Lymphoreticular and Hematopoetic Infections
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Lecture: Dr. Neal R. Chamberlain


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:

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

Table 1; Filoviruses


Human Disease


Marburg virus

Marburg hemorrhagic fever

Humans frequently acquire this viral infection following contact with infected nonhuman primates and bats. Bats are probably the reservoir. Democratic Republic of Congo, Kenya, Uganda, Angola, and South Africa

Ebola virus Zaire

Ebola hemorrhagic fever

Humans frequently acquire this viral infection following contact with infected fruit bats. Nosocomial spread. Democratic Republic of Congo and Gabon. The 2014 outbreak started in Guinea spread across land borders to Sierra Leone and Liberia, by air to Nigeria, by land traveler to Senegal, by air to Spain and the US.

Ebola virus Sudan

Ebola hemorrhagic fever

Unidentified reservoir. Nosocomial spread. Sudan and Uganda

Ebola virus Bundibugyo

Ebola hemorrhagic fever

Cases in Uganda

Ebola virus Cote d’Ivoire

Ebola hemorrhagic fever

Human case after necropsy of dead chimpanzee. Case in Ivory Coast

Ebola virus Reston

Asymptomatic infection in humans

Infections in pigs in Philippines and in infected nonhuman primates imported to U.S. and Italy


Table 2 Flaviviruses


Human Disease


Yellow fever virus

Yellow fever (affects liver)

Nonhuman primates to mosquito and accidentally to humans via mosquito bite. Tropical Africa and South America

Dengue viruses (types 1-4)

Dengue hemorrhagic fever, Dengue shock syndrome

Human to mosquito to human. Southeast Asia, Pacific rim tropics and subtropics, Caribbean islands, tropical and subtropical South America, Central America, Mexico, Florida, and Texas.

Omsk hemorrhagic fever virus

Omsk hemorrhagic fever

Undefined zoonotic cycle of ticks, muskrats, and voles. Humans get via tick bite. Western Siberia

Kyasanur Forest disease virus

Kyasanur Forest disease

Tick transmission to humans. India


Table 3; Arenaviruses


Human Disease


Junin virus

Argentine hemorrhagic fever

Human outbreaks during harvest. Mucosal contact with or inhalation of infected material from mice. Person to person transmission; Nosocomial. Argentina

Machupo virus

Bolivian hemorrhagic fever

Human outbreaks during dry season; increased agricultural activity. Mucosal contact with or inhalation of infected material from mice. Person-to-person transmission; familial or nosocomial. Bolivia

Guanarito virus

Venezuelan hemorrhagic fever

Mucosal contact with or inhalation of infected material from mice during times of increased agricultural activity. Venezuela

Sabia virus

Brazilian hemorrhagic fever

Reservoir is unknown. Brazil

Lassa virus

Lassa hemorrhagic fever

Mucosal contact with or inhalation of infected material from rats. West Africa; Liberia, Guinea, Sierra Leone, Nigeria, and the Central African Republic

Lujo virus

Unnamed disease

Reservoir is unknown. Chain of human cases in Zambia.

Chapare virus

Unnamed disease

Reservoir is unknown. Bolivia

Table 4; Bunyaviruses


Human Diseases


Crimean-Congo hemorrhagic fever virus

Crimean-Congo hemorrhagic fever

Humans infected by tick or aerosols/contact with slaughtered ruminants. Middle East, Southeastern Europe, Western China

Rift Valley fever virus

Rift Valley fever

Humans infected by mosquito bite and contact or aerosol exposure to sheep, goats, and cattle. Africa and Arabian Peninsula

Hantaan, Puumala, Seoul, and Dobrava viruses

Hemorrhagic fever with renal syndrome

Humans infected by aerosols of rodent urine. Eurasia

Sin Nombre, Andes, Choclo and other Hantaviruses

Hantavirus pulmonary syndrome

Humans infected by aerosols of rodent urine in North, Central, and South America



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).


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.


Hantavirus Pulmonary Syndrome

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

Ebola Hemorrhagic Fever



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.


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.

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

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.


Send comments and mail to Dr. Neal R. Chamberlain,
Revised 11/20/14
©2014 Neal R. Chamberlain, Ph.D., All rights reserved.

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