Viral hemorrhagic fevers

Clinical Features

Clinical Characteristics

Although clinical features vary somewhat for the various hemorrhagic fever viruses, the clinical presentations overlap substantially. All of the agents cause a febrile prodrome associated with varying degrees of prostration; other notable features include the following.

  • Bleeding manifestations occur in variable proportions of patients (eg, in about 30% of patients with Ebola or Marburg hemorrhagic fever and in only about 1% of patients with Rift Valley fever).
  • A maculopapular rash may be noted early in the clinical course in some forms of VHF (notably in Ebola and Marburg hemorrhagic fevers).
  • Severe exudative pharyngitis is a characteristic early feature of Lassa fever.
  • Several agents cause meningoencephalitis in addition to VHF (eg, Rift Valley fever, Kyasanur Forest disease, Omsk hemorrhagic fever).
  • Jaundice may be a prominent feature in some infections (eg, Ebola and Marburg hemorrhagic fevers, Lassa fever, Rift Valley fever, yellow fever).

Major clinical features for each of the agents are included in the tables below.

Clinical Features of Ebola Hemorrhagic Fever

Characteristic

Features

Incubation period

2-21 days

Prodromea

—Abrupt onset of fever, severe prostration, headache, myalgias is typical
—Other features may include abdominal pain, nausea/vomiting, diarrhea, chest pain, cough, pharyngitis, lymphadenopathy, photophobia, and conjunctival injection

Clinical signs/symptomsb

—Maculopapular rash (predominantly on trunk) occurs about 5 days after illness onset
—Jaundice and pancreatitis often occur
—As disease progresses, bleeding manifestations may develop (eg, mucous membrane hemorrhages, hematemesis, bloody diarrhea, petechiae, ecchymoses, oozing of blood at puncture sites)
—In 1995 DRC outbreak, some form of bleeding was reported in 37% of 219 patients
—CNS findings include psychosis, delirium, coma, seizures
—Shock (with DIC and end-organ failure) often ensues during second week of illness
—Signs and symptoms recorded for 219 patients in 1995 DRC outbreak (recorded at time of admission or during clinical course) included:
    ~Asthenia (78%)
    ~Diarrhea (74%)
    ~Headache (73%)
    ~Anorexia (73%)
    ~Nausea/vomiting (70%)
    ~Abdominal pain (56%)
    ~Myalgias/arthralgias (51%)
    ~Dysphagia (41%)
    ~Conjunctival inflammation/hemorrhage (34%)
    ~Dyspnea (25%)
    ~Gingival hemorrhage (21%)
    ~Petechiae (15%)
    ~Melena (14%)
    ~Hiccups (14%)
    ~Hematemesis (13%)
—Asymptomatic infections can occur
—Recovery may take up to several weeks

Laboratory featuresc

—Leukopenia early in clinical course; leukocytosis (may occur later)
—Thrombocytopenia early in clinical course
—Elevated amylase and hepatic enzymes (eg, increased ALT, AST) as disease progresses
—Laboratory features of DIC (may occur as disease progresses): prolonged bleeding time, prothrombin time, and activated partial thromboplastin time; elevated fibrin degradation products; decreased fibrinogen

Complicationsd (generally occur at least 2 wk after illness onset)

—Migratory arthralgias
—Ocular disease (unilateral vision loss, uveitis)
—Suppurative parotitis
—Orchitis
—Hearing loss
—Pericarditis
—Illness-induced abortion among pregnant women

Case-fatality ratee

—Varies by virus subtype:
    ~Zaire, 57%-90%
    ~Sudan, about 50%
    ~Cote d'Ivoire, not established
    ~Reston, 0% (not known to cause clinical disease in humans)
—In 1995 DRC outbreak: mean number of days from symptom onset to death, 9.6 days (range, 0-34 days)

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CNS, central nervous system; DIC, disseminated intravascular coagulation; DRC, Democratic Republic of the Congo.

aSee References: Borio 2002; Peters 2005: Marburg and Ebola Virus Hemorrhagic Fevers.
bSee References: Borio 2002; Bwaka 1999; Khan 1999; Leroy 2000: Human asymptomatic Ebola infection; Peters 2005: Marburg and Ebola virus hemorrhagic fevers.
cSee References: WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee, 1984.
dSee References: Bwaka 1999, Kibadi 1999.
eSee References: Kahn 1999; WHO 2007: Ebola hemorrhagic fever; Zaki 1997.


Clinical Features of Marburg Hemorrhagic Fever

Characteristic

Features

Incubation period

2-14 days

Prodromea

—Abrupt onset of fever, severe prostration, headache, myalgias is typical.
—Other features may include abdominal pain, nausea/vomiting, diarrhea, chest pain, cough, pharyngitis, lymphadenopathy, photophobia, and conjunctival injection.
—The following may also occur: enanthem on soft palate, hyperesthesias, and "clouded consciousness."

Clinical signs/symptomsa

—Maculopapular rash occurs on the 5th to 7th day (trunk, face, neck, proximal regions of extremities) and is nonpruritic.
—Jaundice and pancreatitis usually occur.
—As disease progresses, bleeding manifestations may develop (eg, mucous membrane hemorrhages, hematemesis, bloody diarrhea, melena, bleeding from gums, petechiae, ecchymoses, hematuria).
—In one report of 23 patients, bleeding manifestations occurred in 7 (30%).
—CNS findings include restlessness, confusion, apathy, somnolence, meningismus.
—Shock (with DIC and end-organ failure) may ensue during 2nd week of illness
—Recovery may take up to several weeks.

Laboratory featuresb

—Leukopenia early in clinical course (1,000-2,000/mm3); leukocytosis (may occur later)
—Atypical lymphocytes (may be present)
—Marked thrombocytopenia early in clinical course (may be as low as 10,000/mm3)
—Elevated amylase and hepatic enzymes (eg, increased ALT, AST) as disease progresses
—Laboratory features of DIC (may occur as disease progresses): prolonged bleeding time, prothrombin time, and activated partial thromboplastin time; elevated fibrin degradation products; decreased fibrinogen

Complicationsa (generally occur at least 2 wk after illness onset)

—Orchitis
—Alopecia
—Uveitis
—Recurrent hepatitis

Case-fatality rateb

Varies by outbreak (23%-93%)

Abbreviations: ALT, alanine aminotransferase; CNS, central nervous system; AST, aspartate aminotransferase; DIC, disseminated intravascular coagulation.

aSee References: Gear 1975; Martini 1971; Peters 2005: Marburg and Ebola virus hemorrhagic fevers.
bSee References: Martini 1971; WHO: Marburg haemorrhagic fever: situation updates.


Clinical Features of Lassa Fever

Characteristic

Features

Incubation period

5-16 days

Prodromea

—Illness begins gradually with fever, weakness, generalized malaise.
—Arthralgias, back pain, nonproductive cough, retrosternal pain often appear by 3rd to 4th day.

Clinical signs/symptomsa

—Severe exudative pharyngitis may occur (40% in one series of 306 patients).b
—Macolopapular rash may be noted on some fair-skinned patients.
—Severe prostration may occur by 6th to 8th day.
—As disease progresses, bleeding manifestations may develop (eg, mucous membrane hemorrhages, hematemesis, bloody diarrhea, petechiae, ecchymoses).
—In one outbreak in Sierra Leone, bleeding manifestations occurred in 17% of 306 patients.b
—Other findings that may occur include:
    ~Edema of head and neck
    ~Pleural, pericardial effusions
    ~Neurologic involvement (encephalopathy, coma, meningeal signs, cerebellar syndromes, tremors, seizures, eighth cranial nerve involvement)
    ~Capillary leak syndrome
    ~Shock with end-organ failure
—For those with less severe disease, recovery begins at about 10 days, although weakness and fatigue may persist for several weeks.
—Most infections are thought to be mild or subclinical; severe disease occurs in 5%-10% of cases.

Laboratory featuresb

—Leukocyte counts: occasionally decreased but most often normal or moderately increased
—Hemoconcentration, proteinuria, and elevated hepatic enzymes( may occur)
—Thrombocytopenia mild or does not occur (although marked loss of platelet function has been demonstrated in vitro)
—Mean laboratory values at time of admission (and highest recorded) for 441 patients with Lassa fever in Sierra Leone:
    ~ALT: 96.5 U/L (147.1 U/L)
    ~Amylase: 259.1 U/L (381.6 U/L)
    ~AST: 408.2 U/L (602 U/L)
    ~BUN: 27.8 mg/dL (34.5 mg/dL)
    ~CPK: 515.7 U/L (893 U/L)
    ~Hematocrit: 50.6% (50.6%)
    ~Hemoglobin: 10.7 g/dL (14.9 g/dL)
    ~WBC count: 5,976/mm3 (4,603/mm3)

Complicationsc (generally occur in 2nd and 3rd wk of illness)

—8th cranial nerve damage with hearing loss (may improve or may result in permanent hearing loss)
—Pericarditis (about 2% of patients in one series, all male, all recovered)b
—Transient alopecia during convalescence
—Illness-induced abortion among pregnant women

—Uveitis and orchitis (uncommon)

Case-fatality rate

—Overall mortality (including nonhospitalized patients), 1%-2%.d
—Hospitalized patients, 15%-25%e
—Series of 150 hospitalized patients, 9%f
—Series of 441 hospitalized patients, 16.5%b

Abbreviations: ALT, alanine aminotransferase; AST: aspartate aminotransferase; BUN, blood urea nitrogen; CPK, creatine phosphokinase; WBC, white blood cell.

aSee References: Borio 2002; Peters 2005: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers.
bSee References: McCormick 1987: A case-control study.
cSee References: McCormick 1987: A case-control study; Peters 2005: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers.
dSee References: McCormick 1987: A prospective study.
eSee References: Peters 2005: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers.
fSee References: Frame 1989.


Clinical Features of New World Hemorrhagic Fever

Characteristic

Features

Incubation period

7-16 days

Prodrome

Gradual onset of fever, sore throat, myalgias, low back pain, abdominal pain

Clinical signs/symptomsa

—Common early findings include:
    ~Conjunctival injection
    ~Flushing of face, upper body
    ~Enanthem (petechiae and/or small vesicles)
    ~Skin petechiae
    ~Generalized lymphadenopathy
—As disease progresses, vascular or neurologic manifestations may occur (5-7 days after illness onset).
—Vascular manifestations include:
    ~Capillary leak syndrome
    ~Proteinuria
    ~Bleeding manifestations (eg, mucous membrane hemorrhages, hematemesis, bloody diarrhea, petechiae, ecchymoses)
    ~In one series of 14 patients with Venezuelan hemorrhagic fever, bleeding manifestations in 13 (92%)
    ~Vasoconstriction, shock
—Neurologic manifestations include:
    ~Tremors
    ~Myoclonic movements
    ~Seizures
    ~Dysarthria
    ~Coma
—Clinical findings on admission for 14 patients with Venezuelan hemorrhagic fever includedb:
    ~Dehydration (71%)
    ~Pharyngitis (71%)
    ~Somnolence (64%)
    ~Conjunctivitis (50%)
    ~Crackles (43%)
    ~Petechiae (29%)
    ~Cervical adenopathy (21%)
    ~Facial edema (14%)
    ~Tonsillar exudates (14%)
    ~Hand tremors (7%)
    ~Rash (7%)
—Recovery occurs over 2-3 wk.

Laboratory featuresc

—Leukopenia (1,000-2,500/mm3)
—Thrombocytopenia (40,000-80,000/mm3)
—Proteinuria (may be >10 g/day; occurs occasionally)
—Hemoconcentration

Complicationsd

—Transient alopecia and nail furrows may occur.
—Most patients who survive recover without sequelae, although convalescence may require several weeks.

Case-fatality ratee

—Junin (Argentine hemorrhagic fever), 15%-30%
—Machupo (Bolivian hemorrhagic fever), 30%
—Guanarito (Venezuelan hemorrhagic fever),: 25%
—Sabia (Brazilian hemorrhagic fever), 33% (only 3 cases identified, 1 fatal)
—Whitewater Arroyo, 100% only 3 cases identified; all fatal)

aSee References: Borio 2002; Peters 2005: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers.
bSee References: Salas 1991.
cSee References: WHO1985: Viral haemorrhagic fevers: report of a WHO expert committee.
dSee References: Peters 2005: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers.
eSee References: CDC 2000: Fatal illnesses associated with a New World arenavirus; CDC 1994: Bolivian hemorrhagic fever; Peters 2005: Lymphocytic choriomeningitis virus, Lassa virus, and the South American hemorrhagic fevers; Salas 1991.


Clinical Features of Rift Valley Fever

Characteristic

Features

Incubation period

2-6 days

Prodromea

Fever, headache, photophobia, retro-orbital pain

Clinical signs/symptomsb

—Subclinical infection is common.
—Four clinical patterns occur:
    ~Undifferentiated fever lasting 2-7 days (>90% of cases; often associated with nausea, vomiting, and abdominal pain)
    ~Hemorrhagic fever with marked hepatitis and bleeding manifestations (<1% of cases; occurs 2-4 days after onset of fever)
    ~Encephalitis (<1% of cases; occurs 1-4 wk after onset of fever)
    ~Retinitis (up to 10% of cases; occurs 1-4 wk after onset of fever; often bilateral; hemorrhages, exudates, and cotton wool spots may be visible on macula; retinal detachment may occur)
—Common bleeding manifestations include gastrointestinal bleeding and epistaxis.
—Neurologic symptoms include confusion, lethargy, tremors, ataxia, coma, seizures, meningismus, vertigo, and choreiform movements.
—Hepatitis, hepatic failure, and renal failure may occur.
—A report of the 2001 outbreak in Saudi Arabia identiied the following clinical features for 683 laboratory-confirmed cases:
    ~Fever: 92.6%
    ~Nausea: 59.4%
    ~Vomiting: 52.6%
    ~Abdominal pain: 38.0%
    ~Diarrhea: 22.1%
    ~Jaundice: 18.1%
    ~Neurologic manifestations: 17.1%
    ~Hemorrhagic manifestations: 7.1%

Laboratory featuresc

—Initial leukocytosis (may occur, followed by leukopenia)
—Thrombocytopenia in severe cases
—Laboratory features of DIC in severe cases (prolonged bleeding time, prothrombin time, and activated partial thromboplastin time; elevated fibrin degradation products; decreased fibrinogen)
—Elevated hepatic enzymes (eg, ALT, AST) and bilirubin

Complicationsd

—Blindness following retinitis
—Neurologic sequelae following encephalitis

Case-fatality ratee

—Overall, <1%
—For hemorrhagic disease, about 50%

—In 2000 outbreak in Saudi Arabia, 17% among symptomatic patients and 33.3% among hospitalized patients admitted to RVF unit at local referral hospital
—Death usually due to hepatic necrosis and DIC

Abbreviations: ALT, alanine aminotransferase; AST: aspartate aminotransferase; DIC, disseminated intravascular coagulation; RVF, Rift Valley fever.

aSee References: Borio 2002.
bSee References: Al-Hazmi 2003; Borio 2002; CDC 2000: Outbreak of Rift Valley fever--Yemen; CDC: Rift Valley fever fact sheet; Madani 2003; WHO 1984: Viral hemorrhagic fevers: report of a WHO expert committee.
cSee References: Lacy 1996.
dSee References: WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee.
eSee References: Al-Hazmi 2003, Borio 2002, Madani 2003, Morrill 1996.


Clinical Features of Yellow Fever

Characteristic

Features

Incubation period

3-6 days

Prodromea

—Fever, headache, myalgias, facial flushing, conjunctival injection, relative bradycardia (Faget's sign)
—Resembles two of the disease categories below, very mild and mild

Clinical signs/symptomsb

—Subclinical infection is common (5%-50%).
—Five clinical patterns occur:
    ~Very mild (transient fever, mild headache; illness lasting about 1 day)
    ~Mild (more pronounced fever and headache; nausea, vomiting, epigastric pain, myalgias, epistaxis, photophobia, asthenia [may be present]; illness lasting 2-3 days).
    ~Moderately severe (high fever; severe headache/backache; biphasic course with jaundice, albuminuria, oliguria, protracted vomiting, and bleeding manifestations in second phase; illness lasting about 1 wk)
    ~Malignant (fulminant infection with severe hepatic involvement, bleeding manifestations, renal failure, shock, and death [usually 7-10 days after illness onset])
    ~Fever accompanied by only meningeal signs and symptoms
—Bleeding manifestations include hematemesis, bloody diarrhea, epistaxis, gum bleeding, petechial and purpuric hemorrhages.
—Severe disease develops in about 15% of patients; of these, about 50% go on to the malignant form and die.

Laboratory featuresc

—Leukopenia early in clinical course; leukocytosis (may occur later)
—Thrombocytopenia
—Albuminuria
—Elevated hepatic enzymes (eg, ALT, AST)
—Elevated bilirubin (5-10 mg/dL)

Complicationsc

—Myocarditis

Case-fatality rated

—Overall, 5%-7%
—Hospitalized patients or in some epidemics, about 20%
—Patients in whom severe disease develops (jaundice, bleeding manifestations), about 50%

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

aSee References: Tsai 2000.
bSee References: Lacy 1996; Tsai 2000; WHO 2001: Yellow fever; WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee, 1984.
cSee References: Lacy 1996.
dSee References: Borio 2002; Lacy 1996; WHO 2001: Yellow fever.


Clinical Features of Kyasanur Forest Disease

Characteristic

Features

Incubation period

2-9 days (usually 3-8 days)

Prodrome

Sudden onset of fever, myalgias, headache

Clinical signs/symptomsa

—Diarrhea and vomiting occur by the 3rd or 4th day.
—Enanthem with papulovesicular lesions occurs on soft palate.
—Ocular findings include conjunctival congestion, subconjunctival hemorrhage, superficial punctate keratitis, mild iritis, and retinal and vitreous hemorrhage.b
—Cervical and axillary lymphadenopathy are usually present.
—Bleeding manifestations are seen as early as third day (bleeding from nose, gums, gastrointestinal tract).
—In one series of 152 patients, bleeding occurred in 26 patients (17%).b
—The initial illness phase lasts 6 days to 2 wk.
—Illness may be biphasic for up to 50% of cases; after initial illness, afebrile period of 9-21 days occurs, followed by meningoencephalitis.
—Findings associated with meningoencephalitis include tremors, headache, mental status changes, and abnormal reflexes.
—Hemorrhagic pulmonary edema and renal failure occur in severe cases.
—Recovery takes up to 4 wk.

Laboratory featuresc

—Leukopenia (average: 2,000/mm3)
—Lymphopenia or lymphocytosis, atypical lymphocytes (may occur)
—Thrombocytopenia (average: 86,000/mm3)
—Abnormal liver function tests may occur

Complications

Not prominent feature of disease

Case-fatality rate*

3%-10%

aSee References: Borio 2002, Pavri 1989, Pattnaik 2006.
bSee References: Nayak 1983.
cSee References: Pavri 1989.


Clinical Features of Omsk Hemorrhagic Fever

Characteristic

Features

Incubation period

2-9 days (usually 3-8 days)

Prodromea

Fever, headache, vomiting, enanthem on palate, hyperemia of skin on upper body and mucous membranes

Clinical signs/symptomsa,b

—Initial febrile illness lasting 5-12 days occurs, followed by second phase several days later in 30%-50% of patients that is often more severe.
—Generalized lymphadenopathy and splenomegaly commonly occur.
—During second phase, pneumonia occurs in about 30% of patients and meningeal symptoms are common.

—Diffuse encephalitis may occur.
—Recovery may take several weeks.

Laboratory featuresb

—Leukopenia
—Thrombocytopenia
—Monocytosis

Complicationsb

Transient alopecia may occur

Case-fatality ratea,b

0.5%-10%

aSee References: Borio 2002.
bSee References: WHO 1985: Viral haemorrhagic fevers: report of a WHO expert committee.

Pediatric Considerations

In general, the clinical manifestations of VHF are similar in children and adults. One review of 33 pediatric cases of Lassa fever identified the following clinical presentations on the basis of age (see References: Monson 1987):

  • Fetal infection (18 pregnancies):
    • Spontaneous abortion following onset of infection occurred in 16 cases (one mother later died).
    • Fetal death in utero occurred in 2 cases; just prior to death, spontaneous abortion appeared likely in both.
    • All pregnancies terminated between the 3rd and 9th months.
  • Congenital infection (1 case):
    • One child died of Lassa fever 4 days after birth; the mother denied any recent febrile illness at the time of the child's death, but she was lost to follow-up and could not be reached when the positive culture was reported.
  • Nursing infants (7 cases):
    • Presenting symptoms included fever, vomiting, seizures, pneumonia, edema, anorexia, cough, diarrhea, irritability, stomatitis, obtundation, bleeding, lethargy, and abdominal tenderness and distention.
    • Leukocyte counts ranged from 3,600/mm3 to 20,000/mm3.
    • The case-fatality rate was 29%.
  • Children over 2 years of age (7 cases):
    • Presenting symptoms included fever, cough, edema, bleeding, abdominal pain, vomiting, seizures, sore throat, conjunctivitis, and obtundation.
    • Leukocyte counts ranged from 3,000/mm3 to 42,000/mm3.
    • The case-fatality rate was 14%.
  • "Swollen baby syndrome" (4 cases):
    • Four children (aged 4 days, 6 weeks, 7 months, and 9 years) presented with the triad of edema, abdominal distention, and bleeding, which investigators referred to as "swollen baby syndrome."
    • Three of the four children died.

A review of 15 pregnant women with Ebola hemorrhagic fever demonstrated high rates of fetal loss (similar to those just noted for Lassa fever) and also demonstrated a high case-fatality rate for pregnant women (see References: Mupapa 1999):

  • Spontaneous abortion occurred in 10 women
  • All the mothers presented with severe bleeding; all except 1 subsequently died.
    • One woman delivered a stillborn infant and subsequently died.
    • One woman delivered a full-term baby; the infant died 3 days after birth and the mother died from severe postpartum hemorrhage.
    • Three additional women died in their 3rd trimester of pregnancy.

Vertical transmission also has been reported for Rift Valley fever (see References: Adam 2008, Arishi 2006).

Center for Infectious Disease Research & Policy Website. 2007. University of Minnesota. 21 Feb, 2011<http://www.cidrap.umn.edu>.
Diseases classified as VHF can be diverse in clinical presentation. In their most severe form, these diseases manifest as the VHF syndrome, with capillary leak, bleeding diathesis and hemodynamic compromise leading to shock. Early symptoms of VHF are nondescript in most cases, consisting of fever and constitutional symptoms such as malaise, myalgias and headache. This constellation of findings is difficult to discern from any number of viral, bacterial or parasitic diseases.

Diversity of clinical features among the VHF infections probably stems from varying mechanisms of pathogenesis. For example, an immunopathogenic mechanism has been identified for dengue hemorrhagic fever, which usually occurs among patients previously infected with a heterologous dengue serotype. A prominent theory explaining this phenomenon is called "antibody-dependent enhancement." Disseminated intravascular coagulation (DIC) is thought to underlie the hemorrhagic features of Rift Valley, Marburg and Ebola fevers; but in most VHFs, the etiology of the coagulopathy is multifactorial (e.g., hepatic damage, consumptive coagulopathy, and primary marrow dysfunction).

Why some infected persons develop full-blown VHF while others do not remains an unresolved issue. Virulence of the infecting agent clearly plays a large role. The VHF syndrome occurs in a majority of patients manifesting disease from filoviruses, CCHF and the South American hemorrhagic fever viruses, while it occurs in a small minority of patients with dengue, RVF and Lassa fever. The reasons for variation among patients infected with the same virus are still unknown but probably stem from a complex system of virus-host interactions.

Differentiating the various VHF's prior to laboratory diagnosis may be difficult. Epidemiologic features may be helpful, especially the proportion of cases with mild or moderate disease compared to the proportion with severe disease. Astute clinicians who are familiar with the clinical presentations of the various VHF diseases may be able to pick out unique features that implicate one disease over the others. Clinical manifestations of the various VHF's are discussed below. Table 1 provides a summary of disease characteristics.

Table 1. Epidemiologic Clues of a BW or Terrorist Attack

  • The presence of a large epidemic with a similar disease or syndrome, especially in a discrete population
  • Many cases of unexplained diseases or deaths
  • More severe disease than is usually expected for a specific pathogen or failure to respond to standard therapy
  • Unusual routes of exposure for a pathogen, such as the inhalational route for diseases that normally occur through other exposures
  • A disease that is unusual for a given geographic area or transmission season
  • Disease normally transmitted by a vector that is not present in the local area
  • Multiple simultaneous or serial epidemics of different diseases in the same population
  • A single case of disease by an uncommon agent (smallpox, some viral hemorrhagic fevers, inhalational anthrax, pneumonic plague)
  • A disease that is unusual for an age group
  • Unusual strains or variants of organisms or antimicrobial resistance patterns different from those known to be circulating
  • A similar or exact genetic type among agents isolated from distinct sources at different times and or locations
  • Higher attack rates among those exposed in certain areas, such as inside a building if released indoors, or lower rates in those inside a sealed building if released outside
  • Disease outbreaks of the same illness occurring in noncontiguous areas
  • A disease outbreak with zoonotic impact
  • Intelligence of a potential attack, claims by a terrorist or aggressor of a release, and discovery of munitions, tampering, or other potential vehicle of spread (spray device, contaminated letter)

Arenaviridae: The clinical features of the South American hemorrhagic fevers (SAHF's) are quite similar, but they differ significantly from those of Lassa fever. The onset of the SAHF's is insidious, resulting in high unremitting fever and constitutional symptoms. A petechial or vesicular enanthem involving the palate and tonsillar pillars is quite common, as is conjunctival injection and flushing of the upper torso and face. Patients frequently have associated neurologic disease, with initial hyporeflexia followed by gait abnormalities and cerebellar dysfunction. Seizures portend a grave prognosis. Mortality from the SAHF's is high, ranging from 15% to over 30%.

By contrast, most natural infections with Lassa virus are mild or non-apparent. Less than 10% of infections result in severe disease, but mortality in these patients can be as high as 25%. Hemorrhagic phenomena are relatively uncommon, but patients frequently have retrosternal chest pain, sore throat and proteinuria. Syndromes with features of encephalitis and/or meningitis are sometimes present, as are convalescent cerebellar syndromes. Serum AST levels of 115 U/L or greater are indicative of a poor prognosis - this is often considered a criterion for treatment. Eighth nerve deafness is a common feature of Lassa fever. It occurs in the second or third week of illness and may be permanent. Transient alopecia is not uncommon during convalescence.

Bunyaviridae: CCHF is generally a severe, hemorrhagic disease. Onset is abrupt, and GI and meningeal symptoms occur frequently. Petechiae and ecchymoses are common, as is mucosal bleeding. Hepatitis and jaundice probably results from direct viral cytotoxicity. Thrombocytopenia can be profound. Mortality ranges from 20% to 50%.

RVF is usually a self-limited, nondescript febrile illness. About 10% of patients develop retinitis with cotton-wool exudates in or around the macula. This may result in permanent vision loss. Only 1% develop hemorrhagic manifestations or severe hepatic disease, usually occurring as a second febrile phase after defervescence from an initial febrile phase of 3 - 7 days. A small minority of patients develops encephalitis after the initial febrile illness.

The severity of HFRS depends largely on the infecting virus. Puumala virus causes a relatively mild form of disease called nephropathica endemica that is associated with rare mortality. The most severe form of HFRS is caused by Hantaan virus and is known by various names including Korean hemorrhagic fever. Disease onset is usually abrupt and is associated with fever, malaise, myalgia, headache and lassitude. Some characteristic features are flushing of the face and neck, conjunctival and pharyngeal injection, cutaneous and mucosal petechiae (occuring by day 4-5), and profound low back pain. Mild DIC, thrombocytopenia and capillary leak syndrome may ensue leading to hypovolemic shock. Renal dysfunction is pathognomonic, frequently progressing to oliguric renal failure. A subsequent diuretic phase often accompanies convalescence, and fluid management may be a significant challenge. Death occurs in 5% to 15% of Hantaan infections.

Filoviridae: Ebola and Marburg infections present similiarly. Onset is abrupt with fever, constitutional symptoms, nausea, vomiting, diarrhea, abdominal pain, lymphadenopathy, pharyngitis, conjuctival injection, jaundice and pancreatitis. Deleirum, obtundation and coma are common. Hemorrhagic features develop as the disease progresses. A large number of patients develop a maculopapular rash around day 5, but this may be difficult to appreciate in dark-skinned persons. Death occurs at the beginning of the second week of illness. Mortality ranges from 25% (Marburg) to over 80% (Ebola Zaire).

Flaviviridae: Yellow fever is classically described as a severe biphasic illness, but it is apparent that a large number of infections are mild or subclinical. The initial phase of illness lasts about one week and consists of fever, constitutional symptoms, GI symptoms and other undifferentiated symptoms. Objective findings are unimpressive except for the frequent appearance of relative bradycardia (Faget's sign) and leukopenia. Facial flushing and conjuctival injection may also be present. After a period of clinical improvement and defervescence (hours to days) some patients develop a second febrile phase. This so called period of intoxication is characterized by high fever, severe constitutional symptoms, obtundation, skin and mucous membrane hemorrhages, severe hepatitis and profound jaundice. Liver associated enzyme elevation occurs in a pattern consistent with hepatocellular damage, and bilirubin may be quite high. Proteinuria is almost universal and is an excellent diagnostic clue. As severe disease progresses, renal failure consistent with hepatorenal syndrome may ensue. Death occurs in 50% of patients with the hemorrhagic form of yellow fever.

The two members of the TBE complex causing hemorrhagic disease (KFD, OHF) have similar clinical syndromes and are often biphasic. The first phase is a febrile viral syndrome of varying severity, associated with conjuctival suffusion, facial flushing, lymphadenopathy and splenomegaly. In its most severe form, this syndrome may be accompanied by diffuse mucosal hemorrhaging and petechiae. Hemorrhagic pulmonary edema is a relatively common and unique feature. A second phase of illness may occur 1-3 weeks after remission. This second phase involves mainly neurologic disease. Mortality ranges from < 3% (OHF) up to 10% (KFD). Survivors may experience complications of iritis, keratitis or neuropsychiatric abnormalities.

Table 2: Comparison of VHF agents and diseases

Flavivirus

  • Virus: Yellow fever virus
  • Disease: Yellow fever
  • Endemic area: Africa, South America
  • Mortality: Overall 3-12%, 20-50% if severe second phase develops
  • Nosocomial transmission: No
  • Characteristic features: Often biphasic, severe second phase with bleeding, very high bilirubin and transaminases, jaundice, renal failure
  • Countermeasures: 17-D live attenuated vaccine very effective in prevention, no post-exposure countermeasure available

  • Virus: KFD virus
  • Disease: Kyasanur Forest disease
  • Endemic area: Southern India
  • Mortality: 3-5%
  • Nosocomial transmission: No
  • Characteristic features: Flu-like syndrome with addition of cough, GI symptoms, hemorrhage, bradycardia
  • Countermeasures: Formalin-inactivated vaccine available in India

  • Virus: OHF virus
  • Disease: Omsk hemorrhagic fever
  • Endemic area: Siberia
  • Mortality: 0.2-3%
  • Nosocomial transmission: No
  • Characteristic features: Frequent sequelae of hearing loss, neuropsych complaints, alopecia
  • Countermeasures: TBE vaccines (not avail. in US) may offer some cross-protection

Filoviruses

  • Virus: Ebola virus
  • Disease: Ebola hemorrhagic fever
  • Endemic area: Africa, Philippines (Ebola Reston)
  • Mortality: 50-90% for Sudan/Zaire
  • Nosocomial transmission: Common
  • Characteristic features: Severe illness, maculopapular rash, profuse bleeding and DIC
  • Countermeasures: Anecdotal success with immune serum transfusion

  • Virus: Marburg virus
  • Disease: Marburg hemorrhagic fever
  • Endemic area: Africa
  • Mortality: 23-70%
  • Nosocomial transmission: Yes
  • Characteristic features: Severe illness, maculopapular rash, profuse bleeding and DIC
  • Countermeasures: Anecdotal success with immune serum transfusion

Bunyaviruses

  • Virus: CCHF
  • Disease: Crimean-Congo hemorrhagic fever
  • Endemic area: Africa, SE Europe, Central Asia, India
  • Mortality: 30%
  • Nosocomial transmission: Yes
  • Characteristic features: Often prominent petechial/ecchymotic rash
  • Countermeasures: Anecdotal success with ribavirin

  • Virus: RVF
  • Disease: Rift valley fever
  • Endemic area:
  • Mortality:
  • Nosocomial transmission:
  • Characteristic features:
  • Countermeasures:

  • Virus: Hantavirus (Hantaan, Dobrava, Seoul, Puumala)
  • Disease: Hemorrhagic fever with renal syndrome (HFRS)
  • Endemic area: Europe, Asia, South America (rare)
  • Mortality: 5% for Asian HFRS
  • Nosocomial transmission: No
  • Characteristic features: Prominent renal disease, marked polyuric phase during recovery, usually elevated WBC
  • Countermeasures: Effective locally produced vaccines in Asia (not avail in U.S.). Experimental vaccine at USAMRIID. Ribavirin effective in randomized, controlled clinical trial

Arenaviruses

  • Virus: Lassa virus
  • Disease: Lassa fever
  • Endemic area: West Africa
  • Mortality: 1-2%
  • Nosocomial transmission: Yes
  • Characteristic features: Frequent inapparent/mild infection, hearing loss in convalescence common
  • Countermeasures: Ribavirin effective in clinical trial with non-randomized controls

  • Virus: Junin
  • Disease: Argentine hemorrhagic fever
  • Endemic area: Argentinean pampas
  • Mortality: 30%
  • Nosocomial transmission: Rare
  • Characteristic features: Prominent GI complaints, late neurologic syndrome
  • Countermeasures: Immune plasma, Ribavirin effective Candid 1 vaccine

  • Virus: Machupo
  • Disease: Bolivian hemorrhagic
  • Endemic area: Bolivia
  • Mortality: 25-35%
  • Nosocomial transmission: Rare
  • Characteristic features: Similar to AHF
  • Countermeasures: Immune plasma effective, ribavirin probably effective, Candid 1 vaccine protects monkeys
USAMRIID's Medical Management of Biological Casualities Handbook. Sixth ed. Fort Dietrich, Maryland: U.S. Army Medical Research Institute of Infectious Diseases, 2005. 76-80, 9.
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