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:
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Myalgia
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Fever
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Prostration
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Vomiting
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Headache
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Petechial hemorrhages
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Hypotension
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Flushing of the head and the chest
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Edema
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Malaise
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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 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 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 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.
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. 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 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]
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New World Arenavirus - Machupo. Oral mucosal hyperemia and hemorrhage in a patient with Bolivian hemorrhagic fever.
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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.
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Filovirus disease - Ebola fever. Patient with Ebola hemorrhagic fever during 1976 outbreak in Zaire demonstrating palatal petechiae and hemorrhage. Photo courtesy of Joel Breman.
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Patient with morbilliform exanthem of dengue fever. Note islands of sparing characteristics for dengue. Photo courtesy Duane Gubler, PhD.
Tables
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 |
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 |
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 |
