Pediatric Viral Hemorrhagic Fevers 

Updated: Apr 02, 2018
Author: Martha L Muller, MD; Chief Editor: Russell W Steele, MD 

Overview

Practice Essentials

The 12 distinct enveloped RNA viruses that cause most viral hemorrhagic fever (VHF) cases are members of 4 families: Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae. Disease severity resulting from infection by these agents varies widely, but the most extreme manifestations include circulatory instability, increased vascular permeability, and diffuse hemorrhage. In May 1995, these diseases came to worldwide attention with an outbreak of Ebola virus near the city of Kikwik, Zaire.[1] With increased international travel, these primarily tropical viruses may now be imported into nonendemic countries. Furthermore, several of these agents have been associated with nosocomial outbreaks involving health care workers and laboratory personnel.

Ebola virus. Electron micrograph courtesy of the C Ebola virus. Electron micrograph courtesy of the Centers for Disease Control and Prevention.

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

Viral hemorrhagic fevers share many common features. Infectious agents that are arthropod-borne (usually mosquitoes) cause many viral hemorrhagic fevers. For several viral hemorrhagic fevers, person-to-person transmission may occur through direct contact with infected patients, their blood, or their secretions and excretions. Animal reservoirs are generally rats and mice, but domestic livestock, monkeys, and other primates may also serve as intermediate hosts.

Yellow fever (the prototype virus of the Flaviviridae family), dengue, Hantavirus pulmonary syndrome (HPS), and hemorrhagic fever with renal failure syndrome (HFRS) are discussed in separate chapters (see Differentials). The other flaviviral hemorrhagic fevers (HFs), Alkhurma HF virus,[2, 3, 4] Kyasanur Forest disease,[5] and Omsk HF, are described only in cursory detail because they have very limited geographic distribution and/or have virtually disappeared from the endemic zones in which they were previously found.

Novel viruses have recently been identified.[6, 7]

Pathophysiology

Although common themes occur, the different viruses display variable pathophysiology. Hemorrhage is typically present in many organs, and effusions are common in serous cavities (although they may be minimal or absent in some patients). Widespread necrosis generally occurs, may be present in any organ system, and varies from modest and focal to massive in extent. Liver and lymphoid systems are usually extensively involved, and the lung regularly demonstrates varying degrees of interstitial pneumonitis, diffuse alveolar damage, and hemorrhage. Acute tubular necrosis and microvascular thrombosis may also be observed. The inflammatory response is usually minimal.

Epidemiology

Frequency

United States

Aside from the bunyaviral HPS (Bayou, Black Creek Canal, Four Corners, Muleshoe, Sin Nombre), which appears to be associated with rodent-contaminated, abandoned, and closed buildings, and rare cases of HFRS, the only viral hemorrhagic fever to occur in the United States are imported cases, most frequently Lassa fever. The first imported case of Lassa fever in more than 20 years occurred in New Jersey in 2004.[8] More recently, imported Marburg virus disease was identified in a Colorado woman who traveled to Uganda.[9] Lassa fever imported to the US was again reported in 2010.[10]

International

Arenaviridae, including Guanarito (Venezuelan HF), Junin (Argentine HF), Machupo (Bolivian HF), Sabia (Brazilian HF), and Lassa viruses, are found throughout South America, particularly in the Argentine pampas, Bolivia, Venezuela, and rural Brazil near Sao Paulo. The Chapare virus was recently identified in Bolivia.[11] More recently, a novel arenavirus was identified in 5 patients in southern Africa.[12] Arenaviridae are also found in West Africa (eg, Lassa in Nigeria, Sierra Leone, Guinea, Liberia, and Mali).[13] Chronic infection of small field rodents makes rural residents and farmers the most frequently infected, with a strong seasonal predominance for the fall. In Argentina, agricultural workers are disproportionately infected. In Bolivia, rodents can invade towns and cause epidemics. In West Africa, Lassa fever is spread to humans when infected rodents are captured for consumption, as well as by person-to-person exposures. Currently, outbreaks of Lassa fever are occurring in West Africa.

Bunyaviridae (Crimean-Congo HF [CCHF], Rift Valley fever [RVF]) are seen throughout Africa,[14] the Middle East, the Balkans,[15, 16, 17] southern Russia, and western China.[18, 19] CCHF has the widest geographic distribution of the tickborne infections and is increasingly reported in Europe,[20, 21, 22] and Turkey, as well.[23]

Filoviridae (Ebola, Marburg viruses) are found in Africa and possibly in the Philippines.[24] The vector is unknown, but infected primates sometimes provide a link for spread to humans. Later spread among humans or primates by close contact may also occur. Aerosol transmission is suspected in some monkey infections. It appears that outbreaks of Ebola disease often follow uncommonly dry periods, when rainfall resumes and reaches unusually high levels. Outbreaks of Marburg in Angola have been recently identified,[25, 26] as have outbreaks of Ebola in Congo[27] and Uganda.[28, 29, 30]

Flaviviridae include Alkhurma HF virus, Kyasanur Forest disease[31] , and Omsk HF. Alkhurma HF virus is a variant of Kyasanur Forest disease virus found in Saudi Arabia and reported in a small number of patients since the 1990s.[32, 2, 33] Recent reports describe the infection in travelers returning from Egypt, suggesting that the geographic range of the virus may be increasing.[3, 34] Kyasanur Forest disease follows a tick bite in rural areas of the endemic zone, Karnataka, India. Monkey die-offs may accompany increased virus activity. Omsk HF was observed in western Siberia and has a poorly understood vector and reservoir cycle that involves ticks, voles, muskrats, and, possibly, water-borne and mosquito transmission. Very few cases have been reported in recent years.

Mortality/Morbidity

Ebola and Marburg are considered the most severe viral hemorrhagic fevers, with 25-100% mortality rates. The infection rate is high, particularly for the Zaire subtype of Ebola virus. During pregnancy, Ebola infection has been universally fatal. The South American HF has a case-infection ratio of more than 50% of those exposed. The mortality rate is 15-30%. Lassa fever is a milder infection, with a fatality rate of 2-15%, and is probably much more common than is recognized. Approximately 1% of individuals exposed to RVF virus become infected, but the mortality rate of persons infected is 50%. CCHF has an infection rate of 20-100% and a fatality rate of 15-30%.

Race

No racial predilection has been reported.

Sex

No known sex predilection for viral hemorrhagic fever has been noted, except as occupational exposures dictate.

Age

Persons affected are frequently those who have the most occupational exposure, although susceptibility in endemic regions is often highest for young children.

 

Presentation

History

Initial symptoms of viral hemorrhagic fevers (VHFs) are nonspecific and follow an incubation period of 2-14 days. Patients experience an insidious or sudden onset of progressive fever (that may be biphasic), chills, malaise, generalized myalgias and arthralgias, headache, anorexia, and cough. Most patients have a severe sore throat and may have epigastric pain, vomiting, and diarrhea.

Physical

Typical findings are not distinctive, including nonspecific conjunctival injection, facial and truncal flushing, petechiae, purpura, ecchymoses, icterus, epistaxis, gastrointestinal and genitourinary bleeding, and lymphadenopathy. Severe illness is associated with hypotension and shock, relative bradycardia, pneumonitis, pleural and pericardial effusions, hemorrhage, encephalopathy, seizures, coma, and death.

Arenaviridae

Patients with one of the South American HFs may present with conjunctivitis, pharyngeal enanthema with petechiae but without exudate, sore throat, or cough. Retrosternal pain is also a major symptom.

The South American HFs may be marked by encephalopathic changes, including intention tremor, cerebellar signs, convulsions, and coma.

Lassa fever often manifests with classic signs of meningitis.

Swollen baby syndrome describes severe Lassa fever in infants and toddlers with anasarca, abdominal distention, and spontaneous bleeding but pediatric disease is otherwise not distinctive from that observed in older patients.

Bunyaviridae

Patients with Rift Valley Fever (RVF) develop retinal vasculitis that may cause permanent blindness.

Cotton wool spots are visible on the macula.

Severe disease is associated with bleeding, shock, anuria, and icterus.

Encephalitis may also occur without overlapping hemorrhagic fever.

The most severe bleeding and ecchymoses among the viral hemorrhagic fevers characterize Crimean-Congo hemorrhagic fever (CCHF).[35]

Filoviridae

Ebola virus causes clinically similar but more severe disease than the Marburg agent.

On about the fifth day of illness with Ebola or Marburg virus, a distinct morbilliform rash develops on the trunk and an expressionless ghostlike facies has been described during this stage of illness.

Patients with progressive disease hemorrhage from mucous membranes, venipuncture sites, and body orifices.

Disseminated intravascular coagulation may be a feature of late disease.

Flaviviridae

Kyasanur Forest disease and Omsk HF are typical biphasic diseases with a febrile or hemorrhagic period that is often followed by CNS involvement, similar to tick-borne encephalitis (Central European encephalitis, Russian spring-summer encephalitis) except that hemorrhagic manifestations are not characteristic of the first phase of the tick-borne encephalitides. Alkhurma HFV typically produces fever, headache, retroorbital pain, joint pain, myalgias, anorexia, vomiting, leukopenia, thrombocytopenia, and elevated serum hepatic transaminases. Hemorrhagic or encephalitic manifestations occur in some patients.

Causes

South American HF and Lassa fever arise from inhalation of aerosolized fecal matter or urine of infected rodents and from rodent bites, usually during harvest, with work on small farms, or in newly developed areas. Interhuman transmission usually does not occur but is possible.

RVF is acquired from mosquito bites or contact with the blood of infected domestic livestock. No interhuman transmission has been observed.

CCHF results from tick bites,[36] squashing ticks, or exposure to aerosols or fomites from slaughtered sheep and cattle. Nosocomial epidemics have been observed a number of times.

Ebola and Marburg infections occur from unknown sources, but links to primates and contact with other infected humans are observed.

 

DDx

 

Workup

Laboratory Studies

Characteristic hematologic abnormalities in viral hemorrhagic fever (VHF):

  • Leukopenia

  • Leukocytosis

  • Thrombocytopenia

  • Hemoconcentration

  • Occasionally, disseminated intravascular coagulation

Elevated hepatocellular enzyme levels and hypoalbuminemia are typically present.

Proteinuria is a universal finding.

Enzyme-linked immunosorbent assays for virus-specific immunoglobulin M (IgM) and immunoglobulin G (IgG) are the best serologic tests for etiologic diagnosis because of their sensitivity, although antibody may not be detected during the acute stages of Marburg and Ebola virus infections.[37]

Direct examination of blood and tissues (eg, skin biopsies) for viral antigen by enzyme immunoassay and for virions by electron microscopy are specific and sensitive.

Polymerase chain reaction (PCR) on serum during the acute stages of infection has been successfully applied for viral hemorrhagic fever.[38] It is usually more sensitive but also more subject to artifact and contamination than more established methodologies.

Viral cultures of blood and tissues have been performed at the Centers for Disease Control and Prevention.

Recently, MassTag PCR has been applied to the differential diagnosis of these illnesses. Further, panels for real-time PCR identification of filoviruses, arenaviruses, and New World hantaviruses have been developed.[39]

Various assays for CCHF have been evaluated.[40]

Procedures

Skin biopsy may provide material for electron microscopy or immunoassay.

 

Treatment

Medical Care

Early diagnosis and supportive care can be lifesaving for most patients with viral hemorrhagic fever (VHF). The cornerstone of therapy for all these infections is judicious fluid and electrolyte management.

Blood, platelet, and plasma replacement may be useful for Crimean-Congo hemorrhagic fever (CCHF). High-dose corticosteroids, immune globulin intravenous, and fresh frozen plasma have also been reported to be successful in CCHF.[41] Infusion of convalescent plasma during the first 8 days of illness with Argentine HF reduces the mortality rate from 15-30% to less that 1%.

Novel treatment studies using positively-charged phosphorodiamidate morpholino oligomers (PMOplus) demonstrate protection of monkeys infected with Ebola and Marburg viruses.[42] These studies suggest a potential therapeutic modality for human infection for the future.

Studies of high-dose mannose-binding lectin therapy in mice suggest a promising future therapeutic modality for Ebola (and other viruses) infection.[43, 44]

Consultations

See the list below:

  • Infectious diseases specialist (urgent)

  • Hematologist

  • Others as dictated by the clinical circumstances

 

Medication

Medication Summary

Ribavirin is effective for treating patients with Lassa fever and markedly reduces the mortality rate if used within the first week of illness. Oral ribavirin may be of benefit for postexposure prophylaxis in high-risk Lassa fever exposures.[45] Its use is under investigation for the treatment of patients with South American hemorrhagic fever (HF) but it is recommended for infection with all arenaviruses until a more effective alternative treatment becomes available. Widespread clinical trials have not established the efficacy of ribavirin in Crimean-Congo hemorrhagic fever (CCHF).[46] No evidence suggests any benefit of antiviral agents, passive antibodies, or interferon in the treatment for Ebola or Marburg virus infection. Other agents are being sought.[47, 48]

Antiviral agents

Class Summary

Some evidence suggests that ribavirin may be effective in the viral hemorrhagic fevers (VHFs) (in addition to Lassa fever, for which it is effective), particularly among the other arenaviruses and possibly in CCHF.[49] Treatment must be initiated promptly at the onset of the infection to effectively inhibit the replicating virus.

Ribavirin (Virazole)

DOC for VHF caused by arenaviruses, until other more effective drugs are identified and made available. Inhibits viral replication by inhibiting DNA and RNA synthesis.

 

Follow-up

Further Inpatient Care

Intensive care treatment, when available, is most likely required for viral hemorrhagic fevers (VHFs).

Transfer

Transfer to another facility is appropriate when the required level of care and specialists are not available locally.

Deterrence/Prevention

See the list below:

  • The most important measure for preventing viral hemorrhagic fever is avoidance of insect bites from the vectors and exposure to rodent sources of infection.

  • Immunization with live attenuated Junin virus in Argentina has reduced the incidence of disease to fewer than 100 cases in recent years.[32]

  • Elimination of specific reservoir rodents from towns is practical and effective for most South American HFs. Care should be taken before entering or cleaning closed buildings with potential rodent infestation.

  • Infection with one of the Bunyaviridae leads to full immunity.

  • Since 1994, live, attenuated, and inactivated Rift Valley fever (RVF) virus vaccines have been available for domestic livestock and an experimental inactivated RVF virus vaccine is available for human use.[50]

  • Avoidance of ticks and slaughtering of acutely infected animals may eliminate much of the risk of RVF and Crimean-Congo hemorrhagic fever (CCHF). Tick-borne flaviviruses may be suppressed by postexposure prophylaxis with virus-specific IgG.

  • Barrier nursing and needle sterilization in African hospitals are of particular importance to eliminate epidemics of Ebola and Marburg diseases, as is avoidance of close contact with infected patients. Promising vaccines against these viruses are in preliminary primate studies.

  • Careful evaluation of all sick primates should also be undertaken.

  • Vaccines are being sought.[51]

Complications

See the list below:

  • Hearing deficits have been reported in up to one third of patients with severe Lassa fever.

  • Uveitis, orchitis, transverse myelitis, and recurrent hepatitis are late complications of Ebola and Marburg infections.

  • Acute liver failure, multiorgan failure, and cerebral edema may complicate Marburg infection.[52]

  • Infection with RVF may lead to blindness in as many as 20% of patients.

  • CCHF may be complicated by cardiac involvement[53] or pleural effusions and ascites.[54]

  • Nosocomial transmission of CCHF with fatal outcome has been reported.[55]

Prognosis

Individuals who survive and do not experience specific sequelae typically return to their premorbid state.

Patient Education

See the list below:

  • Discussing protective measures with prospective travelers is of utmost importance for avoidance of VHFs and many other infections.

  • For patient education resources, see the patient education article Ticks.