6329 – Hemorrhagic fevers, including dengue, yellow fever, and others

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Definition

Viral hemorrhagic fevers (VHFs) are a group of illnesses caused by various viruses that can damage blood vessels and lead to bleeding (hemorrhaging). These fevers range from mild to severe and potentially life-threatening, and can affect multiple organ systems. Dengue and yellow fever are examples of VHFs, along with others like Ebola, Lassa fever, and Marburg. 

Etiology

Etiology and characteristics of hemorrhagic fevers

Dengue fever

• Cause: Dengue fever is caused by one of four dengue viruses (DENV) transmitted by the bite of infected Aedes mosquitos.
• Transmission: Infected mosquitos transmit the virus when they bite a person who is already infected, and then bite another person.
• Symptoms: Many people with dengue have mild or no symptoms. Common symptoms include high fever, severe headache, pain behind the eyes, joint and muscle pain, nausea, vomiting, swollen glands, and rash. Severe dengue, which can be life-threatening, can develop, presenting with symptoms like severe abdominal pain, persistent vomiting, rapid breathing, bleeding gums or nose, fatigue, and blood in vomit or stool.
• Treatment: There is no specific medication to treat dengue fever. Treatment focuses on supportive care, including rest, fluids, and managing pain with acetaminophen (paracetamol), avoiding ibuprofen or aspirin due to the risk of bleeding. 

Yellow fever

• Cause: Yellow fever is caused by the yellow fever virus, a flavivirus, transmitted by the bite of infected mosquitoes.
• Transmission: The virus is primarily spread to humans through the bite of infected Aedes aegypti mosquitoes in urban areas. In jungle (sylvatic) yellow fever, the virus is transmitted by forest canopy mosquitoes that acquire the virus from wild primates.
• Symptoms: Initial symptoms can include sudden onset of fever, chills, severe headache, back pain, general body aches, nausea, vomiting, fatigue, and weakness. In severe cases, symptoms can include high fever, yellow skin and eyes (jaundice), bleeding, shock, and organ failure, which can be fatal.
• Treatment: There is no specific antiviral treatment for yellow fever. Treatment is supportive, involving managing symptoms and preventing complications. This includes rest, fluids, and pain relievers (avoiding aspirin and ibuprofen). A vaccine is available to prevent yellow fever and is recommended for travelers to risk areas. 

Other viral hemorrhagic fevers (VHFs)

• Causes: Viral hemorrhagic fevers (VHFs) are a group of illnesses caused by viruses from several families, including Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae.
• Transmission: VHFs are typically transmitted through contact with infected animals, particularly rodents, bats, or arthropods (like mosquitoes or ticks). Some VHFs, like Ebola, Marburg, Lassa fever, and Crimean-Congo hemorrhagic fever, can also spread from person-to-person through direct contact with infected bodily fluids or contaminated objects.
• Symptoms: Symptoms can vary depending on the specific virus but often begin with flu-like symptoms, including fever, fatigue, muscle aches, and headache. Severe cases can progress to involve multi-system hemorrhage, shock, and organ failure.
• Treatment: There is no specific cure for most VHFs, according to the Mayo Clinic. Treatment is primarily supportive care, managing symptoms and complications. Antiviral medications like ribavirin may be used for some infections like Lassa fever, and monoclonal antibody therapies are approved for Ebola.

Signs & Symptoms

Viral hemorrhagic fevers (VHFs) are a group of illnesses caused by viruses that damage your blood vessels and can cause bleeding. They are most common in parts of Africa, Asia, and South America. Examples include dengue, Ebola, Marburg, and yellow fever. 

General symptoms

Symptoms can vary depending on the specific virus, but initial symptoms often include: 

• Fever
• Fatigue and weakness
• Headache
• Muscle and joint pain
• Nausea and vomiting
• Diarrhea
• Sore throat or cough
• Chest or abdominal pain
• Rash 

Symptoms potentially becoming life-threatening

In more severe cases, VHFs can lead to: 

• Bleeding under the skin, in internal organs, or from the mouth, eyes or ears.
• Nervous system malfunctions.
• Coma.
• Delirium (confused thinking and not being aware of surroundings).
• Kidney failure.
• Respiratory failure (trouble breathing).
• Liver failure.
• Unexplained nosebleeds or bleeding gums.
• Blood in vomit or stool. 

Specific examples

• Dengue Fever: High fever (often 104°F/40°C), severe headache, pain behind the eyes, muscle and joint pains, nausea, vomiting, swollen glands, and rash.
• Severe Dengue (Dengue Hemorrhagic Fever): Follows after the initial fever subsides. Warning signs include severe abdominal pain, persistent vomiting, bleeding gums or nose, blood in urine, stools, or vomit, according to the Mayo Clinic, and rapid breathing.
• Yellow Fever: Fever, muscle pain, headache, shivers, loss of appetite, nausea or vomiting, jaundice, dark urine, abdominal pain with vomiting, and bleeding.

Tests

Diagnosing hemorrhagic fevers like dengue and yellow fever can be challenging due to overlapping symptoms with other illnesses. However, various diagnostic methods are employed to confirm the presence of the virus and determine the specific type of infection. 

Here are the main categories of tests used for diagnosing hemorrhagic fevers:

1. Molecular tests

• Reverse transcription polymerase chain reaction (RT-PCR): This is a highly sensitive and specific test that detects the viral RNA directly. It is particularly useful for detecting the virus during the early stages of the illness when the viral load is high.
• RT-PCR can also be adapted to detect multiple viruses in a single sample using multiplex assays, according to the National Institutes of Health (NIH). 

2. Serological tests

• Enzyme-linked immunosorbent assay (ELISA): This is a widely used test that detects the presence of antibodies (IgM and IgG) produced by the immune system in response to the infection.
  • IgM antibodies indicate a recent or acute infection, while IgG antibodies can indicate a past infection or vaccination.
• Rapid Diagnostic Tests (RDTs): These tests, often based on immunochromatography, can detect viral antigens or antibodies in a quick and convenient format, suitable for point-of-care settings.
• Other serological tests, including immunofluorescence assays (IFA) and neutralization assays (such as Plaque Reduction Neutralization Test, PRNT), are used to confirm serological results or to differentiate between closely related viruses. 

3. Virus isolation and antigen detection

• Virus Isolation: This involves growing the virus in cell culture, typically in a high-containment laboratory due to the infectious nature of the samples. This method is rarely used as a first-line diagnostic tool due to the time required and the need for specialized facilities, says the World Health Organization (WHO).
• Antigen Detection: Detecting specific viral antigens, such as the NS1 antigen for dengue virus, can be useful for early diagnosis, especially during the acute phase of illness. 

4. Other tests

• Complete Blood Count (CBC) and Metabolic Panels: These tests can reveal abnormalities associated with hemorrhagic fevers, such as low platelet counts (thrombocytopenia), leukopenia, and elevated liver enzymes.
• Urinalysis: This test can detect proteinuria and microhematuria in cases like Hantavirus infection.
• Imaging exams: These may be ordered if organ damage is suspected.

Treatment

Hemorrhagic fevers are a group of severe viral illnesses that can be life-threatening and are characterized by fever, bleeding, and organ damage. These viruses often live in animals like rodents or are transmitted through mosquito or tick bites. 

General treatment approach

• Supportive care is crucial: There's generally no specific cure for most viral hemorrhagic fevers. Treatment focuses on managing symptoms and stabilizing the patient's condition. This may include:
  • Rest.
  • Staying well hydrated with fluids (oral or intravenous).
  • Medications to manage symptoms like fever, pain, vomiting, and diarrhea.
  • Avoiding medications that can increase the risk of bleeding, such as aspirin or ibuprofen.
  • In severe cases, patients may require hospitalization for intensive supportive care, including mechanical ventilation or dialysis, depending on organ involvement.
• Antiviral therapies: For some specific viral hemorrhagic fevers, antiviral medications may be used, according to the University of California - Davis Health. Examples include:
  • Ribavirin, which may be helpful for some viral hemorrhagic fevers like Lassa fever, especially if started early.
  • Monoclonal antibodies like Inmazeb® and Ebanga®, approved for treating Ebola virus disease (Zaire strain). 

Specific examples of hemorrhagic fevers and their treatment

1. Dengue fever

• No specific antiviral treatment is available.
• Treatment focuses on supportive care:
  • Rest and hydration.
  • Pain and fever management using acetaminophen (paracetamol); avoid aspirin or ibuprofen due to the risk of bleeding.
  • Careful monitoring, especially for warning signs of severe dengue which may require hospitalization.
  • IV fluids may be necessary for patients with severe dengue experiencing plasma leakage.
  • In severe cases, patients may need intensive care unit monitoring. 

2. Yellow fever

• No specific antiviral treatment exists.
• Treatment is supportive:
  • Rest, fluids, and medications like acetaminophen for fever and pain.
  • Aspirin and ibuprofen should be avoided.
  • Patients with severe symptoms should be hospitalized for close observation and supportive care.
  • Vaccination is the most effective way to prevent yellow fever. 

3. Ebola disease

• Specific treatments are available for the Ebola Zaire strain, including two FDA-approved monoclonal antibody treatments: Inmazeb® and Ebanga®.
• Supportive care is essential:
  • Managing complications like dehydration, electrolyte imbalances, and bleeding.
  • Intravenous fluids are often needed due to dehydration from vomiting and diarrhea.
  • Supportive care includes maintaining blood pressure and oxygenation, pain control, and nutritional support.
  • Prompt treatment of secondary infections is also important, according to the CDC. 

4. Lassa fever

• The antiviral medication Ribavirin may be used, and is most effective when given early in the illness.
• Supportive care is crucial:
  • Correcting fluid and electrolyte imbalances.
  • Managing specific symptoms.
  • In infected pregnant women, abortion may reduce the risk of maternal death, says Merck Manuals. 

5. Marburg virus disease

• No antiviral medications or vaccines are approved for Marburg virus disease.
• Treatment is supportive:
  • Rest and hydration.
  • Managing oxygen status and blood pressure.
  • Treating secondary infections.
  • In severe cases, hospitalization may be necessary. 

6. Crimean-Congo hemorrhagic fever (CCHF)

• No FDA-approved vaccines or specific treatments for CCHF.
• Supportive care is paramount:
  • Fluid balance and rehydration.
  • Oxygen support and blood pressure management.
  • Treating secondary infections.
  • The antiviral drug Ribavirin is commonly used, but evidence of its benefit is mixed. 

7. Hemorrhagic fever with renal syndrome (HFRS)

• Supportive care is the mainstay of treatment:
  • Careful management of hydration and electrolyte levels.
  • Maintaining oxygen and blood pressure.
  • Treating secondary infections.
  • Dialysis may be required in severe cases.
  • The antiviral drug Ribavirin can be given intravenously early in the disease to potentially reduce illness and death. 

8. Rift valley fever (RVF)

• Most RVF cases are mild and do not require specific treatment, resolving on their own within a few days.
• Supportive care is provided for more severe cases:
  • Rest.
  • Over-the-counter medications like ibuprofen or acetaminophen can be used to manage fever and body aches.
  • Hospitalization may be required for severe cases, where patients will receive supportive care for symptoms and complications.
  • An RVF vaccine is available but not approved for widespread use. 

Residuals

Hemorrhagic fevers, such as dengue and yellow fever, can cause a range of residual effects and long-term complications even after a person has recovered from the initial illness. These effects can vary in duration and severity depending on the specific virus, the severity of the initial infection, and individual factors. 

Common residual effects

• Fatigue and weakness: Persistent fatigue, sometimes referred to as post-viral asthenia, is a common complaint among survivors of various hemorrhagic fevers. This can make it difficult for individuals to return to their normal daily activities for weeks or even months after recovery.
• Musculoskeletal pain: Joint pain (arthralgia) and muscle pain (myalgia) can persist after the acute phase of illness. Dengue, in particular, is sometimes called "breakbone fever" due to the intense pain it can cause in joints and muscles.
• Neurological symptoms: Some survivors experience neurological complications such as headaches, memory loss, difficulty reasoning, and even more severe issues like nerve damage (Guillain-Barré syndrome) or inflammation of the brain (encephalitis). Some studies suggest an increased risk of neurological and psychiatric disorders, including Parkinson's disease and dementia, following dengue infection.
• Ocular complications: Eye-related issues, including vision loss, uveitis (inflammation of the eye's middle layer), and even blindness can occur. A CDC article notes that Ebola virus can persist in the eyes, according to the Centers for Disease Control and Prevention.
• Hair loss: Excessive hair shedding or even alopecia can occur due to the stress the body experiences during the acute phase of hemorrhagic fevers.
• Mental health impacts: Dealing with the prolonged recovery process and ongoing symptoms can lead to anxiety, depression, and other mood changes in some individuals.
• Organ damage: Severe cases of hemorrhagic fevers can cause damage to various organs, including the kidneys, liver, and heart. Yellow fever, for example, can lead to liver and kidney failure. While organ function often recovers, some individuals may experience long-term problems or require ongoing medical care.
• Hemorrhagic complications: Although less common, some individuals may experience lingering issues with bleeding or blood clotting abnormalities, potentially increasing the risk of future hemorrhagic events. 

Factors influencing residual effects

• Virus type: The type of virus causing the hemorrhagic fever can influence the specific residual effects and their severity. For example, Ebola and Marburg are known for their high mortality rates and potential for serious long-term complications.
• Disease severity: Individuals who experienced more severe forms of hemorrhagic fever are generally more prone to developing long-term complications.
• Pre-existing conditions: Underlying health conditions, particularly those affecting the heart, can increase the risk and severity of post-recovery complications.