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Saad Ullah Siddiqui

Get answers to common questions about dengue fever with Meri Sehat. Stay informed for prevention and management

Dengue Fever- Questions And Answers

AL SHIFA CLINIC KARACHI

Syed Intisar Hussain

This article or video has been vetted and verified by Meri Sehat’s specialists. It contains citations and research from validated sources.

Doctor, Do I Have Malaria, Dengue, Or Something Else?

Introduction

The human body is a complex system with multiple defense mechanisms to protect against infections. A fever, often a symptom of disease, is actually an indication that the body&#39;s immune system is doing its job of protecting you. However, fever can result from a wide variety of illnesses and diagnosing the disease based on just one symptom is never enough. Moreover, in a country like Pakistan where several deadly mosquito-borne diseases are endemic, a fever can lead to panic among people. Especially during the months of September to December when these diseases are most common.

According to the World Health Organization (WHO), malaria is a major cause of mortality and morbidity in Pakistan. Moreover, the country shares the highest burden of mosquito-borne diseases, such as <a href="https://www.merisehat.pk/disease/dengue">dengue</a>, <a href="https://www.merisehat.pk/disease/malaria">malaria</a>, and Chikungunya<a href="#accordion">[1]</a>. Climate change, urbanization, poor health conditions, lack of accessible healthcare, and natural disasters are all to blame for the increase in these diseases. Although the exact distribution and magnitude of these diseases remain unclear, it is evident that their prevalence will continue to rise in the coming years.&nbsp;

&nbsp;

Understanding Different Mosquito Borne Diseases

As per estimates, malaria and dengue are the most prevalent mosquito-borne diseases with 214 million and 390 million global cases a year respectively<a href="#accordion">[2]</a>.

&nbsp;

Malaria - In Pakistan, malaria accounts for 50,000 new deaths per year<a href="#accordion">[3]</a>. Transmitted by the bite of a female Anopheles mosquito, malarial parasites can cause a wide variety of symptoms in humans. These include fever with chills, sweating, headache, nausea, fatigue, and muscle or joint pain. There are currently four different Plasmodium parasites that cause malaria in humans: P. falciparum, P. vivax, P. ovale, and P. malariae. P. falciparum and P. vivax account for the greatest number of malaria cases in Pakistan.

&nbsp;

Dengue - In contrast, the dengue virus is transmitted by the bite of the Aedes aegypti mosquito. The mosquito is also responsible for causing other mosquito-borne diseases such as Zika, chikungunya, and yellow fever.

Pakistan recorded its first dengue outbreak in 1994 when 1,000 people got infected. Since then, the country has recorded several outbreaks of the disease. In 2021, Pakistan reported a record 48,906 dengue cases and 183 deaths across all provinces<a href="#accordion">[4]</a>. Every year, the country faces seasonal waves of illness with different dengue viruses (DENV-1, DENV-2, DENV-3, DENV-4) causing outbreaks. The most common symptoms include fever, headache, rash, muscle and joint pain, and, in severe cases, internal or external bleeding.

&nbsp;

Chikungunya - The chikungunya virus first emerged in Pakistan in the 1980s, mostly among the rodent population. However, it wasn&#39;t until 2011 that cases began appearing among the human population. The virus typically causes fever, joint pain, skin rash, headache, and nausea.&nbsp;

In 2016, the city of Karachi recorded one of its worst outbreaks which affected approximately 30,000 individuals<a href="#accordion">[5]</a>. Since the overlap of symptoms of dengue causes doctors to often misdiagnose the cases, experts predict that the actual prevalence of chikungunya might be much higher. The rise in cases and the mosquito levels could likely lead to an increase in other mosquito-borne diseases.

&nbsp;

The presence of various mosquito-borne diseases all in one place at one time can make it confusing for both doctors and patients to determine what&#39;s causing the symptoms. Therefore, it&#39;s important to know the similarities and differences between the different illnesses.&nbsp;

&nbsp;

Malaria Symptoms - These usually appear 10-15 days after a mosquito bite and include:

<ul>
	<li>High fever with chills followed by excessive sweating as the body temperature falls</li>
	<li>Body aches</li>
	<li>Headaches</li>
	<li>Nausea and vomiting</li>
	<li>Diarrhea</li>
	<li>Anemia</li>
	<li>Jaundice</li>
</ul>

&nbsp;

Dengue Symptoms - Symptoms of dengue can begin within 4-10 days of a mosquito bite and usually persist for 2-7 days. These include:

<ul>
	<li>High fever</li>
	<li>Severe headache</li>
	<li>Pain behind the eyes, in muscles, and in joints</li>
	<li>Nausea and vomiting</li>
	<li>Skin rash</li>
	<li>Sever dengue can result in severe stomach pain, bleeding from gums, blood in stool or urine, difficulty breathing, and fatigue.</li>
</ul>

&nbsp;

Chikungunya Symptoms - Symptoms begin within a week of a mosquito bite and is characterized by:

<ul>
	<li>Fever</li>
	<li>Joint pain and swelling</li>
	<li>Headache</li>
	<li>Rash</li>
	<li>Fatigue</li>
</ul>

&nbsp;

Fever, headache, joint or muscle pain, and nausea are common symptoms among all three diseases. However, there are also many differentiating features. For example, in dengue pain behind the eyes and a rash is a characteristic feature. While in malaria, a fever is always accompanied by severe chills and then a period of sweating as the person&#39;s body temperature returns to normal. Moreover, the episodes of fever come every 24-72 hours, depending on the type of malarial parasite causing the infection.&nbsp;

Although all three diseases have similar symptoms, laboratory investigations can often prove helpful in differentiating between the three. Therefore, it is advised to immediately consult a doctor if one lives in an endemic region, especially during a period when mosquito-borne diseases are most prevalent.&nbsp;

&nbsp;

Several precautionary measures can prevent infections and help reduce the burden of disease.&nbsp;

&nbsp;

Personal Protection - Various protection measures help prevent mosquito bites. These include:

<ul>
	<li>Using mosquito repellents, especially when stepping out at hours when mosquitoes are most active.</li>
	<li>Wearing clothes that reduce exposure to mosquitoes.</li>
	<li>Sleeping under insecticide-treated bed nets.</li>
</ul>

&nbsp;

Vector Control - These strategies are aimed at reducing the population of mosquitoes. They include:

<ul>
	<li>Spraying of insecticides and larvicides in areas where mosquitoes are frequently present.</li>
	<li>Preventing water from collecting in old tires, empty pots, or stagnate water ponds as these act as breeding grounds for mosquitoes</li>
</ul>

&nbsp;

Along with these preventive strategies, it is also important to increase patient education regarding various mosquito-borne diseases. A lack of information on the causes and manifestations can lead to panic and a delay in seeking help.&nbsp;

&nbsp;

Conclusion

Mosquito-borne diseases are most prevalent in tropical and subtropical countries. The warm climate not only helps the mosquitoes complete their life cycle but also increases mosquito activity. In Pakistan, the changing climate has caused a shift in the mosquito population. With warmer summers and warmer winters, the diseases have also changed their occurrence. In cities like Karachi, where the temperature remains above 15 degrees Celsius in the winter, outbreaks occur more frequently during the winter. Moreover, the heavy monsoon season causes water to collect in the form of pools and puddles, which then act as breeding grounds for mosquitoes. Thus, contributing to the spread of disease.

The increase in natural disasters such as floods in the country has led to the displacement of people to temporary camps. Overcrowding, poor hygiene, lack of clean drinking water, and the lack of healthcare facilities and resources at these camps have also contributed to an increase in outbreaks and mosquito populations.&nbsp;

However, climate change is not the only factor causing the spread of disease. Deforestation, agriculture, urbanization, poor socioeconomic conditions, failed vector control strategies, and drug resistance has also increased infections. Moreover, the destruction of forests and trees has resulted in the mosquito population breeding indoors.

The increase in mosquito population not only heightens the risk of existing diseases, but also others such as the deadly Zika virus. Therefore, there is a need for proper surveillance methods across the country such as the development of screening labs and educating the public on various vector control methods. Since there are no vaccines available in Pakistan for the prevalent mosquito-borne diseases, vector control measures provide the best protection against these diseases. However, current vector control measures are insufficient due to the rising insecticide resistance among viruses and parasites.&nbsp;

&nbsp;

Key points

<ul></ul><ul><li style="line-height: 1.2; margin-top: 0pt; margin-bottom: 0pt;">Pakistan shares the highest burden of mosquito-borne diseases such as malaria, dengue, and chikungunya.</li><li style="line-height: 1.2; margin-top: 0pt; margin-bottom: 0pt;">Mosquitoes thrive more in tropical and subtropical regions. Therefore, Pakistan's warm climate is a significant factor in the prevalence of these diseases.</li><li style="line-height: 1.2; margin-top: 0pt; margin-bottom: 0pt;">Malaria is a major cause of mortality and morbidity in Pakistan, causing 50,000 new deaths each year.&nbsp;</li><li style="line-height: 1.2; margin-top: 0pt; margin-bottom: 0pt;">The malarial parasite enters humans through the bite of an infected female Anopheles mosquito. This results in symptoms such as fever and chills, sweating, headache, anemia, nausea, and body aches.&nbsp;</li><li style="line-height: 1.2; margin-top: 0pt; margin-bottom: 0pt;">The dengue virus is transmitted via the bite of an infected Aedes aegypti mosquito and results in high fever, joint pain, rash, pain behind the eye, and in severe cases external and internal bleeding.</li><li style="line-height: 1.2; margin-top: 0pt; margin-bottom: 0pt;">The Aedes aegypti mosquito can also spread Zika, chikungunya, and yellow fever.</li><li style="line-height: 1.2; margin-top: 0pt; margin-bottom: 0pt;">In 2016, Pakistan recorded one of its worst chikungunya outbreaks, with almost 30,000 infections.&nbsp;</li><li style="line-height: 1.2; margin-top: 0pt; margin-bottom: 0pt;">Chikungunya typically appears as fever, joint pain, skin rash, headache, and nausea.&nbsp;</li><li style="line-height: 1.2; margin-top: 0pt; margin-bottom: 0pt;">Malaria, dengue, and chikungunya continue to be the most common mosquito-borne diseases in Pakistan. However, an overlap of symptoms often makes it difficult to differentiate between the three. The common symptoms include fever, headache, nausea, and joint or muscle pain.</li><li style="line-height: 1.2; margin-top: 0pt; margin-bottom: 0pt;">Since the diseases can often be fatal, an early and accurate diagnosis is crucial to recovery. Adequate laboratory testing, a complete history, and patient awareness of all three diseases can help identify the infection.</li><li style="line-height: 1.2; margin-top: 0pt; margin-bottom: 0pt;">Vector control strategies, such as destruction of mosquito breeding grounds and protection from mosquito bites, are key to preventing mosquito-borne diseases.&nbsp;</li><li style="line-height: 1.2; margin-top: 0pt; margin-bottom: 0pt;">Climate change, urbanization, poor health conditions, lack of accessible healthcare, population rise, and increasing drug resistance has led to an increase in these diseases in recent years.</li></ul>

[1] WHO, n.d. Pakistan: Malaria and other vector-borne diseases. [Online].

[2] Chong, S. E. et al., 2017. The dangers of accepting a single diagnosis: case report of concurrent Plasmodium knowlesi malaria and dengue infection. Malaria Journal, 16(2).

[3] Qureshi, H., Khan, M. I., Ambachew, H. & Ye, D.-Q., 2020. Baseline survey for malaria prevalence in Khyber Pakhtunkhwa Province, Pakistan. Eastern Mediterranean Health Journal, 26(41).

[4] WHO, 2021. Disease outbreak news - Pakistan. [Online].

[5] Badar, N. et al., 2019. Epidemiological trend of chikungunya outbreak in Pakistan: 2016–2018. PLOS Neglected Tropical Diseases, 13(4).

[6] Ali, I. & Dasti, J. I., 2018. Chikungunya virus; an emerging arbovirus in Pakistan. Journal of the Pakistan Medical Association, 68(2).

Nimrah H. Sattar

<a href="https://merisehat.pk/disease/dengue-hemorrhagic-fever-dengue-shock-syndrome">Dengue fever</a> is the fastest-growing vector-borne ailment in humans that has persistently placed a significant strain on healthcare systems around the globe in general and in tropical and subtropical areas in particular<a href="#accordion">[1]</a>.

According to the WHO, around 100-400 million people are infected every year, with roughly 80% of them categorised as mild and asymptomatic. That&rsquo;s nearly half of the world&rsquo;s population at risk of contracting dengue<a href="#accordion">[6]</a>. 
&nbsp;

Understanding Commonly Asked Questions About Dengue Fever

There are 4 serotypes (groups of microbes within a single species, for example, bacteria or viruses, that share particular surface structures) of the dengue virus:

<ol>
	<li>DENV-1</li>
	<li>DENV-2</li>
	<li>DENV-3</li>
	<li>DENV-4</li>
</ol>

Each of the 4 serotypes is capable of causing dengue fever.

Dengue fever is a term that is commonly used to refer to clinically moderate dengue virus infections, whereas dengue haemorrhagic fever (DHF) is used in more serious instances. 
&nbsp;

<h5>Symptoms Of Moderate Dengue</h5>

Moderate dengue is often mistaken for other diseases since a lot of them cause similar fever, pain, discomfort, and rashes.

However, one of the most frequent signs of dengue is fever presenting along with the following symptoms:

<ul>
	<li>Nausea or vomiting</li>
	<li>Rashes</li>
	<li>Pain and discomfort (e.g., eye pain, muscular pain, joint pain).</li>
</ul>

These symptoms usually last 2-7 days and a majority of individuals get better within a week. 
&nbsp;

<h5>Symptoms Of Severe Dengue</h5>

It&rsquo;s crucial to keep an eye out for signs and symptoms of DHF because it can be life-threatening. The warning signs usually appear 24-48 hours after the fever has subsided:

<ul>
	<li>Belly aches and tenderness</li>
	<li>Vomiting at least thrice a day</li>
	<li>Nose or gum bleeding</li>
	<li>Puking blood or passing blood in the faeces</li>
	<li>Feeling tired, agitated, or restless 
	&nbsp;</li>
</ul>

Note: If any individual or their loved one experiences any of the symptoms, consult a doctor or visit an emergency room immediately. 
&nbsp;

<h5>How Long Does Dengue Fever Last?</h5>

Mostly, dengue resolves within a week or two and has no long-term consequences. It&rsquo;s important to immediately consult a doctor if the illness is serious, or if the symptoms have worsened during the first two days following the dengue fever; DHF is a medical emergency. 
&nbsp;

The Aedes mosquito can carry the dengue virus without becoming ill. These mosquitoes themselves become infected after they bite an infected person. When an infected mosquito bites an otherwise healthy individual, it passes the virus into the person&#39;s bloodstream. As a result, people and mosquitos are continuously exchanging dengue viruses. The dengue virus is present as long as Aedes mosquitos are present in the environment.

It can be transmitted from the mother to the foetus during pregnancy or at the time of birth<a href="#accordion">[7]</a>. 
&nbsp;

<ol>
	<li>
	<h5>&nbsp;Dengue Virus Antigen NS1 Detection </h5>
	</li>
</ol>

<ul>
	<li>NS1 tests detect the dengue virus&#39;s nonstructural protein NS1. This protein is secreted into the bloodstream during the infection.</li>
	<li>NS1 can be detected throughout the acute stage of dengue virus infections. NS1 tests can be as sensitive as molecular tests if conducted on the first seven days of symptoms. These tests are not suggested after the 7th day. 
	&nbsp;</li>
</ul>

<ol start="2">
	<li>
	<h5>&nbsp;IgM Antibody Capture Enzyme-Linked Immunosorbent Assay (MAC-ELISA)</h5>
	</li>
</ol>

<ul>
	<li>The dengue MAC-ELISA is used to qualitatively detect dengue virus IgM antibodies.</li>
	<li>Once the individual gets dengue, their immune system will start combating it. IgM antibodies against the dengue virus can be detected 4-5 days after the onset of signs and symptoms. They are fairly noticeable for up to 12 weeks.</li>
	<li>Positive dengue IgM antibodies are typically used to confirm a recent dengue virus infection; however, these presumed positive IgM antibody test results should be further confirmed through PRNT. 
	&nbsp;</li>
</ul>

<ol start="3">
	<li>
	<h5>&nbsp;Plaque Reduction Neutralization Test (PRNT)</h5>
	</li>
</ol>

<ul>
	<li>PRNT detects particular antibodies that neutralise dengue virus and other flaviviruses.</li>
	<li>It is used to detect the source of infection more accurately in IgM-positive individuals for whom a particular detection is clinically or epidemiologically necessary (e.g., to exclude additional flaviviruses, for example, Zika or yellow fever).</li>
	<li>PRNT is employed in an attempt to verify the virus in dengue or Zika virus IgM-positive samples. In a few instances, it can detect the infecting serotype of the dengue virus.</li>
	<li>PRNT carried out on a dengue IgM-positive sample demonstrating neutralising antibodies to just one dengue virus serotype verifies infection with that serotype<a href="#accordion">[8]</a>. 
	&nbsp;</li>
</ul>

During the febrile phase (2-7 days), individuals with dengue infection are prone to dehydration due to diarrhoea, nausea, throwing up, anorexia, and high fever<a href="#accordion">[1]</a>.

Doctors must assess the severity of dehydration in patients to provide proper care and management. Urine colour correlates directly with the overall hydration status so that can be used as an indicator. According to a study, consuming more than 5 glasses of fluid in the 24 hours right before the clinical evaluation reduced the risk of dengue fever patients getting hospitalised<a href="#accordion">[2]</a>. 
&nbsp;

<h5>Why Does Dengue Fever Cause Low Platelet Count?</h5>

Thrombocytopenia during dengue can result from either reduced bone marrow cell production or increased platelet destruction and clearance from peripheral blood. A high mean platelet volume (MPV) in patients means increased platelet destruction. MPV levels in dengue patients are typically high; thus, excessive platelet destruction can be the primary cause of thrombocytopenia in dengue patients. According to a number of studies, platelet count decreases significantly on the fourth day of the infection<a href="#accordion">[3]</a>. 
&nbsp;

<h5>When Do Patients Need A Platelet Transfusion?</h5>

As specified by clinical guidelines, platelet transfusions should be given to individuals presenting with a severe haemorrhagic exhibition, with platelet counts dropping less than 10&ndash;20 &times; 109 /L.<a href="#accordion">[3]</a>. 
&nbsp;

The WHO considers thrombocytopenia to be a criterion for determining the severity of the ailment. Thrombocytopenia is a rapid drop in platelet count or a platelet count of less than 150,000/mm<a href="#accordion">[3]</a>&nbsp;(&lt; 150 G/L)<a href="#accordion">[9]</a>.

A serious dengue patient with a decreased platelet count will have bleeding spots on the skin in different body parts. Severe dengue affects the lungs, liver, and heart. If the blood pressure falls to dangerously low levels, it can result in shock and, in some instances, death. 
&nbsp;

<ul>
	<li>
	There is no particular medication to treat dengue. Viruses always complete their cycle of either 5 or 7 or 14 days.
	</li>
	<li>Consult a doctor always. Meanwhile, symptomatic treatment can help alleviate the symptoms of dengue fever. 
	&nbsp;</li>
</ul>

<h5>Symptomatic Treatment</h5>

<ul>
	<li>Rest as much as you can.</li>
	<li>Take Panadol to control fever and alleviate pain and discomfort. 
	&nbsp;</li>
</ul>

Avoid aspirin and ibuprofen as they cause more bleeding <a href="#accordion">[10]</a>.

<ul>
	<li>Stay hydrated by drinking plenty of fluids. Drink water or electrolyte-enriched beverages.</li>
	<li>Care for a sick baby, child, or family member at home only if the signs are moderate. 
	&nbsp;</li>
</ul>

<h5>Food That Helps To Boost Platelet Count</h5>

One of the symptoms that incidentally also help with its diagnosis is that dengue affects the platelet count in the body. Especially in case of severe dengue; symptoms usually become life-threatening because the number of platelets in the bloodstream drastically drops.

Treatment recommendations are normally attempts to boost this platelet count to ensure the individual has a greater chance of combating the infection. 
&nbsp;

Hence, it&rsquo;s advised to consume a diet that&rsquo;s rich in

<ul>
	<li>Omega-3</li>
	<li>Iron</li>
	<li>Vitamins</li>
	<li>Other minerals 
	&nbsp;</li>
</ul>

<h5>How To Take Care Of Your Sick Baby At Home</h5>

<ul>
	<li>Paracetamol can help reduce fever<a href="#accordion">[11]</a>.</li>
	<li>Give sponge baths with cool water in summer and with normal water in winter.</li>
	<li>Make sure they drink plenty of liquids. Dehydration occurs when an individual loses excessive body fluid due to fever, vomiting, or not drinking the required amount of liquids.</li>
	<li>Keep an eye out for symptoms of dehydration and seek medical attention right away if the baby exhibits any of them. 
	&nbsp;</li>
</ul>

<ul>
	<li>
	Extreme skin bleeding with blood specks on the skin (petechiae) and huge blotches of blood under the skin (ecchymoses)
	</li>
	<li>
	Black faeces
	</li>
	<li>
	Urine containing blood (hematuria)
	</li>
	<li>
	Leakage
	</li>
	<li>
	Severe plasma respiratory failure
	</li>
	<li>
	Liver failure
	</li>
	<li>
	Heart failure
	</li>
	<li>
	Mental health changes associated with impaired consciousness
	</li>
	<li>
	Patients exhibit warning indications (specifically inactivity and continuous puking)
	</li>
	<li>People with low platelet counts and high haematocrit (high red blood cell counts) have a high likelihood of organ failure problems or even death 
	&nbsp;</li>
</ul>

From Mosquito Bite

<ul>
	<li>Use mosquito repellent</li>
	<li>Keeping the body covered</li>
	<li>Discard any standing water 
	&nbsp;</li>
</ul>

Dengue Virus Vaccine&nbsp;

Dengvaxia is the only dengue vaccine that&rsquo;s been approved by the FDA and suggested for regular use by the Advisory Committee on Immunization Practices. It protects against all 4 dengue virus serotypes<a href="#accordion">[12]</a>.

By the end of 2022, Dengvaxia will be accessible for use in youngsters (aged 9-16) who have previously been infected with dengue virus and who currently reside in a region where dengue is endemic, i.e., takes place commonly or constantly. 
&nbsp;

Can Malaria And Dengue Occur Concurrently?

While there is no denying that malaria and dengue are highly prevalent in tropical countries, it is rare to have both dengue fever and malaria at the same time. Appropriate lab tests should be conducted to confirm the disease condition because the treatment of both diseases is different. Repeated blood smears are a credible test to avoid incorrect negative results and successive malaria misdiagnosis<a href="#accordion">[5].</a>&nbsp;Malaria and dengue fever should be presumed in pyretic patients residing in or returning from areas where malaria and dengue is prevalent<a href="#accordion">[4]</a>. 
&nbsp;

Annually, hundreds of millions of people become infected with dengue. Even if the majority of cases are mild or asymptomatic, the prospect of severe dengue can be frightening.

Fortunately, it can be prevented. Precautions like keeping the skin covered at all times reduce the risk of mosquito bites. While travelling to endemic regions, find out beforehand where emergency medical attention is being provided for the dengue. Recovery is possible if the patient receives proper treatment on time. 
&nbsp;

Key Takeaways

<ul>
	<li>The dengue virus causes dengue fever, which can be transmitted through mosquito bites.</li>
	<li>Dengue fever is frequent in many areas of the world, so individuals travelling to the endemic regions should take precautions against mosquito bites. This includes keeping the body well covered, using mosquito netting, and applying mosquito repellent.</li>
	<li>Dengue fever can be fatal. Make sure to get medical attention right away to avoid symptoms from worsening. 
	&nbsp;</li>
</ul>

[1] Kalayanarooj S, Vaughn DW, Nimmannitya S, Green S, Suntayakorn S, Kunentrasai N, et al. Early clinical and laboratory indicators of acute dengue illness. J Infect Dis. 1997;176(2):313–21.

[2] Harris E, Pérez L, Phares CR, de los Angeles Pérez M, Idiaquez W, Rocha J, et al. Fluid intake and decreased risk for hospitalization for dengue fever, Nicaragua. Emerg Infect Dis. 2003;9(8):1003.

[3] Das S, Abreu C, Harris M, Shrader J, Sarvepalli S. Severe Thrombocytopenia Associated with Dengue Fever: An Evidence-Based Approach to Management of Thrombocytopenia. Case Rep Hematol. 2022;2022.

[4] Carme B, Matheus S, Donutil G, Raulin O, Nacher M, Morvan J. Concurrent dengue and malaria in Cayenne hospital, French Guiana. Emerg Infect Dis. 2009;15(4):668.

[5] Bhagat M, Kanhere S, Phadke V, George R. Concurrent malaria and dengue fever: a need for rapid diagnostic methods. J Fam Med Prim Care. 2014;3(4):446.