Hemorrhagic Fevers Clinical Features

The clinical syndrome that these viruses may cause is generally referred to as viral hemorrhagic fever, or VHF. The organs most affected by VHF are the blood vessels. Microvascular damage leads to internal bleeding.

Not all infected patients develop VHF. There are both divergence and uncertainty about which host factors and viral strain characteristics might be responsible for the mechanisms of disease. For example, the disease mechanism has been identified for dengue hemorrhagic fever, which usually occurs among patients previously infected with a related form of dengue microorganisms. The presence of antibodies directed against the previous strain enhances uptake of dengue virus by circulating white blood cells. These cells express viral antigens on their surfaces. A gradual subsiding of the symptoms of an acute disease of the infected white cells by T-cell responses results in the release of pro-inflammatory immune system responses, which in turn result in vascular injury and permeability, complement activation, and reduce in blood clotting mechanisms.

Symptoms

Common symptoms are fever, muscle pain, and prostration. Physical examination may reveal only mild hypotension, flushing, and skin hemorrhages. Full-blown VHF typically evolves to shock and generalized mucous membrane hemorrhage, and often is accompanied by evidence of pulmonary bleeding, and neurological damage. Renal (kidney) function decrease is proportional to cardiovascular injury, except in HFRS, which features renal failure as an integral part of the disease process.

There are some distinctive clinical features that may suggest a specific viral agent. While liver failure is common among the VHFs, jaundice and other features of hepatitis are only seen in some cases Marburg, and Ebola HFs.

Because of their worldwide occurrence, additional consideration should be given to hantavirus infections. Classic HFRS has a severe course of infection that runs sequentially from fever through hemorrhage, shock, renal failure, and excessive urination. Nephropathia endemica features prominent fever, muscle and abdominal pain, and diminished urination, without shock or severe hemorrhagic symptoms.

North American cases of Hantavirus Pulmonary Syndrome (HPS) due to the Sin Nombre virus lack hemorrhagic symptoms and renal failure, but nevertheless carry a very high mortality due to rapidly progressive and severe pulmonary capillary leak, which presents as ARDS. These syndromes may overlap.

WARNING! VHF are highly contagious - Caution should be exercised in evaluating and treating the patient with suspected VHF. Death rates may be substantial - up to 90 % among Ebola victims.

Diagnosis

Large numbers of the population with VHF symptoms in the same geographic area over a short time period indicate a bioterrorism attack, particularly if this type of disease does not occur naturally in the local area.

VHF should be suspected in any patient with a severe high-fever illness and evidence of vascular problems (abdominally low blood pressure, easy bleeding, flushing of face and chest, swelling and a buildup of fluids in the issues) who has traveled to an area where the virus is known to occur, or where information suggests a biological warfare threat.

Symptoms and signs suggesting additional organ system involvement are common - headache, light sensitivity, sore throat, cough, nausea or vomiting, diarrhea, constipation, abdominal pain, sensitivity to touch, dizziness, confusion, tremor.

A disease with similar symptoms to VHF is malaria. It must be borne in mind that parasites present in the blood of patients partially immune to malaria does not prove that symptoms are due to malaria. VHF may be misdiagnosed as other illnesses such as typhoid fever, non-typhoidal gastrointestinal infections, jaundice and fever, tick borne infections, dysentery, relapsing fever, rapidly occurring hepatitis, and cerebrospinal meningitis.

Definitive diagnosis in an individual case rests on specific virologic diagnosis. Most patients have readily detectable viruses in the blood stream at (exception: hantaviral infections). Blood tests can detect viral antigens in acute patients. Specialized microbiologic containment is required for safe handling of these viruses. Appropriate precautions should be observed in collection, handling, shipping, and processing of diagnostic samples.

Medical Management

General principles of supportive care apply to hemodynamic, hematologic, pulmonary, and neurologic symptoms of VHF. Only intensive care will save the most severely ill patients. Health care providers employing vigorous fluid resuscitation of hypotensive patients must be mindful of the propensity of some VHFs (e.g., HFRS) for pulmonary capillary leak. Drugs to raise blood pressure (Pressor agents) are frequently required. The use of intravascular devices and invasive monitoring must be carefully considered in the context of potential benefit versus the risk of hemorrhage. Restlessness, confusion, muscle pain, and sensitivity to touch, should be managed by conservative measures and the judicious use of sedatives and analgesics.

Secondary infections may occur as with any patient undergoing intensive care utilizing invasive procedures and devices, such as intravenous lines and indwelling catheters.

The management of clinical bleeding should follow the same principles as for any patient with a systemic disease or condition affecting the blood's ability to coagulate assisted by coagulation studies. WARNING! Intramuscular injections, aspirin and other anticoagulant drugs should be avoided.

The antiviral drug ribavirin is available for therapy of HFRS. Trial tests have indicated that ribavirin reduces the incidence of disease in HFRS, and lowers both the rate of incidence and of Lassa fever. In the HFRS field trial, treatment was effective if begun within the first 4 days of fever, and continued for a 7-day course.

The use of intravenous ribavirin as a treatment for Lassa fever is sponsored by the Centers for Disease Control (CDC). Doses are slightly different, and, continued for a 10-day course, treatment is most effective if begun within 7 days of onset. Although ribavirin is known to cause birth defects in laboratory animals, the potential benefits must be weighed against the potential risks to pregnant women with grave illness due to one of these VHFs. Safety in infants and children has not been established. Ribavirin has had poor results when used to combat the filoviruses (Ebola and Marburg).

Preventative Measures

The only licensed vaccine available for any of the hemorrhagic fever viruses is yellow fever vaccine, which is mandatory for travelers to endemic areas of Africa and South America. Argentine hemorrhagic fever vaccine is a live, attenuated, investigational vaccine developed at U.S. Army Medical Research Institute for Infectious Disease (USAMRIID). The vaccine has proved effective both in an animal testing and in a field trial in South America and seems to protect against Bolivian hemorrhagic fever as well. Both inactivated and live-attenuated Rift Valley fever vaccines are currently under investigation. An investigational vaccinia-vectored hantaviruses vaccine is offered to laboratory workers at USAMRIID. There are currently no vaccines for the other VHF agents available for human use in the United States.

Persons exposed to contact with blood, body fluids, secretions, or excretions from a patient with suspected VHF should immediately wash the affected skin surfaces with soap and water. Mucous membranes should be irrigated with copious amounts of water or saline.

Close personal contacts or medical personnel exposed to blood or secretions from VHF patients (particularly Lassa fever, CCHF, and Filoviruses diseases) should be monitored for symptoms, fever and other signs during the established incubation period. Oral ribavirin may be administered to high risk contacts (those who have had direct exposure to body fluids) of Congo-Crimean HF patients. A similar post-exposure strategy has been suggested for high contacts of Lassa fever patients. Most patients will tolerate this dose well, but patients should be under surveillance for breakthrough disease (especially after drug cessation) or adverse drug effects (principally anemia).

Isolation and Containment

These viruses pose special challenges for the control of infection. With the exception of dengue (virus present, but no secondary infection hazard) and hantaviruses (infectious virus not present in blood or excreta at the time of clinical presentation), VHF patients generally have significant quantities of virus in blood and often other secretions. Special caution must be exercised in handling needles, and other potential sources of exposure. Strict adherence to Standard Precautions will prevent transmission of most VHFs. Marburg viruses can be spread through the air.

When one of these diseases is suspected, additional protective measures are indicated. The patient should be hospitalized in a private room. An adjoining anteroom for putting on and removing protective barriers, storage of supplies, and decontamination of laboratory specimen containers, should be used if available. A room with non-recirculated air under negative pressure is advised for patients with significant cough, hemorrhage, or diarrhea. It may be wise to place the patient in such a room initially, to avoid having to transport the patient in the event of clinical deterioration. All persons entering the room should wear gloves and gowns - Contact Isolation. In addition, face shields or surgical masks and eye protection are indicated for those coming within three feet of the patient.

Respiratory protection should be upgraded to airborne isolation, including the use of a fit-tested HEPA filtered respirator, a battery powered air purifying respirator, or a positive pressure supplied air respirator, if patients have prominent cough, vomiting, diarrhea, or hemorrhage.

WARNING! VHF are highly contagious - Caution should be exercised in evaluating and treating the patient with suspected VHF.

Over-reaction on the part of health care providers is inappropriate and detrimental to both patient and staff, but it is prudent to provide as rigorous isolation measures as feasible.

Laboratory specimens should be double-bagged, and the exterior of the outer bag decontaminated prior to transport to the laboratory. Excreta and other contaminated materials should be autoclaved, or decontaminated by the liberal application of hypochlorite or phenolic disinfectants. Clinical laboratory personnel are also at risk for exposure, and should employ a biosafety cabinet (if available) and barrier precautions when handling specimens.

No carrier state has been observed for any VHF, but excretion of virus in urine (e.g., Lassa fever) or semen (e.g., Argentine hemorrhagic fever) may occur during convalescence. Should the patient die, there should be minimal handling of the body, with sealing of the corpse in leak-proof material for prompt burial or cremation.