Viral hemorrhagic fevers

Diagnosis

VHF should be considered in any patient presenting with a severe, acute febrile illness and evidence of vascular involvement (postural hypotension, petechiae, easy bleeding, flushing of face and chest, non-dependent edema). Symptoms and signs suggesting additional organ system involvement are common (headache, photophobia, pharyngitis, cough, nausea or vomiting, diarrhea, constipation, abdominal pain, hyperesthesia, dizziness, confusion, tremor) but usually do not dominate the picture, with the exceptions listed above under ?Clinical Features.? A positive tourniquet test has been particularly useful in dengue hemorrhagic fever, but should be sought in other hemorrhagic fevers as well.

A detailed travel history and a high index of suspicion are essential in making the diagnosis of VHF. Patients with arenavirus or hantavirus infections often recall proximity to rodents or their droppings; but as the viruses are spread to humans by aerosolized excreta or environmental contamination, actual contact with the rodent reservoir is not necessary. Large mosquito populations are common during RVF, yellow fever, or dengue transmission, but a history of mosquito bite is too common to be of diagnostic importance. Tick bites or nosocomial exposure are of some significance in suspecting CCHF. Large numbers of military personnel presenting with VHF manifestations in the same geographic area over a short time period should trigger immediate alarm. A natural outbreak is possible in an endemic setting, but a large number of cases should also suggest a BW attack.

The clinical laboratory can be very helpful in presumptive diagnosis of VHF. Thrombocytopenia (exception: Lassa) and leukopenia (exceptions: Lassa, Hantaan, and CCHF) are the rule. Proteinuria and/or hematuria are common, and their presence is characteristic of AHF, Bolivian hemorrhagic fever, and HFRS. High AST elevation correlates with severity of Lassa fever, and jaundice is a poor prognostic sign in yellow fever.

In most geographic areas, the major differential diagnosis is malaria. Bear in mind that parasitemia in patients partially immune to malaria does not prove that symptoms are due to malaria. Other diseases in the differential diagnosis may include typhoid fever, nontyphoidal salmonellosis, leptospirosis, rickettsial infections, shigellosis, relapsing fever, fulminant hepatitis, and meningococcemia. Non-infectious illnesses that could mimic VHF include acute leukemia, lupus erythematosus, idiopathic or thrombotic thrombocytopenic purpura, hemolytic uremic syndrome and the multiple causes of DIC.

Definitive diagnosis in an individual case rests on specific virologic diagnosis. Most patients have readily detectable viremia at presentation (exception: hantavirus infections). Rapid enzyme immunoassays can detect viral antigens in acute sera from patients with AHF, Lassa fever, RVF, CCHF, and yellow fever. Lassa- and Hantaan-specific IgM often are detectable during the acute illness. Diagnosis by virus replication and identification requires 3 to 10 days or longer. Polymerase chain reaction (PCR) assays are being developed at USAMRIID and the CDC, and they may be helpful in making a presumptive diagnosis. With the exception of dengue, specialized microbiological containment is required for safe handling of these viruses. Appropriate precautions should be observed in collection, handling, shipping, and processing of diagnostic samples. Both the Centers for Disease Control and Prevention (CDC, Atlanta, Georgia) and the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID, Frederick, Maryland) have diagnostic laboratories functioning at the highest (BL-4 or P-4) containment level.

Differential Diagnosis

A wide range of conditions (bacterial, viral, and parasitic infections as well as noninfectious causes) should be considered in the differential diagnosis of VHF. However, most of these conditions do not cause bleeding manifestations as a primary feature and most are not likely to occur epidemiologically as a point-source epidemic with simultaneous presentation of many cases. Primary agents to consider in the differential diagnosis are outlined in the table below.

Differential Diagnosis for Viral Hemorrhagic Fevers That Pose a Bioterrorist Threata,b,c

Condition

Agent(s)

Distinguishing Features

Bacterial and Rickettsial Infections

Septicemia caused by gram-negative bacteria

Various

Underlying illness is usually present.

Staphylococcal or streptococcal toxic shock syndrome

Staphylococcus aureus
Streptococcus pyogenes

—Streptococcal TSS may be associated with necrotizing fasciitis.
—Staphylococcal TSS is often associated with characteristic epidemiologic features (eg, tampon use in menstruating women, antecedent trauma).

Meningococcemia

Neisseria meningitidis

Rapid progression to shock and often death may occur.

Secondary syphilis

Treponema pallidum

—Maculopapular rash that begins on the trunk (palms and soles often involved) is characteristic.
—Constitutional symptoms often occur but are not as severe as would be expected with VHF.

Septicemic plague

Yersinia pestis

Often occurs secondary to bubonic plague (characteristic bubo present in groin, axilla, or cervical region).

Typhoid fever

Salmonella typhi

—Symptoms of enterocolitis and abdominal pain may be more prominent with typhoid fever than with VHF.
—Hemorrhagic manifestations are generally less common than with VHF.

Rocky Mountain spotted fever

Rickettsia rickettsii

—A history of tick exposure may be obtained.
—The disease occurs in April through May.
—Most US cases occur in southeastern and south-central states.

Ehrlichiosis

Ehrlichia chaffeensis
Erhlichia phagocytophilia

—A history of tick exposure history may be obtained.
—Petechial rash is uncommon.
—Peripheral blood smear may show morulae in neutrophils of patients with human granulocytic ehrlichiosis.

Leptospirosis

Leptospira interrogans

—This is most often self-limited but may be severe in about 10% of patients.
—The disease is often associated with aseptic meningitis (characteristic of the immune phase of illness).

Viral Infections

Influenza

Influenza virus

—Respiratory symptoms are prominent.
—It is not associated with bleeding diathesis or rash.
—It is usually seasonal (October to March in United States) or associated with a history of recent cruise ship travel or travel to tropics.

Hemorrhagic smallpox

Smallpox virus

—In late-onset form, a pustular rash usually is present before hemorrhagic manifestations.
—In early-onset form, hemorrhagic manifestations occur soon after illness onset without usual prodrome (ie, bleeding generally will occur sooner than would be expected with VHF).

Measles

Rubeola virus

—Presenting features usually include cough, coryza, conjunctivitis.
—Hemorrhagic features are rare.

Rubella

Rubella virus

—Occurs in persons without history of rubella vaccination (such as migrant workers).
—Hemorrhagic features are extremely rare.

Hemorrhagic varicella

Varicella-zoster virus

—Usually occurs in immunocompromised children.

Viral hepatitis

Usually hepatitis A, B, C viruses (hepatitis E and G virus and other viruses also may cause)

—Hepatic findings predominate.
—Hemorrhagic manifestations are associated with fulminant hepatic failure.
—It is most likely to mimic yellow fever or Rift Valley fever (both characterized by icteric disease).

Parasitic Infections

Malaria

Plasmodium species

—Fever is cyclic (every 48 hr for P vivax or P ovale; every 72 hr for P malariae) or continuous with intermittent spikes (most common pattern for P falciparum).
—Hemolysis commonly occurs; hemorrhagic manifestations are less common.
—Parasites may be seen on microscopic examination of thick or thin smears.

African trypanosomiasis

Trypanosoma brucei complex

—Painful chancre may occur at site of tsetse fly bite.
—Disease is associated with travel to Africa.
—Characteristic features are fever and neurologic manifestations.

Acute Conditions That May Be Associated With a Bleeding Diathesis

Hemolytic uremic syndrome

Usually occurs as complication of infection with Escherichia coli O157:H7 or other Shiga toxin–producing E coli

—Disease involves a triad of renal involvement, thrombocytopenia, and hemolytic anemia.
—It is more common in young children.
—Antecedent diarrheal illness occurs.
—Hemorrhagic manifestations are uncommon, although bloody diarrhea often occurs.

Thrombotic thrombocytopenic purpura

May occur as complication of infection with E coli O157:H7 or other Shiga toxin–producing E coli, although may be noninfectious

—Disease includes renal involvement, thrombocytopenia, hemolytic anemia, neurologic involvement.
—Hemorrhagic manifestations are uncommon.

Idiopathic thrombocytopenic purpura

Noninfectious

—Low platelet count is predominant feature.
—Disease is generally not accompanied by severe systemic toxicity.

Acute leukemia

Noninfectious

Peripheral blood smear shows characteristic features of leukemia.

Collagen vascular disease

Noninfectious

Acute onset of febrile illness not likely.

Abbreviations:; TSS, toxic shock syndrome.

aConditions included: Ebola hemorrhagic fever, Marburg hemorrhagic fever, Lassa fever, New World hemorrhagic fever, Rift Valley fever, yellow fever, Kyasanur Forest disease, and Omsk hemorrhagic fever.
bSeveral diseases caused by hemorrhagic fever viruses are not considered to pose a bioterrorist threat; these conditions also should be considered in the differential diagnosis and include dengue fever or dengue hemorrhagic fever, hantavirus pulmonary syndrome, hantavirus hemorrhagic fever with renal syndrome, and Crimean-Congo hemorrhagic fever.
cMany of the conditions considered in this differential diagnosis would not occur as epidemic diseases; the purpose of this list is to help sort out individual cases that may herald an epidemic of VHF.

When to Consider the Diagnosis of VHF

Most clinicians in the United States have little or no clinical experience with the syndromes that characterize VHF; therefore, a high index of suspicion is needed to make an accurate diagnosis.

The diagnosis of VHF should be considered for any patient who presents with:

  • Acute onset of fever (less than 3 weeks' duration)
  • Severe prostrating or life-threatening illness
  • Bleeding manifestations (ie, at least two of the following: hemorrhagic or purpuric rash, petechiae [particularly in nondependent areas] epistaxis, hematemesis, hemoptysis, blood in stool, or other evidence of bleeding)
  • No predisposing factors for a bleeding diathesis

In naturally occurring cases, an appropriate travel or exposure history will usually be present. In the setting of a bioterrorist event, such a history will not be present and multiple patients will likely present simultaneously.

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