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ARGENTINE HEMORRHAGIC FEVER

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Argentine hemorrhagic fever (AHF), or New World hemorrhagic fever, is a viral hemorrhagic fever caused by an RNA virus (Junin virus), a pantropic virus, of the Arenaviridae family. In nature, this virus resides in a rodent vector endemic to South America. AHF can be a highly fatal viremic disease. Bleeding manifestations often occur as a result of damage to the vascular endothelium. The main features of clinical disease are CNS involvement and hematologic abnormalities. The Centers for Disease Control and Prevention (CDC)have classified Junin virus as a category A bioweapon agent.

Specific Substances

    A) SYNONYMS
    1) Junin Argentine Hemorrhagic Fever
    2) Junin virus
    3) New World Hemorrhagic Fever
    4) Tacaribe Complex Viruses
    5) Viral Hemorrhagic Fever

Available Forms Sources

    A) USES
    1) Junin virus may be a potential agent for terrorist attacks or biological warfare. An aerosol would be the likely method of dissemination, with as few as 1 to 10 organisms capable of resulting in human infection. This virus is stable and highly infectious as a fine-particle aerosol (Franz et al, 1997; PB Jahrling , 1997). Kenyon et al (1992) have demonstrated aerosol infection of Rhesus macaques with Junin virus, with disease closely mimicking the clinical syndrome observed in humans.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) In humans, a clinical picture of Argentine hemorrhagic fever (AHF) consists of a febrile syndrome with hematologic, cardiovascular, digestive, renal and neurologic alterations, which can be fatal in up to 30% of untreated cases. Intercurrent bacterial infections are a prominent feature of AHF. Bleeding manifestations often occur as a result of damage to the vascular endothelium. Incubation period ranges from 7 to 14 days.
    B) Patients initially exhibit a nonspecific influenza-like prodrome, which may last less than a week, with high fever, headache, rash, malaise, myalgias, nausea, abdominal pain and non-bloody diarrhea. After 6 to 10 days of illness, many patients deteriorate, developing predominantly neurological or hemorrhagic manifestations. After 10 to 15 days over 80% of patients improve, with the remainder deteriorating without aggressive treatment.
    C) Distinctive clinical features include fever, myalgias, nausea, abdominal pain, sore throat, cough, conjunctivitis, facial and truncal flushing, and generalized lymphadenopathy. More severe cases may develop petechiae, bleeding, and CNS dysfunction with tremors of the tongue and upper extremities, myoclonic movements, dysarthria, and generalized seizures.
    0.2.3) VITAL SIGNS
    A) Patients may initially present to the ED with increased respirations, increased or decreased blood pressure and initial tachycardia followed by a relative bradycardia. Fever is common.
    0.2.4) HEENT
    A) Conjunctivitis is common in the initial clinical presentation of AHF. Epistaxis and bleeding gums may occur in patients with more severe disease. Pharyngitis and mouth enanthem are typical early in the course of AHF.
    0.2.5) CARDIOVASCULAR
    A) Hypotension and relative bradycardia may develop early in AHF. Circulatory failure may occur in severe, late stages of the disease. In fatal AHF, myocarditis is commonly seen at necropsy.
    0.2.6) RESPIRATORY
    A) Full-blown AHF typically evolves to shock and mucous membrane hemorrhage and is often accompanied by evidence of pulmonary involvement, including dyspnea, hyperventilation and acute lung injury.
    0.2.7) NEUROLOGIC
    A) More severe cases may develop CNS dysfunction with tremors of the tongue and upper extremities, myoclonic movements, dysarthria, and generalized seizures. Late onset of neurological dysfunction may occur.
    0.2.8) GASTROINTESTINAL
    A) Nausea and abdominal pain are common initial complaints in patients with early stage of AHF.
    0.2.9) HEPATIC
    A) Hepatic involvement, with elevated transaminases, is common in AHF, although clinical jaundice is not commonly seen. In fatal AHF, hepatocellular necrosis is commonly seen at necropsy.
    0.2.10) GENITOURINARY
    A) Proteinuria and/or hematuria are very commonly seen in patients with AHF. Renal failure may develop. In fatal AHF, renal papillary necrosis is commonly seen at necropsy.
    0.2.12) FLUID-ELECTROLYTE
    A) Patients are often moderately dehydrated; covert losses of intravascular volume via hemorrhage and increased vascular permeability occurs.
    0.2.13) HEMATOLOGIC
    A) Hemorrhage is a common feature of AHF. The main hematologic features include leukopenia, thrombocytopenia, and bone marrow hypoplasia. Thrombocytopenia is common, although it is usually mild. DIC is rarely seen.
    0.2.15) MUSCULOSKELETAL
    A) Myalgia and low back pain are commonly reported in acute phases of AHF.
    0.2.19) IMMUNOLOGIC
    A) Intercurrent bacterial infections are a prominent feature of AHF. Generalized lymphadenopathy is common in the early phase of illness. Severe immunosuppression may develop.
    0.2.20) REPRODUCTIVE
    A) Transplacental and congenital infections were consistently seen in fetuses of guinea pigs infected either prior to conception or during gestation with an attenuated Junin virus. GUINEA PIGS infected with Junin virus prior to the 7th week of gestation experienced an abortion rate of 33%.

Laboratory Monitoring

    A) In the acute care setting, diagnosis of Argentine hemorrhagic fever (AHF) may be established through antigen-capture ELISA or reverse transcriptase polymerase chain reaction (RT-PCR) methodologies. ELISA is of limited value in early diagnosis because antibodies usually do not appear until the onset of recovery (about the second week of illness). A fourfold rise in titer of IgG antibody between acute- and convalescent-phase serum specimens is diagnostic. Early IgM antibody responses may be detected by ELISA during the acute illness.
    1) All specimens should be handled, at a minimum, in a class 2 biological safety cabinet following BSL-3 practices. Only attempt virus isolation in a BSL-4 laboratory.
    B) Nonspecific laboratory abnormalities include elevated liver enzymes. The combination of fever, pharyngitis, and chest pain appears to be a good diagnostic predictor of AHF in endemic areas.
    1) The absence of proteinuria or hematuria or both rules out AHF.
    C) Monitor fluid and electrolyte balance, blood pressure and circulatory volume as indicated.
    D) Obtain CBC as indicated. A WBC count of <2500/mm(3), a platelet count of <100,000/mm(3), and urinary protein excretion of >1 g/L are significantly associated with AHF.
    E) Monitor for evidence of encephalopathy and seizures.
    F) Cardiac monitoring is indicated in all symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) It is not known if transmission of Junin virus could occur via ingestion of contaminated material. Irrigated exposed mucous membranes.
    0.4.3) INHALATION EXPOSURE
    A) Although arenaviruses are not known to be casually transmitted from human-to-human via inhalation, researchers have shown a potential for infection by Junin virus administered into the respiratory tract. Use of Junin virus as a biological warfare agent has been proposed due to its contagious and lethal properties. Medical personnel working with known Junin virus infected patients should wear protective masks and utilize strict barrier nursing techniques. Respirators should be used when caring for patients with coughing, vomiting, diarrhea or hemorrhage.
    B) Treatment is symptomatic and supportive. Aggressive management of secondary infections and hypotension is important. Currently, there is no antidote or commercial vaccine available for use in humans.
    C) VACCINE is available as an investigational new drug (IND), developed at USAMRIID.
    D) RIBAVIRIN is recommended for treatment of AHF.
    1) Dosage for Adults and Children: Loading dose of 30 mg/kg of body weight IV, followed by 16 mg/kg IV every 6 hours for 4 days, then 8 mg/kg IV every 8 hours for 6 days (total treatment time 10 days).
    E) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    F) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    G) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
    0.4.4) EYE EXPOSURE
    A) Mucocutaneous exposures to blood, body fluids, secretions, or excretions from patients with suspected Argentine hemorrhagic fever (AHF) should be immediately rinsed with copious amounts of water or eyewash solution.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Dermal sites exposed to blood, body fluids, secretions, or excretions from patients with suspected Argentine hemorrhagic fever (AHF) should be immediately washed with soap and water.
    2) Treatment is symptomatic and supportive, and is discussed in detail in the INHALATIONAL EXPOSURE section.

Range Of Toxicity

    A) Mortality in untreated patients is reported to be 15% to 30%.
    B) As few as 1 to 10 organisms are capable of causing infection.
    C) CNS dysfunction imparts a poor prognosis.

Clinical Effects

Summary Of Exposure

    A) In humans, a clinical picture of Argentine hemorrhagic fever (AHF) consists of a febrile syndrome with hematologic, cardiovascular, digestive, renal and neurologic alterations, which can be fatal in up to 30% of untreated cases. Intercurrent bacterial infections are a prominent feature of AHF. Bleeding manifestations often occur as a result of damage to the vascular endothelium. Incubation period ranges from 7 to 14 days.
    B) Patients initially exhibit a nonspecific influenza-like prodrome, which may last less than a week, with high fever, headache, rash, malaise, myalgias, nausea, abdominal pain and non-bloody diarrhea. After 6 to 10 days of illness, many patients deteriorate, developing predominantly neurological or hemorrhagic manifestations. After 10 to 15 days over 80% of patients improve, with the remainder deteriorating without aggressive treatment.
    C) Distinctive clinical features include fever, myalgias, nausea, abdominal pain, sore throat, cough, conjunctivitis, facial and truncal flushing, and generalized lymphadenopathy. More severe cases may develop petechiae, bleeding, and CNS dysfunction with tremors of the tongue and upper extremities, myoclonic movements, dysarthria, and generalized seizures.

Vital Signs

    3.3.1) SUMMARY
    A) Patients may initially present to the ED with increased respirations, increased or decreased blood pressure and initial tachycardia followed by a relative bradycardia. Fever is common.
    3.3.2) RESPIRATIONS
    A) Tachypnea may be common in the early phases of AHF (Borio et al, 2002).
    3.3.3) TEMPERATURE
    A) An acute febrile period generally lasts for 6 to 8 days and sometimes longer, with viremia present throughout the febrile period (Borio et al, 2002; Enria et al, 1984).
    3.3.4) BLOOD PRESSURE
    A) Decreased blood pressure is typical in the initial presentation and may progress to circulatory shock in severe cases (Borio et al, 2002).
    3.3.5) PULSE
    A) Hypotension and relative bradycardia may be early presenting signs of AHF (Borio et al, 2002). An initial tachycardia may be seen (Franz et al, 1997).

Heent

    3.4.1) SUMMARY
    A) Conjunctivitis is common in the initial clinical presentation of AHF. Epistaxis and bleeding gums may occur in patients with more severe disease. Pharyngitis and mouth enanthem are typical early in the course of AHF.
    3.4.3) EYES
    A) Conjunctivitis is common in the initial clinical presentation of AHF (Borio et al, 2002; Harrison et al, 1999).
    3.4.5) NOSE
    A) Epistaxis and bleeding gums may occur in patients with more severe disease (Borio et al, 2002).
    3.4.6) THROAT
    A) Pharyngitis and mouth enanthem are typical early in the course of AHF (Borio et al, 2002; Harrison et al, 1999).

Cardiovascular

    3.5.1) SUMMARY
    A) Hypotension and relative bradycardia may develop early in AHF. Circulatory failure may occur in severe, late stages of the disease. In fatal AHF, myocarditis is commonly seen at necropsy.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) Hypotension and relative bradycardia may develop early in AHF. Circulatory shock may develop later as the disease progresses (Borio et al, 2002).
    B) MYOCARDITIS
    1) In fatal AHF, myocarditis is commonly seen at necropsy. Interstitial myocarditis has been reported in 26.6% of human cases in one series of AHF fatalities. In another case series, 71% of AHF cases were reported to have ECG changes of elevated ST segments and inverted T waves. Necropsy findings in 96 other cases showed evidence of myocardial congestion and edema, hemorrhagic manifestations and microvascular rupture, interstitial reactive change, interstitial myocarditis, and myocardial necrosis (Cummins, 1991; Oubina et al, 1986).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) MYOCARDITIS
    a) Cebus monkeys, intracerebrally infected with Junin virus, all exhibited a varying degree of histologic myocardial lesions, which included focal lymphoblastic infiltrates, vascular rupture, and mild interstitial reactive change, at necropsy (Oubina et al, 1986).

Respiratory

    3.6.1) SUMMARY
    A) Full-blown AHF typically evolves to shock and mucous membrane hemorrhage and is often accompanied by evidence of pulmonary involvement, including dyspnea, hyperventilation and acute lung injury.
    3.6.2) CLINICAL EFFECTS
    A) HYPERVENTILATION
    1) Tachypnea may develop in the early phases of AHF (Borio et al, 2002).
    B) ACUTE LUNG INJURY
    1) Full-blown AHF typically evolves to shock and mucous membrane hemorrhage and is often accompanied by evidence of pulmonary involvement, including dyspnea and acute lung injury. AHF patients often will readily develop acute lung injury during treatment for hypotension and shock; they respond poorly to fluid therapy (Franz et al, 1997).
    C) LACK OF EFFECT
    1) In a study of 31 Argentina patients with laboratory serological evidence of AHF, a lack of upper respiratory tract symptoms was notable on hospital admission (Harrison et al, 1999).

Neurologic

    3.7.1) SUMMARY
    A) More severe cases may develop CNS dysfunction with tremors of the tongue and upper extremities, myoclonic movements, dysarthria, and generalized seizures. Late onset of neurological dysfunction may occur.
    3.7.2) CLINICAL EFFECTS
    A) TOXIC ENCEPHALOPATHY
    1) A neurological syndrome (encephalopathy) develops in many patients infected with Junin virus. The pathogenesis of this is unclear. Neurologic manifestations are much more prominent in AHF patients than in Lassa fever patients. Tremors of the tongue and upper extremities, myoclonic movements, dysarthria, generalized seizures, delirium, cerebellar signs, or coma may occur in more severe cases. Onset of neurological dysfunction usually occurs after 6 to 10 days of illness. CNS dysfunction imparts a poor prognosis (Borio et al, 2002; Franz et al, 1997; Cummins, 1991).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea and abdominal pain are common initial complaints in patients with early stage of AHF.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) Nausea and abdominal pain are common initial complaints in patients with early stage of AHF (Borio et al, 2002; Harrison et al, 1999).

Hepatic

    3.9.1) SUMMARY
    A) Hepatic involvement, with elevated transaminases, is common in AHF, although clinical jaundice is not commonly seen. In fatal AHF, hepatocellular necrosis is commonly seen at necropsy.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) Hepatic involvement, with elevated transaminases, is common in AHF, although clinical jaundice is not commonly seen (Franz et al, 1997). In fatal AHF, hepatocellular necrosis is commonly seen at necropsy. Sites of necrosis generally correspond to sites of viral antigen accumulation (Cummins, 1991).

Genitourinary

    3.10.1) SUMMARY
    A) Proteinuria and/or hematuria are very commonly seen in patients with AHF. Renal failure may develop. In fatal AHF, renal papillary necrosis is commonly seen at necropsy.
    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) Renal failure may develop, and is generally proportional to cardiovascular compromise (Franz et al, 1997). Proteinuria and/or hematuria are very commonly seen in patients with AHF (PB Jahrling , 1997; Cummins, 1991). In fatal AHF, renal papillary necrosis is commonly seen at necropsy. Sites of necrosis generally correspond to sites of viral antigen accumulation (Cummins, 1991).

Hematologic

    3.13.1) SUMMARY
    A) Hemorrhage is a common feature of AHF. The main hematologic features include leukopenia, thrombocytopenia, and bone marrow hypoplasia. Thrombocytopenia is common, although it is usually mild. DIC is rarely seen.
    3.13.2) CLINICAL EFFECTS
    A) HEMORRHAGE
    1) Later in the course of AHF, patients may show signs of progressive hemorrhagic diathesis, e.g., petechiae, mucous membrane and conjunctival hemorrhage, hematuria, hematemesis, and melena. In fatal AHF, widespread hemorrhage is commonly seen at necropsy.
    a) Bleeding appears to be associated with the presence of a circulating inhibitor of platelet aggregation and thrombocytopenia, which is a feature of the acute phase of disease as opposed to the convalescent phase.
    b) Hemorrhagic manifestations are much more prominent in AHF patients than in Lassa fever patients. Bleeding manifestations often occur as a result of damage to the vascular endothelium.
    c) Altered hemostasis may have a common basis in arenavirus-induced hemorrhagic fevers. Disseminated intravascular coagulation does NOT appear to be a central pathogenic mechanism of hemorrhages in AHF (Borio et al, 2002; Franz et al, 1997; Heller et al, 1995; Cummins, 1991; Cummins et al, 1990). Low level, though persistent, blood coagulation and fibrinolysis activation is seen in AHF.
    d) In summary, hemorrhage appears to be due to a combination of thrombocytopenia, abnormal platelet function induced by a plasma component, and alterations in blood coagulation and fibrinolysis activation (Heller et al, 1995).
    B) THROMBOCYTOPENIC DISORDER
    1) Thrombocytopenia in AHF is common, although it is usually mild, with platelet counts rarely falling below 40 x 10(9)/liter. A WBC count of <2500/mm(3), a platelet count of <100,000/mm(3), and urinary protein excretion of >1 g/L are significantly associated with AHF (Harrison et al, 1999). In the acute phase of illness a mild prolongation of activated partial thromboplastin time may also occur, but is of no value in predicting either the course or severity of hemorrhages (Cummins, 1991; Cummins et al, 1990).
    C) LEUKOPENIA
    1) Marked leukopenia is a common manifestation of AHF. Destruction of lymphatic tissue, characteristic of lethal human infection, appears to be responsible for the pronounced lymphopenia. The decrease in number of polymorphonuclear leukocytes appears to be due to a direct cytopathic effect of the Junin virus (Cummins, 1991; Laguens et al, 1986).
    D) MYELOSUPPRESSION
    1) One of the main hematologic features of AHF is bone marrow hypoplasia. In the acute phase of illness, erythropoietin levels are significantly decreased in a large percent of patients; thrombopoietin, G-CSF and TNF-alpha levels are increased. GM-CSF, IL-3 and transforming growth factor-beta (TGF-B) are within normal range in almost all patients. High G-CSF levels appear to be a marker of illness severity. Low levels of erythropoietin, possibly due to an inhibitory effect of high TNF-alpha levels, may contribute to the severe bone marrow erythroblastopenia seen in AHF patients (Marta et al, 2000).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) Flushing of the face and trunk is a common feature of the early phase of AHF (Borio et al, 2002).
    B) ERUPTION
    1) Following a one to two week incubation period, patients commonly develop a diffuse erythematous skin rash. Petechial hemorrhages are common, usually most significant in the axillae (Cummins, 1991).

Musculoskeletal

    3.15.1) SUMMARY
    A) Myalgia and low back pain are commonly reported in acute phases of AHF.
    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) Myalgia and low back pain are commonly reported in acute phases of AHF (Harrison et al, 1999).

Immunologic

    3.19.1) SUMMARY
    A) Intercurrent bacterial infections are a prominent feature of AHF. Generalized lymphadenopathy is common in the early phase of illness. Severe immunosuppression may develop.
    3.19.2) CLINICAL EFFECTS
    A) INFECTIOUS DISEASE
    1) Intercurrent bacterial infections are a prominent feature of AHF, but are not a feature of Lassa fever (Cummins et al, 1990). Secondary bacterial infections should be suspected and treated aggressively (Franz et al, 1997; Ambrosio et al, 1992; Cummins, 1991).
    a) Kenyon et al (1992) reported no septicemia in monkeys administered an aerosol dose of Junin virus; however, other cases of sepsis were reported in animals infected parenterally. The authors suspect sepsis occurred in parenterally infected animals as a consequence of gastrointestinal mucosal damage, which was not seen in aerosol-infected animals.
    2) Viremia is present during the entire acute febrile period, which is usually 6 to 8 days (Enria et al, 1984). Recovery appears to be preceded by cellular and humoral immune responses (Borio et al, 2002).
    B) LYMPHADENOPATHY
    1) Generalized lymphadenopathy is a common feature of the early phase of AHF (Borio et al, 2002). Cervical adenopathy was reported in 27 out of 31 cases of AHF in one study (Harrison et al, 1999).
    2) A marked destruction of lymphatic tissue occurs in AHF. Lymphatic tissue appears to be one of the main sites of viral replication; macrophages are the targets of Junin virus (Gonzalez et al, 1980).
    3) In Rhesus macaques given an aerosol dose of Junin virus, virus was found primarily in lymphatic organs during the early postinfection period (prior to 21 days) (Kenyon et al, 1992).
    C) DISORDER OF IMMUNE FUNCTION
    1) Severe immunosuppression is a prominent feature of AHF. The mechanism of immunosuppression is uncertain, but may involve direct viral effects or cytokines. A direct or indirect result of Junin virus multiplication in lymphohematopoietic tissues may account for the impaired immune response (Ambrosio et al, 1992; Cummins, 1991).

Reproductive

    3.20.1) SUMMARY
    A) Transplacental and congenital infections were consistently seen in fetuses of guinea pigs infected either prior to conception or during gestation with an attenuated Junin virus. GUINEA PIGS infected with Junin virus prior to the 7th week of gestation experienced an abortion rate of 33%.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) GUINEA PIGS - Transplacental and congenital infections were consistently seen in fetuses of guinea pigs infected either prior to conception or during gestation with an attenuated Junin virus (Gomez & Boxaca, 1985).
    3.20.3) EFFECTS IN PREGNANCY
    A) ANIMAL STUDIES
    1) GUINEA PIGS infected with Junin virus prior to the 7th week of gestation experienced an abortion rate of 33%. In animals infected during gestation a 58% mortality rate was reported, while in animals infected prior to conception, a 16.7% mortality rate was reported. Transplacental infection was consistently seen. Junin virus was isolated in CNS tissue, placentas and fetuses of guinea pigs killed just prior to parturition. The clinical course of attenuated Junin virus infection was modified during pregnancy in these animals, with increased severity and higher mortality (Gomez & Boxaca, 1985).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) In the acute care setting, diagnosis of Argentine hemorrhagic fever (AHF) may be established through antigen-capture ELISA or reverse transcriptase polymerase chain reaction (RT-PCR) methodologies. ELISA is of limited value in early diagnosis because antibodies usually do not appear until the onset of recovery (about the second week of illness). A fourfold rise in titer of IgG antibody between acute- and convalescent-phase serum specimens is diagnostic. Early IgM antibody responses may be detected by ELISA during the acute illness.
    1) All specimens should be handled, at a minimum, in a class 2 biological safety cabinet following BSL-3 practices. Only attempt virus isolation in a BSL-4 laboratory.
    B) Nonspecific laboratory abnormalities include elevated liver enzymes. The combination of fever, pharyngitis, and chest pain appears to be a good diagnostic predictor of AHF in endemic areas.
    1) The absence of proteinuria or hematuria or both rules out AHF.
    C) Monitor fluid and electrolyte balance, blood pressure and circulatory volume as indicated.
    D) Obtain CBC as indicated. A WBC count of <2500/mm(3), a platelet count of <100,000/mm(3), and urinary protein excretion of >1 g/L are significantly associated with AHF.
    E) Monitor for evidence of encephalopathy and seizures.
    F) Cardiac monitoring is indicated in all symptomatic patients.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Laboratory findings are nonspecific and variable. Obtain CBC with differential and platelet counts, electrolytes, renal function tests, PT/INR, PTT, fibrinogen, fibrin degradation products, blood cultures, CSF, and liver function tests as indicated.
    a) Leukopenia, thrombocytopenia, and bone marrow hypoplasia are common in the acute phase of illness. Diffuse intravascular coagulation is NOT normally seen in Argentine hemorrhagic fever (AHF). Low level, though persistent, process of blood coagulation and fibrinolysis activation are seen in the early phase of AHF. Hemostatic laboratory alterations do not correlate with hemorrhages (Marta et al, 2000; Heller et al, 1995).
    1) A WBC count of <2500/mm(3), a platelet count of <100,000/mm(3), and urinary protein excretion of >1 g/L are significantly associated with AHF (Harrison et al, 1999).
    b) Nonspecific laboratory abnormalities include progressive neutropenia, lymphopenia, thrombocytopenia, and anemia. Hyperbilirubinemia and elevated liver enzymes are common.
    c) Hematocrit is typically normal, but may be decreased if there is sufficient loss of vascular integrity and dehydration (PB Jahrling , 1997).
    d) Junin virus is not primarily hepatotropic, although AST is frequently elevated. An elevated AST may help to distinguish a viral hemorrhagic fever from a simple febrile disease (PB Jahrling , 1997).
    e) BUN is related to the circulatory status of the patient since the kidney is not a target organ of AHF.
    f) Significantly elevated levels of interferon-alpha (as high as 64,000 IU/mL) and tumor necrosis factor have been reported in the acute phase of AHF in patients with normal levels of interleukin 1. This appears to correlate with clinical severity of disease and may be strong predictors of a fatal outcome (Marta et al, 1999; Cummins, 1991).
    g) All specimens should be handled, at a minimum, in a class 2 biological safety cabinet following BSL-3 practices. Only attempt virus isolation in a BSL-4 laboratory.
    4.1.3) URINE
    A) URINALYSIS
    1) The absence of proteinuria or hematuria or both generally rules out AHF. Proteinuria and/or hematuria are common, and their presence is the rule for AHF (PB Jahrling , 1997).
    4.1.4) OTHER
    A) OTHER
    1) CULTURES
    a) Definitive diagnosis of AHF may be accomplished by isolation of the Junin virus from blood during the first week of illness or detecting rising antibody titer by IRA, complement fixation, or one of several other methods.
    1) Clinical specimens from potentially infected persons should be submitted to a Biosafety Level 4 containment facility (Borio et al, 2002; PB Jahrling , 1997; Franz et al, 1997).

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Monitor chest x-ray in symptomatic patients. Acute lung injury may occur late in illness or in patients receiving fluid therapy for hypotension (Borio et al, 2002; Cummins, 1991).

Methods

    A) IMMUNOASSAY
    1) SUMMARY - Samples used for immunoassay procedures must first be inactivated by treatment with B-propiolactone (BPL), since culture work with the live virus is designated as BSL-4 containment. All specimens should be handled, at a minimum, in a class 2 biological safety cabinet following BSL-3 practices. Only attempt virus isolation in a BSL-4 laboratory.
    a) Diagnosis of Argentine hemorrhagic fever (AHF) may be established through antigen-capture ELISA or reverse transcriptase polymerase chain reaction (RT-PCR) methodologies. ELISA is of limited value in early diagnosis because antibodies usually do not appear until the onset of recovery (about the second week of illness). A fourfold rise in titer of IgG antibody between acute- and convalescent-phase serum specimens is diagnostic. Early IgM antibody responses may be detected by ELISA during the acute illness (Borio et al, 2002; Morales et al, 2002; Franz et al, 1997; PB Jahrling , 1997). RT-PCR is recommended for the routine, rapid test for direct detection of Junin virus in acute infections, early in the course of illness (Lozano et al, 1997; Lozano et al, 1995; Lozano et al, 1993).
    2) RT-PCR - Early and rapid diagnosis of AHF by reverse transcriptase (RT) PCR-based assay has been described. This procedure is sensitive enough to detect low viremia found during a limited period when immune plasma therapy can effectively be used. Up to 0.01 pfu of Junin virus may be detected in a blood sample. RT-PCR is the only current method for rapid diagnosis of AHF (Lozano et al, 1995; Lozano et al, 1993; Bockstahler et al, 1992).
    3) ELISA - Franco et al (1988) demonstrated a clear tendency of ELISA to seroconvert for Junin virus earlier and at a higher frequency than an indirect immunofluorescence (IF) methodology. Sensitivity of ELISA was also superior to the plaque reduction neutralization test (PRNT) (100% vs 97% sensitivity). Riera et al (1997) found no significant difference in the proportions of positive and negative results of ELISA as compared to PRNT for detection of specific anti-Junin virus IgG.
    4) ELISA/RIA - Both indirect ELISA and solid-phase radioimmunoassay (SPRIA), using either anti-human or anti-mouse IgG, have shown high sensitivity detection and specificity for arenaviruses, including Junin virus. Methods are described (Ivanov et al, 1984).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.3) DISPOSITION/INHALATION EXPOSURE
    6.3.3.1) ADMISSION CRITERIA/INHALATION
    A) All patients with suspected Junin fever infection should be admitted to an intensive care unit and strict isolation and barrier nursing techniques should be instituted. Diagnostic work with these agents is limited to laboratories capable of handling biosafety level 4 agents, as discussed previously.
    B) Any person who has had close physical contact with patients should be put under strict surveillance (twice daily body temperature checks; in case of temperature >38.3 degrees C {101 degrees F}, hospitalize immediately in strict isolation). Hospital personnel who come into close contact with patients or contaminated materials without barrier nursing attire must be considered exposed and put under close, supervised surveillance.
    6.3.3.2) HOME CRITERIA/INHALATION
    A) Casual contacts of Junin virus-infected patients should be placed on alert and asked to report any fever. All surveillance should be continued for 3 weeks after the date of the last contact.
    6.3.4) DISPOSITION/EYE EXPOSURE
    6.3.4.3) CONSULT CRITERIA/EYE
    A) Persons with conjunctival exposure to blood, body fluids, secretions, or excretions from a patient with suspected AHF should receive medical evaluation and follow-up management.
    6.3.5) DISPOSITION/DERMAL EXPOSURE
    6.3.5.5) OBSERVATION CRITERIA/DERMAL
    A) High risk contacts (unprotected contact with patient's body fluids or excretions) with exposure to arenaviruses should (McCormick, 1986):
    1) Patients 10 years of age and older, receive prophylaxis with ribavirin therapy (600 mg orally every 6 hours for 7 to 10 days). Children 6 to 9 years of age, receive ribavirin 400 mg orally every 6 hours for 7 to 10 days.
    2) Record temperature twice daily for 3 weeks post-exposure.
    3) Receive further evaluation if fever (greater than 101 degrees F) or other systemic symptoms present within 3 weeks of exposure.

Monitoring

    A) In the acute care setting, diagnosis of Argentine hemorrhagic fever (AHF) may be established through antigen-capture ELISA or reverse transcriptase polymerase chain reaction (RT-PCR) methodologies. ELISA is of limited value in early diagnosis because antibodies usually do not appear until the onset of recovery (about the second week of illness). A fourfold rise in titer of IgG antibody between acute- and convalescent-phase serum specimens is diagnostic. Early IgM antibody responses may be detected by ELISA during the acute illness.
    1) All specimens should be handled, at a minimum, in a class 2 biological safety cabinet following BSL-3 practices. Only attempt virus isolation in a BSL-4 laboratory.
    B) Nonspecific laboratory abnormalities include elevated liver enzymes. The combination of fever, pharyngitis, and chest pain appears to be a good diagnostic predictor of AHF in endemic areas.
    1) The absence of proteinuria or hematuria or both rules out AHF.
    C) Monitor fluid and electrolyte balance, blood pressure and circulatory volume as indicated.
    D) Obtain CBC as indicated. A WBC count of <2500/mm(3), a platelet count of <100,000/mm(3), and urinary protein excretion of >1 g/L are significantly associated with AHF.
    E) Monitor for evidence of encephalopathy and seizures.
    F) Cardiac monitoring is indicated in all symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) DECONTAMINATION
    1) Irrigate exposed mucous membranes with copious amounts of water.
    2) Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. All patients with mucocutaneous exposures to blood, body fluids or excretions with suspected Junin virus infections should receive monitoring for development of systemic infection.
    3) Remove contaminated clothing and wash exposed area extremely thoroughly with soap and water.
    a) Lipid-containing viruses, including enveloped viruses, are readily inactivated by suitable disinfectant solutions, which include a 1:100 aqueous dilution of household bleach, as well as fresh, correctly prepared solution of glutaraldehyde and phenolic disinfectants (0.5%-3%). Liberal use of soaps and detergents are recommended to inactivate the arenaviruses (CDC, 1995).
    4) Accidental spills of potentially contaminated material should be liberally covered with disinfectant solution, left to soak for 30 minutes, and wiped up with absorbent material soaked in disinfectant.
    5) CAREGIVERS need to take strict precautions against contamination by bloody discharges and possibly by airborne transmission (Borio et al, 2002). Observe strict barrier nursing techniques. Protective eye wear should be worn when performing procedures that could involve the patient vomiting or bleeding. When caring for patients with prominent cough, vomiting, diarrhea, or hemorrhage, it is important for caregivers to wear a HEPA filter air-purifying respirator, a battery powered, air-purifying respirator, or a positive pressure supplied air respirator (Borio et al, 2002; CDC, 1995; Fisher-Hoch & McCormick, 1987).
    6) Any person who has had close physical contact with infected patients or body fluids should be put under strict surveillance (twice daily body temperature checks; in case of temperature >38.3 degrees C (101 degrees F), hospitalize immediately in strict isolation). Hospital personnel who come into close contact with patients or contaminated materials without barrier nursing attire must be considered exposed and put under close, supervised surveillance.
    6.5.2) PREVENTION OF ABSORPTION
    A) DECONTAMINATION
    1) It is not known if transmission of Junin virus could occur via ingestion of contaminated material. Irrigate oral mucous membranes copiously.
    6.5.3) TREATMENT
    A) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the INHALATIONAL EXPOSURE section when appropriate.
    B) EVALUATION PROCEDURE
    1) Any person who has had close physical contact with infected patients or body fluids should be put under strict surveillance (twice daily body temperature checks; in case of temperature >38.3 degrees C (101 degrees F), hospitalize immediately in strict isolation). Hospital personnel who come into close contact with patients or contaminated materials without barrier nursing attire must be considered exposed and put under close, supervised surveillance.
    2) High risk contacts with exposure to the virus, should receive post-exposure chemoprophylaxis (ribavirin 500 mg orally every 6 hours for 7 to 10 days for adults and adolescents; ribavirin 400 mg orally every 6 hours for 7 to 10 days for children 6 to 9 years of age) ((Anon, 2000)). Benefits versus risk should be assessed in pregnant patients due to demonstrated teratogenic effects in animal studies.

Inhalation Exposure

    6.7.2) TREATMENT
    A) SUPPORT
    1) Intensive supportive care is the mainstay of therapy. Early, aggressive treatment is imperative. Therapy begun after late symptoms of infection are present may be ineffective. If hemorrhage occurs, IV fluids and transfusion may be indicated.
    2) Isolation precautions against bloody discharges and airborne transmission should be observed. Strict barrier nursing techniques should be enforced to prevent secondary transmission. A negative pressure room is not necessary during early stages of the disease, but may be necessary if patients develop prominent cough, vomiting, diarrhea or hemorrhage.
    3) Ribavirin therapy is recommended; controlled clinical trials have shown an increased survival rate for AHF patients treated with this drug.
    4) Supportive care of patients critically ill with viral hemorrhagic fever is the same as the conventional care provided to other patients with other causes of multisystem failure. Adult respiratory distress syndrome, seizures, and coma may require specific interventions, e.g., mechanical ventilation, dialysis, and neurologic intensive care. Aggressive management of secondary infections is important.
    B) RIBAVIRIN
    1) Ribavirin (Virazole(R)) has been shown to decrease mortality from AHF when given at any stage in the disease. The ability of the drug to prevent fatality in AHF is related to its effect on viral replication. The greater survival rate with early therapy appears to be related to prevention of irreversible tissue damage and cellular dysfunction that occurs with prolonged high serum levels of the virus. Ribavirin is also useful as postexposure prophylaxis. The drug is most effective when given intravenously during the first 6 days of illness; however, it has been effective after this time, and it is recommended at any point during the illness (Borio et al, 2002; Enria & Maiztegui, 1994; Cummins, 1991; Fisher-Hoch & McCormick, 1987; McCormick, 1986; McCormick, 1986). Intravenous ribavirin is available through ICN Pharmaceuticals Inc. for compassionate use under an investigational new drug application (Borio et al, 2002).
    a) The primary adverse effect of ribavirin is a dose-related, reversible hemolytic anemia and thrombocytosis. Monitor patients with COPD and asthma for deterioration of respiratory function.
    2) CONTAINED CASUALTY SETTING: Adults and Children (dosed according to weight): Loading dose of 30 mg/kg IV (maximum, 2 grams) once, followed by 16 mg/kg IV (maximum, 1 gram per dose) every 6 hours for 4 days, followed by 8 mg/kg IV (maximum, 500 mg per dose) every 8 hours for 6 days (Borio et al, 2002; Enria & Maiztegui, 1994).
    3) MASS CASUALTY SETTING (ADULTS) (too many casualties; IV therapy not feasible): Loading dose 2000 mg orally once, followed by 1200 mg/day in 2 divided doses (if weight greater than 75 kg) for 10 days, or, 1000 mg/day orally in 2 divided doses (if weight less than 75 kg) for 10 days (Borio et al, 2002).
    4) MASS CASUALTY SETTING (CHILDREN) (too many casualties; IV therapy not feasible): Loading dose of 30 mg/kg orally once, followed by 15 mg/kg per day orally in 2 divided doses for 10 days (Borio et al, 2002).
    5) PREGNANCY: Ribavirin is contraindicated in pregnancy due to a risk of human teratogenicity. However, the associated mortality of viral hemorrhagic fevers is higher in pregnancy. Thus, the benefits probably outweigh any fetal risk of ribavirin therapy. Dosing is the same as for adults described above (Borio et al, 2002).
    6) RAT STUDIES - In rat studies, experimental use of ribavirin suggested that the drug was able to inhibit viral replication within macrophages and impair their role as primary multiplication sites. Access of the virus to the CNS was restricted. Ribavirin appeared more effective when the virus initially replicates in cells other than those of the target organ, such as macrophages, where amplification occurs (Remesar et al, 1988).
    7) MONKEY STUDIES - When ribavirin was administered intramuscularly at the time of experimental infection, all monkeys were protected. When ribavirin injection was delayed until the onset of illness, improvement and resolution of systemic signs of disease were resolved; however, late-onset CNS infection, which was fatal in 2 of 3 animals, occurred (McKee et al, 1988).
    C) HYPOTENSIVE EPISODE
    1) Treatment of hypotension or shock is difficult. These patients often respond poorly to fluid resuscitation and readily develop acute lung injury (pulmonary edema), possibly due to myocardial involvement and increased pulmonary vascular permeability. Administer colloidal or crystalloid solutions cautiously. Dopamine appears to be the drug of choice for patients with shock who are unresponsive to fluid replacement (Borio et al, 2002; PB Jahrling , 1997).
    2) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    3) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    4) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    D) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    7) PHENYTOIN/FOSPHENYTOIN
    a) Benzodiazepines and/or barbiturates are preferred to phenytoin or fosphenytoin in the treatment of drug or withdrawal induced seizures (Wallace, 2005).
    b) PHENYTOIN
    1) PHENYTOIN INTRAVENOUS PUSH VERSUS INTRAVENOUS INFUSION
    a) Administer phenytoin undiluted, by very slow intravenous push or dilute 50 mg/mL solution in 50 to 100 mL of 0.9% saline.
    b) ADULT DOSE: A loading dose of 20 mg/kg IV; may administer an additional 5 to 10 mg/kg dose 10 minutes after loading dose. Rate of administration should not exceed 50 mg/minute (Brophy et al, 2012).
    c) PEDIATRIC DOSE: A loading dose of 20 mg/kg, at a rate not exceeding 1 to 3 mg/kg/min or 50 mg/min, whichever is slower (Loddenkemper & Goodkin, 2011; Prod Info Dilantin(R) intravenous injection, intramuscular injection, 2013).
    d) CAUTIONS: Administer phenytoin while monitoring ECG. Stop or slow infusion if dysrhythmias or hypotension occur. Be careful not to extravasate. Follow each injection with injection of sterile saline through the same needle (Prod Info Dilantin(R) intravenous injection, intramuscular injection, 2013).
    e) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over next 12 to 24 hours for maintenance of therapeutic concentrations. Therapeutic concentrations of 10 to 20 mcg/mL have been reported (Prod Info Dilantin(R) intravenous injection, intramuscular injection, 2013).
    c) FOSPHENYTOIN
    1) ADULT DOSE: A loading dose of 20 mg phenytoin equivalent/kg IV, at a rate not exceeding 150 mg phenytoin equivalent/minute; may give additional dose of 5 mg/kg 10 minutes after the loading infusion (Brophy et al, 2012).
    2) CHILD DOSE: 20 mg phenytoin equivalent/kg IV, at a rate of 3 mg phenytoin equivalent/kg/minute, up to a maximum of 150 mg phenytoin equivalent/minute (Loddenkemper & Goodkin, 2011).
    3) CAUTIONS: Perform continuous monitoring of ECG, respiratory function, and blood pressure throughout the period where maximal serum phenytoin concentrations occur (about 10 to 20 minutes after the end of fosphenytoin infusion) (Prod Info CEREBYX(R) intravenous injection, 2014).
    4) SERUM CONCENTRATION MONITORING: Monitor serum phenytoin concentrations over the next 12 to 24 hours; therapeutic levels 10 to 20 mcg/mL. Do not obtain serum phenytoin concentrations until at least 2 hours after infusion is complete to allow for conversion of fosphenytoin to phenytoin (Prod Info CEREBYX(R) intravenous injection, 2014).
    E) AIRWAY MANAGEMENT
    1) In cases of airway compromise, supportive measures including endotracheal intubation and mechanical ventilation may be necessary.
    F) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    G) VACCINE
    1) A live attenuated vaccine for AHF (AHF Candid #1) has been developed at USAMRIID, and also appears to be effective for Bolivian hemorrhagic fever, another New World arenavirus. It is an investigational new drug. In clinical studies in Argentina, participants were inoculated with a single intramuscular dose of 10(4) plaque-forming units of Candid #1 virus vaccine. Adverse events due to the vaccinations were minimal, with fever and headaches reported most commonly in 0.17% of participants (n=202,972) in one study (Enria & Barrera, 2002; (Borio et al, 2002; Maiztegui et al, 1998; Franz et al, 1997; PB Jahrling , 1997). This vaccine will not protect against any of the Old World arenaviruses, such as Lassa fever (Oldstone et al, 2001).
    H) PLASMA
    1) IMMUNE PLASMA
    a) Neutralizing viremia with transfusion of immune plasma, containing at least 3000 therapeutic units of neutralizing antibodies per kilogram body weight, has been recommended. Early treatment, within 8 days of the onset of symptoms, appears to afford better clinical outcome. In patients treated late, the outcome does not appear to be directly related to the amount of neutralizing antibodies transfused. Approximately 10% of immune-plasma recipients develop a later neurological syndrome of unknown pathogenesis within 4 to 6 weeks after the acute phase of illness. This therapy would not be feasible in a mass casualty setting due to inadequate stock of immune plasma. This is not an FDA approved therapy (Franz et al, 1997; Enria & Maiztegui, 1994; Cummins, 1991; Enria et al, 1984).
    I) INFECTIOUS DISEASE NOTIFICATION
    1) REPORTING - All confirmed and suspected cases should be reported immediately through local and state health departments to the Special Pathogens Branch, Division of Viral and Rickettsial Diseases, Centers for Disease Control (CDC). The CDC can be reached at telephone number 404-639-1522 (or 404-639-2888 between 4:30PM and 8AM). Specimens for virus-specific diagnostic tests should be sent immediately to CDC per their instructions. Junin virus is classified as a Biosafety Level 4 containment.
    J) CONTRAINDICATED TREATMENT
    1) Immunosuppression with corticosteroids or other agents has no empirical or little theoretical basis. They are contraindicated. Intramuscular injections, aspirin, nonsteroidal anti-inflammatory drugs, and anticoagulant therapies are contraindicated (Borio et al, 2002; PB Jahrling , 1997).
    K) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. All patients with mucocutaneous exposures to blood, body fluids or excretions with suspected AHF should receive monitoring for development of systemic infection.
    6.8.2) TREATMENT
    A) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the INHALATIONAL EXPOSURE section when appropriate.
    B) EVALUATION PROCEDURE
    1) Any person who has had close physical contact with infected patients or body fluids should be put under strict surveillance (twice daily body temperature checks; in case of temperature >38.3 degrees C {101 degrees F}, hospitalize immediately in strict isolation). Hospital personnel who come into close contact with patients or contaminated materials without barrier nursing attire must be considered exposed and put under close, supervised surveillance.
    2) High risk contacts with exposure to the virus, should receive post-exposure chemoprophylaxis (ribavirin 500 mg orally every 6 hours for 7 to 10 days for adults and adolescents; ribavirin 400 mg orally every 6 hours for 7 to 10 days for children 6 to 9 years of age) ((Anon, 2000)). Benefits versus risk should be assessed in pregnant patients due to demonstrated teratogenic effects in animal studies.
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) Dermal sites exposed to blood, body fluids, secretions, or excretions from patients with suspected Argentine hemorrhagic fever (AHF) should be immediately washed with soap and water. Avoid secondary contamination of medical personnel.
    2) Use of an antiseptic solution or hand washing product should be considered, although the efficacy of this supplemental measure is unknown. Lipid-containing viruses, including enveloped viruses, are readily inactivated by suitable disinfectant solutions, which include 0.5% sodium hypochlorite (10% aqueous solution of a 2% household bleach); consider this solution for dermal decontamination.
    B) CLOTHING
    1) Bag soiled clothing or dressings in clearly labeled leak-proof polyethylene bags until autoclaved or incinerated.
    C) EVALUATION
    1) All patients with mucocutaneous exposures to blood, body fluids or excretions with suspected AHF should receive medical evaluation and monitoring for possible systemic infection.
    6.9.2) TREATMENT
    A) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the INHALATIONAL EXPOSURE section when appropriate.
    B) EVALUATION PROCEDURE
    1) Any person who has had close physical contact with infected patients or body fluids should be put under strict surveillance (twice daily body temperature checks; in case of temperature >38.3 degrees C {101 degrees F}, hospitalize immediately in strict isolation). Hospital personnel who come into close contact with patients or contaminated materials without barrier nursing attire must be considered exposed and put under close, supervised surveillance (CDC, 1995).
    2) High risk contacts with exposure to the virus, should receive post-exposure chemoprophylaxis (ribavirin 500 mg orally every 6 hours for 7 to 10 days for adults and adolescents; ribavirin 400 mg orally every 6 hours for 7 to 10 days for children 6 to 9 years of age) ((Anon, 2000)). Benefits versus risk should be assessed in pregnant patients due to demonstrated teratogenic effects in animal studies.
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Range Of Toxicity

Summary

    A) Mortality in untreated patients is reported to be 15% to 30%.
    B) As few as 1 to 10 organisms are capable of causing infection.
    C) CNS dysfunction imparts a poor prognosis.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) Mortality is reported to be as high as 15% to 30% in untreated patients (Borio et al, 2002; Lozano et al, 1995; Enria & Maiztegui, 1994). In Argentina, endemic infections result in a case-fatality rate of greater than 15% if untreated; treatment reduces mortality to less than 1% (Harrison et al, 1999).
    2) Between 1958 and about 1977, approximately 250 laboratory workers were exposed to Junin virus. Approximately 45 clinical cases were recorded, with 6 fatalities (Weissenbacher et al, 1978).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) As few as 1 to 10 aerosolized Junin virus organisms are capable of causing infection in humans (PB Jahrling , 1997; Franz et al, 1997). This virus is stable and highly infectious by aerosol. It replicates sufficiently well in cell culture to permit weaponization (Franz et al, 1997). Transmissibility from man-to-man is considered low to moderate; infectivity is high (PB Jahrling , 1997).
    2) In AHF, viremia is sporadic or of low concentration; it does NOT predict outcome. High-quality neutralizing immunoglobulins are evident in serum within a few days of fever resolution (Cummins, 1991).
    3) A high incidence of secondary bacterial infection in humans is associated with AHF, unlike Lassa fever; this is possibly related to neutropenia (Cummins, 1991).
    4) A neurological syndrome (encephalopathy) develops in many patients infected with Junin virus. The pathogenesis of this is unclear. Neurologic manifestations are much more prominent in AHF patients than in Lassa fever patients. CNS dysfunction imparts a poor prognosis (Borio et al, 2002; Franz et al, 1997; Cummins, 1991).
    5) In laboratory workers, neutralizing antibodies, with inapparent infection, were discovered in 12 of 62 persons who worked directly with Junin virus. None of the 12 had a previous history of AHF. All serum samples were negative when tested by a complement fixation technique. Biosafety laboratory techniques were not mandated at the time of this incident (Weissenbacher et al, 1978).
    B) ANIMAL DATA
    1) Six Rhesus macaques were delivered aerosol doses of Junin virus; 3 received an estimated high dose of 10(4) PFU and 3 received an estimated low dose of 10(2) PFU. Clinical and hematological findings were found to be similar to previous reports of monkeys infected with intramuscular Junin virus. An acute clinical syndrome developed between 10 and 20 days after inoculation. Symptoms began with anorexia, malaise, and weight loss, which progressed to a generalized erythematous vesicular rash, mild thrombocytopenia (<100,000/mcL), leukopenia, lymphadenopathy, gingival bleeding, and variable mucous membrane hemorrhages. In the surviving animals, after 3 weeks cachexia was observed, but neurological signs were absent (Kenyon et al, 1992).
    a) No correlation was seen between administered virus dose and peak viremia level, duration of viremia, or time of viremia onset. Virus was isolated from oropharyngeal secretions on day 10 in 4 of the 5 surviving animals and on day 14 in all of the surviving animals. At necropsy, viral distribution appeared to be similar in visceral organs, regardless of virus dose or time to death.

Pharmacology Toxicology

Toxicologic Mechanism

    A) Junin virus is intracellular. Lymphatic tissue is reported as one of the main sites of Junin virus multiplication and macrophages are the targets of Junin virus. The virus enters into the cell via the endocytic pathway. Glycoprotein-38 production in conjunction with glycoprotein transport to the cell membrane appear to be required for release of infectious virus from Junin virus-infected cells. The common clinical signs of AHF are generally the result of microvascular damage and changes in vascular permeability (Franz et al, 1997; Scolaro & Damonte, 1997; Damonte et al, 1994). The arenaviruses initially infect the nasopharyngeal mucosa. They produce carrier states in rodents where viral multiplication is not associated with extensive cell damage. In vitro studies have shown that Junin virus spreads throughout a variety of different cellular monolayers, with minimal or absent cytopathic effects. It is believed that this virus may exert its effects, at least partly, by inducing secretion of inflammatory mediators from macrophages. Primary marrow injury to megakaryocytes occurs. Studies of infections of non-human primates with Junin virus have shown that virtually all tissues become infected, with little histologic evidence of damage. Cellular viremia (circulating monocytes) is one mechanism of Junin virus spread to the CNS in animal hosts (Borio et al, 2002; Castilla et al, 2001; Medeot et al, 1995; Ambrosio et al, 1986). Intracellularly, the mechanism of an RNA-dependent RNA polymerase allows a switch from primary viral transcription to replication mode of Junin virus (Tortorici et al, 2001).
    1) In spleen and lymph node examination from 7 fatalities due to AHF, destruction of splenic white pulp and of lymph node cortex was observed. A characteristic cytopathic effect on macrophages with presence of intracisternal virus-like particles and occasional virions budding from the plasma membrane were noted. The presence of Junin virus antigenic determinants in the cytoplasm of macrophages of the examined organs was found. These results suggested viral replication occurred in lymphatic tissue and that macrophages are the targets of Junin virus. Circulating monocytes expedite the spread of the virus to various tissues (Ambrosio et al, 1990; Gonzalez et al, 1980). It is suggested that cellular cytoskeletal components may be involved in the initiation of the assembly and budding processes of Junin virus particles at the plasma membrane (Candurra et al, 1999).
    2) Hemorrhage following infection appears to be associated with the presence of a circulating platelet aggregation inhibitor and thrombocytopenia. Disseminated intravascular coagulation does not appear to be a central pathogenic mechanism. Recovery is preceded by cellular and humoral immune responses (Cummins, 1991; Cummins et al, 1990).
    3) Kenyon et al (1992) have suggested a direct entry of virus into the CNS via the olfactory tract and cribriform plate. This observation was based on the finding of virus in the olfactory lobes of infected monkeys dying early, with simultaneous viremia, prior to viral appearance in the cerebrum and cerebellum.
    4) Severe bone marrow erythroblastopenia described in AHF patients is not thought to be a result of Junin virus by itself, since viral particles are not found in bone marrow. Low levels of erythropoietin seen in many AHF patients, possibly due to an inhibitory effect of high TNF-alpha levels also seen in many AHF patients, may contribute to the severe bone marrow erythroblastopenia seen in AHF patients (Marta et al, 2000).
    5) In fatalities due to AHF, no detectable antibody levels have been found at postmortem. Antibody-dependent cell cytotoxicity is expected to be an active mechanism in limiting Junin virus spread in AHF. A limiting factor for this immune mechanism would be low numbers of peripheral blood mononuclear cells and polymorphonuclear leukocytes and/or a shortage of specific antibodies during the first 14 days of illness (Ambrosio et al, 1992).

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