnesses. However, shortly after the onset of fever or 3 to 7 days after the onset of symptoms, there are signs of plasma leakage with the development of hemorrhagic symptoms, for example, hematuria, gastrointestinal bleeding, and bleeding from sites of trauma.&nbsp;

Other signs of dengue hemorrhagic fever include febrile seizures in children, fatigue, continuous vomiting that may contain blood, and severe abdominal pain.&nbsp;

If left untreated, hemorrhagic fever can progress to shock, thus the subsequent 24 hours following the onset of symptoms are frequently critical. Common symptoms of dengue shock include restlessness, abdominal pain, and vomiting. Some patients may also present with symptoms of circulatory failure such as decreased level of consciousness, dizziness/lightheadedness, tachycardia, tachypnea, and pallor.&nbsp;

Dengue hemorrhagic fever can be defined by any of the following symptoms:&nbsp; 
&nbsp;

<ul>
	<li>Severe plasma leakage that may lead to shock&nbsp;</li>
	<li>Fluid accumulation in the lungs with respiratory distress&nbsp;</li>
	<li>Severe bleeding&nbsp;</li>
	<li>Organ impairment</li>
	<li>Impaired consciousness&nbsp;</li>
	<li>Heart impairment&nbsp;</li>
	<li>Hepatic failure&nbsp;</li>
	<li><a href="https://merisehat.pk/disease/encephalitis">Encephalitis</a> 
	&nbsp;</li>
</ul>

Causes

The serotypes of the dengue virus, DEN 1, 2, 3, and 4 cause dengue infection. The serotypes while closely related, have different antigens. The virus is transmitted from the mosquito Aedes aegypti which transmits the virus to humans and between humans. While dengue primarily infects adults and older children, dengue hemorrhagic fever typically occurs in children under the age of 15 years. Humans are infected by dengue viruses by the bite of an infected mosquito, which is a small, black, and white tropical mosquito that is found in stagnant rainwater, rainwater collected in buckets, old automobile tires, and around homes in flower vases and containers used for storage of water.&nbsp;

&nbsp;

The adult mosquito feeds on humans during daylight hours. The mosquito&rsquo;s peak biting activity is in the early morning hours after daybreak and the afternoon before dark. Female mosquitoes are very nervous feeders and may disrupt their feeding process even at the slightest of movements and continue feeding moments later. Due to this behavior, the mosquito will feed on several persons during a single blood meal and may transmit the virus to several persons in a short period.

&nbsp;

For suspected dengue virus disease cases,&nbsp;Nucleic Acid Amplification Tests (NAATs)&nbsp;can be performed. Serum specimens should ideally be collected within 7 days of symptom onset.

&nbsp;

Diagnosis

The WHO criteria for diagnosis of dengue hemorrhagic fever include:&nbsp;

<ul>
	<li>Hemorrhagic fever, 2 to 7 days in duration&nbsp;</li>
	<li>Minor or major hemorrhagic fever&nbsp;</li>
	<li>A positive tourniquet test is a diagnostic method to determine the hemorrhagic tendency of a patient and assesses the fragility of the capillary walls and thrombocytopenia in patients.&nbsp;</li>
	<li>Thrombocytopenia&nbsp;</li>
	<li>Increased capillary permeability</li>
	<li>Chest radiograph or ultrasonography to test for pleural effusion or ascites</li>
	<li>Hypoalbuminemia- a condition in which the body does not produce enough albumin protein that is responsible to keep fluid in the blood vessels</li>
</ul>

&nbsp;

Dengue is diagnosed based on serologic tests by the detection of viral RNA and viral proteins or by isolating the virus from blood leukocytes or acute phase serum. In 2009, the WHO published further guidelines for the diagnosis of dengue hemorrhagic fever.&nbsp;

<ul>
	<li>Severe dengue is a mixture of the syndromes associated with dengue infection, including dengue hemorrhagic fever and dengue shock syndrome. Though in very rare cases it may also be associated with myocardial damage, encephalitis, encephalopathy, or liver damage.&nbsp;</li>
	<li>Severe dengue also manifests with symptoms including respiratory distress and pulmonary edema.&nbsp;</li>
	<li>Detection of viral RNA and viral proteins.</li>
	<li>Following primary and secondary dengue infections immunoglobulin IgM antibodies are detected. However, these antibodies disappear after 6 to 12 weeks, which is a characteristic feature of dengue hemorrhagic fever.&nbsp;</li>
	<li>In secondary dengue infections, there is an appearance of the dengue antibody IgG.&nbsp;</li>
</ul>

&nbsp;

Diagnostic testing for dengue hemorrhagic fever includes:

<ul>
	<li>Complete blood count</li>
	<li>Metabolic panel and liver enzymes</li>
	<li>Coagulation studies for severe hemorrhagic manifestations</li>
	<li>Prothrombin time</li>
	<li>Activate partial thromboplastin time&nbsp;</li>
	<li>Serum studies</li>
	<li>Complete fixation (CF)Hemagglutination inhibitor (HI)</li>
	<li>IgG ELISA</li>
	<li>NS1 strip test</li>
	<li>Neutralization test (NT)</li>
	<li>Serologic tests&nbsp;</li>
	<li>MAC-ELISA&nbsp;</li>
	<li>rRT-PCR</li>
	<li>Ultrasonography for leaked fluid in the chest and abdominal cavities</li>
	<li>The tourniquet test: the test indicates whether the patient has increased capillary fragility, which is a characteristic feature for the diagnosis of dengue hemorrhagic fever.&nbsp;</li>
</ul>

&nbsp;

Dengue hemorrhagic fever is a disease in children under the age of 15 years but may also occur in adults. Dengue hemorrhagic fever presents with sudden onset of fever that lasts for 2 to 7 days. In the acute phase of the disease, it may be difficult to differentiate between dengue hemorrhagic fever, dengue fever, and other fever-causing illnesses that are common in tropical regions.&nbsp;

Dengue hemorrhagic fever presents with circulatory failure or hemorrhagic symptoms that may occur 24 hours before or after the temperature falls to below normal. Blood tests show that the patient has thrombocytopenia and hemoconcentration. Common hemorrhagic symptoms of dengue hemorrhagic fever include ecchymoses, purpuric lesions, and petechiae. Other less frequent symptoms include epistaxis, GI hemorrhage, hematuria, and bleeding gums.&nbsp; 
&nbsp;

Grading of dengue hemorrhagic fever:&nbsp;

<ul>
	<li>Grade I: Positive tourniquet test; easy bruising; plasma leakage and no circulatory compromise.&nbsp;</li>
	<li>Grade II: Spontaneous bleeding in addition to the presentation of grade I; plasma leakage; no circulatory compromise.</li>
</ul>

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<h4>"Fever affects your blood pressure. Head on over to the <a href="https://www.merisehat.pk/page/sehat-scan/" target="_blank">sehat scan</a> and check your reading today."</h4>

Treatment

There is no specific treatment for dengue. Treatment for dengue focuses on symptomatic management with the use of antipyretics and pain relievers, rehydration with fluids containing electrolytes, and avoiding medications that contain aspirin. Bleeding could worsen with aspirin and hence is avoided in the treatment of dengue.&nbsp;&nbsp;

&nbsp;

These include:

<ul>
	<li>Internal bleeding&nbsp;</li>
	<li>Organ damage&nbsp;</li>
	<li><a href="https://merisehat.pk/disease/toxic-shock-syndrome">Shock</a>&nbsp;</li>
	<li>Death</li>
</ul>

&nbsp;

Factors that increase the risk of dengue hemorrhagic fever or severe disease include the following:&nbsp;

<ul>
	<li>Infants and small children</li>
	<li>During pregnancy, the virus can be passed on to the fetus</li>
	<li>Weak immune system&nbsp;</li>
	<li>Older adults</li>
</ul>

&nbsp;

The FDA approved a vaccine to prevent disease in adolescents (aged 9 to 16 years) who have previously been infected. However, there is currently no vaccine to prevent infection in the general population. Thus, the best way to prevent dengue infection is by preventing bites of the infected mosquito, especially if you live in or are traveling to a tropical area. To keep yourself protected:&nbsp;

<ul>
	<li>Use a mosquito repellent&nbsp;</li>
	<li>Wear long-sleeved t-shirts and tuck your pants into your socks when outdoors</li>
	<li>Use air conditioning if available&nbsp;</li>
	<li>Keep windows and doors closed. Use mosquito nets if the sleeping areas are open.&nbsp;</li>
	<li>Get rid of mosquito breeding places, for example, flower pots that collect rain, cans, and old tires</li>
	<li>Avoid outdoor activity during dawn and dusk</li>
	<li>Speak to your doctor if you have any symptoms of dengue</li>
</ul>

&nbsp;

Key Points

<ul>
	<li>Dengue fever or &ldquo;break-bone fever&rdquo; is a painful mosquito-borne disease caused by the dengue virus.</li>
	<li>Some people may also develop a severe form of disease or dengue hemorrhagic fever, it can cause several complications including plasma leakage, severe bleeding, and organ impairment.</li>
	<li>The dengue virus is divided into 4 serotypes DENV-1, DENV-2, DENV-3, and DENV-4, all the viruses are transmitted from the bite of certain species of Aedes mosquitoes and can cause severe and non-severe diseases.&nbsp;</li>
	<li>Dengue is diagnosed based on serologic tests by the detection of viral RNA and viral proteins.</li>
	<li>Treatment for dengue focuses on symptomatic treatment with the use of antipyretics and pain relievers, rehydration with fluids containing electrolytes, and avoiding medications that contain aspirin and worsen bleeding.&nbsp;</li>
	<li>Dengue/ dengue hemorrhagic fevers/ dengue shock syndrome are notification priority diseases in Pakistan and any presenting cases should be notified to the concerned health authorities immediately.</li>
</ul>

&nbsp;

[1] World Health Organization, 2022. Dengue and Severe Dengue.

[2] Alejandria, M.M., 2015. Dengue haemorrhagic fever or dengue shock syndrome in children. BMJ clinical evidence, 2015.

[3] World Health Organization, 2021. Dengue Fever – Pakistan

[4] Waggoner, J.J., Gresh, L., Vargas, M.J., Ballesteros, G., Tellez, Y., Soda, K.J., Sahoo, M.K., Nuñez, A., Balmaseda, A., Harris, E. and Pinsky, B.A., 2016. Viremia and clinical presentation in Nicaraguan patients infected with Zika virus, chikungunya virus, and dengue virus. Clinical Infectious Diseases, p.ciw589.

[5] Bhatt, S., Gething, P.W., Brady, O.J., Messina, J.P., Farlow, A.W., Moyes, C.L., Drake, J.M., Brownstein, J.S., Hoen, A.G., Sankoh, O. and Myers, M.F., 2013. The global distribution and burden of dengue. Nature, 496(7446), pp.504-507.