Dermatologic Manifestations of Viral Hemorrhagic Fevers 

Updated: Jan 06, 2020
Author: Amira M Elbendary, MBBCh, MSc; Chief Editor: William D James, MD 

Overview

Background

Viral hemorrhagic fevers (VHFs) are a group of lethal zoonotic diseases unified by common underlying pathophysiology. These febrile diseases result from infection by enveloped RNA viruses belonging to six taxonomic families: Arenaviridae, Hantaviridae, Nairoviridae, Phenuiviridae, Filoviridae, and Flaviviridae.[1, 2] Bunyavirales are single-stranded RNA viruses in the class Ellioviricetes. As a group, they are still commonly referred to as the Bunyaviridae family of viruses, or simply bunyaviruses.

These viruses share the feature of having a lipid envelope. Survival and perpetuation of the viruses is dependent on an animal host known as a natural reservoir; humans are not the natural reservoir. With the exception of a vaccine for yellow fever and ribavirin, which is used as a drug treatment for some arenaviral infections, no cures or drug treatments for viral hemorrhagic fever exist. Only supportive treatment is possible.

Not all viruses in these families cause viral hemorrhagic fever.

Viral hemorrhagic fevers share certain clinical manifestations, regardless of the virus that causes the disease. However, different viruses can cause a range of various clinical problems in addition to viral hemorrhagic fever. Common clinical manifestations of viral hemorrhagic fever are increased capillary permeability, leukopenia, and thrombocytopenia. Viral hemorrhagic fever is manifested by sudden onset, fever, headache, generalized myalgia, backache, petechiae, conjunctivitis, and severe prostration. Various hemorrhagic symptoms follow, ultimately resulting in focal inflammatory reaction and necrosis with leukocytosis.

Although the viruses are distributed all over the world, they have a higher occurrence in tropical areas, such as South America, Africa, and the Pacific Islands. They have a higher likelihood of importation because of increased travel and scientific research involving the use of imported tropical animals, which often serve as intermediate hosts. The viruses are transmitted by two main categories of natural reservoirs: arthropods and rodents. Arenaviruses and Hantavirus (a Bunyavirus) are primarily rodent-borne, whereas flaviviruses, as well as nairoviruses and phleboviruses (both bunyaviruses), are arthropod-borne.

Transmission occurs mainly by means of contact with the following: natural reservoirs (eg, mosquito bites, rodent bites); reservoir excretions, secretions, or blood; aerosolized particles contaminated by reservoir secretions, excretions, or blood; or intermediate hosts (eg, monkeys, livestock) or their excretions, secretions, or blood. Person-to-person transmission and nosocomial transmission also occur. Nosocomial outbreaks are not uncommon in developing countries, where safe infectious disease practices have not been implemented and supplies are in shortage.

See the Medscape articles CBRNE - Viral Hemorrhagic Fevers and Pediatric Viral Hemorrhagic Fevers for more information.

Also see Ebola: Care, Recommendations, and Protecting Practitioners, a Critical Images slideshow, to review treatment, recommendations, and safeguards for healthcare personnel.

Pathophysiology

Despite the diverse taxonomy of the six virus families involved in viral hemorrhagic fevers (VHFs), they share some common characteristics. They are all RNA viruses that have a lipid envelope, rendering them relatively susceptible to detergents and a low-pH environment, as well as household bleach. On the other hand, they are quite stable at neutral pH; this factor helps these viruses to stay stable in blood for a long period, which allows them to be isolated from a patient’s blood after weeks of storage at refrigerator temperature. In addition, these viruses are stable as fine-particle aerosols, which renders them highly infectious.

Viral-targeted cells in the body include monocytes, dendritic cells, macrophages, and vascular endothelial cells, which then disseminate through lymphatics to other organs.[3]

Recognition of viral infection by the innate immune system occurs through the cytoplasmic recognition of cellular receptors of viral nucleic acids. Following this recognition and activation of cellular receptors, type I interferon is activated, resulting in initiation of interferon signaling.[4]

The main common underlying pathophysiologic feature of viral hemorrhagic fevers is that the vascular bed is attacked, with resultant microvascular damage and changes in vascular permeability. However, specific pathophysiologic findings can vary depending on the virus family and the species involved.

In general, an initial febrile illness is followed by hemorrhaging into the skin and the mucous membranes, hemorrhagic rashes, and hemorrhaging from body orifices, especially gastrointestinal and genitourinary bleeding. Lassa fever, although fatal, is not characterized by significant bleeding. Other clinical findings include thrombocytopenia and leukocytopenia.

Ebola (Filoviridae) viral protein VP35 was found to inhibit interferon regulatory factor 3, which is necessary for the induction of an antiviral immune response and interferon. Ebola virus was also found to alter the immune signaling pathways through its ability to interfere with dendritic cells that link adaptive and innate immune responses,[5] in addition to the release of extensive cytokines, which cause endothelial damage, coagulopathy, and, finally, multiorgan failure.[3]

Similarities regarding the pattern of cytokine production between Ebola virus disease and Crimean-Congo hemorrhagic fever (CCHF) were noted. Positive correlation was noted between viral load and interleukin (IL)‒10 and monocyte chemoattractant protein (MCP)‒1, and negatively correlated with the IL-12/IL-10 ratio.[6]

In severe dengue fever (Flavivirus), marked capillary permeability and coagulopathy are noted as a result of the immune response.[7] HLA-B44 has been found to be protective against dengue hemorrhagic fever.[8] In contrast, diabetic patients were found to be more susceptible to developing severe dengue hemorrhagic fever and dengue shock syndrome.[9] Circulating immune complexes, serum cryoglobulins, and IL-8 were found to be higher by 9-fold and 2.2-fold in dengue hemorrhagic fever and dengue fever, respectively, compared with healthy individuals. Peak levels of circulating immune complexes, IL-8, and cryoglobulins were found to be associated with thrombocytopenia.[10] Serum IgM levels specific for dengue fever virus were found to be significantly higher in dengue fever when compared with dengue hemorrhagic fever cases, while IgG, IgA, and IgE levels were found to be higher in dengue hemorrhagic fever cases. Higher titer of IgG was found to be associated with lower platelet counts.[11]

In Rift Valley fever (Bunyavirus), IL-8, IL-10, and CXCL9 were detected at significantly higher levels when comparing fatal cases to uninfected individuals and infected survivors.[12]

In Hantavirus (Bunyaviridae) infection, endothelial dysfunction is noted, wherein high levels of endothelial glycocalyx degradation is found to correlate with early disease activity, which eventually results in tissue edema, hypotension, and shock.[13]

Etiology

Causes of viral hemorrhagic fevers (VHFs) are the specific RNA viruses mentioned above. Infection by different viruses results in hemorrhagic fever with different complications, symptoms, and severity, as previously discussed. See the list below[2] :

  • Flaviviruses: Yellow fever, dengue, Kyasanur Forest disease, Alkhumra viruses, Omsk hemorrhagic fever
  • Filoviruses: Ebola and Marburg virus
  • Arenaviruses: Lassa and other Old World arenaviruses and New World arenaviruses
  • Hantaviruses, nairoviruses, and phenuiviruses, formerly included in Bunyaviridae family: Rift Valley fever, Congo-Crimean hemorrhagic fever (CCHF), Huaiyangshan virus (alternatively known as severe fever with thrombocytopenia syndrome virus) and hantaviruses

Viruses are usually transmitted by mosquitoes, ticks, or rodents. Some species of bats may also prove to be virus carriers.[14]

In a study that included 200 ticks collected from south of Iran analyzed by reverse-transcription polymerase chain reaction for the presence of CCHF virus genome, viral genome was detected in 4.5% of studied ticks, which indicates that ticks in that area are widely infected and necessitates regular control and monitoring of livestock in order to reduce the dispersion of ticks.[15]

An epidemiologic survey of ticks, rodents, and infected individuals with CCHF in Northern region of Xiniang, China isolated a two new CCHF virus strains, which were different from the previously reported strain in China.[16]

Person-to-person transmission may occur through mucous membranes or through contact with body fluids from the infected patient. Transmission can even occur after the death of the infected person, as their skin is heavily infected.[17]

Contaminated syringes and needles played a role in the recent outbreak of Ebola hemorrhagic fever.

Persistence of Ebola virus in semen was reported in the Ebola virus outbreak of 2014-2015 in three men. The semen was positive for Ebola virus RNA on days 199, 140, and 284 after symptom onset.[18, 19, 20] Evidence of persisting Ebola virus in feces, sweat, saliva, and urine were also reported up to 26 days after initial symptoms.[21, 22]

The strong immunologic response to the viruses may be central to the pathophysiology of plasma leakage associated with these diseases.[23]

Epidemiology

Frequency

United States

Most of the natural reservoirs of these viruses live in tropical areas. Hence, the virus does not typically infect persons in the United States. Random cases of infection occur as a result of the importation of viruses by travelers or the importation of scientific research animal subjects.

Several cases of infection resulting in Hantavirus pulmonary syndrome (HPS), however, have been reported across the United States.[24]

During the 2014 Ebola outbreak, several US healthcare personnel have been infected while in Africa and have been transported to the United States for treatment. A traveller from Liberia also became ill and sought treatment during a visit to Texas, and he later died of the infection. One of his treating nurses then presented with a low-grade fever and tested positive for Ebola virus infection. Further, individuals in several US states who recently travelled to West Africa have developed fever and other symptoms, prompting evaluation for Ebola virus infection at US hospitals.[25]

International

The geographic distribution is dependent on the reservoir host and ecology of each disease.[26]

Table 1. Geographic Distribution of Viral Hemorrhagic Fevers (Open Table in a new window)

Virus Family and Genus

Type of Hemorrhagic Fever

Reservoir Host

Geographic Distribution

Arenaviridae

Guanarito

Junin

Machupo

Lassa

Sabia

 

Venezuelan

Argentinian

Bolivian

Lassa (West Africa)

Brazilian or Sao Paulo

 

Rodents

 

Venezuela

Argentina

Bolivia

West Africa

Brazil

Bunyaviridae

Nairovirus

Phlebovirus

Hantaan virus

 

Crimean-Congo

Rift Valley

Korean

HPS

 

Ticks

Mosquito and contact with infected blood in slaughter houses

Contact with infected rodents and their excreta

Crimea, Central Africa, South Africa, Iraq, Pakistan, Turkey, Iran, Afghanistan, Russia

Africa, Egypt

Korea, Eastern Europe, Russia, Scandinavia

North, Central, and South America

Flaviviridae

Flavivirus

Flavivirus

Flavivirus

Flavivirus

 

Yellow

Dengue

Chikungunya

Omsk

 

Mosquito

Mosquito

Mosquito

Tick

 

Tropical Africa, South America

Entire tropical zone

India, Southeast Asia

Siberia

Filoviridae

Marburg

Ebola

 

Marburg

Ebola

 

Infected monkeys were implicated but no known definite reservoir

 

Africa

West Africa

In West Africa, the 2014-2015 Ebola epidemic was first reported in Guinea in March 2014. It was the largest Ebola virus epidemic documented, with a total of 28,220 reported cases and 11,291 deaths (WHO September 16, 2015). In July 2014, a local outbreak was declared in Sierra Leone, and the affected district was the first to be declared Ebola-free by local authorities on January 10, 2015.[27, 28, 29]

Guinea demonstrated consistent low transmissibility and, accordingly, the smallest number of reported cases. Liberia showed the highest level of transmission before October 2014 and remained low since that time. Sierra Leone showed detectable waves of the disease up to mid March 2015, resulting in the largest number of cases reported.[30]

Four confirmed CCHF outbreaks within the past 2 years have been reported in Uganda after more than 50 years of no reported cases of human CCHF.[31]

A Chikungunya outbreak in southeastern Senegal in 2010 included 45 confirmed cases. In addition, 83% of monkeys that were randomly sampled were found to be seropositive, and Chikungunya virus was detected in 42 pools of mosquitos, mainly Aedes furcifer.[32]

A study conducted on 3,322 confirmed dengue cases in Kaohsiung city in Taiwan found that the outbreak of dengue fever was initiated by imported cases from other endemic countries. It took a median of 5 days after the appearance of symptoms for patients to report to a medical facility.[33] A positive correlation was found between confirmed cases and weather parameters (temperature, relative humidity, and rainfall) at a time lag of 1 month and 2 months. This may help in developing an early warning surveillance system.

Poverty was associated with high rates of transmission in a study done in Montserrado County, Liberia.[34]

In an attempt to understand the heterogenicity in dengue disease transmission, a study analyzing 18 years of monthly dengue surveillance was conducted in a total of 273 provinces in eight countries in Southeast Asia. A strong pattern of synchronous transmission across the entire region was detected. This synchrony in dengue incidence was noted to coincide with elevated temperatures in 1997-1998 and the strongest El Niño episode of the century. A low incidence was noted during the period of 2001-2002. Localized travelling waves of epidemic cycles were detected in Laos, Thailand, and the Philippines.[35]

 

Table 2. Viral Hemorrhagic Fever Outbreaks from January 2018 to April 2019 According to WHO Emergencies Preparedness, Response Disease Outbreak News. [36] (Open Table in a new window)

Year

Disease

Country

2019

2019

2019

2019

2019

2019

2019

2019

2018

2018

2018

2018

2018

2018

2018

2018

2018

2018

Ebola virus disease

Rift Valley fever

Yellow fever

Lassa fever

Dengue fever

HPS

Yellow fever

HPS

Yellow fever

Yellow fever

Yellow fever

Rift Valley fever

Dengue

Ebola virus disease

Lassa fever

Yellow fever

Rift Valley fever

Lassa Fever

Democratic Republic of the Congo

Mayotte (France)

Brazil

Nigeria

Jamaica

Argentine Republic

Nigeria

Republic of Panama

Kingdom of the Netherlands

Democratic Republic of the Congo

French Guyana (France)

Kenya

Reunion, France

Democratic Republic of the Congo

Nigeria

Brazil

Gambia

Liberia

Race

No race is known to be more vulnerable than another to RNA viral infection. Geography is a determining factor.

Sex

Neither sex is known to be more or less vulnerable to RNA viral infection.

Age

Age plays a role in increasing the vulnerability to infection in only 2 circumstances. First, young and elderly persons are more susceptible because of their weaker immune systems. Second, adults are more susceptible if they work in settings in which the exposure risk is increased (eg, clinics or hospitals, agrarian settings).

A shift in dengue fever towards older adults has been noted in the past decade.[37]

Prognosis

Survival may be possible with appropriate support care, depending on the virus.

Table 3. Viral Hemorrhagic Fever Mortality Rates (Open Table in a new window)

Virus Family and Type of VHF

Mortality Rate, %

Arenaviridae

Argentinian and Bolivian

Lassa (West African)

Venezuelan and Sao Paulo

 

10-30

30-40

33

Bunyaviridae

Korean and Seoul

Rift Valley

Congo-Crimean

HPS

 

5-15

1

10-50

15-50

Flaviviridae

Yellow

Dengue

 

< 1

5

Filoviridae

Marburg

Ebola

 

23-25

25-100

The estimated case fatality rate for the recent Ebola outbreak was 76.4%. The proportion of total deaths in Guinea, Sierra Leone, and Liberia was 21.6%, 35.8%, and 42.5%, respectively. The highest risk of dying was among healthcare workers in areas with intense transmission and countries with insufficient bed capacities. Other factors that enhanced the spread and magnitude of this outbreak were the insufficient enforcement of public health regulations and deplorable healthcare delivery infrastructure in war-ravaged regions.[38]  In the recent Ebola virus disease outbreak in Sierra Leone, it was found that chest pain, symptoms of confusion, coma and viral load greater than 106 copies/mL were significantly associated with a poor prognosis. Viral load was the most important factor that affected the survival of patients from the disease.[39]

A total of 278 human cases were confirmed with Rift Valley fever in the recent outbreak in South Africa in 2010-2011, with 25 deaths.

Children can develop dengue hemorrhagic shock syndrome (DHSS), a complication with a mortality rate of 4-12%.

Patient Education

Educate travelers and geographically vulnerable groups, especially health care workers, agrarian workers, and rural populations, about the following risks:

  • Transmission via rodent or arthropod bites

  • Potential contamination of food and/or water reservoirs with excretions or secretions

  • Contact with animals that may be intermediate hosts

Educate health care workers and others about the detrimental effects of nosocomial transmission and about how such spread can be prevented by implementing infectious disease safety and contact precautions, such as the following:

  • Equipment sterilization

  • Isolation of individuals who are infected

  • Barrier nursing

Educate health care workers and others about decontamination procedures, such as the use of hypochlorite or phenolic disinfectants.

 

Presentation

History

The nature of each disease depends on the viral strain characteristics and virulence, dose, routes of exposure, and host factors. For example, dengue fever exhibits a hemorrhagic nature only in patients previously exposed to a heterologous dengue serotype.

Not all individuals who are infected have viral hemorrhagic fever. The target organ is the vascular bed. As a result, the dominant clinical manifestations are due to microvascular damage and changes in vascular permeability.

Viral hemorrhagic fever should be suspected in patients who live in or who have returned from locations of viral occurrence if they have severe fever and evidence of vascular involvement (eg, subnormal blood pressure, postural hypotension, petechiae, easy bleeding, flushing, nondependent edema).

The severity of symptoms varies. Common symptoms include the following:

  • Myalgia

  • Fever

  • Prostration

  • Vomiting

  • Headache

  • Petechial hemorrhages

  • Hypotension

  • Flushing of the head and the chest

  • Edema

  • Malaise

  • Diarrhea

Severe viral hemorrhagic fever evolves to shock and generalized mucous membrane hemorrhage. Viral hemorrhagic fever is often accompanied by neurologic, hematopoietic, or pulmonary involvement. Hepatic damage is also common among viral hemorrhagic fevers, but hepatic failure, as indicated by jaundice and other evidence, is seen in some cases of Rift Valley fever (RVF), Congo-Crimean hemorrhagic fever (CCHF), Marburg fever, Ebola fever, and yellow fever. Neurologic symptoms and thrombocytopenia are common in Argentinian and Bolivian hemorrhagic fevers. Kyasanur Forest disease and Omsk fever are known for their pulmonary involvement and a biphasic illness with central nervous system (CNS) manifestations. Hantavirus pulmonary syndrome (HPS) is known for its pulmonary involvement leading to noncardiogenic pulmonary edema.[24]

Hemorrhagic fevers with renal syndrome may be associated with concomitant central diabetes insipidus. This should be suspected with persistent diuretic phase but normal pituitary MRI.[40]

Physical Examination

In general the illness demonstrates three phases, generalization phase (week 1), early organ phase (week 2), and late organ phase (week 3).

The generalization phase includes fever, chills, sore throat, and gastrointestinal symptoms.

In the early organ phase, endothelial damage starts to occur and is reflected clinically in the form of petechiae, ecchymoses, mucosal hemorrhage, bloody diarrhea, hematemesis, conjunctival congestion, and dyspnea due to pulmonary edema.

The late organ phase shows progression to disseminated intravascular coagulation, shock, and liver and renal failure, which eventually may progress to death.

Arenaviruses[41]

See the image below.

New World Arenavirus - Machupo. Oral mucosal hyper New World Arenavirus - Machupo. Oral mucosal hyperemia and hemorrhage in a patient with Bolivian hemorrhagic fever.

Lassa, Argentinian, and Bolivian viral hemorrhagic fever

The first signs of Lassa, Argentinian, and Bolivian viral hemorrhagic fever are nonspecific and include fever, headache, and sore throat. The second stage is characterized by an exacerbation of symptoms and rashes on the face or the neck. Gastrointestinal and urogenital tract bleeding and shock may follow during the second week. Neurologic sequelae are a main feature, especially in Lassa hemorrhagic fever.

Argentinian viral hemorrhagic fever

Early Argentinian viral hemorrhagic fever findings include high fever, malaise, headache, retro-orbital pain, anorexia, and nausea. Signs are erythematous rash of the face, the neck, and the thorax, and hemorrhages into the skin and the mucous membranes. CNS involvement appears around day 7 in fatal cases. It is an important indicator of severity and is a better indicator than hemorrhage.

Bolivian viral hemorrhagic fever

Bolivian hemorrhagic fever has an insidious onset, leading to high temperature, severe myalgia, headache, vomiting, retrobulbar pain, conjunctival hyperemia, leukopenia, and mild thrombocytopenia. Petechiae of the skin and the oral mucous membranes usually appear around day 4. Epistaxis, gingival bleeding, hematemesis, melena, and metrorrhagia may follow. Hypotension and/or neurologic abnormalities, including tremors, delirium, and seizures, develop between days 6 and 10. Circulatory collapse eventually results in death.

Lassa fever

Lassa fever can vary from a long-lasting acute fever to a fatal disease. Its clinical manifestations include headache, fever, weakness, myalgia, ulcerative pharyngitis, dysphagia, anorexia, nausea, vomiting, cough, and constipation. The aforementioned findings can be followed by diarrhea, melena, dysuria, cutaneous petechiae and ecchymoses, erythema of the face and the thorax, facial and cervical edema, rales, rhonchi, stridor, wheezing, hypotension, hepatic tenderness, pleural effusions, cloudy sensorium, and seizures. Deafness is a frequent sequela of severe cases

Order Bunyavirales: Hantaviridae, Nairoviridae, and Phenuiviridae

See the image below.

Bunyavirus infection. Ecchymoses encompassing left Bunyavirus infection. Ecchymoses encompassing left upper extremity one week after onset of CCHF. Ecchymoses often are accompanied by hemorrhage in other locations: epistaxis, puncture sites, hematemesis, melena, and hematuria. Image provided by Robert Swaneopoel, PhD, DTVM, MRCVS, National Institute of Virology, Sandringham, South Africa.

Rift Valley fever[42]

RVF is an influenzalike disease. Its onset involves chills, fever, headache, retro-orbital pain, myalgia, anorexia, vomiting, and diarrhea. Physical signs include fever, facial erythema, and conjunctival suffusion. Severe RVF can present with the clinical syndrome of fever, large joint arthralgia, and gastrointestinal complaints and is later followed by jaundice, right upper quadrant pain, and delirium.[43] A small percentage of patients present with retinal lesions, which may result in permanent blindness, hemorrhagic diathesis, and encephalitis. RVF may progress to a hemorrhagic fever stage. Clinical manifestations of this stage may include hematemesis, melena, petechial and ecchymotic cutaneous lesions, gingival bleeding, hematuria, epistaxis, and jaundice.

Congo-Crimean hemorrhagic fever

Early symptoms of CCHF include those previously mentioned for RVF. Patients may present with erythema of the pharynx, the conjunctivae, the face, and the neck; a petechial rash on the trunk and the limbs; and hemorrhages of the uvula and the soft palate.

CCHF patients commonly have severe headaches that may resemble migraine. The severity depends on vascular endothelial damage, abnormal release of inflammatory cytokines, and vasodilatation.[44]

CCHF is a severe disease. On days 3-7, patients may have hematemesis; melena; cutaneous purpura; epistaxis; hematuria; hemoptysis; and bleeding from gingival, oral, uterine, and venipuncture sites. Profound disseminated intravascular coagulation is frequently noted

Korean hemorrhagic fever[45]

This infection is a subgroup of hemorrhagic fever with renal syndrome (HFRS). Disease progression is severe and is characterized by fever, hemorrhage, and renal failure. Oliguria has been reported.

Hantavirus pulmonary syndrome

The illness has 5 distinct phases and is marked by deterioration of breathing during the cardiopulmonary phase. Capillary leakage results in noncardiogenic pulmonary edema and may progress to shock. As in HFRS, disease progression is rapid with a high rate of mortality.

Filoviruses

See the image below.

Filovirus disease - Ebola fever. Patient with Ebol Filovirus disease - Ebola fever. Patient with Ebola hemorrhagic fever during 1976 outbreak in Zaire demonstrating palatal petechiae and hemorrhage. Photo courtesy of Joel Breman.

Ebola and Marburg viruses are pantropic, that is, they infect and cause lesions in many organs, especially the liver and the spleen.[46] Both organs become enlarged and dark while undergoing severe degeneration. Disseminated intravascular coagulation may be a feature of late disease. Damage to endothelial cells increases vascular permeability, followed by hemorrhage and shock; these are central features of the infections, which have high mortality rates.

Ebola fever[47, 48]

A confirmed case of Ebola virus disease is currently defined as a suspected case (patient with fever and no response to treatment of usual causes of fever in the area, with at least 1 of the following signs: bleeding from gums, bloody diarrhea, purpura, bleeding into eyes and urine) with laboratory Zaire Ebola virus confirmation (positive polymerase chain reaction, positive immunoglobulin M antibody, or viral isolation).[49]

Early symptoms of Ebola-induced viral hemorrhagic fever are high temperature, headache, myalgia, stomach pain, rashes, sore throat, and red and itchy eyes. Severe watery diarrhea is reported. Rash usually develops at the end of the first week of illness. It is characterized by a morbilliform rash involving the face, neck, arms, and trunk. It may desquamate. This sign was reported rarely in the recent outbreak of Ebola in 2014-2015 in Sierra Leone.[50]

Hemorrhage noted on patients is in the form of petechiae, ecchymoses, blood in the stool, oozing from venipuncture sites, and mucosal hemorrhaging. Major bleeding usually occurs at the terminal stage of the disease. Bleeding was observed in about 20% of patients in the 2014-2015 outbreak.[50]

Within 1 week of disease onset, chest pain, hemorrhaging from body orifices, blindness, and death occur.

In the Ebola outbreak in West Africa, the clinical presentation of patients admitted in Connaught Hospital, Sierra Leone, were analyzed in a retrospective cohort study from May 2014 to December 2014.[51] Fever was present in 83% of cases, intense fatigue in 68% of cases, nausea or vomiting in 50% of cases, and diarrhea in 41% of cases. Of confirmed Ebola virus disease cases, 9% had no history of fever and denied exposure to any risk factor for Ebola virus disease.

Marburg fever[52]

Disease onset is marked by fever, chills, headache, and myalgia. Approximately 5 days after disease onset, a maculopapular rash may appear, with greatest prominence on the trunk. Patients present with jaundice, inflammation of the pancreas, weight loss, delirium, shock, liver failure, and multiorgan dysfunction.

Flaviviruses

See the image below.

Patient with morbilliform exanthem of dengue fever Patient with morbilliform exanthem of dengue fever. Note islands of sparing characteristics for dengue. Photo courtesy Duane Gubler, PhD.

Omsk hemorrhagic fever

Physical findings include congested conjunctivae, papulovesicular eruptions on the soft palate (an important diagnostic sign), severe pain in the back and the limbs, fever, headache, diarrhea, and vomiting. The illness is biphasic, with meningismus or meningoencephalitis occurring in the second phase. The disease is also characterized by hyperemia of the face and the upper body. Bleeding gums, epistaxis, hemoptysis, uterine hemorrhage, hematemesis, melena, and other hemorrhaging may occur.

Yellow fever

After the bite of an infected mosquito and an incubation period of 3-6 days, manifestations classically follow three clinical stages. The first stage is flulike symptoms (viremic period) lasting for 3-5 days and characterized by fever, nausea and vomiting, headache, photophobia, malaise, myalgia, and irritability. This period is followed by a remission period of 1-2 days. Some patients (20-60%) progress to the third phase, characterized by jaundice, midzone necrosis of the liver, flushing of the face, congested conjunctivae, and reddening edges of the tongue. The heart and the kidneys are also damaged. Hemorrhagic symptoms may appear early, with swelling and bleeding of the gums and epistaxis. Hemorrhaging from the gastrointestinal mucosa may cause black vomit and melena. This final stage is characterized by thrombocytopenia, coagulation abnormalities, deficiency of liver clotting factors, and disseminated intravascular coagulation.[53]

Dengue fever[54, 55, 56]

Dengue hemorrhagic fever occurs when individuals are infected with a second serotype of the virus after previous infection. The fever typically begins abruptly and follows three phases: the febrile, critical, and recovery phases. After an incubation period of 4-7 days (maximum of 14 days), the disease manifests as sudden onset of fever, nausea, vomiting, morbilliform rash, retroorbital headache, myalgia, conjunctival congestion, and generalized lymphadenopathy. This phase lasts for 2-7 days. In the critical phase, hemorrhagic manifestations are often observed. Hemorrhages involve the gastrointestinal mucosa, skin, pulmonary alveoli, and serosal surfaces. Vascular permeability is also increased and progression to dengue shock syndrome can occur. A pulse pressure equal to or less than 20 mm Hg defines the state of dengue shock syndrome.[57]

An enlarged liver can be palpated during the later stages of the disease. Signs of worsening of dengue fever include ongoing vomiting, worsening abdominal pain, mucosal bleeding, enlargement of the liver, lethargy or restlessness, serosal effusion, and high hematocrit combined with low platelet count.[58] Children may develop DHSS, a complication with a mortality rate of 4-12%. Transient left ventricular systolic and diastolic dysfunction were found to be common in hospitalized children with dengue fever and was related to the severity of plasma leakage.[59] However, cardiac structural changes were not common.

In a retrospective study that included 667 dengue patients, fever, myalgia, headache, arthralgia, abdominal pain, vomiting, and rash were observed in more than 40% of patients.[60] Dehydration, rash, pleural effusion, shortness of breath, and thick gall bladder were found to be significantly associated with dengue hemorrhagic fever when compared with dengue fever. Predictors noted for dengue hemorrhagic fever included older age, diabetes mellitus, secondary infection, thick gallbladder, lethargy, and delayed hospitalization.

Complications

Rift Valley hemorrhagic fever may lead to blindness in some cases. Individuals who are infected can occasionally have encephalitis due to bunyavirus or flavivirus infections. By the time the patient presents with encephalitis, serum antibody levels are usually detectable. Lassa and Machupo viruses can cause nerve deafness. Patients may develop bacterial sepsis or respiratory failure from fluid resuscitation. Multisystem shock leading to death is possible.

In a study analyzing 277 survivors of the Ebola epidemic in Sierra Leone, clinical sequelae were noted and include arthralgia in 76% of patients, new ocular symptoms in 60% of cases, uveitis in 18% of patients, and auditory symptoms in 24% of cases.[61] A higher viral load at time of presentation was significantly associated with uveitis and with the development of new ocular symptoms. Late-onset encephalitis, alopecia, paraesthesia, depression or anxiety, and polyarthritis were also reported.[62, 63]

Severe rhabdomyolysis, acute kidney injury, immune thrombocytopenia, and postencephalitic parkinsonism are complications reported following dengue virus infection.[64, 65, 66, 67]

In Crimean-Congo hemorrhagic fever (CCHF), cardiac hypokinesia, pericardial effusion, T-wave changes, myocardial involvement, and bundle-branch block are complications reported.[68]

 

DDx

Diagnostic Considerations

Other considerations include the following:

  • Rickettsial infections - Tick bite fever, epidemic typhus, and Q fever

  • Bacterial infections

  • Various septicemias - Meningococcal, staphylococcal, and streptococcal infections; typhoid; and plague

  • Leptospirosis, relapsing fever

  • Protozoal infection - Falciparum malaria and trypanosomiasis

  • Other viral infections - Hepatitis, Chikungunya, Sindbis, herpes, and influenza

  • Infectious mononucleosis

  • Other hemorrhagic fevers

  • Acute anemia

  • Acute leukemias, especially promyelocytic leukemia

  • Disseminated intravascular coagulation

  • Encephalitis

  • Hemolytic uremic syndrome

  • Thrombotic thrombocytopenic purpura

  • Meningitis

  • Pleural effusion

  • Sepsis

Differential Diagnoses

 

Workup

Laboratory Studies

Although the clinical findings can suggest a hemorrhagic fever, laboratory studies are required to identify disease, to distinguish it from other conditions, and to confirm its etiology.

As a rule, clinical blood and/or urine tests reveal leukopenia (except in Lassa fever, Hantaan viral fever, and some severe cases of CCHF), thrombocytopenia (except in Lassa fever), and proteinuria and/or hematuria (in Argentinian viral hemorrhagic fever, Bolivian viral hemorrhagic fever, and hemorrhagic fever with renal syndrome [HFRS]; common in other viral hemorrhagic fevers). Such tests include the following:

  • Full blood cell count determination

  • Red blood cell and sedimentation rate analysis

  • White blood cell differential count determination

  • Platelet count

  • Tests for parasites, malaria, trypanosomiasis, or relapsing fever

  • Coagulation studies

  • Liver and kidney function tests

  • Bacterial culture and virus isolation from feces and urine samples

  • Electron microscopic examination of blood and urine samples

  • Positive tourniquet test in dengue fever (This test may also be helpful in other viral hemorrhagic fevers.)

The specific diagnosis is based on viral isolation or the demonstration of seroconversion, that is, the presence of specific immunoglobulin M (IgM) antibody or a 4-fold increase in the antibody titer.

Specialized infectious disease containment is required for the safe handling of these viruses. Biochemical tests are available for the rapid detection of viral antigen during viremia or in postmortem specimens. Such tests include the following:

  • Immunofluorescence antibody (IFA) tests can be performed.

  • Reversed (or indirect) passive hemagglutination (RPHA) tests may be helpful.

  • Acute serum samples can be tested by using a polymerase chain reaction (PCR).

  • Enzyme-linked immunosorbent assays (ELISA) can be used to detect specific IgM or immunoglobulin G (IgG) antibodies or viral antigens in acute serum samples from patients with Lassa fever, Argentinian fever, RVF, CCHF, or yellow fever. Lassa- and Hantavirus-specific IgM antibodies are often detectable during acute illness.

  • Tests for viral genetic material are favored in diagnoses of acute arenaviral infections.

  • Virus cultivation and identification techniques require 3-10 days or longer for definitive identification. Viral isolation is a lengthy process, especially in Hantaan, Ebola, Marburg, and Congo-Crimean fevers.

  • Postmortem immunocytochemical analyses can be used to identify the viral phenotype.

  • Reverse transcriptase loop-mediated isothermal amplification (RT-LAMP) can be used for the rapid detection of Marburg virus.[69]

  • Reverse-transcription polymerase chain reaction has high sensitivity and specificity to detect the Ebola virus genome. False-negative results may be present in the first 3 days of illness, and repetition of the test may be required.[70]

Other Tests

Electron microscopy of the infected tissue may be helpful.

 

Treatment

Medical Care

Supportive care

Rapidly transfer the patient to a hospital with minimal trauma in order to prevent trauma to the fragile capillary bed.

The judicious use of sedative, pain-relieving, and amnesic medications can be helpful in managing malaise, confusion, myalgia, and hyperesthesia. Intramuscular injections and the use of aspirin and other anticoagulant drugs should be avoided.

Adequate hydration reduces the death rate, and oral rehydration may not be adequate.

Intensive supportive care is necessary for most cases of viral hemorrhagic fever. General supportive care principles apply to the treatment of hemodynamic, hematologic, pulmonary, and neurologic manifestations of viral hemorrhagic fever. Supportive care entails maintaining the patient's oxygen status and blood pressure and balancing fluid and electrolyte levels. Blood, platelet, and plasma replacement and management can be crucial, depending on the case. Convalescent plasma infusions may be effective in Argentinian hemorrhagic fever, if they are administered within the first 8 days of onset.

In Dengue fever, for which the main pathology is capillary leakage, brisk infusion with crystalloids should be instituted, followed by colloids or albumin if there is no response.

In Hantavirus infection, acute renal failure recovery may be accompanied by severe polyuria that should be managed carefully with close observation of fluid balance and electrolytes values.

Antiviral therapy with ribavirin may be useful in several viral hemorrhagic fevers, especially those caused by Arenaviruses. Although ribavirin inhibits viral DNA and RNA synthesis, it is not sensitive to the replication mechanisms of all RNA viruses. Ribavirin is proven effective in the treatment of Lassa fever and Congo-Crimean hemorrhagic fever.[71] It is somewhat effective in the treatment of other arenavirus and Hantavirus infections, in which it decreases mortality rates when used early in the course of the disease. Additionally, discovery of compounds with antiflaviviral activity have shown promise. Currently, several ribavirin analogues are undergoing clinical trials.[72]

Interferon-alfa has shown promising results in Arenaviral infections in vitro as an adjunctive therapy with ribavirin.[73]

Transfer

Patients may require treatment for secondary infections that may arise. Intensive care management may be required for viral hemorrhagic fevers.[74]

If hospitals or clinics are not equipped to deal with such infectious diseases, patients should be transferred to facilities with the following:

  • Specialized and skilled staff

  • Appropriate isolation space

  • Sufficient laboratory and testing facilities

Patient transfer in infectious disease cases may increase the chances of nosocomial transmission if proper precautions are not taken.

Vaccination

Vaccination may be considered. The only approved vaccine is for yellow fever. The WHO Strategic Advisory Group recommends a single primary dose for most travelers; a booster dose of the vaccine is no longer required, as the vaccine was found to confer sustained immunity and lifelong protection against yellow fever disease.[75]

Nonapproved vaccines include that developed for Argentinian viral hemorrhagic fever. This vaccine is a live-attenuated, investigational vaccine. It also seems to offer protection against Bolivian viral hemorrhagic fever. Both inactivated and live-attenuated vaccines for RVF are under investigation.[76] No vaccines are currently available for filovirus infection or dengue. Preliminary results suggest potential for successful prevaccination and postvaccination exposure against Ebola and Marburg viruses.[14, 77, 78]

Caregiver exposure

Persons percutaneously or mucocutaneously exposed to blood, excretions, or secretions of individuals who are infected should wash the affected areas with soap and water. Affected mucous membranes should be irrigated with water or sodium chloride solution.

Further reading

Additional information is available from the Centers for Disease Control and Prevention. See Infection Control for Viral Haemorrhagic Fevers in the African Health Care Setting and Questions and Answers on Ebola.

Consultations

Consultation with the following specialists may be warranted:

  • Infectious disease specialist

  • Hematologist

  • Pathologist

  • Internal medicine specialist

  • Other specialists as necessary

Diet

Fluid and electrolyte balance should be maintained.

Activity

Malaise and myalgia, among other symptoms, dictate bed rest restrictions.

Prevention

Prevention involves the following:

  • Avoiding areas with known rodent and arthropod populations, for example, avoiding rodent or insect bites and exposure to an environment contaminated with reservoir excretions or secretions

  • Avoiding contact with potential intermediate hosts, such as livestock or primates

  • Taking safety precautions when coming in contact with potential intermediate hosts, for example, when handling slaughtered livestock or primates for scientific experimentation

  • Preventing nosocomial transmissions by sterilizing equipment, such as needles; decontaminating and disinfecting facilities; isolating patients who are infected; practicing barrier nursing; and implementing safety infectious disease precautions and procedures

  • Avoiding travel to areas known to have viral hemorrhagic fever outbreaks

  • Administering mandatory vaccinations in susceptible populations (including travelers) against all viral hemorrhagic fevers for which a vaccine is available (eg, yellow fever, Argentinian fever) (see Medical Care)

  • Administering postexposure prophylaxis with virus-specific IgG in an attempt to suppress tick-borne flavivirus infections

Deterrence involves the eradication of rodent and arthropod vectors.

 

Medication

Medication Summary

The goals of pharmacotherapy are to induce remission, to reduce morbidity, and to prevent complications.

Antiviral agents

Class Summary

Antiviral agents inhibit the replication of RNA and DNA viruses.

Ribavirin (Rebetol)

Ribavirin is suggested drug treatment for Hantavirus infections and Arenavirus infections, especially Lassa fever and Crimean-Congo hemorrhagic fever. It is especially effective when administered in the early course of the disease. It inhibits viral replication by inhibiting DNA and RNA synthesis.