Hemorrhagic Fevers

Diverse group of illnesses that results from infection with one of several single-stranded RNA viruses (members of the families Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae)

Dengue, yellow fever, and hantaviruses are discussed separately

The likelihood of acquiring hemorrhagic fevers among travelers is low

Lassa fever (an Old World arenavirus)

• Associated with rodents

• Virus is shed in urine and droppings

• Transmission occurs to humans either by direct contact with urine and droppings or by ingestion or inhalation of aerosolized particles

Junin virus (cause of Argentine hemorrhagic fever) and other members of the New World Arenaviridae (Machupo virus, Sabia virus, Guanarito virus, Whitewater Arroyo virus) have similar modes of transmission

Lujo virus is another Old World arenavirus first described in a 2008 during nosocomial outbreak

Crimean Congo hemorrhagic fever

• Transmitted from ticks and livestock

• Human-to-human transmission can occur in the community or hospital setting by contact with infected body secretions

• The geographic distribution is widespread with cases reported from Africa, Asia, the Middle East, and Eastern Europe, with increased incidence recently in the East Mediterranean region

• Butchers and slaughterhouse workers in Southeastern Iran are at high risk for infection

• In 2002, Turkey reported the largest outbreak with nearly 10,000 cases recorded

Rift Valley fever

• Transmitted by exposure to infected animal products or bite of an infected mosquito or other infected insect)

• Risk factors include

  • Male sex

  • Working with abortive animal tissue

  • Slaughtering, skinning, or sheltering animals

  • Drinking raw milk

• Outbreaks reported in Africa, Madagascar, and Arabian Peninsula

Severe fever with thrombocytopenia syndrome (SFTS)

• A new bunyavirus associated with fever and thrombocytopenia

• Identified in 2010 in central and northeastern China

• Differential diagnosis includes anaplasmosis, hemorrhagic fever with renal syndrome, or leptospirosis

• A mortality of 12% was noted among the first 171 patients

• Transmission can occur via contact with blood and possibly via aerosol

Heartland virus

• Similar to the SFTS virus

• Virus appears to be amplified in deer and raccoons

• Transmission occurs via the Lone Star tick (Amblyomma americanum)

• Virus appears to be amplified in deer and raccoons

• As of July 2017, more than 30 cases are reported in states in the Midwestern and southern United States

Incubation period varies between species, ranging from 2 to 21 days

The early phase of a viral hemorrhagic fever is indistinguishable from other viral illnesses

Due to lack of specific symptoms on presentation, viral hemorrhagic fevers are an important cause to consider in fever of unknown origin in children in endemic areas

The late phase is more specific and is characterized by organ failure, altered mental status, and hemorrhage

Exanthems and mucosal lesions can occur

In advanced stages of Lassa fever and Lujo virus infection the following can develop:

• Significant edema

• Pleural effusion

• Fewer hemorrhagic manifestations compared to Ebola virus disease

• Hearing loss in various degrees is most common complication of Lassa fever infection

In Crimean-Congo hemorrhagic fever

• Patients have more prominent hemorrhagic manifestations

• Red eyes, flushed face, red throat, and petechiae that progress to severe uncontrollable bleeding are present

• Severe headache

Rift Valley fever can present with three distinct syndromes:

• Ocular disease

  • Retinitis is most common complication

  • Permanent vision loss develops in 1–10% of patients

• A meningoencephalitis form

  • Occurs in < 1% of cases

  • Headache, coma, or seizures 1–4 weeks after initial symptoms are presenting symptoms

  • Mortality is low, but morbidity is high with neurologic deficits that can be severe

• A hemorrhagic fever form

  • Patients present 2–4 days after illness

  • Show evidence of severe liver impairment and later hemorrhages

  • Hemorrhagic state occurs in < 1% of patients but the case-fatality ratio reaches about 50%

Thrombocytopenia

Leukopenia (although with Lassa fever leukocytosis is noted)

Anemia

Increased hematocrit

Elevated liver biochemical tests

Findings consistent with disseminated intravascular coagulation

The diagnosis may be made by antigen detection (by ELISA), PCR, or by demonstration of a fourfold rise in antibody titer

Crimean-Congo hemorrhagic fever

• Best diagnosed with an IgM serology

• However, IgG ELISA or immunofluorescence and quantitative reverse transcription PCR are nearly as effective

Newer technologies are emerging with increased sensitivities for detection of viruses causing viral hemorrhagic fever, such as the Luminex MagPix platform using microspheres

Supportive care is mainstay

Patients should be placed in private rooms; standard contact and droplet precautions must be used

• Barrier precautions to prevent contamination of skin or mucous membranes should also be adopted by the personnel caring for patient

• Airborne precautions should be considered in patients with significant pulmonary involvement or undergoing procedures that stimulate cough

There is no approved antiviral medication

However, ribavirin is effective in vitro and in vivo against certain viruses (Lassa virus, Crimean-Congo hemorrhagic fever, and Rift Valley fever pathogens)

Postexposure prophylaxis with ribavirin in the management Crimean-Congo hemorrhagic fever appears to be effective; however, few data exist to support its efficacy for Lassa fever and other arenaviruses

Suramin, an anti-trypanosomal agent, may be effective against the Rift Valley fever virus

Sorafenib, a tyrosine kinase inhibitor approved for treatment of renal cell and hepatocellular carcinoma, has antiviral activity against Rift Valley fever virus

A combination of monoclonal antibodies that cross-react with the glycoproteins of Lassa virus, are tested in non-human primates and shows promising results

A DNA vaccine against Crimean-Congo hemorrhagic is developed and shows high humoral immune responses with significant protection in mouse models

Early diagnosis and management can reduce mortality

The main method of preventing Rift Valley fever is vaccination of susceptible livestock before outbreaks occur

• Several vaccines have been developed for Rift Valley fever control in livestock

• However, only one, the Smithburn vaccine (a live attenuated virus), is produced commercially and used in East Africa

• An inactivated vaccine has been developed for humans but is neither licensed nor commercially available