Viral Hemorrhagic Fevers: From Global to Local Outbreaks

While the world continues to deal with the usual culprits of emerging and reemerging infectious diseases such as influenza, SARS-CoV-2, foodborne outbreaks, and antimicrobial resistance, the appearance and expansion of viral hemorrhagic fevers (VHFs) continues on a global and local scale. Laboratory data and other epidemiology reports show that even though VHFs can be considered neglected tropical diseases, the overall impact of VHFs on public health is significant. Estimates show that roughly one third of the global population lives in VHF at-risk geographical regions—and most of the at-risk population is found at and below the equatorial belt.

What are viral hemorrhagic fevers?

Viral hemorrhagic fevers (VHFs) are a group of diseases that are caused by several distinct families of viruses. The term “hemorrhagic” details what this group of viruses typically does pathologically to one’s body. In a broad definition, the pathology of VHFs usually affects several organ systems, wreaks havoc on the cardiovascular system, and weakens bodily functions. 

VHFs attack and cause the following damage to internal systems:

• Immune impairment: Viruses often initiate an overwhelming inflammatory response. They can also cause other immune dysfunction, such as halting the maturity of dendritic cells, which are responsible for antigen presentation to other immune cells in adaptive immunity, weakening the immune response.
• Coagulation abnormalities: Viruses can also damage the body’s blood clotting ability, which is critical for stopping bleeding, both internal and external.
• Hemorrhage: A viral attack can lead to blood loss from injured blood vessels.
• Vascular damage: Damage to the vasculature can lead to abnormal vascular regulation and vascular permeability resulting in hypotension (low blood pressure), multiorgan failure, and death.

Viruses that cause VHFs are also known for uncontrolled and rapid viral replication, the production of cytokine storms, endothelial activation, and vasodilatation.

VHFs are caused primarily by four families of viruses: Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae. These viruses have a wide range of health effects, with some causing mild illness and others causing death. For example, Ebola and Marburg hemorrhagic fevers have extremely high fatality rates, while yellow fever and dengue viral infections are typically asymptomatic to mild.

      

Transmission of VHFs to humans may occur via contact with or inhalation of contaminated materials from animals (usually rodents, bats, monkeys, gorillas, or other similar wildlife) or arthropods (insects like ticks, sand flies, and mosquitos). VHFs can also be spread through contact with infected blood and other body fluids, such as open wounds with bleeding or needle punctures.

There are many examples of these viruses that are increasingly being seen in outbreaks and popular media. Viruses such as Ebola, Marburg, Lassa, Hantavirus, Crimean-Congo Hemorrhagic Fever, dengue, yellow fever, and Nipah. For a full description of these viruses, see the Centers for Disease Control and Prevention Table characterizing all VHFs. 

The Rwanda Marburg outbreak

Human Marburg virus disease (MVD) has continued to emerge over the past three years—characterized by fever, weakness, vomiting, and diarrhea—in regions without previously recognized cases. In 2023, two concurrent outbreaks occurred in the West African countries of Guinea and Ghana, and in Tanzania. These were suspected to be sparked by separate spillover events. Spillover of novel pathogens typically occurs through the intersection of the agent (e.g., viruses, bacteria, and/or parasites) with livestock, vectors, wildlife, humans, or even the natural environment.

On October 3, the CDC issued a issued a Health Alert Network Health Advisory following 36 laboratory-confirmed cases of MVD and 11 fatalities linked to the first known MVD outbreak in the Republic of Rwanda. On November 3, 2024, Rwanda recorded 66 illnesses and 15 deaths from Marburg virus. The CDC is working with international partners to obtain the latest case counts and updated weekly data. The Rwanda Ministry of Health maintains a webpage with case counts for this outbreak—according to the website, there have been no new reported cases in the last 35 days.

With the high mortality rate of MVD, Rwanda has received approximately 700 doses of a vaccine from the Sabin Vaccine Institute, a US-based non-profit organization. The vaccines were primarily used to protect those most at-risk—healthcare professionals. According to the CDC, about 75 percent of MVD patients have recovered. Contact tracing and testing efforts continue. 

People are infected with Marburg virus when they come into close contact with Rousettus bats, a type of fruit bat that can carry the Marburg virus and are often found in mines or caves. In late October, Nature reported that the first-known case of Marburg infection in the Rwanda outbreak was a man who had visited a cave that hosts a species of bat known to harbor the virus.

Diagnostics, treatment, and prevention of viral hemorrhagic fevers

Due to the pathology of many VHFs, it’s common for patients to show leukopenia, leukocytosis, thrombocytopenia, hemoconcentration, and occasionally, disseminated intravascular coagulation. Elevated hepatocellular enzyme levels and hypoalbuminemia are typically present and proteinuria is a universal finding. 

Unfortunately, VHFs have many nonspecific symptoms that can present like other diseases, such as malaria or typhoid fever. As a result, the CDC urges clinicians to evaluate patients for other causes of illness whether or not testing for a VHF is indicated. 

As we witnessed in the first weeks of the SARS-CoV-2 pandemic, many clinical labs are not equipped with the necessary testing equipment, supplies, and reagents to test for rare viruses. Thus, healthcare providers must first notify their jurisdictional health department when there is a patient in consideration for a highly contagious and infectious VHF. The health department, in coordination with the CDC, will facilitate testing, which is typically performed at a reference laboratory. 

The typical types of laboratory tests used to test for VHFs include:

• Molecular testing: Reverse transcriptase-polymerase chain reaction (RT-PCR) is one of the most sensitive and specific for RNA viruses found with VHFs.
• Serological testing: These are tests for specific antibodies (IgM/IgG), which are helpful for later stages of illness.
• Immunoassays: These tests can detect viral antigens from blood and tissues.
• Isolation for virus and electron microscopy: These tests can take longer while attempting to culture and amplify a virus in cells. Electron microscopy is required to view any virus due to their extremely small size and is costly.

Due to the wide range of virus pathology from VHFs, most treatment algorithms are based on two primary factors: 

1. Antiviral treatment 
2. Life support to prevent multiorgan failure

With the danger of severe disease or higher mortality from VHFs, it is essential that the public understands how important prevention is to avoid an infection. VHFs and other emerging and reemerging diseases often depend on understanding the host reservoir and virus transmission. In most cases, prevention will try to target avoiding the reservoir or vector. For example, one might need to consider insecticides, personal protective equipment and clothing while caring for someone who is infected, bed nets, or home and building exclusion measures for rodents, bats, and other pests.

Challenges necessitate collaboration

Climate change, natural disasters, fragile healthcare systems, financial and/or political instability, immigration, globalization, and socioeconomic imbalances continue to amplify the emergence and reemergence of viral hemorrhagic fevers and other types of infectious diseases. 

As these challenges are transnational in nature, their solutions must be trans-institutional. In other words, these problems cannot be addressed by any one government or institution alone. Collaborative local and international disease control and prevention plans will be required to not only limit the spread of diseases like VHFs but also provide funding and support for early detection and supportive therapies for improving patient outcomes.