Chapter 307. Hemorrhagic Fevers

Viral hemorrhagic fever is a severe, sometimes fatal, multisystem syndrome characterized by diffuse vascular damage and dysregulation; hemorrhage does not necessarily occur; when it does, it is rarely a sufficient cause for demise. The etiologic agents of this syndrome are zoonotic, lipid-enveloped ribonucleic acid (RNA) viruses and include dozens of members from 4 families of viruses: arenaviruses, bunyaviruses, filoviruses, and flaviviruses (Table 307-1). These agents are localized geographically and are associated with specific vector hosts or reservoirs,1-5 although imported cases and infections caused by laboratory accidents and nosocomial transmission can occur outside their respective ranges.6 The diseases they cause are either endemic or episodic with both annual cycles and longer secular trends. Some are associated with high lethality and potential for person-to-person transmission. The challenges for clinicians evaluating suspect cases are to exclude more likely conditions that are potentially life-threatening and treatable (especially malaria and typhoid fever); narrow the differential diagnosis based on the travel history; institute appropriate precautions for the diseases in the narrowed differential that are associated with person-to-person transmission; and seek expert guidance for diagnostic confirmation and treatment guidelines.

Epidemiology

Most arboviruses (arthropod-borne viruses) are maintained in natural cycles of infection between mosquitoes or ticks and vertebrate hosts. The viruses may be carried through the winter or dry months by persistence in dormant vectors, by vertical transovarial transmission in mosquitoes, by transstadial transmission in ticks, or in persistently infected vertebrates. In tropical locations, enzootic transmission can occur throughout the year. Human infections occur through accidental exposure to the enzootic cycle or during epizootics. Large urban epidemics occur as a result of vector-borne interhuman transmission of arboviruses like yellow fever and dengue, which produce sufficient viremia in humans to infect mosquitoes. Some arboviruses are primarily transmitted to humans as zoonoses. Omsk hemorrhagic fever can be transmitted from infected muskrats to trappers during skinning.7 Rift Valley fever and Crimean-Congo hemorrhagic fever can be transmitted from infected livestock to herders and butchers during slaughter.4

Zoonotic transmission to humans also occurs with arenaviruses, which cause Lassa and other hemorrhagic fevers and lymphocytic choriomeningitis, and with the hantaviruses, which cause hantavirus pulmonary syndrome.3 These viruses are spread from the excretions of various persistently or transiently infected rodents to humans through inhalation, ingestion, or direct contact. Filoviruses may be transmitted to humans in rare instances by bats or other infected mammals.5 Person-to-person spread of Crimean-Congo hemorrhagic fever, Ebola, and Marburg viruses has led to sizable outbreaks, often with substantial nosocomial transmission.8 Occasional person-to-person transmission has also been documented for the New World arenaviruses (Junin and Machupo) and Andes virus–related hantavirus pulmonary syndrome.3

Infection in children is determined by a combination of their susceptibility to infection and contact with the reservoir/vector.9 During periods of hyperendemic or epidemic yellow fever or dengue transmission, adults may have preexisting immunity, so the highest proportion of cases occurs in children and adolescents.10-13 Pediatric cases of Lassa fever and town-based Bolivian hemorrhagic fever occur because of peridomestic contact with the vector/reservoir.14 In contrast, children are rarely affected by sylvatic yellow fever or infection with the New World arenaviruses that are predominantly acquired in forests or fields by hunters and farmers.3 Few pediatric cases have been noted during outbreaks of Ebola hemorrhagic fever in otherwise susceptible populations, because this disease is primarily spread through direct contact with patients or inadvertent exposures in the health care setting.5 The notable exception was during the largest Marburg outbreak in northern Angola in 2004–2005 during which around 75% of cases occurred in children under the age of 5 years, possibly due to nosocomial transmission in a pediatric ward and from contaminated medical supplies.8

Diagnosis

Since each of these diseases occurs in a specific geographic and ecologic pattern, diagnosis requires consideration of the possibility of exposure and an estimation of the incubation period. The suspicion of viral hemorrhagic fever should immediately trigger consultation for a specific etiology.

All of these diseases typically present with nonspecific signs and symptoms like fever, myalgia, headache, and sometimes gastrointestinal symptoms. Thus, differentiating viral hemorrhagic fever from other febrile illnesses can be particularly difficult during the initial stages.1-2 The subsequent development of hypotension, a flushed appearance suggesting early vascular injury, petechiae, and hemorrhage should trigger further diagnostic studies. Rash is seen only in Ebola, Marburg, dengue, and Lassa fevers. The major pitfall in diagnosis among travelers is entertaining the possibility of hemorrhagic fever at the expense of performing a thorough evaluation of more common and treatable conditions, such as malaria or typhoid fever.

Disease manifestations of viral hemorrhagic fever in children resemble those in adults, with notable exceptions.9 Dengue hemorrhagic fever and dengue shock syndrome in infants is thought to be precipitated by decreasing levels of maternal antibody, which are cross-reactive but nonprotective at lower levels. The swollen baby syndrome of Lassa fever is another uniquely pediatric disease.

Thrombocytopenia is the only universal clinical laboratory feature of viral hemorrhagic fever, although it may be rare in Lassa fever. Except for hantaviruses, these viruses can be readily isolated from acute-phase samples in specialized laboratories using appropriate biocontainment conditions.2 Enzyme-linked immunosorbent assays for antigen, IgM, and IgG antibodies are rapid, sensitive, and specific. The older indirect immunofluorescent antibody, complement fixation, and hemagglutination inhibition assays are less sensitive and specific than enzyme-linked immunosorbent assays. Plaque-reduction neutralization test can be used to detect neutralizing antibodies to some viruses. Nucleic acid tests like polymerase chain reaction and nucleic acid sequence–based assays provide direct and rapid detection of viral RNA in blood and tissue. Immunohistochemical techniques using virus-specific antibodies have improved postmortem tissue diagnosis. The Centers for Disease Control and Prevention’s Special Pathogens Branch (Tel. 404-639-1115) can provide immediate assistance with appropriate diagnosis and response.

Specific Diseases

Filoviral Hemorrhagic Fevers

The hemorrhagic fevers caused by Marburg and Ebola viruses are among the most lethal: case-fatality rates range from approximately 25% to 90% among those with Marburg hemorrhagic fever and 30% to 90% in outbreaks of Ebola hemorrhagic fever.5 The 5 known subtypes of Ebola virus (Reston, Sudan, Zaire, Cote d’Ivoire, and Bundibugyo, a newly identified subtype from Uganda) differ in virulence.5,16 Growing evidence points to cave-dwelling bats as the natural reservoir for Marburg virus.17 Similarly, forest-dwelling bats may be the natural reservoir for Ebola virus.18 Of the 3 subtypes that have caused large epidemics in humans, the Zaire subtype causes the highest case-fatality rate, followed by Sudan and Bundibugyo. Only 1 human infection with the Cote d’Ivoire subtype has been documented. Human-to-human spread occurs through direct contact with symptomatic individuals, resulting in chains of transmission that are often amplified in the nosocomial setting.8 Illness begins with an abrupt onset of fever, prostration, headache, and myalgia. Patients frequently appear restless and anxious, and they later become apathetic and exhibit other encephalopathic signs.1,2,5 After 3 to 8 days, a morbilliform, usually confluent, nonpruritic rash starts on the upper trunk and spreads centrifugally to involve the entire body except the face and neck, and conjunctival injection and edema can be seen. Profuse vomiting and watery diarrhea commence, accompanied by intense abdominal pain. Chest pain is a variable feature that was often noted in the Ebola-Sudan outbreak in 1976 but not in other Marburg and Ebola-Zaire outbreaks. Bleeding occurs in about 50% of patients, primarily from the gastrointestinal tract in the form of melena and hematemesis, but also from the vagina, gums, and nares. Multisystem organ failure from pneumonitis, hepatitis, pancreatitis, and tubulointerstitial nephritis combined with intractable hypotension usually leads to death. Recovery can occur within 7 to 10 days, but convalescence can take weeks to months.

New World Arenaviral Fevers

Junin, Machupo, Guanarito, and Sabiá viruses, the etiologic agents of Argentine, Bolivian, Venezuelan, and Sabiá hemorrhagic fevers respectively, are maintained by specific sigmodontine rodents indigenous to the Americas.2 Argentine hemorrhagic fever is almost exclusively an occupational disease of agricultural workers, although the proportion of pediatric cases is increasing, to approximately 10% of all cases, as increasing numbers of adults in high-risk areas have been vaccinated.9 Prepartum maternal infection can result in spontaneous abortion, congenital malformations, and neonatal death, as well as maternal death; the virus has also been isolated from breast milk. Bolivian hemorrhagic fever and Venezuelan hemorrhagic fever are acquired in a peridomestic setting, and cases occur in all age groups. All 4 diseases present with a similar nonspecific history of fever, headache, myalgia, weakness, and gastrointestinal symptoms. Retroorbital pain, photophobia, and epigastric abdominal pain may occur, but pharyngitis and other respiratory signs and symptoms are uncommon. Patients become increasingly toxic and develop a flushed appearance, conjunctival injection, and fine petechial eruptions on the oral pharynx, upper trunk, and axillae. Most enter a convalescent phase after the first week of illness, but more than one third develop neurologic complications (altered mental status, ataxia, or tremors) or a hypotensive-hemorrhagic phase associated with a capillary leak syndrome. New World arenaviruses cause an overall case-fatality rate of 10% to 30%.3

Lassa Fever

Lassa fever is a common febrile illness in West Africa, with as many as 300,000 cases and 5000 deaths annually.19 Lassa fever may account for as much as 10% of febrile children admitted to hospitals in disease-endemic areas. The disease is characterized by insidious onset of fever, weakness, myalgia, and generalized malaise followed by lower backache, substernal or epigastric pain, dizziness, cough, and gastrointestinal symptoms. Purulent pharyngitis, conjunctivitis, edema (particularly of the head and neck), and mucosal bleeding are highly specific signs of Lassa fever. Fulminant disease is marked by hypovolemic shock; facial and neck edema; encephalopathy; and respiratory distress due to laryngeal edema, pneumonitis, pulmonary edema, and pleural effusion. Permanent sensorineural hearing loss can occur as a late sequela. Maternal infection can result in maternal and fetal death, especially near term, as well as congenital Lassa fever in neonates. Children younger than 2 years of age with Lassa fever can develop swollen baby syndrome, characterized by widespread edema, abdominal distention, and bleeding.9,19

Hemorrhagic Fever with Renal Syndrome

Hemorrhagic fever with renal syndrome is caused by 4 murine and arvicoline rodent-borne Old World hantaviruses: Hantaan, Dobrova-Belgrade, Seoul, and Puumala, which occur primarily in Asia and Europe.20-21 Men, particularly agricultural and forestry workers, are at greatest risk for infection in sylvatic locations. There is an unexplained paucity of cases among children, and it is possible that symptomatic disease may be milder in children. The most severe form of hemorrhagic fever with renal syndrome is caused by Hantaan virus and is classically associated with 5 consecutive phases with characteristic physiological derangement: febrile, hypotensive, oliguric, diuretic, and convalescence. Hemorrhage is generally noted during the oliguric phase. However, there is considerable variation in the incidence of various manifestations, and the severity of individual phases that may overlap.

Hantavirus Pulmonary Syndrome

Hantavirus pulmonary syndrome is caused by a number of New World sigmodontine rodent-borne hantaviruses indigenous to rural areas of the Americas and is a consequence of sylvatic or peridomestic transmission.3 As with their Old World cousins, there is a relative paucity of pediatric cases. A brief, nondescript febrile prodrome with chills, myalgia, malaise, diarrhea, and headache is generally followed by the precipitous onset of the cardiopulmonary phase with hypotension and increased vascular permeability, resulting in pulmonary edema and hypoxia. Death can occur within 2 days of admission from respiratory failure and cardiogenic shock. In South America, Andes virus infection may be associated with facial flushing, petechiae, and occasionally frank hemorrhage, and it can be transmitted person to person. Overt hemorrhage occurs rarely in severe cases in North America. Bilateral interstitial pulmonary infiltrates in conjunction with shock are a hallmark of severe disease, as is the triad of thrombocytopenia, immature neutrophils, and circulating immunoblasts. Atypical presentations with prominent renal insufficiency and myositis have been reported, as have asymptomatic and mild infections without pulmonary involvement.

Crimean-Congo Hemorrhagic Fever

Congo-Crimean hemorrhagic fever virus (CCHFV) is also a member of the Bunyaviridae family. It has a wide geographic distribution throughout parts of Africa, the Middle East, Asia, and Eastern Europe, which mirrors the distribution of its vector, the Hyalomma genus of ticks (eFig. 307.3). Many types of mammals and perhaps birds serve as reservoirs for the virus as transmitted by ticks, but humans seem to be the only species that develop disease with the infection. In addition to tick bites, contact with human or animal blood (particularly inoculation) also serves as an important route of infection, with numerous nosocomial outbreaks of CCHFV reported. Risk factors for acquisition in endemic areas include outdoor recreational activity, farming, and blood contact through abattoir, veterinary, or health care work. Clinical disease with CCHFV usually follows a 3- to 9-day incubation period. Symptom onset is usually abrupt with severe headache, high fever, myalgia, weakness, anorexia, back and abdominal pain, and nausea often accompanied by vomiting. Hyperemia commonly occurs, most notably on the face, mucous membranes, and upper part of the body. Early nonspecific symptoms are followed by more severe manifestations after the sixth day of illness, including hemorrhage from the nose, mouth, and gastrointestinal tract and large ecchymotic areas on the limbs caused by disseminated intravascular coagulation.1-2 During this stage, most patients become obtunded with halting speech; dizziness and mild meningeal signs are common. Elevated bilirubin and liver enzyme levels are usually present. Patients may become delirious or comatose; death occurs in approximately 30% of cases.

Rift Valley Fever

Rift Valley fevor virus (RVFV) is a member of the Buyaviridae family. Rift Valley fever is a primarily mosquito-borne veterinary disease occurring in sub-Saharan Africa and Madagascar (eFig. 307.4), where intermittent epizootics associated with heavy rainfall cause serious losses of domestic livestock from abortions and death.4 An isolated epidemic also occurred in Saudi Arabia and Yemen from 2000 to 2001. Humans can be infected by direct or aerosol exposure to blood from infected animals, from ingestion of raw milk, as well as by mosquito bite. Usually it manifests as a self-limited but severe illness characterized by fever, headache, chills, anorexia, myalgia, and prostration, with impaired hepatic and renal function. The illness typically resolves after 2 to 5 days, but approximately 1% of infected patients develop hemorrhagic fever; less than 1%, encephalitis; and 15% retinitis. The hemorrhagic fever usually involves severe necrotizing hepatitis. Encephalitis, associated with confusion, meningismus, paresis, hallucinations, convulsions, and recrudescence of fever, can occur 1 to 4 weeks after the initial febrile illness, as can retinitis, which can cause permanent vision loss.2,4 Overall mortality with RVFV infection is 1% or less, but mortality with severe disease in recent series has been 29% to 33%.

Dengue Fever

Dengue fever is the most common arboviral infection worldwide. Dengue hemorrhagic fever causes hundreds of thousands of life-threatening infections annually in the tropics, mostly in children.9 The geographic range of dengue has been expanding dramatically over the past 40 years; it is now hyperendemic in the tropics (eFig. 307.1). Dengue virus is a Flavivirus with 4 serotypes, transmitted by Aedes specie mosquitoes, predominantly Ae aegypti, which are present in most tropical urban areas of the world.11-13Ae albopictus have also been implicated in fairly substantial outbreaks, especially as they have been introduced into new areas, sometimes outcompeting Ae aegypti. In the United States, these mosquitoes can be found in Hawaii year-round and in the southeastern states in the summer months, contributing to an epidemic in Hawaii in 2001–2002 and regular autochthonous transmission in southern Texas. Epidemics arise in susceptible populations after the virus is introduced by viremic persons into areas with competent vectors. In areas where transmission is endemic, dengue is principally a disease of childhood. Infections occur in almost 100% of children before 8 years of age. Infections can occur in all age groups when the people exposed are immunologically naïve, such as when a new strain is introduced in a population or when travelers from nonendemic areas travel to dengue-endemic regions.

Asymptomatic DENV infection is common. The incubation period for disease in symptomatic individuals is typically 4 to 7 days. Dengue fever can be mild in young children but in older children and adults is associated with significant fever, chills, headache, retroorbital pain, myalgia, arthralgia, and low back pain accompanied by anorexia, nausea, and vomiting.22 Facial flushing is common, and in fair-skinned persons, a centrifugally spreading morbilliform rash may be detected late in the illness in more than half of patients. Illness is self-limited and sometimes is complicated by minor hemorrhagic phenomena, such as epistaxis and minor gum, gastrointestinal, and vaginal mucosal bleeding. The tourniquet test (20 or more petechiae appearing below a blood pressure cuff inflated for 5 minutes to halfway between systolic and diastolic pressures) may be positive in one third of patients. Lowered platelet, total leukocyte, and absolute monocyte and neutrophil counts reflect bone marrow suppression and peripheral destruction of platelets.

The self-limited hemorrhagic phenomena should be differentiated from dengue hemorrhagic fever, characterized by thrombocytopenia, generalized bleeding, and evidence of increased vascular permeability (eg, hemoconcentration, pleural effusions, ascites, or hypoalbuminemia). Advanced cases are called dengue shock syndrome, which is dengue hemorrhagic fever with hypotension and a narrow pulse pressure and causes a case-fatality rate as high as 44%.11-13,22 Cross-protective immunity among dengue serotypes is limited, and sequential infection, particularly when dengue 2 virus causes the second infection, increases the risk for dengue hemorrhagic fever and dengue shock syndrome. The onset of hypotension may be precipitous and typically occurs with defervescence. This interval of vascular instability may be as brief as 24 to 48 hours and reverses spontaneously. Hemodynamic monitoring and supportive fluid, cardiovascular support, and avoidance of aspirin reduce dengue hemorrhagic fever mortality from 25% to less than 5%.

Yellow Fever

Yellow fever is transmitted between nonhuman primates in the tropical rainforest by Aedes species mosquitoes in Africa and Haemagogus species mosquitoes in South America.10 A sylvatic cycle occurs in the moist savanna regions of Africa in which forest Aedes species mosquitoes transmit yellow fever between primates and humans. Large epidemics of urban yellow fever can occur in cities in endemic areas of Africa and South America infested by peridomestic Ae aegypti that transmit the disease in a human-mosquito-human cycle, as with dengue (eFig. 307.2).10,13 Yellow fever epidemics mostly affect children and young adults who have not acquired immunity to yellow fever or to heterologous flaviviruses that may offer some cross-protective immunity and who tend to develop more severe disease with high case-fatality ratios.

The disease classically has been divided into three stages: infection, remission, and intoxication.10 The period of infection is characterized by sudden onset of fever, headache, malaise, and musculoskeletal pain, low back pain, and nausea. Physical signs include conjunctival suffusion, flushing of the skin, and relative bradycardia despite fever, known as Faget sign. In about 15% to 25% of cases, the remission phase is temporary, lasting only 2 to 24 hours, and the illness resumes in a more severe form. Patients in the period of intoxication develop fever, vomiting, abdominal pain, jaundice, hematemesis, and other forms of hemorrhage. Patients are typically dehydrated with hypotension, reduced urinary output, and, frequently, proteinuria. Myocarditis, azotemia, encephalopathy, progressive liver damage, bleeding, and shock can occur; 20% to 50% of cases that enter the period of intoxication die.

Tick-Borne Hemorrhagic Fevers

Kyasanur Forest disease and Omsk hemorrhagic fever are tick-borne flavivirus infections that are seasonally transmitted in the areas of southern and central India and southwestern Siberia, respectively.3,7 Kyasanur Forest disease is maintained in a forest cycle involving Haemaphysalis ticks, birds, and small mammals. It is transmitted by tick bite to nonhuman primates and humans, mainly villagers and lumbermen. Omsk hemorrhagic fever is primarily transmitted directly from infected muskrats to humans during hunting through direct contact with blood, urine, or feces; by tick bite; or through ingestion of unpasteurized milk from infected sheep and goats. Kyasanur Forest disease and Omsk hemorrhagic fever are self-limited illnesses characterized by acute fever, chills, myalgia, headache, vomiting, and diarrhea lasting 4 to 10 days in half of all cases, and hypotension, which can persist for several days. Hemorrhagic manifestations tend to be minor in Omsk hemorrhagic fever. Hepatitis and acute renal failure can occur in both illnesses, and bronchitis, pneumonia, alveolar hemorrhage, and pulmonary edema develop in 40% of cases. Signs of encephalitis appear late in the course of illness in 50% of Kyasanur Forest disease cases but are less prominent in Omsk hemorrhagic fever. The case-fatality rate for both illnesses is less than 5%.

Therapy

Acute infection can be asymptomatic or clinically apparent, with resolution. Supportive therapy for shock, hemorrhage, and secondary infection are critical for the management of cases of more severe viral hemorrhagic fevers.1-2,15 Anecdotal experience suggests the use of ribavirin in Rift Valley fever may exacerbate or cause encephalitis, and further evidence is necessary to recommend its use.1-2,23 However, in controlled trials of adults, ribavirin reduced mortality and morbidity in Lassa fever and hemorrhagic fever with renal syndrome.22,24 Retrospective studies have indicated that ribavirin may decrease mortality among patients with Crimean-Congo hemorrhagic fever,24 and anecdotal experience suggests its efficacy in treating New World arenaviral hemorrhagic fevers.3 Early transfusion of immune plasma is an effective therapy for Argentine hemorrhagic fever, and immunoglobulin has been used with some success in a few cases of Crimean-Congo hemorrhagic fever.7

Prevention and Control

Vector-borne infections can be prevented by avoiding at-risk locations during the seasons and/or times of day when risk is greatest. Simple measures include covering exposed areas of the body with clothing, avoiding outdoor activities at dusk and dawn when certain vectors are most active, and using insecticide-treated bed nets. Protective clothing and repellents can reduce arthropod exposure and bites. Repellents containing N,N-diethyl-meta-toluamide (DEET) or picaridin are the most effective formulations; however, no definitive studies have determined what concentrations of DEET are safe to use in children.25 The American Academy of Pediatrics has stated that DEET is not harmful to children in concentrations of up to 30% when used appropriately but does not recommended its use in infants under 2 months old. Oil of lemon eucalyptus has also been approved by the FDA for use as an insect repellent but needs to be applied more frequently and should not be used on children under 3 years of age according to the product label. Permethrin effectively repels and kills mosquitoes and ticks when sprayed on clothing and bed nets and remains effective after several washings.

Minimizing human-rodent interactions is the cornerstone of preventing infections with hantaviruses and arenaviruses.3 Eliminating rodent shelter, excluding rodents, and controlling rodent populations are readily accomplished in urban settings but are more difficult in the rural occupational or recreational setting. Although the reservoir hosts of filoviruses remain uncertain, people should avoid contact with ill or dead primates as well as unprotected exposure to bats and their excreta that may harbor Marburg virus, particularly in enclosed spaces such as caves and mines. The risk of infection from imported nonhuman primates has been minimized by the implementation of new quarantine regulations and reliance on captive-bred animals. Prevention of nosocomial transmission, through contact and droplet precautions and decontamination of clinical specimens, is the most critical aspect of the strategy to minimize the risk for the arenaviral and filoviral infections.8

Live attenuated vaccines are available for both yellow fever13 and Argentine hemorrhagic fever,3 and a formalin-inactivated vaccine for Kyasanur Forest disease virus has been used in India.7 Inactivated tick-borne encephalitis vaccines may provide some cross-protection against Omsk hemorrhagic fever virus.7 Yellow fever vaccine is contraindicated in children under 6 months old and not recommended until 9 months of age because of the risk of vaccine-associated encephalitis. Yellow fever immunization is also contraindicated during pregnancy because of a theoretical risk to the fetus. Yellow fever vaccine has been associated with rare neurotropic and viscerotropic severe adverse events that are more common among the elderly. It is safe and effective overall and is required by some countries for entry.10 Consultation at a travel clinic is advised to provide travelers with appropriate pretravel counseling and immunization.

The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention (Figs. 307-1, 307-2, 307-3, and 307-4).