Lecture: Dr. Neal R. Chamberlain

Overview

Viral hemorrhagic fevers (VHFs) are a group of illnesses that are caused by four families of viruses. VHFs viruses cause a constellation of symptoms due to vascular instability and increased vascular permeability. Most of these viruses cause a multisystem syndrome. Characteristically, the vascular system is damaged and organ function is impaired. Infections with these viruses oftentimes are accompanied by hemorrhage. Rarely does this hemorrhage result in death. Some hemorrhagic fever viruses can cause relatively mild illnesses. Others can cause severe, life-threatening disease (e.g., Ebola, Marburg).

Etiologies: VHFs are caused by viruses of four families: arenaviruses, filoviruses, bunyaviruses, and flaviviruses. Each of these families shares a number of features:

• They are all enveloped RNA viruses
• Their survival is dependent on an animal or insect host
• These viruses are geographically restricted to the areas where their host lives
• Humans are not the natural reservoir for these viruses. These viruses are maintained in specific natural cycles that include nonhuman primates, bats, rodents, domestic ruminants, humans, mosquitoes and ticks. Some VHF viruses can be transmitted from human to human (e.g., ebola)
• Outbreaks of hemorrhagic fevers occur sporadically
• With a few exceptions, there is no cure or established drug treatment for VHFs.

You must know the diseases that are in bold in Tables 1, 2 and 4 below.

Manifestations

Hantavirus Pulmonary Syndrome - Sin Nombre virus causes cardiopulmonary signs and symptoms from 2 to 14 days following inhalation of virus containing aerosolized mouse or rat urine/feces (Table Endo-2).

Table Endo-2. Signs and Symptoms of Hantavirus Pulmonary Syndrome
Stage or Phase of Disease	Signs and Symptoms	Comments
Prodrome	Fever, myalgias, headache, chills, dizziness, nausea, and vomiting	Respiratory tract symptoms are minimal or absent and, thus, the physician may conclude that the patient has viral gastroenteritis. This phase lasts 3–5 days
Late or cardiopulmonary phase (lasts only 24–48 hours)	Shortness of breath, cough, fever, tachypnea, tachycardia, and rales; chest radiographs usually show a pattern of noncardiac pulmonary edema: The cardiac silhouette is not enlarged Perihilar haziness (“shaggy heart” sign) is characteristic Interstitial edema due to pulmonary capillary leak, which manifests as peribronchial cuffing or Kerley B lines	Cough and tachypnea generally do not develop until about day 7. Most patients with pulmonary edema require mechanical ventilation
Convalescence	Resolution of the cardiopulmonary stage is heralded by the onset of the significant diuresis	After diuresis, the patient improves quite rapidly

Dengue Fever (DF), Dengue Hemorrhagic Fever (DHF), Dengue Shock Syndrome (DSS) - Dengue virus is transmitted to humans by mosquitoes. Primary infections of dengue virus are usually asymptomatic (80%) or have only mild symptoms (fever). Most severe cases of Dengue disease occur following a second dengue virus infection. Anti-Dengue virus antibodies that do not neutralize the second infecting Dengue virus increase the entry of this virus into monocytes and increases viral replication. However, some patients develop dengue disease during their first Dengue virus infection. It is due to the greater virulence of the Dengue strain they have been infected with.

The incubation period ranges from 3-14 days. There are three phases of Dengue Fever: febrile, critical, and recovery. Most will have DF. Some may experience DHF. A very few will experience DSS. The febrile phase lasts from 2 to 7 days and is characterized by abrupt onset of fever (over 40oC), significant muscle and joint pain (this disease is sometimes called breakbone fever because of these pains), and a rash (50-80% of patients). The patient may also have nausea and vomiting, and conjunctival congestion. The rash starts as a macular rash followed by a maculopapular rash and generalized lymphadenopathy. The patient may also have some petechial lesions at this stage of the disease. In most patients these signs and symptoms resolve (these are DF patients) and they do not go into the critical phase however, convalescence may be prolonged. Patients may have neutropenia, lymphocytosis, thrombocytopenia, and elevated liver enzymes.

Some patients will experience the critical phase or DHF. The critical phase lasts one to two days. DHF patients experience the symptoms listed above but they also have mild to severe hemorrhages. Plasma leakage and increased hemorrhage occurs between 24 h before and 24 h after defervesecence. Hemorrhage may include petechial rash, conjunctival bleeding, epistaxis, melena, and hematemesis. Fluids may accumulate in the lungs and abdomen. Plasma loss results in hypovolemia and hemoconcentration. Usually the plasma leakage resolves over a 2 day period.

During this critical phase a severe form of shock may occur. This most severe form of dengue viral disease is called DSS. Patients have the manifestations of DHF but also develop severe shock defined as a pulse pressure less than 20 mm Hg.

The recovery phase occurs next with the rapid resorption of fluids back into the bloodstream. This phase usually lasts 2-3 days. Patients improve rapidly. They may experience severe itching and bradycardia. Another either maculopapular or vasculitic rash may appear which is following by skin peeling. The maculopapular rash has been described as white islands in a red sea. Fluid overload may occur in the brain causing seizures or reduced levels of consciousness. Patients may feel weak for weeks after recovering from DF, DHF, and DSS.

Ebola Hemorrhagic Fever (EHF) - Early clinical manifestations of EHF include fever, headache, myalgia, diarrhea, vomiting and abdominal pain. In the terminal state of the disease patient are obtunded and develop tachypnea, anuria, and shock. The body temperature will fall to normal or below normal levels. The incubation period is from 5-21 days with death occurring in 10.2 days after onset of symptoms. Hemorrhage is only seen in 41% of patients and may include petechial rash, conjunctival bleeding, epistaxis, melena, and hematemesis. Symptom onset is abrupt with terminal patients experiencing shock, fluid redistribution, DIC, and an absence of anti-Ebola virus antibody production.

Epidemiology

Hantavirus Pulmonary Syndrome

• Cases of hantavirus pulmonary syndrome have been reported in 31 states in the US.
• A total of 606 cases of the disease were reported in the US from 1993 to 2013. Around 20-30 cases of hantavirus pulmonary syndrome are reported each year
• Case fatality rate is around 36%
• Sin Nombre virus is present in animal urine or feces from mice/rats. The virus is transmitted to humans following aerosolization of mouse/rat urine or feces.

Dengue Fever (DF), Dengue Hemorrhagic Fever (DHF)

• The Dengue fever virus is transmitted to humans by mosquitoes.
• Cases of dengue fever have increased 30-fold since the 1960s.
• Endemic spread of this virus occurs in south Texas and the Florida Keys.
• This disease is also present from Southeast Asia to India; Pakistan; islands in the Indian and Pacific oceans; East and West Africa; the horn of Africa; the Arabian peninsula; the Caribbean islands to Argentina.
• DHF occurs 10 times more frequently in infections with a second serotype of the dengue virus than during a primary dengue virus infection.
• Infants of mothers who have previously had dengue virus infection are at high risk of developing DHF when infected with dengue virus.
• Most DHF cases are imported to the US. However, since 2001, there have been three autochthonous (endemic) DHF outbreaks in the US: Hawaii (2001), Brownsville, Texas (2005), and southern Florida (2009-2011).
• In 2012 there were 544 cases of Dengue fever and 4 cases of DHF in the US.

Ebola Hemorrhagic Fever

• The virus can be transmitted to humans from mammals acquired for food in Africa. African bats and nonhuman primates have been shown to be the reservoir for these viruses.
• Ebola viruses can also be transmitted person to person following contact with bodily fluids from an infected patient or cadaver. Bodily fluids that contain the virus are saliva, tears, blood, vomit, feces, urine, sweat, semen, and breast milk.
• Most cases of EHF have occurred after the person has taken care of an EHF patient or cadaver.
• Patients infected with Ebola are infectious when symptoms begin. However, it requires direct contact with their bodily fluid through a cut or abrasion in the skin or mucous membranes (conjunctiva, ingestion, sexual interactions).
• Ebola virus is present for up to three months in the semen of persons who survive the infection.
• The virus can remain viable for several hours on inanimate objects and for much longer if the bodily fluid it is in remains moist.
• There have been 18 different outbreaks of EHF.
• The 2014 outbreak has been caused by Ebola virus Zaire with a case fatality rate of about 70% and is the largest in recorded history.
• As of October 22, 2014 there have been 9811 confirmed cases of EHF and of those 4546 have died. The countries with the highest number of cases are in West Africa (Liberia, Sierra Leone, and Guinea). The outbreak has yet to be contained in these countries.
• Patient cases in the US were imported EHF cases. In one case the virus spread from that patient to two healthcare workers.
• Thus far no familial contacts or other close contacts have acquired EHF from an infected person in the US.
• The Ebola virus Zaire is the most lethal of the strains of this virus (78% mortality) followed by Ebola virus Sudan (53% mortality), Ebola virus Bundibugyo (25% mortality) and Cote d’Ivoire (only one human case and patient survived; 0%).

Pathogenesis

Sin Nombre virus

Portals of entry for the Sin Nombre virus include the respiratory and digestive tracts. Viral multiplication occurs in the endothelial cells. Viremia and fever occur 2–14 days after infection.

Viral antigens can be seen within the endothelium of capillaries throughout various tissues of the patient with hantavirus pulmonary syndrome. High concentrations of hantaviral antigens are seen in the pulmonary microvasculature and in follicular dendritic cells within the lymphoid follicles of the spleen and lymph nodes. Typical hantaviral inclusions are seen frequently in pulmonary endothelial cells. Antibodies produced to the hantaviral antigens damage the endothelial cells and increase capillary permeability. The increased capillary permeability in the lungs results in leakage of protein-rich plasma from the capillaries into the lungs and the pleura. This leakage causes the cardiopulmonary signs and symptoms detailed in Table Endo-2.

Dengue fever virus

Most cases of DF, DHF and DSS follow a second dengue virus infection. Antibodies to the first infection do not neutralize the virus but rather help by increasing entry of the virus into monocytes by Fc receptor-medicated endocytosis of the virus and thus allowing increased virus replication. Infants born to mothers who have been infected by dengue virus before their pregnancy are more likely to experience DF, DHF, or DSS because they have obtained these non-neutralizing antibodies to dengue virus from the mother though the placenta. These non-neutralizing antibodies are also believed to be important in increasing vascular permeability. Some patients will experience disease symptoms after a primary dengue virus infection and this is likely due to the patient acquiring a more virulent strain of the dengue virus.

Ebola virus

The virus does several things to suppress the immune response and to increase vascular permeability. The virus suppresses the production of interferon. The virus infects dendritic cells, monocytes, macrophages and Kupffer cell. Lymphocytes are not infected however; bystander lymphocytic apoptosis results in significant depletion of NK cells and CD4 and CD8 T lymphocytes. The virus contains a glycoprotein and a viral protein (VP40) that activates endothelial cells to produce intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin. As a result, endothelial permeability is increased. Increases in TNF-alpha are seen and it increases endothelial permeability. Surface viral glycoprotein causes rounding of cells, increased membrane permeability and detachment of cells. The virus also causes increases in proinflammatory cytokines (cytokine storm) which can result in vascular permeability, hemorrhage, and septic shock

.

Ebola viruses cause extensive and severe hemorrhagic lesions. Hemorrhagic lesions include petechiae and ecchymoses of the skin, mucous membranes and organs. Large effusions may occur in body cavities. Multifocal necrosis can occur in the liver, spleen, kidneys, testes, and ovaries. However, there is minimal inflammatory response to the necrosis. The liver lesions include hepatocellular necrosis and apoptosis, microvesicular steatosis and Kupffer cell hyperplasia. Eosinophilic oval or filamentous cytoplasmic inclusions can be seen and are aggregates of Ebola virus nucleoproteins. Lungs contain hemorrhages and diffuse alveolar damage. Viral infection at the time of death involves macrophages and endothelial cells.

Fatal EHF patients don’t mount an effective immune response. Survivors produce IgG against the viral nucleoprotein early in the course of the illness. After anti-viral IgG has been made cytotoxic T cells are activated. In contrast, terminal patients never produce IgG anti-viral antibodies. Only 33% of fatal cases mount a weak IgM response.

Diagnosis

Human Pulmonary Syndrome- A clinical case definition is detailed in Table Endo-3. The white blood cell count of patients with hantavirus pulmonary syndrome is usually elevated, with a marked left shift (bandemia). White blood cell precursors (band cells) may be as high as 50%, and atypical lymphocytes are frequently present.

Atypical lymphocytes usually are observed at the onset of pulmonary edema. The platelet count in about 80% of individuals with hantavirus pulmonary syndrome is below 150,000. A dramatic decrease in the platelet count indicates a transition from the prodrome to the pulmonary edema phase (cardiopulmonary phase) of the illness. Early in the disease, chest radiographs show interstitial pulmonary edema, which progresses to alveolar edema with severe bilateral involvement. Pleural effusions are common and can be large enough to be observed in chest radiographs.

Table Endo-3. Clinical Definition of Hantavirus Pulmonary Syndrome

Hantavirus pulmonary syndrome is an illness characterized by one or more of the following clinical features:

A febrile illness (> 38.3°C) with bilateral diffuse interstitial edema that may radiographically resemble adult respiratory distress syndrome, with respiratory compromise requiring supplemental oxygen, developing within 72 hours of hospitalization, and occurring in a previously healthy person.

An unexplained respiratory illness resulting in death, with an autopsy examination demonstrating noncardiogenic pulmonary edema without an identifiable cause.

Laboratory criteria for diagnosis include detection of hantavirus-specific IgM or rising titers of hantavirus-specific IgG, or detection of hantavirus-specific RNA sequence by PCR in clinical specimens, or detection of hantavirus antigen by immunohistochemistry.

IgM, immunoglobulin M; IgG, immunoglobulin G; RNA, ribonucleic acid; PCR, polymerase chain reaction.

Dengue fever, Dengue Hemorrhagic fever, Dengue shock syndrome- The 2009 clinical diagnosis involves:

• Dengue fever without warning signs; Fever and two of the following: nausea and vomiting, rash, aches and pains, leukopenia, and positive tourniquet test (capillary fragility test: place blood pressure cuff on patient. Inflate cuff to the pressure that is half way between the systolic and diastolic pressure. Leave the cuff inflated for 5 min. If the arm below the cuff has 10-25 petechiae per square inch the test is positive).
• Dengue fever with warning signs: Dengue as defined above with any of the following: abdominal pain or tenderness, persistent vomiting, clinical fluid accumulation (ascites, pleural effusion), mucosal bleeding, lethargy and restlessness, liver enlargement (>2 cm), or increase in hematocrit with concurrent rapid decrease in platelet count.
• Severe dengue- Dengue with at least one of the following: severe plasma leakage leading to shock (DSS) or fluid accumulation with respiratory distress, severe bleeding as determined by a clinician, severe organ involvement (AST or ALT > 1000, impaired consciousness, or failure of heart and other organs.

Several tests can be used to give a definitive diagnosis of a person with dengue viral infection. In acute phases of the disease (0-5 days) an RT-PCR of the patients’ serum can be performed. Serum obtained from 6 days on can be tested for IgM to dengue virus using an IgM ELISA (also called a MAC-ELISA; IgM antibody capture ELISA). A positive IgM ELISA indicates a recent infection. A positive IgG ELISA demonstrates the person has had a past dengue viral infection.

Ebola Hemorrhagic Fever- Diagnosis of a person with Ebola virus infection can be difficult early in the infectious process. Early symptoms like fever are nonspecific. However, if a person has the early symptoms of Ebola infection (fever, severe headache, myalgia, weakness, diarrhea, vomiting, abdominal pain, unexplained hemorrhage (bleeding or bruising)) AND has contact with blood or body fluids of a person sick with Ebola, contact with objects contaminated with the blood or body fluids of a person sick with Ebola, or contact with infected animals they should be isolated and public health officials notified. Blood samples from the patient should be collected and sent for viral culture, serology, or RT-PCR. 

Therapy and Prevention

Treatment of hantavirus pulmonary syndrome involves supportive care. Improved sanitation standards and control of the rodent populations is important in preventing this disease.

Treatment of Dengue virus infection involves good supportive care. Prevention involves elimination of the places mosquitoes can live and multiply. Use of mosquito repellent, mosquito netting to avoid mosquito bites, and going inside during times when mosquitoes feed.

Treatment of Ebola virus infections involves good supportive care. Most Ebola infections can be prevented with proper use of PPE (personal protective equipment) when treating and caring for patients infected with Ebola. Avoid handling animals suspected of being infected with Ebola.

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