Viral hemorrhagic fever is an infectious disease that may lead to internal bleeding. Dengue hemorrhagic fever and Crimean-Congo fever are common hemorrhagic fevers.

Viral Hemorrhagic Fever

Overview

Hemorrhagic fever, in its literal sense, means fever that can cause internal bleeding in humans.

Medically these fevers are called viral hemorrhagic fevers (VHFs) because of their viral origin. VHF can be caused by 4 exclusive families of virus namely: 
&nbsp;

<ol>
	<li>Arenaviridae family</li>
	<li>Bunyaviridae family</li>
	<li>Filoviridae family</li>
	<li>Flaviviridae family 
	&nbsp;</li>
</ol>

All of these families cause illnesses that present with their own set of systemic symptoms. Systemic essentially means involvement of the entire body rather than one specific organ. For example, high blood pressure is a systemic disease as it affects the entire body, whereas an ear infection will be called nonsystemic as it only involves the ear.

VHFs are usually transmitted through either insects or rodents such as rats. Therefore, it was previously assumed that its abundance can only be found in areas or countries populated with these creatures on a bigger scale. However, recent globalization has changed this theory as people are visiting or traveling back and forth to areas where this type of fever is endemic<a href="#accordion">[1]</a>.

Usually VHFs are restricted to places like South America, Africa, and Central Asia. However, Crimean-Congo hemorrhagic fever (CCHF) and dengue fever members of the Bunyaviridae and Flaviviridae families, respectively, are endemic in Pakistan. The last notable outbreak in Pakistan was in 2019, reporting about 53,498 cases and 498 deaths. Whereas, in 2021 almost 48,906 cases and 183 deaths with the highest contribution made by the Punjab province. With respect to CCHF, 356 cases were confirmed between January 2014 and May 2020 by the National Institute of Health situated in Islamabad. They further reported that the mortality ratio was 25%<a href="#accordion">[4][5]</a>.

Ebola Virus is responsible for a 50% fatality rate and as of June 2015, a total of more than 27,000 cases were reported<a href="#accordion">[3]</a>.

Marburg hemorrhagic fever caused by the Marburg Virus from the Filoviridae family is to be blamed for fatality rates as high as 82% in low-income countries<a href="#accordion">[1]</a>. Lassa fever is a type of hemorrhagic fever caused by the Lassa virus that infects 100,000 to 300,000 people annually<a href="#accordion">[6]</a>. 
&nbsp;

There are four families of viruses under which various viruses are classified. With more than 20 viruses in total, the most common ones, according to their families, will be discussed as examples below: 
&nbsp;

<h5>1. Arenaviridae Family</h5>

Lassa Virus is from the family of Arenaviridae, endemic in regions of West Africa, and is usually spread by multimammate rats. Lassa hemorrhagic fever occurs 1-3 weeks after being in contact with the virus. The symptoms patients usually feel are mild and often go undiagnosed. Whereas, 20% of the patients go through severe symptoms like bleeding from the gums and nose, respiratory distress (breathing problems), and pain in the chest, abdomen, and back. During an epidemic, patients hospitalized for Lassa fever have a death rate of about 50%<a href="#accordion">[6]</a>. 
&nbsp;

<h5>2. Bunyaviridae Family</h5>

The most prominent example from this family is the<a href="https://www.merisehat.pk/disease/crimean-congo-hemorrhagic-fever" target="_blank"> Crimean-Congo hemorrhagic virus (CCHFV)</a>. It is essentially found in Eastern Europe and is transmitted through infected ticks. CCHF presents as high-grade fever, red spots on the skin called petechiae on the palate, and joint pain. Regardless of the complications, recovery from CCHF is slow<a href="#accordion">[7]</a>. 
&nbsp;

<h5>3. Filoviridae Family</h5>

A virus of interest in this family is the Ebola virus. Currently, known as the Ebola virus disease (EVD), it attacks humans as well as non-human primates such as chimpanzees and gorillas. It has occasional outbreaks in Africa and spreads to people through direct contact with blood, feces, and urine. EVD can present as severe headache, weakness, and fatigue along with muscle pain. EVD&rsquo;s classic symptom is undefined hemorrhaging. EVD is a rare disease, but a fatal one<a href="#accordion">[8]</a>. 
&nbsp;

<h5>4. Flaviviridae Family</h5>

Dengue virus belongs to the Flaviviridae family and is transmitted by the bite of the Aedes Aegypti mosquito. A population of 4 billion people lives in high-risk areas of dengue. Statistics show that each year, up to 400 million people get infected with dengue and around 40,000 die because of it. The classical symptom of the&nbsp;<a href="https://www.merisehat.pk/disease/dengue-80" target="_blank">dengue </a>virus is retro-orbital pain which means pain behind the eyes. Other than this, symptoms may include high-grade fever, joint pain, and rash<a href="#accordion">[9]</a>. 
&nbsp;

Causes

Viral hemorrhagic fever is essentially transmitted through a living host. Every family of the virus has a special inclination towards a specific creature.

One of the members of the Arenaviridae family is the Lassa virus. As discussed earlier it is most commonly spread by the multimammate rat. When this rat is infected, it can excrete the virus in its urine for the rest of its life. Humans contract the disease by either inhaling or ingesting it. It can also spread if something spoiled with the infected urine comes in contact with your open wound<a href="#accordion">[6]</a>.

The most prominent example from the Bunyaviridae family is the <a href="https://www.merisehat.pk/disease/crimean-congo-hemorrhagic-fever" target="_blank">Crimean-Congo hemorrhagic virus (CCHFV)</a>. It is spread by the Ixodid ticks also known as the hard ticks. Cattle, goats, and sheep are known to be a host for these creatures, and coming in contact with infected animals or their blood is one of the reasons that you can contract CCHF. Another possible cause is coming in contact with another human&rsquo;s blood that is infected with the disease. Moreover, it has been reported that transmission is also quite possible in hospitals due to unsterilized equipment and contaminated medical supplies<a href="#accordion">[7]</a>.

The Ebola virus of the Filoviridae family is one name that scares everyone, and quite rightfully. An important term to understand before understanding how it is transmitted is a &lsquo;spillover event&rdquo;. A spillover event is when Ebola is contracted from a fruit bat or non-human primates such as gorillas to humans through open wounds; hence, can be called a direct contact transmission. After this initial transmission, it is then further transmitted from one person to another through various ways: 
&nbsp;

<ul>
	<li>From the bodily fluids of an infected person like blood, urine, feces, or urine</li>
	<li>From the clothes of an infected person</li>
	<li>Through the semen of a man who has recovered from Ebola<a href="#accordion">[8]</a> 
	&nbsp;</li>
</ul>

Dengue virus has been endemic in many countries, including Pakistan, and is essentially transmitted through the mosquito Aedes Aegypti. The same species of mosquito has been responsible for spreading Chikungunya and Zika. Mosquitoes initially become infected when they bite a patient who has <a href="http://www.merisehat.pk/disease/dengue">dengue</a>. In such cases, water should not be allowed to gather anywhere near residences, as it becomes a breeding ground for this mosquito.

After being infected, the mosquito can spread the virus to other people through bites. Dengue can also be transmitted from the mother to the child during pregnancy<a href="#accordion">[9]</a>. 
&nbsp;

Although there are no specific screening tests available for viral hemorrhagic fever, because the disease presents with exclusively severe symptoms, it can warrant a viral marker assessment. The decision can be supported by a detailed history and physical evaluation of the patient. For example, if a patient complains of high grade fever with severe muscular pain, your healthcare practitioner can confidently order a Nucleic Acid Amplification Test (NAAT) for Dengue. 
&nbsp;

Diagnosis

Viral hemorrhagic fevers need to be diagnosed as soon as possible because of the associated severe complications and fatality. The tests that can be used to diagnose VHFs are as follows<a href="#accordion">[15]</a>: 
&nbsp;

<h5>1. Nucleic Acid Amplification Tests</h5>

NAAT is used to identify a specific nucleic acid sequence in the body. In this case, a virus related to the VHF virus families. 
&nbsp;

<h5>2. Serum IgG/IgM</h5>

These immunoglobulins are a part of the body&rsquo;s defense system and indicate that the body has produced defense against a certain bacterial or viral infection. 
&nbsp;

<h5>3. Real Time PCR</h5>

Also known as the RT-PCR, it works on the concept of regrowth of the isolated antigen sample to check where it belongs from. 
&nbsp;

Treatment

There is no exclusive treatment that can be labeled as an anti-viral hemorrhagic fever treatment. Though some drugs are still in development, the current treatment plan of VHFs includes antiviral medication and supportive therapy. Antiviral medication is given due to the viral origin of the fever, and is considered to be helpful in shortening the disease duration and preventing complications from developing. These drugs include acyclovir, vancyclovir, and ribavirin<a href="#accordion">[12]</a>.

Apart from this, supportive treatment has been advised which includes hydrating the patient efficiently, either orally or intravenously<a href="#accordion">[12]</a>.

Patients diagnosed with a VHF should be isolated in the ICU immediately to prevent it from spreading. Symptomatic treatment should be initiated for its control. For example. antipyretics to bring the fever down<a href="#accordion">[12]</a>.

There are a few herbal remedies that have been reported to show improvements. For example, Nigerian researchers have studied that turmeric, bamboo, onion, and garlic plants are beneficial in treating VHFs. Also, a recent study published in the journal Medicinal &amp; Aromatic Plants showed that the juice of Carica papaya (pawpaw) leaves is an effective herbal therapy for curing dengue fever<a href="#accordion">[13]</a>. 
&nbsp;

Every viral hemorrhagic fever-causing virus can have a distinct complication development, making them even more dangerous. Following are the complications according to some of the most worried fevers: 
&nbsp;

<h5>1. Lassa Fever</h5>

The most common complication of Lassa fever is deafness. It has been seen that the loss of hearing is permanent and is independent of the severity of the disease<a href="#accordion">[6]</a>. 
&nbsp;

<h5>2. CCHF</h5>

If CCHF is not controlled in time, it can cause severe bruising, nosebleeds, and uncontrolled bleeding at injection sites<a href="#accordion">[7]</a>. 
&nbsp;

<h5>3. Ebola Virus</h5>

Although it is rare, Ebola can prove to be fatal if not diagnosed and treated actively<a href="#accordion">[8]</a>. 
&nbsp;

<h5>4. Dengue Hemorrhagic Fever</h5>

Complications regarding dengue include damage to the lymph nodes, blood vessels, liver enlargement, and even circulatory failure.

&nbsp;

In general, all fevers in the VHF group can cause edema (excess amount of fluid in the body), internal bleeding, multi-organ failure, and breathing trouble<a href="#accordion">[9]</a>. 
&nbsp;

Viral hemorrhagic fevers have a worrisome profile, be it their complications or the severity of the disease. Hence, it becomes crucial for the patients who are at high risk to get tested. As there is a long list of viral fevers, some of the risk factors are exclusive. However, there is a set of general risk factors that can be looked out for. Such include: 
&nbsp;

<ul>
	<li>Recent travel history:&nbsp;Trips to areas that have been reported to be an origin, or are highly acclaimed to host a VHF should be avoided. If there is a vaccine available for that disease, you should get it. However, if you get relevant symptoms with or without a vaccination history, a relevant diagnostic test should be taken immediately<a href="#accordion">[11]</a>. 
	&nbsp;</li>
	<li>Coming in contact with dead animals. Different cultures offer different traditions, especially if you are a tourist, you are inclined to try them out. This can range from unorthodox dining experiences to any sacrificial traditions. If you come in contact with any animal&rsquo;s dead body, you are opening yourself to a potential risk of a number of dangerous diseases including VHFs<a href="#accordion">[11]</a>. 
	&nbsp;</li>
	<li>Interaction with the diseased. As mentioned earlier, VHFs cannot be taken lightly and should be stayed away from at any cost. Every human body responds differently. Therefore, an infection can be mildly symptomatic in one and severely symptomatic in other people at the same time. It should be noted that if you were in close proximity with such patients, you should get tested<a href="#accordion">[11]</a>. 
	&nbsp;</li>
	<li>Insect Bites. Little creatures sometimes make their way through all the barriers you set up. If getting relevant symptoms, immediate testing becomes essentia<a href="#accordion">[11]</a>. 
	&nbsp;</li>
</ul>

There are no vaccinations essentially to prevent the disease from occurring, apart from only two, namely: 
&nbsp;

<ol>
	<li>Yellow Fever</li>
	<li>Argentine Hemorrhagic Fever 
	&nbsp;</li>
</ol>

Therefore, control of host creatures that help spread the disease becomes important. Following are the preventive measures that can be taken to help prevent viral hemorrhagic fever. 
&nbsp;

<h5>1. Rodents</h5>

Rodents are responsible for the spread of Arenaviridae family specially. It includes the dangerous Lassa fever which is hard to diagnose because of the non-specific symptoms it presents along with the most common complication, deafness. Rodents can be controlled by safely cleaning their nests and their fecal contents. It should also be ensured that they do not enter your home or workplace as much as possible<a href="#accordion">[10]</a>. 
&nbsp;

<h5>2. Mosquitoes and Ticks</h5>

These creatures are responsible for spreading fevers like dengue and CCHF, both currently endemic in Pakistan as discussed earlier. With <a href="http://merisehat.pk/disease/dengue">dengue </a>and the tick-spread CCHF creating infectivity of about 400 million people annually along with extreme symptoms and slow recovery, their prevention is a must. The effective methods to stop them from getting around you are by using insect repellents, maximum skin covering clothing, bed nets, and nets on your windows. It is also said to not let water accumulate near your surroundings, as it promotes their breeding grounds<a href="#accordion">[10]</a>. 
&nbsp;

<h5>3. Traveling Precautions</h5>

Easy traveling is the reason that these fevers which were geographically restricted at some point are not anymore. Therefore, either avoid traveling to areas that are labeled as high risk, or even if you are traveling anywhere which is at risk for these fevers, you should be cautious. Wear clothes that cover your skin as much as possible so that your chances of getting bitten decrease. Using bed nets and window screens can help you avoid exposure to mosquitoes and ticks that might be carrying the disease. Moreover, the use of insect repellants is a must as well.

As a few types of VHFs viruses survive in livestock, you should avoid all contact with them and with rodents too<a href="#accordion">[10]</a>. 
&nbsp;

A recent research done by the scientists at the Karolinska Institutet in Sweden found drugs that can immensely slow down the reproduction of the CCHF virus. The virus has shown mortality of up to 40% in some regions and is endemic in 30 countries.

The new drug candidates are reported to interfere in two metabolic pathways, glycolysis and glutaminolysis which in turn, reduces the reproduction of the CCHF virus. The drug candidates are soon to go into clinical trials and researchers expect a revolutionary breakthrough soon enough<a href="#accordion">[14]</a>. 
&nbsp;

Key Points

<ul><li style="line-height: 1.38; margin-top: 12pt; margin-bottom: 12pt;">Viral hemorrhagic fevers are caused by four viral families that cause illnesses which can present with their own set of systemic symptoms.</li><li style="line-height: 1.38; margin-top: 12pt; margin-bottom: 12pt;">The four families include the Arenaviridae family, Bunyaviridae family, Filoviridae family and the Flaviviridae family.</li><li style="line-height: 1.38; margin-top: 12pt; margin-bottom: 12pt;">CCHF and Dengue are currently endemic in Pakistan. Whereas Lassa virus infects 100,000 to 300,000 people annually.</li><li style="line-height: 1.38; margin-top: 12pt; margin-bottom: 12pt;">Marburg hemorrhagic fever caused by the Marburg virus from the Filoviridae family is to be blamed for fatality rates as high as 82% in low-income countries. Ebola virus had more than 27,000 cases reported in 2015.</li><li style="line-height: 1.38; margin-top: 12pt; margin-bottom: 12pt;">The most common cause of these fevers is through a host and every family has an inclination for one. The Arenaviridae family chooses rodents usually causing the Lassa fever. <a href="https://www.merisehat.pk/disease/crimean-congo-hemorrhagic-fever" target="_blank">Crimean-Congo hemorrhagic</a> virus from the Bunyaviridae family has a predilection for ticks. Whereas, Ebola and dengue from the Filoviridae&nbsp;and the Flaviviridae family are spread by gorillas and mosquitos, respectively.</li><li style="line-height: 1.38; margin-top: 12pt; margin-bottom: 12pt;">There is no efficient screening method currently available for VHFs. However, your clinician can order tests by physically evaluating and asking for a detailed history.</li><li style="line-height: 1.38; margin-top: 12pt; margin-bottom: 12pt;">Diagnostic tests for viral hemorrhagic fevers include NAATs, RT-PCR, and serum immunology to either check for viral antigen or the body’s immune response.</li><li style="line-height: 1.38; margin-top: 12pt; margin-bottom: 12pt;">Treatment is mainly supportive and the use of antiviral medication can be done to prevent complications from developing.</li><li style="line-height: 1.38; margin-top: 12pt; margin-bottom: 12pt;">Herbal remedies have been studied to cure different VHFs like dengue. Pawpaw and bamboo plants are some of the most acknowledged ingredients.</li><li style="line-height: 1.38; margin-top: 12pt; margin-bottom: 12pt;">Diagnosed patients should be admitted in ICU and isolated.</li><li style="line-height: 1.38; margin-top: 12pt; margin-bottom: 12pt;">Complications of VHFs are grouped according to their viruses, but they can all cause severe symptoms, uncontrolled bleed, and in some cases cause deafness or even death.</li><li style="line-height: 1.38; margin-top: 12pt; margin-bottom: 12pt;">Risk factors involve a recent travel to a geographical stronghold of these viruses, contact with animals, insect bites, and interaction with untreated patients.</li><li style="line-height: 1.38; margin-top: 12pt; margin-bottom: 12pt;">Vaccines are only available for two fevers: Yellow fever and Argentine hemorrhagic fever. Therefore, prevention of the risk factors should be ensured.</li><li style="line-height: 1.38; margin-top: 12pt; margin-bottom: 12pt;">Host specific precautions should be taken as well. For example, destroy breeding grounds for Aedes Aegypti mosquitoes that cause dengue, and use of insect repellants.</li><li style="line-height: 1.38; margin-top: 12pt; margin-bottom: 12pt;">Swedish researchers are working on drugs that have reduced the reproduction of CCHF in the human body drastically.</li><li>Viral hemorrhagic fever is a notification priority disease in Pakistan, and any presenting cases should be notified to the concerned authorities immediately.</li></ul>

[1] Mangat R, Louie T. Viral Hemorrhagic Fevers. [Updated 2022 May 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.

[2] Lakhani, A., Mahmood, H., Laeeq, A., Mansoor, S., Lodhi, S., Majid, S., Kizilbash, Q., & Altaf, A. (2002). Viral hemorrhagic fever in Pakistan: awareness among health care personnel. JPMA. The Journal of the Pakistan Medical Association, 52(5), 214–217.

[3] Ebola report: Ebola by the numbers. Centers for Disease Control and Prevention.

[4] Ahmed, A., Saqlain, M., Tanveer, M. et al. Knowledge, attitude and perceptions about Crimean Congo Haemorrhagic Fever (CCHF) among occupationally high-risk healthcare professionals of Pakistan. BMC Infect Dis 21, 35 (2021).

[5] Dengue fever – Pakistan. World Health Organization.

[6] Lassa fever. Centers for Disease Control and Prevention.

[7] Crimean-Congo Hemorrhagic Fever (CCHF). Centers for Disease Control and Prevention.

[8] Ebola (ebola virus disease). Centers for Disease Control and Prevention.

[9] Dengue. Centers for Disease Control and Prevention.

[10] Viral hemorrhagic fevers. Viral Hemorrhagic Fevers | Johns Hopkins Medicine.

[11] Department of Labor Logo United Statesdepartment of Labor. Viral Hemorrhagic Fevers (VHFs) - Hazard Recognition | Occupational Safety and Health Administration.